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PubMed2001

Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism.

It is known that steroid hormones can affect neuronal susceptibility to different types of insults, including oxidative stress. Using an in vitro/ex vivo model, we have previously shown that cerebellar granule cells prepared from neonatal rats treated with a single dose of testosterone are less vulnerable to oxidative stress-induced cell death, via a mechanism involving an upregulation of the cellular antioxidant defenses. Whether the testosterone protective action on cerebellar granule cells was direct or indirect remained to be clarified. Therefore, in this study we have investigated the effects of in vitro testosterone treatment, to see whether it also protects cerebellar granule cells from oxidative stress-induced damage. Cerebellar granule cells treated with 10(-6) M testosterone for 48 h were found less susceptible to damage induced by 50 microM hydrogen peroxide, as shown by a 30% decrease in the number of cells with apoptotic morphology. The addition of the androgen receptor antagonist flutamide abolished the protective effect of testosterone, suggesting an androgen receptor-mediated mechanism. This hypothesis was further supported by the presence of the androgen receptor in cultured cerebellar granule cells. The activity of the antioxidant enzyme catalase was also measured, and a 2-fold increase was detected in the testosterone treated cells, but not in the cells co-treated with flutamide. The present results demonstrate that cerebellar granule cells treated in vitro with testosterone are protected from oxidative stress via a mechanism mediated by the androgen receptor. Similarly to what we observed after in vivo administration of testosterone, the potentiation of the antioxidant defences seems to play a major role in the protection afforded by testosterone.

Androgen Antagonists↗

PubMed2002

Effects of testosterone on neuromuscular transmission in rat isolated urinary bladder.

Testosterone was examined for its effects on neuromuscular transmission in rat and shrew urinary bladder. In isolated preparations of detrusor muscle from sexually immature male rats (8-10 weeks old) at concentrations of 100-300 microM, it inhibited neuromuscular transmission in a concentration-dependent manner and it also inhibited responses to applied carbachol and diadenosine pentaphosphate (Ap(5)A, a P2X receptor agonist). Ethanol (at or above 38 mM), the solvent for testosterone, also caused significant inhibition of neurogenic contractions as well as carbachol- and Ap(5)A-induced contractions. In older, sexually mature male rats (over 16 weeks old), testosterone and ethanol had similar effects to those observed in the young male rat, although both were slightly less potent. In young virgin female rats (8-12 weeks old), testosterone and ethanol inhibited neuromuscular transmission; testosterone was approximately 1000 times more potent than in male rats, with a threshold concentration of 30 nM. In the insectivore, Suncus murinus, testosterone (0.1 microM-1 x mM) caused inhibition of neurogenic and chemogenic responses, but ethanol had no significant effect. Flutamide (50 microM), a genomic testosterone-receptor antagonist, did not inhibit any of the responses to testosterone. It is concluded that testosterone acts predominantly on a postjunctional nongenomic receptor to inhibit urinary bladder detrusor muscle contraction.

Androgen Antagonists↗

PubMed2003

Mechanisms of vasorelaxation to testosterone in the rat aorta.

We have investigated the role of endothelium-derived relaxing factors, K(+) channels and steroid receptors in vasorelaxation to testosterone in the rat aorta. Testosterone (1 nM-mM) caused acute concentration-dependent vasorelaxation. Both indomethacin (10 microM) and flurbiprofen (10 microM) uncovered relaxant responses to testosterone. The action of indomethacin was inhibited by endothelial removal. N(G)-nitro-L-arginine methyl ester (L-NAME, 300 microM) had no effects on testosterone-induced responses. In the presence of indomethacin, the vasorelaxant potency of testosterone was reduced by depolarization with 60 mM KCl or charybdotoxin (100 nM), but not by glibenclamide (10 microM), 4-aminopyridine (1 mM) or barium chloride (30 microM). The responses to testosterone were not inhibited by flutamide (10 microM) or mifepristone (30 microM). Pre-treatment of the aorta with testosterone (100 microM) inhibited CaCl(2)-induced contraction. In the present study, we have demonstrated that testosterone causes acute vasorelaxations, which are modulated via endothelium-derived prostanoids. The responses uncovered by cyclooxygenase inhibitors are due to the activation of K(Ca) channels, while at higher concentrations, testosterone inhibits Ca(2+) influx.

