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Functional hypothalamic amenorrhea (FHA) is a form of amenorrhea and chronic anovulation, and one of the most common types of secondary amenorrhea. It is classified as hypogonadotropic hypogonadism. It was previously known as "juvenile hypothalamosis syndrome," prior to the discovery that sexually mature females may also have FHA. FHA has multiple risk factors, with links to stress-related, weight-related, and exercise-related factors. FHA is caused by stress-induced suppression of the hypothalamic-pituitary-ovarian (HPO) axis, which results in inhibition of gonadotropin-releasing hormone (GnRH) secretion, and gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FHA is a diagnosis of exclusion  ; "functional" is used to indicate a behavioral cause, in which no anatomical or organic disease is identified, and is reversible with correction of the underlying cause. Diagnostic workup includes a detailed history and physical, laboratory studies, such as a pregnancy test, and serum levels of FSH and LH, prolactin, and thyroid-stimulating hormone (TSH), and imaging/. Patients present with a broad range of symptoms related to severe hypoestrogenism, as well as hypercortisolemia, low serum insulin levels, low serum insulin-like growth factor 1 (IGF-1), and low total triiodothyronine (T3). Treatment is primarily managing the primary cause of the FHA with behavioral modifications. If this fails to work, secondary treatment is aimed at treating the effects of hypoestrogenism, hypercortisolism , and hypothyroidism.

Risk Factors
FHA is caused by a chronic energy deprivation and negative energy balance, with links to three main risk factors: stress, weight, and exercise. It can occur in females of all ages, with the cause usually involving at least two out of the three factors.

Stress-Related Factors
Excessive or intense psychosocial, emotional, or mental stress can lead to hypothalamic dysfunction. In adolescents, this is called "adolescence crisis" and can occur during, or post, puberty. This crisis can cause young adults to develop behavioral or eating disorders (mentioned below), and, if severe and prolonged enough, can result in the menstrual irregularities seen in FHA.

When the body is stressed, the hypothalamic-pituitary-adrenal (HPA) axis is activated, which suppresses the HPO axis via corticotropin-releasing hormone (CRH) inhibiting GnRH secretion in the hypothalamus. CRH stimulates secretion of beta(β)-endorphins, which suppresses release of GnRH and dopamine. Inhibition of dopamine allows for an increase in prolactin secretion and concentration (hyperprolactinemia), which leads to inhibition of LH, and in turn leads to anovulation. Inhibition of the HPO axis also results in inhibition of the hypothalamic-pituitary-thyroid (HPT) axis and a decrease in thyroid hormones, in an attempt to minimize energy depletion. This allows the body to focus on survival, rather than reproduction.

High concentrations of dopamine and low concentrations of prolactin (and serotonin) can also cause FHA. Females with these levels characteristically have higher levels of aggression, higher levels of testosterone, and lower levels of estrogen.

Weight-Related Factors
FHA can affect women who are underweight, normal weight, or overweight. Risk factors for adolescents and young women generally include eating disorders, such as anorexia nervosa or bulimia nervosa. The risk of FHA due to weight-related factors increases across a series of four behaviors: 1) aesthetic dieting; 2) dieting due to obsessive ideals about diet and/or weight; 3) suppression of appetite, whether by drugs or self; 4) eating disorder, generally anorexia nervosa. Patients affected by eating disorders have overactive hypothalamic-pituitary systems, causing increased cortisol release and β-endorphin concentrations, with anorexia nervosa additionally having a decrease in thyroid hormones.

Both significant weight loss and weight gain can cause FHA through insulin. Significant weight loss, as in eating disorders and chronic malnutrition, is characterized by low insulin levels. Significant weight gain can lead to obesity and insulin resistance, which mimics low insulin levels via functional hypoinsulinaemia. As insulin assists in regulating the HPO axis, these low, or functionally low, levels of insulin can cause FHA.

Exercise-Related Factors
Exercise-related factors generally affect athletes who participate in sports that require intensive training and a low body weight, causing a net energy deficiency. FHA in female athletes is commonly part of the female athlete triad, which has been renamed to Relative energy deficiency in sport (RED-S), as the triad is also seen in males, with hypogonadotropic hypogonadism replacing the FHA component. Up to 69% of female athletes practicing these sports (e.g. long-distance runners, gymnasts, ballet dancers, swimmers) can be affected by FHA, as disordered eating is also often a component.

Some studies suggest female athletes with FHA may also be affected by hyperandrogenism in addition to hypoestrogenism, and it is the hyperandrogenism (as seen in polycystic ovary syndrome) that causes the menstrual irregularity, rather than chronic low energy availability and low estrogen levels. However, further studies and analysis is needed in this area.

