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PubMed1990

Autologous down-regulation of androgen receptor messenger ribonucleic acid.

Autoregulation of androgen receptor (AR) mRNA was investigated using Northern blot analysis with AR cDNA fragments as probes. The amount of AR mRNA increased 2- to 10-fold with androgen withdrawal and decreased below control levels after androgen stimulation in rat ventral prostate, coagulating gland, epididymis, seminal vesicle, kidney, and brain, and in a human prostate cancer cell line, LNCaP. In rat ventral prostate, AR mRNA increased 2- to 3-fold within 24 h after castration and remained elevated for 4 days. Treatment with testosterone propionate beginning 24 h after castration reduced ventral prostate AR mRNA 4-fold within 8 h of androgen replacement. Administration of estradiol 24 h after castration had no significant effect on prostatic AR mRNA. Androgens, including testosterone and the synthetic androgen methyltrienolone (R1881), or the antiandrogen cyproterone acetate down-regulated AR mRNA in vitro in LNCaP cells, whereas estradiol was without effect. Administration of testosterone propionate to rats with androgen insensitivity did not decrease AR mRNA. Down-regulation of AR mRNA by androgen is therefore a receptor-mediated process which occurs in vivo in rat tissues that differ in androgen responsiveness and in cultured human prostate cells.

Animals↗
PubMed2000

Steroid implants in the medial preoptic area or ventromedial nucleus of the hypothalamus activate female sexual behaviour in the musk shrew.

Female musk shrews are induced ovulators that do not exhibit a spontaneous behavioural oestrous cycle. Testosterone produced by the ovaries and adrenal glands, is the major steroid hormone in circulation at times of mating, and as such, regulates sexual behaviour. In the first experiment, we identified the neural site(s) of action for testosterone. Hormone implants were placed in one of three targeted brain regions. The neural sites selected were the medial anterior division of the bed nucleus of the stria terminalis (BNSTMA), medial preoptic area (mPOA) and the ventromedial nucleus of the hypothalamus (VMN). Ovariectomized females who received a unilateral testosterone propionate implant in either the mPOA or VMN, were significantly more likely to display sexual behaviour as compared to females who received an implant in the BNSTMA or any other hypothalamic nucleus. In experiments 2 and 3, we investigated whether the behavioural effects of testosterone propionate were mediated by an oestrogen receptor or the androgen receptor. Ovariectomized females that received oestradiol (E2) implants in either the mPOA or VMN were more likely to display receptivity, and had significantly shorter behavioural latencies, as compared to females implanted with either dihydrotestosterone or cholesterol. These data show that neural aromatization of testosterone to E2 in the mPOA or VMN is necessary for optimal activation of female musk shrew sexual behaviour. This finding implies a degree of neural redundancy in the networks that control the expression of sexual receptivity.

Animals↗
PubMed2000

Experimental hyperprolactinemia in a rat model: alteration in centrally mediated neuroerectile mechanisms.

