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PubMed2002

Sexual activity and plasma testosterone levels in hypertensive males.

The aim of this study was to compare sexual activity and plasma testosterone levels of hypertensive men with those of healthy normotensive controls. We investigated 110 newly diagnosed, never treated hypertensive (blood pressure [BP] > or = 140/95 mm Hg) men and 110 healthy normotensive (diastolic BP <90 mm Hg) men. All of them were aged 40 to 49 years, married, without any previous sexual dysfunction, nondiabetic, nonobese (body mass index <28 kg/m2), nonsmoking, and not taking any drug. All subjects were evaluated in the morning after an overnight fast. Clinical evaluation included BP, body weight, and height measurements, determination of testosterone, and an interview about sexual activity, assessed as number of sexual intercourse episodes per month. Hypertensive men presented a 25% reduction in sexual activity as compared to normotensive men (5.9 +/- 2.6 v 7.9 +/- 2.5 sexual intercourse episodes per month, respectively, P < .01) and a 12% reduction in testosterone levels (510.6 +/- 151.9 ng/dL v 578.6 +/- 146.8 ng/dL, P < .01). In both normotensive and hypertensive men Pearson's correlation analysis showed a significant positive correlation between testosterone levels and sexual activity and a significant negative correlation between testosterone and age and between testosterone and BP values. Multiple regression analysis confirmed a significant inverse relationship between testosterone and age in normotensive men, whereas only a nonsignificant trend was found in the hypertensive ones. In addition, a significant inverse correlation between testosterone and BP levels was confirmed in hypertensive men limited to systolic BP, whereas a nonsignificant trend was observed in the normotensive controls. In conclusion, these findings suggest a relationship between essential hypertension and impaired testosterone levels in men. The elucidation of the nature of such a relationship and its physiologic and clinical significance needs further investigation.

Adult↗

PubMed2002

Exposure to octylphenol increases basal testosterone formation by cultured adult rat Leydig cells.

4-Tert-octylphenol (OP) is a breakdown product of 4-tert-octylphenol ethoxylate, which is a surfactant additive widely used in the manufacture of a variety of detergents and plastic products. OP has been reported to exhibit weak estrogenic activity in many assay systems. The studies described herein examined an unusual effect of OP in increasing constitutive testosterone levels of cultured Leydig cells from young adult rats. The increase in testosterone was both dose and time sensitive, and this response was observed in medium lacking both calcium and magnesium and containing a membrane-permeable calcium chelator, suggesting that the increase in testosterone was not mediated by an increase in the permeability of extracellular calcium into cells or the redistribution/release of calcium from intracellular stores, respectively. Cellular cAMP levels also were unaffected by OP alone in cultured Leydig cells. Furthermore, initial exposure to 2000nM OP alone for 4h did not alter the subsequent conversion of endogenous cholesterol or exogenously added 22 (R)hydroxycholesterol to testosterone, suggesting that the increase in testosterone was not due to the enhanced availability of endogenous cholesterol or an increase in cholesterol side-chain cleavage activity, respectively. The increase in testosterone also was observed in the presence of the pure estrogen antagonist, ICI 182,780, or a 5alpha-reductase inhibitor, suggesting that this effect of OP was not mediated through the estrogen receptor alpha or beta pathway or by inhibition of Leydig cell testosterone metabolism, respectively. In addition, exposure of cells to comparable concentrations of two different detergents, Triton X-100 or sodium cholate, did not increase testosterone levels, suggesting that this effect of OP was not due to its potential detergent qualities. Although these studies did not identify specific mechanism(s) that increase constitutive testosterone levels by OP, they identify specific pathways that appear not to be involved. The physiological relevance of this observation is not known; nevertheless, they illustrate potential diverse actions of OP in modulating the level of androgen secreted by Leydig cells, and they emphasize that some actions of OP do not appear to be mediated through the estrogen receptor alpha or beta pathway.

Animals↗

PubMedDate not supplied

Synthesis of 17 beta-hydroxyandrost-4-en-3-one-7 alpha-(biotinyl-6-N-hexylamide), a conjugate useful for affinity chromatography and for testosterone immunoassays.

