Addressing Functional Hypothalamic Amenorrhea

Functional hypothalamic amenorrhea (FAA) is responsible for approximately one third of cases of secondary amenorrhea in women of reproductive age.

Although the hallmark clinical hallmarks of AHF are amenorrhea and infertility, the disorder is a complex neuroendocrinopathy characterized by hypoestrogenemia and other factors that impact the function of multiple systems including bone, psychological, cognitive, and cardiovascular disorders.

To make a timely diagnosis and appropriate management of the disorder in affected women, physicians must be prepared to recognize this condition and understand its pathophysiology.

AHF is the cessation of the menstrual cycle in the absence of an anatomical pathology, which comes from the inadequate stimulation or suppression of the hypothalamic-pituitary-ovarian (eHHO) axis. Both gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) require pulsatility for ovulation and normal menstrual pattern.

In AHF, several triggers, including psychosocial stressors and energy imbalance, alter pulsatile secretion of GnRH and LH, resulting in anovulation and amenorrhea. This condition can be categorized into 3 types based on the primary cause: psychosocial stress, disordered/restrictive eating, and/or excessive exercise. In many cases, it is a combination of more than one etiology, with a possible genetic or epigenetic predisposition.

> Impact of psychosocial stress

Exposure to psychosocial stress increases the activation of eHHO, which in turn increases the secretion of corticotrophin hormone (CRH) and glucocorticoids such as cortisol. It is known that patients with AHF have increased morning and 24-hour cortisol levels. Increased CRH and glucocorticoids can inhibit eHHO at different levels.

Glucocorticoids act directly on GnRH-releasing hypothalamic neurons and inhibit its synthesis and secretion. Recent evidence also suggests that both CRH and glucocorticoids have the potential to interact with kisspeptin neurons in the hypothalamus. Kisspeptin neurons secrete the protein kisspeptin, which directly stimulates the synthesis and release of GnRH.

Increased levels in stress are associated with lower levels of kisspeptin. CRH and glucocorticoid receptors have been identified in kisspeptin neurons, suggesting that both potentially inhibit the synthesis and release of kisspeptin.

>  Impact of energy/metabolic imbalance

The alteration of energy availability is defined as the difference between energy input and energy expenditure. To preserve normal bodily functions it is necessary to maintain a minimum level of energy. A low energy state may be due to excess energy expenditure (excessive exercise, hypermetabolic state) and/or low energy intake (restrictive eating pattern or food shortage). Although the exact mechanism is unknown, low energy availability has been associated with eHHO suppression.

Because GnRH levels are difficult to measure, measurement of LH, an accurate index of GnRH secretion, is useful for human studies. Studies have shown that reducing energy availability by modifying dietary habits and exercising below a certain threshold, in women who menstruate normally, alters LH pulsatility. These results imply that an adaptive response produced in a state of low energy availability prioritizes other reproductive physiological functions.

AHF can occur in the context of a normal body weight situation, since up to 40% of patients exhibit bulimic and food restriction behaviors. When AHF is the result of a restrictive diet, the pattern includes reduced fat intake and increased fiber intake. On the other hand, despite having a higher percentage of lean mass (muscle), total body lean mass in patients with AHF is reduced compared to controls of the same age. These factors result in various metabolic alterations such as low levels of leptin, adiponectin and insulin, and higher levels of ghrelin.

Leptin and adiponectin are anorexigenic (appetite suppressing) hormones secreted by adipose tissue while ghrelin is an orexigenic (appetite stimulating) hormone that is secreted in the stomach. On the other hand, insulin is an anorexigenic hormone secreted in the pancreas. Although these factors influence energy metabolism, they also act directly on kisspeptin neurons in the hypothalamus.

Anorexigenic factors, such as leptin and insulin, stimulate kisspeptin neurons, while orexigenic factors, such as ghrelin, inhibit them. Thus, the net effect of metabolic alterations in patients with AHF is the suppression of kisspeptin neurons that in turn suppress eHHO.

>  Impact of genetics/epigenetics

There is increasing evidence that AHF may be associated with a genetic predisposition.

Several heterozygous variants of genes involved in congenital forms of GnRH deficiency (idiopathic hypogonadotrophic hypogonadism) have been identified in women with AHF. However, these rare genetic variants have also been found in some women with normal menstrual cycles, suggesting that AHF may result from the combination of a genetic predisposition along with external triggering factors.

