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Mechanisms of Hormone Action |
a Department of Psychological and Brain Sciences, Dartmouth College, Hanover, New Hampshire 03755
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-methyltestosterone (0.5–5 mg/kg), and methandrostenolone (0.5–5 mg/kg) on the onset of puberty and estrous cyclicity in the rat. Female rats received daily injections of AASs for 30 days (Postnatal Day [PN] 21–51). Rats receiving the highest dose of each of the AASs (5 mg/kg) displayed vaginal opening at a younger age than rats receiving the oil vehicle. The day of first vaginal estrus was delayed in rats receiving stanozolol (5 mg/kg) or 17-methyltestosterone (0.5–5 mg/kg) but not in rats receiving methandrostenolone. At the highest dose (5 mg/kg), each of the AASs reduced the incidence of regular estrous cyclicity during the treatment period. Concurrent administration (on PN21–51) of the androgen receptor antagonist, flutamide (10 mg/kg, twice daily), reversed the effects of 17-methyltestosterone (5 mg/kg) on vaginal opening. Flutamide administration also eliminated the effects of stanozolol (5 mg/kg) and 17-methyltestosterone (5 mg/kg) on the day of first vaginal estrus. In contrast, rats receiving flutamide and methandrostenolone (5 mg/kg) exhibited first vaginal estrus earlier than controls. The present results indicate that chronic exposure to AASs during development has deleterious effects on the female neuroendocrine axis and that these effects appear be mediated via multiple mechanisms.
androgen receptor, mechanisms of hormone action, puberty, steroid-hormones, vagina
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The female rat has been used as a model system for the examination of the neural and hormonal events underlying puberty (see [12] for a review). Various aspects of female physiology and neuroendocrine function have been used as markers of puberty. Specifically, vaginal opening (VO) is one early and visible indicator of the increasing estrogen titers that accompany the onset of puberty. The culmination of the maturation of the adult pattern of functioning of the hypothalamic-pituitary-gonadal (HPG) axis is signaled by the first vaginal estrus (VE), itself precipitated by ovulation. Last, the adult pattern of estrous cyclicity is established. These three measures were used in the present study to assess the effects of long-term administration of AASs on puberty in female rats.
In a previous study, we reported the effects of a single injection of one AAS, stanozolol, on the onset of puberty. Administration of stanozolol on Postnatal Day 21 (PN21) advanced the day of VO without affecting the day of VE [13]. These results suggest that a brief exposure to stanozolol does not produce the hormonal conditions necessary to elicit true precocious puberty and maturation of the HPG axis. Users of AASs typically take these compounds for prolonged periods of time (weeks or months) as opposed to a single exposure [9]. To determine the effects of chronic use of AASs on the developing neuroendocrine axis, experiments 1–3 in the present study investigated the effects of chronic administration of three AASs on the onset of puberty in female rats. The three AASs chosen for this study are commonly abused and are members of the 17-alkylated class of androgens [1–4, 14]. Because we have found other effects of these AASs to be dependent on the androgen receptor (AR) [15], an additional experiment was conducted to determine whether androgen receptor activation played a role in the effects of AASs on pubertal onset. These studies complement and extend the existing literature on the effects of long-term administration of AASs on adult animals [5–8].
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Timed-pregnancy Long-Evans rats were received in the vivarium of the Department of Psychological and Brain Sciences at Dartmouth College on Embryonic Day 18. The pregnant rats were housed individually in plastic tubs and maintained on a 12L:12D schedule. Food and water were freely available. The temperature and humidity were monitored and held constant. The day of birth was recorded as PN0. On PN3, the litters were culled to nine pups, keeping as many female pups as possible. Upon weaning on PN20/21, they were housed two per hanging metal cage. Investigations were conducted in accordance with the Guide for the Care and Use of Laboratory Animals [16].
