1 Section on Women's Health Research, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, 2 National Cancer Institute, Division of Clinical Sciences, Laboratory of Pathology and 3 Warren Grant Magnuson Clinical Center, Diagnostic Radiology Department, National Institutes of Health, Bethesda, MD 20892, USA
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: autoimmune lymphocytic oophoritis/autoimmune premature ovarian failure/glucocorticoids/osteonecrosis/return of ovarian function
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
At present, the clinician has neither of these (Nelson et al., 1996; Wheatcroft et al., 1997
). This makes autoimmune ovarian failure a frustrating condition for the young couples that it robs of fertility, and a frustrating condition for the clinicians that are caring for them. This frustration may lead to the use of empirical treatments, with which the potential benefits and risks are poorly defined. To bring focus to this issue, we present here two cases of young women with premature ovarian failure who were treated with glucocorticoids in the hopes of restoring fertility. The first case illustrates the potential benefit of such therapy, and the second case illustrates a potential risk.
Autoimmunity is a well established mechanism of ovarian failure (Irvine et al., 1968; Sedmak et al., 1987
; Bannatyne et al., 1990
) and, as a group, patients with karyotypically normal premature ovarian failure are known to have increased peripheral T lymphocyte activation (Rabinowe et al., 1986
; Nelson et al., 1991
). On the other hand, simple elevated follicle stimulating hormone has been shown to be associated with increased peripheral T lymphocyte activation (Hoeck et al., 1995). Nevertheless, increased numbers of activated peripheral T lymphocytes has been described in other autoimmune endocrine disorders, such as recent onset Grave's disease (Jackson et al., 1984
), insulin dependent diabetes mellitus (Jackson et al., 1982
) and Addison's disease (Rabinowe et al., 1984
).
One percent of women by age 40 years spontaneously develop premature ovarian failure (Coulam et al., 1986), a condition characterized by amenorrhoea, infertility, sex steroid deficiency, and elevated serum gonadotrophin concentrations (Rebar and Cedars, 1992
; Nelson et al., 1996
). Anecdotal reports have suggested that glucocorticoid treatment may be useful in treating autoimmune premature ovarian failure (Cowchock et al., 1988
; Taylor et al., 1989
; Luborsky et al., 1990
; Blumenfeld et al., 1993
; Corenblum et al., 1993
).
![]() |
Case reports |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Review of the slides showing the pathology confirmed the diagnosis of lymphocytic oophoritis. Immunohistochemistry utilizing immunoperoxidase staining was used to characterize the nature of the lymphocytic infiltration. The infiltration consisted of T-cells, plasma cells and scattered aggregates of B-cells (Figure 1).
|
At age 29 years, she participated in a National Institute of Child Health and Human Development randomized, prospective, placebo-controlled trial of alternate-day prednisone for treatment of patients with histologically confirmed autoimmune ovarian failure. The protocol was approved by the National Institute of Child Health and Human Development Institutional Review Board. She received alternate day prednisone therapy for 16 weeks (mean daily dose of 11 mg, total cumulative dose of 1225 mg). During the prednisone treatment the patient resumed spontaneous menstrual bleeding six times and had ovulatory progesterone concentrations (>9.5 nmol/l) on four occasions. Her serum gonadotrophin concentrations decreased (Table I). Subsequently, the Pharmacy Department informed us that the patient had been randomized to take the active drug.
|
One month after stopping the dexamethasone treatment, the patient experienced right knee pain that was exacerbated by walking and other physical activity. The knee pain became severe and significantly altered her otherwise very active and athletic lifestyle. A magnetic resonance imaging scan of the right knee was consistent with osteonecrosis (i.e. non-traumatic necrosis of the bone) (Figure 2). Arthroscopy confirmed the diagnosis, showing areas of osteonecrosis involving ~30% of the medial femoral condyle and ~15% of the medial tibial plateau.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Ovarian biopsy is currently the only way to diagnose autoimmune premature ovarian failure with certainty. Nevertheless, there is no treatment proven effective by prospective, randomized, controlled study to restore fertility for these patients. Therefore, ovarian biopsy outside a controlled trial is not clinically indicated (Khastgir et al., 1994; Nelson et al., 1996
).
