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The impact of estrogen deficiency on bone has been extensively studied in the female; however, the effects of androgen deficiency on calcium fluxes in males have been less well characterized. We investigated the effect of short-term, severe androgen deficiency on measures of calcium absorption and kinetics as well as on markers of bone turnover in males. To accomplish this, 11 healthy male volunteers were recruited (mean age 23.3 +/- 0.5 years [SEM], body mass index 25.3 +/- 0.8 kg/m2). They consumed a weight maintenance diet for at least 3 days prior to admission to our Research Unit, with a calcium intake of approximately 1200 mg/day. At baseline (D1), subjects received 42Ca intravenously as well as 44Ca PO mixed with milk or juice. A 29-h urine collection was begun and blood samples collected at frequent intervals for the measurement of the isotopic enrichment of 42Ca and 44Ca using thermal ionization mass spectrometry. Twice daily urine samples were collected for 5 days after the administration of the isotopes. A gonadotropin-releasing hormone agonist (Lupron) was given after D1, again 3 weeks later, and studies repeated identically 4 weeks (D2, n = 6) and 10 weeks from baseline (D3, n = 7) (two subjects completed three studies). Testosterone concentrations were markedly suppressed on both D2 and D3 (-95%, p < 0.006), whereas there were no detectable changes in growth hormone and insulin-like growth factor-1 concentrations. Urinary calcium excretion increased significantly after 4 weeks (43%, p = 0.0007) and 10 weeks (73%, p = 0.003) of sustained hypogonadism. Using a multicompartmental kinetic model, the contribution of oral calcium to the urinary losses was decreased by D3 (-41%, p = 0.01), yet the contribution of bone calcium to urine losses increased by 10 weeks (+11%, p = 0.01). There was a 21% decrease in bone calcium deposition (Vo+) by D3 (p < 0.05) with no significant change in bone resorption rates (Vo-). There was a significant correlation between the decrease in testosterone concentration and the increase in urinary calcium excretion, especially at 10 weeks (R2 = 0.84, p = 0.004). These kinetic changes were accompanied by a decrease in osteocalcin concentrations on D2, with improvements by D3. Urinary N telopeptide, a measure of bone resorption, also increased during the studies. In summary, profound hypogonadism in young males is associated with marked increases in urinary calcium losses, with a greater contribution of bone calcium to those losses and decreased kinetic markers of bone calcium deposition. We conclude that even short-term, severe deficiency in gonadal steroids can have profound negative effects on calcium and bone metabolism in males.
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PMID:Profound hypogonadism has significant negative effects on calcium balance in males: a calcium kinetic study. 1023 79

Peak volumetric bone mineral density (BMD) is determined by the growth in bone size relative to the mineral accrued within its periosteal envelope. Thus, reduced peak volumetric BMD may be the result of reduced mineral accrual relative to growth in bone size. Because sex steroids and growth hormone (GH) influence bone size and mass we asked: What are the effects of gonadectomy (Gx) on bone size, bone mineral content (BMC), areal and volumetric BMD in growing male and female rats? Does GH deficiency (GH-) reduce the amount of bone in the (smaller) bone, i.e., reduce volumetric BMD? Does GH- alter the effect of Gx on bone size and mineral accrual? Gx or sham surgery was performed at 6 weeks in GH- and GH replete (GH+) Fisher 344 male and female rats. Changes in bone size, volume, BMC, areal and volumetric BMD, measured using dual X-ray absorptiometry (DPX-L), were expressed as percentage of controls at 8 months (mean +/- SEM). All results shown were significant (p < 0.05 level) unless otherwise stated. In GH+ and GH- males, respectively, Gx was associated with: lower femur volume (24%, 25%), BMC (43%, 45%), areal BMD (21%, 14%), and volumetric BMD (30%, 28%); lower spine (L1-L3) volume (26%, 28%), BMC (26%, 30%), and areal BMD (28%, 12%), but not volumetric BMD. Following Gx, GH+ females had increased femur volume (11%), no effect on BMC, decreased areal BMD (6%) and decreased volumetric BMD (17%); GH- females had no change in femur volume, but decreased femur BMC (24%), areal BMD (10%), and volumetric BMD (25%). In GH+ and GH- females, respectively, Gx was associated with a decrease in spine (L1-L3) BMC (12%, 15%), areal BMD (16%, 15%), and volumetric BMD (10%, 16%) with no change in volume. Deficits in non-Gx GH- relative to non-Gx GH+ (males, females, respectively) were: femur BMC (49%, 37%), areal BMD (23%, 8%), volume (19%, 19%) and volumetric BMD (37%, 22%); spine (L1-L3) BMC (46%, 42%), areal BMD (37%, 43%), volume (10%, 15%), and volumetric BMD (40%, 33%). Testosterone and GH are growth promoting in growing male rats, producing independent effects on bone size and mass; deficiency produced smaller appendicular bones with reduced volumetric BMD because deficits in mass were greater than deficits in size. At the spine, the reduction in size and accrual were proportional, resulting in a smaller bone with normal volumetric BMD. In growing female rats, estrogen was growth limiting at appendicular sites; deficiency resulted in a GH-dependent increase in appendicular size, relatively reduced accrual, and so, reduced volumetric BMD in a bigger bone. At the spine, accrual was reduced while growth in size was normal, thus volumetric BMD was reduced in the normal sized bone. Understanding the pathogenesis of low volumetric BMD requires the study of the differing relative growth in size and mass of the axial and appendicular skeleton in the male and female and the regulators of the growth of these traits.
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PMID:The effects of gonadectomy on bone size, mass, and volumetric density in growing rats are gender-, site-, and growth hormone-specific. 1032 May 29

