Autoimmune Oophoritis: Clinical Presentation of an Unusual Clinical

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Case report

Autoimmune oophoritis: clinical presentation of an unusual clinical entity Obstetrics & Gynecology M Varras1*, A Anastasiadis2, J Panelos3, E Balassi3, A Demou3, CH Akrivis4

Abstract infertility in women before the age and had regular menses on a 28-day Introduction of 40 years1-4. The aetiologies of this cycle. She had five full-term normal condition include chromosomal pregnancies without any miscar- anomalies (such as X chromosome riages. Autoimmune oophoritis is a rare co- monosomy, translocations or partial On pelvic bimanual examination, ndition, which provokes ovarian fail- deletions), genetic predisposition an anteverted uterus was palpated, ure with either primary amenorrhea (such as fragile X pre-mutations, while both fallopian tubes and ovaries or secondary amenorrhea and a sub- BMP15 or DIAPH2 mutations), infec- were impalpable. Pelvic ultrasonog- sequent loss of fertility and ovarian tious diseases, complications of chem- raphy disclosed normal-sized ovaries hormonal function. The purpose of t- otherapy, pelvic radiotherapy, surgical with bilateral multicystic structures, his report is to document the clinical interventions or surgery, enzymatic with the largest follicle measuring Casesfindings report from two patients with aut- disorders and endometriosis. Prema- 1.2 cm. The thickness of the endo- oimmune oophoritis.

ture ovarian failure might also be idio- metrium was 3.5 mm. Initial inves- manuscript. nal pathic or autoimmune2. Among a total tigation showed her serum gonado- ﬁ Two cases of autoimmune oophorit- of 266 patients with spontaneous POF, tropin concentrations to be elevated: is are presented whose histopathol- 4% were diagnosed to have autoim- follicle stimulating hormone (FSH) at ogical findings were consistent with mune oophoritis3,4. 40 mIU/ml and luteinizing hormone international literature. Both cases Ovarian autoimmunity was first (LH) at 56 mIU/ml. 17-beta oestra- were histopathologically characteri- reported and serologically docu- diol was at 30 pg/ml (normal range: sed by lymphocytic and plasmacytic mented by Vallotton and Forbes in 30–100 pg/ml). Serum prolactin inflammatory infiltrations around t- 19665. Autoimmune oophoritis is a levels were normal and there was he cystic follicles. The inflammation distinct clinical entity and one of the no evidence of hypoparathyroidism. Conclusionwas located both in the theca and gr- causes of POF, particularly in women Thyroid function tests were normal. anular layers. with secondary amenorrhea6-8. Auto- Also, kidneys and liver function tests immune oophoritis generally occurs were normal. Serum electrolytes Patients with autoimmune oophorit- in the setting of autoimmune poly- were normal. Proteinuria was nega- is should be recognised by the histo- endocrine syndromes and is asso- tive. Serum adrenocorticotropin pathology of the ovarian biopsies as ciated commonly with other major hormone levels were normal. The they are at an increased risk of deve- endocrine failures such as diabetes progesterone challenge test was loping other autoimmune disorders. mellitus, Addison’s disease, hypopar- negative. Introduction athyroidism or hypothyroidism8-10. A At exploratory laparoscopy, her wide clinical spectrum has also been ovaries appeared small and inactive.

Premature ovarian failure (POF) is on of the manuscript, as well read and approved a condition characterised by amen- demonstrated11. There were no signs of abdominal or orrhea, some hot flushes, elevated The aim of this was to pelvic inflammatory processes. Biop- serum gonadotropin levels and describe the clinical spectrum and sies from both ovaries were obtained hypo-oestrogenism with associated the interesting pathologicalreport findings and endometrial curettage was originating from small ovarian biop- performed as well. sies from two patients with autoim- Grossly, two specimens had been * Corresponding author Email: [email protected] mune oophoritis. obtained from the right ovary with none declared. ict of Interests: a whitish-grey colour, measuring ﬂ 1 Third Department of Obstetrics and Gynecol- on, design, and prepara Ɵ ogy, ‘Elena Venizelou’ General Maternity Hos- Case report 0.7 cm and 1.2 cm in their greatest Ɵ pital, Athens, Greece Case 1 dimension, respectively, and one

