Primary Ovarian Insufficiency in the Adolescent

The number of reproductive years among women varies, depending on steroid production by the ovaries, but depletion of ovarian follicles with cessation of menses before age 40 years is considered premature menopause. Primary ovarian insufficiency is the term suggested by endocrinologist, Dr. Fuller Albright, and championed by Dr. Lawrence Nelson because in many cases, the ovarian function is impaired or intermittent and some women with primary ovarian insufficiency may even conceive and give birth (1). Primary ovarian insufficiency is estimated to affect approximately 1% of the female population in the United States (2). This committee opinion addresses primary ovarian insufficiency in adolescent patients and young adults younger than 25 years.

Etiology

Adolescent follicle depletion or dysfunction is most often caused by chromosomal abnormalities, damage from chemotherapy or radiation therapy, or is associated with syndromes like premutation for fragile X syndrome. Primary ovarian insufficiency may be a part of a multipleendocrinopathy, including hypoparathyroidism, hypoadrenalism, and mucocutaneous candidiasis or, less frequently, it is caused by viral infections or as a result of surgical extirpation (2).

Chromosomal Abnormalities

A common cause of primary ovarian insufficiency in adolescents is gonadal dysgenesis with or without Turner syndrome (2). When adolescents present with primary amenorrhea and no associated comorbidities, 50% of these patients are found to have abnormal karyotypes. Thirteen percent of patients with secondary amenorrhea have also been noted to have an abnormal karyotype (3). Such affected females may have associated anomalies and failure to develop secondary sexual characteristics or may appear normal with some degree of puberty. 

Fragile X Syndrome

Fragile X syndrome is the most common form of hereditable mental retardation. Six percent of females with primary ovarian insufficiency and a normal karyotype have a premutation in the FMR1 gene (3). 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 (4). Fragile X testing is recommended for young women with elevated follicle-stimulating hormone (FSH) levels, especially if there is a family history of primary ovarian insufficiency, fragile X syndrome, or undiagnosed mental retardation (5).

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 at time of delivery, types of medication, as well as the number of doses, has 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 somefollicles will survive (6–8). 

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 increasesthe 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). 

Diagnosis

There is no consensus on criteria to identify primary ovarian insufficiency in adolescents, and delay in diagnosis is common (10). Although some girls will report hot flashes or vaginal symptoms like dryness or dyspareunia, the most common presenting symptom of primary ovarian insufficiency is primary or secondary amenorrhea. Among patients with amenorrhea, the incidence of primary ovarian insufficiency ranges from 2% to 10% (2). Bleeding patterns also may include oligomenorrhea, dysfunctional uterine bleeding, or polymenorrhea (1). Because irregular menstrual cycles are common during early adolescence, and because this is also an initial symptom of early primary ovarian insufficiency, diagnosis can be difficult in this population. Although less than 10% of women who present with abnormal menses will ultimatelyhave primary ovarian insufficiency, the diagnosis has such detrimental consequences on bone health that early diagnosis of this condition is important (11). As many as two thirds of patients with primary ovarian insufficiency had osteopenia at their first visit, and many patients see three or more physicians before the diagnosis of primary ovarian insufficiency is established (11, 12). For this reason, evaluation for all potential causes of amenorrhea, or a change from regular to irregular menses for 3 or more consecutive months, including pregnancy, polycystic ovary syndrome, hypogonadal amenorrhea, thyroid abnormalities, hyperprolactinemia, or primary ovarianinsufficiency is important for young females (1, 11). Family history should be addressed because females with a family history of early menopause are at risk of primary ovarian insufficiency.

Initial laboratory evaluation for suspected primary ovarian insufficiency includes measurements of FSH and estradiol levels, while also ruling out comorbidities. If gonadotropins are elevated into the menopausal range (typically, FSH levels will be greater than 30–40 mIU/mL based on the laboratory used), a repeat FSH measurement is indicated in 1 month. If the result indicates that FSH is elevated, a diagnosis of primary ovarian insufficiency can be established. Estradiol levels less than 50 pg/mL indicate hypoestrogenism.

Antimüllerian hormone and inhibin B are being evaluated to determine their value in the diagnosis of primary ovarian insufficiency and currently are not required or needed for a diagnosis. Surrogate markers of ovarian reserve (presence of regular menses, serial serum estradiol levels, and antral follicle count by transvaginal ultrasonography) are highly variable and are not predictive of future fertility or hormonal production in this population (6, 7), but are currently undergoing investigation. Once primary ovarian insufficiency is diagnosed, karyotyping is indicated to determine if chromosomal abnormalities exist.

Treatment

Traditionally, the adolescent population with primary ovarian insufficiency has been treated in a manner similar to adult women with primary ovarian insufficiency. Although this may be appropriate on some level, the adolescent population is different from its adult counterpart. For adolescents with primary ovarian insufficiency, the objective of treatment is to replace the hormones that the ovary would be making before the age of menopause. Thus, this diagnosis is truly a chronic problem that emerges during a time of significant developmental changes, both physically and emotionally.

