Dynamics of gonadotropin and thienopyrimidine derivative TP03 effects on ovulation and ovarian steroidogenesis in Follimag-stimulated immature female rats

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Abstract

BACKGROUND: Gonadotropin preparations, particularly human chorionic gonadotropin (hCG), are commonly used to induce ovulation and treat reproductive disorders in women, albeit with associated side effects. Low-molecular-weight allosteric agonists of the luteinizing hormone receptor (LHR), such as thieno[2,3-d]pyrimidine derivatives, offer a potential alternative.

AIM: This study aims to compare the effects of thieno[2,3-d]pyrimidine TP03 and hCG on ovarian weight, corpus luteum formation, and plasma levels of estradiol, progesterone, and luteinizing hormone in immature female rats pre-treated with Follimag®. It also examines their impact on ovarian gene expression related to LHR and steroidogenesis.

MATERIALS AND METHODS: TP03 and hCG were administered 48 h after the Follimag® injection at a dose of 20 mg/kg (i.p.) and 15 IU/rat (s.c.), respectively. Parameters were assessed at 1, 2, 4, 8, 16, and 24 h after TP03 and hCG administration. Plasma hormone levels were measured via ELISA, and ovarian gene expression was analyzed using real-time PCR.

RESULTS: TP03 increased ovarian weight, progesterone levels in the blood, and expression of steroidogenic genes encoding the cholesterol-transporting protein StAR and the cytochromes CYP11A1 and CYP17A1. TP03 also stimulated corpus luteum formation (16–24 h after treatment). The temporal dynamics of its stimulating effects were similar to those of hCG, although their magnitude was slightly inferior to those of gonadotropin. TP03-induced decrease in blood estradiol levels and aromatase gene expression in the ovaries was also more moderate. Unlike hCG, which suppressed LHR gene expression 8 h after treatment, TP03 maintained a high LHR gene expression, preserving ovarian sensitivity to endogenous luteinizing hormone.

CONCLUSIONS: TP03 exhibits potential as an ovulation inducer with milder stimulating effects on ovarian steroidogenesis than hCG, which reduces the risks of developing ovarian hyperstimulation syndrome and resistance to gonadotropins.

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About the authors

Kira V. Derkach

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Author for correspondence.
Email: derkatch_k@list.ru
ORCID iD: 0000-0001-6555-9540
SPIN-code: 6925-1558

Cand. Sci. (Biology)

Russian Federation, Saint Petersburg

Andrey A. Bakhtyukov

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: bahtyukov@gmail.com
ORCID iD: 0000-0002-2060-2020
SPIN-code: 7073-0586

Cand. Sci. (Biology)

Russian Federation, Saint Petersburg

Viktor N. Sorokoumov

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences; Saint Petersburg State University

Email: sorokoumov@gmail.com
ORCID iD: 0000-0002-4917-2175
SPIN-code: 1042-8142

Cand. Sci. (Chemistry)

Russian Federation, Saint Petersburg; Saint Petersburg

Egor A. Didenko

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences; Saint Petersburg State University

Email: didenkoegor58@mail.ru
ORCID iD: 0009-0000-5217-0624
SPIN-code: 5115-8389
Russian Federation, Saint Petersburg; Saint Petersburg

Irina V. Romanova

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: irinaromanova@mail.ru
ORCID iD: 0000-0002-0348-0631
SPIN-code: 8891-8186

Dr. Sci. (Biology)

Russian Federation, Saint Petersburg

Irina Yu. Morina

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: irinamorina@mail.ru
ORCID iD: 0000-0002-2252-0088
SPIN-code: 3489-8842

Cand. Sci. (Biology)

Russian Federation, Saint Petersburg

Ivan A, Lebedev

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: lebedevivan9@gmail.com
ORCID iD: 0000-0003-3917-4414
SPIN-code: 7084-4360
Russian Federation, Saint Petersburg

Lyubov V. Bayunova

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: bayunoval@mail.ru
ORCID iD: 0000-0001-5543-8657
SPIN-code: 2833-2978

