Functional Hypothalamic Amenorrhea: Recognition and Management of a Challenging Diagnosis

Abstract

Functional hypothalamic amenorrhea (FHA) is responsible for approximately a third of the cases of secondary amenorrhea. The condition is a result of disturbances in gonadotropin-releasing hormone (GnRH) pulsatile secretion at the level of the hypothalamus, which in turn disrupts gonadotropin secretion. It is due to psychosocial stress, disordered eating, and/or excessive exercise. Often, however, it is a combination of more than one etiology, with a possible role for genetic or epigenetic predisposition. The dysfunctional GnRH release leads to the cessation of ovarian function, resulting in amenorrhea, infertility, and a long-term impact on affected women’s bone health, cardiovascular risk, cognition, and mental health. Functional hypothalamic amenorrhea is a diagnosis of exclusion, and treatment involves identifying and reversing the underlying cause(s). The aim of this concise review is to summarize the current knowledge of FHA, review its pathophysiology and the adverse health consequences, as well as to provide recommendations for diagnosis and management of this condition. Furthermore, this review will emphasize the gaps in research on this common condition impacting women of reproductive age all over the world.

Functional hypothalamic amenorrhea (FHA) is responsible for approximately a third of the cases of secondary amenorrhea in women of reproductive age and is estimated to affect 1.62 million women in the US, and 17.4 million women worldwide.¹ Although amenorrhea and infertility are the hallmark clinical features of FHA, the disorder is a complex neuroendocrinopathy characterized by hypoestrogenemia and other factors that impact the function of multiple systems including bone, psychological and cognitive, and cardiovascular health.^1–3 Clinicians should be prepared to recognize this condition and understand its pathophysiology in order to make a timely diagnosis and manage the affected women.

FHA types and pathophysiology

Functional hypothalamic amenorrhea is the cessation of the menstrual cycle in the absence of anatomic pathology due to the inadequate stimulation or suppression of the hypothalamic-pituitary-ovarian (HPO) axis.² Both gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) pulsatility are required for ovulation and the normal menstrual pattern.^2,4 In FHA, various triggers including psychosocial stressors and energy imbalance disrupt the pulsatile secretion of GnRH and LH which results in anovulation and lack of menstruation.^4–6 This condition can be categorized into three types according to the primary cause: psychosocial stress, disordered/restrictive eating, and/or excessive exercise (Figure 1).¹ In many cases, it is a combination of more than one etiology, with a possible role for genetic or epigenetic predisposition.⁷

Figure 1:

Functional hypothalamic amenorrhea: the walking unwell

Impact of psychosocial stress

Exposure to psychosocial stress increases the activation of the hypothalamic-pituitary-adrenal axis which in turn increases the secretion of corticotropin-releasing hormone (CRH) and glucocorticoids such as cortisol.⁴ Patients with FHA are known to have increased levels of both morning and twenty-four-hour cortisol levels.⁴ Increased CRH and glucocorticoids can inhibit the HPO axis at different levels. Glucocorticoids act directly on the hypothalamic GnRH neurons and inhibit GnRH synthesis and secretion (Figure 1).⁴ Recent evidence also suggests that both CRH and glucocorticoids potentially interact with the kisspeptin neurons in the hypothalamus. The kisspeptin neurons secrete the protein kisspeptin which directly stimulates GnRH synthesis and release.^8,9 Increased stress levels are associated with decreased kisspeptin levels.⁹ CRH and glucocorticoid receptors have been identified on the kisspeptin neurons, suggesting that CRH and glucocorticoids potentially inhibit kisspeptin synthesis and release (Figure 1).⁹

Impact of energy imbalance/ metabolic disturbances

Energy availability is defined as the difference between energy input and energy expenditure, and a minimum level of energy must be maintained to preserve normal bodily functions.¹⁰ A state of low energy availability can be due to excessive energy expenditure (excessive exercise, hypermetabolic state) and/or low energy input (restrictive eating pattern or food scarcity). While the exact mechanism is unknown, low energy availability has been associated with suppression of the HPO axis.^5,6,11 Because GnRH levels are difficult to measure, measuring LH is an accurate index for GnRH secretion in studies on humans.¹⁰ Studies have shown that decreasing energy availability by altering dietary and exercising habits below a certain threshold in normally menstruating women disrupts LH pulsatility.^5,6,11 These results imply that an adaptive response prioritizes other physiological functions over reproduction in a state of low energy availability.

