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Hormonal Changes
FHA results from a functional reduction in GnRH. Reduced levels of gonadotropins LH and FSH are insufficient to maintain full folliculogenesis and ovulatory ovarian function and results 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. FHA patients have been found to have higher 24-hour mean plasma cortisol levels. The increase in glucocorticoids inhibits the release of GnRH and gonadotropins and contributes to the pathophysiology of stress-related FHA. The hypothalamic-pituitary-thyroid axis is also altered in FHA; TSH levels are low-to-normal and there is an increase in reverse triiodothyronine and low level of triiodothyronine. Other hormonal changes in FHA 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.

Neuroendocrine Changes
The complex mechanisms of FHA 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, leptin, 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. Ghrelin stimulates appetite and inhibits the HPO axis; it is found to be elevated in patients with FHA. Conversely, leptin is reduced in patients with FHA and this may suppress GnRH through a kisspeptin-mediated pathway.

Evaluation and Diagnosis
Females who have menstrual cycles lasting longer than 45 days and/or amenorrhea for three or more months should be evaluated for FHA. Differentiating FHA from the irregular menstrual patterns seen in adolescents during the initial years after menarche due to immaturity of the HPO axis can be challenging. However, studies have shown that even during this period, the length of a menstrual cycle does not exceed 45 days. Furthermore, healthy girls with normal BMI (18.5-25 kg/m2) should develop regular menstrual cycles (every 28 +/- 3-5 days) within 1-2 years after menarche. FHA is a diagnosis of exclusion, and thus the evaluation should be used to rule out organic causes of amenorrhea (e.g., pregnancy, thyroid disorders, inflammatory bowel disease, etc.) Evaluation for FHA may include a thorough history and physical exam, laboratory testing, and imaging if appropriate. The Endocrine Society Clinical Practice Guidelines on Functional Hypothalamic Amenorrhea (FHA) suggests obtaining a baseline bone mineral density measurement by DEXA scan from any patient with 6 or more months of amenorrhea.

History and Physical Exam
To evaluate for FHA, a thorough personal history should be obtained. 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. A full physical exam, external gynecological and bimanual exam can be performed to assess for organic causes of amenorrhea. FHA may present with weight loss, bradycardia, mottled, cool extremities, and/or yellowing of the skin.

Laboratory Testing
In all cases of amenorrhea, pregnancy should be excluded. This can be done by obtaining serum B-hCG levels. In cases of suspected FHA, screening laboratory tests include a complete blood count (CBC), electrolytes, glucose, bicarbonate, blood urea nitrogen (BUN), creatinine, liver panel, and when appropriate, sedimentation rate and/or C-reactive protein levels. The initial endocrine evaluation includes testing for levels of TSH and free T4, prolactin, LH, FSH, estradiol (E2), and anti-Mullerian hormone (AMH). If clinical hyperandrogenism is evident, total testosterone and DHEA-S levels may also be obtained. 17α-hydroxyprogesteone levels should be evaluated if late-onset congenital adrenal hyperplasia (CAH) is suspected. A progestin challenge can also be conducted to evaluate levels of estrogen and the anatomic integrity of the outflow tract. Withdrawal bleeding following the progestin challenge indicates sufficient levels of estradiol (E2) for endometrial thickening, and that the amenorrhea is a result of anovulation and progesterone deficiency.

Imaging
A transvaginal ultrasound (TVUS) can be used to rule out any anatomic Mullerian tract abnormalities that may result in primary amenorrhea. A brain MRI showing the sella turcica should be obtained in cases of unexplained hypogonadotropic hypogonadism, or when patients show evidence of central nervous system (CNS) symptoms such as severe or persistent headaches, persistent vomiting, changes in vision, thirst, or urination with no attributable cause.

Management
The term "functional" in functional hypothalamic amenorrhea implies that the ovulatory ovarian dysfunction is reversible with correction of the underlying cause. 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. Menstruation typically resumes after correction of the underlying energy deficit. Avoidance of chronic stressors and modification of the stress-response with cognitive behavioral therapy (CBT) may also help in cases of FHA associated with significant stress. A multi-disciplinary team approach in management that includes a medical doctor, dietitian, and a psychiatrist or psychologist to provide psychological support is recommended.

If menstruation does not resume spontaneously following lifestyle changes, the patient should be monitored for thyroid function, HPO axis function, and concentrations of ACTH, cortisol, and prolactin every 4-5 months.

Low Bone Density
Bone loss is best treated by correction of the underlying cause. Patients should undergo evaluation of bone marrow density using a DEXA scan and started on Vitamin D and calcium supplementation. If menstruation does not resume after 6 months with reasonable trial of non-pharmaceutical management, loss of bone mass becomes the main concern and hormonal therapy should be implemented. Short-term use of transdermal estradiol E2 with cyclic oral progestin may be used for estrogen replacement. Care must be taken to exclude risks for thromboembolic disease prior to implementation of hormonal therapy given the associated increase in risk for venous thromboembolism. The Endocrine Society Clinical Practice Guidelines on Functional Hypothalamic Amenorrhea (FHA) recommend against oral contraceptives, bisphosphonates, denosumab, testosterone, and leptin for the improvement of bone mass density in FHA. Oral contraceptives may mask the return of spontaneous menstruation while loss of bone mass continues.

Anovulatory Infertility
Following a complete fertility workup, the first line of treatment for anovulatory infertility secondary to FHA is pulsatile exogenous GnRH followed by gonadotropin therapy and induction of ovulation when GnRH is unavailable. Ovulation can be induced with clomiphene citrate. However, this therapy should be restricted to patients with a BMI >18.5 kg/m2 due to the increased risks associated with lower BMI including fetal loss, small for gestational age (SGA) babies, preterm labor, and delivery by Cesarean section.

Psychological Assessment
Patients with FHA should be screened for psychological stressors and referred to appropriate psychiatric care where they can receive psychological support, such as CBT. Psychological disorders (e.g. anorexia nervosa) may be linked to amenorrhea through associated behaviors like hyperexercise and restrictive eating.