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INTRODUCTION

Disruption of normal menstrual cycles and normal ovulation are often associated with a variety of life style factors such as excessive exercise, nutritional deprivation, and psychological stress. In the vast majority of cases, this is associated with normal neuroanatomic findings. In a small subset, neuroendocrine abnormalities such as isolated gonadotropin deficiency (Kallmann syndrome), head trauma, radiation effects, Sheehan syndrome, and pituitary apoplexy are identified (Table 1). Regardless of the etiology, the final common pathway is a change in the normal pattern of episodic secretion by the GnRH pulse generator resulting in disruption of ovulation and amenorrhea. These types of disorders will be discussed in this chapter.

GENERAL MECHANISM OF CENTRAL OVULATORY DYSFUNCTION

The secretion of endogenous GnRH is difficult to assess in the human because this decapeptide is rapidly metabolized within 2 to 4 minutes in the peripheral circulation. Thus, it is not possible to directly assess GnRH secretion, and the majority of clinical investigations utilize frequent measurements of LH concentrations as the surrogate marker for hypothalamic GnRH secretion. In women with regular menstrual cycles, clinical studies have demonstrated a characteristic pulsatile secretion of LH at a frequency of 90-120 minutes during the follicular phase and a frequency of 180-240 minutes during the luteal phase . Small alterations in LH pulsatile frequency and or amplitude can result in a range of disorders including luteal phase defects, oligo-ovulation and anovulation. Thus, most studies have examined for changes in LH pulsatile frequency and amplitude as the major endpoint in studies to investigate functional hypothalamic amenorrhea.

FUNCTIONAL HYPOTHALAMIC AMENORRHEA

A practical definition of functional hypothalamic amenorrhea (HA) is the absence of menstrual cycles for more than 6 months without evidence of anatomic or organic abnormalities . Other more serious organic disorder can mimic HA such as isolated gonadotropin deficiency (table 1). Thus, this diagnosis should be made after exclusion of other causes.

Many individuals with this disorder will provide a history of normal menarche and regular menstrual cycles between 26 and 35 days in length. These women typically are intelligent, high-achievers, who are usually thin or of normal body weight. A detailed interview may identify a stressful event or emotional crisis (divorce, relation breakup, death of a friend or relative) preceding the amenorrhea. Other interpersonal and environmental stressors may also be present such as academic pressures, job stresses, or psychosexual problems. A careful review of the patient's current lifestyle including exercise intensity, dietary choices, and the use of sedatives or hypnotics may be helpful in characterizing the psychogenic stress components.

The physical examination should focus on identifying galactorrhea, thyroid dysfunction, and evidence of hyperandrogenemia (i.e., acne, hirsutism). The pelvic examination should be normal except for a thinned vaginal mucosa or absent cervical mucus which are characteristics of hypoestrogenism. Despite these findings, these patients do not usually experience hot flushes.

Laboratory evaluation should include FSH, prolactin (PRL), and TSH. Most of the other pituitary hormones should be in the normal range (Table 3). In many patients, the progestin challenge test (medroxyprogesterone acetate 10 mg for 7 days) will demonstrate an absence of withdrawal uterine bleeding or vaginal spotting. This test is a bioassay for the absence of estrogen priming of the endometrium and reflects the low circulating levels of estradiol.

The basic defect in women with functional hypothalamic amenorrhea is the failure of the hypothalamus to increase GnRH output in the presence of severe hypoestrogenism. Most investigators believe that there is a slowing of the GnRH pulse generator as reflected by a decrease in peripheral pulsatile LH secretion in these women. The pattern of LH secretion may vary. During the early onset, LH pulse frequency and amplitude may be normal. In more severe cases, regression to a pubertal pattern with sleep- associated increases may be observed (see Figure 1).

The pituitary gland is fully capable of synthesizing and release of LH and FSH. However, responses to exogenous GnRH in these individuals may vary depending on the endogenous GnRH priming of the pituitary gland. LH and FSH responses to exogenous GNRH may be absent, normal, or supranormal . In these patients, after a period of priming with intravenous pulsatile GnRH (1-2 mg/90 minutes), normal levels of LH and FSH can be restored and responses to exogenous GnRH become normal. Taken together, these observations suggest that endogenous GnRH secretion is deficient and gonadotropin secretion and ovarian function can be normalized with physiologic replacement of exogenous, pulsatile GnRH.

