CHAPTER 16: Amenorrhea

Evaluation and management of a patient with amenorrhea is common in gynecology. Specifically, the prevalence of pathologic amenorrhea ranges from 3 to 4 percent in reproductive-aged populations (Bachmann, 1982; Pettersson, 1973). Amenorrhea has classically been defined as primary (no prior menses) or secondary (cessation of menses). Although this distinction does suggest a relative likelihood of finding a particular diagnosis, the approach to diagnosis and treatment is similar for either presentation (Tables 16-1 and 16-2). Of course, amenorrhea is a normal state prior to puberty, during pregnancy and lactation, with certain hormonal medications such as continuous administration of combination oral contraceptives (COCs), and following menopause. Evaluation is considered for an adolescent: (1) who by age 13 has not menstruated or shown other evidence of pubertal development, or (2) who has reached other pubertal milestones but has not menstruated by age 15 or within 3 years of thelarche (American College of Obstetrician and Gynecologists, 2009). Secondary amenorrhea for 3 months or oligomenorrhea involving fewer than nine cycles a year is also investigated (American Society for Reproductive Medicine, 2008). In some circumstances, testing reasonably may be initiated despite the absence of these strict criteria. Examples include a patient with the stigmata of Turner syndrome, obvious virilization, or a history of uterine curettage. An evaluation for delayed puberty is also considered before the ages listed above if the patient or her parents are concerned.

A differential diagnosis for amenorrhea can be constructed based on requirements for normal menses. Ovarian function in a normal menstrual cycle is divided into the follicular phase (preovulatory), ovulation, and luteal phase (postovulatory). Endometrial characteristics are partitioned into the proliferative phase (preovulatory) and secretory phase (postovulatory). Generation of a cyclic, controlled pattern of uterine bleeding requires precise temporal and quantitative regulation of several reproductive hormones (Chap. 15).

First, the hypothalamic-pituitary-ovarian axis must be functional. The hypothalamus releases pulses of gonadotropin-releasing hormone (GnRH) into the hypophyseal portal circulation at defined frequencies and amplitude. GnRH stimulates the synthesis and secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the gonadotrope cells of the anterior pituitary gland. These gonadotropins enter the peripheral circulation and act on the ovary to stimulate both follicular development and ovarian hormone production. These ovarian hormones include estrogens, progesterones, and androgens. Gonadal steroids are typically inhibitory at both the pituitary and the hypothalamus. Development of a mature follicle, however, creates a rapid rise in estrogen levels, which instead act positively to generate an LH surge. This surge is essential for ovulation.

Following ovulation, LH stimulates luteinization of the granulosa and theca cells, which had surrounded the mature oocyte, to form the corpus luteum. The corpus luteum continues to produce estrogen but also secretes high levels of progesterone. The thickened, proliferative endometrial lining produced by high circulating estrogen levels during the follicular phase is now converted to a secretory pattern by this luteal progesterone. If pregnancy occurs, the corpus luteum is “rescued” by human chorionic gonadotropin (hCG) secreted from early placental trophoblast. hCG is similar structurally to LH, shares the same receptor as LH, and assumes the role of corpus luteum support during early pregnancy. If pregnancy does not occur, then progesterone and estrogen secretion ceases, the corpus luteum regresses, and the endometrium sloughs. The pattern of this “progesterone withdrawal bleed” varies in duration and amount among women but is relatively constant across cycles for a given individual.

Amenorrhea may follow disruption of this choreographed communication. However, even with normal hormonal cycling, altered anatomy may prevent menses. The endometrium must be able to respond normally to hormonal stimulation, and the cervix, vagina, and introitus must be present and patent.

Numerous classification systems for the diagnosis of amenorrhea have been developed, and all have their strengths and weaknesses. One useful scheme is outlined in Table 16-3. This system divides causes of amenorrhea into anatomic versus hormonal etiologies, with further division into congenital versus acquired disorders.

As described above, normal menses require adequate ovarian production of steroid hormones. Decreased ovarian function (hypogonadism) may result either from a lack of stimulation by the gonadotropins (hypogonadotropic hypogonadism) or from primary failure of the ovary (hypergonadotropic hypogonadism) (Table 16-4). Several disorders are associated with relatively normal LH and FSH levels (eugonadotropic), however, appropriate cyclicity is lost.

Inherited Disorders

Anatomic abnormalities causing amenorrhea can broadly be viewed as either inherited or acquired disorders of the outflow tract (uterus, cervix, vagina, and introitus). Of these two, an inherited cause is frequent in adolescents, and pelvic anatomy is abnormal in approximately 15 percent of women with primary amenorrhea (American Society for Reproductive Medicine, 2008). Figure 16-1 depicts the range of anatomic defects that may present with amenorrhea. These are additionally discussed in Chapter 18.

Lower Outflow Tract Obstruction

Amenorrhea is associated with imperforate hymen (1 in 2000 women), a complete transverse vaginal septum (1 in 70,000 women), or isolated vaginal atresia (Banerjee, 1998; Parazzini, 1990). Also, although structurally normal, labia in some girls may be severely agglutinated and can lead to obstruction. Most with agglutination are treated early with topical estrogen and/or manual separation, and outflow obstruction is thereby avoided.

Patients with outflow obstruction have a 46,XX karyotype, female secondary sexual characteristics, and normal ovarian function. Thus, the amount of uterine bleeding is normal, but its normal path for egress is obstructed or absent. Patients may note moliminal symptoms, such as breast tenderness, food cravings, and mood changes, which are attributable to elevated progesterone levels. With inherited or acquired outflow obstruction, accumulation of blood behind the blockage frequently results in cyclic abdominal pain. Intrauterine trapping of fluid (hydrometra), pus (pyometra), or blood (hematometra) creates a soft, enlarged uterus. Similarly, the terms hydrocolpos, pyocolpos, and hematocolpos describe distention of the vagina and are seen with distal obstructions. Moreover, in women with outflow blockage, an increase in retrograde menstruation may lead to endometriosis development.

Müllerian Defects

During embryonic development, the müllerian ducts give rise to the upper vagina, cervix, uterine corpus, and fallopian tubes. Agenesis during these ducts’ development may be partial or complete. Accordingly, amenorrhea may result from outflow obstruction or from a lack of endometrium in cases involving uterine agenesis. In complete müllerian agenesis, often called Mayer-Rokitansky-Kuster-Hauser syndrome, patients fail to develop any müllerian structures, and examination reveals only a vaginal dimple (Chap. 18). It ranks second only to gonadal dysgenesis as a cause of primary amenorrhea (Aittomaki, 2001; Reindollar, 1981).

Similar to patients with lower outflow tract obstruction, patients with müllerian anomalies have a 46,XX karyotype and normal ovarian function. Research has begun to identify candidate gene mutations that may contribute to this disorder, but details are lacking. Importantly, complete müllerian agenesis may be confused with complete androgen insensitivity syndrome. In the latter condition, the patient has a 46,XY karyotype and functioning testes. However, underlying androgen receptor mutations prevent normal testosterone binding, normal male ductal system development, and virilization. These two syndromes are compared in Table 16-5 and discussed further in Chapter 18.

