Serum Free Testosterone Concentrations Research Articles

Disparate serum free testosterone concentrations and degrees of hypothalamo-pituitary-luteinizing hormone suppression are achieved by continuous versus pulsatile intravenous androgen replacement in men: a clinical experimental model of ketoconazole-induced reversible hypoandrogenemia with controlled testosterone add-back.

To investigate the neuroendocrine mechanisms underlying the negative feedback actions of testosterone on both the pulsatile mode of LH release and the entropy or disorderliness of the LH release process, we blocked testicular androgen biosynthesis using oral high dose ketoconazole treatment with concomitant low dose glucocorticoid replacement for 48 h in six healthy young men. Volunteers were then infused iv with saline or a total of 8.0 mg testosterone base over the second 24 h via either a continuous or a pulsatile (90-min boluses) delivery pattern. Discrete peak detection (Cluster analysis) was applied to obtain a model-independent estimate of the frequency of serum LH concentration peaks, maximal and incremental LH peak amplitudes, peak area, and interpeak nadir serum LH concentrations. Approximate entropy was used to quantify the relative orderliness/disorderliness of the LH release process over 24 h. Ketoconazole treatment markedly lowered 24-h mean serum total and free testosterone concentrations (by 17- and 9-fold respectively), and significantly increased LH pulse frequency, maximal LH peak height, and interpeak nadir serum LH concentrations. Continuous iv testosterone add-back increased 24-h pooled serum free testosterone concentrations 3-fold more and concomitantly reduced mean (24-h) serum LH concentrations by at least 2-fold more than pulsatile delivery of the same total daily amount of androgen. Both modes of testosterone infusion suppressed pulsatile LH release, but the effects were distinguishable; namely, treatment with continuous vs. intermittent androgen add-back, respectively, decreased LH pulse frequency and incremental LH pulse amplitude. Ketoconazole treatment alone also significantly increased approximate entropy values, indicating greater disorderliness of LH release during androgen removal. Approximate entropy/orderliness was restored to baseline by continuous, but not pulsatile, iv testosterone replacement. In conclusion, the present novel testosterone add-back clinical experimental paradigm indicates that 1) remarkably different 24-h mean serum free testosterone concentrations can result from continuous vs. pulsatile testosterone delivery into the bloodstream; 2) androgen negative feedback can exert frequency- as well as amplitude-dependent suppression of pulsatile LH release; and 3) testosterone is required to maintain an orderly 24-h LH release process in young men.

Disparate Serum Free Testosterone Concentrations and Degrees of Hypothalamo-Pituitary-Luteinizing Hormone Suppression Are Achieved by Continuous Versus Pulsatile Intravenous Androgen Replacement in Men: A Clinical Experimental Model of Ketoconazole-Induced Reversible Hypoandrogenemia with Controlled Testosterone Add-Back

Disparate Serum Free Testosterone Concentrations and Degrees of Hypothalamo-Pituitary-Luteinizing Hormone Suppression Are Achieved by Continuous Versus Pulsatile Intravenous Androgen Replacement in Men: A Clinical Experimental Model of Ketoconazole-Induced Reversible Hypoandrogenemia with Controlled Testosterone Add-Back

Serum Leptin Concentrations in Women with Polycystic Ovary Syndrome

The role of gonadotropins, androgens, and insulin in the regulation of circulating leptin levels is obscure. In order to clarify the relationships of these parameters we studied serum leptin levels in 19 healthy control subjects and in 35 hyperandrogenic and hyperinsulinemic patients with polycystic ovary syndrome (PCOS). Serum leptin concentrations did not differ significantly between PCOS patients and control subjects. When PCOS and control groups were analyzed together by univariate analysis, serum leptin was positively correlated with body mass index (BMI), body weight, serum insulin, serum triglyceride, and serum free testosterone concentrations. Serum leptin was inversely correlated with serum sex hormone binding globulin (SHBG) concentrations. There were no significant correlations between serum leptin and testosterone, androstenedione, or gonadotropin concentrations. Serum insulin, triglyceride, and free testosterone concentrations were positively correlated, and serum SHBG was negatively correlated with BMI. However, when BMI on one hand and serum insulin, triglyceride, free testosterone, or SHBG on other hand were used as independent variables in the partial correlation analysis with leptin, BMI turned out to be the variable primarily responsible for all of the correlations with leptin. In conclusion, the concept that circulating leptin levels would be different in PCOS patients than in regularly menstruating control subjects is not supported by our data.

