Introduction
An optimal level of thyroid hormones is needed for reproductive health. This has been proved clearly in women who have a higher chance of having “autoimmune thyroid diseases (Hashimoto’s thyroiditis and Graves’ disease)” compared to men. Both overt and subclinical thyroid disease and thyroid autoimmunity (TAI) have been shown to be associated with infertility. Thyroid dysfunction can adversely affect follicular development, spermatogenesis, fertilization rates, embryo quality, and live birth rates. The evidence of this association is clearer with hypothyroidism than hyperthyroidism. Overt hypothyroidism leads to menstrual cycle irregularity and ovulatory dysfunction. Through the negative feedback on hypothalamic–pituitary axis, it leads to hyperprolactinemia and ovulatory dysfunction resulting from interference with pulsatile release of GnRH. Thyroid dysfunction causes alteration in sex steroids and sex hormone-binding globulin (SHBG) levels; hyperthyroidism and hypothyroidism affect SHBG levels and thus can impact reproduction.
The classification of thyroid dysfunction is given in Table 9.1 .
| TSH (0.4–4.2 mIU/L) | FT4 (0.89–1.76 ng/dL) | |
|---|---|---|
| Euthyroid | Normal | Normal |
| Subclinical hypothyroidism | High | Normal |
| Overt hypothyroidism | High | Low |
| Subclinical hyperthyroidism | Low | Normal |
| Overt hyperthyroidism | Low | High |
Thyroid imbalance and female subfertility
Association of thyroid dysfunction with menstrual irregularity
Both “overt hypothyroidism” and “overt hyperthyroidism” can entail menstrual irregularity like polymenorrhea, oligomenorrhea, and menorrhagia. As many as 22% of hyperthyroid women can have menstrual irregularity in comparison with 8% of euthyroid controls. Infertile women with menstrual irregularities were prone to have abnormal thyroid function. Among infertile women, 67% had menstrual irregularity, while only 29% fertile women had menstrual disorder. In another study including 171 women with TSH concentrations >15 mU/L, menstrual irregularity was reported in 68% while only 12% women had menstrual irregularities among euthyroid controls.
Association of thyroid dysfunction with subfertility
Thyroid dysfunction is frequently found in infertile women in contrast to fertile women. Infertile women had lesser chances to be euthyroid in comparison with fertile women in a study which reported that 62.6% of infertile women were euthyroid compared to 82.6% of fertile women. In a study on women of reproductive age, the frequency of infertility was 52.3% and 47% in women with Graves’ disease and Hashimoto’s thyroiditis, respectively. However, there are contradictory data as well that reported similar prevalence of subclinical or overt hyperthyroidism in both infertile and fertile women. A retrospective study on 200 subfertile women aged 17–40 years revealed that 14% of women had preexisting hypothyroidism, 14.5% had recently discovered hypothyroidism, while 21% had subclinical hypothyroidism (SCH). Hypothyroidism was significantly associated with higher LH (8.5 IU/L vs 6.8 IU/L) and infertility related to anovulation (47.8% vs 27%) in women with TSH above or below 4.2 mIU/L, respectively. 7 Thus, it provides an insight into altered gonadotropin levels with hypothyroidism.
Association of SCH with subfertility
Many studies have tried to answer this question, but the results are inconsistent. A cross-sectional study found a prevalence of SCH in 2.3% of 704 infertile women, but this prevalence was comparable to background general population. Similar results were reported by another prospective study in which infertile women did not have increased prevalence of SCH. Nevertheless, many studies have shown increased rates of SCH in subfertile women. Higher frequency of SCH (13.9%) was found in infertile women in contrast to 3.9% in fertile women in a retrospective study. Among 454 women presenting for subfertility, TSH > 4.5 mIU/L was found in 24%. Women with ovulatory disorders and “unexplained (UE) infertility” had the highest level of TSH, while it was lower among those women with either tubal disorders or infertility due to male factor. Even euthyroid women with UE infertility had higher TSH values within the specified normal range. {TSH (mIU/L): UE infertility—1.95 vs male factor infertility—1.66; P —0.003}. In addition, women with UE infertility had double the chance of having a TSH of ≥ 2.5 mIU/L in comparison with controls with male factor infertility.
