DAN I. LEBOVIC, MD, MA Premature ovarian failure: Think ‘autoimmune disorder’ A comprehensive look at the causes and co-morbidities of premature ovarian failure leads straight to an emphasis on underlying immunologic disorders—and the need for prompt diagnosis.

✒ KEY POINTS However, an autoimmune process appears to play a major role as many women with POF ■ The incidence of antiovarian in women with POF ranges often have associated autoimmune disorders. widely (0-67%). This review discusses the various causes, di- agnoses, and co-morbidities and presents a ■ Three diagnostic criteria comprise POF: lasting more than diagnostic workup. 4 months, age less than 40 years, and serum follicle-stimulating hormone >40 mIU/mL on two occasions at least one month apart. Diagnostic criteria for POF ■ Several autoimmune disorders have been associated with POF; the most A karyotype and autoimmune evaluation common is hypothyroidism with an incidence of 27%, followed by diabetes should be obtained on all patients present- mellitus (2.5%) and Addison’s disease (2.5%). ing with POF. Although a distinct auto- immune workup has been developed for ■ Approximately 10% of women with Addison’s have POF, and the same women diagnosed with POF, there is no percentage applies conversely, with 10% of women with POF showing definitive test that can precisely herald the evidence of autoimmunity against the adrenal. development of associated autoimmune dis- ■ Women with POF who experience a particularly increased level of sadness orders or precisely anticipate a woman’s and stress will likely benefit from consulting a mental health care chances of conceiving. professional while their medical evaluation is taking place. Three diagnostic criteria comprise POF: • Amenorrhea lasting more than 4 months • Age less than 40 years, and y definition, premature ovarian fail- • Serum follicle-stimulating hormone (FSH) ure (POF) occurs early—by age 40. >40 mIU/mL on two occasions at least one As a result, the patient faces signifi- month apart. cant treatment issues for a decade or Despite all these hits on the reproductive Bmore than a woman who experiences natural axis, Rebar and Conley’s classic series found Dan I. Lebovic, MD, MA menopause at age 51. In addition to subfertil- that women with POF and secondary amen- Reproductive Endocrinology Division ity, there are a number of hypoestrogenic ail- orrhea continue to have intermittent ovarian Department of Obstetrics ments. None of these deficiencies may have function, as evidenced by ovulation in 24% 2 and Gynecology been on a woman’s mind at the time she was and a pregnancy rate of 8% (Table 1). One University of Michigan diagnosed with POF. Entering menopause study reported a 60% rate of follicular activi- Ann Arbor prematurely also may create a significant ty in women with POF, although it is unclear Rajesh Naz, MD physical and emotional impact. how many of them had the autoimmune ver- Division of Research The prevalence of POF varies by ethnici- sus the non-autoimmune variety of ovarian 3 Department of Obstetrics ty: 0.1% to 1.4% among Caucasian, African- failure. and Gynecology American, Hispanic, Chinese, and Japanese Medical College of Ohio women. The estimated incidence of POF in Focus on autoimmune causes Toledo the general population is between 0.3% and The etiology of POF can be divided into two 1 © 2004 American Society 1.1%. broad categories: depletion for Reproductive Medicine Although the pathophysiology of POF is and ovarian follicle dysfunction (see Table 2 Published by Elsevier Inc. diffuse, there is often a genetic component. for an abbreviated list of findings). Our dis-

