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Basic and Clinical Endocrinology 7th International student edition Edition

13

Female Reproductive Endocrinology & Infertility

Mitchell Rosen MD

Marcelle I. Cedars MD

EMBRYOLOGY & ANATOMY

No gene has yet been identified that generates an ovary from an undifferentiated gonad. It is only in the absence of the sex-determining region of the Y gene (SRY) that the gonad will develop into an ovary. (For more details, refer to the discussion of sexual differentiation inChapter 14.) Primordial germ cells originate in the yolk sac endoderm (hindgut) and migrate through the dorsal mesentery into the gonadal ridge, which is located lateral to the dorsal mesentery of the gut and medial to the mesonephros (Figure 13-1). Prior to migration, the germ cells divide mitotically. Once migration starts, mitosis is inhibited until the germ cells reach the gonadal ridge in the sixth week of gestation. Failure of primordial germ cells to develop or to migrate into the gonadal ridge results in failure of ovarian development.

When the germ cells reach the gonadal ridge, mitosis resumes, with primordial germ cells subsequently developing into oogonia (premeiotic germ cells). At 10–12 weeks of gestation, some oogonia leave the mitotic pool and begin meiosis, where they arrest in

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prophase I (dictyotene stage). These arrested germ cells are now called primary oocytes. By 16 weeks, primordial follicles are first identified, making a clear distinction for gonadal differentiation into an ovary. At approximately 20 weeks of gestation, a peak of 6–7 million germ cells (two-thirds of them primary oocytes and one-third oogonia) are present in the ovaries. During the second half of gestation, the rate of mitosis rapidly decreases and the rate of oogonial and follicular atresia increases. Those oogonia that are not transformed into primary oocytes will undergo atresia before birth. This results in a reduction in the number of germ cells, resulting in a total of 1–2 million germ cells at birth. No germ cell mitosis occurs after birth, while follicular atresia continues, with the result that the average girl entering puberty has only 300,000–400,000 germ cells.

 

Figure 13-1. A: Schematic drawing of a 3-week-old embryo showing the primordial germ cells in the wall of the yolk sac, close to the attachment of the allantois. B: Drawing to show the migrational path of the primordial germ cells along the wall of the hindgut and the dorsal mesentery into the genital ridge. (Reproduced, with permission, from Langman J, Sadler TW: Langman's Medical Embryology, 8th ed. Lippincott Williams and Wilkins, 2000.)

The ovary is organized into an outer cortex and an inner medulla. The germ cells are located within the cortex. Along the outer surface of the cortex is the germinal epithelium. This cell layer is composed of cuboidal cells resting on a basement membrane and forms a continuous layer with the peritoneum. Even though it is called the germinal epithelium, there are no germ cells within this layer. During embryonic development, the epithelial cells proliferate and enter the underlying tissue of the ovary to form cortical cords. When the primordial germ cells arrive at the genital ridge, they are incorporated into these cortical cords. At the same time the germ cells migrate from the yolk sac, the stromal cells of the ovary (granulosa and interstitial cells) migrate from the mesonephric tubules into the gonad. Primordial folliclesform within the cortical cords. They are composed of a primary oocyte and one layer of granulosa cells with its basement membrane. Oocytes not surrounded by granulosa cells are lost, probably by apoptosis. It is this finite follicle population that represents the pool of germ cells which will ultimately be available to enter the follicular cycle.

During fetal development, the gonad is held in place by the suspensory ligament at the upper pole and the gubernaculum at the lower pole. The final location of the gonad is dependent on hormone production. In the presence of testosterone, the gubernaculum grows while the suspensory ligament regresses. As the gubernaculum continues to grow, the gonad (testis) descends into the scrotum. In contrast, when testosterone is absent, the suspensory ligament remains and the gubernaculum regresses. This process will maintain the gonad (ovary) in the pelvis.

The remainder of the female internal reproductive organs are formed from the paramesonephric (müllerian) ducts. In the absence of antimüllerian hormone (AMH), the paramesonephric system develops into the uterine (fallopian) tubes, the uterus, the cervix, and the upper third of the vagina. Unlike wolffian duct differentiation, the development of the female reproductive tract is not dependent on hormone production. (For more details, refer to the discussion of sexual differentiation in Chapter 14.) Briefly, the müllerian buds are formed lateral to the wolffian ducts and the gonadal ridge after 37 days of gestation (Figure 13-2). These

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buds elongate, canalize, and extend caudally and medially. The adjacent paired müllerian ducts abut and eventually fuse in the midline as they reach the müllerian tubercle. The intervening septum resorbs after 10 weeks of gestation, resulting in a single uterine cavity. The most cranial parts of the müllerian ducts remain unfused and form the uterine tubes, which remain patent with the coelom (future peritoneal cavity). The caudal segments stimulate solid cords to extend from the müllerian tubercle to the sinovaginal bulbs from the posterior aspect of the urogenital sinus. In turn, the sinovaginal bulbs extend cranially and fuse with the vaginal cords, forming the vaginal plate. The vagina is subsequently formed by canalization of the vaginal plate. It is ultimately the cervix and the upper third of the vagina that are derived from the müllerian structures, while the remaining lower two-thirds is formed from the urogenital sinus.

 

Figure 13-2. Schematic drawing showing the formation of the uterus and vagina. A: At 9 weeks. Note the disappearance of the uterine septum. B: At the end of the third month. Note the tissue of the sinovaginal bulbs. C: Newborn. The upper portion of the vagina and the fornices are formed by vacuolization of the paramesonephric tissue and the lower portion by vacuolization of the sinovaginal bulbs. (Reproduced, with permission, from Langman J, Sadler TW: Langman's Medical Embryology, 8th ed. Lippincott Williams and Wilkins, 2000.)

The uterus is composed of endometrium (innermost lining), myometrium, and serosa. The adult uterus is a pear-shaped hollow organ. The cervical portion extends approximately 2 cm into the vagina, and the remaining corpus extends approximately 6 cm into the abdomen. The normal adult uterus weighs 40–80 g.

The uterus is located in the pelvis and rests on the pelvic floor. Seventy to 80 percent of the time, the uterine position is anteflexed (cervical-uterine corpus angle) and anteverted (cervical-vaginal angle). Therefore, when a woman is standing, the corpus of the uterus is horizontal and resting on top of the bladder. The uterus has several paired ligaments that develop from thickenings of the peritoneum and serve to maintain this anatomic position. The cardinal ligament (Mackenrodt) is the main supporting ligament. It attaches to the lateral margins of the cervix at the upper vagina and extends to the lateral pelvic wall. The remaining ligaments—uterosacral, round, and broad—have a lesser role in supporting the uterus.

The uterine artery originates from the anterior division of the internal iliac artery (hypogastric), enters the cardinal ligament, and supplies the uterus. The uterine artery divides into a descending branch and an ascending branch known as the vaginal and arcuate arteries, respectively. The arcuate arteries anastomose with each other and form a vascular network around the uterus. The radial arteries branch off from the arcuate network and penetrate the uterus to supply the myometrium. Smaller basal branches and spiral arteries supply the endometrium.

The ovary is suspended in the pelvis and has three associated ligaments. The average adult ovary is 2.5-5 × 2.5 × 1 cm in size and weighs 3–8 g. The position of the ovary is variable, but in a nulliparous woman it is often located in a peritoneal depression on the pelvic sidewalls between the ureter and external iliac vein. The suspensory (infundibulopelvic) ligament attaches to the cranial pole of the ovary and extends to the pelvic brim.

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This ligament suspends the ovary in the pelvis and contains the ovarian vessels, lymphatics, and nerves. The utero-ovarian ligament attaches to the inferior pole of the ovary and extends to the uterus. The mesovarium connects the anterior portion of the ovary to the posterior leaf of the broad ligament. The blood supply of the ovary originates from the abdominal aorta, passes through the suspensory ligament, and enters the mesovarium to form an anastomotic network with branches from the uterine artery. The ovarian artery enters the ovarian hilum and branches into spiral arteries that enter the medulla and extend to the ovarian cortex. Other branches from the anastomotic network, located in the mesovarium, supply the uterine tubes.

OVARIAN STEROIDOGENESIS

The ovaries are not only the store for germ cells—they also produce and secrete hormones that are vital for reproduction and the development of secondary sexual characteristics. The next section will briefly discuss the biosynthesis of ovarian hormones. (See also Figures 9-4, 12-2, and 14-14.)

In the ovary, the major source of hormone production is the maturing follicle. The components of the follicle are the theca cells, the granulosa cells, and the primary oocyte. The theca cells produce androgens, and the granulosa cells produce estrogens. The other stromal cells that contribute to androgen production can be divided into two populations of cells: the secondary interstitial cells (derived from theca) and the hilum cells. These cells are the major ones involved in ovarian hormone production during menopause (see below).

The ovarian hormones are derived from cholesterol. Steroidogenic cells acquire the cholesterol substrate from one of three sources. The most common source is plasma lipoprotein carrying cholesterol, primarily in the form of low-density lipoprotein (LDL). Other minor sources include de novo synthesis from acetate and liberation from stored lipid droplets (cholesterol esters). Stimulation of ovarian cells by trophic hormones such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH) facilitate uptake of cholesterol by increasing the number of LDL receptors on the cell surface. The LDL particle is subsequently internalized and degraded in the lysosome. The free cholesterol that is liberated from the lysosome is delivered to the mitochondria by an unknown mechanism, possibly via microfilaments and microtubules. The cholesterol is then translocated into the mitochondria by the steroidogenic acute regulatory protein (StAR).

The initial step that commits cholesterol to steroid synthesis is the cholesterol side chain cleavage enzyme reaction (P450scc) (Figure 13-3). This reaction converts cholesterol to pregnenolone, the precursor of steroid hormones, and takes place in the mitochondria. Acute alterations in steroid production result from changes in delivery of cholesterol to P450scc, while long-term changes in steroid synthesis involve alterations in gene expression.

Once pregnenolone is formed, the hormone secreted is dependent on the synthesizing endocrine organ and cell type. For example, the main sources of sex steroids in the female come from the adrenal gland and the ovary. The specific type of hormone secreted is dependent on the cell type. In the adrenal gland there are three zones: zona glomerulosa, zona fasciculata, and zona reticularis. The cells in the different zones start with the same hormone precursor but differ in their secretory products. The glomerulosa produces mainly aldosterone, while cortisol and androgen are produced by the zona fasciculata and zona reticularis, respectively. The major androgen produced by the adrenal is DHEAS. Differences in enzymatic activity among cells in the various zones are what regulate hormone production. The zona reticularis and zona fasciculata lack 11β-hydroxylase, which is necessary for aldosterone synthesis (Figure 13-3; and see Chapters 9 and 10). The zona glomerulosa lacks 17-hydroxylase and 17,20-lyase (CYP17), which are necessary for sex steroid synthesis.

Ovarian cells similarly secrete different hormones due to differential enzyme activity. The theca interstitial and secondary interstitial cells lack aromatase and hence are the androgen producers in the ovarian cortex. The granulosa cells, on the other hand, lack CYP17 and therefore secrete estrogens—mainly estradiol in the proliferative phase and progesterone in the luteal phase. Differences in androgen secretion between the adrenal and ovary can be explained by the relative activity of type II 3β-hydroxysteroid dehydrogenase and δ5-isomerase (3β-HSD). Both organs can produce all the androgens, but the lack of activity of 3β-HSD, at least during the reproductive years, contributes to adrenal DHEA production. In contrast, ovarian 3β-HSD activity can be stimulated by gonadotrophs, leading to androstenedione and testosterone production.

PHYSIOLOGY OF THE MENSTRUAL CYCLE

The menstrual cycle is regulated by complex interactions between the hypothalamic-pituitary-ovarian (HPO) axis and the uterus. Briefly, the hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the pituitary to release FSH and LH. These gonadotropins then trigger the ovary to release an oocyte that is capable of fertilization. Concurrently, the ovary secretes hormones, which act on the endometrial lining of the uterus to prepare for implantation. In addition,

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the ovarian hormones feed back to the hypothalamus and pituitary, regulating the secretion of gonadotropins during the phases of the menstrual cycle. This complex interaction will be discussed in greater detail below. The hormonal changes associated with menstruation are summarized in Figure 13-4.

 

Figure 13-3. Pathways of steroid biosynthesis. The pathways for synthesis of progesterone and mineralocorticoids (aldosterone), glucocorticoids (cortisol), androgens (testosterone and dihydrotestosterone), and estrogens (estradiol) are arranged left to right. The enzymatic activities catalyzing each bioconversion are written in the boxes. For those activities mediated by specific cytochrome P450, the systematic name of the enzyme (“CYP” followed by a number) is listed in parentheses. CYPB2 and CYP17 have multiple activities. The planar structures of cholesterol, aldosterone, cortisol, dihydrotestosterone, and estradiol are placed near the corresponding labels. (Reproduced, with permission, from White PC, Speiser PW: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000;21:245.)

The Hypothalamic-Pituitary Axis

GnRH-secreting neurons originate in the olfactory placode and migrate to the arcuate nucleus of the medial basal hypothalamus (MBH). These neurons project to the median eminence and secrete GnRH, with inherent rhythmic behavior (“pulse generator”). GnRH is composed of ten amino acids and has a short half-life of 2–4 minutes. The pulsatile frequency of GnRH secretion regulates gonadotropin synthesis and the secretion of pituitary gonadotropes. (See Chapter 5.)

During the late luteal-follicular phase, the slower pulsatile release of GnRH—every 90–120 minutes—favors FSH secretion. In response to FSH, the maturing follicle in the ovary secretes estradiol. This hormone is involved in a negative feedback loop that directly inhibits the release of FSH. Estradiol is involved in a positive feedback loop that increases the frequency of GnRH to every 60 minutes during the follicular phase and acts directly on the pituitary to stimulate LH secretion. LH stimulates the ovary to further increase estradiol production (see two-cell theory, below). Although at this point there is no acute change in GnRH pulsatility, estradiol and other regulatory factors (see below) augment pituitary sensitivity to GnRH. This increased sensitivity results in a rapid elevation of LH production—the LH surge—which stimulates ovulation. After ovulation, the ruptured follicle (corpus luteum) secretes progesterone. This hormone is involved in a negative feedback loop via increased endogenous opioid activity—and possibly directly—to decrease the GnRH pulsatility to every 3–5 hours, favoring FSH synthesis during the luteal-follicular transition. As progesterone levels fall again, GnRH pulsatility increases, favoring FSH release.

 

Figure 13-4. The endocrinology of the luteal-follicular transition in women. Data are mean ą SE of daily serum concentrations of FSH, LH, estradiol, progesterone, and immunoreactive inhibin in women with normal cycles. Note the secondary rise in plasma FSH in the late luteal phase (~ 2 days before menses). (Reproduced with permission from Erickson GF: Ovarian Anatomy and Physiology. Lobo R [ed]. Academic Press, 2000.)

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Role of the Pituitary

Gonadotropes are located in the adenohypophysis and make up approximately 10% of the cells in the pituitary. These cells synthesize and secrete FSH and LH. Pituitary hormones belong to a family of glycoproteins that include thyroid-stimulating hormone (TSH) and human chorionic gonadotropin (hCG) and therefore contain carbohydrate moieties. Gonadotropins are functional as heterodimers and are composed of an alpha subunit and a beta subunit. The alpha subunit amino acid sequence is identical for all of the glycoproteins, while the beta subunit is characterized by different amino acids and confers unique specificity on the glycoprotein.

The differential gene expression that leads to the production and release of gonadotropins by cells in the pituitary is regulated by GnRH and ovarian hormones through feedback loops. Slower GnRH secretion enhances FSH beta subunit expression and favors LH secretion. In turn, rapid GnRH pulses stimulate LH beta subunit expression while promoting FSH release. Thus, ovarian steroid modification of hypothalamic GnRH pulsatility controls pituitary gonadotrophin production.

An intrapituitary network involves several factors that play a role in regulating gonadotropin synthesis and secretion. The gonadotropes produce and secrete peptides that are in the transforming growth factor (TGF) family. Activin is a local regulatory protein that is involved in gonadotrope expression. Slow pulses of GnRH enhance activin synthesis, which subsequently enhances FSH transcription. Follistatin, another TGF-related protein that binds to activin, is stimulated by rapid pulses of GnRH. This decreases the bioavailability of activin and consequently reduces FSH synthesis. In addition to these local modifiers, ovarian transforming growth factors such as inhibin also modulate the expression of gonadotropins (see below).

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Role of the Ovary

The ovary is intimately involved in regulating the menstrual cycle via steroid feedback to alter gonadotropin secretion. In addition, the ovary contains an intraovarian network involving factors that are synthesized locally and have a paracrine and autocrine role in the modulation of gonadotropin activity. The intraovarian regulators include the insulin-like growth factor (IGF) family, the transforming growth factor (TGF) superfamily, and the epidermal growth factor (EGF) family. Furthermore, it is these factors that assist in the coordination of follicular development and ovulation.

The menstrual cycle of the ovary includes a follicular phase and a luteal phase. The follicular phase is characterized by growth of the dominant follicle and ovulation. It typically lasts 10–14 days. It is, however, this phase that is variable in duration and most often accounts for the variability in menstrual cycle length in ovulatory women. The luteal phase starts after ovulation and is the period when the ovary secretes hormones that are essential to accommodate conceptus implantation. This phase is relatively constant and averages 14 days (range, 12–15 days) in duration. The next section will describe the two phases in some detail.

Primordial follicles are the fundamental reproductive units that comprise the pool of resting oocytes. Morphologically, they are composed of a primary oocyte that is surrounded by a single layer of squamous granulosa cells and a basement membrane. They have no blood supply. These primordial follicles develop between the sixth and ninth months of gestation and harbor the complete supply of ovarian follicles.

Prior to ovulation, it is essential for primordial follicles to leave the pool of nongrowing follicles and enter the growth phase. The exact mechanisms controlling the initial recruitment are largely unknown. The resting follicular pool is probably controlled by inhibitory factors. These follicles may remain quiescent for many months or years. This initial recruitment is a continuous process that begins once the germ pool is created and ends with follicular exhaustion. This complex process is gonadotropin-independent. Several studies have suggested that the intraovarian network—especially members of the TGF superfamily—is involved in primordial follicle recruitment. It is the decrease of inhibitory influences and the increase in stimulators that initiate recruitment. Several other factors have been described to date, and many more will be identified in the future. The ongoing search for these growth factors and hormones will ultimately elucidate the physiology of primordial follicle recruitment. There is a finite number of germ cells, and each successive recruitment further depletes the germ pool. Any abnormality that alters the number of germ cells or accelerates recruitment could perhaps lead to early ovarian follicular depletion and, therefore, early reproductive failure. (See section on infertility, below.)

Primary follicle development is the first stage of follicular growth (Figure 13-5). Primary follicles differ from primordial follicles in several ways. The oocyte begins to grow. As growth progresses, the zona pellucida is formed. This is a thick layer of glycoprotein that is most likely synthesized by the oocyte. It completely surrounds the oocyte and is formed between the oocyte and the granulosa cell layer. It serves a number of biologic functions that are critical for conception. Finally, the granulosa cells undergo a morphologic change from squamous to cuboidal. This stage of development may last 150 days.

The progression to a secondary follicle includes attainment of maximal oocyte growth (120 ľm in diameter), proliferation of granulosa cells, and acquisition of theca cells. The exact mechanism involved in acquiring theca cells is not completely understood but is thought to be derived from the surrounding ovarian mesenchyme (stromal fibroblasts) as the developing follicle migrates to the medulla. It is the development of this layer that gives rise to the theca interna and theca externa. With theca cell development, these follicles gain an independent blood supply, although the granulosa cell layer remains avascular. In addition, the granulosa cells in the secondary follicle develop FSH, estrogen, and androgen receptors. This phase of follicular development may take as long as 120 days, probably because of the long doubling time (< 250 hours) of granulosa cells.

Further follicular development leads to the tertiary follicle or early antral phase. This phase is characterized by the formation of an antrum or cavity in the follicle. The antral fluid contains steroids, proteins, electrolytes, proteoglycans, and an ultrafiltrate that forms from diffusion through the basal lamina. Other changes in this phase include further theca cell differentiation. Subpopulations of thecal interstitial cells develop within the theca interna, acquire LH receptors, and are capable of steroidogenesis. The granulosa cells begin to differentiate into distinct cell layers. Starting from the basal lamina, the cells can be stratified into the membrana, periantral, cumulus oophorus, and corona radiata layers. This developmental process is influenced by FSH and unidentified signals originating from the oocyte. In addition, the granulosa cells—most likely in response to FSH—start producing activin, a member of the TGF family. Activin is composed of two types of beta subunits, βA and βB, which are held together by disulfide bonds. It is the combination of these subunits that generates the various activins (activin A [βA,βA], AB [βA,βB], or BB [βB,βB]). Activin most likely does not have an endocrine role given the fact that serum

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levels of activin do not change throughout the menstrual cycle. Activin's primary activity is within the ovary, where it plays an autocrine role by enhancing FSH receptor gene expression in the granulosa cells and accelerating folliculogenesis.

 

Figure 13-5. The chronology of folliculogenesis in the human ovary. Folliculogenesis is divided into two major periods, preantral (gonadotropin independent) and antral (FSH dependent). In the preantral period, a recruited primordial follicle develops into the primary/secondary (class 1) and early tertiary (class 2) stages, at which time cavitation or antrum formation begins. The antral period includes the small graafian (0.9–5 mm, classes 4 and 5), medium graafian (6–10 mm, class 6), large graafian (10–15 mm, class 7), and preovulatory (16–20 mm, class 8) follicles. Time required for completion of preantral and antral periods is approximately 300 and 40 days, respectively. Number of granulosa cells (gc), follicle diameter (mm), and atresia (%) are indicated. (Reproduced, with permission, from Gougeon A: Regulation of ovarian follicular development in primates: facts and hypotheses. Endo Rev 1996;17:121.)

Follicular growth during the early antral phase occurs at a slow and constant pace. The follicle achieves a diameter of 400 ľm. FSH-stimulated mitosis of granulosa cells is the major contributor of follicular growth at this stage. Until this point, follicular growth and survival are largely independent of gonadotropins. In fact, prepubertal females and women taking oral contraceptives may have follicles arrested at various phases up until this point. It is at this phase in follicular development that FSH is critical for growth and survival. If FSH does not rescue these follicles, they undergo atresia.

The morphologic follicular unit, consisting of theca cells and granulosa cells, is also a functional hormonal unit capable of substantial estrogen production. The stimulation of granulosa cells by FSH increases their expression of P450 aromatase. In addition, the granulosa cells produce a third subunit of the TGF family—α—which combines with other β subunits to create a heterodimer known as inhibin A (αβA) or inhibin B (αβB). Given that the predominant β peptide expressed in the follicular phase is βB, inhibin B is the dominant inhibin produced. This hormone peaks in the early follicular phase and is involved in a negative feedback loop that inhibits pituitary expression of FSH. The thecal interstitial cells, under the influence of LH, increase levels of LH receptors on the cell surface and augment the enzyme activity of StAR, 3β-HSD, and

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P450c17 to acutely increase androgen production. The maximal expression of these enzymes occurs just prior to ovulation. The androgens—mainly androstenedione—diffuse through the basal lamina of the follicle and are the precursors that interstitial cells and granulosa cells utilize for maximal estrogen production (two-cell theory; see Figure 13-6). This interaction between the two cell types is essential given that theca cells lack aromatase, while granulosa cells are deficient in P450c17. The estrogen produced then acts on the follicle to increase levels of FSH receptors on the granulosa cells. This promotes granulosa cell proliferation and subsequently plays a very important role in selection of the dominant follicle.

