Physiology - An Illustrated Review

29. Differentiation, Puberty, and Male and Female Reproduction

Reproduction describes processes that maintain the species rather than the individual. These processes help to assure that a viable egg meets a viable sperm. The physiology of reproduction is largely about endocrine control.

29.1 Fetal Sexual Differentiation

Genetic sex is determined by the sex chromosomes: XY in males and XX in females. All spermatozoa have either a 23X or 23Y, and all ova have a 23X. Therefore, the male determines the genetic sex of the offspring.

Klinefelter syndrome

Klinefelter syndrome is one of the most common male genetic abnormalities. Males with this condition usually have an extra sex chromosome (XXY karyotype). Signs and symptoms include delayed puberty, small and firm testes, gynecomastia(benign enlargement of the male breast), sparse or lack of facial and body hair, lack of muscle mass, low libido, infertility, and osteoporosis. Many of these signs and symptoms occur as a result of low testosterone because testicular growth is impaired. Therefore, testosterone therapy can prevent many of them if given around the time of puberty. Surgery may also be indicated for treatment of gynecomastia for aesthetic and psychological reasons. Infertility can be overcome, in some instances, with a procedure known as testicular sperm extraction (TESE), in which sperm are removed directly from the testicle by needle biopsy and injected into an egg to fertilize it(intracytoplasmic sperm injection[ICSI]).

 

Turner syndrome

Turner syndrome occurs in females who lack one sex chromosome(X0 karyotype). Signs and symptoms include short stature, webbed neck, ptosis (drooping eyelid), small lower jaw, broad chest, arms that turn out at the elbows(cubitus valgus), rudimentary or absent gonads, amenorrhea (absence of a menstrual period), infertility, and coarctation of the aorta(a narrowing of part of the aorta). Turner syndrome may also lead to some serious complications, such as aortic dissection(a tear in the inner wall of the aorta and bleeding between the inner and outer layers), renal disease, hearing loss, hypothyroidism, and skeletal deformities, for example, kyphosis(curvature of the upper spine) and/or scoliosis (lateral curvature of the spine). Treatment involves the administration of somatotropin(a growth hormone analogue) prior to epiphyseal closure to increase stature and specialist care for control of the systemic symptoms and complications.

 

Gonadal sex is determined by the presence of testes in males and ovaries in females.

– The presence of a single Y chromosome causes fetal undifferentiated gonads to differentiate into testes. If the Y chromosome is absent, testes fail to develop, and ovaries form.

Phenotypic sex is determined by the formation of a male or female internal genital tract and external genitalia.

Genetic sex, gonadal sex, and phenotypic sex are summarized in Fig. 29.1.

Differentiation of Internal Genitalia

Male Internal Genitalia

Until the seventh week of gestation, the internal genitalia have the rudiments of both male internal genitalia (the wolffian ducts) and female internal genitalia (the müllerian ducts). A genetically male fetus with functional testes secretes antimüllerian hormone (AMH) from Sertoli cells in the testes. AMH causes regression of the müllerian ducts and differentiation of Leydig cells in the testes. Leydig cells then produce testosterone, which stimulates wolffian duct development into the male internal genitalia: the epididymis, vas deferens, and seminal vesicles.

Fig. 29.1 image Fetal sexual differentiation.

image

Female Internal Genitalia

Fetal female development is genetically determined and occurs in the absence of testosterone and AMH. Without testosterone, there is regression of wolffian ducts and the formation of primordial follicles that produce estrogen. The absence of AMH allows the müllerian ducts to differentiate, forming the female internal genitalia: the fallopian tubes, uterus, cervix, and upper one-third of the vagina.

Differentiation of External Genitalia

Until the eighth week of gestation, the external genitalia of the fetus has the potential to develop along either male or female lines. This is because the external genitalia of both sexes develop from common rudiments: the urogenital sinus, the genital swellings, the genital folds, and the genital tubercle.

– In the presence of testosterone, differentiation of the external genitalia proceeds along male lines:

– The urogenital sinus forms the prostate.

– The genital swellings form the scrotum.

– The genital folds form the penile urethra and shaft.

– The genital tubercle forms the glans penis.

– In the absence of testosterone, differentiation of the external genitalia proceeds along female lines:

– The urogenital sinus forms the lower two-thirds of the vagina.

– The genital swellings form the labia majora.

– The genital folds form the labia minora.

– The genital tubercle forms the clitoris.

29.2 Puberty

Puberty is the stage of life when the reproductive system matures and becomes functional.

Up until age 9, gonadotropin-releasing hormone (GnRH) from the hypothalamus and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary are secreted at low levels and fairly evenly over a 24-hour period in both males and females. At puberty, there is a shift to pulsatile GnRH release during various stages of sleep. GnRH causes upregulation of GnRH receptors in the anterior pituitary and a pulsatile release of LH and FSH (LH > FSH). Increased secretion of LH stimulates the production of the male sex hormones testosterone and dihydrotestosterone (DHT) and the female sex hormone estrogen that are responsible for the secondary changes in males and females at puberty (Table 29.1).

image

Fig. 29.2 image Male sex organs.

(A) Seminiferous structures.(B) Right lateral view of seminiferous structures. 
From Atlas of Anatomy, © Thieme2008, Illustration by Markus Voll.

image

29.3 Male Reproduction

Male Sex Organs(Fig. 29.2)

– The penis is a copulatory and urinary organ.

– The urethra is the common pathway for expulsion of urine and sperm.

– The scrotum is involved in protection of the testes and thermoregulation.

