[5] 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.
[16] 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.
[3][13] 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.
[10] 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.
[10] 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.
[13] 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.
[8] 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.
[8] 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 FHA as a mechanism to preserve energy for processes critical to survival.1 Excessive or intense psychosocial, emotional, or mental stress can lead to hypothalamic dysfunction.
[4] 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.
[14] Exercise-related factors generally affect athletes who participate in sports that require intensive training and a low body weight, causing a net energy deficiency.
[8] 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.
[10] While the role of ovulatory status on these cardiovascular adaptations is unclear, moderate negative energy balance has been found to increase vagal tone, thereby lowering resting heart rate and systolic blood pressure in animals.
[3] If exercise contributes to a negative energy balance, either through excess activity or inadequate caloric intake, stress and skeletal fractures, as well as premature bone loss, becomes a significant risk.
The variable expressivity of the disorder, likely resulting from epigenetic modifications and/or multiple genetic defects, has led to the hypothesis that mutations involved in IHH cause increased risk for the functional GnRH deficiency observed in FHA patients.
[22] FHA patients harboring these mutations have been shown to be able to resume regular menses, further reinforcing that while genetic defects may predispose one to the condition, environmental factors play a pivotal role in disease manifestation.
[22] It is possible that heterozygosity at these loci are not sufficient to cause IHH, but decrease the threshold for HPO inhibition due to environmental factors such as weight loss, stress, and excessive exercise.
[22] Functionally speaking, carrying these mutations could confer a selective advantage in a famine conditions, and it is not uncommon for the alleles to be inherited from an asymptomatic parents in both heterozygous and homozygous recessive manifestations of IHH.
[11] 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.
[3] 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 amenorrhea.
[3] It is possible that increased levels of ghrelin in amenorrheic populations sensitizes the adrenal cortex to ACTH and is thereby associated with both hypothalamic CRH release and the frequency of cortisol bursts.
[8] Not insignificant is the necessity of prolonged HPA activation in the ability of this pathway to alter hypothalamic and/or pituitary control of ovulatory function, as mild fluctuations in these hormones do not appear to cause dysfunction.
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.
[11] Thus, hypoleptinemia is often representative of the chronic negative energy balance associated with FHA, and this trend holds true when compared to age-, weight-, and body fat-matched eumenorrheic controls[3][11] 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.
The patient should be asked about weight loss, level of physical activity, diet, low-weight eating disorders, significant stressors, menstrual pattern, bone fractures, and substance abuse.
[4] Clinicians should attempt to identify any recent emotional crises or otherwise stressful environmental factors which may have contributed to cessation of menses, as a multitude of chronic diseases including anxiety and depression may also lead to amenorrhea.
[4] Other specific cases may warrant other useful measures: for example, IGF-1 may be indicated in FHA patients with AN, as resistance to GH can expose a connection between bone metabolism and malnutrition; this population may also present with low DHEA-S, which may work to actively lower IGF-1 levels.
[8] Correcting energy deficits to improve function of the HPO axis often includes lifestyle changes such as increasing caloric intake and reducing the level of physical activity with resultant weight gain for normalization of BMI.
[4] For while the obvious solution to this problem appears to be a natural return to menses through restoration of energy balance and reduction in external stressors, the fact that FHA often presents in women who suffer from patterns of disordered eating and display concerns about body image and/or athletic performance, increased caloric consumption and decreased physical activity may be rejected.
[9] For patients with confounding AN, studies have shown that the prescription of estrogens is not an efficacable way to increase BMD, potentially due to factors stemming from an extreme state of undernutrition and IGF-1 deficiency.
[9] Studies have shown that in comparison to control groups, FHA patients who receive CBT had a heightened ability to restore ovulatory status and improve levels of leptin, TSH, and cortisol.