Discovery points toward new treatments for ovariectomized women

Two Common marmosets rest together on a log at the Wisconsin National Primate Research Center. (Photo by J. Lenon)
Common marmosets at the Wisconsin National Primate Research Center. (Photo by J. Lenon)

By Jordana Lenon
Dec. 14, 2022

Doctors frequently administer synthetic estradiol that mimics ovarian estradiol to alleviate sexual and metabolic dysfunction in women who have had ovariectomies for cysts, cancer or other problems.

But this hormone only works to varying degrees. Furthermore, it may increase the risk of harmful side-effects, including cardiovascular disease and cancer.

Recently, scientists at the Wisconsin National Primate Research Center discovered the first evidence that extra-ovarian estradiol provides key support for healthy female sexual behavior and metabolic function, as well as maintaining a healthy weight. Extra-ovarian estradiol is found in the skin, adipose tissue and brain, specifically in the hypothalamus, so it’s not just a hormone produced by the ovaries.

Marissa Kraynak, Ph.D.
Marissa Kraynak, Ph.D.

The new finding points toward treatments that avoid potentially harmful ovarian-derived estrogen activity by instead delivering bioactive estradiol derived only from the brain, reports first author Marissa Kraynak, Ph.D., was a research fellow in the Endocrinology and Reproductive Physiology Program at the University of Wisconsin–Madison when the study was underway, training under David Abbott, Ph.D., and Jon Levine, Ph.D., at the Primate Center. She is now Director of Health Policy Research at Insure the Uninsured Project in Sacramento.

“These findings have tremendous potential to alleviate female sexual and metabolic dysfunction,” Kraynak and her colleagues wrote in a paper published in the Journal of the Endocrine Society.

Kraynak conducted her research in common marmosets housed and cared for at the National Institutes of Health funded center. Co-authors included David Abbott, professor of obstetrics and gynecology, Jon Levine, professor of neuroscience, and other researchers at the center and in the UW–Madison School of Medicine and Public Health. The NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development funded the work.

The lack of effective treatment options for women with Female Sexual Interest Arousal Disorder (FSIAD) and obesity is likely related to the lack of understanding regarding the biology of female sexuality, as well as the regulation of body weight and metabolism, the authors wrote.

With regard to sexual behavior, the study suggests that, in the absence of ovarian estradiol, extra-ovarian hypothalamic estradiol – that is, neuroestrogen – plays a pivotal role in maintaining sexual receptivity in female nonhuman primates.

“The implications of these findings in marmosets open up a wealth of opportunities to explore new central nervous system–targeted approaches to treating sexual dysfunction in women,” Kraynak said. “Our findings suggest that future treatments delivering bioactive estradiol to only the central nervous system may alleviate both sexual and metabolic dysfunction.”

The NIH-funded study pulls together a lot of new information, Kraynak explained: It identifies key relationships between steroid hormones in circulation and the hypothalamus, behavior and behaviorally related hypothalamic gene expression, neuroendocrine regulation of ovarian function, weight gain and calorie consumption, and other correlations that suggest possible neural mechanisms for estradiol regulation of female sexual behavior, ovarian function, and metabolic homeostasis in nonhuman primates and women.

“Mainly, the study identifies a specific role for extra-ovarian estradiol, possibly neuroestrogens locally produced in the hypothalamus and other brain regions, in regulating female sexual behavior,” she said.

The ovarian estradiol-depleted female monkeys still expressed receptive postures and gestures toward at least 35 percent of male mounting behaviors, she added. Only by removing both ovarian and extra-ovarian estradiol, including hypothalamic sources, were female marmosets consistently sexually unreceptive to male sexual advances. These findings thereby demonstrate that sexual motivation in a primate may depend in part upon estrogens that are made in the brain, and acting locally within the brain to activate brain circuits that mediate female sexual behavior.

These findings follow a 2013 study at the WNPRC demonstrating that the rhesus monkey brain, not just the ovaries, synthesizes estrogens that control neural function. Through this new study with marmosets, scientists are learning more about the how these neuroestrogens may be integral to the support of libido and hence to the maintenance of female sexual health.