We describe the synthesis of 17 beta-hydroxyandrost-4-en-3-one-7 alpha-(biotinyl-6-N-hexylamide) from 17 beta-hydroxyandrost-4-en-3-one (testosterone) via copper-catalyzed 1,6 Michael addition of a 6-(tertbutyldimethylsilyloxyhexyl) chain to 6-dehydrotestosterone 17 beta-acetate. After chromatographic separation of the 7 alpha-isomer from the alpha / beta mixture and cleavage of the silyl ether, the alcohol was oxidized to the 6-hexanal side chain and then subjected to reductive amination. The resulting primary amine is easily biotinylated using biotinyl-N-hydroxysuccinimide ester. The overall yield for the epimeric 7 alpha-end product was 30%. The absolute configurations of the epimers were investigated by 1H NMR studies by the nuclear Overhauser effect. We introduced a biotin label to the testosterone molecule at ring position 7 in compliance with Landsteiner's principle, which states that antibody specificity is directed primarily at that portion of the hapten furthest from the functional group linking it to the carrier protein. Thus, this negligible alteration in comparison to the structure of the respective testosterone hapten used to elicit antibodies offers the feasibility of applying the testosterone derivative as an optimal immunoadsorbent in affinity chromatography. The 7 alpha-biotinylated testosterone was used to obtain active antitestosterone antibodies from a specific antiserum by affinity chromatography. This was achieved by attaching the biotinylated testosterone to agarose-coupled streptavidin beads. Accordingly, a 3H-testosterone-binding test demonstrated a 20-fold increase in affinity of the purified antibody to the steroid compared to the original antiserum, and a recovery of > 80% could be obtained. The antitestosterone antibody, obtained by that method, is an effective component for use in a competitive immunoassay for testosterone in human sera. An assay configuration is conceivable with the same 7 alpha-biotinylated testosterone employed as tracer in combination with a streptavidin-linked reporter enzyme.

Animals↗

PubMed2005

Altered luteinizing hormone and testosterone secretion in middle-aged obese men with obstructive sleep apnea.

OBJECTIVE: To elucidate the causes for the decline in testosterone levels observed in men with obstructive sleep apnea (OSA). RESEARCH METHODS AND PROCEDURES: We determined serum luteinizing hormone (LH) and testosterone levels every 20 minutes between 7 pm and 7 am with simultaneous sleep recordings in five obese middle-aged men with OSA, in five age- and BMI-matched controls, and in six lean young healthy men. RESULTS: The mean and area under the curve (AUC) values of LH and testosterone were significantly lower in men with OSA compared with controls. Young controls had significantly more testosterone pulses of shorter interpulse duration than OSA subjects and middle-aged controls. After adjusting for age and BMI, the three groups differed in mean and AUC values of LH and testosterone. Analysis of covariance, using BMI as a covariate, revealed a statistically significant group effect on mean and AUC testosterone values (p = 0.03; p < 0.003, respectively). Eliminating young controls, there was a significant positive correlation between the amount of LH and testosterone secreted at night. After partialling out age alone and BMI alone, the mean LH and mean testosterone were still positively correlated. DISCUSSION: Thus, OSA is associated with decreased pituitary-gonadal function. The decline in testosterone concentrations is due to obesity and advanced age and to a lesser degree to sleep fragmentation and hypoxia.

Body Mass Index↗

PubMed2004

Testosterone-induced coronary vasodilatation occurs via a non-genomic mechanism: evidence of a direct calcium antagonism action.

