Differential effects of testosterone metabolites in the neonatal period on open-field behavior and lordosis in the rat

Two experiments were done to compare the effects of neonatal exposure to testosterone and its major metabolites, dihydrotestosterone (DHT) and estradiol (E₂), on the development of sex differences in open-field behavior in the rat. In Experiment 1 female rats administered either testosterone propionate (TP), DHT, or estradiol benzoate (EB) were found as adults to have low activity scores, more typical of adult males, when compared to the high scores of oil-treated females. In Experiment 2 the adult open-field behavior of female rats treated neonatally with testosterone or the metabolites was compared to that of male rats treated from Day 1 to 10 of life with the aromatizing enzyme inhibitor, androst-1,4,6-triene-3,17-dione (ATD). These same animals were later tested for lordotic behavior after gonadectomy and priming with EB and progesterone. All male animals and female animals exposed neonatally to testosterone or to either of the metabolites had suppressed open-field activity scores compared to oil-treated females. However, the lordotic behavior of females exposed to DHT and of males exposed to ATD was not defeminized and was comparable to that of oil-treated females. These observations were discussed in terms of a role for the androgenic actions of testosterone in establishing sex differences in nonreproductive behavior in the rat.     

Effects of steroid implants on the prepubertal increase in circulating gonadotropins and sexual receptivity in the female rabbit

The pubertal increase in gonadotropins in the female rabbit was inhibited 14-42-fold with Silastic implants of progesterone (P4) testosterone propionate (TP), estradiol benzoate (EB) or P4/EB placed subcutaneously on Day 24 of life. Rabbits with empty implants showed the normal prepubertal increase in circulating gonadotropins. By contrast, rabbits with implants of P4 only, had a 2-fold decrease in LH secretion when peak areas were compared. However, FSH secretion though slightly depressed was not significantly different from controls. The prepubertal increase in circulating gonadotropins was completely suppressed by implants of EB, TP and combined P4/EB. At 115-days-of-age, sexual receptivity and mating were absent in EB-treated animals and significantly suppressed in P4-treated ones when compared to controls, all of which mated. Mating was not completely inhibited in TP and combined P4/EB animals. Corpora lutea were found in all rabbits that mated. In the sexually non-receptive does, vaginal stimulation induced an LH surge in 2 of 15 animals. Ovarian weights and follicular development were significantly suppressed in rabbits with EB implants. Ovarian estradiol content was significantly increased in P4- and TP-treated rabbits. Maximum specific binding for [3H]naloxone was suppressed in the hypothalami of P4-treated rabbits. These results suggest that the prepubertal increase in circulating gonadotropins may have an essential role in the control of sexual maturation in the female rabbit.     

Cytosol and nuclear estrogen receptor binding in the preoptic area and hypothalamus of female rats during pregnancy and ovariectomized, nulliparous rats after steroid priming: correlation with maternal behavior

In a previous study, high nuclear estrogen receptor concentrations in the preoptic area (POA) were found on Day 16 of pregnancy to prime females to respond to a subsequent low dose of estradiol benzoate (EB) after hysterectomy-ovariectomy by exhibiting maternal behavior in 48 hr. Receptor concentrations in the POA were found to be higher than those in the hypothalamus (HYP). The present study investigated when nuclear estrogen receptors increase during pregnancy in POA and when the difference in receptor concentrations between POA and HYP occurs. An attempt was made to reproduce these pregnancy changes with a 16-day treatment of estrogen and progesterone in ovariectomized (OVX), nulliparous rats. In Experiment 1, we measured cytosol and nuclear estrogen receptor concentrations in the POA and HYP of female rats during pregnancy. Nuclear receptor concentrations in the POA increased beginning on Day 10, increased again on Day 16, and continued at this high level for the remainder of pregnancy. Nuclear estrogen receptor concentrations in the HYP remained at a lower level throughout most of pregnancy until Day 22 when they increased significantly. In Experiment 2, we tested the maternal behavior and measured estrogen receptor concentrations in OVX, steroid-primed, nulliparous rats after hysterectomy (H) and EB treatment. While 90% of estradiol (E) + progesterone (P)-primed females displayed short-latency maternal behavior 48 hr after H and EB treatment, 46% of E + vehicle (V)-treated controls were maternal. At 0 hr (prior to H and EB treatment), there was a significantly larger nuclear receptor accumulation in the POA but significantly attenuated receptor binding in the HYP. P treatment significantly affected cytosol and nuclear estrogen receptor dynamics. Differences in nuclear estrogen receptor concentrations were shown to be based on the number of available binding sites and not to changes in receptor affinity for estradiol.     

