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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 3808-3812
Copyright © 2004 by The Endocrine Society

Impact of Ovarian Hyperstimulation on Thyroid Function in Women with and without Thyroid Autoimmunity

Kris Poppe, Daniel Glinoer, Herman Tournaye, Johan Schiettecatte, Paul Devroey, Andre van Steirteghem, Patrick Haentjens and Brigitte Velkeniers

Department of Endocrinology (K.P., P.H., B.V.), Academisch Ziekenhuis van de Vrije Universiteit Brussel (AZ-VUB), 1090 Brussels, Belgium; Centre Hospitalier Universitaire (D.G.), Saint-Pierre Université Libre de Bruxelles, B-1000 Brussels ULB, Belgium; and Centre for Reproductive Medicine (H.T., J.S., P.D., A.v.S.), AZ-VUB, 1090 Brussels, Belgium

Address all correspondence and requests for reprints to: Kris Poppe, Department of Endocrinology, Free University Brussels [Academisch Ziekenhuis van de Vrije Universiteit Brussel (AZ-VUB)], Laarbeeklaan 101, 1090 Brussels, Belgium. E-mail: hemopek{at}az.vub.ac.be.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Pregnancy is accompanied by changes in thyroid function, but limited data are available on these changes in the very first weeks of pregnancy. Yet, T4 plays a major role in implantation and early fetal development. We sought to determine thyroid function during this period and during the first trimester, in pregnancies achieved by assisted reproductive technology. Furthermore, the thyroid hormone profile was compared between euthyroid women with (TAI+) and without (TAI–) thyroid autoimmunity. We prospectively analyzed data from 35 women who received ovarian hyperstimulation (OH) and presented clinical pregnancies. The mean age of the women was 32 ± 5 yr. Thyroid function tests [serum TSH and free T4 (FT4)] and thyroid antibody status were determined before OH (baseline values) and every 20 d after ovulation induction during the first trimester of pregnancy. Serum TSH and FT4 increased significantly at d 20, compared with baseline values (3.3 ± 2.4 vs. 1.8 ± 0.9 mU/liter; P < 0.0001 and 13.2 ± 1.7 vs. 12.4 ± 1.9 ng/liter; P = 0.005). During the first trimester of pregnancy, there was a significant change over time for TSH and FT4 (P < 0.001 and P = 0.005, respectively). Nine women (27%) were TAI+. The TSH curve among these TAI+ women was significantly higher compared with TAI– women (P = 0.010). The opposite was observed for the FT4 curve (P = 0.020).

In conclusion, the present study showed a significant increase of serum TSH and FT4 levels after OH in the very first period of pregnancy compared with pre-OH levels and a significant impact of TAI on the thyroid hormone profile during the first trimester. This provides evidence for an altered thyroid function in euthyroid TAI+ patients.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THYROID DISORDERS INTERFERE with several aspects of reproduction (1, 2). Euthyroid women with thyroid autoimmunity (TAI+) have an increased risk for miscarriage, and the prevalence of TAI+ is increased in women with female causes of infertility (i.e. endometriosis, tubal disease, and ovulatory dysfunction) (3, 4, 5). The pathophysiology underlying the association between TAI and miscarriage remains to be elucidated. Three major possibilities for the observed association can be considered: first an immune dysfunction (although yet to be defined) can be involved. Second a direct action of antithyroglobulin antibodies (Tg-Ab) on the placenta has been described in mice; to date this has not been described in humans (6). Third, a possible decrease of local thyroid hormones in the presence of TAI during pregnancy can play a role in miscarriage (7).