Androgen Antagonists↗

PubMed2003

Testosterone, but not nonaromatizable dihydrotestosterone, improves working memory and alters nerve growth factor levels in aged male rats.

Recent studies have suggested that testosterone levels are lower in men with Alzheimer's disease and that testosterone treatment improves cognition in older men. Since testosterone can be aromatized to estrogen, testosterone's effects could be due to conversion into estrogen. We treated aged male rats with either testosterone or dihydrotestosterone (DHT), the latter of which is not aromatized to estrogen, in order to determine whether these treatments improve spatial working and reference memory as assessed in the water radial arm maze. We also tested whether such effects are related to beta-amyloid levels in the hippocampus or neurotrophin levels in the hippocampus, entorhinal cortex, frontal cortex, or striatum. Aged rats made more errors than young rats on all memory measures. Testosterone, but not DHT, improved working memory and decreased hippocampal NGF protein in aged rats, while having no effect on beta-amyloid. However, higher beta-amyloid levels were correlated with poorer working memory performance in young rats. Neurotrophin levels in entorhinal cortex were positively correlated with errors for all memory measures in androgen-treated rats. Similar to findings in human studies, in our study androgen treatment lowered circulating estradiol levels in aged rats, suggesting that androgen treatment exerts feedback to the hypothalamic pituitary axis and that conversion to estrogen may not be the underlying biological mechanism of testosterone's effects on memory and growth factor levels. The ratio of estradiol to testosterone, or the actions of the aromatase enzyme itself, may be responsible for the observed effects. These data support the hypothesis that testosterone therapy in aging men may provide positive effects on cognition and that neural regions that are linked to cognition, such as the hippocampus and/or entorhinal cortex, may be involved in such effects.

Aging↗

PubMed2002

Latitudinal variation in plasma testosterone levels in birds of the genus Zonotrichia.

Birds breeding in northern latitudes generally have elevated plasma testosterone levels throughout the breeding season with a peak at the onset of the breeding season. In contrast, tropical birds tend to have extremely low plasma testosterone levels year round with only a slight increase during breeding. While these patterns have been consistent in the species investigated, closely related species have not been investigated across a range of latitudes. Birds of the genus Zonotrichia present an ideal opportunity to investigate latitudinal variation in plasma testosterone levels as breeding populations occur from northern Alaska to southern Argentina. We studied three taxa of Zonotrichia: (1) Gambel's white-crowned sparrows, Zonotrichia leucophrys gambelii, breeding at high latitude in northern Alaska, (2) Puget Sound white-crowned sparrows, Z. l. pugetensis, breeding at mid-latitude in Washington state, and (3) an equatorial population of the rufous-collared sparrow, Z. capensis, in Ecuador. To compare both baseline breeding and maximal testosterone levels, males from the three taxa were either bled immediately upon capture during the breeding season or first challenged with gonadotropin-releasing hormone (GnRH) and then bled. As a control, another group of birds experienced a saline challenge. Two-way ANCOVA, with treatment and taxa as factors and testis volume as a covariate, showed a significant effect of treatment on plasma testosterone levels. There was also a significant interaction between taxa and treatment. Contrary to expectations, the equatorial species exhibited greater plasma testosterone levels in response to the GnRH challenge than the high latitude species. There were no differences between the mid- and high-latitude species. The equatorial species had the smallest average testis size and within each taxa there were no relationships between plasma testosterone and testis size. These data suggest that latitudinal clines in plasma testosterone levels in Zonotrichia do not follow previously described patterns and that tropical birds can have levels of testosterone similar to northern latitude species.

Animals↗

PubMed1998

Delayed puberty in obese boys: comparison with constitutional delayed puberty and response to testosterone therapy.

