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The task force developed a priori protocols for two systematic reviews to evaluate the effect of hormonal therapy and bisphosphonates in preventing bone loss in patients with FHA. After a comprehensive search of several databases for original controlled and noncontrolled studies, nine were eligible patients that received different hormonal therapies, none with bisphosphonate. None of the studies reported on fractures. Random-effects meta-analysis showed a statistically significant increase in BMD of the lumbar spine in patients receiving hormonal therapy compared with patients receiving control and no significant effect on BMD of the femoral neck.

The quality of this evidence was low due to the high risk of bias, imprecision very small sample size , and indirectness for example, BMD is a surrogate outcome. FHA is a form of chronic anovulation that is not due to identifiable organic causes 4. The proximate cause of the anovulation is a functional reduction in GnRH drive, which manifests as reduced LH pulse frequency 5.

Providing exogenous GnRH or gonadotropins restores folliculogenesis 6, 7. Klinefelter et al. Additionally, there may be a genetic predisposition for the development of FHA, such as heterozygosity for congenital hypogonadotropic hypogonadism 9. The neuromodulatory signals that alter GnRH function are many and include both inhibitory and stimulatory inputs that align GnRH function with the internal and external milieu Fig.

There is a tight link between activation of the hypothalamic—pituitary—adrenal HPA axis and reduction in GnRH drive in those with FHA, including hypercortisolemia in both amenorrheic athletes and nonathletes 5, 11— Given the energetic expense of reproduction, metabolic factors play a fundamental role in gating reproductive function. We commonly see this phenomenon in female athletes who may expend more calories through exercise than they consume in their diets. Military personnel who sustain grueling training regimens, or may have experienced traumatic brain injury, represent another example Psychosocial influences, including externally imposed stressors and stressful attitudes toward commonplace conditions 19—21 , also activate the HPA axis and alter the neuromodulatory cascade that modulates GnRH drive Reversing amenorrhea by behavioral modifications 12 is associated with a reduction in cortisol levels 24 and resumption of ovarian function in some women with FHA Kisspeptin is the G protein—coupled receptor ligand for its receptor, GPR Schematic representation of neural interactions between metabolic and reproductive functions depicting likely sites of action of leptin, insulin, and ghrelin to control the release of gonadotropin-releasing hormone.

Stressors, regardless of type, activate the HPA axis and autonomic nervous system, resulting in a constellation of neuroendocrine alterations, including hypothalamic hypothyroidism that conserves and diverts energetic expenditure 5, Many of the health consequences linked to FHA are likely due to the combined alterations in metabolism, neuroendocrine function, and anovulation classically associated with FHA Available data suggest that appropriate behavioral interventions have the potential to foster ovarian, neuroendocrine, and metabolic recovery.

Studies have demonstrated a higher prevalence of disordered eating patterns and food attitudes in females with FHA compared with controls 29— Studies reported that females with FHA had higher scores on scales of eating behavior, indicating a higher occurrence of dieting, bulimia, food preoccupation, and dietary restraint 33, These findings build on an earlier study that showed altered diets in women runners Additionally, women with FHA had higher measured serum hour cortisol concentrations when compared with controls, similar to women with eating disorders 16, A study using frequent nighttime sampling has also reported higher cortisol levels in adolescent and young adult athletes with amenorrhea, compared with eumenorrheic athletes and nonathletes Preclinical evidence in primates suggests a synergy between metabolic and psychosocial stressors, which are additive and contribute to the reproductive dysfunction Monkeys, similar to women, vary in their sensitivity to reproductive disruption when exposed to metabolic and psychosocial stressors.

One study reported dysfunction of the serotonin system in stress-sensitive monkeys, and that administering the serotonin reuptake inhibitor citalopram reversed the effect, suggesting that the neurobiology is fundamentally different Other studies have reported that socially subordinate monkeys develop reproductive dysfunction, which includes anovulation and luteal phase defects shortened phase after ovulation , which can reflect underlying progesterone deficiency 36, 38— The most significant acute risks of FHA include delayed puberty, amenorrhea, infertility, and long-term health consequences of hypoestrogenism.

Generally, the infertility is due to anovulation, although patients might also experience prolongation of the follicular phase of the cycle or inadequate luteal phases 41, Amenorrhea may be prolonged and associated risks may differ according to its etiology. Lack of menses may accompany weight loss from restrictive eating, and in some cases, indicates an eating disorder. Typically, a longer duration of insult will result in a longer time to reversal and return of normal menses.

