1. Hypothyroidism & Infertility CONSULTANT ENDOCRINOLOGIST
-DR. SANJAY KUMAR ROY
MD, DM
CONSULTANT ENDOCRINOLOGIST

2. Outline Prevalence of Hypothyroidism in women
Mechanisms of Ovulatory Dysfunction
Infertility and Thyroid Dysfunction
PCOD ,Infertilty and Thyroid Dysfunction
Autoimmunity Impact on Infertilty and Pregnancy Outcome
Simple Algorithms for Clinicians

3. Prevalence of hypothyroidism
The prevalence of hypothyroidism in the overall study population was 10.95% (3.47% Newly-diagnosed & 7.48% self-reported cases). 
Kolkata recorded the highest prevalence of hypothyroidism (21.67%).
Cities located in the in-land regions of India (Delhi, Ahmedabad, Kolkata, Bangalore and Hyderabad) reported a significantly higher prevalence of hypothyroidism (11.73%) than those (Mumbai, Chennai and Goa) in the coastal areas (9.45%), P = 0.01.
The prevalence of hypothyroidism was the highest in the age-group of 46 to 54 years (13.11%) and the lowest in that of 18 to 35 years (7.53%).
Women were three times more likely to be affected by hypothyroidism than men (15.86 per cent vs per cent).

4. Hypothyroid dysfunction and infertility
The prevalence of infertility is estimated to range between 10% and 15%.
Krassas et al., reported prevalence of menstrual irregularities (mainly oligomenorrhoea) > 23% among hypothyroid patients, compared to 8% in 214 controls.
Probable mechanism was through an impact on the ovaries and indirectly by SHBG, PRL and GnRH secretion and coagulation factors.
Kris Poppe et al.; Thyroid Disease and Female Reproduction; Clin Endocrinol. 2007;66(3):  

5. Hypothyroidism & infertility (Ovulatory disturbances)
The prevalence of infertility is estimated to range 10% - 15%
Ovulatory disturbance
↓SHBG pool—
Androgen Clearance ↓
↑ TSH (analogy to FSH)Pseudo-Feed back inhibition of FSH/LH
Hypothalamo-pituitary changes in Hypothyroidism  impair LH response To GnRH-stimuli
High TRH Hyper-prolactinemia
↑ Ovarian Vol
↑ Stromal Depots
Kris Poppe et al.; Thyroid Disease and Female Reproduction; Clin Endocrinol. 2007;66(3):  
11/14/2018
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6. In Hypothyroidism ? Stromal Depots
Mech-5
Ovarian Volume Rises
In Hypothyroidism ? Stromal Depots

7. AITD and female infertility
Reference Thyroid Infertility Control description AITD AITD RR P
(country, year) antibody cause Study Control (95%CI) value
All studies pooled Relative Risk ( ) <0.0001
Poppe K et. Al. Clin Endocrinol 2007;66:309–321

8. Thyroid autoimmunity
TPO Ab+ women are more likely to have 1st trimester miscarriages even if NORMAL range TSH1
Increased incidence of preterm delivery2
Antithyroid antibodies are an independent marker for miscarriage [OR 2.3 meta-analysis of 18 studies]1
984 pregnant women
115 (11.7%) TPOAb+
Group A (n = 57) LT4 Rx (dosed by initial TSH)
Group B (n = 58) No LT4 Rx
869 TPOAb- Group C (controls)
Main outcomes: obstetrical complications
Gestational hypertension, preeclampsia, preterm birth (<37 weeks)
Mean age:
TPOAb yrs
TPOAb yrs* (p<0.05)
TSH in Group A L-T4 dosing 10.4 wks)
< 1.0mIU/L ug/kg/day
mIU/L ug/kg/day
> 2.0mIU/L ug/kg/day
L-T4 initiated: 40% by 8 weeks
79% by 12 weeks
RX: 0.5mcg/kg/d 8pts (av 31mcg);0 75mcg/kg/d 35pts (av 48mcg); 1mcg/kg/d 14pts (av 65mcg)
Results:
Serum TSH levels in the L-T4 group were constant throughout the pregnancy, whereas they rose in the group not given L-T4
The rates of miscarriage and prematurity were lower in the thyroxine-treated group, and were comparable to rates in the 869 TPO antibody negative comparison group
1Prummel et al, Eur J Clin Endocrinol 2004; 2Stagnaro Green, J Clin Endocrinol Metab, 2009

