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PubMed2003

Normal ontogeny of perineal muscles and testosterone levels in Mongolian gerbils; response to testosterone in developing females.

The spinal nucleus of the bulbocavernosus (SNB) of Mongolian gerbils (Meriones unguiculatus) becomes sexually dimorphic during postnatal life, rather than prenatally as in rats. We therefore examined the early postnatal ontogeny of Mongolian gerbils, focusing on growth, serum testosterone (T) levels, and the sexually dimorphic perineal musculature innervated by the SNB. Serum T levels were higher in males than in females from birth through adulthood, with several early postnatal peaks and a large increase in T occurring during puberty in males. The SNB target muscles-the bulbocavernosus (BC) and levator ani (LA)-were present in both sexes on postnatal day 1 (PND1). Cross-sectional areas of BC fibers in males increased with age, and concurrently the myofibers of the BC became more fully developed and organized. In PND10 female pups, the BC muscle was virtually absent, while the LA muscle remained (although it was reduced in size). Postnatal treatment of female gerbils with androgen caused the BC muscle to remain and the LA muscle to become larger by PND10. Sexual dimorphism of the SNB develops differently in gerbils compared to other species, although its target muscles appear to respond to androgen in a manner similar to that in rats.

Animals↗
PubMedDate not supplied

Circadian variation in testosterone, sex hormone-binding globulin, and calculated non-sex hormone-binding globulin bound testosterone in healthy young and elderly men.

The circadian pattern in levels of serum total testosterone (T) in men becomes blunted with normal aging. However, because T not bound to sex hormone-binding globulin (non-SHBG-T) is felt to be a better representative of biologically available T than is total T, the possibility of a 24-h variation in non-SHBG-T in young men and the possibility that aging is associated with a blunting of that rhythm were investigated. Hourly blood samples were drawn on 10 normal young men (mean age 27.3 years) and 10 normal elderly men (mean age 70.7 years) over a 24-h period and the serum was assayed for total T, sex hormone-binding globulin (SHBG), and total protein; non-SHBG-T was calculated. SHBG was determined by radioimmunoassay as well as by a steroid-binding assay. Young men had a significantly higher (p less than 0.05) mean 24-h level of non-SHBG-T (1.91 +/- 0.62 nm/l) than did the elderly men (0.86 +/- 0.01 nM/l). Also, each young man showed a significant circadian rhythm in non-SHBG-T, with a group mean daily variation of 1.42 +/- 0.38 nM/l. In contrast, only 60% of the elderly men demonstrated a significant circadian rhythm in non-SHBG-T, and the group mean rhythm was blunted (maximum excursion 0.38 +/- 0.07 nM/l) compared with that of the young men. SHBG and total protein levels demonstrated similar 24-h variations in the two age groups. It was concluded that non-SHBG-T serum levels, similar to serum total T levels, demonstrate a circadian pattern in young men and this circadian rhythmicity becomes blunted with normal aging.

Adult↗
PubMedDate not supplied

Preservation of spermatogenesis in spinal cord injured rats with exogenous testosterone. Relationship with serum testosterone levels and cellular localization of cAMP responsive element modulator.

UNLABELLED: The current experiment examined the effects of exogenous testosterone (T) on spermatogenesis in rats with spinal cord injury (SCI) and their relationship with the cellular distribution of a cyclic AMP-responsive element modulator (CREM) in testicular cells. Implantation of T-filled Silastic capsules (TCs, 1-20 cm) resulted in dose-dependent, biphasic changes in testicular T levels and spermatogenesis in SCI rats. However, dose responsiveness of spermatogenesis to exogenous T in SCI rats differed from that in sham control rats. Specifically, implantation of 2-cm TCs enhanced the effects of SCI on spermatogenesis, resulting in total regression of the seminiferous epithelium. Although 3-cm TCs maintained complete spermatogenesis in sham control rats, this regimen failed to support complete spermatogenesis in SCI rats. Although complete spermatogenesis was maintained in SCI rats given 5-20-cm TC implants, various abnormalities persisted. Cellular distribution of CREM remained normal in SCI rats but was altered in those SCI rats that received 3- or 5-cm TC implants. Such effects were associated with reduced CREM proteins in testicular tissues. These results were consistent with altered cAMP signaling and its regulation in testicular cells after SCI and provided possible mechanistic explanations for the effects of SCI on spermatogenesis. CONCLUSION: SCI resulted in changes in the responsiveness of spermatogenesis to exogenous T. These effects were associated with altered cAMP/CREM signaling in testicular cells. Further studies, including a study of the relationship between serum T levels and normalcy of sperm functions and the role of neural-endocrine interactions in mediating the effects of SCI on spermatogenesis and sperm function, are needed so that therapeutic regimens can be designed for clinical use.

