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Prevalence and clinical associations with premature ovarian insufficiency, early menopause, and low ovarian reserve in systemic sclerosis

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Abstract

The low prevalence of pregnancy in women with systemic sclerosis (SSc) is due to multi-factorial causes, including premature ovarian insufficiency (POI). The study aimed to determine the prevalence of POI, early menopausal status, and any clinical associations of these among Thai female SSc patients. An analytical cross-sectional study was conducted among female SSc patients between 18 and 45 years of age. The eligible patients underwent blood testing for follicle stimulating hormone and anti-mullerian hormone levels, gynecologic examination, and transvaginal ultrasound for antral follicle count. We excluded patients having surgical amenorrhea, previous radiation, and history of hormonal contraception < 12 weeks and pregnancy. A total of 31 patients were included. The majority (67.7%) had diffuse cutaneous systemic sclerosis. Three patients were POI with a prevalence of 9.7%. The factors associated with POI were a high cumulative dose of cyclophosphamide (CYC) (p = 0.02) and the long duration of CYC used (p = 0.02). After excluding POI, early menopause was detected in 10 patients with a prevalence of 35.7%. The factors associated with early menopause were long disease duration (p = 0.02), high cumulative dose of CYC (p = 0.03), and high cumulative dose of prednisolone (p = 0.02). Low ovarian reserve according to POSEIDON definition was found in 28 patients with the prevalence of 90.3%. POI in Thai SSc was uncommon, whereas early menopause and low ovarian reserve were frequently revealed. A high cumulative dose of CYC was associated with both POI and early menopause. Physicians should be aware of reproductive outcomes and advise patients at risk.

Key Points

• POI is revealed in patients with SSc particularly in who received high cumulative dose of cyclophosphamide, while early menopause and low ovarian reserve were major reproductive problem among SSc.

• Prescriptions for CYC for female SSc—both for young patients of reproductive age and premenopausal middle-aged women—should be concerned of the long-term effects on gonadal function.

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References

  1. Alba MA, Velasco C, Simeón CP, Fonollosa V, Trapiella L, Egurbide MV, Sáez L, Castillo MJ, Callejas JL, Camps MT, Tolosa C, Ríos JJ, Freire M, Vargas JA, Espinosa G, RESCLE Registry (2014) Early- versus late-onset systemic sclerosis: differences in clinical presentation and outcome in 1037 patients. Medicine (Baltimore) 93:73–81. https://doi.org/10.1097/MD.0000000000000018

    Article  CAS  Google Scholar 

  2. Arias-Nuñez MC, Llorca J, Vazquez-Rodriguez TR, Gomez-Acebo I, Miranda-Filloy JA, Martin J, Gonzalez-Juanatey C, Gonzalez-Gay MA (2008) Systemic sclerosis in northwestern Spain: a 19-year epidemiologic study. Medicine (Baltimore) 87:272–280. https://doi.org/10.1097/MD.0b013e318189372f

    Article  Google Scholar 

  3. Mayes MD, Lacey JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, Schottenfeld D (2003) Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 48:2246–2255. https://doi.org/10.1002/art.11073

    Article  PubMed  Google Scholar 

  4. Panicheewa S, Chitrabamrung S, Verasertniyom O, Vanichaphantu M, Kraisit SO, Chiewsilp P, Vatanasuk M (1991) Diffuse systemic sclerosis and related diseases in Thailand. Clin Rheumatol 10:124–129. https://doi.org/10.1007/BF02207649

    Article  CAS  PubMed  Google Scholar 

  5. Salang L, Buppasiri P, Foocharoen C (2018) Outcome of pregnancy in systemic sclerosis. J Med Assoc Thail 101:S227–S233

    Google Scholar 

  6. European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M et al (2016) ESHRE guideline: management of women with premature ovarian insufficiency. Hum Reprod 31:926–937. https://doi.org/10.1093/humrep/dew027