Testosterone decreases myocardial ischaemia in men with coronary artery disease via a coronary vasodilatory action. However, long-term therapy may increase the risk of prostatic carcinoma via activation of the nuclear AR (androgen receptor). In the present study, we have investigated the mechanism of testosterone-induced vasodilatation using isolated rat coronary arteries and thoracic aortae from control and AR-deficient testicular-feminized mice. Vasodilatation induced by testosterone, T-3-OCMO [testosterone 3-(O-carboxymethyl)oxime] or T-3-OCMO conjugated to BSA was initially measured in preconstricted vessels that had undergone endothelial denudation or incubation with flutamide (10 microM). Cellular fluorescence was also measured in primary aortic SMCs (smooth muscle cells) following exposure to the above fluorescent-labelled agents. Subsequently, vessels were incubated with testosterone (100 microM) or vehicle prior to constriction with KCl (1-100 mM). Testosterone-induced vasodilatation was unaffected by endothelial denudation, flutamide treatment, AR deficiency or conjugation to BSA. Cells exposed to T-3-OCMO-BSA (10 microM) had a higher fluorescence than control cells (32.8+/-4.5 compared with 14.5+/-1.8 arbitrary units respectively; P<0.01). Incubation with testosterone (100 microM) reversibly attenuated coronary vasoconstriction to KCl (1-100 mM; 0.08+/-0.09 compared with 0.79+/-0.08 mN/mm respectively; P<0.0001). Testosterone-induced vasodilatation is independent of the vascular endothelium and nuclear AR, and is initiated at the SMC membrane, which contains testosterone binding sites. A direct calcium antagonistic action is implicated.

Androgen Antagonists↗

PubMed1997

Long-term efficacy and safety of a permeation-enhanced testosterone transdermal system in hypogonadal men.

OBJECTIVE: An important aim in treating male hypogonadism is restoration of physiological concentrations of testosterone and its metabolites. We have assessed hormone levels, pharmacokinetics and clinical response, including safety, of a permeation-enhanced testosterone transdermal system (TTD) in the treatment of hypogonadal men for a 12-month period. DESIGN: Open-label, multicentre study with four consecutive periods: Period I (3 weeks)--evaluation of patients' current androgen therapy, which consisted primarily of testosterone enanthate injections (mean dose 229 mg; mean interval 26d); Period II (8 weeks)--androgen washout; Period III (3-4 weeks)--single-dose pharmacokinetic studies of TTD systems; Period IV (12 months)--efficacy, safety, and steady-state pharmacokinetic evaluation of TTD systems (5 mg/day nominal delivery rate of testosterone). Results from Periods I, II, and IV were compared. PATIENTS: Thirty-seven hypogonadal men 21-65 years old enrolled; 34 entered Periods III and IV; 29 (9 primary, 20 secondary hypogonadism) completed the study. Four patients withdrew because of adverse events (Period II, one; Period IV, three). MEASUREMENTS: Morning serum levels of total testosterone (T), bioavailable testosterone (BT), dihydrotestosterone (DHT), and oestradiol (E2) levels. Circadian pattern of T profiles and 24-hour time-average T level. LH levels in patients with primary hypogonadism. Reduction of hypogonadal symptoms. Safety assessments including skin tolerability, prostate parameters, lipid profile, and systemic parameters. RESULTS: Twelve months of TTD therapy normalized morning serum T levels in 93% of patients, and produced greater than 80% normalization of BT, DHT and E2 levels. The TTD system mimicked the circadian variation in T levels seen in healthy young men and normalized 24-hour time-average T levels in 86% of patients. Luteinizing hormone was suppressed in 8 of 9 men with primary hypogonadism, and normalized in 5 of these. Subjective symptoms of hypogonadism, including decreased libido and fatigue, showed improvement after 2-4 weeks of TTD treatment in most patients. The majority of adverse events were local skin reactions, and 3 patients (9%) discontinued the study for this reason. Prostate assessments showed a lower prostate-specific antigen level during TTD therapy compared to IM injections (0.66 vs 1.00 microgram/l P < 0.001), while prostate size did not differ significantly between the two treatment regimens. CONCLUSIONS: The permeation-enhanced testosterone transdermal system produces physiological levels and circadian patterns of testosterone, and its metabolites, in hypogonadal men. Although transient erythema and itching is commonly reported, the TTD is generally well tolerated by most patients. This system offers a new treatment option for testosterone replacement therapy that results in physiological serum levels of sex hormones in hypogonadal men.

