http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(10): 708–711 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.926324

OVARIAN RESERVE IN HASHIMOTO THYROIDITIS

Evaluation of ovarian reserve in Hashimoto’s thyroiditis Abdullah Tuten1, Esra Hatipoglu2, Mahmut Oncul1, Metehan Imamoglu1, Abdullah Serdar Acikgoz1, Nevin Yilmaz1, Mustafa Dogan Ozcil3, Baris Kaya4, Ali Mesut Misirlioglu5, and Sezai Sahmay1 1

Department of Obstetrics & Gynecology, 2Department of Endocrinology, Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey, Department of Obstetrics & Gynecology, Mustafa Kemal University School of Medicine, Antakya, Hatay, Turkey, 4Department of Obstetrics & Gynecology, Near East University School of Medicine, Lefkosa Mersin, Turkey, and 5Gaziantep Maternity Hospital, Gaziantep, Turkey

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Abstract

Keywords

Human ovary is commonly the target of an autoimmune attack in cases of organ- or nonorgan-specific autoimmune disorders. Hashimoto’s thyroiditis (HT) is likely to be associated with ovarian dysfunction and diminished ovarian reserve. In this study, we aimed to evaluate the possible negative association between this significantly prevalent autoimmune disease and the ovarian reserve. Thirty-two premenopausal women with primary hypothyroidism, who under replacement therapy with thyroxine were recruited. Forty-nine healthy female subjects who had normal anti-thyroid antibody levels and were comparable with the HT group in terms of age and BMI values, comprised the control group. There was no statistically significant difference between the study and the control patients in terms of antral follicle count. Serum anti-Mu¨llerian hormone (AMH) levels were significantly higher in woman with HT compared to the control group. The results of this study found no impairment in ovarian reserve parameters of patients with HT. Interestingly, the results revealed a significant increase in serum AMH levels of the patients with HT compared to controls. Hashimoto’s thyroiditis may share a common etiologic linkage with polycystic ovary syndrome; therefore, leading to elevated serum AMH levels, which we are currently unable to define elaborately.

AFC, AMH, Hashimoto’s thyroiditis, ovarian reserve, PCOS

Introduction Human ovary is commonly the target of an autoimmune attack in cases of organ- or non-organ-specific autoimmune disorders, leading to the ovarian dysfunction which can eventually end up in premature ovarian failure (POF) in its most extreme clinical presentation. Clinically, the ensuing ovarian dysfunction often results in POF but also other pathologies involving the ovaries, such as unexplained infertility, polycystic ovary syndrome (PCOS) and endometriosis have been associated with anti-ovarian autoimmunity [1,2]. Among autoimmune disorders, autoimmune thyroid diseases are the most prevalent pathologies associated with POF [3,4]. Hashimoto’s thyroiditis (HT) is the most common organ-specific autoimmune disorder affecting approximately 18% of population, characterized by diffuse lymphocytic infiltration of the thyroid gland, elevated levels of serum anti-thyroid antibodies, evidence of goitrous or atrophic gland, and frequent thyroid dysfunction in varying degrees [5]. Belvisi et al. [6] reported that 40% of 45 women with POF were positive for at least one organ-specific auto-antibody, the most common being anti-thyroid antibodies (20%). In addition, a recent study investigated the presence of thyroid peroxidase auto-antibodies in a large cohort of POF and found it in 24% of these cases [7].

Address for correspondence: Abdullah Tuten, MD, Department of Obstetrics and Gynecology, Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey. Tel: +90-541-564-38-76. E-mail: [email protected]

History Received 23 December 2013 Accepted 17 May 2014 Published online 6 June 2014

In this context, HT is likely to be associated with ovarian dysfunction and diminished ovarian reserve. Assessment of ovarian reserve has crucial importance. Various hormonal markers and ultrasound parameters are used to estimate ovarian reserve. These markers and parameters include age; concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, inhibin B, anti-Mu¨llerian hormone (AMH); ovarian volume, ovarian antral follicle count (AFC) and ovarian biopsy. Further studies have introduced the use of dynamic tests – using a gonadotropin-releasing hormone agonist (GnRH-a), FSH or clomiphene citrate – to assess ovarian function [8]. Association between ovarian dysfunction and HT, which is mentioned above, brings out the further need to investigate whether if HT plays a key role on the impairment of ovarian reserve to any extent. In this context, we aimed to evaluate the possible negative association between this significantly prevalent autoimmune disease and the ovarian reserve.