    Article  Google Scholar 

  7. Nelson LM (2009) Primary ovarian insufficiency. N Engl J Med 360:606–614. https://doi.org/10.1056/NEJMcp0808697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Grisendi V, Mastellari E, La Marca A (2019) Ovarian reserve markers to identify poor responders in the context of Poseidon classification. Front Endocrinol (Lausanne) 10:281. https://doi.org/10.3389/fendo.2019.00281

    Article  Google Scholar 

  9. Luisi S, Orlandini C, Regini C, Pizzo A, Vellucci F, Petraglia F (2015) Premature ovarian insufficiency: from pathogenesis to clinical management. J Endocrinol Investig 38:597–603. https://doi.org/10.1007/s40618-014-0231-1

    Article  CAS  Google Scholar 

  10. Tal R, Seifer DB (2017) Ovarian reserve testing: a user’s guide. Am J Obstet Gynecol 217:129–140. https://doi.org/10.1016/j.ajog.2017.02.027

    Article  PubMed  Google Scholar 

  11. van der Stege JG, Groen H, van Zadelhoff SJN et al (2008) Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure. Menopause 15:23–31. https://doi.org/10.1097/gme.0b013e3180f6108c

    Article  PubMed  Google Scholar 

  12. Cordts EB, Christofolini DM, Dos Santos AA et al (2011) Genetic aspects of premature ovarian failure: a literature review. Arch Gynecol Obstet 283:635–643. https://doi.org/10.1007/s00404-010-1815-4

    Article  PubMed  Google Scholar 

  13. Haller-Kikkatalo K, Uibo R, Kurg A, Salumets A (2015) The prevalence and phenotypic characteristics of spontaneous premature ovarian failure: a general population registry-based study. Hum Reprod 30:1229–1238. https://doi.org/10.1093/humrep/dev021

    Article  CAS  PubMed  Google Scholar 

  14. Ebrahimi M, Akbari Asbagh F (2015) The role of autoimmunity in premature ovarian failure. Iran J Reprod Med 13:461–472

    PubMed  PubMed Central  Google Scholar 

  15. Hoek A, Schoemaker J, Drexhage HA (1997) Premature ovarian failure and ovarian autoimmunity. Endocr Rev 18:107–134. https://doi.org/10.1210/edrv.18.1.0291

    Article  CAS  PubMed  Google Scholar 

  16. Bhadauria S, Moser DK, Clements PJ, Singh RR, Lachenbruch PA, Pitkin RM, Weiner SR (1995) Genital tract abnormalities and female sexual function impairment in systemic sclerosis. Am J Obstet Gynecol 172:580–587

    Article  CAS  Google Scholar 

  17. Nigam A, Prakash A, Sharma S, Kumar N (2017) Premature ovarian failure – an unusual manifestation of systemic sclerosis. J Hum Reprod Sci 10:58–60. https://doi.org/10.4103/jhrs.JHRS_77_16

    Article  PubMed  PubMed Central  Google Scholar 

  18. Vural B, Caliskan E, Doger E, Ercin C (2005) Uterine prolapse in a young nulligravida with scleroderma and premature ovarian failure. Int Urogynecol J Pelvic Floor Dysfunct 16:415–417. https://doi.org/10.1007/s00192-004-1269-y

    Article  PubMed  Google Scholar 

  19. Vinet É, Bernatsky S, Hudson M, Pineau CA, Baron M, the Canadian Scleroderma Research Group (2014) Effect of menopause on the modified Rodnan skin score in systemic sclerosis. Arthritis Res Ther 16:R130. https://doi.org/10.1186/ar4587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Scorza R, Caronni M, Bazzi S et al (2002) Post-menopause is the main risk factor for developing isolated pulmonary hypertension in systemic sclerosis. Ann N Y Acad Sci 966:238–246

    Article  Google Scholar 

  21. Omair MA, Pagnoux C, McDonald-Blumer H, Johnson SR (2013) Low bone density in systemic sclerosis. A systematic review. J Rheumatol 40:1881–1890. https://doi.org/10.3899/jrheum.130032