Administration, Cutaneous↗

PubMed1999

Serum leptin levels in healthy ageing men: are decreased serum testosterone and increased adiposity in elderly men the consequence of leptin deficiency?

OBJECTIVE: The limited information on serum leptin levels in elderly men suggests the occurrence of an age-related decrease, with disruption of the relationship between fat mass and leptin levels. A relative leptin deficiency might thus be implicated in the increase of fat mass and decrease of serum testosterone levels in elderly men. Therefore, we have reevaluated the age-related changes in serum leptin levels and their relationship with adiposity and androgen levels in a large group of community dwelling men. SUBJECTS AND MEASUREMENTS: Serum leptin and androgen levels were measured in 271 healthy, ambulatory elderly men (median age 74 years), as well as in 61 middle-aged (median 43 years) and 40 young (median 25.5 years) controls. Adiposity was assessed by anthropometrical measurements (body mass index; BMI) and by estimation of fat mass by the bio-impedance method. RESULTS: Serum leptin levels, whether or not adjusted for BMI, were found to increase with age, the values tending to level off after the age of 45 years, and were strongly correlated to BMI (r = 0.77) and fat mass assessed by the bio-impedance method (r = 0.81). Linear regression analysis showed a similar slope for the relationship between BMI and serum leptin in the three age groups. Multiple linear regression analysis indicated BMI, age and serum insulin, but not serum testosterone, as significant independent correlates of serum leptin. Serum (free) testosterone levels were negatively correlated with age and serum leptin, also after partialization for BMI: rank correlation coefficients vs. age and serum leptin, respectively, were - 0.20 (P < 0.001) and - 0.16 (P < 0.01) for total testosterone and - 0.60 (P < 0.001) and - 0.23 (P < 0.001) for free testosterone. Dehydroepiandrosterone sulphate (DHEAS) and leptin levels emerged as significant independent correlates in a multiple linear regression model for total serum testosterone; BMI and serum insulin became highly significant correlates in the same model when leptin was omitted from the independent variables. CONCLUSION: Ageing in men is accompanied by a rise of serum leptin levels with a maintained strong association between serum leptin and adiposity in elderly men. Testosterone does not appear to be a major determinant of serum leptin in healthy men, while leptin does emerge as a negative correlate of serum testosterone. Increased fat mass and decreased testosterone production in elderly men cannot be attributed to a relative leptin deficiency.

Adult↗

PubMed1999

Manipulation of postnatal testosterone levels affects phallic and clitoral development in infant rhesus monkeys.

Male primates exhibit marked elevation of circulating testosterone levels during the early postnatal period. The aim of this project was to test whether experimental manipulation of circulating testosterone levels in male and female infant rhesus monkeys affected development of the external genitalia during the first six months of life. Four groups of infants were studied. Seven control male infants exhibited high circulating testosterone levels during the first three months of life. Seven males were treated with a GnRH agonist (avorelin) from the first week of life onwards, which suppressed the postnatal testosterone surge. Ten control females exhibited low circulating testosterone levels during the early postnatal period. Administration of testosterone to 10 females resulted in high circulating levels in these infants. Fortnightly blood samples and genital measurements were taken from all infants during the first six months of life. Growth of the penis of avorelin-treated males was significantly retarded when compared to control males. Average length of the penis at six months of age was significantly (p = 0.012) smaller for avorelin-treated males (25.2 +/- 2.8 mm) than for control males (37.3 +/- 3.0 mm). Avorelin-treated males attained only around 50% detachment of the prepuce from the glans of the penis, while control males averaged 90% detachment. Treatment of females with testosterone resulted in significant growth of the clitoris in comparison to control females. The growth rates of the penis of control males and clitorides of testosterone-treated females were similar and greatest during the first two months of life. Gain in body weight was not affected by either hormonal manipulation. It is concluded that manipulation of circulating testosterone levels during the early postnatal period affects penile and clitoral development of infant rhesus monkeys. This postnatal period may therefore represent an important stage in penile development in primates.