Association of TAI and subfertility in women
TAI identified by the existence of thyroid peroxidase antibodies (TPOAbs) or thyroglobulin antibodies (TgAbs) is frequently stated in subfertile women. Specifically, TPOAb has been related to lower fertilization rates and unstable embryogenesis.
TPOAb was likely to be positive in euthyroid women having female factor infertility in comparison with fertile, age-matched euthyroid women. In women with polycystic ovarian syndrome (PCOS), the frequency of TAI may be higher in comparison with controls. In subfertile women with PCOS, the existence of TAI has been correlated with a lower probability of maturing ovarian follicles with the use of clomiphene citrate for ovulation induction. However, other studies have failed to prove such associations. Among infertile women with PCOS, a study conducted on 436 women undergoing 530 antral follicular count (AFC) measurements, no correlation was found with regard to thyroid function or TPOAb positivity with AFC. Conversely, the same study reported that lower free T3 and TPOAb positivity were coupled with a lower AFC in females with diminished ovarian reserve (DOR) or UE infertility.
Consequences of “assisted reproductive technology (ART)” in women with SCH
There are inconsistent data on adverse outcomes of ART in women with SCH. Most of the evidence shows that rates of success of in vitro fertilization (IVF) for women with serum TSH < 2.5 mU/L and those with TSH between 2.5 and 5 mU/L are not very different.
SCH is accompanied by DOR in women during later reproductive age. Out of 2568 women seeking infertility treatment who were more than 35 years old, SCH was considerably related to follicular-stimulating hormone (FSH), anti-Mullerian hormone concentrations, and AFC.
In a prospective study of female cohort with baseline serum TSH within the range of 0.4–4.99 mU/L who went through intrauterine insemination (IUI), no association was found with variables of IUI, rates of pregnancy, and live birth in each cycle. Multiple studies investigated the effect of TSH ≤ 2.5 mIU/L vs TSH > 2.5 or < 4.5 mIU/L on outcomes of ART, i.e., rates of pregnancy, miscarriages, or live births with no significant difference reported. Similarly, aggregate of rates of pregnancy and miscarriages was comparable between women with TSH < 2.5 and 2.5–3.5 mIU/L and presence of TAI. In contrast, a retrospective study of IVF on 164 women reported higher clinical pregnancy rates in women with TSH ≤ 2.5 (22%) vs those with TSH > 2.5 mU/L (9%). Other researchers have looked at the difference in embryo quality during IVF cycle in women with serum TSH 0.45–2.5 mU/L vs 2.5–4.5 mU/L and observed no significant change in embryo quality, implantation, pregnancy loss, or live birth rates. Thus, the existing evidence suggests that SCH may or may not impact outcomes of ART but at the same time highlights the fact that this impact can worsen as TSH continues to rise. Based on these data, treatment of SCH can be offered to infertile women undergoing ART for levels of > 2.5 mU/L, keeping in mind that low-dose thyroid hormone replacement is generally safe. Nevertheless, it should be noted that high-quality data verification is not available in favor of this recommendation.
Effect of treatment of SCH on ART results
Different studies have shown varying results in infertile women having SCH who received treatment. Similarly, there have been inconsistent results in women with SCH with or without TAI. However, there is general understanding based on existing scientific evidence that the treatment of substantial elevation of TSH (though still categorized as SCH) may benefit the ART outcome. Sixty-four women having SCH (TSH > 4.5 mU/L with normal FT4) undergoing IVF were randomized to levothyroxine (LT4) treatment 50 μg/day commenced during controlled ovarian hyperstimulation (COH) vs placebo. The LT4 was titrated in the treated women to attain TSH < 2.5 mU/L, and this level was maintained during pregnancy in women who became pregnant. Women treated with LT4 had greater proportions of achieving pregnancy, lesser chances of miscarriage, and superior rates of delivery. Similar outcomes were observed in another randomized trial. However, other studies did not show improved outcomes with LT4 treatment. A prospective study on 270 women who experienced initial IVF cycle while they were treated for SCH did not observe difference in rate of pregnancy, miscarriage, and live birth in women with basal TSH level between 0.2 and 2.5 mIU/L in comparison with those with baseline TSH level between 2.5 and 4.2 mIU/L.