INTRODUCTION: The purpose of this study was to induce hyperprolactinemia in adult male rats and determine its effect on the central and peripheral mediated neurogenic as well as myogenic mechanisms of erectile function/dysfunction in a rat model. The use of penile reflexes in awake animals was used to test the effect of both central and peripheral mechanisms. Electrical stimulation of the cavernous nervous was used to test peripheral neural function and intracorporal injection of papaverine was used to test the intactness of the corporal smooth muscles. These mechanisms were further explored by administration of testosterone. METHODS: Eighteen Fisher-344 200-250 g rats aged 10 weeks were used in this study. Group 1 (n = 6) hyperprolactinemia was induced with subcutaneous (SQ) injection of 5 mg rat prolactin (NIDDK-r-PRL-B-7, biopotency 25 IU/mg) in two divided doses daily for 1 week. Testosterone propionate 100 mg/kg dissolved in sesame oil was given intramuscularly on day 1 (weekly dose). Group 2 (n = 6) control animals received SQ injection of vehicle twice daily and sesame oil I/M on day 1. Group 3 (n = 6) received testosterone propionate. Penile reflexes (erections, cups, flips and clusters) were assessed prior to induction (x 3) of and following one-week state of hyperprolactinemia (day 5, 6 and 7). All animals were trained three times before recording the penile reflexes. The penile reflexes being averaged to give a single composite score for each animal. All animals underwent dissections that isolated the cavernosal bodies and cavernosal nerves. Cavernous nerves were activated and intracorporal pressures were recorded at increasing current magnitude (range 0.5-10 mA). Following that corporal smooth muscle reactivity was determined by increasing injection of papaverine (100-3000 microg). Concentration response curves (CRCs) were then generated by plotting percent change (fractional change to make standardized comparison) to increasing neurostimulation or papaverine concentrations at half-log increments. Serum prolactin was determined by rPRL radioimmunoassay Kit-Amersham while serum testosterone was determined Testosterone ELISA Kit-Neogen. RESULTS: Penile reflexes were normal in all groups at the start of experiment but after 1 week of hyperprolactinemia, reflexes were totally abolished in hyperprolactinemia rats (Group 1) and unchanged in Groups 2 and 3. Response to cavernous nerve activation and resulting rise in intracorporal pressure to increasing current (range 0.5-10 mA) were statistically non-significant in any groups. Similarly the intracorporal pressure response to pharmacologic erection induced by papaverine (100-3000 microg) were also non-statistically significant in any groups. Serum prolactin level in all rats receiving prolactin were > 500 ng/ml and the rat group receiving testosterone, serum level were > 20 x higher than the control rat. CONCLUSIONS: This approach allowed more clear separation of central and peripheral mechanism of erection. This study shows a central neurological effect of hyperprolactinemia on erectile function. Hypogonadism does not seem to contribute to the impaired penile reflexes as documented by replacement of testosterone did not recover the centrally mediated penile reflexes. Lowered serum testosterone is secondary phenomenon. These observations may have important implications for the understanding, the mechanism and treatment of men with hyperprolactinemia as well as future research in this field.

Animals↗
PubMed1979

[Effect of progesterone on male and female sex behavior induced by steroid hormones in adult ovariectomized ewes].

Ovariectomized adult Ewes daily treated with I/M injections of testosterone propionate (10 mg/day) or oestradiol benzoate (200 microgram/day) show male-like sexual behaviour and simultaneously a permanent female receptivity. Additional daily treatment with 100 mg of progresterone results in a rapid decrease in male sexual responses both when Ewes are treated with testosterone and with oestradiol. No effect is observed on the female receptivity. Cyproterone acetate (100 mg/day) given to Ewes in addition to daily injection of testosterone propionate (10 mg/day) has effects similar to those of progesterone. These results show that progesterone has antiandrogen and antioestrogen properties and that this hormone administered at high doses is able to inhibit male activity.

Animals↗
PubMed1976

Effects of postnatal thyroxine administration on brain development, response to postnatal androgen and thyroid regulation in female rats.

Some developmental and functional manifestations of thyroxine (T4) administered on the first 2 days of postnatal life were studied in the female rat. Brain myelinogenesis estimated by brain esterified cholesterol concentration, and brain myelin age estimated by brain total cholesterol concentration, were subsequently determined. Thyroxine treatment resulted in a greater concentration of esterified cholesterol in the brain that saline treatment, but the latter appeared to delay the normal increase shown by non-injected controls. Thyroxine treatment resulted in total and free cholesterol levels similar to those of non-injected controls, these again being greater than those in saline-treated rats. Cholesterol concentrations in liver and serum were not affected by T4 or saline treatment. Administration of T4 to female rats before administration of 1-25 mg testosterone propionate on day 7 resulted in an ovarian and uterine weight response to human chorionic gonadotrophin (HCG, 1 i.u./day on days 23-26) on day 27 that was greater than that in litter-mates given saline at birth before testosterone propionate and HCG treatment. Postnatal T4 treatment alone in the female was also associated with a reduced thyroid and pituitary gland enlargement after 7 days of propylthiouracil feeding (0-015% in tap water, days 24-31 of life) when compared with either saline or non-injected controls.

