DEFINITION AND PREVALENCE
Amenorrhea refers to the absence of menstrual periods. Amenorrhea is classified as primary if menstrual bleeding has never occurred in the absence of hormonal treatment or secondary if menstrual periods cease for 3–6 months. Primary amenorrhea is a rare disorder that occurs in <1% of the female population. However, between 3 and 5% of women experience at least 3 months of secondary amenorrhea in any specific year. There is no evidence that race or ethnicity influences the prevalence of amenorrhea. However, because of the importance of adequate nutrition for normal reproductive function, both the age at menarche and the prevalence of secondary amenorrhea vary significantly in different parts of the world.
Oligomenorrhea is defined as a cycle length >35 days or <10 menses per year. Both the frequency and the amount of vaginal bleeding are irregular in oligomenorrhea, and moliminal symptoms (premenstrual breast tenderness, food cravings, mood lability), suggestive of ovulation, are variably present. Anovulation can also present with intermenstrual intervals <24 days or vaginal bleeding for >7 days. Frequent or heavy irregular bleeding is termed dysfunctional uterine bleeding if anatomic uterine and outflow tract lesions or a bleeding diathesis have been excluded. Oligo- or anovulation are most frequently associated with polycystic ovarian syndrome (PCOS).
The absence of menarche (the first menstrual period) by age 16 has been used traditionally to define primary amenorrhea. However, other factors, such as growth, secondary sexual characteristics, and the presence of cyclic pelvic pain, also influence the age at which primary amenorrhea should be investigated. Recent studies suggest that puberty is occurring at an earlier age, particularly in obese girls. However, it is important to note that these data reflect earlier breast development alone with minimal change in the age of menarche. Thus, an evaluation for amenorrhea should be initiated by age 15 or 16 in the presence of normal growth and secondary sexual characteristics; age 13 in the absence of secondary sexual characteristics or if height is less than the third percentile; age 12 or 13 in the presence of breast development and cyclic pelvic pain; or within 2 years of breast development if menarche, has not occurred.
Secondary Amenorrhea or Oligomenorrhea
Irregular cycles are relatively common for up to 3 years after menarche and for 1–2 years before the final menstrual period. In the intervening years, menstrual cycle length is ~28 days, with an intermenstrual interval normally ranging between 25 and 35 days. Cycle-to-cycle variability in an individual woman who is ovulating consistently is generally +/− 2 days. Pregnancy is the most common cause of amenorrhea and should be excluded early in any evaluation of menstrual irregularity. However, many women occasionally miss a single period. Three months of secondary amenorrhea, or 6 months in women with previously irregular cycles, should prompt an evaluation, as should a history of intermenstrual intervals >35 or <21 days or bleeding that persists for >7 days.
Pregnancy is the most common cause of amenorrhea, and must be excluded in all cases, regardless of patient history. Evaluation of menstrual dysfunction depends on understanding the interrelationships between the four critical components of the reproductive tract: (1) the hypothalamus, (2) the pituitary, (3) the ovaries, and (4) the uterus and outflow tract (Fig. 386-1; Chap. 385). This system is maintained by complex negative and positive feedback loops involving the ovarian steroids (estradiol and progesterone) and peptides (inhibin B and inhibin A) and the hypothalamic (gonadotropin-releasing hormone [GnRH]) and pituitary (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) components of this system (Fig. 386-1).
Role of the hypothalamic-pituitary-gonadal axis in the etiology of amenorrhea. Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion from the pituitary to induce ovarian folliculogenesis and steroidogenesis. Ovarian secretion of estradiol and progesterone controls the shedding of the endometrium, resulting in menses, and, in combination with the inhibins, provides feedback regulation of the hypothalamus and pituitary to control secretion of FSH and LH. The prevalence of amenorrhea resulting from abnormalities at each level of the reproductive system (hypothalamus, pituitary, ovary, uterus, and outflow tract) varies depending on whether amenorrhea is primary or secondary. PCOS, polycystic ovarian syndrome.
Disorders of menstrual function can be thought of in two main categories: disorders of the uterus and outflow tract and disorders of ovulation. Many of the conditions that cause primary amenorrhea are congenital but go unrecognized until the time of normal puberty (e.g., genetic, chromosomal, and anatomic abnormalities). All causes of secondary amenorrhea also can cause primary amenorrhea.