During pregnancy, the thyroid is submitted to stressors and undergoes several adaptations to maintain sufficient output of thyroid hormones for both the mother and fetus. Changes known to affect thyroid function during gestation are the human chorionic gonadotropin (hCG) peak values (8th–10th weeks), the increased estrogen levels inducing a progressive increase in serum thyroxine-binding globulin (TBG) concentrations, followed in turn by a reduction in free T4 (FT4) and a compensatory increase in serum TSH. However, both serum TSH and FT4 remain within normal reference ranges, unless pregnancy is associated with iodine deficiency (8, 9, 10). Ovarian hyperstimulation (OH) used in preparation of assisted reproductive technology (ART) has been shown to impair thyroid function (11). Moreover, in euthyroid pregnant women with positive thyroid antibodies, it has been shown that 16% had increased serum TSH at delivery (12).

By measuring TSH and FT4 before ART and subsequently every 20 d after ovulation induction (OI; or the end of OH, considered as time 0) during the first trimester of pregnancy, our aim was to investigate changes in thyroid function occurring in the very early phases of pregnancy, i.e. before the impact of high hCG levels. A further aim was to assess the TSH and FT4 changes over time during the first trimester of pregnancy and to explore the potential impact of TAI+ on thyroid function.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Overall study design

Women of infertile couples presenting at the Centre of Reproductive Medicine (Brussels, Belgium) were included prospectively after informed consent. Causes of infertility among women studied were as follows: male infertility (57%), tubal diseases (17%), endometriosis (14%), ovulatory disorders (6%), and idiopathic cause (6%).

Only euthyroid women, with an ongoing pregnancy after having received OH, were included in the study; no particular thyroid characteristic that might have influenced the success of ART was evidenced in the present cohort.

Thyroid function tests (serum TSH and FT4) and thyroid peroxidase antibodies (TPO-Ab) were determined before (≥20 d) a first ART procedure, and thyroid function was further monitored every 20 d after OI during the first trimester of pregnancy. The end of OH was considered as time 0 (or OI). To evaluate thyroid function in the earliest stages of the first trimester (i.e. before the impact of high hCG levels), thyroid function tests obtained 20 d after OI were compared with pre-OH values. The pattern of change of thyroid function during the first trimester was further determined by measuring TSH and FT4 at d 20, 40, 60, 80, and 100 after successful OH. To assess the potential impact of TAI on thyroid function, women were stratified according to the presence or absence of TAI.

ART treatment

All female partners received controlled ovarian superovulation treatment by a combination of the GnRH agonist (Suprefact nasal spray, Aventis, Strasbourg, France) and uFSH (Menopur; Ferring Pharmaceuticals, Copenhagen, Denmark) or recFSH (Puregon, Organon International Inc., West Orange, NJ; and Gonal-F; Serono, Geneva, Switzerland). When the patient had at least three follicles with a diameter of 17 mm and serum estradiol levels of 1000 ng/liter, administration of both GnRH agonist and FSH were discontinued, and ovulation was induced with 10,000 IU of hCG (Pregnyl; Organon).

All patients had a transvaginal ultrasound-guided ovum aspiration approximately 36 h after hCG injection under local anesthesia.

In conventional in vitro fertilization, each oocyte was inseminated within 3–4 h after retrieval by adding 5,000–20,000 motile spermatozoa per oocyte. For intracytoplasmic sperm injection, only mature metaphase II oocytes were injected after denuding their cumulus cells. The intracytoplasmic sperm injection procedure was carried out as described earlier (13). After fertilization, one to three embryos were transferred depending on their morphological quality. The luteal phase was supplemented by vaginal administration of 3 x 600 mg natural micronized progesterone (Utrogestan; Besins, Brussels, Belgium) starting 1 d after oocyte retrieval.

Pregnancy was diagnosed at least 10 d after transfer by rising hCG levels of at least 20 IU/ml in serum on two occasions. Clinical pregnancies were diagnosed by ultrasonography performed 5 weeks after embryo transfer.

Serum assay

Serum TSH and FT4 were measured using a third-generation electro-chemiluminescence immunoassay (Roche, Mannheim, Germany). The reference values were 0.27–4.2 mU/liter for TSH and 9.3–18.0 ng/liter (12–23.2 pmol/liter) for FT4 [conversion factor for FT4 (nanograms per liter -> picomoles per liter), 1.29]. Thyroid autoimmunity was demonstrated by the presence of TPO-Ab (positive when >100 kU/liter or TAI+). TPO-Ab was determined using a RIA kit (B.R.A.H.M.S. Diagnostica, Berlin). The reference range was 0–100 kU/liter.