Procedures and Analysis
The following drugs were administered: stanozolol (17-methyl-5-androstan-17ß-olo(3,2-c)pyrazole, 17-methyltestosterone (17ß-hydroxy-17-methyl-4-androsten-3-one), methandrostenolone (17ß-hydroxy-17-methyl-androsta-1,4-dien-3-one), and flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)-phenyl]propanamide). Drugs were obtained from Sigma Chemical Co. (St. Louis, MO). Drugs were administered from Days 21–51 by s.c. injection in a sesame oil vehicle, with the exception of flutamide, which was administered in a 10% ethanol/90% propylene glycol (pg) vehicle. Administration of AASs by injection was conducted to facilitate comparison of the findings from the present study with research examining the effects of these synthetic AASs on behavior and physiology in laboratory animals from a number of previous reports [5–8, 13]. Drugs were coded so that the experimenter was unaware of the treatment conditions. The female pups were monitored daily for VO. Once VO had occurred, daily vaginal lavages were collected until PN65, allowing for continuing assessment of vaginal cytology after cessation of the treatment period on PN51 [17, 18]. The period PN51–PN65 is referred to as the recovery period. Rats that did not exhibit VO during the experimental timeframe (i.e., by PN65) were assigned a day of VO and VE of PN65 for statistical analyses. Rats that exhibited normal 4- to 5-day-long estrous cycles were considered to be regularly cycling. Rats were weighed every fifth day of the treatment period.
Four independent experiments were conducted. Experiments 1–3 investigated the dose-response characteristics of chronic administration of stanozolol, 17-methyltestosterone, and methandrostenolone, respectively, on aspects of pubertal onset. Experiment 4 examined pubertal events and estrous cyclicity in rats treated concurrently with AASs (5 mg/kg) and an androgen receptor antagonist. In each experiment, female pups were weaned, weighed, and randomly assigned to treatment groups on PN21 [13, 19]. Daily injections of AAS/vehicle began on PN21 and continued for 30 days. The doses of AASs administered to rats in the present experiments were selected to be comparable with the middle to upper end of the dose range for self-administration by human users [20]. In experiments 1–3, the following doses of AASs were administered: stanozolol, 0.05, 0.5, 1, or 5 mg/kg; 17-methyltestosterone, 0.5, 1, 2.5, or 5 mg/kg; methandrostenolone, 0.5, 1, 2.5, or 5 mg/kg. In experiment 4, the androgen receptor antagonist (flutamide, 10 mg/kg) was injected twice daily [13, 19]. In each experiment, there were 6–9 rats per group.
Day of VO and day of VE were evaluated by one-way analysis of variance, and post hoc analysis was performed with a Newman-Keuls test. The treatment period measures of VO and VE in experiments 1, 3, and 4 did not exhibit homogeneity of variance and were subject to nonparametric analyses (Kruskal-Wallis followed by Mann-Whitney U-test). The incidences of regular estrous cyclicity were compared using a Fisher exact probability test. Body weight data were examined by regression analysis to determine individual growth curves, and the slopes of the growth curves were compared between treatment groups using a one-way ANOVA and post hoc Newman-Keuls tests. Results are expressed as means ± SEM for each group. Differences were considered significant at P < 0.05; significant results reported for Mann-Whitney U-tests met levels adjusted with a Bonferroni correction.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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As shown in Figure 1, the day of VO was advanced by each of the AASs relative to the control group (stanozolol, H = 25.2; 17-methyltestosterone F(4, 32) = 11.1, methandrostenolone, H = 19.9; all AASs, P < 0.05), although the maximal effect varied across compounds. Day of VO was advanced between 3 and 10 days, i.e., from PN35 in the oil group to 
PN32 (2.5 and 5 mg/kg 17-methyltestosterone, P < 0.05 vs. control) or PN25 (1 and 5 mg/kg stanozolol and 1, 2.5, and 5 mg/kg of methandrostenolone, P < 0.05 vs. control).
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AASs Delay Day of First Vaginal Estrus
Heterogeneous effects of AASs were observed on day of VE (Fig. 1). VE occurred on PN40 in the control group, compared with PN51 for the highest dose of stanozolol (5 mg/kg) and PN61 for the highest dose of 17-methyltestosterone (5 mg/kg). Chronic administration of either stanozolol (5 mg/kg) or 17-methyltestosterone (0.5–5 mg/kg) delayed day of VE relative to the control group (stanozolol, H = 20.7; 17-methyltestosterone, F(4, 32) = 6.3; both AASs, P < 0.05). Methandrostenolone had no significant effect on the timing of VE at any dose administered (0.5–5 mg/kg).
Chronic AASs Suppress Estrous Cyclicity
As illustrated in Figure 2, rats receiving high doses of AASs did not display regular estrous cycles. The incidence of regular estrous cyclicity in the control group was significantly (P < 0.05) greater than in the groups receiving 1 and 5 mg/kg stanozolol, 2.5 or 5 mg/kg 17-methyltestosterone, and 2.5 or 5 mg/kg methandrostenolone. The lavages from rats receiving high doses of AASs exhibited a pattern of persistent diestrus cytology.
