JOURNAL OF PATHOLOGY, VOL.
167: 357-363 (1992)
REVIEW ARTICLE
THE PATHOLOGY OF PREMATURE OVARIAN FAILURE HAROLD FOX
Department of Pathological Sciences, University of Manchester, Manchester. U.K.
INTRODUCTION
AFOLLICULAR OVARIAN FAILURE
Ovarian failure is usually a physiological event with a well-defined associated clinical picturenamely, the menopause. Premature ovarian failure is therefore often assumed simply to represent one extreme of a temporal spectrum and hence has been the subject of comparative neglect by pathologists. Premature ovarian failure may be secondary to hypothalamic or pituitary disease (hypogonadotrophic hypogonadism) or may be due to a primary ovarian unresponsiveness to gonadotrophins (hypergonadotrophic hypogonadism). This review is concerned only with the latter form of premature ovarian failure, a condition which may be defined as 'secondary amenorrhoea with persistently raised gonadotrophin levels before the age of 35 years'.' Within this definition there are two subsets of patients. In one, there has been a true premature menopause with a total depletion of ovarian follicles and hence a presumed permanent loss of ovarian function; in the other, follicular structures are still present and a clear possibility of either spontaneous or induced return of ovarian functional activity exists.''2 A histological separation into follicular and afollicular types of hypergonadotrophic premature ovarian failure therefore seems logical, though it has to be admitted that some of the known aetiological factors, such as galactosaemia and blepherophimosis, fit uneasily into this framework and straddle the histological divide: this suggests that some cases of ovarian failure that were originally of follicular type may progress to an afollicular stage.
Chromosomal abnormalities Phenotypic females with an XO monosomy have usually lost all their ova long before the expected age of puberty but about 3 per cent of non-mosaic patients retain sufficient ova to have a short period of normal gonadal activity3-' followed by a very early menopause. A relatively brief period of normal ovarian function also occurs in about 12 per cent of individuals with an XOjXX mosaic chromosomal constit~tion."~ Premature ovarian failure occurs unduly frequently in women with a 46,XX karotype and partial deletion of one X chromosome,''-'2 such cases being sometimes familial,13 and in those with polysomy of the X chromosome (the triple X s y n d r ~ m e ) . ' ~ ? ' ~
Addressee for correspondence: Professor H. Fox, Department of Pathological Sciences, Stopford Building, University of Manchester, Manchester M I 3 9PY, U.K.
0022-341 7/92/080357-07 $08.50 0 1992 by John Wiley & Sons, Ltd
Radiution injury Irradiation of the ovaries may destroy their content of ova, with the ovaries of older women being much more sensitive than those of their younger counterparts; the gonads of prepubertal girls are particularly resistant to irradiation.'"'' Radiation damage may cause either temporary or permanent amenorrhoea but a return of normal menstruation does not necessarily mean that the ovaries have escaped permanent damage, this often only becoming apparent years later as premature ovarian failure. Ovaries severely damaged by radiation show loss of primordial and developing follicles, fibrosis and hyalinization of the stroma, and vascular sclerosis with retention of hilar cell^;^'-^^ the formation of decidua-like tissue in the superficial cortex has, somewhat surprisingly, been occasionally noted.23
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Cherno therapy Ovarian failure may complicate the use of either multiple or single agent chemotherapy and, as with radiotherapy, the ovaries of older women appear to be much more susceptible to cytotoxic druginduced damage than those of younger women or children,17.19,26?6 As with radiotherapy, the return of normal menses after a temporary period of druginduced amenorrhoea may conceal covert ovarian damage which later becomes overt as a premature menopause. Histological studies of chemotherapy-damaged ovaries have generally revealed capsular thickening, cortical stromal fibrosis, and either loss of follicles or arrest of follicular maturation.27-" Infection The ovaries are remarkably resistant to infection but it is thought that about 10 per cent of women suffering from mumps develop a diffuse oophoritis and that this may, in an unidentified proportion of cases, result in a premature menopause.32 Histological examination of healed cases of mumps oophoritis has shown ovarian atrophy and fibrosis with loss of follicular structure^.^^
Mucopolysaccharidosis An association between this disorder and premature ovarian failure has been r e p ~ r t e d , this ~ ' being a result of premature oocyte depletion which has been attributed, perhaps rather simplistically, to an accumulation of toxic substances within the ovary. Blepharophirnosis Patients with this syndrome have a high incidence of menstrual irregularities and the condition appears, on admittedly scanty evidence, to be associated with hypergonadotrophic premature ovarian failure.44 Ovarian biopsy in two such patients showed a resistant ovary appearance in one, and a premature menopause, characterized by follicular depletion, in the other.' Autoimmune oophoritis It is likely that some cases of afollicular premature ovarian failure represent 'end stage' or 'burnt out' autoimmune oophoritis, a point discussed below.
Idiopathic Galactosaemia Women with galactosaemia have a high incidence of premature ovarian failure which appears to occur despite adequate dietary control, from infancy, of the metabolic a b r ~ o r m a l i t y . ~The ~ - ~ovar~ ian damage has been attributed to a toxic effect of galactose, or one of its metabolites, on follicular structures during fetal life,36337 but it has also been suggested that carbohydrate residues on gonadotrophin molecules may be altered in such a way as to render them biologically i n a ~ t i v e . ~Experimental '.~~ studies on rats have shown that high maternal galactose levels inhibit the migration of embryonic germ cells to the gonadal ridge;40this may well be relevant to the human disorder. The few reported studies of ovarian histology in galactosaemia complicated by premature gonadal failure have usually described follicular dep l e t i ~ n . ~However, ',~~ in one report of two sisters with galactosaemia and premature ovarian failure, ovarian biopsy in the younger sibling showed an appearance consistent with the resistant ovary syndrome (see below) whilst the ovary of the elder sister showed follicular depleti~n,~' this suggesting that a phase of follicular resistance may precede follicular loss.