Effects of estradiol benzoate on learning-memory behavior and synaptic structure in ovariectomized mice

There is increasing evidence that estrogen is involved in CNS activity, particularly memory. Several studies have suggested that estrogen improves memory by altering neuronal plasticity, including increased hippocampus CA1 dendritic spine density and enhanced long-term potentiation (LTP). In the present study, we investigated the effects of estrogen on the ultrastructural modifications in cerebral frontal cortex and hippocampus of female ovariectomized mice. One week after ovariectomy (Ovx), ICR female mice received daily injection of estradiol benzoate (EB, 20, 100, 200 microg/kg, s.c.) for 4-5 weeks. Spatial memory was then tested in the water maze, and the overall locomotor activity was monitored in open field. Synaptic morphologic parameters were examined using a graph analyzer. The results from open field did not show any alterations in locomotor activity following Ovx and EB replacement. Both the latency to find the platform and the distance to reach the platform were significantly reduced in Ovx mice by EB at 20 or 100 microg/kg when compared to vehicle treated Ovx mice. The results from synaptic ultrastructural measurement and analysis did not show any differences in hemispheric or hippocampal volumes, the numeric synaptic density, the length of active zones, or the curvature of synaptic interface among Sham, Ovx, and Ovx plus EB replacement mice. However, EB replacement effectively normalized the changes induced by Ovx, reducing the width of the synaptic cleft, enlarging the thickness of postsynaptic density (PSD), and increasing the number of synaptic vesicles in the presynapse in both cerebral cortex Fr1 and hippocampus CA1 areas. These results suggest that the beneficial effects of EB on improving memory behavior of Ovx female mice are associated with the changes of some subtle structural parameters of synapses, including the width of PSD and synaptic cleft rather than some basic and permanent structure in frontal cortex and hippocampus regions.     

Blockade of lordosis by androst-1,4,6-triene-3,17-dione (ATD) and tamoxifen in female hamsters primed with testosterone propionate

Normal female hamsters display lordosis after testosterone propionate (TP) plus progesterone (P) treatments. Such effect is probably mediated through aromatization of testosterone (T) into estradiol. If so, then an aromatase inhibitor (ATD) or an estrogen antagonist (tamoxifen, TAM) should be able to block the activational effect of T on lordosis. To test this hypothesis, 48 ovariectomized female hamsters were assigned into six groups which, according to treatments received, were ATD + TP, TAM + TP, OIL + TP, ATD + EB (estradiol benzoate), TAM + EB, and OIL + EB groups. The groups received assigned treatments for 2 days and were injected with P on the third day. Five minutes of behavior test was conducted 4 hr after P injection. The OIL + TP, OIL + EB, and ATD + EB groups all had averaged total lordosis duration (TLD) longer than 200 sec. The TLD of the TAM + EB group was only 117 sec. The ATD + TP and TAM + TP groups showed almost no lordosis. The results showed that the estrogen antagonist (TAM) impaired lordosis no matter whether the animals were primed with TP or EB, but the aromatase inhibitor (ATD) blocked lordosis only in TP primed females. It is concluded that the aromatization of T to estrogen is required for testosterone activation of lordosis in female hamsters.     