The next stage of follicular development is the antral growth phase. It is characterized by rapid growth (1–2 mm/d) and is gonadotropin-dependent. In response to FSH, the antral follicle rapidly grows to a diameter of 20 mm, primarily as a result of accumulation of antral fluid. The theca interna continues to differentiate into interstitial cells that produce increasing amounts of androstenedione for aromatization to estradiol. The granulosa cell layers have continued to differentiate from each other. The membrana layer, through the action of FSH, acquires LH receptors. This differs from the cumulus layer, which lacks LH receptors. The final progression to a mature graafian follicle is a selection process that in most cases generates one dominant follicle destined for ovulation.

 

Figure 13-6. Gonadotropin regulation of follicular estrogen biosynthesis in the two-cell, two-gonadotropin model. ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CYP, P450scc; CYP17, P450c17; CYP19, P450arom; 17β-HSD, 17-β-hydroxy steroid dehydrogenase; LDL, low-density lipoprotein; StAR: steroidogenic acute regulatory protein. (Reproduced, with permission, from DeGroot LJ et al [editors]: Endocrinology, 4th ed. Saunders, 2001.)

The selection process begins in the midluteal phase of the previous cycle. The rise in estrogen level that is generated by the preovulatory follicle augments FSH activity within the follicle while exerting negative feedback on the pituitary release of FSH. The decrease in pituitary release of FSH results in withdrawal of gonadotropin support from the smaller antral follicles, promoting their atresia. The dominant follicle continues to grow despite decreasing levels of FSH by accumulating a greater mass of granulosa cells with more FSH receptors. Increased vascularity of the theca cells allows preferential FSH delivery to the dominant follicle despite waning FSH levels. Increased estrogen levels in the follicle facilitate FSH induction of LH receptors on the granulosa cells, allowing the follicle to respond to the ovulatory surge of LH levels. Without estrogen, LH receptors do not develop on the granulosa cells.

A positive feedback loop involving estrogens stimulates the pituitary and results in an LH surge. This surge results in the resumption of meiosis I in the oocyte with release of a polar body just prior to ovulation. Evidence suggests that the granulosa membrana cells secrete an oocyte maturation inhibitor (OMI) which interacts with the cumulus to block the progression of meiosis during most of folliculogenesis. It is theorized that OMI exerts its inhibitory influence by stimulating the cumulus to increase cAMP production, which diffuses into the oocyte and halts meiotic maturation. The LH surge overcomes the arrest of meiosis by inhibiting OMI secretion, thereby decreasing cAMP levels and increasing intracellular calcium, allowing the resumption of meiosis (see Figure 13-7).

With the LH surge, progesterone production increases, and this may be responsible at least in part for the midcyle peak in FSH. The FSH peak stimulates the production of an adequate number of LH receptors on the granulosa cells for luteinization. FSH, LH, and progesterone induce expression of proteolytic enzymes that degrade the collagen in the follicular wall, thereby making it prone to rupture. Prostaglandin production increases and may in part be responsible for contraction of smooth muscle cells on the ovary, aiding the extrusion of the oocyte.

The LH surge lasts approximately 48–50 hours. Thirty-six hours after onset of the LH surge, ovulation

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occurs. The feedback signal to terminate the LH surge is not known. Perhaps the rise in progesterone production results in a negative feedback loop and inhibits pituitary LH secretion by decreasing the pulsatility of GnRH. In addition, just prior to ovulation LH down-regulates its own receptors, which decreases the activity of the functional hormonal unit (two-cell theory). As a result, estradiol production decreases.

 

Figure 13-7. Current concepts of control of meiotic maturation. (Reproduced, with permission, from Felig P, Frohman LA [editors]: Endocrinology and Metabolism, 4th ed. McGraw-Hill, 2001.)

Following ovulation and in response to LH, the granulosa cells (membrana) and thecal interstitial cells that remain in the ovulated follicle differentiate into granulosa lutein and theca lutein cells, respectively, to form the corpus luteum. In addition, LH induces the granulosa lutein cells to produce vascular endothelial growth factor (VEGF), which plays an important role in developing the corpus luteum vascularization. This neovascularization penetrates the basement membrane and provides the granulosa lutein cells with LDL for progesterone biosynthesis. After ovulation, the luteal cells up-regulate their LH receptors by an unknown mechanism. This is critical in that it allows basal levels of LH to maintain the corpus luteum. Rescue of the corpus luteum with human chorionic gonadotropin (hCG) from the developing conceptus works through the LH receptor, which is vital for embryonic life. In response to LH and hCG, the luteal cells increase their expression of P450scc and 3β-hydroxysteroid dehydrogenase (HSD) to increase the production of progesterone, 17α-progesterone, androstenedione, estradiol, and inhibin A. The secretion of progesterone and estradiol is episodic and correlates with the LH pulses. FSH has minimal influence on progesterone production but continues to stimulate estrogen production during the luteal phase. The progesterone levels continue to rise and reach a peak on approximately day 8 of the luteal phase. The luteal phase lasts approximately 14 days.

The corpus luteum starts to undergo luteolysis (programmed cell death) approximately 9 days after ovulation. The mechanism of luteal regression is not completely known. Once luteolysis begins, there is a rapid decline in progesterone levels. A number of studies suggest that estrogen has a role in luteolysis. It has been shown that direct injection of estrogen into the ovary containing a corpus luteum induces luteolysis and a fall in progesterone levels. Experimental data suggest that there is increased aromatase activity in the corpus luteum just prior to luteolysis. The rise in aromatase activity is secondary to gonadotropin (FSH and LH) stimulation, but later in the luteal phase FSH probably plays a more important role. Consequently, estrogen production increases, and this decreases 3β-HSD activity. This may result in a decline in progesterone levels and lead to luteolysis. Furthermore, local modifiers such as oxytocin, which is secreted by luteal cells, have been shown to modulate progesterone synthesis. Other evidence supports prostaglandin's role in luteolysis. Experimental data suggest that prostaglandin F, which is secreted from the uterus or ovary during the luteal phase, stimulates the synthesis of cytokines such as tumor necrosis factor; this causes apoptosis and therefore may be linked to corpus luteum degeneration.

The process of luteolysis is known to involve proteolytic enzymes. Evidence suggests that matrix metalloproteinase (MMP) activity is increased during luteolysis. hCG is a known modulator of MMP activity. This may play an important role in early pregnancy, when hCG rescues the corpus luteum

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and prevents luteal regression. However, in the absence of pregnancy, the corpus luteum regresses, resulting in a decrease in progesterone, estradiol, and inhibin A levels. The decrease in these hormones allows for increased GnRH pulsatility and FSH secretion. The rise in FSH will rescue another cohort of follicles and initiate the next menstrual cycle.

Role of the Uterus

The sole function of the uterus is to accommodate and support a fetus. Furthermore, it is the endometrium, the lining of the uterine cavity, that differentiates during the menstrual cycle so that it can support and nourish the conceptus. Histologically, the endometrium is made up of an epithelium composed of glands and a stroma that contains stromal fibroblasts and extracellular matrix. The endometrium is divided into two layers based on morphology: the basalis layer and the functionalis layer. The basalis layer lies adjacent to the myometrium and contains glands and supporting vasculature. It provides the components necessary to develop the functionalis layer. The functionalis is the dynamic layer that is regenerated every cycle. More specifically, it is this layer that can accommodate implantation of the blastocyst.

During the menstrual cycle, the endometrium responds to hormones secreted from the ovaries. Somewhat like the other endocrine organs, it contains a network of local factors that modulate hormonal activity. The endometrial phases are coordinated with ovulatory phases. During the follicular phase, the endometrium goes through the proliferative phase. It begins with the onset of menses and ends at ovulation. During the luteal phase, the endometrium undergoes the secretory phase. It starts at ovulation and ends just before menses. If implantation does not occur, a degenerative phase follows the secretory phase within the endometrium. It is this phase that results in menstruation. The next section will discuss the phases of the endometrium in more detail.

During the follicular phase, the ovary secretes estrogen, which stimulates the glands in the basalis to initiate formation of the functionalis layer. Estrogen promotes growth by enhancing gene expression of cytokines and a variety of growth factors, including EGF, TGFα, and IGF. These factors provide a microenvironment within the endometrium to modulate the effects of hormones. At the beginning of the menstrual cycle, the endometrium is thin and is usually less than 2 mm in total thickness. The endometrial glands are straight and narrow and extend from the basalis toward the surface of the endometrial cavity. As the epithelium and the underlying stroma develop, they acquire estrogen and progesterone receptors. The spiral blood vessels from the basalis layer extend through the stroma to maintain blood supply to the epithelium. Ultimately, the lining (functionalis) surrounds the entire uterine cavity and achieves a thickness of 3–5 mm in height (total thickness 6–10 mm). This phase is known as the proliferative phase.

After ovulation, the ovary secretes progesterone, which inhibits further endometrial proliferation. This mechanism may be mediated by antagonizing estrogen effects. Progesterone down-regulates estrogen receptors in the epithelium and mediates estradiol metabolism within the endometrium by stimulating 17β-HSD activity and converting estradiol into a weaker estrogen known as estrone. During the luteal phase, the glandular epithelium accumulates glycogen and begins to secrete glycopeptides and proteins—along with a transudate from plasma—into the endometrial cavity. It is this fluid that provides nourishment to the free-floating blastocyst. Progesterone also stimulates differentiation of the endometrium and causes characteristic histologic changes. The glands become progressively more tortuous, and the spiral vessels coil and acquire a corkscrew appearance. The underlying stroma becomes very edematous as a result of increased capillary permeability and the cells begin to appear large and polyhedral, with each cell developing an independent basement membrane. This process is termed predecidualization. These cells are very active and respond to hormonal signals. They produce prostaglandins along with other factors that play an important role in menstruation, implantation, and pregnancy. This phase is known as the secretory phase.

If there is no embryo implantation, the endometrium undergoes the degenerative phase. Estrogen and progesterone withdrawal promotes prostaglandin production—PGF and PGE2. These prostaglandins stimulate progressive vasoconstriction and relaxation of the spiral vessels. These vasomotor reactions lead to endometrial ischemia and reperfusion injury. Eventually there is hemorrhage within the endometrium with subsequent hematoma formation. The progesterone withdrawal triggers MMP activity, which facilitates degradation of the extracellular matrix. As ischemia and degradation progress, the functionalis becomes necrotic and sloughs away as menstruum consisting of endometrial tissue and blood. The amount of blood lost in normal menses ranges from 25 mL to 60 mL. Although PGF is a potent stimulus for myometrial contractility and limits postpartum bleeding, it has minimal impact on cessation of menstrual bleeding. The major mechanisms responsible for limiting blood loss involve the formation of thrombin-platelet plugs and estrogen-induced healing of the basalis layer by reepithelialization of the endometrium, which begins in the early follicular phase of the next menstrual cycle.

If conception takes place, implantation can occur in the endometrium during the midsecretory (midluteal) phase, at which time it is of sufficient thickness and full of sustenance. The syncytiotrophoblast subsequently secretes hCG, which rescues the corpus luteum and

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maintains progesterone secretion, essential for complete endometrial decidual development.

In summary, the ovary has two phases during the menstrual cycle: the follicular phase and the luteal phase. The endometrium has three phases and is synchronized by the ovary. The complex feedback loops between the ovary and the hypothalamic-pituitary axis regulate the menstrual cycle. During the follicular phase, the ovary secretes estradiol, which stimulates the endometrium to undergo the proliferative phase. After ovulation (luteal phase), the ovary secretes estrogen and progesterone, which maintains the endometrial lining and promotes the secretory phase. In a nonpregnant cycle, luteolysis occurs, resulting in cessation of hormone production. This hormone withdrawal results in the degenerative phase and the onset of menses.

MENSTRUAL DISTURBANCES

Amenorrhea

Amenorrhea can be defined as either the absence of menarche by age 16 or no menses for more than three cycles in an individual who has previously had cyclic menses. The definition, though arbitrary, nonetheless gives a general guideline to the clinician for further evaluation. Although amenorrhea does not cause harm, in the absence of pregnancy it may be a sign of genetic, endocrine and/or anatomic abnormalities. If the outflow tract is intact, amenorrhea is most likely the result of disruption in the hypothalamic-pituitary-ovarian (HPO) axis. These aberrations can affect any level of control in the menstrual cycle and thus result in menstrual abnormalities.

Amenorrhea was formerly classified as primary or secondary depending on whether or not the individual had experienced menses in the past. This classification may lead to misdiagnosis of the cause of amenorrhea. Although primary amenorrhea is more often associated with genetic and anatomic abnormalities, each individual should be assessed by means of the history and clinical findings, including the presence or absence of secondary sexual characteristics (see Table 13-1). The causes of amenorrhea will be grouped according to the level of involvement in the regulatory systems that govern normal menstrual activity, ie, hypothalamic, pituitary, ovarian, and uterine amenorrhea.

HYPOTHALAMIC AMENORRHEA

Isolated GnRH Deficiency

The hypothalamus is the source of GnRH, which directs the synthesis and secretion of pituitary gonadotropins. Dysfunction at this level leads to hypogonadotropic hypogonadism or eugonadotropic hypogonadism. Disorders of GnRH production can result in a wide range of clinical manifestations. The individual's appearance will be dependent upon the age at onset and the degree of dysfunction.

Isolated GnRH deficiency results in hypogonadotropic hypogonadism. Female patients present with amenorrhea, and females and males present with absent or incomplete pubertal development secondary to absent or diminished sex steroids (estradiol in females, testosterone in males). They have normal stature with a eunuchoidal body habitus. Since the adrenal glands are unaffected by the absence of GnRH, body hair distribution is not affected.

  1. GENETIC ORIGIN

Several genetic lesions associated with GnRH deficiency have been described. The best-characterized form of GnRH deficiency is Kallmann's syndrome, which involves the Kal-1 gene. This gene normally codes for anosmin, an adhesion molecule that appears to be involved in the migration of GnRH and olfactory neurons from the olfactory placode to the hypothalamus. The Kal-1 gene is located on the short arm of the X chromosome. Most cases of Kallmann's syndrome are sporadic, though the disorder has also been observed to have a familial pattern, and most often it occurs by X-linked recessive inheritance. Autosomal recessive and dominant patterns have been reported but are much less common. When mutations exist in the Kal-1 gene, there may be associated defects, including anosmia and, less frequently, midline facial defects, renal anomalies, and neurologic deficiency. The disorder affects both sexes, but because of the X-linked inheritance pattern it is more common in boys. Unlike males, the specific genetic mutations in the Kal-1 gene in females with hypogonadotropic hypogonadism have not been identified, suggesting that there may be other genetic mutations that cause this disorder. Several studies have shown that females with presumed Kallmann's syndrome demonstrate variable responses to exogenous GnRH administration, which suggests a GnRH receptor defect. In fact, mutations in the GnRH receptor have been identified in both sexes and are inherited in an autosomal recessive fashion.

Management of hypogonadotropic hypogonadism involves scheduled hormone replacement therapy to stimulate the development of secondary sexual characteristics and increase bone mineral density. If pregnancy is desired, treatment involves the administration of pulsatile GnRH or gonadotropin treatment. This will be discussed further later in this chapter in the section on infertility.

Table 13-1. Assessment of patients with amenorrhea.1

1. Absent breast development; uterus present

1. Gonadal failure

1. Gonadal agenesis

2. Gonadal dysgenesis

1. 45,X (Turner's syndrome)

2. 46,X abnormal X (eg, short- or long-arm deletion)

3. Mosaicism (eg, X/XX, X/XX/XXX)

4. 46,XX or 46,XY (Swyer syndrome) gonadal dysgenesis

2. Defects in estrogen biosynthesis (46, XX)

1. 17,20-Lyase deficiency

2. CYP 17α deficiency

3. Hypothalamic failure secondary to inadequate GnRH release

1. Insufficient GnRH secretion

1. FHA

2. Anorexia nervosa and bulimia

3. CNS neoplasm (craniopharyngioma, gliomas)

4. Excessive exercise

5. Constitutional delay

2. Inadequate GnRH synthesis (Kallman's syndrome)

3. Developmental anatomic abnormalities in central nervous system

4. Pituitary failure

1. Isolated gonadotropin insufficiency

2. GnRH resistance
2. Pituitary tumors (hyperprolactinemia)

3. Pituitary insufficiency

1. Infections (mumps, encephalitis)

2. Newborn kernicterus

4. Prepubertal hypothyroidism

2. Breast development; uterus absent

1. Androgen resistance (androgen insensitivity syndrome)

2. Congenital absence of uterus (utero-vaginal agenesis)

3. Absent breast development; uterus absent

1. Defects in testosterone biosynthesis (46,XY)

1. 17,20-Lyase deficiency

2. CYP17α deficiency

3. 17β-Hydroxysteroid dehydrogenase deficiency

2. Testicular regression syndrome (46,XY)

4. Breast development; uterus present

1. Pregnancy

2. Hypothalamic etiology

1. FHA

2. Anorexia nervosa and bulimia

3. Psychogenic (depression)

4. CNS neoplasm

5. Chronic disease

3. Pituitary etiology

1. Pituitary tumors (hyperprolactinemia)

2. Pituitary insufficiency

1. Hypotensive event (Sheehan's syndrome)

2. Infections

3. Autoimmune destruction

4. Iatrogenic (surgery, radiation)

4. Ovarian etiology

1. POF

1. Mosaicism (46,XX/XO,XX/XY)

2. Autoimmune destruction

3. Iatrogenic (radiation, chemotherapy)

4. Fragile X syndrome

5. Infections

2. Resistant ovarian syndrome (Savage's syndrome)

5. Chronic estrogenized anovulation

1. Hyperandrogenic

1. PCOS

2. NCAH

3. Cushing's syndrome

4. Androgen secreting tumors

2. Other

1. Adrenal insufficiency

2. Thyroid disorders

6. Outflow tract

1. Congenital abnormalities

1. Transvaginal septum

2. Imperforate hymen

2. Asherman's syndrome

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  1. ENDOCRINE CAUSES
  2. Functional hypothalamic amenorrheaFunctional hypothalamic amenorrhea is one of the most common types of amenorrhea and accounts for 15–35% of cases. It is an endocrine disorder, though the exact mechanism has not been definitively determined. It is characterized by dysfunctional release of GnRH (decrease in pulse frequency and amplitude) leading to low or low-normal serum levels of FSH and LH and resulting in anovulation. The ratio of serum FSH and LH in these patients is often equivalent to that of a prepubertal female with a relative FSH dominance.

The adipocyte hormone leptin has been implicated in the development of this disorder. Leptin is an important nutritional satiety factor, but it is also necessary for maturation of the reproductive system. The potential link to the reproductive system is thought to be through leptin receptors, which have been identified in the hypothalamus and gonadotropes. This is supported by the observation that leptin can stimulate GnRH pulsatility

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and gonadotropin secretion. Several studies suggest that women with functional hypothalamic amenorrhea have lower serum leptin levels in comparison with eumenorrheic controls. This relative deficiency may lead to dysfunctional release of GnRH and subsequent development of functional hypothalamic amenorrhea.

Abnormal activation of the hypothalamic-pituitary-adrenal axis is associated with functional hypothalamic amenorrhea as evidenced by small increases in serum cortisol levels. The inciting event may be excessive production of corticotropin-releasing hormone (CRH), which has been shown to decrease the pulse frequency of GnRH and increase cortisol levels in vivo. In contrast, another study suggests that although acute elevations of CRH can suppress GnRH release, this suppression cannot be maintained with CRH alone.

The cause of functional hypothalamic amenorrhea often remains unclear, but the associated hypercortisolemia suggests that it is preceded by psychologic stress, strenuous exercise, or poor nutrition. There is support for the concept that these factors may act synergistically to further suppress GnRH drive. In fact, patients with functional hypothalamic amenorrhea resulting from psychologic stress are usually high achievers who have dysfunctional coping mechanisms when dealing with daily stress. The severity of hypothalamic suppression is reflected by the clinical manifestations. The significant interpatient variability in the degree of psychologic or metabolic stress required to induce a menstrual disturbance explains the heterogeneity of clinical presentations, ranging from luteal phase defects to anovulation with erratic bleeding to amenorrhea.

Functional hypothalamic amenorrhea is reversible. Interestingly, the factors that have predicted the rate of recovery are body mass index and basal cortisol levels. When patients recover, ovulation is preceded by return of cortisol levels to baseline. Some experts have shown that cognitive behavioral therapy, teaching the patient how to cope with stress—and nutritional consultation—reverse this condition. Complete reversal may be less likely if the functional insult occurs during the period of peripubertal maturation of the HPO axis.

Many of these patients are hypoestrogenic but do not have symptoms. However, the estrogen status should still be evaluated given the strong correlation between hypoestrogenemia and the development of osteoporosis. Estrogen status can be determined by means of the progesterone withdrawal test or by measurement of serum estradiol. If there is no withdrawal, hormone replacement therapy (HRT) with combination contraceptive hormones—or traditional HRT—should be instituted. If withdrawal bleeding occurs, any cyclic progestin-containing therapy will be adequate to combat unopposed estrogen and the development of endometrial hyperplasia.

  1. Amenorrhea in the female athleteHypothalamic dysfunction has been observed in female athletes. Competitors in events such as gymnastics, ballet, marathon running, and diving can show menstrual irregularities ranging from luteal phase defects to amenorrhea. The female athletic triadas defined by the American College of Sports Medicine is characterized by disordered eating, amenorrhea, and osteoporosis. The associated nutritional deficiencies can lead to impaired growth and delayed sexual maturation. The neuroendocrine abnormalities are similar to those of women with functional hypothalamic amenorrhea.

These patients have very low body fat, often below the tenth percentile. There is evidence that a negative correlation between body fat and menstrual irregularities exists. In addition, there appears to be a critical body fat level that must be present in order to have a functioning reproductive system. Several studies have shown that these amenorrheic athletes have significantly lower serum leptin levels, which further supports leptin's role as a mediator between nutritional status and the reproductive system. The strenuous exercise these athletes engage in amplifies the effects of the associated nutritional deficiency. This synergism causes severe suppression of GnRH, leading to the low estradiol levels.

Amenorrhea alone is not harmful. However, low serum estradiol over a period of time may lead to osteoporosis and delayed puberty. An analysis of estrogen status may be obtained with measurement of serum estradiol levels or with the progestin withdrawal test (see above). If estrogen is low, a bone mineral density scan should be performed. All patients diagnosed with female athletic triad need combination contraceptive therapy or hormone replacement.

  1. Amenorrhea associated with eating disordersAnorexia nervosais a disorder characterized by relentless dieting in pursuit of a thin body habitus. Approximately 95% of cases occur in females, and the onset is chiefly in adolescence. The clinical features include extreme weight loss leading to a body weight less than 85% of normal for age and height, a distorted body image, and intense fear of gaining weight. These patients usually have a preoccupation with food and are hyperactive, with an obsessive-compulsive personality. The associated symptoms include hypothermia, mild bradycardia, dry skin, constipation, and symptoms of hypoestrogenemia. Furthermore, as part of the diagnostic criteria they must experience at least 3 months of no menses.

The dysfunction in the neuroendocrine system is similar to but often more severe than that described in association with functional hypothalamic amenorrhea. The severe reduction in GnRH pulsatility leads to suppression

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of FSH and LH secretion, possibly to undetectable levels, and results in anovulation and low serum estradiol levels. Given the severe psychologic and metabolic stress experienced by these individuals, the hypothalamic-pituitary-adrenal axis is activated. The circadian rhythm of adrenal secretion is maintained, but both cortisol production and plasma cortisol levels are persistently elevated secondary to increased pituitary secretion of ACTH. Serum leptin levels in these individuals are significantly lower than normal healthy controls and correlate with percentage of body fat and body weight. A rise in leptin levels in response to dietary treatment is associated with a subsequent rise in gonadotropin levels. This further suggests leptin's role as a potential link between energy stores and the reproductive system.