Serum leptin concentrations in women with polycystic ovary syndrome.

The role of gonadotropins, androgens, and insulin in the regulation of circulating leptin levels is obscure. In order to clarify the relationships of these parameters we studied serum leptin levels in 19 healthy control subjects and in 35 hyperandrogenic and hyperinsulinemic patients with polycystic ovary syndrome (PCOS). Serum leptin concentrations did not differ significantly between PCOS patients and control subjects. When PCOS and control groups were analyzed together by univariate analysis, serum leptin was positively correlated with body mass index (BMI), body weight, serum insulin, serum triglyceride, and serum free testosterone concentrations. Serum leptin was inversely correlated with serum sex hormone binding globulin (SHBG) concentrations. There were no significant correlations between serum leptin and testosterone, androstenedione, or gonadotropin concentrations. Serum insulin, triglyceride, and free testosterone concentrations were positively correlated, and serum SHBG was negatively correlated with BMI. However, when BMI on one hand and serum insulin, triglyceride, free testosterone, or SHBG on other hand were used as independent variables in the partial correlation analysis with leptin, BMI turned out to be the variable primarily responsible for all of the correlations with leptin. In conclusion, the concept that circulating leptin levels would be different in PCOS patients than in regularly menstruating control subjects is not supported by our data.

Pulsatile intravenous gonadotropin-releasing hormone administration averts fasting-induced hypogonadotropism and hypoandrogenemia in healthy, normal weight men.

Fasting or severe caloric restriction in the human or experimental animal suppresses serum LH and sex steroid concentrations. In healthy men undergoing prolonged (5-day) nutrient deprivation, the daily LH secretion rate, the mass of LH secreted per burst, and the serum testosterone concentration fall markedly, with no decrease in responsiveness to a single bolus of GnRH. Here we test the hypothesis that the hypogonadotropic hypoandrogenemia accompanying fasting reflects decreased endogenous GnRH release. To this end, six healthy young men were studied on a fed day and during two 83-h fasting sessions with concurrent saline or pulsatile GnRH administration (100 ng/kg, i.v., every 90 min for 24 h) followed by a single bolus of 10 microg GnRH, i.v., to evaluate pituitary responsiveness. We employed a highly sensitive LH immunoradiometric assay, which correlates well with an in vitro Leydig cell bioassay, and deconvolution analysis to calculate in vivo LH secretory burst frequency, amplitude, duration, mass, and LH half-life. Fasting resulted in 30-50% declines in serum total and free testosterone and LH concentrations, and a 3-fold decrease in the calculated 24-h LH secretion rate (fed, 42 +/- 12; fasting, 14 +/- 1.9 U/L distribution volume x day; mean +/- SEM; P < 0.05, by ANOVA). Reduced LH secretion was accounted for by dual mechanisms, viz. a fall in both the apparent number of computer-resolved LH secretory bursts per 24 h (fed, 16 +/- 1.1; fasting, 10 +/- 1.2; P < 0.01) and the mass of LH secreted per burst (fed, 2.5 +/- 0.5; fasting, 1.5 +/- 0.1 U/L; P < 0.05). Fasting also decreased the mean value of the 24-h (nyctohemeral) rhythm in serum LH concentrations and reduced the approximate entropy (disorderliness) of LH release. Exogenous pulsatile GnRH injections prevented both the reduction in the calculated daily LH secretion rate (fed, 42 +/- 12; fasting plus GnRH, 64 +/- 16 IU/L; P = NS) and the decline in serum testosterone concentrations (fed, 556 +/- 71 ng/dL; fasting, 391 +/- 41; fasting plus GnRH, 859 +/- 65). Pulsatile GnRH treatment also restored the nyctohemeral mesor of serum LH concentrations and the approximate entropy value to baseline. Administration of a submaximal dose of exogenous GnRH (10 microg, i.v.) at the end of the fasting interval revealed statistically identical LH release in the three study groups, suggesting that pituitary responsiveness to GnRH was unchanged in this paradigm. In summary, a pulsatile iv GnRH infusion in young men averts completely the fasting-induced decline in LH secretory burst mass/amplitude and frequency, reinstates serum total and free testosterone concentrations, and restores the mesor of LH's nyctohemeral rhythmicity and the approximate entropy of LH release. Rescue of hypogonadism by pulsatile GnRH stimuli supports the thesis that nutrient withdrawal decreases the output of the human hypothalamic GnRH burst generator.