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Role of the Androgen Receptor
AASs bind to the AR [21, 22] and activation of the AR by AASs is necessary for some of the functional effects of these compounds [15]. Therefore, experiment 4 tested the role of the AR in the modulation of puberty by AASs. Concurrent administration of the AR-specific antagonist flutamide and AASs had effects on day of VO, VE, and estrous cyclicity that varied as a function of the specific compound and dose administered. For all measures, there were no differences between the oil/pg and oil/flutamide groups, and the oil/flutamide group was designated as the control group for statistical comparisons.
Day of VO
As expected, administration of AASs alone advanced the day of VO (H = 47, P < 0.05; Fig. 3A). Rats receiving stanozolol/flutamide and methandrostenolone/flutamide displayed VO earlier than the control group (P < 0.05). In contrast, VO did not differ between the 17-methyltestosterone/flutamide and control groups.
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Day of VE
Figure 3B shows that stanozolol and 17-methyltestosterone delayed the day of VE relative to the control group (P < 0.05). Day of VE did not differ significantly between the control group and the groups receiving stanozolol/flutamide and 17-methyltestosterone/flutamide. Although methandrostenolone alone did not affect day of VE, VE was advanced in the group treated with methandrostenolone/flutamide compared with controls (P < 0.05).
Estrous cyclicity
Figure 3C illustrates estrous cycle regularity in experiment 4. The incidence of regular estrous cyclicity in the control group was significantly (P < 0.05) greater than in the groups receiving stanozolol, 17-methyltestosterone, 17-methyltestosterone/flutamide, methandrostenolone, and methandrostenolone/flutamide. Rats receiving stanozolol and 17-methyltestosterone, in the presence or absence of flutamide, and methandrostenolone alone exhibited a pattern of persistent diestrus cytology similar to that observed in experiments 1–3. In contrast, the vaginal cytology of rats receiving methandrostenolone in combination with flutamide was characterized by multiple episodes of 2–3 consecutive days of vaginal estrus.
Resumption of Estrous Cyclicity
In experiments 1–3 during the 14-day recovery period (PN51–65), rats displayed regular vaginal estrous cycles (data not shown). In experiment 4, the incidence of regular estrous cyclicity in the control group was significantly (P < 0.05) greater than in rats treated with methandrostenolone/flutamide.
Body Weight
Rate of growth was affected only in rats receiving the high dose of stanozolol (5 mg/kg, experiment 1, F(4, 31) = 5.7; experiment 4, F(7, 48) = 3; both P < 0.05). In experiments 1 and 4, rats receiving stanozolol had a significantly (P < 0.05) higher rate of growth (5.9 ± 0.7 g and 5.6 ± 0.4 g per weigh period, respectively) than controls (4.9 ± 0.1 and 4.7 ± 0.6 g per weigh period, respectively).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The present series of experiments examined the effects of chronic administration of individual AASs on the day of vaginal opening as well as the initiation and the maintenance of estrous cyclicity in rats. Chronic administration of AASs advanced the day of vaginal opening; stanozolol and methandrostenolone advanced VO by about 10 days (to PN25), whereas the highest dose of 17-methyltestosterone advanced VO by only 3 days (to PN32). These results confirm and extend previous research from our laboratory showing that VO is advanced in response to a single, acute exposure to stanozolol [13, 19]. In addition, our results indicate that AASs vary in efficacy to induce VO. Although the dose of 5 mg/kg of stanozolol and of methandrostenolone advanced VO to PN25, the same dose of 17-methyltestosterone advanced VO to PN32. As noted below, 17-methyltestosterone was a potent stimulus for other endpoints (day of first vaginal estrus, estrous cyclicity), suggesting that the relative inefficacy of 17-methyltestosterone on VO may be specific to this response. We observed a similar variation in efficacy in rats receiving a single injection of an AAS compound on PN21 such that VO was advanced by a single injection of stanozolol or methandrostenolone, whereas a single injection of 17-methyltestosterone was without effect [19]. Whether a higher dose of 17-methyltestosterone would achieve the maximal observed effect (VO at PN25) remains to be tested.
