Guideline sources The following summarized guidelines for the evaluation and management of amenorrhea are prepared by our editorial team based on guidelines from the Endocrine Society (ES 2020; 2018; 2017; 2013; 2011), the American College of Obstetricians and Gynecologists (ACOG 2018; 2017), the Society of Obstetricians and Gynaecologists of Canada (SOGC 2018), the American Society for Reproductive Medicine (ASRM 2017), the European Society of Human Reproduction and Embryology (ESHRE 2016), the Royal College of Obstetricians and Gynaecologists (RCOG 2014), the American Association of Family Physicians (AAFP 2013), and the American College of Sports Medicine (ACSM 2007). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Calculator Revised Rotterdam diagnostic cr Guidelines 1. Diagnostic investigations Exclusion of pregnancy: exclude pregnancy in all patients presenting with amenorrhea. B Evaluation for etiology, functional hypothalamic amenorrhea: https://web.pathway.md/diseases/recpFmHfW5s3URMrr 1/9 6/23/23, 2:34 AM Amenorrhea Pathway gy yp As per ES 2017 guidelines, consider obtaining diagnostic evaluation for functional hypothalamic amenorrhea in adolescent and female patients if the menstrual cycle interval persistently exceeds 45 days and/or presenting with amenorrhea for 3 months. C Show 9 more As per ACSM 2007 guidelines, exclude other causes of amenorrhea to diagnose functional hypothalamic amenorrhea. B Evaluation for etiology (pimary ovarian insufficiency): exclude premature ovarian insufficiency in < 40 years old patients with amenorrhea/oligomenorrhea or estrogen-deficiency symptoms. B Evaluation for etiology (hyperprolactinemia): obtain a single measurement of serum prolactin for the diagnosis of hyperprolactinemia and confirm the diagnosis with a level above the ULN as long as the serum sample is obtained without excessive venipuncture stress. A Evaluation for etiology (polycystic ovary syndrome): Consider diagnosing PCOS in patients meeting 2 of the following criteria, in the absence of disorders mimicking PCOS (such as thyroid disease, hyperprolactinemia, non-classic congenital adrenal hyperplasia, primarily 21-hydroxylase deficiency by serum 17-hydroxyprogesterone): androgen excess ovulatory dysfunction polycystic ovaries. C Show 2 more Evaluation for etiology, congenital adrenal hyperplasia: As per ES 2018 guidelines: Consider obtaining early morning 17-hydroxyprogesterone levels in the follicular phase (or on a random day) to screen for nonclassical congenital adrenal hyperplasia due to 21- hydroxylase deficiency in patients with hyperandrogenemia and amenorrhea or infrequent menses. C Consider obtaining early morning 17-hydroxyprogesterone levels to screen for nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in patients with hirsutism at high risk of congenital adrenal hyperplasia (positive family history, member of a high-risk ethnic group), even if serum total and free testosterone are normal. C As per ES 2017 guidelines, obtain total testosterone and DHEA sulfate in patients with clinical hyperandrogenism and 8 AM 17-hydroxyprogesterone levels when suspecting late-onset congenital adrenal hyperplasia. A Evaluation for etiology, M llerian tract anomalies: As per ACOG 2018 guidelines, recognize that patients with M llerian agenesis usually are identified during evaluations for primary amenorrhea with otherwise typical growth and pubertal development. E https://web.pathway.md/diseases/recpFmHfW5s3URMrr 2/9 6/23/23, 2:34 AM Amenorrhea Pathway As per ES 2017 guidelines, consider performing a physical examination, administering a progestin challenge test, and obtaining abdominal or transvaginal ultrasound and/or MRI, depending on the context and patient preferences, for the evaluation of M llerian tract anomalies in patients with primary amenorrhea. C Evaluation of primary ovarian insufficiency (karyotyping and genetic testing): obtain chromosomal analysis in all patients with non-iatrogenic premature ovarian insufficiency. B Show 2 more Evaluation of primary ovarian insufficiency (adrenocortical and thyroid antibodies): Obtain screening for 21-hydroxylase