Materials and methods Total number of 32 premenopausal women with HT all of whom were under replacement therapy with thyroxine and were followed-up at Istanbul University Cerrahpasa School of Medicine, Endocrinology and Metabolism outpatient clinic composed the study group. Patients aged between 18 and 45 with regular menstrual cycles were included. Among healthy females who had admitted to our department; 49 patients who were comparable for age and body mass index (BMI) and had negative results for the antibodies to thyroglobulin (anti-TG)

Ovarian reserve in Hashimoto’s thyroiditis

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DOI: 10.3109/09513590.2014.926324

and/or thyroid peroxidase (anti-TPO) were randomly selected. Patients with other endocrine and/or autoimmune disorders, PCOS and any history of previous surgical, medical and/or radiotherapy which could decrease ovarian reserve were excluded. The study protocol was approved by the Ethics Committee of Cerrahpasa School of Medicine, Istanbul University. An informed consent was obtained from all subjects prior to enrollment in the study. Diagnosis of HT (chronic autoimmune thyroiditis) was determined by the presence of anti-TG and/or anti-TPO and/or pathologic verification after a fine needle aspiration biopsy, which was previously performed for a nodule evaluation. Demographic features and a medical history which included any history of surgery and medical treatment, number of pregnancies, parity and abortion in the past and periods of menstrual cycles were obtained from every subject. Body weight and height were measured for every woman, body mass index (BMI) was calculated with electronic digital scales (Mercury, AMZ 14, Tokyo, Japan) and in light clothing; height was measured barefoot with a stadiometer (G-Tech International Co Ltd, Kyonggi Province, Korea). Venous blood samples from each patient were obtained to determine follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin (PRL), thyrotropin (TSH), free thyroxine (FT4), free triiodothyronine (fT3), anti-TPO, antiTG and AMH before 10:00 am in the early follicular phase. Chemiluminescence immunoassay was done to assess PRL (N: 3.4–23.3 ng/mL), LH (N: 2.4–12.6 mIU/mL), FSH (N: 3.6–12.5 mIU/mL), E2 (N: 12.5–166 pg/mL), TSH (N:0.4–4.0 mIU/mL), fT4 (N: 0.8–1.9 ng/dL), fT3 (N: 1.8–4.2 pg/mL), anti-TPO (N: 0– 35.5 IU/mL) and anti-TG (N 0–40 IU/mL). AMH concentrations were measured with an enzymatically amplified two-sided immunoassay [DSL-10-14400 Active Mu¨llerian Inhibiting Substance/AMH enzyme linked immunosorbent assay (ELISA) kit, Diagnostic Systems Laboratories (DSL), Webster, TX]. The theoretical sensitivity of the method is 0.006 ng/mL, the intraassay coefficient of variation for high values is 3.3%, and the inter-assay coefficient of variation for high values is 6.7%. Transvaginal ultrasonographic evaluation was performed by experienced sonographers who participated in the study with a 7-MHz transvaginal transducer (Sonoline Elegra; Siemens SAS, Saint-Denis, France). Antral follicles within the bilateral ovaries between 2 and 6 mm in diameter were recorded.

All statistical analyses were performed using the Predictive Analytics Software (PASW) version 18.0 (IBM Corporation, NY, USA). Results were presented as median (25th–75th percentile) or mean ± standard deviation. In the beginning of the analysis, the Kolmogorov–Smirnov test was performed for confirming the normality of the distribution in both groups. Independent samples t-test was used as a parametric test and the Mann–Whitney U-test was used as a non-parametric test for comparison of numeric variables. Pearson’s correlation coefficient was used to determine the relationship between the variables AMH. All reported confidence interval (CI) values are calculated at the 95% level. p Values 50.05 were considered statistically significant.