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 (11). Although it is well established that sex steroid replacement is necessary, pediatric health care providers vary in their replacement strategies in the prepubertal patient. There are currently no controlled studies addressing when secondary sexual characteristics should be induced or how to provide hormone therapy in this population (2). Practitioners must balance attainment of adult height with overall development of secondary sex characteristics when determining the timing and dose of hormone replacement (13). Combined hormonal contraception should not be used as first-line therapy in adolescents who have not completed puberty because they provide more hormones than physiologic replacement (1). For those who have not initiated or completed pubertal growth, consultation with a specialist in growth and development and hormonal therapy in children is desirable.

Treatment involves daily therapy with low doses of estrogen until breakthrough bleeding occurs (but no longer than 2 years) (14). A progestin is then added to induce regular withdrawal bleeding. The dosage of estrogen and progesterone can then be increased to adult levels at 6–12-month intervals over a 2–4 year period as deemed appropriate based on the patient's state of pubertal development (2, 14). There are several options for providing hormone replacement therapy in the prepubertal patient (Box 1). Although treatment should be individualized to the patient, one study in girls with Turner syndrome has shown that the use of transdermal estrogen, rather than oral estrogen, for pubertal induction can help optimize height in this population (15).

Fertility and Contraception

Fertility may persist even when few functional follicles are present. Because of occasional spontaneous resumption of ovarian function, there is a 5–10% chance of spontaneous pregnancy despite a diagnosis of primary ovarian insufficiency (4). Unless pregnancy is desired, a discussion of effective contraception should take place. Nelson recommends use of barrier methods or possibly an intrauterine device because oral contraceptive effectiveness has not been studied in patients with primary ovarian insufficiency, and there are anecdotal reports of women conceiving while adhering to oral contraceptive regimens (1). If a patient chooses a nonestrogen method of contraception, estrogen also should be administered to preserve bone mineral density and prevent other adverse effects of hypoestrogenemia. A missed menstrual cycle should warrant a pregnancy test.

Associated Comorbidities

Bone Loss

Loss of ovarian function at a very early age affects bone architecture at the very time when bone accrual is at its maximum. Because exogenous estrogen is not completely effective in preventing osteoporosis in these women, calcium and vitamin D intake should be maximized and weight-bearing exercises encouraged as preventive measures. 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 during early to midpuberty 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 osteopenia or low bone mass. To date, long-term use of bisphosphonates are not recommended in the pediatric 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 cardiovascular mortality (16). Although data in the adolescent population are lacking and there are no standard screening regimens for cardiovascular disease in this population, vigilant monitoring is warranted and practitioners should help patients optimize cardiovascular health. Routine visits should include counseling on tobacco avoidance and appropriate diet and exercise to optimize cardiovascular health. Screening blood pressure at least annually and lipid levels every 5 years is recommended. Patients with Turner syndrome have additional cardiovascular risks, including aortic aneurysm. Additional guidelines for patients with Turner syndrome and no obvious cardiovascular 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 (14). Although early loss of ovarian function has been associated as a risk factor for cardiovascular mortality, there are no data indicating that these patients are at increased risk of cardiovascular adverse effects from hormone replacement (16, 17).

Endocrine Disorders

Approximately 20% of adults with idiopathic primary ovarian insufficiency will experience hypothyroidism, most commonly Hashimoto thyroiditis (3, 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 antibodies 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 have also 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 (19).

Psychologic Effects

When primary ovarian insufficiency is diagnosed in the adolescent female, the patient and her family are often unprepared for such news. It is best to inform the patient and family by having a direct conversation in the office (11). Adolescents may demonstrate myriad emotions ranging from apathy or denial to remorse or sadness and these emotions may be different from those of her parents or guardians. Practitioners can consider telling the parents separately from the child 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. Practitioners 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 (2). "Insufficiency" is a more accepted terminology 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 discussions on available reproductive treatments. Psychologic counseling should also be offered because an association between primary ovarian insufficiency, impaired self-esteem, and emotional distress has been reported after this diagnosis (20–22). Because many patients will use the Internet to learn more about their diagnosis, referral to appropriate sources for support is an efficient means to enhance patient care (see Resources.)

Long-Term Follow-Up

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 follow-up at least annually for evaluation. Physicians should address the special needs of this population and counsel family members on the risks of primary ovarian insufficiency given the potential for genetic inheritance. Referral to accurate medical information is encouraged.

Resources

The American College of Obstetricians and Gynecologists has provided information on the following organizations and web sites for access to information that may be of interest to health care providers. The American College of Obstetricians and Gynecologists does not necessarily endorse the views expressed or the facts presented bythese organizations on their web sites. Further, the American College of Obstetricians and Gynecologists does not endorse any commercial products that may be advertised or available from these organizations or on these web sites.

• International Premature Ovarian Failure Association www.pofsupport.org
• Eunice Kennedy Shriver National Institute of Child Health and Human Development Primary Ovarian Insufficiency
  http://poi.nichd.nih.gov
• National Fragile X Foundation
  www.fragilex.org/html/poi.htm
• Project Vital Sign
  http://www.projectvitalsign.org/primary-ovarian-insufficiency-poi

References

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