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 ruling out other etiologies of amenorrhea. The terms functional hypothalamic amenorrhea and hypothalamic amenorrhea (HA) are often used interchangeably.

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

EPIDEMIOLOGY — One of the most common types of secondary amenorrhea is FHA, which by definition excludes organic disease. Risk factors for FHA include low-weight eating disorders (in particular anorexia nervosa [AN]) and other causes of low weight, excessive exercise, and stress. FHA is responsible for approximately 25 to 35 percent and 3 percent of secondary and primary amenorrhea cases, respectively. (See "Epidemiology and causes of secondary amenorrhea" and "Causes of primary amenorrhea".)

Low-weight eating disorders are reported in 0.2 to 4 percent of adolescents and young adult women [1]. Although amenorrhea is no longer a required diagnostic criterion for AN per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [2], FHA is commonly seen in this condition. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis".)

Many, if not most, women of reproductive age engage in some form of exercise. Most obtain health benefits, but some develop menstrual dysfunction, particularly when caloric intake cannot keep pace with exercise energy expenditure [3]. In addition, excessive exercise and/or inadequate caloric intake leading to relative energy deficiency at a critical time in development may delay menarche [4].

Emotional stress is also associated with FHA and has been considered both a cause and effect of the condition [5,6]. In female athletes, the combination of low energy availability, subsequent hypothalamic-pituitary-gonadal (HPG) axis inhibition resulting in menstrual dysfunction, and low bone density is called the "female athlete triad" (Triad) [7,8]. (See 'Female athlete triad' below.)

PATHOPHYSIOLOGY — Multiple factors may contribute to the pathogenesis of FHA, including eating disorders (such as anorexia nervosa [AN]) and other causes of weight loss, excessive exercise, and stress. However, in a few women with FHA, no obvious precipitating factor is evident.

Effects on endocrine axes

●Hypothalamic-pituitary-ovarian axis – FHA is a diagnosis of exclusion, made after ruling out organic disease. It is characterized by a presumed decrease in hypothalamic gonadotropin-releasing hormone (GnRH) secretion [9], leading to decreased amplitude and/or frequency of gonadotropin pulses, absence of normal follicular development, absent midcycle surges in luteinizing hormone (LH) secretion, anovulation, and low serum estradiol concentrations [9-12]. Variable neuroendocrine patterns of LH secretion can be seen [9,12]. Serum concentrations of follicle-stimulating hormone (FSH) are low or normal, but often exceed those of LH, similar to the pattern in prepubertal girls. (See "Physiology of gonadotropin-releasing hormone" and "Physiology of the normal menstrual cycle".)

In contrast, amenorrheic swimmers, who tend to have higher body weight, are reported to have higher serum LH and adrenal androgen concentrations (dehydroepiandrosterone sulfate [DHEA-S]) [13]. Thus, the amenorrhea in swimmers may not secondary to GnRH deficiency.

●Growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis – In a state of energy deficiency (from reduced caloric intake, excessive energy expenditure, or both), levels of IGF-1 decrease despite increases in levels of GH, subsequent to a nutritionally acquired resistance to GH [14]. This topic is reviewed in detail separately. (See "Anorexia nervosa: Endocrine complications and their management", section on 'Growth hormone'.)

●Hypothalamic-pituitary-adrenal axis – Conditions of low energy availability (either from decreased caloric intake and/or excessive exercise) and increased stress are associated with relative hypercortisolemia [15,16]. High levels of cortisol can adversely impact GnRH secretion.

●Conditions such as AN and exercise-induced amenorrhea are associated with higher serum cortisol, as well as higher 24-hour urinary free cortisol levels, than observed in controls [15-17].

●Higher cortisol levels are a consequence of increased cortisol secretory pulse frequency and/or pulse amplitude and a longer half-life [15,18].

●Overnight or 24-hour cortisol area under the curve (AUC) correlates inversely with body-weight parameters and fat mass [15].

