Is it really the impact of controlled ovarian hyperstimulation on thyroid function?

1 06 2011

To the Editor:

I read with great interest the article by Poppe et al.(1) in which they found that serum TSH and fT4 levels increased 2 weeks after embryo transfer (ET) in both the ovarian hyperstimulation syndrome (OHSS) and no-OHSS groups compared with prestimulation levels and they addressed that controlled ovarian hyperstimulation (COH) had an important impact on thyroid function. They have done a good work. However, we have a question according to their data: is it really the impact of COH on thyroid function?

If transfering D2 or D3 embryos, two weeks after embryo transfer is equal to 16 or 17 days plus 36 hours after the administration of hCG. The agents in their COH treatment consisting of GnRH agonist (GnRH-a; Suprefact nasal spray; Hoechst) and 150 IU of uFSH or recFSH have been excreted after more than 17 days. The authors selected pregnant women. Two weeks after ET is equal to gestational day 30 or 31. The pregnancy itself has effects on thyroid hormonal levels.

During pregnancy, trophocyte cells secrete human chorionic gonadotrophin (hCG), which is a glycoprotein composed of α and β subunits. HCG has an almost identical α subunit and similar β subunit to that found in TSH (2). The LH/hCG receptors share 45% homology with thos of TSH (3). The effect of hCG on the thyroid is expected to occur because of molecular mimicry between hCG subunits and TSH subunits (4). The potency of hCG for TSH receptors is some 4000 times less than TSH. However, the HCG blood level increases quickly, doubling every 2 to 3 days during early pregnancy.

On the other hand, the women will restore to normal state without pregnancy and complication at the time of 2 weeks after ET. In my personal and institutional experience, women without pregnanct or complication will restore normal ovarian volume on transvaginal ultrasound at 12-14 days after ET. At the same time, their serum hormonal levels also restore to normal status when luteal support only uses Dydrogesterone 10 mg three times a day (the serum β-HCG level is < 0.1 mIU/mL, serum E2 level is < 30 pg/mL and serum P level is < 10 ng/mL. Therefore, thyroid function should be expected to normalize without pregnancy at the time of 2 weeks after ET.

Xin Chen, M.D., M.Sc.
Center for Reproductive Medicine
Department of Obstetrics and Gynecology
Nanfang Hospital
Southern Medical University,
Guangzhou, People’s Republic of China

References
1. Poppe K, Unuane D, Haeseleer MD, Tournaye H, Schiettecatte J, Haentjens P, et al. Thyroid function after controlled ovarian hyperstimulation in women with and without the hyperstimulation syndrome. Fertil Steril 2011; Published online May 12, 2011.

2. Hershman JM. Physiological and pathological aspects of the effects of human chorionic gonadotropin on the thyroid. Best Prac Res Clin Endocrinol Metab 2004;18:249–65.

3. Nagayama Y, Rapoport B. The thyrotropin receptor 25 years after its discovery: new insight after its molecular cloning. Mol Endocrinol 1992;6:145–56.

4. Fisher PM, Hancock BW. Gestational trophoblastic diseases and their treatment. Cancer Treat Rev 1997;23:1–16.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.06.007

The Authors Respond:

We appreciated the comment by Xin Chen in the letter to the editor regarding our manuscript (1). The increase in free thyroxine (FT4) might indeed result from thyroid stimulation through increasing hCG values in the first trimester. Few patients with pregnancy day 30 after spontaneous pregnancies have been studied and most time points examined start at day 45 or later. Glinoer et al. showed that FT4 increased and serum TSH decreased during that time period of pregnancy (2).

Data from infertile patients after assisted reproductive technology (ART) offer the advantage of a very early analysis of thyroid hormones. Our data show a significant increase in serum TSH after ART, and only followed later by a decrease in serum TSH. Therefore, this early increase probably does not result from the hCG rise, but results from the events preceding pregnancy, as is the rise in FT4.
In a previous study, we also demonstrated that this early transient rise in serum TSH was more pronounced in patients with thyroid autoimmunity, triggering a stress to the thyroid prior to hCG rise and related tot the ART procedure.

Our a priori hypothesis for this study was, therefore, that very high estradiol levels as seen in hyperstimulation syndrome might further enhance the serum TSH rise. In the present study, we were unable to show a difference in TSH and FT4 patterns between both OHSS and COH groups. The mechanisms involved in the very changes in thyroid function parameters during the early phase of pregnancy after ART, as compared to pre-pregnancy values, therefore, needs further investigation.

Kris Poppe, M.D., Ph.D.
Department of Endocrinology
Universitair Ziekenhuis Brussel
Brussels, Belgium

References
1. Poppe K, Unuane D, D’Haeseleer M, Tournaye H, Schiettecatte J, Haentjens P, Velkeniers B. Thyroid function after controlled ovarian hyperstimulation in women with and without the hyperstimulation syndrome. Fertil Steril. 2011 May 11.

2. Glinoer D, de Nayer P, Bourdoux P, Lemone M, Robyn C, van Steirteghem A, Kinthaert J, Lejeune B. Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab. 1990 Aug;71(2):276-87.

3. Poppe K, Glinoer D, Tournaye H, Schiettecatte J, Devroey P, van Steirteghem A, Haentjens P, Velkeniers B. Impact of ovarian hyperstimulation on thyroid function in women with and without thyroid autoimmunity. J Clin Endocrinol Metab. 2004 Aug;89(8):3808-12.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.06.008

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