Dihydrotestosterone Implants Research Articles

Ovarian Androgens Maintain High GnRH Neuron Firing Rate in Adult Prenatally-Androgenized Female Mice.

Changes in gonadotropin-releasing hormone (GnRH) release frequency from the brain help drive reproductive cycles. In polycystic ovary syndrome (PCOS), persistent high GnRH/luteinizing hormone (LH) frequency disrupts cycles and exacerbates hyperandrogenemia. Adult prenatally-androgenized (PNA) mice exhibit increased GnRH neuron firing rate, elevated ovarian androgens, and disrupted cycles, but before puberty, GnRH neuron activity is reduced in PNA mice compared with controls. We hypothesized that ovarian feedback mediates the age-dependent change in GnRH neuron firing rate in PNA vs control mice. Extracellular recordings of green fluorescent protein (GFP)-identified GnRH neurons were made 5 to 7 days after sham-surgery, ovariectomy (OVX), or, in adults, after OVX plus replacement of sub-male androgen levels with dihydrotestosterone implants (OVX + DHT). In 3-week-old mice, OVX did not affect GnRH neuron firing rate in either group. In adult controls, OVX increased GnRH neuron firing rate, which was further enhanced by DHT. In adult PNA mice, however, OVX decreased GnRH neuron firing rate, and DHT restored firing rate to sham-operated levels. In contrast to the differential effects of ovarian feedback on GnRH neuron firing rate, serum LH increased after OVX in both control and PNA mice and was not altered by DHT. Pituitary gene expression largely reflected changes expected with OVX, although in PNA but not control mice, DHT treatment increased Lhb expression. These results suggest prenatal androgen exposure programs marked changes in GnRH neuron regulation by homeostatic steroid feedback. PNA lowers GnRH neuron activity in low-steroid states (before puberty, OVX), and renders activity in adulthood dependent upon ongoing exposure to elevated ovarian androgens.

SAT-412 Effects of the Ovary and Dihydrotestosterone on Firing Rate of GnRH Neurons in Prenatally Androgenized Mice

GnRH pulse frequency drives downstream reproductive function by signaling for differential release of gonadotropins, which subsequently control ovarian function. In patients with polycystic-ovary syndrome (PCOS), neuroendocrine defects, including persistent high-frequency LH (and presumably GnRH) pulses, are coupled with dysregulated ovarian function. Prenatally androgenized (PNA) animal models exhibit features similar to PCOS, including increased androgens and high-frequency LH pulses. Adult PNA mice exhibit these phenotypes and also have increased GnRH neuron firing rate and increased excitatory GABAergic transmission to GnRH neurons. In contrast to adults, GnRH neuron firing rate at 3 weeks of age is reduced in PNA females. The causes of this age-dependent difference in firing rate are not known, however puberty occurs between these ages and androgens can increase GnRH neuron firing rate in adulthood. Consistent with this, ovariectomy in adult PNA mice decreased firing rate to that in control diestrous mice. Here we tested the hypothesis that a lack of ovarian androgens mediated this decrease. We also investigated if ovariectomy changed firing rate in 3-week old PNA mice. PNA mice were born from dams injected daily on days 16-18 of gestation with 225µg dihydrotestosterone (DHT). Ovariectomy (OVX) or sham surgery was performed and at this time some mice received constant-release DHT implants that produce sub-male levels of androgen (400 µg/implant) 5-7 days before recordings (surgery at 14-16 days of age for prepubertal mice). Hour-long extracellular recordings were made to ascertain spontaneous firing rate of GFP-identified GnRH neurons in acutely-prepared brain slices. In adult OVX PNA mice, DHT increased firing rate of GnRH neurons relative to OVX PNA, but firing rate was still less than in sham-operated PNA animals (two-way ANOVA/Fisher’s LSD, n= 7-11 cells/group). In adult OVX control mice, preliminary data indicate that DHT replacement alone does not alter firing rate, in contrast to previous results with DHT plus estradiol. At three weeks of age, there was no difference in firing rate between PNA sham and OVX mice (unpaired two-tailed Student’s t-test, n=7-8 cells/group). These studies suggest that increased GnRH firing rate in adult PNA females is driven at least in part by ovarian androgens, whereas changes in firing rate in 3-week-old PNA females are driven by a different mechanism, such as prenatal programming, rather than ovarian factors.