Figure 1. Examples of LH pulsatile secretion at various stages of hypothalamic-pituitary activation. GnRH-LH secretion can progress from an apulsatile stage; to a high amplitude infrequent pulse stage; to a sleep-entrained pulse stage; and to regular every ninety minute pulses(2).

MODULATION OF GNRH SECRETION BY OPIOIDERGIC, DOPAMINERGIC, AND EXCITATORY AMINO ACIDS

As with most neurosecretory hormones, the GnRH pulse generator localized in the arcuate nucleus is modulated by input from other neuronal systems. Animal studies have shown that neurotransmitter agents such as dopamine, norephinephrine, and serotonin can regulate GnRH or LH secretion. These studies suggest that activation of the noradrenergic system is associated with increased release of GnRH whereas dopaminergic or serotonergic activation can either inhibit or stimulate GnRH release , . These observations can explain in part the CNS-associated disruption of normal menstrual cycles in patients who take phenothiazines (dopamine receptor antagonists), stimulants, antidepressants, and sedatives on a chronic basis.

Excitatory amino acids such as glutamate and aspartate have recently been shown to be localized to the arcuate nucleus in the media basal hypothalamus adjacent to GnRH neurons and have been implicated in a regulatory role for GnRH secretion primarily during pubertal maturation . These two amino acids appear to activate GnRH secretion during puberty in monkeys.

Endogenous opiates peptides such as endorphins, enkephalins, and dynorphins appear to play largely an inhibitory role in GnRH and LH secretion. In patients with hypothalamic amenorrhea, blockade of endogenous opiate receptors with receptor antagonists such as naloxone or naltrexone will induce an increase in pulsatile release of GnRH and LH . Long term treatment of hypothalamic amenorrhea patients with naltrexone can result in return of normal menstrual cycles in some individuals . These findings indirectly suggest that endogenous opiate activity is suppressing GnRH secretion.

LINK BETWEEN STRESS AND REPRODUCTIVE DYSFUNCTION

Exposure to chronic stress can disrupt reproductive function in animals and humans. As first described by Hans Selye, the stress response results in activation of the hypothalamic-pituitary adrenal (HPA) axis and is characterized by increased secretion of a "stress response complex" of hormones such as CRH, ACTH, cortisol, PRL, oxytocin, vasopressin, norepinephrine, and epinephrine (Table 4). These hormonal effects appear to impact on reproductive function at several levels. For example, CRH has been shown to directly inhibit GnRH secretion in rats, monkeys, and humans at the hypothalamic level in in vitro and in vivo experimental models . This inhibition can be negated by administration of a CRH receptor antagonist or by naloxone, an opiate receptor antagonist. Taken together, these observations suggest that the inhibitory effect of CRH is mediated in part by increased opioidergic activity.

The increased secretion of ACTH at the pituitary level may also suppress pituitary response to GnRH . In addition, increased cortisol levels may also dampen pituitary response to GnRH . It must be emphasized that an acute stress response will be unlikely to alter ovulatory function since the H-P-O axis is quite resilient. On the other hand, it appears that chronic environmental stressors lead to long term activation of the HPA axis which in turn can induce ovulatory dysfunction at either the hypothalamic or the pituitary level.

CLINICAL MANAGEMENT OF FUNCTIONAL HYPOTHALAMIC AMENORRHEA

The clinical evaluation of HA should focus on a carefully conducted history and physical examination that reviews life style variables and interpersonal relationships. Since this is a diagnosis of exclusion, significant organic diseases (Table 1) must be excluded. In many patients, spontaneous recovery of menstrual function will take place following accommodation to environmental stressors or after modification of life style. Psychological counseling may also be appropriate for these individuals. Because of the functional nature of HA, an individualized and expectant management should be considered the initial approach. In those who remain amenorrheic, periodic evaluation of menstrual status every 4 to 6 months is prudent.

In the infertile patient with this diagnosis who fails to resume normal cycles, a trial of low dose clomiphene citrate (25-50 mg for 5 days) is appropriate. In these patients, higher doses of clomiphene may suppress the H-P axis due to the weak estrogenic properties of clomiphene in an already hypoestrogenic environment. For clomiphene failures, use of human menopausal gonadotropins as an alternative method is highly successful. If available, pulsatile administration of GnRH 5 mg/90 minutes intravenously using a modified insulin pump will successfully induce ovulation after a 13 to 14 day treatment period . This latter approach is associated with ovulation rates of greater than 90% with generation of a single dominant ovarian follicle and much lower rates of ovarian hyperstimulation. In these patients, corpus luteum support can be maintained with either GnRH or human chorionic gonadotropin 1500 units intramuscularly every three days for 4 doses.