2 rules of disclosure. (AME) ethical Ethics Medical on for Fourth Department of Obstetrics and Gyne- A 33-year-old woman presented with specimen had been obtained from Ɵ cology, ‘Elena Venizelou’ General Maternity Hospital, Athens, Greece a 10-month history of secondary the left ovary with white tan to 3 Department of Pathology, ‘G. Chatzikosta’ amenorrhoea and hot flushes. grey colour measuring 1.6 cm in its General State Hospital, Ioannina, Greece Menarche had occurred at an age of 14 greatest dimension. Also, the spec- 4 Department of Obstetrics and Gynecology, ‘G. Chatzikosta’ General State Hospital, Ioannina, years, she had developed secondary imen from the endometrial biopsy Greece sex characteristics appropriately measured 3.5 × 3 × 0.2 cm. At micro-

Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY) none declared. Con ng interests: Ɵ F : Varras M, Anastasiadis A, Panelos J, Balassi E, Demou A, Akrivis CH. Autoimmune oophoritis: All authors abide by the Associa All authors contributed to the concep to All authors contributed clinical presentation of an unusual clinical entity. OA Case Reports 2013 Jan 31;2(1):7. Compe Page 2 of 5

Case report

Figure 1: Case 1: dense inflammation of Figure 3: Case 1: primordial folli- Figure 5: Case 1: T8 positive lympho- the ovary (haematoxylin-eosin × 100). cles are spared by the inflammation cytes (CD8 stain × 200). (haematoxylin-eosin × 400). nal manuscript. nal ﬁ

Figure 2: Case 1: dense inflamma- Figure 6: Case 1: CD138 positive tory infiltrate destroys the follicle Figure 4: Case 1: T4 positive lympho- plasma cells (× 100). (haematoxylin-eosin × 200). cytes (CD4 stain × 200). history of hypothyroidism; she was was identified in the endometrium. scopic examination, the ovarian biop- stable on thyroxine 0.1 mg daily. The final pathological diagnosis was sies contained primordial, developing On pelvic bimanual examination, autoimmune oophoritis. and atretic follicles. Dense inflamma- an anteverted uterus was palpated The patient was diagnosed as tion of the ovary was found (Figure and a painful cystic mass in the having POF due to autoimmune 1). The most striking feature was right adnexa was palpated as well. oophoritis, and she was started on the destruction of the developing Pelvic ultrasonography revealed oestrogen and progesterone replace- follicles by lymphocytic and plasma- a well-defined cystic mass with a ment therapy. Laboratory tests were cytic infiltration (Figure 2), while the hypoechogenic appearance in the negative for rheumatoid factor, anti- primordial follicles were apparently right adnexa uteri, measuring 8 cm nuclear antibodies (ANA), compo-

and entirely spared from this process in its maximum diameter and a on of the manuscript, as well read and approved nents 3 and 4 of the complement (C3 (Figure 3). The inflammation was small multicystic structure in the left and C4), immunoglobulin (Ig) G and located both in the theca and granular adnexa. Free liquid in the posterior IgM alpha cardiolipin antibodies and layers. The ovarian stroma was unre- space of Douglas was not found. C-reactive protein (CRP). The patient markable. Immunohistochemically, Initial investigation showed was missed from further follow-up. the inflammatory population was normal blood cell counts, as well composed mainly from T-lympho- Case 2 as normal function tests for liver, cytes (CD4+, CD8+) (Figures 4 A 32-year-old woman presented with kidneys and thyroid. The INR and none declared. ict of interests: and 5) and plasma cells (CD138+) acute lower abdominal pain. Last activated partial thromboplastin ﬂ on, design, and prepara Ɵ (Figure 6). The endometrium had menstrual period was three months time ratios were normal. Elevated Ɵ an oedematous appearance with previous to the date of presentation. levels of serum carbohydrate antigen rules of disclosure. (AME) ethical Ethics Medical on for focal haemorrhagic infiltration of the Menarche had occurred at the age (CA)-19.9 (81 IU/ml, normal range Ɵ stroma. The endometrial glands were of 15 years and her menstrual cycle <37) and CA-125 (39.7 U/ml, normal small, round, coated with cylinder had been regular previously on a range: <37) were found, while the epithelium and without any remark- 29-day cycle. She had two previous serum levels of CA-15.3, carcinoem- able mitotic activity. No inflammation caesarean sections and a medical bryonic antigen and alpha fetoprotein