Animals↗
PubMed1979

Effect of aromatizable androgens and estradiol on prolactin secretion in prepuberal male rats.

Intact and castrated male rats were injected daily for 10 days, beginning at 35 days of age, with either oil or one of the following steroids: testosterone propionate, dihydrotestosterone benzoate, androsterone acetate, androstenedione, androstandiol, or estradiol benzoate. Doses were 200 micrograms/rat/day for all androgens and 0.5 microgram or 2 micrograms/rat/day for estradiol. Significant increments in prolactin levels (fourfold over control values) in intact and castrated males were obtained after testosterone propionate and androstenedione treatment. Dihydrotestosterone, androsterone, and androstandiol did not induce any changes in either intact or castrated rats. Estradiol-treated males showed a four- and sevenfold increment in serum prolactin with the 0.5- and 2-microgram doses, respectively. These results suggest that androgens have a role in the control of prolactin secretion, particularly those that can be aromatized to estrogens by different tissues, including the hypothalamus.

Androgens↗
PubMed1991

Lichen sclerosus and squamous hyperplasia of the vulva. A clinical study of medical treatment.

One hundred thirty-eight cases of nonneoplastic epithelial disorders of the vulva treated with medical therapy from 1984 to 1988 were evaluated at the University of Florence, Florence, Italy. The 67 cases of lichen sclerosus were treated with testosterone propionate or progesterone ointment for 32 weeks. The 31 cases of squamous hyperplasia were treated with corticosteroid ointment for 16 weeks. The 40 patients with lichen sclerosus associated with squamous hyperplasia were treated with corticosteroid ointment for 12 weeks and then with testosterone propionate ointment for another 20. To evaluate the efficacy of the treatments, the patients were examined before and after therapy. The evaluation took into account the symptoms and gross appearance of the lesions, which were given a score of 1-3. Considering all the cases evaluated, a total regression of symptoms occurred in 82 patients (59.4%), while a partial regression occurred in 37 (26.8%). Furthermore, there was a total regression of gross changes in 68 cases (49.3%) and a partial one in 43 (31.1%). The best results were obtained with squamous hyperplasia, which lichen sclerosus, alone or associated with squamous hyperplasia, yielded less successful results.

Adolescent↗
PubMed1998

Effect of diazepam and sex hormones on EEG of gonadectomized male and female rats.

Waking EEG was recorded from left and right parietals in 60 adult Wistar rats gonadectomized after puberty during 5 days, 1 as baseline, 1 with vehicle and 1 with 10 mg/kg i.m. of diazepam with hormonal treatment (either testosterone propionate, 5-alpha-dihydrotestosterone or vehicle in males and progesterone, estradiol benzoate or vehicle in females). Quantitative EEG analysis showed that: diazepam in gonadectomized males increased absolute power of alpha, beta 1 and beta 2, increased interparietal correlation of delta and decreased interparietal correlation of slow theta, fast theta and beta 1, whereas in gonadectomized females, diazepam additionally decreased slow and fast theta absolute power. EEG effects were not modified by testosterone propionate or 5-alpha-dihydrotestosterone treatment in males. Diazepam plus estradiol rendered the female EEG response similar to the gonadectomized or testosterone-treated males response; diazepam plus progesterone induced the same response in females as in gonadectomized females and additionally induced interparietal asymmetry and decreased interparietal correlation of all EEG bands. Present results and information on the effects of diazepam on interparietal coupling of EEG and demonstrate that the EEG response to diazepam in adult rats is sexually dimorphic and depends on sex as well as on activational effects of gonadal steroids.

Animals↗
PubMed1985

The influence of testosterone in the brain of the male rat on levels of serotonin (5-HT) and hydroxyindole-acetic acid (5-HIAA).

