Females who have menstrual cycles lasting longer than 45 days and/or<unk>  for three or more months should be evaluated for<unk> . Differentiating<unk>  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 (18.5–24.9 kg/m2) should develop regular menstrual cycles (every 28 +/- 3–5 days) within 1–2 years after menarche.<unk>  is a diagnosis of exclusion, because the diagnosis can only be made when menstruation has ceased in that absence of organic or anatomic pathology, and thus the evaluation should be used to rule out organic causes of<unk>  (e.g., pregnancy, thyroid disorders, inflammatory bowel disease, etc.) Endocrinologic etiologies of the thyroid, pituitary, and adrenal glands, ovarian failure, and hyperandrogenism including polycystic ovarian syndrome (PCOS) must be excluded before a diagnosis of<unk>  can be given. A GnRH stimulation or challenge test should be used to identify<unk>  as the cause hypogonadotropic hypogonadism in women presenting with symptoms, as<unk>  dysfunction due to delayed-onset puberty or other pituitary disease will not respond to exogenous GnRH.<unk>  disorders are differentiated when GnRH administration results in abnormal increases of gonadotropins. Combined pituitary and<unk>  impairment is differentiated when there is a decreased or absent response to GnRH secretion; as a result, it impossible to determine if the observed low levels of FSH/LH are due to<unk>  or pituitary dysfunction, and pulsatile GnRH administration with cyclomate is required to diagnose this distinction (pulsatile LH-RH challenge). Evaluation for<unk>  may include a thorough history and physical exam, laboratory testing, and imaging if appropriate. The Endocrine Society Clinical Practice Guidelines on<unk>  suggests obtaining a baseline bone mineral density measurement by DEXA scan from any patient with 6 or more months of<unk> . It should be ordered earlier if there is suspicion of skeletal fragility, energy deficit, or nutritional deficiency. Baseline BMD Z-scores of -2.0 or less at any spot should warrant further monitoring in nutritional intake; for athletes involved in weight-bearing sports this monitoring should begin at -1.0 or less. The spine and hip are the most common site of low BMD in young<unk> c females as well as predictors of fracture risk. Lower strength estimates, abnormal bone microarchitectures, and deficient volumetric bone density has been found in young adult<unk> c athletes. History and physical exam To evaluate for<unk> , 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. Acknowledgement that one is categorized by one or more risk factors for<unk>  is a vulnerable point of discussion for many patients, and psychological consultations may be needed in order to reach a proper diagnosis. 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<unk> . In addition, physicians should also inquire about eating and reproductive disorders within the family. In patients presenting with structural abnormalities that may preclude regular menses, it is still necessary to take emotional history and lifestyle into account before establishing a diagnosis. These patients may still demonstrate patterns of excessive exercise or restrictive eating, proving the important role of behavioral etiology in<unk>  diagnosis. A full physical exam, external gynecological and bimanual exam can be performed to assess for organic causes of<unk> . Symptoms of hypoestrogenism, whose severity will positively correlate with the duration of hypoestrogenism, will be present in<unk>  patients; these can include lack of cervical mucus, pale areola and nipples, thinned, reddened vaginal and vestibular epithelium, and uterine hyperplasia, though<unk>  is not typically associated with hot flashes.<unk>  may present with weight loss, bradycardia, mottled, cool extremities, and/or yellowing of the skin. Laboratory testing In all cases of<unk> , pregnancy should be excluded. This can be done by obtaining serum B-hCG levels. In cases of suspected<unk> , 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. Liver function tests may be abnormal in females with extreme energy restriction. The initial endocrine evaluation includes testing for levels of TSH and free T4, prolactin, LH, FSH, estradiol (E2), and anti-Müllerian hormone (AMH).<unk>  patients may display a combination of the following: FSH concentrations that are normal but lower than LH levels, low or low normal LH, E2 <50 pg/mL, and progesterone <1 ng/mL. LH and FSH are often normal in<unk>  patients. No single E2 value can confirm<unk>  as each reflects only a certain time point, but in individuals whose E2 is <20 pg/mL persistently, an acute gonadotropin response to GnRH stimulation may distinguish<unk>  from hypogonadotropic hypogonadism. Testosterone and prolactin are expected to be in low normal ranges, and gonadotropins will be in a range lower than that which is characteristic of PCOS. In cases of stress-induced<unk> , cortisol secretion, both basal and pulsatile, may be altered—increased concentrations are greatest in the early morning hours and overnight. However, these values may still be in the normal range. 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 is suspected. A progestin challenge can also be conducted to evaluate levels of estrogen and the anatomic integrity of the outflow tract, as low endometrial estrogen exposure or obstruction of the outflow tract can be consequences of the absence of withdrawal bleeding. It can also provide information about estrogen status when there are questions of whether<unk>  or PCOS should be the diagnosis. Withdrawal bleeding following the progestin challenge indicates sufficient levels of E2 for endometrial thickening, and that the<unk>  is a result of anovulation and progesterone deficiency. Other specific cases may warrant other useful measures: for example, IGF-1 may be indicated in<unk>  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. Imaging A transvaginal ultrasound (TVUS) can be used to rule out any anatomic Mullerian tract abnormalities that may result in primary<unk> . 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.
Functional hypothalamic amenorrhea
Hyperprolactinemic SAHA syndrome
Gonadotropin-resistant ovary syndrome
Primary ovarian insufficiency
Hypergonadotropic hypergonadism
Isolated hypogonadotropic hypogonadism
Polycystic ovary syndrome
Exercise amenorrhoea