Paternal behavior in the Mongolian gerbil (Meriones unguiculatus): Estrogenic and androgenic regulation

Here, we analyzed the effects of testosterone (T) and its metabolites, estradiol (E2) and dihydrotestosterone (DHT), on the onset of paternal behavior in virgin male Mongolian gerbils (Meriones unguiculatus). We hypothesized that T and E2, but not DHT, would facilitate the onset of paternal behavior. Seventy males displaying aggression toward pups were selected through a paternal behavior screening test. Forty males were bilaterally castrated. Of them, 10 were implanted with T, 10 with E2, and 10 with DHT, and 10 received no treatment. Another 30 males underwent a sham procedure. In these gerbils, T, E2 and DHT were measured to obtain the basal levels of these hormones. After treatment, the paternal behavior test was conducted again. Blood samples were obtained immediately after the administration of the test for the quantification of T, E2 and DHT by radioimmunoassay. Surprisingly, 100% of the males that received T, E2 and DHT implants stopped being aggressive and became paternal. Castrated and sham-operated males displayed no changes in their aggressive behaviors. This is the first report that T and its metabolites are involved in neuroendocrine mechanisms that inhibit aggression toward pups and facilitate paternal behavior in virgin male Mongolian gerbils. In addition, this is the first report of regulation of paternal behavior in a rodent by estrogenic and androgenic pathways.

Estrogen Receptor-α Mediates Diethylstilbestrol-Induced Feminization of the Seminal Vesicle in Male Mice

Background: Studies have shown that perinatal exposure to the synthetic estrogen diethylstilbestrol (DES) leads to feminization of the seminal vesicle (SV) in male mice, as illustrated by tissue hyperplasia, ectopic expression of the major estrogen-inducible uterine secretory protein lactoferrin (LF), and reduced expression of SV secretory protein IV (SVS IV).Objectives: The present study was designed to evaluate the role of the estrogen receptor (ER) in this action by using ER-knockout (ERKO) mice.Methods: Wild-type (WT), ERα-null (αERKO), and ERβ-null (βERKO) male mice were treated with either vehicle or DES (2 μg/day) on neonatal days 1–5. These mice were divided into two groups: In the first group, intact mice were sacrificed at 10 weeks of age; in the second group, mice were castrated at 10 weeks of age, allowed to recover for 10 days, treated with dihydrotestosterone (DHT) or placebo, and sacrificed 2 weeks later. Body weights and SV weights were recorded, and mRNA expression levels of Ltf (lactoferrin), Svs4, and androgen receptor (Ar) were assessed.Results: In DES-treated intact mice, SV weights were reduced in WT and βERKO mice but not in αERKO mice. DES-treated WT and βERKO males, but not αERKO males, exhibited ectopic expression of LF in the SV. DES treatment resulted in decreased SVS IV protein and mRNA expression in WT males, but no effect was seen in αERKO mice. In addition, DES-treated βERKO mice exhibited reduced Svs4 mRNA expression but maintained control levels of SVS IV protein. In DES-treated castrated mice, DHT implants restored SV weights to normal levels in αERKO mice but not in WT mice, suggesting full androgen responsiveness in αERKO mice.Conclusions: These data suggest that DES-induced SV toxicity and feminization are primarily mediated by ERα; however, some aspects of androgen response may require the action of ERβ.