– The testes synthesize and secrete of testosterone. They are also involved in spermiogenesis.

– The epididymis is involved in the maturation of sperm.

– The prostate gland secretes fluid that promotes sperm motility and neutralizes the acidic secretions in the vagina.

– The seminal vesicles secrete fluid that nourishes ejaculated sperm, help sperm penetrate cervical mucus, and aid in sperm propulsion (by stimulating contractions of the uterus and fallopian tubes).

– The bulbourethral glands secrete mucus.

Male Sex Hormones: Testosterone and Dihydrotestosterone

Synthesis

– Testosterone is the principal androgen synthesized and secreted by Leydig cells in the testes following stimulation by LH. LH increases the activity of cholesterol desmolase, which is needed to convert cholesterol to pregnenolone, the precursor of testosterone (Fig. 29.3). Other androgens synthesized by Leydig cells are androstenidone and dehydroepiandrosterone (DHEA).

Fig. 29.3 image Synthesis of testosterone and dihydrotestosterone.

(LH, luteinizing hormone)

image

– Some target cells express the enzyme 5α-reductase, which reduces testosterone to its more active form, dihydrotestosterone (DHT). DHT is 29- to 50-fold more potent than testosterone on many tissues.

5α-reductase inhibitors

Finasteride, among other 5α-reductase inhibitors, block the conversion of testosterone to DHT by inhibiting the enzyme 5α-reductase. This results in the inhibition of androgenic activity in tissues where DHT is the active form(e.g., the prostate); h owever, it has little or no effect on testosterone-dependent tissues(e.g., skeletal muscle). These drugs are used in the treatment of benign prostate hyperplasia and male pattern baldness.

 

Note: Leydig cells in the testes cannot produce cortisol or aldosterone (as occurs in the adrenal cortex), as they lack the enzymes 21β-hydroxylase and 11β-hydroxylase (see Fig 29.3).

Regulation of Synthesis and Secretion

In hypothalamic−anterior pituitary control:

–GnRH release from the hypothalamus is pulsatile. In men, the pulse is relatively constant in frequency (once every 90 min), amplitude, and duration. GnRH stimulates the anterior pituitary to release LH and FSH in a pulsatile manner.

–LH stimulates testosterone synthesis in Leydig cells.

– FSH acts on Sertoli cells in the testes to promote spermatogenesis. The Sertoli cells also produce inhibin, a polypeptide hormone that is a potent and selective inhibitor of FSH release from the anterior pituitary.

In negative feedback control:

–Testosterone causes feedback inhibition of GnRH release (↓ frequency and amplitude) with subsequent inhibition of LH and FSH release.

– Testosterone directly inhibits the release of LH by the anterior pituitary.

– Inhibin acts at the anterior pituitary to inhibit the secretion of FSH (Fig. 29.4).

Fig. 29.4 image Control of testosterone and follicle-stimulating hormone (FSH) secretion in the testes. (GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone)

image

Actions

Table 29.2 lists the actions of testosterone and DHT.

image

Spermatogenesis

Spermatogenesis is the production of mature sperm from spermatogonia. These spermatogonia remain quiescent until they are stimulated to begin spermatogenesis by the increase in FSH and LH that occurs at puberty.

Spermatogenesis occurs in the seminiferous tubules. The process begins when spermatogonia divide to form primary spermatocytes, which migrate to Sertoli cells and become embedded within the cytoplasm. Within Sertoli cells, the following developmental changes occur:

– Primary spermatocytes undergo meiosis, forming two secondary spermatocytes, each of which has 23 chromosomes.

– The two secondary spermatocytes then undergo a second meiotic division, producing four spermatids, each of which has 23 chromosomes.

– Spermatids then form an acrosome, which is the specialized compartment at the head of the sperm containing hydrolytic enzymes and proteolytic enzymes. The nucleus and cytoplasm condense, and the flagellum is formed. The fully formed sperm are then released into the lumen of the seminiferous tubule.

– Sperm are protected from attack by the immune system by a blood–testes barrier, a physical barrier between the blood vessels and the seminiferous tubules of the testes. The barrier is formed by tight connections between Sertoli cells in the testes.

Thermoregulation of the scrotum

The temperature of the testes needs to be lower than body temperature (37°C, 98.6°F) for optimal spermiogenesis to occur. This is the reason that the testes descend to lie outside the body. There are several features of the scrotum that allow for thermoregulation: the skin of the scrotum is thin and has many sweat glands, and there is an absence of fat; the scrotum has a pampiniform plexus in which a testicular artery is surrounded by a mesh of veins, allowing for countercurrent heat exchange; contraction of the tunica dartos muscle of the scrotum decreases the surface area of scrotal skin available for heat loss and so warms the testes, whereas relaxation has the opposite effect; and contraction of the cremaster muscle causes the scrotum to rise, bringing it closer to the body, resulting in warming of the testes, whereas relaxation of this muscle allows the scrotum to hang farther from the body, resulting in cooling of the testes.

 

Hormonal Regulation of Spermatogenesis

FSH and testosterone are needed for spermatogenesis (Table 29.3).

image

Decline of male reproductive capacity

Men experience a gradual decline in their reproductive capacity with aging. They have~29% less sperm at age 80 years than at age 50 years, but viable sperm are still produced. Plasma levels of testosterone decrease, plasma levels of DHT remain unchanged, and plasma levels of estradiol increase. There is hyperplasia of the prostate gland, partly due to greater conversion of testosterone to DHT. This hyperplasia constricts the ureter and slows urination.

