by Judith L. Luborsky, Ph.D., and Seerin V. Shatavi, M.D., Departments of Pharmacology & Obstetrics and Gynecology, Rush University Medical Center, 1735 W Harrison, Chicago, IL 60612
InFocus, Vol.12, No.3,September 2004

Introduction Over three decades ago Irvine (1) observed a high rate of premature ovarian failure associated with polyendocrine autoimmune disease and suggested that there might be an autoimmune disease of the ovary. At about the same time Vallotton and Forbes (2) observed autoantibodies to eggs in the ovary in women with infertility and also suggested there might be an autoimmune disease of the ovary. Since that time, the concept of ovarian autoimmune disease has become more widely recognized but significant advances in our understanding are only just beginning to occur.

Definitions Ovarian autoimmune disease is principally associated with Premature Ovarian Failure (POF) and with unexplained infertility. It is possible that autoimmune unexplained infertility is an early stage of autoimmune POF but this remains to be demonstrated conclusively.

POF is the onset of menopause before age 40 and occurs in one to two percent, or about one to two million women. Like natural menopause around age 50, premature menopause is identified by cessation of menstrual cycles for one year, accompanied by elevated follicle stimulating hormone (FSH) and reduced estradiol levels in blood (3). While some cases of POF have a genetic cause (such as Turner syndrome), or are due to chemotherapy, recent studies suggest that about half the cases of premature menopause are due to an autoimmune attack on ovarian follicles and the eggs (oocytes).

Infertility is defined as the inability of a couple to conceive for at least one year during unprotected intercourse (4). There are different causes of infertility. The suspected cause of infertility is determined by a standard infertility clinical evaluation. In some cases, no cause is identified. Thus, unexplained infertility is identified by exclusion, after normal results for semen analysis, postcoital test, ovulation (luteal phase progesterone) and tubal patency are obtained in a standard clinical evaluation (5). About half of women with unexplained infertility have antibodies that react specifically with the ovary or oocytes.

Features of ovarian autoimmunity There is still a lack of information on the specific features of autoimmune POF. Some women with POF may have a family history of POF but most do not. However, women with POF have a higher risk for other autoimmune endocrine diseases, such as thyroid disease, Addison disease, type 1 diabetes, and autoimmune polyglandular syndromes.

Women with infertility and ovarian autoantibodies tend to have lower than expected estradiol responses to gonadotropin hormone stimulation (i.e. ?poor responders?) (6) and lower pregnancy rates following infertility treatment (7). Poor responders with ovarian antibodies were younger than poor responders without ovarian antibodies (8). This suggests that although some poor responses are associated with early stages of the menopause progression and reduced number of functional follicles, others are associated with an autoimmune process.

Diagnosis Ovarian autoimmunity is identified by the presence of anti-ovarian antibodies. There are several different types of tests and consequently different names for these antibodies. Antibodies specifically to eggs and to the zona pellucida (an area surrounding the eggs), or to ovarian cells have been described (9). We found that about 70% of women with POF or unexplained infertility have ovary specific autoantibodies. Some women have antibodies to both ovarian cells and to eggs and others have only one of these antibodies. There are tests available to detect anti-ovarian autoantibodies; you can ask your doctor to send a blood sample to the company that has licensed the tests (ReproMedix in Woburn, Massachusetts www.ReproMedix.com).

Ovarian autoimmunity is not identified by traditional tests for ovarian function, such as elevated pituitary follicle stimulating hormone in POF. Although the cause may differ, the symptoms of autoimmune and non-autoimmune POF are the same as in a normal menopause, including hot flashes, dry vaginal tissues, painful sex, infertility, bone loss, and an increased risk of cardiovascular disease. Likewise, autoimmune infertility can only be distinguished from non-autoimmune infertility by specific antibody tests.

Clinical treatment and outcome As with other endocrine disorders, POF is treated by replacing the lost hormone, in this case hormone replacement therapy (HRT) with estrogen and progesterone to protect the heart, bones, genital and urinary tract tissues, and the nervous system.

However, if a woman with infertility or POF wants to become pregnant, treatment with hormones that stimulate ovarian follicles to grow and produce eggs can be tried. If hormone stimulation alone does not result in a pregnancy, women may be treated by more aggressive methods such as in vitro fertilization (IVF). There have been reports of success in combination with low dose immuosuppression. However, success rates are relatively low and there are concerns about the side effects of immunosuppressant therapy. In some rare cases of POF, follicular function may spontaneously resume, and a pregnancy can occur.

Future prospects The next significant advance in characterizing ovarian autoimmune disease will be identification of the specific ovarian proteins recognized by the autoantibodies. We recently began a systematic and rigorous, NIH funded study to identify the target autoantigens using the newest technology for the study of proteins (proteomics). This will permit development of tests based on use of specific antigens, which will improve clinical diagnosis. An understanding of how these proteins become targets of an autoimmune attack would be a significant step toward designing therapies for reversing the effects of this disorder.

1. Irvine WJ, Premature menopause in autoimmune diseases. Lancet, 1969; Feb 1: 264.

2. Vallotton MB, Forbes AP, Antibodies to cytoplasm of ova. Lancet, 1966; 2: 264-265.

3. WHO. Research on Menopause in the 1990. WHO technical report series 866. World Health Organization, Geneva, Switzerland: 1996.

4. WHO. Recent Advances in Medically Assisted Reproduction. WHO Technical Report series 820. World Health Organization, Geneva: 1992.

5. Forti G, Krausz C, Evaluation and treatment of the infertile couple. Fertil Steril, 1998; 83: 4177-4188.

6. Meyer W, Lavy G, DeCherney A, Visintin I, Economy K, Luborsky J, Evidence of gonadal and gonadotropin antibodies in women with a suboptimal ovarian response to exogenous gonadotropin. Obstet Gynecol, 1990; 75: 795-799.

7. Luborsky J, Pong R, Pregnancy outcome and ovarian autoimmunity in infertility patients undergoing controlled ovarian hyperstimulation. Am J Reprod Immunol, 2000; 44: 261-265.

8. Luborsky J, Thiruppathi P, Rivnay B, Roussev R, Coulam C, Radwanska E, Evidence for different etiologies of low estradiol response to FSH: age related accelerated luteinization of follicles or presence of ovarian autoantibodies. Human Reproduction, 2002; 17: 2641-2649.

9. Luborsky JL, Ovarian autoimmune disease and ovarian autoantibodies: a review. J Womens Health & Gender Based Medicine, 2002; 11: 585-599.