Estradiol Induction of Spermatogenesis Is Mediated via an Estrogen Receptor-α Mechanism Involving Neuroendocrine Activation of Follicle-Stimulating Hormone Secretion

Both testosterone and its nonaromatizable metabolite dihydrotestosterone (DHT) induce spermatogenesis in gonadotropin-deficient hpg mice. Surprisingly, because aromatization is not required, estradiol (E2) also induces spermatogenesis and increases circulating FSH in hpg mice, but the mechanism remains unclear. We studied E2-induced spermatogenesis in hpg mice on an estrogen receptor (ER)-alpha (hpg/alphaERKO) or ERbeta (hpg/betaERKO) knockout or wild-type ER (hpg/WT) background treated with subdermal E2 or DHT implants for 6 wk. In hpg/WT and hpg/betaERKO, but not hpg/alphaERKO mice, E2 increased testis and epididymal weight, whereas DHT-induced increases were unaffected by ERalpha or ERbeta inactivation. E2 but not DHT treatment increased serum FSH (but not LH) in hpg/WT and hpg/betaERKO but not hpg/alphaERKO hpg mice. DHT or E2 alone increased (premeiotic) spermatogonia and (meiotic) spermatocytes without significant change in Sertoli cell numbers. DHT alone increased postmeiotic spermatids, regardless of ER presence, compared with variable ERalpha-dependent E2 postmeiotic responses. An ERalpha-mediated effect was confirmed by treating hpg mice for 6 wk by subdermal selective ER-alpha (16alpha-LE(2)) or ERbeta (8beta-VE(2)) agonist implants. ERalpha (but not ERbeta) agonist increased testis and epididymal weight, Sertoli cell, spermatogonia, meiotic, and postmeiotic germ cell numbers. Only ERalpha agonist markedly increased serum FSH, whereas either agonist induced small rises in serum LH. Administration of ERalpha agonist or E2 in the presence of functional ERalpha induced prominent gene expression of specific Sertoli (Eppin, Rhox5) and Leydig cell (Cyp11a1, Hsd3b1) markers. We conclude that E2-induced spermatogenesis in hpg mice involves an ERalpha-dependent neuroendocrine mechanism increasing blood FSH and Sertoli cell function.

Androgenic and Oestrogenic Influences on Tyrosine Hydroxylase‐Immunoreactive Cells of the Prairie Vole Medial Amygdala and Bed Nucleus of the Stria Terminalis

The posterodorsal medial amygdala (MeApd) and principal nucleus of the bed nucleus of the stria terminalis (pBST) are densely interconnected sites integrating steroid hormone and olfactory information necessary for sociosexual behaviours in many rodents. Our laboratory recently reported sexually dimorphic populations of cells containing tyrosine hydroxylase (TH) located in the MeApd and pBST of prairie voles (Microtus ochrogaster), with males having many more TH-immunoreactive (-ir) cells in these sites than do females. Gonadal hormones circulating during adulthood were showm to regulate this sex difference because it was eliminated by castrating adult males or implanting females with testosterone-filled capsules. In the present study, we demonstrate that many (25-65%) TH-ir cells in the MeApd and pBST of adult virgin male and female prairie voles also contain immunoreactivity for either the androgen receptor or oestrogen receptor alpha. Subcutaneous implants of oestradiol benzoate mimicked the effects of testosterone and maintained high numbers of TH-ir cells in these sites in castrated males. However, implants of dihydrotestosterone (DHT) did not, and these males had low numbers of TH-ir cells similar to castrated males given empty capsules. A similar effect was found in females, where testosterone or oestradiol benzoate greatly increased the number of TH-ir cells in these sites compared to intact or ovariectomised controls, but DHT did not. DHT implants did, however, maintain high seminal vesicle weights in males. Thus, many of the TH-ir cells in the prairie vole MeApd and pBST are potentially sensitive to androgens and oestrogens, although maintaining immunocytochemically detectable levels of TH in these cells may depend more on an oestrogen-mediated mechanism in both sexes. These data have implications for understanding how gonadal hormone release across the reproductive cycle modulates these species-specific groups of catecholaminergic cells and socially monogamous behaviours in prairie voles.

Administration of dihydrotestosterone to rhesus monkeys inhibits gonadotropin-stimulated ovarian steroidogenesis.

