<unk>  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. When energy levels are low,<unk>  has been postulated to present as an adaptive mechanism that enables energy to be properly allocated for the purpose of survival rather than high energetic cost of reproduction. Thus, inadequate energy intake to fuel these processes results in the initiation of a number of energy conservation strategies, including suppression of T3, IGF-1, leptin, insulin, as well as increases in peptide YY (PYY), cortisol, growth hormone (GH), and ghrelin. All of these modulators cause energy to be moved away from growth and reproduction in order to maintain vital cellular processes, thereby suppressing the aforementioned processes. The effect of nutrition/metabolic status on reproduction is mediated through GnRH secretion. GABA neurons, KNDy neurons, and leptin are specifically responsible for alterations in GnRH secretion. GABA and KNDy neurons synapse with GnRH neurons at sites where leptin receptors are absent to favor LH release. Decreased leptin results in decreased LH release and is observed in periods of long term caloric restriction and fasting. These effects appear to be dose-dependent, where cases of more severe energy restriction (due to inadequate caloric intake or excess exercise) result in greater alterations of LH pulsatility. It is easy to see from these interplays why anorexics with decreased leptin and athletes who consume less calories than they expend are likely to present with<unk>  as a mechanism to preserve energy for processes critical to survival.1 Stress-related Excessive or intense psychosocial, emotional, or mental stress can lead to<unk>  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<unk> . When the body is stressed, the sympathetic adrenal-medullary (SAM) axis, followed by the<unk> -pituitary-adrenal (HPA) axis. These events suppress the HPO axis because the corticotropin-releasing hormone (CRH) released by the HPA axis inhibit the secretion of GnRH by the hypothalamus. CRH also 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<unk> -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<unk> . Females with these levels characteristically have higher levels of aggression, higher levels of testosterone, and lower levels of estrogen. Weight-related<unk>  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. Even in normal-weight patients, it is important to watch for the presentation of symptoms of anorexia in both the physical and laboratory work-ups; this is especially true when recent encounters with emotional stress and conflicts are reported. Weight loss in the context of systemic illness may also cause<unk> , especially in the presence of narcotics. These are known to inhibit GnRH pulsations and shut down the pituitary-ovarian axis, and therefore, the effects of narcotics on reproductive health should be considered for women of reproductive age. The risk of<unk>  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<unk> -pituitary systems, causing increased cortisol release and elevated β-endorphin concentrations. Hyperactivation of the<unk> -pituitary system appears to be manifested through increased secretion of CRH and beta-endorphin by the central nervous system, both of which can alter GnRH pulsatility. LH secretion may return to prepubertal levels, which is likely due to decreased GnRH secretion. While weight gain may restore patterns of LH and GnRH secretion, up to 50% may remain anovulatory; patients with anorexia nervosa additionally having a decrease in thyroid hormones. One reason for hypercortisolemia in these patients is due to an effort to maintain euglycemia in a low energy availability (EA) state, which works in conjunction with GH. Mobilization of lipid stores have been indicated by the inverse relationship between cortisol levels and fat free mass (FFM): AN patients with the lowest BMIs, FFM, and fasting glucose levels have been found to exhibit the highest levels of cortisol. Both significant weight loss and weight gain can cause<unk>  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<unk>  hypoinsulinaemia. As insulin assists in regulating the HPO axis, these low, or<unk> ly low, levels of insulin can cause<unk> , as mice models suggest that low insulin levels decrease levels of circulating LH. Several other compounds may also influence the onset of weight-induced<unk> . Fibroblast growth factor (FGF-21), a liver-derived hormone, is up-regulated in response to starvation and has been linked to starvation-induced<unk>  in mice via its negative effects on the<unk>  signalling. Mice transgenic for FGF-21 are anovulatory, and LH surges can only be induced with administration of GnRH; These mice also display decreased expression of the Kiss-1 gene in the anteroventral periventricular nuclei of the hypothalamus. The product of this gene, kisspeptin is known to be a dominant stimulator of GnRH secretion. A correlation has also been found between anorexic patients and decreased levels of mean total and free testosterone which has not been consistently demonstrated in non-anorexic patients with<unk> . Exercise-related Exercise-related factors generally affect athletes who participate in sports that require intensive training and a low body weight, causing a net energy deficiency.<unk>  due to excessive exercise has been defined as an at least 6-month absence of menses in otherwise healthy females lacking chronic severe illness who exercise eight or more hours per week. Compared to non-exercising women, whose rate of<unk>  is 2-5%, the rate of<unk>  in competitive and recreational athletes ranges from 2-46%; it is also common for women with highly active jobs who do not engage in exercise to also have menstrual dysfunction.<unk>  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<unk>  component. Projected effects of RED-S on performance include decreases in endurance performance, muscle strength, training response, coordination, concentration, and glycogen stores, as well as increases in irritability, impaired judgement, and risk of depression and injuries.<unk>  is found in 5 to 25% of female athletes depending on the sport and level of competition level, with a higher prevalence in sports in which a low body weight is favorable. Up to 69% of female athletes practicing these sports (e.g. long-distance runners, gymnasts, ballet dancers, swimmers) can be affected by<unk> , as disordered eating is also often a component. Exercise alone is known to hyperactivate the HPA axis, but the fact that LH pulsatility is altered in<unk> c female athletes indicates the role of negative energy balance, rather than exercise intensity per se, in menstrual irregularities. When energy balance is maintained, exercise alone has not been indicated as a factor which leads to menstrual dysfunction; however, disturbances are common in weight-stable exercising women without extreme caloric deficiency who experience negative energy balance due to high energy expenditure. This negative energy balance, in turn, causes both a state of hypometabolism as well as hormonal and metabolic alterations. Genetic predisposition, psychological stress, and hypoleptinemia caused by low FFM may in some cases some combine with the negative energy state to inhibit the<unk>  generation of GnRH pulses required for regular menstrual cycling, thereby causing hypoestrogenism. Additionally, in athletes with exercise-induced<unk> , there have been specific associations between hypercortisolism and decreased LH pulsatility. In endurance athletes with varying menstrual status, the number of menses in the past 12 months has been found to be negatively associated with diurnal cortisol secretion. It is also possible that factors such as exercise intensity and duration as well as athletic discipline have differing effects on GnRH pulsatility; this may be especially relevant for women participating in sports that emphasize strength over leanness. However, excessive exercise can cause<unk>  in normal weight patients who present no abnormal metabolic or gonadotropic laboratory results. In these cases, combined hormonal contraceptive pills will not address the primary cause of menstrual cessation: inhibition of the HPO axis due to excessive exercise. Thus, behavioral modifications should be pursued. While hypoestrogenemia has been linked to
Functional hypothalamic amenorrhea
Hyperprolactinemic SAHA syndrome
Gonadotropin-resistant ovary syndrome
Primary ovarian insufficiency
Hypergonadotropic hypergonadism
Isolated hypogonadotropic hypogonadism
Polycystic ovary syndrome
Exercise amenorrhoea