    Article  PubMed  Google Scholar 

  22. La Montagna G, Vatti M, Valentini G, Tirri G (1991) Osteopenia in systemic sclerosis. Evidence of a participating role of earlier menopause. Clin Rheumatol 10:18–22

    Article  Google Scholar 

  23. (1980) Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 23:581–590

  24. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE (2013) Classification criteria for systemic sclerosis: an ACR-EULAR collaborative initiative. Arthritis Rheum 65:2737–2747. https://doi.org/10.1002/art.38098

    Article  PubMed  PubMed Central  Google Scholar 

  25. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N, Wollheim F (1988) Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 15:202–205

    CAS  PubMed  Google Scholar 

  26. De Vos M, Devroey P, Fauser BC (2010) Primary ovarian insufficiency. Lancet 376:911–921. https://doi.org/10.1016/S0140-6736(10)60355-8

    Article  PubMed  Google Scholar 

  27. Shuster LT, Rhodes DJ, Gostout BS, Grossardt BR, Rocca WA (2010) Premature menopause or early menopause: long-term health consequences. Maturitas 65:161–166. https://doi.org/10.1016/j.maturitas.2009.08.003

    Article  PubMed  Google Scholar 

  28. Esteves SC, Roque M, Bedoschi GM (2018) Defining low prognosis patients undergoing assisted reproductive technology: POSEIDON Criteria—The Why. Front Endocrinol 9:461. https://doi.org/10.3389/fendo.2018.00461

    Article  Google Scholar 

  29. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R (2019) Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 53. https://doi.org/10.1183/13993003.01913-2018

  30. Savarino E, Furnari M, de Bortoli N, Martinucci I, Bodini G, Ghio M, Savarino V (2014) Gastrointestinal involvement in systemic sclerosis. Presse Med 43:e279–e291. https://doi.org/10.1016/j.lpm.2014.03.029

    Article  PubMed  Google Scholar 

  31. Arunsurat I, Mahakkanukrauh A, Foocharoen C et al (2020) Outcome of pulse oral cyclophosphamide therapy in scleroderma interstitial lung disease. Clin Rheumatol. https://doi.org/10.1007/s10067-020-05217-x

  32. Laing TJ, Gillespie BW, Toth MB et al (1997) Racial differences in scleroderma among women in Michigan. Arthritis Rheum 40:734–742. https://doi.org/10.1002/art.1780400421

    Article  CAS  PubMed  Google Scholar 

  33. Roofeh D, Jaafar S, Vummidi D, Khanna D (2019) Management of systemic sclerosis-associated interstitial lung disease. Curr Opin Rheumatol 31:241–249. https://doi.org/10.1097/BOR.0000000000000592

    Article  PubMed  PubMed Central  Google Scholar 

  34. Jacob M, Laar V (2017) Immunosuppressive drugs. In: Kelley and Firestein’s textbook of rheumatology, 10th edn. Elsevier, Philadelphia, pp 983–998

    Google Scholar 

  35. Oktem O, Guzel Y, Aksoy S, Aydin E, Urman B (2015) Ovarian function and reproductive outcomes of female patients with systemic lupus erythematosus and the strategies to preserve their fertility. Obstet Gynecol Surv 70:196–210. https://doi.org/10.1097/OGX.0000000000000160

    Article  PubMed  Google Scholar 

  36. Spears N, Lopes F, Stefansdottir A, Rossi V, de Felici M, Anderson RA, Klinger FG (2019) Ovarian damage from chemotherapy and current approaches to its protection. Hum Reprod Update 25:673–693. https://doi.org/10.1093/humupd/dmz027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mok CC, Lau CS, Wong RW (1998) Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis Rheum 41:831–837. https://doi.org/10.1002/1529-0131(199805)41:5<831::AID-ART9>3.0.CO;2-1