FHA can occur in the setting of a normal body weight, as up to 40% of patients exhibit bulimic behaviors and restrictive eating.^12,13 When FHA results from restrictive eating, the pattern includes reduced fat intake and increased fiber intake.^1,12,13 Further, despite having higher lean (muscle) mass percentage, the total lean body mass in patients with FHA is reduced when compared to age-matched controls.¹⁴ The above results in various metabolic disturbances that include lower leptin, adiponectin, and insulin levels and higher ghrelin levels.^10,12,13 Leptin, and adiponectin are anorexigenic hormones (appetite suppressors) that are secreted by adipose tissue, while ghrelin is an orexigenic hormone (appetite stimulator) that is secreted from the stomach.^12,13 Moreover, insulin is an anorexigenic hormone secreted in the pancreas.¹⁰ While these factors influence energy metabolism, they also act directly on kisspeptin neurons in the hypothalamus (Figure 1).^4,10 Anorexigenic factors such as leptin and insulin, stimulate the kisspeptin neurons, while orexigenic factors such ghrelin inhibit them. Thus, the net effect of the metabolic disturbances in patients with FHA is the suppression of the kisspeptin neurons which in return suppresses the HPO axis.⁴ (see figure)

Impact of Genetics / epigenetics

There is growing evidence that there may be a genetic predisposition for FHA. Several heterozygous variants of genes involved in the congenital forms of GnRH deficiency (idiopathic hypogonadotropic hypogonadism, IHH) were identified in women with FHA.¹⁵ However, these rare gene variants have also been found in some women with normal menstrual cycles, suggesting that FHA may be the result of the combination of a genetic predisposition along with external triggering factors.⁷ Response to stress is also regulated by genetics. For example, patients with FHA have decreased expression of the brain-derived neutrotrophic factor (BDNF) gene expressed in the hypothalamus and involved in neuroplasticity.¹⁶ Neuroplasticity is the ability of the nervous system to undergo adaptive structural and functional changes through alteration of the strengths of neuronal connections.¹⁶ Thus, women with FHA may have altered responses to stress that predispose them to this condition. Epigenetic factors have not yet been studied in women with FHA, and therefore are potential areas for future research. However, recent animal models highlight the importance of epigenetics in regulating GnRH neuronal development and function; this includes transcription factors, micro-RNAs, and DNA methylation and demethylation.⁷ While FHA is a consequence of stress, dietary patterns and excessive exercise, some women may be more predisposed to FHA due to their genetic makeup and epigenetic factors which alter the production and function of GnRH.

Health consequences of functional hypothalamic amenorrhea

Bone health

Estrogen stimulates bone formation and inhibits bone resorption, and hypoestrogenemia reduces these benefits.¹⁷ Peak bone mass for long bones is acquired prior to the age of 20 years in women, and the total skeletal mass peaks 6–10 years later with 40–60% of bone growth occurring in the late adolescent stage.¹⁸ Given the young age of patients who develop FHA, a major concern is the adverse impact on their bone health.¹ In addition to hypoestrogenemia, low lean mass in patients with FHA is an independent predictor of lower bone mineral density (BMD).¹⁷ Moreover, energy deficiency in FHA is associated with growth hormone (GH) resistance and low insulin-like growth factor-1 (IGF-1), both of which are needed to stimulate bone growth.¹⁷ High cortisol levels in FHA are associated with reduced osteoblastic activity, increased osteoclastic activity, impaired calcium absorption, impaired renal handling of calcium, and reduced secretion of GH and IGF-1, all of which decrease BMD.¹⁷ Women with FHA have lower leptin which normally stimulates bone growth and inhibits resorption.¹⁷

Psychological and cognitive health

Women with FHA have been shown to have higher rates of perfectionism, including higher levels of concern over mistakes and personal standards when compared to eumenorrheic peers.¹ Functional hypothalamic amenorrhea and psychological distress have a bidirectional relationship. Hypoestrogenism is linked with impaired cognitive function in women with FHA, potentially due to estrogen’s role in inducing synapse formation in multiple areas of the brain including the hippocampus and cerebral cortex.¹⁹ Moreover, estrogen modulates the synthesis and secretion of multiple neurotransmitters including dopamine and serotonin, which may explain the increased rates of depression and anxiety in women with FHA, compared to their eumenorrheic counterparts.¹⁷ Increased stress in women with depression and anxiety can further suppress the HPO axis and trigger amenorrhea. Aside from the effects of hypoestrogenemia, decreased leptin and increased cortisol levels have been identified in patients with eating disorders, anxiety, and depression, and thus might be responsible for some of these psychological symptoms.¹⁷