THE INTER-RELATIONSHIP AMONG ENDURANCE TRAINING, CONSUMPTION OF A VEGETARIAN DIET AND SERUM TESTOSTERONE CONCENTRATION 1681

Both endurance training and chronic consumption of a vegetarian diet have been associated with lowering the basal level of testosterone in men. However, studies that have proposed an endurance training effect, failed to recognize that differences in dietary practices may have been a confounding factor. The present study examined the independent effects of diet and endurance training on basal serum testosterone concentration. [METHODS] Endurance trained individuals were currently competing in a sport involving cycling. Vegetarian individuals had abstained from red meat and poultry for a least one year. [RESULTS] The aerobic ability of the endurance trained group was significantly greater than that of the sedentary group,(F[1,22]=32.045, p=.000) verifying that they were indeed trained individuals. Nutrient intake, however, was similar across groups, with the exception of dietary fiber (F[1,22]=12.635), p=.002) which was higher among the vegetarian subjects. Serum total and free testosterone concentrations were not statistically different for either main effect (i.e., diet and exercise). [CONCLUSION] Although the subjects from both the vegetarian and meat eating groups were highly trained individuals, the lack of a difference in androgen concentration may be explained by the observed similarities in nutrient intake across groups.

17 alpha-Hydroxyprogesterone responses to leuprolide and serum androgens in obese women with and without polycystic ovary syndrome offer dietary weight loss.

Insulin resistance and increased ovarian cytochrome P450c17 alpha activity (i.e. increased 17 alpha-hydroxylase and, to a lesser extent, increased 17,20-lyase) are both features of the polycystic ovary syndrome (PCOS). Evidence suggests that hyperinsulinemia may stimulate ovarian P450c17 alpha activity in obese women with PCOS. We hypothesized that weight loss would decrease serum insulin and P450c17 alpha activity in PCOS. Therefore, we measured serum steroid concentrations and 17 alpha-hydroxyprogesterone responses to leuprolide administration and performed oral glucose tolerance tests before and after 8 weeks of a hypocaloric diet in 12 obese women with PCOS (PCOS group) and 11 obese women with normal menses (control group). Serum insulin decreased in both groups. In the PCOS group, basal serum 17 alpha-hydroxyprogesterone decreased from 4.2 +/- 0.6 to 3.0 +/- 0.5 nmol/L (P < 0.05), and leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone decreased from 14.9 +/- 2.6 to 8.9 +/- 0.8 nmol/L (P < 0.025). Serum testosterone decreased from 2.47 +/- 0.52 to 1.56 +/- 0.33 nmol/L (P < 0.05), and free testosterone decreased from 9.03 +/- 1.39 to 5.95 +/- 0.50 pmol/L (P < 0.02). None of these values changed in the control group. Serum sex hormone-binding globulin increased by 4.5- and 3-fold in the PCOS (P < 0.003) and control (P < 0.007) groups, respectively. We conclude that dietary weight loss decreases ovarian P450c17 alpha activity and reduces serum free testosterone concentrations in obese women with PCOS, but not in obese ovulatory women. The changes in women with PCOS may be related to a reduction in serum insulin.

Decreases in Ovarian Cytochrome P450c17α Activity and Serum Free Testosterone after Reduction of Insulin Secretion in Polycystic Ovary Syndrome

