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PubMed1976

Effect of testosterone administration on the epiphyseal cartilage of hypophysectomized rats.

For the study of the mechanism of action of testosterone histological, carbohydrate-, and enzyme histochemical investigations were carried out on the epiphyseal cartilage of (1) hypophysectomized rats treated with testosterone [(THX group); (2)] hypophysectomized rats without hormonal treatment (HX group), and (3) intact, untreated control rats. The results were compared with the data obtained in a previous experiment in which intact rats were treated with testosterone (T group). The experiments showed that testosterone exerts a peripheral direct effect on the enzyme system of the epiphyseal cartilage cells by changing their metabolism in the direction of early ageing. This effect elicits characteristic changes in enzyme activity of the cartilage cells if normal hypophyseal activity is present. Impairment and ossification of the epiphyseal cartilage ensue also in hypophysectomized animals treated with testosterone (THX), even faster than in animals subjected only to hypophysectomy (HX), but this process has lost its characteristic feature: the initial increase of enzyme activity in the cartilage cells. Thus, the presence or absence of the hypophysis only modifies the effect of testosterone. Presumably, the latter effect - though not asserting itself through the hypophysis - is highly dependent on hypophyseal activity, that is, on the presence of the hormones produced or mediated by the hypophysis. If testosterone does influence the secretion of these hormones and the activity of the hypothalamus, a central effect of testosterone seems also to be involved in the changes of the epiphyseal cartilage disc.

Alkaline Phosphatase↗

PubMed2000

Effect of testosterone on the number of NADPH diaphorase-stained nerve fibers in the rat corpus cavernosum and dorsal nerve.

OBJECTIVES: To elucidate the effect of testosterone on penile nerve supply. METHODS: Three groups of 10 rats each were assessed; two groups were castrated and the third underwent a sham operation (control). After castration, one group received subcutaneous injection of testosterone while the others received sesame oil. At 8 weeks, the rats underwent a functional analysis. The evaluation included a subcutaneous injection with apomorphine to study centrally mediated erection, and cavernous nerve electrostimulation and papaverine injection to study peripherally mediated erection. At death, a penile midshaft specimen was taken for nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining. RESULTS: In the apomorphine study, castrated rats had no erections, but the erectile function of those receiving testosterone was restored to the level of the controls. The mean numbers of NADPH-diaphorase-stained nerve fibers in the copora cavernosa and both dorsal nerves of castrated rats, at 165.8 +/- 20.0 and 271.3 +/- 21.1, respectively, were significantly lower than those of the controls, at 271.7 +/- 14.6 and 471.2 +/- 27.6, respectively. Those of the testosterone replacement group, at 290.7 +/- 10.1 and 500.7 +/- 23.9, respectively, recovered to the control level. The intracavernosal pressure decreased significantly in the absence of testosterone, both after electrostimulation and intracavernosal papaverine injection, and recovered to the control level after testosterone replacement. CONCLUSIONS: Our results indicate that testosterone acts on the nervous system to mediate erection. When it is absent, there may be downregulation of both the production and activity of nitric oxide (NO), thereby decreasing the response to peripheral stimulation via the NO pathway. Testosterone replacement may upregulate NO activity to the control level.

Animals↗

PubMed1999

Effects of testosterone on the synaptology of the medial preoptic nucleus of male Japanese quail.

The medial preoptic nucleus (POM) of male Japanese quail is a sexually dimorphic testosterone-dependent structure that plays a key role in the activation of male sexual behavior. Both the total volume of the nucleus and the size of the dorsolateral neurons are decreased in gonadectomized males. Immunocytochemical studies have revealed a complex pattern of innervation: immunopositive fibers for several neuropeptides and neurotransmitters have been detected in the POM; some of them (e.g. vasotocin-immunoreactive fibers) are sexually dimorphic and testosterone-dependent To understand the anatomical bases of these testosterone-dependent neurochemical changes, we performed an ultrastructural study of the POM neuropil in intact sexually mature, gonadectomized, or testosterone-treated gonadectomized males. A complex synaptic organization of the POM neuropil was observed in intact male quail reflecting the heterogeneity of the neurotransmitters and neuropeptides present in this nucleus. Changes in this organization were observed after the endocrine manipulations. The number of axosomatic synapses per cell body decreased after gonadectomy and was restored to the level observed in the intact group after the administration of testosterone. By contrast, no significant change was observed in the density of axodendritic and axospinal synapses after hormonal manipulations which suggests that the total number of synapses in the nucleus should be affected by testosterone (constant density in a changing total volume). The cross-sectional area of synaptic boutons was also decreased by castration and restored to intact level by testosterone. The action of testosterone on the activation of male copulatory behavior in gonadectomized birds is hence paralleled by an extensive rearrangement of neuropil in the POM.