This is, to a considerable extent, a diagnosis of exclusion, hypergonadotrophic premature ovarian failure of afollicular type occurring in a chromosomally normal woman with no history of mumps, with no evidence of any other disease process, with no history of exposure to radiation or cytotoxic drugs, and lacking anti-ovarian antibodies. A proportion of these cases appear to be familial, possibly with an autosomal dominant sex-linked inheritan~e,~ whilst ~ ~ ' there is an association between premature ovarian failure and HLA-DR3.49 Idiopathic premature menopause of afollicular type could be due to either a primary paucity of germ cells or an increased rate of attrition of a normal complement of ovarian germ cells. Mathematical modelling has suggested that increased attrition is the predominant mechanism,48but some of these patients may, nevertheless, represent the human equivalent of the Wx/W" strain of mice in which, because of a genetically determined defect in the migration of embryonal cells, there is decreased migration of germ cells from the yolk sac and developing foregut to the gonadal anlage.50 Before accepting too enthusiastically this genetically determined failure of cell migration as a model for human disease, it has to be borne in mind that, as a result
OVARIAN FAILURE
of this defect, there is a high incidence of sex cord stromal tumours in W"/W" mice,5' a feature absent in women with premature ovarian failure. If an increased rate of follicular atresia is indeed the key factor in most cases of afollicular premature ovarian failure, then what is the basic mechanism for this accelerated loss? Experimental studies have indicated that pituitary gonadotrophins play an important role in ovarian follicular retenti01-1,~~ and it has been suggested that accelerated follicular atresia in women may be due to the secretion of abnormal forms of gonadotrophins with reduced biological activity;39 evidence to support this hypothesis is, however, currently lacking. An alternative view is one based on the increasing evidence that cytokines are involved in both follicular development and follicular a t r e ~ i a The . ~ ~ normal process of follicular atresia is thought to be initiated by interferon gamma, which is secreted both by ovarian resident macrophages and by follicular granulosa cells;54interferon stimulates the granulosa cells to express MHC antigens55with subsequent activation of T lymphocytes to produce interleukin-1 . This, in turn, activates resident ovarian macrophages to secrete cytokines involved in ovarian follicular atresia, such as transforming growth factor beta, tumour necrosis factor alpha, fibrocyte growth factor, interleukin- 1, and interferon It is therefore postulated that accelerated follicular atresia may be due to increased interferon gamma production as a result of viral infection, other environmental factors, or genetic p r e d i s p ~ s i t i o ncyto,~~ kines being released continuously rather than intermittently and follicular attrition being increased. The ovaries in cases of idiopathic afollicular premature ovarian failure are usually small and without macroscopically visible follicles. Histologically, the cortical stroma is hypercellular and devoid of follicular structures; atretic follicles and corpora albicantes may, however, be pre~ent.'.~' Small foci of chronic inflammatory cells, unrelated to follicular remnants, are sometimes present and are thought by some to represent the residue of a previous autoimmune oophoritis. FOLLICULAR OVARIAN FAILURE
Resident ovary syndrome This is characterized by high levels of pituitary gonadotrophins, numerous primordial follicles in an ovarian biopsy, and insensitivity of the ovaries to stimulation by exogenous gonadotrophin^.'^^^
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Women with this condition may complain of primary amenorrhoea but 60 per cent present with secondary amenorrhoea, usually during their third decade. I The ovaries are usually macroscopically normal in the resistant ovary syndrome, though some are unduly small. The cortical stroma appears dense and fibrotic, and numerous primordial follicles are present; most show no evidence of development but a few will have attained the pre-antral stage and occasional follicles will have developed to, but not beyond, the antral stage. Some follicles may show focal or diffuse hyaline change23 whilst atypical follicles, bearing some resemblance to the cell nests seen in the sex cord tumour with annular tubules, may be e n ~ o u n t e r e d . ' . In ~ ~ cases of secondary amenorrhoea, stigmata of previous ovulation are usually present. The resistant ovary syndrome is almost certainly a heterogeneous condition, some cases. for example, being associated with galactosaemia or blepharophimosis. Other possible causes include the secretion of an abnormal form of follicle-stimulating hormone (FSH), a FSH receptor defect, and an autoimmune disease with the production ofanti-FSH receptor antibodies.71All studies of FSH in this condition have shown this hormone to be normal, and the failure of the ovaries to respond to exogenous gonadotrophins also argues against a primary abnormality in the FSH m o l e c ~ l e . A ~ ~belief , ~ ~ that the resistant ovary syndrome is due to an absolute or relative deficiency of FSH receptor is one which has often been rnooted7*~"but never specifically tested. Other hypotheses include a post-receptor defect, such as a failure of the gonadotrophin-receptor complex to activate adenylate c y c l a ~ eor~ ~a functionally abnormal FSH r e ~ e p t o r . ~The ' possibility of an immunological basis for this syndrome has been raised by the description of women with both myasthenia gravis and hypergonadotrophic ovarian failure who had a substance in their serum which inhibited in vitro binding of FSH to its receptor;74 this concept has been bolstered by a report of a patient with systemic lupus erythematosus and resistant ovary syndrome who had a serum antibody specifically directed against the FSH receptor." Further, in some patients with the resistant ovary syndrome an IgG antibody is present which, in an in vitro system, blocks FSH-induced DNA synthesis by granulosa cells.76 A final, and perhaps rather negative, view is that the resistant ovary syndrome simply represents an accentuation of the perimenopausal relative gonadotrophin resistance which
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occurs as a physiological event in the near-terminal stages of foIIicuIar Ovarian resistance may be relative rather than a b ~ o l u t e and ~ ~ ?temporary ~~ rather than permanent,69'77and a return to normal ovarian function has been noted in some patients treated by oestrohigh doses of gonadotrophins," or corticosteroids.82 Autoimmune oophoritis Views on autoimmune oophoritis as a specific clinicopathological entity capable of causing premature ovarian failure are currently polarized between those who consider that 'the existence of autoimmune ovarian disease has not been formally e~tablished''~and those who regard such an immunological disorder as a major factor in hypergonadotrophic h y p o g o n a d i ~ r n . ~ ~ . ~ ~ ~ ~ Despite this conflict of views, there is one clearly defined form of autoimmune oophoritis that can, and does, cause hypergonadotrophic premature ovarian failure. A proportion of women with autoimmune adrenal failure also suffer premature ovarian failure: such patients have circulating antisteroid cell antibodies which are directed against the steroid-synthesizing cells of the adrenal cortex and cross-react with steroid-synthesizing cells of the ovary." 93 These anti-steroid cell antibodies are of the IgG type and localize within the ovary to the hilar cells, the cells of the developing follicle, and to the thecal cells of the corpus l u t e ~ m .They ~ ~ ,show ~~ complement-dependent cytotoxicity to granulosa cells in culturey5and are associated with histological evidence of an oophoritis (see below); whether this oophoritis is antibody-mediated or whether it results from an antibody-dependent cell mediated cytotoxicity is a moot point which is discussed below. Autoimmune oophoritis associated with autoimmune adrenalitis is a clear-cut clinical and immunological entity which can, quite legitimately, be extended to include patients with a polyendocrinopathy in which both ovarian and adrenal failure are and, perhaps more debatably, to cases of premature ovarian failure in which there are circulating anti-adrenal antibodies but no clinical evidence of adrenal failure.y9 More controversial is the question of whether a true autoimmune oophoritis occurs which is independent of anti-adrenal antibodies and which develops either in association with other autoimmune disorders or in isolation. The literature on