The self-induced starvation state associated with anorexia nervosa leads to additional endocrine abnormalities not observed in other causes of hypothalamic amenorrhea. For instance, thyroid hormone metabolism is altered. TSH and T4 levels are in the low normal range, but T3 levels are usually below normal. This is attributable to decreased peripheral conversion of T4 to T3 and increased conversion of T4 to the metabolically inactive thyroid hormone, reverse T3—a change that often resembles other states of starvation. This may be a protective mechanism in that the relative hypothyroid state attempts to reduce basal metabolic function in response to a highly catabolic state.

Bulimia occurs in about half of anorectic patients and is defined as binge eating followed by self-induced purging. Not all bulimics have low body weight—in fact, normal-weight bulimic individuals are much more common. These patients also have a variety of neuroendocrine aberrations—often to a lesser degree than those with anorexia—which also lead to menstrual disturbances. Leptin levels are lower than in matched controls but not as low as in individuals with anorexia nervosa. They also have neurotransmitter abnormalities—notably low serotonin levels—which might help explain the often coexisting psychologic difficulties.

Anorexia nervosa is a life-threatening illness with a significant mortality rate due to its metabolic consequences. Anorexic patients should be considered for inpatient therapy and management with a multidisciplinary approach that includes nutritional counseling and psychotherapy. Force-feeding may be necessary in some patients. If weight gain cannot be achieved with oral intake, meals may need to be supplemented by enteral or parenteral feeding. Because anorexia nervosa is a hypoestrogenic state and there is a high potential for the development of osteoporosis, all patients should receive hormone therapy either in the form of hormone replacement or combination contraceptive pills.

In summary, the hypothalamic amenorrhea endocrine syndromes are probably a continuum of disordered eating and nutritional deficiencies resulting in increasingly severe abnormalities in the reproductive system. Furthermore, the age at onset impacts the potential complications of these disorders. If low estradiol levels are present before age 20, bone mineralization may be profoundly affected since this period is critical for building peak bone mass. In addition, if these conditions occur prior to puberty, it may result in stunted growth and delayed development of secondary sexual characteristics.

  1. ANATOMIC CAUSES

There are numerous anatomic abnormalities within the central nervous system that can result in a menstrual disturbance. These include developmental defects, brain tumors and infiltrative disorders. The most common anatomic lesion associated with delayed puberty and amenorrhea is a craniopharyngioma. It is derived from Rathke's pouch, and extends into the hypothalamus, pituitary and third ventricle. The symptoms include headaches, visual loss and hypoestrogenism.

Infiltrative disorders that involve the hypothalamus are uncommon. This rare manifestation can result from systemic diseases including sacrcoidosis, histiocytosis, hemochromatosis, and lymphoma. These diseases do not initially present with amenorrhea. However, in the presence of these diseases, the hypothalamus may be affected, so they should be part of the differential diagnosis of amenorrhea.

PITUITARY AMENORRHEA

There are a few genetic mutations affecting the pituitary that cause amenorrhea. Rare autosomal recessive mutations may cause deficiencies in FSH, LH, TSH, prolactin, and GH. The clinical manifestations may include delayed puberty, a hypoestrogenic state, and infertility.

  1. GENETIC CAUSES

A deficiency in FSH and LH may be a result of GnRH receptor gene mutations. Such mutations are primarily compound heterozygous mutations that affect GnRH receptor-dependent signal transduction. The phenotype of these individuals is similar to that of those with isolated GnRH deficiency. In fact, some investigators speculate that these receptor mutations may be the cause of isolated GnRH deficiency in women, given that no mutations have yet been identified in the ligand or Kal-1 gene. The estimated prevalence of GnRH receptor mutations in women with hypothalamic amenorrhea is 2%. In a family with other affected females, the prevalence is 7%.

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Other rare genetic defects have been associated with amenorrheic women. Mutations in the FSHβ gene have been reported. These have an autosomal recessive pattern of inheritance and lead to low serum FSH and estradiol levels and high plasma LH levels. The clinical features include minimal development of secondary sexual characteristics and amenorrhea with no history of menses. Combined hormone deficiencies have also been described. Mutations in PROP-1, a pituitary transcription factor, lead to deficiencies in gonadotropins, TSH, prolactin, and GH. These patients present with stunted growth, hypothyroidism, and delayed puberty in addition to amenorrhea.

  1. ENDOCRINE CAUSES

Hyperprolactinemia is one of the most common causes of amenorrhea, accounting for 15–30% of cases. In the absence of pregnancy or postpartum lactation, persistently elevated prolactin is almost always associated with a hypothalamic-pituitary disorder. Normal prolactin secretion is regulated by several stimulatory and inhibitory factors (see Chapter 5). Prolactin secretion is primarily under tonic inhibition by dopamine, so that any interference with dopamine synthesis or transport from the hypothalamus may result in elevated prolactin levels. In addition to menstrual disturbances, individuals with hyperprolactinemia may present with galactorrhea. In fact, hyperprolactinemia is a common cause of galactorrhea, and up to 80% of patients with amenorrhea and galactorrhea have elevated prolactin levels. Other associated symptoms include headaches, visual field defects, infertility, and osteopenia.

The mechanism whereby hyperprolactinemia causes amenorrhea is not completely known. Studies have shown that prolactin can affect the reproductive system in several ways. Prolactin receptors have been identified on GnRH neurons and may directly suppress GnRH secretion. Others have postulated that elevated prolactin levels inhibit GnRH pulsatility indirectly by increasing other neuromodulators such as endogenous opioids. There is also evidence that GnRH receptors on the pituitary may be down-regulated in the presence of hyperprolactinemia. Furthermore, prolactin may affect the ovaries by altering ovarian progesterone secretion and estrogen synthesis. The best data now available suggest that hyperprolactinemia causes amenorrhea primarily by suppression of GnRH secretion.

Approximately half of patients with elevated prolactin levels have radiologic evidence of a pituitary tumor. The most common type is a prolactin-secreting tumor (prolactinoma), accounting for 40–50% of pituitary tumors. Prolactinomas are mainly composed of lactotrophs; however, these tumors may rarely be mixed with other cell types present in the pituitary. The most common of these mixed tumors secretes both GH and PRL.

The diagnosis of a pituitary adenoma is usually made by examination of the pituitary with MRI. These tumors are categorized into two groups based on their dimensions—microadenomas are those less than 10 mm in diameter, and macroadenomas are the larger ones. These tumors are usually located in the lateral wings of the anterior pituitary. Rarely, a microadenoma will infiltrate the surrounding tissue, including the dura, cavernous sinus, or adjacent skull base. A macroadenoma may expand farther and grow out of the sella to impinge on surrounding structures, including cranial nerve areas such as the optic chiasm; or may extend into the sphenoid sinus. As a result, macroadenomas are more frequently associated with severe headaches, visual field defects, and ophthalmoplegia. The incidence of a microadenoma progressing to a macroadenoma is relatively low, only 3–7%. During pregnancy the risk of a microprolactinoma enlarging is also low, but in the presence of a macroprolactinoma the chance of tumor growth is up to 25%.

Some investigators have found a correlation between pituitary adenoma size and serum prolactin levels. If the serum prolactin level was less than 100 ng/mL, a microprolactinoma was more likely, whereas if the level was greater than 100 ng/mL a macroprolactinoma was more often present. Although this correlation has been reported, the evidence supporting it is not strong. In fact, low prolactin levels may be associated with other pituitary tumors such as nonfunctioning macroadenomas. These “nonfunctioning” tumors may synthesize glycoproteins such as FSH, LH, or their free alpha and beta subunits. Rarely, functioning tumors may arise from other pituitary cells, resulting in excessive hormone secretion. If a macroadenoma is present, measurement of IGF-I, alpha subunit, TSH, and 24-hour urinary cortisol will exclude other functioning adenomas or pituitary insufficiency.

Other tumors of nonpituitary origin may also result in delayed puberty and amenorrhea. The most common of these, is a craniopharyngioma. Although it is most commonly located in the suprasellar region, anatomically, these tumors originate from the anterior surface of the pituitary and can disort the infundibulum of the pituitary. This tumor has not been shown to produce hormones, but because it may compress the infundibulum, it can interfere with the tonic inhibition or prolactin and result in mildly elevated prolactin levels.

Hyperprolactinemia in a patient with amenorrhea is defined as a prolactin level greater than 20 ng/mL, though the limit of normal may vary between laboratories. Normal prolactin release follows a sleep-circadian rhythm, but prolactin may also be secreted in response to stress, physical exercise, breast stimulation, or a meal. Therefore, prolactin should be measured in the mid morning hours and in the fasting state. Other causes of

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mildly elevated prolactin include medications such as oral contraceptives, neuroleptics, tricyclic antidepressants, metoclopramide, methyldopa, and verapamil. Hyperprolactinemia has also been observed in several chronic diseases, including cirrhosis and renal disease. Furthermore, inflammatory diseases such as sarcoidosis and histiocytosis can infiltrate the hypothalamus or pituitary and result in hyperprolactinemia. Elevated prolactin levels may be a physiologic response. During pregnancy, prolactin levels may be two to four times baseline. With postpartum breast-feeding, the prolactin level should be below 100 ng/mL after 7 days and below 50 ng/mL after 3 months. If a woman is not breast-feeding, prolactin levels should return to baseline by 7 days postpartum (see Table 5-8).

Persistently elevated prolactin levels may also be present in primary hypothyroidism. Approximately 40% of patients with primary hypothyroidism present with a minimal increase in prolactin (25–30 ng/mL), and 10% present with even higher serum levels. Individuals with primary hypothyroidism have an increase in thyrotroph-releasing hormone (TRH) from the hypothalamus, which stimulates TSH and prolactin release and leads to hyperprolactinemia. Patients with long-standing primary hypothyroidism may eventually manifest profound pituitary enlargement due to hypertrophy of thyrotrophs. This mass effect with elevated prolactin levels mimics a prolactinoma. Therefore, all patients with hyperprolactinemia should have their thyroid function investigated to exclude hypothyroidism as the cause.

Prolactinomas are the most common cause of persistent hyperprolactinemia. All patients with elevated prolactin levels should have the test repeated. In addition to blood tests, a careful clinical and pharmacologic history and physical examination should be performed to exclude other causes of hyperprolactinemia. If elevated prolactin levels persist or if any measurement is found to be above 100 ng/mL, MRI of the hypothalamic-pituitary region should be performed. If a microadenoma is observed, the diagnosis of microprolactinoma can be made. If a macroadenoma is observed, other pituitary hormones should be measured to exclude other functioning adenomas or hypopituitarism. All patients diagnosed with macroadenoma should have a visual field examination.

The treatment of choice for prolactinoma is dopamine agonist therapy. These drugs (bromocriptine, cabergoline, pergolide, quinagolide) are very effective at lowering prolactin levels, resolving symptoms, and stimulating tumor shrinkage. Treatment will result in a rapid reduction in prolactin levels in 60–100% of cases. Following diminution of prolactin levels, 60–100% of women resume ovulatory menses within 6 weeks, and galactorrhea disappears within 1–3 months after starting treatment. Reduction in tumor size is usually evident after 2–3 months of drug therapy, but it may occur within days after initiation of treatment. The extrasellar portion of the tumor appears to be particularly sensitive to drug therapy, which explains the improvement in symptoms such as visual impairment or ophthalmoplegia with drug therapy. In patients diagnosed with a microadenoma that is manifested only as a menstrual disturbance, observation should be considered. These individuals may be offered oral contraceptives to control the bleeding pattern or to protect bone from estrogen deficiency. However, the long-term sequelae of persistently elevated prolactin levels are unknown. If dopamine agonist treatment is initiated for a microadenoma, therapy may be continued long-term. If the tumor responds, the dose may be tapered and stopped after menopause. In contrast, individuals with a macroadenoma should take dopamine agonist therapy indefinitely. All patients diagnosed with a prolactinoma should have follow-up imaging, determination of serum prolactin levels, and visual field examinations.

An alternative to medical management of pituitary tumors is transsphenoidal surgery, after which resolution of symptoms may be immediate. However, the success and recurrence rates vary and are dependent on the size of the tumor and the depth of invasion. The larger and more invasive the tumor is, the less chance there is for complete resection and the greater the chance for recurrence. In general, the success rate of surgery for a microadenoma may be up to 70% and for a macroadenoma less than 40%. Overall, the recurrence rate with surgery is approximately 50%. Surgery is a good alternative for resistant tumors or for patients intolerant of medical treatment. Since non-prolactin-secreting pituitary tumors often do not respond well to medical therapy, operation is the treatment of choice for these tumors as well. The risks of surgery include infection, diabetes insipidus, and panhypopituitarism. Complete pituitary testing should be performed prior to surgery.

  1. ANATOMIC CAUSES
  2. Pituitary destructionAmenorrhea may be the result of not only pituitary neoplasms, but also pituitary destruction. Similar infiltrative disorders that can involve the hypothalamus can affect the pituitary, and is slightly more vulnerable. Other disorders that cause pituitary insufficiency may be situational. A rare autoimmune disease, lymphocytic hypophysitis can cause pituitary destruction during the puerperium and ultimately results in panhypopituitarism. Pituitary necrosis may also occur secondary to a hypotensive event. Typically, 80–90% of the pituitary must be damaged before pituitary failure ensues and the robust blood supply to the pituitary makes this an uncommon event. If pituitary ischemia and necrosis are related to postpartum hemorrhage,

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it is known as Sheehan's syndrome, otherwise, it is called Simmond's disease. Since this type of injury typically affects the entire pituitary, most often more than one or all the pituitary hormones may be deficient. Observation has suggested that hormone loss follows a pattern, starting with the gonadotropins, followed by GH and PRL. Fortunately, ACTH and TSH are the last to be lost, since they are vital.

OVARIAN AMENORRHEA

The physiologic period in a woman's life when there is permanent cessation of menstruation and regression of ovarian function is known as menopause (see below). The cause of ovarian failure is thought to be depletion of ovarian follicles. The median age at menopause is 51.1 years. Premature menopause is defined as ovarian failure prior to age 40, which is reported to occur in 1% of the population. The etiology of premature ovarian failure may have a genetic basis. Several mutations that affect gonadal function have been identified and include defects in hormone receptors and steroid synthesis. Other potential causes include autoimmune ovarian destruction, iatrogenic ovarian injury, and idiopathic ovarian failure. The most severe form of premature ovarian failure presents with absent secondary sexual characteristics and is most often due to gonadal agenesis or dysgenesis (see Chapter 14). Less severe forms may result only in diminished reproductive capacity.

The other ovarian cause of amenorrhea is repetitive ovulation failure or anovulation. Other than meno-pause, it is the most common cause of amenorrhea. Chronic anovulation may be secondary to disorders of the hypothalamic-pituitary axis and has been previously discussed. Anovulation may also be due to systemic disorders. The causes of ovarian failure and anovulation due to peripheral disorders will be discussed below.

Ovarian failure is diagnosed based on the clinical picture of amenorrhea and the demonstration of elevated FSH (> 40 IU/L). This may occur at any time from embryonic development onward. If it occurs prior to age 40, it is called premature ovarian failure. The presence or absence of secondary sexual characteristics is evidence of whether ovarian activity was present in the past. The most common cause of hypergonadotropic amenorrhea in the absence of sexual characteristics is abnormal gonadal development, which occurs in more than half of these individuals. When the gonad fails to develop, this is known as gonadal agenesis. The karyotype of these individuals is 46,XX, and the cause of failure is usually unknown. If streak gonads are present, this indicates at least partial gonadal development and is called gonadal dysgenesis. The karyotype of these individuals may be normal, but it is more likely that there will be alterations in sex chromosomes (seeChapter 14).

Premature Ovarian Failure

  1. GENETIC ORIGIN OF PREMATURE OVARIAN FAILURE

Two intact X chromosomes are necessary for the maintenance of oocytes during embryogenesis, and the loss of or any alteration in the sex chromosome leads to accelerated follicular loss. This implies that two intact alleles are required for the normal function of some genes on the X chromosome. Turner's syndrome is a classic example of complete absence of one X chromosome. It manifests as short stature, sexual infantilism, amenorrhea, and ovarian dysgenesis. This is a well-recognized condition that occurs in 1:2000–1:5000 females at birth. Turner's syndrome is associated with a number of other phenotypic abnormalities, including a webbed neck, broad chest, low hairline, and cardiovascular and renal defects. It is interesting that fewer than half of patients with Turner's syndrome have a single cell line with the karyotype 45,X. The majority of patients actually present with a mosaic karyotype such as 45,X/46,XX. These patients have varying degrees of the Turner syndrome phenotype and may display some secondary sexual development or may have a history of menstrual function. Some pregnancies have been reported.

Another mosaic pattern that has been associated with Turner's syndrome is the 45,X/46,XY karyotype. This chromosomal anomaly has been termed mixed gonadal dysgenesis. These patients may have some functional testicular tissue and present with varying degrees of genital ambiguity. If enough testicular tissue is present to produce antimüllerian hormone (AMH), these patients may also present with abnormalities of the internal genitalia. An extreme case of this would be a patient with 46,XX/46,XY karyotype who has both ovarian tissue and testicular tissue along with wolffian and müllerian structures internally. These patients are true hermaphrodites.

Patients with gonadal dysgenesis may be phenotypically normal and the abnormality may be manifested only as delayed pubertal development and amenorrhea. They probably have normal müllerian structures and streak gonads. These individuals can display an array of karyotypes, including 46,XY (Swyer's syndrome). Patients with a male karyotype but a female phenotype presumably underwent testicular failure prior to internal or external genitalia differentiation. If a dysgenetic gonad contains a Y chromosome or a fragment of the Y chromosome, there is a 10–30% risk for future gonadal malignancy, and gonadal extirpation is indicated at the time of diagnosis.

Premature ovarian failure may also be defined as ovarian failure before age 40 but after puberty. Since complete absence of an X chromosome results in a dysgenetic gonad, candidate genes for premature ovarian failure are probably those that escape X inactivation. In

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mammals, X inactivation occurs in all cells in order to provide dosage compensation for X-linked genes between males and females (Lyon hypothesis). Further observation has illustrated that terminal deletions in Xp lead to the classic stigmas of Turner's syndrome while deletions in Xp or Xq present with varying degrees of early reproductive failure. However, most of the genes involved in folliculogenesis appear to be located on the long arm of the X chromosome. Several regions on the X chromosome, including POF 1 and POF 2, have been evaluated with knockout models in animals and have shown varying effects on ovarian development (Figure 13-8).

Limited observations have found that deletions occurring closer to the centromere manifest a more severe phenotype that includes disruption of pubertal development. In contrast, deletions that occur in the distal regions tend to present with early reproductive aging and infertility. An example of a distal mutation on the long arm is the FMR1 gene (fragile X gene). An association has been described between the FMR1 permutation state and premature ovarian failure. The prevalence of FMR1 gene permutations approximates 2–3% of patients who present with sporadic premature ovarian failure and may be as high as 15% in familial cases. Although a number of genes on the X chromosome have demonstrated involvement in ovarian physiology, the majority of premature ovarian failure patients have no identifiable mutations on the X chromosome.

 

Figure 13-8. Candidate genes on the X chromosome for premature ovarian failure (POF). (Reproduced, with permission, from Davison RM, Davis CJ, Conway GS: The X chromosome and ovarian failure. Clin Endocrinol 1999;51:673.)

Autosomal recessive genes that have shown contributions to premature ovarian failure are very rare. FSH receptor mutations have been identified in humans with premature ovarian failure. These individuals present with a phenotype that ranges from absent secondary sexual development to normal development and early reproductive failure. The prevalence of FSH receptor mutations varies but is most common in the Finnish population (1% carriers). This mutation has not been observed in North America. An inactivated LH receptor has been identified in patients with normal puberty and amenorrhea but is quite rare. Mutations in genes involved in steroidogenesis have also been associated with premature ovarian failure. These enzymes include CYP17α and aromatase. Patients with CYP17α mutations may have a 46,XX or 46,XY karyotype. They have a similar phenotype except that those with 46,XY have absent müllerian structures since AMH is produced from their testes. Individuals with aromatase deficiency present with sexual ambiguity and clitoromegaly. Several other autosomal genetic mutations have been discovered that may have a role in ovarian physiology. However, at this time, most cases of premature ovarian failure with normal pubertal development have not been associated with any specific genetic mutation (see Chapter 14).

  1. AUTOIMMUNE ORIGIN OF PREMATURE OVARIAN FAILURE

Autoimmune ovarian destruction is another potential cause of premature ovarian failure. This diagnosis is difficult to make unless it presents with one of the autoimmune polyglandular syndromes (see Chapter 4). The circumstantial evidence supporting the diagnosis is found in the high incidence of concomitant autoimmune disease—20% or more in patients with premature ovarian failure. The strongest association is with autoimmune thyroid disease. In addition, 10–20% of individuals with autoimmune adrenal disease experience premature ovarian failure. Conversely, 2–10% of patients with idiopathic premature ovarian failure develop adrenal insufficiency.

Premature ovarian failure patients are often diagnosed as having autoimmune disease if autoimmune antibodies are identified. Thyroid antibodies are most frequently screened. If abnormal, thyroid function should be evaluated. All patients with suspected autoimmune premature ovarian insufficiency should be screened regularly for adrenal insufficiency.

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  1. IATROGENIC CAUSES OF PREMATURE OVARIAN FAILURE

Iatrogenic causes of premature ovarian failure include radiation therapy, chemotherapy, and ovarian insults resulting from torsion or surgery. The risk of premature ovarian failure following radiation and chemotherapy is proportionate to the patient's age. If the radiation dose is higher than 800 Gy, all women experience ovarian failure. Chemotherapy alone may induce temporary or permanent ovarian failure. In general, younger individuals with chemotherapy-induced ovarian injury are more likely to recover.

  1. RESISTANT OVARY SYNDROME

A rare cause of hypergonadotropic amenorrhea associated with numerous unstimulated ovarian follicles is the resistant ovary syndrome. These patients classically have no history of ovulatory dysfunction and present with secondary sexual characteristics and symptoms suggestive of estrogen deficiency. This diagnosis was established in an era when ovarian biopsy was used to determine the cause of menstrual disturbances. However, the definition of resistant ovary syndrome is not universally accepted. In fact, in the original series, cases were included in which patients had demonstrated ovulatory function in the past but later developed a clinical picture suggestive of ovarian resistance. This pattern is more typical of ovarian aging and follicular depletion.

The cause is not known. Histologic features of ovarian biopsy demonstrate that there is no plasma cell or lymphocytic infiltration, indicating that it is not caused by autoimmune destruction. The presence of numerous follicles indicates that premature ovarian failure is not due to follicular depletion. Several studies have looked at gonadotropins, FSH receptors, and antibodies that serve as blockers to the gonadotropin receptors, and the literature to date is inconclusive about the cause.

A certain diagnosis can only be established with ovarian biopsy. However, current recommendations for management of amenorrhea do not include surgery to make a diagnosis. The diagnosis is therefore one of exclusion. In the absence of autoimmune disease and of any history of ovulation, karyotyping should be performed to exclude chromosomal abnormalities. In patients with normal karyotypes, the diagnosis of premature ovarian failure and resistant ovary syndrome will be hard to make without biopsy. Improvements in ultrasound technology may make it possible to differentiate these entities by the measurement of ovarian volumes and antral follicle counts.

  1. SUMMARY

In over half of patients with premature ovarian failure, no specific cause can be identified. The age defining premature ovarian failure is somewhat arbitrary. By definition, menopause is preceded by reproductive failure. It is thought that the time interval between menopause and the end of fertility may be approximately 10 years, and we know that approximately 10% of women reach menopause by 46 years of age and 1% by 40 years. Therefore, women who experience menopause at 45 years of age probably encounter a decline in reproductive potential or even reproductive failure at 35 years of age. This has obvious implications for women who are delaying childbearing. Several studies have described a significant association between the menopausal ages of mothers and daughters, twins, and sisters. A number of studies have identified new genes that are involved in ovarian physiology. It is hoped that these investigations will help in the treatment of subfertility and result in a reduction in infertility. At a minimum, they may allow better prospective individual prediction of reproductive risk.