Case report

Figure 7: Case 2: severe inflamma- Figure 9: Case 2: characteristic Figure 11: Case 2: PanT (CD45RO) tory infiltrate destroys the follicle destruction of the developing follicle (haematoxylin- eosin × 200). by the inflammatory infiltration stain × 100. (haematoxylin-eosin × 400). virus. Also, the serum Ig concentrations were negative for IgM (162 mg/ dl; normal range: 46–304 mg/dl) and IgA (165 mg/dl; normal range: 82–453 mg/dl). Positive serum laboratory tests were found for antistrep- nal manuscript. nal tolysin O (333 IU/ml; normal range: ﬁ 0–116 IU/ml) and IgG (1730 mg/dl; normal: 751–1560 mg/dl). Also, the titres of ANA were positive. During the six-month follow-up Figure 8: Case 2: dense inflamma- postoperatively, her serum gonado- tory infiltrations around the follicle tropins were slightly elevated with (haematoxylin-eosin × 200). Figure 10: Case 2: layers of granu- FSH levels of 15.8 mIU/ml and losa cells surround an unremark- LH levels of 18.4 mIU/ml. 17-beta able oocyte in a secondary follicle were in normal ranges. The patient (haematoxylin-eosin × 400). oestradiol levels were 99 pg/ml. underwent exploratory laparoscopy Prolactin levels were normal. High with an ovarian cystectomy and a titres of anti-thyroglobulin anti- wedge resection of the right ovary. of granulosa cells surrounding an bodies (1/20; negative <1/20) and The left ovary appeared small and unremarkable oocyte (Figure 10), antimicrosomal antibodies (1/3.200; inactive. There were no signs of while the primordial follicles were negative <1/100) were found. The abdominal or pelvic inflammatory apparently and entirely spared from thyroid-stimulating hormone levels processes. this process. The ovarian stroma were normal (0.54 microIU/ml; Grossly, the largest specimen had was otherwise unremarkable. The normal range: 0.3–0.6 microIU/ml). Also, the cortisol levels were normal dimensions of 6 × 3 × 0.5 cm. Also, scattered lymphocytes were positive on of the manuscript, as well read and approved the other two histological pieces for CD4, CD8, CD138 and CD45RO (21.56 microg/dl; normal morning measuring 2.5 cm and 3.5 cm in their (PanT) (Figure 11). range: 10.4–26.4 microg/dl). maximum diameter were sent for After the pathology results, the frozen biopsy. Cut sections revealed patient was diagnosed as having POF Discussion two cystic follicles measuring 0.4 cm due to autoimmune oophoritis and Autoimmune oophoritis is caused and 1.0 cm in their maximum diam- she was started on oestrogen and by ovarian autoimmune inflamma- eter, respectively. progesterone replacement therapy. tion resulting in ovarian destruction, none declared. ict of Interests: Microscopically, the ovarian cyst During the one-month follow-up atrophy and fibrosis. It provokes ﬂ on, design, and prepara Ɵ was benign and the ovarian segments postoperatively, laboratory tests ovarian failure with either primary Ɵ showed dense lymphocytic and plas- were negative for CRP, erythrocyte or secondary amenorrhea. There rules of disclosure. (AME) ethical Ethics Medical on for macytic inflammatory infiltrations sedimentation rate, rheumatoid is a subsequent loss of fertility and Ɵ around the cystic follicles. The inflam- factor, anti–double-stranded DNA ovarian hormonal function12. The mation was located both in the theca antibodies, C3 and C4, IgG and IgM autoimmunity accounts for up of and granular layers (Figures 7–9). alpha cardiolipin antibodies and 30% of all POF cases10,13. Also, coex- The secondary follicles showed layers surface antigen of the hepatitis B istence of autoimmune POF with