Impairment of spatial learning by estradiol treatment in female mice is attenuated by estradiol exposure during development

High doses of estradiol (E(2)) can impair spatial learning in the Morris water maze, in ovariectomized mice, but the same dose has no effect on adult castrated males. Here, we test the hypothesis that this sex difference is caused by neonatal actions of E(2). In Experiment 1, C57BL/6J pups were given daily estradiol benzoate (EB) or oil injections from the day of birth until postnatal Day 3. Adults were gonadectomized and received EB (s.c.) or oil 28 h before the first day of training, and 4 h before each of four daily training sessions on the Morris water maze. Females given oil as neonates, and EB prior to training displayed the poorest performance. Females that received EB as neonates and EB prior to training were insensitive to the deleterious effects of adult EB and performed better than males given the same hormone treatments. We conducted a second experiment using aromatase enzyme knockout (ArKO) mice. Adult male and female ArKO and wild-type (WT) littermates were gonadectomized and received either injections of oil or EB prior to and during water maze training (as described above). Hormone treatment failed to affect performance, yet, female but not male ArKO mice showed impaired learning compared to WT littermates. Thus, exposure to estradiol during neonatal development can counteract the deleterious effects of EB on adult spatial learning.     

雌激素和孕激素对雌性小鼠甲状腺C细胞的影响

探讨降钙素在老年女性骨质疏松症发病中的作用 ,观察了雌、孕激素对雌性小鼠甲状腺 C细胞的影响。去卵巢小鼠 (OVX)分别肌肉注射苯甲酸雌二醇 (FB)、己烯孕酮 (HPC)和苯甲酸雌二醇加乙烯孕酮 (EB+HPC)两个月。用药剂量根据小鼠口龄和体重的不同而不同。采用免疫组织化学方法显示降钙素 (CT)阳性细胞并对其进行细胞形态计量学分析。结果显示 :(1)去卵巢小鼠与正常对照组相比 ,甲状腺 C细胞数目剧增 ,给予 EB、HPC、EB+HPC治疗的各组小鼠甲状腺C细胞数目与正常对照组水平相近。 (2 )各组小鼠甲状腺 C细胞的大小无明显改变 ,平均直径间无显著性差异 (P>0 .0 5 )。雌、孕激素缺乏可引起雌性小鼠甲状腺 C细胞增生。 C细胞增生也可能是雌激素缺乏引起的骨质疏松的后果     

Anti-estrogenic suppression of the lordosis response in female rats

The anti-estrogen, CI 628, was used to suppress the lordosis response induced by sequential injections of estrogen and progesterone in ovariectomized (OVX) female rats. Appropriate doses of CI 628 completely abolished sexual receptivity in females administered estradiol benzoate (EB) in sesame oil. This behavioral effect could be attenuated by providing increased quantities of EB or decreased quantities of CI 628. Anti-estrogenic effects on lordosis induced by free estradiol in saline (E) were assessed after first establishing behaviorally equivalent doses of EB and E. This was accomplished by determining thresholds for E-induced lordosis. OVX females were approximately seven times less sensitive to E than to EB. CI 628 had no significant effects on E-induced lordosis, in contrast to the complete abolition of lordosis in females treated with behaviorally equivalent EB doses. A possible mechanism to explain this differential responsiveness of EB- and E-treated females is discussed.     

Estradiol regulates susceptibility following primary exposure to genital herpes simplex virus type 2, while progesterone induces inflammation