The stress response is also genetically regulated. For example, patients with AHF have lower expression of brain-derived neurotrophic factor, a gene expressed in the hypothalamus and involved in neuroplasticity. Neuroplasticity is the ability of the nervous system to undergo structural and functional changes by altering the strengths of neuronal connections. Therefore, women with AHF may have altered stress responses that predispose them to this condition.

Epigenetic factors have not yet been studied in women with AHF and are therefore potential areas for future research. However, recent work in animal models highlights the importance of epigenetics in the development and functioning of neuronal regulation of GnRH; which includes transcription factors, microRNA, and DNA methylation and demethylation. Although AHF is a consequence of stress, dietary patterns, and excessive exercise, some women may be more predisposed to AHF due to their genetic makeup and epigenetic factors that alter GnRH production and function.

>  Bone health

Estrogen stimulates bone formation and inhibits bone resorption while hypoestrogenism reduces these benefits.

In women, peak bone mass of long bones is acquired before 20 years of age, and total skeletal mass peaks between 6 and 10 years of age. later. Between 40% and 60% of bone growth occurs in the late adolescence stage.

Given the youth of patients with AHF, a major concern is the adverse impact on bone health. In addition to hypoestrogenemia, low lean mass in AHF patients is an independent predictor of lower bone mineral density (BMD). On the other hand, energy deficiency is associated with resistance to growth hormone and low levels of insulin-like growth factor (IGF-1), necessary to stimulate bone growth.

Elevated cortisol levels in AHF are associated with reduced osteoblastic activity, increased osteoclastic activity, impaired calcium absorption, impaired renal calcium handling, and reduced secretion of growth hormone and IGF- 1, all of which decreases BMD. Women with AHF have lower levels of leptin, which normally stimulates bone growth and inhibits resorption.

>  Psychological and cognitive health

Women with AHF have been found to have higher rates of perfectionism, including higher levels of concern about mistakes and personal standards compared to their eumenorrheic peers.

AHF and psychological disorders have a bidirectional relationship. In women with AHF, hypoestrogenism is related to impaired cognitive function, potentially due to estrogen’s role in inducing synapse formation in multiple brain areas, including the hippocampus and cerebral cortex. Furthermore, estrogen modulates the synthesis and secretion of multiple neurotransmitters such as dopamine and serotonin, which may explain the higher rates of depression and anxiety in women with AHF compared to their eumenorrheic peers.

Increased stress in women with depression and anxiety can further suppress eHHO and lead to amenorrhea. Apart from the effects of hypoestrogenemia, lower levels of leptin and higher levels of cortisol have been found in patients with eating disorders, anxiety and depression, which could be responsible for some of these psychological symptoms.

>  Cardiovascular health

Endogenous estrogen has been associated with a favorable effect on the cardiovascular system, including improving vasodilation and maintaining endothelial homeostasis. On the other hand, it reduces the production of reactive oxygen species, reduces the oxidation of low-density lipoproteins and inhibits the proliferation of smooth muscle, these mechanisms being potential protectors against atherosclerotic disease.

Vascular function is also influenced by multiple neuroendocrine hormones such as adiponectin and cortisol, which are dysregulated in women with AHF, potentially predisposing them to vascular dysfunction. In the Nurses Health Study, greater irregularity or absence of the menstrual cycle was associated with up to a 50% increased risk of a future cardiovascular disease event. However, this study did not differentiate the AHF phenotype from other etiologies of menstrual irregularity, such as polycystic ovary syndrome (PCOS).

The Women’s Ischemia Syndrome Evaluation (WISE) study found that hypoestrogenemia of hypothalamic origin was associated with an increased risk of angiographic coronary artery disease in premenopausal women. Even after adjustment for multiple cardiovascular risk factors, hypothalamic hypoestrogenemia remained a significant predictor of coronary artery disease.

>  Sterility

Although amenorrhea is the hallmark of AHF, women often seek treatment when they cannot conceive. Most patients with AHF are amenorrheic, but a smaller subgroup presenting with infertility without amenorrhea still have evidence of hypothalamic dysregulation.

