Primary ovarian insufficiency (POI), also known as premature ovarian failure, is a condition characterized by the depletion or dysfunction of ovarian follicles, leading to the cessation of menstruation before the age of 40. While the term “primary ovarian insufficiency” is now favored by the National Institutes of Health due to the intermittent nature of ovarian function in many cases, understanding and diagnosing this condition, sometimes referred to as premature menopause or premature ovarian failure, remains critical for adolescent and young women’s health. This article provides a comprehensive guide to diagnosing premature ovarian failure, addressing its causes, diagnostic approaches, and the importance of early identification.
Understanding Premature Ovarian Failure Etiology
The reasons behind follicle depletion or dysfunction in adolescents are diverse. Chromosomal abnormalities and damage from cancer treatments like chemotherapy or radiation therapy are significant contributors. Furthermore, a premutation in the FMR1 gene, linked to fragile X syndrome, is also associated with POI. In some instances, premature ovarian failure can be linked to multiple endocrinopathies, such as hypoparathyroidism and hypoadrenalism. Less frequently, infiltrative or infectious processes or pelvic surgery can impair ovarian function. Autoimmune mechanisms are suspected in approximately 4% of women with POI, indicated by the presence of adrenal or ovarian antibodies. However, in a significant number of cases, the exact cause remains unidentified.
Chromosomal Factors in Ovarian Failure
Gonadal dysgenesis, with or without Turner syndrome, is a prevalent chromosomal abnormality leading to premature ovarian failure in adolescents. In adolescents presenting with primary amenorrhea without other health issues, chromosomal abnormalities are found in 50% of cases. Among younger women (aged 30 years or younger) with secondary amenorrhea, 13% also exhibit abnormal karyotypes. While delayed puberty and growth are common in this population, menstrual irregularities are often the first sign leading to diagnosis.
Impact of Cancer Treatments on Ovarian Function
Chemotherapy and radiation therapy can lead to “acute ovarian failure,” which is the immediate loss of ovarian function. This condition can sometimes be temporary. The likelihood of gonadotoxicity from chemotherapy depends on the patient’s age at treatment, the type of drugs used, and the dosage. Alkylating agents and procarbazine are particularly associated with acute ovarian failure. However, younger patients are more likely to have some follicles survive chemotherapy. Radiation therapy, especially whole-body, whole-brain, pelvic, and spinal irradiation, also elevates the risk of acute ovarian failure. Pelvic irradiation at doses exceeding 10 Gy is a significant risk factor. Combined chemotherapy and radiation therapy further increase this risk. Importantly, even females who resume menstruation after chemotherapy face an increased lifetime risk of premature ovarian failure.
Fragile X Syndrome and Premature Ovarian Insufficiency
Fragile X syndrome, the most common inherited cause of intellectual disability, has a notable connection to premature ovarian failure. Approximately 6% of women with POI and a normal karyotype carry a premutation in the FMR1 gene. Although menstruation onset is typically normal in adolescent premutation carriers, about 1% will experience menopause before age 18. Fragile X premutation carrier testing is recommended for women with a personal or family history of early ovarian failure or unexplained elevated follicle-stimulating hormone (FSH) levels before age 40.
Diagnosis of Premature Ovarian Failure in Adolescence
Diagnosing premature ovarian failure in adolescents presents unique challenges, with no universally agreed-upon diagnostic criteria and frequent delays in diagnosis. While some adolescents may experience symptoms like hot flashes or vaginal dryness, the most common presenting symptom is primary or secondary amenorrhea. Among patients with amenorrhea, premature ovarian failure is found in 2% to 10% of cases. Other menstrual irregularities such as oligomenorrhea (infrequent bleeding), nonstructural abnormal uterine bleeding (e.g., due to ovulatory dysfunction), or polymenorrhea (frequent bleeding) can also occur. Because irregular cycles are common in early adolescence and can also signal early POI, diagnosis can be complex in this age group. Although less than 10% of adolescents with menstrual irregularities will be diagnosed with POI, the significant impact of this condition on bone health underscores the importance of early diagnosis. Therefore, evaluating amenorrhea or a shift from regular to irregular menses for three or more consecutive months in young females, excluding hormonal contraceptive use and other potential causes like pregnancy, polycystic ovary syndrome, hypothalamic amenorrhea, thyroid disorders, and hyperprolactinemia, is crucial. Family medical history, particularly a history of early menopause, should also be considered as a risk factor for premature ovarian failure.