We report here that sex hormones modulate susceptibility to a sexually transmitted viral agent, herpes simplex virus type 2 (HSV-2), in a mouse model. Ovariectomized mice were administered either saline (control), estradiol (E(2)), progesterone (P(4)), or a combination of both estradiol and progesterone (E+P) and infected intravaginally with HSV-2. With an inoculation dose of 10(5) PFU, the saline- and P(4)-treated mice were found to be highly susceptible to genital HSV-2 infection. Both groups had extensive pathology and high viral titers in vaginal secretions, and 100% of mice succumbed by day 4 postinfection. E(2)-treated mice were protected from HSV-2 infection at the same dose and did not display any vaginal pathology or viral shedding. There was a slow progression of genital pathology in the combination hormone-treated group, along with prolonged viral shedding; 80% of animals succumbed by day 13. With lower inoculation doses of 10(3) and 10(2) PFU, 50 and 100%, respectively, of the combination hormone-treated mice survived. Localization of HSV-2 infection showed extensive infection in the vaginal epithelium of P(4)- and saline-treated animals within 24 h of inoculation. E(2)-treated animals were clear of infection, while the E+P-treated group had focal infection at 24 h that had progressed extensively by day 3. Infection was accompanied by persistent inflammation and infiltration of neutrophils in the P(4)-treated group. An analysis of the genes in the vaginal tissue showed that inflammation in the P(4)-treated group correlated with local induction of chemokines and chemokine receptors that were absent in the E(2)-treated mice and in uninfected P(4)-treated mice. The results show that sex hormones regulate initiation of infection and immune responses to genital HSV-2 infection.     

The estrogenic arousal of aggressive behavior in female mice

Experiments were conducted to determine the conditions under which estrogen would promote male-like aggressive behavior in female mice. The results of the first experiment showed that most females chronically exposed to testosterone propionate (TP) in adulthood fought, whereas females similarly treated with estradiol benzoate (EB) did not display aggression. Another experiment found that, when either TP or EB was administered on the day of birth, adult females displayed aggression in response to daily EB injections during adult life. Also, the potentiating effect of neonatal hormone exposure declined over the first 12 days postpartum, as 100% of the Day 0, 75% of the Day 6, and 0% of the Day 12 and 18 TP-treated females fought in response to daily injections of 40 μg of EB in adulthood. The final study showed that, under the test conditions employed, the failure of a chronic adult EB regimen to promote aggression was not due to a competing tendency to display female sexual behavior.     

Organizational effects of testosterone,estradiol, and dihydrotestosterone on vasopressin mRNA expression in the bed nucleus of the stria terminalis

In adulthood, male rats express higher levels of arginine vasopressin (AVP) mRNA in the bed nucleus of the stria terminalis (BST) than do female rats. We tested whether this sex difference is primarily due to differences in neonatal levels of testosterone. Male and female rats were gonadectomized on the day of birth and treated with testosterone propionate (TP) or vehicle on postnatal days 1, 3, and 5 (P1, P3, and P5). Three months later, all rats were implanted with testosterone‐filled capsules. Two weeks later, brains were processed for in situ hybridization to detect AVP mRNA. We found that neonatal TP treatment significantly increased the number of vasopressinergic cells in the BST over control injections. We then sought to determine the effects of testosterone metabolites, estradiol and dihydrotestosterone, given alone or in combination, on AVP expression in the BST. Rat pups were treated as described above, except that instead of testosterone, estradiol benzoate (EB), dihydrotestosterone propionate (DHTP), a combination of EB and DHTP (EB+DHTP), or vehicle was injected neonatally. Neonatal treatment with either EB or EB+DHTP increased the number of vasopressinergic cells in the BST over that of DHTP or oil treatment. However, treatment with DHTP also significantly increased the number of vasopressinergic cells over that of oil treatment. Hence, in addition to bolstering evidence that estradiol is the more potent metabolite of testosterone in causing sexual differentiation of the brain, these data provide the first example of a masculinizing effect of a nonaromatizable androgen on a sexually dimorphic neuropeptide system. © 2003 Wiley Periodicals, Inc. J Neurobiol 54: 502–510, 2003     

Hormonal Modulation of the Cutaneous Initiation of Lordosis in Infant and Adult Rats