Animals↗

PubMed2002

Evaluation of assays available to measure free testosterone.

This study compared the results of various testosterone assays in a cross-sectional study of 50 male subjects age 28 to 90 years. The purpose of the study was to determine the relationship of the various testosterone assays to one another. In addition, we determined week-to-week variability in testosterone and bioavailable testosterone in 16 subjects. The following assays were undertaken: total testosterone (T), free testosterone by equilibrium dialysis (FT(D)), bioavailable testosterone (BT), free testosterone by ultracentrifugation (FT(U)), and direct estimation of serum free T by an analog ligand radioimmunoassay (FT(A)). In addition, using total T and sex hormone-binding globulin (SHBG), we calculated the free androgen index (FAI = T/SHBG) and the free testosterone index (FTI) using the method of Vermeulen. In a second study, we measured the week-to-week variation in T and BT in a group of older males. Lastly, we demonstrated excellent stability of serum stored at -70 degrees C for up to 7 years for T and BT. Correlations of the various assays to increasing age were significant for all assays except total T (r = -.126). The best correlation was found with BT (r = -.744, P <.001). All measures were statistically significantly correlated with FT. The best correlations were FTI (r =.807, P <.007) and BT (r =.670, P <.001). If T was used to classify hypogonadism in comparison to BT, it resulted in misclassification in 42% of cases. In addition, we demonstrated a marked week-to-week variability in T and BT in older men with the T and BT being in the eugonadal range some weeks and hypogonadal on other occasions. This occurred in 8 of 16 men for T and 10 of 16 men for BT. Based on these data, we suggest that the FTI or BT are the most practical methods to determine hypogonadism. There is a need for increased awareness that marked week-to-week variability within a single individual can occur for measurements of both T and BT.

Adult↗

PubMed2001

The growth hormone (GH)-insulin-like growth factor axis during testosterone replacement therapy in GH-treated hypopituitary males.

Several studies suggest a direct effect of sex steroids on insulin-like growth factor-I (IGF-I) production. Oestrogen has been hypothesized directly to inhibit hepatic IGF-I production, but the role of androgens is not clarified. We aimed to investigate whether testosterone exerts a pituitary-independent effect on IGF-I and related parameters. Eight adult hypopituitary men (39.9 +/- 5.7 years) receiving growth hormone (GH) and testosterone replacement therapy (250 mg testosterone enantate every fourth week) participated in this prospective study. Frequent blood samples were drawn over a 5 week period in relation to two testosterone injections. Mean baseline IGF-I levels were 352 +/- 135 microg/L, and they remained unaltered during the study period (analysis of variance (ANOVA), P = 0.88). Free IGF-I levels did not change either (ANOVA, P = 0.35). Serum IGF binding protein-3 (IGFBP-3) and acid-labile subunit decreased (ANOVA, P = 0.04 and P = 0.02 respectively) but post hoc analysis did not reveal a particular difference between days. IGFBP-1 increased following testosterone administration (ANOVA, P = 0.05), whereas GH binding protein levels tended to decrease following testosterone administration (ANOVA, P = 0.08). Prostate-specific antigen tended slightly to increase after each testosterone injection (ANOVA, P = 0.08, post hoc, NS). We conclude that major changes in total IGF-I are not induced during conventional intramuscular testosterone replacement in GH-treated hypopituitary males, suggesting that testosterone effects on IGF-I are likely to be secondary to a stimulation of endogenous GH release.

Adult↗

PubMed2001

Effects of testosterone either alone or with IGF-I on growth of cells derived from the proliferation zone of regenerating antlers in vitro.