ANOVULATION

Chronic anovulation may be defined as repetitive ovulation failure, which differs from ovarian failure in that viable oocytes remain in the ovary. Anovulation is the most common cause of amenorrhea during the reproductive years. There are several causes; those associated with hypothalamic and pituitary disorders have previously been mentioned and will not be considered in this section. Other conditions that cause anovulation include the peripheral endocrinopathies. These disorders result in a hormonal imbalance—mainly elevated androgens or estrogens—and lead to inappropriate feedback mechanisms and ovulatory failure. The peripheral endocrine disorders will be discussed below in greater detail.

Polycystic Ovarian Syndrome

Hyperandrogenic anovulation accounts for over 30% of cases of amenorrhea. Most often it is due to polycystic ovarian syndrome (PCOS). The reported prevalence of PCOS depends on the criteria used to define it. Although there is considerable controversy over the definition, most investigators have focused on the 1990 NIH-NICHD diagnostic criteria (see Table 13-2). That definition includes ovulatory dysfunction, with evidence of hyperandrogenism either clinically or by laboratory testing, in the absence of identifiable causes of hyperandrogenism. Using these criteria, the prevalence of unexplained hyperandrogenic chronic anovulation approximates 4–6%, and it is considered the most common endocrine disorder in women of reproductive age. In fact, PCOS is responsible for over 20% of all cases of amenorrhea and up to 75% of all cases of anovulatory infertility.

Table 13-2. Diagnostic criteria for polycystic ovary syndrome (PCOS)percentage of participants agreeing at 1990 NICHD PCOS Conference.1

Definite or Probable

Possible

Hyperandrogenemia, 64%

Insulin resistance, 69%

Exclusion of other causes, 60%

Perimenarchal onset, 62%

Exclusion of CAH, 59%

Elevated LH/FSH, 55%

Menstrual dysfunction, 52%

Polycystic ovary by ultra-sound, 52%

Clinical hyperandrogenism, 48%

Clinical hyperandrogenism, 52%
Menstrual dysfunction, 45%

1Reproduced, with permission, from Dunaif A: Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774.

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The clinical manifestations of PCOS are oligomenorrhea or amenorrhea with symptoms suggestive of hyperandrogenism such as acne or hirsutism. Approximately 50% of women diagnosed with PCOS are obese, and most have polycystic ovaries present on sonography (see below). Underlying these features are numerous biochemical abnormalities that have been associated with this syndrome, including elevated circulating total testosterone, free testosterone, DHEAS, and insulin as well as decreased sex hormone binding globulin (SHBG) and an elevated LH/FSH ratio. However, these abnormalities are not present in all PCOS patients. In fact, only 40% of women who present with only hirsutism have elevated total testosterone levels, and 30–70% have elevated DHEAS levels. Similarly, the LH/FSH ratio is not a reliable diagnostic test. Although elevated LH/FSH ratios are common findings in thin women, in obese PCOS patients the ratio is within the normal range about half of the time. Hyperinsulinemia has recently been hypothesized to play a major role in the pathogenesis of PCOS (see below). The prevalence of insulin resistance may approximate 50–60%, compared with 10–25% observed in the general population. However, insulin resistance is difficult to measure. Part of the difficulty is that there is no universally agreed upon definition of insulin resistance and the laboratory tests are not standardized. Furthermore, baseline insulin levels vary depending on the population and body weight. For example, up to 60% of ovulatory obese patients have demonstrated some form of insulin resistance. Nonetheless, there is good evidence that a subset of normal-weight women and obese women with PCOS have a greater degree of insulin resistance and compensatory hyperinsulinemia compared with weight-matched controls.

  1. DIAGNOSIS OF PCOS

The diagnosis of PCOS is typically based on clinical features, though additional information may be obtained with biochemical testing and sonographic examination. In most situations, however, measurement of serum androgen levels should play only a limited role in the evaluation. Most patients who have hyperandrogenemia present with obvious clinical manifestations, and the presence of normal androgen levels in a patient with hirsutism or acne does not exclude the diagnosis of PCOS. However, there are subsets of amenorrheic patients who are hyperandrogenemic without clinical manifestations, most likely as a result of relative insensitivity to circulating androgens. It is in these patients that assessing androgen levels may be of value in determining the cause of amenorrhea. More commonly, androgens such as DHEAS and testosterone are measured to exclude other causes of hyperandrogenic anovulation such as nonclassic adrenal hyperplasia and androgen-secreting tumors (see below).

In Europe (particularly in England), sonography is used to identify morphologic evidence of PCOS. Polycystic ovaries tend to be enlarged and are characterized by the presence of ten or more cysts that are between 2 mm and 8 mm in diameter and arranged along the subcapsular edge of the ovary in a “string of pearls” fashion. Even so, the finding of polycystic ovaries does not establish the diagnosis of PCOS. In fact, over 80% of hirsute women with normal menses demonstrate polycystic ovaries. Polycystic ovaries are common in any woman with hyperandrogenism presenting with acne, seborrhea, or male pattern alopecia independent of menstrual disturbances. Furthermore, over 20% of normal women have this ovarian morphologic feature. Thus, the finding of polycystic ovaries alone is not diagnostic of polycystic ovarian syndrome as understood in the USA, and ovarian morphology is not a useful marker for defining the cause of chronic anovulation.

  1. MECHANISM OF ANOVULATION

The mechanism of anovulation in PCOS remains unclear. It is evident that the population of preantral follicles is increased and that follicular development is arrested. It is also known that the development of preantral follicles is not primarily under hormonal control. Evidence supports the components of the intraovarian network as regulators of antral follicle development. It is known that many of the accumulated follicles in PCOS remain steroidogenically competent and are capable of producing estrogen and progesterone. In fact, it is interesting that women with PCOS produce both androgens and estrogen in excess (estrone).

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Under normal conditions, follicles respond to LH after they reach approximately 10 mm in diameter. However, polycystic ovarian follicles acquire responsiveness to LH at a much smaller diameter, which may lead to inappropriate terminal differentiation of granulosa cells and result in disorganized follicular development. The elevated LH levels and relative hyperinsulinemia that exist in some PCOS patients may synergistically potentiate disordered folliculogenesis. Although hyperandrogenism is part of the diagnostic criteria for PCOS, its direct impact on folliculogenesis is not clear. It is conceivable that androgens contribute to the effects of LH and insulin on follicular maturation. It is also possible that the excess estrogens may result in a negative feedback loop to inhibit FSH release and prevent further follicular development.

A fundamental abnormality in PCOS is excess androgen production. Both the adrenal glands and the ovaries contribute to circulating androgens. The relative strengths of androgens are listed in Table 13-3.

During the reproductive years, both the ovaries and the adrenals contribute up to 25% of the circulating testosterone by direct secretion. The remaining 50% arises from peripheral conversion of androstenedione, which is produced equally by the adrenal gland and the ovary. This differs from males, in whom only 5% of the circulating testosterone is derived from androstenedione. It is also estimated that androstenedione conversion contributes to the increased circulating estrogen levels. This weaker androgen is peripherally converted to estrone by adipose tissue, hair follicles, and the liver. Furthermore, it is estimated that over 60% of the most potent androgen, dihydrotestosterone, is derived from androstenedione in women. DHEAS is the major androgen produced by the adrenal gland. It is responsible for over 95% of the circulating DHEAS levels. Although it is the most abundant androgen circulating in the body, it contributes minimally to serum testosterone levels (Figure 13-3).

Androgen production within the ovary is mainly by the thecal interstitial cells that surround the follicle and to a lesser extent the secondary interstitial cells located in the stroma. The CYP17α complex is thought to be the key enzyme in biosynthesis of ovarian androgens. Under normal conditions, a large proportion of the androgens produced by the theca cells diffuse into the granulosa cell layer of the follicle where they are rapidly converted to estrogen as shown in Figures 13-6 and 13-9 (two-cell theory). The intrinsic control of androgen production in the ovary is modulated by intraovarian factors and hormones (see section on ovarian steroidogenesis at the beginning of this chapter). It is the dysregulation of hormone production that is most likely responsible for PCOS.

Several studies have shown that women with PCOS have an exaggerated ovarian androgen response to various stimuli. To illustrate: hyperstimulation of 17-hydroxyprogesterone levels was noted when women diagnosed with PCOS were given a GnRH agonist or hCG, suggesting increased CYP17α activity. This study is supported by in vitro studies in which measurement of steroids in cultured human theca cells from polycystic ovaries revealed concentrations of androstenedione, 17α-hydroxyprogesterone, and progesterone that were respectively twentyfold, tenfold, and fivefold higher than levels in control cells. Additional studies have found increased expression of the genes encoding CYP17α hydroxylase, P450scc, the LH receptor, and StAR. These findings reflect a global enhancement of steroidogenesis. This situation is compounded by the hypertrophy of theca cells that is present in women with PCOS.

Table 13-3. Relative androgenic activity of androgens.1

Steroid

Activity

Dihydrotestosterone

300

Testosterone

100

Androstenedione

10

DHEA, DHEAS

5

1Reproduced, with permission, from Yen SSC, Jaffe RB, Barbieri RL (editors). Reproductive Endocrinology. Saunders, 1999.

Several studies have evaluated the intraovarian modulators as participants in the pathogenesis of PCOS. IGF-binding proteins (BPs), especially BP2 and BP4, are found to be increased in the follicular fluid of PCOS ovaries. They may act locally to decrease free IGF-I and thus decrease the effects of FSH on the oocyte and granulosa cells. Inhibin also is a likely candidate since a large proportion of women with PCOS have relative FSH suppression. However, studies have not shown consistent results, suggesting that if inhibin is involved, the effect is minimal. Follistatin, the activin-binding protein, was in the past thought to play an important role in the development of PCOS. It was initially implicated because activin functions to inhibit androgen production and enhance FSH expression. However, current studies do not demonstrate a significant association between abnormalities in follistatin and PCOS.

The adrenal gland may be significantly involved in the pathogenesis of some cases of PCOS. The connection seems plausible since adrenal androgens can be converted to more potent androgens in the ovary. Furthermore, a significant portion of women with congenital adrenal hyperplasia have polycystic ovaries (see below). Several studies have shown that DHEAS is elevated

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in 25–60% of patients with PCOS. It has also been reported that there is an increased response of androstenedione and 17α-hydroxyprogesterone to exogenous ACTH. These findings suggest an underlying abnormality in the CYP17α expressed in the adrenal gland as well as in the ovary. However, there are minimal data to support CYP17α dysfunction in the adrenal gland. It has also been shown that ovarian steroids can stimulate adrenal androgen production; however, additional findings suggest that the ovary is not the primary cause of adrenal hyperresponsiveness. The critical role played by adrenal androgens during the pubertal transition has not been fully investigated as a potential contributor to the development of PCOS.

 

Figure 13-9. Major steroid pathways in the ovary according to the two-cell hypothesis of ovarian function. (Reproduced, with permission, from Ehrmann DA, Barnes RB, Rosenfield RL: Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev 1995;16:322.)

Hyperinsulinemia

A relationship between insulin and hyperandrogenism has been postulated based on several observations. Various case reports have shown that acanthosis nigricans—hyperpigmentation of skin in the intertriginous areas—is associated with severe insulin resistance. A number of these patients also presented with hyperandrogenism and anovulation. The relationship was substantiated when it was observed that the degree of hyperinsulinemia was correlated with the degree of hyperandrogenism. Further studies revealed that hyperinsulinemia is frequently identified in women with PCOS. It has been shown that the cause of hyperinsulinemia is insulin resistance and that the dysfunction lies in the postbinding signaling pathway. The frequency and degree of hyperinsulinemia in women with PCOS is amplified in the presence of obesity. Although many women with PCOS exhibit insulin resistance, some do not. However, insulin resistance is also observed in some thin PCOS patients.

Insulin may cause hyperandrogenism in several different ways, though the exact mechanism has not been well defined. It is suggested that insulin has a stimulatory effect on CYP17α. There is evidence from in vitro models that insulin may act directly on the ovary. It has been shown that the ovary possesses insulin receptors and IGF-I receptors. In addition, several studies have reported that insulin stimulates ovarian estrogen, androgen, and progesterone secretion and that its effect is greatly enhanced by the addition of gonadotropins. Administration of an insulin-sensitizing agent (eg, metformin or a thiazolidinedione) to obese women with PCOS leads to a substantial reduction in 17α-hydroxyprogesterone levels, reflecting decreased CYP17α activity.

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However, clinical studies in which insulin infusions were administered to normal women failed to demonstrate increased testosterone production, and there were no changes in androgen levels when normal women were given insulin-sensitizing agents. These observations suggest that insulin's effect on androgen production is more likely a modifier rather than a predisposing agent.

The relationship between insulin and adrenal androgen production is less clear. Some studies have shown that insulin increases secretion of 17α-hydroxyprogesterone and DHEAS in response to ACTH. Other studies have shown that DHEAS decreases after acute insulin infusions are administered to normal men and women. Furthermore, when insulin-sensitizing agents were administered to women with PCOS, a decrease in DHEAS was observed. Although there is less evidence to support the association of insulin and adrenal androgen production, if there is an insulin effect it is as a modulator of adrenal secretory activity.

Insulin may indirectly affect androgen levels. Several studies have reported that insulin directly inhibits SHBG production. There is an inverse correlation between insulin levels and SHBG, so that decreasing insulin levels would decrease the circulating bioavailable androgen level (via increases in SHBG). It has also been shown that insulin decreases insulin-like growth factor binding protein-1 (IGFBP-1). This would increase free IGF-I, which could modulate ovarian androgen production in a fashion similar to insulin. Although these indirect mechanisms may play a role, the literature suggests that insulin acts directly to augment androgen production. However, it appears that a dysregulation in steroidogenesis must also exist in order for insulin to cause hyperandrogenism.

There is increasing evidence for a strong genetic component in the etiology of PCOS. Several candidate genes have been investigated, including genes involved in steroidogenesis and carbohydrate metabolism, but none have been conclusively linked with the disease. PCOS is heterogeneous clinically, raising the possibility of different genetic causes and a variable environmental contribution to the syndrome.

Increasing attention is being directed to the possibility that PCOS begins before adolescence. In fact, the initial insult may begin in utero, where there is ample exposure to androgens derived from the fetal adrenal and ovary. This hormonal environment may reprogram the ovary and alter steroidogenesis in a manner that predisposes to PCOS. The phenotypic expression of PCOS would then be determined by environmental factors such as diet and exercise.

The various biochemical abnormalities associated with PCOS have led to studies investigating metabolic sequelae of this syndrome. Long-term health problems such as the development of cardiovascular disease and diabetes have been linked to PCOS. However, there are limited studies looking at whether women with PCOS actually experience increased cardiovascular events. Several observational studies have demonstrated that women with PCOS have alterations in their lipid profiles, including increased triglycerides and LDL and decreased HDL compared with weight-matched controls. Furthermore, the degree of dyslipidemia has been correlated with the magnitude of insulin resistance. The fact that insulin resistance occurs with greater frequency in women with PCOS suggests that they are at higher risk for the development of diabetes mellitus. It is known that up to 30–40% of women with PCOS have impaired glucose tolerance, though it is most often seen in patients who are obese. Limited retrospective studies have suggested that women with PCOS have an increased frequency of developing type 2 diabetes. In summary, as demonstrated by surrogate markers, the available data show that these patients have increased risk factors for cardiovascular events and diabetes. Long-term prospective studies will be required to determine if these patients are really at risk for increased mortality and morbidity.

The fact that hyperinsulinemia underlies many of the potential adverse sequelae raises a question about whether insulin resistance should be assessed in all patients diagnosed with PCOS. However, the potential impact of hyperinsulinemia is unknown. Furthermore, there is no universal laboratory criterion or standardization for establishing the diagnosis of insulin resistance, which raises doubts about whether any potential adverse sequelae can be prevented if insulin resistance is identified. Further data are necessary prior to widespread use of medications such as metformin or a thiazolidinedione to reduce insulin resistance in patients with PCOS and to determine (1) if these patients are indeed at risk for cardiovascular events, (2) if hyperinsulinemia is an independent risk factor, and (3) whether long-term treatment with any insulin-sensitizing agent will decrease the potential sequelae.

  1. ADDITIONAL RISKS ASSOCIATED WITH ANOVULATION

Another concern is that women who are anovulatory do not produce a significant amount of progesterone. This leads to an unopposed estrogen environment on the uterine lining, which is a significant risk factor for development of endometrial cancer. In fact, an association has been found between endometrial cancer and PCOS. There is also some evidence to suggest an association of PCOS with both breast cancer and ovarian cancer, but PCOS has not been conclusively shown to be an independent risk factor for either disease.

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  1. TREATMENT

The treatment of PCOS should be directed toward prevention of potential malignant endometrial sequelae and the patient's symptoms. Combination oral contraceptives have been shown to promote a significant reduction in endometrial cancer in the general population. It makes sense to think that a similar benefit would accrue to women with PCOS since the ovarian stimulation is minimized and the progestin would counteract the estrogenic environment. Oral contraceptives also improve menstrual irregularities, and combination oral contraceptives improve hirsutism and acne in PCOS. The mechanism is not completely known, but oral contraceptives decrease the amount of bioavailable androgens via increased SHBG production and by ovarian suppression. It has also been shown that progestins can inhibit 5α-reductase activity, which further decreases the production of dihydrotestosterone, the major androgen that stimulates hair growth. The maximal effect is evident after 6 months of treatment (the hair cycle length is estimated to be 4 months). If hirsutism is severe or if oral contraceptives alone are not effective, the addition of spironolactone may be beneficial. Spironolactone is an antimineralocorticoid agent that inhibits androgen biosynthesis in the adrenal and ovary, inhibits 5α-reductase, and is a competitive inhibitor of the androgen receptor. Side effects are minimal and include diuresis in the first few days, dyspepsia, breast tenderness, and abnormal bleeding which can be alleviated with concomitant use of oral contraceptives. Because oral contraceptives and spironolactone act by different mechanisms, the combined effect is synergistic. Long-acting GnRH agonists and 5α-reductase inhibitors (finasteride) have been used for refractory cases with some success.

ADRENAL CAUSES OF AMENORRHEA

Androgen Excess

  1. CONGENITAL ADRENAL HYPERPLASIA

Congenital adrenal hyperplasia is another disorder that may cause hyperandrogenism. It presents with a wide range of clinical forms, ranging from severe—which may be classified as “classic,” “salt-wasting,” or “simple virilizing”—to milder forms known as “acquired,” “adult-onset,” “nonclassic,” or “late-onset” congenital hyperplasia. The clinical manifestations reflect the severity of the enzymatic defect. Severe or classic forms are discussed in Chapter 14 and will not be considered here. This section will discuss the nonclassic forms, ranging in prevalence from 1% to 10% depending on the ethnicity of the patient. The clinical features are similar to those of patients diagnosed with PCOS and include menstrual irregularities, hyperandrogenism, infertility, and polycystic ovaries.

The adrenal gland consists of a cortex and a medulla. The cortex is divided into three functional zones based on location and the principal hormone secreted (see Chapter 9). The zona glomerulosa is the outermost zone and lies adjacent to the adrenal capsule. It is primarily responsible for aldosterone production. The zona fasciculata lies immediately below the glomerulosa. It principally secretes glucocorticoids, though it is capable of producing androgens. The zona reticularis is located beneath the zona fasciculata and overlies the adrenal medulla. It is this zone that principally secretes androgens. Both the zona fasciculata and the zona reticularis are regulated by ACTH. It is the secretory activity of these two zones that results in nonclassic adrenal hyperplasia.

Congenital adrenal hyperplasia is an inherited autosomal recessive disorder that is caused by mutations of genes involved with adrenal steroidogenesis. The mutations mostly occur in the 21-hydroxylase genes (P450c21A and P450c21B) and rarely in the 3β-hydroxysteroid dehydrogenase gene or 11β-hydroxylase genes (P450c11B and P450c11AS). In classic forms, the enzymatic defects are severe and result in cortisol deficiency diagnosed at birth. Owing to the cortisol deficiency, there is corticotropin excess and hyperstimulation of the adrenal gland. The adrenal precursors produced proximal to the enzymatic defect accumulate and are converted in the periphery to more potent androgens, resulting in symptoms of hyperandrogenism. However, most patients with nonclassic adrenal hyperplasia do not demonstrate deficient cortisol production or excess ACTH. It is suggested that most of the androgen excess in nonclassic adrenal hyperplasia arises as a consequence of subtle alterations in enzyme kinetics. Furthermore, some studies report a generalized adrenocortical hyperactivity rather than deficient enzyme activity.

The diagnosis can be established by measuring early morning basal 17-hydroxyprogesterone levels. Levels greater than 800 ng/dL (24.24 pmol/L) are diagnostic of 21-hydroxylase deficiency. However, the elevation in 17-hydroxyprogesterone is often not impressive and does not differ from that observed in PCOS. If the basal 17-hydroxyprogesterone levels are greater than 200 ng/dL (6.06 pmol/L) and less than 800 ng/dL (24.2 pmol/L), a provocative test with ACTH (250 ľg intravenously) should be performed. If 17-hydroxyprogesterone levels are greater than 1000 ng/dL (30.30 pmol/L) 1 hour after administration of ACTH, the diagnosis of 21-hydroxylase deficiency can be made. (Elimination of a false elevation in 17-hydroxyprogesterone due to ovulation must be excluded by simultaneous measurement of progesterone.) The other rare enzymatic defects that result in nonclassic adrenal

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hyperplasia can similarly be tested with measurements of steroid products proximal to the blockade following provocative testing.

Treatment of nonclassic adrenal hyperplasia is similar to that of PCOS, raising a question about whether an etiologic diagnosis is necessary. It is certainly an expense, leading to no change in management except in regard to infertility treatment (see below). Diagnosis may also be advisable in the woman with adrenal hyperplasia who intends future childbearing for genetic counseling and to prepare for in utero treatment should an affected fetus be identified by amniocentesis. While some experts suggest dexamethasone treatment for symptoms of hyperandrogenism, studies show inconsistent results, and there is concern about the consequent adrenal suppression.

  1. CUSHING'S SYNDROME

Chronic glucocorticoid excess, whatever its cause, leads to the constellation of symptoms and physical features known as Cushing's syndrome. The most common cause is iatrogenic as a result of glucocorticoid treatment. However, an ACTH-secreting microadenoma (Cushing's disease) accounts for more than 70% of cases of endogenous hypercortisolism. Less common causes include primary adrenal disease (tumors or hyperplasia) and ectopic (not hypothalamic-pituitary) ACTH-producing or CRH-producing tumors. Patients with Cushing's syndrome have a range of clinical manifestations that vary with age at onset and etiology. This section will discuss the adult clinical presentation briefly. For a more detailed discussion, see Chapter 9.

Cushing's syndrome (noniatrogenic) is rare and occurs in approximately 2.6 per million individuals. It may be responsible for less than 1% of those individuals who present with hirsutism. Although it is uncommon, it can present similarly to PCOS and congenital adrenal hyperplasia and needs to be considered in the differential diagnosis of hyperandrogenism and anovulation. Patients with corticotropin excess typically have additional clinical features suggestive of glucocorticoid or mineralocorticoid hypersecretion. The most common features include obesity with increased centripetal fat, moon facies, muscle weakness, and striae. Other manifestations may include diabetes, hypertension, and osteoporosis. Women with primary tumors tend to have a rapid onset of symptoms and often manifest with severe hyperandrogenism (frank virilization) which includes male pattern baldness, deepening voice, clitoromegaly, and defeminization.

Hirsutism or acne is present in about 60–70% of women with Cushing's syndrome. However, the exact mechanism of hyperandrogenic effects is not completely known. It is evident that excess corticotropin causes hyperstimulation of the zona fasciculata and zona reticularis and results in hypersecretion of cortisol and androgens. It is also known that adrenal tumors may selectively overproduce androgens.