The aim of this study was to determine the influence of testosterone replacement therapy in elderly men on mood, bone mineral density, and lipids. We investigated thirty men (mean +/- SD; age 61.1 +/- 5.6 yr) with testosterone concentrations (mean +/- SEM) 2.1 +/- 0.2 ng/ml. Testosterone deficiency was replacement by intramuscular injections of testosterone enanthate 200 mg every second week from 1.5 to 6 yr. (mean +/- SD; 3.35 +/- 1.6 yr.). During the treatment serum testosterone increased reaching normal levels (mean +/- SEM; 6.6 +/- 0.2 ng/ml). This was associated with significant increase in positive mood parameters and a decrease in negative mood parameters. Also self assessment of libido, potence and dream were improved. Bone mineral density (BMD) of lumbar spine increased. We noticed significant decrease in total cholesterol, and LDL-cholesterol. Hematocrit was increase Prostate-specific antigen concentration statistically increased from 0.65 +/- 0.1 to 1.35 +/- 0.1 ng/ml (mean +/- SEM), but in the cases of its levels were in normal range. Patients with coronary heart disease demonstrated decreasing ing symptoms of angina pectoris and nitrate requirement. In summary, long-term testosterone replacement therapy in elderly men may have beneficial effects on well-being, libido, potence, dream, bone mineral density, lipids, blood cell count and body mass (BMI). This therapy appears to be safe and there is no adverse effection on prostate.
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PMID:[The influence of testosterone replacement therapy on well-being, bone mineral density and lipids in elderly men]. 1033 26