●Hormones regulating energy intake or expenditure – Low energy availability is associated with alterations in many hormones that serve as peripheral metabolic signals to (1) regulate reproductive function, as well as appetite and satiety and, thus, energy consumption (such as ghrelin, which is orexigenic, and leptin, insulin, and peptide YY [PYY], which are anorexigenic), and (2) reduce energy expenditure (such as reductions in the thyroid hormones). There are also other neural stimulatory and inhibitory signals that affect GnRH secretion, often via the hypothalamic neuropeptide kisspeptin, which is encoded by KISS1. KISS1 neurons contact GnRH neurons directly and are critical for the induction of puberty and the maintenance of fertility [19,20]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)

Hormonal changes include:

•Higher levels of ghrelin, an appetite-stimulating hormone secreted by the oxyntic cells of the gastric fundus, in low-weight conditions such as AN [21] and in exercise-induced amenorrhea (even when associated with normal weight) [22]. This is likely an adaptive response to stimulate caloric intake in undernourished states. Ghrelin administration in both animals and humans impairs FSH and LH secretion, suggesting that these high ghrelin levels [21-26] may also contribute to impaired GnRH secretion and hypogonadism. (See "Ghrelin".)

•Lower levels of leptin, an adipokine secreted by fat cells in proportion to body fat stores, which reduces appetite [22,27]. This is an appropriate adaptive response to encourage food intake in conditions of undernutrition. The observation from two different studies that exogenous leptin therapy reversed HA in these women, some of whom were low weight and some exercisers, supports the concept that a minimal amount of body fat and leptin are required for normal reproductive function [28,29]. In addition, weight gain and increases in fat mass lead to increases in leptin levels, associated with a resumption of menses [30,31]. (See "Physiology of leptin".)

•Higher levels of PYY, a hormone secreted by the gut that suppresses appetite [32-35] and does not appear to normalize with weight recovery [32,35]. One study, however, showed suppressed levels of PYY in patients with AN [36]. An increase in PYY is not the expected adaptive response to a state of energy deficit, and the cause of high PYY levels in HA remains unclear. (See "Pancreatic polypeptide, peptide YY, and neuropeptide Y".)

•Lower levels of the thyroid hormones, particularly triiodothyronine (T3), in energy-deficit states and FHA, while thyroid-stimulating hormone (TSH) and free thyroxine (T4) levels are normal to low-normal [37-40] (see "Thyroid function in nonthyroidal illness"). Accordingly, resting energy expenditure is low in states of low energy availability.

•Brown adipose tissue activity is reduced in conditions of energy deficit compared with controls and is positively associated with levels of T3 [41,42]. This, again, suggests an adaptive response and an attempt to conserve energy by reducing energy expenditure.

Inadequate caloric intake and assimilation — One of the primary causes of FHA is an energy intake/expenditure mismatch or decreased energy availability. Energy availability is the daily amount of energy consumed minus the amount of energy expended during exercise activity, normalized to fat-free mass (kcal/kg lean body mass/day [8]).

Low energy availability from increased caloric expenditure and/or insufficient caloric intake can suppress the hypothalamic-pituitary-ovarian (HPO) axis, diverting energy away from reproductive processes to more vital systems [8]. In a study of healthy women ages 18 to 30 years who increased their energy expenditure by increasing exercise while consuming structured diets that set energy availability at varying levels, LH pulse frequency (a reflection of hypothalamic GnRH secretion) decreased when energy availability was below 30 kcal/kg lean body mass/day [43].

Additionally, appropriate weight loss in conditions of extreme energy surplus (eg, after bariatric surgery in severe obesity) can lead to FHA. However, low body weight alone is not sufficient to explain the onset of amenorrhea, because women with similar body mass indices (BMIs) vary in their menstrual response to exercise. It appears that amenorrhea occurs when there is relative caloric deficiency due to inadequate nutritional intake for the amount of energy expended [44-46]. This often manifests as a reduction in fat mass, the latter serving as an indicator of energy stores.