Young women with premature ovarian failure have intermittent ovarian follicle function (Rebar and Cedars, 1992; Nelson et al., 1994
) and nearly 20% of these women ovulate spontaneously during 4 months of observation (Nelson et al., 1994
). Spontaneous pregnancies have occurred after the diagnosis of premature ovarian failure (Polansky and DePapp, 1976
; Shangold et al., 1977
; Szlachter et al., 1979
; Aiman and Smentek, 1985
; Ohsawa et al., 1985
; Alper et al., 1986
; Kreiner et al., 1988
) and we have had patients who have ovulated after placebo treatment (Nelson et al., 1996
). Although autoimmune lymphocytic oophoritis is a known cause of premature ovarian failure, it is not known what proportion of women with premature ovarian failure develop the condition on an autoimmune basis. Indirect immunofluorescence using various sources of ovarian tissue (Damewood et al., 1986
; Ho et al., 1988
) and enzyme-linked immunosorbent assay (ELISA) (Luborsky et al., 1990
; Gobert et al., 1992
; Wheatcroft et al., 1994
; Fenichel et al., 1997
; Wheatcroft et al., 1997
) have been the most commonly used techniques to identify ovarian antibodies. The two methods used for the detection of ovarian antibodies, indirect immunofluorescence and ELISA, were compared, and neither was found to be reliable (Wheatcroft et al., 1997
). Also, using ELISA, it was found that these antibodies are frequently detected in Turner's syndrome and iatrogenic ovarian failure as well (Wheatcroft et al., 1994
). Furthermore, ovarian antibodies detected by this method are non-specific, as they cross-react with other antigens such as those in the Fallopian tube (Wheatcroft et al., 1994
). In addition, immunoblotting studies failed to reveal a consistent pattern of binding using the sera of patients with premature ovarian failure on two antigen preparations (Wheatcroft et al., 1997
).
Steroid cell antibodies have been identified in patients with premature ovarian failure associated with Addison's disease (Elder et al., 1981; Uibo et al., 1994
; Winqvist et al., 1995
). Nevertheless, steroid cell antibodies are not usually present in patients with isolated premature ovarian failure (Betterle et al., 1993
; Weetman, 1995
; Chen et al., 1996
).
Antibodies against membrane-bound receptors are known to cause diseases, such as myasthenia gravis (Lindstrom et al., 1976) and autoimmune hypothyroidism (Drexhage et al., 1981
). In addition, anti-FSH receptor antibodies, detected using animal systems, have been reported in a few patients with premature ovarian failure. We have found that immunoglobulin G (IgG) from patients with premature ovarian failure does not interfere with either the FSH-receptor or the LH-receptor interaction, using a recombinant system expressing human FSH and LH receptors (Anasti et al., 1995
).
Autoimmune lymphocytic oophoritis is characterized by a selective attack against only developing follicles with sparing of primordial follicles (Irvine et al., 1968; Sedmak et al., 1987
; Bannatyne et al., 1990
). In most cases follicle development progresses to the Graafian stage. Autoimmune lymphocytic oophoritis sometimes presents with markedly enlarged ovaries containing luteinized cysts, as illustrated by the first case and as previously reported (Rabinowe et al., 1986
).
The defect in immune regulation that leads to autoimmune premature ovarian failure is not understood. Although most autoimmune diseases, such as multiple sclerosis, diabetes, and rheumatoid arthritis, appear to be T helper 1 (Th1) cell mediated, experimental data suggests that some autoimmune diseases, such as murine autoimmune post-thymectomy oophoritis and murine autoimmune encephalomyelitis, may be Th2 cell mediated (Lafaille et al., 1997; Maity et al., 1997
). The recent identification of a single gene defect on chromosome 21q22.3 causing autoimmune polyglandular failure type 1 (Nagamine et al., 1997
; The FinnishGerman APECED Consortium, 1997
), which in many cases includes autoimmune ovarian failure, may provide a basis for gaining insight into immune regulation and organ specific autoimmunity.
Anecdotal reports have suggested that glucocorticoid treatment may restore ovarian function in women with premature ovarian failure (Cowchock et al., 1988; Taylor et al., 1989
; Luborsky et al., 1990
; Blumenfeld et al., 1993
; Corenblum et al., 1993
). There are presently no controlled studies, however, to tell us what proportion of women with autoimmune premature ovarian failure will ovulate in response to immune modulation therapy. More importantly, there are presently no controlled studies to tell us what proportion of women with autoimmune premature ovarian failure will have major complications in response to treatment with glucocorticoids. Glucocorticoid administration is the most frequent cause of osteonecrosis of the hip or knee (Mankin, 1992
). Pain is usually the presenting symptom of osteonecrosis, and the pain exacerbates with the use of the joint. The condition may be debilitating and require prosthetic hip or knee replacement (Mankin, 1992
). In fact, osteonecrosis accounts for ~50 000 joint replacements performed annually in the USA (Mankin, 1992
). Iatrogenic Cushing syndrome is also a well-known major sequela of chronic corticosteroid administration (Zizic et al., 1985
).
