Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline

Potential Etiologies of Amenorrhea

Congenital malformation

Septo-optic dysplasia

Holoprosencephaly

Encephalocele

Constitutional delay

Genetic conditions

Congenital deficiency of hypothalamic or pituitary transcription factors (gonadotropin deficiency)

Single-gene mutations (hypogonadotropic hypogonadism)

Hyperprolactinemia

Pituitary gland or stalk damage

Tumors and cysts [hypothalamic or pituitary tumor (hormone-secreting), craniopharyngioma, Rathke cleft cyst, other cysts, and tumors]

Infiltrative disorders (germinoma, autoimmune hypophysitis, sarcoidosis, hemochromatosis, tuberculosis, Langerhans cell histiocytosis, IgG4-related hypophysitis)

Irradiation

Infarction [apoplexy in pre-existing pituitary tumors, or following postpartum hemorrhage (Sheehan syndrome)]

Surgery

Trauma

Others

Eating disorders

Competitive athletics

Chronic disease

Mood disorders

Stress or psychiatric illness

Drugs

Thyroid

Hypothyroidism or hyperthyroidism

Adrenals

Congenital adrenal hyperplasia (select types)

Cushing syndrome

Addison disease (adrenal insufficiency)

Tumor (androgen-secreting)

Ovaries

Associated with high levels of gonadotropins

Gonadal agenesis or dysgenesis (in the setting of Turner syndrome/other)

Ovarian insufficiency

Autoimmune oophoritis

Irradiation or surgery

Not associated with high levels of gonadotropins

Polycystic ovary syndrome

Tumor (estrogen- or androgen-secreting)

Uterus (eugonadism)

Müllerian anomalies (obstructive outflow anomalies)

Asherman syndrome

Synechiae (integral to Asherman syndrome)

Pregnancy

Infectious (e.g., tuberculous endometritis)

Agenesis (uterine or cervical)

Vagina (eugonadism)

Agenesis

Transverse septum

Hymen (eugonadism)

Imperforate

Table 1.

Potential Etiologies of Amenorrhea

Congenital malformation

Septo-optic dysplasia

Holoprosencephaly

Encephalocele

Constitutional delay

Genetic conditions

Congenital deficiency of hypothalamic or pituitary transcription factors (gonadotropin deficiency)

Single-gene mutations (hypogonadotropic hypogonadism)

Hyperprolactinemia

Pituitary gland or stalk damage

Tumors and cysts [hypothalamic or pituitary tumor (hormone-secreting), craniopharyngioma, Rathke cleft cyst, other cysts, and tumors]

Infiltrative disorders (germinoma, autoimmune hypophysitis, sarcoidosis, hemochromatosis, tuberculosis, Langerhans cell histiocytosis, IgG4-related hypophysitis)

Irradiation

Infarction [apoplexy in pre-existing pituitary tumors, or following postpartum hemorrhage (Sheehan syndrome)]

Surgery

Trauma

Others

Eating disorders

Competitive athletics

Chronic disease

Mood disorders

Stress or psychiatric illness

Drugs

Thyroid

Hypothyroidism or hyperthyroidism

Adrenals

Congenital adrenal hyperplasia (select types)

Cushing syndrome

Addison disease (adrenal insufficiency)

Tumor (androgen-secreting)

Ovaries

Associated with high levels of gonadotropins

Gonadal agenesis or dysgenesis (in the setting of Turner syndrome/other)

Ovarian insufficiency

Autoimmune oophoritis

Irradiation or surgery

Not associated with high levels of gonadotropins

Polycystic ovary syndrome

Tumor (estrogen- or androgen-secreting)

Uterus (eugonadism)

Müllerian anomalies (obstructive outflow anomalies)

Asherman syndrome

Synechiae (integral to Asherman syndrome)

Pregnancy

Infectious (e.g., tuberculous endometritis)

Agenesis (uterine or cervical)

Vagina (eugonadism)

Agenesis

Transverse septum

Hymen (eugonadism)

Imperforate

Overall, we recognize three main underlying causes of FHA: weight loss, and/or vigorous exercise, and/or stress (5, 20, 21, 65, 71). 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. Regardless of the trigger, FHA is characterized by abnormalities in GnRH secretion or dynamics (4, 33, 72). 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. In 2003, Loucks and Thuma (17) set the threshold for energy availability at 30 kcal/kg (in an acute setting), below which LH pulsatility is disrupted (73). Williams et al. (74) estimated that experimental reduction of energy by 470 and 810 kcal per day led to an increased frequency of menstrual disturbance. 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.e., luteal phase deficiency in progesterone secretion) (76); and abnormalities in peptide YY and other adipokines (Fig. 1) (77, 78). These hormonal changes occur as a consequence of low energy availability and can directly impact the HPO axis, thus disrupting menstrual function.

In adolescents or women with FHA manifesting an energy deficit, there is a spectrum of presentations and/or diseases. 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.g., gymnastics, cheerleading, figure skating, running) (65, 79–81). 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, 83). The severity of the menstrual dysfunction has been shown to increase in proportion to indices of energy conservation in exercising women (84). One study suggested that increasing energy to >30 kcal/kg of fat free mass per day may reverse the amenorrhea, but more data are needed to confirm this finding (85). Another report on exercising women showed a reversal of amenorrhea in three of four amenorrheic athletes with nutritional intervention (86). 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.g., hyperexercise, restricting eating) may reflect underlying obsessions and anxiety (20, 21, 87). 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 (88). 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. In a study of 50 patients on antipsychotic medications, 90% reported eumenorrhea prior to the initiation of their treatment, whereas 54% and 12% reported menstrual abnormalities and amenorrhea, respectively, during antipsychotic usage (90). 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 (91–93).

1.2 We suggest diagnostic evaluation for FHA in adolescents and women whose menstrual cycle interval persistently exceeds 45 days and/or those who present with amenorrhea for 3 months or more. (2|⊕⊕○○)

Evidence

Adolescents or young women with FHA typically report amenorrhea for 6 months or longer (35, 65, 94–96). 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, 98). 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, 83). 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 (99). Women with functional hypothalamic hypogonadism may thus also present with eumenorrhea and infertility rather than amenorrhea. Lastly, it is noteworthy that as many as half of patients with PCOS with a nonhyperandrogenic PCOS phenotype (i.e., oligomenorrhea and polycystic ovarian morphology on ultrasound) may have FHA (100).

Remarks

The absence of menses or by irregular menstrual cycles due to insufficient stimulation and/or suppression of the HPO axis is characteristic of FHA. It can be related to stress, anxiety, weight change, energy imbalance, and/or excessive exercise.

1.3 We suggest screening patients with FHA for psychological stressors (patients with FHA may be coping with stressors, and stress sensitivity has multiple determinants). (2|⊕⊕⊕○)

Evidence

Available evidence suggests that psychogenic stimuli, both external and internal, activate the HPA axis. Any psychogenic event (e.g., start of college, profound grief, loss of weight) that may elicit an increase in cortisol secretion results in metabolic adaptation. 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, 101, 102). Studies have also suggested that energy imbalance sensitizes the HPO axis to psychological stress (21, 103). Both animal and human studies have shown that an actual stressor (e.g., psychological stress, decreased energy availability, drive for thinness), as well as perception or anticipation of a threat, may elicit similar endocrine consequences to alter menses (104–111). Data indicate that women who exercise or are under dietary restriction develop FHA as an adaptive response to chronic metabolic energy deficiency (33, 112). The physiological process of adaptation diverts energy and other resources (e.g., emotion, vigilance) to systems needed for survival (101). 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.e., the pattern of low thyrotropin-releasing hormone, normal/low TSH, and decreased triiodothyronine (T3) and T4 indicates an increased negative feedback of thyroid hormones at the hypothalamus level and reduced thyroidal responsivity to TSH] (5, 24, 65).

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.g., liver, adipose tissue, pancreas, stomach, duodenum, and hindbrain) detect short-term reduced amounts of fuels available for oxidation (e.g., oxidizable glucose, fatty acids, or ketone bodies) through neural or humoral afferents (with the hindbrain being the main detection site) (113–115). 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 (116). These findings were not conclusively confirmed (17, 117–119) 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 (120, 121). 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, 35).

1.4 Once clinicians establish the diagnosis of FHA, we suggest they provide patient education about various menstrual patterns occurring during the recovery phase. We suggest clinicians inform patients that irregular menses do not require immediate evaluation and that menstrual irregularity does not preclude conception. (Ungraded Good Practice Statement)

Evidence

Adolescents and women who are recovering from a restrictive eating disorder and/or female athletes can exhibit a larger spectrum of hypogonadotropic hypogonadism in addition to amenorrhea. Women recovering from anorexia nervosa, as well as some female athletes, may go through a stage of inadequate luteal phase (with disordered folliculogenesis and follicular dynamics), exhibiting elements of the “female athlete triad” (i.e., decreased energy availability, menstrual dysfunction, and low bone density) as they modify their caloric intake and/or activity level (95).

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.e., long menstrual cycles with prolonged follicular phases and short luteal phases with premenstrual spotting or early arrival of menses due to reduced progesterone secretion) (95, 122). In one study of eumenorrheic runners, a larger proportion of the women had anovulatory cycles or a shortened luteal phase compared with sedentary women (99). 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.

2.0 Evaluation

2.1 In patients with suspected FHA, we recommend obtaining a detailed personal history with a focus on diet; eating disorders; exercise and athletic training; attitudes, such as perfectionism and high need for social approval; ambitions and expectations for self and others; weight fluctuations; sleep patterns; stressors; mood; menstrual pattern; fractures; and substance abuse. Clinicians should also obtain a thorough family history with attention to eating and reproductive disorders. (Ungraded Good Practice Statement)

Evidence

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 (123–125). 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 (126). A short, reliable tool (that corresponds to the patient’s native language) can help clinicians better understand eating disordered cognitions and behaviors (127). 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, 64). Additionally, multiple seemingly insignificant stressors may be more disruptive to reproductive function than an easily identified stressor (22).

Medications, including antipsychotics, antidepressants, contraceptive agents, and opioids, can alter menses, as discussed (89, 90). 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 obtain a full family history, including queries regarding eating disorders and/or reproductive endocrine issues among family members (65). Clinicians should ask about miscarriages and obstetrical complications, which are more common in women with a history of restrictive eating disorders (128). Many endocrine conditions are familial, which may affect age of menarche and menstrual function.

2.2 In a patient with suspected FHA, we recommend excluding pregnancy and performing a full physical examination, including a gynecological examination (external, and in selected cases, bimanual), to evaluate the possibility of organic etiologies of amenorrhea. (1|⊕⊕⊕○)

Evidence

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, 70). 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 (129). Signs of androgen excess (e.g., acne, hirsutism, male pattern alopecia, clitoromegaly) and hyperinsulinism (e.g., acanthosis nigricans and skin tags) should raise concerns of PCOS or other causes of androgen excess (e.g., nonclassic CAH and virilizing ovarian and adrenal tumors) (130). 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. It is most critical in cases of primary amenorrhea, to evaluate for imperforate hymen, Müllerian anomaly (with a shortened vagina and absent or rudimentary uterus), or androgen insensitivity (blind vaginal pouch) (123–125). Depending on the skills of the clinician and the preference/cooperation of the patient, patients with amenorrhea (and some young adolescents) might consider a transabdominal or transvaginal pelvic sonogram on initial presentation instead of the bimanual examination.

2.3 In adolescents and women with suspected FHA, we recommend obtaining the following screening laboratory tests: β-human chorionic gonadotropin, complete blood count, electrolytes, glucose, bicarbonate, blood urea nitrogen, creatinine, liver panel, and (when appropriate) sedimentation rate and/or C-reactive protein levels. (1|⊕⊕⊕⊕)

Evidence

General laboratory testing, beginning with a β-human chorionic gonadotropin to rule out pregnancy, initiates a comprehensive workup for the adolescent or young woman with FHA. Clinicians should obtain a complete blood count, chemistry panel, liver panel, sedimentation rate, and/or C-reactive protein level in those suspected to have a chronic illness manifesting as hypogonadism. An elevated random or fasting glucose level should prompt clinicians to measure hemoglobin A1C. A high sedimentation rate and/or C-reactive protein level suggests a chronic inflammatory condition. Studies have shown that liver function tests are altered in adolescents and young women with extreme energy restrictions (131–133). However, data to support the cost-effectiveness of specific screening assessments are lacking (65).

2.4 As part of an initial endocrine evaluation for patients with FHA, we recommend obtaining the following laboratory tests: serum TSH, free T4, prolactin, LH, FSH, E2, and AMH. Clinicians should obtain total testosterone and DHEA-S levels in patients with clinical hyperandrogenism and 8 am 17-hydroxyprogesterone levels if clinicians suspect late-onset CAH. (1|⊕⊕⊕⊕)

Evidence

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. Patients with FHA have characteristically low or low normal LH, normal FSH concentrations (which are usually higher than LH concentrations), E2 <50 pg/mL, and progesterone <1 ng/mL; the acute gonadotropin response to GnRH stimulation is preserved (defined as a twofold to threefold rise in LH and FSH compared with baseline levels). 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. However, in patients whose E2 is persistently <20 pg/mL, the response to GnRH is the only feature that may differentiate FHA from hypogonadotropic hypogonadism. 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 (134). 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, 134). Testosterone will be in the lower range of normal, and prolactin will be in the low normal range (65).

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). Elevated FSH and LH levels with low E2 (<20 pg/mL) and progesterone (<1 ng/mL) indicate low or absent ovarian reserve consistent with complete or impending ovarian insufficiency. In contrast, high FSH and LH levels with E2 >150 pg/mL and progesterone <2 ng/mL indicate the midcycle gonadotropin surge. In FHA, LH and FSH are often normal, a confusing point to clinicians, as E2 levels are low and LH/FSH ratios may be elevated when a patient has underlying PCOS. 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.

Table 2.

Common Causes of Anovulation and Accompanying Laboratory Patterns

	LH (IU/L)	FSH (IU/L)	LH/FSH	E2 (pg/mL)	P4 (ng/mL)	AMH (ng/mL)	PRL (ng/mL)	TSH (µU/mL)	T4 (µg/dL)	DHEA-S (µg/dL)	17OHP (ng/dL)	T (ng/dL)
Functional hypothalamic anovulation	<10	<10	∼1	<50	<1	>1	Low nl	Low nl	Low nl	nl	nl	Low nl
Ovarian insufficiency menopause	>15	>15	FSH > LH	<50	<1	<0.5	nl	nl or ↑	nl or ↓	nl	nl	Low nl
PCOS	<15	<10	LH > FSH	<50	<1	nl or ↑	High nl	nl	nl	High nl	nl	High nl or slight↑
Nonclassical CAH	<15	<10	LH > FSH	<50	≤1	nl	nl	nl	nl	High nl	↑	↑
Hyperprolactinemia	<10	<10	LH < FSH	<50	<1	nl	↑	nl or ↑	nl	nl or slight ↑	nl	nl

	LH (IU/L)	FSH (IU/L)	LH/FSH	E2 (pg/mL)	P4 (ng/mL)	AMH (ng/mL)	PRL (ng/mL)	TSH (µU/mL)	T4 (µg/dL)	DHEA-S (µg/dL)	17OHP (ng/dL)	T (ng/dL)
Functional hypothalamic anovulation	<10	<10	∼1	<50	<1	>1	Low nl	Low nl	Low nl	nl	nl	Low nl
Ovarian insufficiency menopause	>15	>15	FSH > LH	<50	<1	<0.5	nl	nl or ↑	nl or ↓	nl	nl	Low nl
PCOS	<15	<10	LH > FSH	<50	<1	nl or ↑	High nl	nl	nl	High nl	nl	High nl or slight↑
Nonclassical CAH	<15	<10	LH > FSH	<50	≤1	nl	nl	nl	nl	High nl	↑	↑
Hyperprolactinemia	<10	<10	LH < FSH	<50	<1	nl	↑	nl or ↑	nl	nl or slight ↑	nl	nl

Abbreviations: 17OHP, 17-hydroxyprogesterone; nl, normal; P4, progesterone; PRL, prolactin; T, testosterone.