The purpose of these experiments is to compare the regional specificity (Experiment 1) and the hormonal modulation (Experiment 2) of the cutaneous initiation of lordosis in 4- to 6-day-old male and female rats (infants) and in 60- to 90-day-old female rats (adults). In Experiment 1, subjects were primed with 100 μg estradiol benzoate (EB) and 0.5 mg progesterone (P) and were denervated on the Waist (dermatomes L1-L3), Midriff (dermatomes T10-L3), Flanks (dermatomes L4-L6), or Sides (dermatomes T10-L6). In infants, there were no significant differences between males and females. Denervation of the Waist. Midriff, or Sides but not of the Flanks significantly decreased the percentage of subjects displaying lordosis, lordosis quotient (LQ), and mean lordosis duration; no significant differences were obtained among Waist-, Midriff-, or Sides-denervated infants. In contrast, denervation of the Sides but not of the Waist significantly decreased LQ and mean lordosis intensity among adults. In Experiment 2, Waist-denervated infants and their surgical Controls were treated either with 100 μg EB and 0.5 mg P or with the oil vehicle; Waist-denervated adults and their surgical Controls received either 100 or 10 μg EB (no P). Regardless of hormone treatment, denervation of the Waist significantly decreased LQ and lordosis duration in infants and decreased LQ and lordosis intensity in adults. In infants, the only effect of priming with EB and P was to increase the percentage of pups showing lordosis and lordosis duration among the surgical Controls. In contrast, priming with 100 μg EB significantly increased the percentage of rats displaying lordosis, LQ, and lordosis intensity among Waist-denervated adults. These data suggest that cutaneous input from the Waist is important for eliciting lordosis in both infant and adult rats, and that the importance of this input is modulated by hormone priming in adult but not infant rats.     

Estradiol initially enhances but subsequently suppresses (via adrenal steroids) granule cell proliferation in the dentate gyrus of adult female rats

In the dentate gyrus of adult female meadow voles, a high dose of estradiol benzoate (EB) increases (within 4 h) then decreases (within 48) the number of dividing progenitor cells (Ormerod BK, Galea LAM. 2001. Reproductive status regulates cell proliferation within the dentate gyrus of the adult female meadow vole: A possible regulatory role for estradiol. Neurosci 2:169-179). We investigated whether time-dependent EB exposure differentially influences the number of new granule cells produced in the adult female rat dentate gyrus and whether EB-stimulated adrenal activity mediates the decrease in cell proliferation. Ovariectomized rats received either an EB (10 microg in 0.1 mL) or vehicle (0.1 mL) injection either 4 or 48 h (Experiment 1) before a BrdU injection (200 mg/kg) and were perfused 24 h later to assess the number of new cells. Relative to vehicle, the number of new cells increased following a 4 h exposure (p < or = 0.04) but decreased following a 48 h exposure (p < or = 0.006) to EB. In Experiment 2, the number of new cells within the dentate gyrus of ovariectomized and adrenalectomized females did not significantly differ between groups exposed to EB versus vehicle for 48 h prior to BrdU administration, suggesting the decreased number of new cells observed within the dentate gyrus of adrenal-intact adult female rats is mediated by EB-stimulated adrenal activity. We conclude that estradiol dynamically regulates cell proliferation within the dentate gyrus of adult female rats in the time-dependent manner observed previously in voles and suppresses cell proliferation by influencing adrenal steroids. Investigating how estradiol dynamically regulates neurogenesis could provide insight into the mechanisms by which the proliferation of progenitor cells is controlled within the adult rodent hippocampus.     