this topic is extremely confusing partly because a clear distinction has not always been drawn between antibodies directed against the FSH receptor and those directed against follicular components, partly because of lack of rigour in the exclusion of epiphenomenal anti-ovarian antibodies, and partly because it has commonly been assumed that premature ovarian failure occurring in a woman with a presumed autoimmune disease is itself due to an autoimmune process. Many reported cases of presumed autoimmune oophoritis occurring in patients with such conditions as hypothyroidism, hypoparathyroidism, rheumatoid arthritis, or pernicious anaemia80.98, 100-103 have lacked demonstrable antiovarian antibodies, have had no lymphocytic infiltrate of their ovaries, and appear to have been examples of non-immunological premature menopause occurring coincidentally in a patient with an autoimmune disorder. A further cause of confusion is the fact that the mere presence of anti-ovarian antibodies does not necessarily imply a diagnosis of autoimmune disease, for such antibodies have been detected in cases of Addison's disease due to t u b e r c ~ l o s i s ; ' ~in~ association with neoplastic lesions of the endometrium, kidney, and bladder;Io5 in women with inflammatory or neoplastic disease of the ovary;Io6 and in patients with XO gonadal dysgenesi~.'~'Such antibodies have not been shown to be complementbinding or cytotoxic to ovarian cells in culture and are clearly epiphenomenal. It is in the context of these findings that claims of a high incidence of antiovarian antibodies, not cross-reacting with adrenal steroid-synthesizing cells, in cases of premature m e n o p a ~ s e ~have ~ . ' ~to be evaluated. It is probable therefore that, with one exception, the diagnosis of autoimmune premature ovarian failure should be restricted to cases in which antiadrenal-steroid cell antibodies are present. The one exception is those rare cases of chronic mucocutaneous candidiasis and chronic vaginal candidiasis in which anti-Candida antibodies that cross-react with ovarian follicular cells develop and cause an autoimmune oophoritis with ovarian failure. 'O8.'O9 The ovaries from women with an autoimmune oophoritis may be enlarged, sometimes with cystic change, 1.1 10,Il I or of normal size. Histological examination',' l4 shows a mononuclear chronic inflammatory cell infiltrate around developing and atretic follicles with complete sparing of primordial follicles. In the earlier lesions the infiltrate is principally in the thecal layer of the follicles, but in
36 1
O V A R I A N FAILURE
more advanced lesions the granulosa cell layer is also infiltrated and many of the follicular cells show degenerative changes. The inflammatory infiltrate does not extend into the stroma to any extent from the perifollicular areas, though a hilar infiltrate, presumably related to hilar cells, may be present. Perifollicular granulomata have been described in one case of autoimmune oophoritis,”4whilst abnormal follicles, similar to those seen in the resistant ovary syndrome, may be present. Immunocytochemical stainingiI3 identifies the cells in the infiltrate as polyclonal B cells, T4- and TR-positive lymphocytes (with a predominance of the former), macrophages, and occasional NK cells. The overall appearances are suggestive of an antibody-dependent cell-mediated cytotoxicity.
OVARIAN BIOPSY IN PREMATURE OVARIAN FAILURE Ovarian biopsy is still commonly undertaken in cases of premature ovarian failure with the aim of distinguishing between apparently irreversible and potentially reversible loss of ovarian function, i.e., between follicular and afollicular groups. The pathologist can readily make this distinction but should refrain from commenting on the permanency or otherwise of the patient’s loss of reproductive capacity. The histological sections from an average ovarian biopsy comprise only 0.1 5 per cent of an ovary of normal size”’ and the absence of follicles from this tissue does not necessarily mean that the ovary is totally depleted of primordial follicles, a fact emphasized by reports of subsequent pregnancies occurring in women whose ovaries had showed no oocytes in a biopsy ~ p e c i m e n . ~This, ~.”~ together with the fact that both follicular and afollicular types of premature ovarian failure require treatment with oestrogens, suggests that ovarian biopsy is not only unnecessary in cases of premature ovarian failure, but may also give misleading, albeit histologically accurate, results. It can be argued that ovarian biopsy is necessary to identify those cases of premature ovarian failure due to an autoimmune oophoritis, for such women may respond well to corticosteroid or immunosuppressive therapy with a return of normal ovarian f ~ n c t i o n . ”The ~ diagnosis of an autoimmune oophoritis should, however, rest principally on serological findings, as is the case with autoimmune organ disease elsewhere in the body, e.g., autoimmune thyroiditis.
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53. Coulam CB, Stern JJ. Immunology of ovarian failure. Am J Reprod Immuno/1991;2 5 169-174. 54. Grass0 G, Muscettola M, Traina V, el a/. Presence of interferons in human follicular fluid after ovarian hyperstimulation for in vitro fertilization. MetlSci Res 1988; 1 6 167-168. 55. Hill JA, Welch WR, Faris HMP, Anderson DJ. Induction of class II major histocompatibility complex antigen expression in human granulosa cells by interferon gamma: a potential mechanism contributing to autoimmune ovarian failaure. Am J Ohsrer Gynecol 1990;162: 534-540. 56 Gotishall PE, Uehara A. Hoffman S, Arimura A. Interleukin-1 inhibits follicle stimulating hormone-induced differentiation of porcine granulosa cells in vitro. Biochem Biophys Res Commun 1987; 1 4 9 502-509. 57 Fukuoka M, Mori T, Taii S, Yasuda K. Interleukin-l inhibits luteiniration of porcine granulosa cells in culture. Endocrin0log.v 1988: 122:367 369 58. Adashi DY. Resnick CE. Antagonistic interactions of transforming growth factors in the regulation of granulosa cell differentiation. Endocrinology 1986;1 1 9 1878-1881 59. Gorospe WC, Tuchel T, Kasson BG. Interferon inhibits rat S granulosa cell differentiation in culture. Biochem B I O P ~ VRes Commun 1988;157:891-897. 60. Channing CP, Garett R, Kroman N , Conn T, Gospodarowicz D . Ability of EGF and F G F to cause a decrease in progesterone secretion by cultured porcine granulosacells: changes in responsiveness throughout follicular maturation. In: Greenwald GS, Terranova PF, eds. Factors Regulating Ovarian Function. New York: Raven Press, 1983: 215 220. 61. Roby RF, Terranova PF. Tumor necrosis factor alpha alters follicular steroidogenesis in v i m . Endocrinology 1988;123: 2952-2954. 62. Emoto N, Baird A. The effect of tumor necrosis factoricachectin on follicle-stimulating hormone-induced aromatase activity in cultured rat granulosa cells. Biochem Biophys Res Commun 1988; 153:792-798. 63. Darhon JM, Oury F , Lardo J, Bayard F. Tumor necrosis factor inhibits follicle-stimulating hormone-induced differentiation in cultured rat granulosa cells. Biocheni Biophys Res Commun 1989; 1 6 3 1038 1045. 64. Jones GS, Moraes-Ruehesen MD. A new syndrome of amenorrhea in association with hypergonadotropism and apparently normal ovarian follicular apparatus. Am J Ohstet G,vnecol 1969; 104 597-600. 65. Zourlas PA. Comninos AC. Primary amenorrhea with normally developed secondary sex characteristics Obsrer Gynecol I971 ; 38: 298-303.