Table 2.

Common Causes of Anovulation and Accompanying Laboratory Patterns

	LH (IU/L)	FSH (IU/L)	LH/FSH	E2 (pg/mL)	P4 (ng/mL)	AMH (ng/mL)	PRL (ng/mL)	TSH (µU/mL)	T4 (µg/dL)	DHEA-S (µg/dL)	17OHP (ng/dL)	T (ng/dL)
Functional hypothalamic anovulation	<10	<10	∼1	<50	<1	>1	Low nl	Low nl	Low nl	nl	nl	Low nl
Ovarian insufficiency menopause	>15	>15	FSH > LH	<50	<1	<0.5	nl	nl or ↑	nl or ↓	nl	nl	Low nl
PCOS	<15	<10	LH > FSH	<50	<1	nl or ↑	High nl	nl	nl	High nl	nl	High nl or slight↑
Nonclassical CAH	<15	<10	LH > FSH	<50	≤1	nl	nl	nl	nl	High nl	↑	↑
Hyperprolactinemia	<10	<10	LH < FSH	<50	<1	nl	↑	nl or ↑	nl	nl or slight ↑	nl	nl

	LH (IU/L)	FSH (IU/L)	LH/FSH	E2 (pg/mL)	P4 (ng/mL)	AMH (ng/mL)	PRL (ng/mL)	TSH (µU/mL)	T4 (µg/dL)	DHEA-S (µg/dL)	17OHP (ng/dL)	T (ng/dL)
Functional hypothalamic anovulation	<10	<10	∼1	<50	<1	>1	Low nl	Low nl	Low nl	nl	nl	Low nl
Ovarian insufficiency menopause	>15	>15	FSH > LH	<50	<1	<0.5	nl	nl or ↑	nl or ↓	nl	nl	Low nl
PCOS	<15	<10	LH > FSH	<50	<1	nl or ↑	High nl	nl	nl	High nl	nl	High nl or slight↑
Nonclassical CAH	<15	<10	LH > FSH	<50	≤1	nl	nl	nl	nl	High nl	↑	↑
Hyperprolactinemia	<10	<10	LH < FSH	<50	<1	nl	↑	nl or ↑	nl	nl or slight ↑	nl	nl

Abbreviations: 17OHP, 17-hydroxyprogesterone; nl, normal; P4, progesterone; PRL, prolactin; T, testosterone.

Assessing thyroid function and prolactin levels is important in adolescents and women with FHA (65). Food, sleep, exercise, coitus, nipple stimulation, breast examination, lactation, and many medications can elevate prolactin concentrations. If a patient has more profound hyperprolactinemia (serum prolactin >100 ng/mL), she will require additional evaluation that is beyond the scope of this guideline. 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) (135). Clinicians should also consider measuring serum DHEA-S to rule out adrenal etiologies (136). 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 (137). However, defining an absolute level that is diagnostic of PCOS or other causes of hyperandrogenism is difficult; familiarity with local assays is paramount (138). Levels of adrenal androgens tend to be higher in normal-weight compared with overweight women with PCOS (139). A serum AMH concentration is an indicator of ovarian reserve (140, 141) and can be an additional helpful assessment measure in women with PCOS (142). In FHA, gonadotropins will be lower than expected for PCOS. Similarly, in a patient with primary ovarian insufficiency, the diagnosis could be delayed because hypothalamic amenorrhea attenuates gonadotropin secretion.

If the patient has signs of virilization and/or substantial elevations in DHEA-S and/or testosterone (free or total), an 8 am 17-hydroxyprogesterone level can serve as an initial screen for nonclassic CAH, although a high-dose ACTH stimulation test may be necessary to confirm the diagnosis. Clinicians should also consider this type of morning testing in patients at risk based on ethnicity or family history (143). High DHEA-S levels in concentrations that far exceed the normal range (e.g., DHEA-S >600 μg/dL) might indicate an adrenal tumor (144). Some patients with poorly differentiated adrenal tumors may have higher circulating levels of DHEA than DHEA-S (145).

If clinicians suspect Cushing syndrome, a 24-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 (146). 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 (147) 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 (148). Poorly controlled diabetes may present as oligomenorrhea or amenorrhea from reduced GnRH drive and is diagnosed with an elevated hemoglobin A1C level (149).

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 (150, 151). 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 (152). Similarly, studies have shown low DHEA-S levels in adolescents and young women with FHA in the setting of anorexia nervosa, despite the presence of hypercortisolemia and adequate ACTH (153–155). The actions of DHEA may be mediated through IGF-I (156). Thus, this hormonal deficiency may further mediate low concentrations of IGF-I.

2.5 After excluding pregnancy, we suggest administering a progestin challenge in patients with FHA to induce withdrawal bleeding (as an indication of chronic estrogen exposure) and ensure the integrity of the outflow tract. (2|⊕⊕⊕○)

Evidence

Absence of withdrawal bleeding after a course of progestin may indicate outflow tract obstruction or low endometrial estrogen exposure (157, 158). The response to a progestin challenge can provide additional information about a patient’s estrogen status, especially in those cases in which there is overlay between FHA and PCOS. Options include medroxyprogesterone acetate (5 to 10 mg/d for 5 to 10 days), norethindrone acetate (5 mg/d for 5 to 10 days), or micronized progesterone (200 to 300 mg/d for 10 days).

Remarks

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. Follow-up with a pelvic ultrasound may be necessary if the patient does not have a withdrawal bleed and is useful in determining endometrial thickness and Müllerian tract integrity. The latter may require confirmation with MRI.

2.6 We recommend a brain MRI (with pituitary cuts and contrast) in adolescents or women with presumed FHA and a history of severe or persistent headaches; persistent vomiting that is not self-induced; change in vision, thirst, or urination not attributable to other causes; lateralizing neurologic signs; and clinical signs and/or laboratory results that suggest pituitary hormone deficiency or excess. (1|⊕⊕⊕○)

Evidence

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 (159). Of note, starvation-induced patterns of thyroid function tests can resemble central hypothyroidism in patients with eating disorders (65, 70). A history of significant head trauma should raise suspicions of pituitary stalk damage and associated pituitary hormone deficiencies.

2.7 We suggest that clinicians obtain a baseline BMD measurement by DXA from any adolescent or woman with 6 or more months of amenorrhea, and that clinicians obtain it earlier in those patients with a history or suspicion of severe nutritional deficiency, other energy deficit states, and/or skeletal fragility. (2|⊕⊕⊕○)

Evidence

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 (160). Clinicians should more attentively monitor nutritional intake and a patient’s skeletal status if a baseline BMD Z-score is −2.0 or less at any skeletal site (160). For athletes involved in weight-bearing sports, the American College of Sports Medicine recommends increased surveillance when the BMD Z-score is −1.0 or less, considering that an athlete should have a higher than average BMD from ongoing continuous skeletal loading (45). 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.g., anorexia nervosa) (44, 150, 161), as low bone density measures of the total body predict fracture risk and also provide an assessment of body composition (160). 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 (150, 162–166). 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 (160). Two studies have noted deficits in bone geometry and strength at the hip in older adolescents with anorexia nervosa (156, 167), and another study noted deficits in adolescent and young adult athletes (168). 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, 65).

Restrictive eating disorders, such as anorexia nervosa, represent the extreme end of the spectrum of energy availability. Affected patients exhibit skeletal losses and/or lack of bone accretion (50, 52, 169–172) and are known to be at high risk for fracture (173, 174) compared with normal-weight peers. Although we know that weight-bearing exercise is beneficial for healthy youth, with beneficial effects on bone accrual and peak bone mass (175, 176), 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 (163, 165, 166, 169, 171, 177). 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 (167, 174, 178, 179) and in adolescent and young adult amenorrheic athletes (165, 166, 180).

Young women with eating disorders are known to be at a sevenfold higher risk of fracture (181), and stress fractures are a recurrent problem among female athletes with amenorrhea (45, 50, 182). 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, 182). 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, 64).

Fractures are much more common in athletes with distorted eating patterns than in those with normal dietary habits (54). 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 (183), whereas young adult women with the condition have an uncoupling of bone turnover (43, 150). The uncoupling of bone turnover is seen even in short-term starvation in normal exercising women (184); this pattern of uncoupling is unique to nutritional deprivation (55–57). 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 (185) or had multiple risk factors (186). One study showed that a combination of risk factors, including a high exercise load (>12 h/wk), participation in a low-weight sport (e.g., gymnastics, long distance running, figure skating), and dietary restraint was associated with a 46% incidence of bone stress injury (51). When the energy status of exercising women is adequate, there appears to be no perturbation of bone formation, regardless of estrogen status (53, 185). 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.

2.8 In cases of primary amenorrhea, we suggest evaluating Müllerian tract anomalies (congenital or acquired). Diagnostic options include physical examination, progestin challenge test, abdominal or transvaginal ultrasound, and/or MRI, depending on the context and patient preferences. (2|⊕⊕⊕○)

Evidence

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) (65). Outflow tract anomalies often present as primary amenorrhea and require both a physical examination (which is critical in the identification of an imperforate hymen) and imaging with pelvic ultrasound or MRI to exclude and/or define anatomic anomalies.

Remarks

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.

2.9 In patients with FHA and underlying PCOS, we suggest:
- a baseline BMD measurement by DXA in those with 6 or more months of amenorrhea and earlier in those with history or suspicion of severe nutritional deficiency, other energy deficit states, and/or skeletal fragility (2/⊕⊕○○); and
- clinical monitoring for hyperresponse in those treated with exogenous gonadotropins for infertility. (2|⊕⊕○○)

Evidence

PCOS is a common endocrine diagnosis among premenopausal women, which can manifest as oligomenorrhea or amenorrhea, and FHA can conceal the diagnosis of PCOS. In some adolescents and women, overzealous dieting masks PCOS symptoms. Normoandrogenic, oligomenorrheic women with PCO morphology and FHA and an elevated AMH level are at high risk for hyperandrogenic PCOS when hypothalamic function normalizes (187). Clinicians should pay close attention to concerns about weight and appearance (including signs of hyperandrogenism) in the patient’s history. One study compared the hormonal/clinical profiles and markers of bone health among women with FHA to women with suspected FHA and underlying PCOS (188). Compared with women with FHA, women with FHA and underlying PCOS had higher BMI, BMD, LH and testosterone concentrations, and incidence of hyperandrogenism; they also exhibited increased hyperandrogenism and irregular menses with weight gain. Recovered FHA patients with underlying PCOS may never resume regular menses and may develop other phenotypic characteristics of PCOS. However, they seem to be at similar risk for developing osteopenia and osteoporosis, based on World Health Organization criteria (188). These patients are also hyperresponsive to exogenous gonadotropins when treated for infertility and need to be monitored carefully (189–192).

Remarks

FHA and PCOS may coexist, and as patients recover from FHA, manifestations of PCOS may emerge, including irregular menses.

3.0 Treatment of functional hypothalamic amenorrhea and concomitant medical conditions

3.1 We recommend that clinicians evaluate patients for inpatient treatment who have FHA and severe bradycardia, hypotension, orthostasis, and/or electrolyte imbalance. (1|⊕⊕⊕○)

Evidence

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 (193). Careful monitoring of the very low weight patient is warranted, as the mortality rate associated with eating disorders, and especially anorexia nervosa, is high (193–195).

3.2 In adolescents and women with FHA, we recommend correcting the energy imbalance to improve HPO axis function; this often requires behavioral change. Options for improving energy balance include increased caloric consumption, and/or improved nutrition, and/or decreased exercise activity. This often requires weight gain. (1|⊕⊕⊕○)

Remarks

Clinicians often need to refer patients to a dietitian or nutritionist to provide individualized dietary instructions.

Evidence

It is well established that low energy availability from decreased energy intake and/or high-energy exercise expenditure leads to HPO disruption, as reflected in menstrual dysfunction, LH pulsatility disruption, and changes in other hormone levels (17, 74, 109, 112). 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 (45). Weight gain through refeeding and improved energy availability in amenorrheic patients with anorexia nervosa correlated with the resumption of menses (196). Increased energy availability through diet or diet and exercise modification in dancers and athletes with FHA also improved menstrual function (85, 86, 197, 198). 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, 64).

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. 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 2.0 kg higher than the weight at which menses stopped (199). 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, 129, 199, 200).

3.3 In adolescents and women with FHA, we suggest psychological support, such as CBT. (2|⊕⊕○○)

Evidence

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, 21). 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 (25). The CBT group also had improvements in cortisol, leptin, and TSH (24). CBT not only restores ovarian function, it also alters metabolic function. The long-term impact of CBT on the acute and chronic health sequelae of FHA remains to be shown. 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.

3.4 We suggest against patients with FHA using OCPs for the sole purpose of regaining menses or improving BMD. (2|⊕⊕○○)
3.5 In patients with FHA using OCPs for contraception, we suggest educating patients regarding the fact that OCPs may mask the return of spontaneous menses and that bone loss may continue, particularly if patients maintain an energy deficit. (2|⊕⊕○○)

Evidence

OCPs provide a progestin and various doses and types of estrogen (typically ethinyl E2) in a daily pill. 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 (201–203). Clinicians often prescribe OCPs for women and adolescents with FHA, but most studies have shown limited to no benefit of this intervention on BMD. Several studies have shown a lack of a protective effect of oral contraceptives on bone (172, 204).

The Endocrine Society conducted a recent systematic review of studies that evaluated the impact of oral hormonal therapy on BMD in FHA. The review included nine studies reported in 10 publications (six had a control arm and three were before/after single cohort studies) (172, 205–213). The studies reported mean BMD changes, but not Z-scores, T-scores, or the incidence of fractures. In a pooled data analysis, the lumbar, femoral neck, trochanteric region, Ward’s triangle, and total body BMD demonstrated clinically insignificant changes over a median of 12 months. The lack of clear benefit is likely related to the persistence of neuroendocrine concomitants, including hypercortisolism and decreased thyroid levels. The findings are consistent with the concept that FHA is more than an isolated disruption of the HPO axis. There are no published prospective studies of fracture risk with OCP treatment in FHA.

3.6 We suggest short-term use of transdermal E2 therapy with cyclic oral progestin (not oral contraceptives or ethinyl E2) in adolescents and women who have not had return of menses after a reasonable trial of nutritional, psychological, and/or modified exercise intervention. (2|⊕○○○)

Evidence

One study has examined combined therapy with transdermal estrogen and oral progesterone in adolescents with anorexia nervosa. The study randomized 96 female adolescents with a bone age ≥15 years to receive 100 μg of 17β-E2 transdermally with cyclic progesterone orally (medroxyprogesterone 2.5 mg daily for 10 days each month) or placebo patches and cyclic placebo pills for 18 months. 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. That same study titrated incremental low-dose oral ethinyl E2 over the 18 months in those girls with a bone age of <15 years (3.75 µg daily from 0 to 6 months, 7.5 µg from 6 to 12 months, and 11.25 µg from 12 to 18 months) to mimic pubertal estrogen increases (vs placebo) (214). Transdermal estrogen likely has a more positive effect on BMD than OCPs because it does not affect IGF-I secretion, a bone-trophic hormone that OCPs downregulate (162, 215–217). In contrast, a 2-year study of ballet dancers showed no effect of daily oral estrogen (conjugated estrogens 0.625 mg) plus medroxyprogesterone acetate (10 mg for 10 days/month) therapy vs placebo on BMD (172). Another study examined combined antiresorptive/anabolic therapy [50 mg DHEA plus oral ethinyl E2 (20 μg)/levonorgestrel ([100 μg)] in older adolescents and young women with eating disorders (218). 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.