Acquired Disorders

Cervical Stenosis

Other abnormalities of the uterus that cause amenorrhea include cervical stenosis and extensive intrauterine adhesions. With stenosis, postoperative scarring and cervical os narrowing may follow dilatation and curettage (D & C), cervical conization, loop electrosurgical excision procedures, infection, and neoplasia. Severe atrophic or radiation changes are other sources. Stenosis most commonly involves the internal os, and symptoms in menstruating women include amenorrhea or abnormal bleeding, dysmenorrhea, and infertility. Management seeks to reopen the os and is discussed in Chapter 4.

Intrauterine Adhesions

Also known as uterine synechiae and, when symptomatic, as Asherman syndrome, the spectrum of scarring includes filmy adhesions, dense bands, or complete obliteration of the uterine cavity (Fig. 16-2). Normally, the endometrium is divided into a functional layer, which lines the endometrial cavity, and a basal layer, which regenerates the functional layer with each menstrual cycle. Destruction of the basal endometrium prevents endometrial thickening in response to ovarian steroids. Thus, no tissue is produced or subsequently sloughed when steroid hormone levels fall at the end of the luteal phase.

Endometrial damage may follow vigorous curettage, usually in association with postpartum hemorrhage, miscarriage, or elective abortion complicated by infection. In a series of 1856 women with Asherman syndrome, 88 percent followed postabortal or postpartum uterine curettage (Schenker, 1982). Damage may also result from other uterine surgery, including metroplasty, myomectomy, or cesarean delivery, or from infection related to an intrauterine device. Although rare in the United States, tuberculous endometritis is a relatively common cause of Asherman syndrome in developing countries (Sharma, 2009). Of course, Asherman syndrome may also be an intentional outcome following uterine ablation for heavy menstrual bleeding.

Depending on the degree of scarring, patients may describe amenorrhea; in less severe cases, hypomenorrhea; or recurrent pregnancy loss due to inadequate placentation (March, 2011). In their evaluation of 292 women with intrauterine adhesions, Schenker and Margalioth (1982) noted delivery of term pregnancies in only 30 percent of 165 pregnancies. The remaining pregnancies either were spontaneously aborted (40 percent) or delivered prematurely.

If intrauterine adhesions are suspected, radiologic evaluation of the uterine cavity is performed. If information regarding tubal patency is needed, then hysterosalpingography (HSG) offers information regarding both uterine cavity and fallopian tube patency. Otherwise, saline infusion sonography (SIS) provides an excellent alternative. Intrauterine adhesions characteristically appear as irregular, angulated filling defects within the cavity (Fig. 19-6 and Fig. 2-23). At times, uterine polyps, leiomyomas, air bubbles, and blood clots may masquerade as adhesions. Definitive diagnosis requires hysteroscopy. To improve fertility rates or to relieve symptomatic hematometra, hysteroscopic lysis of adhesions is the preferred surgical treatment. The procedure is described in Section 44-19, and fertility advantages are discussed in Chapter 20.

The term hypergonadotropic hypogonadism describes any process in which: (1) ovarian function is decreased or absent (hypogonadism) and (2) due to absent negative sex-steroid feedback, the gonadotropins, LH and FSH, have increased serum levels (hypergonadotropic). This category of disorders implies primary dysfunction within the ovary rather than hypothalamic or pituitary dysfunction (Table 16-6). This process can also be termed premature menopause or premature ovarian failure (POF), with a current trend toward the term premature ovarian insufficiency or primary ovarian insufficiency (POI). The term ovarian insufficiency conveys the fact that ovarian function may fluctuate before complete oocyte depletion and may lead to occasional transient menses resumption or even pregnancy (Bidet, 2011). For our purposes, the term premature ovarian failure, implying permanent cessation of menses, will be used.

POF is defined as loss of oocytes and the surrounding support cells prior to age 40 years. The diagnosis is determined by two serum FSH levels that measure greater than a threshold range of 30 to 40 mIU/mL and are obtained at least 1 month apart. This definition distinguishes POF from the physiologic loss of ovarian function, which occurs with normal menopause. The incidence of POF has been estimated at 1 in 1000 women younger than 30 years and at 1 in 100 women younger than 40 (Coulam, 1986).

Careful evaluation is mandatory as the diagnosis and effective treatment may have significant implications for the patient’s psychologic, cardiovascular, bone, and sexual health. The finding of a genetic disorder may also require evaluation of family members. Nevertheless, in most cases, an etiology for POF is not determined (American College of Obstetricians and Gynecologists, 2014).

Heritable Disorders

Gonadal Dysgenesis

Gonadal dysgenesis is the most frequent cause of POF. In this disorder, a normal complement of germ cells is present in the early fetal ovary. However, oocytes undergo accelerated atresia, and the ovary is replaced by a fibrous streak—termed a streak gonad (Figs. 16-3 and 16-4)(Simpson, 1975; Singh, 1966). Individuals with gonadal dysgenesis may present with various clinical features and can be divided into two broad groups based on whether their karyotype is normal or abnormal (Schlessinger, 2002). These are all discussed further in Chapter 18.

Those with normal karyotype (46,XX or 46,XY) are described as having “pure” gonadal dysgenesis. Patients with a 46,XY genotype and gonadal dysgenesis (Swyer syndrome) are phenotypically female due to absent testosterone and absent antimüllerian hormone (AMH) secretion by the dysgenetic testes. The etiology of the gonadal failure in both genetically male and female patients is poorly understood but is likely due to single gene defects or destruction of gonadal tissue in utero, perhaps by infection or toxins (Hutson, 2014).

Those with abnormal karyotype include Turner syndrome (45,X) and chromosomal mosaics such as 45,X/46,XX or 45,X/46,XY. In general, approximately 90 percent of individuals with gonadal dysgenesis from a loss of X genetic material never menstruate. The remaining 10 percent have sufficient residual follicles to experience menses and rarely may achieve pregnancy. However, the menstrual and reproductive lives of such individuals are invariably brief (Kaneko, 1990; Simpson, 1975; Tho, 1981).

As noted, in some cases of gonadal dysgenesis, a Y chromosome is present. If Y chromosomal material is found, the streak gonads are removed because nearly 25 percent of these patients will develop a malignant germ cell tumor (Chap. 36) (Manuel, 1976). Thus, chromosomal analysis is performed in all cases of amenorrhea associated with POF, particularly before age 30. The presence of a Y chromosome cannot be determined clinically, as only a few patients will demonstrate signs of androgen excess.