Impact of pubertal and adult estradiol treatments on cocaine self-administration

Estradiol is thought to play a critical role in the increased vulnerability to psychostimulant abuse in women. Sex differences in the ability of estradiol to influence cocaine self-administration in adult rats have been hypothesized to depend upon pubertal estradiol exposure. The current study investigated whether the presence of gonadal hormones during puberty affected cocaine self-administration behavior and its sensitivity to adult estradiol treatment in male and female Sprague–Dawley rats. Subjects were gonadectomized or SHAM-operated at postnatal day (PD) 22, and received either OIL or estradiol benzoate (EB) during the approximate time of puberty (PD27 to PD37). Adult rats were subsequently treated with either EB or OIL 30 min before cocaine self-administration (0.3 mg/kg/inf) in order to examine the effects of pubertal manipulations on the estradiol sensitivity of acquisition on a fixed ratio (FR) 1 schedule, total intake on a FR5 schedule and motivation on a progressive ratio schedule. Adult EB treatment only affected cocaine self-administration in females, which is consistent with previous research. Adult EB treatment enhanced acquisition in all females irrespective of puberty manipulations. All females, except those treated with EB during puberty, displayed increased cocaine intake following adult EB treatment. Adult EB treatment only enhanced motivation in females that were intact during puberty, whereas those treated with EB during puberty showed reduced motivation. Therefore, the sensitivities of different self-administration behaviors to adult estradiol treatment are organized independently in females, with pubertal estradiol exerting a greater influence over motivational processes, and negligible effects on learning/acquisition.     

Estrogen effects on thyroid iodide uptake and thyroperoxidase activity in normal and ovariectomized rats

Sex steroids interfere with the pituitary-thyroid axis function, although the reports have been controversial and no conclusive data is available. Some previous reports indicate that estradiol might also regulate thyroid function through a direct action on the thyrocytes. In this report, we examined the effects of low and high doses of estradiol administered to control and ovariectomized adult female rats and to pre-pubertal females. We demonstrate that estradiol administration to both intact adult and pre-pubertal females causes a significant increase in the relative thyroid weight. Serum T3 is significantly decreased in ovariectomized rats, and is normalized by estrogen replacement. Neither doses of estrogen produced a significant change in serum TSH and total T4 in ovariectomized, adult intact and pre-pubertal rats. The highest, supraphysiological, estradiol dose produced a significant increase in thyroid iodide uptake in ovariectomized and in pre-pubertal rats, but not in control adult females. Thyroperoxidase activity was significantly higher in intact adult rats treated with both estradiol doses and in ovariectomized rats treated with the highest estradiol dose. Since serum TSH levels were not significantly changed, we suggest a direct action of estradiol on the thyroid gland, which depends on the age and on the previous gonad status of the animal.     

Protection against genital herpes infection in mice immunized under different hormonal conditions correlates with induction of vagina-associated lymphoid tissue

The present study was undertaken to examine the effect of the hormonal environment on immunization with an attenuated strain of herpes simplex virus type 2 (HSV-2 TK(-)) and subsequent protection against challenge. Ovariectomized mice were administered saline (S; control), estradiol (E(2)), progesterone (P(4)), or a combination of estradiol and progesterone (E+P) and immunized intravaginally (IVAG) with HSV-2 TK(-). Three weeks later, the immunized mice were challenged IVAG with wild-type HSV-2. Mice that were immunized following E treatment were not protected, whereas complete protection against the challenge was seen in mice from the S- and P(4)-treated groups. In the P(4)-treated group, 15% of mice developed chronic pathology following TK(-) immunization. Interestingly, about 40% of the E+P-treated mice were also protected. Upon examination of viral shedding in the vaginal secretions, it was clear that protection against challenge was dependent on the ability of the TK(-) virus to cause productive genital infection under different hormonal conditions. In the protected mice (the S and P groups and part of the E+P group), induced vagina-associated lymphoid tissues composed of CD11c(+) dendritic cells and CD3(+) and CD4(+) T cells were formed transiently in the vaginal lamina propria from day 2 to day 5 postchallenge. These aggregates were absent in the unprotected mice (the E group and part of the E+P group). Significant HSV-2-specific activation of lymphocytes was observed in the local draining lymph nodes of protected mice. This response was absent in the unprotected groups. High titers of gB-specific local immunoglobulin A (IgA) antibodies were present in the vaginal secretions of S- and P(4)-treated immunized mice following HSV-2 challenge. The S-treated group of mice also had high gB-specific IgG titers. These studies show that sex hormones modify the induction of protective immune responses following IVAG immunization.     