Eating disorders — While amenorrhea is no longer a criterion for the diagnosis of AN according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [2], many girls and women with AN have FHA, with an LH pulsatility pattern similar to the prepubescent or early pubescent state [47].

Adolescents and adults with AN have marked reductions in body weight from a restriction of caloric intake (particularly a decrease in fat intake and increased consumption of fiber) [48] that may or may not be associated with purging behavior (self-induced vomiting or excessive exercise). Multiple studies have demonstrated that girls and women with FHA have higher scores on eating attitude and behavior questionnaires than their eumenorrheic counterparts, indicating a higher prevalence of dieting, bulimia, food preoccupation, eating restraint, drive for thinness, and other associated feelings [44,49-52]. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis" and "Anorexia nervosa: Endocrine complications and their management", section on 'Reproductive'.)

Specific dietary restrictions — Evidence suggests that even mild dieting with restrictions of specific dietary components in those with normal BMIs can be associated with FHA. Women with FHA tend to have a lower fat consumption and higher intake of dietary fiber and carbohydrate compared with women without FHA [44,53,54].

Malabsorption — Specific disease states that cause malabsorption have been implicated in hypothalamic-pituitary-gonadal (HPG) axis disruption leading to menstrual dysfunction. Celiac disease (ie, celiac sprue, gluten enteropathy) is an intolerance to gluten, which causes gut mucosal damage, leading to villous atrophy and malabsorption of nutrients. Some studies have demonstrated a later age of menarche and earlier age of menopause in those with celiac disease compared with healthy controls and a higher frequency of secondary amenorrhea [55]. The menstrual and reproductive issues seen in women with celiac disease are reviewed separately. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Menstrual and reproductive issues'.)

Other conditions leading to malabsorption, including inflammatory bowel disorders, could similarly result in varying degrees of menstrual dysfunction, but they are not considered to be a cause of FHA, given the presence of organic pathology. (See "Epidemiology and causes of secondary amenorrhea", section on 'Systemic illness'.)

Excessive caloric expenditure

Excessive exercise — Those who exercise strenuously for long periods are at increased risk of FHA. Exercise alone, when supported with adequate nutritional intake in a low-stress environment, does not typically cause FHA. However, strenuous exercise that is not matched by energy intake (ie, low energy availability) increases the likelihood of menstrual dysfunction [56]. Specific nutritional deficiencies have also been associated with FHA.

In a study of 70 female ultramarathon runners, short-term menstrual irregularity was reported by 41 percent of the runners during times of intense training and competition. Those who experienced chronic FHA were younger, started running at a younger age, had lower body weight, and tended to be faster [57]. Such performance enhancements are often short-lasting as athletes who maintain amenorrhea often develop significant injuries [58] or benefit less from training than eumenorrheic athletes [59]. In a second report, women who lost weight while undergoing a two-month exercise intervention were more likely to experience menstrual dysfunction than those who maintained their weight [60]. However, energy availability was not measured.

Female athlete triad — The "female athlete triad" (Triad) refers to the interrelationship between energy availability, menstrual function, and bone density. Each component of the Triad includes a spectrum, and Triad patients may be at different points on the three spectra at any given time [8,61]:

●Energy availability – Ranges in athletes from normal to inadvertent undereating to disordered eating to a frank eating disorder

●Menstrual function – Ranges from normal ovulatory cycles to luteal phase defects and anovulatory eumenorrhea to oligomenorrhea and hypothalamic amenorrhea (HA)

●Bone density – Ranges from normal to low to frank osteoporosis

Adolescents and young women with the Triad may be of normal or low weight. In one study, 28 percent of adolescent athletes with menstrual dysfunction were low weight (percent ideal body weight less than 90 percent), whereas the rest were normal weight; girls with percent ideal body weight <85 percent were approximately four times more likely to report menstrual dysfunction and have low bone density [62]. In a study of elite Danish and Swedish athletes in weight-sensitive endurance sports (eg, middle- and long-distance running, triathlon, and orienteering) that excluded women with disordered eating behavior/eating disorders, there was no significant difference in energy availability (assessed using food records) between the FHA and eumenorrheic athletes. However, the FHA group had lower energy-density diets with less fat content, lower intake of carbohydrate-rich foods, higher fiber content, and a higher drive for thinness score on eating disorder questionnaires [63].

