Functional hypothalamic amenorrhea: Evaluation and management

INTRODUCTION — Low energy availability (from decreased caloric intake, excessive energy expenditure, or both) and stress are common causes of hypogonadotropic hypogonadism in women. Functional hypothalamic amenorrhea (FHA) is the term used to describe amenorrhea that results from such causes and is diagnosed after excluding other etiologies of amenorrhea. The terms FHA and hypothalamic amenorrhea (HA) are often used interchangeably.

FHA is presumed to be a consequence of functional disruption of pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) secretion. Abnormal GnRH secretion leads to reduced gonadotropin secretion, absent midcycle surges of luteinizing hormone (LH) secretion, absence of normal follicular development, anovulation, and low serum estradiol (E2) concentrations. Variable neuroendocrine patterns of LH secretion are reported, including reduced frequency and/or amplitude of LH pulses. Serum concentrations of follicle-stimulating hormone (FSH) are low or normal, and often exceed those of LH, similar to the pattern observed in prepubertal girls.

This topic will review the diagnosis, evaluation and management of FHA. The pathophysiology and clinical manifestations of FHA, as well as the approach to women with primary and secondary amenorrhea, are presented separately. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Evaluation and management of primary amenorrhea" and "Evaluation and management of secondary amenorrhea".)

DIAGNOSIS — The diagnosis of FHA is based upon:

●Amenorrhea with normal or low serum gonadotropin concentrations (often with a higher follicle-stimulating hormone [FSH] than luteinizing hormone [LH]), low serum estradiol (E2) concentrations,

●In most cases, evidence of a precipitating factor (exercise, low weight, or stress). As in every woman with new-onset amenorrhea, other causes should first be excluded before diagnosing this condition.

●Our approach to the diagnosis and management of FHA is consistent with the Endocrine Society's 2017 Clinical Practice Guideline for the diagnosis and treatment of FHA [1]. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Evaluation and management of primary amenorrhea" and "Evaluation and management of secondary amenorrhea".)

Exclude other disorders — Women with FHA usually present with secondary amenorrhea, although some may present with primary amenorrhea. The evaluation of both types of amenorrhea includes a thorough history and physical examination, biochemical testing, assessment of estrogen status, and, in some cases, imaging. These are reviewed in detail separately (algorithm 1 and algorithm 2). (See "Evaluation and management of primary amenorrhea" and "Evaluation and management of secondary amenorrhea".)

EVALUATION

History and physical examination — The characteristic history of FHA (with secondary amenorrhea) is that of a woman with previously normal cycles in whom the cycles became irregular and then ceased after she lost weight, increased exercise activity, or experienced significant stress. In some women, menses may stop without a preceding period of oligomenorrhea. If a woman had exercise-induced amenorrhea in the past that remitted when she decreased exercising, it is likely to recur if she resumes exercising without a compensatory increase in caloric intake. Some women (more commonly adolescents) may present with primary amenorrhea, although this is less common.

The patient should be asked if she has had weight loss or has a history of disordered eating/eating disorder, excessive exercise, or psychogenic stressors. One way to ascertain whether weight is a potential cause is to ask the patient what her approximate weight was when she was having regular menses. This weight can then be used as a benchmark for comparison with her weights during times of menstrual dysfunction/amenorrhea. In order to exclude other causes of amenorrhea, as FHA is a diagnosis of exclusion, it is also important to ask about pregnancy and symptoms that might suggest inflammatory bowel disease, celiac disease, thyroid disease, primary ovarian insufficiency, polycystic ovary syndrome (PCOS), nonclassic congenital adrenal hyperplasia, hyperprolactinemia, hypopituitarism (including anosmia), intracranial space occupying lesion, or other disorders associated with amenorrhea or oligomenorrhea, as reviewed in detail separately (table 1). (See "Evaluation and management of secondary amenorrhea", section on 'History' and "Evaluation and management of primary amenorrhea", section on 'History'.)