Deer antlers are male secondary sexual characters and are the fastest growing mammalian tissue. As such, both androgens and growth factors play a major role in antler development. The timing of the antler cycle is controlled by the seasonal fluctuations of testosterone, and the actual growth of antlers is mainly stimulated by growth factors including insulin-like growth factor-1 (IGF-I). However, whether or not testosterone at low levels plays a growth-promoting role during antler formation is controversial. In the present study, we took an in vitro approach to investigate whether testosterone either alone or with IGF-I had mitogenic effects on mesenchymal or cartilaginous cells derived from the proliferation zone of regenerating antlers. In addition, a binding assay was carried out to determine whether the specific binding sites for testosterone were preserved after cell disaggregation. The results showed that testosterone either in physiological concentrations or at low levels did not exert direct mitogenic effects on antler cells derived from the proliferation zone in serum-free medium in vitro (P>0.05), even if the specific binding sites for testosterone in these cells were well preserved. Likewise, testosterone in a very wide range of concentrations not only failed to enhance (P>0.05), but at certain levels (0.1-5 nM) impaired the mitogenic effects of IGF-I on these antler cells in vitro (P<0.001). Therefore, these results support neither a conclusion that low level testosterone has growth-promoting effects on antler formation nor the hypothesis that testosterone effects may be achieved through sensitizing these antler cells to the mitogenic effects of IGF-I.

Animals↗

PubMed1988

Gonadotrophin- and androgen precursor-stimulated testosterone secretion by interstitial cells from Mongolian gerbil testes: influence of plasma proteins and elevated temperature.

Interstitial cells isolated from Mongolian gerbil testes have been used to investigate the effects of plasma proteins and incubation temperature on HCG- and androgen precursor-stimulated testosterone secretion. Short term (15 min) incubation of interstitial cells with various precursors resulted in a significant increase of testosterone release. On the other hand, no stimulatory effect of HCG (10 mIU) could be observed. Precursor (e.g. progesterone)-stimulated testosterone secretion linearly increased with cell concentrations (0.5 x 10(5) to 4.0 x 10(5) cells/0.7 ml medium, r = less than 0.99, p less than 0.001). In the presence of 50% horse plasma, progesterone-stimulated testosterone secretion was even more pronounced. Similarly, also gerbil, rat, calf or human plasma significantly increased progesterone-stimulated testosterone output. Interestingly, this effect was markedly reduced in the presence of cortisol. While incubation of interstitial cells for 15 min at either 40 degrees C or 42 degrees C had no significant effect on androgen precursor- or HCG-stimulated testosterone secretion, incubation of cells at 44 degrees C resulted in a drastic reduction of HCG-stimulated testosterone release, without affecting progesterone- or DHEA-stimulated testosterone secretion. Taken the simplicity to make interstitial cells unresponsive to HCG into account, heat-treated cells might prove to be a versatile tool to distinguish between HCG- and protein-/androgen precursor-stimulated testosterone secretion in vitro.

Androgens↗

PubMed1998

Effects of endurance exercise on free testosterone concentration and the binding affinity of sex hormone binding globulin (SHBG).

Our purpose was to examine the changes in free testosterone concentration following moderately prolonged endurance exercise to determine whether such changes were due to alterations in the binding affinity of sex hormone binding globulin (SHBG). Ten trained men completed control (45 min rest) and exercise (45 min @ 70% VO2max) experimental sessions. Blood samples were collected before (pre-) and immediately after (post-) each of the sessions and analyzed for total testosterone, free testosterone, LH, FSH, cortisol, estradiol, SHBG, epinephrine and norepinephrine. The association constant (Ka) of SHBG for testosterone was assessed to evaluate binding affinity. No significant difference was seen between the pre-control and the pre-exercise session values for any of the measures. However, within the exercise session significant (p<0.01) increases in post samples were evident for total testosterone (+32.0%), free-testosterone (+39.6%), cortisol (+38.0%), norepinephrine (+365.2%) and epinephrine (+225.8%). All other hormonal changes and the responses for Ka were non-significant. The results of the correlation analysis indicated that only norepinephrine was significantly (p<0.05) related to the changes observed in free testosterone (r = +0.92). We conclude that the free testosterone increase with moderately, prolonged endurance exercise was not associated with the change in the binding affinity of SHBG. Furthermore, the data suggest that the exercise induced increase in testosterone involves increased production which may be mediated by sympathetic stimulation of the testicles.

