Brain Aromatase and the Regulation of Sexual Activity in Male Mice

Abstract

The biologically active estrogen estradiol has important roles in adult brain physiology and sexual behavior. A single gene, Cyp19a1, encodes aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol in the testis and brain of male mice. Estradiol formation was shown to regulate sexual activity in various species, but the relative contributions to sexual behavior of estrogen that arises in the brain versus from the gonads remained unclear. To determine the role of brain aromatase in regulating male sexual activity, we generated a brain-specific aromatase knockout (bArKO) mouse. A newly generated whole-body total aromatase knockout mouse of the same genetic background served as a positive control. Here we demonstrate that local aromatase expression and estrogen production in the brain is partially required for male sexual behavior and sex hormone homeostasis. Male bArKO mice exhibited decreased sexual activity in the presence of strikingly elevated circulating testosterone. In castrated adult bArKO mice, administration of testosterone only partially restored sexual behavior; full sexual behavior, however, was achieved only when both estradiol and testosterone were administered together. Thus, aromatase in the brain is, in part, necessary for testosterone-dependent male sexual activity. We also found that brain aromatase is required for negative feedback regulation of circulating testosterone of testicular origin. Our findings suggest testosterone activates male sexual behavior in part via conversion to estradiol in the brain. These studies provide foundational evidence that sexual behavior may be modified through inhibition or enhancement of brain aromatase enzyme activity and/or utilization of selective estrogen receptor modulators.

Efficacy and safety of letrozole or anastrozole in the treatment of male infertility with low testosterone‐estradiol ratio: A meta‐analysis and systematic review

“…Therefore, the use of LE or AZ in men with low testosterone appears to reduce libido by reducing estradiol. In addition, Brooks's research 40 confirmed that the conversion of testosterone to estrogen in the brain is essential for maintaining full sexual function and libido in men. Aromatase drives this process.…”

“…Summary of side effects Other side effects (8/243): transient weakness, mild diarrhea, joint and tendon pain and swelling in limbs, irritability and depression, bilateral breast tenderness, gradual ocular pruritus, ocular pain, and dry mouth.Therefore, the use of LE or AZ in men with low testosterone appears to reduce libido by reducing estradiol. In addition, Brooks's research40 …”

Effect of Chronic Moderate Caloric Restriction on the Reproductive Function in Aged Male Wistar Rats

“…This also occurred in experiments with Macaca mulata subjected to CR at 30%, where improved functionality of the HPG axis and stable T levels were found compared to a control group [ 41 ]. This indicates that aromatase activity is necessary for the aromatization of T to E 2 , which increases its concentration during the aging process [ 42 ]. In contrast, E 2 levels in the control group were increased, likely due to high aromatase activity in animals with greater body weight [ 42 ].…”

“…This indicates that aromatase activity is necessary for the aromatization of T to E 2 , which increases its concentration during the aging process [ 42 ]. In contrast, E 2 levels in the control group were increased, likely due to high aromatase activity in animals with greater body weight [ 42 ]. In other hand, prolactin has been reported to participate in controlling masculine behavior [ 20 ], and also, an increase in its levels can inhibit MSB during aging [ 23 , 43 ].…”

Inhibition of androgenic pathway impairs encoding of cerebellar‐dependent motor learning in male rats

“…Thus, it has been suggested that 3α‐diol may exert its action due to high GABAergic (type A) binding activity, whereas 3β‐diol preferentially binds to the estrogen receptor beta (Edinger & Frye, 2007a; Kuiper et al., 1998; Reddy & Jian, 2010; Steckelbroeck et al., 2004). Furthermore, the conversion from T to estradiol by the p‐450 aromatase enzyme in the CNS may also be responsible for some androgen effects on behavior via estradiol activating estrogen receptors (Brocca & Garcia‐Segura, 2019; Brooks et al., 2020; Grassi et al., 2010; Rosenfeld et al., 2018).…”