The efficacy of treatment modalities should be documented by randomized controlled trials (Grimes, 1995). A prospective randomized controlled study of alternate day prednisone therapy for autoimmune premature ovarian failure is now underway at the Clinical Center of the National Institutes of Health. This study will provide evidence for management decisions regarding patients with suspected autoimmune premature ovarian failure. In this study, since there is no diagnostic serum marker available, histological confirmation of the disease is a prerequisite for prednisone administration. We performed an ovarian biopsy when an antral follicle was detected on ultrasound in six patients with karyotypically normal spontaneous premature ovarian failure (Nelson et al., 1994
). Interestingly, we found no autoimmune oophoritis in any of these specimens (Nelson et al., 1994
).
The patient (case 1) presented in this case report did have histologically proven autoimmune oophoritis. While taking low-dose alternate day glucocorticoid treatment she had had return of menstrual bleeding six times and ovulatory progesterone concentrations four times over the 16 week period. Autoimmune premature ovarian failure is not a life threatening condition, so aggressive immunosuppression with glucocorticoids is not indicated. We developed our alternate day regimen dose with the objective of giving a dose that might have a beneficial effect yet be very unlikely to harm anyone. This case report suggests this regimen of prednisone given in an alternate day fashion might meet these objectives.
Identifying patients with autoimmune premature ovarian failure presents the opportunity to restore ovarian function by treating these patients with the proper immune modulation therapy. On the other hand, potent immune modulation therapy can have major complications. In our opinion, there is no role for empirical corticosteroid treatment of this disorder. There is need for an international collaborative research effort to make progress in this condition. In our view, immunosuppression by corticosteroids for the treatment of premature ovarian failure should be limited to patients with proven autoimmune oophoritis who are participating in placebo-controlled trials designed to determine safety and efficacy.
![]() |
Acknowledgments |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Alper, M.M., Jolly, E.E. and Garner, P.R. (1986) Pregnancies after premature ovarian failure. Obstet. Gynecol., 7, 5962.
Anasti, J.N., Flack, M.R., Froehlich, J. and Nelson, L.M. (1995) The use of human recombinant gonadotropin receptors to search for immunoglobulin G-mediated premature ovarian failure. J. Clin. Endocrinol. Metab., 80, 824828.[Abstract]
Bannatyne, P., Russell, P. and Shearman R.P. (1990) Autoimmune oophoritis: a clinicopathologic assessment of 12 cases. Int. J. Gynecol. Pathol., 9, 191207.[ISI][Medline]
Betterle, C., Rossi, A., Dalla-Pria, S. et al. (1993) Premature ovarian failure: autoimmunity and natural history. Clin. Endocrinol. (Oxf.), 39, 3543.[ISI][Medline]
Blumenfeld, Z., Halachmi, S., Peretz, B.A. et al. (1993) Premature ovarian failure: the prognostic application of autoimmunity on conception after ovulation induction. Fertil. Steril., 59, 750755.[ISI][Medline]
Chen, S., Sawicka, J., Betterle, C. et al. (1996) Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome, Addison's disease, and premature ovarian failure. J. Clin. Endocrinol. Metab., 81, 18711876.[Abstract]
Corenblum, B., Rowe, T. and Taylor, P.J. (1993) High-dose, short term glucocorticoids for the treatment of infertility resulting from premature ovarian failure. Fertil. Steril., 59, 988991.[ISI][Medline]
Coulam, C.B. and Ryan, R.J. (1979) Premature menopause. I: Etiology. Am. J. Obstet. Gynecol., 133, 639643.[ISI][Medline]
Coulam, C.B., Adamson, S.C. and Annegers, J.F. (1986) Incidence of premature ovarian failure. Obstet. Gynecol., 67, 604606.[Abstract]
Cowchock, F.S., McCabe, J.L. and Montgomery, B.B. (1988) Pregnancy after corticosteroid administration in premature ovarian failure (polyglandular endocrinopathy syndrome). Am. J. Obstet. Gynecol., 158, 118119.[ISI][Medline]
Damewood, M.D., Zacur, H.A., Hoffman, G.J. and Rock, J.A. (1986) Circulating antiovarian antibodies in premature ovarian failure. Obstet. Gynecol., 68, 850854.[Abstract]
Drexhage, H.A., Bottazzo, G.F., Bitensky, L. et al. (1981) Thyroid growth-blocking antibodies in primary myxoedema. Nature, 289, 594596.[ISI][Medline]
Elder, M., MacLaren, N. and Riley, W. (1981) Gonadal autoantibodies in patients in patients with hypogonadism and/or Addison's disease. J. Clin. Endocrinol. Metab., 52, 11371142.[Abstract]
Fenichel, P., Sosset, C., Barbarino-Monnier, P. et al. (1997) Prevalence, specificity and significance of ovarian antibodies during spontaneous premature ovarian failure. Hum. Reprod., 12, 26232628.[Abstract]
Gobert, B., Barbarino-Monnier, P., Guillet-May, F. et al. (1992) Anti-ovary antibodies after attempts at human in vitro fertilization induced by follicular puncture rather than hormonal stimulation. J. Reprod. Fertil., 96, 213218.[Abstract]
Grimes, D.A. (1995) Introducing evidence-based medicine into a department of obstetrics and gynecology. Obstet. Gynecol., 86, 451457.