Remarks

Clinicians may consider estrogen replacement if reasonable attempts to modify nutritional, psychological, and exercise-related variables are not successful in establishing menses. Bone outcomes may be compromised even after 6 to 12 months of amenorrhea, and thus clinicians may consider short-term hormone replacement therapy after 6 to 12 months of nutritional, psychological, and exercise-related interventions in those with low bone density and/or evidence of skeletal fragility. Of note, bone health may not be protected with E2 replacement therapy if nutritional factors/energy deficit continue.

3.7 We suggest against using bisphosphonates, denosumab, testosterone, and leptin to improve BMD in adolescents and women with FHA. (2|⊕⊕○○)

Evidence

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 4.9% at the lumbar spine at 9 months in adults, and increases at the femoral neck (but not the spine) in adolescents] (219–222). 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).

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 (223). However, we need to carefully balance the theoretical risks with potential treatment benefits.

Denosumab is a human monoclonal antibody directed against receptor activator of nuclear factor-κB ligand, which limits bone resorption by inhibiting osteoclast maturation. It has not been tested in premenopausal women. 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 (224). In postmenopausal women with osteoporosis, denosumab use has resulted in decreased fracture risk and improved BMD compared with placebo (225). We need studies in premenopausal women, specifically those with FHA.

In a small study, subcutaneous recombinant human leptin (n = 8) or no treatment (n = 6) was given for 2 to 3 months to women with FHA secondary to increased exercise and/or low weight. All had stable weight (within 15% of ideal body weight for 6 months or more prior to enrollment). 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 (226). The controls had no significant changes in LH pulsatility, body weight, ovarian variables, or other hormone levels (226).

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 (227). 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, 2.2% to 10.8% and 1.4% to 6.5% from baseline, respectively) in the four subjects who completed the entire 2-year intervention. 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 (228). 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.

3.8 In rare adult FHA cases, we suggest that short-term use of rPTH is an option in the setting of delayed fracture healing and very low BMD. (2|⊕○○○)

Evidence

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, 6.0% ± 1.4%; lateral spine, 10.5% ± 2.5%) compared with placebo (posteroanterior spine, 0.2% ± 0.7%, P < 0.01; lateral spine, −0.6% ± 1.0%; P < 0.01) (229).

A recent systematic review of the role of rPTH in human fracture healing included 16 case reports/case series; two randomized, prospective, double-blind placebo-controlled trials; and one retrospective subgroup analysis. 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 (230). There are no published studies on effects of rPTH treatment and fracture risk reduction in premenopausal women. There is a black box warning on teriparatide describing an increased incidence of osteosarcoma in rats [these rats received a 3- to 60-fold greater systemic exposure than did humans, who receive (typically) a 20-μg daily dose for up to 2 years]. There have been no reported cases of osteosarcoma after teriparatide therapy in humans. However, we need more studies in the FHA population.

3.9 In patients with FHA wishing to conceive, after a complete fertility work-up, we suggest:
- treatment with pulsatile GnRH as a first line, followed by gonadatropin therapy and induction of ovulation when GnRH is not available (2|⊕○○○);
- cautious use of gonadotropin therapy (2|⊕○○○);
- a trial of treatment with clomiphene citrate for ovulation induction if a woman has a sufficient endogenous estrogen level (2|⊕○○○);
- against the use of kisspeptin and leptin for treating infertility (2|⊕○○○); and
- given that there is only a single, small study suggesting efficacy, but minimal potential for harm, clinicians can consider a trial of CBT in women with FHA who wish to conceive, as this treatment has the potential to restore ovulatory cycles and fertility without the need for medical intervention. (2|⊕⊕○○)

Evidence

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 (231, 232). However, GnRH is currently unavailable in the United States.

Large case series favor the use of GnRH. Leyendecker et al. (233) administered pulsatile GnRH treatments in 359 cycles in 73 patients and reported pregnancy rates of 29% per cycle in women with no other infertility factors present. Filicori et al. (234) reported on the outcomes of 600 cycles of pulsatile GnRH administration. Of the 600, approximately half were in women with hypogonadotropism. Overall ovulatory rates were 75%, but were highest in the primary hypogonadotropic amenorrhea subgroups. Per cycle conception rates were 23% in ovulatory cycles. Only 3.8% of these cycles resulted in multiple pregnancy.

Martin et al. (235) compared pulsatile GnRH (41 women; 118 cycles) to gonadotropins (30 women; 111 cycles). Although not a randomized trial, the cumulative incidence of conception after six cycles of GnRH treatment was 96% compared with 72% with exogenous gonadotropin. The study observed three or more follicles in 16.6% of the gonadotropin cycles vs in 5.4% of the GnRH cycles and multiple gestations in 14.8% of gonadotropin cycles compared with 8.3% of GnRH cycles, a difference that was not statistically significant. The gonadotropin preparation Martin et al. used was human menopausal gonadotropin, which contains both FSH and LH activity. Women with FHA may require both LH and FSH activity for an optimal gonadotropin response. Schoot et al. (236) found inadequate E2 responses in seven women treated with recombinant FSH without LH activity who had hypophysectomy, isolated gonadotropin deficiency, or Kallmann syndrome. The researchers suggested that LH activity was essential in individuals without endogenous LH. Although overall safety considerations favor GnRH treatment of women with FHA, as mentioned above, GnRH therapy is not currently available in the United States.

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 (237). Djurovic et al. (238) reported that a 10-day course of clomiphene citrate induced menses in nine out of 17 women who had recovered normal body weight, but not menstrual function, after an anorexia nervosa diagnosis. All 17 had significant increases in LH and E2 levels. Clinicians have induced ovulation in women with PCOS using the aromatase inhibitor letrozole (239), but studies have not tested its efficacy in FHA or overlapping FHA/PCOS.

Researchers have investigated kisspeptin as a possible modality for restoring LH pulsatility and gonadal function in women with FHA. Jayasena et al. (240) administered kisspeptin-54 via constant infusion for 10 hours at variable doses to five women with FHA and demonstrated an increase in LH pulsatility in all women without evidence of desensitization. This dosing regimen may prove more effective than the twice daily and twice weekly subcutaneous injections previously studied (241, 242). We need more research on therapeutic uses of kisspeptin, which is not yet clinically available.

As discussed previously, one small 20-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, 25). However, further research is needed to understand the long-term effect of this therapy on health outcomes in adolescents and women with FHA.

3.10 We suggest that clinicians should only induce ovulation in women with FHA that have a BMI of at least 18.5 kg/m² and only after attempts to normalize energy balance, due to the increased risk for fetal loss, small-for-gestational-age babies, preterm labor, and delivery by Cesarean section for extreme low weight. (2|⊕⊕○○)

Evidence

A BMI of 18.5 kg/m² is the weight threshold under which we consider an adult woman very underweight and possibly malnourished. 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 (59). A case control study associated a BMI of <20 kg/m² with a fourfold higher likelihood of preterm labor (odds ratio, 3.96; 95% confidence interval, 2.61 – 7.09) after adjusting for other known factors (243). Undernutrition is also associated with lower birth weight (3233 g compared with 3516 g for normal controls) (244). Limited data suggest fetal loss as a possible consequence of FHA, particularly in those patients with eating disorders. Because ovulation induction is often successful, it should be noted that these complications might ensue. Women with anorexia nervosa are also at risk for preterm labor and delivery by Cesarean section (58–60). Therefore, clinicians should limit ovulation induction to women of satisfactory body weight (59).

Future Directions

It is possible that prolonged exercise-induced amenorrhea has adverse cardiovascular consequences (245). In a study of 68 women athletes, 24 with amenorrhea and 44 with regular cycles, the women with amenorrhea had significantly higher serum concentrations of total cholesterol [210 vs 186 mg/dL (5.47 vs 4.84 mmol/L)], triglycerides [68 vs 55 mg/dL (0.75 vs 0.61 mmol/L)], low-density lipoprotein cholesterol [121 vs 108 mg/dL (3.2 vs 2.8 mmol/L)], and high-density lipoprotein cholesterol [75 vs 66 mg/dL (1.95 vs 1.73 mmol/L)].

Studies have also noted impaired endothelial function and increased vascular resistance (246–248). Whether the cardiovascular consequences of these differences are clinically important or whether the increased serum high-density lipoprotein cholesterol concentration is protective is not known. There is also evidence of increased visceral fat (a known risk factor for cardiovascular disease) in women nutritionally rehabilitated from anorexia nervosa (249) and evidence that estrogen levels are inversely related to abdominal fat. Women with FHA had more central fat than did healthy controls (250). Preclinical primate evidence suggests that stress-associated hypoestrogenism causes a precocious acceleration of coronary artery atherosclerosis. Studies found a similar effect across all individuals following oophorectomy, which eliminates the “protection” typically observed in nonstressed animals (40, 251, 252).

Other evidence that FHA may be associated with adverse cardiovascular consequences comes from the Women’s Ischemia Syndrome Evaluation, an angiographic study in premenopausal women. Those with angiographic evidence of coronary disease were more likely to have a serum E2 of <50 pg/mL and low gonadotropins of LH <10 IU/L and FSH <10 IU/L when compared with women with normal coronaries. The diagnosis of FHA by this definition remains an independent predictor of coronary disease, even after adjustment for other risk factors such as diabetes. However, this criterion for FHA is broad, with no recognition given to menstrual history, and we often see E2 levels <50 pg/mL in normal women during the follicular phase of the cycle (253).

In women with hypothalamic hypogonadism, clinicians can get an estimation of ovarian reserve using AMH measurements, because gonadotropins will be falsely low (140). An antral follicle count can also provide a reliable estimate. In a patient with primary ovarian insufficiency, the diagnosis could be delayed because of FHA-attenuated gonadotropin secretion.

It should be recognized that adolescents and young women with type 1 diabetes mellitus represent a group at high risk for the development of disordered eating behaviors and purging (e.g., vomiting, hyperexercise, and insulin omission) (254, 255). Future studies should identify strategies that lead to the prevention of energy deficit situations in this population. Data indicate that HPO dysfunction is also common in these patients, although the underlying mechanisms beyond hypothalamic disturbances are not entirely clear (256).

Research has yet to determine the acute and chronic consequences of ovulation induction and pregnancy in the face of elevated cortisol, low T3 and T4, and the other neuroendocrine concomitants associated with FHA, but available data suggest reason for concern (257), and the risks include preterm labor and neurodevelopmental disorders, such as autism spectrum disorder and cardiovascular disease.

Another area of concern is the impact of prolonged hypogonadism on cognitive status and anxiety and mood symptoms. However, implications of FHA in these areas are currently unclear. Recent studies have reported that physiologic estrogen administration improves anxiety outcomes in adolescents with anorexia nervosa (258).

We need more research into the treatment of amenorrhea and low BMD in FHA, with careful consideration of the effects on weight and body composition and the need for appropriate dosing adjustments, and we need more research regarding the impact of FHA on other body systems and neural function. Risk factors for the development and persistence of FHA include conditions that chronically activate the HPA axis. These risk factors include: greater energy expenditure than intake, as with excessive exercise and/or nutritional restriction; unrealistic expectations of self and others; and attitudes that increase reactivity to common and uncommon stressors, including perfectionism, high need for social approval, and conditional love (19–21). Exercise per se can be considered as a stress situation (259), and stressors are likely synergistic rather than additive (22).

Financial Disclosures of the Task Force*

Catherine M. Gordon (chair)—Financial or Business/Organizational Interests: Janssen Pharmaceuticals (member, data safety monitor board): Department of Justice, Health Resources and Services Administration (consultant), National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development (council member), Significant Financial Interest or Leadership Position: none declared. Kathryn E. Ackerman—Financial or Business/Organizational Interests: Walden Behavioral Care Eating Disorder Treatment Center (clinical advisory board), Significant Financial Interest or Leadership Position: Walden Behavioral Care Eating Disorder Treatment Center (clinical advisory board). Sarah L. Berga—Financial or Business/Organizational Interests: Ferring Pharmaceuticals Inc. (consultant), Vermillion Pelvic Mass Registry (advisory panel), What’s My Fertility (advisory board), American College of Obstetrics and Gynecology (editorial board), American Journal of Obstetrics and Gynecology (editorial board), International Society for Gynecological Endocrinology (editorial board), Menopause (editorial board), Society for Women’s Health Research (editorial board), Ferring Pharmaceuticals Inc. (principal investigator), National Institutes of Health/EuniceKennedy Shriver National Institute of Child Health and Human Development (grant/consultant), National Institutes of Health/EuniceKennedy Shriver National Institute of Child Health and Human Development (grant), National Institutes of Health/National Cancer Institute (grant/principal investigator), National Institutes of Health/Office of the Director (grant), Significant Financial Interest or Leadership Position: none declared. Jay R. Kaplan—Financial or Business/Organizational Interests: none declared, Significant Financial Interest or Leadership Position: none declared. George Mastorakos—Financial or Business/Organizational Interests: European Society of Endocrinology (ex official member of executive committee), Hellenic Endocrine Society (president), Significant Financial Interest or Leadership Position: European Society of Endocrinology (ex official member of executive committee), Hellenic Endocrine Society (president). Madhusmita Misra—Financial or Business/Organizational Interests: none declared, Significant Financial Interest or Leadership Position: none declared. M. Hassan Murad**—Financial or Business/Organizational Interests: The Mayo Clinic, Division of Preventive Medicine, Significant Financial Interest or Leadership Position: none declared. Nanette F. Santoro—Financial or Business/Organizational Interests: Bayer, Inc. (grant investigator, initiated grant support), Menogenix (ownership interest), Significant Financial Interest or Leadership Position: none declared. Michelle P. Warren—Financial or Business/Organizational Interests: Pfizer (grantee), Significant Financial Interest or Leadership Position: none declared.

* Financial, business, and organizational disclosures of the task force cover the year prior to publication. Disclosures prior to this time period are archived.

**Evidence-based reviews for this guideline were prepared by the Mayo Clinic, Division of Preventive Medicine, under contract with the Endocrine Society.

Abbreviations:

AMH
anti-Müllerian hormone

BMD
bone mineral density

BMI
body mass index

CAH
congenital adrenal hyperplasia

CBT
cognitive behavior therapy

DHEA
dehydroepiandrosterone

DHEA-S
dehydroepiandrosterone sulfate

DXA
dual-energy X-ray absorptiometry

E2
estradiol

FHA
functional hypothalamic amenorrhea

FSH
follicle-stimulating hormone

GnRH
gonadotropin-releasing hormone

HPA
hypothalamic–pituitary–adrenal

HPO
hypothalamic–pituitary–ovarian

IGF
insulin-like growth factor

LH
luteinizing hormone

MRI
magnetic resonance imaging

OCP
oral contraceptive pill

PCOS
polycystic ovary syndrome

rPTH
recombinant parathyroid hormone 1-34

TSH
thyroid-stimulating hormone

T3
triiodothyronine

T4
thyroxine.

Acknowledgments

Special thanks are extended to Drs. Ana Claudia Latronico and Robert W. Rebar for their careful review and thoughtful suggestions, and Eric Vohr, medical writer, and Linda Wilkins for excellent editorial assistance.

Disclosure Summary: See Financial Disclosures.

References

1.

Atkins

D

,

Best

D

,

Briss

PA

,

Eccles

M

,

Falck-Ytter

Y

,

Flottorp

S

,

Guyatt

GH

,

Harbour

RT

,

Haugh

MC

,

Henry

D

,

Hill

S

,

Jaeschke

R

,

Leng

G

,

Liberati

A

,

Magrini

N

,

Mason

J

,

Middleton

P

,

Mrukowicz

J

,

O’Connell

D

,

Oxman

AD

,

Phillips

B

,

Schünemann

HJ

,

Edejer

T

,

Varonen

H

,

Vist

GE

,

Williams

JW

, Jr ,

Zaza

S

;

GRADE Working Group

.

Grading quality of evidence and strength of recommendations

.

BMJ

.

2004

;

328

(

7454

):

1490

.

2.