Androgens↗
PubMed2002

Testosterone 17beta-N,N-dimethylglycinate hydrochloride: A prodrug with a potential for nasal delivery of testosterone.

The purpose of this study was to examine the potential of the nasal route for the systemic delivery of the poorly water-soluble drug testosterone (TS) using a water-soluble prodrug, TS 17beta-N,N-dimethylglycinate hydrochloride. The physicochemical properties of the prodrug, in vitro hydrolysis in human liver homogenate, and in vivo nasal and intravenous experiments were performed in rats. The aqueous solubility of the prodrug was more than 100 mg/mL, compared with 0.01 mg/mL for TS, and its log partition coefficient between 0.05 M, phosphate buffer (pH 6) and octanol was 2.4. The prodrug was found to generate TS in 33% human liver homogenate and was absorbed from the nasal cavity rapidly and quantitatively. The bioavailabilities of both the prodrug and TS after nasal administration of the prodrug were similar to that after equivalent intravenous doses. These studies in rats suggest that this water-soluble prodrug of TS may have therapeutic utility for the management of TS deficiency.

Administration, Intranasal↗
PubMed1998

In vitro action of testosterone in potentiating gonadotropin-releasing hormone-stimulated gonadotropin-II secretion in goldfish pituitary cells: involvement of protein kinase C, calcium, and testosterone metabolites.

Overnight preincubation of goldfish pituitary cell culture with testosterone (T) enhanced the gonadotropin (GTH)-II responses to GTH-releasing hormone (GnRH). In this study, the involvement of GnRH signal transduction components and the requirement for T metabolism in mediating this direct, pituitary cell action of T were examined using cultured pituitary cells from both male and female goldfish. Each sets of related experiments were done in at least two different stages of the gonadal reproductive cycle and similar effects were observed. Overnight treatment with 10 nM T increased GTH-II responses to maximal stimulatory doses (100 nM) of either salmon (s)GnRH or chicken (c)GnRH-II, but not the total cellular GTH-II contents measured prior to and after a 2-h GnRH challenge. T increased the efficacy and sensitivity of the GTH-II response to stimulation by a protein kinase C (PKC) activator, tetradecanoyl phorbol acetate (TPA) without altering the ED50 of the dose-response curve. In T-treated cells, addition of a PKC inhibitor attenuated GTH-II responses to 100 nM doses of sGnRH, cGnRH-II, or TPA. T did not affect the GTH-II release stimulated by high concentrations of the Ca2+ ionophore ionomycin (100 microM) and the voltage-sensitive Ca2+ channel (VSCC) agonist Bay K 8644 (10 microM); similarly, the sensitivity of the GTH-II response to ionomycin and Bay K 8644 was also unaltered. Taken together, these data suggest that T potentiates GnRH-stimulated GTH-II release by enhancing the effectiveness of PKC-dependent pathways, but not by increasing the total Ca2+-sensitive GTH-II pool, the sensitivity of the release response to increases in intracellular Ca2+, or the amount of available GTH-II. However, the VSCC agonist nifedipine reduced sGnRH- and cGnRH-II-elicited GTH-II release in T-treated as well as in non-T-treated cells, suggesting that VSCC dependence is still present in the GnRH-induced response following exposure to T. Since total cGnRH-II binding to pituitary cells was not increased by T, increases in GnRH receptor capacity are unlikely following T treatment. The ability of T to increase GnRH-stimulated GTH-II secretion was not mimicked by 11-ketotestosterone or dihydrotestosterone, but was abolished by coincubation with an aromatase inhibitor. When viewed together, these observations suggest that aromatization of T may be required for the pituitary action of T on GnRH-induced GTH-II release.

Animals↗
PubMed2002

Fecal testosterone immunoreactivity as a non-invasive index of functional testosterone dynamics in male Japanese macaques (Macaca fuscata).