Insulin resistance and increased ovarian cytochrome P450c17 alpha activity are both features of the polycystic ovary syndrome. P450c17 alpha, which is involved in androgen biosynthesis, has both 17 alpha-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17 alpha-hydroxyprogesterone in response to stimulation by gonadotrophin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17 alpha activity. We measured fasting serum steroid concentrations and the response of serum 17 alpha-hydroxyprogesterone to leuprolide, a gonadotrophin-releasing hormone agonist, and performed oral glucose-tolerance tests before and after oral administration of either metformin (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome. In the 11 women given metformin, the mean (+/- SE) area under the serum insulin curve after oral glucose administration decreased from 9303 +/- 1603 to 4982 +/- 911 microU per milliliter per minute (56 +/- 10 to 30 +/- 6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reduction in the basal serum 17 alpha-hydroxyprogesterone concentration from 135 +/- 21 to 66 +/- 7 ng per deciliter (4.1 +/- 0.6 to 2.0 +/- 0.2 nmol per liter) (P = 0.01) and a reduction in the leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone concentration from 455 +/- 54 to 281 +/- 52 ng per deciliter (13.7 +/- 1.6 to 8.5 +/- 1.6 nmol per liter) (P = 0.01). The serum 17 alpha-hydroxyprogesterone values increased slightly in the placebo group. In the metformin group, the basal serum luteinizing hormone concentration decreased from 8.5 +/- 2.2 to 2.8 +/- 0.5 mlU per milliliter (P = 0.01), the serum free testosterone concentration decreased from 0.34 +/- 0.07 to 0.19 +/- 0.05 ng per deciliter (12 +/- 3 to 7 +/- 2 pmol per liter) (P = 0.009), and the serum sex hormone-binding globulin concentration increased from 0.8 +/- 0.2 to 2.3 +/- 0.6 microgram per deciliter (29 +/- 7 to 80 +/- 21 nmol per liter) (P < 0.001). None of these values changed significantly in the placebo group. In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism.

Urinary excretion of testosterone and estradiol in chinese men and relationships with serum lipoprotein concentrations

Urinary excretion of total and free testosterone and estradiol was measured in 46 healthy Chinese men, along with serum concentrations of total testosterone and estradiol and the calculated free (unbound) concentrations. Associations with serum concentrations of total, low-density lipoprotein (LDL), high-density lipoprotein-2 (HDL 2), and HDL 3 cholesterol, apolipoproteins (apos) A-I and B, and lipoprotein(a) [Lp(a)] were studied. Serum total and free testosterone concentrations were positively correlated with HDL and HDL 2 cholesterol and apo A-I. Serum total and free estradiol levels showed borderline-significant negative associations with total and LDL cholesterol levels. Among urinary variables, total estradiol excretion was negatively associated with apo B levels and showed borderline-significant associations with total and LDL cholesterol. Adjustment for potential confounders, including age, body mass index (BMI), and waist to hip ratio (WHR), strengthened the associations between urinary total estradiol and serum total cholesterol, LDL cholesterol, and apo B. Urinary free estradiol showed a significant correlation with HDL 3 cholesterol. Urinary excretion of total testosterone was significantly negatively associated with serum cholesterol and LDL cholesterol levels only after controlling for confounding variables. There were no significant associations between hormone variables and Lp(a) values. This study suggests that variation in sex hormone production accounts for some of the variation in serum lipid levels.

Serum testosterone and its relation to bone mineral density and body composition in normal males.

Bone mineral density (BMD) declines with age in both men and women, predisposing the elderly to osteoporosis and fractures. Although there are extensive data about post-menopausal osteoporosis, there is relatively little information concerning the decrease in BMD with age in normal men, particularly the contribution of declining gonadal function with age to BMD. In the present study, we investigated the effect of age on the pituitary-gonadal axis in normal males and its relation to BMD and body composition. Ninety healthy Thai males in the Bangkok Metropolitan area without a history of smoking or significant alcohol consumption were studied. Serum testosterone (T), free testosterone (FT), LH and FSH were measured by radioimmunoassay in fasting blood samples obtained in the morning between 0600 and 1000 h. BMD at anteroposterior L2-L4, lateral L2-L4, femoral neck, femoral trochanter and Ward's triangle were determined by dual-energy X-ray absorptiometry. There were significant declines with age in BMD at lateral L2-L4 (r = -0.37, P < 0.001), femoral neck (r = -0.49, P < 0.0001), Ward's triangle (r = -0.54, P < 0.0001) but not at anteroposterior L2-L4 or femoral trochanter. Serum FT (r = -0.56, P < 0.0001) but not T (r = -0.19, P = 0.07) decreased with age. Serum LH (r = 0.27, P < 0.001) and FSH (r = 0.4, P < 0.0001) increased with age suggesting a defect in gonadal androgen synthesis or possibly a secretion of bioinactive LH. Serum FT concentrations were significantly correlated to lateral L2-L4 (r = 0.27, P < 0.05), femoral neck (r = 0.48, P < 0.0001) and Ward's triangle (r = 0.50, P < 0.0001) BMD. After controlling for age, declining FT with age was still associated with a decrease in BMD in femoral neck (P < 0.05) and Ward's triangle (P < 0.05) but not in lateral L2-L4. The proportion of body fat increased with age (r = 0.3, P < 0.01). Decreased serum T, but not FT, was associated with increased body fat after age was taken into account (P < 0.0001). There is a decline in serum free testosterone together with increases in LH and FSH with age in healthy males. The decrease in serum free testosterone is partially associated with the age-related decline in bone mineral density added to the effect of age at the femoral neck and Ward's triangle. Testosterone but not free testosterone is associated with age-related increase in body fat.