Initial diagnostic steps for suspected premature ovarian failure involve measuring basal FSH and estradiol levels, along with tests to rule out pregnancy, thyroid disease, and hyperprolactinemia. These hormone levels should be assessed when patients are not taking hormonal medications, including oral contraceptives, as these can alter results. Elevated gonadotropin levels in the menopausal range (typically FSH greater than 30–40 mIU/mL, depending on lab standards) necessitate a repeat FSH measurement after one month. If FSH remains elevated, a diagnosis of premature ovarian failure can be confirmed. Estradiol levels below 50 pg/mL indicate hypoestrogenism.
Antimüllerian hormone (AMH) and inhibin B are being researched for their diagnostic value in POI. AMH testing may become increasingly valuable in assessing ovarian reserve before and after cancer treatments or ovarian surgery, and in females at high risk of POI. However, inhibin B levels show significant variability across menstrual cycles and are not currently recommended for routine testing.
Surrogate markers like regular menses, serial estradiol levels, and antral follicle count via transvaginal ultrasound are variable and not reliable predictors of future fertility or hormone production in young cancer survivors, but are areas of ongoing research. Once premature ovarian failure is diagnosed, further investigations, including karyotype analysis, adrenal antibody testing, FMR1 premutation analysis, and pelvic ultrasound, may be indicated to explore potential underlying causes.
Treatment Strategies for Premature Ovarian Failure
Optimal management of adolescent premature ovarian failure requires a sensitive approach to both the physical and emotional needs of young women facing this diagnosis during critical developmental years. Patients may be emotionally unprepared and need comprehensive information and support to process the immediate and long-term implications.
Hormone Therapy for POI
Hormone therapy for adolescents with premature ovarian failure aims to replace the hormones normally produced by the ovaries before menopause age. This differs from hormone therapy for menopause, which primarily targets symptom relief. The goals extend beyond symptom management to supporting bone, cardiovascular, and sexual health. Regardless of the cause, patients with POI are estrogen deficient and may require higher estrogen doses than menopausal women to ensure adequate replacement and optimal bone health. In girls with absent or incomplete breast development, estrogen therapy should be initiated and gradually increased before adding graduated progesterone dosages, ensuring complete breast development and preventing tubular breast formation. Consultation with specialists in growth and development and pediatric hormone therapy is recommended for patients who have not completed puberty.
Long-term hormone therapy is crucial for ongoing health after puberty. This typically involves daily estradiol therapy to maintain normal ovarian function levels. Transdermal, oral, or occasionally transvaginal estradiol at 100 micrograms daily is preferred to mimic physiological doses and relieve symptoms. Cyclic progesterone for 10–12 days each month is added to protect against endometrial hyperplasia and cancer, risks associated with unopposed estrogen. Oral estradiol carries a higher thromboembolism risk compared to transdermal estradiol due to liver metabolism. Oral contraceptives, containing higher estrogen doses than needed for hormone therapy, are not recommended as first-line treatment.
Fertility Considerations and Contraception in POI
Fertility can persist even with reduced functional follicles. Spontaneous resumption of ovarian function occurs in 5–10% of women with diagnosed premature ovarian failure, leading to a chance of spontaneous pregnancy. Unless pregnancy is desired, effective contraception is necessary. While oral contraceptives are often prescribed, barrier methods or intrauterine devices are encouraged. If a non-estrogen contraceptive method is chosen, estrogen should still be administered to maintain bone mineral density and prevent other hypoestrogenism effects. A missed menstrual cycle should always prompt a pregnancy test.
Associated Health Risks with Premature Ovarian Failure
Premature ovarian failure increases the risk of bone loss, cardiovascular disease, and endocrine disorders. Healthcare providers must also address the potential psychological impact of POI and counsel patients and families about these comorbidities.