Validation of a simple method for the extraction and quantification of testosterone (T) from the excreta of male Japanese macaques (Macaca fuscata) is presented. Radioimmunoassay of paired fecal and serum samples collected from four intact sexually mature males during the breeding season provided profiles that were significantly correlated when samples were offset by approximately 48 hr. Additionally, no significant differences were observed in the pattern of temporal variation of T levels in serum and feces. Two castrated males were injected with radioinert T, and the patterns of excretion were observed by analysis of serial fecal and urine samples. Approximately 48 hr after the steroid was administered, a significant peak in the average fecal T levels was apparent. The injection event was also registered in the urine of both males, although qualitative differences were observed. These data suggest that measures of fecal T provide a reliable and non-invasive means of assessing gonadal function in this species. As the analysis of hormone levels in feces allows for frequent, stress-free sampling with minimal disruption, this method should be preferred in long-term or in situ applications requiring endocrine monitoring.

Animals↗
PubMed1979

Prenatal exposure to testosterone and its precursors influences morphology and later behavioral responsiveness to testosterone of female mice.

Prenatal exposure to testosterone (T), dehydroepiandrosterone or progesterone significantly increased ano-genital distance of female mice. In addition, prenatal exposure to T or pregnenolone significantly reduced the duration of T exposure during adult life required to induce intraspecific fighting behavior. However, the most masculinized females, those exposed to T prenatally, still had significantly shorter ano-genital distances and required a longer exposure period to T in order to establish fighting than did prenatally oil-exposed male mice. Additional experiments revealed that pregnenolone augments later responsiveness to the aggression-promoting property of T only if it is administered during the prenatal period of development.

Aggression↗
PubMed1979

Percentage binding of testosterone and dihydrotestosterone and unbound testosterone and dihydrotestosterone in rabbit maternal and fetal plasma during sexual organogenesis.

The percentages of bound testosterone (17 beta-hydroxy-4-androsten-3-one; T) and dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one; DHT) and their unbound concentrations were determined in pregnant rabbits and their fetuses from the 18th day of gestation to birth. T and DHT were also measured in fetal testes. In the testis, the total T/total DHT ratio, very high at 22 days (73.7 +/- 15.2), decreased until birth (6.7 +/- 0.8). In male fetuses the concentrations of total and unbound circulating T and DHT were always low and did not show any peak during sexual organogenesis. The percent binding of T (from 73.0 +/- 0.5 to 77.6 +/- 0.6) and DHT (from 76.5 to 83.7 +/- 1.1) in fetuses were similar in both sexes and significantly lower than those measured in mothers (T: from 87.2 +/- 0.6 to 91.6 +/- 0.9; DHT: from 87.3 +/- 0.9 to 93.8 +/- 0.9).

Animals↗
PubMed1992

Testosterone-induced diminution of two peptides in spleen cells from testosterone-immunosuppressed B10 mice.

High-performance liquid chromatography (HPLC) is used to detect testosterone (T)-sensitive peptides in spleen cells isolated from female C57BL/10 mice immunosuppressed against Plasmodium chabaudi malaria by T treatment. Two peaks with retention times of about 25 min and 34 min, respectively, were identified to be diminished by about 52% and 47%, respectively, in spleen cells from T-treated mice compared to those from untreated mice. Amino acid sequencing revealed that the 24 min peak consisted of the dipeptide Met-Phe and the 34 min peak contained a degradative fragment of the alpha-chain of hemoglobin. Our data suggest that the immunosuppressive T treatment of B10 mice induces a perturbation of erythrophagocytosis in spleens.

Amino Acid Sequence↗
PubMed1983

The effect of medial preoptic-anterior hypothalamic lesions on testosterone plasma levels and testosterone conversion in the hypothalamus of male rats.

Male Wistar rats were submitted to bilateral high frequency lesions in the medial preoptic-anterior hypothalamic area or to sham procedure. The behavioral effect of the lesions was observed and plasma testosterone (T) and estradiol (E2) were measured by radioimmunoassay. In vitro metabolism of T was studied in the hypothalamus. Lesions produced a permanent deficit in male sexual behavior, an increase of plasma T and E2, and of hypothalamic T aromatization, and a decrease of T conversion to 5 alpha-dihydrotestosterone (DHT).

Animals↗
PubMed1993

Long-term administration of testosterone enanthate to normal men: alterations of the urinary profile of androgen metabolites potentially useful for detection of testosterone misuse in sport.

