Clinical Pearls & Morning Reports
Published January 11, 2023
In the majority of patients with primary ovarian insufficiency, the cause remains unidentified. Read the NEJM Clinical Practice Article here.
Q: How is the diagnosis of primary ovarian insufficiency made?
A: Laboratory evaluation includes a serum pregnancy test and tests for levels of prolactin, thyrotropin, and follicle-stimulating hormone (FSH). Elevated levels of FSH point to an ovarian source of amenorrhea and should be remeasured concurrently with serum estradiol 1 month after the first measurement. If the level of FSH remains high and the estradiol level is low, the diagnosis of primary ovarian insufficiency is confirmed, and further evaluation is indicated to identify the cause.
Q: How often can primary ovarian insufficiency be attributed to a genetic cause?
A: In the past, more than 70% of cases of primary ovarian insufficiency were considered to be of idiopathic origin; however, more recent studies that used sequencing of the whole genome or whole exome have identified new gene mutations that are involved in normal gonadogenesis, oogenesis, folliculogenesis, mitochondrial and immune function, metabolism, apoptosis, DNA replication and repair (including in BRCA1 and BRCA2), mRNA processing, cell-cycle progression, meiosis, and hormonal signaling, which suggests that in at least 30% of patients, and probably more, primary ovarian insufficiency can be attributed to a genetic cause. In routine clinical practice, genetic testing is usually limited to karyotype and screening for premutation of the fragile X gene.
A: Autoimmune disorders have historically been considered to account for up to 30% of cases of primary ovarian insufficiency, but recent data suggest that number is closer to 4to 5%. Autoimmune polyendocrine syndromes include primary ovarian insufficiency in constellation with other endocrinopathies. Autoimmune primary ovarian insufficiency can occur in isolation or in association with nonendocrine systemic autoimmune disorders. Testing for thyroid peroxidase antibodies and thyrotropin, adrenal 21-hydroxylase antibodies, and fasting blood glucose or glycosylated hemoglobin levels is recommended. Clinicians require a high index of suspicion and low threshold to test for other possible autoimmune disorders, since virtually all these disorders (most commonly hypothyroidism) have been described in association with primary ovarian insufficiency.
A: Effective treatment of primary ovarian insufficiency includes psychological counseling, management of symptoms, hormone-replacement therapy (HRT), provision of contraception, fertility assistance, and, depending on the specific cause, family genetic counseling and management of associated conditions. Psychological counseling should be initiated promptly, since unexpected infertility can precipitate symptoms of anxiety and depression. Reflecting expert consensus and limited evidence from randomized, controlled trials, guiding principles include initiating HRT promptly after diagnosis, prescribing higher doses of estrogen (to emulate the levels of endogenous estrogen in younger, menstruating women) than those recommended in women who have natural menopause, and continuing HRT until the age of natural menopause, at which point the advisability of extending HRT therapy should be reassessed. Most guidelines and expert groups recommend the initiation of therapy with transdermal estradiol, which is biochemically similar to endogenous estradiol and, as compared with oral estrogen therapies, avoids first-pass metabolism by the liver. Alternatively, oral estrogens or a vaginal ring that delivers systemic doses of estrogen can be used.