The most significant chronic risk is bone loss or inability to obtain peak bone mass 43— Women who have exercise-induced amenorrhea, especially those engaged in activities associated with restrictive eating habits and low weight, may have decreased bone density, in spite of the bone-building effect of weight-bearing exercise 48, Some patients with FHA develop osteoporosis and fractures, particularly stress fractures 50, Repeated fractures can also be a sign of poor eating habits The etiology is partly due to low bone mass, but researchers also think that it is related to a low-energy state, which leads to low bone formation and low bone turnover, favoring a resorptive state.

This, in turn, impairs the normal mechanisms, which repair bone and injuries due to overuse.

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The uncoupling of bone turnover including suppressed bone formation and increased resorption is unique, and although it can be reproduced by short-term starvation in normal exercising women, it is not typical of estrogen loss but, rather, nutritional deprivation 55— Limited data support risks of fetal loss and small-for-gestation babies as possible consequences of FHA, particularly when associated with eating disorders.

Women with anorexia nervosa are also at risk for preterm labor and delivery by Cesarean section 58— Finally, although it is not known whether prolonged hypoestrogenism is associated with cardiovascular risk in premenopausal women, several studies using premenopausal monkeys have linked socially induced reproductive suppression to exacerbated coronary artery atherosclerosis 61, Clinicians can use the menstrual period in adolescent girls to recognize estrogen status and identify underlying problems 53, 63, Absent or irregular menses and estrogen deficiency due to insufficient stimulation or suppression of the HPO axis in the absence of anatomic or organic pathology characterizes FHA.

We must consider a broad differential diagnosis in these cases to make certain that we have excluded underlying etiologies that may be manifesting as amenorrhea Table 1 65— These distinctions allow for the inclusion of underweight and normal-weight women and acknowledge that the etiology may vary and represent a combination of factors. An energy deficit which can occur independent of changes in body weight appears to be the critical factor in both the weight loss and exercise-induced forms of FHA.

Williams et al. We need more studies to determine the average threshold below which women who exercise or have low dietary intake are at risk for developing menstrual disturbances. It is possible that energy thresholds vary among and within individuals, and that growing adolescents may require even more available energy than older women for normal HPO axis function. Many studies have reported hormonal alterations among amenorrheic hyperexercisers compared with eumenorrheic hyperexercisers and nonexercisers, including: higher cortisol and ghrelin and lower leptin secretion accompanying lower LH secretion 14, 72, 75 ; a blunted elevation in FSH during the luteal—follicular transition, which may predispose to luteal phase defects i.

These hormonal changes occur as a consequence of low energy availability and can directly impact the HPO axis, thus disrupting menstrual function. The spectrum ranges from those who inadvertently or knowingly consume insufficient calories to match their caloric expenditure to those who have eating disorders and are severely undernourished. These adolescents or women can thus range from normal-weight to severely underweight. Similarly, there is a spectrum of menstrual status that includes ovulatory eumenorrhea, subclinical menstrual dysfunction luteal phase defects and anovulatory eumenorrhea , and amenorrhea.

Among these young women, bone density ranges from normal to low. A higher prevalence rate of exercise-induced amenorrhea may occur in those sports and activities in which leanness may confer an advantage e. When weight is near normal, amenorrhea may reverse during intervals when training is decreased or absent, suggesting that the energy demands of training cause the dysfunction 82, The severity of the menstrual dysfunction has been shown to increase in proportion to indices of energy conservation in exercising women Another report on exercising women showed a reversal of amenorrhea in three of four amenorrheic athletes with nutritional intervention Of note, some young women do not resume menses after a nutritional intervention, highlighting the underlying psychological issues that may be at play.

Mood disorders and chronic diseases may be linked to amenorrhea, as associated behaviors e. Although subjects may initiate the behaviors to reduce stress, the behaviors often function as stress amplifiers. Thus, a psychological assessment to exclude or verify a mental disorder is critical In the case of a DSM-5 diagnosis, we recommend referral to appropriate psychiatric care. In particular, it is important to determine the presence of modifiable Axis I mood disorders as contrasted with less easily modified Axis II personality disorders.

It is important to recognize that medications such as antipsychotics typical and atypical , certain antidepressants, contraceptive agents, and opioids commonly alter menses 89, 90 , and we should not confuse the consequent amenorrhea or irregular menses with FHA. This is due to their antagonistic effects at pituitary dopamine receptors, which lessen the inhibitory effect of dopamine on prolactin secretion. Resultant hyperprolactinemia then suppresses pulsatile GnRH release.