Swiglo

BA

,

Murad

MH

,

Schünemann

HJ

,

Kunz

R

,

Vigersky

RA

,

Guyatt

GH

,

Montori

VM

.

A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system

.

J Clin Endocrinol Metab

.

2008

;

93

(

3

):

666

–

673

.

3.

Guyatt

GH

,

Schünemann

HJ

,

Djulbegovic

B

,

Akl

EA

.

Guideline panels should not GRADE good practice statements

.

J Clin Epidemiol

.

2015

;

68

(

5

):

597

–

600

.

4.

Yen

SS

,

Rebar

R

,

VandenBerg

G

,

Judd

H

.

Hypothalamic amenorrhea and hypogonadotropinism: responses to synthetic LRF

.

J Clin Endocrinol Metab

.

1973

;

36

(

5

):

811

–

816

.

5.

Berga

SL

,

Mortola

JF

,

Girton

L

,

Suh

B

,

Laughlin

G

,

Pham

P

,

Yen

SS

.

Neuroendocrine aberrations in women with functional hypothalamic amenorrhea

.

J Clin Endocrinol Metab

.

1989

;

68

(

2

):

301

–

308

.

6.

Miller

DS

,

Reid

RR

,

Cetel

NS

,

Rebar

RW

,

Yen

SS

.

Pulsatile administration of low-dose gonadotropin-releasing hormone. Ovulation and pregnancy in women with hypothalamic amenorrhea

.

JAMA

.

1983

;

250

(

21

):

2937

–

2941

.

7.

Hurley

DM

,

Brian

RJ

,

Burger

HG

.

Ovulation induction with subcutaneous pulsatile gonadotropin-releasing hormone: singleton pregnancies in patients with previous multiple pregnancies after gonadotropin therapy

.

Fertil Steril

.

1983

;

40

(

5

):

575

–

579

.

8.

Klinefelter

HF

, Jr ,

Albright

F

,

Griswold

GC

.

Experience with a quantitative test for normal or decreased amounts of follicle stimulating hormone in the urine in endocrinological diagnosis

.

J Clin Endocrinol

.

1943

;

3

:

529

–

544

.

Crossref

9.

Caronia

LM

,

Martin

C

,

Welt

CK

,

Sykiotis

GP

,

Quinton

R

,

Thambundit

A

,

Avbelj

M

,

Dhruvakumar

S

,

Plummer

L

,

Hughes

VA

,

Seminara

SB

,

Boepple

PA

,

Sidis

Y

,

Crowley

WF

, Jr ,

Martin

KA

,

Hall

JE

,

Pitteloud

N

.

A genetic basis for functional hypothalamic amenorrhea

.

N Engl J Med

.

2011

;

364

(

3

):

215

–

225

.

10.

Navarro

VM

,

Kaiser

UB

.

Metabolic influences on neuroendocrine regulation of reproduction

.

Curr Opin Endocrinol Diabetes Obes

.

2013

;

20

(

4

):

335

–

341

.

11.

Berga

SL

,

Daniels

TL

,

Giles

DE

.

Women with functional hypothalamic amenorrhea but not other forms of anovulation display amplified cortisol concentrations

.

Fertil Steril

.

1997

;

67

(

6

):

1024

–

1030

.

12.

Berga

SL

,

Loucks

TL

.

Use of cognitive behavior therapy for functional hypothalamic amenorrhea

.

Ann N Y Acad Sci

.

2006

;

1092

:

114

–

129

.

13.

Michopoulos

V

,

Embree

M

,

Reding

K

,

Sanchez

MM

,

Toufexis

D

,

Votaw

JR

,

Voll

RJ

,

Goodman

MM

,

Rivier

J

,

Wilson

ME

,

Berga

SL

.

CRH receptor antagonism reverses the effect of social subordination upon central GABAA receptor binding in estradiol-treated ovariectomized female rhesus monkeys

.

Neuroscience

.

2013

;

250

:

300

–

308

.

14.

Ackerman

KE

,

Patel

KT

,

Guereca

G

,

Pierce

L

,

Herzog

DB

,

Misra

M

.

Cortisol secretory parameters in young exercisers in relation to LH secretion and bone parameters

.

Clin Endocrinol (Oxf)

.

2013

;

78

(

1

):

114

–

119

.

15.

Biller

BM

,

Federoff

HJ

,

Koenig

JI

,

Klibanski

A

.

Abnormal cortisol secretion and responses to corticotropin-releasing hormone in women with hypothalamic amenorrhea

.

J Clin Endocrinol Metab

.

1990

;

70

(

2

):

311

–

317

.

16.

Villanueva

AL

,

Schlosser

C

,

Hopper

B

,

Liu

JH

,

Hoffman

DI

,

Rebar

RW

.

Increased cortisol production in women runners

.

J Clin Endocrinol Metab

.

1986

;

63

(

1

):

133

–

136

.

17.

Loucks

AB

,

Thuma

JR

.

Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women

.

J Clin Endocrinol Metab

.

2003

;

88

(

1

):

297

–

311

.

18.

Guerrero

AF

,

Alfonso

A

.

Traumatic brain injury-related hypopituitarism: a review and recommendations for screening combat veterans

.

Mil Med

.

2010

;

175

(

8

):

574

–

580

.

19.

Berga

SL

,

Girton

LG

.

The psychoneuroendocrinology of functional hypothalamic amenorrhea

.

Psychiatr Clin North Am

.

1989

;

12

(

1

):

105

–

116

.

20.

Giles

DE

,

Berga

SL

.

Cognitive and psychiatric correlates of functional hypothalamic amenorrhea: a controlled comparison

.

Fertil Steril

.

1993

;

60

(

3

):

486

–

492

.

21.

Marcus

MD

,

Loucks

TL

,

Berga

SL

.

Psychological correlates of functional hypothalamic amenorrhea

.

Fertil Steril

.

2001

;

76

(

2

):

310

–

316

.

22.

Williams

NI

,

Berga

SL

,

Cameron

JL

.

Synergism between psychosocial and metabolic stressors: impact on reproductive function in cynomolgus monkeys

.

Am J Physiol Endocrinol Metab

.

2007

;

293

(

1

):

E270

–

E276

.

23.

Gore

AC

,

Chappell

VA

,

Fenton

SE

,

Flaws

JA

,

Nadal

A

,

Prins

GS

,

Toppari

J

,

Zoeller

RT

.

EDC-2: The Endocrine Society’s second scientific statement on endocrine-disrupting chemicals

.

Endocr Rev

.

2015

;

36

(

6

):

E1

–

E150

.

24.

Michopoulos V, Mancini F, Loucks TL, Berga SL. Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized, controlled trial. Fertil Steril. 2013;99(7):2084–2091.e1.

25.

Berga

SL

,

Marcus

MD

,

Loucks

TL

,

Hlastala

S

,

Ringham

R

,

Krohn

MA

.

Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy

.

Fertil Steril

.

2003

;

80

(

4

):

976

–

981

.

26.

Gottsch

ML

,

Cunningham

MJ

,

Smith

JT

,

Popa

SM

,

Acohido

BV

,

Crowley

WF

,

Seminara

S

,

Clifton

DK

,

Steiner

RA

.

A role for kisspeptins in the regulation of gonadotropin secretion in the mouse

.

Endocrinology

.

2004

;

145

(

9

):

4073

–

4077

.

27.

McCarthy

MM

.

A piece in the puzzle of puberty

.

Nat Neurosci

.

2013

;

16

(

3

):

251

–

253

.

28.

Mastorakos

G

,

Pavlatou

MG

,

Mizamtsidi

M

.

The hypothalamic pituitary adrenal and the hypothalamic pituitary gonadal axes interplay

.

Pediatr Endocrinol Rev

.

2006

;

3

(

Suppl 1

):

172

–

181

.

29.

Schwartz

B

,

Cumming

DC

,

Riordan

E

,

Selye

M

,

Yen

SS

,

Rebar

RW

.

Exercise-associated amenorrhea: a distinct entity?

Am J Obstet Gynecol

.

1981

;

141

(

5

):

662

–

670

.

30.

Warren

MP

,

Voussoughian

F

,

Geer

EB

,

Hyle

EP

,

Adberg

CL

,

Ramos

RH

.

Functional hypothalamic amenorrhea: hypoleptinemia and disordered eating

.

J Clin Endocrinol Metab

.

1999

;

84

(

3

):

873

–

877

.

31.

Williams

NI

,

Leidy

HJ

,

Flecker

KA

,

Galucci

A

.

Food attitudes in female athletes: association with menstrual cycle length

.

J Sports Sci

.

2006

;

24

(

9

):

979

–

986

.

32.

Cano Sokoloff

N

,

Eguiguren

ML

,

Wargo

K

,

Ackerman

KE

,

Baskaran

C

,

Singhal

V

,

Clarke

H

,

Slattery

M

,

Lee

H

,

Eddy

KT

,

Misra

M

.

Bone parameters in relation to attitudes and feelings associated with disordered eating in oligo-amenorrheic athletes, eumenorrheic athletes, and nonathletes

.

Int J Eat Disord

.

2015

;

48

(

5

):

522

–

526

.

33.

Laughlin

GA

,

Dominguez

CE

,

Yen

SS

.

Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea

.

J Clin Endocrinol Metab

.

1998

;

83

(

1

):

25

–

32

.

34.

Warren

MP

,

Holderness

CC

,

Lesobre

V

,

Tzen

R

,

Vossoughian

F

,

Brooks-Gunn

J

.

Hypothalamic amenorrhea and hidden nutritional insults

.

J Soc Gynecol Investig

.

1994

;

1

(

1

):

84

–

88

.

35.

Drew

FL

.

The epidemiology of secondary amenorrhea

.

J Chronic Dis

.

1961

;

14

:

396

–

407

.

36.

Kaplan

JR

,

Manuck

SB

.

Ovarian dysfunction, stress, and disease: a primate continuum

.

ILAR J

.

2004

;

45

(

2

):

89

–

115

.

37.

Lima

FB

,

Centeno

ML

,

Costa

ME

,

Reddy

AP

,

Cameron

JL

,

Bethea

CL

.

Stress sensitive female macaques have decreased fifth Ewing variant (Fev) and serotonin-related gene expression that is not reversed by citalopram

.

Neuroscience

.

2009

;

164

(

2

):

676

–

691

.

38.

Kaplan

JR

,

Manuck

SB

,

Fontenot

MB

,

Mann

JJ

.

Central nervous system monoamine correlates of social dominance in cynomolgus monkeys (Macaca fascicularis)

.

Neuropsychopharmacology

.

2002

;

26

(

4

):

431

–

443

.

39.

Adams

MR

,

Kaplan

JR

,

Clarkson

TB

,

Koritnik

DR

.

Ovariectomy, social status, and atherosclerosis in cynomolgus monkeys

.

Arteriosclerosis

.

1985

;

5

(

2

):

192

–

200

.

40.

Kaplan

JR

,

Chen

H

,

Appt

SE

,

Lees

CJ

,

Franke

AA

,

Berga

SL

,

Wilson

ME

,

Manuck

SB

,

Clarkson

TB

.

Impairment of ovarian function and associated health-related abnormalities are attributable to low social status in premenopausal monkeys and not mitigated by a high-isoflavone soy diet

.

Hum Reprod

.

2010

;

25

(

12

):

3083

–

3094

.

41.

Pirke

KM

,

Schweiger

U

,

Lemmel

W

,

Krieg

JC

,

Berger

M

.

The influence of dieting on the menstrual cycle of healthy young women

.

J Clin Endocrinol Metab

.

1985

;

60

(

6

):

1174

–

1179

.

42.

Schweiger

U

.

Menstrual function and luteal-phase deficiency in relation to weight changes and dieting

.

Clin Obstet Gynecol

.

1991

;

34

(

1

):

191

–

197

.

43.

Grinspoon

S

,

Miller

K

,

Coyle

C

,

Krempin

J

,

Armstrong

C

,

Pitts

S

,

Herzog

D

,

Klibanski

A

.

Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea

.

J Clin Endocrinol Metab

.

1999

;

84

(

6

):

2049

–

2055

.

44.

Miller

KK

,

Lee

EE

,

Lawson

EA

,

Misra

M

,

Minihan

J

,

Grinspoon

SK

,

Gleysteen

S

,

Mickley

D

,

Herzog

D

,

Klibanski

A

.

Determinants of skeletal loss and recovery in anorexia nervosa

.

J Clin Endocrinol Metab

.

2006

;

91

(

8

):

2931

–

2937

.

45.

Nattiv

A

,

Loucks

AB

,

Manore

MM

,

Sanborn

CF

,

Sundgot-Borgen

J

,

Warren

MP

;

American College of Sports Medicine

.

American College of Sports Medicine position stand. The female athlete triad

.

Med Sci Sports Exerc

.

2007

;

39

(

10

):

1867

–

1882

.

46.

Cohen

A

,

Fleischer

J

,

Freeby

MJ

,

McMahon

DJ

,

Irani

D

,

Shane

E

.

Clinical characteristics and medication use among premenopausal women with osteoporosis and low BMD: the experience of an osteoporosis referral center

.

J Womens Health (Larchmt)

.

2009

;

18

(

1

):

79

–

84

.

47.

Warren

MP

.

Endocrine manifestations of eating disorders

.

J Clin Endocrinol Metab

.

2011

;

96

(

2

):

333

–

343

.

48.

Young

N

,

Formica

C

,

Szmukler

G

,

Seeman

E

.

Bone density at weight-bearing and nonweight-bearing sites in ballet dancers: the effects of exercise, hypogonadism, and body weight

.

J Clin Endocrinol Metab

.

1994

;

78

(

2

):

449

–

454

.

49.

Robinson

TL

,

Snow-Harter

C

,

Taaffe

DR

,

Gillis

D

,

Shaw

J

,

Marcus

R

.

Gymnasts exhibit higher bone mass than runners despite similar prevalence of amenorrhea and oligomenorrhea

.

J Bone Miner Res

.

1995

;

10

(

1

):

26

–

35

.

50.

Warren

MP

,

Brooks-Gunn

J

,

Hamilton

LH

,

Warren

LF

,

Hamilton

WG

.

Scoliosis and fractures in young ballet dancers. Relation to delayed menarche and secondary amenorrhea

.

N Engl J Med

.

1986

;

314

(

21

):

1348

–

1353

.

51.

Barrack

MT

,

Gibbs

JC

,

De Souza

MJ

,

Williams

NI

,

Nichols

JF

,

Rauh

MJ

,

Nattiv

A

.

Higher incidence of bone stress injuries with increasing female athlete triad-related risk factors: a prospective multisite study of exercising girls and women

.

Am J Sports Med

.

2014

;

42

(

4

):

949

–

958

.

52.

Warren

MP

,

Brooks-Gunn

J

,

Fox

RP

,

Holderness

CC

,

Hyle

EP

,

Hamilton

WG

.

Osteopenia in exercise-associated amenorrhea using ballet dancers as a model: a longitudinal study

.

J Clin Endocrinol Metab

.

2002

;

87

(

7

):

3162

–

3168

.

53.

De Souza

MJ

,

Nattiv

A

,

Joy

E

,

Misra

M

,

Williams

NI

,

Mallinson

RJ

,

Gibbs

JC

,

Olmsted

M

,

Goolsby

M

,

Matheson

G

;

Female Athlete Triad Coalition

;

American College of Sports Medicine

;

American Medical Society for Sports Medicine

;

American Bone Health Alliance

.

2014 Female Athlete Triad Coalition consensus statement on treatment and return to play of the female athlete triad: 1st International Conference held in San Francisco, CA, May 2012, and 2nd International Conference held in Indianapolis, IN, May 2013

.

Clin J Sport Med

.

2014

;

24

(

2

):

96

–

119

.

54.

Frusztajer

NT

,

Dhuper

S

,

Warren

MP

,

Brooks-Gunn

J

,

Fox

RP

.

Nutrition and the incidence of stress fractures in ballet dancers

.

Am J Clin Nutr

.