Results Thirty-two women with HT and 49 normal women were included in the study. Clinical and hormonal characteristics of the subjects are shown in Table 1. There was no statistically significant difference between the study and the control patients in terms of age, BMI, the length of menstrual cycle, FSH, LH, E2, PRL, TSH, fT4 and AFC (p40.05 for all). Serum AMH and fT3 levels were significantly higher in woman with HT compared to the control group (4.82 [1.47–7.38] versus 2.44 [1.63–3.29], p: 0.025; 2.84 ± 0.56 versus 2.55 ± 0.59, p: 0.033; respectively). Serum fT3 levels are found to be within the normal range, even though the results indicate higher levels. Anti-TPO and anti-thyroglobulin antibodies were both higher in the HT group compared to the controls (290.88 [90.64–421.17] versus 24.13 [18.71–31.12], p: 0.001; 330.51 [53.67–444.62] versus 18.89 [11.29–29.74], p: 0.001). Correlation analysis between AMH and other parameters are shown in Table 2. Mean serum AMH levels are found to be correlated with age, E2, anti-TPO, anti-TG and antral follicle count (r: 0.361, p: 0.001; r: 0.226, p: 0.044; r: 0.283, p: 0.010; r: 0.411, p: 0.001; r: 0.341, p: 0.002, respectively) (Table 2).

Discussion Ovarian reserve plays a crucial role in achieving pregnancy and menstrual regularity in reproductive-age women. The estimation of ovarian reserve is routinely performed through various ovarian reserve tests in an effort to predict the ovarian response and pregnancy outcome in couples [9]. Many parameters have been

Table 1. Comparison of the clinical and hormonal characteristics between HT patients and the control group.

Age (years) BMI (kg/m2) Length of menstrual cycle (days) Antral follicle count (n) AMH (ng/mL) FSH (mIU/mL) LH (mIU/mL) E2 (pg/mL) PRL (ng/mL) TSH (mIU/mL) FT3 (pg/mL) FT4 (pg/mL) Anti-TPO (IU/mL) Anti-TG (IU/mL)

709

HT N: 32

Control N: 49

p

34.93 ± 8.87 24.33 ± 3.12 30.21 ± 10.24 6.84 ± 3.81 4.82 (1.47–7.38) 7.16 ± 2.29 6 ± 2.77 50.42 (31.12–66.89) 15.67 (9.16–17.35) 2.22 ± 1.63 2.84 ± 0.56 1.27 ± 0.32 290.88 (90.64–421.17) 330.51 (53.67–444.62)

34.16 ± 4.74 23.57 ± 1.62 28.34 ± 2.08 6.08 ± 2.72 2.44 (1.63–3.29) 6.53 ± 2.55 5.56 ± 1.92 44.18 (31.25–53) 17.47 (11.51–21) 1.84 ± 1.07 2.55 ± 0.59 1.22 ± 0.31 24.13 (18.71–31.12) 18.89 (11.29–29.74)

0.611y 0.155y 0.262y 0.297y 0.025*,z 0.257y 0.301y 0.867z 0.112z 0.207y 0.033*,y 0.544y 0.001*,z 0.001*,z

Continuous variables are presented as median (25th–75th percentile) or mean ± standard deviation. BMI: Body Mass Index; AMH: Anti-Mu¨llerian Hormone; FSH: Follicle Stimulating Hormone; LH: Luteinizing Hormone; E2: Estradiol; PRL: Prolactin; TSH: Thyroid Stimulating Hormone; FT3: Free Thyroxine 3; FT4: Free Thyroxine 4; Anti-TPO: Anti-Thyroid Peroxidase; Anti-TG: Anti-Thyroglobulin. yIndependent samples t-test (two-tailed). zMann–Whitney U-test. *p Value 50.05.