There were two groups of rats: one was injected with testosterone propionate (10 mg/kg) every 7 days starting from weaning (23 days old); the other group had gonadectomy on the same day. The levels of 5-HT and 5-HIAA were measured by spectrofluorometry. The concentrations of 5-HT in the diencephalon of the testosterone propionate injected rats decreased significantly at 45 days, tending to become reestablished at 60 days; the rest of the brain followed the same pattern, but was less pronounced. The concentrations of 5-HIAA in the diencephalon and the rest of the brain decrease throughout postnatal development, although the differences are not significant. The castrated rats showed a marked increase at 45 days and later decreased at 60 days without recovering their initial values, in both brain areas. 5-HIAA concentrations were similar to those found in the injected animals. These facts can have various interpretations: early modifications in the brain, feed-back regulation mechanisms at the level of the hypothalamus, decrease in the release of the amine or reduction of its catabolism.

Animals↗
PubMed1975

Influence of testosterone on blood sugar, serum insulin and free fatty acid responses to glucose in normal male dog.

The influence of testosterone propionate chronic treatment on blood sugar, serum immunoreactive insulin and free fatty acid levels of male, normal, fasted, unanesthetized dogs, basally and during an intravenous glucose tolerance test has been studied. Control experiments using uninjected or vehicle-injected dogs were also performed. Blood sugar and serum immunoreactive insulin basal levels were not affected by testosterone propionate and/or its vehicle, but serum free fatty acids basal values were increased. The blood sugar curve during the test observed in the dogs in the three conditions differed little; neither glucose space nor glucose "k" value were affected by treatments. Testosterone administration reduced by 50% the serum immunoreactive insulin peak following glucose load, as compared to vehicle-injected controls. Hyperglycemia and hyperinsulinaemia induced a fall in serum free fatty acid levels in control groups, followed by a recovery period at the end of the test. Either the fall or the recovery were more intense in testosterone-treated dogs than in vehicle-injected controls. Results are discussed, emphasizing that testosterone exerts a moderate "diabetogenic" action in male dog, inasmuch as although it intensely promotes lipid mobilization and moderately reduces the insulin response to glucose, fails to induce any glucose intolerance.

Animals↗
PubMed1985

Effect of castration and administration of testosterone on cytosol and nuclear androgen receptor in mouse submandibular gland.

The effect of castration or administration of testosterone propionate on the subcellular distribution of androgen receptor in mouse submandibular gland was investigated. Within 10 h after castration of male mice, most of the androgen receptor in nuclei was significantly reduced, the androgen receptor in cytosol increased and the increased cytosol receptor retained for at least 40 h. A single injection of testosterone propionate to female mice resulted in the translocation of cytosol androgen receptor to the nuclei by 30 min. The nuclear receptor level remained for at least 24 h and the cytosol receptor was replenished by 24-72 h. These results reveal that the endocrine manipulations such as castration and testosterone injection cause the change in the subcellular distribution of androgen receptor from mouse submandibular gland in both sexes.

Animals↗
PubMed2003

Effects of testosterone in the treatment of immune-mediated sensorineural hearing loss.

Testosterones have beneficial effects not only on the modulation of expression of autoimmunity of B/W mice, but on other unrelated models such as autoimmune thyroiditis as well. This study was performed to evaluate the effect of testosterone in the treatment of immune-mediated sensorineural hearing loss (IMSNHL). To induce IMSNHL, 29 female Wistar rats were sensitized with bovine inner ear antigen three times weekly. Fourteen of 29 rats were injected subcutaneously three times a week with 250 microg of testosterone propionate from 1 week prior to the first sensitization to 1 week following the second booster sensitization. An auditory brain-stem response (ABR) test was performed prior to each antigen challenge and at 1, 2, 3, 4, 6 and 8 weeks following sensitization. On ABR testing, the testosterone-treated animals showed better results than the control animals with IMSNHL in the degree of hearing loss (10 to 20 dB vs. 10 to 40 dB) and incidence of hearing loss over 20 dB (25.0% vs. 53.3%). None of testosterone-treated animals showed a hearing loss over 20 dB, whereas 40% of the control animals with IMSNHL revealed hearing loss over 20 dB. These results suggest that testosterone propionate may be effective in the prevention of and early recovery from IMSNHL and may be used in the future as a one treatment modality for IMSNHL.