 

Sperm Transport and Maturation

Spermatozoa are transferred to the epididymis by Sertoli cell–derived fluid following their release from Sertoli cells. The epididymis lining has specialized ciliated epithelium and smooth muscle cells that are largely responsible for sperm movement. This lining is maintained by androgens.

Sources of components in semen

Sperm comprise < 10% of the semen. The prostate gland adds secretions that account for ~20%. These secretions include osmotically active compounds (e.g., glycerophosphorylcholine and carnitine), Ca2+, zinc, and acid phosphatase. The alkalinity of prostatic fluid aids in the neutralization of acidic epididymal fluid and acidic female genital tract secretions. Seminal vesicles add secretions that account for ~60%. These secretions include fructose, which is an oxidative substrate for spermatozoa, and prostaglandins, which may stimulate female reproductive tract smooth muscle contraction. Secretions from the epididymis lining contributes to the remaining 10% of semen.

 

Emission, Ejaculation, and Capacitation

Emission is the deposition of semen into the posterior urethra. It depends on sympathetic activation of smooth musculature of the epididymis, vas deferens, prostate, and seminal vesicles. There is a coordinated contraction of the smooth muscle of the internal bladder sphincter to prevent urine leakage from the urethra and semen entering the bladder.

Ejaculation of sperm from the urethra occurs due to a series of rapid skeletal muscle contractions. It is controlled by the somatic motor system. Ejaculated sperm are not immediately viable and cannot fertilize the ovum. To become viable, they must undergo capacitation.

Capacitation is a biochemical process that occurs within the female reproductive tract to produce sperm that are capable of fertilizing an ovum. It occurs 4 to 6 hours after ejaculation, producing “whiplike” movement of sperm. Capacitation also causes cholesterol and acrosome-stabilizing proteins to be removed from sperm membranes.

– Capacitation is a necessary precondition for the acrosome reaction, which is the final development in sperm. During the acrosomal reaction, the acrosomal membrane fuses with the outer sperm membrane, creating “pores” that allow hydrolytic and proteolytic enzymes to exit. These enzymes allow the sperm to penetrate the zona pellucida of the oocyte (Fig. 29.5).

Penile erection and impotence

Tactile stimulation of the genitalia initiates an erection by a sacral spinal reflex, causing the release of nitric oxide(NO). NO binds to guanylate cyclase, stimulating the conversion of guanosine triphosphate(GTP) to cyclic guanosine monophosphate(cGMP). cGMP causes arteriolar dilation, blood to fill the cavernosus sinuses, and erection of the penis. Venous constriction adds to the engorgement of the penis. In erection, the parasympathetic nervous system is dominant over the sympathetic. Impotence is the inability to develop an erection in at least half of the attempts at intercourse. It can be caused by vascular impairment, neurologic disorders, hormonal disturbances, drugs, or psychological problems. Impotence or erectile dysfunction is commonly treated with sildenafil(Viagra, Pfizer Inc., New York) that inhibits cGMP-specific phosphodiesterase type5, which delays the degradation of cGMP. This maintains the arteriolar dilation of penile blood vessels that are responsible for penile erection.

 

Fig. 29.5 image Acrosome reaction.

The acrosome of the sperm head contains hydrolyzing enzymes that are necessary for the penetration of the oocyte. These enzymes are firmly linked to the inner membrane of the acrosome. Just prior to encountering the oocyte, the acrosome reaction occurs, causing the cell membrane and the external membrane of the acrosome to fuse at many points (A). Pores develop at these points of fusion through which the enzymes are released (B). The perforated remains of the membrane are cast off as the sperm penetrates the corona radiata of the oocyte. The inner acrosomal membrane now covers the sperm head (C).

image

29.4 Female Reproduction

The female reproductive system exhibits regular cyclical changes that affect the chance of fertilization and pregnancy. Its function is dependent upon the hypothalamic–anterior pituitary–ovarian axis.

Female Sex Organs (Fig. 29.6)

– The labia majora and minora are organs of copulation.

– The clitoris is an organ of copulation.

– The greater and lesser vestibular glands produce secretions.

– The mons pubis protects the pubic bone.

Fig. 29.6 image Female sex organs.

(A) Internal and external genitalia. (B) Right lateral view of internal and external genitalia. 
From Atlas of Anatomy, © Thieme 2008, Illustration by Markus Voll.

image

– The ovaries are involved in oocyte production and the secretion of estrogen and progesterone.

– The fallopian tubes are the site of fertilization and are involved in transportation of zygotes.

– The uterus is the site of implantation and incubation and is an organ of parturition (birth).

– The vagina is an organ of copulation and parturition.

Female Sex Hormones: Estrogens and Progesterone

The ovaries secrete estrogens (estrone [E1], estradiol [E2], and estriol [E3]), and progesterone.

Synthesis

– LH stimulates the synthesis of pregnenolone, the precursor of testosterone, and progesterone by activating cholesterol desmolase (Fig. 29.7).

– Pregnenolone is converted to androstenedione and testosterone in thecal (ovarian endocrine) cells. Androstenedione and testosterone then diffuse to nearby granulosa (follicular) cells, where FSH stimulates secretion of aromatase that catalyzes the conversion of andro-stenedione to estrone and the conversion of testosterone to estradiol (the principal estrogen secreted by the ovaries).

Fig. 29.7 image Synthesis of estradiol and progesterone. 
(FSH, follicle-stimulating hormone; LH, luteinizing hormone)

image

– Pregnenolone is converted to progesterone in thecal cells and in the corpus luteum.