Continuous progesterone use, combined OCPs as continuous extended preparations , depot medroxyprogesterone acetate injections, and long-term use of progesterone-releasing intrauterine devices can result in amenorrhea 91— Adolescents or young women with FHA typically report amenorrhea for 6 months or longer 35, 65, 94— In adolescents, this condition may be difficult to differentiate from delayed maturation of the HPO axis during the initial postmenarchal years.

However, several reports indicate that menstrual cycles in adolescents typically do not exceed 45 days, even during the first postmenarchal year 71, 97, Athletes may report varying durations of amenorrhea corresponding with intervals of intense physical activity followed by intervals of irregular menstrual cycles or eumenorrhea after training season ends 82, Of note, FHA is at the extreme end of functional hypothalamic hypogonadism, which includes anovulatory eumenorrhea and eumenorrhea with luteal phase defects, both which may be associated with infertility Women with functional hypothalamic hypogonadism may thus also present with eumenorrhea and infertility rather than amenorrhea.

Available evidence suggests that psychogenic stimuli, both external and internal, activate the HPA axis.

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Any psychogenic event e. Likewise, metabolic adaptations engender psychogenic concomitants. Although the blend of psychological and metabolic factors associated with FHA may vary, the final common pathway is suppression of GnRH drive 13, 17, 20, 21, 87, , Studies have also suggested that energy imbalance sensitizes the HPO axis to psychological stress 21, Both animal and human studies have shown that an actual stressor e.

Data indicate that women who exercise or are under dietary restriction develop FHA as an adaptive response to chronic metabolic energy deficiency 33, The physiological process of adaptation diverts energy and other resources e. The HPA axis in women who exercise regularly and present with amenorrhea is activated, which helps to mobilize glucose.

Furthermore, neuroendocrine adaptations in the hypothalamic—pituitary—thyroid axis minimize energy expenditure [ i.

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There are two major hypotheses to explain the mechanism by which negative energy balance causes FHA. The metabolic fuel hypothesis posits that peripheral tissues e. Subsequently, numerous hormones and neuropeptides are secreted that alter feedback sensitivity in the hindbrain. A second hypothesis the critical body fat hypothesis posits that a minimum amount of adipose tissue is necessary for the onset of puberty and for the preservation of reproductive function These findings were not conclusively confirmed 17, — and are not mutually exclusive, as body fat is a reflection of energy stores.

Adipose tissue likely participates in the pathogenesis of FHA via adipokines, such as leptin and adiponectin , Recovery from FHA associated with CBT resulted in reduced nocturnal cortisol secretion and increased leptin and TSH without weight gain, suggesting that reducing stress corrects the neuroendocrine and metabolic signature independent of weight gain per se 24, Some women may have a mild hypogonadotropic state that persists for many years with lower gonadotropin and sex steroid concentrations than would be expected for their age. Clinically, these patients may present with a luteal phase defect phenotype i.

In one study of eumenorrheic runners, a larger proportion of the women had anovulatory cycles or a shortened luteal phase compared with sedentary women The long-term clinical significance of these milder menstrual abnormalities, especially with respect to risk for low bone density, cardiovascular disease, and fertility, is unknown. In patients with suspected FHA, it is imperative to elicit a history of galactorrhea, severe or persistent headache, nausea, vomiting, or changes in vision, thirst, or urination both volume and frequency , suggesting the possibility of a prolactinoma or other pituitary or intracranial tumor.

Clinicians should also obtain a history of symptoms suggesting thyroid dysfunction hypothyroidism or hyperthyroidism , symptoms suggesting androgen excess and PCOS, or those consistent with other chronic health conditions — In patients with primary amenorrhea, anosmia or hyposmia can indicate Kallmann syndrome, which is associated with a failure of GnRH neurons to migrate from the olfactory placode to the hypothalamus.

Anxiety, depression, and chronic diseases may also be associated with amenorrhea, and clinicians should look for signs and symptoms of each of these conditions. Clinicians should ask patients about recent exercise and dietary habits and potential changes therein , including a history of binging and purging, current or recent weight changes, and stressors Clinicians should also consider energy availability, which is defined as the energy remaining for normal body functioning after subtracting exercise energy expenditure from the energy ingested.

There is no clear exercise threshold that leads to an energy deficit and eventual amenorrhea. Furthermore, some female athletes have energy deficits from increasing exercise energy expenditure more than energy intake, and others have energy deficits simply from reducing energy intake 45, 51, Additionally, multiple seemingly insignificant stressors may be more disruptive to reproductive function than an easily identified stressor Medications, including antipsychotics, antidepressants, contraceptive agents, and opioids, can alter menses, as discussed 89, Chronic illicit drug use is often a marker of stress and undernutrition.