OBJECTIVE: To evaluate the results of a brief course of testosterone therapy in boys with delayed puberty and to compare the responses seen in boys with constitutional delayed puberty (CDP), boys with obesity, and boys with possible gonadotropin deficiency. DESIGN AND SETTING: A retrospective chart review was done for 36 boys aged 14 years or older, seen between 1983 and 1996 because of delayed puberty, who were given 4 monthly injections of testosterone, 100 mg/mo, and had adequate follow-up. RESULTS: There were 23 boys whose findings before and after treatment were consistent with a diagnosis of CDP. Testosterone treatment increased the growth rate from 4.3 cm/y to 11.2 cm/y (P <.00001), and mean testis length increased 0.6 to 0.8 cm in all (from a mean of 2.9 to 3.6 cm, P <.00001) in the 4 months after testosterone treatment. Serum testosterone 4 months after therapy was higher than that before therapy (P =.00003). Of 5 boys with growth hormone deficiency but unknown gonadotropin status, 2 had lack of progression after testosterone therapy and were believed to have permanent gonadotropin deficiency. Seven of the 36 boys were obese (body mass index, >25), and 6 had a response to testosterone similar to boys with CDP with clear pubertal progression. One obese boy and one nonobese boy were diagnosed as having isolated gonadotropin deficiency. CONCLUSIONS: Monitoring the growth and genital responses to a 4-month course of testosterone injections helps to differentiate CDP from gonadotropin deficiency in boys with delayed puberty. Obese boys constitute a distinct category of boys with pubertal delay in terms of their growth, but their response to testosterone is similar to that observed in boys with classic CDP.

Adolescent↗

PubMed1988

The response of autonomic receptors to castration and testosterone in the urinary bladder of the rabbit.

The effects of castration and testosterone on the autonomic receptor density and contractility in the urinary bladder smooth muscle of male rabbits were compared to untreated animals. Four groups of rabbits were studied over a similar time span with Group 1 animals serving as the untreated controls. Two groups (Groups 2 and 3) were castrated 28 days prior to sacrifice, Group 2 animals received corn oil for 14 days, and Group 3 animals received testosterone, 10 mg./day, for 14 days. The Group 4 animals were non-operated and received testosterone 10 mg./day for 14 days. Ligand saturation binding studies for alpha adrenoceptors in the bladder base and proximal urethra were performed with [3H]dihydroergocryptine ([3H]DHE). Muscarinic cholinergic receptors (MChR) were assayed with [3H]quinuclidinyl benzilate ([3H]QNB) and beta adrenoceptors with [125I]iodocyanopindolol ([125I]CYP) on the detrusor smooth muscle. Castrated Group 2 animals showed no significant change in receptor density with either [3H]QNB or [125I]CYP in detrusor muscle, but did exhibit a significant reduction (59%) of alpha adrenoceptors in the bladder base-urethra. The testosterone treated castrate and testosterone treated non-operated animals had significant increases in the MChR density, but no change in the alpha adrenergic, or beta adrenergic receptor density as compared to untreated controls. Cumulative dose response contractile studies were performed with carbachol on detrusor muscle strips and with phenylephrine on bladder base strips in isolated organ baths. The contractile studies on muscles from Groups 1, 2 and 3 showed no change in the ED50 or maximal contractile strength between control, castration or testosterone treated castrated animals. The ratio of wet bladder weight as compared to total body weight between each of the treatment groups showed a slight increase in both of the testosterone treatment groups. It was concluded that castration down regulates the alpha adrenergic receptors of the bladder base, while testosterone treatment increases the density of MChRs, and increases the ratio of the bladder to total body weight. Although no contractile changes were observed in the bladder base tissue it is conceivable that longer chronic testosterone deficits might ultimately affect the bladder outlet resistance in the male because of the reduced alpha adrenergic receptor density.

Animals↗

PubMed2001

Chronic subordination stress in male tree shrews: replacement of testosterone affects behavior and central alpha(2)-adrenoceptors.