Portal insulin concentrations rather than insulin sensitivity regulate serum sex hormone-binding globulin and insulin-like growth factor binding protein 1 in vivo.

Serum sex hormone-binding globulin (SHBG) and insulin-like growth factor-binding protein 1 (IGFBP-1) concentrations have been suggested to be useful markers of insulin sensitivity. As the production of both proteins is inhibited by insulin in the liver, we postulated that their concentrations reflect whole body insulin sensitivity only when the latter parallels changes in endogenous insulin secretion. To test this hypothesis, we determined SHBG and IGFBP-1 concentrations, whole body insulin sensitivity (euglycemic insulin clamp; serum free insulin, approximately 400 pmol/L), and serum insulin and C peptide concentrations in 13 type 1 diabetic patients lacking endogenous insulin secretion and 34 matched normal subjects. Whole body insulin sensitivity was 50% lower in the type 1 diabetic patients (20 +/- 3 mumol/kg.min) than that in the normal subjects (40 +/- 3 mumol/kg.min; P < 0.001). Despite this, serum SHBG (45 +/- 4 vs. 29 +/- 2nmol/L; P < 0.002) and IGFBP-1 (14 +/- 3 vs. 2 +/- 1 micrograms/L; P < 0.002) concentrations were increased in the type 1 diabetic patients. In the normal subjects, SHBG (r = -0.49; P < 0.01) and IGFBP-1 (r = -0.49; P < 0.01) were inversely correlated with serum C peptide and positively correlated with whole body insulin sensitivity (r = 0.54; P < 0.005 and r = 0.54; P < 0.005, respectively). In the type 1 diabetic patients, SHBG and IGFBP-1 concentrations were disproportionately increased when related to insulin sensitivity, but appropriate when related to estimated portal insulin concentrations. Serum T4, free testosterone, and estradiol concentrations were similar in both groups. We conclude that SHBG and IGFBP-1 reflect hepatic insulinization and can only be used as markers of insulin sensitivity in individuals with intact insulin secretion.

A method for measurement of free testosterone in premenopausal women involving equilibrium dialysis, chromatography, and radioimmunoassay

A three-step procedure to evaluate the quantity of true free testosterone in female serum was established. Unbound and bound testosterone were first separated by equilibrium dialysis using undiluted serum. Testosterone in dialysate was extracted and separated from cross-reactive steroids by column chromatography and finally quantified with a sensitive radioimmunoassay. The detection limit of the radioimmunoassay was 2.7 pmol/L and the detection limit of the whole method was 6 pmol/L. The intra-assay coefficients of variation of the method were 20.6%, 16.8%, and 9.5% for free testosterone concentrations 12.0 pmol/L, 21.4 pmol/L, and 31.4 pmol/L, respectively. The interassay coefficients of variation were 26.3% and 14.8% for free testosterone concentrations 10.4 pmol/L and 21.3 pmol/L, respectively. Serum free testosterone concentrations were determined in 27 regularly menstruating control women. The mean concentration of actual free testosterone was 10.0 ± 4.9 pmol/L (mean ± SD, range from below 6 to 19 pmol/L, n = 27).

Differential responses of biologically active luteinizing hormone secretion in older versus young men to interruption of androgen negative feedback.