66. Starup J, Sele V, Hendriksen B. Amenorrhea associated with increased production of gonadotropins and a morphologically normal ovarian follicular apparatus. Acta Endocrinol 1971:66:246-256. 67. van Campenhout J, Vauclair R, Maraghi K. Gonadotropin-resistant ovaries in primary amenorrhea. Ohstet Gyneco/ 1972:4 0 6-12. 68. Kim MH. Gonadotropin resistant ovaries syndrome in association with secondary amenorrhea. Am JObstet Gynecol1974;120 257-262. 69. Dewhurst CJ, DeKoos EB, Ferreira HP. The resistant ovary syndrome. Br J Ohsret Gynrrecoi 1975;82 341-345. 70. Koninckx PR, Brosens IA. The gonadotropin resistant syndrome as a cause of secondary amenorrhea and infertility. Ferril Sreril 1977; 28: 926-93 I. 71. Maxson WS, Wentr AC. The gonadotropin resistant ovary syndrome. Semin ReprodEndocrinol1983; 1: 147-160. 72. Veroeven GFM, Wilson JD. The syndromes of primary hormone resistance. Prog Endocrinol Merab 1979;28: 253-289. 73. Talbert LM, Raj M H G , Hammond MG, Greer T. Endocrine and immunologic studies in a patient with resistant ovary syndrome. Fertil Steril 1984;45: 741-744. 74. Escobar ME, Cigorraga SB, Chiauzzu VA, Charreau EH, Rivarola MA. Development of the gonadotrophic resistant ovary syndrome in myasthenia gravis: suggestion of similar autoimmune mechanisms. Acra Endouinol 1982;9 9 431-436. 75. Case Records of the Massachusetts General Hospital: Case 4 6 1986.New EnglJ Mer/1986;3151336-1343. 76. van Weissenbruch MM, Hoek A, van Vliet-Bleeker 1, Schoemaker J, Drexhage HAD. Evidence for existence of immunoglobulins that
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block ovarian granulosa cell growth in virro: a putative role in resistant ovary syndrome? J Clin Endocrinol Merah 1991: 13: 360-367. Shangold M M , Turksoy RN, Bashford RA, Hammond CB. Pregnancy following the ‘insensitive ovary’ syndrome. Ferril SrerI” 1977; 2 8 1179-1181. Evers JLH, Rolland R. The gonadotrophin resistant ovary syndrome: a curable disease? Clin Endocrinol 1981: 14: 99-103. Lim HT, Meinders AE, de Haan LD, Bronkhorst FB. Anovulation presumably due to the gonadotrophin-resistant ovary syndrome. Eur J Obsrer Gynecol Reprod B i d 1984: 1 6 327-377. Alper MM, Garner PR. Premature ovarian failure: its relationship to autoimmune disease. Obsrer Gynecol1985; 6 6 27-30. Friedman CI, Barrows H, Kim MH. Hypergonadotropic hypogonadism. Am JOhsrer Gynecol1983: 145: 360-372. Meldrum D R , Frumar AM, Shamonki IM, Benirschke K, Judd HL. Ovarian and adrenal steroidogenesis in a patient with gonadotropinresistant ovaries and hilus cell hyperplasia. Obsrer Gynecul 1980; 5 6 216-221. Tung KSK, Lu CY. Immunologic basis of reproductive failure. In: Kraus FT, Damjanov I, Kaufman N, eds. Pathology of Reproductive Failure. Baltimore: Williams & Wilkins, 1991; 309-333. Coulam C C, Ryan R. Premature menopause. I. Etiology. Am J Ohsrer Gynecol1979; 133 639-643. Coulam C, Kempers RD, Randall RV. Premature ovarian failure: evidence for an autoimmune mechanism. Fertil Steril1981: 36: 238-240. Coulam C, Ryan R. Prevalence ofcirculating antibodies directed to ovaries among women with premature ovarian failure. Am J Reprod lmmunol1985; 9 23-24. Damewood M, Zacur H, Hoffman G , Rock J. Circulating antiovarian antibodies in premature ovarian failure. Ohsrer Gynecol 1986: 68:850-854. Pekonen F, Siegberg R, Makinen T, Miettinen A, YIi-Korkala 0. Immunological disturbances in patients with premature ovarian failure. Clin Endocrinol 19x6; 2 5 1-6. Ho PC, Tang G W , Fu KH, Fan MC, Lawton JW. Immunologic studies in patients with premature ovarian failure. Ohsrer Gynecol 1988; 71: 622-626. Cohen 1, Speroff L. Premature ovarian failure: update. Obsrer GynecolSurv 1991;46 156-162. Irvine WJ, Chan MW, Scarth L, er al. Immunological aspects of premature ovarian failure associated with idiopathic Addison’s disease. Lancer 1968; 2 883-887. Irvine WJ, Chan MW, Scarth L. The further characterization of autoantihodies reactive with extra-adrenal steroid-producing cells in patients with adrenal disorders. Clin Exp Immunoll969: 4 489-503. Irvine WJ, Barn EW. Addison’s disease, ovarian failure and hypoparathyroidism. Clin Endocrinol Merah 1975; 4 379-434. Sotsiou F, Bottazzo G F , Donniach D. Immunofluorescence studies of autoantibodies in steroid-producing cells, and to germ cell lines in endocrine disease and infertility. Clin Exp Immunol1980; 3 9 97-1 1 1. McNatty KP, Short RV, Barnes EW, Irvine WJ. The cytotoxic effect of serum from patients with Addison’s disease on human granulosa cells in culture. Clin Exp Immunol 1975: 2 2 378-384. Golonka JE, Goodman AD. Coexistence of primary ovarian insufficiency, primary adrenocortical insufficiency and idiopathic hypoparathyroidism. J CIin Endocrinol Merah 1968; 2 8 78-82.