The physical examination can help exclude other causes of amenorrhea, as described in detail separately, and should include an assessment of the external and internal genitalia. Vaginal mucosa that appears red on inspection suggest hypoestrogenism. The bimanual pelvic examination to assess internal genitalia is typically deferred in adolescent girls who are not sexually active (algorithm 1 and algorithm 2). (See "Evaluation and management of secondary amenorrhea", section on 'Physical examination' and "Evaluation and management of primary amenorrhea", section on 'Physical examination'.)

Biochemical testing — Women suspected to have FHA should undergo biochemical testing to rule out other causes of amenorrhea, including serum or urine human chorionic gonadotropin (hCG) for pregnancy and serum concentrations of prolactin, thyroid-stimulating hormone (TSH), free thyroxine (T4), and follicle-stimulating hormone (FSH) to rule out hyperprolactinemia, thyroid dysfunction, and primary ovarian insufficiency, respectively. FSH is the best test for primary ovarian insufficiency, but we also measure luteinizing hormone (LH) and E2 when we suspect FHA (algorithm 1). If there is evidence of hyperandrogenism, we measure serum androgens (total testosterone, sex hormone binding globulin [SHBG], dehydroepiandrosterone sulfate [DHEAS]). While many individuals with PCOS are overweight, athletic women with PCOS may present with a leaner phenotype and/or less obvious signs of hyperandrogenism [2,3]. For example, an athlete with PCOS who also has very low weight may have hormonal suppression of androgens and estrogen until weight is restored. At a higher weight, the same athlete may then demonstrate increased androgens on laboratory testing. (See "Evaluation of premenopausal women with hirsutism", section on 'Biochemical testing'.)

Low levels of LH, FSH, and E2 are observed in FHA, but this pattern is also seen in other causes of hypogonadotropic hypogonadism, including hypothalamic or pituitary tumors. In many women with FHA, random FSH and LH levels are in the "normal" range with higher FSH than LH concentrations, particularly during recovery (algorithm 1). (See "Evaluation and management of secondary amenorrhea", section on 'Low or normal serum FSH'.)

We typically also measure a complete blood count, sedimentation rate or C-reactive protein, and basic metabolic panel to exclude inflammatory conditions, and also serologic screening to exclude celiac disease. (See "Evaluation and management of secondary amenorrhea", section on 'Low or normal serum FSH'.)

Estrogen status — A progestin challenge test may be useful in differentiating between FHA, a condition associated with E2 deficiency and scant or no withdrawal bleeding, and conditions such as PCOS in which E2 levels are not low and bleeding occurs following administration of exogenous progestin. Measurement of a serum E2 concentration at the time of the LH and FSH measurements is another way to assess estrogen status. If LH, FSH, and E2 are all low, the patient has hypogonadotropic hypogonadism (and likely FHA if the patient's history is consistent with the diagnosis). Women with PCOS alone are not estrogen deficient, LH levels are typically higher than FSH levels, and androgen levels are high. In women with primary amenorrhea, withdrawal bleeding following the progestin challenge test also indicates an intact uterus, cervix, and vagina. An imaging study to assess the internal genitalia may be of value in adolescents with primary amenorrhea before the progestin challenge test. This issue is reviewed in detail separately. (See "Evaluation and management of secondary amenorrhea", section on 'Assessment of estrogen status'.)

Imaging

●The role of transabdominal or transvaginal ultrasound and other imaging modalities for uterine and uterine outflow tract disorders are reviewed separately (algorithm 1 and algorithm 2).

●Magnetic resonance imaging (MRI) of the sella region is indicated in all women with unexplained hypogonadotropic hypogonadism and in all women with central nervous system-localizing symptoms such as visual field defects or headaches, or other pituitary hormone deficiencies. In contrast, no further testing is required if the hypogonadotropic hypogonadism is easily explained (history of weight loss, exercise with decreased energy availability, or stress) and there are no symptoms suggestive of other disease. (See "Evaluation and management of secondary amenorrhea", section on 'Low or normal serum FSH'.)