The day of first vaginal estrus follows the first ovulation and has been used as an indirect measure of ovulation [23] and thus permitted an assessment of the effects of AASs on estrous cyclicity both during and after the treatment period. The acute administration of stanozolol at doses up to 25 mg/kg had no effect on the timing of first vaginal estrus [13]. In contrast, in experiments performed here, the chronic administration of both stanozolol (1–5 mg/kg) and 17-methyltestosterone (0.5–5 mg/kg), although not methandrostenolone, delayed the onset of estrous cyclicity. 17-Methyltestosterone elicited the most robust response, suspending vaginal estrus for a large part of the treatment period. Moreover, a significant delay in first vaginal estrus was elicited in response to the lowest tested dose of 17-methyltestosterone (0.5 mg/kg). In addition to effects on first vaginal estrus, all of the AASs (5 mg/kg) suppressed the incidence of regular estrous cyclicity during the treatment period, a finding consistent with research on androgens and the rat estrous cycle [5–8, 24]. Regular estrous cyclicity resumed within the 2-wk observation period after the end of the treatment with AASs, a timeframe consistent with the resumption of estrous cycles in adult rats treated for 14 days with AASs [5, 8].
Treatment with AASs was not accompanied by marked changes in body weight in the peripubertal period. Stanozolol (5 mg/kg), however, increased the rate of growth in developing female rats. In a study in adult female rats, stanozolol (1 mg/kg/day for 14 days) also increased rate of growth and protein synthesis in muscle [25]. It is not known whether changes in muscle growth also occur in peripubertal female rats treated with stanozolol.
Analysis of Mechanisms
One approach to the analysis of the mechanism(s) underlying the effects of chronic treatment with AASs on pubertal onset is to utilize antagonists to the AR. It is known that the AASs used in the present study bind to the AR [21, 22] and act via an AR-dependent mechanism to inhibit sexual behavior in adult female rats [15]. The present study used the AR antagonist flutamide to block effects of AASs that require activation of the AR. Although the administration of flutamide in adulthood has little effect on the estrous cycle of normal female rats [26, 27], in the estrogen-primed ovariectomized immature rat, flutamide suppresses the secretion of luteinizing hormone, follicle stimulating hormone, and prolactin [28]. During the course of our present experiments, a report appeared showing that, in Sprague-Dawley rats, the oral administration of flutamide (25 mg/kg) from PN21 through PN41 advanced VO relative to control rats and that, during the treatment period, rats receiving flutamide displayed fewer days of estrus than controls [29]. In contrast with these results, we observed no differences in the measures of VO, VE, and estrous cyclicity between the group receiving oil/vehicle and the group receiving oil/flutamide. The bases for these disparities are unclear but could be related to several factors, including the dose of flutamide (25 mg/kg once daily vs. 10 mg/kg two times a day), route of administration (oral vs. systemic), and strain of rat (Sprague-Dawley vs. Long-Evans) used in that study [29] and the present study, respectively.
Day of VO
In a previous study, the systemic administration of the antiestrogen ICI 182,780 on PN20–22 blocked the advancement of VO by a single s.c. injection of stanozolol on PN21 [13]. In the present study, we observed a lack of effect of flutamide on the advancement of VO by chronic stanozolol. Collectively, these findings support a role of the ER in the advancement of VO by stanozolol. Nonetheless, because chronic administration of the antiestrogen ICI 182,780 alone disrupts the cyclical display of vaginal cornification [30], the concomitant administration of ICI 182,780 and AASs was not tenable in the chronic experimental paradigm. Given that the AR does not appear to play a role in the observed effects, the induction of VO by stanozolol and methandrostenolone could be mediated by the binding of these AASs directly to the ER or binding to the ER after aromatization to estrogen. To our knowledge, the relative binding affinities of stanozolol or methandrostenolone for the ER have not been determined. In addition, although the structure of stanozolol precludes aromatization [31, 32], it is not known whether metabolites of stanozolol or methandrostenolone activate the ER [31, 32]. Future studies will use estrogen response element assays to evaluate the hypothesis that stanozolol and methandrostenolone bind to and activate the ER. Research has shown that both isoforms of the ER (ER and ERß) are expressed in the vaginal epithelium, although ER may be more abundant [33]. As antagonists for ER and ERß become available [34], the role of these two ER subtypes in the advancement of VO by AASs can also be tested.