Subordination stress induced by social defeat in male animals is known to inhibit gonadal functions and it has been discussed whether the resulting deficit in testosterone might play a role in subordination behavior. One of the major transmitter systems involved in regulation of behavior is the noradrenergic system. To analyze whether a testosterone replacement can alter subordination behavior and whether this might be related to changes in the brain noradrenergic system, we quantified alpha(2)-adrenoceptors (alpha(2)-ARs) in the central nervous system of male tree shrews. Animals were submitted to chronic subordination stress and received testosterone at the same time. Behavior was monitored during all phases of the experiment: the control period of 10 days, the period of social stress lasting 10 days when subordinates were confronted daily with a dominant male, and, subsequently, the stress and treatment period of 18 days when in parallel to the stress, animals received either injections of testosterone or vehicle. Brain alpha(2)-ARs were quantified by in vitro receptor autoradiography using the antagonist ligand (3)H-RX821002. Locomotor activity decreased significantly during the stress period and was not re-normalized by testosterone. In contrast, testosterone re-normalized scent marking behavior and autogrooming, parameters that had both been reduced due to the subordination stress. Vehicle injections improved none of these behaviors. In 8 of 10 brain regions that were analyzed, numbers of alpha(2)-adrenergic binding sites were increased in stressed animals that received vehicle injections, but a difference between testosterone and vehicle injected animals was only observed in five regions. These brain regions are all known to be involved in emotional behavior (anterior hypothalamus, medial nucleus of the amygdala, cingulate cortex) or autonomic regulation, respectively (solitary tract nucleus, dorsal motor nucleus of vagus). Therefore, our data show that testosterone influences behavior of male subordinates and modulates alpha(2)-AR expression in their brains. Androgen-mediated alterations in receptors occur in brain regions that are known to be involved in emotionality, e.g., in the anterior hypothalamus which regulates aggressive behavior. One can therefore conclude that alpha(2)-ARs contribute to neuronal functions that are responsible for subordination of stress behavior, and that testosterone-induced receptor changes are related to the partial restoration of normal behavior.

Animals↗

PubMedDate not supplied

Organization of territorial marking behavior by testosterone during puberty in male tree shrews.

According to current hypotheses, in mammals male-specific behavior is organized perinatally, and activated in adulthood by male gonadal hormones. However, this strict differentiation between early organizational and late activational hormone effects has been criticized recently. Around puberty the testosterone levels of male mammals rise far above adult levels. In this study we examined the relevance of this pubertal testosterone peak on marking behavior of adult tree shrews (Tupaia belangeri). Male tree shrews were castrated before puberty and treated with testosterone either around puberty or in adulthood. Several months later, the marking behavior of the castrated adult animals was examined in standard tests in different scent conditions before and after a second testosterone treatment. Males castrated as adults as well as fertile females were used as controls. The testosterone peak during puberty did not influence male marking behavior in the absence of scent from conspecifics (familiarization marking) or in the presence of female scent (sexual marking). However, testosterone during puberty determined both the male-specific reaction patterns to male scent (territorial marking) and the male-specific regulation of this behavior by testosterone. These results indicate that testosterone during puberty specifically organizes male territorial-marking behavior. To our knowledge, these are the first results demonstrating organizational effects of testosterone during puberty on male behavior.

Animals↗

PubMedDate not supplied

Effects of testosterone on aggressive behaviour after social mixing in male lambs.

The aim of this article was to study the effects of testosterone administration on the aggressive behaviour of male prepubertal lambs after mixing unacquainted individuals. Forty male lambs from two different flocks (1 and 2), 20-22 kg body weight and 10-12 weeks old, were distributed into four groups: C1 and C2 (control groups), and T1 and T2 (testosterone-treated groups). Groups C1 and T1 came from flock 1, while groups C2 and T2 came from flock 2. Animals in groups T1 and T2 were given 250 mg of testosterone enantate intramuscularly on the first experimental day. Animals from the same flock were kept as a group during the first 15 days; on Day 16, control animals (C1 and C2) were moved into one pen and testosterone-treated animals (T1 and T2) into another one, where they were kept for 3 additional days. Aggressive interactions and hormone plasma levels were recorded both before and after social mixing. Before social mixing, testosterone did not modify the frequency of aggressive interactions, while it increased the probability of an animal to receive an aggression. After social mixing testosterone-treated animals initiated and received more aggressions than control animals. Moreover, after social mixing, testosterone-treated animals directed their aggressions mainly towards unfamiliar animals, whereas control animals directed theirs aggressions towards familiar and unfamiliar animals in the proportion expected by chance. It is suggested that the effects of testosterone on aggressive behaviour are context dependent, and that testosterone increases an animal's tendency to establish dominance relationships, rather than its aggressiveness per se.

Aggression↗

PubMed2003

Mouse Leydig tumor cells produce C-19 steroids, including testosterone.

