Functional hypothalamic amenorrhea (FHA) is a form of amenorrhea and chronic anovulation and is 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 are equally affected. FHA has multiple risk factors, including 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).
Severe and potentially prolonged hypoestrogenism is perhaps the most dangerous hormonal pathology associated with the disease, because consequences of this disturbance can influence bone health, cardiovascular health, mental health, and metabolic functioning in both the short and long-term. Because many of the symptoms overlap with those of organic hypothalamic, pituitary, or gonadal disease and therefore must be ruled out, FHA is a diagnosis of exclusion.
"Functional" is used to indicate a behavioral cause, in which no anatomical or organic disease is identified, and which 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. Additional tests may be indicated in order to distinguish FHA from organic hypothalamic or pituitary disorders. Patients present with a broad range of symptoms related to severe hypoestrogenism (including cardiovascular and skeletal irregularities) 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. While hormonal-based therapies can potentially restore menses, weight gain and behavioral modifications can have an even more potent impact on reversing neuroendocrine abnormalities, preventing further bone loss, and re-establishing menses, making this the recommended line of treatment. If this fails to work, secondary treatment is aimed at treating the effects of hypoestrogenism, hypercortisolism, and hypothyroidism.
Presentation FHA can be caused by chronic stress, whether it be from psychosocial, emotional or 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. It therefore follows that there may also be symptoms of the female athlete triad, eating disorders, low bone density, or osteoporosis. Some may willingly consume insufficient calories in conjunction with, or independent of, an underlying eating disorder, meaning that women with FHA may be normal weight or underweight. In amenorrheic athletes who have a near-normal weight, menses may be restored during periods of decreased training. The fact that nutritional restoration is insufficient for restoring menses in some women highlights the influence that psychological issues, including mood disorders and obsessive patterns of behavior such as hyper-exercise and/or restrictive eating behavior, impart on the etiology of FHA.
The disease can present in a variety of ways in both adolescents and adult women. Patients may present with subclinical menstrual dysfunction, ovulatory amenorrhea, amenorrhea, or have a history of combination of these disturbances. In most cases, there is a gradual loss of ovulation and menses demonstrated as the diseases manifests, followed by the eventual cessation of menstrual cycles altogether. According to the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists, menstrual status should be considered a “vital sign” for all routine clinical visits because of the known effects of hypoestrogenism on bone and tissue health.
Reproductive 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 a 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. When diagnosing individuals with FHA, it is important take prior menstrual disorders into consideration. Patients with a history of, or who currently have, FHA and 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 Decreased fat tissue mass and imbalances between bodyweight, fat tissue mass, and lean body mass has been linked to reduced BMD in FHA patients; however, absolute bone strength has not always been found to be affected. 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. When FHA occurs in adolescence, inability to reach PBM becomes a primary concern, as 40-60% of factors contributing to PBM are of hormonal and nutritional influence. Estrogens, androgens, GH, and IGF-1 are the main determinants of PBM formation. In women, estrogens are the main component in proper bone formation. Through the stimulation of growth factors such as transforming growth factor beta (TGF-B), bone morphogenetic protein 6 (6-BMP-6), and IGF-1 and inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL), estrogen tends to suppress bone resorption and activate bone formation and remodeling units. 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. The profile of low serum IGF-1, low serum insulin, and high serum cortisol also contribute to low BMD. Adiponectin has also been found to regulate the activity of osteoblasts and osteoclasts, possibly providing a link between the abnormal concentrations found in FHA patients with altered bone metabolism. 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 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, NO bioactivity, autonomic function, the renin-angiotensin system, and lipid profiles. It has been hypothesized that premenopausal hypoestrogenemia caused by ovarian disruption, including that induced by FHA, increases the risk for the premature acquisition and accelerated development of atherosclerosis in these patients. In hypoestrogenic women with FHA, measures of flow-mediated dilation (FMD) indicate that the positive effects on endothelial function typically conferred by exercise are not realized, but possibly reversed. It has been suggested that long term estrogen deficiency may alter vasculature structure and responsiveness, as an impaired response to exogenous NO by arterial smooth muscle has been demonstrated in patients with FHA.
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. As is expected from the presence of heightened levels of superoxides and decreased NO bioavailability in women with FHA, it has been found that LDLc is mildly elevated at rest in these women, and it is more susceptible to oxidation after intense exercise; these levels inversely relate to brachial artery FMD in the same population. While it is not known if reported endothelial dysfunction is caused by LDLc oxidation in these women, the positive relationship between LDLc and atherosclerosis risk are well documented.
A relationship between FHA and diabetes mellitus has been studied, with women who have both FHA and diabetes mellitus having a higher risk for CVD than women who have only diabetes mellitus. Studies indicate that the loss of endogenous estrogens through hypothalamic suppression may worsen an already-existing hyperglycemia, further antagonizing estrogen-mediated NO release and compounding the risk for vascular dysfunction in patients with both FHA and diabetes mellitus.
Neurological 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 causes 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