Specific Genetic Defects

In addition to chromosomal abnormalities, patients may experience POF due to single gene mutations (Cordts, 2011; Goswami, 2005). First, a significant relationship is noted between fragile X syndrome and POF (American College of Obstetricians and Gynecologists, 2010). This syndrome is caused by a triple repeat sequence mutation in the X-linked FMR1 (fragile X mental retardation) gene. This gene is unstable, and its size can expand during parent-to-child transmission. The fully expanded mutation (>200 CGG repeats) becomes hypermethylated, resulting in silencing of gene expression. As such, this fully expanded mutation is the most common known inherited genetic cause of mental retardation and of autism. Males with the so-called premutation (50 to 200 CGG repeats) are at risk for fragile-X associated tremor/ataxia syndrome (FXTAS). Females with the premutation have a 13- to 26-percent risk of developing POF, although the mechanism is unclear. An estimated 0.8 to 7.5 percent of sporadic POF and 13 percent of familial POF cases are due to premutations in this gene. The prevalence of premutations in women approximates 1 in 129 to 300 (Wittenberger, 2007).

Less common gene defects are CYP17 mutations. These decrease 17α-hydroxylase and 17,20-lyase activity and thereby prevent production of cortisol, androgens, and estrogens (Fig. 15-5). Affected patients have sexual infantilism and primary amenorrhea due to absent estrogen secretion. Sexual infantilism describes patients with a lack of breast development, absent pubic and axillary hair, and a small uterus. Mutations in CYP17 also increase adrenocorticotropin hormone (ACTH) release, thereby stimulating mineralocorticoid secretion. This, in turn, leads to hypokalemia and hypertension (Goldsmith, 1967).

Mutations in genes that encode LH and FSH receptors have also been reported. These defects prevent normal responses to circulating gonadotropins, a condition termed resistant ovary syndrome (Aittomaki, 1995; Latronico, 2013). Identification of other single gene mutations that can cause POF is an area of active investigation. The list of implicated genes now includes those that encode both estrogen receptors (ERα and ERβ), extracellular signaling proteins (specifically, BMP15), and transcription factors FOXL2, FOX03, and SF-1 (Cordts, 2011; Goswami, 2005). The importance of these factors in maintaining ovarian function is providing further insights into normal ovarian physiology and may lead to new infertility treatments and contraceptive options.

Although frequently cited, galactosemia is a rare cause of POF. Classic galactosemia affects 1 in 30,000 to 60,000 live births. Inherited as an autosomal recessive disorder, this condition leads to abnormal galactose metabolism due to a deficiency of galactose-1-phosphate uridyl transferase, encoded by the GALT gene (Rubio-Gozalbo, 2010). Galactose metabolites are believed to have a direct toxic effect on many cell types, including germ cells. Potential complications include neonatal death, ataxic neurologic disease, cognitive disabilities, and cataracts. POF will develop in almost 85 percent of females if left untreated. Treatment is lifelong dietary restriction of galactose, which is present in milk-based foods. Galactosemia is frequently diagnosed during newborn screening programs or during pediatric evaluation of impaired growth and development and long before a patient would present to a gynecologist (Kaufman, 1981; Levy, 1984).

Acquired Abnormalities

Hypergonadotropic hypogonadism can be acquired from infection, environmental exposures, autoimmune disease, or medical treatments. Of these, infectious causes of POF are relatively rare and poorly understood, with mumps oophoritis being the most frequently reported (Morrison, 1975). Various environmental toxins have a clear detrimental effect on follicular health. These include cigarette smoking, heavy metals, solvents, pesticides, and industrial chemicals (Jick, 1977; Mlynarcikova, 2005; Sharara, 1998).

Autoimmune disorders account for an estimated 40 percent of POF cases (Hoek, 1997; LaBarbera, 1988). Ovarian failure may be one component of autoimmune pituitary polyglandular failure and accompanied by hypothyroidism and adrenal insufficiency, or it may follow other autoimmune disorders such as systemic lupus erythematosus. POF has also been associated with myasthenia gravis, idiopathic thrombocytopenic purpura, rheumatoid arthritis, vitiligo, and autoimmune hemolytic anemia (de Moraes, 1972; Jones, 1969; Kim, 1974). Although several antiovarian antibodies have been characterized, there is currently no validated serum antibody marker to assist in the diagnosis of autoimmune POF (American Society for Reproductive Medicine, 2008).

Iatrogenic ovarian failure is relatively common. This group includes patients who have undergone surgical removal of the ovaries or cystectomy due to recurrent ovarian cysts, endometriosis, or severe pelvic inflammatory disease. Alternatively, a woman may experience amenorrhea following pelvic radiation for cancer or following chemotherapy for treatment of malignancies or severe autoimmune disease.

With the latter two, the chance of developing POF is correlated with increasing radiation and chemotherapeutic dose. Patient age is also a significant factor, with younger patients less likely to develop failure and more likely to regain ovarian function over time (Gradishar, 1989). With radiotherapy, ovaries are preventively repositioned using surgery (oophoropexy), if possible, out of the anticipated radiation field prior to therapy (Terenziani, 2009). Of chemotherapeutic drugs, alkylating agents are believed to be particularly damaging to ovarian function. As discussed in Chapter 27, preventive adjuvant GnRH analogues may lower rates of chemotherapy-induced POF, although the efficacy of this approach remains controversial. Importantly, recent advances in oocyte and ovarian tissue cryopreservation make it likely that oocyte harvest prior to treatment will become the preferred approach when feasible. Of interest, persistent chemotherapy-induced amenorrhea appears to confer a decreased risk of breast cancer recurrence, possibly beyond that attributable to the low estrogen levels (Swain, 2010; Zhao, 2014). Nevertheless, a substantial menopause-specific decrease in quality of life is observed in these patients (Yoo, 2013).

The term hypogonadotropic hypogonadism implies that the primary abnormality lies in the hypothalamic-pituitary axis. As a result, poor gonadotropin stimulation of the ovaries leads to impaired follicular development. Generally in these patients, LH and FSH levels, although low, will still be in the detectable range (<5 mIU/mL). However, levels may be undetectable in patients with complete absence of hypothalamic stimulation, such as occurs in Kallmann syndrome. In addition, absent pituitary function due to abnormal development or severe pituitary damage may lead to similarly low levels. Thus, the group of hypogonadotropic hypogonadism disorders may be viewed as a continuum with perturbations leading to luteal dysfunction, oligomenorrhea, and, in the most severe presentation, amenorrhea.

Hypothalamic Disorders

Inherited Hypothalamic Abnormalities

Inherited hypothalamic abnormalities primarily consist of those patients with idiopathic hypogonadotropic hypogonadism (IHH). A subset has associated defects in the ability to smell (hyposmia or anosmia) and are said to have Kallmann syndrome. This syndrome can be inherited as an X-linked, autosomal dominant, or autosomal recessive disorder (Cadman, 2007; Waldstreicher, 1996). The X-linked form was the first to be characterized and follows mutation in the KAL1 gene on the short arm of the X chromosome. Expressed during fetal development, this gene encodes an adhesion protein, named anosmin-1. As this protein is critical for normal migration of both GnRH and olfactory neurons, loss of normal anosmin-1 expression results in both reproductive and olfactory deficits (Fig. 16-5) (Franco, 1991; Soussi-Yanicostas, 1996). Kallmann patients have a normal complement of GnRH neurons, however, these neurons fail to migrate and instead remain near the nasal epithelium (Quinton, 1997). As a result, locally secreted GnRH is unable to stimulate gonadotropes in the anterior pituitary gland to release LH and FSH. In turn, marked decreases in ovarian estrogen production result in absence of breast development and menstrual cycles.