Androgens↗
PubMed2002

Neonatal sex steroids affect ventilatory responses to aspartic acid and NMDA receptor subunit 1 in rats.

We hypothesized that administration of estradiol benzoate to males and testosterone propionate to female neonatal rat pups alters sex-specific ventilatory responses to aspartic acid with correspondent changes in N-methyl-D-aspartate receptor subunit 1 (NR1) expression determined by Western blot in specific brain regions. One-day-old rat pups received estradiol benzoate, testosterone propionate, or vehicle and were studied at weanling and adulthood. Different groups had distinct patterns of changes in tidal volume and frequency of breathing after aspartic acid administration. NR1 expression in hypothalamus was altered by age, sex, and treatment. Medullary and pontine NR1 expression correlated with baseline ventilation and magnitude of the ventilatory response to aspartic acid in some groups. Thus 1) tidal volume and breathing frequency patterns in response to aspartic acid are gender, age, and treatment dependent; 2) sex, age, and exogenous steroid hormones affect NR1 expression primarily in the hypothalamus; and 3) there is correlation between NR1 expression in pons and medulla with ventilatory parameters.

Animals↗
PubMed1992

The effect of testosterone on serum gonadotropins of castrated rats kept under different lighting conditions.

Testosterone feedback sensitivity was measured as the ability of testosterone propionate to decrease serum LH and FSH of long-term castrated (4 wk) rats under four different lighting conditions: periodic light (12L:12D), constant light (LL), constant darkness (DD), and dim night illumination (1 lx) with a 12L:12D photoperiod. Rats were exposed to the different lighting conditions for 1 wk, during which they received daily testosterone propionate (125 micrograms or 250 micrograms s.c.). At the end of the experiment the rats were decapitated at 1100 h, and serum gonadotropin levels were measured by RIA. Serum LH of the rats kept under LL was reduced to the level of the intact rats with the smaller testosterone dose (125 micrograms/day). Under all other lighting conditions only the large dose (250 micrograms/day) was able to restore the serum LH concentration to the level of the intact rats. Serum FSH was restored only partially, and the effect was the same with both doses and similar under all lighting conditions. We conclude that the increase in testosterone negative feedback sensitivity was not caused by the lack of periodicity of illumination alone, but that sufficient intensity of lighting throughout the 24 h was needed as well.

Animals↗
PubMed1978

Effects of anti-oestrogen treatment of neonatal male rats on lordosis behaviour and mounting behaviour in the adult.

Male rats were treated daily with 100 microgram of the anti-oestrogen ethamoxytriphetol (MER-25) or oil during the first 10 days of life and tested for lordosis behaviour and mounting behaviour as intact adults, after castration and after castration and oestradiol benzoate or testosterone propionate treatment. The MER-25-treated rats showed higher levels of lordosis behaviour than oil-treated rats in all four treatment groups. Under each of these endocrine conditions, except after castration alone, the MER-25-treated rats showed a reduced capacity to ejaculate. Treatment of the neonatal rat with MER-25 reduced body weight in adulthood but did not change the weight of the accessory sexual glands, the testes, the number of cornified papillae on the glans penis or plasma testosterone concentrations during development. The response of the accessory sexual glands and cornified papillae on the glans penis to treatment with oestradiol benzoate or testosterone propionate after castration in adulthood was unaffected by treatment with MER-25. It is suggested that formation of oestrogen in the neonatal male rat brain from testosterone in the circulation inhibits the capacity to show lordosis behaviour and facilitates the capacity to ejaculate in response to ejaculate in response to gonadal hormone treatment in adulthood.

Animals↗
PubMed1976

Testicular chromatin activation in hypophysectomized rats.

