Skip to main content
SpringerLink
Log in

The Potential Role of GnRH Agonists and Antagonists in Inducing Thyroid Physiopathological Changes During IVF

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

We conducted an observational cohort study to evaluate whether drugs used for hypothalamic inhibition may impact thyroid function of infertile women scheduled for fresh nondonor in vitro fertilization/intracytoplasmic sperm injection treatment. We considered eligible for inclusion in the study only women with normal thyroid function (serum thyroid-stimulating hormone [TSH] range: 0.2-4.0 mIU/L, serum thyroxin values: 9–22 pmol/L) and negative personal history for previous thyroid disorders. According to which protocols were implemented to gain hypothalamic inhibition, patients were assigned to group A (70 women treated by long gonadotropin-releasing hormone [GnRH] agonist protocol) or to group B (86 women treated by flexible GnRH antagonist protocol). Before initiating controlled ovarian stimulation (COS), both groups were further stratified into 4 subgroups: A1 (46 of the 70 women) and B1 (61 of the 86 women) in women with a baseline TSH value <2.5 mIU/L, whereas those with a baseline value ≥2.5 mIU/L were assigned to groups A2 (24 of the 70 women) and B2 (25 of the 86 women). Prior to initiating stimulation (T-0), 17-β-estradiol (E2) and TSH serum values were dosed in all women and repeated on T-5 (day 5 of COS) and subsequently every 2 days until T-ov-ind (ovulation induction day) and T-pick-up (oocytes retrieval day). In case of detection of TSH levels above the cutoff, patients were screened for thyroxin and thyroid autoantibody serum values. In group A, E2 at T-ov-ind was significantly increased compared to group B (P < .01), whereas TSH values showed an opposite trend (not significantly modified in group A, whereas significantly increased in group B; P < .001). A total of 64 women were found to have TSH values above the cutoff during COS: 7 in group A (11%) and 57 in group B (89%). Among them, 5 (71.4%) of the 7 in group A displayed hypothyroidism (and 4 of the 5 autoantibody positivity), whereas in group B, 6 (10.5%) of the 57 displayed hypothyroidism (and 2 of the 6 autoantibody positivity; P < .001). No pregnancies were observed in women with hypothyroidism, whereas in the 53 women with “isolated” increased TSH (normal T4, negative antibodies), we reported a 20.7% clinical pregnancy rate and a 54.5% ongoing pregnancy rate. Our preliminary data, despite requiring further confirmation, seem to suggest that the various drugs used for gaining hypothalamic control during COS could interfere through different mechanisms with physiological function of thyroid axis, potentially affecting its regulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Gizzo S, Andrisani A, Esposito F, et al. Ovarian reserve test:an impartial means to resolve the mismatch between chronological and biological age in the assessment of female reproductive chances. Reprod Sci. 2014; 21(5):632–639.

    Article  PubMed  Google Scholar 

  2. Vitagliano A, Quaranta M, Noventa M, Gizzo S. “Empiric” inositol supplementation in normal-weight non insulin resistant women with polycystic ovarian disease:from the absence of benefit to the potential adverse effects. Arch Gynecol Obstet. 2015; 291(5):955–857.

    Article  PubMed  Google Scholar 

  3. Gizzo S, Capuzzo D, Zicchina C, et al. Could empirical low-dose-aspirin administration during IVF cycle affect both the oocytes and embryos quality via COX 1–2 activity inhibition. J Assist Reprod Genet. 2014; 31(3):261–268.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Vitagliano A, Noventa M, Gizzo S. Emerging evidence regarding statins use as novel endometriosis targeted treatment:real “magic pills” or “trendy” drugs? Some considerations. Eur J Obstet Gynecol Reprod Biol. 2015; 184:125–126.

    Article  PubMed  Google Scholar 

  5. Mintziori G, Goulis DG, Toulis KA, Venetis CA, Kolibianakis EM, Tarlatzis BC. Thyroid function during ovarian stimulation:a systematic review. Fertil Steril. 2011; 96(3):780–785.