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cussion will focus on the autoimmune causes TABLE 1 within each category. The evidence for an au- toimmune etiology is threefold: the presence Clinical findings in 115 women with POF2 of lymphocytic oophoritis, autoantibodies to Primary amenorrhea Secondary amenorrhea ovarian antigens, and associated autoimmune Karyotypic abnormalities 56% 13% disorders. Using microsomal ovarian antibodies and Y-chromosome present 10% None oocyte antibodies, an autoimmune basis has Symptoms of estrogen deficiency 22% 85% been detected in as many as 69% of women Ovulation after diagnosis None 24% with POF.4 In fact, with a 1.1% prevalence of POF, the autoimmune version calculates to Pregnancy after diagnosis None 8% nearly 1.1 million women with premature ovarian autoimmunity in the United States, and autoimmune oophoritis.11 compared to about 1.4 million women with Several reports describe an elaborate par- Hashimoto’s thyroiditis.5 Viewed in this way, acrine mechanism for lymphocytic oophoritis. POF is a fairly common . A schematic representation is shown in Fig- Possessing an autoantibody does not ure 1.10,12-13 prove that one has clinical evidence of a dis- ease. Conversely, an absence of ovarian au- Autoantibodies to ovarian antigens toantibodies does not prove that POF is ab- The published incidence of antiovarian anti- sent. Ovarian autoantibodies have not been bodies in patients with POF ranges widely consistently identified due to the multiple (0–67%), attesting to the difficulties in inter- ovarian targets as well as variation in preting their role and understanding their antibody test format and antigen presentation. clinical significance.14-15 A number of factors Nevertheless, most studies have found a high- account for the uncertainty—highly variable er prevalence of antibodies in serum or follic- ELISA assays, transient appearance of anti- ular fluid samples from women with POF. ovarian antibodies, and poor correlation be- The extracellular matrix, or zona pelluci- tween antibody levels and severity of disease. da, surrounding a developing oocyte provides Antibodies interfering with FSH-cell-surface a barrier to protect the oocyte from immune receptors have yet to be identified.16-17 cells (leukocytes, macrophages, T-lympho- Steroid cell antibodies of the IgG type cytes, neutrophils, and eosinophils) as well as have been found bound to ovarian hilar, gran- their products, such as antibodies.6 The im- ulosa, and theca cells. Overall, though, these mune cells eventually populate the corpora antibodies are found in patients with Addison’s lutea granulosa-lutein and theca-lutein cells in disease rather than isolated POF. In a study of addition to the connective tissue stroma. In seven women with steroid cell autoantibodies fact, macrophage secretory products, tumor and adrenal failure, 42.8% developed ovarian necrosis factor-α, and interferon-γ have been shown to facilitate cellular apoptosis.7 TABLE 2 Lymphocytic oophoritis The etiology of premature ovarian failure A review of the literature on oophoritis and Ovarian follicle depletion POF turned up an 11% incidence of histo- Deficient initial follicle number logic evidence of oophoritis in 215 POF ovar- Accelerated follicular atresia ian biopsies.8 The oophoritis is characterized Autoimmunity primarily by a cellular infiltrate of macro- Ovarian follicle dysfunction phages, natural killer cells, T-lymphocytes, Enzyme deficiencies plasma cells, and a few B-lymphocytes.9 A Autoimmunity possible trigger for the influx of lymphocytes Lymphocytic oophoritis may be the class II MHC molecules that Gonadotropin-receptor blocking antibodies have been identified on granulosa cells.10 Antibodies to gonadotropins Early thymectomy in the mouse model can Signal defects arrest immune development and lead to a Gene mutations (inhibin α gene) deficiency in T-suppressor cells so that these Iatrogenic mice demonstrate follicular degeneration Idiopathic

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Figure 1. Mechanism of Destroyed granulosa cell lymphocytic oophoritis. T-cells within the Triggered T-cell invade granulosa cells and TC become activated, secreting interferon-γ (IFN-γ). The Primary follicle IFN-γ enhances expression of class I and II MHC on Natural killer cell granulosa cells with the help of elevated follicle- MHC II stimulating hormone (FSH) values (secondary to dimin- TH IFN-γ ished inhibin production by these cells). Type I MHC- expressing granulosa cells present their antigens to Granulosa cell FSH cytotoxic T-cells that result MHC I in the destruction of granulosa cells. In addition, the