Menstrual irregularities occur in over 80% of patients with Cushing's syndrome. The exact cause of anovulation is unclear. It has already been observed that hyperandrogenemia may have a significant impact on ovulation. However, several studies have shown that glucocorticoids can also suppress the hypothalamic-pituitary axis. Thus, the elevated glucocorticoids may be an additional factor in the pathophysiology of anovulation associated with this syndrome. (See Chapters 5 and 9 for the diagnosis and treatment of Cushing's syndrome.)

  1. ANDROGEN-SECRETING TUMOR

If there is a rapid onset of androgenic symptoms, an androgen-secreting adrenal tumor should be suspected. Elevated testosterone (> 200 ng/dL; 6.9 nmol/L) and DHEAS (> 700 ng/mL; 19 ľmol/L) levels should raise the suspicion of a tumor. However, more than 50% of adrenal androgen-secreting tumors have testosterone levels below 200 ng/dL (6.9 nmol/L). Furthermore, the majority of patients with high testosterone levels do not have tumors. Measurement of levels of DHEAS in these patients yields similar inconsistencies. This suggests that laboratory tests have limited value in screening for androgen-secreting tumors, and a better predictor is a clinical history and physical examination. Additional symptoms include weight loss, anorexia, bloating, and back pain. If suspicion is high, an abdominal CT scan will confirm the diagnosis. The treatment involves surgical resection, mitotane (adrenolytic), and steroid synthesis inhibitors.

Androgen-secreting tumors can also originate from the ovary. The incidence approximates 1:500–1:1000 hyperandrogenic patients. Testosterone levels > 200 ng/dL (6.9 nmol/L) arouse the suspicion, though in 20% of patients with ovarian androgen-producing tumors, testosterone levels are below this value. Again, the best screening procedures are the clinical history and physical examination. In the absence of cushingoid features, adrenal and ovarian tumors present similarly. Ovarian tumors often have unilateral ovarian enlargement that can be palpated on pelvic examination. Ultrasonography often confirms the diagnosis. In selected cases, selective venous sampling may be performed if CT-scan or sonography cannot identify the source of androgen production.

Anovulation Unrelated to Excess Sex Steroid Production

  1. ADRENAL INSUFFICIENCY

Adrenocortical insufficiency may be categorized as primary or secondary. Primary adrenal insufficiency (Addison's

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disease) is caused by destruction of cortical tissue. Secondary adrenal insufficiency is due to defects in the hypothalamic-pituitary axis resulting in a deficiency in ACTH. Both types lead to cortisol deficiency, which is life-threatening.

The main cause of primary adrenal failure is autoimmune destruction confined to the adrenal cortex. In fact, in the industrialized world, it accounts for more than 60% of cases of primary adrenocortical deficiency. The symptoms are typically those of chronic insufficiency and include weakness, fatigue, menstrual disturbances, and gastrointestinal symptoms such as nausea, abdominal pain, and diarrhea. Additional signs may include weight loss, hypotension, and pigmentary changes of the skin and mucous membranes. These symptoms may appear insidiously with a mean duration of approximately 3 years. Symptoms usually wax and wane until there is complete decompensation.

Autoimmune adrenal failure may occur as an isolated event, but estimates link more than 70% to a polyglandular failure syndrome. This syndrome has two subtypes: type I and type II. Type I is an illness of childhood that consists of hypoparathyroidism, chronic mucocutaneous candidiasis, celiac disease, and ovarian failure in addition to adrenal failure. It is associated with a mutation in the autoimmune regulator gene (AIRE) and has a recessive pattern of inheritance. Type II (Schmidt's syndrome) is an adult form of autoimmune adrenal insufficiency. The most common age at onset is the third decade. The most common manifestations include type 1 diabetes mellitus, myasthenia gravis, thyroiditis, ovarian failure, and adrenal insufficiency. Susceptibility to this disorder seems to be inherited as a dominant trait in linkage dysequilibrium with the HLA-B region of chromosome 6. The pathogenesis of adrenal insufficiency involves autoantibodies that are directed toward enzymes involved with steroidogenesis. Several studies suggest that the antigens in this disorder include 17α-hydroxylase, 21-hydroxylase, and P450scc. Detection of antibodies directed at these enzymes is helpful in making the diagnosis of autoimmune adrenal failure (see Chapter 4).

Worldwide, infection—especially tuberculosis—is the most common cause of primary adrenal failure. The adrenal cortex and medulla are involved and may be completely replaced by caseating granulomas. This phenomenon is always associated with other evidence of a tuberculous infection. Fungal, viral, and bacterial pathogens are less common causes.

The most common cause of secondary adrenal insufficiency is adrenal suppression after exogenous glucocorticoid administration. Less common settings are post treatment of Cushing's disease, hypothalamic-pituitary lesions, and hypopituitarism (Sheehan's syndrome). These patients more commonly present with symptoms suggestive of acute adrenal insufficiency. The clinical features include abdominal pain, hypotension, fever, severe volume depletion, and possibly profound shock.

Menstrual disturbances are a frequent presentation in patients with adrenal insufficiency. Autoimmune adrenal insufficiency is often accompanied by gonadal failure. In the polyglandular syndromes, premature ovarian failure develops in type I 50% of the time and in type II 10% of the time. It has been shown that antibodies—particularly to CYP17α and P450scc—are associated with premature ovarian failure. The other causes of adrenal failure are associated with menstrual disorders more than 25% of the time. The cause of anovulation is not certainly known, but chronic illness itself is probably responsible.

Diagnosis and treatment are discussed in Chapter 9. The screening process includes blood chemistries and basal cortisol levels. The diagnosis is confirmed with provocative tests using exogenous ACTH.

  1. THYROID DISORDERS

Thyroid disorders result from altered thyroid hormone secretion. The prevalence of overt thyroid dysfunction is 1–2% in women of reproductive age. Thyroid disorders can develop secondary to an insult in the hypothalamus, pituitary, or thyroid, the latter being most common. In order to understand the pathophysiology of these disorders, it is important to be familiar with the normal physiologic regulation (see Chapter 7). This section will briefly review the common causes of hyperthyroidism and hypothyroidism, their manifestations after the onset of puberty, and their impact on reproductive function.

  1. HyperthyroidismHyperthyroidism is the clinical syndrome associated with excessive thyroid hormone activity. The clinical presentation of hyperthyroidism (thyrotoxicosis) depends on the age at onset and the degree of thyrotoxicosis. The clinical manifestations can involve most organ systems, and the presentation ranges from asymptomatic to thyroid storm. The typical features include nervousness, malaise, palpitations, heat intolerance, weight loss, and inability to concentrate. Additional features may involve the eyes and include lid lag, proptosis, and ophthalmoplegia. The reproductive abnormalities include menstrual abnormalities, infertility, and spontaneous abortions.

The most common variety of hyperthyroidism is due to autoimmune disease that affects intrinsic thyroid function (Graves' disease). Antibodies bind to the TSH receptor and stimulate the thyroid gland to secrete increased amounts of thyroid hormone. Less common causes include subacute thyroiditis, toxic multinodular goiter, and struma ovarii.

Excess thyroid hormone has an impact on sex-steroids. It stimulates hepatic production of SHBG. As a result, total serum estradiol, estrone, testosterone, and

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dihydrotestosterone are increased, yet free levels of these hormones remain within the normal range. The metabolic clearance pathways appear to be altered, which can be explained in part by the increased binding. The conversion rates of androstenedione to estrogen and testosterone are increased. The significance of the alterations in metabolism has not been determined.

Menstrual irregularities frequently occur in hyperthyroid states. The exact mechanism is unclear. Altered levels of TRH and TSH do not appear to have a significant impact on the HPO axis. The LH surge may be impaired, though studies have shown that hyperthyroid patients have normal FSH and LH responses to exogenous GnRH. It is possible that the weight loss and psychologic disturbances associated with this disease may contribute to the menstrual abnormalities. It is interesting to note that endometrial biopsies of many amenorrheic patients with hyperthyroidism have demonstrated a secretory endometrium, indicating that many of these women remain ovulatory. Menstrual abnormalities return to normal with treatment.

  1. HypothyroidismHypothyroidism—a more common disorder than hyperthyroidism in women of reproductive age—results from inadequate thyroid hormone production. The manifestations can involve almost any organ system, and the presentation can range from asymptomatic to myxedema coma. The common symptoms include lethargy, memory defects, cold intolerance, dry skin, hair loss or occasionally excess hair growth, deepening of the voice, nausea, and constipation. Physical findings include somnolence, bradycardia, mild hypertension, dry skin, periorbital puffiness, nonpitting edema of the hands, face, and ankles, and decreased tendon reflexes. Reproductive abnormalities include menstrual disorders, infertility, and spontaneous abortions.

The most common cause is autoimmune destruction of the thyroid (Hashimoto's thyroiditis). It is mediated by humoral and cell-mediated processes. The antibodies are directed toward thyroglobulin (anti-Tg) and thyroid microsomal peroxidase (thyroperoxidase antibody). Histologic specimens show lymphocytic infiltration. Other causes include ablative therapy of the thyroid gland (post surgery or radioactive iodine), end-stage Graves' disease, and transient thyroiditis (viral, drug-induced, postpartum).

Inadequate thyroid levels influence the metabolism of sex-steroids. The production of SHBG is decreased. As a result, serum estradiol and testosterone concentrations are decreased but free hormone levels remain within normal range. However, the metabolism of these steroids is altered and differs from that found in individuals with hyperthyroidism. The significance of the metabolites formed in consequence is not known.

The mechanism underlying menstrual abnormalities in hypothyroidism is incompletely understood. Since primary hypothyroidism is associated with elevated serum prolactin in up to one-third of patients, it is plausible that the hyperprolactinemia is a contributing factor (see Chapter 5). However, menstrual abnormalities are also observed in the absence of elevated prolactin. Alterations in FSH and LH levels have been investigated, and studies have shown inconclusive results, although several studies suggest that the midcycle surge is absent. Menstrual function returns to normal with replacement therapy.

Thyroid dysfunction often presents with nonspecific symptoms, which often delays the diagnosis. If only menstrual abnormalities are present, it is prudent to screen for thyroid abnormalities. Most cases will be detected by TSH assays. Confirmation is obtained with a repeat TSH level and serum thyroid hormone levels.

OUTFLOW TRACT DISORDERS

The true prevalence of müllerian tract abnormalities is not known. It is reported in as many as 4–5% of women. The reproductive consequences depend on the type of abnormality identified. A septate uterus is the most common defect described. These patients often present with infertility or obstetric complications. Other abnormalities include unicornous, bicornous, and didelphic uteri. These abnormalities present most commonly with reproductive or obstetric complications. Müllerian agenesis, androgen insensitivity syndrome, and congenital outflow obstruction defects are abnormalities that present with primary amenorrhea with no history of menses. In the following section these two abnormalities are discussed in greater detail.

  1. MÜLLERIAN AGENESIS

Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) is the second most common cause of primary amenorrhea. It is a congenital condition that occurs in one in 5000 female births. These individuals have normal ovarian development, normal endocrine function, and normal female sexual development. The physical findings are a shortened or absent vagina in addition to absence of the uterus, though small masses resembling a rudimentary uterus may be noted (see the section on embryology at the beginning of this chapter). About one-third of patients have renal abnormalities, and several have had bone abnormalities and eighth nerve deafness. These individuals have a 46,XX karyotype.

The exact cause has not been identified. It is known that regression of müllerian structures in males is controlled by AMH, which is secreted by the Sertoli cells of the testis. One hypothesis assigns the underlying defect to an activating mutation of either the AMH gene or its receptor. The genes for both AMH and AMH receptor

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have been investigated, but no mutations have yet been identified with this syndrome.

  1. ANDROGEN INSENSITIVITY SYNDROME

Androgen insensitivity syndrome (AIS) presents in somewhat the same way as müllerian agenesis. The presentation differs in that individuals with complete AIS have minimal sexual hair. These patients have a male karyotype with a mutation of the androgen receptor on the X chromosome. They have normal testicular development and endocrine function. However, since the internal and external male sexual structures need testosterone for development, they are absent. This results in a female phenotype. Since the testis still secretes AMH, müllerian regression does occur. Secondary sexual characteristics (female) develop as a result of peripheral conversion of testosterone to estradiol, effectively resulting in unopposed estrogen stimulation.

The diagnosis of either disorder is entertained when pelvic examination reveals a short or absent vagina and no uterus on rectal examination. Confirmation of absent uterus can be obtained with ultrasound, MRI, or laparoscopy. These two disorders can usually be differentiated based on physical examination since patients with AIS have no pubic hair. However, the differential diagnosis becomes more difficult when patients have incomplete AIS. A testosterone level and karyotype can easily differentiate the two syndromes.

For further discussion, refer to Chapter 14.

  1. CONGENITAL OUTFLOW OBSTRUCTION

Transvaginal septum and imperforate hymen are typical obstructive abnormalities. These patients usually present with cyclic lower abdominal pain and amenorrhea. The physical findings are a shortened or absent vagina. However, this syndrome differs from müllerian agenesis in that the pelvic organs are present. Behind either defect is old blood that has not escaped with menses. The differential diagnosis is sometimes difficult, though bulging of the introitus suggests imperforate hymen since the defect is thinner than a transvaginal septum.

The embryologic formations of the transvaginal septum and imperforate hymen are similar but not identical. Transvaginal septum is due to failure of complete canalization of the vaginal plate (see the section on embryology at the beginning of this chapter). The septum can vary in thickness and can be located at any level in the vagina. The hymen represents the junction of the sinovaginal bulbs and urogenital sinus. Typically, the hymen is perforated during fetal development. The hymen is thin and is always at the junction of the vestibule and vagina. It is important to distinguish these defects because the surgical correction procedures are different and require different levels of expertise.

  1. ASHERMAN'S SYNDROME

Intrauterine adhesions or synechiae (Asherman's syndrome) are an acquired condition that may obliterate the endometrial cavity. These patients usually present with a range of menstrual disturbances, infertility, and recurrent spontaneous abortions. The most frequent symptom is amenorrhea.

Intrauterine adhesions result from damage to the endometrial basal layer. A common antecedent factor is a surgical procedure within the uterine cavity, and most often it is endometrial curettage that occurs shortly after pregnancy. The concurrent presence of infection or heavy bleeding increases the risk. Endometrial tuberculosis and septic abortion are rare causes.

The diagnosis is entertained after demonstrating no withdrawal bleeding after administration of estrogen and progesterone. Confirmation is made with a hysterosalpingogram, saline sonogram, or hysteroscopy. Treatment involves lysis of adhesions and hormonal therapy.

MENOPAUSE

The ovary is unique in that the woman's age at which it ceases to function appears to have remained constant despite the increase in longevity experienced by women over the last century. Because the loss of ovarian function has a profound impact on the hormonal milieu in women and the subsequent risk for the development of disease resulting from the loss of estrogen production, improving our understanding of reproductive aging is critical for optimal female health.

Human follicles begin development in the fourth gestational month. Approximately 1000–2000 germ cells migrate to the gonadal ridge and multiply, reaching a total of six to seven million around the fifth month of intrauterine life. At this point, multiplication stops and follicle loss begins, declining to approximately 1 million by birth. In the human male, the germ cells become quiescent and maintain their stem cell identity. In contrast, in the human female, between weeks 12 and 18, the germ cells enter meiosis and differentiate. Thus, in the female, all germ stem cells have differentiated prior to birth. In the adult woman, the germ cells may remain quiescent, may be recruited for further development and ovulation, or may be destroyed by apoptosis. Over time, the population of oocytes will be depleted (without regeneration) through recruitment and apoptosis until less than a thousand oocytes remain and menopause ensues. Approximately 90% of women experience menopause with a mean age of 51.2 years. The remainder experience menopause prior to age 46 years (often termed early menopause),

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with 1% of women experiencing menopause before age 40 years (premature menopause; premature ovarian failure).

Understanding ovarian aging has been quite difficult. The variability in definitions has made comparisons from study to study difficult. The participants in the recent Stages of Reproductive Aging Workshop (STRAW) study developed criteria for staging female reproductive aging. They utilized menstrual cyclicity and early follicular FSH levels as the primary determinants for this staging system. Five stages precede the final menstrual period and two stages follow it. Stages -5 to -3 include the reproductive interval; stages -2 to -1 are termed the menopausal transition; and stages +1 and +2 are the postmenopause (Figure 13-10). The menopausal transition begins with increased variability in menstrual cyclicity (> 7 days) in women with elevated FSH levels. This stage ends with the final menstrual period, which cannot be recognized until after 12 months of amenorrhea. Early postmenopause is defined as the first 5 years following the final menstrual period. Late postmenopause is variable in length, beginning 5 years after the final menstrual period and continuing until death.

While this system is said to include endocrinologic aspects of ovarian aging, it still depends largely on menstrual cyclicity as a key indicator of ovarian age. The system includes measurement of FSH; however, by the time FSH is elevated, even in the face of cyclic menstrual cycles, oocyte depletion has already proceeded to such an extent that fertility (as a marker of reproductive aging) is significantly diminished. Evidence suggests that genetic and environmental factors influence both age at menopause and the decline in fertility, though the specific nature of these relationships is poorly characterized. Premature menopause can be due to failure to attain adequate follicle numbers in utero or to accelerated depletion thereafter. Potentially, either of these causes could be affected by genetic and environmental factors. The timing of menopause has a consistent impact on overall health with respect to osteoporosis, cardiovascular disease, and cancer risk. Over the next decade, it is estimated that more than 40 million women in the USA will enter menopause.

OOCYTE DEPLETION

As discussed above, the leading theory regarding the onset of menopause relates to a critical threshold in oocyte number. The theory that menopause is primarily triggered by ovarian aging is supported by the coincident occurrence of follicular depletion, elevation of gonadotropins, and menstrual irregularity with ultimate cessation.

Faddy et al (1992) developed a mathematical model to predict the rate of follicular decline (Figure 13-11). These workers utilized existing data to construct a model that ultimately showed a biexponential decline with an acceleration in oocyte loss when the remaining oocyte number equaled approximately 25,000. In their model, this occurred at 37.5 years of age. At this point, the rate of follicular atresia accelerates. In the absence of this acceleration, the model suggests that menopause would be delayed until age 71. The cause of this accelerated

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depletion is not well defined. It is also clear—if the factor predicting the rate of decline is follicle number and not age—that other factors which might account for a diminished follicle number (genetic risk and possible toxic exposure) would lead to an earlier rate of accelerated decline and an earlier age at menopause.

 

Figure 13-10. Stages of reproductive aging. (Reproduced, with permission, from Soules MR et al: Stages of Reproductive Aging Workshop [STRAW]. J Womens Health Gend Based Med 2001;10:843.)

 

Figure 13-11. Bi-exponential model of declining follicle numbers in pairs of human ovaries from neonatal age to 51 years old. Data were obtained from the studies of Block (+, n=6; + n=43), Richardson et al. (1987) (squares, n=9) and Gougeon (unpublished) (*, n=52). (Reproduced, with permission, from Faddy MJ et al: Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992;7:1342.)

ENDOCRINE SYSTEM CHANGES WITH AGING

The entire endocrine system changes with advancing age. The somatotrophic axis begins to decline in the fourth decade, prior to the decline in ovarian function. This decline is accelerated in the face of ovarian failure and may act to accelerate the decline in ovarian function. However, pituitary concentrations of growth hormone as well as ACTH and TSH remain constant into the ninth decade. While the thyroid gland undergoes progressive fibrosis with age and concentrations of T3 decline by 25–40%, elderly patients still remain euthyroid. B cell function also undergoes degeneration with aging such that by age 65 years, 50% of subjects have abnormal glucose tolerance tests. Frank diabetes is rare, however, occurring in only 7% of the population. The female reproductive system, on the other hand, undergoes complete failure at a relatively early age.

As noted above, in the late fourth decade, FSH levels begin to rise even in the face of continued cyclic menses. The most likely cause is a decrease in functional granulosa cells from the oocyte pool with a decrease in inhibin B negative feedback, permitting a monotropic rise in FSH. Early on, there is also a decline in luteal phase progesterone levels. As ovarian aging progresses, estradiol levels may be quite variable, with chaotic patterns and occasionally very high or very low levels. This dramatic variability may lead to an increase in symptomatology during the perimenopausal years (stages -2 to -1). As peripheral gonadotropins rise, LH pulsatile patterns become abnormal. There is an increase in pulse frequency, with a decrease in GnRH inhibition by opioids.

Estrogens

The main circulating estrogen during the premenopausal years is 17β-estradiol. Levels of this hormone are controlled by the developing follicle and resultant corpus luteum. The fact that oophorectomy will reduce peripheral estradiol levels from 120 pg/mL (440 pmol/L) to 18 pg/mL (66.1 pmol/L) suggests that over 95% of circulating estradiol is derived from the ovary. Other sources of estrogen include estrone and the peripheral conversion of testosterone to estradiol. Very small amounts are secreted by the adrenal gland. As the two-cell theory (see above) requires aromatization of theca-produced androgens in the granulosa cell, follicular exhaustion is associated with gradual declines in estradiol concentrations.

The predominant estrogen in the postmenopausal woman is estrone, with a biologic potency approximately one-third that of estradiol. Estrone is derived largely from peripheral conversion of androstenedione. Extraglandular aromatase is found in liver, fat, and certain hypothalamic nuclei. This activity increases with aging and increased fat content (also an age-related change). Estrone and estradiol production rates during the postmenopausal years are 40 ľg/d and 6 ľg/d, respectively. This compares with 80–500 ľg/d for estradiol during the reproductive years. Essentially all estradiol in postmenopausal women is derived from conversion of estrone.

Androgens

Dehydroepiandrosterone sulfate (DHEAS) levels decrease in both men and women with aging. The decline is greater in women and may be due to the relative estrogen deprivation. Changes in DHEAS levels have been associated with alterations in body composition with aging. Androstenedione is the predominant androgen

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during the reproductive years, and production declines from 1500 pg/mL to 800 pg/mL in postmenopausal women. The postmenopausal ovary contributes only 20% to circulating androstenedione levels. Testosterone levels also decline postmenopausally, but not to the same extent as estradiol levels. Postmenopausal testosterone is derived from the ovary (25%), from the adrenal gland (25%), and—by extraglandular conversion—from androstenedione (50%). The postmenopausal ovary produces a larger percentage of testosterone (50%) than does the premenopausal ovary.

MENOPAUSAL CONSEQUENCES

Given the endocrinologic changes associated with aging, many symptoms appearing in the aging female may be due to estrogen deficiency or diminished androgen or growth hormone secretion. Disorders that are definitely due to estrogen deprivation include vasomotor symptoms and urogenital atrophy. Osteoporosis is thought to be due largely to estrogen deficiency, but this may be exacerbated by the relative decline in growth hormone levels. The same may be said for the hormone-related increase in the prevalence of atherosclerotic cardiovascular disease and psychosocial symptoms, including insomnia, fatigue, short-term memory changes, and possibly depression. Both DHEAS and growth hormone may impact on these phenomena as well.

Vasomotor Symptoms

Vasomotor symptoms (hot flushes) are experienced with greatest frequency during stages -1 and +1, with about 75–85% of women complaining of this symptom. While 80% of U.S. women have symptoms lasting for at least a year, only 25% of women are still symptomatic at 5 years after the final menstrual period. Studies of hot flushes with external monitoring of skin temperature and resistance have shown a frequency of approximately 54 ą 10 minutes. In sleep studies, hot flush frequency has been shown to interrupt REM sleep and may contribute to some of the psychosocial complaints. Hot flushes are temporarily correlated with pulses of LH—but exogenous LH does not induce a flush, suggesting that there is some central mediator leading to both the flush and the elevation in LH.