A recent meta-analysis of four RCTs including 787 women with TAI and SCH undergoing IVF/intracytoplasmic sperm injection (ICSI) did not find an appreciable interrelation of LT4 treatment with the clinical pregnancy rate, live birth rate, or preterm birth rate. However, women getting LT4 treatment had a suggestively lower miscarriage rate in comparison with those on placebo/no treatment (RR = 0.51, 95% CI 0.31–0.82). A meta-analyses of 13 studies comprising of 7970 women showed that in women having SCH; LT4 treatment lowered the chances of miscarriage in pregnancies attained by ART but not in spontaneously conceived pregnancies. Cochrane database of systematic reviews included four RCTs with 850 women undergoing IVF/ICSI who were either having SCH or were euthyroid with positive TAI. Women who were already on LT4 were excluded. Women were assigned LT4 or placebo/no treatment in these RCTs. The analysis implied that women having SCH with either positive or negative TPOAb who are using LT4 had a 27% and 100% chance of live birth compared to 25% probability of a live birth in the groups receiving placebo/no treatment. This was based on RCT from Kim et al. that stated that LT4 replacement in women with SCH with positive or negative TPOAb may help in improving live birth rates. Due to low-quality evidence, the review did not draw a conclusion.
Outcomes of ART in treated hypothyroid women as compared to healthy controls
Studies have looked at the impact of ART in women with treated hypothyroidism. A study included 240 women with age less than 37 years who went through first IVF cycles; compared to euthyroid women, inferior pregnancy rates were reported in 21 hypothyroid women well controlled on LT4 replacement. Similarly, another study on women undertaking IVF/ICSI that included 137 hypothyroid women on LT4 treatment and 274 euthyroid controls did not find significant association of optimally treated hypothyroidism with lesser rates of pregnancy and live births. In a countrywide study of all women who received ART in Denmark from 1994 till 2017, the chances of a pregnancy and a live birth after embryo transfer were studied. Those with thyroid imbalance were divided into two categories: hypothyroid/hyperthyroid disorders. In women with hypothyroidism, the adjusted odds ratio (aOR) was 1.03 (95% CI 0.94–1.12) for biochemical/clinical pregnancy or live birth.
Consequences of ART in euthyroid women with TAI
Research on question of ART results in euthyroid women with TAI is heterogeneous and has included women with varying causes of subfertility. Only a few studies were limited to euthyroid women. In addition, there was heterogeneity in terms of ART/IVF protocols used in these studies. “Idiopathic DOR” was related to more frequent occurrence of positive TPOAb instead of thyroid imbalance or positive TgAb. A meta-analysis concluded that pregnancy rates subsequent to IVF do not vary by presence or absence of TAI; however, there is advanced possibility of pregnancy loss in women with TAI. No variances in pregnancy, pregnancy loss, or live birth rates in women with or without TAI undergoing IVF with ICSI were reported in few retrospective studies. A study on euthyroid women undergoing IUI did not show any substantial variation among TPOAb positive and negative groups with regard to live birth, pregnancy, or miscarriage rate. Comparison of euthyroid women in subgroups with TSH ≥ 2.5 mIU/L vs TSH < 2.5 mIU/L failed to show any noteworthy differences in the outcomes. Similar results were shown by different researchers. In euthyroid women with UE infertility who do not have TAI, a preconception TSH between 0.5 and 4.5 mIU/L does not have a noteworthy impact on results of IUI. In contrast, a retrospective study on women with or without TAI undergoing IVF reported that “fertilization,” “implantation,” and “pregnancy rates” were inferior in 90 women with TAI vs 676 women without TAI, but the details of thyroid status were not stated in each group.