Bone density testing

●A baseline bone mineral density (BMD), as measured by dual-energy x-ray absorptiometry (DXA), should be performed if amenorrhea is present for greater than six months, or even earlier in those with a history or suspicion of severe nutritional deficiency, other energy deficit states, or a history of fragility fractures, consistent with the Endocrine Society guidelines for management of FHA. If BMD is low, we measure serum 25-hydroxyvitamin D levels to rule out vitamin D deficiency. Additional work-up includes serum levels of calcium, phosphorus, magnesium, PTH, alkaline phosphatase, a celiac screen, thyroid function tests (if not previously obtained), and a urine calcium/creatinine ratio.

In patients with ongoing FHA, we repeat the BMD evaluation every one to two years to monitor for further decreases over time. (See "Evaluation and treatment of premenopausal osteoporosis".)

●We agree with recommendations from the Female Athlete Triad Coalition for BMD evaluation in amenorrheic exercisers based on female athlete triad (Triad) risk factors (table 2), which include the following [4]:

•≥1 "high-risk" Triad risk factors:

-History of a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)-diagnosed eating disorder

-Body mass index (BMI) ≤17.5 kg/m², <85 percent expected weight, or recent weight loss of ≥10 percent in one month

-Menarche at ≥16 years of age

-History of <6 menses over 12 months (current or past history)

-Two prior stress reactions or fractures, one high-risk stress reaction/fracture, or a low-energy nontraumatic fracture

-Prior Z-score of <-2

or

•≥2 "moderate-risk" Triad risk factors:

-Current or history of disordered eating for ≥6 months

-BMI between 17.5 to 18.5 kg/m², 85 to 90 percent expected weight, or recent weight loss of 5 to 10 percent in one month

-Menarche between 15 to 16 years

-Current or history of six to eight menses over 12 months

-One prior stress reaction/fracture

-Prior Z-score between -1 and -2

or

•History of ≥1 nonperipheral or ≥2 peripheral long-bone, traumatic (nonstress) fractures if there are ≥1 moderate- or high-risk Triad risk factors.

•Athletes taking medications for ≥6 months that may impact bone (depot medroxyprogesterone acetate [DMPA], oral prednisone, and others) should also be considered for DXA testing depending on duration of therapy and history of fractures.

The optimal sites for DXA testing per the 2013 International Society for Clinical Densitometry (ISCD) guidelines [5] include (see "Overview of dual-energy x-ray absorptiometry"):

●Bone mineral content (BMC) or areal BMD of the lumbar spine and/or whole body (preferably without including the head in the assessment of the whole body scan) in children, adolescents, and young women <20 years old (adjust for growth delay with height or height age and for maturational delay with a bone age). Of note, a 2019 ISCD official position indicates that the proximal femur site (total hip and femoral neck) may be assessed in adolescents at risk for bone fragility who would benefit from continuity of DXA measurements through the transition into adulthood, particularly if linear growth is complete [6].

●BMC or areal BMD of weightbearing sites (lumbar spine, total hip, and femoral neck) in adult women 20 years or older. (The 33 percent radius may be assessed if weightbearing sites cannot be assessed for any reason.)

Screening for anxiety and mood disorders — Anxiety and mood disorders are important to consider in women with FHA given the high prevalence of these comorbid conditions. (See "Screening for depression in adults".)

Infertility — Women with FHA have anovulatory infertility. For those who recover from their FHA, fertility should then be normal. If not, the couple should undergo a standard infertility evaluation. (See "Overview of infertility", section on 'Infertility evaluation'.)