Estrogen is the drug of choice for the treatment of vasomotor symptoms. Other drugs have been tried in women for whom estrogen is contraindicated, though none have the efficacy associated with estrogen replacement. These alternatives include transdermal clonidine, ergot alkaloids, and, more recently, selective serotonin reuptake inhibitors. High-dose progestins may also produce some relief.

Genital Atrophy

The vagina, vulva, urethra, and bladder trigone not only share embryonic proximity but all contain estrogen receptors. Atrophy begins (again) in stage -2 to -1. The most common symptoms include itching and vaginal thinning, with decreased distensibility and reduced secretions, leading to vaginal dryness and pain with intercourse. This and the change in pH with resultant changes in vaginal flora increase the incidence of vaginal and urinary tract infections. Estrogen is the treatment of choice, and treatment must continue for at least 1–3 months for symptomatic improvement to be noted. The systemic dosage necessary for vaginal protection is somewhat higher than that needed for bone protection (see below), and local therapy by means of creams or vaginal rings may thus be advisable to limit systemic absorption. It should be noted, however, that vaginal absorption of steroids is quite efficient once estrogenization and revascularization have occurred. If the goal is to limit systemic absorption, slow-release rings may be superior to estrogen creams.

Vaginal estrogen will frequently improve symptoms of urinary frequency, dysuria, urgency, and postvoid dribbling. Its direct effect to improve stress incontinence is less clear.

Osteoporosis

Osteoporosis is a condition in which bone loss has been sufficient to allow mechanical fracture with limited stress. The risk for development of osteoporosis is dependent on the peak bone density attained in early childhood (stressing the importance of bone building in the young) and the rate of loss (accelerated with estrogen deficiency). Primary or “senile” osteoporosis usually affects women between the ages of 55 and 70 years. The most common sites include the vertebrae and the long bones of the arms and legs. Secondary osteoporosis is caused by a specific disease (such as hyperparathyroidism) or medication usage (such as glucocorticoids) (see Chapter 8).

Menopausal bone loss begins before the final menstrual period during stage -1. Postmenopausal osteoporosis causes over 1.3 million fractures annually in the USA. Most of the more than 250,000 hip fractures are due to primary osteoporosis, and—given that 15% of patients die within a year after a hip fracture and 75% of patients lose their independence—the social costs, not to mention the financial costs, are great.

Bone loss following natural menopause is approximately 1–2% per year compared with 3.9% per year following oophorectomy. A woman's genetic background, lifestyle, dietary habits, and coexisting disease will also impact the development of osteoporosis. Cigarette smoking, caffeine usage, and alcohol consumption

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also negatively impact bone loss, while weight-bearing activity appears to have a positive influence. See Chapter 8 for a detailed discussion of bone mineral metabolism.

  1. TREATMENT
  2. Estrogen therapyEstrogen therapy acts via inhibition in bone resorption. Both bone mineral density and fracture rate are improved with estrogen therapy. However, with cessation of estrogen therapy, there is a rapid and progressive loss of bone mineral content. By 4 years after therapy, bone density is no different from that of patients who were never treated with estrogen. While estrogen is approved for prevention of osteoporosis, there is also some support for its usage in treatment. Dosages of 0.625 mg of conjugated estrogens orally daily—and, more recently, as low as 0.3 mg—have been shown to slow bone loss and provide adequate protection against the development of osteoporosis. Higher dosages may be required to treat existing disease.
  3. Alternative therapies for osteoporosis
  4. CalcitoninCalcitonin is a hormone normally secreted by the thyroid gland. Calcitonin (salmon) is available as a nasal spray, specifically developed to decrease local side effects caused by subcutaneous injection. While few studies have been performed and no data are available regarding reduction in hip fracture, it does seem to be especially beneficial for women with a recent and still painful vertebral fracture. Intranasal calcitonin has also been shown to improve spinal bone density and decrease the vertebral fracture rate in established osteoporosis. The increase in bone density appears to peak in as little as 12–18 months. This may be due to down-regulation of the calcitonin receptors and the development of neutralizing antibodies. It also appears that some patients do not respond to this therapy, and those nonresponders cannot be prospectively identified.
  5. BisphosphonatesThese compounds are ana-logs of pyrophosphates that have an affinity for a hydroxyapatite in bone. The basic structure of bisphosphonates allows a large number of manipulations of the basic molecule, producing different types of bisphosphonates that vary considerably in their potency on bone. The first bisphosphonate to be used was etidronate, and on a scale of potency it is the weakest agent. In order of increasing potency appeared pamidronate, alendronate, and risedronate. Etidronate, if given continuously for more than 6 months, impairs mineralization of bone and may cause osteomalacia. There have been occasional reports of pamidronate also causing impaired mineralization of bone. However, continuous administration of alendronate or risedronate has not caused these changes.

Alendronate has been evaluated more extensively than calcitonin and has reduced fracture rates in patients with osteoporosis. Alendronate has been shown to inhibit markers of bone remodeling and increase bone mineral density at the lumbar spine, hip, and total body. Alendronate is taken orally; the recommended daily dose of 10 mg, however, must be taken according to a very strict dosing schedule (in the morning on an empty stomach, with the patient required to remain upright for 30 minutes thereafter). The medication has very poor bioavailability (approximately 1%), and for that reason these instructions must be meticulously obeyed. Alendronate also has a propensity for causing irritation of the esophagus and stomach, especially in women with preexisting esophageal reflux or gastric or duodenal disease. A newer formulation allows for once-weekly administration, and efforts are continuing to develop a once-yearly formulation. Risedronate is equally effective in lower dosage.

Increases in bone density with alendronate are greater than with calcitonin and equal to what is seen with HRT. The escape phenomenon seen with calcitonin is also not seen with alendronate.

The final question concerning alendronate has to do with the near-permanent changes in bone that occur with the incorporation of this agent into the bone matrix. While short-term fracture data appear favorable, the long-term effects of these agents and the ability of alendronate-treated bone to heal (eg, following hip fracture) are not known.

  1. SERMsRaloxifene is the first of a new generation of compounds known as selective estrogen receptor modulators (SERMs). We will begin to see an explosion in the development of these agents. They may represent a new alternative for breast cancer patients or for long-term use in osteoporotic patients. These new agents act as selective estrogen receptor agonists in some tissues (bone and heart) and antagonists in others (breast and uterus and possibly brain). Data with raloxifene are now available and suggest good preservation of bone density, albeit less than that seen with alendronate or HRT, and fracture data support a protective effect.

It is believed that the differential effect of estrogens and antiestrogens is related to the transcriptional activation of specific estrogen response elements. Two different domains of the estrogen receptor (AF-1 and AF-2) appear to be responsible for this transcriptional activation. Estrogens and antiestrogens appear to act via different domains, leading to their differential effects. Both appear to act to maintain bone density—at least partially—via regulation of the gene for transforming growth factor β.

  1. Calcium and vitamin DThese are important components of all three antiresorptive agents. Decreased

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ability to absorb calcium among older women is due in part to impaired vitamin D activation and effect. Older women may have limited exposure to sunlight, and their dietary vitamin D intake may be lower than that of younger women.

Daily intake of 1500 mg of calcium and 400–800 IU of vitamin D per day is probably sufficient to reduce the risk of fragility fractures by about 10%.

Atherosclerotic Cardiovascular Disease

Cardiovascular disease is the number one killer of both men and women in Western societies. This is largely attributed to age and lifestyle. Lifestyle modifications are known to decrease the incidence. For women, cardiovascular disease is largely a disease of the postmenopause. Women will now spend more than a third of their lives in the postmenopausal years, and preventive measures are thus of paramount importance. There has been a large body of observational evidence to support a protective effect of estrogen replacement therapy on cardiovascular disease. Observational data, however, are limited by the confounding variables of patient self-selection. Animal and in vitro studies as well as assessment of surrogate markers in women have also shown a positive effect of estrogen and hormone replacement therapy (HRT) against cardiovascular disease development. However, recent randomized, controlled studies have failed to support a protective role for HRT.

HRT was first evaluated in secondary prevention trials. The HERS trial evaluated the use of daily HRT (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) in 2763 postmenopausal women with a mean age of 66.7 years and pre-existing vascular disease. The study failed to demonstrate any overall difference in vascular events. This occurred despite improvements in lipid parameters in those patients receiving HRT. The Estrogen Replacement and Atherosclerosis (ERA) Trial, published in 2000, compared 3.2 years of treatment with estrogen, combined estrogen and progestin, and placebo in postmenopausal women aged 42–80 years. This, again, was a secondary prevention trial and also failed to demonstrate a significant difference in the rate of progression of coronary atherosclerosis between the three groups. The importance of this study was the inclusion of an estrogen-only arm.

The Women's Health Initiative (WHI) is the first large randomized study to look at primary prevention of cardiovascular disease. The combined HRT regimen utilized in the HERS trial was also utilized for this study. The study was recently stopped when interim analysis demonstrated an unacceptable risk profile for the HRT arm. There was an increase in the incidence in breast cancer (an increase of eight cases per 10,000 women) with no cardiovascular protection (and potentially increased cardiovascular risk). There was, in fact, an increase in blood clots, strokes, and coronary heart disease. The risk of stroke and clot continued for the 5 years of study, while most of the coronary heart disease was limited to the first year of treatment. There were, however, documented decreases in the risk of fracture and colon cancer.

The WHI study did not address the effect of hormone treatment on hot flushes and vaginal atrophy. Clearly, there are alternatives for the treatment of osteoporosis and cardiovascular disease that are superior if prevention is the sole reason for HRT. Every woman should discuss with her caregiver the optimal management for her as an individual. This should take into account the medical and family history as well as symptomatology. It can be uniformly recommended, however, that menopausal women maintain appropriate nutrition, weight reduction, and exercise along with moderation in alcohol and caffeine intake and cessation of smoking.

INFERTILITY

Infertility is defined as the inability of a couple to conceive after 1 year of frequent unprotected intercourse without contraception. This definition is based on observational data showing that over 90% of couples achieve pregnancy after 1 year of unprotected coitus. Using this definition, a 1995 survey reported that approximately 7% of married couples of reproductive age experienced infertility. However, the diagnosis of infertility does not mean that they cannot conceive—a more precise diagnosis term would be “subfertility,” or a diminished capacity to conceive. The actual probability of the fertility potential of a population may be better assessed with variables that can quantify a monthly cycle rate. The concepts that have been used for quantitative analysis are fecundability and fecundity. Fecundability is defined as the probability of achieving a pregnancy within one menstrual cycle, and in normal couples the chance of conception after 1 month is approximately 25%. Fecundity is a related concept that is defined as the ability to achieve a live birth within one menstrual cycle.

In the United States, demands for infertility treatment have dramatically increased. The 1995 National Survey of Family Growth reported that 9.3 million women received infertility treatment in their lifetime compared with 6.8 million in 1988. This rise in treatment is due not only to increased public awareness—it also reflects the significant demographic, societal, and economic changes in our society. These include the aging of the “baby boom” generation, which has increased the size of the reproductive age population. Perhaps

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more important is the increased use of contraception and postponement of childbearing until the last 2 decades of a woman's reproductive life. Approximately 20% of women in the United States now have their first child after 35 years of age.

Age alone has a significant impact on fertility and affects a woman many years before the onset of menopause. One factor is the age-dependent loss of ovarian follicles (see above). A 38-year-old woman has 25% of the fecundability of a woman under 30 years of age. Another age-related subfertility factor is that the spontaneous abortion rate increases with advancing age. The overall incidence of clinical abortion increases from 10% in women under age 30 to more than 40% in women over 40. The increased pregnancy loss can be largely attributed to abnormalities in the aging oocyte; older follicles have an increased rate of meiotic dysfunction, resulting in higher rates of chromosomal abnormalities.

The main causes of female subfertility can be classified in the following way: (1) ovulatory defects, (2) pelvic disorders, and (3) male factors. These factors account for 80–85% of couples diagnosed with infertility. They are not mutually exclusive—about 15% of couples have more than one cause of subfertility. In approximately 20% of couples, the cause remains unknown and is classified as unexplained infertility. This section will briefly discuss the causes of subfertility and review the diagnosis and management.

DIAGNOSIS OF INFERTILITY

Ovulatory Defects

Ovulatory disorders are responsible for 25% of cases of infertility. Ovulatory status can be obtained from the history. If a woman experiences cyclic, predictable menses at monthly intervals, ovulation can be predicted 98% of the time. This is not an invariable rule, however, and irregular menstrual cycles are not a sure sign of anovulation.

The only way to confirm ovulation is by achieving pregnancy. However, a variety of methods can indicate that ovulation has occurred. For example, a thermal shift occurs around the time of ovulation. Prior to ovulation, morning basal body temperature (BBT) is below 98 °F (36.7 °C), and after ovulation the temperature increases at least 0.4 °F (0.2 °C) for at least 10–13 days. This rise in temperature reflects the progesterone that is secreted from the corpus luteum, which consequently raises the hypothalamic set-point for BBT. The temperature rise occurs approximately 2 days after ovulation because of the time and“dose” required for the progesterone effect at the hypothalamus. BBT can therefore not be utilized to prospectively predict ovulation.

Measurements of midluteal serum progesterone concentration can also be performed to document the occurrence of ovulation. If this level is greater than 3 ľg/L (9.5 nmol/L), it is a strong indication that ovulation has occurred. An endometrial biopsy can confirm ovulation. It is performed during the luteal phase and gives a qualitative assessment of ovulation since the duration of progesterone exposure produces predictable endometrial histology. Lastly, a sonographic examination documenting a decrease in follicle size—or disappearance altogether of the previously developed follicle—is suggestive of ovulation. All of these methods indicate that ovulation has occurred. There are only a few ways to predict that ovulation is going to occur. The most common way is to detect the LH surge. Ovulation typically occurs 34–36 hours after the onset of the LH surge.

Although ovulation may occur, some women may have a luteal-phase defect. This is characterized by an inadequate quantity or duration of progesterone secretion by the corpus luteum. There is a distinct window of time for implantation. The theory is that the progesterone deficiency desynchronizes ovulation (egg) and implantation (endometrium). However, the incidence of luteal phase defects is difficult to assess because the definition is not standardized. Typically, the diagnosis is established by luteal phase endometrial dating; if the histologic development of the endometrium lags more than 2 days beyond the day of the cycle, it is diagnostic of a luteal phase defect. However, up to 30% of women with normal cycles meet this criterion. Another method involves measuring midluteal progesterone levels. If progesterone is less than 10 ng/mL, it suggests a luteal phase defect. This is not reliable because progesterone is intermittently secreted, and the serum progesterone level can change from 1 hour to the next in the same individual. Furthermore, the lack of valid tests questions the existence of luteal phase defects and its association with subfertility. Lastly, as empiric treatment for unexplained infertility has developed, delaying treatment (see below: superovulation with IUI) for exact diagnoses has less importance. More sophisticated testing of endometrial proteins required for implantation (eg, integrins, glycodelin) may revive enthusiasm for making a specific diagnosis in the future.

The cause of ovulatory dysfunction has been previously discussed. All anovulatory patients should have determination of prolactin and TSH levels—and, if necessary, androgen levels—to identify the cause of the ovulatory disturbance. Treatment should be directed toward the cause, which is discussed in greater detail below. It could be argued that all patients should have evaluation of early follicular cycle (days 2–4) FSH, LH, and estradiol to assess ovarian “reserve” (age).

Pelvic Disorders

Pelvic disorders account for over 30% of couples with the diagnosis of infertility. Uterine tube damage and

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adhesion formation are responsible for most pelvic pathologic processes causing infertility, while endometriosis is the primary pelvic disorder causing subfertility. The causes of tubal damage and adhesions include postinfectious state (pelvic inflammatory disease [PID], endometriosis, and a history of pelvic surgery (especially surgery for ruptured appendicitis).

Pelvic inflammatory disease is defined as infection of upper genital tract structures and is usually caused by a sexually transmitted disease. The known initiating organisms are chlamydiae and Neisseria gonorrhoeae. The symptoms are variable but usually include lower abdominal pain, nausea, and vaginal discharge. However, in up to 30% of chlamydial infections, PID may be clinically inapparent and may remain undiagnosed until presenting with subfertility.

Endometriosis is the presence of endometrial glands and stroma outside of the uterus. There may be no manifestations other than infertility, or symptoms may progress to include severe pelvic pain, dysmenorrhea, and dyspareunia. The diagnosis is suspected if findings on surgical exploration show characteristic lesions. Lesions can be staged according to published criteria. Diagnosis is confirmed with biopsy of the peritoneal lesions. The disease occurs in approximately 3–10% of reproductive age women and may be responsible for up to 25–35% of the female factors responsible for subfertility.

The pathogenesis of endometriosis is not completely known. A prominent theory (Sampson) involves retrograde menstruation. It is well established that menses can flow through the uterine tubes into the abdominal cavity. In fact, this phenomenon is thought to occur in almost all menstruating women. There is good evidence that the endometrial tissue subsequently invades and proliferates into the peritoneum. It is theorized that the immune system should normally dispose of the tissue and that altered immunity may result in implantation of this endometrial tissue outside the uterus in those women who subsequently develop endometriosis.

There is a strong association between adhesive disease and endometriosis. In these cases, the cause of subfertility is a result of distorted anatomy and consequently altered function. However, in mild cases of endometriosis, where only peritoneal lesions are identified and no anatomic distortion exists, the cause of infertility remains uncertain and controversial. There is evidence that the peritoneal fluid is altered in the presence of endometrial tissue with increased macrophages and inflammatory mediators. Several studies suggest that inflammatory changes result in adverse effects on folliculogenesis, ovum transport, fertilization, and implantation.

Tubal damage can be diagnosed with a hysterosal-pingogram or surgical exploration. Hysterosalpingography involves the introduction of radiopaque contrast media into the pelvis through the cervix and then fluoroscopy, revealing an outline of contrast in the uterine cavity, uterine tubes, and peritoneal cavity. The diagnosis of pelvic endometriosis can only be made by surgery, and most often the surgical procedure is laparoscopy. Diagnostic laparoscopy is usually done when there is a high suspicion of endometriosis based on the clinical history or adhesive disease based on a history of PID or pelvic surgery. Laparoscopy may also be performed if all other tests are normal and the couple continues not to achieve a pregnancy.

Male Factor Causes

The male factor contributes in 40–50% of cases of diagnosed infertility, and all evaluations should include the male partner. The diagnostic test for male factor infertility is the semen analysis. While this is a largely descriptive test (volume; sperm count, motility, and morphology), there is some correlation with pregnancy outcome. This should be used solely as a screening test. To understand the pathophysiology of male factor, it is important to review the physiology of spermatogenesis and the anatomy of the male reproductive tract as described in Chapter 12.

Unexplained Infertility

Approximately 15–20% of the couples diagnosed with infertility have no identifiable cause after a full investigation. The term“unexplained” implies that there is a potential explanation for the subfertility but the cause has not yet been identified. The cause may be subtle abnormalities in folliculogenesis, sperm-ovum interactions, or defective implantation.

Several studies have evaluated the natural history of unexplained infertility. It is estimated that fecundity in younger couples (female partner under the age of 40) with unexplained infertility is 3–5% compared with 20–25% in the age-matched couples with normal fertility. Treatment involves methods that increase fecundability and are discussed later.

MANAGEMENT OF THE INFERTILE COUPLE

It is important to remember that in most couples there is a chance for spontaneous conception. Recent studies estimate the average probability for live birth without treatment at 25–40% during the 3 years after the first infertility consultation. This translates into a cycle fecundity rate of 0.7–1% per month. The presence of endometriosis, abnormal sperm, or tubal disease independently reduced the chance of spontaneous pregnancy and live birth by approximately 50% for each variable. Infertility for more than 3 years, female age over 30 years, and primary infertility were important negative prognostic factors.

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Evaluation should focus on known causes of infertility or subfertility: ovulatory defects, pelvic disorders (tubal disease, endometriosis), and male factor issues.

Ovulatory Disorders

Treatment should be diagnosis-specific, if possible. For the female, this means that the cause of any ovulatory defect should be determined and specific treatment then instituted. This will enhance outcome and decrease the risk of complications (spontaneous abortion and multiple gestation). This treatment might include the use of dopamine agonists (hyperprolactinemia), thyroid replacement (hypothyroidism), pulsatile gonadotropin-releasing hormone (hypogonadotropic hypogonadism), or clomiphene citrate (for PCOS). The most common cause of anovulation is inappropriate feedback such as in PCOS. Ovulation in PCOS patients can be induced with clomiphene citrate, which is a nonsteroidal agonist-antagonist of estrogen that blocks the hypothalamic-pituitary axis from feedback by circulating estrogens. As a result, there is increased gonadotropin release to stimulate follicular recruitment and ovulation. In addition, since PCOS has recently been associated with insulin resistance, insulin sensitizers such as metformin have been used to enhance ovulatory response in women with PCOS.

Pelvic Disorders

In general, adhesive tubal lesions should be treated surgically. However the location and extent of disease should be evaluated. Patients with distal tubal occlusion—unless it is very mild—are most often better served by assisted reproduction (IVF). Other possible causes of infertility should also be examined. If a patient has a history of documented tubal disease in addition to other abnormalities (ovulatory dysfunction or male factor infertility) or if they are over 35, the likelihood for successful surgical management decreases by approximately 50% and consideration for avoiding surgery and moving directly to assisted reproduction is paramount. The exception to this rule is documentation of hydrosalpinges on ultrasound. The presence of hydrosalpinges that retain fluid when nondistended (ie, not seen only with hysterosalpingography) leads to a significant reduction in outcome with assisted reproductive therapy (ART). Prior removal or proximal occlusion of the tube to prevent“contamination” of the uterine cavity should be performed before ART is offered.

There are conflicting data in the literature concerning the appropriate treatment for mild endometriosis. A well-designed randomized trial from Canada evaluated the effect of surgical treatment on pregnancy outcome for patients diagnosed with mild endometriosis without anatomic distortion. It showed that pregnancy rates at 9 months post laparoscopy were 27% in the surgically treated group compared with 18% in the untreated group. Severe endometriosis (disease that alters the pelvic anatomy or involves the ovary with endometriomas) should be surgically treated to restore normal pelvic anatomy. There appears to be no advantage to medical therapy for endometriosis in women seeking fertility.

Male Factor Infertility

Male factor infertility is discussed in Chapter 12. Like female partner treatment, therapy if possible should be targeted toward the cause of subfertility. Obstructive disease may be treated surgically. A prominent varicocele with a “stress” pattern on semen analysis (decreased motility with increased abnormal morphology) may suggest a need for surgical repair. Any endocrinologic abnormalities (while less common in the male) should be treated (eg, prolactinoma). Unfortunately, beyond this point, most treatments require a combined approach very similar to that discussed below for unexplained infertility.

Unexplained Infertility

The treatment of unexplained infertility can be frustrating for the physician and the patients because the recommendations for therapy are not targeted toward a specific diagnosis. Although there are very limited evidence-based data to guide treatment, therapy should be directed toward increasing the fecundability rate. The two main treatments are superovulation plus intrauterine insemination (IUI) and in vitro fertilization (IVF).

Superovulation methods are designed to qualitatively improve the cycle and to hyperstimulate the ovary with rescue of more follicles (quantitative improvement). Administration of clomiphene citrate or of gonadotropins alone can be used for superovulation. However, higher success rates are observed when superovulation is combined with intrauterine insemination (IUI) of washed sperm (Table 13-4). In vitro fertilization provides a higher fecundability rate. However, these procedures are significantly more costly and more invasive, and they should only be used after a trial (three or four cycles) of superovulation and IUI has failed. With older patients, aggressive therapy should be considered earlier in the treatment effort.