Analysis of Variance↗

PubMed1999

Determination of testosterone and 6beta-hydroxytestosterone by gas chromatography-selected ion monitoring-mass spectrometry for the characterization of cytochrome p450 3A activity.

A method for the determination of testosterone and its metabolite, 6beta-hydroxytestosterone, in liver microsomal incubates employing gas chromatography with selected ion monitoring mass spectrometric detection (GC-SIM-MS) has been developed. The method is more rapid than previously reported methods. Testosterone and its metabolites are extracted from the incubation mixture in a single step with methylene chloride. The method does not require derivatization and testosterone and its metabolites are separated on a HP-5MS fused-silica capillary column in less than 15 min. The retention times of testosterone (m/z 288), methyltestosterone (m/z 302), and 6beta-hydroxytestosterone (m/z 304) are approximately 12.7, 12.8, and 13.4 min, respectively. There are no interferences from other known CYP450 metabolites of testosterone. In addition, the selectivity and specificity of the mass spectrometer helps eliminate possible interferences from drugs and new chemical entities evaluated using this methodology. Calibration curves for testosterone and 6beta-hydroxytestosterone are linear from 0.25 to 100 microM. Extraction recoveries are better than 92% for both analytes and the internal standard, methyltestosterone. Over the course of five separate runs, within-day and inter-day precision (expressed as relative standard deviation) was less than 5% for all concentrations of testosterone and 6beta-hydroxytestosterone. Accuracies ranged from 95.8 to 105.8% for testosterone and 94.6 to 104.2% for 6beta-hydroxytestosterone. The assay has been used to characterize the CYP3A metabolic activity of multiple preparations of human, rat, and dog liver microsomes.

Animals↗

PubMed2004

The associations of endogenous testosterone and sex hormone-binding globulin with glycosylated hemoglobin levels, in community dwelling men. The Tromsø Study.

OBJECTIVES: Low levels of endogenous testosterone have been associated with increased risk of cardiovascular disease and atherosclerosis in men. Long-term hyperglycemia, as measured by glycosylated hemoglobin (HbA1c), is related to cardiovascular mortality, and HbA1c across its normal range is also positively related to coronary heart and cardiovascular disease mortality in men. We therefore undertook an analysis of the cross-sectional associations of total testosterone and SHBG levels with HbA1c levels, in a general population of 1419 men aged 25-84. METHODS: Total testosterone, sex hormone-binding globulin (SHBG) and HbA1c were measured by immuno-assay. Partial correlation and multiple regression analyses were used to estimate the associations between total testosterone and SHBG with HbA1c. Analyses of variance and covariance were used to compare men with or without diabetes. RESULTS: In age-adjusted partial correlation HbA1c was inversely associated with total testosterone (p<0.01) and SHBG (p<0.001). HbA1c was positively associated with body mass index (BMI) and waist circumference (WC) (p<0.001). In multiple regression analyses total testosterone, SHBG, age, number of cigarettes smoked, BMI and WC were independently associated with HbA1c levels. Men with a history of diabetes had lower levels of total testosterone in age-adjusted analyses (p<0.05) and lower levels of SHBG in both age- and WC-adjusted analyses (p<0.001 and p<0.01, respectively). CONCLUSION: Lower levels of total testosterone and SHBG were associated with increased HbA1c levels and diabetes independent of concomitant variations in obesity and body fat distribution.

Adult↗

PubMed2004

Waist circumference and testosterone levels in community dwelling men. The Tromsø study.