Anti-Müllerian hormone, produced by ovarian follicle development and a marker of ovarian functional reserve, is normal to slightly increased in women with AHF, reflecting the potential reversibility of infertility.

As such, studies have reported that pulsatile administration of GnRH may restore ovulation and increase the chances of conception in these patients. However, women with AHF may be at risk for adverse pregnancy outcomes due to their unhealthy behaviors such as restrictive eating and malnutrition, low body weight, or possibly vascular consequences associated with hypoestrogenism.

Although AHF is one of the most common causes of secondary amenorrhea in nonpregnant women of reproductive age, it is a diagnosis of exclusion. Secondary amenorrhea is defined as the absence of menstruation for at least 3 consecutive months. AHF is characterized by a pattern of low levels of estrogen (often <50 pg/ml), follicle-stimulating hormone (FSH) (often <10 mIU/ml), and LH (often <10 mIU/ml). .

On the other hand, the LH:FSH ratio is normal to low vs. increased LH:FSH ratio in PCOS while testosterone levels are normal (vs. typically decreased in PCOS). In addition to AHF and pregnancy, the differential diagnosis of secondary amenorrhea includes PCOS, premature ovarian failure, thyroid dysfunction, and hyperprolactinemia. The diagnosis of AHF should also be considered in women with primary amenorrhea because it constitutes 3% of these cases.

A complete clinical history and semiology will help in the differential diagnosis of secondary amenorrhea. For example, a history of radiotherapy, chemotherapy, autoimmune disease, or a family history of premature ovarian failure could confirm this etiology, while hirsutism, acne, weight gain, or the presence of central obesity may suggest a diagnosis of PCOS. The complete history should also include a review of dietary and exercise habits, changes in weight, and an evaluation for psychological stress. Although not all women with AHF are diagnosed with an eating disorder as such, many of them report symptoms of disordered eating.

The Eating Disorder Examination Questionnaire is a validated tool that can be used to identify people with eating disorders. Alternatively, the 26-question Eating Attitudes Test is a 26-question questionnaire that can screen for body image and weight concerns, especially in patients who do not have a defined eating disorder.

Because there is no validated tool to detect excessive exercise, some researchers suggest using the Perceived Stress Scale to detect excessive stress and facilitate conversation about other extreme practices, such as excessive exercise and restrictive eating.

The use of a remote patient monitoring device that tracks exercise may be a novel way to quantify weekly minutes or hours of exercise. Furthermore, a detailed medical history should focus on the detection of malabsorption diseases such as Crohn’s disease or celiac disease, which can exert chronic bodily stress and therefore influence eHHO.

The tests help further distinguish AHF from other causes of secondary amenorrhea.

After ruling out pregnancy, it is recommended to measure the hormones LH, FSH and thyrotropin, in addition to performing a pelvic ultrasound.

Women with AHF have low FSH and LH and normal thyrotropin (often with low total T3). Pelvic ultrasound can provide information about the volume and morphology of the ovaries. However, it is important to make the distinction between AHF and certain PCOS phenotypes such as PCOS type D without signs of hyperandrogenism and lean PCOS, with a low to normal body mass index, particularly because some patients with AHF present with ovarian morphology. polycystic

Polycystic ovary morphology alone indicates that a PCOS 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). Furthermore, women with AHF may exhibit features of PCOS, such as hyperandrogenism. Therefore, clinical features alone may not help confirm the diagnosis in this specific group of patients. It is important to consider the clinical picture combined with the ultrasound findings and laboratory results, especially the LH:FSH ratio.

Progesterone suppression testing can provide information on estrogenic status or, alternatively, estrogen levels can be measured. An estrogen level < 50 pg/ml in the context of low FSH and LH levels and evidence of impairment, physiological or psychological stress and should be indicative of AHF. Correct identification of the etiology of secondary amenorrhea is exceptionally important due to differences in the underlying pathophysiology and therapeutic modalities for these conditions.

Given the multifactorial etiology of AHF, its management involves accurate identification and reversal of the underlying causes. One of the main areas of interest is intensive lifestyle modification to replace maladaptive behaviors related to caloric intake and physical activity. Whenever possible, the therapeutic approach should be multidisciplinary, consisting of doctors, dietician and mental health specialist. Although the evidence on cognitive behavioral therapy is limited, it should be incorporated into the treatment plan whenever possible.