MANAGEMENT — Our approach to management is consistent with the Endocrine Society's 2017 Clinical Practice Guideline for the diagnosis and treatment of FHA [1]. Treatment of women with FHA includes treatment of the underlying cause of hypogonadotropic hypogonadism (energy deficit from insufficient caloric intake or excessive exercise, or emotional stress) and its consequences:

●Anovulatory oligo-amenorrhea and infertility

●Sexual dysfunction and genitourinary symptoms (vaginal dryness and dyspareunia) with longstanding estrogen deficiency

●Low bone mineral density (BMD)

Further, it is important to treat associated anxiety and mood disorders as these are common comorbid conditions in women with FHA. Management of such conditions should typically involve a psychologist or psychiatrist.

If the patient with FHA presents with bradycardia, orthostatic hypotension, and/or electrolyte imbalance, she should be evaluated for inpatient treatment of the underlying cause of low energy availability (usually a low-weight eating disorder [anorexia nervosa (AN)]) (see "Anorexia nervosa in adults and adolescents: Medical complications and their management"). One consensus statement proposes a risk stratification system to assist the clinician in decision making about sport participation, clearance, and return to play (table 2) [4]. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis".)

Reproductive issues

Estrogen deficiency/amenorrhea

Weight gain/lifestyle changes — Recovery in women with FHA is related to increases in body mass index (BMI) [7] and/or fat mass and reversal of the inciting factor (insufficient caloric intake and/or excessive exercise, or stress). The first step of management is to encourage weight gain through lifestyle changes, such as (i) increased caloric intake to match energy, and/or (ii) reduced exercise. Other potential interventions include stress reduction, cognitive behavioral therapy, and family-based therapy. For some women with FHA who are inadvertently undereating or practicing simple dieting, simply explaining the need for adequate caloric intake to match energy expenditure may result in increased caloric intake or reduced exercise, followed by resumption of menses [8].

●Team approach – A team approach is important to address concerns of eating disorders or disordered eating. The team should include an internal medicine, pediatrics, family, or adolescent medicine clinician with eating disorder expertise; a psychiatrist and/or psychologist; and a dietitian with expertise in eating disorders. Other team members may include an endocrinologist and family members.

Similarly, patients with exercise-induced amenorrhea require a team approach that includes their primary care or sports medicine clinician, a sports dietitian, psychologist and/or psychiatrist (when there is an associated eating disorder), and optimally an athletic trainer, exercise physiologist, and/or coach. Together this team can provide insight to increase energy intake, reduced energy expenditure, or both. Input from an endocrinologist, teammates, and the family may also be helpful [9].

●Adequate caloric intake for energy expenditure – Once a diagnosis of FHA has been confirmed, treatment should begin with an explanation of the need to treat the underlying cause. Recovery is related to increases in BMI [7] and/or fat mass and reversal of the inciting factor (eating disorder, low body weight, or stress) [10]. When the cause is insufficient caloric intake (from an eating disorder, disordered eating, or inadvertent undereating) or excessive exercise, it is important to emphasize the need for adequate caloric intake to compensate for daily energy expenditure. The dietician in the treatment team typically helps assess caloric needs and energy expenditure and monitors energy status over the duration of treatment.

Patients should be instructed to increase caloric intake and/or reduce exercise and to work to increase their body weight if they are less than 90 percent of ideal body weight, have a BMI <18.5 kg/m² (if ≥18 years) or are at <10^th percentile for age and sex (if <18 years), or have very low percent body fat. In those with secondary amenorrhea, a better strategy is to aim for the weight at or above the weight at which menses were lost. In one study of girls with low-weight eating disorders, it took an average of nine months at >90 percent ideal body weight before menses resumed, and they were, on average, 2 kg heavier at the time their menses resumed than when they became amenorrheic [11]. Of note, there was significant variability in the extent of weight gain that led to menstrual recovery, indicating that the set point for menstrual resumption varies across individuals.

Low dietary fat and high fiber intake are common in low-weight women with FHA, and such diets are associated with lower bone density. Optimizing the macronutrient composition of diet is thus important [12-14].