Kallmann syndrome is also associated with midline facial anomalies such as cleft palate, unilateral renal agenesis, cerebellar ataxia, epilepsy, neurosensory hearing loss, and synkinesis (mirror movements of the hands) (Winters, 1992; Zenaty, 2006). Kallmann syndrome can be distinguished from IHH by olfactory testing. This is performed easily in the office with strong odorants such as ground coffee or perfume. Interestingly, many of these patients are unaware of their deficit.

During the past 10 years, an array of autosomal genes has been identified that contribute to normal development, migration, and secretion by GnRH neurons (Caronia, 2011; Layman, 2013). Mutations in several of these genes have been described in patients with hypothalamic amenorrhea. Genes include FGF8, KAL1, NELF, PROK2, PROKR2, and CHD7. As a result, the percentage of patients in whom this disorder need be considered idiopathic is gradually decreasing. Of note, mutation in the CHD7 gene may cause either normosmic IHH or Kallmann syndrome, thereby blurring the distinction between these disorders.

Acquired Hypothalamic Dysfunction

Acquired hypothalamic abnormalities are much more frequent than inherited deficiencies. Most commonly, gonadotropin deficiency leading to chronic anovulation is believed to arise from functional disorders of the hypothalamus or higher brain centers. Also called “hypothalamic amenorrhea,” this diagnosis encompasses three main categories: eating disorders, excessive exercise, and stress. From a teleologic perspective, amenorrhea in time of starvation or extreme stress can be seen as a mechanism to prevent pregnancy at a time in which resources are suboptimal for raising a child. Each woman appears to have her own hypothalamic “setpoint” or sensitivity to environmental factors. For example, individual women can tolerate markedly different amounts of stress without developing amenorrhea.

Eating Disorders

Anorexia nervosa and bulimia, both described in Chapter 13, can lead to amenorrhea. Hypothalamic dysfunction is severe in anorexia and may affect other hypothalamic-pituitary axes in addition to the reproductive axis. Amenorrhea in anorexia nervosa can precede, follow, or appear coincidentally with weight loss. In addition, even with return to normal weight, not all women with anorexia will regain normal menstrual function. Patients with premenarchal onset of anorexia are at particular risk for protracted amenorrhea (Dempfle, 2013).

Exercise-induced Amenorrhea

This is most common in women whose exercise regimen is associated with significant loss of fat, including ballet, gymnastics, and long-distance running (De Souza, 1991; Frisch, 1980). In those women who continue to menstruate, cycles are notable for their variability in cycle interval and length due to reduced hormonal function (De Souza, 1998). Puberty may be delayed in girls who begin training before menarche (Frisch, 1981).

An appreciation for the link between exercise and reproductive health has led to the concept of the female athlete triad, which consists of menstrual dysfunction, low energy availability with or without disordered eating, and low bone mineral density in extreme athletes. Two international symposia held in this field have begun to develop risk stratification and recommendations for this population (Duckham, 2012; Joy, 2014).

In 1970, Frisch and Revelle proposed that an adolescent girl needed to achieve a critical body weight to begin menstruating (Frisch, 1970). This mass was initially postulated to approximate 48 kilograms and was subsequently refined to a minimal body mass index (BMI) approaching normal, which is ≥19. Subsequent studies suggest that, although there is a clear correlation between body fat and reproductive function at both ends of the weight spectrum, overall energy balance better predicts the onset and maintenance of menstrual cycles (Billewicz, 1976; Johnston, 1975). For example, many elite athletes regain menstrual cyclicity following a decrease in exercise intensity prior to any gain in weight (Abraham, 1982).

Stress-induced Amenorrhea

This may be associated with clearly traumatic life events. Nevertheless, less severe life events and even positive events may be associated with stress. For example, stress-related amenorrhea is frequently associated with leaving for college, test taking, or wedding planning.

Functional Hypothalamic Amenorrhea Patho­physio­logy

Eating disorders, exercise, and stress may disturb menstrual function through overlapping mechanisms. This observation may be in part because these problems are often concurrent. For example, women with eating disorders frequently exercise excessively and are undoubtedly under stress as they attempt to control their eating patterns. Figure 16-6 depicts a simplified model for the development of amenorrhea in these patients. It must be emphasized that each cause of functional hypothalamic amenorrhea may act via one or all of these pathways. Furthermore, in many cases, the factors known to affect reproductive function are likely acting indirectly on GnRH neurons through various neuronal subtypes that have synaptic connections to GnRH neurons.

Exercise in particular has been associated with an increase in levels of endogenous opioids (β-endorphins), producing the so-called runner’s high. Opioids alter GnRH pulsatility.

As part of the stress response, each of these conditions may lead to an increase in corticotropin-releasing hormone (CRH) release by the hypothalamus, which in turn results in cortisol secretion by the adrenal gland. CRH alters the pattern of pulsatile GnRH secretion, whereas cortisol may act directly or indirectly to disrupt GnRH neuronal function.

Eating disorders are thought to disturb ovulatory function through several hormonal factors including insulin, insulin-like growth factor-1, cortisol, adiponectin, ghrelin, and leptin (Misra, 2014). First identified in 1994, leptin is a 167-amino-acid protein encoded by the ob gene and produced in white adipose tissue (Zhang, 1994). Leptin receptors have been identified in the central nervous system (CNS) and a wide range of peripheral tissues (Chen, 1996; Tartaglia, 1995).

Primarily produced in adipose tissue, leptin provides an important link between energy balance and reproduction, albeit one of many mechanisms (Chou, 2014; Schneider, 2004). Leptin has been termed a “satiety factor” as human leptin gene mutation results in morbid obesity, diabetes mellitus, and hypogonadism. This trio of abnormalities can be successfully reversed with recombinant human leptin treatment (Licinio, 2004).

Patients with anorexia nervosa have been found to have low circulating leptin levels (Mantzoros, 1997). It has been hypothesized that a decrease in leptin production due to weight loss could secondarily stimulate neuropeptide Y, which is known to stimulate hunger and alter GnRH pulsatility. Leptin likely acts through various additional neurotransmitters and neuropeptides including the β-endorphins and α-melanocyte-stimulating hormone (Tartaglia, 1995).

Pseudocyesis

Although rare, pseudocyesis is considered in any woman with amenorrhea and pregnancy symptoms. Pseuodocyesis exemplifies the ability of the mind to control physiologic processes. More than 500 cases of pseudocyesis have been reported in the medical literature in women ranging from ages 6 to 79 years. These patients fervently believe that they are pregnant and subsequently demonstrate several pregnancy signs and symptoms, including amenorrhea.

Endocrine evaluation in a limited number of patients has suggested a pattern of hormonal derangements. These include alterations in LH pulse frequency concurrent with elevated serum androgen levels, which may explain the observed amenorrhea. Elevated serum prolactin levels and resultant galactorrhea have been noted in a subset of patients. Nocturnal growth hormone secretion also appears blunted (Tarin, 2013).

