<unk>  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<unk>  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 willing consume insufficient calories in conjunction with or independent of an underlying eating disorder, meaning that women with<unk>  may be normal weight or underweight. In<unk> c athletes who have a near-normal weight, menses may be restored during periods of deceased 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<unk> . The disease can present in a variety of ways in both adolescents and adult women. Patients may present with subclinical menstrual dysfunction, ovulatory<unk> ,<unk> , 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<unk>  can have long and short term consequences in a patient's reproductive development and fertility. Anovulation and<unk>  is the characteristic feature of<unk> . If hypoestrogenism and impaired HPO axis occurs during puberty, primary<unk>  occurs. If the impairment occurs after puberty, secondary<unk>  occurs, which is more common. On a physical exam,<unk>  presents with delayed development, with patients halted in the secondary and tertiary sex characteristics of the pubertal stage before they developed<unk> . The severity of the symptoms depends on the duration and severity of hypoestrogenism. In adolescents,<unk>  presents with delayed menarche and non-specific development of pubertal stages, and underdevelopment of secondary and tertiary sex characteristics. In adult women,<unk>  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<unk>  it is important to do so while taking prior menstrual disorders into consideration. Patients with a history of, or who currently have,<unk> , 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 Decreased fat tissue mass and imbalances between bodyweight, fat tissue mass, and lean body mass has been linked to reduced BMD in<unk>  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<unk>  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<unk>  causes hypoestrogenism, women with<unk>  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.8 Adiponectin has also been found to regulate the activity of osteoblasts and osteoclasts, possibly providing a link between the abnormal concentrations found in<unk>  patients with altered bone metabolism. Additionally, women with<unk>  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<unk>  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<unk>  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<unk> , increases the risk for the premature acquisition and accelerated development of atherosclerosis in these patients. In hypoestrogenic women with<unk> , 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<unk> . Although hypoestrogenism is the main cause of impaired cardiovascular health in<unk> , patients also suffer from metabolic disturbances and an overall negative energy balance that further increases the risk of CVD. Women with<unk>  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<unk> , 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 has been studied with<unk>  and diabetes mellitus, with women who have both<unk>  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<unk>  suppression may worsen an already-existing hyperglycemia, further antagonizing estrogen-mediated NO release and compounding the risk for vascular dysfunction in patients with both<unk>  and diabetes mellitus. Neurological High levels of cortisol caused by<unk>  is seen not just in peripheral tissues, but also in the cerebrospinal fluid (CSF), where it is unbound and therefore more biologically available.<unk>  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<unk>  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<unk>  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<unk> , the lack of adequate estrogen levels, combined with the chronic stress that caused<unk> , 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<unk>  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<unk>  and mental and sexual health. Links to serotonin, dopamine, and allopregnanolone fluctuations have been found in<unk>  women. Ghrelin concentrations have been found to be linked higher levels of disordered eating behaviors in<unk>  patients compared to both exercising and sedentary controls. The degree of disordered and restrictive eating behaviors have been positively associated with PYY concentrations in women with AN, and fasting PYY has been linked to drive for thinness in exercising women. This suggests that increased PYY may decrease the drive to increase energy intake which
Functional hypothalamic amenorrhea
Hyperprolactinemic SAHA syndrome
Gonadotropin-resistant ovary syndrome
Primary ovarian insufficiency
Hypergonadotropic hypergonadism
Isolated hypogonadotropic hypogonadism
Polycystic ovary syndrome
Exercise amenorrhoea