A patient may require a formal psychiatric evaluation, as conditions associated with inappropriate HPA axis activation can suppress GnRH drive, which might require management with medication. Clinicians should ask about miscarriages and obstetrical complications, which are more common in women with a history of restrictive eating disorders Many endocrine conditions are familial, which may affect age of menarche and menstrual function.

A full physical examination, including weight, height, and an external gynecologic and bimanual examination, enables a clinician to consider the broad differential diagnosis for adolescents and young women with FHA 65, This should include evaluating fundi and visual fields to rule out papilledema or visual field deficits and examining for galactorrhea, thyromegaly, hirsutism, acne, or clitoromegaly.

Lateralizing neurologic signs might indicate intracranial pathology. In addition to weight loss, FHA also manifests symptoms such as bradycardia, mottled, cool extremities, and dermal manifestations of hypercarotenemia Signs of androgen excess e. Occasionally, young women with severe hyperandrogenism will present with amenorrhea, reflecting the atrophic effect of a sustained androgen load on the endometrium. The external gynecologic examination may reveal reddened, thin vaginal mucosa in estrogen-deficient young women, and a bluish bulge in patients with an imperforate hymen.

The bimanual examination can be helpful in some cases, such as to rule out the presence of an adnexal mass. An elevated random or fasting glucose level should prompt clinicians to measure hemoglobin A1C. Studies have shown that liver function tests are altered in adolescents and young women with extreme energy restrictions — However, data to support the cost-effectiveness of specific screening assessments are lacking Clinicians should obtain total testosterone and DHEA-S levels in patients with clinical hyperandrogenism and 8 am hydroxyprogesterone levels if clinicians suspect late-onset CAH.

If properly interpreted, a panel that includes TSH, free T4, prolactin, FSH, E2, and total testosterone detects the most important causes of amenorrhea. The pattern of hormone levels is more critical than absolute values. E2 measurements are typically limited by the fact that a measurement reflects a single time point, and no single E2 value can confirm a diagnosis of FHA. With the latter diagnosis, the acute LH response would be low, but normalizes with prolonged pulsatile GnRH therapy.

For E2, clinicians should follow Endocrine Society guidelines to assure assay validity and reliability In FHA, thyroid function is similar to that seen with any chronic illness, that is, TSH and free T4 levels in the lower range of normal, which generally reverse to normal with weight gain and psychological recovery 5, 24, Testosterone will be in the lower range of normal, and prolactin will be in the low normal range In the absence of signs of androgen excess, measuring FSH, LH, prolactin, TSH, and free T4 will generally provide sufficient information to rule out organic causes of amenorrhea or irregular menstrual cycles, including ovarian insufficiency, hyperprolactinemia, and thyroid dysfunction primary.

Very low and often undetectable LH and FSH levels suggest organic hypothalamic amenorrhea due to genetic mutations affecting GnRH ontogeny and function or central causes, such as pituitary, hypothalamic, or other brain tumors, and infiltrative lesions Table 2. Evaluating basal pituitary hormones is usually sufficient to establish hypopituitarism, and pituitary stimulation tests often do not determine the causes of the pituitary hypofunction.

Assessing thyroid function and prolactin levels is important in adolescents and women with FHA Food, sleep, exercise, coitus, nipple stimulation, breast examination, lactation, and many medications can elevate prolactin concentrations. If TSH is low, one should consider a diagnostic assessment for thyrotoxicosis, especially if the free T4 is high. Similarly, if TSH is high, and free T4 is low or in the lower range of normal, then clinicians must consider subclinical hypothyroidism or hypothyroidism. Conversely, a normal or minimally elevated TSH with a low free T4 may indicate central hypothyroidism.

In the workup for hyperandrogenism, familiarity with local reference ranges is important, as assays are not standardized across laboratories. Clinicians should obtain total or free testosterone levels depending on assay reliability and noting that the former is usually more accurate Some experts consider an elevated free testosterone level measuring both total and free testosterone using a gold standard assay the most useful indicator of PCOS However, defining an absolute level that is diagnostic of PCOS or other causes of hyperandrogenism is difficult; familiarity with local assays is paramount Levels of adrenal androgens tend to be higher in normal-weight compared with overweight women with PCOS A serum AMH concentration is an indicator of ovarian reserve , and can be an additional helpful assessment measure in women with PCOS Similarly, in a patient with primary ovarian insufficiency, the diagnosis could be delayed because hypothalamic amenorrhea attenuates gonadotropin secretion.