For the woman who remains amenorrheic for more than 1 year, the long term risks of hypoestrogenism including reduced bone mineral density and osteoporosis become factors. In young women with persistent hypoestrogenism, the bone mass can decrease at a rate of 2-5% per year for the first three to five years. Dual energy X-ray absorptiometry (DEXA) is often necessary to convince patients to begin estrogen therapy. The minimal dose of estrogen necessary to conserve bone has been established in menopausal women. At least 0.3 mg of conjugated estrogen, 1 mg of micronized estradiol, or 0.025 mg of transdermal estrogen is necessary to protect against bone loss. Use of a progestin on a cyclic basis such as medroxyprogesterone acetate for 10 to 12 days each month is necessary to ensure regularly shedding of endometrium and prevent endometrial hyperplasia. The use of bisphosphonates in reproductive-aged women should be carefully considered.

BULIMIA AND ANOREXIA NERVOSA

Severe eating disorders such as bulimia and anorexia nervosa are also associated with disruption of reproductive function. Bulimia is characterized by alternating episodes of consumption of large amounts of food over a short time (binge eating) followed by periods of self-induced vomiting, excessive use of laxatives or diuretics and food restriction. The incidence of bulimia is estimated to be 4.5 to 18 percent among high school and college students . Bulimia usually begins between the ages of 17 to 25 years.

Anorexia nervosa is a severe eating disorder characterized by extreme weight loss (greater than 25% of ideal body weight), body-image disturbance, and an intense fear of becoming obese . Anorexia patients are usually between the age of 12 yrs and the mid-thirties and have a bimodal age of onset at 13-14 years and 17-18 years. There is a 90 to 95 % female predominance, with the majority of patients coming from Caucasian, middle-class or upper-middle class families. The overall incidence of anorexia ranges from 0.64 per 100,000 to 1.12 per 100,000. The mortality associated with anorexia has been reported to be as high as 9 percent, usually secondary to cardiac arrythythmia which is precipitated by electrolyte abnormalities and/or diminished heart muscle mass. Suicide has also been more common (2 to 5%) in patients with anorexia nervosa. These statistics are sobering, making it extremely important for the clinician to recognize early signs of this disorder so that appropriate intervention and treatment can be initiated.

The clinical features of bulimia and anorexia are listed in Tables 5 and 6. Due to the marked reduction in caloric intake in anorexia, basal metabolism is lowered by decreased conversion of thyroxine to triiodothyroxine to maintain homeostasis. Thyroxine is converted via an alternative pathway to reverse triiodothyroxine, an inactive isoform (Table 7). This mechanism is also commonly seen in severely ill patients and during prolonged starvation. Anorectics also suffer from defects in thermoregulation and are hypothermic. Because secretion of vasopressin is impaired, anorectics also have partial diabetes insipidus and are unable to concentrate their urine.

Anorectic and bulimic patients have hyperactivation of the HPA axis . Studies show a persistent hypersecretion of cortisol throughout the day with an increase in 24 hour free cortisol secretion. Despite the increased cortisol production, the manifestations of hypercortisolism are not present due to a decrease in cellular glucocorticoid receptors . The reduced number of these receptors may also provide an explanation for the incomplete suppression of the pituitary-adrenal axis by dexamethasone. Pituitary CRH responses are also blunted in bulimics and anorectics. As with other stress response syndromes, anorectics have evidence for increased central opioid activity with reported increases in cerebrospinal fluid levels of b-endorphins .

Like functional hypothalamic amenorrhea, anorectics have a prepubertal pattern of LH secretion presumably due to a marked decrease in GnRH secretion. With weight gain, anorectics can display transitional patterns of LH secretion and may have normal or supranormal responses to GnRH (Figure 1). Despite return to normal body weight, up to 50% remain anovulatory.

The success rates for treatment of anorexia nervosa and bulimia remain low. Therapeutic approaches include behavior modification, group therapy, and individual psychotherapy. Generally, a team approach consisting of a psychiatrist and a general medicine specialist with expertise in eating disorders is desirable. Because of the high mortality rate and the significant morbidity associated with anorexia, it is important to obtain psychiatric consultation and follow-up in all patients with eating disorders. For patients who fail to resume menstrual function even after restoration of body weight, estrogen replacement therapy is indicated.