Note:

– Estriol (E3) is only secreted in significant amounts during pregnancy. It is made by the placenta from dehydroepiandrosterone-sulfate (DHEA-S), an androgen made in the fetal liver and adrenal glands.

– Thecal and granulosa cells in the ovaries cannot produce cortisol or aldosterone (as occurs in the adrenal cortex), as they lack the enzymes 21β-hydroxylase and 11β-hydroxylase (see Fig 27.2).

Polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) is the most common hormonal disorder of women of reproductive age. It may occur around menarche (first menstrual cycle) or later in life following weight gain. In PCOS, the pituitary gland may secrete high levels of LH, and the ovaries may produce excess androgens (androstenedione and testosterone). The ovaries appear enlarged and polycystic (due to failure of the follicles to rupture) on ultrasound examination. Symptoms of PCOS include menstrual abnormalities, for example, prolonged cycles (> 35 days), prolonged periods, failure to menstruate for > 4 months, or fewer than eight cycles per year; excess facial and body hair (hirsutism); and adult acne. Complications of PCOS include infertility due to infrequent ovulation or lack of ovulation, type 2 diabetes, hypertension, cholesterol abnormalities, abnormal uterine bleeding, and endometrial cancer (due to continuous exposure to high levels of estrogen). Birth control pills (BCPs) may be used to regulate ovulation and reduce excess hair growth. Metformin may also be given to manage type 2 diabetes (if present) and to augment ovulation regulation with BCPs. If ovulation induction is necessary to become pregnant, then clomiphene (an antiestrogen drug) is given, followed by injectable gonadotro-pins (FSH and LH) if this fails.

 

Regulation of Synthesis and Secretion

Hypothalamic–anterior pituitary control: GnRH release from the hypothalamus is pulsatile. In females, GnRH pulses vary in accordance with the stage of the menstrual cycle, and the ovarian production of estrogen and progesterone. GnRH stimulates the anterior pituitary to produce FSH and LH in a corresponding pulsatile manner. FSH and LH act on the ovaries to cause the following:

– FSH stimulates estradiol synthesis and the development of multiple follicles.

– LH stimulates the synthesis of pregnenolone, and the LH surge causes ovulation.

Negative feedback control:

– Low levels of estrogen inhibit GnRH release from the hypothalamus and LH release from the anterior pituitary in the early and midfollicular phase of the menstrual cycle (the phase in which follicles in the ovary mature) and in the luteal phase of the menstrual cycle (the latter phase that starts with the formation of the corpus luteum and ends in pregnancy or the onset of menses).

– Progesterone inhibits GnRH release from the hypothalamus and FSH and LH release from the anterior pituitary during the luteal phase of the menstrual cycle.

– Inhibin is a protein complex that is released from follicular granulosa cells in response to stimulation by FSH. It, in turn, is a potent inhibitor of FSH release.

Positive feedback control:

–Rising levels of estrogen stimulate GnRH release during the late follicular phase. This change in response to estrogen is critical for triggering ovulation (LH surge). There is a corresponding increase in the sensitivity of the anterior pituitary to GnRH at this time.

Female hormonal contraceptives

The hormones used for contraception are usually a combination of a synthetice strogen and progesterone (e.g., ethinyl estradiol or mestranol, combined with norethindrone, ethynodiol, or norgestrel). These agents primarily act by negative feedback inhibition of gonadotropins (FSH and LH) to inhibit ovulation, but they also inhibit the proliferation of the endometrium (to prevent successful implantation) and increase the viscosity of cervical mucus (to prevent sperm transport to the ova). Combination oral contraceptives are usually taken for 21 days, then stopped for 7 days, which induces withdrawal bleeding. If one or two contraceptive pills are missed, steroid levels decline, and gonadotropins are rapidly released. This stimulates follicular development, and ovulation may occur. Common side effects of these drugs are headache, yeast infections, nausea, depression, weight gain, and breast discomfort. Severe side effects include hypertension, thromboembolic disorders, and an increased risk of cervical cancer and breast cancer.

 

Progesterone-only Contraceptives

Progesterone-only contraceptives (the “mini pill”) are used when there are severe side effects of estrogen-containing contraceptives. Progesterone prevents ovulation by inhibiting gonadotropin secretion. It also causes thickening of cervical mucus and endometrial atrophy. The success rate is slightly lower for progestin-only pills: 97 to 98% effective versus 99+% for pills containing estrogen and progesterone. Some side effects of progestin-only contraceptives are “break-through bleeding,” amenorrhea (absence of menstrual periods), increases in the ratio of low-density lipoprotein (LDL) to high-density lipoprotein (HDL) in plasma, and abnormal responses to glucose tolerance tests. Diabetic women are not advised to use these contraceptives. Progestin-only contraceptives can also be implanted subcutaneously (levonorgestrel, Norplant) or given via a skin patch.

 

Actions

Table 29.4 lists the actions of estrogen and progesterone.

image

Pathophysiology

Figures 29.8 and 29.9 summarize the effects of estrogen and progesterone deficiency and excess, respectively.

Oogenesis

Oogenesis is the production of mature oocytes from oogonia. Oogonia within follicles in the ovary enter the prophase of meiosis and become primary oocytes approximately between 8 weeks gestation and 6 months after birth. They then remain quiescent until they complete the first meiotic division following recruitment into the menstrual cycle and ovulation many years later.