Tg-Ab were not measured because our preliminary unpublished data showed that Tg-Ab, in the absence of TPO-Ab, were observed in less than 5% of TAI women.

Statistical analysis

Serum TSH and FT4 values, in this cohort of infertile women, passed the Kolmogoroff-Smirnoff test for normal distribution and were therefore expressed as mean ± SD. To compare changes between pre- and post-OH values of TSH and FT4 in the early stage of pregnancy (i.e. between baseline values and values at d 20 after successful OH), the paired Student’s t test was used. The unpaired Student’s t test was used to compare differences in thyroid function between TAI+ and TAI– patients at baseline and at d 20. A one-way (single group) repeated-measures ANOVA was conducted to explore the impact of time on TSH and FT4 serum values collected at six periods: before OH (time 0), and at d 20, 40, 60, 80, and 100 after OI. A two-way (between groups) repeated-measures ANOVA was conducted to explore the impact of thyroid antibodies on thyroid function, as measured by serum TSH and FT4 values during the first trimester of pregnancy. TPO-Ab titers were not normally distributed and were expressed as the median value (and the range). Titers were compared between TAI+ and TAI– patients by a Mann-Whitney U test. All data analyses were performed using SPSS version 11.5 (SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Baseline characteristics

Table 1Go shows the clinical and biochemical characteristics of all women enrolled (n = 35) and stratified according to the presence (TAI+ group, n = 9) or absence of thyroid autoimmunity (TAI– group, n = 27). In the entire study group, the women’s mean age was 32 ± 5 yr (range, 23–40 yr), and their mean serum TSH and FT4 at baseline were 1.8 ± 0.9 mU/liter and 12.4 ± 1.9 ng/liter, respectively. There were no significant differences between the TAI+ group and the TAI– group with regard to mean age, mean serum TSH, mean serum FT4, and mean serum hCG levels at the different time points. Individual titers of TPO antibodies, in the nine TAI+ patients, ranged between 132, 165, 179, 279, 364, 1221, 2155, 3753, and 3666 kU/liter.


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  		TABLE 1. Baseline characteristics and hCG levels at different time periods after OH for all patients and for patients stratified according to their TAI status1

 
Thyroid function in the very early phases of pregnancy

Figure 1Go shows changes in thyroid function occurring in the very early phases of pregnancy, i.e. before the impact of high hCG levels.



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  		FIG. 1. TSH and FT4 serum values (mean ± SD) before OH (baseline values) and during the early stages of pregnancy (20 d after OI; i.e. before the impact of high hCG levels) for all patients (left panels) and stratified according to TPO-Ab status (TPO+ vs. TPO; right panels). The paired Student’s t test was used to compare changes between pre- and post-OI values (i.e. between baseline values and values at d 20 after successful OI). The unpaired Student’s t test was used to compare differences between TPO+ and TPO– patients at one particular point in time. Conversion factor for FT4 (nanograms per liter -> picomoles per liter), 1.29.

 
In the entire study group, serum TSH increased significantly 20 d after OI, compared with baseline values (3.3 ± 2.4 vs. 1.8 ± 0.9 mU/liter; P < 0.0001). Similarly, serum FT4 increased significantly 20 d after OH, compared with baseline values (13.2 ± 1.7 vs. 12.4 ± 1.9 ng/liter; P = 0.005; Fig. 1Go, left panels). When stratified according to the presence (TAI+ group) or absence (TAI– group) of thyroid autoimmunity, similar trends were observed, although with the numbers available, these trends did not always reach statistical significance (Fig. 1Go, right panels).

