This chapter deals primarily with APGO Educational Topic Areas:
TOPIC 43 AMENORRHEA
TOPIC 45 NORMAL AND ABNORMAL UTERINE BLEEDING
Students should be able to recognize abnormal patterns of bleeding, particularly amenorrhea and oligomenorrhea. They should be able to explain the pathophysiology and etiology of abnormal bleeding as well as outline a basic approach to evaluation and management of amenorrhea, oligomenorrhea, and other patterns of abnormal bleeding. They should be able to identify risk factors, common presenting signs and symptoms, physical examination findings, and consequences of lack of treatment.
Clinical Case
A 19-year-old woman presents because her normally regular menstrual period is now 3 weeks overdue. She reports fatigue, bloating, and breast fullness similar to what she normally experiences prior to menses. She began menstruating at age 12 years and, after her first year, the periods have been regular every 28 to 32 days and are associated with mild menstrual pain.
Amenorrhea (absence of menstruation) and abnormal uterine bleeding are the most common gynecologic disorders of reproductive-age women. Amenorrhea and abnormal uterine bleeding are discussed as separate topics in this chapter. However, the pathophysiology underlying amenorrhea and abnormal uterine bleeding is often the same.
Abnormal uterine bleeding is a difference in frequency, duration, and amount of menstrual bleeding (Box 39.1). A logical approach to terminology is to separate abnormal bleeding into two broad categories: abnormal bleeding associated with ovulatory cycles, which usually have organic causes, and bleeding due to anovulatory causes, which is usually diagnosed through exclusion based on history.
AMENORRHEA
If a young woman has never menstruated by age 13 years without secondary sexual development or by age 15 years with secondary sexual development, she is classified as having primary amenorrhea. If a menstruating woman has not menstruated for 3 to 6 months or for the duration of three typical menstrual cycles for the patient with oligomenorrhea, she is classified as having secondary amenorrhea. The designation of primary or secondary amenorrhea has no bearing on the severity of the underlying disorder or on the prognosis for restoring cyclic ovulation. Terms often confused with these include oligomenorrhea, defined as a reduction of the frequency of menses, with cycle lengths of greater than 40 days but less than 6 months, and hypomenorrhea, defined as a reduction in the number of days or the amount of menstrual flow. Amenorrhea not caused by pregnancy occurs in 5% or less of all women during their menstrual lives.
Causes of Amenorrhea
When endocrine function along the hypothalamic–pituitary–ovarian axis is disrupted or an abnormality develops in the genital outflow tract (obstruction of the uterus, cervix, or vagina or scarring of the endometrium), menstruation ceases. Causes of amenorrhea are divided into those arising from 1) pregnancy, 2) hypothalamic–pituitary dysfunction, 3) ovarian dysfunction, and 4) alteration of the genital outflow tract.
Pregnancy
Because pregnancy is the most common cause of amenorrhea, it is essential to exclude pregnancy in the evaluation of amenorrhea. A history of breast fullness, weight gain, and nausea suggests the diagnosis of pregnancy, which is confirmed by a positive β-human chorionic gonadotropin assay. It is important to rule out pregnancy to allay the patient’s anxiety and to avoid unnecessary testing. Also, some treatments for other causes of amenorrhea can be harmful to an ongoing pregnancy. Lastly, the diagnosis of ectopic pregnancy should be entertained in the presence of abnormal menses and a positive pregnancy test, insofar as this would necessitate medical or surgical intervention.
BOX 39.1 Types of Abnormal Uterine Bleeding
Polymenorrhea—frequent menstrual bleeding (frequency, 21 days or less)
Menorrhagia—prolonged or excessive uterine bleeding that occurs at regular intervals (the loss of 80 mL or more of blood that lasts for more than 7 days)
Metrorrhagia—irregular menstrual bleeding or bleeding between periods
Menometrorrhagia—frequent menstrual bleeding that is excessive and irregular in amount and duration
Modified from American College of Obstetricians and Gynecologists. Diagnosis of Abnormal Uterine Bleeding in Reproductive-Aged Women. Practice Bulletin 128. Washington, DC: American College of Obstetricians and Gynecologists; July, 2012.
Hypothalamic–Pituitary Dysfunction
Release of hypothalamic gonadotropin-releasing hormone (GnRH) occurs in a pulsatile fashion, modulated by catecholamine secretion from the central nervous system and by feedback of sex steroids from the ovaries. When this pulsatile secretion of GnRH is disrupted or altered, the anterior pituitary gland is not stimulated to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an absence of folliculogenesis despite estrogen production, no ovulation, and a lack of corpus luteum with its usual production of estrogen and progesterone. Because of the lack of sex hormone production with no stimulation of the endometrium, there is no menstruation.