Androgens, in addition to serving as a substrate for estrogen biosynthesis, exert autocrine/paracrine actions on ovarian function. However, much of the information regarding the actions of androgens on the ovary has been obtained using rodents, and the extent to which these results can be extrapolated to higher primates is uncertain. The current study was initiated to determine the effects of dihydrotestosterone (DHT) and testosterone (T) on the responsiveness of the rhesus monkey ovary to exogenous FSH and LH in vivo. Rhesus monkeys whose spontaneous gonadotropin secretion was interrupted with a GnRH antagonist received s. . implants of either DHT or T for 5 d before and continuing throughout a 15-d i.v. infusion of human FSH and LH. Neither T nor DHT treatment synergized with FSH/LH to stimulate estrogen production or increases in ovarian weight. Rather, administration of DHT significantly reduced estrogen secretion and the augmentation of ovarian weight in response to exogenously administered FSH and LH. These results indicate that high concentrations of DHT are antagonistic to gonadotropin-stimulated ovarian function in primates.

Testosterone decreases CA1 plasticity in vivo in gonadectomized male rats

Estrogen has been reported to enhance CA1 functional plasticity in adult rats, as measured by the induction of long-term potentiation (LTP). In the present study, the effects of androgens on CA1 LTP were assessed in adult male Sprague-Dawley rats in vivo following peripubertal castration. Castrated rats with cholesterol implants showed significantly greater plasticity, both in degree and duration of potentiation, than castrated rats given testosterone or dihydrotestosterone implants. An LTP paradigm reported to produce decremental LTP in vitro produced nondecremental LTP in androgen-deprived rats, but decremental LTP in androgen-treated rats. These results suggest that androgens, unlike estrogens, act to reduce CA1 plasticity in the adult rat. Hippocampus 2000;10:693–697. © 2000 Wiley-Liss, Inc.

Testosterone decreases CA1 plasticity in vivo in gonadectomized male rats.

Estrogen has been reported to enhance CA1 functional plasticity in adult rats, as measured by the induction of long-term potentiation (LTP). In the present study, the effects of androgens on CA1 LTP were assessed in adult male Sprague-Dawley rats in vivo following peripubertal castration. Castrated rats with cholesterol implants showed significantly greater plasticity, both in degree and duration of potentiation, than castrated rats given testosterone or dihydrotestosterone implants. An LTP paradigm reported to produce decremental LTP in vitro produced nondecremental LTP in androgen-deprived rats, but decremental LTP in androgen-treated rats. These results suggest that androgens, unlike estrogens, act to reduce CA1 plasticity in the adult rat.

Androgen-Induced Regrowth in the Castrated Rat Ventral Prostate: Role of 5 -Reductase

Testosterone (T), the major circulating androgen, must be converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase (5α-R) to be maximally active in the prostate. The present study was designed to determine the relative potency of T and DHT on regrowth of the involuted prostate and to elucidate the role of 5α-R in the growing prostate. To create dose-response curves for intraprostatic T or DHT, rats were castrated for 2 weeks to allow their prostates to fully regress and then given T implants of various sizes in the presence or absence of the 5α-R inhibitor, finasteride. Markers for androgen effects on regrowth of the prostate were prostate weight, duct mass (a measure of secretory activity) and DNA content (a measure of cell number). To assess the relative uptake of T and DHT by the prostate, a comparison was made of intraprostatic DHT levels resulting from T and DHT implants. In the prostate, 1.6–1.9 times more T than DHT was required to achieve a half-maximal response for each of the three markers of prostate regrowth. The dose-response curves revealed that thresholds for intraprostatic T and DHT had to be attained before significant growth was observed. The threshold for T was 2- to 3-fold greater than that for DHT. However, at high intraprostatic concentrations, the effects of T mimicked those of DHT. When the relationship between serum T levels and prostate regrowth was considered, 13 times more serum T was required for half-maximal prostate regrowth when its conversion to DHT was blocked by finasteride. This is partly due to decreased androgen accumulation in the prostate when T was the major intraprostatic androgen. Finally, T or DHT implants in the absence of finasteride resulted in similar intraprostatic DHT levels, indicating that uptake of each serum androgen into the prostate was similar. However, to achieve similar levels of DHT or T in serum, much larger DHT pellets were needed, suggesting more rapid metabolism of DHT in tissues other than the prostate. We conclude that the role of 5α-R is 2-fold: it converts testosterone into a modestly more potent androgen and enhances prostatic accumulation of androgen. DHT, in principle, could serve equally well as T as the circulating androgen, although the rate of DHT production would have to be considerably higher to counter the apparent rapid clearance from serum. In addition, we hypothesize that T has arisen as the major circulating androgen instead of DHT because it can be aromatized to estradiol, which itself has important roles in male reproductive function and bone physiology.

