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.
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.
Normal GnRH neuron migration and the pathogenesis of Kallmann syndrome. A. During normal development, olfactory neurons arising in the olfactory epithelium extend their axons through the cribriform plate of the ethmoid bone to reach the olfactory bulb. Here, these axons synapse with dendrites of mitral cells, whose axons form the olfactory tract. Mitral cells secrete anosmin-1, which is the protein product of the KAL1 gene. This protein is necessary to direct the olfactory axons to their correct location in the olfactory bulb. The GnRH-secreting neurons use this axonal path to migrate from the olfactory placode to the hypothalamus. B. Patients with Kallmann syndrome due to a KAL1 mutation lack anosmin-1 expression. As a result, the axons of the olfactory neurons cannot interact properly with mitral cells, and their migration ends between the cribriform plate and olfactory bulb. As GnRH neuronal migration is dependent on this axonal trail, the GnRH secretion pathway likewise ends at this location. (Reproduced with permission from Rugarli E, Ballabio A: Kallmann syndrome. From genetics to neurobiology, JAMA 1993 Dec 8;270(22):2713–2716.)
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.
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).
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).
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.
Diagram depicting a simplified model for the development of amenorrhea in women with eating disorders, high stress levels, or rigorous exercise. CRH = corticotropin-releasing hormone; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone; NPY = neuropeptide Y.
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).
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).
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.
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).