Clinicians should also consider this type of morning testing in patients at risk based on ethnicity or family history If clinicians suspect Cushing syndrome, a hour urinary free cortisol, late-night salivary cortisol, or a 1-mg overnight dexamethasone suppression test are reasonable screening tests. If hypercortisolism is present, clinicians should obtain one additional positive test to confirm the diagnosis When the cause of FHA is stress, the increase in cortisol secretion is less than that seen with Cushing syndrome, and the circadian pattern although amplified is preserved 5.

Thus, increases in cortisol concentrations compared with controls are greatest overnight and in the early morning hours, but are typically still within the normal range. Studies have variably reported an increase in basal or pulsatile 14 cortisol secretion in patients with FHA compared with controls, depending on the method researchers used to assess cortisol secretory dynamics. Rarely, secondary adrenal insufficiency presents as fatigue and anovulation, and it may require an ACTH stimulation test for diagnosis.

Acromegaly may present with amenorrhea or irregular menstrual cycles, along with an elevation in growth hormone, insulin-like growth factor IGF -I, and occasionally prolactin concentrations Poorly controlled diabetes may present as oligomenorrhea or amenorrhea from reduced GnRH drive and is diagnosed with an elevated hemoglobin A1C level IGF-I, a nutrition-dependent factor that stimulates osteoblast function and bone formation, can be another useful factor to measure, especially in cases of FHA with a low bone mass , In those patients with overlapping FHA and anorexia nervosa, there may be relative GH resistance—a pattern that is common in the setting of malnutrition, associated with metabolic bone alterations, and that shows improvement with nutritional rehabilitation Thus, this hormonal deficiency may further mediate low concentrations of IGF-I.

Absence of withdrawal bleeding after a course of progestin may indicate outflow tract obstruction or low endometrial estrogen exposure , Progestins are not well tolerated by some patients. Therefore, some clinicians may start with a shorter, 5-day course and repeat in a few weeks if there is no withdrawal bleed.

The latter may require confirmation with MRI. In the absence of the clinical features listed above, there are limited studies to inform the need for obtaining a pituitary MRI, and the number of cases where MRI provides valuable additional information is small. However, if there are no clear indications or other explanations for the amenorrhea such as anorexia nervosa or history of excessive exercise, weight loss, or an eating disorder , clinicians should consider ordering a brain MRI.

Empty sella syndrome can also be present as an underlying diagnosis Of note, starvation-induced patterns of thyroid function tests can resemble central hypothyroidism in patients with eating disorders 65, A history of significant head trauma should raise suspicions of pituitary stalk damage and associated pituitary hormone deficiencies. The goal of bone densitometry is to identify individuals at risk for skeletal fragility, determine the magnitude of compromised bone mass in patients with established bone fragility, and guide and monitor treatment Although current scanners typically generate both Z -scores and T-scores, clinicians should only consider a BMD Z -score in adolescents or premenopausal women.

The Z -score compares the BMD measure to age-, sex-,and often race- or ethnicity-matched controls. DXA is the most commonly used densitometric technique for adolescents and adults throughout the world because of its speed, precision, safety, low cost, and widespread availability.

Studies have used total body BMD measurements to assess many chronic conditions, including eating disorders e. However, the spine a trabecular-rich site is the most common site of low bone density in adolescents and young women with amenorrhea and also predicts fracture risk; it is therefore an important site to monitor , — In older adolescents above age 15 years and women with FHA, measuring hip bone density affords additional information about weight-bearing cortical bone and can be useful to monitor bone density longitudinally Two studies have noted deficits in bone geometry and strength at the hip in older adolescents with anorexia nervosa , , and another study noted deficits in adolescent and young adult athletes Therefore, hip BMD measures can provide important information in the older adolescent or young woman.

After 6 months of amenorrhea, clinicians should consider a baseline DXA evaluation in any adolescent or woman with FHA 45, 53, 64, Restrictive eating disorders, such as anorexia nervosa, represent the extreme end of the spectrum of energy availability.