Adult↗

PubMed1996

Plasma and urinary markers of oral testosterone misuse by healthy men in presence of masking epitestosterone administration.

There is a potential need for the official criterion of testosterone abuse in sport (the urinary concentration ratio of testosterone glucuronide/epitestosterone glucuronide, TG/EG > 6) to be backed-up by some complementary markers, more particularly in cases of physiologically high TG/EG and when there is suspicion of joint administration of testosterone and epitestosterone. Testosterone, epitestosterone, their glucuro- and sulfoconjugates, 5-androstene-3 beta, 17 alpha-diol glucuronide and 17-hydroxyprogesterone have been analysed by isotope dilution-gas chromatography-mass spectrometry in plasma and urine of seven subjects supplemented with a single oral dose of undecanoates of testosterone and epitestosterone (respectively 40 mg and 1.5 mg). Adequate plasma criteria for testosterone abuse were the ratios of testosterone glucuronide/17-hydroxyprogesterone and testosterone glucuronide/testosterone which increased significantly above basal values for up to 10 h. The same trend was observed for the ratio of urinary glucuronides of testosterone/5-androstene-3 beta, 17 alpha-diol, while TG/EG was not affected by simultaneous administration of epitestosterone. One subject with low basal TG/EG failed to respond to testosterone administration by any significant increase of analysed parameters.

Adult↗

PubMed2001

Müllerian Inhibiting Substance lowers testosterone in luteinizing hormone-stimulated rodents.

Müllerian Inhibiting Substance (MIS) expression is inversely proportional to the serum concentration of testosterone in males after birth and in vitro studies have shown that MIS can lower testosterone production by Leydig cells. Also, mice overexpressing MIS exhibited Leydig cell hypoplasia and lower levels of serum testosterone, but it is not clear whether this is a result of MIS affecting the development of Leydig cells or their capacity to produce testosterone. To examine the hypothesis that MIS treatment will result in decreased testosterone production by mature Leydig cells in vivo, we treated luteinizing hormone (LH)-stimulated adult male rats and mice with MIS and demonstrated that it can lead to a several-fold reduction in testosterone in serum and in testicular extracts. There was also a slight decrease in 17-OH-progesterone compared to the more significant decrease in testosterone, suggesting that MIS might be regulating the lyase activity of cytochrome P450c17 hydroxylase/lyase (Cyp17), but not its hydroxylase activity. Northern analysis showed that, in both MIS-treated rats and mice, the mRNA for Cyp17, which catalyzes the committed step in androgen synthesis, was down-regulated. In rats, the mRNA for cytochrome P450 side-chain cleavage (P450scc) was also down-regulated by MIS. This was not observed in mice, indicating that there might be species-specific regulation by MIS of the enzymes involved in the testosterone biosynthetic pathway. Our results show that MIS can be used in vivo to lower testosterone production by mature rodent Leydig cells and suggest that MIS-mediated down-regulation of the expression of Cyp17, and perhaps P450scc, contributes to that effect.

17-alpha-Hydroxyprogesterone↗

PubMed1996

Localization of 17beta-hydroxysteroid dehydrogenase and characterization of testosterone in the brain of the male frog.

Several enzymes involved in the formation of steroids of the pregnene and pregnane series have been identified in the brain, but the biosynthesis of testosterone has never been reported in the central nervous system. In the present study, we have investigated the distribution and bioactivity of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) (EC 1.1.1.62; a key enzyme that is required for the formation of testosterone and estradiol) in the brain of the male frog Rana ridibunda. By using an antiserum against human type I placental 17beta-HSD, immunoreactivity was localized in a discrete group of ependymal glial cells bordering the telencephalic ventricles. HPLC analysis of telencephalon and hypothalamus extracts combined with testosterone radioimmunoassay revealed the existence of two peaks coeluting with testosterone and 5alpha-dihydrotestosterone. After HPLC purification, testosterone was identified by gas chromatography/mass spectrometry. Incubation of telencephalon slices with [3H]pregnenolone resulted in the formation of metabolites which coeluted with progesterone, 17alpha-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone, and 5alpha-dihydrotestosterone. The newly synthesized steroid comigrating with testosterone was selectively immunodetected by using testosterone antibodies. These data indicate that 17beta-HSD is expressed in a subpopulation of gliocytes in the frog telencephalon and that telencephalic cells are capable of synthesizing various androgens, including dehydroepiandrosterone, androstenedione, testosterone, and 5alpha-dihydrotestosterone.

