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interfering with the function of the hypothalamic-pituitary-gonadalaxis, thus modifying ovarian function and gonadotropin release.Female athletes who self-administer a combination of AAS com-pounds, including stanozolol, exhibit suppressed gonadotropin lev-els in the presence of elevated serum testosterone levels (21).Additionally, postmenopausal women receiving a low dose of stanozolol (10 mg/day) in the treatment of osteoporosis showsuppressed serum levels of luteinizing hormone, follicle stimulat- FIG. 4. Mean (  SEM) percentage of days of lordosis behavior and vaginal estrus displayed during each 2-weekobservation period: baseline, treatment, and recovery. During the AAS treatment period, rats received dailyinjections of a 7.5 mg/kg dose of either stanozolol, oxymetholone, testosterone cypionate, or the oil vehicle. *, p  0.05 vs. all other groups. §, p  0.05 vs. oil. #, p  0.05 vs. oxymetholone and oil. ANABOLIC STEROIDS AND THE ESTROUS CYCLE 293

ing hormone, and sex hormone-binding globulin (31). These clin-ical ﬁndings support the claim that stanozolol disrupts the functionof the hypothalamic-pituitary-gonadal axis. A similar responsemay occur in the female rat, however no studies exist that couldsupport or refute this possibility.Stanozolol may act on the brain to interfere with the display of lordosis. The inhibitory effects of stanozolol on lordosis behaviorin cycling female rats may parallel the actions of another nonaro-matizable androgen, 5  -dihydrotestosterone (DHT), on lordosisbehavior in ovariectomized hormone-primed animals (11,13).Brown and colleagues (9) observed a downregulation of estrogenreceptors in the ventromedial hypothalamus of female rats treatedwith DHT. They propose that androgens may indirectly inhibitfemale sexual behavior by altering brain estrogen receptor levels.The effects of stanozolol and DHT on brain steroid receptors maydiffer, however, since DHT is a potent androgen, but stanozololbinds poorly to androgen receptors in the prostate (23) and in thebrain (C. E. Roselli, personal communication).The 12 mg/kg dose of oxymetholone (Experiment 2) disruptedthe cyclical display of lordosis behavior and vaginal estrus. At alower dose (7.5 mg/kg, Experiment 4), oxymetholone disruptedvaginal estrus without interfering with sexual receptivity. Thus,oxymetholone appeared to be the least disruptive AAS compoundadministered in the present study. No data are available on therelationship between oxymetholone and the function of the hypo-thalmic-pituitary-gonadal axis in humans or in rats. Further studiesof steroid hormone and gonadotropin levels in cycling female ratstreated with oxymetholone may clarify the nature of its inﬂuenceon female reproductive function.Testosterone cypionate generated an altogether different behav-ioral and physiological response than either stanozolol or oxy-metholone. Rats receiving the 7.5 mg/kg dose (Experiments 1 and4) displayed few days of estrous smears during the treatmentperiod and no days of vaginal estrus during the recovery period.Rats that failed to exhibit estrous smears showed a dramaticincrease in the frequency of lordosis behavior during the treatmentand the recovery periods. The seemingly disparate effects of tes-tosterone cypionate on vaginal cytology (i.e., persistent diestrous)and sexual behavior (i.e., persistent lordosis) may be reconciled byconsidering the different pathways of testosterone metabolism inthe body and their relationship to reproductive function. Thecessation of vaginal estrus in the presence of high levels of testosterone has been shown previously and may be due to thedegenerative effects of elevated androgen levels on ovarian gran-ulosa cells (1,2). Browman (8) observed that rats treated with0.5–3.0 mg of testosterone in an oil vehicle exhibited diestrouscytology beginning 3 days after the initiation of hormone treat-ment. Recently, Bronson et al. (7) reported that vaginal cyclicityceased in mice exposed to a combination of AAS compounds,including testosterone, testosterone cypionate, 17  -methyltestos-terone, and norethandrolone, for 9 weeks. Thus, in agreement withprevious studies, testosterone cypionate disrupted the cyclical dis-play of vaginal estrus.The increased frequency of lordosis observed with testosteronecypionate administration probably reﬂects the metabolism andaromatization of testosterone cypionate into estrogen and the sub-sequent direct actions of locally synthesized estrogens in the brainregions important for female sexual behavior. Thus, rats in thehigh and medium dose groups may have been exposed to contin-uously high levels of estrogen, resulting in the maintenance of lordosis responding for an extended period of time. In a previousstudy (6), we observed an increase in the frequency of lordosisresponding during the recovery period in some rats treated withanother AAS, nandrolone decanoate. Given that both nandrolonedecanoate and testosterone cypionate are subject to aromatization,the facilitative effects on lordosis responding may be due to theactions of their estrogenic metabolites. This hypothesis is consis-tent with the ﬁnding that an aromatase inhibitor blocks the induc-tion of lordosis in ovariectomized female rats following the ad-ministration of testosterone propionate in combination withprogesterone (15). Furthermore, estrogenic metabolites of testos-terone have been shown to have uterotrophic actions in the uterus.For example, Whalen and Hardy (27) reported that the uteri of ovariectomized females receiving 1.0 mg of testosterone propi-onate daily for 1 month were signiﬁcantly heavier than the uteri of untreated intact female rats.Women who self-administer AAS compounds report a varietyof side-effects including changes in libido and menstrual function;however the literature on this topic is sparse. Because there aremarked differences in the degree to which sexual behavior iscontrolled by gonadal hormones in the female rat versus the humanfemale, the relevance of our ﬁndings in rats to human AAS usersmust be interpreted with caution. Nonetheless, through research onlaboratory animals a better grasp of the inﬂuence of individualAAS compounds on the hypothalamic-pituitary-gonadal axis canbe achieved which may elucidate the potential risks associatedwith AAS use in humans. The results of the present studiesillustrate that the short-term administration of stanozolol, oxy-metholone, and testosterone cypionate elicits measurable and dis-tinct effects on the rat estrous cycle. ACKNOWLEDGEMENTS This research was supported by National Institute of Drug Abuse Grant08574 and a Burke Award from Dartmouth College to A. S. C. We thankSiobhan Robinson for technical assistance and Elizabeth Harrold and Dr.Leslie Henderson for comments on the manuscript. REFERENCES 1. Anderson, E. In vivo and in vitro effects of androgens on rat ovariangranulosa cells. Am. J. Obstet. Gynecol. 160:782–788; 1989.2. Anderson, E.; Little, B.; Lee, G. S. Androgen-induced changes in ratovarian granulosa cells in vitro. Tissue Cell 19:217–234; 1987.3. 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