A common link in these patients is a history of severe grief, such as recent miscarriage, infant death, or longstanding infertility. Pseudocyesis may be more common in developing countries, where societal pressure to produce children may be strong (Seeman, 2014). Psychiatric treatment is generally required to treat the associated depression, which is often exacerbated when the patient is informed that she is not pregnant (Whelan, 1990).

Anatomic Destruction

Any process that destroys the hypothalamus can impair GnRH secretion and lead to hypogonadotropic hypogonadism and amenorrhea. Due to the complex neurohormonal input to the GnRH neurons, abnormalities do not need to directly interact with GnRH neurons but may operate indirectly by altering the activity of modulatory neurons.

The tumors most often associated with amenorrhea include craniopharyngiomas, germinomas, endodermal sinus tumors, eosinophilic granuloma (Hand-Schuller-Christian syndrome), gliomas, and metastatic lesions. The most common of these tumors, craniopharyngiomas, are located in the suprasellar region and frequently present with headaches and visual changes. Alternatively, impaired GnRH secretion may follow trauma, radiation, infections such as tuberculosis, or infiltrative diseases such as sarcoidosis.

Anterior Pituitary Gland Disorders

The anterior pituitary gland consists of gonadotropes (producing LH and FSH), lactotropes (prolactin), thyrotropes (thyroid-stimulating hormone), corticotropes (adrenocorticotropic hormone), and somatotropes (growth hormone) (Chap. 15). Although various disorders may directly affect gonadotropes, many causes of pituitary-derived amenorrhea may also follow abnormalities in other pituitary cell types, which in turn alter gonadotrope function.

Inherited Abnormalities

In addition to mutations that underlie hypothalamic dysfunction, our understanding of genetic mechanisms that regulate normal pituitary development and function is rapidly advancing. First, patient cohorts have been described that have pituitary hormone deficiency combined with central facial and/or neurologic defects due to a failed midline fusion, a syndrome known as septo-optic dysplasia. Many of these patients carry mutations in the PROP1 gene (Cadman, 2007). Second, mutations in genes that encode the LH or FSH β-subunits or the GnRH receptor have also been identified as rare causes of hypogonadotropic hypogonadism. Last, mutations in genes encoding the nuclear hormone receptors SF-1 and DAX1 (NR0B1) as well as genes encoding the G-protein-coupled receptor 54 (GPR54) for kisspeptin-1 are associated with hypothalamic and pituitary dysfunction (Matthews, 1993; Pallais, 2006; Seminara, 2006; Weiss, 1992).

Acquired Pituitary Dysfunction

Most pituitary dysfunction is acquired after menarche and therefore presents with normal pubertal development followed by secondary amenorrhea. Nevertheless, in rare cases, these disorders may begin prior to puberty, resulting in delayed puberty and primary amenorrhea (Howlett, 1989).

Pituitary adenomas are the most frequent cause of acquired pituitary dysfunction (Chap. 15). These most commonly secrete prolactin, but excessive secretion of any pituitary-derived hormone can result in amenorrhea. For example, excessive ACTH secretion results in Cushing disease, which is associated with menstrual abnormalities and signs of cortisol excess. Significantly elevated serum prolactin levels (>100 ng/mL) are almost always due to a pituitary mass.

Increased serum prolactin levels are found in as many as one-tenth of amenorrheic women, and more than half of women with both galactorrhea and amenorrhea have elevated prolactin levels (the “galactorrhea-amenorrhea syndrome”). Mechanistically, dopamine is released by the hypothalamus and acts on the anterior pituitary. Dopamine is the primary regulator of prolactin biosynthesis and secretion and plays an inhibitory role. Thus, elevated prolactin levels feed back to the hypothalamus and are associated with a reflex increase in central dopamine production to lower prolactin concentrations. This rise in central dopamine levels alters GnRH neuronal function.

Pituitary tumors also may indirectly alter gonadotrope function by a mass effect. First, tumor growth may compress neighboring gonadotropes. Second, damage to the pituitary stalk can disrupt dopamine’s pathway to inhibit prolactin secretion. In this latter case, resulting elevated prolactin levels lead to elevated central dopamine levels that presumably interfere with menstrual function through the same mechanisms described in the previous paragraph.

As in the hypothalamus, pituitary function may also be diminished by inflammation, infiltrative disease, metastatic lesions, surgery, or radiation treatment. Although a rare condition, peripartum lymphocytic hypophysitis can be a dangerous cause of pituitary failure. Infiltrative diseases include sarcoidosis and hemochromatosis. Spontaneous hemorrhage into a pituitary adenoma, termed pituitary apoplexy, also may result in acute loss of pituitary function (Chap. 15).

Sheehan syndrome refers to panhypopituitarism. It classically follows massive postpartum hemorrhage and associated hypotension. The abrupt, severe hypotension leads to pituitary ischemia and necrosis (Kelestimur, 2003). Patients with the most severe form develop shock due to pituitary apoplexy. Pituitary apoplexy is characterized by a sudden onset of headache, nausea, visual deficits, and hormonal dysfunction due to acute hemorrhage or infarction within the pituitary. In less severe forms, loss of gonadotrope activity in the pituitary leads to anovulation and subsequent amenorrhea. Damage to the other specific pituitary cell types lead to a failure to lactate, loss of sexual and axillary hair, and hypothyroidism or adrenal insufficiency symptoms. Pituitary cell types are differentially sensitive to damage. For this reason, prolactin secretion deficiency is the most common, followed by loss of gonadotropin and growth hormone release, loss of ACTH production, and least commonly, by decreases in thyroid-stimulating hormone (TSH) secretion (Veldhuis, 1980).

Other Causes of Hypogonadotropic Hypogonadism

Hypogonadotropic amenorrhea may be observed in various chronic diseases including end-stage kidney disease, liver disease, malignancies, acquired immunodeficiency syndrome, and malabsorption syndromes. The mechanisms by which these disorders result in menstrual dysfunction are poorly understood. End-stage kidney disease is associated with increased serum prolactin and altered leptin levels, both of which may disrupt normal GnRH pulsatility (Ghazizadeh, 2007). Of patients with nonalcoholic chronic liver disease, the cause of the low gonadotropin levels is unknown and is observed only in a subset of amenorrheic women (Cundy, 1991). Chronic diseases may produce amenorrhea through common mechanisms, such as stress and nutritional deficiencies. For example, patients with malabsorption due to celiac disease may have delayed menarche, secondary amenorrhea, and early menopause, which have been attributed to deficiencies in trace elements such as zinc and selenium. These are required for normal gonadotropin biosynthesis and secretion (Özgör, 2010).

Several disorders that produce amenorrhea are not associated with significantly abnormal gonadotropin levels, at least as measured at a single point in time, as is done in clinical settings. Even so, gonadotropin amplitude or pulse frequency is likely disturbed in these patients. As a result, chronic sustained sex-steroid secretion interferes with the normal feedback between the ovary and the hypothalamic-pituitary axis. Normal oocyte maturation and ovulation are impaired, and menstruation fails to occur.