Ho, P.C., Tang, G.W.K., Fu, K.H. et al. (1988) Immunologic studies in patients with premature ovarian failure. Obstet. Gynecol., 71, 622626.[Abstract]
Hoek, A., van Kasteren, Y., de Haan-Meulman, M. et al. (1995) Analysis of peripheral blood lymphocyte subsets, NK cells, and delayed type hypersensitivity skin test in patients with premature ovarian failure. Am. J. Reprod. Immunol., 33, 495502.[ISI][Medline]
Hoek, A., Schoemaker, J. and Drexhage, H.A. (1997) Premature ovarian failure and ovarian autoimmunity. Endocr. Rev., 18, 107134.
Irvine, W.J., Chan, M.M.W., Scarth, L. et al. (1968) Immunological aspects of premature ovarian failure associated with idiopathic Addison's disease. Lancet, ii, 883890.
Jackson, R.A., Morris, M.A., Haynes, B.F. and Eisenbarth, G.S. (1982) Increased circulating Ia antigen-bearing T cells in type I diabetes mellitus. N. Engl. J. Med., 306, 785788.[ISI][Medline]
Jackson, R.A., Haynes, B.F., Burch, W.M. et al. (1984) Ia +T cells in new onset Grave's disease. J. Clin. Endocrinol. Metab., 59, 187190.[Abstract]
Khastgir, G., Abdalla, H. and Studd, J.W.W. (1994) The case against ovarian biopsy for the diagnosis of premature menopause. Br. J. Obstet. Gynaecol., 101, 9698.[ISI][Medline]
Kreiner, D., Droesch, K., Navot, D. et al. (1988) Spontaneous and pharmacologically induced remissions in patients with premature ovarian failure. Obstet. Gynecol., 73, 926928.
Lafaille, J.J., Keere, F.V., Hsu, A.L. et al. (1997) Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease. J. Exp. Med., 186, 307312.
Lindstrom, J.M., Seybold, M.E., Lennon, V.A. et al. (1976) Antibody to acetylcholine receptor in myasthenia gravis. Neurology, 26, 10541059.[Abstract]
Luborsky, J.L., Visintin, I., Boyers, S. et al. (1990) Ovarian antibodies detected by immobilized antigen immunoassay in patients with premature ovarian failure. J. Clin. Endocrinol. Metab., 70, 6975.[Abstract]
Maity, R., Caspi, R.R., Nair, S. et al. (1997) Murine post-thymectomy autoimmune oophoritis develops in association with a persistent neonatal-like Th2 response. Clin. Immunol. Immunopathol., 83, 230236.[ISI][Medline]
Mankin, H.J. (1992) Nontraumatic necrosis of bone (osteonecrosis). N. Engl. J. Med., 326, 14731479.[ISI][Medline]
Muir, A. and MacLaren, N.K. (1991) Autoimmune diseases of the adrenal glands, parathyroid glands, gonads, and hypothalamicpituitary axis. Endocrinol. Metab. Clin. N. Am., 20, 619644.[ISI][Medline]
Nagamine, K., Peterson, P. and Scott, H.S. (1997) Positional cloning of the APECED gene. Nature Genet., 17, 393398.[ISI][Medline]
Nelson, L.M., Kimzey, L.M., Merriam, G.R. and Fleisher, T.A. (1991) Increased peripheral T lymphocyte activation in patients with karyotypically normal spontaneous premature ovarian failure. Fertil. Steril., 55, 10821087.[ISI][Medline]
Nelson, L.M., Anasti, J.N., Kimzey, L.M. et al. (1994) Development of luteinized graafian follicles in patients with karyotypically normal spontaneous premature ovarian failure. J. Clin. Endocrinol. Metab., 79, 14701475.[Abstract]
Nelson, L.M., Anasti, J.N. and Flack, M.R. (1996) Premature ovarian failure. In Adashi, E.Y., Rock, J.A. and Rozenwaks, Z. (eds), Reproductive Endocrinology, Surgery, and Technology. Lippincott-Raven, Philadelphia, pp. 13941410.