Bone Health and Premature Ovarian Insufficiency
Early loss of ovarian function affects bone development during peak bone mass accrual. Specific guidelines for dual-energy X-ray absorptiometry (DEXA) scans in estrogen-deficient adolescents are lacking. Some experts recommend annual bone density monitoring in early to mid-puberty and every 2 years in late adolescence, while others question the clinical implications of low bone mineral density in this young population. Long-term bisphosphonate use is not currently recommended in adolescents due to uncertain long-term effects and safety profiles. Further research is needed in this area.
Cardiovascular Disease Risks
Early estrogen loss is linked to increased cardiovascular mortality risk. While adolescent-specific data and standard cardiovascular screening regimens are absent, vigilant monitoring and cardiovascular health optimization are crucial. Routine visits should include counseling on tobacco avoidance, diet, and exercise. Annual blood pressure measurement and lipid level checks every 5 years are recommended. Patients with Turner syndrome have additional cardiovascular risks, including aortic aneurysm, requiring regular cardiac imaging. Despite the association of early ovarian function loss with cardiovascular mortality, hormone therapy has not been shown to increase cardiovascular risks in these patients.
Endocrine Disorders and POI
Approximately 20% of adults with idiopathic premature ovarian failure develop hypothyroidism, often Hashimoto thyroiditis. Thyrotropin and thyroid peroxidase antibody levels should be tested after POI diagnosis. While routine thyroid screening guidelines are lacking, annual or bi-annual thyroid disease testing is reasonable given the high prevalence in POI patients. Adrenal insufficiency risk is also elevated in patients with adrenal autoimmunity, requiring adrenal antibody testing and yearly corticotropin stimulation testing if positive. Diabetes mellitus, pernicious anemia, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, and dry eye syndrome have also been linked to POI, and testing should be guided by symptoms. Antiovarian antibodies may be present but lack validated specificity and clinical utility.
Patient Counseling and Support
A premature ovarian failure diagnosis in adolescence is often unexpected and emotionally challenging for patients and families due to implications for fertility, self-image, and the need for long-term hormone therapy. Direct, in-office conversations are recommended for delivering this news. Adolescents may exhibit diverse emotional responses, and parents may react differently. Separate discussions with parents can allow them to understand the diagnosis and better support their daughters. Parents can also offer insights into their daughters’ understanding and guide the healthcare team’s approach. Sensitivity to the diagnosis’s nature and cultural significance within the family is vital. Using “primary ovarian insufficiency” rather than “premature ovarian failure” is often preferred, reflecting the possibility of intermittent ovarian function. Counseling should address the impact on future fertility, and referrals to reproductive endocrinology and infertility specialists should be offered to discuss reproductive options, such as in vitro fertilization with donor oocytes. While not ideal, this option can provide hope. However, it’s not advised for Turner syndrome patients due to pregnancy-related aortic rupture risks. Psychological counseling is recommended to address reported self-esteem and emotional distress following POI diagnosis. Providing resources for reliable online information and support groups enhances patient care.
A deeper understanding of reproductive biology and the effects of premature ovarian failure enables healthcare providers to offer effective counseling and management. Annual evaluations are crucial after POI diagnosis to address the unique needs of this population and counsel patients and families about comorbidities and potential genetic inheritance. Referral to accurate medical information is encouraged.
Resources
The following resources are for informational purposes only. Referral to these sources and web sites does not imply the endorsement of the American College of Obstetricians and Gynecologists. These resources are not meant to be comprehensive. The exclusion of a source or web site does not reflect the quality of that source or web site. Please note that web sites are subject to change without notice.
International Premature Ovarian Failure Association
PO Box 23643
Alexandria, VA 22304
(703) 913-4787
http://www.ipofa.org
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Fragile X Foundation
References
Copyright July 2014 by the American College of Obstetricians and Gynecologists, 409 12th Street, SW, PO Box 96920, Washington, DC 20090-6920. All rights reserved.
ISSN 1074-861X
Primary ovarian insufficiency in adolescents and young women. Committee Opinion No. 605. American College of Obstetricians and Gynecologists. Obstet Gynecol 2014;123:193–7.
Topics Adnexal diseases Counseling Infertility Primary ovarian insufficiency