Cognitive behavioral therapy or family-based therapy is indicated if there is a history of irregular eating behavior or distorted body image and resistance to weight gain and/or decreasing exercise.

Patients working towards reversing the state of low energy availability should be followed for three to six months to determine if menstrual cyclicity resumes. If not, efforts toward improving nutritional and emotional status should be increased and bone density assessment should be performed (if not done already). (See 'Low bone density' below.)

●Stress reduction – If stress is considered a significant factor, discussing stress reduction and setting goals for decreasing stress are important. One small study found a positive impact of cognitive behavioral therapy in treating FHA [15,16]. In women with psychogenic stressors who do not respond to counseling and behavioral techniques, pharmacotherapy may be necessary, particularly to treat underlying anxiety and mood disorders.

●Hormone therapy – The use of physiologic hormone therapy (eg, transdermal estrogen plus a progestin may give a false sense of security in the form of hormonally induced menses. However, we do suggest starting hormone replacement therapy if there is no evidence of recovery after 6 to 12 months of lifestyle interventions. Of note, we do not suggest the use of pharmacologic estrogen-progestin therapy in this population (eg, combined oral contraceptives) (see 'Estrogen replacement' below). Some studies suggest an impact of estrogen replacement in improving cognitive flexibility, drive for thinness and body dissatisfaction, and reducing anxiety scores in young women with FHA [17-19].

Anovulatory infertility — Increased caloric intake is the first step to restore ovulation. Therefore, we suggest that ovulation induction therapies not be initiated until the patient has achieved a healthy weight and understands the need for continued focus on adequate caloric intake, because of increased risk of preterm birth and low birth weight newborns. First-line therapy for women with FHA (caused by decreased energy availability) and anovulatory infertility is therefore increased caloric intake as it is highly effective and can result in restored ovulation or possibly sufficient endogenous estrogen production that the individual may respond to clomiphene citrate. If a woman does not eat enough to have regular cycles and normal fertility, her nutrient intake during a hormonally induced pregnancy is likely to be inadequate for normal fetal growth and development. Further, in those with low weight, the spontaneous abortion rate is high [20] and low birth weight of the newborn is common [21].

Ovulation induction should thus be limited to women of normal weight (BMI ≥18.5 kg/m²).

Anovulatory infertility associated with FHA can be overcome with pulsatile administration of gonadotropin-releasing hormone (GnRH) or exogenous gonadotropin administration (both luteinizing hormone [LH] and follicle-stimulating hormone [FSH] are required). Pulsatile GnRH is available in some countries, but not the United States. In women with FHA and underlying PCOS, use of exogenous gonadotropins therapy requires careful dosing and close monitoring to avoid ovarian hyperstimulation syndrome. As noted, in women who have sufficient endogenous estrogen production, a trial of clomiphene citrate should be tried first [22-25]. (See "Overview of ovulation induction", section on 'Hypogonadotropic hypogonadism' and "Overview of ovulation induction", section on 'Gonadotropin therapy'.)

Of note, intermittent ovulation may still occur in women with FHA, and women need to be counseled on the need for contraception if they are sexually active.

Sexual function — Replacement of estrogen can help with treatment of vaginal dryness and dyspareunia, if this is an issue. Topical (vaginal) estrogen applications are a good option.

Low bone density

Initial nonpharmacologic therapy — Evidence suggests that recovery of normal bone metabolism may require both nutritional recovery, causing improved bone formation, and activation of the hypothalamic-pituitary-ovarian (HPO) axis, which both increases bone formation and decreases bone resorption. The best strategy to improve bone density is to increase caloric intake, reduce exercise activity, or both [26], depending on the underlying cause of FHA. This often involves weight gain, which should eventually lead to a resumption of menses (see 'Weight gain/lifestyle changes' above). Weight gain and resumption of menses affect bony sites slightly differently, with weight gain (without menstrual resumption) causing preferential increases in bone density of the total hip and whole body, whereas menses resumption leads to preferential increases in bone density at the lumbar spine [27]. The magnitude of change in bone density following weight gain and menstrual resumption is variable, with studies reporting increases ranging from 3 to 17 percent [27-29]. However, despite these increases in bone density, normalization of bone mass does not always occur [30].