1990

;

51

(

5

):

779

–

783

.

55.

Hotta

M

,

Fukuda

I

,

Sato

K

,

Hizuka

N

,

Shibasaki

T

,

Takano

K

.

The relationship between bone turnover and body weight, serum insulin-like growth factor (IGF) I, and serum IGF-binding protein levels in patients with anorexia nervosa

.

J Clin Endocrinol Metab

.

2000

;

85

(

1

):

200

–

206

.

56.

Dominguez

J

,

Goodman

L

,

Sen Gupta

S

,

Mayer

L

,

Etu

SF

,

Walsh

BT

,

Wang

J

,

Pierson

R

,

Warren

MP

.

Treatment of anorexia nervosa is associated with increases in bone mineral density, and recovery is a biphasic process involving both nutrition and return of menses

.

Am J Clin Nutr

.

2007

;

86

(

1

):

92

–

99

.

57.

Viapiana

O

,

Gatti

D

,

Dalle Grave

R

,

Todesco

T

,

Rossini

M

,

Braga

V

,

Idolazzi

L

,

Fracassi

E

,

Adami

S

.

Marked increases in bone mineral density and biochemical markers of bone turnover in patients with anorexia nervosa gaining weight

.

Bone

.

2007

;

40

(

4

):

1073

–

1077

.

58.

Hoffman

ER

,

Zerwas

SC

,

Bulik

CM

.

Reproductive issues in anorexia nervosa

.

Expert Rev Obstet Gynecol

.

2011

;

6

(

4

):

403

–

414

.

59.

ESHRE Capri Workshop Group

.

Nutrition and reproduction in women

.

Hum Reprod Update

.

2006

;

12

(

3

):

193

–

207

.

Crossref

60.

Mazer-Poline

C

,

Fornari

V

.

Anorexia nervosa and pregnancy: having a baby when you are dying to be thin—case report and proposed treatment guidelines

.

Int J Eat Disord

.

2009

;

42

(

4

):

382

–

384

.

61.

Kaplan

JR

,

Manuck

SB

.

Ovarian dysfunction and the premenopausal origins of coronary heart disease

.

Menopause

.

2008

;

15

(

4 Pt 1

):

768

–

776

.

62.

Kaplan

JR

,

Chen

H

,

Manuck

SB

.

The relationship between social status and atherosclerosis in male and female monkeys as revealed by meta-analysis

.

Am J Primatol

.

2009

;

71

(

9

):

732

–

741

.

63.

Adams Hillard

PJ

.

Menstruation in adolescents: what’s normal, what’s not

.

Ann N Y Acad Sci

.

2008

;

1135

:

29

–

35

.

64.

Mountjoy

M

,

Sundgot-Borgen

J

,

Burke

L

,

Carter

S

,

Constantini

N

,

Lebrun

C

,

Meyer

N

,

Sherman

R

,

Steffen

K

,

Budgett

R

,

Ljungqvist

A

.

The IOC consensus statement: beyond the female athlete triad—relative energy deficiency in sport (RED-S)

.

Br J Sports Med

.

2014

;

48

(

7

):

491

–

497

.

65.

Gordon

CM

.

Clinical practice. Functional hypothalamic amenorrhea

.

N Engl J Med

.

2010

;

363

(

4

):

365

–

371

.

66.

Balasubramanian

R

,

Dwyer

A

,

Seminara

SB

,

Pitteloud

N

,

Kaiser

UB

,

Crowley

WF

, Jr .

Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons

.

Neuroendocrinology

.

2010

;

92

(

2

):

81

–

99

.

67.

Cohen

LE

.

Genetic disorders of the pituitary

.

Curr Opin Endocrinol Diabetes Obes

.

2012

;

19

(

1

):

33

–

39

.

68.

Lippincott

MF

,

True

C

,

Seminara

SB

.

Use of genetic models of idiopathic hypogonadotrophic hypogonadism in mice and men to understand the mechanisms of disease

.

Exp Physiol

.

2013

;

98

(

11

):

1522

–

1527

.

69.

Castinetti

F

,

Taieb

D

,

Henry

JF

,

Walz

M

,

Guerin

C

,

Brue

T

,

Conte-Devolx

B

,

Neumann

HP

,

Sebag

F

.

Management of endocrine disease: outcome of adrenal sparing surgery in heritable pheochromocytoma

.

Eur J Endocrinol

.

2016

;

174

(

1

):

R9

–

R18

.

70.

Golden

NH

,

Carlson

JL

.

The pathophysiology of amenorrhea in the adolescent

.

Ann N Y Acad Sci

.

2008

;

1135

:

163

–

178

.

71.

Meczekalski

B

,

Podfigurna-Stopa

A

,

Warenik-Szymankiewicz

A

,

Genazzani

AR

.

Functional hypothalamic amenorrhea: current view on neuroendocrine aberrations

.

Gynecol Endocrinol

.

2008

;

24

(

1

):

4

–

11

.

72.

Ackerman

KE

,

Slusarz

K

,

Guereca

G

,

Pierce

L

,

Slattery

M

,

Mendes

N

,

Herzog

DB

,

Misra

M

.

Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls

.

Am J Physiol Endocrinol Metab

.

2012

;

302

(

7

):

E800

–

E806

.

73.

Loucks

AB

,

Kiens

B

,

Wright

HH

.

Energy availability in athletes

.

J Sports Sci

.

2011

;

29

(

Suppl 1

):

S7

–

S15

.

74.

Williams

NI

,

Leidy

HJ

,

Hill

BR

,

Lieberman

JL

,

Legro

RS

,

De Souza

MJ

.

Magnitude of daily energy deficit predicts frequency but not severity of menstrual disturbances associated with exercise and caloric restriction

.

Am J Physiol Endocrinol Metab

.

2015

;

308

(

1

):

E29

–

E39

.

75.

Scheid

JL

,

De Souza

MJ

,

Hill

BR

,

Leidy

HJ

,

Williams

NI

.

Decreased luteinizing hormone pulse frequency is associated with elevated 24-hour ghrelin after calorie restriction and exercise in premenopausal women

.

Am J Physiol Endocrinol Metab

.

2013

;

304

(

1

):

E109

–

E116

.

76.

De Souza

MJ

,

Toombs

RJ

,

Scheid

JL

,

O’Donnell

E

,

West

SL

,

Williams

NI

.

High prevalence of subtle and severe menstrual disturbances in exercising women: confirmation using daily hormone measures

.

Hum Reprod

.

2010

;

25

(

2

):

491

–

503

.

77.

Russell

M

,

Misra

M

.

Influence of ghrelin and adipocytokines on bone mineral density in adolescent female athletes with amenorrhea and eumenorrheic athletes

.

Med Sport Sci

.

2010

;

55

:

103

–

113

.

78.

Scheid

JL

,

De Souza

MJ

.

Menstrual irregularities and energy deficiency in physically active women: the role of ghrelin, PYY and adipocytokines

.

Med Sport Sci

.

2010

;

55

:

82

–

102

.

79.

Weiss Kelly

AK

,

Hecht

S

;

Council on Sports Medicine and Fitness

.

The female athlete triad

.

Pediatrics

.

2016

;

138

(

2

):

e20160922

.

80.

Nichols

JF

,

Rauh

MJ

,

Barrack

MT

,

Barkai

HS

,

Pernick

Y

.

Disordered eating and menstrual irregularity in high school athletes in lean-build and nonlean-build sports

.

Int J Sport Nutr Exerc Metab

.

2007

;

17

(

4

):

364

–

377

.

81.

Beals

KA

,

Hill

AK

.

The prevalence of disordered eating, menstrual dysfunction, and low bone mineral density among US collegiate athletes

.

Int J Sport Nutr Exerc Metab

.

2006

;

16

(

1

):

1

–

23

.

82.

Benson

JE

,

Engelbert-Fenton

KA

,

Eisenman

PA

.

Nutritional aspects of amenorrhea in the female athlete triad

.

Int J Sport Nutr

.

1996

;

6

(

2

):

134

–

145

.

83.

Warren

MP

.

The effects of exercise on pubertal progression and reproductive function in girls

.

J Clin Endocrinol Metab

.

1980

;

51

(

5

):

1150

–

1157

.

84.

De Souza

MJ

,

Lee

DK

,

VanHeest

JL

,

Scheid

JL

,

West

SL

,

Williams

NI

.

Severity of energy-related menstrual disturbances increases in proportion to indices of energy conservation in exercising women

.

Fertil Steril

.

2007

;

88

(

4

):

971

–

975

.

85.

Dueck

CA

,

Matt

KS

,

Manore

MM

,

Skinner

JS

.

Treatment of athletic amenorrhea with a diet and training intervention program

.

Int J Sport Nutr

.

1996

;

6

(

1

):

24

–

40

.

86.

Kopp-Woodroffe

SA

,

Manore

MM

,

Dueck

CA

,

Skinner

JS

,

Matt

KS

.

Energy and nutrient status of amenorrheic athletes participating in a diet and exercise training intervention program

.

Int J Sport Nutr

.

1999

;

9

(

1

):

70

–

88

.

87.

Berga

SL

.

Stress and reprodution: a tale of false dichotomy?

Endocrinology

.

2008

;

149

(

3

):

867

–

868

.

88.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatry Association; 2013.

89.

Perkins

RB

,

Hall

JE

,

Martin

KA

.

Neuroendocrine abnormalities in hypothalamic amenorrhea: spectrum, stability, and response to neurotransmitter modulation

.

J Clin Endocrinol Metab

.

1999

;

84

(

6

):

1905

–

1911

.

90.

Thangavelu

K

,

Geetanjali

S

.

Menstrual disturbance and galactorrhea in people taking conventional antipsychotic medications

.

Exp Clin Psychopharmacol

.

2006

;

14

(

4

):

459

–

460

.

91.

Kantartzis

KL

,

Sucato

GS

.

Menstrual suppression in the adolescent

.

J Pediatr Adolesc Gynecol

.

2013

;

26

(

3

):

132

–

137

.

92.

Dhamangaonkar

PC

,

Anuradha

K

,

Saxena

A

.

Levonorgestrel intrauterine system (Mirena): an emerging tool for conservative treatment of abnormal uterine bleeding

.

J Midlife Health

.

2015

;

6

(

1

):

26

–

30

.

93.

Benagiano

G

,

Carrara

S

,

Filippi

V

.

Safety, efficacy and patient satisfaction with continuous daily administration of levonorgestrel/ethinylestradiol oral contraceptives

.

Patient Prefer Adherence

.

2009

;

3

:

131

–

143

.

94.

Liu

JH

,

Bill

AH

.

Stress-associated or functional hypothalamic amenorrhea in the adolescent

.

Ann N Y Acad Sci

.

2008

;

1135

:

179

–

184

.

95.

Santoro

N

.

Update in hyper- and hypogonadotropic amenorrhea

.

J Clin Endocrinol Metab

.

2011

;

96

(

11

):

3281

–

3288

.

96.

Pettersson

F

,

Fries

H

,

Nillius

SJ

.

Epidemiology of secondary amenorrhea. I. Incidence and prevalence rates

.

Am J Obstet Gynecol

.

1973

;

117

(

1

):

80

–

86

.

97.

Flug

D

,

Largo

RH

,

Prader

A

.

Menstrual patterns in adolescent Swiss girls: a longitudinal study

.

Ann Hum Biol

.

1984

;

11

(

6

):

495

–

508

.

98.

Legro

RS

,

Lin

HM

,

Demers

LM

,

Lloyd

T

.

Rapid maturation of the reproductive axis during perimenarche independent of body composition

.

J Clin Endocrinol Metab

.

2000

;

85

(

3

):

1021

–

1025

.

99.

De Souza

MJ

,

Miller

BE

,

Loucks

AB

,

Luciano

AA

,

Pescatello

LS

,

Campbell

CG

,

Lasley

BL

.

High frequency of luteal phase deficiency and anovulation in recreational women runners: blunted elevation in follicle-stimulating hormone observed during luteal-follicular transition

.

J Clin Endocrinol Metab

.

1998

;

83

(

12

):

4220

–

4232

.

100.

Lauritsen

MP

,

Pinborg

A

,

Loft

A

,

Petersen

JH

,

Mikkelsen

AL

,

Bjerge

MR

,

Nyboe Andersen

A

.

Revised criteria for PCOS in WHO Group II anovulatory infertility—a revival of hypothalamic amenorrhoea?

Clin Endocrinol (Oxf)

.

2015

;

82

(

4

):

584

–

591

.

101.

Pauli

SA

,

Berga

SL

.

Athletic amenorrhea: energy deficit or psychogenic challenge?

Ann N Y Acad Sci

.

2010

;

1205

:

33

–

38

.

102.

Bomba

M

,

Gambera

A

,

Bonini

L

,

Peroni

M

,

Neri

F

,

Scagliola

P

,

Nacinovich

R

.

Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents

.

Fertil Steril

.

2007

;

87

(

4

):

876

–

885

.

103.

Edozien

LC

.

Mind over matter: psychological factors and the menstrual cycle

.

Curr Opin Obstet Gynecol

.

2006

;

18

(

4

):

452

–

456

.

104.

Kirschbaum

C

,

Wüst

S

,

Hellhammer

D

.

Consistent sex differences in cortisol responses to psychological stress

.

Psychosom Med

.

1992

;

54

(

6

):

648

–

657

.

105.

Reed

JL

,

De Souza

MJ

,

Mallinson

RJ

,

Scheid

JL

,

Williams

NI

.

Energy availability discriminates clinical menstrual status in exercising women

.

J Int Soc Sports Nutr

.

2015

;

12

:

11

.

106.

Gibbs

JC

,

Williams

NI

,

Scheid

JL

,

Toombs

RJ

,

De Souza

MJ

.

The association of a high drive for thinness with energy deficiency and severe menstrual disturbances: confirmation in a large population of exercising women

.

Int J Sport Nutr Exerc Metab

.

2011

;

21

(

4

):

280

–

290

.

107.

Williams

NI

,

Reed

JL

,

Leidy

HJ

,

Legro

RS

,

De Souza

MJ

.

Estrogen and progesterone exposure is reduced in response to energy deficiency in women aged 25–40 years

.

Hum Reprod

.

2010

;

25

(

9

):

2328

–

2339

.

108.

Schneider

JE

,

Wade

GN

.

Decreased availability of metabolic fuels induces anestrus in golden hamsters

.

Am J Physiol

.

1990

;

258

(

3 Pt 2

):

R750

–

R755

.

109.

Bullen

BA

,

Skrinar

GS

,

Beitins

IZ

,

von Mering

G

,

Turnbull

BA

,

McArthur

JW

.

Induction of menstrual disorders by strenuous exercise in untrained women

.

N Engl J Med

.

1985

;

312

(

21

):

1349

–

1353

.

110.

Gibbs

JC

,

Williams

NI

,

Mallinson

RJ

,

Reed

JL

,

Rickard

AD

,

De Souza

MJ

.

Effect of high dietary restraint on energy availability and menstrual status

.

Med Sci Sports Exerc

.

2013

;

45

(

9

):

1790

–

1797

.

111.

Williams

NI

,

Helmreich

DL

,

Parfitt

DB

,

Caston-Balderrama

A

,

Cameron

JL

.

Evidence for a causal role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training

.

J Clin Endocrinol Metab

.

2001

;

86

(

11

):

5184

–

5193

.

112.

Loucks

AB

,

Verdun

M

,

Heath

EM

.

Low energy availability, not stress of exercise, alters LH pulsatility in exercising women

.

J Appl Physiol (1985)

.

1998

;

84

(

1

):

37

–

46

.

113.

Schneider

JE

.

Energy balance and reproduction

.

Physiol Behav

.

2004

;

81

(

2

):

289

–

317

.

114.

Wade

GN

,

Jones

JE

.

Neuroendocrinology of nutritional infertility

.

Am J Physiol Regul Integr Comp Physiol

.

