The term<unk> " in<unk>  implies that the ovulatory ovarian dysfunction is reversible with correction of the underlying cause. Therefore, it is said that<unk>  can be reversed by removal of the stressor. Weight restoration is the best predictor of<unk>  recovery of the HPO axis and therefore the main driver to restoration of menstrual function. 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. Patients diagnosed with<unk>  should be informed that varied menstrual patterns may occur during the recovery phase, and that irregular menses during this time do not preclude conception or require examination. As women with<unk>  work to correct energy balance, especially female athletes and those recovering from eating disorder, recovery from hypogonadotropic hypogonadism may occur in a series of phases; there can be stages where the luteal phase is inadequate or may display lower sex steroid and gonadotropin levels for many years. These patients may present with long menstrual phases with premenstrual spotting or early arrival of menses. A minimum weight required to restore menses has not been defined, but AN patients with BMI above 18 kg/m2, those who are 95% of their expected body weight, and those who were in the 25th to 50th percentiles of their BMI have been shown in various studies to exhibit a restoration of menses within a short period of time. Leptin concentrations >1.85 ng/mL have been found to regulate the recovery of LH pulsatility. IGF-1 has been linked to nutritional recovery, as women who exhibit menstrual restoration tended to display increases in this compound; this holds true regardless of GH status. Improving energy balance status, often through behavioral change, is the recommended means for restoring HPO function, and this commonly requires the adoption of behaviors which promote weight gain. Avoidance of chronic stressors and modification of the stress-response with cognitive behavioral therapy (CBT) may also help in cases of<unk>  associated with significant stress. 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<unk>  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. In this population, where success in sport is highly emphasized, decreasing training intensity is typically not an option. Parents and legal guardians should be made aware of the long-term risk factors for osteoporosis and infertility which underlie this condition when deciding on a treatment plan. 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. Exogenous estrogen administration through ethinyl estradiol-based oral contraceptives have been shown to restore endothelial function in<unk>  patients. While sexually active patients may be prescribed low-dose contraceptives in some circumstances, these drugs are not recommended for sexually inactive adolescents. Transdermal estradiol and micronized progesterone are the safest options for<unk>  patients requiring long-term care. Depending on the duration, patches can be cut into quarters to gradually decrease the dose of estrogens administered over the course of treatment. If energy deficit continues, however, this treatment may not protect bone health (see below). Cyclic doses of progestin may be used to ensure endometrial shedding and prevent endometrial hyperplasia. 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. 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<unk>  <unk>  recommend against oral contraceptives, bisphosphonates, denosumab, testosterone, and leptin for the improvement of bone mass density in<unk> . The limited numbers of studies evaluating the effect of bisphosphonates on BMD did not provide significant evidence of improvement, and the scope of studies are inadequate to ensure safety and efficacy in<unk>  patients. While denosumab has been used to improve fracture risk in postmenopausal women with osteoporosis, it has not been adequately studied in premenopausal women and may pose a risk of inadvertent fetal exposure. Oral contraceptives for the purpose of regaining menses and improving BMD is not suggested as a first-line treatment due to their role in the suppression of ovarian function in women who were eumenorrheic prior to treatment and because these drugs may mask the return of spontaneous menstruation while loss of bone mass continues. Many studies have shown that oral contraceptives do not confer a protective advantage on BMD; this is likely because neuroendocrine aberrations, thyroid functions, and hypercortisolism are not corrected. 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. As oral contraceptive use is known to decrease androgen levels, this raises questions about the efficacy of prescribing of oral contraceptives to<unk>  patients who also suffer from hypoandrogenemia in conjunction with AN in order to avoid further bone loss. If behavioral modifications are not successful, transdermal estrogen with cyclic oral progestin is recommended, as this combination does not alter IGF-1 secretion. Oestrogens may also prescribed on a case-by-case basis depending on the patient's goals and expectations with regards to therapeutic outcomes and risks of further bone loss. These drugs, which can include conjugated estrogen, micronized estradiol, and transdermal estrogen may be implicated to prevent further bone loss and can be administered transdermally or orally. Recombinant parathyroid hormone 1-34 (rPTH) may be used in rare cases of adults with<unk>  whose BMD is extremely low or display delayed fracture healing. Anovulatory infertility Following a complete fertility workup, the first line of treatment for anovulatory infertility secondary to<unk>  is pulsatile exogenous GnRH followed by gonadotropin therapy and induction of ovulation when GnRH is unavailable. this therapy is recommended for avoiding multiple gestation and severe ovarian hyperstimulation syndrome. Specifically in patients where changes in exercise intensity or alterations in diet do not restore eumenorrhea, ovulation can be induced with clomiphene citrate. However, induction of ovulation by clomiphene citrate 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. Clomiphene citrate or letrozole may also be used to induce follicular development when endogenous estrogen levels are low. It has been found that teenagers with<unk>  who present as low responders to clomiphene do not necessarily face a poor prognosis with regards to future menses or fertility. Despite a growing body of research, leptin and kisspeptin therapies are not yet recommended for treating infertility. Psychological assessment Patients with<unk>  should be screened for the presence of modifiable Axis I (mood) disorders or modified Axis II (personality) disorders and referred to appropriate psychiatric care where they can receive psychological support, such as CBT. This is especially true when psychological disorders (e.g. anorexia nervosa) co-present with<unk>  through associated behaviors like hyperexercise and restrictive eating; in many of these cases, recovery may require CBT to modify the attitudes of patients who display abnormal behaviors related to diet, body image, exercise, and/or stress management. CBT may become a necessary consideration for this group of patients when general education about the health risks associated with long-term<unk>  do not motivate a change in behavior. Behavioral modifications which lead to a reversal of<unk>  can simultaneously reduce cortisol levels and restore of ovarian function. It is also postulated that metabolic and neuroendocrine aberrations can be corrected with behavioral modifications. Studies have shown that in comparison to control groups,<unk>  patients who receive CBT had a heightened ability to restore ovulatory status and improve levels of leptin, TSH, and cortisol. Thus, stress reduction through CBT may correct the metabolic and neuroendocrine defects of energy deficiency independent of direct weight gain.
Functional hypothalamic amenorrhea
Hyperprolactinemic SAHA syndrome
Gonadotropin-resistant ovary syndrome
Primary ovarian insufficiency
Hypergonadotropic hypergonadism
Isolated hypogonadotropic hypogonadism
Polycystic ovary syndrome
Exercise amenorrhoea