Androgen-induced regrowth in the castrated rat ventral prostate: role of 5alpha-reductase.

Testosterone (T), the major circulating androgen, must be converted to dihydrotestosterone (DHT) by the enzyme 5alpha-reductase (5alpha-R) to be maximally active in the prostate. The present study was designed to determine the relative potency of T and DHT on regrowth of the involuted prostate and to elucidate the role of 5alpha-R in the growing prostate. To create dose-response curves for intraprostatic T or DHT, rats were castrated for 2 weeks to allow their prostates to fully regress and then given T implants of various sizes in the presence or absence of the 5alpha-R inhibitor, finasteride. Markers for androgen effects on regrowth of the prostate were prostate weight, duct mass (a measure of secretory activity) and DNA content (a measure of cell number). To assess the relative uptake of T and DHT by the prostate, a comparison was made of intraprostatic DHT levels resulting from T and DHT implants. In the prostate, 1.6-1.9 times more T than DHT was required to achieve a half-maximal response for each of the three markers of prostate regrowth. The dose-response curves revealed that thresholds for intraprostatic T and DHT had to be attained before significant growth was observed. The threshold for T was 2- to 3-fold greater than that for DHT. However, at high intraprostatic concentrations, the effects of T mimicked those of DHT. When the relationship between serum T levels and prostate regrowth was considered, 13 times more serum T was required for half-maximal prostate regrowth when its conversion to DHT was blocked by finasteride. This is partly due to decreased androgen accumulation in the prostate when T was the major intraprostatic androgen. Finally, T or DHT implants in the absence of finasteride resulted in similar intraprostatic DHT levels, indicating that uptake of each serum androgen into the prostate was similar. However, to achieve similar levels of DHT or T in serum, much larger DHT pellets were needed, suggesting more rapid metabolism of DHT in tissues other than the prostate. We conclude that the role of 5alpha-R is 2-fold: it converts testosterone into a modestly more potent androgen and enhances prostatic accumulation of androgen. DHT, in principle, could serve equally well as T as the circulating androgen, although the rate of DHT production would have to be considerably higher to counter the apparent rapid clearance from serum. In addition, we hypothesize that T has arisen as the major circulating androgen instead of DHT because it can be aromatized to estradiol, which itself has important roles in male reproductive function and bone physiology.

Regulation of Noncontact Erection in Rats by Gonadal Steroids

Male rats exhibit erections in the presence of inaccessible estrous females, and we investigated which gonadal steroids regulate these noncontact erections (NCEs). Sexually experienced Wistar males (n ≥ 8/group) were tested for NCE four times (every 3 days) before castration, after castration, and after receiving subcutaneous implants of 10-mm Silastic capsules that were empty or filled with crystalline testosterone propionate (TP), dihydrotestosterone (DHT), estradiol benzoate (EB), or DHT + EB (10 mm each). Before castration, males responded with NCE in approximately 50% of tests. No males had NCEs after castration, beginning 3 days after surgery. Also, no males responded after treatment with EB or empty capsules. After receiving implants of TP, DHT, or DHT + EB, 50% of males had NCEs, beginning with the first test 3 days after treatment. On every measure of NCE, males treated with DHT or DHT + EB were indistinguishable from each other and from TP-treated males. Among the sexual responses of male rats, NCE appears to be more sensitive than other behaviors to changes in gonadal condition. In its profile of response to gonadal steroids (testosterone+, dihydrotestosterone+, estradiol−), NCE is similar to reflexive erection, for which spinal systems are sufficient, and unlike copulation (T+, DHT−, E+), which depends on discrete areas of the brain. We nonetheless conclude that NCE depends on androgen-sensitive systems in the brain, but androgen-sensitive neurons in the lumbosacral spinal cord may also play a role.