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Gynecol Endocrinol, 2014; 30(10): 708–711

Table 2. The correlation between AMH and the other parameters. AMH

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Age BMI FSH LH E2 PRL TSH FT3 FT4 Anti-TPO Anti-TG Antral follicle count

r

p

0.361 0.132 0.135 0.085 0.226 0.014 0.054 0.049 0.036 0.283 0.411 0.341

0.001* 0.240 0.230 0.449 0.044* 0.900 0.634 0.665 0.748 0.010* 0.001* 0.002*

Anti-TPO: Anti-Thyroid Peroxidase; Anti-TG: AntiThyroglobulin. *p Value 50.05.

introduced and utilized in clinical practice so far but AMH is suggested as a relatively sensitive marker of reproductive aging compared with AFC, FSH and inhibin B. Serum AMH levels are also shown to decrease before FSH rises in normally cycling women [10,11]. In this study, which is the first evaluation of ovarian reserve in HT patients, we found no evidence of diminished ovarian reserve in any aspect. Instead, our results revealed significantly higher levels of AMH, which is suggested as one of the most sensitive indicator of ovarian reserve, in the HT group. Indeed, the results demonstrated that AMH was positively correlated with antithyroid antibodies and AFC, and negatively correlated with age and E2. Several studies have investigated the relationship between autoimmune diseases and diminished ovarian reserve so far. Systemic lupus erythematosus (SLE) is an autoimmune disease which may negatively influence fertility. Treatment with cyclophosphamide (CYC) can damage the ovaries. The ovarian function can also be reduced by autoimmune oophoritis in lupus patients. SLE patients at their reproductive age who had no prior history of CYC administration had lower levels of ovarian reserve parameters including AMH, compared to healthy controls [12]. However, in another study, Aikawa et al. [13] found no impairment in ovarian reserve parameters of a cohort of patients with juvenile SLE without any history of CYC therapy. Further evaluation of patients treated with CYC and those without this treatment revealed higher median FSH levels, while no other significant differences were found in terms of ovarian reserve parameters. Two other studies also showed lower levels of AMH in SLE patients who had received CYC therapy [14,15]. Clowse et al. [16] investigated the relation between ovarian reserve and Wegener’s granulomatosis (WG). Patients who were previously exposed to CYC had lower AMH and higher FSH levels with a higher rate of premature menstrual cessation. Indeed, the patients who had normal baseline ovarian function and received CYC during the trial developed diminished ovarian reserve. Brouwer et al. [17] investigated the ovarian reserve of rheumatoid arthritis patients and their results revealed no difference in ovarian reserve parameters, compared to healthy controls. In addition, AMH levels of patients with RA were not affected by disease activity or by short-term (6 months) of methotrexate therapy. Several studies which investigated the reproductive functions of the patients with HT revealed higher anti-thyroid and anti-TPO antibodies in the subgroup of unexplained infertility. Women with

infertility seem to have an increased prevalence of thyroid autoimmunity. Prevalence of thyroid autoimmunity is especially high in association with PCOS and endometriosis, and both conditions have been associated with autoimmunity, inflammation and infertility [18]. The results of this study found no impairment in ovarian reserve parameters of patients with HT. Interestingly, the results revealed a significant increase in serum AMH levels of the patients with HT compared to controls. In addition, serum AMH levels were positively correlated with AFC and negatively correlated with E2 and age, as expected. Serum AMH levels were also found to be positively correlated with anti-TPO and anti-thyroid antibodies. Hereby, it should be emphasized that PCOS stands as an exclusive disorder which is both characterized with autoimmunity and elevated AMH levels [19]. In addition, elevated anti-thyroid antibodies in PCOS have been documented before [20–22]. None of the patients recruited for this study met the criteria necessary to establish the diagnosis of PCOS. However, HT may share a common etiologic linkage with PCOS, therefore leading to elevated serum AMH levels, which we are currently unable to define elaborately. In conclusion, this is the first study to evaluate the ovarian reserve in patients with HT. Ovarian reserve parameters were not decreased. Furthermore, serum AMH levels were elevated in patients with HT compared with controls and also were positively correlated with anti-thyroid antibodies. Future studies with larger populations are absolutely needed for an elaborate definition of the ovarian reserve parameters in HT.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