Correlation of follicular fluid TAI and TSH with serum TAI and TSH in women undergoing ART
Researchers examined the effect of follicular fluid TAI and thyroid function test in euthyroid TAI-positive ( n = 26) vs euthyroid TAI-negative (n = 26) women undergoing ART. Among the two groups, no substantial differences were noticed between the TSH and FT4 measured in follicular fluid. Considerable relationship was observed between the levels of serum thyroid and follicular fluid thyroid antibodies. Pregnancy rates differed per embryo transfer cycle between TAI-positive women (34.8%) and TAI-negative women (66.7%). A further multivariate analysis indicated that TAI-positive women had reduced chances to attain pregnancy. This led to the conclusion that in TAI-positive women, higher levels of thyroid autoantibodies in follicular fluid are intensely interrelated with the serum levels and may have an adverse influence on embryo development in postimplantation period. In women with TAI, the follicular fluid has detectable thyroid antibodies at levels which correlate with that in the woman’s serum. Follicular fluid thyroid hormone levels correlate strongly with maternal serum thyroid hormone levels on the day of human chorionic gonadotropin (hCG) administration, and thyroid hormones on the hCG day may impact the ART outcome. However, the data on whether thyroid antibodies can affect the fertilization potential of the maturing follicles are still lacking.
ART outcome of euthyroid women with TAI on treatment
There is a lot of controversy surrounding this question. Few studies have used prednisolone 5 mg compared to placebo in euthyroid women with TAI, and other studies have used low-dose thyroid hormones compared to placebo in randomized controlled trials. The outcomes were heterogeneous. A trial including 60 euthyroid women (TSH < 2.5 mU/L) with TAI going through IVF were given prednisolone 5 mg/day commencing from the day of ovum pickup, which was continued during the first trimester. Better rates of pregnancy and live birth were observed in the women who received treatment. Additional clinical trial with 48 infertile women with positive TPOAb was given prednisone vs placebo for 1 month prior to IUI. The rate of pregnancy was superior (33.3%) in women who received treatment as compared to almost 8% in the placebo group. There was no noteworthy difference in rates of pregnancy loss between the two groups. Despite these small trials showing positive results, we are still unaware of positive recommendations for corticosteroid use in early pregnancy. The “American Thyroid Association” endorses against the use of corticosteroids in euthyroid women with TAI going through ART.
The use of low-dose thyroid hormones in doses of 25–50 μg daily compared with placebo in women with TAI undergoing ART has mixed results. Two studies on the use of LT4 in euthyroid women with TAI undergoing ART did not improve outcomes. An RCT from China on 600 TPOAb-positive euthyroid women randomized to receive LT4 treatment vs no treatment; the authors did not observe a reduction in miscarriage rates or increase in live birth in either group. The TABLET trial randomized 952 euthyroid women with positive TPOAb into LT4 50 μg vs placebo. The use of LT4 failed to exhibit a superior rate of live births as compared to placebo. Cochrane database of systematic reviews included four RCTs with 850 women undergoing IVF/ICSI who were either having SCH or were euthyroid with positive thyroid antibodies. Women who were already on LT4 were excluded. Women were assigned LT4 or placebo/no treatment in these RCTs. The evidence suggested that euthyroid women with TAI are likely to exhibit 31% probability of a live birth with placebo/no treatment and that the probability of a live birth in women receiving LT4 is likely to vary from 26% to 40%. This review could not draw a conclusion due to low-quality evidence.
Outcome of ART with hyperthyroidism
Little evidence is available on outcome of ART with hyperthyroidism. From Denmark, a countrywide study of women receiving ART showed that the likelihood of a biochemical pregnancy was significantly reduced (aOR = 0.80, 95% CI 0.69–0.93) in women with hyperthyroidism. Thus, there was a reduced probability of a live birth per embryo transfer in hyperthyroid vs euthyroid women.