Thyroid function during the first trimester of pregnancy

Figure 2Go shows the pattern of changes in serum TSH and FT4 during the first trimester of pregnancy in the entire study group (Fig. 2Go, left panels) and after stratification according to the presence (TAI+ group) or absence (TAI– group) of thyroid autoimmunity (Fig. 2Go, right panels). In the entire study group, there was a statistically significant effect for time on TSH and on FT4 (one-way repeated-measures ANOVA for TSH and FT4, P < 0.001 and P = 0.005, respectively). The peak values for TSH and for FT4 occurred at d 20 and 40, respectively. When stratified according to TAI status, there was a statistically significant effect, both for serum TSH and FT4. For serum TSH, the curve was significantly higher among TAI+ women (two-way repeated-measures ANOVA for TSH, P = 0.010). Conversely, for serum FT4, the curve was significantly lower among TAI+ women (two-way repeated-measures ANOVA for FT4, P = 0.020).



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  		FIG. 2. Pattern of change over time for the TSH and FT4 serum values (mean ± SD) collected at six periods: before OH (time 0), and at d 20, 40, 60, 80, and 100 after successful OI. Left panels, Among all patients, a significant difference exists in the TSH and FT4 measures over time (one-way repeated-measures ANOVA for TSH and FT4, P < 0.001 and P = 0.005, respectively). Right panels, The pattern of change over time is different for TPO+ ({blacksquare}) and TPO– ({square}) (two-way repeated-measures ANOVA for TSH and FT4, P = 0.010 and P = 0.020, respectively) patients. Conversion factor for FT4 (nanograms per liter -> picomoles per liter), 1.29. NS, Not significant.

 
The outcome of induced pregnancies, as of the end of the study period (first trimester), showed a miscarriage rate of 56 and 39%, respectively, among the TAI+ vs. TAI– groups. These percentages were not statistically different between the groups, due to the small number of patients. Thyroid hormone levels were not statistically different between those (last available) in the miscarriage group and the ongoing group. Mean (±SD) serum TSH levels at time point 80 d was 3.3 ± 2.2 mU/liter in the miscarriage group vs. 2.0 ± 1.3 mU/liter in the ongoing pregnancy group (P = 0.116). FT4 levels were, respectively, 12.5 ± 1.7 and 13.4 ± 1.5 ng/liter (P = 0.223). At the time point 100 d, serum TSH was 2.9 ± 2.1 mU/liter in the miscarriage group and 2.2 ± 1.5 mU/liter in the ongoing pregnancies group (P = 0.422).

FT4 levels were 11.9 ± 1.3 and 12.5 ± 1.6 ng/liter, respectively, in the miscarriage and ongoing pregnancy groups (P = 0.509).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The present prospective study presented a unique opportunity to study the very early changes in thyroid function during the first trimester of pregnancy after ART and especially during the first month, when hCG levels were still too low (<1000 IU/liter) to directly influence thyroid function. We observed a significant increase in serum TSH and FT4 levels compared with baseline values. Previously, only Muller et al. (11) investigated thyroid function after OH. These authors measured thyroid function tests in the immediate period after OH but did not precisely specify the timing in relation to the OI, nor did they precisely specify the outcome (pregnancy status) of the patients included. Interestingly, they found a significant increase in serum TSH and a decrease in FT4 levels compared with pre-OH levels. The postulated mechanism whereby OH leads to these changes in thyroid tests is by inducing a rapid increase in the estrogen levels and in turn TBG production and hypersialylation, with the latter increasing TBG’s half-life. The increase in TBG results in an increase in total T4 that tends to lower serum FT4, thereby stimulating serum TSH through the pituitary-thyroid feedback mechanisms (8). In line with those results, we found significantly increased values for TSH levels at 20 d after OI compared with baseline values. By contrast, in the present study, we found significantly increased values for both TSH and FT4 serum levels at 20 d after OI (compared with baseline values). The increase in serum TSH might be related to the high estrogen levels resulting from FSHinduced OH, whereas the injection of hCG for the induction of ovulation might have counteracted the lowering in serum FT4 levels by directly stimulating the thyroid gland (14). A central mechanism to explain these changes in the thyroid hormonal profile is unlikely, because evidence for a direct stimulating effect of estrogen and hCG is lacking at the hypothalamo-pituitary level. The changes in both serum TSH and FT4 during the first trimester were comparable with the thyroid function patterns observed in spontaneous pregnancies. After the early peak value in serum TSH, a decrease in TSH and a further slightly delayed peak value in FT4 are subsequently mediated through rising hCG levels.

