Thyroid Disorders and Female Infertility Kris Poppe MD; PhD

1. Thyroid Disorders and Female InfertilityKris Poppe MD; PhD

2. Introduction • The impact of thyroid disorders during/after spontaneous pregnancies has well been studied in case of : • Hypothyroidism during P • Impaired neuro-intellectual outcome in children • Increased pregnancy morbidity • Thyroid autoimmunity during and after P • Increased miscarriage rate • Post-partum thyroiditis • The association between thyroid disorders and infertility (thus before pregnancy) much less…

3. Agenda • Normal interaction • thyroid - gonadal axis • Thyroid - infertility • thyroid function / - autoimmunity (TAI) • association (with a particular cause of infertility) ? • impact of thyroid disorders on the outcome of assisted reproductive technology (ART) ?

4. Thyroid & Gonadal function

5. Impact of thyroid hormones (TH) on gonadal function has been described through: • direct effects • T3-receptors are present on • Theca cells • Corpus luteum • Throphoblast & • indirect effects • GnRH secretion • PRL secretion • SHBG levels • Coagulation factors Poppe K - Velkeniers B. Female infertility and the thyroid.Best Pract Res Clin Endocrinol Metab. 2004 Jun;18(2):153-65

6. Evidence

7. 46/214 = 22 % 18/124 = 15 %

9. Conclusions 1/ TH have direct and indirect effects on (normal) gonadal function 2/ Treatment with TH can reverse - menstrual symptoms in women with hypothyroidism - but infertility ?

10. Thyroid & Infertility

11. Evidence TAI - hypothyroidism - infertility

13. Thyroid antibodies and cause of infertility TPO Ab + (n=25) TPO Ab - (n=148) Male or tubal 60 % 66 % n.s. Endometriosis 0 % 7 % n.s. PCOS 20 % 6 % n.s. Idiopathic 20 % 21 % n.s. 100 % 100 % Muller et al. 1999 Fertil Steril. Jan;71:30-4.

14. Thyroid antibodies and cause of infertility TPO Ab + (n=106) TPO Ab - (n=381) Tubal pelvic 33 % 34 % Male factor 24 % 27 % Unexplained 23 % 19 % n.s. OD 20 % 18 % Uterine cervical 0 % 2 % Singh et al. 1995 Fertil Steril. Feb 63 : 277-281

15. Prevalence of subclinical hypothyroidism in women with infertility # 1/185 patients had a basal serum TSH > 6 mU/l (0.5 %) ^ prevalence in the Finnish population TSH *: peak serum TSH after TRH-stimulation test

16. Comment • No clear cut association between thyroid disorders and infertility • less sensitive older methods for thyroid antibodies • definition of hypothyroidism ? • all causes or only one cause were considered • different types of controls or no controls were included • Referral bias

18. Background • Causes • female • endometriosis (cf next slides) • tubal pathology • PID, post sterilisation, infectious disease • ovulatory dysfunction • male • WHO sperm criteria • idiopathic

21. Aim of the study • Is there an increased prevalence of TAI and/or – thyroid dysfunction in infertile women compared to fertile controls ? • Is thyroid pathology associated with a particular cause of infertility ? • Is there an association between thyroid antibodies and thyroid function ?

22. Case-control study • 438 consecutive women of infertile couples • 100 controls • age matched, spontaneous pregnancies, no history of miscarriage • screened for • - TSH : normal range : 0.27 – 4.2 mU/L • - FT4 : normal range : 9.3 – 18 ng/l • - TPO-Abs : positive when > 100 kU/L (ie TAI +) • infertility cause was allocated to each patient after full gynaecological work-up

23. Results

24. # mean  SD ° median (interquartile) ^ % positive * p < 0.05 against controls

25. # mean  SD ° median (interquartile) ^ % positive * p < 0.05 against controls

26. *p < 0.05 and**p < 0.01 Ab + against Ab - patients TSH i > 4.2 mU/l and TSH-s < 0.27 mU/l

31. Conclusions • Female infertility, especially endometriosis and PCOS are • associated with an increased risk of TAI • TAI is correlated with an altered TSH • The present study indicates that • women with identifiablefemale causes of infertility could • be screened for TPO-Abs and TSH • ... But the prevalence of infertility in women with • thyroid dysfunction remains unknown !

32. Thyroid Autoimmunity & ART outcome

33. Evidence

34. Miscarriage rate in TAI + versus TAI – women spontaneously pregnant 552 723 363 1179 876 R.R. from 1.9-4.4 ; mean : 3.0

36. Comment • No clear cut association between TAI and the outcome of ART • some measured thyroid antibodies during pregnancy • sample size • the number of cycles was not mentioned

38. Aim of the study • Is the outcome of ART different in • infertile women • with TAI (TAI +) • without TAI (TAI -) ?

39. Patients 438 234 only first attempt of ART overt thyroid dysfunction moved to other centers refused ART

40. Patients • Prospective analysis of ART outcome in • 234 women of infertile couples screened prior to ART for • TSH : 0.27 – 4.2 mU/L • FT4 : 9.3 – 18 ng/l • TPO-Abs : positive when > 100 kU/L

41. ET : number of transferred embryos  # mean  SD ° median (range)

42. Results

45. P < 0.05

46. Conclusions • Thyroid Autoimmunity before ART • is associated with an increased first trimester miscarriage rate • like in spontaneous pregnancies • not impairing the pregnancy rate • TPO-Abs could be screened in all women of • infertile couples

47. Aetiology of miscarriage? • age • higher in TAI + women • “hypo”thyroidism due to TAI • Abalovic 2002 - Negro 2006 • immune imbalance • T-cell defect, B-cell (CD5/CD20) • direct actions of thyroid antibodies • animal model (anti-Tg) • no clear dose response

48. TH : 0.5-1 ug/kg/d n= 57 n= 58 n= 869 Negro et al. J Clin Endocrinol Metab. 2006 Apr 18;

50. 13.8 3.5 2.4