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97. Edmonds M, Lanki L, Killinger DW, Volpe R. Autoimmune thyroiditis, adrenalitis and oophoritis. Am J Med 1973: 5 4 782-787. 98. Vasquez AM, Kenney FM. Ovarian failure and antiovarian antibodies in association with hypoparatbyroidism, moniliasis and Addison’s and Hashimoto’s disease. Obsret Gjwecol 1973: 41: 414-418. 99. Coulam C. The prevalence of autoimmune disorders among patients with primary ovarian failure. Am J Reprod Immunol1983; 4 63-66. 100. Kleerekoper M, Basten A, Panny R, Rosen S. Idiopathic hypoparathyroidism with primary ovarian failure. Arch lnlern Med 1974; 134: 944-947. 101. Ayala A, Canales ES, Karchmer S, Alarcon D, Zarate A. Premature ovarian failure and hypothyroidism associated with sicca syndrome. Ohsrer Gynecol1979: 5 3 98s-101s. 102. Collen RJ, Lippe BM, Kaplan SA. Ovarian failure, juvenile rheumatoid arthritis and vitiligo. Am JDi.7 Child 1979: 136 353-356. 103. Wolffenbuttel BHR, Weber RFA, Prins MEF, Verschoor L. Premature ovarian failure and autoimmune hypothyroidism in the absence of Addison’s disease. Nerh J Med 1987; 3 0 128-1 34. 104. Kamp P, Platz P, Nerup J. ‘Steroid cell’ antibody in Addison’s disease. Acra Endocrinol1974: 16 729-740. 105. Forbes AP, Luke JR, Block KG. Clinical significance of antibodies to ovarian antigens associated with cancer of the urogenital tract. Clin Exp lmmunol1976: 2 3 436-443. 106. Zbroja-Sontag W, Sikorski R , Kadel E. Antibodies to ovarian antigensin different diseases oftheovary. Am J Reprodlmmunul1982: 2 58-63. 107. Mathur S, Jerath PS, Mather PS, Williamson HO, Fudenberg HH. Serum immunoglobulin levels, autoimmunity and cell mediated immunity in primary ovarian failure. J Reprod Immunol 1980; 2 83-92. 108. Mathur S, Melchers JT, Ades EW, Williamson HO. Fudenburg HH. Antiovarian and antilymphocyte antibodies in patients with chronic vaginal candidiasis. J Reprod ImmunolI980: 2: 247-262. 109. Dempsey AT, de Swiet M, Dewhurst J. Premature ovarian failure associated with the candida endocrinopathy syndrome. Br J Ohsrer Gynaecol1981; 8 8 776-777. 110. Friedman C1, Gurgen-Varol F, Lucas J, Neff J. Persistent progesterone production associated with autoimmune oophoritis-a case report. J Reprod Med 1987: 3 2 293-296. 1 1 1. Biscotti CV, Hart WR, Lucas JG. Cystic ovarian enlargement resulting from autoimmune oophoritis. Obsier Gvnecol 1989: 7 4 492-495. 112. Gloor E. Hurlimann J. Autoimmune oophoritis. Am J Clin Pathol 1984: 81: 105-109. 113. Sedmak DD, Hart WR, Tubbs RR. Autoimmune oophoritis: a histopathologic study of involved ovaries with immunologic characterization of the mononuclear cell infiltrate. Inr J Gynccol Parhol 1987; 6 73-81. 114. Bannatyne P, Russel P, Shearman RP. Autoimmune oophoritis: a clinicopathologic assessment of 12 cases. In1 J Gynecol Pathol 1990; 9 191-207. 115. Aiman J , Smentek C. Premature ovarian failure. Ohsrer Gynecol 1985; 6 6 9-14.
167: 357-363 (1992)
REVIEW ARTICLE
THE PATHOLOGY OF PREMATURE OVARIAN FAILURE HAROLD FOX
Department of Pathological Sciences, University of Manchester, Manchester. U.K.
INTRODUCTION
AFOLLICULAR OVARIAN FAILURE
Ovarian failure is usually a physiological event with a well-defined associated clinical picturenamely, the menopause. Premature ovarian failure is therefore often assumed simply to represent one extreme of a temporal spectrum and hence has been the subject of comparative neglect by pathologists. Premature ovarian failure may be secondary to hypothalamic or pituitary disease (hypogonadotrophic hypogonadism) or may be due to a primary ovarian unresponsiveness to gonadotrophins (hypergonadotrophic hypogonadism). This review is concerned only with the latter form of premature ovarian failure, a condition which may be defined as 'secondary amenorrhoea with persistently raised gonadotrophin levels before the age of 35 years'.' Within this definition there are two subsets of patients. In one, there has been a true premature menopause with a total depletion of ovarian follicles and hence a presumed permanent loss of ovarian function; in the other, follicular structures are still present and a clear possibility of either spontaneous or induced return of ovarian functional activity exists.''2 A histological separation into follicular and afollicular types of hypergonadotrophic premature ovarian failure therefore seems logical, though it has to be admitted that some of the known aetiological factors, such as galactosaemia and blepherophimosis, fit uneasily into this framework and straddle the histological divide: this suggests that some cases of ovarian failure that were originally of follicular type may progress to an afollicular stage.
Chromosomal abnormalities Phenotypic females with an XO monosomy have usually lost all their ova long before the expected age of puberty but about 3 per cent of non-mosaic patients retain sufficient ova to have a short period of normal gonadal activity3-' followed by a very early menopause. A relatively brief period of normal ovarian function also occurs in about 12 per cent of individuals with an XOjXX mosaic chromosomal constit~tion."~ Premature ovarian failure occurs unduly frequently in women with a 46,XX karotype and partial deletion of one X chromosome,''-'2 such cases being sometimes familial,13 and in those with polysomy of the X chromosome (the triple X s y n d r ~ m e ) . ' ~ ? ' ~
Addressee for correspondence: Professor H. Fox, Department of Pathological Sciences, Stopford Building, University of Manchester, Manchester M I 3 9PY, U.K.