A further aim of the study was to assess whether the evolution of thyroid function was similar in women with/without TAI. In a previous case-control study of women from infertile couples, we found an impact of TAI+ on thyroid function, and a clear statistically significant correlation was established between TPO-Ab titers and serum TSH levels before OH. In that study, we also showed that women with a female cause of infertility had an increased risk of being TAI+, compared with fertile controls (5). In a subsequent prospective cohort study of infertile women with TAI+ submitted to OH, we found an increased risk for miscarriage during the first trimester, compared with TAI– women (4). A similar tendency was found in the present study; namely an increased miscarriage rate in the TAI+ compared with the TAI– group. However, the difference was not statistically different because of the small number of patients investigated. The reasons for such an association remain to be elucidated. Although the hypothesis of a generalized deregulation of immunity is plausible, the development of a relative thyroid dysfunction in women with TAI+ during pregnancy is possible (12). The present study confirmed that there was a difference in the dynamics of thyroid function changes between TAI+ and TAI– women, based on the significantly different serum levels for TSH and FT4 collected at several time periods during the first trimester of pregnancy. The increase in serum TSH was more pronounced, whereas the serum FT4 response was attenuated in TAI+ patients. These results point to a diminished thyroid functional reserve during the ART procedure and subsequent early pregnancy in this subset of patients. Thus, both OH and TAI are factors that can attenuate the normal thyroid response needed for maintaining an ongoing pregnancy after OH. We also should be aware that reference values for thyroid function are normal values during nonpregnant states and that they may be inappropriate for a certain time point of pregnancy. In the present study, we did not find differences in the thyroid hormone levels between the miscarriage and ongoing group; however, a larger number of patients should be investigated to be conclusive on this issue. To date, one study investigated the impact of thyroid hormones on the outcome of spontaneous pregnancy in TAI+ women. In that small (n = 16) nonplacebo controlled study, only women with a history of recurrent miscarriage were included. Thyroid hormones before and during pregnancy yielded a significantly better outcome than treatment with Igs during gestation (15).

Clearly, prospective randomized studies comparing the outcome of pregnancy in euthyroid TAI+ women treated by T4 or placebo are needed to answer the remaining question of whether the impaired pregnancy in those patients can be reversed. Previous studies associating TAI+ and thyroid dysfunction with infertility, miscarriage, postpartum thyroiditis, depression, and minor thyroid dysfunction with impaired neuro-intellectual outcome in children (2, 5, 16, 17, 18, 19), together with the present study, provide strong evidence to propose systematic screening of infertile women for TSH, FT4, and TPO-Ab before an ART procedure. We also recommend surveillance of thyroid function during subsequent pregnancy in the TAI+ women.

In conclusion, the present study showed a significant increase in serum TSH and FT4 levels after OH in the very first period of pregnancy compared with pre-OH levels and a significant impact of TAI on thyroid function during the first trimester, providing evidence for an altered thyroid function in TAI+ patients.

These changes may be markers of the underlying thyroid alterations possibly associated with the increased miscarriage risk.


   Acknowledgments
 
The authors thank W. Meul and D. Coomans for data support and I. DeWannemacker for the secretarial help.


   Footnotes
 
This work was supported by grants of the Willy Gepts foundation AZ-VUB.

Abbreviations: ART, Assisted reproductive technology; FT4, free T4; hCG, human chorionic gonadotropin; OH, ovarian hyperstimulation; OI, ovulation induction; TAI, thyroid autoimmunity; TBG, thyroxine-binding globulin; Tg-Ab, antithyroglobulin antibodies; TPO-Ab, thyroid peroxidase antibodies.