2004

;

287

(

6

):

R1277

–

R1296

.

115.

Friedman

MI

.

Fuel partitioning and food intake

.

Am J Clin Nutr

.

1998

;

67

(

3

,

Suppl

)

513S

–

518S

.

116.

Frisch

RE

,

McArthur

JW

.

Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset

.

Science

.

1974

;

185

(

4155

):

949

–

951

.

117.

Glick

Z

,

Yamini

S

,

Lupien

J

,

Sod-Moriah

U

.

Estrous cycle irregularities in overfed rats

.

Physiol Behav

.

1990

;

47

(

2

):

307

–

310

.

118.

Clark

AM

,

Ledger

W

,

Galletly

C

,

Tomlinson

L

,

Blaney

F

,

Wang

X

,

Norman

RJ

.

Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women

.

Hum Reprod

.

1995

;

10

(

10

):

2705

–

2712

.

119.

Wade

GN

,

Schneider

JE

,

Li

HY

.

Control of fertility by metabolic cues

.

Am J Physiol

.

1996

;

270

(

1 Pt 1

):

E1

–

E19

.

120.

Rodriguez-Pacheco

F

,

Martinez-Fuentes

AJ

,

Tovar

S

,

Pinilla

L

,

Tena-Sempere

M

,

Dieguez

C

,

Castaño

JP

,

Malagon

MM

.

Regulation of pituitary cell function by adiponectin

.

Endocrinology

.

2007

;

148

(

1

):

401

–

410

.

121.

Mitchell

M

,

Armstrong

DT

,

Robker

RL

,

Norman

RJ

.

Adipokines: implications for female fertility and obesity

.

Reproduction

.

2005

;

130

(

5

):

583

–

597

.

122.

Reading

KJ

,

McCargar

LI

,

Harber

VJ

.

Energy balance and luteal phase progesterone levels in elite adolescent aesthetic athletes

.

Int J Sport Nutr Exerc Metab

.

2002

;

12

(

1

):

93

–

104

.

123.

Illingworth

P

.

Amenorrhea, anovulation, and dysfunctional uterine bleeding

. In:

Jameson

JL

,

De Groot

LJ

, eds.

Endocrinology: Adult and Pediatric

.

Philadelphia, PA

:

Saunders/Elsevier

;

2010

:

2341

–

2355

.

Google Preview

124.

Rebar R. Evaluation of amenorrhea, anovulation, and abnormal bleeding. In: DeGroot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, eds. Endotext. South Dartmouth, MA: MDText.com, Inc.; 2000

.

125.

Bulun

S

.

Physiology and pathology of the female reproductive axis

. In:

Melmed

S

,

Kenneth

S

,

Larsen

PR

,

Kronenberg

H

, eds.

Williams Textbook of Endocrinology

. 13th ed.

Philadelphia, PA

:

Elsevier

;

2016

:

590

–

664

.

Google Preview

126.

Fries

H

,

Nillius

SJ

,

Pettersson

F

.

Epidemiology of secondary amenorrhea. II. A retrospective evaluation of etiology with special regard to psychogenic factors and weight loss

.

Am J Obstet Gynecol

.

1974

;

118

(

4

):

473

–

479

.

127.

Dotti

A

,

Lazzari

R

.

Validation and reliability of the Italian EAT-26

.

Eat Weight Disord

.

1998

;

3

(

4

):

188

–

194

.

128.

Kimmel

MC

,

Ferguson

EH

,

Zerwas

S

,

Bulik

CM

,

Meltzer-Brody

S

.

Obstetric and gynecologic problems associated with eating disorders

.

Int J Eat Disord

.

2016

;

49

(

3

):

260

–

275

.

129.

Frumar

AM

,

Meldrum

DR

,

Judd

HL

.

Hypercarotenemia in hypothalamic amenorrhea

.

Fertil Steril

.

1979

;

32

(

3

):

261

–

264

.

130.

Lizneva

D

,

Suturina

L

,

Walker

W

,

Brakta

S

,

Gavrilova-Jordan

L

,

Azziz

R

.

Criteria, prevalence, and phenotypes of polycystic ovary syndrome

.

Fertil Steril

.

2016

;

106

(

1

):

6

–

15

.

131.

Fong

HF

,

DiVasta

AD

,

DiFabio

D

,

Ringelheim

J

,

Jonas

MM

,

Gordon

CM

.

Prevalence and predictors of abnormal liver enzymes in young women with anorexia nervosa

.

J Pediatr

.

2008

;

153

(

2

):

247

–

253

.

132.

Rosen

E

,

Sabel

AL

,

Brinton

JT

,

Catanach

B

,

Gaudiani

JL

,

Mehler

PS

.

Liver dysfunction in patients with severe anorexia nervosa

.

Int J Eat Disord

.

2016

;

49

(

2

):

151

–

158

.

133.

Singhal

V

,

de Lourdes Eguiguren

M

,

Eisenbach

L

,

Clarke

H

,

Slattery

M

,

Eddy

K

,

Ackerman

KE

,

Misra

M

.

Body composition, hemodynamic, and biochemical parameters of young female normal-weight oligo-amenorrheic and eumenorrheic athletes and nonathletes

.

Ann Nutr Metab

.

2014

;

65

(

4

):

264

–

271

.

134.

Rosner

W

,

Hankinson

SE

,

Sluss

PM

,

Vesper

HW

,

Wierman

ME

.

Challenges to the measurement of estradiol: an endocrine society position statement

.

J Clin Endocrinol Metab

.

2013

;

98

(

4

):

1376

–

1387

.

135.

Rosner

W

,

Auchus

RJ

,

Azziz

R

,

Sluss

PM

,

Raff

H

.

Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement

.

J Clin Endocrinol Metab

.

2007

;

92

(

2

):

405

–

413

.

136.

Pinola

P

,

Piltonen

TT

,

Puurunen

J

,

Vanky

E

,

Sundström-Poromaa

I

,

Stener-Victorin

E

,

Ruokonen

A

,

Puukka

K

,

Tapanainen

JS

,

Morin-Papunen

LC

.

Androgen profile through life in women with polycystic ovary syndrome: a Nordic multicenter collaboration study

.

J Clin Endocrinol Metab

.

2015

;

100

(

9

):

3400

–

3407

.

137.

Tosi

F

,

Fiers

T

,

Kaufman

JM

,

Dall’Alda

M

,

Moretta

R

,

Giagulli

VA

,

Bonora

E

,

Moghetti

P

.

Implications of androgen assay accuracy in the phenotyping of women with polycystic ovary syndrome

.

J Clin Endocrinol Metab

.

2016

;

101

(

2

):

610

–

618

.

138.

Legro

RS

,

Arslanian

SA

,

Ehrmann

DA

,

Hoeger

KM

,

Murad

MH

,

Pasquali

R

,

Welt

CK

;

Endocrine Society

.

Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline

.

J Clin Endocrinol Metab

.

2013

;

98

(

12

):

4565

–

4592

.

139.

Moran

C

,

Arriaga

M

,

Arechavaleta-Velasco

F

,

Moran

S

.

Adrenal androgen excess and body mass index in polycystic ovary syndrome

.

J Clin Endocrinol Metab

.

2015

:

jc00009999

.

140.

Tran

ND

,

Cedars

MI

,

Rosen

MP

.

The role of anti-müllerian hormone (AMH) in assessing ovarian reserve

.

J Clin Endocrinol Metab

.

2011

;

96

(

12

):

3609

–

3614

.

141.

Christiansen

SC

,

Eilertsen

TB

,

Vanky

E

,

Carlsen

SM

.

Does AMH reflect follicle number similarly in women with and without PCOS?

PLoS One

.

2016

;

11

(

1

):

e0146739

.

142.

Kushnir

VA

,

Halevy

N

,

Barad

DH

,

Albertini

DF

,

Gleicher

N

.

Relative importance of AMH and androgens changes with aging among non-obese women with polycystic ovary syndrome

.

J Ovarian Res

.

2015

;

8

:

45

.

143.

Martin

KA

,

Chang

RJ

,

Ehrmann

DA

,

Ibanez

L

,

Lobo

RA

,

Rosenfield

RL

,

Shapiro

J

,

Montori

VM

,

Swiglo

BA

.

Evaluation and treatment of hirsutism in premenopausal women: an Endocrine Society clinical practice guideline

.

J Clin Endocrinol Metab

.

2008

;

93

(

4

):

1105

–

1120

.

144.

Terzolo

M

,

Alì

A

,

Osella

G

,

Reimondo

G

,

Pia

A

,

Peretti

P

,

Paccotti

P

,

Angeli

A

.

The value of dehydroepiandrosterone sulfate measurement in the differentiation between benign and malignant adrenal masses

.

Eur J Endocrinol

.

2000

;

142

(

6

):

611

–

617

.

145.

Lee

PD

,

Winter

RJ

,

Green

OC

.

Virilizing adrenocortical tumors in childhood: eight cases and a review of the literature

.

Pediatrics

.

1985

;

76

(

3

):

437

–

444

.

146.

Nieman

LK

,

Biller

BM

,

Findling

JW

,

Newell-Price

J

,

Savage

MO

,

Stewart

PM

,

Montori

VM

.

The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline

.

J Clin Endocrinol Metab

.

2008

;

93

(

5

):

1526

–

1540

.

147.

Rickenlund

A

,

Thorén

M

,

Carlström

K

,

von Schoultz

B

,

Hirschberg

AL

.

Diurnal profiles of testosterone and pituitary hormones suggest different mechanisms for menstrual disturbances in endurance athletes

.

J Clin Endocrinol Metab

.

2004

;

89

(

2

):

702

–

707

.

148.

Kaltsas

GA

,

Mukherjee

JJ

,

Jenkins

PJ

,

Satta

MA

,

Islam

N

,

Monson

JP

,

Besser

GM

,

Grossman

AB

.

Menstrual irregularity in women with acromegaly

.

J Clin Endocrinol Metab

.

1999

;

84

(

8

):

2731

–

2735

.

149.

Strotmeyer

ES

,

Steenkiste

AR

,

Foley

TP

, Jr ,

Berga

SL

,

Dorman

JS

.

Menstrual cycle differences between women with type 1 diabetes and women without diabetes

.

Diabetes Care

.

2003

;

26

(

4

):

1016

–

1021

.

150.

Gordon

CM

,

Goodman

E

,

Emans

SJ

,

Grace

E

,

Becker

KA

,

Rosen

CJ

,

Gundberg

CM

,

Leboff

MS

.

Physiologic regulators of bone turnover in young women with anorexia nervosa

.

J Pediatr

.

2002

;

141

(

1

):

64

–

70

.

151.

Trombetti A, Richert L, Herrmann FR, Chevalley T, Graf JD, Rizzoli R. Selective determinants of low bone mineral mass in adult women with anorexia nervosa. Int J Endocrinol. 2013;2013:897193.

152.

Misra

M

,

Miller

KK

,

Bjornson

J

,

Hackman

A

,

Aggarwal

A

,

Chung

J

,

Ott

M

,

Herzog

DB

,

Johnson

ML

,

Klibanski

A

.

Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism

.

J Clin Endocrinol Metab

.

2003

;

88

(

12

):

5615

–

5623

.

153.

Zumoff

B

,

Walsh

BT

,

Katz

JL

,

Levin

J

,

Rosenfeld

RS

,

Kream

J

,

Weiner

H

.

Subnormal plasma dehydroisoandrosterone to cortisol ratio in anorexia nervosa: a second hormonal parameter of ontogenic regression

.

J Clin Endocrinol Metab

.

1983

;

56

(

4

):

668

–

672

.

154.

Devesa

J

,

Pérez-Fernández

R

,

Bokser

L

,

Gaudiero

GJ

,

Lima

L

,

Casanueva

FF

.

Adrenal androgen secretion and dopaminergic activity in anorexia nervosa

.

Horm Metab Res

.

1988

;

20

(

1

):

57

–

60

.

155.

Ostrowska

Z

,

Ziora

K

,

Oświęcimska

J

,

Swiętochowska

E

,

Wołkowska-Pokrywa

K

.

Dehydroepiandrosterone sulfate, osteoprotegerin and its soluble ligand sRANKL and bone metabolism in girls with anorexia nervosa

.

Postepy Hig Med Dosw (Online)

.

2012

;

66

:

655

–

662

.

156.

DiVasta

AD

,

Feldman

HA

,

Beck

TJ

,

LeBoff

MS

,

Gordon

CM

.

Does hormone replacement normalize bone geometry in adolescents with anorexia nervosa?

J Bone Miner Res

.

2014

;

29

(

1

):

151

–

157

.

157.

Nakamura

S

,

Douchi

T

,

Oki

T

,

Ijuin

H

,

Yamamoto

S

,

Nagata

Y

.

Relationship between sonographic endometrial thickness and progestin-induced withdrawal bleeding

.

Obstet Gynecol

.

1996

;

87

(

5 Pt 1

):

722

–

725

.

158.

Kletzky

OA

,

Davajan

V

,

Nakamura

RM

,

Thorneycroft

IH

,

Mishell

DR

, Jr .

Clinical categorization of patients with secondary amenorrhea using progesterone-induced uterine bleeding and measurement of serum gonadotropin levels

.

Am J Obstet Gynecol

.

1975

;

121

(

5

):

695

–

703

.

159.

Guitelman

M

,

Garcia Basavilbaso

N

,

Vitale

M

,

Chervin

A

,

Katz

D

,

Miragaya

K

,

Herrera

J

,

Cornalo

D

,

Servidio

M

,

Boero

L

,

Manavela

M

,

Danilowicz

K

,

Alfieri

A

,

Stalldecker

G

,

Glerean

M

,

Fainstein Day

P

,

Ballarino

C

,

Mallea Gil

MS

,

Rogozinski

A

.

Primary empty sella (PES): a review of 175 cases

.

Pituitary

.

2013

;

16

(

2

):

270

–

274

.

160.

Crabtree

NJ

,

Arabi

A

,

Bachrach

LK

,

Fewtrell

M

,

El-Hajj Fuleihan

G

,

Kecskemethy

HH

,

Jaworski

M

,

Gordon

CM

;

International Society for Clinical Densitometry

.

Dual-energy X-ray absorptiometry interpretation and reporting in children and adolescents: the revised 2013 ISCD pediatric official positions

.

J Clin Densitom

.

2014

;

17

(

2

):

225

–

242

.

161.

Soyka

LA

,

Grinspoon

S

,

Levitsky

LL

,

Herzog

DB

,

Klibanski

A

.

The effects of anorexia nervosa on bone metabolism in female adolescents

.

J Clin Endocrinol Metab

.

1999

;

84

(

12

):

4489

–

4496

.

162.

Bachrach

LK

,

Guido

D

,

Katzman

D

,

Litt

IF

,

Marcus

R

.

Decreased bone density in adolescent girls with anorexia nervosa

.

Pediatrics

.

1990

;

86

(

3

):

440

–

447

.

163.

Soyka

LA

,

Misra

M

,

Frenchman

A

,

Miller

KK

,

Grinspoon

S

,

Schoenfeld

DA

,

Klibanski

A

.

Abnormal bone mineral accrual in adolescent girls with anorexia nervosa

.

J Clin Endocrinol Metab

.

2002

;

87

(

9

):

4177

–

4185

.

164.

Grinspoon

S

,

Thomas

E

,

Pitts

S

,

Gross

E

,

Mickley

D

,

Miller

K

,

Herzog

D

,

Klibanski

A

.

Prevalence and predictive factors for regional osteopenia in women with anorexia nervosa

.

Ann Intern Med

.

2000

;

133

(

10

):

790

–

794

.

165.

Ackerman

KE

,

Nazem

T

,

Chapko

D

,

Russell

M

,

Mendes

N

,

Taylor

AP

,

Bouxsein

ML

,

Misra

M

.

Bone microarchitecture is impaired in adolescent amenorrheic athletes compared with eumenorrheic athletes and nonathletic controls

.

J Clin Endocrinol Metab

.