Cand. Sci. (Biology)

Russian Federation, Saint Petersburg

Alexander O. Shpakov

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: alex_shpakov@list.ru
ORCID iD: 0000-0002-4293-3162
SPIN-code: 6335-8311

Dr. Sci. (Biology)

Russian Federation, Saint Petersburg

References

  1. Martinez F, Racca A, Rodríguez I, Polyzos NP. Ovarian stimulation for oocyte donation: a systematic review and meta-analysis. Hum Reprod Update. 2021;27(4):673–696. doi: 10.1093/humupd/dmab008
  2. Segaloff DL, Wang HY, Richards JS. Hormonal regulation of luteinizing hormone/chorionic gonadotropin receptor mRNA in rat ovarian cells during follicular development and luteinization. Mol Endocrinol. 1990;4(12):1856–1865. doi: 10.1210/mend-4-12-1856
  3. Menon B, Sinden J, Franzo-Romain M, et al. Regulation of LH receptor mRNA binding protein by miR-122 in rat ovaries. Endocrinology. 2013;154(12):4826–4834. doi: 10.1210/en.2013-1619
  4. Menon B, Gulappa T, Menon KM. miR-122 regulates LH receptor expression by activating sterol response element binding protein in rat ovaries. Endocrinology. 2015;156(9):3370–3380. doi: 10.1210/en.2015-1121
  5. Jiang X, Dias JA, He X. Structural biology of glycoprotein hormones and their receptors: insights to signaling. Mol Cell Endocrinol. 2014;382(1):424–451. doi: 10.1016/j.mce.2013.08.021
  6. Casarini L, Simoni M. Recent advances in understanding gonadotropin signaling. Fac Rev. 2021;10:41. doi: 10.12703/r/10-41
  7. Namavar Jahromi B, Parsanezhad ME, Shomali Z, et al. Ovarian hyperstimulation syndrome: a narrative review of its pathophysiology, risk factors, prevention, classification, and management. Iran J Med Sci. 2018;43(3):248–260.
  8. Shen X, Yang Q, Li L, Lu W. Clinical pregnancy and incidence of ovarian hyperstimulation syndrome in high ovarian responders receiving different doses of hCG supplementation in a GnRH-agonist trigger protocol. Evid Based Complement Alternat Med. 2021;2021:2180933. doi: 10.1155/2021/2180933
  9. Cerrillo M, Rodríguez S, Mayoral M, et al. Differential regulation of VEGF after final oocyte maturation with GnRH agonist versus hCG: a rationale for OHSS reduction. Fertil Steril. 2009;91(4 Suppl): 1526–1528. doi: 10.1016/j.fertnstert.2008.08.118
  10. Miller I, Chuderland D, Ron-El R, et al. GnRH agonist triggering modulates PEDF to VEGF ratio inversely to hCG in granulosa cells. J Clin Endocrinol Metab. 2015;100(11):E1428–E1436. doi: 10.1210/jc.2015-2312
  11. Engmann LL, Maslow BS, Kaye LA, et al. Low dose human chorionic gonadotropin administration at the time of gonadotropin releasing-hormone agonist trigger versus 35 h later in women at high risk of developing ovarian hyperstimulation syndrome — a prospective randomized double-blind clinical trial. J Ovarian Res. 2019;12(1):8. doi: 10.1186/s13048-019-0483-7
  12. Heitman LH, Oosterom J, Bonger KM, et al. [3H]Org 43553, the first low-molecular-weight agonistic and allosteric radioligand for the human luteinizing hormone receptor. Mol Pharmacol. 2008;73(2):518–524. doi: 10.1124/mol.107.039875
  13. van Koppen CJ, Zaman GJ, Timmers CM, et al. A signaling-selective, nanomolar potent allosteric low molecular weight agonist for the human luteinizing hormone receptor. Naunyn Schmiedebergs Arch Pharmacol. 2008;378(5):503–514. doi: 10.1007/s00210-008-0318-3
  14. Nataraja SG, Yu HN, Palmer SS. Discovery and development of small molecule allosteric modulators of glycoprotein hormone receptors. Front Endocrinol (Lausanne). 2015;6:142. doi: 10.3389/fendo.2015.00142
