Hormonal<unk>  results from a<unk>  reduction or disruption in GnRH release due to chronic negative energy balance, metabolism, body composition, and stress; such risk factors become relevant in cases of emotional stress, excessive exercise, and nutrient starvation. Metabolic cues, including an increase in body weight, are influential in the initiation of pulsatile GnRH release from the hypothalamus during puberty; this event allows for the pituitary to begin producing and releasing pulses of LH. Full folliculogenesis cannot occur if the initial GnRH drive is disrupted, and this can be caused by reduced leptin from loss of body fat due to nutritional deprivation, excessive exercise in which the calories burned are more than those consumed, and states of hypercortisolism due to stress-inducing attitudinal or environmental pressures. Specifically, this underlies why the hypothalamus is necessarily sensitive to internal and external stimuli in its regulation of menstruation. Complete synchrony or the HPO axis is required for ovulation and reproduction in order to ensure pulsatile release of GnRH. Without this pulsatile release, the reduced levels of gonadotropins LH and FSH are insufficient to maintain full folliculogenesis and ovulatory ovarian function, resulting in profound hypoestrogenism. Additionally, external stress factors activate the HPA axis; increased corticotropin-releasing hormone (CRH) secretion results in increased secretion of ACTH from the pituitary gland, and thus increased secretion of cortisol from the adrenal glands. CRH, a regulator of the HPA and HPO axis, can be stimulated for release by the central nervous system in states of physical or mental stress that accompany the lifestyle factors contributing to<unk> . As a result, ACTH is released from the pituitary along with other pro-opiomelanocortin-related peptides such as beta-endorphin and b-lipotropic hormone. It is possible that increased levels of ghrelin in<unk> c populations sensitizes the adrenal cortex to ACTH and is thereby associated with both<unk>  CRH release and the frequency of cortisol bursts. Glucocorticosteroids are generally associated with inhibition of GnRH, adding strength to the stress-induced hypothesis of<unk>  in some patients. By stimulating beta-endorphin, a<unk>  and pituitary endogenous peptide, CRH can indirectly alter LH function by acting upstream on GnRH. A combination of this factor, along with the direct inhibition of GnRH caused by elevated CRH, may suggest a relationship between the incidence of stress- and exercise-related<unk>  and opioidergic activity.<unk>  patients have been found to have higher 24-hour mean plasma cortisol levels as well as increased cerebrospinal and urinary free cortisol levels; cortisol has negative effects on reproduction at the level of the hypothalamus, pituitary, and uterus. The increase in glucocorticoids inhibits the release of GnRH and gonadotropins and contributes to the pathophysiology of stress-related<unk> . It is currently unknown whether recovery from AN or<unk>  result in restoration of normal levels of cortisol, as there has not been a strong trend defined towards normalization associated with increases in BMI or changes in body composition. Not insignificant is the necessity of prolonged HPA activation in the ability of this pathway to alter<unk>  and/or pituitary control of ovulatory function, as mild fluctuations in these hormones do not appear to cause dysfunction. Thus, reproductive function can be altered through psychological or physiological stress through the HPA axis due to the modulatory effects that this pathway has on the HPO axis: its activation, which can occur in states of low energy availability (LEA) as an adaptive response to physical, nutritional, or extreme emotional stress, causes the release of CRH; In turn, this leads to the inhibition of GnRH pulsatility directly at the level of the hypothalamus and therefore precludes multilevel inhibition of the HPO axis. The<unk> -pituitary-thyroid axis is also altered in<unk> ; TSH levels are low-to-normal and there is an increase in reverse triiodothyronine and low level of triiodothyronine. Relative energy expenditure (REE) is also closely linked to T3, as is evidenced by a correlation between macronutrient intake, REE, and thyroid hormone levels. It has been found that AN patients who regain weight can restore T3 and REE independent of changes in FFM. Other hormonal changes in<unk>  include increased levels of nighttime serum growth