Although we know that weight-bearing exercise is beneficial for healthy youth, with beneficial effects on bone accrual and peak bone mass , , we can see a lack of skeletal gains and even frank bone loss in both female athletes with eating disorders and low weight and female athletes with normal-weight amenorrhea during adolescence , , , , , In addition to deficits in areal bone density as assessed by DXA , studies have reported deficits in volumetric bone density, abnormal bone microarchitecture, and lower strength estimates in patients with eating disorders , , , and in adolescent and young adult amenorrheic athletes , , Young women with eating disorders are known to be at a sevenfold higher risk of fracture , and stress fractures are a recurrent problem among female athletes with amenorrhea 45, 50, Recent work has indicated that athletes with eating disorders or other evidence of compromised energy availability should meet established weight goals and other clinic criteria before continue exercising, and these athletes may need to modify their training and competition 51, Recent sports consensus groups, including the Female Athlete Triad Coalition and International Olympic Committee, recommend that athletes undergo screening for components of the triad and potentially meet certain energy availability requirements before continuing to exercise 53, Fractures are much more common in athletes with distorted eating patterns than in those with normal dietary habits A low-energy state leads to low bone formation and low bone turnover rates, whereas postpubertal hypogonadism favors a resorptive state.

Low bone turnover impairs the normal mechanisms that repair bone microdamage and injuries due to overuse, leading to a higher risk for fracture. Adolescents with anorexia nervosa are characterized by reduced bone turnover , whereas young adult women with the condition have an uncoupling of bone turnover 43, The uncoupling of bone turnover is seen even in short-term starvation in normal exercising women ; this pattern of uncoupling is unique to nutritional deprivation 55— Researchers also reported the uncoupling of bone turnover markers in exercise-associated amenorrhea, with the most significant effects on bone mass occurring in women who were both energy deficient and estrogen deficient or had multiple risk factors When the energy status of exercising women is adequate, there appears to be no perturbation of bone formation, regardless of estrogen status 53, These studies present compelling evidence that the bone loss of anorexia nervosa and exercise-associated amenorrhea is not analogous to the bone loss seen with ovarian insufficiency or castration, which represent a pure form of hypogonadism with isolated estrogen deficiency but without hypercortisolemia and other endocrine alterations.

Bone accretion can be adversely affected by elevated cortisol, reduced T3 and T4, reduced E2, and alterations in other hormones that result in a catabolic metabolic state. Defining reproductive tract anatomies is always the first step in excluding anatomic causes of amenorrhea, and it is especially important in primary amenorrhea Table 1 In some women with FHA, clinicians may consider a hysterosalpingogram, sonohysterogram, or saline infusion sonogram or hysteroscopy to establish acquired gynecologic tract abnormalities.

Asherman syndrome from intrauterine synechiae, adhesions, or unintended endometrial ablation may present as secondary amenorrhea. A history of a postpartum dilation and curettage or pelvic infection may raise suspicion of endometrial injury. Irregular and erratic bleeding may be due to intrauterine polyps or intramural fibroids rather than functional hypothalamic hypogonadism. In some adolescents and women, overzealous dieting masks PCOS symptoms. However, they seem to be at similar risk for developing osteopenia and osteoporosis, based on World Health Organization criteria These patients are also hyperresponsive to exogenous gonadotropins when treated for infertility and need to be monitored carefully — Adolescents and young women who exhibit a severe energy deficit as in a restrictive eating disorder can ultimately develop hemodynamic instability, exhibiting hypotension, bradycardia, and orthostasis.

International experts have developed guidelines to address criteria for an inpatient medical admission Careful monitoring of the very low weight patient is warranted, as the mortality rate associated with eating disorders, and especially anorexia nervosa, is high — Clinicians often need to refer patients to a dietitian or nutritionist to provide individualized dietary instructions.

Energy availability is dietary energy intake minus exercise energy expenditure, normalized to fat free mass. This concept encompasses the amount of energy remaining for other bodily functions after exercise training Weight gain through refeeding and improved energy availability in amenorrheic patients with anorexia nervosa correlated with the resumption of menses Increased energy availability through diet or diet and exercise modification in dancers and athletes with FHA also improved menstrual function 85, 86, , First ovulation may occur before resumption of the first menstrual period, and sexually active young women need to be especially cognizant of this fact.

Because FHA often includes a combination of etiologic factors, including stress, low weight, excessive exercise, and poor nutrition, a multidisciplinary approach is ideal. The approach should include dietary evaluation and counseling through work with a registered dietitian to optimize calories and intake of vitamin D, calcium, and other nutrients , as well as psychological support for treating stress and enhancing behavioral change through work with a psychotherapist, licensed social worker, psychologist, or psychiatrist 45, 53, Some think that physiological adaption to inadequate caloric intake is an etiologic factor for metabolic changes and ensuing reproductive dysfunction.

Multiple physiologic changes occur, but are reversible.

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The reversal of these with weight gain or a decrease in exercise may point to precipitating factors, although few studies have examined the precise weight gain needed for the resumption of HPO function. Amenorrhea may persist for some time after the reversal of precipitating factors.