Alterations in catecholamine secretion and metabolism in sex steroid hormone feedback or an alteration of blood flow through the hypothalamic–pituitary portal plexus can disrupt the signaling process that leads to ovulation. This latter disruption can be caused by tumors or infiltrative processes that impinge on the pituitary stalk and alter blood flow.
The most common causes of hypothalamic–pituitary dysfunction are presented in Box 39.2. Most hypothalamic– pituitary amenorrhea is of functional origin and can be corrected by modifying causal behavior, by stimulating gonadotropin secretion, or by giving exogenous human menopausal gonadotropins.
The physician cannot differentiate hypothalamic–pituitary causes of amenorrhea from ovarian or genital outflow causes by medical history or even physical examination alone. However, there are some clues in the medical history and physical examination that would suggest a hypothalamic– pituitary etiology for amenorrhea. A history of any condition listed in Box 39.2 should cause the physician to consider hypothalamic–pituitary dysfunction. The definitive method to identify hypothalamic–pituitary dysfunction is to measure FSH, LH, and prolactin levels in the blood. In these conditions, FSH and LH levels are in the low range. The prolactin level is normal in most conditions but is elevated in prolactin-secreting pituitary adenomas.
BOX 39.2 Causes of Hypothalamic–Pituitary Amenorrhea
Functional Causes
Weight loss
Excessive exercise
Obesity
Drug-Induced Causes
Marijuana
Psychoactive drugs, including antidepressants
Neoplastic Causes
Prolactin-secreting pituitary adenomas
Craniopharyngioma
Hypothalamic hamartoma
Psychogenic Causes
Chronic anxiety
Pseudocyesis
Anorexia nervosa
Other Causes
Head injury
Chronic medical illness
Ovarian Dysfunction
In ovarian failure, the ovarian follicles are either exhausted or are resistant to stimulation by pituitary FSH and LH. As the ovaries cease functioning, blood concentrations of FSH and LH increase. Women with ovarian failure experience the symptoms and signs of estrogen deficiency. A summary of causes is presented in Box 39.3.
Alteration of the Genital Outflow Tract
Obstruction of the genital outflow tract prevents overt menstrual bleeding even if ovulation occurs. Most cases of outflow obstruction result from congenital abnormalities in the development and canalization of the müllerian ducts.Imperforate hymen as well as the absence of the uterus or vagina are the most common anomalies that result in primary amenorrhea. Surgical correction of an imperforate hymen allows for menstruation and fertility. Less commonly encountered anomalies, such as a transverse vaginal septum, are more difficult to correct, and, even with attempted surgical correction, menstruation and fertility are often not restored.
BOX 39.3 Causes of Ovarian Failure
Chromosomal Causes (see Chapter 7)
Turner syndrome (45,X gonadal dysgenesis)
X chromosome long-arm deletion (46,XX q5)
Other Causes
Gonadotropin-resistant ovary syndrome (Savage syndrome)
Premature natural menopause
Autoimmune ovarian failure (Blizzard syndrome)
Asherman Syndrome
Scarring of the uterine cavity (Asherman syndrome) is the most frequent anatomic cause of secondary amenorrhea (Fig. 39.1). Women who undergo dilation and curettage (D&C) for retained products of pregnancy (especially when infection is present) are at risk for developing scarring of the endometrium. Cases of mild scarring can be corrected by surgical lysis of the adhesions performed by hysteroscopy and D&C. However, severe cases are often refractory to therapy. Estrogen therapy should be added to the surgical treatment postoperatively to stimulate endometrial regeneration of the denuded areas. In some cases, a balloon or intrauterine (contraceptive) device may be placed in the uterine cavity to help keep the uterine walls separated to prevent recurrence of adhesions.
Treatment of Amenorrhea
The first step is to establish a cause for the amenorrhea. The “progesterone challenge” test is commonly used to determine whether or not the patient has adequate estrogen, a competent endometrium, and a patent outflow tract. A 10- to 14-day course of oral medroxyprogesterone acetate or micronized progesterone is expected to induce progesterone withdrawal bleeding within a week after completing the oral course. An injection of 100 mg of progesterone in oil can also be used. If bleeding does occur, estrogen effect on the endometrium is established, and the patient is presumed to be anovulatory or oligo-ovulatory. If withdrawal bleeding does not occur, the patient may be hypoestrogenic or have an anatomic condition such as Asherman syndrome or outflow tract obstruction.