Hypermetabolic states — During times of dramatically increased basal metabolic rate, such as severe illness or injury, the HPO axis is suppressed, and FHA may occur. Examples include severe infections, burns, traumatic brain injury [64], organ transplant [65], and hyperthyroidism [66].

Stress — Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis, with increased secretion of hypothalamic corticotropin-releasing hormone (CRH), corticotropin (ACTH), and adrenal cortisol secretion. Extreme physical, nutritional, and/or emotional stress negatively affect reproduction throughout the HPO axis. CRH inhibits GnRH pulse frequency [67,68], and cortisol suppresses reproductive function at the hypothalamic, pituitary, and uterine levels [69]. Women with FHA generally have higher basal cortisol levels and a blunted ACTH and cortisol response to CRH stimulation, likely secondary to negative feedback from hypercortisolemia and elevated ACTH. One study found that these blunted responses to CRH improved after menstrual recovery in FHA patients [70].

It has been postulated that energy imbalance may sensitize the HPO axis to stress [71,72]. FHA has been associated with environmental stressors, certain personality traits, and psychological disorders [71]. Compared with eumenorrheic age-matched controls, adolescents with FHA show more susceptibility to common life events, disordered eating, depressive traits, and psychosomatic disorders [50].

Genetic predisposition — There is marked interpatient variability in the degree of weight loss or exercise required to induce amenorrhea. This may, in part, be due to an underlying genetic predisposition in susceptible women. A number of gene mutations have been identified in patients with congenital GnRH deficiency; heterozygous mutations in some of the same genes (KAL1, FGFR1, PROKR2, GNRHR) have been identified in some women with FHA [73]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Genetics'.)

CLINICAL MANIFESTATIONS — Because women with FHA are estrogen deficient, they are at increased risk for the consequences of estrogen deficiency, including low bone density, infertility, breast and possibly vaginal atrophy, and sexual dysfunction. Hot flashes rarely occur in women with hypothalamic amenorrhea (HA) unless they have recently discontinued estrogen therapy; the presence of hot flashes should suggest another diagnosis, such as primary ovarian insufficiency. Women with FHA are also at risk for psychiatric comorbidities, including anxiety and mood disorders [74].

Low bone density/fractures — One of the main clinical concerns in women with FHA is impaired bone accrual during adolescence and low bone density during adulthood.

Anorexia nervosa — Females with anorexia nervosa (AN) can experience profound bone loss and failure to accrue normal bone mass. This is reviewed in detail separately. (See "Anorexia nervosa: Endocrine complications and their management", section on 'Bone'.)

Exercise-induced amenorrhea — Women with exercise-induced amenorrhea, especially those engaged in activities associated with restrictive eating habits and low weight (or leanness sports), may have decreased bone density, in spite of the bone-building effect of weightbearing exercise [75,76]. However, the changes in bone density may be unevenly distributed.

A study of ballet dancers found that bone density was normal or increased at weightbearing sites and decreased at non-weightbearing sites [76]. In one study comparing adolescent and young adult amenorrheic overexercisers (predominantly normal-weight runners) with eumenorrheic overexercisers and nonexercisers [77], the amenorrheic group had lower bone mineral density (BMD) Z-scores at the lumbar spine (a predominantly trabecular, weightbearing site) than the other two groups [58]. However, at the total hip and whole body (predominantly cortical, weightbearing sites), BMD Z-scores in amenorrheic overexercisers did not differ from nonexercisers but were lower than in eumenorrheic exercisers [77,78]. This suggests that trabecular sites are more negatively affected by the disruption in hormones in amenorrheic athletes but that cortical sites are still affected as the amenorrheic athletes did not experience the gain in cortical BMD observed with weightbearing exercise in the eumenorrheic athletes. Studies using high-resolution peripheral quantitative computed tomography (HRpQCT) have demonstrated impaired bone microarchitecture with resulting decrease in estimated bone strength in amenorrheic overexercisers [77-79].