EXERCISE-INDUCED HYPOTHALAMIC AMENORRHEA

With the increased participation of women in all types of recreational and competitive athletic activities, health issues related to exercised-induced amenorrhea have become common. Depending on the type of sport and competition level, the incidence of amenorrhea varies from 5 to 25%. The incidence of menstrual irregularities appears to be greatest in activities that favor a low body weight physique such as ballet (6-43%) and middle and long distance running (24-26%). The incidence appears to be less frequent in bicycling (12%) and swimming (12%) .

In those athletes with menstrual irregularity, LH pulsatility is altered and can range from a decreased frequency to a transitional pattern (Figure 1). It is well known that acute exercise leads to hyperactivation of the HPA axis. Is it the stress of exercise or the low energy availability that alters LH pulsatility in exercising women? This key question has been answered in part by controlled studies in which women undergo dietary caloric restriction imposed in the face of increasing exercise demands. It would appear that LH pulsatility is not disrupted by the stress of exercise but rather LH pulsatility is disrupted because of reduced energy availability .

It is important to emphasize that for so many of these athletes the "female athlete triad" ofamenorrhea, osteoporosis, and eating disorders coexist. Management of these patients should emphasize measurement of bone density, counseling about diets, weight change, trying to keep weight near normal levels, and calcium intake. One goal of therapy should be to decrease the level of exercise, improve the diet, and achieve weight gain. For others, exercise may not induce amenorrhea but may be associated with longer menstrual cycles, luteal phase defects, and intermenstrual spotting. These reproductive defects may be reversible with a decrease in exercise level or intensity. Alternatively, clomiphene given at doses between 25-100 mg for 5 days may increase GnRH pulsatility sufficiently to correct this defect. If amenorrhea persists for over 6 months, it may be prudent to begin estrogen replacement therapy or oral contraceptive pills. Long term health risks in these individuals are reproductive dysfunction and skeletal abnormalities.

OTHER CAUSES OF HYPOGONADO-TROPINISM

Isolated Gonadotropin Deficiency (IGD)

This disorder is characterized by a decrease or absence of endogenous GnRH secretion resulting in very low to undetectable LH and FSH levels. Individuals with this disorder have incomplete development of secondary sexual characteristics, primary amenorrhea, eunuchoid features, and in some cases a decreased sense of smell or anosmia (Kallmann syndrome) . This disorder can have an autosomal dominant inheritance pattern. The underlying defect is due to a failure of GnRH neurons to form completely in the olfactory placode or to migrate from the olfactory bulb to the media basal hypothalamus during early embryo development. For individuals with anosmia or hyposmia, there is evidence of hypoplasia of the olfactory bulbs on magnetic resonance scan .

Baseline levels of LH and FSH may be in the prepubertal or normal range. However, levels of other pituitary hormones such as TSH, GH, PRL, and ACTH are normal. Due to the failure to increase gonadal sex steroid secretion during puberty, secondary sex characteristics fail to develop and closure of the epiphyseal plates of the long bones is delayed resulting in a eunuchoid habitus where the arm span is greater than the height.

In many cases individuals are started on birth control pills without the diagnosis being made, such that there is partial or complete development of secondary sexual characteristics. In the untreated patient, breast development is usually Tanner stage I or II while pubic hair development will be Tanner IV or V. Treatment of IGD will require estrogen therapy to induce progressive pubertal maturation (100 ng/kg/day of estinyl estradiol). Patients should be monitored at 2 or 3 month intervals to determine the rate of skeletal growth and development. The addition of a progestin such as medroxyprogesterone acetate 5 to 10 mg/day for 12 days can then be used to shed the endometrium. Once sexual maturation is completed, patients can be maintained on 2 mg of micronized estradiol or 0.625 mg to 1.25 mg of conjugated estrogens with 12 days of progestin each month. When fertility is desired, ovulation induction can be carried out with either human menopausal gonadotropins or pulsatile GnRH administration.