To examine the relationship of total and free testosterone and sex hormone-binding globulin (SHBG) with central obesity in men, we studied 1548 men aged 25-84 years that took part in the 1994--1995 survey of the Tromsø study. Total testosterone and SHBG were measured by immuno-assay and the free testosterone fraction was calculated. These measurements were analyzed in relation to anthropometric data and lifestyle factors. The age-adjusted correlation between waist circumference (WC) and total testosterone was -0.34 (p < 0.001), between WC and free testosterone -0.09 (p < 0.001) and, between WC and SHBG -0.44 (p < 0.001). Adjusting for BMI and lifestyle factors weakened, but did not eliminate these associations. All hormone and SHBG associations were stronger for WC than for waist-hip ratio or BMI. In age- and BMI-adjusted analyses men with a WC > or = 102 cm had significantly lower levels of total testosterone and SHBG compared to men with an optimal WC, defined as < 94 cm (12.3 vs. 13.9 nmol/l; p < 0.01 and 48.5 vs. 55.1 nmol/l; p < 0.001, respectively). The lowest levels of total and free testosterone were observed in men with relatively high WC despite relatively low overall obesity (BMI), suggesting that WC should be the preferred anthropometric measurement in predicting endogenous testosterone levels.

Adult↗

PubMed2003

Gender moderates the relationship between testosterone and marital interaction.

Higher testosterone levels are related to assertiveness and dominance. Given the relevance of those behavioral correlates to spouses' daily transactions, links between testosterone levels and marital interaction were explored among 92 newlywed couples. Marital problem-solving and social support transactions were assessed, and saliva was collected and assayed for testosterone. Whether marital behavior was related to husbands' and wives' testosterone levels was examined. The link between spouses' testosterone and their behavior was contingent on the partner's testosterone levels. Husbands exhibited more adaptive problem-solving behaviors and social support provision when husbands and wives were concordant for lower testosterone levels. In contrast, wives exhibited more adaptive support provision when spouses had discordant testosterone levels such that wives had higher levels and husbands had lower levels.

Adult↗

PubMed2006

Testosterone replacement therapy for late-onset hypogonadism.

Cross-sectional and longitudinal studies have shown that testosterone levels fall with increasing age. Low testosterone levels are reported in 20% of men aged 60-69 years, and 30% of men in this age-group are thought to have low free testosterone levels. The prevalence of low testosterone levels increases in older men and, therefore, as the average age of men in developed countries is increasing, there will be even more hypogonadal men in the future. Many of the symptoms and signs associated with testosterone deficiency in younger men are present in aging men. Several small studies suggest that testosterone replacement therapy (TRT) can be beneficial for some aging men, but men in these studies have not been uniformly testosterone-deficient, and responses have been inconsistent. TRT might be more beneficial and safer in men aged below 65 years than in men aged 65 years or older. There is a need for large clinical trials in both age-groups to provide more definitive information for patients and clinicians as to the safety and efficacy of TRT. Before such data are available, clinicians must be cautious in offering these treatments to aging men. Close monitoring of patients undergoing testosterone supplementation is essential.

Age Factors↗

PubMed2006

Drug insight: testosterone preparations.

Testosterone has been used for substitution therapy in testicular and hypothalamopituitary diseases for almost six decades, with injectable testosterone esters and implanted testosterone pellets being the mainstay of treatment. Growing interest in the possible use of testosterone in nonclassical situations such as male contraception, aging (late-onset hypogonadism), muscle-wasting conditions like HIV, erectile dysfunction, and female hypoactive sexual disorder has stimulated research, leading to the development of several new modes of administration of testosterone. Transdermal patches, gels, mucoadhesive sustained-release buccal tablets and long-acting testosterone esters are designed to provide testosterone levels that approximate normal physiologic levels, to improve patient acceptability, and to further increase the number of treatment options available. In this Review, we briefly describe the chemistry, mechanism of action, and metabolism of testosterone. We then discuss the pharmacokinetics, advantages, and disadvantages of various formulations and summarize the various preparations currently available.