type II MHC allows the B-lymphocyte granulosa cells to act as antigen-presenting cells to Plasma cell T-helper cells, with resultant B-cell differentiation into © KEVIN SOMERVILLE 2004 autoantibody-secreting plasma cells. A decrease failure within 10–15 years.18 The role of zona APS type I is a rare autosomal recessive in natural killer cell activity pellucida antibodies and POF is yet to be de- disorder characterized by multiple organ-spe- in women with premature termined.19-20 cific autoimmunity secondary to a variety of ovarian failure could poten- autoantibodies directed against key intracel- tiate the B and T cells. Associated autoimmune disorders lular enzymes. POF develops in 60% of A genetic component to developing autoim- patients with APS type I. Recently, 31% of 90 mune POF is supported by the familial prop- patients with APS I were found to have hypo- erties of both POF and autoimmune disor- gonadism, and the side-chain cleavage enzyme ders. Approximately 3% of women with POF was identified as the major gonadal autoanti- have an associated endocrine dysfunction gen associated with APS I.21 However, to date known as autoimmune polyglandular syn- there is no clear definition of risk to develop drome (APS) type I or II.18 clinical hypogonadism based on the presence of the side-chain cleavage enzyme autoantibody. TABLE 3 The more common APS type II, an auto- somal dominant disorder, is associated with Autoimmune diseases affecting other organs in women with POF gonadal failure in only 4% of patients. Addi- Addison’s disease (2.5%) Juvenile rheumatoid arthritis son’s disease is a component of both APS Alopecia Malabsorption syndrome types, although POF is often seen with isolat- Asthma ed Addison’s disease.22 Approximately 10% of Autoimmune polyglandular syndrome Pernicious anemia women with Addison’s have POF, and the Chronic active hepatitis Primary biliary cirrhosis Crohn’s disease Quantitative immunoglobulin abnormalities same percentage applies conversely, with 10% Diabetes mellitus (2.5%) Rheumatoid arthritis of POF women showing evidence of autoim- 23 Glomerulonephritis Sjögren’s syndrome munity against the adrenal. Hypoparathyroidism Systemic erythematosus Several other autoimmune disorders have Hypophysitis Thyroid disease (27%) been associated with POF and are listed Idiopathic thrombocytopenic purpura Vitiligo in Table 3. The most common of these is Autoimmune polyglandular syndrome (APS) type I and II: hypothyroidism with an incidence of 27%, • 60% of APS I have concomitant POF followed by diabetes mellitus (2.5%) and • 4% of APS II have concomitant POF Addison’s disease (2.5%).24 The clinical impli- Most common progression of subsequent autoimmune deficits: cations of these associated autoimmune dis- thyroid ➔ pancreas ➔ adrenal eases mandate a thorough initial screening POF, premature ovarian failure. and diagnostic workup, set forth in Table 4.

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Is autoimmune POF reversible? TABLE 4 If the subset of autoimmune POF could be ameliorated by immunosuppression, this Diagnostic tests for women with POF would suggest that not all follicles have been Karyotype If onset < age 30 and primary amenorrhea affected by the immune inactivation. Very few clinical studies, all uncontrolled and nonran- Y-chromosome necessitates gonadectomy to prevent domized, have addressed this question using gonadoblastoma corticosteroids as immunosuppressive thera- 50% of gonadoblastomas will transform into dysgerminomas py. While there has been modest success with this approach,25-27 placebo-controlled ran- All patients domized clinical trials have yet to determine Type I diabetes Glucose tolerance test the optimal dose, safety profile, and efficacy of immune modulators for autoimmune Thyroid disease Thyroid-stimulating hormone, antithyroperoxidase antibodies oophoritis. In most instances, treatment fails Hypoestrogenism- Dual-energy X-ray absorptiometry (DEXA) scan bone to reverse the course of the disease. osteoporosis densitometry The emotional side If signs and symptoms warrant This review would not be complete without Pernicious anemia CBC with