Due to relatively normal gonadotropin levels, these patients will secrete estrogen and therefore can also be said to have chronic anovulation with estrogen present. This is in contrast to patients with ovarian failure or hypothalamic-pituitary failure, in whom estrogen levels are low or absent. This distinction may be useful during evaluation and treatment.

Polycystic Ovarian Syndrome

This syndrome is by far the most common cause of chronic anovulation with estrogen present and is discussed fully in Chapter 17. Patients with PCOS may have various menstrual presentations. First, complete amenorrhea may follow anovulation. Without ovulation, progesterone is lacking, and an absent progesterone withdrawal fails to prompt menses. In some women with PCOS, however, amenorrhea may be attributable to the ability of androgens, which are elevated in PCOS patients, to atrophy the endometrium. Alternatively, heavy menstrual or intermenstrual bleeding can result from unopposed estrogen stimulation of the endometrium. Within this unstable, thickened proliferative-phase endometrium, episodic stromal breakdown and shedding leads to irregular bleeding. Vessels may be abnormally dilated in anovulatory endometria, and bleeding may be severe. Last, women with PCOS may experience occasional ovulatory cycles, and normal withdrawal menses or pregnancy may occur.

Nonclassic Congenital Adrenal Hyperplasia

This condition closely mimics the presentation of PCOS with hyperandrogenism and irregular menstrual cycles. Most commonly, nonclassic congenital adrenal hyperplasia (CAH), also termed adult-onset CAH or late-onset CAH, is due to a mutation in the CYP21A2 gene, which encodes the 21-hydroxylase enzyme. With a mild mutation, patients are asymptomatic until adrenarche, a time that requires increased adrenal steroidogenesis. Patients with CAH are unable to convert an adequate percentage of progesterone to cortisol and aldosterone, thus increasing the production of androgens (Fig. 15-5). As in PCOS, chronically elevated androgen levels blunt follicular maturation and prevent normal cyclic feedback at the hypothalamus and pituitary gland, and thereby result in anovulation and amenorrhea.

Ovarian Tumor

Although uncommon, chronic anovulation with estrogen present can also be observed with ovarian tumors producing either estrogens or androgens. As discussed in Chapter 36, examples include granulosa cell tumors, theca cell tumors, and mature cystic teratomas (Aiman, 1977; Pectasides, 2008; Thomas, 2012).

Hyperprolactinemia and Thyroid Disorders

Although hyperprolactinemia can cause hypogonadotropic hypogonadism, as described on page 378, many hyperprolactinemic women may instead have relatively normal gonadotropin levels. As a group, however, their estrogen levels will be mildly depressed. Aside from pituitary adenomas, other circumstances significantly raise prolactin levels. First, many medications and herbs have been associated with hyperprolactinemia, galactorrhea, and disrupted menstrual cycling (Table 12-2). The antipsychotic group of medications is a frequent cause.

Second, primary hypothyroidism may result in mildly elevated prolactin levels. One example is Hashimoto thyroiditis. In this disorder, the decrease in circulating thyroid hormone levels results in a compensatory increase in hypothalamic thyrotropin-releasing hormone (TRH) secretion. TRH prompts pituitary gland thyrotropes to produce TSH. In addition, TRH also binds to pituitary lactotropes, increasing prolactin secretion. This tight link between thyroid function and prolactin levels justifies measurement of a TSH with prolactin levels when initiating evaluation for galactorrhea or amenorrhea.

Whether due to adenoma, medications, or hypothyroidism, prolactin elevation creates a compensatory rise in central levels of dopamine, the primary inhibitor of prolactin secretion. Increased central dopamine levels alter GnRH secretion, thereby disrupting normal cyclic gonadotropin secretion and preventing ovulation. With thyroid disease, additional proposed mechanisms include direct effects of thyroid hormone and prolactin on peripheral cells as thyroid receptors are found in most cell types. Specifically, prolactin receptors have been identified in the ovary and in the endometrium. Moreover, thyroid hormone increases sex hormone-binding globulin levels, altering the levels of unbound, and thereby active, ovarian steroids.

These potentially discordant effects are reflected in the various bleeding patterns seen with thyroid disease (Krassas, 2010). Classically, hypothyroidism is stated to cause anovulation and subsequent heavy menstrual bleeding (Chap. 8). Hyperthyroidism is implicated in amenorrhea. Nevertheless, these patterns are not strictly observed. As might be expected, the likelihood of menstrual abnormality correlates with the severity of the thyroid function disturbance (Kakuno, 2010).

History

Figure 16-7 offers an algorithm for approaching the patient with amenorrhea. Initial questions investigate whether pubertal Tanner stages have been reached and whether menses have begun (Chap. 14). The cycle interval, duration, and amount of menstrual flow are also characterized. Menstrual pattern changes and a description of these changes are sought. Also, the development of amenorrhea may be temporally correlated with pelvic infection, surgery, radiation therapy, chemotherapy, or other illnesses.

Surgical history focuses on prior pelvic surgery, especially intrauterine or ovarian surgery. Patients are questioned regarding postoperative infection or other surgical complications.

A review of symptoms can also be helpful. For example, new-onset headaches or visual changes may suggest a tumor of the CNS or pituitary gland. Pituitary tumors may impinge on the optic chiasm, resulting in bitemporal hemianopsia, that is, the loss of both right and left outer visual fields. Bilateral milky breast discharge may reflect hyperprolactinemia. Thyroid disease can be associated with heat or cold intolerance, weight changes, and sleep or bowel motility abnormalities. Hirsutism and acne are often seen with PCOS or with nonclassic CAH. Cyclic pelvic pain would suggest a reproductive tract outlet obstruction. Hot flushes and vaginal dryness point to hypergonadotropic hypogonadism, that is, POF. Of note, the range, severity, and persistence of symptoms observed in women with POF appear to exceed those experienced by women with age-appropriate menopause (Allshouse, 2015).

Important questions regarding family history include premature cessation of menses or a history of autoimmune disease, including thyroid disease, which would suggest an increased risk for POF. A history of irregular menses, infertility, or signs of excess androgen production is often noted with PCOS. Sudden neonatal death may have occurred in family members carrying mutations in the CYP21A2 gene responsible for CAH.

The social history investigates exposure to environmental toxins, including cigarettes. Any medications are inventoried, especially those such as antipsychotics that increase prolactin levels.

Physical Examination

General appearance can be helpful in the evaluation of amenorrhea. A low BMI, perhaps in conjunction with tooth enamel erosion from recurrent vomiting, is highly suggestive of an eating disorder. Signs of Turner syndrome are evaluated, including short stature, webbed neck, shield-shaped chest, and others listed in Table 18-3 (Turner, 1972). Midline facial defects, such as cleft palate, are consistent with a developmental defect of the anterior pituitary gland. Hypertension in a prepubertal girl may reflect mutation in the CYP17 gene and shunting of the steroidogenic pathway toward aldosterone.