17-Hydroxysteroid Dehydrogenases↗

PubMed1996

24R,25-(OH)2 vitamin D3 inhibits 1alpha,25-(OH)2 vitamin D3 and testosterone potentiation of calcium channels in osteosarcoma cells.

Calcium influx via L-type calcium channels in osteoblast cells causes a rapid (in seconds) elevation in intracellular calcium initiated by plasma membrane receptors for 1alpha, 25-dihydroxyvitamin D3 (1alpha,25-D3). 24R,25-Dihydroxyvitamin D3 (24,25-D3) alone, in concentrations up to 200 nM, does not cause potentiation of calcium currents in osteoblasts, but it does inhibit the current potentiation by 1alpha,25-D3. To determine how various steroids interact in their potentiation of calcium channels, the action of vitamin D3 analogues and testosterone with calcium channels in the rat osteoblast-like cell line ROS 17/2.8 was investigated. Bath additions of both 1alpha,25-D3 and testosterone at doses below K1/2 (the dose causing 50% left shift in the current-voltage relationship) are additive in their ability to potentiate calcium channels. When 1alpha,25-D3 and testosterone are added together at concentrations that would cause a maximal shift in the current-voltage relationship by each agent alone (Vmax), the effect of these steroids is not additive. Taken together these data suggest one population of calcium channels is activated by 1alpha, 25-D3 or testosterone. The shift in the current-voltage relationship caused by 1alpha,25-D3 is reduced by 1beta,25-dihydroxyvitamin D3 (1beta,25-D3), an agent which is thought to act specifically on the plasma membrane receptor for 1alpha,25-D3, but the potentiation caused by testosterone is not blocked by 1beta,25-D3. However, 24, 25-D3 inhibits the left shift in the peak current-voltage relationship mediated by either 1alpha,25-D3 and testosterone. This result implies that 1) 1beta,25-D3 directly displaces 1alpha,25-D3 but not testosterone from its plasma membrane receptor, and 2) the rapid (in seconds) stimulatory effects of 1alpha,25-D3 and testosterone on calcium channels are mediated by separate plasma membrane receptors for testosterone and 1alpha,25-D3, which are blocked by another receptor for 24,25-D3. The interaction of these three receptors with L-type calcium channels is pertussis toxin-sensitive.

24,25-Dihydroxyvitamin D 3↗

PubMedDate not supplied

Reproductive maturation, somatic growth and testosterone among Zimbabwe boys.

BACKGROUND: Little is known about the role of energetic status in the timing of puberty among males across populations. AIM: To determine the relationship of testosterone production and bioavailability to energetic status and somatic growth in a sub-Saharan population. SUBJECTS AND METHODS: Anthropometric measures, secondary sexual characteristics, blood spot and salivary samples were obtained from 441 Zimbabwe school boys, aged 12-18, from four high schools in the Harare area. RESULTS: Salivary and blood testosterone both showed their first significant increase between 14 and 15 years of age. Both salivary and blood testosterone were positively related to subscapular, but not triceps skinfold, when controlled for Tanner genital stage and age. Controlled for Tanner genital stage and age, salivary, but not blood testosterone was related to suprailiac skinfolds. Blood testosterone, but not salivary testosterone, showed a significant relationship with Tanner genital stage, controlled for age and suprailic skinfolds. Blood and salivary testosterone showed similar relationships with height and arm muscle plus bone area. CONCLUSION: These results provide support for the hypothesis that energetic status, especially abdominal fat plays a role in bioavailable testosterone during male puberty. However, they fail to demonstrate a clear effect of bioavailable testosterone on somatic growth.

Adolescent↗