– Ovulation is the release of a primary oocyte from an ovary into the peritoneal cavity. The first meiotic division is completed, and the resulting secondary oocyte enters the fallopian tube. Within the fallopian tube, the second meiotic division commences but is only completed if the oocyte is fertilized by a sperm. The result is a haploid ovum with 23 chromosomes.

Fig. 29.8 image Deficiency of female sex hormones.

Deficiency of female sex hormones leads to amenorrhea, as well as a number of other systemic complications. (25-OH-D3, calcitriol; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.)

image

Fig. 29.9 image Excess of female sex hormones.

An excess of estrogens and progesterone causes infertility, as well as a number of systemic complications.

image

FSH, LH, and estrogen are needed for the development of a secondary oocyte from a primar y oocyte. The role of these hormones in relation to the menstrual cycle is discussed in the next section.

Menstrual Cycle

The menstrual cycle occurs every 24 to 35 days, with an average of 28 days. It has two phases: the follicular and the luteal (Fig. 29.10).

Fig. 29.10 image Menstrual cycle.

Over the course of an average 28-day menstrual cycle, LH (as well as FSH) peaks around cycle day 14, resulting in ovulation. Estrogen increases just prior to ovulation, and it is this positive feedback that stimulates the LH surge. Basal body temperature increases by 0.5°C (32.9°F) probably just after ovulation and remains elevated until the end of the cycle. The progression of follicular development and endometrial changes over time is also shown.

image

Follicular Phase (Days 0–15)

Premenstrual syndrome

Premenstrual syndrome (PMS) typically occurs 7 to 14 days before menstruation (after ovulation). It may be caused by fluctuations in progesterone and estrogen, which cause fluid retention. Symptoms of PMS include nervousness, irritability, emotional upset, depression, headaches, tissue swelling, and breast tenderness. PMS is treated symptomatically. Combination oral contraceptives reduce the variations in estrogen and progesterone levels. Fluid retention can be treated by reducing salt intake and using a mild diuretic, such as spironolactone. Nervous system symptoms are treated with relaxation techniques, antidepressants (e.g., fluoxetine), or antianxiety drugs (e.g., buspirone or alprazolam).

 

Menses

– Menses is the vaginal discharge consisting of blood and cellular debris from the lining of the uterus (endometrium) that occurs at the end of an infertile cycle. The first day of menses marks day 1 of the menstrual cycle.

Early Follicular Phase

–FSH stimulates the growth of ~20 primordial follicles, each containing a primary oocyte.

– LH is also secreted in smaller amounts.

– FSH and LH stimulate the enzymes needed for androgen synthesis in ovarian cells, leading to estrogen production.

– FSH and LH cause feedback inhibition at the anterior pituitary.

– Estrogen causes endometrial thickening throughout the follicular phase. A thickened endometrium is necessary for successful implantation of an embryo if pregnancy is achieved later in the menstrual cycle.

Midfollicular Phase

–The follicle with the highest estrogen content is the most sensitive to FSH and therefore becomes the dominant follicle (graafian follicle). The remaining nondominant follicles undergo atresia (hormonally controlled apoptosis) and are resorbed by the ovary.

– Inhibin is released by the dominant follicle, causing FSH levels to fall.

Late Follicular Phase

– Estrogen causes LH receptors to be upregulated in the dominant follicle. The dominant follicle loses most of its responsiveness to FSH.

– Increased quantities of FSH and LH are secreted, leading to maximal estrogen production. There is positive feedback from estrogen on the anterior pituitary, which increases LH secretion (both the amount and frequency). This rapid rise in LH (LH surge) induces ovulation from the dominant follicle.

– The FSH surge does not affect the dominant follicle and is not involved in ovulation. It is necessary to stimulate the growth of a new batch of primordial follicles in the next cycle.

Ovulation

– Ovulation is the release of a secondary oocyte from an ovary. It marks the end of the follicular phase.

– At ovulation, basal body temperature rises (0.5°C, 32.9°F) and stays elevated until the end of the cycle, and cervical mucus changes consistency (becomes watery, clear, and elastic) to facilitate sperm transport.

– Estrogen primes the endometrium by inducing the expression of progesterone receptors and by sensitizing the endometrium to the effects of progesterone (Fig. 29.11), which is mainly secreted during the luteal phase.

Mechanism of oocyte release at ovulation

The LH surge at ovulation induces prostaglandin synthesis in the granulosa cell layer. Prostaglandin E2 (PGE2) is produced first, causing vasodilation and infiltration of the follicular wall with leukocytes and macrophages. As ovulation nears, prostaglandin F (PGF) synthesis is preferentially induced by progesterone. PGF is a potent vasoconstrictor and inflammatory mediator. Histamine and kinin release contributes to inflammation. Prostaglandins cause ische mia of the thecal layer, and tight junctions and gap junctions between granulosa cells are disrupted. These changes allow the oocyte to be released from an ovary.

 

Luteal Phase (Days 15–28)

– LH, FSH, and estrogen transform the remnants of the graafian follicle into a corpus luteum. The corpus luteum is maintained by LH.

– The corpus luteum secretes large quantities of progesterone that cause the endometrium to thicken and become more vascular and secretory as it prepares the uterus for embryo implantation and pregnancy.

– The cervical mucus becomes opaque, thickened, and dehydrated under the influence of progesterone. This type of mucus acts as a barrier to sperm.

Fig. 29.11 image Hormonal control of the menstrual cycle.

(FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone)

image

– If fertilization of the ovum does not occur, estrogen and progesterone inhibit FSH and LH both directly and by feedback inhibition on the hypothalamus and anterior pituitary. This causes a marked reduction in plasma estrogen and progesterone, which, in turn, causes the endometrial blood vessels to constrict (via PGFα), endometrial ischemia, and discharge of the endometrium (menses). Uterine myometrial contractions, stimulated by oxytocin and prostaglandins, help slough the endometrium. The corpus luteum also regresses at this time.

– If fertilization does occur, human chorionic gonadotropin (hCG) from the developing embryo maintains the corpus luteum, allowing it to produce the progesterone needed to sustain pregnancy. The rapid rise in concentration of hCG in the urine is used to test for pregnancy even before the missed period.

Pregnancy

Fertilization

– The secondary oocyte is directed into the lumen of the oviduct by fimbria of the fallopian tube. Fertilization normally occurs in the ampulla (upper one-third of the oviduct).

– Capacitated sperm contact the surrounding corona radiata cells of the oocyte. The acrosome reaction then occurs, causing proteolytic enzymes to be released from the head of the sperm. This allows the sperm to penetrate the oocyte (corona radiata and zona pellucida).

– Oocyte activation occurs in response to the first sperm that makes contact with the oocyte’s plasma membrane. This activation causes biophysical changes in the oocyte that prevent fertilization by more than one sperm.

– The sperm and oocyte membranes fuse, and the sperm is engulfed into the oocyte.

– Male and female DNA fuse within the oocyte to complete the fertilization process.

– Mitosis of the one cell zygote into a morula preembryo (16 cells) occurs within the oviduct. At the late morula stage (32 cells), the preembryo reaches the uterine lumen, where blastocyst development occurs. A blastocyst consists of an outer layer of trophoectoderm (trophoblast), which will become the fetal placenta, an inner cell mass (embryoblast), which will become the fetus, and a blastocele (fluid-filled cavity) (Figs. 29.12 and 29.13).

Infertility

Infertility is the inability of a couple to conceive a baby after repeated intercourse for 1 year. It affects approximately one in five couples in the United States. More than half of couples who have not conceived a fter 1 year will eventually conceive. In about one-third of cases of infertility, there are problems with sperm; in about one-third, there are problems with the fallopian tubes; and in about one-sixth, there are ovulation problems. Rarely are there problems with cervical mucus. The cause of infertility is unidentified in the remainder of cases. Many causes of infertility can be reversed with hormone therapy or surgery.

 

Fig. 29.12 image Fertilization.

(1) The acrosome reaction occurs as the sperm approaches the oocyte (see Fig. 29.5). (2) The corona radiata of the oocyte plays a role in chemotaxis of sperm and induction of the acrosome reaction. The sperm penetrates the epithelium of the corona radiata within a few seconds with powerful tail movements, then adheres to the zona pellucida for several minutes. (3) The zona pellucida is penetrated after a few minutes. Sperm pass through this layer at an angle and meet the cell membrane of the oocyte tangentially. (4) Contact of the sperm with the oocyte cell membrane releases cortical granules that induce an excitatory potential that is responsible for initiating the zona pellucida reaction (blocking polyspermy), removing the block on metaphase II, and activating oocyte metabolism. Embryonic development begins. (4 a) The sperm head dips into the microvilli on the surface of the oocyte membrane. (4 b) Incorporation of sperm into the membrane. (4 c) Sperm head, neck, and tail sink into the yolk sac. (5) Fertilization causes completion of the second meiotic division, and the second polar body is expelled. (6) The chromosomes of the sperm and oocyte (haploid sets) decondense and form the female and male pronuclei. The flagellum disintegrates in the oocyte.

image

Fig. 29.13 image Development of oocyte to blastocyst.

Stage1: Fertilization activates the oocyte. The haploid egg nucleus and the haploid sperm nucleus are transformed into female and male pronuclei. Both pronuclei go through a phase of DNA synthesis, and their replicated chromosomes are arranged on a common spindle. Stage 2: As the oocyte travels along the fallopian tube toward the uterus, its cells divide within the zona pellucida. Stage 3: A blastocyst forms consisting of an inner cell mass (embryoblast) and an outer cell mass (trophoblast). The blastocyst hatches out of the zona pellucida, allowing it to attach to the uterine endothelium.

image

Implantation

–The blastocyst must “hatch” out of the zona pellucida before implantation into the endometrium can occur. Trophoblast cells in the attachment zone differentiate into cytotrophoblast cells. These cells fuse together to form the syncytiotrophoblast, which is able to penetrate into the endometrium. Implantation is complete by the second week of pregnancy, marking the end of the preembryonic stage.

– Stromal cells in the endometrium surround the endometrial spiral arteries and “cuff” them. This protects maternal tissues from the invading trophoblast and helps protect the fetoplacental unit from rejection by the maternal immune system.

Ectopic pregnancy

Ectopic pregnancy is when the fertilized ovum implants outside the uterine cavity, usually in the fallopian tubes. So-called tubal pregnancies are not viable. This is a rare condition, but it is more likely in salpingitis (inflammation of the fallopian tubes), following tubal infection, tubal damage (e.g., from previous ectopic pregnancies or endometriosis), when a woman is taking fertility medication to stimulate ovulation, and when contraceptive failure occurs. The woman may not be aware that she is pregnant, or there may be signs of early pregnancy, such as a missed period, nausea, breast tenderness, and fatigue. Other signs of ectopic pregnancy are abdominal pain, vaginal bleeding, cramping, shoulder tip pain (blood in peritoneum irritates the phrenic nerve of the diaphragm), and faintness. Treatment depends on how early the ectopic pregnancy is detected. If detected early, methotrexate may be given to arrest the development of the fertilized ovum, which is then resorbed. Laparoscopy may be needed to stop any bleeding into the peritoneum. If severe tubal damage has occurred, laparotomy is usually needed to remove the damaged tube.