Cardiovascular health

Endogenous estrogen has been associated with a favorable effect on the cardiovascular system, including enhancement of vasodilation and maintaining endothelial homeostasis.¹ In addition, estrogen reduces the production of reactive oxygen species (ROS), diminishes the oxidation of low density lipoproteins (LDL), and inhibits smooth muscle proliferation, which are all potentially protective mechanisms against atherosclerotic disease.^1,20 Vascular function is also influenced by multiple neuroendocrine hormones, including adiponectin and cortisol which are dysregulated in women with FHA and may predispose them to vascular dysfunction.²⁰ In the Nurses’ Health Study, greater irregularity or absence of menstrual cycle was associated with up to a 50% increased risk for a future cardiovascular disease event. However, this study did not differentiate the FHA phenotype from other causes of menstrual irregularity such as polycystic ovary syndrome (PCOS).²¹ The Women Ischemia Syndrome Evaluation (WISE) study showed that hypoestrogenemia of hypothalamic origin was associated with increased risk of angiographic coronary artery disease in premenopausal women.²² Even after adjusting for multiple cardiovascular risk factors, hypothalamic hypoestrogenemia remained a strong predictor of coronary artery disease (OR 7.4, p=0.008).²²

Infertility

While amenorrhea is the hallmark of FHA, women often seek treatment when they are unable to conceive.¹ The majority of patients with FHA are amenorrheic, but a smaller subset who present with infertility without amenorrhea still have evidence of hypothalamic dysregulation.² Anti-mullerian hormone (AMH), a hormone produced by the developing ovarian follicles and a marker of ovarian functional reserve, is normal to slightly increased in women with FHA, which reflects the potential reversibility of infertility. As such, studies have shown that pulsatile GnRH administration can successfully restore ovulation and increase the chances of conception in these patients.^3,23 Nevertheless, women with FHA may be at risk for adverse pregnancy outcomes,³ due to their unhealthy behaviors such as restrictive eating and malnutrition, low body weight, or possibly due to vascular consequences associated with hypoestrogenemia. This highlights an important area of future research.

DIAGNOSIS

Although FHA is one of the most common causes of secondary amenorrhea in non-pregnant women of reproductive age, it is a diagnosis of exclusion. Secondary amenorrhea is defined as the absence of menses for at least 3 consecutive months. Functional hypothalamic amenorrhea is characterized by a pattern of low estrogen (often <50 pg/mL), low FSH (often <10 mIU/mL), low LH (often <10 mIU/mL), normal to low LH:FSH ratio (vs increased LH:FSH ratio in PCOS), and normal testosterone levels (vs typically increased levels in PCOS).¹ In addition to FHA and pregnancy, the differential diagnosis of secondary amenorrhea includes PCOS, premature ovarian insufficiency (POI), thyroid dysfunction, and hyperprolactinemia.³ The diagnosis of FHA should also be considered in women with primary amenorrhea as it constitutes 3% of these cases.²⁴

A complete medical history and physical examination are needed to differentiate other potential causes of secondary amenorrhea. For example, a history of radiotherapy, chemotherapy, autoimmune disease or family history of POI might indicate POI as the etiology, whereas hirsutism, acne, weight gain or the presence of central obesity may suggest a diagnosis of PCOS (See Table 1).²⁵ A complete history should also include a review of dietary and exercise habits, changes in weight and an assessment of psychological stress. While not all women with FHA are diagnosed with eating disorders as such, many of them report symptoms of disordered eating.²⁶ The Eating Disorder Examination Questionnaire (EDE-Q) is a validated tool that can be used to identify individuals with eating disorders.²⁷ Alternatively, the 26-question Eating Attitude Test is a validated questionnaire that can screen for body-image and weight concerns, especially in patients who do not have a defined eating disorder.² Because there is no validated tool to screen for excessive exercise, some researchers suggest using the perceived stress scale (PSS) to screen for excessive stress and to facilitate the conversation about other extreme practices such as excessive exercise and restrictive eating.²⁸ The use of remote patient monitoring devices that track exercise may be a novel way to quantify minutes or hours of exercise per week. In addition, a detailed medical history should focus on screening for malabsorptive diseases such as Crohn’s or celiac disease, which may impose chronic stress on the body, and thus influence the HPO axis.²⁸ Specific laboratory tests help to further distinguish FHA from other causes of secondary amenorrhea (See Table 1). After ruling out pregnancy, it is recommended to measure serum LH, FSH and thyroid stimulating hormone (TSH), in addition to performing a pelvic ultrasound.²⁹ Women with FHA have low FSH, low LH and normal TSH (often with low total T3) (Figure 1).