CONTRACEPTION

Approximately 50% of all pregnancies in the USA are unplanned. In adolescents and in women of older reproductive age, the unplanned pregnancy rate is higher,

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approaching 82% and 77%, respectively. This equates to 3.5 million unplanned pregnancies in the USA per year. With the advent of oral contraceptives, women were able to postpone childbearing. However, approximately 50% of unplanned pregnancies are due to contraceptive failures. Possible causes of failure include lack of education, poor compliance, and side effect profiles. In this section we discuss the different methods of hormonal contraception. We shall discuss also the target population for the various modalities of contraception and their mechanisms, side effects, and ways to decrease failure rates. At the end of the section, emergency contraception will be briefly discussed.

Table 13-4. Pregnancy rates after treatment for unexplained infertility. Aggregate data for each treatment.1

Treatment

No. of Studies

No. (%) of Pregnancies per Initiated Cycle

Percent of Quality-Adjusted Pregnancies per Initiated Cycle

Control groups

11

64/3,539 (1.8)

1.3

Control groups, randomized studies

6

  23/597 (3.8)

4.1

IUI

9

  15/378 (4)

3.8

Clomiphene citrate

3

  37/617 (6)

5.6

Clomiphene citrate + IUI

5

  21/315 (6.7)

8.3

hMG

13

139/1806 (7.7)

7.7

hMG + IUI

14

207/1133 (18)

17.1

IVF

9

  378/683 (22.5)

20.7

GIFT

9

  158/607 (26.0)

27.0

1Reproduced, with permission, from Guzick DS et al: Efficacy of treatment of unexplained infertility. Fertil Steril 1998;70:207. GIFT = gamete intrafollicular transfer; hMG = human menopausal gonadotrophin; IVF = in vitro fertilization; IUI = intrauterine insemination.

ORAL CONTRACEPTIVES

Combination

In the United States, oral contraceptive pills are the most widely used method for contraception. There are two types of oral contraception: combination pills and progestin-only pills. The various hormones used in birth control pills are illustrated in Figure 13-12.

The development of oral contraceptive agents began with the isolation of progesterone. However, progesterone was very expensive and difficult to isolate. Ethisterone, a derivative of an androgen, was found to have progestin activity and was much easier to isolate than progesterone. With removal of carbon 19, the progestational activity was increased and the new compound was termed norethindrone. When this hormone was administered to women, ovulation was inhibited. During the process of norethindrone purification, an estrogen contaminant was found. When this contaminant was removed, women would experience breakthrough bleeding. The estrogen was added back, thereby creating the first-generation combination birth control pill, which was FDA-approved in 1960.

Oral contraceptives can be divided into generations based on dose and type of hormone. The first-generation birth control pills contained more than 50 ľg of ethinyl estradiol or mestranol and a progestin. The adverse events associated with high-dose estrogen, such as coronary thrombosis, led to development of the second-generation pill, which contained less than 50 ľg of ethinyl estradiol and progestins other than levonorgestrel derivatives. Next, attention was directed toward the progestin, which was thought to have adverse androgenic effects such as affecting lipid profiles and glucose tolerance. This led to the development of third-generation pills that contain both a lower dose of estrogen (20–30 ľg of ethinyl estradiol) and newer progestins (gonanes: desogestrel or norgestimate). Indeed, studies have shown a reduction in metabolic changes associated with these progestins, but limited data are available to demonstrate any actual reduction of cardiovascular events. Another recently developed progestin, drospirenone, has antimineralocorticoid and antiandrogenic activity in addition to its pharmacologic progestational effects. As an analog of spironolactone rather than androgen, it competitively binds to aldosterone receptors, and it may counteract the estrogen stimulation of the renin-angiotensin system, resulting in more weight stability and less water retention. A new combination oral contraceptive, Yasmin, which contains 3 mg drospirenone and 30 ľg ethinyl estradiol, has recently been approved by the FDA and will be prescribed for women with hyperandrogenism or other side effects attributable to oral contraceptives. However, the relative antiandrogenic activity of drospirenone is small compared

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with cyproterone acetate or the therapeutic dose of spironolactone used for the treatment of hirsutism.

 

Figure 13-12. Oral contraceptive pill hormonal components. All are synthetic steroids.

Contraceptives can be classified also on formulas or schedules of administration. The theory behind phasic preparations was to further decrease the amount of total progestin administered in an attempt to reduce metabolic changes attributed to the progestin, thereby decreasing adverse effects. The traditional monophasic pill (eg, Loestrin) contains 30 ľg of ethinyl estradiol and 1.5 mg of norethindrone. This dose is given every day for 3 weeks with a 1-week hormone-free interval. The progestin dose remains constant throughout the cycle. The second type is the biphasic pill (eg, Ortho-Novum 10/11), which contains 35 ľg of ethinyl estradiol and either 0.5 mg or 1 mg of norethindrone. The 0.5 mg of norethindrone is administered in the first 10 days of the month and the 1 mg is administered for the following 11 days. The last 7 days of the cycle are free of hormone. With this combination, there was a theoretical increase in breakthrough bleeding and an increased pregnancy rate. A meta-analysis revealed no difference, but limited data were available.

Because of concerns that this regimen might result in both breakthrough bleeding and pregnancies, another phasic formulation was developed. The triphasic pills (eg, Triphasil, Ortho-Novum 7/7/7) contain 0.5, 0.75, and 1 mg norethindrone combined with 35 ľg ethinyl estradiol. Theoretically, this formulation improves cycle control. There are several other regimens, some of which alter estrogen doses to simulate the estrogen cyclic rhythm (Triphasil-30, 40, 30 ľg ethinyl estradiol) and possibly decrease breakthrough bleeding. A meta-analysis comparing biphasic versus triphasic pills revealed that triphasic pills significantly improved cycle control. However, the progestins in each pill tested were different, and this could account for better cycle control rather than the phasic formulation. An additional meta-analysis was performed on triphasic versus monophasic pills to assess cycle control and metabolic effects. This analysis revealed no difference between the formulations. Therefore, there is little scientific rationale for prescribing phasic preparations in preference to the monophasic pill.

The pharmacologic activity of progestins is based on the progestational activity and bioavailability of each progestin as well as the dose. The relative potencies of the different progestins are levonorgestrel > norgestrel > norethindrone. The active estrogen component of oral

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contraceptives is ethinyl estradiol (even if mestranol is administered).

When the hormones are administered for 21 days of the cycle, there is enough progestin to inhibit rapid follicle growth for about 7 more days. Figure 13-13 demonstrates that during the steroid-free interval there is no rise in estrogen, indicating no follicular maturation. It is likely that pills missed after this time are responsible for some of the unintended pregnancies. Therefore, it is important that this interval not be extended.

Pharmacologic doses of progestin inhibit ovulation by suppressing GnRH pulsatility and possibly inhibiting release of pituitary LH. Progestins also impair implantation and produce thick, scanty cervical mucus that retards sperm penetration. These latter methods play a minor role in the mechanism of oral contraception.

 

Figure 13-13. Progestin activity on steroidogenesis and ovulation. (Reproduced, with permission, from Brenner PF et al: Serum levels of d-norgestrel, luteinizing hormone, follicle-stimulating hormone, estradiol and progesterone in women during and following ingestion of combination oral contraceptives containing dl-norgestrel. Am J Obstet Gynecol 1997;129:133.)

Ethinyl estradiol helps prevent the selection of a dominant follicle by suppressing pituitary FSH. In addition to FSH suppression, ethinyl estradiol provides stability to the endometrium, decreasing breakthrough bleeding. It also up-regulates the progesterone receptor and decreases clearance, thereby potentiating the activity of the progestin.

Traditionally, a pill is administered daily for 3 weeks out of 4, preferably at the same time each day (more

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critical with progestin-only pills). This regimen was designed to mimic the menstrual cycle with monthly withdrawal bleeding. The conventional start date is on the first Sunday after menses (first day of menses for triphasics). An alternative method is to start at the time of the clinic visit regardless of the day of the menstrual cycle with a backup method for 7 days (“Quick-Start”). This method has the advantage of immediate contraception without adverse bleeding events. In addition, with the “Quick-Start”method, women are more likely to start the second pack of oral contraceptives, suggesting increased compliance. During the 28-day regimen, there is a 1-week steroid-free interval. If the steroid-free interval is prolonged beyond the 7-day window, ovulation is possible. Therefore, this is a critical time not to neglect taking pills. On the other hand, a woman may continue to take the hormone pills and skip the steroid-free interval to avoid monthly bleeding. A randomized trial comparing continuous oral contraception with the traditional cyclic method revealed a significantly greater incidence of erratic bleeding with (overall) the same number of days of bleeding, albeit a smaller amount of bleeding. New formulations have been developed for those who do not desire cyclic bleeding. This regimen involves 84 days of continuous hormone administration followed by a steroid-free interval of 1 week. This can easily be done with the traditionally packaged oral contraceptive pills.

A routine for daily administration improves adherence and contraceptive efficacy. Failure to take the pill at the same time every day and not understanding the package insert are associated with missing two or more pills during the cycle. In order to decrease failure rates, women should understand that if they forget to take the pill, they must use barrier prophylaxis.

Postpartum women who are not breast-feeding may begin combination oral contraceptives 3 weeks after delivery. For women who are breast-feeding, it is advised that institution of combination oral contraceptives be delayed until 3 months postpartum. The recommendation for this delay is due to decreased milk letdown secondary to estrogen but may be waived once lactation is well established.

Noncompliance increases the incidence of unwanted pregnancies. Appropriate use of birth control is achieved 32–85% of the time in the general population. Teenagers have at most a 50% continuation rate, and 25% of pill users discontinue the practice in the first year. The efficacy of the oral contraceptive under conditions of perfect use is 0.1 failures per 100 woman-years (or 0.1 per 100 users). With typical use, the failure rate is 3%, with first-year failure rates approaching 7.3–8.5%. Side effects contribute to noncompliance. The most common side effect is breakthrough bleeding. Other unwanted symptoms include bloating, breast tenderness, nausea, and possibly headaches, weight gain, and depression. Some studies suggest that altering estrogen doses may improve symptoms. Failure rates may also be associated with concomitant use of drugs (eg, rifampin, hydantoins) that accelerate hormone metabolism.

Other Benefits

There are noncontraceptive benefits to the pill. These include reduced monthly blood loss (less iron deficiency) and less dysmenorrhea as well as reduced benign breast disease and mastalgia. Oral contraceptives also reduce the incidence of PID and ectopic pregnancies. Other significant benefits include a reduction in risk of ovarian cancer, endometrial cancer, and colorectal cancer. Oral contraceptive use also has cosmetic benefits where it can improve excess hair growth and acne (see PCOS). It is not unusual for the pill to be administered for noncontraceptive problems.

Potential Risks

In general, oral contraceptives have proved to be safe for most women, but the possibility of adverse effects has received much attention. Unfortunately, the literature is full of conflicting reports. Data concerning controversial adverse effects will be discussed in the following section.

While estrogen in combination oral contraceptives tends to increase triglycerides and total cholesterol, these levels are still within the normal range, and they appear to increase HDL and decrease LDL. Progestins attenuate these effects, which suggests an adverse metabolic milieu. Although it is known that low HDL/LDL ratios are associated with cardiovascular events, the importance of lipid changes associated with birth control pills is unknown. To date there is no strong evidence of an increased incidence of myocardial infarctions in healthy nonsmoking oral contraceptive users. In patients with other cardiovascular risk factors such as hypertension—at least in Europe—there is an up to twelvefold increased risk of cardiovascular events. Women who are over 35 years of age and smoke are at increased risk for cardiovascular events. This risk is amplified with use of the birth control pill. If more than 15 cigarettes per day are consumed, there is a RR of 3.3 for a cardiovascular event compared with a RR of 20.8 with concomitant use of oral contraceptives. However, if a woman smokes fewer than 15 cigarettes per day, there is a 2.0 RR of a cardiovascular event compared with 3.5 RR with concomitant contraceptive use. Former smokers after 1 year have no significant increased risk. First-generation oral contraceptives (> 50 ľg ethinyl estradiol) imposed a 5.8 RR of stroke (ischemic

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or hemorrhagic). With low-dose agents (> 50 ľg ethinyl estradiol), there appears to be no significant increased risk of stroke among healthy normotensive nonsmoking women. Hypertensive women have a 10.2–14.2 RR of hemorrhagic stroke. Since the potential exists for adverse outcomes, women taking oral contraceptives should be screened regularly for cardiovascular risk factors to ensure safe administration.

The risk of deep vein thrombosis and pulmonary embolism is increased twofold to threefold with administration of the pill. The mechanism by which oral contraceptives enhance venous thrombosis is unknown, but there may be estrogen-related changes in coagulation parameters. These include increased clotting factors and activation of platelets and a decrease in protein S and fibrinolytic activity. However, these changes in measured serum clotting factors do not predict the occurrence of deep vein thrombosis. Genetic thrombophilias increase the risk of venous thrombosis. The prevalence of factor V Leiden in the general population is 5%. The incidence of deep vein thrombosis among this population is 60 per 100,000 per year, and with use of oral contraceptives the incidence approaches 280–300 per 100,000 per year. The baseline incidence of deep vein thrombosis in women is approximately 3 per 100,000 per year, while with current oral contraceptive uses it is 9.6–21.1 per 100,000 per year. For comparison, during pregnancy, the incidence of deep vein thrombosis is 60 per 100,000 per year. Older age (40–44) increases the incidence twofold to threefold but does not affect the relative risk. There is no evidence that smoking has an effect on deep vein thrombosis incidence with oral contraceptive use. At this time, universal screening for thrombophilias is not cost-effective. However, any history of deep vein thrombosis warrants a workup for thrombophilias.

The association of oral contraceptives and cancer risk has been evaluated for breast, cervical, and liver cancer. Observational studies investigating a possible association between oral contraceptive use and breast cancer have reported conflicting results. The most recent information is that oral contraceptive usage (current or past users) has no impact on the incidence of breast cancer—RR 1.0 (CI 95% 0.8–1.3)—among women 35–64 years of age. Several observational studies have linked oral contraceptive use with invasive cervical cancer, though it is not clear if this association is causally related. A recent study investigating the association between oral contraception use and cervical cancer revealed a nearly threefold increased risk among human papillomavirus carriers with 5–9 years of use (RR 2.82; 95% CI 1.46–5.42). This evidence suggests that women taking oral contraceptives should be screened yearly with Pap smears to prevent cervical cancer. In the 1980s there was an association between hepatocellular carcinoma in women under 50 years of age and oral contraceptive use. With further investigation there appears to be no increased risk of hepatic cancer with the use of oral contraceptives.

After discontinuation of oral contraceptives, the activity of the HPO axis gradually returns to a precontraceptive state. After a 2- to 4-week prolongation of the follicular phase, the LH peak is observed, which suggests that the suppressive effects of the oral contraceptive have dissipated and that cyclic menses will resume.

Contraindications to oral contraceptive administration are summarized in Table 13-5.

Progestin Only

Progestin-only pills (Ortho Micronor, Nor-QD, 0.35 mg norethindrone; Ovrette, 0.075 mg levonorgestrel) are also available for contraception. The target population for administration of progestin-only contraception includes women with contraindications to estrogen, breast-feeding mothers, and older women.

The circulating levels of progestin following ingestion of progestin-only pills (minipill) are 25–50% of that following ingestion of estrogen-progestin oral contraceptive pills. Serum levels that peak 2 hours after administration are followed by rapid elimination (see graphs inFigure 13-14). The peak levels of norethindrone and levonorgestrel vary (4–14 ng/mL and 0.9–2 ng/mL, respectively), but 24 hours after pill ingestion, serum levels are 0.2–1.6 ng/mL and 0.2–0.5 ng/mL, respectively. Thus, there is no accumulation of progestin over time. Progestin-only administration results in lower steady state levels and a shorter half-life compared with concomitant administration with estrogen.

Owing to the lower levels of progestin in the progestin-only pill, there is less influence on the inhibition of ovulation and more impact of thickening cervical mucus (“hostile environment”) inhibiting sperm penetration. Sperms that are able to penetrate have decreased mobility. Progestins also alter the endometrial

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lining (inhibition of progesterone receptor synthesis and reduction in endometrial glandular development, preventing implantation) and perhaps inhibit the motility (number and motility of the cilia) of the uterine tube. LH peaks—as well as FSH peaks—are suppressed compared with pretreatment levels. The change in cervical mucus takes place 2–4 hours after the first dose. However, after 24 hours, thinning of the cervical mucus is evident, allowing unimpaired sperm penetration. This is why it is critical to take the progestin-only pills at the same time every day.

Table 13-5. Contraindications to combination oral contraceptive use.

Pregnancy
History of thromboembolic disease
Smoking and age ≥ 35 years
Hepatoma
Breast cancer
Endometrial cancer
History of cerebrovascular or cardiovascular disease
Undiagnosed vaginal bleeding
First-degree relative with history of thromboembolic disease
Uncontrolled hypertension

 

Figure 13-14. Progestin-only pill serum levels. (Reproduced, with permission, from McCann MF, Potter LS: Progestin-only oral contraception: a comprehensive review. Contraception 1994;50[6 Suppl 1]:S1.)

The progestin-only pill should be started on the first day of menses. This pill should be taken at the same time every day. If administration is 3 hours late, a backup method should be used for 48 hours. If a pill is missed, a backup method should be used for 48 hours. If two or more pills are missed, a backup method should be used for 48 hours (due to rapid resumption of the cervical mucus effect). If there is no menses in 4 weeks, one should obtain a pregnancy test. Progestin-only pills may be administered immediately postpartum.

The efficacy of progestin-only pills under conditions of perfect use is 0.3–3.1 failures per 100 woman-years (failure rates of 1.1–9.6% in the first year) or 0.5 per 100 users. This efficacy rate is achieved only with careful compliance. The typical use is associated with a greater than 5% failure rate. Failure rates were lowest in women over 38˝ years of age and those who were breast-feeding. The efficacy may also be influenced by body weight and by concomitant use of anticonvulsants. The major disadvantage is that the pill must be administered at the same time every day. As a result of even slight flexibility in the schedule, there is increased contraceptive failure.

The risks associated with progestin-only pills are minimal. Various studies have revealed no significant

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impact on lipids, carbohydrate metabolism, blood pressure, or the incidence of myocardial infarction and stroke. Furthermore, no adverse coagulation parameters have been associated with its use. There are almost no data on the association of progestin-only pills and endometrial, ovarian, cervical, or breast cancer. The major side effect is breakthrough bleeding (40–60%). Other side effects include acne and persistent ovarian cysts. With discontinuation of the pill, menses resume with no impact on subsequent pregnancy rates or future fertility.

CONTRACEPTION: LONG-ACTING CONTRACEPTIVES

The high rate of unintended pregnancies has led to the development of long-acting reversible contraceptive modalities. Interest in long-acting methods is increasing because they offer convenience, obviate problems of compliance, and therefore offer higher efficacy. Most long-acting systems contain either combination or progestin-only hormones. The effectiveness of these hormones is prolonged, mostly due to the sustained system that results in a gradual release. The modes of administration include injectables, transdermal patches, subdermal rods, vaginal rings, and intrauterine devices. The various types of long-acting contraceptives are discussed below.

Injectable Contraceptives

  1. PROGESTIN ONLY

Injectable progestins that contain medroxyprogesterone acetate (Depo-Provera) are beneficial when women have contraindications to estrogen, use antiepileptics, are mentally handicapped, or have poor compliance. Furthermore, there is good evidence that its use is safe in the presence of coronary artery disease, congestive heart failure, diabetes, tobacco use, and a history of venous thromboembolism.

Other uses of medroxyprogesterone acetate include treatment of metastatic endometrial or renal carcinoma.

Although most other long-acting contraceptives are sustained-release formulations, Depo-Provera (150 mg medroxyprogesterone acetate) is provided as an aqueous microcrystalline suspension that gradually declines throughout the cycle (see Figure 13-15). Pharmacologic levels (> 0.5 ng/mL) are achieved within the first 24 hours and peak (at 2 ng/mL) within the first week after the injection. Serum concentrations are maintained at 1 ng/mL for approximately 3 months. Interestingly, estrogen concentration is in the early to mid follicular level (below 100 pg/mL) and persists for 4 months after the last injection. The serum concentration of medroxyprogesterone acetate decreases to 0.2 ng/mL during the last 5–6 months (ovulation occurs when levels are < 0.1 ng/mL). However, one study observed progesterone levels to rise after 3˝ months.

The mechanism of action depends on the higher peaks of hormone to mainly inhibit ovulation (LH surge). Like other progestins, medroxyprogesterone acetate increases cervical mucus viscosity, alters the endometrium, and decreases the motility of the uterine tubes and uterus. FSH levels are minimally suppressed with Depo-Provera.

The manufacturer's recommendation is to administer the agent every 3 months, starting within 5 days of menses with a grace period of 1 week. The agent is injected deeply into the upper outer quadrant of the buttock or deltoid without massage to ensure slow release. If the grace period exceeds 1 week, a pregnancy test should be performed. If the subject is postpartum and not breast-feeding, Depo-Provera should be given within 3 weeks after delivery and if lactating within 6 weeks (see Table 13-6).

Since compliance is not an issue, the failure rate is minimal at 0 to 0.7 per 100 woman-years (0.3 per 100 users). Weight and use of concurrent medications do not affect the efficacy. However, continuation rates are poor at 50–60% because of the side effect profile. The major dissatisfaction that leads to discontinuation is breakthrough bleeding, which approaches 50–70% in the first year of use. Other side effects include weight gain (2.1 kg per year), dizziness, abdominal pain, anxiety, and possibly depression. Another disadvantage with the use of Depo-Provera is a delay in fertility after discontinuation. Ovulation returns when serum levels are less than 0.1 ng/mL. The time from discontinuation to ovulation is prolonged. Only 50% of patients ovulate at 6 months after discontinuing the medication, and although this agent does not cause infertility, achieving pregnancy may be delayed for more than 1 year. (The length of time for release at the injection site is unpredictable.) After the first year, 60% of women become amenorrheic, and at 5 years the incidence of amenorrhea approaches 80%, which can be considered a potential benefit. Other benefits with use of medroxyprogesterone acetate include prevention of iron deficiency anemia, ectopic pregnancy, PID, and endometrial cancer. In addition, Depo-Provera is a recommended contraceptive for women with sickle cell disease (decreased crisis) and seizure disorders (raises seizure threshold). Other therapeutic uses include dysmenorrhea and endometrial hyperplasia or cancer.

  1. Potential RisksOne major concern with use of Depo-Provera is the development of osteopenia, with possible advancement to osteoporosis later in life. Several observational studies have evaluated the potential impact on bone. A prospective trial revealed that current users, after 12 months of use, experience a mean bone mineral density (BMD) loss of 2.74%. However,

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on examining former users 30 months later, it was found that mean BMD was similar to that of nonusers, indicating that the loss is reversible and of minimal clinical importance. An ongoing multicenter study assessing bone density in users versus nonusers should clarify the impact of Depo-Provera on bone. BMD in adolescents has also been investigated because of this critical time of bone mineralization. A small prospective study revealed that BMD was decreased by 1.5–3.1% after 1 and 2 years of use, compared with an increased BMD of 9.3% and 9.5% in Norplant users and controls, respectively. This is a potential concern and has also led to a prospective multicenter study investigating the use of Depo-Provera in adolescents. Although one possible cause is less exposure to estrogen, an alternative and perhaps not exclusive theory involves medroxyprogesterone-dependent glucocorticoid activity that impairs osteoblast differentiation. Other potential risks include an adverse lipid profile (increase in LDL, decrease in HDL) and a slightly increased risk of breast cancer. The association of breast cancer with use of Depo-Provera is minimal within the first 4 years of use, with no risk after 5 years of use. Paradoxically, medroxyprogesterone has been used for treatment of metastatic breast cancer.

 

Figure 13-15. MPA levels following injection of Depo-Provera. (Reproduced, with permission, from Ortiz A et al: Serum medroxyprogesterone acetate [MPA] and ovarian function following intramuscular injection of depo-MPA. J Clin Endocrinol Metab 1977;44:32.)