0022-341 7/92/080357-07 $08.50 0 1992 by John Wiley & Sons, Ltd
Radiution injury Irradiation of the ovaries may destroy their content of ova, with the ovaries of older women being much more sensitive than those of their younger counterparts; the gonads of prepubertal girls are particularly resistant to irradiation.'"'' Radiation damage may cause either temporary or permanent amenorrhoea but a return of normal menstruation does not necessarily mean that the ovaries have escaped permanent damage, this often only becoming apparent years later as premature ovarian failure. Ovaries severely damaged by radiation show loss of primordial and developing follicles, fibrosis and hyalinization of the stroma, and vascular sclerosis with retention of hilar cell^;^'-^^ the formation of decidua-like tissue in the superficial cortex has, somewhat surprisingly, been occasionally noted.23
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Cherno therapy Ovarian failure may complicate the use of either multiple or single agent chemotherapy and, as with radiotherapy, the ovaries of older women appear to be much more susceptible to cytotoxic druginduced damage than those of younger women or children,17.19,26?6 As with radiotherapy, the return of normal menses after a temporary period of druginduced amenorrhoea may conceal covert ovarian damage which later becomes overt as a premature menopause. Histological studies of chemotherapy-damaged ovaries have generally revealed capsular thickening, cortical stromal fibrosis, and either loss of follicles or arrest of follicular maturation.27-" Infection The ovaries are remarkably resistant to infection but it is thought that about 10 per cent of women suffering from mumps develop a diffuse oophoritis and that this may, in an unidentified proportion of cases, result in a premature menopause.32 Histological examination of healed cases of mumps oophoritis has shown ovarian atrophy and fibrosis with loss of follicular structure^.^^
Mucopolysaccharidosis An association between this disorder and premature ovarian failure has been r e p ~ r t e d , this ~ ' being a result of premature oocyte depletion which has been attributed, perhaps rather simplistically, to an accumulation of toxic substances within the ovary. Blepharophirnosis Patients with this syndrome have a high incidence of menstrual irregularities and the condition appears, on admittedly scanty evidence, to be associated with hypergonadotrophic premature ovarian failure.44 Ovarian biopsy in two such patients showed a resistant ovary appearance in one, and a premature menopause, characterized by follicular depletion, in the other.' Autoimmune oophoritis It is likely that some cases of afollicular premature ovarian failure represent 'end stage' or 'burnt out' autoimmune oophoritis, a point discussed below.
Idiopathic Galactosaemia Women with galactosaemia have a high incidence of premature ovarian failure which appears to occur despite adequate dietary control, from infancy, of the metabolic a b r ~ o r m a l i t y . ~The ~ - ~ovar~ ian damage has been attributed to a toxic effect of galactose, or one of its metabolites, on follicular structures during fetal life,36337 but it has also been suggested that carbohydrate residues on gonadotrophin molecules may be altered in such a way as to render them biologically i n a ~ t i v e . ~Experimental '.~~ studies on rats have shown that high maternal galactose levels inhibit the migration of embryonic germ cells to the gonadal ridge;40this may well be relevant to the human disorder. The few reported studies of ovarian histology in galactosaemia complicated by premature gonadal failure have usually described follicular dep l e t i ~ n . ~However, ',~~ in one report of two sisters with galactosaemia and premature ovarian failure, ovarian biopsy in the younger sibling showed an appearance consistent with the resistant ovary syndrome (see below) whilst the ovary of the elder sister showed follicular depleti~n,~' this suggesting that a phase of follicular resistance may precede follicular loss.
This is, to a considerable extent, a diagnosis of exclusion, hypergonadotrophic premature ovarian failure of afollicular type occurring in a chromosomally normal woman with no history of mumps, with no evidence of any other disease process, with no history of exposure to radiation or cytotoxic drugs, and lacking anti-ovarian antibodies. A proportion of these cases appear to be familial, possibly with an autosomal dominant sex-linked inheritan~e,~ whilst ~ ~ ' there is an association between premature ovarian failure and HLA-DR3.49 Idiopathic premature menopause of afollicular type could be due to either a primary paucity of germ cells or an increased rate of attrition of a normal complement of ovarian germ cells. Mathematical modelling has suggested that increased attrition is the predominant mechanism,48but some of these patients may, nevertheless, represent the human equivalent of the Wx/W" strain of mice in which, because of a genetically determined defect in the migration of embryonal cells, there is decreased migration of germ cells from the yolk sac and developing foregut to the gonadal anlage.50 Before accepting too enthusiastically this genetically determined failure of cell migration as a model for human disease, it has to be borne in mind that, as a result
OVARIAN FAILURE
of this defect, there is a high incidence of sex cord stromal tumours in W"/W" mice,5' a feature absent in women with premature ovarian failure. If an increased rate of follicular atresia is indeed the key factor in most cases of afollicular premature ovarian failure, then what is the basic mechanism for this accelerated loss? Experimental studies have indicated that pituitary gonadotrophins play an important role in ovarian follicular retenti01-1,~~ and it has been suggested that accelerated follicular atresia in women may be due to the secretion of abnormal forms of gonadotrophins with reduced biological activity;39 evidence to support this hypothesis is, however, currently lacking. An alternative view is one based on the increasing evidence that cytokines are involved in both follicular development and follicular a t r e ~ i a The . ~ ~ normal process of follicular atresia is thought to be initiated by interferon gamma, which is secreted both by ovarian resident macrophages and by follicular granulosa cells;54interferon stimulates the granulosa cells to express MHC antigens55with subsequent activation of T lymphocytes to produce interleukin-1 . This, in turn, activates resident ovarian macrophages to secrete cytokines involved in ovarian follicular atresia, such as transforming growth factor beta, tumour necrosis factor alpha, fibrocyte growth factor, interleukin- 1, and interferon It is therefore postulated that accelerated follicular atresia may be due to increased interferon gamma production as a result of viral infection, other environmental factors, or genetic p r e d i s p ~ s i t i o ncyto,~~ kines being released continuously rather than intermittently and follicular attrition being increased. The ovaries in cases of idiopathic afollicular premature ovarian failure are usually small and without macroscopically visible follicles. Histologically, the cortical stroma is hypercellular and devoid of follicular structures; atretic follicles and corpora albicantes may, however, be pre~ent.'.~' Small foci of chronic inflammatory cells, unrelated to follicular remnants, are sometimes present and are thought by some to represent the residue of a previous autoimmune oophoritis. FOLLICULAR OVARIAN FAILURE
Resident ovary syndrome This is characterized by high levels of pituitary gonadotrophins, numerous primordial follicles in an ovarian biopsy, and insensitivity of the ovaries to stimulation by exogenous gonadotrophin^.'^^^