Hyperprolactinemia associated with some pituitary adenomas (or other medical conditions) results in amenorrhea and galactorrhea (a milky discharge from the breasts). Approximately 80% of all pituitary tumors secrete prolactin, causing galactorrhea, and these patients are treated with either cabergoline (Dostinex) or the dopamine agonist bromocriptine (Parlodel). In approximately 5% of patients with hyperprolactinemia and galactorrhea, the underlying etiology is hypothyroidism. A low serum thyroxine level eliminates negative feedback signaling to the hypothalamic– pituitary axis. As a result, thyrotropin-releasing hormone (TRH) levels increase. Positive feedback signaling, which normally stimulates dopamine secretion, is also absent, causing a decrease in dopamine levels. Elevated TRH stimulates the release of prolactin from the pituitary gland. The reduced dopamine secretion results in elevated levels of thyroid-stimulating hormone and prolactin.
FIGURE 39.1. Asherman syndrome. (A) Hysterosalpingogram of a patient with Asherman syndrome. Note the thin sliver of endometrial cavity. (B) The same patient after hysteroscopic resection of intrauterine adhesions. Both fallopian tubes are now visualized. (Knockenhauer ES, Blackwell RE. Operative hysteroscopic procedures. In: Azziz R, Murphy AA, eds. Practical Manual of Operative Laparoscopy and Hysteroscopy. 2nd ed. New York: Springer-Verlag; 1997:290.)
In patients who desire pregnancy, ovulation can be induced through the use of clomiphene citrate, human menopausal gonadotropins, pulsatile GnRH, or aromatase inhibitors. In patients who are oligo-ovulatory or anovulatory as commonly encountered with polycystic ovary syndrome (PCOS), ovulation can usually be induced with clomiphene citrate. In patients with hypogonadotropic hypogonadism, ovulation can be induced with pulsatile GnRH or human menopausal gonadotropins. Women with genital tract obstruction require surgery to create a vagina or to restore genital tract integrity. Menstruation will never be established if the uterus is absent. Women with premature menopause may require exogenous estrogen therapy in order to treat or prevent the effects of the loss of endogenous estrogen production.
ABNORMAL UTERINE BLEEDING
Failure to ovulate results in either amenorrhea or irregular uterine bleeding. Irregular bleeding that is unrelated to anatomic lesions of the uterus is referred to as anovulatory uterine bleeding. It is most likely to occur in association with anovulation as found in PCOS, exogenous obesity, or adrenal hyperplasia.
Women with hypothalamic amenorrhea (hypothalamic–pituitary dysfunction) and no genital tract obstruction are in a state of estrogen deficiency. Estrogen is inadequate to stimulate growth and development of the endometrium. Therefore, there is inadequate endometrium for uterine bleeding to occur. In contrast, women with oligo-ovulation and anovulation with abnormal uterine bleeding have constant, noncyclic blood estrogen concentrations that stimulate growth and development of the endometrium. Without the predictable effect of ovulation, progesterone-induced changes do not occur. Initially, these patients have amenorrhea because of the chronic, constant estrogen levels, but, eventually, the endometrium outgrows its blood supply and sloughs from the uterus at irregular times and in unpredictable amounts (see Box 39.1).
When there is chronic stimulation of the endometrium from low plasma concentrations of estrogens, the episodes of uterine bleeding are infrequent and light. In contrast, with chronic stimulation of the endometrium from increased plasma concentrations of estrogens, the episodes of uterine bleeding can be frequent and heavy. Because amenorrhea and abnormal uterine bleeding both result from anovulation, it is not surprising that they can occur at different times in the same patient.
Luteal Phase Defect
Subtle alterations in the mechanisms of ovulation can produce abnormal cycles, even when ovulation occurs such as seen with the luteal phase defect. In cases of luteal phase defect, ovulation does occur; however, the corpus luteum of the ovary is not fully developed to secrete adequate quantities of progesterone to support the endometrium for the usual 13 to 14 days and is not adequate to support a pregnancy if conception does occur. The menstrual cycle is shortened, and menstruation occurs earlier than expected. Although this is not a classic anovulatory uterine bleeding, its clinical presentation of shortened cycles can present diagnostic and therapeutic challenges.