Chemistry, Pharmaceutical↗

PubMed2002

Redefining gonadotropin-releasing hormone (GnRH) cell groups in the male Syrian hamster: testosterone regulates GnRH mRNA in the tenia tecta.

Gonadotropin-releasing hormone (GnRH) regulates the production of testosterone via the hypothalamic-pituitary-gonadal axis and testosterone, in turn, regulates the GnRH system via negative feedback. We compared testosterone regulation of GnRH mRNA expression in four anatomically defined GnRH cell groups in juvenile and adult male Syrian hamsters, including a rostral population of GnRH cells in the tenia tecta. In situ hybridization histochemistry (ISHH) was used to measure GnRH mRNA in brains from castrated juveniles and adults treated with 0 mg or 2.5 mg testosterone pellets for one week. ISHH was performed on coronal sections using a 35S-cRNA probe generated from Syrian hamster GnRH cDNA. Testosterone treatment resulted in a significant reduction in mean area of GnRH neurones covered by silver grains within the tenia tecta, but only a trend toward decreased GnRH mRNA in the diagonal band of Broca/organum vasculosum of the lamina terminalis (DBB/OVLT), medial septum (MS), and caudal preoptic area (cPOA). The effects of testosterone were independent of age. Frequency distribution analyses unveiled a significant reduction in the number of heavily labelled cells following testosterone treatment within the tenia tecta and MS. Simple regression analyses revealed a significant positive correlation between plasma luteinizing hormone concentrations and GnRH mRNA only in the tenia tecta. These data indicate that, overall, GnRH mRNA is modestly reduced by testosterone, and the most robust attenuation of GnRH mRNA occurs within the tenia tecta. This is the first report to link mechanisms of steroid negative feedback with tenia tecta GnRH neurones, providing a new focus for investigating brain region-specific steroidal regulation of GnRH synthesis.

Animals↗

PubMed2004

Serial follow-up study of serum testosterone and antisperm antibodies in patients with non-obstructive azoospermia after conventional or microdissection testicular sperm extraction.

Testicular sperm extraction (TESE) combined with intracytoplasmic sperm injection is becoming a first-line treatment even for non-obstructive azoospermia. The current focus of TESE is the identification of seminiferous tubules that contain spermatozoa and minimization of testicular damage. Although microdissection TESE has been introduced as a preferred procedure for sperm retrieval, no serial follow-up studies of testicular damage have been reported. In the present study, we assayed serum testosterone concentrations and for the presence of antisperm antibodies (ASA) for 1 year after conventional multiple TESE or microdissection TESE and compared postoperative testicular damage between procedures. Thirteen patients who underwent conventional multiple TESE and 12 patients who underwent microdissection TESE were included in this study. Serum total and free testosterone concentrations were evaluated before operation and 1, 6 and 12 months after TESE. Serum ASA was also evaluated before and 12 months after TESE. Serum total and free testosterone concentrations in all patients in both groups showed no significant postoperative decrease. A comparison between the two groups of serum total and free testosterone concentrations showed no significant difference (total testosterone, p = 0.2477; free testosterone, p = 0.3098). No incidence of new ASA formation was identified in the present study. In conclusion, TESE procedures cause neither a decrease of serum testosterone nor formation of ASA. Serum testosterone concentration are similar between patients in the conventional multiple TESE and microdissection groups. Therefore, microdissection TESE is safe with respect to testicular damage, particularly for patients with hypogonadism.

Adult↗

PubMed1997

Correlation of clinical, endocrine and molecular abnormalities with in vivo responses to high-dose testosterone in patients with partial androgen insensitivity syndrome.