 

First Trimester

– With the formation of the primary germ layers (ectoderm, mesoderm, and endoderm) and extraembryonic membranes (amnion, yolk sac, allantois, and chorion), the embryonic stage begins (weeks 3–8). During the first trimester, the placenta becomes firmly established, and embryonic/fetal organ development occurs.

– The corpus luteum is the major source of progesterone (and estrogen) during the first 6 to 8 weeks of gestation. The function of the corpus luteum is stimulated by hCG (from the syncytiotrophoblast).

Fig. 29.14 image Hormonal concentrations in plasma during pregnancy.

Human chorionic gonadotropin (hCG), secreted by the placenta during pregnancy, is the predominant hormone during the first trimester. It stimulates the synthesis of dehydroepiandrosterone sulfate (DHEA-S) from the fetal adrenal cortex, suppresses follicle maturation in the maternal ovaries, and maintains the production of estrogen and progesterone in the corpus luteum. Maternal concentrations of human placental lactogen (hPL), corticotropin-releasing hormone (CRH), and estrogen rise sharply during the third trimester. hPL stimulates lactogenesis after parturition. CRH concentration plays a role in the timing of parturition by increasing adrenocorticotropic hormone (ACTH) production by the fetal pituitary, which increases cortisol. It also stimulates fetal lung development. Estrogen also plays a critical role in parturition by counteracting the pregnancy-sustaining effects of progesterone and helping to propagate uterine contractions.

image

– At around the eighth week of gestation, the trophoblast takes over progesterone (and estrogen) secretion, making the placenta the main source of progesterone during pregnancy (Fig. 29.14).

Placental abruption

Placental abruption is the separation of the placenta from the uterus. The consequences of this depend on the extent of the placental separation and the amount of blood loss. In severe abruptions, the fetus may not receive an adequate supply of oxygen, causing neurologic defects or death. The mother’s life may also be at risk from shock or disseminated intravascular coagulation (DIC). DIC is a pathological activation of clotting that ultimately consumes the body’s supply of clotting factors and platelets, causing bleeding from the skin, mucous membranes, and viscera. Signs of placental abruption include shock that is out of keeping with visible vaginal blood loss, backache (if the abruption is posterior), abdominal pain, uterine tenderness, fetal distress, lack of fetal heartbeat, and DIC. Treatment also depends on the extent of the abruption. If it is a small abruption, then the mother is monitored frequently, but the pregnancy is allowed to progress. If severe, urgent delivery of the baby is necessary, along with supportive treatment such as blood transfusion.

 

Placenta previa

Placenta previa is a condition in which the placenta is situated low in the uterus, partially or completely covering the cervix. As the cervix begins to dilate later in pregnancy, the placenta stretches and tears, leading to painless vaginal blood loss. Shock may occur if the blood loss is severe. In contrast to placental abruption, there are usually no coagulation problems or uterine tenderness. Fetal distress is also less common, as the frank vaginal bleeding alerts the mother and health care providers to the problem before the fetus becomes distressed. Placenta previa is more common in women who have uterine damage (e.g., from previous births, cesarean sections, or fibroids) or when the placenta is larger than usual (e.g., with twins). Treatment depends on the severity of the placenta previa and blood loss. Minor cases are often monitored and the mother put on bed rest for the remainder of the pregnancy; more severe cases may warrant immediate delivery of the baby by cesarean section and blood transfusions.

 

Second and Third Trimesters

– The placenta takes over progesterone synthesis, and there is degeneration of the corpus luteum.

– The placenta is unable to convert progesterone to estrogens because of a deficiency of 17α-hydroxylase, so it must rely on the conversion of DHEA-S from both the fetal and maternal adrenal glands to synthesize estriol, estradiol, and estrone.

– Human placental lactogen (hPL) is produced by the placenta, with its peak blood concentrations occurring in the third trimester. hPL is very similar in structure and function to growth hormone and prolactin (Fig. 29.15). Its secretion causes an increase in lipid metabolism, enhanced carbohydrate-stimulated insulin secretion, and increased insulin resistance in some maternal tissues. Collectively, these maternal alterations in metabolism are thought to enhance maternal free fatty acid utilization while sparing glucose for use by the growing fetus. hPL may also play an important role in mammary gland development.

Fig. 29.15 image Hormone synthesis in the placenta, mother, and fetus. (1) The placenta produces hCG, which stimulates the synthesis of steroids, for example, dehydroepiandrosterone (DHEA) and DHEA-S, by the fetal adrenal cortex. hCG also maintains the production of estrogen and progesterone in the corpus luteum until the placenta is able to produce sufficient quantities of these hormones. (2) The placenta has to receive cholesterol or androgens from the maternal or fetal adrenal cortex, respectively, before it can synthesize progesterone and estrogen. Progesterone is then transported to the fetal adrenal cortex, where it is converted to DHEA and DHEA-S. DHEA and DHEA-S pass to the placenta, where they are used for estrogen synthesis. Progesterone is converted to testosterone in the testes of the male fetus.

image

Maternal Changes during Pregnancy

Pregnancy involves severe but tolerable changes from normal in the mother’s physiology and anatomy. These changes are listed in Table 29.5.