2011

;

96

(

10

):

3123

–

3133

.

166.

Mitchell

DM

,

Tuck

P

,

Ackerman

KE

,

Cano Sokoloff

N

,

Woolley

R

,

Slattery

M

,

Lee

H

,

Bouxsein

ML

,

Misra

M

.

Altered trabecular bone morphology in adolescent and young adult athletes with menstrual dysfunction

.

Bone

.

2015

;

81

:

24

–

30

.

167.

DiVasta

AD

,

Beck

TJ

,

Petit

MA

,

Feldman

HA

,

LeBoff

MS

,

Gordon

CM

.

Bone cross-sectional geometry in adolescents and young women with anorexia nervosa: a hip structural analysis study

.

Osteoporos Int

.

2007

;

18

(

6

):

797

–

804

.

168.

Ackerman

KE

,

Pierce

L

,

Guereca

G

,

Slattery

M

,

Lee

H

,

Goldstein

M

,

Misra

M

.

Hip structural analysis in adolescent and young adult oligoamenorrheic and eumenorrheic athletes and nonathletes

.

J Clin Endocrinol Metab

.

2013

;

98

(

4

):

1742

–

1749

.

169.

Bachrach

LK

,

Katzman

DK

,

Litt

IF

,

Guido

D

,

Marcus

R

.

Recovery from osteopenia in adolescent girls with anorexia nervosa

.

J Clin Endocrinol Metab

.

1991

;

72

(

3

):

602

–

606

.

170.

Misra

M

,

Aggarwal

A

,

Miller

KK

,

Almazan

C

,

Worley

M

,

Soyka

LA

,

Herzog

DB

,

Klibanski

A

.

Effects of anorexia nervosa on clinical, hematologic, biochemical, and bone density parameters in community-dwelling adolescent girls

.

Pediatrics

.

2004

;

114

(

6

):

1574

–

1583

.

171.

Franzoni

E

,

Ciccarese

F

,

Di Pietro

E

,

Facchini

G

,

Moscano

F

,

Iero

L

,

Monaldi

A

,

Battista

G

,

Bazzocchi

A

.

Follow-up of bone mineral density and body composition in adolescents with restrictive anorexia nervosa: role of dual-energy X-ray absorptiometry

.

Eur J Clin Nutr

.

2014

;

68

(

2

):

247

–

252

.

172.

Warren

MP

,

Brooks-Gunn

J

,

Fox

RP

,

Holderness

CC

,

Hyle

EP

,

Hamilton

WG

,

Hamilton

L

.

Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy: a longitudinal study

.

Fertil Steril

.

2003

;

80

(

2

):

398

–

404

.

173.

Vestergaard

P

,

Emborg

C

,

Støving

RK

,

Hagen

C

,

Mosekilde

L

,

Brixen

K

.

Fractures in patients with anorexia nervosa, bulimia nervosa, and other eating disorders—a nationwide register study

.

Int J Eat Disord

.

2002

;

32

(

3

):

301

–

308

.

174.

Faje

AT

,

Fazeli

PK

,

Miller

KK

,

Katzman

DK

,

Ebrahimi

S

,

Lee

H

,

Mendes

N

,

Snelgrove

D

,

Meenaghan

E

,

Misra

M

,

Klibanski

A

.

Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa

.

Int J Eat Disord

.

2014

;

47

(

5

):

458

–

466

.

175.

Duckham

RL

,

Baxter-Jones

AD

,

Johnston

JD

,

Vatanparast

H

,

Cooper

D

,

Kontulainen

S

.

Does physical activity in adolescence have site-specific and sex-specific benefits on young adult bone size, content, and estimated strength?

J Bone Miner Res

.

2014

;

29

(

2

):

479

–

486

.

176.

Janz

KF

,

Letuchy

EM

,

Burns

TL

,

Eichenberger Gilmore

JM

,

Torner

JC

,

Levy

SM

.

Objectively measured physical activity trajectories predict adolescent bone strength: Iowa Bone Development Study

.

Br J Sports Med

.

2014

;

48

(

13

):

1032

–

1036

.

177.

Christo

K

,

Prabhakaran

R

,

Lamparello

B

,

Cord

J

,

Miller

KK

,

Goldstein

MA

,

Gupta

N

,

Herzog

DB

,

Klibanski

A

,

Misra

M

.

Bone metabolism in adolescent athletes with amenorrhea, athletes with eumenorrhea, and control subjects

.

Pediatrics

.

2008

;

121

(

6

):

1127

–

1136

.

178.

Lawson

EA

,

Miller

KK

,

Bredella

MA

,

Phan

C

,

Misra

M

,

Meenaghan

E

,

Rosenblum

L

,

Donoho

D

,

Gupta

R

,

Klibanski

A

.

Hormone predictors of abnormal bone microarchitecture in women with anorexia nervosa

.

Bone

.

2010

;

46

(

2

):

458

–

463

.

179.

Milos

G

,

Spindler

A

,

Rüegsegger

P

,

Seifert

B

,

Mühlebach

S

,

Uebelhart

D

,

Häuselmann

HJ

.

Cortical and trabecular bone density and structure in anorexia nervosa

.

Osteoporos Int

.

2005

;

16

(

7

):

783

–

790

.

180.

Ackerman

KE

,

Putman

M

,

Guereca

G

,

Taylor

AP

,

Pierce

L

,

Herzog

DB

,

Klibanski

A

,

Bouxsein

M

,

Misra

M

.

Cortical microstructure and estimated bone strength in young amenorrheic athletes, eumenorrheic athletes and non-athletes

.

Bone

.

2012

;

51

(

4

):

680

–

687

.

181.

Rigotti

NA

,

Neer

RM

,

Skates

SJ

,

Herzog

DB

,

Nussbaum

SR

.

The clinical course of osteoporosis in anorexia nervosa. A longitudinal study of cortical bone mass

.

JAMA

.

1991

;

265

(

9

):

1133

–

1138

.

182.

Ackerman

KE

,

Cano Sokoloff

N

,

DE Nardo Maffazioli

G

,

Clarke

HM

,

Lee

H

,

Misra

M

.

Fractures in relation to menstrual status and bone parameters in young athletes

.

Med Sci Sports Exerc

.

2015

;

47

(

8

):

1577

–

1586

.

183.

Misra

M

,

Soyka

LA

,

Miller

KK

,

Herzog

DB

,

Grinspoon

S

,

De Chen

D

,

Neubauer

G

,

Klibanski

A

.

Serum osteoprotegerin in adolescent girls with anorexia nervosa

.

J Clin Endocrinol Metab

.

2003

;

88

(

8

):

3816

–

3822

.

184.

Ihle

R

,

Loucks

AB

.

Dose-response relationships between energy availability and bone turnover in young exercising women

.

J Bone Miner Res

.

2004

;

19

(

8

):

1231

–

1240

.

185.

De Souza

MJ

,

West

SL

,

Jamal

SA

,

Hawker

GA

,

Gundberg

CM

,

Williams

NI

.

The presence of both an energy deficiency and estrogen deficiency exacerbate alterations of bone metabolism in exercising women

.

Bone

.

2008

;

43

(

1

):

140

–

148

.

186.

Gibbs

JC

,

Nattiv

A

,

Barrack

MT

,

Williams

NI

,

Rauh

MJ

,

Nichols

JF

,

De Souza

MJ

.

Low bone density risk is higher in exercising women with multiple triad risk factors

.

Med Sci Sports Exerc

.

2014

;

46

(

1

):

167

–

176

.

187.

Robin

G

,

Gallo

C

,

Catteau-Jonard

S

,

Lefebvre-Maunoury

C

,

Pigny

P

,

Duhamel

A

,

Dewailly

D

.

Polycystic ovary-like abnormalities (PCO-L) in women with functional hypothalamic amenorrhea

.

J Clin Endocrinol Metab

.

2012

;

97

(

11

):

4236

–

4243

.

188.

Sum

M

,

Warren

MP

.

Hypothalamic amenorrhea in young women with underlying polycystic ovary syndrome

.

Fertil Steril

.

2009

;

92

(

6

):

2106

–

2108

.

189.

Reyss

AC

,

Merlen

E

,

Demerle

C

,

Dewailly

D

.

[Revelation of a polymicrocystic ovary syndrome after one month’s treatment by pulsatile GnRH in a patient presenting with functional hypothalamic amenorrhea]

.

Gynecol Obstet Fertil

.

2003

;

31

(

12

):

1039

–

1042

.

190.

Shoham

Z

,

Conway

GS

,

Patel

A

,

Jacobs

HS

.

Polycystic ovaries in patients with hypogonadotropic hypogonadism: similarity of ovarian response to gonadotropin stimulation in patients with polycystic ovarian syndrome

.

Fertil Steril

.

1992

;

58

(

1

):

37

–

45

.

191.

Mattle

V

,

Bilgyicildirim

A

,

Hadziomerovic

D

,

Ott

HW

,

Zervomanolakis

I

,

Leyendecker

G

,

Wildt

L

.

Polycystic ovarian disease unmasked by pulsatile GnRH therapy in a subgroup of women with hypothalamic amenorrhea

.

Fertil Steril

.

2008

;

89

(

2

):

404

–

409

.

192.

Wang

JG

,

Lobo

RA

.

The complex relationship between hypothalamic amenorrhea and polycystic ovary syndrome

.

J Clin Endocrinol Metab

.

2008

;

93

(

4

):

1394

–

1397

.

193.

Golden

NH

,

Katzman

DK

,

Sawyer

SM

,

Ornstein

RM

,

Rome

ES

,

Garber

AK

,

Kohn

M

,

Kreipe

RE

;

Society for Adolescent Health and Medicine

.

Position paper of the Society for Adolescent Health and Medicine: medical management of restrictive eating disorders in adolescents and young adults

.

J Adolesc Health

.

2015

;

56

(

1

):

121

–

125

.

194.

Fichter

MM

,

Quadflieg

N

.

Mortality in eating disorders—results of a large prospective clinical longitudinal study

.

Int J Eat Disord

.

2016

;

49

(

4

):

391

–

401

.

195.

Mendolicchio

L

,

Maggio

G

,

Fortunato

F

,

Ragione

LD

.

Update on eating disorders: epidemiology, mortality and comorbidity

.

Psychiatr Danub

.

2014

;

26

(

Suppl 1

):

85

–

88

.

196.

Dempfle

A

,

Herpertz-Dahlmann

B

,

Timmesfeld

N

,

Schwarte

R

,

Egberts

KM

,

Pfeiffer

E

,

Fleischhaker

C

,

Wewetzer

C

,

Bühren

K

.

Predictors of the resumption of menses in adolescent anorexia nervosa

.

BMC Psychiatry

.

2013

;

13

:

308

.

197.

Łagowska

K

,

Kapczuk

K

,

Jeszka

J

.

Nine-month nutritional intervention improves restoration of menses in young female athletes and ballet dancers

.

J Int Soc Sports Nutr

.

2014

;

11

(

1

):

52

.

198.

Mallinson

RJ

,

Williams

NI

,

Olmsted

MP

,

Scheid

JL

,

Riddle

ES

,

De Souza

MJ

.

A case report of recovery of menstrual function following a nutritional intervention in two exercising women with amenorrhea of varying duration

.

J Int Soc Sports Nutr

.

2013

;

10

:

34

.

199.

Golden

NH

,

Jacobson

MS

,

Schebendach

J

,

Solanto

MV

,

Hertz

SM

,

Shenker

IR

.

Resumption of menses in anorexia nervosa

.

Arch Pediatr Adolesc Med

.

1997

;

151

(

1

):

16

–

21

.

200.

Martin-Du Pan

RC

,

Hermann

W

,

Chardon

F

.

[Hypercarotenemia, amenorrhea and a vegetarian diet]

.

J Gynecol Obstet Biol Reprod (Paris)

.

1990

;

19

(

3

):

290

–

294

.

201.

Westhoff

CL

,

Torgal

AH

,

Mayeda

ER

,

Stanczyk

FZ

,

Lerner

JP

,

Benn

EK

,

Paik

M

.

Ovarian suppression in normal-weight and obese women during oral contraceptive use: a randomized controlled trial

.

Obstet Gynecol

.

2010

;

116

(

2 Pt 1

):

275

–

283

.

202.

Klipping

C

,

Duijkers

I

,

Trummer

D

,

Marr

J

.

Suppression of ovarian activity with a drospirenone-containing oral contraceptive in a 24/4 regimen

.

Contraception

.

2008

;

78

(

1

):

16

–

25

.

203.

Legro

RS

,

Pauli

JG

,

Kunselman

AR

,

Meadows

JW

,

Kesner

JS

,

Zaino

RJ

,

Demers

LM

,

Gnatuk

CL

,

Dodson

WC

.

Effects of continuous versus cyclical oral contraception: a randomized controlled trial

.

J Clin Endocrinol Metab

.

2008

;

93

(

2

):

420

–

429

.

204.

Cobb

KL

,

Bachrach

LK

,

Sowers

M

,

Nieves

J

,

Greendale

GA

,

Kent

KK

,

Brown

BW

, Jr ,

Pettit

K

,

Harper

DM

,

Kelsey

JL

.

The effect of oral contraceptives on bone mass and stress fractures in female runners

.

Med Sci Sports Exerc

.

2007

;

39

(

9

):

1464

–

1473

.

205.

Castelo-Branco

C

,

Vicente

JJ

,

Pons

F

,

Martínez de Osaba

MJ

,

Casals

E

,

Vanrell

JA

.

Bone mineral density in young, hypothalamic oligoamenorrheic women treated with oral contraceptives

.

J Reprod Med

.

2001

;

46

(

10

):

875

–

879

.

206.

Cumming

DC

.

Exercise-associated amenorrhea, low bone density, and estrogen replacement therapy

.

Arch Intern Med

.

1996

;

156

(

19

):

2193

–

2195

.

207.

De Crée

C

,

Lewin

R

,

Ostyn

M

.

Suitability of cyproterone acetate in the treatment of osteoporosis associated with athletic amenorrhea

.

Int J Sports Med

.

1988

;

9

(

3

):

187

–

192

.

208.

Gibson

JH

,

Mitchell

A

,

Reeve

J

,

Harries

MG

.

Treatment of reduced bone mineral density in athletic amenorrhea: a pilot study

.

Osteoporos Int

.

1999

;

10

(

4

):

284

–

289

.

209.

Hergenroeder

AC

,

Smith

EO

,

Shypailo

R

,

Jones

LA

,

Klish

WJ

,

Ellis

K

.

Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months

.

Am J Obstet Gynecol

.

1997

;

176

(

5

):

1017

–

1025

.

210.

Rickenlund

A

,

Carlström

K

,

Ekblom

B

,

Brismar

TB

,

Von Schoultz

B

,

Hirschberg

AL

.

Effects of oral contraceptives on body composition and physical performance in female athletes

.

J Clin Endocrinol Metab

.

2004

;

89

(

9

):

4364

–

4370

.

211.

Sowińska-Przepiera

E

,

Andrysiak-Mamos

E

,

Syrenicz

J

,

Jarząbek-Bielecka

G

,

Friebe

Z

,

Syrenicz

A

.

Polymorphism of the vitamin D₃ receptor gene and bone mineral density in girls with functional hypothalamic amenorrhea subjected to oestroprogestagen treatment

.

Endokrynol Pol

.

2011

;

62

(

6

):

492

–

498

.

212.

Sowińska-Przepiera

E

,

Syrenicz

A

,

Friebe

Z

,

Jarząbek-Bielecka

G

,

Chełstowski

K

.

PvuII and XbaI polymorphisms of estrogen receptor-α and the results of estroprogestagen therapy in girls with functional hypothalamic amenorrhea—preliminary study

.

Arch Med Sci

.

2012

;

8

(

5

):

841

–

847

.

213.

Warren

MP

,

Miller

KK

,

Olson

WH

,

Grinspoon

SK

,

Friedman

AJ

.

Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study

.