To investigate the responsiveness of the healthy aging male hypothalamo-pituitary-gonadal axis to short term interruption of androgen negative feedback, we administered a selective nonsteroidal competitive antagonist of the androgen receptor, flutamide hydrochloride (250 mg, orally, three times daily for 3.5 days), to five older (aged 63-72 yr) and eight young (aged 21-30 yr) men. Pulsatile bioactive LH release was assessed by the rat interstitial cell testosterone bioassay in plasma sampled at 10-min intervals for 8 h overnight at baseline and after flutamide administration. Pituitary responsiveness was evaluated after two successive i.v. injections of 10 micrograms GnRH. Deconvolution analysis was used to estimate the number, amplitude, duration, and mass of bioactive LH secretory bursts and the half-life of biologically active hormone. At baseline, older men exhibited a significantly lower spontaneous bioactive LH secretory burst frequency than young men, with a median of 5 events/8 h (older) vs. 7.5 bursts/8 h (younger, P < 0.05). In older men, mean 8-h plasma bioactive LH concentrations increased significantly in response to flutamide (P = 0.006), and the 8-h calculated secretion rate of bioactive LH rose concomitantly. These increases were similar to responses in young men. However, during antiandrogen administration, the frequency of bioactive LH secretory bursts failed to rise in older men to the baseline value seen in young men. Moreover, older (but not young) men showed a significant prolongation of the LH secretory burst duration in response to flutamide treatment. On the other hand, the estimated half-life of endogenous bioactive LH increased significantly after flutamide ingestion in young compared to older individuals. After GnRH injections, older and young men secreted similar amounts of LH before flutamide administration, but during flutamide treatment, older men released more biologically active LH after the first GnRH stimulus [older men, 104 +/- 11 IU/L (median, 110); younger men, 44 +/- 8.4 IU/L (median, 40); P < 0.05]. Serum free testosterone concentrations rose significantly during flutamide exposure in both young and older men, but estradiol concentrations increased significantly only in young men. In summary, healthy older men exhibit a reduced (overnight) spontaneous bioactive LH secretory burst frequency. Pharmacological attenuation of androgen-mediated negative feedback increases mean serum free testosterone concentrations and plasma bioactive LH concentrations to a similar degree in older and young individuals, but different mechanisms operate in the two age groups. In older men, flutamide treatment amplifies the mass of bioactive LH secreted per burst by prolonging the LH secretory burst duration, whereas in young men, flutamide administration increases the apparent half-life of biologically active LHG significantly relative to values in older men. We conclude that competitive nonsteroidal blockade of the androgen receptor unmasks qualitatively altered mechanisms of increased bioactive LH release in healthy older men.

Combined deficits in the somatotropic and gonadotropic axes in healthy aging men: An appraisal of neuroendocrine mechanisms by deconvolution analysis

We have employed deconvolution analysis of 24-h serum GH, LH, and FSH concentration profiles to evaluate the nature of age-associated changes in GH, LH, and FSH secretion and disappearance in healthy older individuals. Our findings indicate that healthy aging results in a diminished frequency of detectable GH secretory episodes and an apparent decrease in estimated GH half life in men. These combined effects lead to a significant reduction in mean serum GH concentrations over 24 h. In contrast, we find that LH secretory burst frequency tends to increase with a reciprocal decrease in amplitude as serum total and free testosterone concentrations decline during healthy aging. There is also a prolongation of LH secretory burst duration, and a putative increase in basal LH secretion rates. The changes in LH secretory dynamics are specific, because the half life of immunoradiometric LH and the mass of hormone secreted per burst are not altered. In contrast, the apparent half life of FSH increases with age, and the secretory burst duration may decrease. This spectrum of distinct neuroendocrine sequelae of aging has interesting implications to both investigative and therapeutic strategies for modifying the somatotropic and gonadotropic axes in aging individuals.

Amplitude suppression of the pulsatile mode of immunoradiometric luteinizing hormone release in fasting-induced hypoandrogenemia in normal men.

