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 antibodies 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: amenorrhea 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: ovarian follicle 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- 230 Sexuality, Reproduction & Menopause VOL. 2, NO. 4, DECEMBER 2004 Premature ovarian failure: Think ‘autoimmune disorder’ 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 autoimmune disease. 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 antibody 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 VOL. 2, NO. 4, DECEMBER 2004 Sexuality, Reproduction & Menopause 231 Premature ovarian failure: Think ‘autoimmune disorder’ Figure 1. Mechanism of Destroyed granulosa cell lymphocytic oophoritis. T-cells within the ovary 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-