The mouse Leydig tumor cells (MLTC-1) were derived from a transplantable Leydig cell tumor carried in C57BL/6 mice. The original cell line (M5480) produced testosterone and little progesterone. However, it was later shown that there were two subtypes of the cell line, one producing mainly progesterone and termed M5480P and the other which produced androgens and termed M5480A. MLTC-1 cells are reportedly derived from the former. We studied the production of testosterone by MLTC-1 cells using a specific and sensitive testosterone RIA, tandem mass spectrometry (TMS) and examined the expression of mRNA of some key enzymes involved in steroidogenesis. Although the molar yields were 1:20:60 for testosterone, androstenedione and progesterone, respectively, in response to human chorionic gonadotropin (hCG), testosterone measured by our RIA accounted for 94% of the testosterone immunoreactivity. Both MLTC-1 and Balb/c Leydig cells expressed Steroidogenic Acute Response (StAR) protein mRNA in response to hCG. Cytochrome P450 17alpha-hydroxylase/17,20-lyase mRNA was expressed constitutively in MLTC-1 and Balb/c Leydig cells. Whereas the latter expressed 17beta-hydroxydehydrogenase/17-ketoreductase isoform Type 3mRNA in response to hCG, MLTC-1 cells expressed isoform Type 7 constitutively. The absence of isoform Type 3 in MLTC-1 cells thus may account for the low conversion of androstenedione to testosterone in this cell line. However, with a very specific and sensitive RIA even the low production of testosterone becomes meaningful. In conclusion MLTC-1 cells produce testosterone.

17-Hydroxysteroid Dehydrogenases↗

PubMed2003

Testosterone treatment induces behavioral disinhibition in adult male rats.

The importance of testosterone for impulsive-like behavior is unclear. Here we studied the effect of testosterone administration during 6 and 14 days (separate experiments) with one, three and five testosterone-filled silastic capsules implanted subcutaneously on shock-induced behavioral inhibition and on flunitrazepam-induced disinhibition in a modified Vogel's drinking conflict model in rats. Alleviation of shock-induced behavioral inhibition has been suggested to reflect impulsive-like behavior and/or anxiolysis. Treatment with the highest testosterone dose used for 6 (Experiment 1) and 14 (Experiment 3) days increased the number of shocks accepted. Testosterone treatment affected serum levels of testosterone and accessory sex organ weights. Flunitrazepam induced behavioral disinhibition in both testosterone-treated (for 14 days) and sham-treated rats. Moreover, testosterone treatment for 14 days resulted in enhanced GABA-induced 36Cl- uptake into synaptoneurosomes as compared to controls. In conclusion, testosterone produces behavioral disinhibition and may enhance brain GABAA receptor function.

Androgens↗

PubMed2002

A six-month, open-label study assessing a new formulation of leuprolide 7.5 mg for suppression of testosterone in patients with prostate cancer.

OBJECTIVE: The safety, efficacy, and pharmacokinetics of monthly subcutaneous injections of a new leuprolide acetate (LA) depot formulation were investigated in patients with advanced prostate cancer. METHODS: The 2-part, 6-month (168-day), open-label, multicenter study enrolled male patients diagnosed with adenocarcinoma of the prostate (Jewett stage C or D). LA-2500 7.5-mg (a new subcutaneous depot formulation containing 7.5 mg of LA) injections were administered at monthly (28-day) intervals. The primary efficacy parameter was total serum testosterone level. A breakthrough response was defined as a single testosterone measurement > 50 ng/dL after achieving castration testosterone levels. Testosterone was isolated from sera by alumina column chromatography and measured by radioimmunoassay (RIA). LA was purified by solid-phase extraction and high-performance liquid chromatography and was then quantitated by RIA. RESULTS: One hundred seventeen of the 120 enrolled patients completed the 6-month study. Three patients withdrew for reasons not related to treatment. LA had a mean (SD) maximal concentration of 26.3 (12.6) ng/mL at 4.66 (1.44) hours and was detected for a mean of 37 days (range, 28-49 days). By day 28, 94.1% (112/119) of the patients achieved medical castration (serum testosterone < or = 50 ng/dL). By day 42, 100.0% (118/118) of the patients remaining in the study had serum testosterone levels < or = 50 ng/dL and 97.5% (115/118) had levels < or = 20 ng/dL. At study completion, the mean (SD) serum testosterone level was 6.12 (4.3) ng/dL (range, 3.0-27.0 ng/dL). No breakthrough or acute-on-chronic responses were reported throughout the study. From baseline to month 6, mean (SD) luteinizing hormone level decreased from 8.0 (7.3) mIU/mL to 0.09(0.1) mIU/mL, and mean (SD) prostate-specific antigen level decreased from 32.9 (86.3) ng/mL to 3.2 (12.0) ng/mL. Treatment-related adverse events were reported by 74.2% (89/120) of patients, the most common being hot flashes (56.7%). CONCLUSION: This 6-month, open-label, noncontrolled study showed LA-2500 7.5-mg depot was well tolerated and maintained testosterone suppression (< or = 50 ng/dL) in the patients completing the study without any testosterone breakthrough responses.