Testosterone (T) in a hydroalcoholic gel has been developed as an effective and convenient open system for transdermal delivery of the hormone to men. Because the gel can be applied either to small or large areas of skin, it was important to assess whether the skin surface area on which the gel was applied was an important determinant of serum T levels. To answer this question, the pharmacokinetics of a transdermal 1% hydroalcoholic gel preparation of T was studied in nine hypogonadal men. The subjects applied in random order a 25-mg metered dose of T gel either four times at one site (left arm/shoulder) or at four different sites (left and right arms/shoulders and left and right abdomen) once daily (6-8 min) for 7 consecutive days. After 7 days of washout, each subject was then crossed over to the opposite regimen for another 7 days of treatment. Serum samples were collected for measurements of T, 5alpha dihydrotestosterone (DHT), and estradiol before, during (days 1, 2, 3, 5, and 7), and after (days 8, 9, 11, 13, and 15) application of T gel. Multiple blood samples were drawn on the 1st and 7th day after gel application; single samples were obtained just before the next T gel application on other days (24 h after the previous gel application). The T gel dried in less than 5 min, left no residue, and produced no skin irritation in any of the subjects. Mean serum T levels, irrespective of application at one site or four sites followed the same pattern: rising to 2- to 3- and 4- to 5-fold above baseline at 0.5 and 24 h after first application, respectively. Thereafter, serum T levels reached steady state and remained at 4- to 5-fold above baseline (at the upper limit of the normal adult range) for the duration of gel application and returned to baseline within 4 days after stopping application. The application of T gel at four sites (application skin area approximately four times that of one site) resulted in a mean area under the curve (AUC0-24h) for serum T levels on the 7th day (868 +/- 72 nmol*h/L, mean +/- SEM), which was 23% higher but not significantly different (P = 0.06) than repeated application at one site (706 +/- 59 nmol*h/L). This could be due to the limited number of subjects studied (n = 9). Mean serum DHT levels followed the same pattern as serum T, achieving steady-state levels by 2 days. The mean concentration of serum DHT on the 7th day was significantly higher after application at four sites (9.15 +/- 1.26 nmol/L, P < 0.05) than at one site (6.9 +/- 0.77 nmol/L). These serum DHT levels were at or above the normal adult male range. Serum DHT:T ratio was not significantly altered by T gel application. Serum estradiol levels followed the same pattern as serum T and showed no significant difference between the one- or four-site application. We conclude that transdermal daily application of 100 mg T gel resulted in similar steady levels of serum T. The surface area of the skin to which the gel was applied had only a modest impact on serum T and DHT levels. Mean serum levels of T and DHT was higher by 23% and 33%, respectively, despite application of the gel to four times the skin area in the four sites compared with the one site group. Because of the greater dosage flexibility provided, hydroalcoholic T gel application over multiple sites seems to be an effective and nonskin-irritating method of transdermal T delivery for hypogonadal men. Dose-ranging studies are required to determine dosage regimens for T gel application as a replacement therapy in hypogonadal men.
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PMID:Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel at one site versus four sites: a General Clinical Research Center Study. 1099 79

The clinical consequences of androgen deficiency in human immunodeficiency virus (HIV)-infected women remain underappreciated. The pharmacokinetics of transdermally administered testosterone in premenopausal women and HIV-infected women have not been studied. In this study we compared the pharmacokinetics of a novel testosterone matrix transdermal system (TMTDS) in healthy premenopausal women and women infected with HIV. Eight menstruating HIV-infected women, 18-50 yr of age, who had been receiving stable antiretroviral therapy, including a protease inhibitor, for at least 12 weeks and nine healthy, menstruating women of comparable age were enrolled. After baseline sampling during a 24-h control period in the early follicular phase (days 1-6), two TMTDS patches were applied with an expected delivery rate of 300 microg testosterone daily over an application period of 3-4 days. After 72 h, the patches were removed, a second set of two patches was applied, and blood samples were drawn over 96 h. Baseline serum total and free testosterone levels were lower in HIV-infected women than in healthy women. A diurnal rhythm of testosterone secretion, with higher levels in the morning and lower levels in the late afternoon, was apparent in both groups of women. Free testosterone levels were in the midnormal range at baseline in healthy women and increased above the upper limit of normal during TMTDS application. In HIV-infected women, free testosterone levels were in the low normal range at baseline and rose into the upper normal range during patch application. Serum total testosterone levels increased into the midnormal range in HIV-infected women and into the upper normal range in healthy women during patch application. The mean increments in free and total testosterone levels were significantly lower in HIV-infected women than in healthy women. Testosterone bioavailability, expressed as the mean +/- SEM baseline-subtracted area under the total testosterone curve, was significantly greater in healthy women than in HIV-infected women [3323 +/- 566 ng/dL x h (115 +/- 20 nmol/L x h) vs. 1506 +/- 316 ng/dL x h (52 +/- 11 nmol/ L x h); P = 0.016]. Assuming a daily testosterone delivery rate of 300 microg/day, the apparent plasma clearance was significantly higher in HIV-infected women than in healthy women (2531 +/- 469 vs. 1127 +/- 217 L/day1 P = 0.022), respectively. There was no significant change from baseline in serum LH, sex hormone-binding globulin, and estradiol levels in either group. Serum FSH levels showed a greater decrease from baseline in healthy women. A regimen of two testosterone patches applied twice a week can maintain serum total and free testosterone levels in the mid- to upper normal range, respectively, in HIV-infected women with low testosterone levels. During TMTDS application, the increments in serum total and free testosterone levels are lower in HIV-infected women than in healthy women, presumably due to increased plasma clearance or decreased absorption. Further studies are needed to assess the effects of physiological androgen replacement in HIV-infected women.
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PMID:Pharmacokinetics of a novel testosterone matrix transdermal system in healthy, premenopausal women and women infected with the human immunodeficiency virus. 1090 84