The ability of flutamide to block 17-methyltestosterone-induced advancement of VO was unexpected. As mentioned above, research points to the ER as a key substrate for the hormonal induction of VO; the administration of estrogen or aromatizable androgens such as testosterone can elicit premature vaginal opening [12, 35–37]. Furthermore, studies conducted in the androgen-insensitive (tfm+/tfm+) mouse demonstrated that VO occurs at the normal age in the absence of androgen receptor stimulation [38]. We are not aware of other evidence supporting a role for the AR in VO in normally developing (untreated) rats. To the contrary, it has been shown that the nonaromatizable androgen dihydrotestosterone (DHT) does not evoke VO and in fact delays pubertal onset [13, 35]. It is unlikely that binding affinity for the AR can account for the apparent AR-dependent effects of 17-methyltestosterone. The AASs included in the present study are relatively weak agonists for the AR [21]. The relative binding affinities of AASs for the prostate AR are as follows (with a DHT standard of 1.0): 17-methyltestosterone = 0.13; stanozolol = 0.03; and, methandrostenolone = 0.03 [21]. In other physiological and behavioral assays, 17-methyltestosterone has been shown to be a slightly more potent androgen than stanozolol or methandrostenolone [39–42]. Nonetheless, because the potent nonaromatizable AR agonist DHT does not advance VO, differences in binding affinity among the AASs are unlikely to explain the AR-dependent nature of 17-methyltestosterone-induced VO. Analysis of the site of 17-methyltestosterone action (perivaginal vs. extravaginal), the dose-response characteristics of the antagonism by flutamide, and assessment of gonadotropin and steroid hormone levels will establish the basis for the advancement of VO by 17-methyltestosterone.
Day of VE
AASs appear to act via an androgen receptor-dependent pathway to delay the display of VE. Rats receiving stanozolol or 17-methyltestosterone in combination with flutamide displayed VE at the same age as controls. Similarly, nonaromatizable androgens (DHT) delay the day of VO and the day of VE, supporting a role of the AR in this process [13, 35]. The mechanisms for the delay of VE in rats receiving AASs are not known. In normal female rats, the first ovulation is preceded by a cascade of events, including the establishment of a diurnal pattern of LH release followed by ovarian maturation necessary for the first preovulatory gonadotropin surge [12]. Thus, interference with gonadotropin release and ovarian function by AASs could result in the delay in VE observed in the present study. We hypothesize that the suppression of VE by stanozolol and 17-methyltestosterone reflects the androgen receptor-dependent antigonadotropic actions of AASs. Dramatic effects of AASs on gonadotropin secretion in adult female mice have been reported previously [7]. Specifically, female mice receiving a combination of four AASs (including 17-methyltestosterone) for 20 days showed a significant reduction in serum and pituitary LH levels and in pituitary FSH levels [7]. Antigonadotropic effects of 17-methyltestosterone have been reported in adult male rats [43], and others have shown that the suppression of gonadotropin secretion by androgens is reversed by flutamide [44]. Although gonadotropin levels were not measured in the present study, the hypothesis to be tested in future studies is that AASs that delay VE also suppress LH and FSH secretion and that flutamide reverses the inhibitory effects of AASs on gonadotropin secretion.
Estrous cyclicity
In contrast with playing a role in estrous cycle initiation, activation of the AR does not appear to be critical for the ongoing suppression of estrous cyclicity in rats receiving AASs. Specifically, flutamide failed to reverse the suppression of estrous cyclicity by stanozolol or 17-methyltestosterone. Androgens have been shown to affect multiple levels of the HPG axis in normal cycling rats. It is known that androgens not only provide a substrate for estrogen synthesis in the ovary but can also inhibit follicular maturation, hence interfering with the local biosynthesis of estrogen [45]. The role of the AR in the modulation of ovarian function in the normal female rat is not well understood [45, 46]. Furthermore, analyses of the effects of high doses of AASs on ovarian function have not been conducted. Because all of the rats in the present study were followed into a recovery period, we did not have the opportunity to examine ovarian histology. Such an analysis will expand our understanding of the mechanism(s) underlying the suppression of estrous cyclicity by AASs. In addition to actions at the ovary, androgens can also have direct actions on the pituitary gonadotropes [47, 48]. Finally, androgens decrease ER binding in both the hypothalamus and anterior pituitary [49, 50]. Additional research evaluating the role of each of these aspects of the HPG axis is necessary to determine the site(s) and mechanism(s) for the disruption of estrous cyclicity by AASs.