Dihydrotestosterone Prevents Spontaneous Adenocarcinomas in the Prostate-Seminal Vesicle in Aging L-W Rats

Background Gene-regulated mechanisms govern tumor development, but the actual development of tumors can be suppressed or promoted by epigenetic factors. Lobund-Wistar (L-W) rats are genetically predisposed to development of spontaneous and induced metastasizing moderately differentiated adenocarcinomas in the prostate-seminal vesicle (P-SV) complex. In L-W rats with one slow-release subcutaneous implant of dihydrotestosterone (DHT) (5alpha-Androstan-17beta-ol-3-one), the development of induced P-SV tumors 14 months later was significantly suppressed, with involution of testes, aspermia, and absence of detectable serum testosterone. The tumor-suppressive effect of DHT was confirmed. Spontaneous P-SV tumors developed in 57 of 220 control L-W rats (26%) at an average age 20 months. Methods At age 12 months, 70 L-W rats were administered an implant of 40 mg of DHT, and 75 untreated rats served as controls. All rats that developed palpable P-SV tumors were autopsied, and surviving rats were autopsied at age 24 months. Results At age 24 months, 9 of 70 DHT-treated rats (12.8%) and 20 of 75 DHT-free control rats (26.6%) had developed P-SV tumors spontaneously at average age 20.5 and 20 months, respectively. Conclusions Slow-release implants of DHT administered to L-W rats at age 12 months reduced by 50% the development of spontaneous P-SV tumors by age 24 months.

Dihydrotestosterone prevents spontaneous adenocarcinomas in the prostate-seminal vesicle in aging L-W rats.

Gene-regulated mechanisms govern tumor development, but the actual development of tumors can be suppressed or promoted by epigenetic factors. Lobund-Wistar (L-W) rats are genetically predisposed to development of spontaneous and induced metastasizing moderately differentiated adenocarcinomas in the prostate-seminal vesicle (P-SV) complex. In L-W rats with one slow-release subcutaneous implant of dihydrotestosterone (DHT) (5alpha-Androstan-17beta-ol-3-one), the development of induced P-SV tumors 14 months later was significantly suppressed, with involution of testes, aspermia, and absence of detectable serum testosterone. The tumor-suppressive effect of DHT was confirmed. Spontaneous P-SV tumors developed in 57 of 220 control L-W rats (26%) at an average age 20 months. At age 12 months, 70 L-W rats were administered an implant of 40 mg of DHT, and 75 untreated rats served as controls. All rats that developed palpable P-SV tumors were autopsied, and surviving rats were autopsied at age 24 months. At age 24 months, 9 of 70 DHT-treated rats (12.8%) and 20 of 75 DHT-free control rats (26.6%) had developed P-SV tumors spontaneously at average age 20.5 and 20 months, respectively. Slow-release implants of DHT administered to L-W rats at age 12 months reduced by 50% the development of spontaneous P-SV tumors by age 24 months.