To examine neuromuscular and hormone changes during 2 weeks of heavy strength training, 18 weight-trained male students were recruited either into a heavy training group (HT, n = 11) or into a control group (Ctr, n = 7). The heavy training protocol consisted of leg-extensor workouts performed daily, while workouts were performed twice a week in the Ctr group. A test of one repetition maximum (1 RM) was performed before heavy training and on the 2nd day after heavy training. Isokinetic knee extensions, electrical stimulation, and squat jumps were performed before, on the 8th day of heavy training, and on the 4th day after heavy training. Morning blood samples (0800 hours) were drawn before, on the 8th day of heavy training, and on the 4th day after heavy training. Before, and on the 5th day after heavy training, 24 h urine samples were collected. The 1 RM leg press increased by 6 (SEM 2)% in the HT group. Testosterone and insulin-like growth factor-1 concentrations were respectively 12 (SEM 5)% and 11 (SEM 3)% lower than baseline on the 8th day of heavy training; however, hormone levels were back to baseline on the 4th day after heavy training. A significant correlation between individual changes in 1 RM leg press and changes in testosterone concentrations was observed in the HT group (r = 0.69). In the HT group, 24 h urinary catecholamine excretion increased by 26 (SEM 12)%, 3-methylhistidine excretion increased by 21 (SEM 6)% and creatinine excretion increased by 11 (SEM 5)%. There were no significant changes in the Ctr group. This work addresses the role of changes in basal hormone status (morning samples) for skeletal muscle adaptation to heavy strength training.
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PMID:Changes in human skeletal muscle contractility and hormone status during 2 weeks of heavy strength training. 1139 54

To understand the role of estrogen in testicular and epididymal function of rhesus monkeys, we measured steroids in the spermatic and peripheral venus circulation and aromatase activity and its mRNA in testis and epididymis. Testosterone, estradiol-17beta, and estrone, but not androstenedione, were elevated in the spermatic vein serum compared to the peripheral circulation. Aromatase activity in testis and in caput epididymis (259+/-16 [SEM] vs 274+/-47 fmol of 3H2O/mg of protein/h [n = 10], respectively) was significantly higher (p < 0.01) than in corpus and cauda (124+/-28 and 113+/-33 fmol of 3H2O/mg of protein/h [n = 10], respectively). In the ribonuclease protection assay, two P450arom mRNA transcripts were identified in testis and epididymis. One corresponded with the aromatase full-length transcript and the other was a truncated isoform. The latter was significantly more abundant than the former (p < 0.01). Our results demonstrate that the monkey testis and, to a lesser extent, the epididymis can aromatize androgens. However, in the epididymis, like in some areas of the brain, there was a discrepancy between the aromatase activity and the mRNA. The fact that P450arom mRNA and aromatase activity do not correlate in the epididymis may indicate that aromatase activity is not strictly regulated at the level of RNA expression and that other mechanisms for this regulation should be considered.
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PMID:Cytochrome P450 aromatase in testis and epididymis of male rhesus monkeys. 1182 22