Contraception

.

2005

;

72

(

3

):

206

–

211

.

214.

Misra

M

,

Katzman

D

,

Miller

KK

,

Mendes

N

,

Snelgrove

D

,

Russell

M

,

Goldstein

MA

,

Ebrahimi

S

,

Clauss

L

,

Weigel

T

,

Mickley

D

,

Schoenfeld

DA

,

Herzog

DB

,

Klibanski

A

.

Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa

.

J Bone Miner Res

.

2011

;

26

(

10

):

2430

–

2438

.

215.

Weissberger

AJ

,

Ho

KK

,

Lazarus

L

.

Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women

.

J Clin Endocrinol Metab

.

1991

;

72

(

2

):

374

–

381

.

216.

Cardim

HJ

,

Lopes

CM

,

Giannella-Neto

D

,

da Fonseca

AM

,

Pinotti

JA

.

The insulin-like growth factor-I system and hormone replacement therapy

.

Fertil Steril

.

2001

;

75

(

2

):

282

–

287

.

217.

Kam

GY

,

Leung

KC

,

Baxter

RC

,

Ho

KK

.

Estrogens exert route- and dose-dependent effects on insulin-like growth factor (IGF)-binding protein-3 and the acid-labile subunit of the IGF ternary complex

.

J Clin Endocrinol Metab

.

2000

;

85

(

5

):

1918

–

1922

.

218.

DiVasta

AD

,

Feldman

HA

,

Giancaterino

C

,

Rosen

CJ

,

Leboff

MS

,

Gordon

CM

.

The effect of gonadal and adrenal steroid therapy on skeletal health in adolescents and young women with anorexia nervosa

.

Metabolism

.

2012

;

61

(

7

):

1010

–

1020

.

219.

Golden

NH

,

Iglesias

EA

,

Jacobson

MS

,

Carey

D

,

Meyer

W

,

Schebendach

J

,

Hertz

S

,

Shenker

IR

.

Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial

.

J Clin Endocrinol Metab

.

2005

;

90

(

6

):

3179

–

3185

.

220.

Nakahara

T

,

Nagai

N

,

Tanaka

M

,

Muranaga

T

,

Kojima

S

,

Nozoe

S

,

Naruo

T

.

The effects of bone therapy on tibial bone loss in young women with anorexia nervosa

.

Int J Eat Disord

.

2006

;

39

(

1

):

20

–

26

.

221.

Miller

KK

,

Grieco

KA

,

Mulder

J

,

Grinspoon

S

,

Mickley

D

,

Yehezkel

R

,

Herzog

DB

,

Klibanski

A

.

Effects of risedronate on bone density in anorexia nervosa

.

J Clin Endocrinol Metab

.

2004

;

89

(

8

):

3903

–

3906

.

222.

Miller

KK

,

Meenaghan

E

,

Lawson

EA

,

Misra

M

,

Gleysteen

S

,

Schoenfeld

D

,

Herzog

D

,

Klibanski

A

.

Effects of risedronate and low-dose transdermal testosterone on bone mineral density in women with anorexia nervosa: a randomized, placebo-controlled study

.

J Clin Endocrinol Metab

.

2011

;

96

(

7

):

2081

–

2088

.

223.

Djokanovic

N

,

Klieger-Grossmann

C

,

Koren

G

.

Does treatment with bisphosphonates endanger the human pregnancy?

J Obstet Gynaecol Can

.

2008

;

30

(

12

):

1146

–

1148

.

224.

Bussiere

JL

,

Pyrah

I

,

Boyce

R

,

Branstetter

D

,

Loomis

M

,

Andrews-Cleavenger

D

,

Farman

C

,

Elliott

G

,

Chellman

G

.

Reproductive toxicity of denosumab in cynomolgus monkeys

.

Reprod Toxicol

.

2013

;

42

:

27

–

40

.

225.

Cummings

SR

,

San Martin

J

,

McClung

MR

,

Siris

ES

,

Eastell

R

,

Reid

IR

,

Delmas

P

,

Zoog

HB

,

Austin

M

,

Wang

A

,

Kutilek

S

,

Adami

S

,

Zanchetta

J

,

Libanati

C

,

Siddhanti

S

,

Christiansen

C

;

FREEDOM Trial

.

Denosumab for prevention of fractures in postmenopausal women with osteoporosis

.

N Engl J Med

.

2009

;

361

(

8

):

756

–

765

.

226.

Welt

CK

,

Chan

JL

,

Bullen

J

,

Murphy

R

,

Smith

P

,

DePaoli

AM

,

Karalis

A

,

Mantzoros

CS

.

Recombinant human leptin in women with hypothalamic amenorrhea

.

N Engl J Med

.

2004

;

351

(

10

):

987

–

997

.

227.

Chou

SH

,

Chamberland

JP

,

Liu

X

,

Matarese

G

,

Gao

C

,

Stefanakis

R

,

Brinkoetter

MT

,

Gong

H

,

Arampatzi

K

,

Mantzoros

CS

.

Leptin is an effective treatment for hypothalamic amenorrhea

.

Proc Natl Acad Sci USA

.

2011

;

108

(

16

):

6585

–

6590

.

228.

Sienkiewicz

E

,

Magkos

F

,

Aronis

KN

,

Brinkoetter

M

,

Chamberland

JP

,

Chou

S

,

Arampatzi

KM

,

Gao

C

,

Koniaris

A

,

Mantzoros

CS

.

Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women

.

Metabolism

.

2011

;

60

(

9

):

1211

–

1221

.

229.

Fazeli

PK

,

Wang

IS

,

Miller

KK

,

Herzog

DB

,

Misra

M

,

Lee

H

,

Finkelstein

JS

,

Bouxsein

ML

,

Klibanski

A

.

Teriparatide increases bone formation and bone mineral density in adult women with anorexia nervosa

.

J Clin Endocrinol Metab

.

2014

;

99

(

4

):

1322

–

1329

.

230.

Zhang

D

,

Potty

A

,

Vyas

P

,

Lane

J

.

The role of recombinant PTH in human fracture healing: a systematic review

.

J Orthop Trauma

.

2014

;

28

(

1

):

57

–

62

.

231.

Martin

K

,

Santoro

N

,

Hall

J

,

Filicori

M

,

Wierman

M

,

Crowley

WF

, Jr .

Clinical review 15: management of ovulatory disorders with pulsatile gonadotropin-releasing hormone

.

J Clin Endocrinol Metab

.

1990

;

71

(

5

):

1081A

–

1081G

.

232.

Santoro

N

,

Wierman

ME

,

Filicori

M

,

Waldstreicher

J

,

Crowley

WF

, Jr .

Intravenous administration of pulsatile gonadotropin-releasing hormone in hypothalamic amenorrhea: effects of dosage

.

J Clin Endocrinol Metab

.

1986

;

62

(

1

):

109

–

116

.

233.

Leyendecker

G

,

Wildt

L

,

Hansmann

M

.

Pregnancies following chronic intermittent (pulsatile) administration of Gn-RH by means of a portable pump (“Zyklomat”)—a new approach to the treatment of infertility in hypothalamic amenorrhea

.

J Clin Endocrinol Metab

.

1980

;

51

(

5

):

1214

–

1216

.

234.

Filicori

M

,

Flamigni

C

,

Dellai

P

,

Cognigni

G

,

Michelacci

L

,

Arnone

R

,

Sambataro

M

,

Falbo

A

.

Treatment of anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles

.

J Clin Endocrinol Metab

.

1994

;

79

(

4

):

1215

–

1220

.

235.

Martin

KA

,

Hall

JE

,

Adams

JM

,

Crowley

WF

, Jr .

Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea

.

J Clin Endocrinol Metab

.

1993

;

77

(

1

):

125

–

129

.

236.

Schoot

DC

,

Harlin

J

,

Shoham

Z

,

Mannaerts

BM

,

Lahlou

N

,

Bouchard

P

,

Bennink

HJ

,

Fauser

BC

.

Recombinant human follicle-stimulating hormone and ovarian response in gonadotrophin-deficient women

.

Hum Reprod

.

1994

;

9

(

7

):

1237

–

1242

.

237.

Borges

LE

,

Morgante

G

,

Musacchio

MC

,

Petraglia

F

,

De Leo

V

.

New protocol of clomiphene citrate treatment in women with hypothalamic amenorrhea

.

Gynecol Endocrinol

.

2007

;

23

(

6

):

343

–

346

.

238.

Djurovic

M

,

Pekic

S

,

Petakov

M

,

Damjanovic

S

,

Doknic

M

,

Dieguez

C

,

Casanueva

FF

,

Popovic

V

.

Gonadotropin response to clomiphene and plasma leptin levels in weight recovered but amenorrhoeic patients with anorexia nervosa

.

J Endocrinol Invest

.

2004

;

27

(

6

):

523

–

527

.

239.

Seyedoshohadaei

F

,

Tangestani

L

,

Zandvakili

F

,

Rashadmanesh

N

.

Comparison of the effect of clomiphene estradiol valerate vs letrozole on endometrial thickness, abortion and pregnancy rate in infertile women with polycystic ovarian syndrome

.

J Clin Diagn Res

.

2016

;

10

(

8

):

QC10

–

QC13

.

240.

Jayasena

CN

,

Abbara

A

,

Veldhuis

JD

,

Comninos

AN

,

Ratnasabapathy

R

,

De Silva

A

,

Nijher

GM

,

Ganiyu-Dada

Z

,

Mehta

A

,

Todd

C

,

Ghatei

MA

,

Bloom

SR

,

Dhillo

WS

.

Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of kisspeptin-54

.

J Clin Endocrinol Metab

.

2014

;

99

(

6

):

E953

–

E961

.

241.

Jayasena

CN

,

Nijher

GM

,

Chaudhri

OB

,

Murphy

KG

,

Ranger

A

,

Lim

A

,

Patel

D

,

Mehta

A

,

Todd

C

,

Ramachandran

R

,

Salem

V

,

Stamp

GW

,

Donaldson

M

,

Ghatei

MA

,

Bloom

SR

,

Dhillo

WS

.

Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis

.

J Clin Endocrinol Metab

.

2009

;

94

(

11

):

4315

–

4323

.

242.

Jayasena

CN

,

Nijher

GM

,

Abbara

A

,

Murphy

KG

,

Lim

A

,

Patel

D

,

Mehta

A

,

Todd

C

,

Donaldson

M

,

Trew

GH

,

Ghatei

MA

,

Bloom

SR

,

Dhillo

WS

.

Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea

.

Clin Pharmacol Ther

.

2010

;

88

(

6

):

840

–

847

.

243.

Moutquin

JM

.

Socio-economic and psychosocial factors in the management and prevention of preterm labour

.

BJOG

.

2003

;

110

(

Suppl 20

):

56

–

60

.

244.

Koubaa

S

,

Hällström

T

,

Lindholm

C

,

Hirschberg

AL

.

Pregnancy and neonatal outcomes in women with eating disorders

.

Obstet Gynecol

.

2005

;

105

(

2

):

255

–

260

.

245.

Friday

KE

,

Drinkwater

BL

,

Bruemmer

B

,

Chesnut

C

III ,

Chait

A

.

Elevated plasma low-density lipoprotein and high-density lipoprotein cholesterol levels in amenorrheic athletes: effects of endogenous hormone status and nutrient intake

.

J Clin Endocrinol Metab

.

1993

;

77

(

6

):

1605

–

1609

.

246.

O’Donnell

E

,

De Souza

MJ

.

The cardiovascular effects of chronic hypoestrogenism in amenorrhoeic athletes: a critical review

.

Sports Med

.

2004

;

34

(

9

):

601

–

627

.

247.

O’Donnell

E

,

Harvey

PJ

,

Goodman

JM

,

De Souza

MJ

.

Long-term estrogen deficiency lowers regional blood flow, resting systolic blood pressure, and heart rate in exercising premenopausal women

.

Am J Physiol Endocrinol Metab

.

2007

;

292

(

5

):

E1401

–

E1409

.

248.

Hoch

AZ

,

Papanek

P

,

Szabo

A

,

Widlansky

ME

,

Schimke

JE

,

Gutterman

DD

.

Association between the female athlete triad and endothelial dysfunction in dancers

.

Clin J Sport Med

.

2011

;

21

(

2

):

119

–

125

.

249.

Mayer

L

,

Walsh

BT

,

Pierson

RN

, Jr ,

Heymsfield

SB

,

Gallagher

D

,

Wang

J

,

Parides

MK

,

Leibel

RL

,

Warren

MP

,

Killory

E

,

Glasofer

D

.

Body fat redistribution after weight gain in women with anorexia nervosa

.

Am J Clin Nutr

.

2005

;

81

(

6

):

1286

–

1291

.

250.

Puder

JJ

,

Monaco

SE

,

Sen Gupta

S

,

Wang

J

,

Ferin

M

,

Warren

MP

.

Estrogen and exercise may be related to body fat distribution and leptin in young women

.

Fertil Steril

.

2006

;

86

(

3

):

694

–

699

.

251.

Kaplan

JR

,

Manuck

SB

,

Anthony

MS

,

Clarkson

TB

.

Premenopausal social status and hormone exposure predict postmenopausal atherosclerosis in female monkeys

.

Obstet Gynecol

.

2002

;

99

(

3

):

381

–

388

.

252.

Kaplan

JR

,

Adams

MR

,

Clarkson

TB

,

Manuck

SB

,

Shively

CA

,

Williams

JK

.

Psychosocial factors, sex differences, and atherosclerosis: lessons from animal models

.

Psychosom Med

.

1996

;

58

(

6

):

598

–

611

.

253.

Ahmed

B

,

Bairey Merz

CN

,

Johnson

BD

,

Bittner

V

,

Berga

SL

,

Braunstein

GD

,

Hodgson

TK

,

Smith

K

,

Shaw

L

,

Kelsey

SF

,

Sopko

G

;

WISE Study Group

.

Diabetes mellitus, hypothalamic hypoestrogenemia, and coronary artery disease in premenopausal women (from the National Heart, Lung, and Blood Institute sponsored WISE study)

.

Am J Cardiol

.

2008

;

102

(

2

):

150

–

154

.

254.

Neumark-Sztainer

D

,

Patterson

J

,

Mellin

A

,

Ackard

DM

,

Utter

J

,

Story

M

,

Sockalosky

J

.

Weight control practices and disordered eating behaviors among adolescent females and males with type 1 diabetes: associations with sociodemographics, weight concerns, familial factors, and metabolic outcomes

.

Diabetes Care

.

2002

;

25

(

8

):

1289

–

1296

.

255.

Rydall

AC

,

Rodin

GM

,

Olmsted

MP

,

Devenyi

RG

,

Daneman

D

.

Disordered eating behavior and microvascular complications in young women with insulin-dependent diabetes mellitus

.

N Engl J Med

.

1997

;

336

(

26

):

1849

–

1854

.

256.

Arrais

RF

,

Dib

SA

.

The hypothalamus pituitary ovary axis and type 1 diabetes mellitus: a mini review

.

Hum Reprod

.

2006

;

21

(

2

):

327

–

337

.

257.

Howerton

CL

,

Bale

TL

.

Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction

.

Proc Natl Acad Sci USA

.

2014

;

111

(

26

):

9639

–

9644

.

258.

Misra

M

,

Katzman

DK

,

Estella

NM

,

Eddy

KT

,

Weigel

T

,

Goldstein

MA

,

Miller

KK

,

Klibanski

A

.

Impact of physiologic estrogen replacement on anxiety symptoms, body shape perception, and eating attitudes in adolescent girls with anorexia nervosa: data from a randomized controlled trial

.

J Clin Psychiatry

.

2013

;

74

(

8

):

e765

–

e771

.

259.

Mastorakos

G

,

Pavlatou

M

,

Diamanti-Kandarakis

E

,

Chrousos

GP

.

Exercise and the stress system

.

Hormones (Athens)

.

2005

;

4

(

2

):

73

–

89

.