Calcium and vitamin D supplementation — Since bone loss is the most important short-term consequence of FHA, patients should be encouraged to take 1200 to 1500 mg of calcium daily and supplemental vitamin D to maintain levels above 32 ng/mL and below the upper limit of normal for the specific assay. However, calcium and vitamin D supplementation alone is not sufficient to prevent or treat low BMD. (See "Vitamin D insufficiency and deficiency in children and adolescents" and "Bone health and calcium requirements in adolescents".)

Pharmacologic therapy — After a baseline measurement of bone density is obtained, we suggest following women with a reasonable trial of lifestyle intervention to determine if menses resume before considering hormonal or other pharmacologic therapy. However, earlier therapy may be warranted in a patient with delayed behavioral change in the setting of significantly low BMD and recurrent fractures or bone stress injuries.

Expert guidelines — The Endocrine Society 2017 guidelines suggest initiating hormonal therapy with transdermal estradiol and cyclic progesterone in women with FHA who do not have a return of menses after "a reasonable trial of nutritional, psychological, and/or modified exercise intervention" [1]. Because bone outcomes may be compromised even with 6 to 12 months of amenorrhea, these guidelines suggest that clinicians may consider hormonal intervention (transdermal estradiol with cyclic progestin) even after 6 to 12 months of nutritional, psychological, and/or modified exercise intervention. For chronic over-exercisers with FHA, the recommendations from the Female Athlete Triad Coalition for hormonal therapy are as follows [4]:

●BMD Z-scores of ≤-2 with a clinically significant fracture history (per ISCD 2013 guidelines [5]) and lack of response to nonpharmacologic therapy for ≥1 year. (Lack of response was defined as a clinically significant reduction in BMD Z-scores or occurrence of new clinically significant fractures during this period.)

●BMD Z-scores between -1 and -2 with a clinically significant fracture history and ≥2 additional female athlete triad (Triad) risk factors (table 2) and lack of response to nonpharmacologic therapy for ≥1 year.

●For girls ≥16 and <21 years old – Transdermal estradiol (E2) replacement with cyclic progesterone during this critical period of bone accrual to avoid further bone loss if they have BMD Z-scores of ≤-2 (even without a clinically significant fracture) and at least one other Triad risk factor (table 2).

Estrogen replacement — Consistent with the 2017 Endocrine Society guidelines, we currently suggest physiologic doses and formulations of estrogen to prevent further bone loss and improve bone density in adolescents and young women with FHA who have not had resumption of menses after 6 to 12 months of nonpharmacologic therapy. We typically use transdermal 17-beta E2 patches (100 mcg) applied continuously with cyclic micronized progesterone 200 mg for 12 days every month (for endometrial protection). Other cyclic progestin options include 5 to 10 mg of medroxyprogesterone or 5 mg of norethindrone for 10 to 14 days.

These guidelines are based on randomized controlled trials in adolescent and young adult athletes with oligomenorrhea and adolescent girls with AN that demonstrate increased bone accrual rates following 12 to 18 months of physiologic doses of transdermal E2 (100 mcg daily; with cyclic progestin) [31-33]. Although physiologic E2 replacement leads to a near-normalization of bone accrual rates in girls with anorexia nervosa, complete catch-up of bone density Z-scores does not occur, likely because other hormonal alterations that contribute to reduced bone accrual persist (such as low IGF-1 and leptin and high cortisol levels).

In contrast to physiologic E2 replacement, pharmacologic doses and formulations of estrogen (eg, in combined estrogen-progestin OCs) are ineffective for increasing bone density in adolescent and young adult athletes with oligomenorrhea [32,33], and adolescents and adults with AN [28,34,35], except in adults with very low bone density Z-scores [28,34]. (See "Anorexia nervosa: Endocrine complications and their management", section on 'Estrogen therapy'.)