Doses equivalent to 18, 72 and 216 mg testosterone (T)/week were administered for 6 months to eugonadal men. Urinary excretions of androgen glucuronides (G) were quantitatively analyzed by gas chromatography-mass spectrometry with stable isotope dilution during periods of control (without hormone treatment), T administration and recovery. The lowest dosage T administration did not affect the androgen profile, while higher dosages generally increased urinary excretions of T metabolites (TG, T sulfate, glucuronides of androsterone, etiocholanolone, 5 alpha- and 5 beta-androstane-3 alpha,17 beta-diol) and decreased excretions of conjugates of epitestosterone (ET) and its precursor androgen 5-androstene-3 beta,17 alpha-diol. A dose-dependent decrease of urinary LH in response to T was also observed. The ratio (T/ET)G, which is the sole official criterium for assessment of T self-administration by athletes, increased above the threshold value of 6 in most of the subjects, but not all, after the two highest dosage T regimens, and returned to normal during the recovery period. False positive or negative testing emphasizes the need for improvement of testing procedures. In this regard, valuable complementary information may be gained from ratios such as TG/ET(Total), TG/LH, (T/5-androstene-3 beta,17 alpha-diol)G, (5 alpha/5 beta)androstane-3 alpha,17 alpha-diol and (5 alpha/5 beta)androstane-3 alpha,17 beta-diol.

Adult↗
PubMed2005

Intercollegiate soccer: saliva cortisol and testosterone are elevated during competition, and testosterone is related to status and social connectedness with team mates.

Men and women from a southern university's intercollegiate varsity soccer teams gave saliva samples before and after league matches. For the men, samples were collected for a single game ending in victory. For the women, samples were collected for two games, one of which ended in victory and the other in defeat. For both men and women, match competition substantially increased saliva cortisol (C) and testosterone (T). For women, play-related increases in saliva C and T were similar in victory and defeat. For both men and women, saliva T (but not C) was highly correlated with teammate ratings of playing abilities--one measure of status with teammates--and self-ratings of social connectedness with teammates, but the nature of the relationship was different according to sex. For men, play-related changes in T were positively correlated with these variables, but before-game T was not. For women, before-game T was positively related to each of these variables, but play-related changes in T were not. Status and social connectedness are pertinent to understanding interpersonal dynamics in most social groups, and these results--which link T and these variables in an athletic context--may have relevance for understanding social relationships in other settings.

Adolescent↗
PubMed1994

Salivary excretory pattern of testosterone in substitutive therapy with testosterone enanthate.

OBJECTIVE: To determine salivary and serum T levels by an RIA method after a single injection of 250 mg IM of commercially available T enanthate. DESIGN: Research study. SETTING: Patients attended in a hospital environment. PATIENTS: Sixteen men with secondary hypogonadism. INTERVENTIONS: Testosterone enanthate was administered, and salivary samples were taken before the injection. Thereafter, these samples were obtained daily until day 7 and then on alternate days until day 28 after injection. Blood samples were taken previously and after the injection (5 samples during the month). MAIN OUTCOME MEASURE: Salivary and serum T. RESULTS: Salivary T levels rose from 3.46 +/- 3.16 to 13.82 +/- 7.78 ng/100 mL (0.12 +/- 0.11 to 0.48 +/- 0.27 nmol/L) within 24 hours and remained in that range until day 7. From day 9, 7.20 +/- 2.88 ng/100 mL (0.25 +/- 0.10 nmol/L), a progressive decrease of these values was observed until day 14: 5.18 +/- 2.88 ng/100 mL (0.18 +/- 0.10 nmol/L). From day 16 until day 28, salivary concentrations returned to hypogonadal levels. CONCLUSION: We conclude that T salivary concentrations may be applied to assess the effectiveness of T substitutive therapy in hypogonadal men and could replace serum in the monitoring of this type of therapy.

Adult↗
PubMed2001

The testosterone metabolite and neurosteroid 3alpha-androstanediol may mediate the effects of testosterone on conditioned place preference.