In the male rodent and primate, fasting or severe caloric restriction significantly decreases serum testosterone concentrations, putatively via inducing secondary hypogonadotrophism. To clarify this presumptive pathophysiology, we have used: 1) a high sensitivity immunoradiometric assay, which correlates well with an in vitro Leydig cell bioassay of LH; 2) blood sampling every 5 min for 24 h basally and every 10 min for 3 h after GnRH injection before and after a 5-day (water only) fast in eight healthy young men; and 3) deconvolution analysis to evaluate in vivo LH secretory burst frequency, amplitude, duration, and mass, and LH half-life simultaneously. We documented a 50% fall in serum total and free testosterone concentrations, and a 30% decrease in 24-h mean serum LH concentrations (viz., fed 3.0 +/- 0.47 vs. fasted 2.1 +/- 0.39 U/L, P = 0.043). Deconvolution analysis revealed preservation of LH secretory pulse frequency (fed 12.9 +/- 0.48 vs. fasted 12.6 +/- 0.78 secretory bursts/day, P = NS) during fasting-induced hypogonadotropism. The duration of computer-resolved LH secretory bursts, the interburst interval, and the calculated endogenous half-life of LH also did not change, whereas LH secretory burst mass declined significantly; viz. from 28 +/- 5 in the fed to 14 +/- 3.2 U/L of distribution volume/day in the fasted state (P = 0.034). In contrast, LH release after a 10 micrograms pulse of GnRH iv was enhanced during fasting in seven of the eight men. Fasting also decreased mean (24 h) serum TSH and PRL, increased cortisol, dehydroepiandrosterone sulfate and GH, and did not affect FSH concentrations or the radioiodinated albumen distribution space. In summary, in young men 5 days of nutrient deprivation selectively attenuates the mass of LH secreted per burst without altering LH secretory event frequency or LH half-life. We infer that decreased LH release per burst is due to decreased hypothalamic GnRH impulse strength, since LH release induced by a submaximally effective pulse of exogenous GnRH is amplified rather than attenuated.

The effect of short and long duration exercise on serum erythropoietin concentrations.

The effects of short and long duration exercise on serum erythropoietin concentrations [EPO]s were studied in seven male cross-country skiers of national team standard and eight male marathon runners, respectively. The short duration exercise was performed as 60 min of cycling at an intensity of 80%-95% of maximal heart rate. Arterial blood oxygen saturations monitored by pulse-oximetry remained unchanged throughout exercise. The partial pressure of O2 at which haemoglobin was half-saturated with O2 calculated from forearm venous blood gas tension and blood O2 saturation, and the erythrocyte 2,3-diphosphoglycerate did not change significantly during the exercise. Blood lactate concentrations were increased at the end of exercise [from 1.3 (SEM 0.1) to 3.6 (SEM 0.3) mmol.l-1]. The [EPO]s determined (by enzyme-linked immunosorbent assay) pre-exercise, 5 min, 6 h, 19 h, and 30 h after the exercise were unchanged [from 16.1 (SEM 2.6) to 19.1 (SEM 3.2), 17.9 (SEM 3.0), 17.0 (SEM 2.5), and 18.6 (SEM 2.9) U.l-1, respectively]. The [EPO]s were not correlated to the earlier parameters. The long duration exercise consisted of habitual training, a 3 week break from training followed by 2 and 4 weeks of re-training. The [EPO]s, body fat (BF), and serum free-testosterone concentrations determined at the end of each period remained unchanged. The maximal oxygen uptakes were decreased after the break from training and increased during retraining (P = 0.04). Body mass (mb) increased after the break in training (P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Attenuation of luteinizing hormone secretory burst amplitude as a proximate basis for the hypoandrogenism of healthy aging in men.

To evaluate the impact of healthy aging on specific features of endogeneous LH secretion and clearance, we applied deconvolution analysis to 24-h serum immunoradiometric LH concentration series obtained in normal men whose ages ranged from 21-73 yr. Deconvolution analysis was employed to quantitate the number, amplitude, duration, and mass of individual LH secretory bursts underlying the serum LH concentration profiles, and simultaneously estimate the half-life of LH in individual men. Plasma total and free testosterone and estradiol concentrations and body mass index (a measure of relative adiposity) were studied as possible significant covariates of age and LH secretion. We found that age was a negative determinant of LH secretory burst amplitude (r = -0.519, P = 0.013), and a positive predictor of LH secretory burst frequency (r = +0.435, P = 0.043) and basal LH secretory rates (r = +0.486, P = 0.029). Increasing age also correlated positively with LH secretory burst half-duration (duration of the secretory event at half-maximal amplitude, r = +0.656, P less than 0.001). In contrast, age did not relate to daily pulsatile LH production rate, the mass of LH secreted per burst, or the mean (24-h) serum concentration of immunoradiometric LH. Age correlated negatively with serum free testosterone (r = -0.622, P = 0.0034) but not estradiol concentrations. The serum free testosterone concentration also declined significantly with increasing body mass index (r = -0.519, P = 0.023). Although there were strong combined effects of age, body mass index, and LH secretory burst amplitude on serum free testosterone concentrations (P = 0.0006, multi-r value 0.820), LH secretory burst amplitude was the most prominent single determinant of blood androgen concentrations.