Steroidal influences on pup-killing behavior in mice

Four experiments were conducted in order to examine the biochemical pathway through which testosterone (T) acts to produce pup-killing behavior in ovariectomized female mice. Estradiol benzoate (EB) and testosterone propionate (TP) were both effective in stimulating the pup-killing response (Experiment 1). The nonaromatizable androgen dihydrotestosterone (DHT) and the aromatizable androgen testosterone (T) were equipotent in eliciting the behavior while the nonaromatizable androgen androstanedione (AA) was ineffective (Experiment 2). Pup-killing behavior was activated by the aromatizable androgen androstenedione (AE) but only if it was administered chronically at very high doses (Experiment 3). The combination of subthreshold doses of EB and DHT synergized to produce the pup-killing response (Experiment 4). These findings suggest that both aromatization and reduction may be important for the stimulation of pup-killing behavior in mice.     

Effects of sex steroid implants on reproductive tissues of female garter snakes (Thamnophis sirtalis)

Female Thamnophis sirtalis were administered intraperitoneal implants of either estradiol 17β (E2), testosterone (T), 5α-dihydrotestosterone (DHT), or empty silastic capsules for 3 weeks. Plasma levels of E2 and T, measured by specific radioimmunoassay, were significantly elevated in E2 and T-implanted females when compared to controls. T-implanted females did not have elevated circulating E2 levels, suggesting that E2 in the plasma normally is not derived from peripheral conversion of T to E2. Implantation of DHT did not significantly change circulating levels of E2, T, or DHT. All three sex steroid—treated groups of animals had increased oviductal mass compared to controls, while hepatic mass of only E2-treated animals was significantly greater. None of the steroid treatments influenced ovarian mass. Oviductal epithelial cell height and area were greater in the three steroid-treated groups. Testosterone increased myometrial area while DHT drastically altered oviductal morphology. Hepatic cell area and number increased significantly in E2-treated females. However, a small increase in both hepatic cell area and number was noted in T- and DHT-treated females as well. These results suggest that androgen in both an aromatizable and non-aromatizable form can affect the oviduct of females but that the liver primarily responds to estrogenic steroids. © 1992 Wiley-Liss, Inc.     

Paradoxical hypermasculinization of the zebra finch song system by an antiestrogen

Exogenous estrogens, when administered to hatchling female zebra finches, masculinize the morphology and function of their neural vocal control system. The first of two experiments evaluated whether tamoxifen citrate is an antiestrogen in zebra finches, and the second determined whether it would block the masculinization hypothesized to be caused in hatchling males by the males' endogenous estradiol. In the first experiment adult female zebra finches were ovariectomized and injected for 10 days with estradiol benzoate (EB), tamoxifen, EB and tamoxifen combined, or vehicle (control). The dependent variable was oviduct weight. The EB-stimulated growth of the oviduct was blocked by tamoxifen, which had no effects when administered alone. Thus, tamoxifen acts as an antiestrogen in the zebra finch oviduct. In Experiment 2, male and female zebra finches were treated with tamoxifen or vehicle for the first 20 days after hatching. The males were castrated at 20 days. At 60 days we compared the song control regions of experimental and control males and females. In both sexes tamoxifen increased the somatic areas of neurons in RA (robust nucleus of the archistriatum), HVc (caudal nucleus of the ventral hyperstriatum), and MAN (magnocellular nucleus of the anterior neostriatum). Tamoxifen also increased the volumes of HVc, RA, MAN, and Area X in males. Thus, tamoxifen failed to block masculinization of males, but masculinized females and hypermasculinized males. Tamoxifen's hypermasculinization of the male and masculinization of the female song system is paradoxical given that (1) estradiol does not have similar effects on the male song system, and (2) tamoxifen antagonizes the effects of EB in the oviduct.