OBJECTIVE: To investigate the responses of two patients previously diagnosed as Reifenstein's syndrome to graded high-dose testosterone in terms of hormone levels, nitrogen balance and sebum secretion and to attempt to correlate these parameters with the properties of their androgen receptors and mutations in the androgen receptor gene. DESIGN: Nitrogen balance was determined by comparing controlled nitrogen intake to the amount excreted. Sebum excretion was measured on the forehead. Patients were studied during control periods (no treatment) and during administration of testosterone propionate. Blood samples were used as a source of genomic DNA and to measure peripheral hormone levels; androgen receptor binding was determined using genital skin fibroblasts. PATIENTS: Two patients of XY karyotype, with ambiguous external genitalia and problems of testicular descent who had required mastectomy as teenagers. Normal male controls of proven fertility. MEASUREMENTS: Nitrogen balance, sebum excretion rate and peripheral hormone levels (testosterone, dihydrotestosterone, LH and FSH) were studied before and after testosterone therapy (1 or 5 mg/kg/day). Genomic DNA was extracted from peripheral blood leucocytes and regions of the androgen receptor gene amplified by polymerase chain reaction using pairs of specific primers. Mobility of amplified DNA from patients was analysed on denaturing gradient acrylamide gels and fragments differing in mobility from those of normal controls were sequenced. Fibroblasts were cultured from scrotal skin biopsies and androgen receptor binding parameters, subcellular localization and up-regulation were determined. RESULTS: Testosterone therapy resulted in raised plasma testosterone, dihydrotestosterone and oestradiol in both patients. In patient 1 (lesser genital abnormality), LH was suppressed by 5 mg/kg/day testosterone to the upper limit of the normal range but FSH remained low normal. Both LH and FSH were suppressed by testosterone treatment in patient 2 (greater genital abnormality). Nitrogen retention was increased in both patients (4.2 and 3.0 g/24 h respectively); sebum excretion rate increased to normal in patient 1 but showed no change in patient 2. Mutations in the androgen receptor gene were identified in both patients. In patient 1 a single nucleotide change from adenosine to guanosine resulted in the substitution of glycine for glutamic acid at position 772 within the hormone binding domain of the receptor. In patient 2 a single nucleotide mutation from guanosine to adenosine resulted in the substitution of lysine for arginine at position 608 (exon 3) situated in the second zinc finger of the DNA binding domain. Both patients had a normal number of androgen binding sites in genital skin fibroblasts but those in patient 1 showed reduced binding affinity and rapid dissociation of receptor/ligand complexes while those in patient 2 showed defective nuclear localization. CONCLUSION: In patients with partial androgen insensitivity syndrome the type of androgen receptor mutation and responses to short-term androgen treatment can be correlated with the individual's potential to virilize. If there is a mutation in the androgen receptor DNA binding domain the patient may show little ability to virilize either spontaneously at puberty or after androgen treatment. Sebum excretion appears to be more discriminating than nitrogen balance or gonadotrophin suppression as an index of tissue response to androgens.

Adult↗

PubMed1997

Effect of low dose oxandrolone and testosterone treatment on the pituitary-testicular and GH axes in boys with constitutional delay of growth and puberty.

OBJECTIVE: To investigate the effect of low dose oxandrolone and testosterone on the pituitary-testicular and GH-IGF-I axes. DESIGN: Prospective double-blind placebo-controlled trial. PATIENTS: Sixteen boys with constitutional delay of growth and puberty (CDGP) with testicular volumes 4-6 ml were randomized to 3 months treatment: Group 1 (n = 5), daily placebo: Group 2 (n = 5), 2.5 mg oxandrolone daily or Group 3 (n = 6), 50 mg testosterone monthly intramuscular injections with assessment (growth, pubertal development and overnight hormone profiles) at 0, 3, 6 and 12 months. MAIN OUTCOME MEASURES: LH and GH profiles (15-minute samples) were analysed by peak detection (Pulsar), Fourier transformation and autocorrelation. Testosterone levels were measured hourly and insulin, SHBG, IGF-I, and IGFBP-3 levels at 0800 h. Statistical analysis was by multivariate analysis of variance for repeated measures. RESULTS: LH and testosterone parameters increased significantly with time in all 16 (LH AUC, P < 0.001; peak amplitude, P = 0.02; number of peaks, P = 0.02; testosterone AUC, P = 0.02; morning testosterone, P = 0.002). In Group 2, however, LH and testosterone parameters decreased at 3 months followed by a rebound increase at 6 and 12 months. SHBG levels were markedly reduced at 3 months (P = 0.006) and a wider range of dominant GH frequencies was present although GH AUC was not increased until 6 months, with an increase in GH pulse frequency but not amplitude. IGF-I levels were increased at both 3 and 12 months. In Group 3, pituitary-testicular suppression was not apparent, but GH levels increased with an increase in GH amplitude at 3 and 12 months. CONCLUSION: Oxandrolone transiently suppressed the pituitary-testicular axis and altered GH pulsatility. Testosterone increased GH via amplitude modulation.