Fractures, particularly stress fractures, occur at a much higher frequency in patients with exercise-induced amenorrhea [58,80-82], consistent with the reduction in bone strength estimates. Repeated stress fractures occur in up to 30 percent of ballet dancers and 32 percent of adolescent and young adult runners [58]. Stress fractures are much more common in athletes with distorted eating patterns than in those with normal eating patterns [80]. This is thought to be due, in part, to the low bone mass but also the low-energy state, which leads to low bone turnover and/or favors a resorptive state. Alterations in bone turnover with suppression of bone formation and decreases or increases in resorption reflect not just estrogen deficiency but also nutritional deprivation [83,84].

A marked improvement in bone density and bone geometry following physiologic estrogen replacement in females with AN and in oligomenorrheic athletes confirms the key contribution of estrogen deficiency to bone outcomes in FHA [85-89]. Other hormonal contributors include lower levels of insulin-like growth factor 1 (IGF-1) and higher levels of cortisol than observed in control populations, as well as alterations in hormones such as leptin, peptide YY (PYY), insulin, adiponectin, and oxytocin.

Anovulatory infertility — FHA is a reversible cause of infertility, which resolves over time after energy availability normalizes or any underlying stress contributing to FHA resolves [12]. Infertility or subfertility may also occur in menstruating women in a state of reduced energy availability. (See "Overview of ovulation induction", section on 'Hypogonadotropic hypogonadism' and "Functional hypothalamic amenorrhea: Evaluation and management", section on 'Anovulatory infertility'.)

The most subtle menstrual cycle abnormality associated with exercise is an abnormal luteal phase [90,91], which may prevent implantation or nourishment of the developing embryo. In one report, women who exercised more than four hours per week were significantly less likely to have a live birth with in vitro fertilization [92].

Dyspareunia — Estrogen deficiency can lead to vaginal dryness and dyspareunia, which resolve with improved energy availability and normalization of estrogen levels. However, this does not appear to be as common a symptom in FHA as it is in postmenopausal women. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Clinical manifestations and diagnosis".)

Cardiovascular — In general, lipid profiles are not negatively affected in women with FHA, particularly if polycystic ovary syndrome (PCOS) has been ruled out. A few studies, however, have reported adverse cardiovascular consequences, including effects on lipids, endothelial function, and angiographic evidence of coronary artery disease (CAD) in women with prolonged, exercise-induced amenorrhea [93-95]. 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 [94]:

●Total cholesterol – 210 versus 186 mg/dL (5.47 versus 4.84 mmol/L)

●Triglycerides – 68 versus 55 mg/dL (0.75 versus 0.61 mmol/L)

●Low-density lipoprotein (LDL) cholesterol – 121 versus 108 mg/dL (3.2 versus 2.8 mmol/L)

●High-density lipoprotein (HDL) cholesterol – 75 versus 66 mg/dL (1.95 versus 1.73 mmol/L)

CAD is the leading cause of death in premenopausal women in the United States and Canada, with retrospective data suggesting the development of early CAD in some older premenopausal women with a history of FHA [96].

In addition to the adverse lipid changes seen in women with FHA, estrogen deficiency has adverse effects on endothelial function, vascular resistance, and nitric oxide production [97-101]. Whether these changes are predictive of adverse cardiovascular consequences is not yet known.

However, in a study of premenopausal women with coronary risk factors who underwent coronary angiography for suspected CAD, FHA was associated with angiographic CAD [95].

