Aromatase Inhibition Eliminates Sexual Receptivity Without Enhancing Weight Gain in Ovariectomized Marmoset Monkeys

Abstract

Context: Ovarian estradiol supports female sexual behavior and metabolic function. While ovariectomy (OVX) in rodents abolishes sexual behavior and enables obesity, OVX in nonhuman primates decreases, but does not abolish, sexual behavior, and inconsistently alters weight gain.

Objective: We hypothesize that extra-ovarian estradiol provides key support for both functions, and to test this idea, we employed aromatase inhibition to eliminate extra-ovarian estradiol biosynthesis and diet-induced obesity to enhance weight gain.

Methods: Thirteen adult female marmosets were OVX and received (1) estradiol-containing capsules and daily oral treatments of vehicle (E2; n = 5); empty capsules and daily oral treatments of either (2) vehicle (VEH, 1 mL/kg, n = 4), or (3) letrozole (LET, 1 mg/kg, n = 4).

Results: After 7 months, we observed robust sexual receptivity in E2, intermediate frequencies in VEH, and virtually none in LET females (P = .04). By contrast, few rejections of male mounts were observed in E2, intermediate frequencies in VEH, and high frequencies in LET females (P = .04). Receptive head turns were consistently observed in E2, but not in VEH and LET females. LET females, alone, exhibited robust aggressive rejection of males. VEH and LET females demonstrated increased % body weight gain (P = .01). Relative estradiol levels in peripheral serum were E2 >>> VEH > LET, while those in hypothalamus ranked E2 = VEH > LET, confirming inhibition of local hypothalamic estradiol synthesis by letrozole.

Conclusion: Our findings provide the first evidence for extra-ovarian estradiol contributing to female sexual behavior in a nonhuman primate, and prompt speculation that extra-ovarian estradiol, and in particular neuroestrogens, may similarly regulate sexual motivation in other primates, including humans.

Keywords: androgen excess; bone density; diet-induced obesity; estrogen depletion; neuroestrogen; nonhuman primate model.

Figure 1.

Species typical sexual behavior is observed in the behavioral transitions most likely to occur with (A) estradiol (E₂) replacement. In contrast, (B) loss of ovarian estradiol illustrates the switch in likelihood of behavioral transition from sexual receptivity to sexual rejection, while (C) loss of both ovarian and extra-ovarian estradiol results in not only a high probability of sexual rejection, but also the likelihood that sexual rejection will lead to aggressive hitting behavior. Each black arrow represents a statistically significant (P < .05) transition between connected behaviors. Green circles indicate sexually receptive behavior, blue circles indicate male intromission and red circles indicate sexual rejection.

Figure 2.

(A) Calories consumed (mean ± SEM) by both males and females combined in the male–female pairs (symbols illustrate individual male–female pair consumption) comprising the treatment groups E2 (black circles), VEH (light gray squares), and LET (dark gray triangles) from ovariectomy (OVX) until 5 months (months) after OVX, (B) amount of chow (mean ± SEM wet weight) provided to singly housed females during months 6 to 7 following OVX (E2 black bar, VEH light gray bar, LET dark gray bar), and (C) % calories consumed (mean ± SEM) by singly housed females during months 6 to 7 following OVX (E2 black bar, VEH light gray bar, LET dark gray bar).

Figure 3.

Changes in female sexual behavior (mean ± SEM) in OVX adult female marmosets receiving estradiol replacement (E2), vehicle (VEH), or an aromatase inhibitor, letrozole (LET): (A) percent sexual receptivity (black filled bars) is diminished in OVX (a, P = .001) compared to E2 females, and further diminished in LET compared with E2 (a, P = .001) and VEH (b, P = .04) females, while frequency of sexual rejection (red filled bars) is increased in both OVX (a, P = .03) and LET (a, P = .03) females compared with the E2 female group, and (B) frequency of receptive female head turns (gray dotted bars) is diminished in the absence of both ovarian (VEH, a, P = .003) and extra-ovarian (LET, a, P = .003) E2, and LET females exhibit both an increase in sexual rejection of males, and escalation of their rejection into hitting the male partner (black diagonal banded red bars; a,b: P = .004). (a = compared with E2 females; b = compared with VEH females; c = compared with LET females).

Figure 4.

(A) Monthly body weights (mean ± SEM) of adult female marmoset monkeys from baseline until 7 months following ovariectomy, and (B) AUC body weights (mean ± SEM) incorporating all increments in body weight across the entire study, in E2 (open circles and black bars), VEH (light gray circles and bars), and LET (dark gray squares and bars) female groups.

Figure 5.

Actical collar determined body motion activity over 21 consecutive days (mean ± SEM) in adult female marmosets in VEH (light gray circles and bars) and LET (dark gray squares and bars) groups (a) at baseline illustrating (A) hourly activity during 12 hour daytime and 12 hour nighttime and (B) AUC activity for daytime and nighttime, a, b: P = .001, at (b) 6 months (months) following OVX illustrating (A) hourly activity during 12 hour daytime and 12 hour nighttime and (B) AUC activity for daytime and nighttime, a, b: P = .01, and (c) % change in activity from baseline to 6 months following OVX during 12 hour daytime and 12 hour nighttime and AUC % activity change for 24 hours/day, daytime only and nighttime only, a, b: P = .01.