autoantibodies, or alternatively adrenocortical antibodies, in patients with premature ovarian insufficiency of unknown cause or if an immune disorder is suspected. B Refer patients with premature ovarian insufficiency with positive 21-hydroxylase autoantibodies/adrenocortical antibodies to an endocrinologist for testing of adrenal function and to rule out Addison's disease. Obtain screening for anti-TPO antibodies in patients with premature ovarian insufficiency of unknown cause or if an immune disorder is suspected. B Measure TSH annually in patients with positive thyroid antibodies. Evaluation of primary ovarian insufficiency (cardiac evaluation): assess cardiovascular risk in patients diagnosed with premature ovarian insufficiency. Monitor at least BP, weight, and smoking status annually and assess other risk factors if indicated. B Show 2 more Evaluation of primary ovarian insufficiency (bone mineral testing): recognize that premature ovarian insufficiency is associated with reduced bone mineral density, B and reduced bone mineral density is very likely to indicate that premature ovarian insufficiency is associated with an increased risk of fracture later in life. B Show 3 more Evaluation of polycystic ovary syndrome, cardiac evaluation: As per ES 2020 guidelines, obtain a fasting lipid panel at diagnosis to assess cardiovascular risk in patients with PCOS. B As per ACOG 2018 guidelines, assess cardiovascular risks by determination of BMI, fasting lipid and lipoprotein levels, and metabolic syndrome risk factors in patients with PCOS. B As per RCOG 2014 guidelines: Recognize that conventional cardiovascular risk calculators are not validated for patients with PCOS. B Assess CVD risk in all patients with PCOS at the time of initial diagnosis by individual CVD risk factors (obesity, lack of physical activity, cigarette smoking, family history of T2DM, dyslipidemia, hypertension, impaired glucose tolerance, T2DM). B As per ES 2013 guidelines, screen for CVD risk factors, including a family history of early CVD, cigarette smoking, impaired glucose tolerance/T2DM, hypertension, dyslipidemia, obstructive sleep apnea, and obesity, especially increased abdominal adiposity, in adolescent and adult https://web.pathway.md/diseases/recpFmHfW5s3URMrr 3/9 6/23/23, 2:34 AM Amenorrhea Pathway patients with PCOS. B Assess for increased adiposity by BMI calculation and measurement of waist circumference in adolescent and adult patients with PCOS. B Evaluation of polycystic ovary syndrome, screening for diabetes: As per ACOG 2018 guidelines, screen for T2DM and impaired glucose tolerance with a fasting glucose level followed by a 2-hour glucose level after a 75-g glucose load in patients with PCOS. B As per RCOG 2014 guidelines: Obtain a 2-hour post 75 g oral glucose tolerance test in patients presenting with PCOS with overweight (BMI 25 kg/m ) or with normal weight (BMI < 25 kg/m ) but having additional risk factors, such as advanced age (> 40 years), personal history of gestational diabetes, or family history of T2DM. B Obtain oral glucose tolerance test annually in patients with impaired fasting glucose (fasting plasma glucose level 6.1-6.9 mmol/L) or impaired glucose tolerance (plasma glucose of 7.8 mmol/L but < 11.1 mmol/L after a 2-hour oral glucose tolerance test). B Evaluation of polycystic ovary syndrome, screening for endometrial cancer: As per RCOG 2014 guidelines, recognize that oligomenorrhea or amenorrhea may predispose to endometrial hyperplasia and later carcinoma in patients with PCOS. Consider initiating progesterone to induce withdrawal bleeding at least every 3-4 months. B Show 4 more As per ES 2013 guidelines, avoid obtaining routine ultrasound screening for endometrial thickness in patients with polycystic ovarian syndrome. D Evaluation of polycystic ovary syndrome, psychosocial assessment: As per RCOG 2014 guidelines, screen for depression and/or anxiety routinely in patients with PCOS. Obtain further assessment, provide appropriate counseling, and offer intervention by a qualified professional in patients with depression and/or anxiety. A As per ES 2013 guidelines, consider