Ohsawa, M., Wu, M.C., Masahashi, T. et al. (1985) Cyclic therapy resulted in pregnancy in premature ovarian failure. Obstet. Gynecol., 66, 6467.
Pekonen, F., Siegberg, R., Makinen, T. et al. (1986) Immunological disturbances in patients with premature ovarian failure. Clin. Endocrinol. (Oxf.), 25, 16.[ISI][Medline]
Polansky, S. and DePapp, E.W. (1976) Pregnancy associated with hypergonadotropic hypogonadism. Obstet. Gynecol., 47, 4751.
Rabinowe, S.L., Jackson, R.A., Dluhy, R.G. and Williams, G.H. (1984) Ia +T lymphocytes in recently diagnosed idiopathic Addison's disease. Am. J. Med., 77, 597601.[ISI][Medline]
Rabinowe, S.L., Berger, M.J., Welch, W.R. and Dluhy, R.G. (1986) Lymphocyte dysfunction in autoimmune oophoritis. Resumption of menses with corticosteroids. Am. J. Med., 81, 347350.[ISI][Medline]
Rebar, R.W. and Cedars, M.I. (1992) Hypergonadotrophic forms of amenorrhea in young women. Endocrinol. Metab. Clin. N. Am., 21, 173191.[ISI][Medline]
Sedmak, D.D., Hart, W.R. and Tubbs, R.R. (1987) Autoimmune oophoritis: a histopathologic study of involved ovaries with immunologic characterization of the mononuclear cell infiltrate. Int. J. Gynecol. Pathol., 6, 7381.[ISI][Medline]
Shangold, M.M., Turksou, R.N., Bashford, R.A. et al. (1977) Pregnancy following the `insensitive ovary syndrome'. Fertil. Steril., 28, 11791181.[ISI][Medline]
Szlachter, B.N., Nachtigall, L.E., Epstein, J. et al. (1979) Premature ovarian failure: a reversible entity? Obstet. Gynecol., 54, 396398.[Abstract]
Taylor, R., Smith, N.M., Angus, B. et al. (1989) Return of fertility after twelve years of autoimmune ovarian failure. Clin. Endocrinol., 31, 305308.[ISI][Medline]
The FinnishGerman APECED Consortium (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nature Genet., 17, 399403.[ISI][Medline]
Uibo, R., Aavik, E., Peterson, P. et al. (1994) Autoantibodies to cytochrome P450 enzymes P450scc, P450c17, and P450c21 in autoimmune polyglandular disease types I and II and in isolated Addison's disease. J. Clin. Endocrinol. Metab., 78, 323328.[Abstract]
Weetman, A.P. (1995) Autoimmunity to steroid-producing cells and familial polyendocrine autoimmunity. Bailliere's Clin. Endocrinol. Metab. 9, 157174.
Weetman, A.P. and McGregor, A.M. (1994) Autoimmune thyroid disease: Further developments in our understanding. Endocr. Rev., 15, 788830.[Abstract]
Wheatcroft, N.J., Toogood, A.A., Li, T.C. et al. (1994) Detection of antibodies to ovarian antigens in women with premature ovarian failure. Clin. Exp. Immunol., 96, 122128.[ISI][Medline]
Wheatcroft, N.J., Salt, C., Ward-Milford, A. et al. (1997) Identification of ovarian antibodies by immunofluorescence, enzyme-linked immunosorbent assay or immunoblotting in premature ovarian failure. Hum. Reprod., 12, 26172622.[Abstract]
Winqvist, O., Gebre-Medhin, G., Gustafsson, J. et al. (1995) Identification of the main gonadal autoantigens in patients with adrenal insufficiency and associated ovarian failure. J. Clin. Endocrinol. Metab., 80, 17171723.[Abstract]
Zizic, T.M., Marcoux, C., Hungerford, D.S. et al. (1985) Corticosteroid therapy associated with ischemic necrosis of bone in systemic lupus erythematosus. Am. J. Med., 79, 596604.[ISI][Medline]
Submitted on October 20, 1998; accepted on March 12, 1999.