Visual field defects, particularly bitemporal hemianopsia, may indicate a pituitary gland or CNS tumor. Skin is inspected for acanthosis nigricans, hirsutism, or acne, which may indicate PCOS or other hyperandrogenism causes. Supraclavicular fat, abdominal striae, and hypertension may be noted in those with Cushing syndrome. Hypothyroidism can present with an abnormally enlarged thyroid gland, delayed reflexes, and bradycardia. During breast examination, bilateral spontaneous galactorrhea implies hyperprolactinemia.

Examination of the genitalia starts by noting hair pattern. Sparse or absent axillary or pubic hair may reflect either lack of adrenarche or androgen insensitivity syndrome. Conversely, elevated androgen levels will result in a male pattern of genital hair growth. Markedly elevated levels of androgens can produce signs of virilization, most noticeably clitoromegaly (Chap. 17). These women may also note voice deepening and male pattern balding.

Evidence of estrogen production includes a pink, moist vagina and cervical mucus. With estrogen present, vaginal smears demonstrate mostly superficial epithelial cells, whereas with atrophy, parabasal cell numbers increase (Fig. 21-9). Low estrogen levels also manifest with a pale, thin, unrugated vagina.

Determination of reproductive tract anomalies by physical examination is described in Chapter 18. Rectal and digital vaginal examination may help identify a uterus above an obstruction at the level of the introitus or in the vagina. Hematocolpos suggests normal ovarian and endometrial function.

Testing

The differential diagnosis of amenorrhea is extensive, but evaluation of most women is relatively straightforward. For all disorders, testing may be modified by patient history and physical examination. All reproductive-aged women with amenorrhea are assumed pregnant until proven otherwise. Thus, a urinary or serum β-hCG level is almost always obtained.

Progesterone Withdrawal

Classically, patients are given exogenous progesterone and monitored for a progesterone withdrawal bleed, which follows a few days after progesterone completion (the progesterone challenge test). One regimen is medroxyprogesterone acetate (Provera) given as a 10-mg daily oral dose for 10 days. If bleeding ensues, then a woman is assumed to produce estrogen and to have a developed endometrium and patent outflow tract. If bleeding does not follow, then a patient is given estrogen followed by progesterone treatment. A single pack of COCs works nicely for this. If a woman again fails to bleed several days after completing the 21 hormone-containing pills, then an anatomic abnormality is diagnosed.

Several factors can lead to an incorrect test interpretation. First, estrogen levels may fluctuate both in hypothalamic amenorrhea and in the early stages of ovarian failure. As a result, patients with these disorders may have at least some bleeding after progesterone withdrawal. Furthermore, women with high androgen levels, such as occurs with PCOS and CAH, may have an atrophic endometrium and fail to bleed. Specifically, up to 20 percent of women in whom estrogen is present will fail to bleed following progesterone withdrawal (Rarick, 1990). Conversely, menses may be observed after progesterone administration in up to 40 percent of women with hypothalamic amenorrhea due to stress, weight loss, or exercise and in up to 50 percent of women with POF (Nakamura, 1996; Rebar, 1990). This bleeding derives from endometrium that grew prior to amenorrhea onset.

Serum Hormone Levels

As suggested by the American Society for Reproductive Medicine (2008), it may be more reasonable to begin with hormonal evaluation in any woman found to have a normal pelvic examination (Table 16-7). First, serum FSH levels are typically assessed, and levels that are low suggest hypothalamic-pituitary dysfunction. An elevated FSH level is consistent with POF. FSH levels in the normal range suggest an anatomic defect or eugonadotropic hypogonadism, such as occurs in PCOS, hyperprolactinemia, or thyroid disease. Although many patients with PCOS have elevated LH to FSH level ratios >2, testing for this relationship is unnecessary as a normal ratio does not exclude this diagnosis.

If an FSH value is low, repeating this measurement and adding an LH level, which will also be low, can help confirm hypogonadotropic hypogonadism. Additional testing may include a GnRH stimulation test. Several different protocols can be employed, but one common approach provides 100 μg of GnRH as an intravenous bolus and then measures LH and FSH levels at 0, 15, 30, 45, and 60 minutes. In patients with hypogonadotropic hypogonadism or delayed puberty, although both LH and FSH levels will be blunted, FSH levels will be high relative to LH ratios during the test (Job, 1977; Yen, 1973). Although informative, use of this test has been constrained by the lack of consistently available clinical grade GnRH. More recently, providers have begun to use GnRH agonist protocols.

In contrast, an elevated FSH level strongly suggests the presence of hypergonadotropic hypogonadism, namely, POF. This diagnosis requires two FSH levels greater than a threshold range of 30 to 40 mIU/mL and obtained at least 1 month apart. At least two elevated values are required because the course of POF may fluctuate over time. This variation likely explains the occasional pregnancy that has been reported in these women. Patients keep a menstrual calendar while testing is completed because bleeding 2 weeks following an elevated serum FSH level may simply indicate that the sample was obtained during a normal midcycle gonadotropin surge.

As adjuncts to FSH testing, ancillary markers that will increase the sensitivity and specificity of ovarian reserve testing have been investigated. Many clinicians obtain measurements for estradiol in addition to FSH, although this has not been consistently shown to increase diagnostic accuracy. Attention has turned more recently to the use of circulating serum AMH levels (Chap. 19) (Visser, 2012).

Prolactin and thyroid-stimulating hormone levels are tested in most patients with amenorrhea as prolactin-secreting adenomas and thyroid disease are relatively common and require specific treatment. Because of the relationship between hypothyroidism and prolactin levels, both hormones are measured simultaneously. If present, treatment for hypothyroidism will also normalize prolactin levels. If a TSH level is elevated, an unbound thyroxine (T₄) level is drawn to confirm clinical hypothyroidism.

Serum testosterone levels are measured in women with suspected PCOS or with clinical signs of androgen excess. Hormonal evaluation includes measurement of serum total testosterone levels. Measurement of free testosterone levels is generally unwarranted as these assays are more expensive and less reliable unless sent to a specialized laboratory. Mild elevations in testosterone levels are consistent with the diagnosis of PCOS. However, values >200 ng/dL may suggest an ovarian tumor and warrant pelvic sonography.

Serum dehydroepiandrosterone sulfate (DHEAS) production is essentially limited to the adrenal gland. Levels in high-normal range or mildly above are consistent with PCOS. Adrenal adenomas may produce circulating DHEAS levels above 700 μg/dL and merit investigation with magnetic resonance (MR) imaging or computed tomography (CT) scanning of the adrenals. Measurement of 17-hydroxyprogesterone (17-OHP) aims to identify patients with nonclassic CAH. However, confirmation of this diagnosis can be difficult due to the overlapping values among normal patients and heterozygote and homozygote carriers of mutations in the 21-hydroxylase (CYP21A2) gene. Accordingly, adrenal stimulation with ACTH, often colloquially termed the cort stim test, may be required as described in Chapter 17.