Effect of COH on thyroid status
During IVF/ICSI protocols, the woman undergoes COH by the administration of “gonadotropins,” “gonadotropin-releasing hormone analogs (GnRH-a),” or “gonadotropin-releasing hormone antagonists” in combination with gonadotropins. Maturation of follicles is tracked by ultrasound, and when the predominant follicles attain a sufficient size, then hCG is administered to induce ovulation. COH results in a rapid rise of serum estradiol to increased levels (4000–6000 ng/L), and these levels are similar to those observed in the third trimester of pregnancy. Since estradiol increases thyroxine-binding globulin, these hormonal influences may modify thyroid function resulting in reduced FT4 levels and subsequent TSH elevation through feedback mechanisms. Additionally, hCG has structural homology to TSH and its administration can directly act on TSH receptors located on the thyroid gland albeit having a weak thyrotropin activity. This causes increased thyroid hormone levels and drop in TSH through feedback mechanism. Studies have shown inconsistent effects of COH on serum thyroid hormones. Few studies have reported increase in TSH or FT4 levels, while other studies have reported either a reduction in TSH or even no change during COH. Elevations in serum levels of both TSH and FT4 were reported during COH that reached the maximum concentration 1 week after hCG administration. As many as 44% of the women with baseline TSH below 2.5 mIU/L noticed TSH increasing to > 2.5 mIU/L. This increase in serum TSH occurs in correspondence to rising estradiol levels during COH but is reported to be more marked in women with positive TPOAb.
Another study investigated the impact of long-acting GnRH-a on thyroid status in 207 euthyroid women undergoing IVF/ICSI. TSH was checked at six distinct points during stimulation. 57.7% of women with baseline TSH between 0.35 and 2.5 mIU/L showed an increase in TSH after COH: As many as 2.2% had a simultaneous rise in TPOAb, 2.9% were diagnosed as SCH, and the remaining 42.3% had reduced TSH with a single woman discovered with subclinical hyperthyroidism. 74.3% of women with basal TSH of 2.5–4.5 mIU/L showed increasing trend in TSH after COH with 22.9% diagnosed as SCH and 25.7% had decreased TSH, out of whom one had a diagnosis of subclinical hyperthyroidism. Women with baseline TSH < 2.5 mIU/L had significantly greater clinical pregnancy rate than those with TSH > 2.5 mIU/L. In a recent meta-analysis of 12 studies comprising of more than 7000 euthyroid women undertaking IVF/ICSI, a high TSH level > 2.5 mIU/L did not influence clinical pregnancy rate or miscarriage rate. The available evidence suggests that the therapeutic regimen used for COH induces a deterioration of thyroid function and increased risk of untimely elevation of TSH during fertilization in patients who are suffering from TAI. Experts agree that a woman with TAI should have a TSH value < 2.5 mIU/L before undergoing COH and the TSH should be strictly monitored to start or increase LT4 treatment, when necessary.
Studies have shown that the impact of COH on TSH is more marked in women with hypothyroidism on adequate LT4 replacement. More marked TSH elevation at the time of egg retrieval is reported in hypothyroid women compared to their euthyroid counterparts. In one study on hypothyroid women, basal TSH of 1.7 ± 0.7 mIU/L increased to 2.9 ± 1.3 mIU/L on the day of hCG administration and subsequently rose to 3.2 ± 1.7 mIU/L on day 16 after hCG administration.
Due to these changes in TSH during COH, experts recommend against measuring TSH during COH as the levels will be difficult to interpret. If needed, TSH should be measured either before COH or 1–2 weeks after COH. If TSH elevation (> 2.5 mIU/L) persists after COH and the woman is pregnant, she should receive LT4, and if pregnancy is not achieved, her TSH should be monitored within few weeks to confirm that the level has returned to baseline.
Table 9.2 summarizes the management of thyroid dysfunction in women seeking subfertility management.