Adenocarcinoma↗

PubMed1998

Transdermal testosterone delivery in castrated Yucatan minipigs: pharmacokinetics and metabolism.

The feasibility of using the castrated Yucatan minipig as a hypogonadal animal model to investigate the transdermal controlled systemic delivery of testosterone was studied. During a 24 h application of a testosterone transdermal delivery device (T-TDD), serial blood samples were withdrawn from the minipigs, without anesthesia, at predetermined time intervals and the plasma concentrations of testosterone as well as its major metabolites, dihydrotestosterone and estradiol, were assayed by radioimmunoassay. The compartmental pharmacokinetic modeling analysis of the plasma profiles of total testosterone indicated that as much as 92% of the total testosterone dose released from the T-TDD had been delivered transdermally into the systemic circulation during the initial rapid input period (the first 11 h of the application), while only 8% was delivered during the slow input period (up to 23h). Good correlation was observed between the in vivo input doses [1.9 (+/- 0.2), 4.8 (+/- 0.2) and 6.4 (+/- 0.5) mg/day], determined by the Wagner-Nelson equation, and the daily doses released [1.9 +/- (0.2), 4.7 (+/- 0.2) and 6.6 (+/- 0.5) mg/day, respectively, for 1, 2, and 3 units of T-TDD]. While the in vivo rate of input in the castrated minipigs was observed to be similar to that in hypogonadal men treated with the T-TDD during the first 8 h period, the input rate was found to be slower during the last 12 h. The agreement could suggest that the mechanism for the transdermal systemic delivery of testosterone in the castrated minipig could be similar to that in the hypogonadal men. However, the plasma testosterone profiles attained in the castrated minipigs were observed to be similar to, but slightly lower than that in the hypogonadal men reported in the literature. The delta Cmax (baseline normalized peak plasma concentration) and delta Cavg (baseline normalized average plasma concentration) data in the castrated minipigs were 40 and 44%, respectively, of that in hypogonadal men. The approximately 2.4 fold lower values in delta Cmax and delta Cavg data could result from the difference in the clearance rate of testosterone which approximately 2.8 fold higher in minipigs than in the human. Despite the difference in clearance rate, the castrated minipigs could be a suitable large animal model for studying the pharmacokinetics of testosterone delivered transdermally in human with hypogonadism.

Administration, Cutaneous↗

PubMed1997

Testosterone pretreatment mitigates cadmium toxicity in male C57 mice but not in C3H mice.

Previous work has indicated that testosterone pretreatment protects against cadmium-induced toxicity in male rats while other data indicate that pretreatment of mice with testosterone offers no such protection against cadmium. Since cadmium toxicity may vary widely with species and strain, we examined the effect of testosterone pretreatment on cadmium toxicity in two strains of mice, one that is sensitive (C3H) and one that is resistant (C57) to cadmium toxicity. A single sc injection of 20 micromol CdCl2/kg to C3H mice or 45 micromol CdCl2/kg to C57 mice proved very toxic, causing 50%, and 44% mortalities, respectively. However, when C57 mice were pretreated with testosterone (5 mg/kg, s.c., at - 48, - 24, and 0 h) prior to cadmium (45 micromol/kg), complete resistance to cadmium-induced lethality developed. Testosterone had no effect on cadmium-induced lethality in C3H mice. Testosterone prevented extensive hepatocellular damage caused by cadmium in C57 mice and also significantly reduced cadmium-induced elevations in serum lactate dehydrogenase (LDH) activity and blood urea nitrogen (BUN), which are indicators of hepatic and renal function, respectively. The toxicokinetics of cadmium were apparently not affected by testosterone pretreatment, as the distribution of cadmium to liver in either strain was unchanged by the steroid. Cadmium-induced metallothionein (MT) levels in liver and kidney of C57 mice were increased in testosterone-pretreated mice given the higher doses of metal but no such enhancement of MT synthesis occurred in C3H mice. This increase in MT may provide some level of protection against cadmium toxicity in the C57 mice. These results indicate that testosterone pretreatment prevents toxicity of cadmium in male C57 mice, possibly through enhancement of MT synthesis, but has no effect in male C3H mice.

