Guideline sources The following summarized guidelines for the evaluation and management of primary ovarian insufficiency (POI) are prepared by our editorial team based on guidelines from the American College of Obstetricians and Gynecologists (ACOG 2017), the European Society of Human Reproduction and Embryology (ESHRE 2016), and the Endocrine Society (ES 2015). 1 2 3 Guidelines 1. Screening and diagnosis Definition: As per ACOG 2017 guidelines, recognize that POI is a pathologic condition and not a hastening of natural menopause. E As per ESHRE 2016 guidelines, recognize that the cause of premature ovarian insufficiency in a significant number of patients is not identified and these patients are described as having unexplained or idiopathic premature ovarian insufficiency. Diagnostic criteria: Diagnose premature ovarian insufficiency based on the presence of menstrual disturbance and biochemical confirmation: oligo-/amenorrhea for at least 4 months FSH level > 25 IU/L on two occasions > 4 weeks apart. B https://web.pathway.md/diseases/reclcwRVZpnNhSj7P 1/4 6/29/23, 11:30 PM Primary ovarian insufficiency Pathway Indications for testing (symptomatic patients): exclude premature ovarian insufficiency in < 40 years old patients with amenorrhea/oligomenorrhea or estrogen-deficiency symptoms. B Indications for testing (family relatives): Offer genetic counseling and testing to relatives of patients with the fragile-X premutation. B Inform relatives of patients with non-iatrogenic premature ovarian insufficiency concerned about their risk for developing premature ovarian insufficiency that: currently there is no proven predictive test to identify individuals that will develop premature ovarian insufficiency, unless a mutation known to be related to premature ovarian insufficiency is detected there are no established measures to prevent premature ovarian insufficiency fertility preservation appears as a promising option, although studies are lacking their potential risk of earlier menopause should be taken into account when planning a family. B 2. Classification and risk stratification Health risks: As per ACOG 2017 guidelines, ensure a distinct approach to health maintenance in patients with POI from that used in natural menopause, although these two conditions share common health risks. E As per ESHRE 2016 guidelines, recognize that untreated premature ovarian insufficiency is associated with reduced life expectancy, largely due to CVD. B 3. Diagnostic investigations Medical history: elicit symptoms of estrogen deficiency in patients presenting with oligomenorrhea or amenorrhea. B Karyotyping: obtain chromosomal analysis in all patients with non-iatrogenic premature ovarian insufficiency. B Genetic testing: Obtain fragile-X premutation testing in patients with premature ovarian insufficiency. B Discuss the implications of the fragile-X premutation before testing. B Do not obtain autosomal genetic testing in patients with premature ovarian insufficiency unless evidence suggests a specific mutation, such as blepharophimosis, ptosis, and epicanthus inversus syndrome. D Screening for adrenocortical 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. https://web.pathway.md/diseases/reclcwRVZpnNhSj7P 2/4 6/29/23, 11:30 PM Primary ovarian insufficiency Pathway Screening for thyroid antibodies: 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. Screening for diabetes: insufficient evidence to recommend routine screening for diabetes in patients with premature ovarian insufficiency. I Screening for infection: do not obtain screening for infection in patients with premature ovarian insufficiency. D Cardiovascular 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 Bone mineral density 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 4. Medical management Hormone therapy: initiate systemic hormone therapy, if not contraindicated, to treat hypoestrogenism symptoms and mitigate long-term health risks in patients with POI. E Show 3 more Duration of treatment: As per ACOG 2017 guidelines, continue treatment until the average age of natural menopause is reached (age 50-51 years). E As per ES 2015 guidelines, consider continuing menopausal hormone therapy until the time of anticipated natural menopause (reassess the need for continuation at that time) in young patients with POI, premature or early menopause, without contraindications. C Contraception: Consider offering combined hormonal contraceptives in patients deeming pregnancy prevention a priority, as it prevents ovulation and pregnancy more reliably than hormone therapy despite only modest odds of spontaneous pregnancy. E Prefer insertion of a levonorgestrel intrauterine device over oral progestin therapy in patients preferring non-contraceptive estrogen replacement and wishing highly effective contraception. E 5. Patient education Pre-pregnancy counseling: Assess BP, renal function, and thyroid function before pregnancy in patients with premature ovarian insufficiency. B https://web.pathway.md/diseases/reclcwRVZpnNhSj7P 3/4 6/29/23, 11:30 PM Primary ovarian insufficiency Pathway Reassure patients that spontaneous pregnancies after idiopathic premature ovarian insufficiency or most forms of chemotherapy do not show any higher obstetric or neonatal risk than in the general population. B Clinical findings Symptoms Past medical history Amenorrhea Addison's disease Decreased libido Adrenal insufficiency Dyspareunia Diabetes mellitus type 1 Night sweats Exposure to chemotherapy Oligomenorrhea Exposure to radiation therapy Skin flushing Fragile X syndrome Graves' disease Social history Hashimoto's disease Hyperthyroidism Tobacco use Hypoparathyroidism Lab findings Hypothyroidism Infertility serum FSH Mumps serum estradiol Myasthenia gravis Turner syndrome Gynecologic exam Vaginal dryness Genetic testing Brca2 gene mutation References 1. 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 2. No authors listed. Committee Opinion No. 698 Hormone Therapy in Primary Ovarian Insufficiency. Obstet Gynecol. 2017 May;129 5):e134-e141. Open 3. Stuenkel CA, Davis SR, Gompel A et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015 Nov;100 11 3975 4011. Open https://web.pathway.md/diseases/reclcwRVZpnNhSj7P 4/4