The abuse of androgens may be related to their ability to produce positive, hedonic interoceptive effects. Conditioned Place Preference (CPP) has been used in many experiments to examine hedonic effects of drugs. This review is focused on studies from our laboratory that utilized CPP to examine potential positive hedonic effects of testosterone (T), and its androgenic metabolite dihydrotestosterone (DHT), and its metabolite 3alpha-androstanediol (3alpha-diol). We hypothesized that administration of a high concentration of 3alpha-diol would produce a CPP, pharmacological concentrations of plasma androgens, and alter androgen receptors (AR) and the function of GABA(A)/benzodiazepine receptor complexes (GBR). In our studies, we observed that systemic 3alpha-diol (1.0 mg/kg) prior to exposure to the non-preferred side of a CPP chamber significantly increased preference for the non-preferred side of the chamber compared to baseline preference and homecage controls. Furthermore, administration of T, DHT, or 3alpha-diol increased levels of these androgens, decreased ARs (decreased seminal vesicle weight and intrahypothalamic AR) and GBR function (decreased GABA-stimulated chloride influx in cortical synaptoneurosomes, and muscimol binding in the hippocampus compared to control groups). With systemic administration of 3alpha-diol that enhanced CPP, concentrations of 3alpha-diol were increased in the nucleus accumbens (NA). Central implants of T, DHT, or 3alpha-diol to the NA also produced a CPP compared to baseline preference and vehicle controls. These data indicate that systemic 3alpha-diol is more effective at enhancing CPP and increasing circulating 3alpha-diol levels than is T or DHT and that central administration of 3alpha-diol to the NA can condition a place preference. These findings indicate that 3alpha-diol produces positive hedonic effects and suggest that T's variable effects on CPP may be due in part to T's metabolism to 3alpha-diol.

Androstane-3,17-diol↗
PubMed1990

Testosterone, sex hormone-binding globulin, calculated free testosterone, and oestradiol in male vegans and omnivores.

Total testosterone (T), total oestradiol (E2) and sex hormone-binding globulin (SHBG) concentrations were measured in plasma samples from fifty-one male vegans and fifty-seven omnivores of similar age. Free T concentration was estimated by calculation. In comparison with the omnivores, the vegans had 7% higher total T (P = 0.250), 23% higher SHBG (P = 0.001), 3% lower free T (P = 0.580), and 11% higher E2 (P = 0.194). In a subset of eighteen vegans and twenty-two omnivores for whom 4 d diet records were available, there were statistically significant correlations between T and polyunsaturated fatty acids (r 0.37), SHBG and fat (r 0.43 for total fat, 0.46 for saturated fatty acids and 0.33 for polyunsaturated fatty acids), and SHBG and alcohol (r-0.39). It is concluded that a vegan diet causes a substantial increase in SHBG but has little effect on total or free T or on E2.

Adult↗
PubMedDate not supplied

Dementia and low testosterone and bioavailable testosterone levels in men: possible increased risk.

This study examines associations of serum total and bioavailable testosterone (T) with dementia in a community-based cohort of men. Study subjects (n=128; ages 65 y and older at baseline) were recruited in 1990 and followed through 2006. Dementia was assessed from the subject medical records on the basis of the criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Serum from a blood draw performed in 1994 was assayed for total and bioavailable T. Twenty-one men developed dementia over 1186 person-years of follow-up. The cumulative incidence of dementia was 14.7% in men with total T <410 ng/mL (median) and 8.0% in men with higher levels [>/=410 ng/mL; age-adjusted hazard ratio (HR)=2.09; 95% confidence interval (CI)=0.76, 5.75]. Similarly, the cumulative incidence of dementia was 18.8% in men with bioavailable T <12 ng/mL (median) and 2.2% in men with bioavailable T >/=12 ng/mL; age-adjusted HR=1.22 (95% CI=0.38, 3.87). These findings do not demonstrate a significant association between T levels and dementia. However, they suggest a need for further investigation of these potential associations.

Aged↗
PubMedDate not supplied

Short-term effects of an LHRH-agonist alone or in combination with testosterone propionate or indomethacin on rat testes. Evidence of testosterone independent effects. I.

The treatment of adult male Wistar rats with a LHRH-agonist (lutrelin Wyeth/WY 40972) resulted in severe damage of the seminiferous tubules as well as in remarkable changes of the blood vessels within 24 hours. First striking signs of alterations within the blood vessels were already found 6 hours after the injection of lutrelin: the blood vessels were almost totally filled with leucocytes. Neither the effects on the germinal epithelium nor the effects on the blood vessels were prevented by the simultaneous treatment with 3 mg testosterone propionate (TP). The treatment with indomethacin, however, clearly antagonized both events. The complete inefficiency of TP to overcome the inhibitory effects of lutrelin on the testes does argue against an androgen deficiency as the primary cause. The results obtained with indomethacin strengthen the hypothesis, that the early deleterious effects of LHRH-agonists on the germinal epithelium of the rat are primarily caused by circulatory disturbances in the testes and that prostaglandins may act as mediators.

Animals↗