Animals↗

PubMed2001

Effects of lesions of the medial preoptic nucleus on the testosterone-induced metabolic changes in specific brain areas in male quail.

The effects of bilateral lesions of the medial preoptic nucleus in association with testosterone on the metabolic activity in discrete brain regions was studied quantitatively by the in vivo autoradiographic 2-deoxyglucose method. Adult male quail were castrated and then left without hormone replacement therapy or treated with testosterone or treated with testosterone and submitted to a bilateral lesion of the medial preoptic nucleus, a brain region that plays a key role in the activation of male copulatory behavior by testosterone. Treatment for about 10 days with testosterone activated the expression of the full range of male sexual behaviors and these behaviors were completely suppressed by the medial preoptic nucleus lesions. Mapping of 2-deoxyglucose uptake revealed both increases and decreases of metabolic activity in discrete brain regions associated with the systemic treatment with testosterone as well as with the lesion of the medial preoptic nucleus. Testosterone affected the oxidative metabolism in brain areas that are known to contain sex steroid receptors (such as the nucleus taeniae and the paraventricular and ventromedial nuclei of the hypothalamus) but also in nuclei that are believed to be devoid of such receptors. Effects of testosterone in these nuclei may be indirect or reflect changes in terminals of axons originating in steroid-sensitive areas. Bilateral medial preoptic nucleus lesions affected 2-deoxyglucose uptake in a variety of brain regions. Some of these regions are known to be mono-synaptically connected to the medial preoptic nucleus. Metabolic depression in these areas may reflect retrograde changes in the neurons projecting to the damaged field.The metabolic changes identified in the present study confirm the prominent role of the preoptic area in the control of sexual behavior, show that changes in the physiology of the visual system represent one of the ways through which testosterone influences the occurrence of this behavior and demonstrate that the medial preoptic nucleus has marked effects on the metabolic activity in a variety of limbic and telencephalic structures. This study also indicates that the medial preoptic nucleus affects the activity of the area ventralis of Tsai, a dopaminergic area known to send projections to a variety of hypothalamic, thalamic and mesencephalic nuclei that are implicated in the control of male sexual behavior. These data therefore support the notion that the control of the dopaminergic activity in the area ventralis of Tsai by the medial preoptic nucleus represents one of the ways through which the medial preoptic area regulates male reproductive behavior.

Animals↗

PubMedDate not supplied

Octylphenol inhibits testosterone biosynthesis by cultured precursor and immature Leydig cells from rat testes.