One study suggested that the weight gain needed for the restoration of menses was 2. At least 6 to 12 months of weight stabilization may be required for the resumption of menses. In some cases, regular menses may never resume after weight stabilization, emphasizing the importance of psychological factors and stress. In-depth nutritional studies of women with FHA have suggested nutritional aberrations or an incipient eating disorder 33, 34, 41, 42, 50, , , Women with FHA have been found to exhibit more dysfunctional attitudes, have greater difficulty in coping with daily stresses, and tend to have more interpersonal dependence than do eumenorrheic women.

They also more often have a history of psychiatric disorders and primary mood disorders than do eumenorrheic women 20, A study of 16 women with FHA normal body weight and no reported psychiatric conditions, eating disorders, or excessive exercise randomized eight subjects to CBT and eight to observation for 20 weeks. Most of the CBT-treated group six of eight achieved ovulatory recovery compared with only in one of eight in the observation group CBT not only restores ovarian function, it also alters metabolic function.

However, in most studies that tested the use of CBT for psychosomatic conditions, the effect size accrued across time as subjects incorporated the lessons into daily living. Effects of other forms of psychotherapy, including dialectical behavior therapy and family-based treatment among others , have not been well described in FHA and thus merit investigation. OCPs provide a progestin and various doses and types of estrogen typically ethinyl E2 in a daily pill.

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Patients use OCPs to prevent pregnancy and treat dysmenorrhea, menorrhagia, hyperandrogenism, and acne, among other conditions. OCP treatment is not intended for the resumption of normal menses with normal endogenous hormonal fluctuations, as OCP formulations modulate endogenous hormone levels and suppress ovarian function even in women who report previously normal cycles — Several studies have shown a lack of a protective effect of oral contraceptives on bone , The lack of clear benefit is likely related to the persistence of neuroendocrine concomitants, including hypercortisolism and decreased thyroid levels.

One study has examined combined therapy with transdermal estrogen and oral progesterone in adolescents with anorexia nervosa. At 6, 12, and 18 months, there were significant increases in lumbar BMD in the treatment vs placebo groups; these increases approximated bone accrual rates in normal-weight healthy controls. There were also significant improvements in hip BMD at 18 months in the treatment vs placebo groups. In contrast, a 2-year study of ballet dancers showed no effect of daily oral estrogen conjugated estrogens 0.

The study reported that bone loss was arrested at the hip, spine, and whole body in the treatment group, whereas there were progressive skeletal losses during 18 months in subjects randomized to placebo. None of these studies assessed fracture outcomes following study-related interventions. The optimal type of estrogen and optimal estrogen replacement dose for bone and other tissues deserves further study. Clinicians may consider estrogen replacement if reasonable attempts to modify nutritional, psychological, and exercise-related variables are not successful in establishing menses.

The systematic review commissioned by the Endocrine Society did not identify published studies that have evaluated the use of bisphosphonates to prevent bone loss in patients with FHA. Four studies have evaluated their use in premenopausal women with anorexia nervosa and associated amenorrhea. The studies reported small but significant increases in BMD in both adolescents and adults [up to 4. However, the studies were small, used different bisphosphonate formulations and protocols, and no study examined efficacy and safety in patients with FHA outside of an eating disorder.


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Importantly, note that bisphosphonates are incorporated into bone and retained for years in the human skeleton. Animal models have demonstrated risks to fetuses of mothers receiving bisphosphonates. Thus, there are concerns that even prepregnancy administration of bisphosphonates may result in drug mobilization from the maternal skeleton during pregnancy, with transplacental passage that can result in the potential for fetal teratogenicity.

A review of available published cases of human exposure to bisphosphonates before or during pregnancy 51 cases did not identify any skeletal or other fetal anomalies However, we need to carefully balance the theoretical risks with potential treatment benefits. It has not been tested in premenopausal women.

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However, inadvertent fetal exposure is a theoretical risk in reproductive age women who use denosumab, as a study in nonhuman primates reported transplacental transfer and potential for teratogenicity In postmenopausal women with osteoporosis, denosumab use has resulted in decreased fracture risk and improved BMD compared with placebo We need studies in premenopausal women, specifically those with FHA. Those on treatment had increased mean LH levels and pulse frequency after 2 weeks and improved follicular development, ovarian volume, and E2 levels by 3 months.

Three patients had an ovulatory menstrual cycle and two others had preovulatory follicular development and withdrawal bleeding during treatment. Recombinant leptin significantly increased levels of free T3, free T4, IGF-I, IGF-binding protein-3, bone alkaline phosphatase, and osteocalcin, but did not increase levels of cortisol, corticotropin, or urinary N-terminal telopeptides.