    Article  CAS  PubMed  Google Scholar 

  6. Benaglia L, Busnelli A, Somigliana E, et al. Incidence of elevation of serumthyroid-stimulatinghormoneduringcontrolledovarianhyper stimulation for in vitro fertilization. Eur J Obstet Gynecol Reprod Biol. 2014; 173:53–57.

    Article  CAS  PubMed  Google Scholar 

  7. La Rosa S, Celato N, Uccella S, Capella C. Detection of gonadotropin-releasing hormone receptor in normal human pituitary cells and pituitary adenomas using immunohistochemistry. Virchows Arch. 2000; 437(3):264–269.

    Article  PubMed  Google Scholar 

  8. Hong IS, Klausen C, Cheung AP, Leung PC. Gonadotropin-releasing hormone-I or -II interacts with IGF-I/Akt but not con-nexin 43 in human granulosa cell apoptosis. J Clin Endocrinol Metab. 2012; 97(2):525–534.

    Article  CAS  PubMed  Google Scholar 

  9. Tan O, Carr BR, Beshay VE, Bukulmez O. The extrapituitary effects of GnRH antagonists and their potential clinical implications:a narrated review. Reprod Sci. 2013; 20(1):16–25.

    Article  PubMed  Google Scholar 

  10. Han EJ, Song HD, Yang JH, et al. Thyroid dysfunction associated with administration of the long-acting gonadotropin-releasing hormone agonist. Endocrinol Metab (Seoul). 2013; 28(3):221–225.

    Article  Google Scholar 

  11. Rizvi T, Rehm PK. Recombinant human thyrotropin use resulting in ovarian hyperstimulation:an unusual side effect. Eur Thyroid J. 2014; 3(2):125–129.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Aghajanova L, Lindeberg M, Carlsson IB, et al. Receptors for thyroid-stimulating hormone and thyroid hormones in human ovarian tissue. Reprod Biomed Online. 2009; 18(3):337–347.

    Article  CAS  PubMed  Google Scholar 

  13. Orvieto R. GnRH agonist versus GnRH antagonist in ovarian stimulation:has the ongoing debate resolved. Reprod Biomed Online. 2014; 29(5):647–649.

    Article  CAS  PubMed  Google Scholar 

  14. Gizzo S, Andrisani A, Noventa M, et al. Menstrual cycle length:a surrogate measure of reproductive health capable of improving the accuracy of biochemical/sonographical ovarian reserve test in estimating the reproductive chances of women referred to ART. Reprod Biol Endocrinol. 2015; 13:28.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Patrelli TS, Berretta R, Gizzo S, et al. CA 125 serum values in surgically treated endometriosis patients and its relationships with anatomic sites of endometriosis and pregnancy rate. Fertil Steril. 2011; 95(1):393–396.

    Article  CAS  PubMed  Google Scholar 

  16. Gizzo S, Patrelli TS, Rossanese M, et al. An update on diabetic women obstetrical outcomes linked to preconception and pregnancy glycemic profile:a systematic literature review. Scientific-World J. 2013; 2013:254901.

    Article  Google Scholar 

  17. Saccardi C, Conte L, Fabris A, et al. Hysteroscopic enucleation in toto of submucous type 2 myomas:long-term follow-up in women affected by menorrhagia. Minim Invasive Gynecol. 2014; 21(3):426–430.

    Article  Google Scholar 

  18. Litta P, Cosmi E, Saccardi C, Esposito C, Rui R, Ambrosini G. Outpatient operative polypectomy using a 5 mm-hysteroscope without anaesthesia and/or analgesia:advantages and limits. Eur J Obstet Gynecol Reprod Biol. 2008; 139(2):210–214.

    Article  PubMed  Google Scholar 

  19. Vitagliano A, Noventa M, Gizzo S. Is it time to consider patients suffering from endometriosis-related infertility as “novel candidates” for targeted peri-conceptional D-chiro inositol supplementation? Hypothesis, rationale and some considerations. J Assist Reprod Genet. 2015; 32(3):407–408.

    Article  PubMed  Google Scholar 

  20. Gizzo S, Andrisani A, Esposito F, et al. Which luteal phase support is better for each IVF stimulation protocol to achieve the highest pregnancy rate? A superiority randomized clinical trial [published online September 30, 2014]. Gynecol Endocrinol. 2014:1–7.