9. Meta analysis of thyroid antibodies and miscarriage risk (19 cohort studies)
4.3 [ ]
9 studies
3.1 [ ]
7 studies
Evaluate assoc of thyroid Ab and miscarriage in women with nl thyroid func
19 Cohort studies of about 8000 pts overall tripling of odds of miscarriage in presence of thyroid autoantibodies OR 3.9[ ] all 19 showed pos association
OR unselected 4.28 ( ) 9 studies
OR subfertility undergoing ART 3.15 ( ) 7 studies Negro study RCT no difference in preg rates if Ab pos and ART but higher miscarraige
OR recurrent mis 4.22 ( ) 3 studies
Similar for case control studies
4.2 [ ]
3 studies
Thangaratinam BMJ :d2616

10. Meta analysis of thyroid antibodies and preterm delivery risk (11 prospective cohort studies)* * * * *
14 indiv data from 11 PROSPECTIVE cohort studies participants preterm delivery <37-36 wks (14 entries because studies with TPO and Tg Ab listed twice)
Overall RR 1.41, 41% higher for all studies
Significant heterogeneity between studies as 5 included women with thyroid dysfunction and 6 did not.
In fact, status of thyroid function explained 64% of between study variance
Therefore sensitivity analysis performed
For studies excluding women with thyroid dysfnc overall RR for perterm delivery and pos Ab was 1.98 [ ]
Strength of association for TPO Ab but if just looked at studies that included thyroid dysfnc, not sig association
Only 1 study reported and analyzed info about potential confounders of age BMI gravidity race smoking gest age, educational level and site Haddow In fact 64% of variablit
Prev of TPO Ab 5.26% to 14.89%
9 with TPO Ab, 3 Tg Ab and 2 with both. Overall combined RR for preterm delivery risk for preg women with pos Ab c/w ref pop was 1.41 (CI )
ONLY 6 studies in green excluded women with thyroid dysfunction, all eval TPO AB
However, 5 studies included women with thyroid dysfunc
Therefore significant heterogeneity
New recent study just published in JCEM from Greece (Karakosta) supports that autoimmunity WITHOUT TSH elevation in early pregnancy associated with preterm delivery whereas combination was not *
1.41 [ ]
1.98 [ ]
He Eur J Endocrinol :455

11. 115 pregnant TPO Ab+ women, TSH <3, randomized to LT4 Rx or placebo
Effect of Rx with LT-4 in Thyroid autoimmunity and miscarriage/Pre-term delivery
115 pregnant TPO Ab+ women, TSH <3, randomized to LT4 Rx or placebo *
*P<0.05 vs. others *
No difference in PIH, Preeclampsia, or abruption
LT4 Rx in euthyroid TPOAb+ women ↓ miscarriage & preterm delivery
Negro et al, J Clin Endocrinol Metab, 2006

12. L-T4 in Pregnant Euthyroid TPOAb+ Women
TPOAb+ pregnant women with normal serum TSH were randomly assigned to receive L-T4 or no treatment
0.5 mcg/kg/d for TSH <1 mU/L
0.75 mcg/kg/d for TSH 1-2 mU/L
1 mcg/kg/d for TSH >2 mU/l or TPO Ab titers > 1:1500
L-T4 doses:
984 pregnant women
115 (11.7%) TPOAb+
Group A (n = 57) LT4 Rx (dosed by initial TSH)
Group B (n = 58) No LT4 Rx
869 TPOAb- Group C (controls)
Main outcomes: obstetrical complications
Gestational hypertension, preeclampsia, preterm birth (<37 weeks)
Mean age:
TPOAb yrs
TPOAb yrs* (p<0.05)
TSH in Group A L-T4 dosing 10.4 wks)
< 1.0mIU/L ug/kg/day
mIU/L ug/kg/day
> 2.0mIU/L ug/kg/day
L-T4 initiated: 40% by 8 weeks
79% by 12 weeks
RX: 0.5mcg/kg/d 8pts (av 31mcg);0 75mcg/kg/d 35pts (av 48mcg); 1mcg/kg/d 14pts (av 65mcg)
Results:
Serum TSH levels in the L-T4 group were constant throughout the pregnancy, whereas they rose in the group not given L-T4
The rates of miscarriage and prematurity were lower in the thyroxine-treated group, and were comparable to rates in the 869 TPO antibody negative comparison group
Negro et al, J Clin Endocrinol Metab, 2006

13. Prevalence of different thyroid disorders in PCOS
Significantly higher rate of thyroid abnormalities among PCOS group, specially of autoimmune thyroiditis
Uma Sinha et. al; Thyroid disorders in polycystic ovarian syndrome subjects: A tertiary hospital based cross-sectional study from Eastern India; Indian J Endocr Metab 2013;17:304-9