Table 1:

The differential diagnosis of functional hypothalamic amenorrhea

Top differential diagnoses to rule out*
PCOS	POI	Hyperthyroidism/Hypothyroidism	Hyperprolactinemia
History and PE  - Hirsutism  - Acne  - Weight gain  - Central Obesity	History and PE  - History of radiotherapy/ chemotherapy  - History of autoimmune disease  - Family history of POI  - Diagnosis of Turner Syndrome	History and PE  - Heat/ cold intolerance  - Diarrhea/ constipation  - Weight loss/ gain  - Sweating/ dry skin  - Tremors  - Palpitations  - Sleep disturbances	History and PE  - Galactorrhea  - Headache  - Visual changes
Laboratory Values  - Elevated LH: FSH ratio (elevated LH and normal to low FSH)  - Elevated AMH  - Often elevated androgens	Laboratory Values  - Elevated FSH  - Low AMH	Laboratory Values - Abnormal TSH levels	Laboratory Values  - Elevated fasting prolactin levels

PCOS: polycystic ovarian syndrome; PE: physical exam; LH: luteinizing hormone; FSH: follicle stimulating hormone; AMH: anti-mullerian hormone; POI: primary ovarian insufficiency; TSH: thyroid stimulating hormone.

^*After a negative pregnancy test

A pelvic ultrasound provide insight on ovarian volume and morphology. However, it is important to distinguish certain phenotypes of PCOS such as PCOS-D (PCOS phenotype D with no signs of hyperandrogenism) and lean PCOS (PCOS with low to normal BMI) from FHA, particularly because some patients with FHA present with polycystic ovarian morphology (PCOM).²⁵ A polycystic ovarian morphology is indicative of PCOS only if it meets the ultrasound diagnostic criteria (≥ 12 follicles measuring 2–9 mm in diameter and/or an ovarian volume > 10 mL in at least one ovary).³⁰ More so, women with FHA can exhibit features of PCOS such as hyperandrogenism.³¹ Therefore, clinical features alone may not help confirm the diagnosis in this specific group of patients. It is important to consider the clinical picture in combination with the ultrasound findings and laboratory results, especially the LH:FSH ratio (Table 1).²⁵ A progesterone withdrawal test can provide insight on estrogen status, or alternatively estrogen levels can be measured. An estrogen level <50 pg/mL in the setting of low FSH and LH, and evidence of physiological or psychological stress should be indicative of FHA. Correct identification of the etiology of secondary amenorrhea is exceptionally important because of the differences in underlying pathophysiology and treatment modalities for these conditions.

MANAGEMENT

Given the multifactorial etiology of FHA, the management involves accurate identification and reversal of the underlying cause(s).³ One of the main focus areas is intensive life style modification to replace the maladaptive behaviors relating to caloric intake and physical activity.³ Whenever feasible, the treatment approach should be multidisciplinary with engagement of a medical provider, dietician, and mental health provider.¹⁷ Although the evidence is limited, cognitive behavioral therapy (CBT), should be incorporated in the treatment plan whenever available.^32,33 One trial showed that 16 CBT sessions, geared towards establishing healthy eating patterns, identifying maladaptive attitudes towards weight and eating and challenging them, and improving the coping mechanisms for stress, over a 20-week period, restored ovulatory function and reversed the neuroendocrine dysregulation associated with FHA.^32,33 Specifically, CBT significantly decreased nocturnal cortisol levels, and increased leptin and TSH levels, thus improving both the ovulatory and the metabolic function in patients with FHA.³³ However the outcome of CBT is largely dependent on the willingness of patients to participate in the treatment plan. Moreover, the current recommendation for CBT is based on limited sample sizes and exclusively in those with psychological stress as the underlying cause.^32,34 It is unclear if this treatment is equally effective in women with FHA due to an eating disorder, excessive weight loss, and/or to excessive exercise.^32,33

