Effects of the Fertility Drugs Clomiphene Citrate and Letrozole on Kiss-1 Expression in Hypothalamic Kiss-1-Expressing Cell Models

• Published in: Reproductive sciences (Thousand Oaks, Calif.) Calif.), 2020-03, Vol.27 (3), p.806-814
• Main Authors: Oride, Aki, Kanasaki, Haruhiko, Tumurbaatar, Tuvshintugs, Zolzaya, Tumurgan, Okada, Hiroe, Hara, Tomomi, Kyo, Satoru
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Clomiphene - administration & dosage; Embryology; Estradiol - administration & dosage; Estrogen Receptor Antagonists - administration & dosage; Fertility Agents, Female - administration & dosage; Gene Expression - drug effects; Hypothalamus - drug effects; Hypothalamus - metabolism; Kisspeptins - metabolism; Letrozole - administration & dosage; Medicine; Medicine & Public Health; Mice; Neurons - drug effects; Neurons - metabolism; Obstetrics/Perinatology/Midwifery; Original Article; Receptors, Estrogen - metabolism; Reproductive Medicine
• ISSN: 1933-7191; 1933-7205
• DOI: 10.1007/s43032-020-00154-1

Clomiphene citrate (CC) and letrozole stimulate the hypothalamic-pituitary-ovarian axis and are used widely as oral fertility drugs to induce folliculogenesis. We examined whether these drugs increase Kiss-1 expression in hypothalamic cell models. We utilized two hypothalamic cell models, mHypoA-50 and mHypoA-55, which originated from Kiss-1 neurons in the anteroventral periventricular (AVPV) nucleus and arcuate (ARC) nucleus of the mouse hypothalamus, respectively. The cells were stimulated with CC or letrozole, after which Kiss-1 mRNA expression was determined. CC stimulated Kiss-1 gene expression in mHypoA-50 and mHypoA-55 cells. The basal expression of Kiss-1 was significantly increased in the presence of estradiol (E2) in mHypoA-50 cells, and the CC-induced increase in Kiss-1 expression was not observed in the presence of E2 in these cells. In contrast, E2 did not modify the basal expression of Kiss-1 in mHypoA-55 cells, and CC-induced Kiss-1 expression was still observed in the presence of E2. The significant increase in Kiss-1 gene expression in mHypoA-50 and mHypoA-55 cells was blunted in the presence of estrogen receptor antagonists. Aromatase was expressed in mHypoA-50 and mHypoA-55 cells. Letrozole, an aromatase inhibitor, increased Kiss-1 expression in mHypoA-55 ARC cells but not in mHypoA-50 AVPV cells. Although the basal expression of Kiss-1 was increased by E2, letrozole did not modulate Kiss-1 expression in mHypoA-50 cells. Letrozole-induced Kiss-1 gene expression in mHypoA-55 cells was not modulated in the presence of E2. The fertility drugs CC and letrozole modulated Kiss-1 expression in hypothalamic cell models.