15. Parameters analyzed in PCOS patients and control group
Mean TSH & anti-TPO levels were significantly ↑ in the PCOS pts as compared to controls
Parameters analyzed in PCOS patients and control group
Uma Sinha et. al; Thyroid disorders in polycystic ovarian syndrome subjects: A tertiary hospital based cross-sectional study from Eastern India; Indian J Endocr Metab 2013;17:304-9
11/14/2018
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16. Hypothyroidism and infertility- role of LT4
Normalizes PRL and LH levels
Reverses menstrual abnormalities
↑ spontaneous fertility 
↑ chance of conception in otherwise asymptomatic infertile women
LT4 administration:
76.6% infertile women with hypothyroidism conceived after 6 weeks to 1 year of treatment
Verma I, Sood R, Juneja S, Kaur S. Prevalence of hypothyroidism in infertile women and evaluation of response of treatment for hypothyroidism on infertility. Int J App Basic Med Res 2012;2:17-9
11/14/2018
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17. Prevalence of miscarriage in four studies carried out in women who achieved pregnancy after ART
It is therefore advisable to measure thyroid function and detect AITD in infertile women before ART, and to F/U these parameters after COH and during pregnancy.

18. IVF Miscarriage rate higher in TPOAb+ vs TPOAb- [RR 2.01 (1.13-3.56)]
Thyroid hormone
Group A
LT4
N=43
50%
Miscarriage
N=8, 33%
TPOAb+
N=86
13%
Group B
placebo
N=43
50%
Miscarriage
N=11, 52%
Group C
TPOAb-
N=576
87%
Miscarriage
N=82, 26%
IVF
Negro R et al. Hum Reprod 2005;20:1529

19. In summary, TSH level ≥ 2.5 mIU/L in an oocyte donor may negatively impact implantation and clinical pregnancy among donor oocyte recipients
J Assist Reprod Genet (2016) 33:489–494

20. Screening for thyroid disorders in women after SpA and treatment with levothyroxine is cost-saving and it improves the subsequent pregnancy rate
Bartáková et al. BMC Pregnancy and Childbirth 2013, 13:217

21. The effect of LT4 substitution on the conception rate among hypothyroid women undergoing IVF
LT-4 substitution increases the conception rate among hypothyroid women undergoing IVF
European Review for Medical and Pharmacological Sciences. 2015; 19:

22. There is fair evidence that SCH, defined as TSH >4 mIU/L, is associated with miscarriage, but insufficient evidence that TSH 2.5–4 mIU/L are associated with miscarriage.
There is fair evidence that treatment of SCH when TSH levels are >4.0 mIU/L is associated with improved pregnancy rates and decreased miscarriage rates.
During the 1st trimester of pregnancy it is advisable to treat when the TSH is >2.5 mIU/L. (Grade B)
Fertil Steril 2015;104:545– by American Society for Reproductive Medicine

23. There is fair evidence that thyroid autoimmunity is associated with miscarriage and fair evidence that it is associated with infertility.
While thyroid antibody testing is not routinely recommended, one might consider testing anti-TPO for repeated TSH values >2.5 mIU/L or when other risk factors for thyroid disease are present. (Grade C)
If anti-TPO antibodies are detected, TSH levels should be checked and treatment should be considered if the TSH level is over 2.5 mIU/L. (Grade B)
Fertil Steril 2015;104:545– by American Society for Reproductive Medicine

24. Thyroid hormone disorders and TPO-Ab are associated with disturbed:
Folliculogenesis
Spermatogenesis
Fertilization
Embryogenesis
Human Reproduction Update, Vol.21, No.3 pp. 378–387, 2015

25. Available evidence on effect of thyroid hormones on reproduction

27. Euthyroid autoimmune thyroid disease (AITD) & Infertility
AITD is more prevalent in infertile women and has been associated with:
↑miscarriage rate [spontaneous conception/ ART]
↓ oocyte fertilisation and pregnancy rates in women with AITD undergoing ART
Presence of thyroid autoantibodies (TPO, Tg) in the follicular fluid of all women with AITD
Endometriosis and polycystic ovarian syndrome (PCOS)
Premature ovarian failure
AITD affects 5% to 20% of women of child-bearing age

28. Possible mechanism of AITD causing Infertility
Reproductive failures and miscarriages
IL-2 mediated NK cell activation
Increase IL-2 production
It is suggested that the presence of thyroid antibodies and an ↑TSH
AITD is associated with impaired cellular and humoral immune responses
↑NK cell concentrations in women with unexplained infertility
No significant differences in NK cytotoxic activity

30. On treatment of SCH/AITD patients with LT4 planned for ART likelihood of live birth is 2.78 times than untreated….[Effect In favor of efficacy LT4 Rx]
On treatment of SCH/AITD patients with LT4 planned for ART Relative Risk of ADRs is 0.36 times only….[Effect In favor of safety of LT4 Rx]

31. Meta-analyses provide evidence that LT4 supplementation should be recommended to improve clinical pregnancy outcome in women with subclinical hypothyroidism and/or thyroid autoimmunity undergoing ART

32. Algorithm for screening of thyroid dysfunction & AITD in infertility

33. Thank you