Other Serum Testing

At times, other serum testing may be prudent. If an eating disorder is suspected, an immediate assessment of serum electrolytes is warranted as imbalances can be life-threatening. An electrocardiogram is also considered in those patients perceived to have more severe disease. A reverse triiodothyronine (T₃) level is often elevated in patients with functional hypothalamic amenorrhea. Women with PCOS are screened for insulin resistance and lipid abnormalities as these are often found in affected patients and increase risks for diabetes and cardiovascular disease (Chap. 17). Although no consensus exists, repeating these tests every few years is sensible.

Many patients with POF will not have a clear etiology for their disorder based on medical history or genetic testing and may reasonably be assumed to have an autoimmune cause. Recommendations for testing vary among experts, but the current recommendations focus on measurement of antiadrenal antibodies, specifically antibodies directed against 21-hydroxylase. Addition of antithyroid antibodies such as antimicrosomal/thyroid peroxidase antibodies (TPOAb) is also logical if thyroid dysfunction is suspected.

Chromosomal Analysis

Patients with gonadal dysgenesis, such as Turner syndrome, are considered for karyotyping. Classic teaching suggests that this test is unnecessary after age 30. However, consideration is given to testing patients up to age 35 because a rare individual mosaicism may retain functional oocytes and thus sustain cyclic menses longer than expected. As previously indicated, a Y-containing cell line requires bilateral oophorectomy because of the increased risk for ovarian germ cell tumors. Due to the close association between stature and abnormalities in the X-chromosome, many specialists advise karyotyping all women with POF who are shorter than 60 inches (Saenger, 2001). Chromosomal studies are also considered in any woman with a family history of POF.

Radiologic Evaluation

Any patient with hypogonadotropic hypogonadism is assumed to have an anatomic CNS or pituitary gland abnormality until proven otherwise by MR imaging or CT scanning. Thus, functional hypothalamic amenorrhea due to stress, exercise, or eating disorder is a diagnosis of exclusion. Imaging is highly sensitive for identification of destructive disorders such as tumors or infiltrative diseases of the hypothalamus or pituitary gland. Although fundamentally normal, a subset of patients with genetic causes for Kallmann syndrome or IHH will demonstrate developmental defects of the hypothalamus, olfactory bulbs, or pituitary gland during MR imaging (Klingmuller, 1987).

Reproductive tract anatomic disorders can be evaluated with several modalities depending on the suspected cause. Sonographic examination is frequently useful as a first screen for a uterus deemed grossly normal by physical examination. HSG or SIS is excellent for the detection of intrauterine synechiae or developmental anomalies. Changing trends favor SIS unless information on tubal patency is also required. Three-dimensional (3-D) sonography and 3-D SIS can also add information. MR imaging is frequently used for delineation of more complex uterine structures, such as a noncommunicating or hypoplastic uterine horn. Imaging of congenital reproductive tract anomalies is discussed further in Chapter 18.

Treatment of amenorrhea depends on its etiology and patient goals such as a desire to treat hirsutism or seek pregnancy. Anatomic abnormalities often require surgical correction, if possible, and are discussed in Chapter 18. Hypothyroidism is treated with thyroid replacement, and a suggested dosage of levothyroxine is 1.6 μg/kg of body weight per day (Baskin, 2002). For most, a suitable starting dose is 50 to 100 μg of levothyroxine orally daily. TSH response is slow and levels are rechecked 6 to 8 weeks following initiation. A TSH level in the lower range of normal is the therapeutic goal. If needed, the dose may be increased by an increment of 12.5 or 25 μg (Jameson, 2012). Women with hyperprolactinemia receive a dopamine agonist, such as bromocriptine or cabergoline. Macroadenomas may require surgery if secondary deficits such as visual changes are observed. Both medical and surgical specifics of pituitary disease treatment are found in Chapter 15.

Estrogen Replacement

This therapy is instituted in essentially every patient with hypogonadism to avoid osteoporosis. Exceptions include patients with an estrogen-sensitive tumor. As in postmenopausal women, bone loss is accelerated in the first few years following estrogen deprivation. Thus, treatment is instituted quickly. Women with a uterus also require continuous or intermittent progesterone administration to protect against endometrial hyperplasia or cancer (Chap. 22). There is no consensus, however, on an optimal regimen in these patients. Some experts recommend that women in their 20s receive higher doses of estrogen than is routinely given to postmenopausal women as this is a time of ongoing bone deposition. Frequently, it is easiest to prescribe COCs. Younger women may prefer this treatment as their friends may also use these pills, and in their minds, hormone replacement therapy may be associated with aging. Additionally, consensus is lacking on treatment duration in this patient population. For most individuals, continuation until approximately age 50, the usual age of menopause, seems reasonable.

Patients who have eating disorders or who exercise excessively will require behavior modification. In a patient with an eating disorder, psychiatric intervention is imperative due to the significant morbidity and mortality associated with this diagnosis (American Psychiatric Association, 2013; Michopoulos, 2013). Elite athletes may choose not to alter their exercise regimens and will therefore require estrogen treatment.

Polycystic Ovarian Syndrome

Treatment of women with PCOS may include cyclic or chronic progesterone treatment as outlined in Chapter 17. Insulin-sensitizing agents such as metformin (Glucophage) may be indicated in those with diabetes mellitus. In women with hyperandrogenism due to PCOS, COCs and/or spironolactone are often helpful.

Depending on its severity, nonclassic CAH in some women may be treated with low-dose corticosteroids. This partially blocks ACTH stimulation of adrenal function and thereby decreases adrenal androgen overproduction.

Infertility

Alternative approaches may be required in a patient who desires conception. Adequate treatment of hyperprolactinemia and thyroid disease typically results in ovulation and in normal fertility for most women. If clearly linked to infertility, anatomic abnormalities are surgically corrected whenever possible. However, depending on the type and severity of the abnormality, a surrogate to carry a gestation may be needed. POF is not reversible, and affected individuals can be offered in vitro fertilization using a donor oocyte to conceive. Assuming that behavioral modification is not successful, women with hypogonadotropic hypogonadism are referred to an infertility specialist for treatment with pulsatile GnRH or with gonadotropins. Most patients will receive gonadotropin therapy because pulsatile GnRH is more complex to administer, and GnRH is not reliably available. Women with PCOS will frequently ovulate following treatment with the selective estrogen-receptor modulator clomiphene citrate, or with an aromatase inhibitor such as letrozole. Clomiphene citrate is believed to act by transient inhibition of estrogen feedback at the hypothalamus and pituitary gland (Fig. 20-1). This treatment, however, is not effective in those with hypogonadotropic hypogonadism as they lack significant levels of circulating estrogen.

Patient Education

Patients are adequately counseled regarding their diagnosis, its long-term implications, and treatment options. All women with an intact endometrium must understand the risks of unopposed estrogen action, whether the estrogen is exogenous, such as through hormone therapy, or endogenous, such as in PCOS. For hypoestrogenic women, clinicians explain the importance of estrogen replacement to protect against bone loss. As described in Chapter 22, estrogen may have additional benefits, which are also detailed. Last, even if not raised by the patient, the potential or lack of potential for future child-bearing is discussed.