Disorders of the Uterus or Outflow Tract
Abnormalities of the uterus and outflow tract typically present as primary amenorrhea. In patients with normal pubertal development and a blind vagina, the differential diagnosis includes obstruction by a transverse vaginal septum or imperforate hymen; müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome), which can be caused by mutations in the WNT4 gene; and androgen insensitivity syndrome (AIS), which is an X-linked recessive disorder that accounts for ~10% of all cases of primary amenorrhea (Chap. 384). Patients with AIS have a 46,XY karyotype, but because of the lack of androgen receptor responsiveness, those with complete AIS lack features of androgenization and have female external genitalia. The absence of pubic and axillary hair distinguishes them clinically from patients with müllerian agenesis, as does a testosterone level in the male range. The rare patient with 5α reductase type 2 enzyme deficiency has a similar presentation, but undergoes virilization at the time of puberty. Asherman’s syndrome presents as secondary amenorrhea or hypomenorrhea and results from partial or complete obliteration of the uterine cavity by adhesions that prevent normal growth and shedding of the endometrium. Curettage performed for pregnancy complications accounts for >90% of cases; genital tuberculosis is an important cause in regions where it is endemic.
TREATMENT Disorders of the Uterus or Outflow Tract
Obstruction of the outflow tract requires surgical correction. It is important that this be performed as soon as the diagnosis is made as the risk of endometriosis is increased with retrograde menstrual flow. Müllerian agenesis may require surgical intervention to allow sexual intercourse, although vaginal dilatation is adequate in some patients. Because ovarian function is normal, assisted reproductive techniques can be used with a surrogate carrier. Androgen resistance syndrome requires gonadectomy because there is risk of gonadoblastoma in the dysgenetic gonads, although surgery is generally delayed until after breast development and the pubertal growth spurt. Estrogen replacement is indicated after gonadectomy, and vaginal dilatation may be required to allow sexual intercourse.
Once uterus and outflow tract abnormalities have been excluded, other causes of amenorrhea involve disorders of ovulation. The differential diagnosis is based on the results of initial tests, including a pregnancy test, an FSH level (to determine whether the cause is likely to be ovarian or central), and assessment of hyperandrogenism (Fig. 386-2).
Algorithm for evaluation of amenorrhea. β-hCG, human chorionic gonadotropin; FSH, follicle-stimulating hormone; GYN, gynecologist; MRI, magnetic resonance imaging; PRL, prolactin; R/O, rule out; TSH, thyroid-stimulating hormone.
Low estrogen levels in combination with normal or low levels of LH and FSH are seen with anatomic, genetic, or functional abnormalities that interfere with hypothalamic GnRH secretion or normal pituitary responsiveness to GnRH. Although relatively uncommon, tumors and infiltrative diseases should be considered in the differential diagnosis of hypogonadotropic hypogonadism (Chap. 373). These disorders may present with primary or secondary amenorrhea. They may occur in association with other features suggestive of hypothalamic or pituitary dysfunction, such as short stature, diabetes insipidus, galactorrhea, and headache. Hypogonadotropic hypogonadism also may be seen after cranial irradiation. In the postpartum period, amenorrhea occurs normally in association with breast feeding, but may also be caused by pituitary necrosis (Sheehan’s syndrome) or lymphocytic hypophysitis. Because reproductive dysfunction is commonly associated with hyperprolactinemia from neuroanatomic lesions or medications, prolactin should be measured in all patients with hypogonadotropic hypogonadism (Chap. 373).
Isolated hypogonadotropic hypogonadism (IHH) occurs in women, although it is three times more common in men. IHH generally presents with primary amenorrhea, although 50% have some degree of breast development, and ~10% report one to two menses. IHH is associated with anosmia in half of women (termed Kallmann’s syndrome). Genetic causes of IHH have been identified in ~50% of patients (Chaps. 384 and 385).
Functional hypothalamic amenorrhea (HA) is a diagnosis of exclusion of other causes of hypogonadotropic hypogonadism including chronic diseases (type 1 diabetes, celiac disease, hyperthyroidism, Cushing Syndrome) and use of opioids, glucocorticoids or psychotropic medications that increase prolactin levels. Functional HA is most commonly associated with conditions causing a mismatch between energy expenditure and energy intake and/or significant stress. Variants in genes associated with IHH may increase susceptibility to these environmental inputs, accounting in part for the clinical variability in this disorder. Metabolic and stress signaling is transduced to the reproductive axis, at least in part, through leptin signaling from the periphery and via hypothalamic kisspeptin control of GnRH. The diagnosis of HA generally can be made on the basis of a careful history, a physical examination, and the demonstration of low levels of gonadotropins and normal prolactin levels. Eating disorders and chronic disease must be specifically excluded. An atypical history, headache, signs of other hypothalamic dysfunction, or hyperprolactinemia, even if mild, necessitates cranial magnetic resonance imaging (MRI) to exclude a neuroanatomic cause. Up to 10% of women with HA may have some features of PCOS (increased ovarian volume, higher anti-mullerian hormone [AMH] levels, and slightly elevated androgen levels).