    Article  CAS  PubMed  Google Scholar 

  38. Laskari K, Zintzaras E, Tzioufas AG (2010) Ovarian function is preserved in women with severe systemic lupus erythematosus after a 6-month course of cyclophosphamide followed by mycophenolate mofetil. Clin Exp Rheumatol 28:83–86

    CAS  PubMed  Google Scholar 

  39. Ioannidis JPA, Katsifis GE, Tzioufas AG, Moutsopoulos HM (2002) Predictors of sustained amenorrhea from pulsed intravenous cyclophosphamide in premenopausal women with systemic lupus erythematosus. J Rheumatol 29:2129–2135

    CAS  PubMed  Google Scholar 

  40. D’Angelo S, Cuomo G, Paone C, Colutta E, la Montagna G, Valentini G (2003) Low-dose intravenous cyclophosphamide in systemic sclerosis: a preliminary safety study. Clin Rheumatol 22:393–396. https://doi.org/10.1007/s10067-003-0756-8

    Article  PubMed  Google Scholar 

  41. Stanbury RM, Graham EM (1998) Systemic corticosteroid therapy—side effects and their management. Br J Ophthalmol 82:704–708. https://doi.org/10.1136/bjo.82.6.704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Luo X, Feng H, Jiang L, Chen Q (2016) Abnormal uterine bleeding induced by glucocorticoid treatment for pemphigus. Saudi Med J 37:1025–1028. https://doi.org/10.15537/smj.2016.9.14929

    Article  PubMed  PubMed Central  Google Scholar 

  43. Hermankova B, Spiritovic M, Smucrova H, et al Sexual dysfunction in systemic sclerosis female patients. In: ACR Meeting Abstracts https://acrabstracts.org/abstract/sexual-dysfunction-in-systemic-sclerosis-female-patients/. Accessed 6 Jun 2020

  44. Wright VC, Chang J, Jeng G, Macaluso M (2006) Assisted reproductive technology surveillance--United States, 2003. MMWR Surveill Summ 55:1–22

    PubMed  Google Scholar 

  45. Practice Committee of the American Society for Reproductive Medicine (2015) Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril 103:e9–e17. https://doi.org/10.1016/j.fertnstert.2014.12.093

    Article  Google Scholar 

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Acknowledgments

The authors thank (a) the Scleroderma Research Group and the Faculty of Medicine, Khon Kaen University for support (Grant Number IN62236), (b) the Thai Rheumatism Association for the support, and (c) Mr. Bryan Roderick Hamman under the aegis of the Publication Clinic Khon Kaen University, Thailand, for assistance with the English language presentation.

Funding

The study received funding support from Faculty of Medicine, Khon Kaen University, Thailand (Grant Number IN62236).

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Authors and Affiliations

  1. Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Arporn Jutiviboonsuk, Ajanee Mahakkanukrauh, Siraphop Suwannaroj & Chingching Foocharoen

  2. Department of Obstetrics-Gynecology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Lingling Salang & Nuntasiri Eamudomkarn

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  1. Arporn Jutiviboonsuk
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  3. Nuntasiri Eamudomkarn
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  4. Ajanee Mahakkanukrauh
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  6. Chingching Foocharoen
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Contributions

AJ did the data collection and drafted the manuscript. CF designed the study and did data analysis. LS did the data collection and study design. NE did the data collection. LS, NE, AM, SS, and CF proofread the manuscript. CF approved the manuscript.

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Correspondence to Chingching Foocharoen.

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The Human Research Ethics Committee of Khon Kaen University reviewed and approved the study per the Helsinki Declaration and the Good Clinical Practice Guidelines (HE621005). All eligible patients signed informed consent before enrollment.

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Jutiviboonsuk, A., Salang, L., Eamudomkarn, N. et al. Prevalence and clinical associations with premature ovarian insufficiency, early menopause, and low ovarian reserve in systemic sclerosis. Clin Rheumatol 40, 2267–2275 (2021). https://doi.org/10.1007/s10067-020-05522-5

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