4-tert-octyphenol (OP) is a surfactant additive widely used in the manufacture of a variety of detergents and plastic products. OP has been reported to mimic the actions of estrogen in many cellular systems. The present studies evaluated the direct effects of OP on human chorionic gonadotropin (hCG)-stimulated testosterone biosynthesis by cultured precursor and immature Leydig cells from 23-day old (prepubertal) rats. Exposure to increasing OP concentrations (1 to 2000 nM) progressively decreased hCG-stimulated testosterone formation in both precursor and immature Leydig cells at higher OP concentrations (100 or 500 to 2000 nM). Testosterone levels were reduced approximately 30 to 70% below control at the highest concentration in both cell types. Similar reductions in testosterone associated with OP exposure were observed in cells stimulated with 1 mM 8-Br-cAMP, suggesting that the main actions of OP occur after the generation of cAMP. Increasing concentrations of 17beta-estradiol (1 to 1000 nM) had no effect on hCG-stimulated testosterone formation in both precursor and immature Leydig cells and the inclusion of 100 nM ICI 182,780, a pure estrogen antagonist, in precursor and immature Leydig cells exposed to OP and hCG, did not alter the inhibition by higher OP concentrations of testosterone formation in both cell types. These results suggest that OP is a hormonally active agent, but that some of its actions are distinct from those of 17beta-estradiol and are not mediated through the estrogen receptor alpha or beta pathway. To further localize the potential site(s) of action of OP, cultured precursor and immature Leydig cells were exposed to increasing concentrations of OP and hCG for 24 h. Next, fresh media containing 1 microM 22(R)-hydroxycholesterol, 1 microM pregnenolone, 1 microM progesterone, or 1 microM androstenedione was added, and the conversion of each substrate to testosterone was determined after incubation for 4 h. The conversion of androstenedione to testosterone was unaffected by exposure to OP, suggesting that the 17beta-hydroxysteroid dehydrogenase step is not inhibited. However, the conversion of 22(R)-hydroxycholesterol, pregnenolone and progesterone all were inhibited by prior exposure to OP and hCG. This finding suggests that the 17alpha-hydroxylase/c17-20-lyase step, which converts progesterone to androstenedione, is inhibited by OP, and that the cholesterol side-chain cleavage and 3beta-hydroxysteroid dehydrogenase -isomerase steps, which convert cholesterol to pregnenolone and pregnenolone to progesterone, respectively, are other potential sites of OP action. Because concomitant exposure to the antioxidants alpha-tocopherol or ascorbate did not alter the inhibition of testosterone formation by higher OP concentrations, it does not appear that OP is acting as a pseudosubstrate for the generation of free radicals, which can damage P450 enzymes.

Androstenedione↗

PubMedDate not supplied

Biphasic effects of octylphenol on testosterone biosynthesis by cultured Leydig cells from neonatal rats.

The present studies evaluated the suitability of using cultured dispersed testicular cells from neonatal rats as a source for fetal Leydig cells and the use of these cells to examine direct toxic effects of environmental/occupational chemicals on androgen biosynthesis. For the current studies, the direct actions of octylphenol (OP), a surfactant additive widely used in the manufacture of various detergents, on testosterone biosynthesis by cultured rat neonatal Leydig cells were examined. Octylphenol is considered a xenoestrogen and has been reported to mimic the actions of estrogen in many cellular systems. Following exposure of cultured cells for 24 h to varying concentrations of OP (1 to 2000 nM) together with 10 mlU/mL human chorionic gonadotropin (hCG), the lower concentrations of OP (1 and 10 nM) consistently enhanced testosterone levels (approximately 10 to 70% above control), whereas higher OP concentrations (100 to 2000 nM) progressively decreased testosterone from peak levels to approximately 40 to 80% below control at the highest OP concentration. Interestingly, increasing concentrations of 17beta-estradiol (1 to 1000 nM) were without effect on testosterone biosynthesis under the same conditions, and the biphasic pattern of testosterone biosynthesis elicited by increasing OP concentrations was unaffected by concomitant treatment with 10 or 100 nM ICI 182,780, which is considered a pure estrogen antagonist. Therefore, the actions of OP on testosterone biosynthesis by cultured neonatal Leydig cells do not appear to be mediated through the classic estrogen receptor alpha or beta pathway. Although the increase in testosterone levels after exposure to lower OP concentrations and to 0.1 and 1.0 mM 8-Br-cAMP was attenuated, suggesting that lower OP concentrations may alter cellular cAMP levels, because hCG-stimulated cAMP levels were unaffected by any of the OP concentrations evaluated, it appears that its main site(s) of action occurs after the generation of cAMP. In addition, because pretreatment of cells with increasing OP concentrations and hCG had no effect on the conversion of steroid precursors (22(R)-hydroxycholesterol, pregnenolone, progesterone, or androstenedione) to testosterone, it seems that the main actions of OP under the present conditions occur before the mitochondrial cholesterol side-chain cleavage step. Furthermore, because concomitant treatment of cells with various antioxidants (alpha-tocopherol, butylated hydroxyanisole, or ascorbic acid) did not alter the biphasic pattern of testosterone response to increasing concentrations of OP and hCG, it seems that OP is not acting as an anti- or pro-oxidant in producing these effects. It will be important to determine whether this dose-sensitive response to OP is observed in vivo, and whether the maturational status of Leydig cells influences their pattern of response to OP and similar chemicals.

8-Bromo Cyclic Adenosine Monophosphate↗