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Women with this condition may complain of primary amenorrhoea but 60 per cent present with secondary amenorrhoea, usually during their third decade. I The ovaries are usually macroscopically normal in the resistant ovary syndrome, though some are unduly small. The cortical stroma appears dense and fibrotic, and numerous primordial follicles are present; most show no evidence of development but a few will have attained the pre-antral stage and occasional follicles will have developed to, but not beyond, the antral stage. Some follicles may show focal or diffuse hyaline change23 whilst atypical follicles, bearing some resemblance to the cell nests seen in the sex cord tumour with annular tubules, may be e n ~ o u n t e r e d . ' . In ~ ~ cases of secondary amenorrhoea, stigmata of previous ovulation are usually present. The resistant ovary syndrome is almost certainly a heterogeneous condition, some cases. for example, being associated with galactosaemia or blepharophimosis. Other possible causes include the secretion of an abnormal form of follicle-stimulating hormone (FSH), a FSH receptor defect, and an autoimmune disease with the production ofanti-FSH receptor antibodies.71All studies of FSH in this condition have shown this hormone to be normal, and the failure of the ovaries to respond to exogenous gonadotrophins also argues against a primary abnormality in the FSH m o l e c ~ l e . A ~ ~belief , ~ ~ that the resistant ovary syndrome is due to an absolute or relative deficiency of FSH receptor is one which has often been rnooted7*~"but never specifically tested. Other hypotheses include a post-receptor defect, such as a failure of the gonadotrophin-receptor complex to activate adenylate c y c l a ~ eor~ ~a functionally abnormal FSH r e ~ e p t o r . ~The ' possibility of an immunological basis for this syndrome has been raised by the description of women with both myasthenia gravis and hypergonadotrophic ovarian failure who had a substance in their serum which inhibited in vitro binding of FSH to its receptor;74 this concept has been bolstered by a report of a patient with systemic lupus erythematosus and resistant ovary syndrome who had a serum antibody specifically directed against the FSH receptor." Further, in some patients with the resistant ovary syndrome an IgG antibody is present which, in an in vitro system, blocks FSH-induced DNA synthesis by granulosa cells.76 A final, and perhaps rather negative, view is that the resistant ovary syndrome simply represents an accentuation of the perimenopausal relative gonadotrophin resistance which
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occurs as a physiological event in the near-terminal stages of foIIicuIar Ovarian resistance may be relative rather than a b ~ o l u t e and ~ ~ ?temporary ~~ rather than permanent,69'77and a return to normal ovarian function has been noted in some patients treated by oestrohigh doses of gonadotrophins," or corticosteroids.82 Autoimmune oophoritis Views on autoimmune oophoritis as a specific clinicopathological entity capable of causing premature ovarian failure are currently polarized between those who consider that 'the existence of autoimmune ovarian disease has not been formally e~tablished''~and those who regard such an immunological disorder as a major factor in hypergonadotrophic h y p o g o n a d i ~ r n . ~ ~ . ~ ~ ~ ~ Despite this conflict of views, there is one clearly defined form of autoimmune oophoritis that can, and does, cause hypergonadotrophic premature ovarian failure. A proportion of women with autoimmune adrenal failure also suffer premature ovarian failure: such patients have circulating antisteroid cell antibodies which are directed against the steroid-synthesizing cells of the adrenal cortex and cross-react with steroid-synthesizing cells of the ovary." 93 These anti-steroid cell antibodies are of the IgG type and localize within the ovary to the hilar cells, the cells of the developing follicle, and to the thecal cells of the corpus l u t e ~ m .They ~ ~ ,show ~~ complement-dependent cytotoxicity to granulosa cells in culturey5and are associated with histological evidence of an oophoritis (see below); whether this oophoritis is antibody-mediated or whether it results from an antibody-dependent cell mediated cytotoxicity is a moot point which is discussed below. Autoimmune oophoritis associated with autoimmune adrenalitis is a clear-cut clinical and immunological entity which can, quite legitimately, be extended to include patients with a polyendocrinopathy in which both ovarian and adrenal failure are and, perhaps more debatably, to cases of premature ovarian failure in which there are circulating anti-adrenal antibodies but no clinical evidence of adrenal failure.y9 More controversial is the question of whether a true autoimmune oophoritis occurs which is independent of anti-adrenal antibodies and which develops either in association with other autoimmune disorders or in isolation. The literature on
this topic is extremely confusing partly because a clear distinction has not always been drawn between antibodies directed against the FSH receptor and those directed against follicular components, partly because of lack of rigour in the exclusion of epiphenomenal anti-ovarian antibodies, and partly because it has commonly been assumed that premature ovarian failure occurring in a woman with a presumed autoimmune disease is itself due to an autoimmune process. Many reported cases of presumed autoimmune oophoritis occurring in patients with such conditions as hypothyroidism, hypoparathyroidism, rheumatoid arthritis, or pernicious anaemia80.98, 100-103 have lacked demonstrable antiovarian antibodies, have had no lymphocytic infiltrate of their ovaries, and appear to have been examples of non-immunological premature menopause occurring coincidentally in a patient with an autoimmune disorder. A further cause of confusion is the fact that the mere presence of anti-ovarian antibodies does not necessarily imply a diagnosis of autoimmune disease, for such antibodies have been detected in cases of Addison's disease due to t u b e r c ~ l o s i s ; ' ~in~ association with neoplastic lesions of the endometrium, kidney, and bladder;Io5 in women with inflammatory or neoplastic disease of the ovary;Io6 and in patients with XO gonadal dysgenesi~.'~'Such antibodies have not been shown to be complementbinding or cytotoxic to ovarian cells in culture and are clearly epiphenomenal. It is in the context of these findings that claims of a high incidence of antiovarian antibodies, not cross-reacting with adrenal steroid-synthesizing cells, in cases of premature m e n o p a ~ s e ~have ~ . ' ~to be evaluated. It is probable therefore that, with one exception, the diagnosis of autoimmune premature ovarian failure should be restricted to cases in which antiadrenal-steroid cell antibodies are present. The one exception is those rare cases of chronic mucocutaneous candidiasis and chronic vaginal candidiasis in which anti-Candida antibodies that cross-react with ovarian follicular cells develop and cause an autoimmune oophoritis with ovarian failure. 'O8.'O9 The ovaries from women with an autoimmune oophoritis may be enlarged, sometimes with cystic change, 1.1 10,Il I or of normal size. Histological examination',' l4 shows a mononuclear chronic inflammatory cell infiltrate around developing and atretic follicles with complete sparing of primordial follicles. In the earlier lesions the infiltrate is principally in the thecal layer of the follicles, but in
36 1
O V A R I A N FAILURE
more advanced lesions the granulosa cell layer is also infiltrated and many of the follicular cells show degenerative changes. The inflammatory infiltrate does not extend into the stroma to any extent from the perifollicular areas, though a hilar infiltrate, presumably related to hilar cells, may be present. Perifollicular granulomata have been described in one case of autoimmune oophoritis,”4whilst abnormal follicles, similar to those seen in the resistant ovary syndrome, may be present. Immunocytochemical stainingiI3 identifies the cells in the infiltrate as polyclonal B cells, T4- and TR-positive lymphocytes (with a predominance of the former), macrophages, and occasional NK cells. The overall appearances are suggestive of an antibody-dependent cell-mediated cytotoxicity.