Persistence of infertility in GnRH immunized male rats treated with subdermal implants of dihydrotestosterone (DHT)

Male hormonal contraception has been limited to date because two fundamental requirements have not been concurrently satisfied, these are, consistent and dependable azoospermia and infertility coupled with maintenance of libido. The objective of this study was to determine the extent to which implants of potent androgen (DHT) will restore androgenization and spermatogenesis in hypogonadotropic infertile male rats. Twenty-five sexually mature male rats of proven fertility were actively immunized against gonadotropin releasing hormone (GnRH) to induce azoospermia. After azoospermia was achieved, GnRH immunized rats received subdermal DHT-filled Silastic implants of 2, 4, 6, or 8 cm, or empty implants (n=5/group). Five untreated control rats received empty capsules. Eight weeks later, fertility was evaluated, sperm number was obtained from the testis, and weights of androgen-dependent organs were measured. The results indicate that immunoneutralization of GnRH induced complete azoospermia, and subsequent treatment with DHT implants of 2 or 4 cm for 8 wk restored accessory organ weights, but did not restore spermatogenesis or fertility. In addition, DHT implants of 6 to 8 cm partially restored spermatogenesis, but not fertility. We conclude that low-dose DHT supplementation of GnRH-immunized rats may be a suitable alternate therapy able to maintain androgenization in the face of persistent azoospermia in the rat. This may be an effective model for development of a male contraceptive.

Adrenal steroid precursors exert potent androgenic action in the hamster sebaceous glands of flank organs and ears.

To assess the effect of the androgen precursors dehydroepiandrosterone (DHEA) and androstenedione (4-ene-dione) on androgen-sensitive parameters in the skin of the hamster, these two steroids were released from SILASTIC implants inserted sc into castrated male hamsters. The pigmented area of the flank organs, the size of the underlying sebaceous glands, [3H]thymidine incorporation into these sebaceous glands, and the size of the ear sebaceous glands were measured. The decrease in flank organ size caused by orchidectomy was partially reversed by DHEA and completely reversed by 4-ene-dione, testosterone (T), or dihydrotestosterone (DHT) implants. Similarly, the size of the sebaceous glands of the flank organs was reduced 88.1% by castration, whereas DHEA, 4-ene-dione, T, and DHT implants reversed the effect of orchidectomy. Orchidectomy also decreased the sizes of the sebaceous glands of the ears; DHEA, 4-ene-dione, T, and DHT implants increased their sizes to 50.6%, 81.9%, 91.6%, and 105.8% of the values found in intact hamsters, respectively. Parallel results were observed on the labeling of flank organ sebaceous glands with [3H]thymidine as well as on prostate weight. Serum concentrations of T and DHT became undetectable in castrated hamsters and were increased to intact or slightly elevated values in animals receiving implants of DHEA, 4-ene-dione, or T. The present results show that DHEA and 4-ene-dione are potent stimulators of androgen-sensitive parameters in the sebaceous glands of both the flank organs and ears in the hamster and illustrate the importance of extragonadal or peripheral intracrine formation of active steroids. It is suggested that the castrated hamster supplemented with adrenal precursor steroids is a good model that can closely mimic the human situation, where adrenal steroids play an important role in androgen formation and action in peripheral tissues.

Sex steroids and vasotocin interact in a female amphibian ( Taricha granulosa) to elicit female-like egg-laying behavior or male-like courtship

Female egg-laying behaviors and male amplectic clasping behaviors in the rough-skinned newt ( Taricha granulosa) are similar in that animals clasp an object. In the case of egg-laying, females clasp submerged inanimate objects, whereas in amplexus, males clasp conspecific females. Considering these behavioral similarities and differences, we investigated the possibility that gonadal steroids and vasotocin (AVT) interact to control egg-laying behaviors, as has been shown for the control of amplexus in Taricha males. Intact, gravid T. granulosa females injected ip with AVT, unlike those injected with saline, exhibited egg-laying behaviors and oviposition. In ovariectomy-steroid-implant studies, no saline-injected female exhibited egg-laying behaviors, whereas AVT-injected ovariectomized females exhibited egg-laying behaviors if implanted with estradiol (E 2), testosterone, or dihydrotestosterone (DHT), and not if implanted with empty capsules. When given a choice between clasping aquatic vegetation or other females (amplectic clasping), following an AVT injection, unoperated and shamoperated control females and ovariectomized females with E 2 implants did not preferentially clasp aquatic vegetation over other females. In contrast, AVT-injected ovariectomized females with DHT implants preferentially clasped other females. Thus, exposure of Taricha females to estrogens or androgens appears to determine whether the AVT-induced clasping is egg-laying or amplectic clasping.