Adolescent↗

PubMed2000

Intramuscular testosterone undecanoate with or without oral levonorgestrel: a randomized placebo-controlled feasibility study for male contraception.

OBJECTIVE: Approaches to hormonal male contraception are based on injectable testosterone esters alone or in combination with gestagens or GnRH analogs but the short half-life of clinically used testosterone esters have long hindered further development. This study was designed to prove the efficacy of the long-acting testosterone undecanoate ester (TU) alone or in combination with oral levonorgestrel (LNG) in a phase II clinical trial. DESIGN AND SUBJECTS: Twenty-eight healthy men were randomized to receive injections of 1000 mg TU every 6 weeks in combination with daily oral LNG (250 microg) or daily oral placebo treatment over a period of 24 weeks, followed by a control period of 28 weeks. MEASUREMENTS: During the course of the study semen analysis, reproductive hormone analysis, analysis of clinical chemistry and lipid parameters, well-being and sexual function, sonography of scrotal contents and prostate were performed. RESULTS: Marked suppression of gonadotrophins in both treatment groups resulted in azoospermia in 8/14 and 7/14 volunteers and severe oligozoospermia (< 3 x 1012/l) in 4/14 and 7/14 in the placebo and gestagen treated groups, respectively. Time to induction of azoospermia (mean +/- SEM) was not significantly different between the placebo (week 19.5 +/- 2.2) and LNG groups (week 15.4 +/- 2.2). During the whole treatment period mean testosterone serum concentrations remained within normal limits. Although not significant, it was evident that volunteers who became azoospermic had a better suppression of gonadotrophins and lower SHBG levels during treatment compared to non-azoospermic volunteers. Despite better gonadotrophin suppression in the LNG group no significant differences compared to placebo could be observed in the extent and kinetics of suppression of spermatogenesis, thus not demonstrating a major beneficial effect of LNG in the combination with injectable TU. Treatment led in both groups to a decrease of HDL and Lp(a) which was more pronounced in the LNG group (P > 0.05). CONCLUSION: Treatment with 1000 mg testosterone undecanoate injected at 6 weekly intervals or in combination with levonorgestrel showed suppression of spermatogenesis comparable to weekly injections of 200 mg testosterone enanthate. Because of its long half-life and in the absence of severe side-effects, testosterone undecanoate can be considered as first choice testosterone ester in further studies of hormonal male contraception.

Adolescent↗

PubMed2003

Bone mineral density outcomes following long-term treatment with subcutaneous testosterone pellet implants in male hypogonadism.

BACKGROUND: Osteoporosis is a common complication of untreated male hypogonadism. Even mild hypogonadism due to suboptimal testosterone replacement may result in decreased bone mineralization and osteoporosis. OBJECTIVE: To assess bone mineral density in hypogonadal men following long-term long-acting subcutaneous testosterone pellet implants as replacement therapy. PATIENTS: A cross-sectional study of 37 patients with primary or secondary hypogonadism receiving long-term (mean 6.6 years) subcutaneous testosterone pellet implants as replacement therapy. MEASUREMENTS: Bone mineral density was measured in all patients using dual energy X-ray absorptiometry. Serum testosterone 3-4 months after insertion of pellets was measured in all patients to assess adequacy of replacement therapy. RESULTS: Mean areal bone mineral density were 1.02 (SD 0.14) g/cm2 with a mean Z score of -0.64 (SD 1.3) and 0.87 (SD 0.13) g/cm2 with a mean Z score of -0.72 (SD 1.2) at lumbar spine and neck of femur, respectively. Mean serum testosterone 3-4 months after pellets insertion was 15.45 nmol/l (SD 4.2 nmol/l). There was no significant correlation between bone mineral density and patient's age at start or duration of testosterone therapy. CONCLUSIONS: Bone mineral density in long-term regularly treated hypogonadal men was not different from the age-matched reference range for normal men. Long-acting subcutaneous testosterone pellet implants as replacement therapy in male hypogonadism are safe, acceptable to the patient, result in adequate bone mass accumulation and maintenance of normal bone mineral density. By provision of sustained physiological levels of testosterone they may contribute to increased androgen effect at the receptor level.