POSTPARTUM PITUITARY NECROSIS (SHEEHAN SYNDROME)

Postpartum pituitary necrosis is usually preceded by a history of severe obstetrical hemorrhage with hypotension, circulatory collapse, and shock. After fluid resuscitation of the patient, this condition may be manifested by clinical evidence of partial or panhypopituitarism. Simmonds was the first to describe this clinical syndrome although the most complete description has been attributed to Sheehan . This condition constitutes an endocrine emergency that can be life-threatening.

The pathophysiology of this process is not entirely clear. With pregnancy, there is an increase in blood supply to the pituitary bed and the pituitary gland enlarges. During the period of profound hypotension, Sheehan postulated that occlusive spasm of the arteries that supply the pituitary and stalk occurs. This leads to venous stasis and thrombosis of the pituitary portal vessels causing a variable degree of pituitary ischemia and cell death. Many patients initially present with a failure to have breast engorgement and lactation due to a deficiency in PRL secretion. These women may also have other anterior pituitary deficiencies. The posterior pituitary is usually spared because it is less dependent on the portal blood supply. In some patients, the absence of ACTH secretion leads to inadequate cortisol secretion resulting in postural hypotension, nausea, vomiting, and lethargy. Hypothyroidism may be noted later in this scenario. Recovery of pituitary function has been reported in a few cases.

The extent of pituitary deficiencies can be characterized by provocative testing with combined intravenous injection of the hypothalamic releasing factors GnRH, TRH, GHRH, and CRH . Appropriate replacement therapy can be instituted once the pituitary reserve is defined. For the patient who presents with hypotension, immediate administration of glucocorticoids is required (cortisone acetate 100 mg, im ). Once the patient stablizes, a maintenance dose of cortisone acetate 20-25 mg/day or prednisone 5 mg/day can be given. With increased stressful conditions such as an infection, a doubling or tripling of daily doses should be used. For hypothyroid patients, thyroxine replacement should be replaced gradually beginning, at 50 mg/day and increased at 50 mg increments at 1 week intervals until full replacement doses are reached (0.1 to 0.2 mg/day). Patients should be instructed to wear a medical alert bracelet. Estrogen replacement therapy will be required for persistent amenorrheic patients. If fertility is desired, ovulation induction with exogenous gonadotropins is required.

POST-TRAUMATIC HYPOPITUITARISM

This condition can arise following severe head trauma as a result of a sudden deceleration of the head and occult damage to the pituitary stalk or hypothalamus during a traffic accident . Trauma may also be associated with a basal skull fracture or an episode of unconsciousness. These individuals will often manifest a delay from injury to presentation and may display evidence for partial or panhypopituitarism. These symptoms can include amenorrhea, galactorrhea, hypogonadism, loss of axillary and pubic hair, anorexia, and weight loss. For these patients, evaluation of the pituitary-adrenal axis is most important because hypocortisolism can be potentially life-threatening. The diagnostic evaluation and management is similar to that described for Sheehan syndrome.

PITUITARY APOPLEXY

This medical emergency is characterized by an acute infarction of the pituitary gland. Patients will complain of a sudden onset of a severe retro-orbital headache and visual disturbances which may be accompanied by lethargy or loss of consciousness . These symptoms may mimic other neurological emergencies such as hypertensive encephalopathy, cavernous sinus thromobosis, ruptured aneurysm, or basilar artery occlusion. CT or MRI imaging may indicate hemorrhagic changes in the pituitary sella region. Patients with pituitary tumors are at higher risk for this complication. For some patients, neurosurgical consultation and emergency decompression may become necessary. Provocative testing as described for Sheehan syndrome should be performed to evaluate for multiple pituitary deficits. Appropriate replacement of target tissue hormones should be instituted based on testing.

POSTRADIATION-INDUCED HYPOPITUITARISM

Exposure to therapeutic radiation sources for treatment of midline CNS tumors can place patients at increased risk for delayed development of hypopituitarism . In general, sensitivity to radiation is greatest for gonadotropes, followed by corticotropes and thyrotropes. The onset of pituitary deficiencies may be insidious but can occur within 1 year of radiotherapy. Periodic assessment of hypothalamic-pituitary function should be performed for an indefinite period of time and appropriate replacement hormone therapy should be instituted as these deficiencies develop.

SUMMARY

In this chapter, we have reviewed a variety of disorders that can disrupt the normal menstrual cycle. Whether the disorder is linked to central organic lesions, changes in life style, or functional, stress components, all appear to have a common pathway(s) resulting in alterations in the secretion of the GnRH pulse generator.