One trial reported that 16 sessions of this therapy conducted over a 20-week period, aimed at establishing healthy eating patterns, identifying maladaptive attitudes toward weight loss and eating, combating them, and improving stress coping mechanisms, restored ovulatory function and reversed the deregulation of the neuroendocrine system present in AHF.

Specifically, cognitive behavioral therapy significantly decreased nocturnal cortisol levels with increased leptin and thyrotropin levels, thereby improving ovulatory and metabolic functions in patients with AHF. However, the outcome of that therapy depends largely on the patients’ willingness to participate in the treatment plan. On the other hand, the current recommendation is based on a small sample and exclusively on patients with psychological stress problems as an underlying cause. It is unclear whether this treatment is equally effective in women with AHF caused by an eating disorder, excessive weight loss, and/or excessive exercise.

According to Endocrine Society guidelines, if menstruation has not resumed after 6 to 12 months of lifestyle modifications, treatment with a short course of transdermal estrogen with cyclical progesterone is recommended. This specific recommendation is based on a study of patients with anorexia nervosa and amenorrhea for at least 3 consecutive months who improved BMD after 6, 12, and 18 months of treatment with transdermal estradiol (100-mg patch applied 2 times/week). and medroxyprogesterone (2.5 mg/day for 10 days per month) compared to placebo. However, the recommendation for dosage and duration of use is unclear.

Oral hormone therapy and hormonal contraceptive therapy are not recommended.

This guideline is based on a systematic review that found a lack of significant benefit from these bone health interventions in patients with AHF. This result could be due to a negative regulatory effect of oral estrogens on IGF-1, a crucial mediator of bone growth and mineralization during puberty. It may also be explained by the neuroendocrine complexity of AHF such as hypercortisolism and decreased thyroid hormone levels that influence bone health in this patient population.

Furthermore, the effect of hormone replacement therapy on vascular health is unknown. The implantable subcutaneous pulsatile GnRH pump (not available in the US) has been shown to be safe and effective in restoring ovulation in some patients with AHF associated with infertility and, theoretically, in restoring GnRH pulsatility, which may reverse some of the metabolic dysfunction in women with AHF.

Once the diagnosis of AHF is established, it is recommended to evaluate baseline BMD with dual-energy X-ray absorptiometry in patients with ≥6 months of amenorrhea. This recommendation is due to the high prevalence of eating disorders combined with excessive exercise observed in patients with AHF. Patients should also be evaluated for nutritional deficiencies such as vitamin D (levels should exceed 30 ng/ml) and calcium (daily calcium intake should be 1000 to 1500 mg/day), and supplements should be provided if was necessary.

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

Some studies have reported kisspeptin protein as a potential therapeutic target. One study documented the preservation of temporal coupling of kisspeptin and LH secretory episodes in AHF, such that despite eHHO suppression, GnRH discharge is still driven by kisspeptin. Another study found that intravenous infusion of high doses of kisspeptin protein can temporarily increase LH pulsatility in women with AHF and can therefore potentially restore the menstrual cycle.

A more recent study reported the potential use of a kisspeptin receptor agonist instead of the native kisspeptin protein. In this study, single-dose bolus injection of the kisspeptin receptor agonist increased LH and FSH levels more rapidly in patients with AHF than in eumenorrheic patients. The kisspeptin receptor agonist also induced a more potent and prolonged stimulation of neuronal GnRH expression than the native kisspeptin protein. These findings suggest the need for additional studies with larger sample sizes that evaluate the systemic effects of kisspeptin receptor agonists, beyond the menstrual cycle.

Functional hypothalamic amenorrhea is a complex neuroendocrinopathy and a common disease that causes secondary amenorrhea in young women. This condition results in hypothalamic hypogonadism and infertility due to psychosocial stress, disordered eating, and/or excessive exercise.

Although most women with AHF appear healthy, there are long-term consequences on their bone, cardiovascular, psychological, and cognitive health.

Addressing the underlying inciting events can reverse this condition and potentially restore both the hypothalamic-pituitary-ovarian axis and the hypothalamic-pituitary-adrenal axis. It is very important to recognize this diagnosis and understand the pathophysiology, to plan appropriate management and interventions.