Adult↗

PubMed2003

Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men.

BACKGROUND: Conflicting views are reported on the association between advancing age and gradually diminishing concentrations of serum total testosterone in men. The putative loss of diurnal rhythm in serum total testosterone in older men is reported to be in part due to low concentrations in the morning when compared to concentrations found in young men. We have measured total, free and bioavailable testosterone along with SHBG in samples taken every 30 min throughout a 24-h period in 10 young and eight middle-aged men. RESULTS: Both young and middle-aged men displayed a significant diurnal rhythm in all variables, with a minimum fall of 43% in total testosterone from peak to nadir in all subjects. Subjecting the data to a time series analysis by least squares estimation revealed no significant difference in mesor (P = 0.306), amplitude (P = 0.061) or acrophase (P = 0.972) for total testosterone between the two groups. Comparing bioavailable testosterone in the two groups revealed no significant difference in mesor (P = 0.175) or acrophase (P = 0.978) but a significant difference (P = 0.031) in amplitude. Both groups display a significant circadian rhythm (middle-aged group P < 0.001; young group P = 0.014). Free testosterone revealed a highly significant rhythm in both the young group (P < 0.001) and the middle-aged group (P = 0.002), with no significant difference between the groups in mesor (P = 0.094) or acrophase (P = 0.698). Although analysis of the SHBG data revealed a significant rhythm in the young group (P = 0.003) and the older group (P < 0.001), the acrophase occurred in the mid afternoon in both groups (15.12 h in the young and 15.40 h in the middle-aged). The older men had a significantly greater amplitude (P = 0.044) but again no significant difference was seen in mesor (P = 0.083) or acrophase (P = 0.477) between the two groups. Acrophases for total, bioavailable and free testosterone occurred between 07.00 h and 07.30 h; for SHBG the acrophase occurred at 15.12 h in the young group and 15.40 h in the middle-aged group. CONCLUSIONS: The study suggests that the diurnal rhythm in these indices of androgen status is maintained in fit, healthy men into the 7th decade of life.

Adult↗

PubMed1997

Primary gonadal failure in men selectively amplifies the mass of follicle stimulating hormone (FSH) secreted per burst and increases the disorderliness of FSH release patterns: reversibility with testosterone replacement.

The neuroendocrine mechanisms by which primary gonadal failure in men increases mean serum FSH concentrations (castration-like response) are not known. To investigate the testosterone-dependent mechanisms of the FSH castration response: (i) blood was sampled at 10-min intervals for 24 h for later FSH assay in seven normal middle-aged men and in six patients with primary testicular failure, during testosterone withdrawal and after 6 weeks of parenteral testosterone replacement; (ii) using a specific two-site IRMA, serum FSH concentrations were measured, since this assay correlates well with an in-vitro Sertoli cell bioassay; (iii) multiparameter deconvolution analysis was then applied to estimate the frequency, amplitude, duration, and mass of underlying FSH secretory bursts, and the half-life of endogenous FSH, and (iv) approximate entropy was calculated to quantify the relative orderliness of FSH release over 24 h. Mean (+/- SEM) 24-h serum FSH concentrations were 3.9 +/- 0.8 IU/L in control subjects and 39 +/- 10 IU/L in unreplaced hypogonadal patients (p = 0.034). Deconvolution analysis revealed similar estimated mean FSH half-lives of 346 +/- 40 min (control) and 321 +/- 47 min (untreated patients), and indistinguishable FSH secretory burst frequencies, namely, 20 +/- 0.95 (normal) and 21 +/- 1.3 (patients) pulses per 24 h. In contrast, the daily production rate of FSH was markedly increased in testosterone-withdrawn hypogonadal men at 117 +/- 25 vs. 9.3 +/- 1.8 IU/L/day (control) (p < 0.01). This was due to a 10-fold higher calculated maximal rate (amplitude) of FSH secretion achieved within each FSH release episode (normal 0.078 +/- 0.02 vs. gonadal failure 0.74 +/- 0.087 IU/L/min, p < 0.01), yielding a 10-fold increase in the mass of FSH secreted per burst (control 0.53 +/- 0.06 vs. patients 5.3 +/- 0.81 IU/L, p < 0.01). In contrast, the mean half-duration of FSH secretory bursts was unaltered in unreplaced hypogonadal men at 8.2 +/- 2.2 min (control) vs. 7.0 +/- 1.0 min (patients). Approximate entropy (ApEn), a scale- and model-independent statistic designed to quantify the orderliness or regularity of hormone release, revealed greater irregularity of serum FSH concentrations in the hypoandrogenic state: ApEn = 1.8 +/- 0.025 (testosterone-withdrawn) vs. 1.6 +/- 0.037 (control) (p < 0.05). Parenteral testosterone replacement for 6 weeks significantly decreased mean serum FSH concentrations by reducing the daily FSH secretion rate and FSH secretory burst amplitude and mass, and concomitantly restored the orderliness of FSH release patterns. Testosterone treatment did not change FSH secretory burst half-duration, number, interburst interval, or half-life. It is concluded that primary gonadal failure in men evokes FSH hypersecretion which is marked by more disorderly FSH release patterns and a selectively amplified mass of FSH secreted per burst. These hypergonadotrophic mechanisms are, to a significant extent, testosterone-suppressible.