This lack of effect has been attributed to ethinyl estradiol in combined estrogen-progestin OCs causing hepatic insulin-like growth factor 1 (IGF-1) suppression through first-pass hepatic metabolism [36]. IGF-1 is an important bone-trophic hormone that is already low in low-weight conditions, and a further suppression of IGF-1 following use of OCs is a key contributor to the limited efficacy of OCs. Ethinyl estradiol also increases levels of sex hormone-binding globulin, with a reduction in levels of bioavailable gonadal steroids [36].

Unlike ethinyl estradiol (the estrogen formulation in most combined hormonal contraceptive pills and patches), oral E2 is a physiologic form of estrogen, but there are no data regarding its impact on bone outcomes in FHA. A theoretical advantage of transdermal E2 over oral E2 is its lack of hepatic IGF-1 suppression.

One caveat is that bone health may not be protected by estrogen if nutritional deficits persist.

Therapies if estrogen ineffective

Antiresorptive agents (bisphosphonates and denosumab) — We suggest that bisphosphonates should be avoided in women with FHA and low BMD, unless estrogen replacement therapy is contraindicated or has been demonstrated to be ineffective in preventing fractures. Guidelines from the Endocrine Society and the Female Athlete Triad Coalition recommend against the use of bisphosphonates in women with FHA.

One 12-month study in adolescents with AN found no effect of oral alendronate (compared with placebo) at the lumbar spine. However, there was some improvement of bone density at the hip [37]. In adults with AN, oral risedronate (compared with placebo) over 12 months was effective in increasing bone density at the spine and the hip [38]. Bisphosphonates reside in bone for up to 10 years, and there are concerns for teratogenicity in women of reproductive age (though data thus far are not concerning). There are no available data on the use of bisphosphonates in athletes with amenorrhea.

Data are also lacking regarding the impact of newer agents, such as denosumab, on bone in women with FHA. One study demonstrated an improvement in spine BMD following 12 months of denosumab use (60 mg subcutaneously every six months) in women with anorexia nervosa compared with placebo [39]. The 2017 guidelines from the Endocrine Society and the Female Athlete Triad Coalition recommend against the use of denosumab in women with FHA.

Bone anabolic agents — Only one small study has examined the effect of teriparatide versus placebo on bone density, and this was performed in older adult women with AN. The study found a marked increase in bone density at the anterior-posterior and lateral spine in women who received teriparatide compared with placebo over six months, with no effect at the hip [40]. This may be an option for patients with FHA who have delayed fracture healing and very low bone density (per the 2017 Endocrine Society guidelines). If considered, it should be given with great caution after a thorough discussion of the possible risks of teriparatide use in younger people [41]. There are no data for the use of abaloparatide or romosozumab in women with FHA.

Therapies not recommended

Leptin — Women with FHA have relative leptin deficiency. Two studies of recombinant leptin therapy have reported restoration of ovulatory cycles in some women with FHA [42,43]. Leptin is also bone anabolic. Although metreleptin, an analog of human leptin, is approved in some countries (including the United States) for treatment of leptin deficiency in patients with congenital generalized or acquired generalized lipodystrophy, we do not suggest its use for women with FHA, because it is an anorexigenic hormone and its administration has been associated with subjective loss of appetite and also objective weight loss in adult women with FHA [43]. (See "Lipodystrophic syndromes", section on 'Persistent metabolic disturbances'.)