image

image

Preeclampsia

Preeclampsia is hypertension, proteinura (excess protein in urine), and edema in pregnancy. It is seen after 20 weeks gestation. The patient presents with severe headaches, changes in vision, upper right quadrant abdominal pain, nausea and vomiting, dizziness, sudden weight gain, and swelling, particularly of the hands and face. Signs include blood pressure >140/90 mm Hg on two occasions at least 6 hours apart but no more than 7 hours apart. There is also proteinura. Preeclampsia can cause fetal distress, low birth weight, and pre-term birth due to lack of blood flow to the placenta. It also increases the occurrence of placental abruption. Other complications include HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) and eclampsia (preeclampsia symptoms plus generalized seizures). Both of these conditions are life-threatening to both mother and baby. Delivery of the baby is curative for preeclampsia, but if the baby is not mature enough for delivery, it may be appropriate in some cases to manage hypertension with antihypertensive drugs plus bed rest.

 

Parturition (Birth)

– During a normal pregnancy consisting of 270 predetermined days, the secretion of progesterone prevents uterine contractions by increasing the threshold for myometrial contractility. This is referred to as the progesterone block.

– Just prior to parturition, placental estrogen production is increased relative to progesterone, thereby increasing the estrogen-to-progesterone ratio. This removes the progesterone block and allows estrogen to increase the synthesis of receptors for estrogen, prostaglandins, and oxytocin on myometrial cells. This upregulation of receptors is necessary for the increase in myometrial contractility at parturition.

– Myometrial stretching and pressure exerted on the cervix by the fetus cause a reflexive release of oxytocin from the posterior pituitary (Ferguson reflex). Oxytocin binds to myometrial receptors, where it stimulates the production of uterine and placental prostaglandins, which, in turn, increase intracellular Ca2+ and promote myometrial contractility.

– Estrogen also affects the cervix by increasing its responsiveness to relaxin (secreted by the corpus luteum and the placenta) and prostaglandins (secreted by the uterus and placenta). These hormones cause the cervix to become more vascular and change its structure. This results in cervical dilation and effacement (cervix becomes softer and shorter) during labor (Fig. 29.16).

Stages of labor

Stage 1: This is the period from the onset of regular contractions until the cervix is fully dilated. Contractions originate in the fundus and progress toward the cervix, forcing the head of the fetus against the cervix. The cervix starts to dilate from the effects of estrogen and relaxin and the mechanical force from fetal pressure. During this time the cervix becomes softer and shorter (e ffaces). Changes in the cervix result from physical breakdown of connective tissue of the cervix with increased water content, vascularization, and mass. The fetal membranes rupture, so the contents of the amniotic sac are lost. This enhances the effects of contraction for applying fetal pressure on the cervix.

Stage 2: This is the period from full dilation of the cervix until parturition. Uterine muscle contractions are of high frequency and high amplitude. This stage typically lasts < 1 hour but can be longer.

Stage 3: The placenta separates and is delivered. This occurs within ~10 minutes after birth and is associated with weak muscle contractions.

 

Lactation

– During pregnancy, estrogen, growth hormone, hPL, and cortisol continue to stimulate the development of the mammary glands, which started at puberty. Progesterone converts duct epithelium to a secretory epithelium.

Fig. 29.16 image Endocrine control of parturition.

(1) Relaxation of the cervix: the cervix remains tightly closed during pregnancy but is stimulated to relax around the time of parturition by relaxin, secreted by the corpus luteum and placenta. (2) Onset of labor: locally, prostaglandins cause contractions of the uterine muscles. Systemically, oxytocin, from the posterior pituitary gland, is released in response to cervical irritation caused by pressure from the fetal head (Ferguson reflex). Oxytocin causes further prostaglandin secretion.

image

– During the latter stages of pregnancy, estrogen acts on the anterior pituitary, causing levels of prolactin to rise. This is accompanied by a fall in prolactin-inhibiting hormone (PIH). Prolactin is the hormone after delivery that initiates lactogenesis (milk production).

– Lactation does not occur during pregnancy because placental estrogen and progesterone prevent prolactin from acting on the mammary glands. However, when estrogen and progesterone are withdrawn at birth, lactation is able to occur.

– Suckling is a mechanical stimulus for the continuation of lactation, as it stimulates increased levels of prolactin (by inhibiting PIH) and oxytocin.

– Nursing an infant is moderately effective in preventing pregnancy because prolactin inhibits ovarian function by the following mechanisms:

– Inhibition of hypothalamic GnRH secretion

– Indirect inhibition of FSH and LH secretion by the anterior pituitary (by decreasing GnRH)

– Inhibition of FSH and LH actions on the ovaries

Letdown reflex

Mechanical sensory input to the spinal cord from the breast nipple ascends to the hypothalamus and posterior pituitary, causing the release of oxytocin from the posterior pituitary. Oxytocin stimulates smooth muscle contractions. This helps shrink the uterus to pre-pregnancy size and creates high pressure in the milk ducts, which can squirt milk into the infant’s mouth. This can also contribute to leakage of milk. Mechanical stimulation of the cervix can also release oxytocin.

 

Menopause

– Female fertility declines rapidly after age 35, culminating in menopause. Menopause is a natural process in which there is a gradual reduction in the response of the ovaries to gonadotropins (FSH and LH) and a reduced number of responsive ovarian follicles. Ultimately, the ovaries become functionally inactive (ovulation ceases), and they are therefore unable to synthesize estrogen. This usually occurs between 45 and 55 years of age (mean age 51 years).

Table 29.6 lists the signs associated with premenopause and menopause.

image