Case report other autoimmune diseases such as treated with corticosteroid replace- Consent those associated with the thyroid ment therapy. An uneventful preg- Written informed consent was gland (e.g. Hashimoto’s and Graves’s nancy was achieved one year after obtained from all patients for publi- disease) and adrenal gland (e.g. Addi- commencement of corticosteroid cation of this series study and accom- son’s disease) is often observed14, as replacement therapy24. Luborsky panying images. A copy of the written in our case 2. Approximately 60% of et al. described two patients with consents is available for review by POF cases without adrenal autoim- documented POF who became preg- the Editor-in-Chief of this journal. mune disease lack ovarian follicles, nant, and each patient delivered and in these cases, fibrotic ovaries are a healthy infant after treatment Abbreviations list found15. Moreover, ANA and rheuma- with high doses of corticoster- ANA, antinuclear antibodies; CA, toid factors have been reported with oids. However, in both cases, POF carbohydrate antigen; CRP, C-reactive a higher frequency in POF patients has resumed after delivery14. Also, protein; C3 and C4, components 3 than normal4. Moncayo-Naveda et al. Barbarino-Monnier et al. reported a and 4 of the complement; FSH, follicle reported the presence of anti-ovarian pregnancy and delivery after in vitro stimulating hormone; Ig, immuno- antibodies in 84% of the cases with fertilisation in a patient with anti- globulin; LH, luteinizing hormone; system lupus erythematosus16. ovarian autoimmunity treated with POF, premature ovarian failure. The patient of our case 2 presented corticosteroids25. Apart from the case with a large ovarian cyst measuring reports, Corenblum et al. studied References 8 cm in its maximum diameter 11 chromosomally normal patients 1. Forges T, Monnier- Barbarino P, Faure and this is in agreement with the with POF who received high doses of GC, Bene MC. Autoimmunity and antigenic nal manuscript. nal observations of other studies with corticosteroids for 15 days and found targets in ovarian pathology. Hum Reprod ﬁ autoimmune POF17-21. The possible that two of them had resumed ovarian Update. 2004 Mar–Apr;10(2):163–75. mechanism for the development of function and became pregnant26. In 2. Bats AS, Barbarino PM, Bene MC, ovarian cysts in patients with auto- addition, Blumenfeld et al. studied Faure GC, Forges T. Local lymphocytic immune POF is due to the elevated 15 patients with autoimmune POF and epithelial activation in a case of auto- gonadotropin levels because of the treated with human menopausal immune oophoritis. Fertil Steril. 2008 impaired negative feedback and the gonadotropins and corticosteroids Sep;90(3):849.e5–8. 3. Bakalov VK, Anasti JN, Calis KA, Vander- subsequent overstimulation of the after pituitary desensitisation with hoof VH, Premkumar A, Chen S, et al. Auto- 21 ovarian tissues . Both of our cases a gonadotropin-releasing hormone immune oophoritis as a mechanism of were amenorrheic for 10 months agonist. Eight of 15 patients had follicular dysfunction in women with 46,XX (case 1) and three months (case 2) become pregnant at least once, spontaneous premature ovarian failure. with increased FSH levels compared and in total, 14 pregnancies were Fertil Steril. 2005 Oct;84(4):958–65. to women with regular cycles. In achieved. All of these pregnancies 4. La Marca A, Brozzetti A, Sighinolfi G, patients with autoimmune oophor- were obtained within the first three Marzotti S, Volpe A, Falorni A. Primary itis, hormone replacement should months after the onset of treatment27. ovarian insufficiency: autoimmune be used as in our patients. During causes. Curr Opin Obstet Gynecol. 2010 hormone-replacement therapy, Conclusion Aug;22(4):277–82. elevated gonadotropin levels usually Autoimmune oophoritis is diagnosed 5. Vallotton MB, Forbes AP. Antibodies to cytoplasm of ova. Lancet. 1966 return to physiologically normal by laparoscopic ovarian biopsy,

Jul;2(7457):67–85. on of the manuscript, as well read and approved 22 ranges . As a result, folliculogen- which on microscopic examination 6. Sedmak DD, Hart WR, Tubbs RR. Auto- esis may occur and less frequently is reveals a folliculotropic, lymphoid immune oophoritis: a histopathologic followed by ovulation and rarely by infiltrate that affects developing folli- study of involved ovaries with immuno- pregnancy23. Both of our patients had cles with a theca layer, corpora lutea logic characterization of the mononu- completed their families. However, and atretic follicles, and it indicates clear cell infiltrate. Int J Gynecol Pathol. for patients who desire a child, there the patient’s risk of developing other 1987;6(1):73–81. are multiple case reports in which autoimmune diseases. Autoimmune 7. Suh SL. Autoimmune oophoritis–

a case report. J Korean Med Sci. 1992 none declared. ict of interests:

corticosteroid treatment has resulted oophoritis should be kept in mind by ﬂ Sep;7(3):284–90. in pregnancies in women with auto- gynaecologists when treating women on, design, and prepara Ɵ Ɵ immune oophoritis and amenor- with POF. These patients should be 8. Welt CK. Autoimmune oophoritis in the adolescent. Ann N Y Acad Sci.

20 rules of disclosure. (AME) ethical Ethics Medical on for rhea . Cowchock et al. described a treated with hormone replacement Ɵ 2008;1135:118–22. patient who had been treated with therapy. For young patients with 9. Friedman CI, Gurgen-Varol F, Lucas J, oestrogen replacement therapy autoimmune POF who desire a preg- Neff J. Persistent progesterone produc- because of POF for more than 15 nancy, high doses of corticosteroids tion associated with autoimmune years. However, the patient devel- might help in the achievement of oophoritis. A case report. J Reprod Med. oped Addison’s disease and was pregnancy. 1987 Apr;32(4):293–6.