Serum hormones in male strength athletes during intensive short term strength training

Training-induced adaptations in the endocrine system and strength development were investigated in nine male strength athletes during two separate 3-week intensive strength training periods. The overall amount of training in the periods was maintained at the same level. In both cases the training in the first 2 weeks was very intensive: this was followed by a 3rd week when the overall amount of training was greatly decreased. The two training periods differed only in that training period I included one daily session, while during the first 2 weeks of period II the same amount of training was divided between two daily sessions. In general, only slight and statistically insignificant changes occurred during training period I in mean concentrations of serum hormones examined or sex hormone-binding globulin as well as in maximal isometric leg extensor force. However, during training period II after 2 weeks of intensive strength training a significant decrease (P less than 0.05) was observed in serum free testosterone concentration [from 98.4 (SD 24.5) to 83.8 (SD 14.7) pmol.l-1] during the subsequent week of reduced training. No change in the concentration of total testosterone was observed. This training phase was also accompanied by significant increases (P less than 0.05) in serum luteinizing hormone (LH) and cortisol concentrations. After 2 successive days of rest serum free testosterone and LH returned to (P less than 0.05) their basal concentrations. Training period II led also to a significant increase (P less than 0.05) [from 3942 (SD 767) to 4151 (SD 926) N] in maximal force.(ABSTRACT TRUNCATED AT 250 WORDS)

Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels

Twenty-three healthy men (age 25 to 50 years), covering a wide range of fatness and body fat distribution, were studied. An oral glucose tolerance test was performed and adipose tissue areas were calculated from computed tomography (CT) scans made at the level of L4 L5 . Visceral fat area was associated with elevated concentrations of insulin and C-peptide and with glucose intolerance before and after the oral glucose load. Concentrations of sex-hormone-binding glubolin (SHBG), as well as total and free testosterone, were negatively correlated with waist/hip circumference ratio and visceral fat area and also negatively associated with increased glucose, insulin, and C-peptide concentrations. In multiple linear regression, adjusting for age, body mass index, and visceral fat area, serum concentrations of free testosterone were still negatively correlated with glucose, insulin, and C-peptide levels. Without claiming any causality in the observed associations, we conclude that, unlike in women, abdominal fat distribution, insulin, glucose, and C-peptide levels are negatively associated with serum testosterone levels in men.

Gynecomastia and Cirrhosis of the Liver

Hepatic cirrhosis is frequently listed as a cause of gynecomastia. We found previously that in hospitalized men the prevalence of gynecomastia was correlated with body mass index and with age. The mean body mass index and the prevalence of gynecomastia in the cirrhotic subjects (nonedematous) did not differ from those in the overall population. Because more severely cirrhotic subjects with ascites, peripheral edema, or both usually are thin, we examined 18 more severely cirrhotic subjects and 18 nonobese (mean body mass index, 20.9 +/- 0.6 kg/m2), age-matched control subjects for the prevalence of palpable gynecomastia. Total testosterone, free testosterone, total estrogen, and estradiol concentrations also were measured. Fifty percent of the control subjects had gynecomastia. Breast tissue diameter was correlated with body mass index. The prevalence of gynecomastia in the cirrhotic subjects was 44%. In these subjects no significant correlation was noted between breast tissue diameter and body mass index, presumably because the body mass index was increased owing to fluid retention. The results could not be accounted for based on medications. Serum free testosterone concentrations were lower in the cirrhotic patients than in the controls (0.11 +/- 0.02 vs 0.22 +/- 0.03 nmol/L). The total estrogen-free testosterone ratio was higher in cirrhotic patients (10.3 +/- 2.5 vs 2.6 +/- 0.5), as was the estradiol-free testosterone ratio (2.2 +/- 0.7 vs 0.5 +/- 0.1). These ratios did not differ significantly in cirrhotic subjects with and without gynecomastia. Therefore, these data indicate that factors other than the estrogen-testosterone ratio are playing a role in the development of gynecomastia in both cirrhotic subjects and controls or that breast tissue sensitivity to an elevated estrogen-testosterone ratio is highly varible.