Thyroid Disorders and Female Infertility Kris Poppe MD; PhD                                                                                 

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…

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

Thyroid & Gonadal function

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

Evidence

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

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 ?

Thyroid & Infertility

Evidence TAI - hypothyroidism - infertility

Muller et al. 1999 Fertil Steril. Jan;71:30-4. 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.

Singh et al. 1995 Fertil Steril. Feb 63 : 277-281 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

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

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

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

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 ?

Case-control study 438 consecutive women of infertile couples 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

Results

n (%) Age# TSH° FT4° Female Male All Controls Cause of infertility n (%) Age# TSH° FT4° TPO-Abs^ Female 197 (45) 34  6 1.3 (0.9) * 12 (2) 18 % * Male 168 (38) 31  5 * 11 % Idiopathic 73 (17) 32  5 1.2 (1.1) * 7 % All 438 (100) 14 % Controls 100 33  4 1.1 (0.8) 11 (2) 8 % # mean  SD ° median (interquartile) ^ % positive * p < 0.05 against controls

n (%) Age# TSH° FT4° Tubal OD Controls Female causes n (%) Age# TSH° FT4° TPO-Abs^ Endometriosis 21 (11) 32  4 1.2 (1.0) 12 (1) * 29 % * Tubal 60 (30) 34  5 1.2 (0.8) 12 (3) 18 % OD 116 (59) 34  6 1.5 (1.0) * 12 (2) 16 % Controls 100 33  4 1.1 (0.8) 11 (2) 8 % # mean  SD ° median (interquartile) ^ % positive * p < 0.05 against controls

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

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 identifiable female causes of infertility could be screened for TPO-Abs and TSH ... But the prevalence of infertility in women with thyroid dysfunction remains unknown !

Thyroid Autoimmunity & ART outcome

Evidence

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

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

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

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

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

TAI + TAI – n (%) 32 (14) 202 (86) age# (yrs) 33  5 32  5 TSH° (mU/l) 1.6 (0.02 - 4.1) 1.3 (0.05 - 3.6) FT4° (ng/l) 12.2 (9.1 - 18) 11.7 (9.1 - 18) ET# (n) 2.1  0.4 2.0  0.5 ET : number of transferred embryos  # mean  SD ° median (range)

Results

P < 0.05

Conclusions TPO-Abs could be screened in all women of 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

Aetiology of miscarriage? 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

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

13.8 3.5 2.4

General conclusions (1) Thyroid autoimmunity is more frequent in female infertilty especially in endometriosis and PCOS is associated with an increased miscarriage rate after ART even in euthyroid women

General conclusions (2) Thyroid function is not clearly more frequently abnormal in female infertility (compared to fertile women) is more frequently altered in TAI + women

Thyroid & COH

Introduction The impact estrogens on thyroid function during spontaneous pregnancies has well been studied (cf next slides) The impact of high estrogen levels in the preparation of ART (assisted reproductive technologies) however much less…

Introduction

?

Evidence

(R= 0.5; p < 0.0001)

------- before ART _______ after ART p < 0.0001 p < 0.0001 ------- before ART _______ after ART

Aim of the study Is there an impact of COH on thyroid function? Is this impact different in TAI + women versus TAI - women ? How is thyroid function in earliest pregnancy stages i.e. before the hCG impact ?

All patients TAI + TAI - n (%) 35 (100) 9 (26) 26 (74) age (yrs) 32  5 33  5 31  5 TSH (mU/l) 1.8  0.9 2.2  0.9 1.6  0.9 ET (n) 2.1  0.6 hCG* (IU/l) 188  122 175  121 193  124 ET : number of transferred embryos  all values expressed as mean  SD * levels at day 20

Results

Effect over time p < 0.001 for TSH and p = 0.005 for FT4

Serum TSH and FT4 according to TAI status p< 0.001 p=0.005

Conclusions Serum TSH and FT4 significantly increase after COH Thyroid hormone profile is significantly different between women with - and without TAI lower FT4 and higher serum TSH over time in TAI + women

Thyroid function & ART - outcome

Case - Report Thyroid function in TAI + woman and the hyperstimulation syndrome

Background Previous papers have reported on the impact of COH on The ovarian hyperstimulation syndrome (OHSS) is a complication of controlled ovarian hyperstimulation (COH) used for assisted reproduction OHSS occurs after triggering ovulation clinically it can vary from a slight abdominal discomfort, over pleural & peritoneal effusion to collapsing shock biological very high estradiol (E2) level (≥ 5000 ng/L) are present Previous papers have reported on the impact of COH on thyroid function, but not in case of OHSS - Muller et al. JCEM 2000 - Poppe et al. JCEM 2004

Case - Report Woman (35 years) with a known Hashimoto’s disease treated with LT4 125 ug/ day She underwent ART for idiopathic infertility Pre-COH thyroid tests were : TSH: 3.6 (nl: 0.27-4.2 miU/L) FT4: 11.4 (nl: 9.3-17 ng/l) Anti-TPO: 5.2 (nl < 34 KU/L) Anti-Tg: 201 (nl < 115 KiU/L)

LT4 125 ug/d and refusal to take 150 ug/d

LT4 125 ug/d and refusal to take 150 ug/d C O H

The patient asked for treatment (including abortion) LT4 125 ug/d and refusal to take 150 ug/d C O H The patient asked for treatment (including abortion)

After discussion … C O H LT4 200 ug/d LT4 125 ug/d and refusal to take 150 ug/d C O H After discussion … LT4 200 ug/d

C O H LT4 125 ug/d and refusal to take 150 ug/d LT4 200 ug/d E2 decreasing and hCG increasing

C O H LT4 125 ug/d and refusal to take 150 ug/d LT4 200 ug/d E2 decreasing and hCG increasing

Conclusions OHSS has an important impact on thyroid function Especially when TAI is associated Thyroid function should be measured before and after COH A high normal serum TSH should be interpreted according to the clinical setting

Screening proposal in infertility …

Treat according to the cause # TSH, TPO-Ab   TSH  TSH nl TSH  FT4, FT3, TSI TPO - TPO + LT4 / FU after COH Treat according to the cause # : consider screening in other causes than female infertility

Literature

Dankbetuigingen Endocrinology department B. Velkeniers - D. Glinoer (ULB) - L. Vanhaelst – P. Haentjens Centre for reproductive medicine P. Devroey - H. Tournaye - J. Schiettecatte - A. Van Steirteghem