Testosterone (T) is known to affect the growth hormone (GH) axis. However, the mechanisms underlying the activation of GH secretion by T still remain to be clarified. Available data in animals and humans have shown that withdrawal of somatostatin (SRIH) infusion induces a GH-releasing hormone (GHRH)-mediated rebound release of GH, and there is accumulating evidence that SRIH infusion withdrawal may be a useful test to probe the GHRH function in vivo. With the aim of investigating whether the stimulatory effect of androgens on GH release in man could be accounted for by activation of the hypothalamic GHRH tone, we evaluated the plasma GH response to SRIH withdrawal in 10 patients aged 29.6 +/- 2.4 years (mean +/- SEM), diagnosed with hypergonadotropic hypogonadism, before and after a 6-month replacement therapy with T enanthate (250 mg every 3 weeks, i.m.), and in 10 healthy men, aged 26.7 +/- 2.8 years. To verify whether the modulation of GH secretion by T could also be mediated through changes in SRIH tone and/or pituitary releasable pool, we examined GH secretory responses to combined GHRH and L-arginine (ARG) in the same individuals. Basal plasma concentrations of GH (0.48 +/- 0.11 microg/l) and IGF-I (23.79 +/- 1.83 nmol/l) were significantly lower in untreated hypogonadal patients than in healthy men, and significantly increased after T replacement therapy (GH 1.13 +/- 0.28 microg/l; IGF-I 28.71 +/- 1.46 nmol/l). The mean Delta GH peak after SRIH withdrawal recorded in untreated hypogonadal men (2.65 +/- 0.86 microg/l) was significantly (p < 0.05) lower than that observed in healthy men (6.53 +/- 1.33 microg/l) and significantly increased after T replacement therapy (5.52 +/- 1.25 microg/l). The GH responses to GHRH combined with ARG (a functional SRIH antagonist) were not significantly different between healthy men and untreated hypogonadal patients, and were not significantly affected by T treatment. Plasma T and estradiol (E(2)) levels significantly correlated with Delta GH peak after SRIH withdrawal in healthy men and in T-treated hypogonadal patients, whereas in untreated patients they did not. No significant correlation was found between GH areas under the curve after GHRH + ARG test and T and E(2) plasma levels in either healthy men or in hypogonadal patients (both before and after T replacement). These findings are consistent with the view that in humans the stimulatory action of T on the GH axis appears to be mediated at the hypothalamic level primarily by promoting GHRH function.
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PMID:Activation of the somatotropic axis by testosterone in adult men: evidence for a role of hypothalamic growth hormone-releasing hormone. 1284 24

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.
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PMID: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. 1613 Feb 74

Forty-four purebred Yorkshire boars, reared outdoors on concrete, were randomly assigned to one of three age groups (150 +/- 7, 200 +/- or 250 +/- 7 days of age) for the purpose of examining endogenous testosterone concentration in response to one of four exogenously administered treatments. Four boars from each age group were administered either human chorionic gonadotrophin (hCG; 1000 U.S.P. units intravenous), adrenocorticotrophin (ACTH; 100 IU intravenous), or testosterone proprionate (TP; 25 mg intramuscular). The remaining boars served as controls and were given saline (S; 5 ml IV). Blood samples were collected from each boar at -120, -90, -60, -30, and 0 min pre-treatment and at 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, 240, 270, 300, 330, and 360 min post-treatment via an indwelling anterior vena cava catheter. Plasma testosterone was quantified by radioimmunoassay. Within treatment, boars receiving hCG, ACTH or S responded similarly (P>.10) across the three age groups for measured testosterone. Plasma testosterone was elevated (P<.05) by 30 min (4.7 +/- .5 ng/ml; X +/- SEM) and 15 min (5.5 +/- 1.1 ng/ml) post-treatment in boars administered hCG and ACTH, respectively, when compared with the S (1.0 +/- .3 ng/ml) group. Testosterone in hCG treated boars peaked by 90 min (21.8 +/- 1.8 ng/ml) post-treatment, declined slightly until 210 min (18.8 +/- 1.8 ng/ml) post-treatment and increased thereafter. Hormone levels in ACTH treated boars plateaued by 45 min (7.5 +/- 1.4 ng/ml) post-treatment and began to decline by 90 min post-treatment. Plasma testosterone for TP treated boars differed (P<.05) over time among the three age groups. Boars 150 +/- 7 and 200 +/- 7 days of age had an increase in plasma testosterone at 150 and 240 min post-treatment with TP, respectively. Results suggest that the testosterone biosynthetic and secretory capabilities of the boar testes are fully operational by 150 days of age.
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PMID:Peripheral testosterone in boars after administration of hCG, ACTH and testosterone at three ages. 1672


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