Clinical Presentation
FHA can be caused by chronic stress, whether it be from psychosocial/emotional/mental factors, weight-related factors, or exercise-induced factors. As such, the clinical manifestations of the disorder are the result of this chronic stress caused by the above three factors. The "classic" description was previously a "thin woman who undereats and overexercises," but recent studies are finding FHA can also present as a "high-achieving individual" with poor stress-management behaviors that include under- or over-eating and overexercising.

Reproductive Health
FHA can have long and short term consequences in a patient's reproductive development and fertility. Anovulation and amenorrhea is the characteristic feature of FHA. If hypoestrogenism and impaired HPO axis occurs during puberty, primary amenorrhea occurs. If the impairment occurs after puberty, secondary amenorrhea occurs, which is more common.

On physical exam, FHA presents with delayed development, with patients halted in the secondary and tertiary sex characteristics of the pubertal stage before they developed FHA. The severity of the symptoms depends on the duration and severity of hypoestrogenism.

In adolescents, FHA presents with delayed menarche and non-specific development of pubertal stages, and underdevelopment of secondary and tertiary sex characteristics. In adult women, FHA can lead to atrophic changes, such as lack of cervical mucus, thinning of vaginal epithelium, and uterine muscle atrophy (hypoplasia), which can lead to painful intercourse (dyspareunia).

Because anovulation is a characteristic feature, patients often suffer from infertility. Patients with a history of, or who currently have, FHA, who become pregnant, require extra care and monitoring during pregnancy to avoid the increased risks of inadequate weight gain, intrauterine fetal growth restrictions, miscarriage, and/or preterm labor.

Bone Health
The majority of people reach their peak bone mass (PBM) around 30 years of age, however, 40-50% of that mass is formed during puberty. In women, estrogens are the main component in proper bone formation. Because FHA causes hypoestrogenism, women with FHA may lack age-appropriate bone density and have an increased risk of skeletal fragility, stress fractures, osteopenia, and osteoporosis. Additionally, women with FHA may have improper diets or malnutrition, leading to low calcium and vitamin D intake, and may have a tendency to overexercise, which further increases the risk for osteopenia. This improper dieting and tendency to overexercise, leading to low bone density, is also seen in RED-S. Unlike in males diagnosed with RED-S, females are at an increased risk for the consequences of decreased bone density, since females have a PBM 25-30% lower than males. Although this decreased bone density is also seen in anorexia nervosa, the severity of peak bone density loss is less in FHA patients.

Cardiovascular Health
Cardiovascular disease (CVD) is the leading cause of death in women in developed countries, and it is well studied that hypoestrogenism has many regulatory functions in the cardiovascular system. Estradiol (E2), an estrogen steroid hormone and the major female sex hormone, has a cardio-protective effect. As such, hypoestrogenism caused by FHA causes significant impairment in the endothelial and vascular function. Although hypoestrogenism is the main cause of impaired cardiovascular health in FHA, patients also suffer from metabolic disturbances and an overall negative energy balance that further increases the risk of CVD. Women with FHA caused by exercised-induced factors tend to have a higher lipid profile and an increased frequency of diabetes mellitus, with women who have both FHA and diabetes mellitus having a higher risk for CVD than women who have only diabetes mellitus.

Neurological Health
High levels of cortisol caused by FHA is seen not just in peripheral tissues, but also in the cerebrospinal fluid (CSF), where it is unbound and therefore more biologically available. FHA accelerates the onset of aging syndromes, such as osteoporosis and vaginal atrophy. Because of the high levels of cortisol in the CSF, it is suggested that the chronic stress that causes FHA may alter not just the endocrinological secretory patterns, but also the neurological secretory patterns. This altering can impact brain health, and can lead to an increased risk in neurological aging syndromes, such as dementia and Alzheimer's Disease (AD).

The low levels of estrogen seen in FHA may also contribute to the increased neurodegenerative risk. Microglia are the main immune cells of the central nervous system (CNS) and protect the brain. Estrogen is a significant regulator of microglia, and limits the inflammation that occurs when the brain is stressed (e.g. due to bacteria, viruses, hypoxia). In FHA, the lack of adequate estrogen levels, combined with the chronic stress that caused FHA, promotes a neuroinflammatory state that can cause impaired neuron formation and neuronal stem cell survival, and promote neurodegenerative diseases . However, more research is needed to find a direct link between FHA and its long term effects on neurological health.

Mental and Sexual Health
While it is known that mental and sexual health is related to estrogen levels in women, there are limited studies concerning FHA and mental and sexual health. The increased cortisol release caused by FHA can contribute to fluctuating moods, difficulty coping with common life events and stresses, and disordered eating, as serum cortisol levels correlate with the Hamilton Rating Scale for Depression (HAM-D) and Anxiety (HAM-A). Studies have shown similarities between women affected with FHA and women affected with anorexia nervosa, including a tendency towards depression and an obsession with dieting and weight.

Women with FHA tend to have more sexual problems, contributing to the mental health issues and hormonal imbalances associated with FHA. However, more studies are needed to determine the effects of FHA on sexual health.