  1. COMBINATION

The development of monthly combination injectables (Lunelle) has responded to the erratic bleeding associated with Depo-Provera (seeFigure 13-16). The cycle control is similar to what is achieved with combined oral contraceptives. The monthly withdrawal bleeding

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occurs 2 weeks after the injection. The target populations are adolescents and women who have difficulty with compliance. Lunelle is an aqueous solution containing 25 mg of medroxyprogesterone acetate and 5 mg of estradiol cypionate per 0.5 mL. In women who receive repeated administration of Lunelle, peak estradiol levels occur approximately 2 days after the third injection and are 247 pg/mL (similar to peak ovulatory levels). The estradiol level returns to baseline 14 days after the last injection (100 pg/mL); the drop in estradiol is associated with menstrual bleeding (2–3 weeks after the last injection). Peak medroxyprogesterone acetate (MPA) levels (2.17 ng/mL) occur at 3˝ days after the third monthly injection. The mean MPA level is 1.25 ng/mL. The level at day 28 of the cycle is 0.44–0.47 ng/mL (level needed for contraceptive effect is 0.1–0.2 ng/mL). The earliest return of ovulation seen in women with multiple injections has been 60 days after the last dose. The mechanism of action is similar to that of combined oral contraceptives.

Table 13-6. Scheduling for injectable contraceptives.1

Method

DMPA

MPA/E2C

First injection

   Spontaneous menstrual cycle

Within 5 days of menses onset

Within 5 days of menses onset

   Spontaneous or elective first-trimester abortion

Within 7 days

Within 7 days

   Term delivery

Within 3 weeks postpartum if not lactating; within 6 weeks postpartum if lactating

Between 21 and 28 days postpartum if not lactating

   Switching from combination OCs

While administered active pills or within 7 days after administering the pill pack's last active tablet

While administered active pills or within 7 days after administering the pill pack's last active tablet

   Switching from DMPA

Within 13 weeks after last DMPA injection

   Switching from MPA/E2C

Within 33 days after previous injection

   Switching from levonorgestrel implant

Any time within 5 years of implant insertion; use of a condom back-up is recom mended for 1 week

Any time within 5 years of implant insertion; use of a condom backup is recommended for 1 week

   Switching from Copper T 380A IUD

First injection should occur before IUDremoval and within 10 years after IUDinsertion; a condom should be used as a back-up if the first injection is not adminstered within 5 days of menses onset

First injection should occur before IUDremoval and within 10 years after IUDinsertion; a condom should be used as a back-up if the first injection is not administered within 5 days of menses onset

Subsequent injections

   Injection interval

   Grace period

Every 12 weeks or 3 months; earlier reinjections are acceptable
2 weeks (14 weeks from last injection); after 1 week manufacturer recommends pregnancy testing before repeat injection

Every 28 days or 4 weeks or monthly; reinjection earlier than 23 days may impair cycle control ą 5 days (23–33 days from last injection); thereafter, pregnancy testing needed before repeat injection

DMPA = depot medroxyprogesterone acetate; MPA/E2C = medroxyprogesterone acetate and estradiol cypionate; OCs = oral contraceptives; IUD = intrauterine device.

1Reproduced, with permission, from Kaunitz AM: Injectable long-acting contraceptives. Clin Obstet Gynecol 2001;44:73.

Lunelle is administered intramuscularly in the buttock or deltoid every month. The first injection should be given within the first 5 days of the menstrual cycle (see Table 13-6). Even though pharmacokinetic analysis reveals a delay in ovulation, the manufacturer recommends a 5-day grace period. The failure rate is 0.1 per 100 woman-years. Neither body weight nor use of concomitant drugs appears to affect the efficacy. Although this contraceptive has the advantages of the oral contraceptives and is associated with better compliance, the continuation rate is only 55%. This may be due to its side effect profile, which is similar to that of the combined oral contraceptives with the addition of monthly injections.

  1. Potential RisksThere are limited data on potential risks. The risk potential is probably similar to that of the combined oral contraceptives, with a potentially lower incidence of deep vein thrombosis secondary to the absence of the first-pass effect. Upon discontinuation

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of Lunelle, achieving pregnancy may be delayed for as long as to 3–10 months after the last injection.

 

Figure 13-16. Serum MPA and estradiol levels following Lunelle injection. (Reproduced, with permission, from Rahimmy MH, Ryan KK, Hopkins NK: Lunelle monthly contraceptive injection [medroxyprogesterone acetate and estradiol cypionate injectable suspension]: steady-state pharmacokinetics of MPA and E2 in surgically sterile women. Contraception 1999;60;209.)

Subdermal Implants

The Norplant package consists of six capsules (34 mm in length, 2.4 mm in diameter), with each capsule providing 36 mg of levonorgestrel (total 216 mg). The target population is women who have contraindications to or adverse side effects from estrogen, women who are postpartum or breast-feeding, and adolescent mothers. This method provides long-term continuous contraception (approved for 5 years) that is rapidly reversible. The advantages, side effects, risks, and contraindications are similar to those of oral progestins. The major disadvantage—not present with use of oral progestins—is the surgical insertion and removal of the rods. A newer system, Norplant II, contains two rods (4 cm in length, 3.4 cm in diameter) and releases 50ľg/d of norgestrel (approved for 3 years). The two-rod system has the same mechanism of action and side effect profile as its predecessor. However, it is much easier and faster to insert and remove than the capsules.

Within the first 24 hours, serum concentrations of levonorgestrel are 0.4–0.5 ng/mL. The capsules release 85 ľg of levonorgestrel per 24 hours for the first year (equivalent to the daily dose of progestin-only pills) and then 50 ľg for the remaining 5 years. The mean serum levels of progestin after the first 6 months are 0.25–0.6 ng/mL, slightly decreased at 5 years to 0.17–0.35 ng/ mL). A levonorgestrel concentration below 0.2 ng/mL is associated with increased pregnancy rates. The site of implantation (leg, forearm, and arm) does not affect circulating progestin levels. Even though progestin levels are sufficient to prevent ovulation within the first 24 hours, the manufacturer recommends use of a backup method for 3 days after insertion. Upon removal, the progestin levels rapidly decline and undetectable serum levels are achieved after 96 hours. As a result, most women ovulate within 1 month after removal of the implants.

There are several ways in which Norplant provides contraception. In the first 2 years, the levonorgestrel concentration is high enough to suppress the LH surge—most likely at the hypothalamic level—and thereby inhibits ovulation. However, given the low concentrations of progestin, there is no real effect on FSH. The estradiol levels approximate those in ovulatory women. In addition, there are irregular serum peaks (often prolonged) and declines in serum estrogen levels that may contribute to erratic bleeding. By 5 years, more than 50% of the cycles are ovulatory. However, ovulatory cycles while using Norplant have been associated with luteal phase insufficiency. Other mechanisms of contraception are similar to oral progestins and include thickening of the cervical mucus, alterations of the endometrium, and changes in tubal and uterine motility.

The failure rate is 0.2–2.1 failures per 100 woman-years (0.9 per 100 users). Like oral progestins, body weight affects circulating levels and may result in more failures in the fourth or fifth year of use. Similar to oral progestins, the incidence of ectopic pregnancy among failures is increased to 20% (overall incidence is 0.28–1.3 per 1000 woman-years). The continuation rate (discontinuation rate of 10–15% per year) is age-dependent and ranges from 33% to 78%. Menstrual disturbances are the most frequent side effect, approaching

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40–80% especially in the first 2 years. Although the incidence of abnormal uterine bleeding is similar to the experience with Depo-Provera, a significant difference between these methods is that Norplant provides only a 10% amenorrhea rate at 5 years. Other side effects reported include headache (30% indication for removal) and possibly weight gain, mood changes, anxiety, and depression—as well as ovarian cyst formation (eightfold increase), breast tenderness, acne, galactorrhea (if insertion occurs upon discontinuation of lactation), possible hair loss, and pain or other adverse reactions at the insertion site (0.8% of cases at discontinuation).

Transdermal Patch

The transdermal patch (Ortho Evra) is another approach to contraception. The thin 20 cm2 patch is composed of a protective layer, a middle (medicated) layer, and a release liner that is removed prior to application. The system delivers 150 ľg of norelgestromin (active metabolite of norgestimate) and 20 ľg of ethinyl estradiol per day to the systemic circulation. The target population is similar to that described above for Lunelle. One advantage of this system over Lunelle is that there are no monthly injections and as a result there is greater autonomy for the patient. The patch is applied once a week for 3 consecutive weeks, followed by a patch-free week for monthly withdrawal bleeding. The patch should be changed on the same day each week. The mechanism of action, contraindications, and side effects are similar to what has been described in the section on oral contraceptives.

With use of the transdermal patch, the peak ethinyl estradiol and norelgestromin levels are 50–60 pg/mL and 0.7–0.8 ng/mL, respectively. Because of this unique delivery system, hormone levels achieve a steady state condition throughout the cycle (see below and Figure 13-17). After the seventh day of application, there are adequate hormone levels to inhibit ovulation for 2 more days. With each consecutive patch, there is minimal accumulation of norelgestromin or ethinyl estradiol. The amount of hormone delivered is not affected by the environment, activity, or site of application (abdomen, buttock, arm, torso). The adhesive is very reliable in a variety of conditions, including exercise, swimming, humidity, saunas, and bathing. Complete detachment occurs in 1.8% of cases and partial detachment in 2.9% of cases.

The failure rate is 0.7 per 100 woman-years under conditions of perfect use. Body weight has not been shown to affect the efficacy. The compliance with perfect use ranges from 88.1–91% among all age groups. This is significantly different from what is achieved with oral contraceptives (67–85%), especially with women under 20 years of age. The side effect profile is similar to that of oral contraceptives except that there is slightly more breakthrough bleeding with the transdermal patch in the first 1–2 months (up to 12.2% versus 8.1%) and less breast tenderness (6.1% versus 18.8%). The incidence of skin reaction was 17.4%, characterized as mild in 92%, resulting in discontinuation in under 2%.

Vaginal Rings

Since the early 1900s, the vagina has been recognized as a place where steroids can be rapidly absorbed into the circulation. A study in the 1960s revealed that silicone rubber pessaries containing sex steroids would release the drug at a continuous rate. These studies led to the development of contraceptive vaginal rings.

Similar to oral contraceptives, there are combination and progestin-only formulations. Several progestin-only rings have been introduced since the 1970s. However, they were associated with significant menstrual disturbances. More recently, combination types have been developed. The most recent (2002) FDA-approved vaginal ring is a combination type called the NuvaRing.

The NuvaRing is made of ethylene vinyl acetate that provides 0.015 mg of ethinyl estradiol and 0.120 mg of etonogestrel per day. Maximum serum concentrations are achieved within 1 week after placement. The ring is designed to be used for 21 days and then removed for 1 full week to permit withdrawal bleeding. This device is capable of inhibiting ovulation within 3 days after insertion. After removal, the time to ovulation is 19 days. The mechanism of action, contraindications, and risks are similar to those of oral contraceptives. However, when assessing systemic exposure, use of the vaginal ring allows for 50% of the total exposure to ethinyl estradiol (15 ľg in the ring compared with a 30 ľg ethinyl estradiol-containing oral contraceptive).

The failure rate is similar to that reported with oral contraceptives. The continuation rate was 85.6–90%. Irregular bleeding was minimal (5.5%), and overall the device was well tolerated with an associated 2.5% discontinuation rate. Side effects are similar to those of oral contraceptives, but cycle control appears to be improved. The reported incidence of vaginal discharge is 23%, versus 14.5% with use of oral contraceptives. The ring does not appear to interfere with intercourse (1–2% of partners reported discomfort); however, the device can be removed for 2–3 hours during intercourse without changing efficacy.

Intrauterine Devices

Intrauterine devices (IUDs) are another modality of contraception that has been used clinically since the 1960s. Historically, these devices were made of plastic (polyethylene) impregnated with barium sulfate to make

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them radiopaque. Several other devices were subsequently developed, including the Dalkon Shield. After the introduction of the Dalkon Shield, an increase in pelvic infections was observed secondary to its multifilament tail. Furthermore, tubal infertility and septic abortions were increasing, and massive litigation was the result. Consequently, even though the modern IUD has negligible associated risk, the use of IUDs in the United States is minimal—less than 1% of married women.

 

Figure 13-17. Comparative serum steroid levels of norelgestromin (NGMN) and ethinyl estradiol (EE) following patch administration. (Reproduced, with permission, from Abrams LS et al: Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants. Contraception 2001;64:287.)

Currently two types of IUDs are used in the United States: the copper and the hormone-containing devices. The most recent FDA-approved intrauterine system contains levonorgestrel (Mirena) and is approved for 5 years of use. Several studies have demonstrated that these devices are unlike the Dalkon shield, and are very safe and efficacious. The target population is women who desire highly effective contraception that is long-term and rapidly reversible.

The copper (TCu-380A) IUD is a T-shaped device. The mechanism of action is mostly spermicidal due to the sterile inflammatory reaction that is created secondary to a foreign body in the uterus. The abundance of white blood cells that are present as a result kills the spermatozoa by phagocytosis. The amount of dissolution of copper is less than the daily amount ingested in the diet. However, with release of copper, salts are created that alter the endometrium and cervical mucus. Sperm transport is significantly impaired, limiting access to the oviducts.

There are two hormone-containing intrauterine devices: the progesterone-releasing device (Progestasert) and the levonorgestrel-releasing device (Mirena). The Progestasert contains progesterone and is released at a rate of 65 mg/d (approved for 1 year). This diffuses into the endometrial cavity, resulting in decidualization and atrophy of the endometrium. Serum progesterone levels do not change with the use of Progestasert. The main mechanism of action is to impair implantation. Mirena contains 52 mg of levonorgestrel and is gradually released at a rate of 20 ľg/d (approved for 5 years). Unlike Progestasert, systemic absorption of levonorgestrel inhibits ovulation about half the time. Although

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women may continue to have cyclic menses, over 40% have impaired follicular growth, with up to 23% developing luteinized unruptured follicles. Other mechanisms of action are similar to those described for Progestasert and the progestin-only pills. Mirena has the added advantage of significantly decreasing menstrual flow and has been used to treat menorrhagia.

The IUD should be placed within 7 days after onset of the menstrual cycle or at any time postpartum. The protection begins immediately after insertion. The failure rates after the first year of use are for copper IUD 0.5–0.8%, Progestasert 1.3–1.6%, and Mirena 0.1–0.2%. The expulsion rate is approximately 10%. If a woman becomes pregnant with an IUD in place, the incidence of an ectopic pregnancy is 4.5–25%, with higher rates associated with use of Progestasert. The incidence of ectopic pregnancies with IUDs varies depending on the type of device. With Progestasert, the ectopic rate is slightly higher (6.80 per 1000 woman-years), most likely because its mechanism of action is limited to inhibiting implantation in the endometrium—in contrast to the copper or levonorgestrel IUD (0.2–0.4 per 1000 woman-years), both of which also interfere with conception.

The continuation rate range for the current IUDs is 40–66.2% (Mirena). The side effects of the copper IUD include dysmenorrhea and menorrhagia. The most common adverse effect associated with the hormone-containing devices is erratic bleeding, albeit significantly less bleeding. In fact, 40% experienced amenorrhea at 6 months and 50% at 12 months. The incidence of spotting in the first 6 months was 25% but decreased to 11% after 2 years. Other side effects of levonorgestrel that have been reported include depression, headaches, and acne. There is a tendency to develop ovarian cysts early after insertion with the levonorgestrel-containing device that resolves after 4 months of use.

The nominal risks associated with IUD use include pelvic infection (within 1 month after insertion), lost IUD (ie, perforation into the abdominal cavity; 1:3000), and miscarriage. There is no association between IUD use and uterine or cervical cancer.

Contraindications to IUD use are active genital infection and unexplained bleeding.

EMERGENCY CONTRACEPTION

Postcoital contraception is a method that may be used by a woman who believes her contraceptive method has failed or who has had unprotected intercourse and feels that she may be at risk for an unintended pregnancy. The first study to evaluate the efficacy of emergency contraception with hormones was in 1963. Subsequently, several studies have been performed with various contraceptives that paved the way for more widespread use. In 1997, the FDA approved the use of high-dose oral contraceptives for postcoital contraception. Since then, pharmaceutical companies have marketed specific packaging for the use of emergency contraception. Other methods, including mifepristone (RU-486) and the IUD have also been effective for postcoital contraception.

Similar to the formulas of oral contraception, there are both combination and progestin-only types of emergency contraception. The combination method (Yuzpe regimen) entails administration of two doses of two tablets (Ovral: 50 ľg ethinyl estradiol, 0.5 mg norgestrel) 12 hours apart (total: 200 ľg ethinyl estradiol, 2 mg norgestrel). Other oral contraceptives may be used with adjustment in the number of pills for equivalence (ie, two doses of four tablets: any second-generation oral contraceptive 12 hours apart). The specific medication (Preven) that is FDA-approved and marketed for postcoital contraception contains two doses of four tablets (ethinyl estradiol 50 ľg, levonorgestrel 0.25 mg) 12 hours apart. The progestin-only method involves two doses of ten pills (Ovrette 0.075 mg) 12 hours apart (Plan A). The marketed form (Plan B) contains two doses of one tablet (levonorgestrel 0.75 mg) 12 hours apart.

Following a single oral dose of 0.75 mg of levonorgestrel, the serum concentration peak (5–10 ng/mL) was at 2 hours with a rapid decline during the first 24 hours. The mechanism of action is uncertain, but levonorgestrel most likely inhibits ovulation and alters the endometrium to prevent implantation. Studies have shown decreased sperm recovery from the uterine cavity, possibly due to thickened cervical mucus, or the alkalinization of the intrauterine environment. Others have shown that decreased factors such as integrins can alter endometrial receptivity. The mode of action most likely depends on the timing of intercourse relative to ovulation and to the administration of emergency contraception.

Maximum efficacy is achieved if the first dose is administered within 72 hours after intercourse and repeated in 12 hours. The failure rate with combination formulas is 2–3% and with progestin only 1%. Emergency contraception effectively reduces the rate of unintended pregnancies from 8% to 2%, a 75% reduction. However, with increasing time since unprotected intercourse, the efficacy changes from 0.4% to 1.2% to 2.7% for the first, second, or third 24-hour period after unprotected intercourse. For maximum efficacy, emergency contraception may be prescribed in advance so women will already have the correct dosing. No increase in risk-taking behavior has been noted with this strategy.

Significant nausea or emesis (51.7%) is associated with use of emergency contraception, though substantially less with progestin-only formulations. An

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antiemetic should be administered 1 hour before each treatment. If a patient vomits within 1 hour after ingestion, additional pills need to be administered.

Contraindications to emergency contraception with the combination regimen are possibly the same as those described for oral contraceptives; for progestin-only pills, there are no contraindications. Emergency contraception should be an optional function of the rape management protocol.

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Abbott DH, Dumesic DA, Franks S: Developmental origin of polycystic ovary syndrome—A hypothesis. J Endocrinol 2002;174:1.

Dunaif A: Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774.

Ehrmann DA, Barnes RB, Rosenfield RL: Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev 1995;16:322.

Ibanez L et al: Premature adrenarche—normal variant or forerunner of adult disease? Endocr Rev 2000;21:671.

Legro RS: Polycystic ovary syndrome: the new millennium. Mol Cell Endocrinol 2001;184:87.

Nestler JE, Jakubowicz DJ: Decreases in ovarian cytochrome P450c17α activity and serum free testosterone after reduction of insulin secretion in polycystic ovarian syndrome N Engl J Med 1996;335:617.

Poretsky L et al: The insulin-related ovarian regulatory system in health and disease. Endocr Rev 1999;20:535.

Anovulation Due to Adrenal Disorders

Betterle C et al: Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 2002;23:327.

Newell-Price J et al: The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states. Endocr Rev 1998;19:647.

White PC, Speiser PW: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000;21:245.

Müllerian Anomalies

Homer HA, Li T-C, Cooke ID: The septate uterus: a review of management and reproductive outcome. Fertil Steril 2000;73:1.

Raga F et al: Reproductive impact of congenital Müllerian anomalies. Hum Reprod 1997;12:2277.

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Menopause: General References

Faddy MJ et al: Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992;7:1342.

Nelson HD et al: Postmenopausal hormone replacement therapy: scientific review. JAMA 2002;288:872.

Nair GV, Herrington DM: The ERA trial: Findings and implications for the future. Climacteric 2000;3:227.

Prior J: Perimenopause: the complex endocrinology of the menopausal transition. Endocr Rev 1998;19:397.

Soules MR et al: Stages of Reproductive Aging Workshop (STRAW). J Womens Health Gend Based Med 2001; 10:843.

Menopause Due to Cardiovascular Disease

Barrett-Connor E et al: Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002;287:847.

Grady D et al: Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49.

Hulley S et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605.

Postmenopausal hormone replacement therapy for primary prevention of chronic conditions: recommendations and rationale. Ann Intern Med 2002;137:834.

Rossouw JE et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321.

Menopause: Osteoporosis

Meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23:495.

Menopause: Selective Estrogen Receptor Modulators

Cosman F, Lindsay R: Selective estrogen receptor modulators: clinical spectrum. Endocr Rev 1999;20:418.

Miller CP: SERMs: Evolutionary chemistry, revolutionary biology. Curr Phar Des 2002;8:2089.

Hormone Replacement and Alzheimer's Disease

Fillit HM: The role of hormone replacement therapy in the prevention of Alzheimer disease. Arch Intern Med 2002;162:1934.

Infertility

Cedars, MI: Infertility in obstetrics and gynecology: a longitudinal approach. In: Gynecology and Obstetrics: A Longitudinal Approach.Moore TR et al (editors). Churchill Livingstone, 1993.

Collins JA et al: Treatment-independent pregnancy among infertile couples. N Engl J Med 1983;309:1201.

Guzick DS et al: Efficacy of treatment for unexplained infertility. Fertil Steril 1998;70:207.

te Velde ER, Dorland M, Broekmans FJ: Age at menopause as a marker of reproductive ageing. Maturitas 1998;30:119.

Contraception

Abma JC et al: Centers for Disease Control and Prevention, National Center for Health Statistics. Fertility, family planning, and women's health: new data from the 1995 National Survey of Family Growth, Report No. 19, Series 23, 1997.

Abrams LS et al: Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants. Contraception 2001;64:287.

Archer DF: New contraceptive options. Clin Obstet Gynecol 2001;44:122.

Brenner PF et al: Serum levels of d-norgestrel, luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone in women during and following ingestion of combination oral contraceptives containing dl-norgestrel. Am J Obstet Gynecol 1977;129:133.

Burkman RT et al: Current perspectives on oral contraceptive use. Am J Obstet Gynecol 2001;185(2 Suppl):S4.

Cedars MI: Infertility in obstetrics and gynecology: a longitudinal aproach. In: Gynecology and Obstetrics: A Longitudinal Approach.Moore TR et al (editors). Churchill Livingstone, 1993.

Croxatto HB et al: Mechanism of action of hormonal preparations used for emergency contraception: a review of the literature. Contraception 2001;63:111.

Kaunitz AM: Injectable long-acting contraceptives. Clin Obstet Gynecol 2001;44:73.

Marchbanks PA et al: Oral contraceptives and the risk of breast cancer. N Engl J Med 2002;346:2025.

McCann MF, Potter LS: Progestin-only oral contraception: a comprehensive review. Contraception 1994;50(6 Suppl):S1.

Ortiz A et al: Serum medroxyprogesterone acetate (MPA) and ovarian function following intramuscular injection of depo-MPA. J Clin Endocrinol Metab 1977;44:32.

Rahimy MH, Ryan KK, Hopkins NK: Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): steady-state pharmacokinetics of MPA and E2 in surgically sterile women. Contraception 1999;60;209.


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