Based on the Endocrine Society’s guidelines, if 6–12 months of lifestyle modification does not result in resumption of menses, a short course of transdermal estrogen with cyclic progesterone is recommended.³ This specific recommendation is based on one study conducted in patients with anorexia nervosa, and amenorrhea for at least 3 consecutive months, that showed improved BMD at 6,12, and 18 months of treatment with transdermal estradiol (100-μg patch applied twice weekly) and medroxyprogesterone (2.5 mg daily for 10 days each month) when compared to placebo.³⁵ The recommendation on dose and duration of use, however is unclear. Oral hormone therapy and hormonal contraceptive therapy are not recommended.³ This guidance is based on a systematic review which showed lack of significant benefit of these interventions on bone health in FHA patients.³⁶ This could be due to downregulatory effect of oral estrogens on IGF-1, a crucial mediator of bone growth and mineralization during puberty.³ It also can be explained by the neuroendocrine complexity of FHA such as hypercortisolism and decreased thyroid hormone levels which influence bone health in this population of patients. Moreover, the effect on the vascular health of hormonal replacement therapy is unknown.³ An implantable subcutaneous pulsatile GnRH pump (not available in the U.S.) is proven to be safe and effective in restoring ovulation in some patients with FHA seeking fertility, and theoretically in restoring GnRH pulsatility which may reverse some of the metabolic dysfunction in women with FHA.^3,23

Once a diagnosis of FHA is established, a baseline bone density assessment with dual energy X-ray absorptiometry (DXA) scan is recommended in patients with 6 or more months of amenorrhea.³ This is due to the high prevalence of disordered eating habits in combination with high intensity exercise noted in patients with FHA. Patients should also be evaluated for nutritional deficiencies, such as vitamin D (normal Vitamin D levels should be above 30ng/ml) and calcium (daily calcium intake should be 1000–1500 mg daily), and provided with supplements if needed.³

Treatment and Research Gap

Although FHA has been described in the literature since the 1950’s, there is a dearth of research on this condition, and most of the management recommendations are based on expert opinion and studies with limited sample sizes. Importantly, there is a need to assess different treatment modalities and to develop new ones to address the potential adverse long-term outcomes in these patients including cognitive, psychological, bone and cardiovascular health outcomes.

A few studies have reported on the kisspeptin protein as a potential target for treatment.^8,37,38 One study demonstrated the conservation of the temporal coupling of kisspeptin and LH secretory episodes in FHA, such that despite the suppression of the HPO axis, the GnRH discharge is still driven by kisspeptin.⁸ Another study has shown that intravenous infusion of high dose kisspeptin protein can temporarily increase the LH pulsatility in women with FHA, and thus can potentially restore the menstrual cycle.³⁷ A more recent study reported the potential use of a kisspeptin receptor agonist instead of the native kisspeptin protein.³⁸ In this study, injecting a single dose bolus of kisspeptin receptor agonist increased LH and FSH levels more rapidly in FHA patients than it did in eumenorrheic patients.³⁸ Kisspeptin receptor agonist also induced a more potent and prolonged stimulation of the GnRH neuron, than the native kisspeptin protein.³⁸ These findings suggest the need for additional studies with larger sample sizes assessing the systemic effects of kisspeptin receptor agonists beyond the menstrual cycle.

Conclusion

Functional hypothalamic amenorrhea is a complex neuroendocrinopathy and a common cause of secondary amenorrhea in young women. This condition results in hypothalamic hypogonadism and infertility due to psychosocial stress, disordered eating and/or excessive exercise. While most women with FHA appear healthy, there are long-term consequences on the bone, cardiovascular, psychological, and cognitive health. Addressing the underlying inciting events can reverse this condition and potentially restore both the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes. Recognizing this diagnosis and understanding the pathophysiology is crucial for planning appropriate management interventions.

Learning Objectives.

Upon completion of this activity, you should be able to:

1. Identify and diagnose functional hypothalamic amenorrhea

2. Recognize the inciting events that cause functional hypothalamic amenorrhea and predict the consequences of this condition on women’s health

3. Review the current evidence-based options for the treatment of functional hypothalamic amenorrhea

Abbreviations:

CRH

corticotropin-releasing hormone

FHA

functional hypothalamic amenorrhea

FSH

follicle-stimulating hormone

GnRH

gonadotropic releasing hormone

HPO

hypothalamic pituitary ovarian axis

LH

luteinizing hormone

PCOS

polycystic ovarian syndrome