OVARIAN BIOPSY IN PREMATURE OVARIAN FAILURE Ovarian biopsy is still commonly undertaken in cases of premature ovarian failure with the aim of distinguishing between apparently irreversible and potentially reversible loss of ovarian function, i.e., between follicular and afollicular groups. The pathologist can readily make this distinction but should refrain from commenting on the permanency or otherwise of the patient’s loss of reproductive capacity. The histological sections from an average ovarian biopsy comprise only 0.1 5 per cent of an ovary of normal size”’ and the absence of follicles from this tissue does not necessarily mean that the ovary is totally depleted of primordial follicles, a fact emphasized by reports of subsequent pregnancies occurring in women whose ovaries had showed no oocytes in a biopsy ~ p e c i m e n . ~This, ~.”~ together with the fact that both follicular and afollicular types of premature ovarian failure require treatment with oestrogens, suggests that ovarian biopsy is not only unnecessary in cases of premature ovarian failure, but may also give misleading, albeit histologically accurate, results. It can be argued that ovarian biopsy is necessary to identify those cases of premature ovarian failure due to an autoimmune oophoritis, for such women may respond well to corticosteroid or immunosuppressive therapy with a return of normal ovarian f ~ n c t i o n . ”The ~ diagnosis of an autoimmune oophoritis should, however, rest principally on serological findings, as is the case with autoimmune organ disease elsewhere in the body, e.g., autoimmune thyroiditis.
REFERENCES I . Russell P, Bannatyne P. Surgical Pathology of the Ovaries. Edinburgh: Churchill Livingstone, 1989: 57. 2. Kinch RAH, Plunkett E R , Smout MS, Carr DH. Primary ovarian failure. Am J Ob.s/e/Gjnecol 1965: 91: 630-644. 3 Philip J, Sele V, 45,XO Turner’s syndrome without evidence of mosaiciam in a patient with two pregnancies. A c ~ aOhsrer Gynecol Scand 1976: 5 5 283-286. 4. Wray HL, Freeman NVR, Ming PL. Pregnancy in the Turner syndrome with only 45.X chromosomal constitution. Ferlil S f r r i l 1981; 35: 509-514. 5. Baudier MM, Chihal HJ, Dickey RP. Pregnancy and reproductive function in a patient with non-mosaic Turner syndrome. Oh.s/e/ Gjnecol1985; 6 5 60s-64s. 6. Gondoa B. Disorders of ovarian development. In: Gondos B. Riddick DH, eds. Pathology of Inrertility. New York: Thieme. 1987; 10 1-1 22. 7 . Swapp G H , Johnston AW, Watt JL, Couzin DA. Stephen GS. A fertile woman with non-mosaic Turner’s syndrome: case report and review of the literature. B r J Ohstet Gjnaecol1989;96 8 7 6 ~880. 8. Simpson JL. Disorders of Sexual Differentiation. New York: Academic Press, 1976. 9 McCorquodale M M M , Bowdle FC. Two pregnancies and the loss of the 46,XX cell line in a 45,X/46,XX Turner mosaic patient. Fertil Sreri/ 1985; 43 229 233. 10. Fitch M, de Saint Victor J, Richer C-L, Pinsky L. Sitahal S. Premature menopause due to a small deletion in the long arm of the X chromosome: a report of three cases and a review Am J Ohsrrr Gjnecol 1982; 142: 968-973. 1 I . Bates A, Howard PJ. Distal long arm deletion o f t h e X chromosome and ovarian failure. J M e d G m e / 1990; 27: 722-723 12. Therman E. Susman B. The similarity ofphenotypiceffectscaused by X p and Xq deletions in the human female: a hypothesis. H u m Gene/ 1990;85: 175-183. 13. Venernan TF. Beverstock GC, Exalto N, Mollevanger P. Premature menopause because of an inherited deletion in the long arm of the X chromosome. FerrilSteri/1991; 55: 631-633. 14. Michalak DP, Zacur HA, Rock JA. Woodruff JD. Autoimmunity in a patient with 47,XXX karotype. 0hste.r Gynecol 1983; 62: 667-669. 15. Villanueva AL, Rebar RW. Triple-X syndrome and premature ovarian failure. Ohsrer GjnrcoI 1983: 6 2 70s-73s. 16. Shalet SM. Beardwell CG. Morris-Jones PH, Pearson D, Orrell DH Ovarian failure following abdominal irradi;ition in childhood. Br J Cancer 1976; 33: 655-658. 17. Stillrnann RJH. Schinfeld JS, Schiff I, E I a/ Ovarian failure in longterm survivors of childhood malignancy. Am J Ohsrer Gynecol 198 I: 1 3 9 62-66. 18. Gradishar WJ, Schilsky RL. Ovarian function following radiation and chemotherapy. Scmin Oncol 1989; 1 6 425 436. 19. Wallace WH, Shalet SM. Crowne EC. Morris-Jones PH, Gattamanen HR. Ovarian failure following abdominal irradiation in childhood: natural history and prognosis. C/in Oncol 1989; 1: 75-79. 20. Verp MS. Environmental causes of ovarian failure. Semin Rrprod Endocrind 1983: 1: 101-1 I I 21. Himelstein-Bra- R. Peters H, Faber M. Influence of irradiation and chemotherapy on the ovaries of children with abdominal tumours. B r J Cancer 1977; 36: 269-275. 22. Casarett G W . Radiation Histopathology. V o l 2 . Boca Raton: C R C Press, 1980. 75-94. 23. Young RH. Scully RE. Ovarian pathology of infertility. In: Kraus FT. Dainjanov I , Kaufman N, eds. Pathology of Reproductive Failure Baltimore: Williams& Wilkins, 1991; 104-139. 24. Schilsky RL, Sherins RJ, Aubbard SM, er al. Long term follow-up of ovarian function in women treated with M O P P chemotherapy for Hodgkin’s disease. A h J Med 1981;71: 552-556. 25. Andrieu JM. Ochos-Molina ME. Menstrual cycle, pregnancies and oKspring before and after M O P P therapy for Hodgkin’s disease. Cuncer 1983; 5 2 435- 438. 26. Bryne J. Mulvihill JJ, Myers MH. er a/. Effects of treatment on fertility in long-term survivors of childhood cancer. N €ng/ J M r d 1987;317: 1315 1321.
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