Primary Ovarian Insufficiency in Adolescents and Young Women

Chromosomal Abnormalities

A common cause of primary ovarian insufficiency in adolescents is gonadal dysgenesis, with or without Turner syndrome 3. When adolescents present with primary amenorrhea and no associated comorbidities, 50% are found to have abnormal karyotypes. Among younger women (aged 30 years or younger) with secondary amenorrhea, 13% also have been noted to have an abnormal karyotype 5. Although pubertal and growth delays are common in this group, many affected females may first be recognized at the time of evaluation for menstrual abnormalities.

Chemotherapy and Radiation Therapy

The immediate loss of ovarian function after chemotherapy or radiation therapy is termed “acute ovarian failure,” which may be transient. With chemotherapy, the age of the patient when she received chemotherapy, types of medication, and number of doses all have an effect on the possibility of gonadotoxicity. Although the highest incidence of acute ovarian failure occurs after the use of alkylating agents or procarbazine, the younger the patient at the time of receiving the chemotherapy, the more likely it is that some follicles will survive 6 7 8. Whole-body, whole-brain, pelvic, and spinal irradiation also increase the risk of acute ovarian failure 9. Pelvic irradiation (especially doses more than 10 Gy) is a significant risk factor for acute ovarian failure 8. Chemotherapy combined with radiation therapy increases the chance of acute ovarian failure. It should be noted that even females who menstruate after chemotherapy have an increased lifetime risk of primary ovarian insufficiency 9.

Fragile X Syndrome

Fragile X syndrome is the most common form of hereditable mental retardation. Among females with primary ovarian insufficiency and a normal karyotype, 6% have a premutation in the FMR1 gene 5. Although the onset of menstruation appears to be normal among premutation carriers in adolescence, approximately 1% of premutation carriers will experience their final menses before age 18 years 10. If a woman has a personal or family history of ovarian failure or an elevated follicle-stimulating hormone (FSH) level before age 40 years without a known cause, fragile X premutation carrier testing should be offered 11.

Hormonal Therapy

For adolescents with primary ovarian insufficiency, the objective of treatment is to replace the hormones that the ovary would be producing before the age of menopause, making the treatment distinctly different from hormonal therapy for menopause that focuses on the treatment of menopausal symptoms. The goals of hormonal therapy extend beyond simply symptom relief to levels that support bone, cardiovascular (CV), and sexual health. Regardless of the etiology, patients with primary ovarian insufficiency are estrogen deficient. Thus, young women with primary ovarian insufficiency may need higher doses of estrogen than menopausal women to ensure adequate replacement and optimal bone health 12. In girls with absent or incomplete breast development, estrogen therapy should be initiated and increased slowly before administration of graduated progesterone dosages until breast development is complete to prevent tubular breast formation. For those patients who have not initiated or completed pubertal growth and sexual maturity, consultation with a specialist in growth and development and hormonal therapy in children is recommended.

Once pubertal development is complete, ongoing hormonal therapy will be necessary for long-term health. Hormonal support involves daily therapy with the goal of maintenance of normal ovarian functioning levels of estradiol. Transdermal, oral, or occasionally transvaginal estradiol in doses of 100 micrograms daily is the therapy of choice to mimic a physiologic dose range and to achieve symptomatic relief. The addition of cyclic progesterone for 10–12 days each month is protective against endometrial hyperplasia and endometrial cancer, risks of unopposed estrogen. Oral estradiol may be used, but it increases the potential for thromboembolism relative to transdermal estradiol due to the first-pass effect on the liver. Oral contraceptives contain higher doses of estrogen than are necessary for hormonal therapy; therefore, they are not recommended as first-line hormonal therapy.

Bone Loss

Loss of ovarian function at an early age affects bone architecture at the very time when bone accrual is at its maximum. There are no published data to support specific recommendations for dual-energy X-ray absorptiometry scanning in adolescents with estrogen deficiency. Although some experts suggest monitoring bone density annually in adolescents with estrogen deficiency during early to mid puberty to document peak bone accrual and then every 2 years in late adolescence, others do not because the implications of a low bone mineral density result in this population are unclear given the low risk of fracture and the potential for long-term treatment of low bone mass. To date, long-term use of bisphosphonates is not recommended in the adolescent population because of uncertain adverse effects and safety profiles. Further research in this area is needed.