screening for depression and anxiety by history in adolescents with PCOS and, if identified, provide appropriate referral and/or treatment. C Bone mineral density testing: Consider obtaining a baseline bone mineral density measurement by DEXA in all adolescent and adult patients with 6 months of amenorrhea, and earlier in patients with a history or suspicion of severe nutritional deficiency, other energy deficit states, and/or skeletal fragility. C Consider obtaining clinical monitoring for hyperresponse in patients treated with exogenous gonadotropins for infertility. C 2. Medical management Management of functional hypothalamic amenorrhea (general principles): Consider educating patients about various menstrual patterns occurring during the recovery phase once the diagnosis of functional hypothalamic amenorrhea is established. Consider https://web.pathway.md/diseases/recpFmHfW5s3URMrr 4/9 6/23/23, 2:34 AM Amenorrhea Pathway informing patients that irregular menses do not require immediate evaluation and that menstrual irregularity does not preclude conception. C Evaluate patients with functional hypothalamic amenorrhea and severe bradycardia, hypotension, orthostasis, and/or electrolyte imbalance for inpatient treatment. B Management of functional hypothalamic amenorrhea, correction of energy imbalance: As per ES 2017 guidelines, offer increased caloric consumption (often weight gain is required), and/or improved nutrition, and/or decreased exercise activity to correct the energy imbalance in order to improve hypothalamic-pituitary-ovarian axis function in adolescent and adult patients with functional hypothalamic amenorrhea. B As per AAFP 2013 guidelines, offer nutritional rehabilitation and decreased exercise to restore weight as primary treatment in patients with functional hypothalamic amenorrhea, especially with the female athlete triad. B Management of functional hypothalamic amenorrhea, hormonal therapy: As per ES 2017 guidelines, consider offering short-term transdermal estradiol therapy with cyclic oral progestin (not oral contraceptives or ethinyl estradiol) in adolescent and adult patients with no return of menses after a reasonable trial of nutritional, psychological, and/or modified exercise intervention. C Show 2 more As per AAFP 2013 guidelines, do not use combined oral contraceptives for the sole purpose of improving bone density in patients with functional hypothalamic amenorrhea. D Management of functional hypothalamic amenorrhea (psychological support): consider offering psychological support, such as CBT, in adolescent and adult patients with functional hypothalamic amenorrhea. C Management of functional hypothalamic amenorrhea (management of infertility): Consider offering the following in patients with functional hypothalamic amenorrhea wishing to conceive, after a complete fertility workup: treatment with pulsatile GnRH as first-line therapy, followed by gonadotropin therapy and induction of ovulation when GnRH is not available C cautious use of gonadotropin therapy, C a trial of treatment with clomiphene citrate for ovulation induction if the patient has a sufficient endogenous estrogen level C do not use kisspeptin and leptin for the treatment of infertility C consider offering a trial of CBT to restore ovulatory cycles and fertility. C Consider inducing ovulation only in patients with functional hypothalamic amenorrhea having a BMI of at least 18.5 kg/m and only after attempts to normalize energy balance, due to the increased risk for fetal loss, small-for-gestational-age babies, preterm labor, and delivery by C- section for extremely low weight. C Management of functional hypothalamic amenorrhea (management of osteoporosis): Avoid using bisphosphonates, denosumab, testosterone, or leptin to improve bone mineral density in adolescents and adult patients with functional hypothalamic amenorrhea. D https://web.pathway.md/diseases/recpFmHfW5s3URMrr 5/9 6/23/23, 2:34 AM Amenorrhea Pathway Consider administering short-term teriparatide as an option for delayed fracture healing and very low bone mineral density in rare adult cases of functional hypothalamic amenorrhea. C