Androgens — Although women with AN have low levels of testosterone, replacement of testosterone (administered as a low-dose testosterone patch) was not effective for improving bone density over a 12-month period in adult women with AN compared with placebo [42]. A second randomized controlled trial examined the effect of oral dehydroepiandrosterone (DHEA; 50 mg) with estrogen-progestin OCs (20 mcg ethinyl estradiol/0.1 mg levonorgestrel) versus placebo on bone density in 13 to 27-year-old adolescents and young adults with AN and reported that bone density Z-scores were maintained over time in those who received combination therapy compared with those who received placebo [37,43]. However, a subsequent study in younger girls 11 to 17 years found no beneficial effect of the same combination of DHEA and OCs in girls with closed epiphyses and reported that the placebo group did better than the combination active arm in those with open epiphyses [44].

Guidelines from the Endocrine Society and the Female Athlete Triad Coalition recommend against the use of leptin or testosterone in women with FHA.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Amenorrhea".)

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●Basics topics (see "Patient education: Absent or irregular periods (The Basics)")

●Beyond the Basics topics (see "Patient education: Absent or irregular periods (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition - Functional hypothalamic amenorrhea (FHA) can occur from severe energy restriction, increased energy expenditure, stress, or combinations of the three. Some women of reproductive age engage in excessive exercise that may result in menstrual cycle disorders and infertility. FHA is a disorder that, by definition, excludes organic disease. (See 'Introduction' above.)

●Diagnosis - The diagnosis of FHA is based upon the findings of amenorrhea, low serum gonadotropins and estradiol (E2), and, usually, evidence of a precipitating factor (exercise, low weight, stress). As in every woman with new-onset amenorrhea, other causes should first be excluded before diagnosing this condition. The evaluation of amenorrhea includes a thorough history and physical examination, biochemical testing, assessment of estrogen status, and, in some cases, imaging. (See 'Diagnosis' above and 'Exclude other disorders' above.)

●Management

•Team approach - For restoration of menses and improvement in bone density, we use a team approach with attention to increasing caloric intake, decreasing exercise, or both, along with work to increase body weight if less than 90 percent of ideal body weight (or 90 percent of median body mass index [BMI] for age) (see 'Weight gain/lifestyle changes' above). A dietician is critical to determine energy needs based on caloric intake and expenditure.

•Behavioral therapy - We suggest behavioral therapy if there is a history of irregular eating behavior or distorted body image and resistance to decreasing exercise and/or weight gain. (See 'Weight gain/lifestyle changes' above.)

•Low bone density - After a baseline measurement of bone density is obtained, women should be followed for at least 6 to 12 months to determine if menses resume before considering estrogen replacement therapy. (See 'Pharmacologic therapy' above.)

-Although hormonal therapies may sometimes give a false sense of security in the form of hormonally induced menses, we do suggest physiologic 17-beta-estradiol rather than pharmacologic (oral contraceptive [OC]) doses of estrogen for treating low bone density in adolescents and young women with FHA who have not had resumption of menses after 6 to 12 months of nonpharmacologic therapy (Grade 2C). We typically use transdermal E2 patches (100 mcg) administered continuously with cyclic micronized progesterone 200 mg for 12 days every month (for endometrial protection). Other progesterone preparations may also be used cyclically. (See 'Estrogen replacement' above.)

-Bisphosphonates should be avoided in these women, even when bone density is low, unless estrogen replacement therapy is contraindicated or has been demonstrated to be insufficient in preventing fractures. Data for denosumab use are limited to one small study that demonstrated an improvement in spine bone density in women with anorexia nervosa. Data for teriparatide are also sparse with one small study demonstrating a marked increase in spine bone density in older adult women with anorexia nervosa compared with placebo. Teriparatide may be an option for patients with FHA who have delayed fracture healing and very low bone density if estrogen replacement therapy is ineffective/insufficient. (See 'Therapies if estrogen ineffective' above.)

•Ovulation induction - We suggest that ovulation induction therapies not be initiated unless the patient has achieved a healthy weight and understands the need for continued focus on adequate caloric intake (Grade 2C) (see 'Anovulatory infertility' above). We also suggest the use of contraception in sexually active women with FHA if pregnancy is not desired given the chances of intermittent ovulation.