Methandrostenolone/flutamide in combination
Rats receiving methandrostenolone and flutamide exhibited an unexpected pattern of results. First, day of VE was advanced in rats treated with methandrostenolone plus flutamide relative to controls. Second, the vaginal cytology of rats receiving flutamide in combination with methandrostenolone consisted of multiple periods of 2–3 consecutive days of vaginal estrus, in contrast with the persistent diestrus cytology exhibited by rats receiving stanozolol and 17-methyltestosterone. The pattern of an earlier onset of first vaginal estrus and an increased number of days of estrus during the treatment period suggest that the combined effect of methandrostenolone and flutamide is estrogenic with respect to estrous cyclicity. A similar pattern of responses has been observed with another synthetic androgen, danazol [51]. Specifically, although immature rats treated with either danazol alone or flutamide alone did not exhibit vaginal cornification (an estrogen-dependent response), rats receiving danazol plus flutamide exhibited vaginal cornification to a greater extent than control rats [51]. The authors argue that danazol has both androgenic and estrogenic activity but that the estrogenic actions of the androgen are only fully expressed when the androgenic activity is blocked (by flutamide) [52]. Perhaps the lack of effect of methandrostenolone alone on the timing of VE is also indicative of the mixed androgenic/estrogenic activities of this compound and removal of antagonistic AR action is needed to reveal the estrogenic effects of methandrostenolone on day of VE. Whether the findings for methandrostenolone combined with flutamide in the present study are also indicative of dual activation of androgen and estrogen receptor-mediated events remains to be investigated.
The most recent assessments of the use of AASs indicate that adolescent girls are the group of individuals showing the largest increase in the use of AASs [9]. Because no information is available on pubertal events or neuroendocrine function in girls that use AASs, very little is known about the effects of synthetic AASs on the developing female body and nervous system. The studies reported here indicate that AASs have heterogeneous effects on measures of pubertal onset in the female rat. The finding that AASs suppress estrous cyclicity in the rat is in agreement with the reports of menstrual cycle irregularity by adult women using AASs [3, 4, 14]. The results of the present study predict that adolescent users of high doses of AASs will also experience a delay in the onset of regular menstrual cycles and irregular menstrual cycles. We are not aware of any published studies examining menstrual cycle patterns or neuroendocrine function in women that have stopped self-administering AASs. Some of the physiological effects of AASs on women are long lasting, however, such as voice changes [53, 54]. Although the effect of AASs on estrous cyclicity in the present study appeared to be transient, the issue of reversibility of effects of AASs on neuroendocrine function must be evaluated using a longitudinal analysis of fertility as well as gonadotropin and steroid hormone levels. The present results provide new information about the consequences of administration of AASs on the maturing neuroendocrine system and point to a role for multiple biochemical and neuroendocrine substrates.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Ann S. Clark, Department of Psychological and Brain Sciences, Dartmouth College, 6207 Moore Hall, Hanover, NH 03755. FAX: 603 646 1419; ann.s.clark{at}dartmouth.edu
Received: 4 June 2002.
First decision: 25 June 2002.
Accepted: 22 August 2002.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-methyltestosterone, methandrostenolone, and nandrolone decanoate on the rat estrous cycle. Physiol Behav 1997 61:265-272[CrossRef][Medline]-methyltestosterone in vitro to human sex hormone binding globulin and rat ventral prostate androgen receptors. Ther Drug Monit 1995 17:377-380[Medline]-methyltestosterone in rats, based on the ‘Enhanced OECD Test Guideline 407’ for screening the endocrine-disrupting chemicals. Arch Toxicol 2001 75:635-642[CrossRef] and B in the female reproductive tract of the rat during the estrous cycle. Biol Reprod 2000 63:1331-1340. Endocrinology 2002 143:941-947-methyltestosterone, methandrostenolone, and nandrolone decanoate on the sexual behavior of castrated male rats. Behav Neurosci 1996 110:1476-1486-reduction involved. J Steroid Biochem Molec Biol 1995 52:105-112[CrossRef][Medline]-dihydrotestosterone and dexamethasone on estrogen receptors in the anterior pituitary and uterus. Steroids 1992 57:18-26[CrossRef][Medline]
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