Cognition and anxiety — Stress and mood disorders have been correlated with luteinizing hormone (LH) pulse patterns in women with FHA. In one report, women who recalled stressful life events at the onset of their amenorrhea had lower LH pulse frequency than those without such life events [102]. In addition, LH pulse amplitude was lower in women with anxiety and depression compared with those without mood disorders.

In one study, women with FHA reported more dysfunctional attitudes and difficulty coping with daily stresses compared with women with normal menstrual cycles [5]. In addition, more women with FHA had mood disorders compared with the normally cycling women but not compared with a group of women with amenorrhea due to other causes. One study reported an improvement in trait anxiety scores in adolescents with AN following physiologic estrogen replacement, suggesting a direct role for estrogen deficiency in emotional regulation in FHA [103].

Psychological testing of adolescents with FHA and AN suggests that those with FHA fall on the less severe end of a psychological spectrum that includes tendencies of disordered eating (social insecurity, depression tendencies, excessive concerns with dieting, and fear of gaining weight) [1]. In contrast, those with AN have more severe psychopathology.

Oligomenorrheic, normal-weight athletes, when compared with normally cycling women and non-athletes, have more drive for thinness, feelings of ineffectiveness, and scored higher for cognitive eating restraint [51]. In one study, they also performed less favorably than normally cycling athletes for verbal memory and did not demonstrate the higher cognitive flexibility reported in normally cycling athletes compared with non-athletes [104]. A key contribution of estrogen deficiency to these effects is suggested by an improvement in eating behavior, verbal memory, and executive function following physiologic estrogen replacement [105,106]. Similarly, in adolescents with AN, physiologic estrogen replacement prevented the increase in body dissatisfaction noted with weight regain in those who remained estrogen deficient [103].

Excess mortality — It is also possible that low body weight per se is associated with excess mortality, as illustrated by an analysis of the National Health and Nutrition Examination Survey (NHANES). In this report, being underweight (body mass index [BMI] <18.5 kg/m²; excluding subjects with illness-related weight loss) was associated with excess mortality (33,746 excess annual deaths in the United States); excess risk was present for both smokers and nonsmokers [107]. However, this study did not separate women from men. The mechanism for this finding is not known, and further studies are required to confirm this observation. (See "Overweight and obesity in adults: Health consequences", section on 'Mortality at low BMI ranges'.)

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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SUMMARY AND RECOMMENDATIONS

●Functional hypothalamic amenorrhea (FHA) can occur from severe energy restriction, increased energy expenditure, stress, or combinations of the three. (See 'Epidemiology' above.)

●FHA is a disorder that, by definition, excludes organic disease. It is characterized by a presumed dysregulation in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. The abnormal GnRH secretion characteristic of FHA leads to decreased amplitude and/or frequency of pulses of gonadotropins, absence of normal follicular development, absent midcycle surges in luteinizing hormone (LH) secretion, anovulation, and low serum estradiol concentrations. (See 'Pathophysiology' above and "Physiology of the normal menstrual cycle".)

●Some women of reproductive age engage in excessive exercise that may result in menstrual cycle disorders and infertility. Amenorrhea occurs only when there is relative caloric deficiency due to inadequate nutritional intake for the amount of energy expended. Women with this disorder are considered to have "exercise-induced amenorrhea" or "functional hypothalamic amenorrhea." (See 'Inadequate caloric intake and assimilation' above.)

●Young, exercising women with restrictive eating disorders and amenorrhea have been referred to as having the "female athlete triad" (Triad), which consists of decreased energy availability, menstrual dysfunction, and low bone mineral density (BMD). (See 'Female athlete triad' above.)

●There is marked interpatient variability in the degree of weight loss or exercise required to induce amenorrhea. This may, in part, be due to an underlying genetic predisposition in susceptible women. (See 'Genetic predisposition' above.)

●Because women with FHA are estrogen deficient, they are at increased risk for the consequences of estrogen deficiency, most notably, low bone density. In addition to their anovulatory infertility, women with FHA are at risk for psychiatric comorbidities, including anxiety and mood disorders. (See 'Clinical manifestations' above.)