Case report

10. Meskhi A, Seif MW. Premature ovarian autoimmune oophoritis. Obstet Gynecol. randomized, controlled trial of estradiol failure. Curr Opin Obstet Gynecol. 2006 1989 Sep;74(3 Pt 2):492–5. replacement therapy in women with Aug;18(4):418–26. 18. Burrell LM, Murdoch A, Angus B, hypergonadotropic amenorrhea. J Clin 11. Russell P, Bannatyne P, Shearman RP, White MC. Autoimmune ovarian failure Endocrinol Metab. 1996 Oct;81(10): Fraser IS, Corbett P. Premature hypergon- with elevated serum levels of lutein- 3615–21. adotropic ovarian failure: clinicopatho- izing hormone and enlarged ovaries. 24. Cowchock FS, McCabe JL, Mont- logical study of 19 cases. Int J Gynecol Case report. Br J Obstet Gynaecol. 1990 gomery BB. Pregnancy after corticosteroid Pathol. 1982;1(2):185–201. Apr;97(4):362–4. administration in premature ovarian 12. Goswami D, Conway GS. Prema- 19. Lonsdale RN, Roberts PF, Trowell JE. failure (polyglandular endocrinopathy ture ovarian failure. Horm Res. 2007; Autoimmune oophoritis associated with syndrome). Am J Obstet Gynecol. 1988 68(4):196–202. polycystic ovaries. Histopathology. 1991 Jan;158(1):118–9. 13. Calongos G, Hasegawa A, Komori S, Jul;19(1):77–81. 25. Barbarino-Monnier P, Gobert B, Koyama K. Harmful effects of antizona 20. Welt CK, Falorni A, Taylor AE, Guillet-May F, Béné MC, Barbarino A, pellucida antibodies in folliculogenesis, Martin KA, Hall JE. Selective theca cell Foliguet B, et al. Ovarian autoimmunity oogenesis, and fertilization. J Reprod dysfunction in autoimmune oophoritis and corticotherapy in an in-vitro ferti- Immunol. 2009 Jan;79(2):148–55. results in multifollicular development, lization attempt. Hum Reprod. 1995 14. Luborsky JL, Visintin I, Boyers decreased estradiol, and elevated inhibin Aug;10(8):2006–7. S, Asari T, Caldwell B, DeCherney A. B levels. J Clin Endocrinol Metab. 2005 26. Corenblum B, Rowe T, Taylor PJ. High- Ovarian antibodies detected by immo- May;90(5):3069–76. dose, short-term glucocorticoids for the bilized antigen immunoassay in patients 21. Çakır ED, Özdemir Ö, Eren E, Sağlam treatment of infertility resulting from with premature ovarian failure. J Clin H, Okan M, Tarım ÖF. Resolution of auto- Endocrinol Metab. 1990 Jan;70(1):69–75. immune oophoritis after thymectomy in premature ovarian failure. Fertil Steril. nal manuscript. nal 15. Dewhurst CJ, De Koos EB, Ferreira HP. a myasthenia gravis patient. J Clin Res 1993 May;59(5):988–91. ﬁ The resistant ovary syndrome. Br J Obstet Pediatr Endocrinol. 2011;3(4):212–5. 27. Blumenfeld Z, Halachmi S, Alik Gynecol. 1975 Apr;82(4):341–5. 22. Laml T, Huber JC, Albrecht AE, Sintenis Peretz B, Shmuel Z, Golan D, Makler A, et 16. Moncayo-Naveda HE, Moncayo R, WA, Artmann BW. Unexpected pregnancy al. Premature ovarian failure–the prog- Benz R, Wolf A, Lauritzen C. Organ-specific during hormone-replacement therapy nostic application of autoimmunity on antibodies against ovary in patients in a woman with elevated follicle-stimu- conception after ovulation induction. with system lupus erythematosus. Am J lating hormone levels and amenorrhea. Fertil Steril. 1993 Apr;59(4):750–5. Obstet Gynecol. 1989 May;160(5 Pt 1): Gynecol Endocrinol. 1999 Apr;13(2): 1227–9. 89–92. 17. Biscotti CV, Hart WR, Lucas JG. Cystic 23. Taylor AE, Adams JM, Mulder JE, ovarian enlargement resulting from Martin KA, Sluss PM, Crowley WF Jr. A on of the manuscript, as well read and approved none declared. ict of Interests: ﬂ on, design, and prepara Ɵ Ɵ rules of disclosure. (AME) ethical Ethics Medical on for Ɵ