Differential response of gonadotropin-releasing hormone (GNRH1 and GNRH2) expressing cells to estrogen feedback

Urbanski Henryk F; Appleman Maria Luisa; Fecteau Kristopher M; Erikson David W; Sathya Srinivasan; Kohama Steven G; Alejandro Lomniczi

doi:10.1530/endoabs.109.OP4.2

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Endocrine Abstracts (2025) 109 OP4.2 | DOI: 10.1530/endoabs.109.OP4.2

SFEBES2025 Poster Oral Presentations Thyroid and Reproduction (4 abstracts)

Differential response of gonadotropin-releasing hormone (GNRH1 and GNRH2) expressing cells to estrogen feedback

Henryk F Urbanski ¹ , Maria Luisa Appleman ¹ , Kristopher M Fecteau ¹ , David W Erikson ¹ , Sathya Srinivasan ¹ , Steven G Kohama ¹ & Alejandro Lomniczi ²

Author affiliations

¹Oregon Health & Science University, Beaverton, USA. ²Dalhousie University, Halifax, Canada

Gonadotropin-releasing hormone (GNRH) represents the primary hypothalamic component of the reproductive neuroendocrine axis. It plays a key role in stimulating the pulsatile release of luteinizing hormone (LH) as well as the preovulatory LH surge. However, it remains enigmatic how hypothalamic GNRH neurons are capable of differentially responding to ovarian estrogen feedback (i.e., in a negative manner during the early follicular phase of the menstrual cycle but in a positive manner at the time of the mid-cycle LH surge). In the present study we show: (1) that female rhesus macaques, like women, express not one but two different molecular forms of GNRH (i.e., GNRH1 and GNRH2), (2) that GNRH1 and GNRH2 mRNAs are expressed by two completely distinct neuronal populations in the hypothalamus, and (3) that GNRH2 mRNA is also expressed within the anterior pituitary gland itself. Moreover, we show that estrogen differentially affects GNRH1 and GNRH2 peptide concentrations in the pituitary gland, causing a significant increase in GNRH2 but not in GNRH1. Taken together, these findings suggest that different aspects of reproductive function in humans and nonhuman primates are likely to be controlled by two separate populations of GNRH producing cells, with GNRH1 peptide being responsible for maintaining tonic pulsatile LH release and GNRH2 peptide playing a primary role in triggering the estrogen-induced preovulatory LH surge. Consequently, it may be possible to block ovulation by selectively targeting GNRH2 expressing cells pharmacologically without negatively impacting the rest of the neuroendocrine reproductive axis, thus opening a novel approach to contraception. The findings may also shed new light on possible causes of idiopathic infertility and help with the development of effective therapies.