Management of primary ovarian insufficiency: initiate systemic hormone therapy, if not contraindicated, to treat hypoestrogenism symptoms and mitigate long-term health risks in patients with primary ovarian insufficiency. E Show 3 more Management of hyperprolactinemia (medical therapy): initiate dopamine agonist therapy to lower prolactin levels, decrease tumor size, and restore gonadal function in patients with symptomatic prolactin-secreting microadenomas or macroadenomas. A Show 8 more Management of hyperprolactinemia (radiotherapy and surgery): Consider performing transsphenoidal surgery in symptomatic patients with prolactinomas not tolerating high doses of cabergoline or not responsive to dopamine agonist therapy. C Consider offering radiation therapy in patients with aggressive or malignant prolactinomas or when surgery fails. C Management of polycystic ovary syndrome, lifestyle modifications: As per ACOG 2018 guidelines: Advise exercising and dietary changes to reduce diabetes risk in patients with PCOS. A Advise weight loss to improve pregnancy rates, decrease hirsutism, and improve glucose tolerance and lipid levels in patients with PCOS. B As per SOGC 2018 guidelines: Consider advising weight loss through exercise and lifestyle modifications with a target of BMI < 35 kg/m and/or 5-10% of body weight if overweight for restoring ovulatory cycles and achieving pregnancy in patients with overweight and PCOS. B Refer patients with morbid obesity (BMI 40 kg/m ) to qualified providers for expert advice about safe weight loss strategies and pregnancy risk in this condition. B As per RCOG 2014 guidelines, advise lifestyle changes, including diet, exercise, and weight loss, preceding and/or accompanying pharmacological treatment, for improvement of long-term outcomes in patients with PCOS. B Management of polycystic ovary syndrome, hormonal contraceptives: As per ACOG 2018 guidelines, initiate combination low-dose hormonal contraceptives, frequently used for the long term, as primary treatment of menstrual disorders. B As per ES 2013 guidelines, initiate hormonal contraceptives (such as oral contraceptives, patches, or vaginal rings) as first-line therapy for menstrual abnormalities and hirsutism/acne in patients with polycystic ovarian syndrome. B Show 3 more Management of polycystic ovary syndrome, insulin sensitizers: As per ACOG 2018 guidelines, consider initiating insulin-sensitizing agents for improving insulin sensitivity to decrease circulating androgen levels, improve ovulation rate, and improve glucose https://web.pathway.md/diseases/recpFmHfW5s3URMrr 6/9 6/23/23, 2:34 AM Amenorrhea Pathway tolerance in patients with PCOS. B As per SOGC 2018 guidelines: Recognize that metformin combined with clomiphene citrate may increase ovulation and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone. A Consider adding metformin to clomiphene citrate in patients with clomiphene resistance aged > 28 years and having visceral obesity (waist-to-hip ratio > 0.85). B As per ASRM 2017 guidelines, consider initiating metformin to increase the ovulation rate in patients with polycystic ovarian syndrome B , recognizing that metformin alone is less effective than clomiphene citrate alone for the achievement of ovulation induction, clinical pregnancy, and live birth. C As per AAFP 2013 guidelines, consider offering metformin to improve abnormal menstruation in patients with PCOS. B As per ES 2013 guidelines, initiate metformin in patients with PCOS and T2DM or impaired glucose tolerance failed lifestyle modification. B Consider initiating metformin if the goal is to treat impaired glucose tolerance/metabolic syndrome. B Show 3 more Management of polycystic ovary syndrome, ovulation induction: As per ACOG 2018 guidelines, consider initiating letrozole as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate in patients with PCOS. B Show 2 more As per SOGC 2018 guidelines, consider initiating clomiphene citrate where available as first-line medical therapy for ovulation induction in patients with PCOS. Inform patients regarding the increased risk of twin pregnancy or higher order multiples