peripheral smear discussing the intense emotional response to Addison’s disease* Adrenal antibody test (titer <1:10 is normal) with adrenocortico- developing early menopause or POF. Feelings tropic hormone (ACTH) stimulation test to confirm diagnosis28 of despair may overwhelm any proposed treat- ment regimen. But if hopeful treatments can Low-dose ACTH stimulation test: Administer 1 mcg cosyntropin IM (cortisol should be >18 mcg/dL at 30 or 60 minutes)29 be developed, this would alleviate the huge distress currently felt by patients with POF, Hypoparathyroidism Calcium and phosphorus especially those who have not completed IgA deficiency Total serum protein; albumin/globulin ratio childbearing. Women in this situation not only (if frequent respiratory face a sense of being “prematurely old” in a tract infections) society that places a premium on youth, but also face a reality that they may not be able to Pituitary tumor MRI of sella turcica if signs and symptoms of central nervous system mass lesion become a biologic parent. An understanding of the pathophysiology * Signs and symptoms include hyperpigmentation of gums and hand skinfolds, loss of pubic/axillary hair. of POF is paramount to devising preventive POF, premature ovarian failure. strategies in affected families as well as devel- oping therapeutic measures to aid in fertility REFERENCES outcome. Since a majority of POF has an au- 1. Luborsky JL, Meyer P, Sowers MF, et al. Premature menopause in toimmune characteristic, this is a valuable tar- a multi-ethnic population study of the menopause transition. Hum Re- prod 2003;18:199-206. get of future research. Activated CD4+ T-lym- 2. Rebar RW, Connolly HV. Clinical features of young women with hy- phocytes produce predominantly one of two pergonadotropic amenorrhea. Fertil Steril 1990;53:804-10. 3. Conway GS, Kaltsas G, Patel A, et al. Characterization of idiopathic characteristic cytokine profiles, T-helper1 premature ovarian failure. Fertil Steril 1996;65:337-41. (TH1) and T-helper2 (TH2). Further investi- 4. Luborsky JL, Visintin I, Boyers S, et al. Ovarian antibodies detected by immobilized antigen immunoassay in patients with premature ovar- gation should determine if the immune re- ian failure. J Clin Endocrinol Metab 1990;70:69-75. sponse seen with POF is due to a predomi- 5. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the nance of one profile or the other. United States. Clin Immunol Immunopathol 1997;84:223-43. Beyond the POF findings, it will be inter- 6. Dunbar BS, Prasad S, Carino C, Skinner SM. The ovary as an im- mune target. J Soc Gynecol Investig 2001;8:S43-S48. esting to examine whether similar etiologic 7. Cataldo NA, Jaffe RB. Human luteinizing granulosa cells express factors play a role during the perimenopause Apo-1/FAS, and interferon gamma (IFN-g) increases their susceptibil- ity to anti-Apo-1-mediated apoptosis. in Meeting of the Society for Gy- period transitioning into menopause. For the necologic Investigation. 1996. Philadelphia, PA. moment, it is prudent to diagnose POF as 8. Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity. Endocr Rev 1997;18:107-34. soon as possible in addition to obtaining the 9. Sedmak,DD, Hart WR, Tubbs RR. Autoimmune oophoritis: a histo- appropriate diagnostic tests for related au- pathologic study of involved with immunologic characterization of the mononuclear cell infiltrate. Int J Gynecol Pathol 1987;6:73-81. toimmune disorders. Those women with POF 10. Hill JA, Welch WR, Faris HM, Anderson DJ. Induction of class II who experience a particularly increased level major histocompatibility complex antigen expression in human granu- Dan I. Lebovic, MD, MA losa cells by interferon gamma: a potential mechanism contributing to Department of Obstetrics of sadness and stress will likely benefit from autoimmune ovarian failure. Am J Obstet Gynecol 1990;162:534-40. and Gynecology consulting a mental health professional while See the complete listing of references for this article at University of Michigan their medical evaluation is taking place. ■ www.srmjournal.org [email protected]

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