  15. Derkach K.V., Dar’in D.V., Bakhtyukov A.A., et al. In vitro and in vivo studies of functional activity of new low molecular weight agonists of the luteinizing hormone receptor. Biochem Mosc Suppl Ser A. 2016;10:294–300. doi: 10.1134/S1990747816030132
  16. Bakhtyukov AA, Derkach KV, Sorokoumov VN, et al. The effects of separate and combined treatment of male rats with type 2 diabetes with metformin and orthosteric and allosteric agonists of luteinizing hormone receptor on steroidogenesis and spermatogenesis. Int J Mol Sci. 2021;23(1):198. doi: 10.3390/ijms23010198
  17. van de Lagemaat R, Timmers CM, et al. Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor. Hum Reprod. 2009;24(3):640–648. doi: 10.1093/humrep/den412
  18. van de Lagemaat R, Raafs BC, van Koppen C, et al. Prevention of the onset of ovarian hyperstimulation syndrome (OHSS) in the rat after ovulation induction with a low molecular weight agonist of the LH receptor compared with hCG and rec-LH. Endocrinology. 2011;152(11):4350–4357. doi: 10.1210/en.2011-1077
  19. Fokina EA, Derkach KV, Bakhtyukov AA, et al. stimulation of ovulation in immature female rats using orthosteric and allosteric luteinizing hormone receptor agonists. Dokl Biochem Biophys. 2022;507(1):345–349. doi: 10.1134/S1607672922340063
  20. Pedersen T, Peters H. Proposal for a classification of oocytes and follicles in the mouse ovary. J Reprod Fertil. 1968;17(3):555–557. doi: 10.1530/jrf.0.0170555
  21. Hirshfield AN. Development of follicles in the mammalian ovary. Int Rev Cytol. 1991;124:43–101. doi: 10.1016/s0074-7696(08)61524-7
  22. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101–1108. doi: 10.1038/nprot.2008.73
  23. Hsueh AJ, Adashi EY, Jones PB, Welsh TH Jr. Hormonal regulation of the differentiation of cultured ovarian granulosa cells. Endocr Rev. 1984;5(1):76–127. doi: 10.1210/edrv-5-1-76
  24. Palermo R. Differential actions of FSH and LH during folliculogenesis. Reprod Biomed Online. 2007;15(3):326–337. doi: 10.1016/s1472-6483(10)60347-1
  25. Conforti A, Vaiarelli A, Cimadomo D, et al. Pharmacogenetics of FSH Action in the Female. Front Endocrinol (Lausanne). 2019;10:398. doi: 10.3389/fendo.2019.00398
  26. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32(1):81–151. doi: 10.1210/er.2010-0013
  27. Singh P, Krishna A. Effects of GnRH agonist treatment on steroidogenesis and folliculogenesis in the ovary of cyclic mice. J Ovarian Res. 2010;3:26. doi: 10.1186/1757-2215-3-26
  28. Riccetti L, Yvinec R, Klett D, et al. human luteinizing hormone and chorionic gonadotropin display biased agonism at the LH and LH/CG receptors. Sci Rep. 2017;7(1):940. doi: 10.1038/s41598-017-01078-8
  29. Soares SR. Etiology of OHSS and use of dopamine agonists. Fertil Steril. 2012;97(3):517–522. doi: 10.1016/j.fertnstert.2011.12.046
  30. Li Y, Fang L, Zhang R, et al. Melatonin stimulates VEGF expression in human granulosa-lutein cells: A potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome. Mol Cell Endocrinol. 2020;518:110981. doi: 10.1016/j.mce.2020.110981
  31. Veldhuis JD, Liu PY, Takahashi PY, Keenan DM. Dynamic testosterone responses to near-physiological LH pulses are determined by the time pattern of prior intravenous LH infusion. Am J Physiol Endocrinol Metab. 2012;303(6):E720–E728. doi: 10.1152/ajpendo.00200.2012

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