Effects of intracranial implants of dihydrotestosterone on the reproductive physiology and behavior of male guinea pigs

An experiment was conducted to determine whether the intracranial application of dihydrotestosterone (DHT), a nonaromatizable androgen, would stimulate male guinea pig mating. Of three castrate groups studied, one was a control group in which subjects were implanted both in the medial preoptic area (MPOA) and under the skin with cannulae containing cholesterol (NoDHT). Males in one of the experimental groups received implants of cholesterol in the MPOA plus subcutaneous implants containing DHT (ScDHT). Members of the other experimental group were subcutaneously implanted with cholesterol and simultaneously given intracranial implants of DHT (IcDHT). Compared to either the NoDHT control group or the ScDHT experimental group, greater numbers of males in the IcDHT group displayed mounts ( P < 0.01), intromissions ( P < 0.01), and ejaculations ( P < 0.001). Additionally, the hypothalamic implants of DHT had no significant effects on peripheral target tissues. These data indicate that androgenic stimulation of the guinea pig brain is sufficient to activate masculine sexual behavior in this species.

Effects of Intermittent Pulsatile Infusion of Luteinizing Hormonereleasing Hormone on Dihydrotestosterone-suppressed Gonadotropin Secretion in Castrate Rams

The feedback effects of dihydrotestosterone (DHT) on gonadotropin secretion in rams were investigated using DHT-implanted castrate rams (wethers) infused with intermittent pulsatile luteinizing hormone-releasing hormone (LHRH) for 14 days. Castration, as anticipated, reduced both serum testosterone and DHT but elevated serum LH and follicle-stimulating hormone (FSH). Dihydrotestosterone implants raised serum DHT in wethers to intact ram levels and blocked the LH and FSH response to castration. The secretory profile of these individuals failed to show an endogenous LH pulse during any of the scheduled blood sampling periods, but a small LH pulse was observed following a 5-ng/kg LHRH challenge injection. Dihydrotestosterone-implanted wethers given repeated LHRH injections beginning at the time of castration increased serum FSH and yielded LH pulses that were temporally coupled to exogenous LHRH administration. While the frequency of these secretory episodes was comparable to that observed for castrates, amplitudes of the induced LH pulses were blunted relative to those observed for similarly infused, testosterone-implanted castrates. Dihydrotestosterone was also shown to inhibit LH and FSH secretion and serum testosterone concentrations in intact rams. In summary, it appears that DHT may normally participate in feedback regulation of LH and FSH secretion in rams. These data suggest androgen feedback is regulated by deceleration of the hypothalamic LHRH pulse generator and direct actions at the level of the adenohypophysis.

Administration of constant low doses of androgens to steers by silastic implant. Suppression of gonadotropins and peripheral conversion of androgens.

Yearling Hereford calves approximately 300 kg in weight were castrated and assigned to one of six treatment groups receiving subcutaneous implants (3 implants, 0.5 cm diameter by 10 cm length, 10% steroid by weight) of either androstenedione (D); testosterone (T); 5 alpha-androstane-3 beta, 17 beta-diol (3 beta-diol); dihydrotestosterone (DHT); androsterone (A); or control (no steroid). Blood samples were obtained at half-hour intervals for eight hours one day prior to, and one week after, castration. The castration-induced elevation in FSH secretion was suppressed or modified by the DHT, T, and 3 beta-diol implants. LH levels were not significantly suppressed. The T implants elevated serum T concentrations; DHT implants elevated serum 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) and 3 beta-diol, but not DHT concentrations; 3 beta-diol implants elevated serum 3 beta-diol concentrations. The effects of D and A implants upon serum androgen concentrations were not statistically significant, although observations in vitro suggested an adequate release rate. These data imply that T and DHT, or metabolites of DHT, suppress FSH secretion and suggest that extensive peripheral androgen metabolism occurs.