with ovulation induction using clomiphene citrate. B Show 2 more As per ASRM 2017 guidelines, consider initiating letrozole as first-line therapy for ovulation induction in patients with polcystic ovary syndrome. C As per ES 2013 guidelines, initiate clomiphene citrate (or comparable estrogen modulators such as letrozole) as first-line therapy for anovulatory infertility in patients with PCOS. B Management of polycystic ovary syndrome, statin therapy: As per ES 2020 guidelines, avoid using lipid-lowering therapies for the treatment of hyperandrogenism or infertility in patients with PCOS. D As per RCOG 2014 guidelines, do not initiate routine lipid-lowering treatment in patients with PCOS. Prescribe only by a specialist. D As per ES 2013 guidelines: Avoid using statins for the treatment of hyperandrogenism and anovulation in patients with PCOS. D https://web.pathway.md/diseases/recpFmHfW5s3URMrr 7/9 6/23/23, 2:34 AM Amenorrhea Pathway Consider initiating statins in patients with PCOS meeting current indications for statin therapy. C 3. Specific circumstances Female athletes (evaluation): screen for female athlete triad at the preparticipation or annual health screening examination. Assess athletes with one component of the triad for the others. B Show 2 more Female athletes, management: As per AAFP 2013 guidelines, offer nutritional rehabilitation and decreased exercise to restore weight as primary treatment in patients with the female athlete triad. B As per ACSM 2007 guidelines, include a physician (or another healthcare professional), a registered dietitian, and, for athletes with disordered eating or an eating disorder, a mental health practitioner for multidisciplinary treatment of the female athlete triad. B Show 4 more References 1. Catherine M Gordon, Kathryn E Ackerman, Sarah L Berga et al. Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017 May 1;102 5 1413 1439. Open 2. No authors listed. Committee Opinion No. 698 Hormone Therapy in Primary Ovarian Insufficiency. Obstet Gynecol. 2017 May;129 5):e134-e141. Open 3. Practice Committee of the American Society for Reproductive Medicine. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome PCOS a guideline. Fertil Steril. 2017 Sep;108 3 426 441. Open 4. European Society for Human Reproduction and Embryology ESHRE Guideline Group on POI, Webber L, Davies M et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016 May;31 5 926 37. Open 5. Royal College of Obstetricians and Gynaecologists. Long-term Consequences of Polycystic Ovary Syndrome. Green-top Guideline No. 33. RCOG. 2014 Nov. Open 6. David A Klein, Merrily A Poth. Amenorrhea: an approach to diagnosis and management. Am Fam Physician. 2013 Jun 1;87 11 781 8. Open 7. Melmed S, Casanueva FF, Hoffman AR et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Feb;96 2 273 88. Open 8. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins Gynecology. ACOG Practice Bulletin No. 194 Polycystic Ovary Syndrome. Obstet Gynecol. 2018 Jun;131 6):e157-e171. Open 9. Martin KA, Anderson RR, Chang RJ et al. Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 Apr 1;103 4 1233 https://web.pathway.md/diseases/recpFmHfW5s3URMrr 8/9 6/23/23, 2:34 AM Amenorrhea Pathway 1257. Open 10. Legro RS, Arslanian SA, Ehrmann DA et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013 Dec;98 12 4565 92. Open 11. Committee on Adolescent Health Care. ACOG Committee Opinion No. 728 M llerian Agenesis: Diagnosis, Management, And Treatment. Obstet Gynecol. 2018 Jan;131 1):e35-e42. Open 12. Connie B Newman, Michael J Blaha, Jeffrey B Boord et al. Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2020 Dec 1;105 12):dgaa674. Open 13. Aurelia Nattiv, Anne B Loucks, Melinda M Manore et al. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc. 2007 Oct;39 10 1867 82. Open 14. David S Smithson, Tannys D R Vause, Anthony P Cheung. No. 362 Ovulation Induction in Polycystic Ovary Syndrome. J Obstet Gynaecol Can. 2018 Jul;40 7 978 987. Open 15. American Society for Reproductive Medicine. Choosing Wisely ASRM recommendations. Choosing Wisely. 2015. Open https://web.pathway.md/diseases/recpFmHfW5s3URMrr 9/9