1. Thyroid Disorders and Female Infertility Kris 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 - 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) ?

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 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. 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 % % n.s.
Endometriosis 0 % % n.s.
PCOS 20 % % n.s.
Idiopathic 20 % % n.s.
100 % %
Muller et al Fertil Steril. Jan;71:30-4.

14. 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 % %
Male factor % %
Unexplained % % n.s.
OD % %
Uterine cervical % %
Singh et al Fertil Steril. Feb 63 :

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 male idiopathic
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
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. 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

25. 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

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 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 !

32. Thyroid Autoimmunity
&
ART outcome

33. Evidence

34. Miscarriage rate in TAI + versus TAI – women spontaneously pregnant
R.R. from ; 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. 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

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

42. Results

45. P < 0.05

46. 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

47. Aetiology of miscarriage?
higher in TAI + women
“hypo”thyroidism due to TAI
Abalovic 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 : ug/kg/d
n= 57
n= 58
n= 869
Negro et al. J Clin Endocrinol Metab Apr 18;

50. 13.8
3.5
2.4

51. 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

52. 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

53. Thyroid
&
COH

54. 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…

55. Introduction

57. ?

59. Evidence

60. (R= 0.5; p < )

61. ------- before ART _______ after ART
p <
p <
before ART _______ after ART

63. 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 ?

64. 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

65. Results

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

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

68. 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

69. Thyroid function
&
ART - outcome

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

71. 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

72. 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: miU/L)
FT4: 11.4 (nl: ng/l)
Anti-TPO: 5.2 (nl < 34 KU/L)
Anti-Tg: 201 (nl < 115 KiU/L)

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

74. LT4 125 ug/d and refusal to take 150 ug/dC O H

75. 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)

76. 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

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

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

79. 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

80. Screening proposal in infertility …

81. 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

82. Literature

83. 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