Cardiovascular Disease

Individuals with early loss of endogenous estrogen have been shown to have an increased risk of CV mortality 15. Although data in the adolescent population are lacking and there are no standard screening regimens for CV disease in this population, vigilant monitoring is warranted, and practitioners should help patients optimize CV health. Routine visits should include counseling on tobacco avoidance and appropriate diet and exercise to optimize CV health. Measuring blood pressure at least annually and lipid levels every 5 years is recommended. Patients with Turner syndrome have additional CV risks, including aortic aneurysm. Additional guidelines for patients with Turner syndrome and no obvious CV pathology include either routine cardiac imaging every 5–10 years or focused imaging when transitioning from a pediatric to adult health care provider, before attempting pregnancy, or with the appearance of hypertension to assess for coarctation or aortic stenosis 16. Although early loss of ovarian function has been associated as a risk factor for CV mortality, there are no data indicating that these patients are at an increased risk of CV adverse effects from hormonal therapy 15 17.

Endocrine Disorders

Approximately 20% of adults with idiopathic primary ovarian insufficiency will experience hypothyroidism, most commonly Hashimoto thyroiditis 5 18. Following initial diagnosis of primary ovarian insufficiency, it is appropriate to test thyrotropin levels for the presence of thyroid peroxidase antibodies. Although no recommendations for routine thyroid screening exist in this population, given the high prevalence of this disorder in patients with primary ovarian insufficiency, it is acceptable to test for thyroid disease every 1–2 years. Patients with primary ovarian insufficiency also have a 50% chance of developing adrenal insufficiency if they have adrenal autoimmunity. Patients should be tested for adrenal anti-bodies and if results are positive, should undergo yearly corticotropin stimulation testing. Data are lacking on the follow-up of patients with negative test results 1. Diabetes mellitus, pernicious anemia, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, and dry eye syndrome also have been associated with primary ovarian insufficiency, and testing should be based on symptomatology. Antiovarian antibodies may be present in these patients, but their specificity and pathogenic usefulness has not been validated 17.

Patient Counseling

When primary ovarian insufficiency is diagnosed in the adolescent female, the patient and her family are often unprepared for such news with its implications for compromised fertility and impaired self-image and the need for long-term hormonal therapy. It is best to inform the patient and family by having a direct conversation in the office 12. Adolescents may demonstrate myriad emotions ranging from apathy or denial to remorse or sadness, and these emotions may be different from those of their parents or guardians. Practitioners can consider telling the parents separately from their children so that the parents will have an opportunity to understand the diagnosis and adjust their demeanor to be most supportive of their daughters. Parents also can provide valuable insights about their daughters’ ability to appreciate the significance of the diagnosis of primary ovarian insufficiency and guide the clinician or team. Health care providers who make this clinical diagnosis should be mindful of the sensitive nature of this medical condition as well as the cultural significance of the diagnosis within the family unit. Use of the term “premature ovarian failure” can be particularly troubling to a young woman and her family 3. “Insufficiency” is the more accepted term in this population and more truly reflects the possibility of intermittent resumption of function. Patients and their families should be counseled on the effect of the patient’s condition on future fertility. Referrals to a reproductive endocrinology and infertility specialist should be made when desired by the patient and family to further discuss available reproductive treatments. In vitro fertilization with donor oocytes is often the most appropriate treatment; there are otherwise limited therapeutic options. Although the procedure may not be ideal, it may provide some hope for the patient who is told that her fertility is severely compromised. However, this is not a recommended option for patients with Turner syndrome because of the risk of aortic rupture during pregnancy. Psychologic counseling also should be offered because impaired self-esteem and emotional distress have been reported after diagnosis of primary ovarian insufficiency 19 20 21. Because many patients will use the Internet to learn more about their diagnoses, referral to appropriate sources for support is an efficient means to enhance patient care (see Resources).

A greater understanding of female reproductive biology and the physiologic effect of primary ovarian insufficiency enables health care providers to offer counseling for these young women. Once primary ovarian insufficiency is diagnosed, patients should be evaluated at least annually. Physicians should address the special needs of this population and counsel family members and patients on the risk of comorbidities associated with primary ovarian insufficiency and the condition’s potential for genetic inheritance. Referral to accurate medical information is encouraged.