    Google Scholar 

  21. Gracia CR, Morse CB, Chan G, et al. Thyroid function during controlled ovarian hyperstimulation as part of in vitro fertilization. Fertil Steril. 2012; 97(3):585–591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Poppe K, Glinoer D, Toumaye H, Schiettecatte J, Haentjens P, Velkeniers B. Thyroid flmction after assisted reproductive technology in women free of thyroid disease. Fertil Steril. 2005; 83(6):1753–1757.

    Article  PubMed  Google Scholar 

  23. Kutteh WH, Yetman DL, Carr AC, Beck LA, Scott RT Jr. Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing assisted reproduction. Fertil Steril. 1999; 71(5):843–848.

    Article  CAS  PubMed  Google Scholar 

  24. Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003; 13(1):3–126.

    Article  PubMed  Google Scholar 

  25. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease:scientific review and guidelines for diagnosis and management. JAMA. 2004; 291(2):228–238.

    Article  CAS  PubMed  Google Scholar 

  26. Ghosh BR, Wu JC, Strahl BD, Childs GV, Miller WL. Inhibin and estradiol alter gonadotropes differentially in ovine pituitary cultures:changing gonadotrope numbers and calcium responses to gonadotropin-releasing hormone. Endocrinology. 1996; 137(11):5144–5154.

    Article  CAS  PubMed  Google Scholar 

  27. Millar R, Lowe S, Conklin D, et al. A novel mammalian receptor for the evolutionarily conserved type II GnRH. Proc Natl Acad Sci USA. 2001; 98(17):9636–8641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Krsmanovic LZ, Martinez-Fuentes AJ, Arora KK, et al. Autocrine regulation of gonadotropin-releasing hormone secretion in cultured hypothalamic nsurons. Endocrinology. 1999; 140(3):1423–1431.

    Article  CAS  PubMed  Google Scholar 

  29. Winkler N, Bukulmez O, Hardy DB, Carr BR. Gonadotropin releasing hormone antagonists suppress aromatase and anti-Miil-lerian hormone expression in human granulosa cells. Fertil Steril. 2010; 94(5):1832–1839.

    Article  CAS  PubMed  Google Scholar 

  30. Minaretzis D, Alper MM, Oskowith SP, Lobel SM, Mortola JF, Pavlou SN. Gonadotropin-releasing hormone antagonist vs agonist administration in women undergoing controlled ovarian hyperstimulation:cycle performance and in vitro steroidogenesis of granu-losa-lutein cells. Am J Obstet Gynecol. 1995; 172(5):1518–1525.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Woman and Child Health, University of Padua, Padua, Italy

    Salvatore Gizzo MD, Marco Noventa MD, Amerigo Vitagliano MD, Federica Esposito MD, Alessandra Andrisani MD, PhD, Michele Gangemi MD, Giovanni Battista Nardelli MD & Donato D’Antona MD

  2. Department of Obstetrics and Gynecology, University of Verona, Verona, Italy

    Michela Quaranta MD

  3. Department of Obstetrics and Gynecology, University of Catanzaro, Catanzaro, Italy

    Roberta Venturella MD

  4. Department of Neurosciences and Reproductive Science, University Federico II of Naples, Naples, Italy

    Carlo Alviggi MD, PhD

  5. Department of Laboratory Medicine, University of Padua, Padua, Italy

    Mario Plebani MD

Authors
  1. Salvatore Gizzo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco Noventa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michela Quaranta MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amerigo Vitagliano MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Federica Esposito MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alessandra Andrisani MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Roberta Venturella MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carlo Alviggi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mario Plebani MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michele Gangemi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Giovanni Battista Nardelli MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Donato D’Antona MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Salvatore Gizzo MD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gizzo, S., Noventa, M., Quaranta, M. et al. The Potential Role of GnRH Agonists and Antagonists in Inducing Thyroid Physiopathological Changes During IVF. Reprod. Sci. 23, 515–523 (2016). https://doi.org/10.1177/1933719115608000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719115608000

Keywords

Search

Navigation