hormone (GH), decreased levels of 24 hour prolactin, low serum insulin and IGF-1, and increased insulin sensitivity. GH has been found to be higher systemically in AN and exercise-induced<unk> , with women who have the lowest FFM and body mass index BMI displaying the highest levels of circulating GH The result is peripheral resistance to GH, and this underlies the reduction in hepatic IGF-1 synthesis observed in many of these patients. GH may also modulate reproduction at the level of the pituitary and ovaries by altering LH/FSH secretion as well as estradiol and progesterone production. Some studies suggest that GH is needed for the maturation and survival of dominant follicles and corpora lutea. Increased insulin sensitivity is likely common in many<unk>  patients because a state of chronic low EA incentivizes high GH secretion to maintain euglycemia; thus, euglycemia can be maintained in<unk>  patients despite low levels of IGF-1. Neuroendocrine The complex mechanisms of<unk>  are unclear, though it is known that many neuromodulatory signals are involved in the regulation of pulsatile GnRH secretion. Some notable substances include kisspeptin, neuropeptide Y (NPY), ghrelin, peptide YY (PYY), leptin, adiponectin, CRH, β-endorphin, and allopregnanolone. Kisspeptin and its G-protein coupled receptor, GPR54, activate the HPO axis to directly stimulate GnRH secretion from the hypothalamus. NPY regulates energy balance and affects feeding behavior and appetite. If estradiol (E2) levels are sufficient, NPY induces GnRH secretion.<unk> c women have been found to have lower serum NPY than controls. Thus, in these hypoestrogenic subjects, decreased concentrations of this peptide may contribute to the observed disruption of GnRH release. Ghrelin stimulates appetite and inhibits the HPO axis, and it is found to be elevated in patients with<unk> . Despite this, many patients with<unk>  display behaviors which result in low energy intake and therefore weight loss. It can be additionally noted that this trend may also be observed to a lesser extent in ovulatory women who are in negative energy balance due to imposed dieting and exercise strategies. Alternatively, PYY binds to<unk>  neurons in order to decrease both energy intake and body weight. It has been suggested that the anorexigenic effects of PYY may hide the anticipated orexigenic effects of increased ghrelin levels in exercising and anorexic<unk>  patients. The combination of these factors could help explain why populations whose conditions have been triggered by low weight or excess exercise are not only more prone to display elevated serum ghrelin levels, but also commonly engage in abnormal eating behaviors. Ghrelin not only reduces fat utilization and stimulates appetite, but increased ghrelin is linked to alterations in GnRH and LH pulsatility, which can ultimately inhibit the HPO axis. Its elevation in women with<unk>  may account for the inability of some patients who have returned to a healthy weight to return to regular menses. Conversely, leptin is reduced in patients with<unk>  and this may suppress GnRH through a kisspeptin-mediated pathway. Leptin and adiponectin are secreted by adipocytes and are directly related to FFM, with the former being directly related and the latter being inversely related. Leptin coordinates metabolic and hormonal signals with reproductive function, and decreased levels of leptin have been shown to decrease LH pulsatile frequency. As leptin mainly decreases feeding behavior, negative energy states have been linked to decreased leptin levels when fat mass is at critically low levels. Thus, hypoleptinemia is often representative of the chronic negative energy balance associated with<unk> , and this trend holds true when compared to age-, weight-, and body fat-matched eumenorrheic controls Further, the arcuate nucleus of the hypothalamus, which is known for its regulation of food intake, is considered to be the most concentrated source of both leptin and GnRH receptors in the brain. While GnRH receptors in the hypothalamus do not contain receptors for leptin, a positive correlation has been shown to exist between leptin receptor mRNA and the kisspeptin-expressing cells which are known to stimulate GnRH release.
Functional hypothalamic amenorrhea
Hyperprolactinemic SAHA syndrome
Gonadotropin-resistant ovary syndrome
Primary ovarian insufficiency
Hypergonadotropic hypergonadism
Isolated hypogonadotropic hypogonadism
Polycystic ovary syndrome
Exercise amenorrhoea