Midcycle Spotting
Another example of abnormal bleeding in patients who do ovulate is midcycle spotting, in which patients report bleeding at the time of ovulation. In the absence of demonstrable pathology, this self-limited bleeding can be attributed to the sudden drop in estrogen level that occurs at this time of the cycle. The bleeding is attributed to the sudden drop in estrogen level around the time of ovulation, which destabilizes the endometrium.
Diagnosis of Abnormal Uterine Bleeding
Diagnosis of abnormal uterine bleeding should be suspected when vaginal bleeding is not regular, not predictable, and not associated with premenstrual signs and symptoms that usually accompany ovulatory cycles. These signs and symptoms include breast fullness, abdominal bloating, mood changes, edema, weight gain, and uterine cramps.
Before anovulatory uterine bleeding can be diagnosed, anatomic causes including neoplasia should be excluded. In a reproductive-aged woman, complications of pregnancy as a cause of irregular vaginal bleeding should be excluded. Other anatomic causes of irregular vaginal bleeding include uterine leiomyomata, inflammation or infection of the genital tract, hyperplasia or carcinoma of the cervix or endometrium, cervical and endometrial polyps, and lesions of the vagina (Figure 39.2). Pelvic ultrasonography or sonohysterography may assist in diagnosing these lesions. Women with organic causes for bleeding may have regular ovulatory cycles with superimposed irregular bleeding.
If the diagnosis is uncertain based on history and physical examination alone, a woman may keep a basal body temperature chart for 6 to 8 weeks to look for the shift in the basal temperature that occurs with ovulation. An ovulation predictor kit may also be used. Luteal phase serum progesterone may also be measured. In cases of anovulation and abnormal bleeding, an endometrial biopsy may reveal endometrial hyperplasia. Because abnormal uterine bleeding results from chronic, unopposed estrogenic stimulation of the endometrium, the endometrium appears proliferative or, with prolonged estrogenic stimulation, hyperplastic. Without treatment, these women are at increased risk for endometrial cancer.
FIGURE 39.2. Basic PALM-COEIN classification system for the causes of abnormal uterine bleeding. This system, approved by the International Federation of Gynecology and Obstetrics, uses the term AUB paired with descriptive terms that describe associated bleeding patterns (HMB or IMB), or a qualifying letter (or letters), or both to indicate its etiology (or etiologies). (American College of Obstetricians and Gynecologists. Diagnosis of Abnormal Uterine Bleeding in Reproductive-Aged Women. Practice Bulletin 128. Washington, DC: American College of Obstetricians and Gynecologists; July, 2012).
Treatment of Abnormal Uterine Bleeding
The risks to a woman with anovulatory uterine bleeding include anemia, incapacitating blood loss, endometrial hyperplasia, and carcinoma. Uterine bleeding can be severe enough to require hospitalization. Both hemorrhage and endometrial hyperplasia can be prevented by appropriate management.
The primary goal of treatment of anovulatory uterine bleeding is to ensure regular shedding of the endometrium and consequent regulation of uterine bleeding. If ovulation is achieved, conversion of the proliferative endometrium into secretory endometrium will result in predictable uterine withdrawal bleeding.
A progestational agent may be administered for a minimum of 10 days. The most commonly used agent is medroxyprogesterone acetate. When the progestational agent is discontinued, uterine withdrawal bleeding ensues, thereby mimicking physiologic withdrawal of progesterone.
As an alternative, administration of oral contraceptives suppresses the endometrium and establishes regular, predictable withdrawal cycles. No particular oral contraceptive preparation is better than any of the others for this purpose. Women who take oral contraceptives as treatment for abnormal uterine bleeding often resume abnormal uterine bleeding after therapy is discontinued.
If a patient is being treated for a particularly heavy bleeding episode, once organic pathology has been ruled out, treatment should focus on two issues: 1) control of the acute episode and 2) prevention of future recurrences. Both high-dose estrogen and progestin therapy as well as combination treatment (oral contraceptive pills, three pills per day for 1 week) have been advocated for management of heavy abnormal bleeding in the acute phase. Long-term preventive management may include either intermittent progestin treatment or oral contraceptives. Uterine bleeding lasting an extended period of time that does not respond to medical therapy is often managed surgically with endometrial ablation or hysterectomy. Before proceeding with endometrial ablation, endometrial carcinoma must be ruled out.
Clinical Follow-Up
A urine pregnancy test is positive and the patient reluctantly admits to unprotected intercourse.
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