Received January 22, 2004.

Accepted April 13, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Krassas GE 2000 Thyroid disease and female reproduction. Fertil Steril 74:1063–1070[CrossRef][Medline]
  2. Poppe K, Glinoer D 2003 Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update 9:149–161[Abstract/Free Full Text]
  3. Abramson J, Stagnaro-Green A 2001 Thyroid antibodies and fetal loss: an evolving story. Thyroid 11:57–63[CrossRef][Medline]
  4. Poppe K, Glinoer D, Tournaye H, Devroey P, Van Steirteghem A, Velkeniers B 2003 Assisted reproduction and thyroid autoimmunity: an unfortunate combination? J Clin Endocrinol Metab 88:4149–4152[Abstract/Free Full Text]
  5. Poppe K, Glinoer D, Van Steirteghem A, Tournaye H, Devroey P, Schiettecatte J, Velkeniers B 2002 Thyroid dysfunction and autoimmunity in infertile women. Thyroid 12:997–1001[CrossRef][Medline]
  6. Matalon ST, Blank M, Levy Y, Carp HJ, Arad A, Burek L, Grunebaum E, Sherer Y, Ornoy A, Refetoff S, Weiss RT, Rose NR, Shoenfeld Y 2003 The pathogenic role of anti-thyroglobulin antibody on pregnancy: evidence from an active immunization model in mice. Hum Reprod 18:1094–1099[Abstract/Free Full Text]
  7. Maruo T, Katayama K, Matuso H, Anwar M, Mochizuki M 1992 The role of maternal thyroid hormones in maintaining early pregnancy in threatened abortion. Acta Endocrinol (Copenh) 127:118–122[Medline]
  8. Glinoer D 1997 The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 18:404–433[Abstract/Free Full Text]
  9. Glinoer D, Delange F 2000 The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny. Thyroid 10:871–887[Medline]
  10. Glinoer D, De Nayer P, Delange F, Lemone M, Toppet V, Spehl M, Grun JP, Kinthaert J, Lejeune B 1995 A randomized trial for the treatment of mild iodine deficiency during pregnancy: maternal and neonatal effects. J Clin Endocrinol Metab 80:258–269[Abstract]
  11. Muller AF, Verhoeff A, Mantel MJ, De Jong FH, Berghout A 2000 Decrease of free thyroxine levels after controlled ovarian hyperstimulation. J Clin Endocrinol Metab 85:545–548[Abstract/Free Full Text]
  12. Glinoer D, Riahi M, Grun JP, Kinthaert J 1994 Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol Metab 79:197–204[Abstract]
  13. Van Steirteghem AC, Liu J, Joris H, Nagy Z, Janssenswillen C, Tournaye H, Derde MP, Van Assche E, Devroey P 1993 Higher success rate by intracytoplasmic sperm injection than by subzonal insemination. Report of a second series of 300 consecutive treatment cycles. Hum Reprod 8:1055–1060[Abstract/Free Full Text]
  14. Noppen M, Velkeniers B, Buydens P, Devroey P, Van Steirteghem A, Vanhaelst L 1986 Hyperthyroidism after gonadotrophic ovarian stimulation. Br Med J (Clin Res Ed) 16:171–172
  15. Vaquero E, Lazzarin N, De Carolis C, Valensise H, Moretti C, Ramanini C 2000 Mild thyroid abnormalities and recurrent spontaneous abortion: diagnostic and therapeutical approach. Am J Reprod Immunol 43:204–208
  16. Pop VJ, de Vries E, van Baar AL, Waelkens JJ, de Rooy HA, Horsten M, Donkers MM, Komproe IH, van Son MM, Vader HL 1995 Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development? J Clin Endocrinol Metab 80:3561–3566[Abstract]
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  19. Stagnaro-Green A 2002 Clinical review 152: postpartum thyroiditis. J Clin Endocrinol Metab 87:4042–4047[Free Full Text]




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