Follicle Stimulating Hormone↗

PubMed1998

Enhancement of long-term testosterone secretion and steroidogenic enzyme expression in human Leydig cells by co-culture with human Sertoli cell-enriched preparations.

We have shown previously that long-term testosterone secretion, which decreases when human Leydig cells are cultured alone, increases when purified human Leydig and Sertoli cells are cultured together. In this work, human Leydig cell functions were studied further during in vitro culture, either alone or with human Sertoli cells, on a basal membrane derived from bovine corneal endothelial cells. The secretion of testosterone increased during the first week of co-culture and remained elevated up to day 12 of culture. In one prolonged co-culture, testosterone secretion decreased progressively after day 12 and, after 1 month of culture, was at a level similar to that observed during the first 48 h. After culture for 48 h, testosterone secretion in the co-culture was enhanced by 162 +/- 5% (p < 0.0001) compared with values observed when Leydig cells were cultured alone (42.6 +/- 10.6 ng/10(6) Leydig cells/48 h; mean +/- SEM). This change was associated with increase in mRNA levels for 3 beta-hydroxysteroid dehydrogenase delta 5-delta 4-isomerase (2.49 +/- 0.58-fold), cytochrome P450c17 (2.81 +/- 0.99-fold), cytochrome P450scc (5.20 +/- 0.13-fold) and cytochrome P450 aromatase (1.73 +/- 0.21-fold) when Leydig cells were co-cultured with Sertoli cells (p < 0.05 for each enzyme). IGF-I mRNA levels were higher (2.77 +/- 0.72-fold for 7.6 kb and 1.41 +/- 0.07-fold for 1.1-1.3 kb transcripts) in the Leydig-Sertoli cell co-cultures than the sum of the levels in Leydig and in Sertoli cells cultured alone. Both basal and hCG-induced testosterone secretion were enhanced by treatment of the co-culture with human recombinant FSH (50 mIU/mL). For basal testosterone secretion, this increase amounted to 163 +/- 5% compared with Leydig cells cultured alone (p < 0.0001) and by 112 +/- 4% compared with non-FSH treated co-cultures (p < 0.01); for hCG-stimulated testosterone secretion this increase was 220 +/- 12% compared with Leydig cells cultured alone (p < 0.0001) and 132 +/- 8% compared with non-FSH treated co-cultures (p < 0.01). This study confirms the enhancement of long-term testosterone secretion by adult human Leydig cells by co-culture with adult human Sertoli cells and shows that this effect is associated with an enhancement of the expression of several steroidogenic enzymes; it might be mediated, as in other species, through increased production of IGF-I by co-culture.

Adult↗