Hypothalamic Estrogen Receptor α Is Essential for Female Marmoset Sexual Behavior Without Protecting From Obesity.

IF 3 Q2 ENDOCRINOLOGY & METABOLISM Journal of the Endocrine Society Pub Date : 2025-02-05 eCollection Date: 2025-02-04 DOI:10.1210/jendso/bvaf012

Marissa Kraynak, Molly M Willging, Daniel J Uhlrich, Robert A Shapiro, Matthew T Flowers, Karen A Manning, Sara D John, Samantha M Williams, Lukas J Henjum, Rebecca C Marrah, Hannah R Yohnk, Carter B Berg, Kevin Brunner, Ricki J Colman, Andrew L Alexander, David H Abbott, Jon E Levine

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Abstract

Context: Estrogen receptor α (ERα) in the ventromedial (VMN) and arcuate (ARC) nuclei of female rodent mediobasal hypothalami (MBHs) provides a crucial molecular gateway facilitating estradiol (E₂) regulation of sexual behavior, reproductive neuroendocrinology, and metabolic function. In female nonhuman primates (NHPs) and women, however, its hypothalamic counterpart remains unknown.

Objective: We hypothesized that knockdown (KD) of ERα expression in the hypothalamic VMN and ARC of female marmosets would diminish sexual receptivity, while simultaneously disrupting gonadotropic and metabolic homeostasis.

Methods: We ovariectomized (OVX) adult female marmosets of comparable age and weight, immediately replaced E₂ at midcycle levels, and approximately 1 month later assigned monkeys to diet-induced obesity (DIO) within group (1) control, receiving scrambled short hairpin RNA (shRNA), or (2) ERαKD, receiving selective ERα gene silencing shRNA. Magnetic resonance imaging-guided neural surgery enabled hypothalamic infusion of viral vector shRNA and subsequent brain immunohistochemistry enabled observer-validated, NIS-elements computer software quantification of ERα knockdown.

Results: ERα expression was significantly diminished in the VMN and ARC, but not the preoptic area (POA), of ERαKD females coincident with elimination of timely female sexual responses, more than 80% loss of female receptivity, modestly elevated gonadotropin levels, hyperglycemia, and diminished calorie consumption. Density and intensity of ERα-expressing cells in the VMN correlated positively with female sexual receptivity and calorie consumption, negatively with timeliness of female sexual responses, and in the ARC, correlated negatively with calorie consumption.

Conclusion: ERα activation in the female NHP MBH is critically important for female sexual behavior and modestly contributes to gonadotropic and metabolic control.

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