Unfortunately, the study reported subjective reductions in appetite and significant decreases in weight and fat mass in the treatment group, which has called into question the use of leptin in this patient group The controls had no significant changes in LH pulsatility, body weight, ovarian variables, or other hormone levels A follow-up study in women with exercise-associated FHA found that seven of 10 women recovered menses after a 9-month treatment period with metreleptin a synthetic analog of leptin vs only two of the nine women who received placebo.

Researchers noted weight loss and decreased body fat and therefore made adjustments to metreleptin dosages. Despite these adjustments, women receiving metreleptin had a reduction in body fat mass. The study did not find BMD differences between treatment groups, although bone mineral content increased in the treatment group In a study extension, after a 3-month washout period, six subjects chose to continue on open-label metreleptin treatment for another 12 months.

Metreleptin significantly increased BMD and bone mineral content at the lumbar spine range, 2. Changes in hormonal and metabolic parameters and bone markers were moderate during the first year of treatment, but metreleptin further increased IGF-I and decreased cortisol and bone resorption markers serum C-terminal telopeptides during the second year However, because of the small numbers studied and the serious weight loss side effect, we need more exploration before recommending metreleptin as an FHA treatment. Small studies of parathyroid hormone in adult premenopausal women with idiopathic osteoporosis and premenopausal women with anorexia nervosa have reported short-term improvements in BMD, but there has been no long-term follow-up.

In a randomized controlled trial of adults with anorexia nervosa randomized to rPTH or placebo for 6 months, spine BMD increased significantly more with teriparatide posteroanterior spine, 6. Although there were differences noted in type of fracture, time since fracture prior to initiating rPTH, age of patients, duration of treatment, and other discrepancies, this review suggests there may be a role for rPTH to improve fracture healing in selected patients There are no published studies on effects of rPTH treatment and fracture risk reduction in premenopausal women.

There have been no reported cases of osteosarcoma after teriparatide therapy in humans. However, we need more studies in the FHA population. In most patients, exogenous GnRH or exogenous gonadotropin would likely be efficacious for inducing ovulation and pregnancy in women with FHA. Because GnRH allows pituitary—ovarian feedback mechanisms to remain intact, pulsatile GnRH is widely accepted as an ideal treatment of FHA that leads to a more physiologic ovulatory menstrual cycles with monofollicular development and minimal if any increase in multiple pregnancy , Large case series favor the use of GnRH.

Leyendecker et al. Filicori et al. Of the , approximately half were in women with hypogonadotropism. Only 3. Martin et al. The study observed three or more follicles in The gonadotropin preparation Martin et al. Schoot et al. The researchers suggested that LH activity was essential in individuals without endogenous LH. There are no randomized clinical trials that have evaluated the use of clomiphene citrate for treating infertility in women with FHA.

Most case series do not favor its use, as we do not expect that women with FHA would be able to respond successfully to opening the estrogen negative feedback loop. One case series of eight women with FHA suggested that a prolonged clomiphene protocol might be more successful than the 5-day regimen typically used in clinical practice Djurovic et al. All 17 had significant increases in LH and E2 levels. Researchers have investigated kisspeptin as a possible modality for restoring LH pulsatility and gonadal function in women with FHA. Jayasena et al.

This dosing regimen may prove more effective than the twice daily and twice weekly subcutaneous injections previously studied , We need more research on therapeutic uses of kisspeptin, which is not yet clinically available. As discussed previously, one small week study of normal-weight women with FHA randomized to CBT vs observation showed that CBT not only leads to recovery of ovulation, but also improves metabolic function 24, However, further research is needed to understand the long-term effect of this therapy on health outcomes in adolescents and women with FHA.

A BMI of Therefore, we also considered this weight the minimal threshold that a woman needs to optimize her chances for fertility, and higher would be better. There are data suggesting that an extremely low BMI is associated with a higher risk for adverse pregnancy outcomes This volume represents an up-to-date overview on the major areas of gynecological endocrinology, providing the reader with a complete explanation of female endocrine regulation and metabolism and relevant disorders and treatment.

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Medicine Gynecology. A comprehensive, high-level clinical reference on the female endocrine metabolism and relevant disorders Provides the latest clinical experience of well-known experts in this continuously evolving field Offers practical guidance on the evaluation and treatment of female endocrine problems and infertility and discusses future trends in human reproduction see more benefits. Buy eBook. Buy Hardcover. Buy Softcover. Rent the eBook. FAQ Policy.