References 1. Petrikova J, Lazurova I. Ovarian failure and polycystic ovary syndrome. Autoimmun Rev 2012;11:A471–8. 2. Luborsky J. Ovarian autoimmune disease and ovarian autoantibodies. J Womens Health Gend Based Med 2002;11:585–99. 3. Alper MM, Garner PR. Premature ovarian failure: its relationship to autoimmune disease. Obstet Gynecol 1985;66:27–30. 4. Betterle C, Rossi A, Dalla Pria S, et al. Premature ovarian failure: autoimmunity and natural history. Clin Endocrinol (Oxf) 1993;39: 35–43. 5. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489–99. 6. Belvisi L, Bombelli F, Sironi L, Doldi N. Organ-specific autoimmunity in patients with premature ovarian failure. J Endocrinol Invest 1993;16:889–92. 7. Goswami R, Marwaha RK, Goswami D, et al. Prevalence of thyroid autoimmunity in sporadic idiopathic hypoparathyroidism in comparison to type 1 diabetes and premature ovarian failure. J Clin Endocrinol Metab 2006;91:4256–9. 8. Coccia ME, Rizzello F. Ovarian reserve. Ann N Y Acad Sci 2008; 1127:27–30. 9. Jirge PR. Ovarian reserve tests. J Hum Reprod Sci 2011;4:108–13. 10. de Vet A, Laven JS, de Jong FH, et al. Anti-Mullerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril 2002; 77:357–62. 11. van Rooij IA, Broekmans FJ, Scheffer GJ, et al. Serum antiMullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertil Steril 2005;83:979–87. 12. Lawrenz B, Henes J, Henes M, et al. Impact of systemic lupus erythematosus on ovarian reserve in premenopausal women: evaluation by using anti-Muellerian hormone. Lupus 2011;20:1193–7. 13. Aikawa NE, Sallum AM, Pereira RM, et al. Subclinical impairment of ovarian reserve in juvenile systemic lupus erythematosus after cyclophosphamide therapy. Clin Exp Rheumatol 2012;30:445–9.

DOI: 10.3109/09513590.2014.926324

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14. Morel N, Bachelot A, Chakhtoura Z, et al. Study of anti-Mullerian hormone and its relation to the subsequent probability of pregnancy in 112 patients with systemic lupus erythematosus, exposed or not to cyclophosphamide. J Clin Endocrinol Metab 2013;98:3785–92. 15. Mok CC, Chan PT, To CH. Anti-mullerian hormone and ovarian reserve in systemic lupus erythematosus. Arthritis Rheum 2013;65: 206–10. 16. Clowse ME, Copland SC, Hsieh TC, et al. Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener’s). Arthritis Care Res (Hoboken) 2011; 63:1777–81. 17. Brouwer J, Laven JS, Hazes JM, et al. Levels of serum antiMullerian hormone, a marker for ovarian reserve, in women with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2013;65:1534–8.

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18. Poppe K, Velkeniers B, Glinoer D. Thyroid disease and female reproduction. Clin Endocrinol (Oxf) 2007;66:309–21. 19. Petrikova J, Lazurova I, Yehuda S. Polycystic ovary syndrome and autoimmunity. Eur J Intern Med 2010;21:369–71. 20. Kachuei M, Jafari F, Kachuei A, Keshteli AH. Prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome. Arch Gynecol Obstet 2012;285:853–6. 21. Garelli S, Masiero S, Plebani M, et al. High prevalence of chronic thyroiditis in patients with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 2013;169:248–51. 22. Ganie MA, Marwaha RK, Aggarwal R, Singh S. High prevalence of polycystic ovary syndrome characteristics in girls with euthyroid chronic lymphocytic thyroiditis: a case-control study. Eur J Endocrinol 2010;162:1117–22.

Evaluation of ovarian reserve in Hashimoto's thyroiditis.

Human ovary is commonly the target of an autoimmune attack in cases of organ- or non-organ-specific autoimmune disorders. Hashimoto's thyroiditis (HT)...
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