Incorporation of labeled thymidine into testicular DNA of hypophysectomized rats began to increase after the administration of testosterone propionate and choriogenic gonadotrophin. While the thymidine incorporation reached maximum in 4 days, the DNA polymerase activity did not culminate until 8 days after the initiation of hormone treatment. The high molecular weight (6--8 S), presumably cytoplasmic DNA polymerase accounted almost entirely for this increase. Administration of testosterone propionate and chorionic gonadotrophin to hypophysectomized rats results in an increase of testicular RNA polymerase and chromatin templating activity. Chain elongation and initiation studies revealed that the increased templating capacity of androgen-stimulated testicular chromatin was almost entirely caused by the increase in the number of initiation sites. While the nuclear polymerase I responded relatively rapidly to hormone stimulation and reached a prominent maximum in about three days, the activity of polymerase II was more sluggish and not as prominent. The in vivo incorporation of ortho[32P]phosphate into chromosomal phosphoproteins occurred early during the androgen treatment and reached a maximum in about 20 h. The protein phosphokinase activity peaked later, approx. 72 h after the first administration of hormones.

Animals↗
PubMed1976

Effect of alpha-melanocyte-stimulating hormone and testosterone on cutaneous and modified sebaceous glands in the rat.

The effects of alpha-MSH and testosterone propionate on sebum secretion, sebaceous gland volume, dermal lipogenesis, and preputial gland weight and lipogenesis were examined in hypophysectomized rats. Hypophysectomy reduced sebum secretion, sebaceous and preputial gland size, and dermal and preputial gland lipogenesis. The greatest effects were seen on the biosynthesis of wax esters and squalene. Testosterone propionate (TP) increased sebum secretion, sebaceous gland volume and preputial gland weight and lipogenic activity, but had no significant effect on the pattern of lipid labelling. alpha-MSH had no effect on sebaceous or preputial gland size, but increased sebum secretion and dermal lipogenesis, especially wax ester biosynthesis. When given together TP and alpha-MSH had a synergistic effect on sebum secretion and on dermal and preputial gland lipogenesis, and the pattern of lipid labelling was shifted towards normal. TP and alpha-MSH also showed synergism in increasing preputial gland weight, but together they had no greater effect on sebaceous gland volume than that achieved with TP alone. These results suggest that TP and alpha-MSH have different actions on the sebaceous glands with alpha-MSH acting predominantly on lipogenesis and TP on cellualr proliferation and turnover leading to an increase in gland size. Preputial glands differ from cutaneous sebaceous glands in their response to alpha-MSH and androgen which could be a reflection of their more specilized function.

Animals↗
PubMed1995

Hormonal regulation of human follicle-stimulating hormone-beta subunit gene expression: GnRH stimulation and GnRH-independent androgen inhibition.

Previous studies from our laboratory demonstrated that chronic testosterone administration to castrated transgenic mice suppressed human follicle-stimulating hormone-beta (FSH beta) mRNA levels transcribed from a human transgene to approximately 20% of control values. In the present study we used primary pituitary cultures prepared from the transgenic mice and in vivo experiments in hypogonadal (hpg) mice carrying the human transgene to assess the role of hypothalamic gonadotropin-releasing hormone (GnRH) in this inhibitory action. The levels of human FSH beta mRNA in monolayer cultures of pituitary cells were decreased by 24-hour treatments with 10 nM testosterone propionate or 5 alpha-dihydrotestosterone to 13 and 26% of control values, respectively, in the absence of GnRH. For the in vivo experiments we introduced the 10-kb human FSH beta transgene into the hpg genetic background by selective crossbreeding. Daily injections of 1 microgram GnRH for 14 days induced expression of the human FSH beta gene in male and female mice. Maximal effects were obtained by GnRH treatment of gonadectomized, hpg transgenic mice. Human FSH beta mRNA levels rose to approximately 4- or 10-fold that of control males and females, respectively. The stimulation was blocked completely by simultaneous administration of testosterone propionate in males and partially by estradiol in females. Pituitary content of immunoreactive FSH paralleled the mRNA changes. These data suggest that testosterone feedback inhibits the human FSH beta subunit gene directly at the pituitary gland in addition to the indirect mechanism of GnRH suppression. Furthermore, the in vitro data indicate that the suppression of human FSH beta gene expression is at least partly a direct androgen effect that does not require aromatization of testosterone to estradiol.

Androgens↗