Ovarian failure is considered premature when it occurs in women <40 years old and accounts for ~10% of secondary amenorrhea. Primary ovarian insufficiency (POI) has replaced the terms premature menopause and premature ovarian failure in recognition of the continuum of impaired ovarian function encompassed by this disorder. Ovarian insufficiency is associated with the loss of negative-feedback restraint on the hypothalamus and pituitary, resulting in increased FSH and LH levels. FSH is a better marker of ovarian failure because of loss of negative feedback effects of both estradiol and the inhibins and because its levels are less variable than those of LH. AMH levels will also be low in patients with POI, but are more frequently used in management of infertility. As with natural menopause, POI may wax and wane, and serial measurements may be necessary to establish the diagnosis.
Once the diagnosis of POI has been established, further evaluation is indicated because of other health problems that may be associated with POI. Although POI is most commonly of unknown cause, it also occurs in association with a variety of chromosomal abnormalities (most often Turner’s syndrome), autoimmune polyglandular failure syndromes, and other rare disorders. Radiotherapy and chemotherapy may reduce ovarian reserve, with effects on both the oocytes and the supporting granulosa cells. New approaches, including ovarian preservation, are being developed to support long-term fertility choices in women of reproductive age prior to oncologic treatment. The recognition that early ovarian failure occurs in premutation carriers of the fragile X syndrome is important because of the increased risk of severe mental retardation in male children with FMR1 mutations. Thus, follow-up testing should include a karyotype in all POI patients, serum anti-cortical and 21-hydroxylase antibodies (specific but not sensitive for subsequent adrenal insufficiency), thyroid function and thyroid peroxidase antibodies, FMR1 premutation screening, and assessment of bone mineral density. Ovarian biopsy is of no diagnostic or prognostic value. Although the number of genetic causes POI is increasing, routine testing for mutations other than FMR1 is currently not recommended.
Hypergonadotropic hypogonadism occurs rarely in other disorders, such as mutations in the FSH or LH receptors. Aromatase deficiency and 17α-hydroxylase deficiency are associated with decreased estrogen and elevated gonadotropins and with hyperandrogenism and hypertension, respectively. Gonadotropin-secreting tumors in women of reproductive age generally present with high, rather than low, estrogen levels and cause ovarian hyperstimulation or dysfunctional bleeding.
TREATMENT Hypo- and Hypergonadotropic Causes of Amenorrhea
Amenorrhea almost always is associated with chronically low levels of estrogen, whether it is caused by hypogonadotropic hypogonadism or ovarian insufficiency. Development of secondary sexual characteristics requires gradual titration of estradiol replacement with eventual addition of progestin. Hormone replacement with either low-dose estrogen/progesterone regimens or oral contraceptive pills is recommended until the usual age of menopause for bone and cardiovascular protection. In women with functional HA or anorexia nervosa, hormone replacement alone may not be sufficient to restore or maintain bone density. Patients with hypogonadotropic hypogonadism who are interested in fertility require treatment with both exogenous FSH and LH or pulsatile GnRH. Patients with ovarian failure can consider oocyte donation, which has a high rate of success in this population, although its use in women with Turner’s syndrome is limited by significant maternal cardiovascular risk.
POLYCYSTIC OVARIAN SYNDROME
PCOS is diagnosed based on a combination of clinical or biochemical evidence of hyperandrogenism, amenorrhea or oligomenorrhea, and the ultrasound appearance of polycystic ovaries. Approximately half of patients with PCOS are obese, and abnormalities in insulin dynamics are common, as is metabolic syndrome. Symptoms generally begin shortly after menarche and are slowly progressive. Lean oligo-ovulatory patients with PCOS generally have high LH levels in the presence of normal to low levels of FSH and estradiol, although these may be suppressed by undernutrition or stress. The LH/FSH ratio is less pronounced in obese patients in whom insulin resistance is a more prominent feature.
TREATMENT Polycystic Ovarian Syndrome
A major abnormality in patients with PCOS is the failure of regular, predictable ovulation. Thus, these patients are at risk for the development of dysfunctional bleeding and endometrial hyperplasia associated with unopposed estrogen exposure. Endometrial protection can be achieved with the use of oral contraceptives or progestins (medroxyprogesterone acetate, 5–10 mg, or prometrium, 200 mg daily for 10–14 days of each month). Oral contraceptives are also useful for management of hyperandrogenic symptoms, as are spironolactone and cyproterone acetate (not available in the United States), which function as weak androgen receptor blockers. Management of the associated metabolic syndrome may be appropriate for some patients (Chap. 401). For patients interested in fertility, weight control is a critical first step. Clomiphene citrate is highly effective as a first-line treatment, as is the aromatase inhibitor letrozole. Exogenous gonadotropins can be used by experienced practitioners; a diagnosis of polycystic ovaries increases the risk of hyperstimulation, even in women with regular, ovulatory menstrual cycles. Metformin is frequently used in patients with PCOS, and is appropriate as an adjunct with diet and exercise for obese women with PCOS, or for treatment of diabetes or impaired glucose tolerance, as in non-PCOS patients. However, metformin is not recommended for endometrial protection or treatment of hyperandrogenic symptoms, infertility, pregnancy loss or prevention of gestational diabetes.