Weeks Of Testosterone Treatment Research Articles

Chronic high-dose testosterone treatment: impact on rat cardiac contractile biology.

Androgen therapy provides cardiovascular benefits for hypogonadism. However, myocardial hypertrophy, fibrosis, and infarction have been reported in testosterone or androgenic anabolic steroid abuse. Therefore, better understanding of the factors leading to adverse results of androgen abuse is needed. The aim of the present study was to examine the impact of high dose of androgen treatment on cardiac biology, and whether exposure duration modulates this response. Male rats were treated with 10 mg/kg testosterone, three times a week, for either 4 or 12 weeks; vehicle injections served as controls. Four weeks of testosterone treatment induced an increase in ventricular wall thickness, indicative of concentric hypertrophy, as well as increased ejection fraction; in contrast, both parameters were blunted following 12 weeks of high‐dose testosterone treatment. Cardiac myocyte contractile parameters were assessed in isolated electrically stimulated myocytes (sarcomere and intracellular calcium dynamics), and in chemically permeabilized isolated myocardium (myofilament force development and tension‐cost). High‐dose testosterone treatment for 4 weeks was associated with increased myocyte contractile parameters, while 12 weeks treatment induced significant depression of these parameters, mirroring the cardiac pump function results. In conclusion, chronic administration of high‐dose testosterone initially induces increased cardiac function. However, this initial beneficial impact is followed by significant depression of cardiac pump function, myocyte contractility, and cardiac myofilament function. Our results indicate that chronic high‐testosterone usage is of limited use and may, instead, induce significant cardiac dysfunction.

The Effects of Testosterone Supplementation on Cognitive Functioning in Older Men.

Reduction in testosterone levels in men during aging is associated with cognitive decline and risk of dementia. Animal studies have shown benefits for testosterone supplementation in improving cognition and reducing Alzheimer’s disease pathology. In a randomized, placebo-controlled, crossover study of men with subjective memory complaint and low testosterone levels, we investigated whether testosterone treatment significantly improved performance on various measures of cognitive functioning. Forty-four men were administered a battery of neuropsychological tests to establish the baseline prior to being randomly divided into two groups. The first group (Group A) received 24 weeks of testosterone treatment (T treatment) followed by 4 weeks washout, and then 24 weeks of placebo (P); the second group (Group B) received the same treatments, in reverse order (Placebo, washout, and then T treatment). In group A (TèP), compared to baseline, there was a modest (1 point) but significant improvement in general cognitive functioning as measured by the Mini Mental State Examination (MMSE) following testosterone treatment. This improvement from baseline was sustained following the washout period and crossover to placebo treatment. Similar Mini Mental State Examination (MMSE) scores were observed when comparing testosterone treatment with placebo. In group B (PèT) a significant increase was observed from baseline following testosterone treatment and a trend towards an increase when compared to placebo treatment. Improvements in baseline depression scores (assessed by Geriatric Depression Scale) were observed following testosterone/placebo treatment in both groups, and no difference was observed when comparing testosterone with placebo treatment. Our findings indicate a modest improvement on global cognition with testosterone treatment. Larger clinical trials with a longer follow- up and with the inclusion of blood and brain imaging markers are now needed to conclusively determine the significance of testosterone treatment.

Testosterone affects language areas of the adult human brain

Although the sex steroid hormone testosterone is integrally involved in the development of language processing, ethical considerations mostly limit investigations to single hormone administrations. To circumvent this issue we assessed the influence of continuous high‐dose hormone application in adult female‐to‐male transsexuals. Subjects underwent magnetic resonance imaging before and after 4 weeks of testosterone treatment, with each scan including structural, diffusion weighted and functional imaging. Voxel‐based morphometry analysis showed decreased gray matter volume with increasing levels of bioavailable testosterone exclusively in Broca's and Wernicke's areas. Particularly, this may link known sex differences in language performance to the influence of testosterone on relevant brain regions. Using probabilistic tractography, we further observed that longitudinal changes in testosterone negatively predicted changes in mean diffusivity of the corresponding structural connection passing through the extreme capsule. Considering a related increase in myelin staining in rodents, this potentially reflects a strengthening of the fiber tract particularly involved in language comprehension. Finally, functional images at resting‐state were evaluated, showing increased functional connectivity between the two brain regions with increasing testosterone levels. These findings suggest testosterone‐dependent neuroplastic adaptations in adulthood within language‐specific brain regions and connections. Importantly, deteriorations in gray matter volume seem to be compensated by enhancement of corresponding structural and functional connectivity. Hum Brain Mapp 37:1738–1748, 2016. © 2016 Wiley Periodicals, Inc.

Testosterone Improves Erectile Function in Hypogonadal Patients With Venous Leakage

The goal of this study was to assess the therapeutic benefits of long-acting testosterone therapy in hypogonadal patients with erectile dysfunction (ED). We recruited 29 patients with ED, ranging in age from 32 to 65 years (mean +/- SD, 47 +/- 9.7 years), with low plasma testosterone, who did not respond to phosphodiesterase type 5 inhibitor therapy. To evaluate penile arterial and venous blood flow, we employed duplex Doppler ultrasonography. For confirmation of diagnosis of venous leakage, pharmacocavernosography was carried out in 9 patients and magnetic resonance imaging with intracavernous contrast enhancement was carried out in 8 patients. All patients were treated with 1000 mg injectable testosterone undecanoate on day 1, followed by another injection after 6 weeks and every 3 months thereafter, in accordance with Nebido therapy protocol. Plasma testosterone levels were determined in all patients at baseline and after 18 and 30 weeks of testosterone treatment. The International Index of Erectile Function (IIEF-5) was administered at baseline and after 18 and 30 weeks of testosterone treatment. At baseline total testosterone ranged from 7 to 11.8 nmol/L (200 to 345 ng/dL) in 25 patients. Eighteen and 30 weeks after testosterone treatment, the mean testosterone plasma levels were 18 and 21.5 nmol/L (520 and 625 ng/dL), respectively. After 18 and 30 weeks of testosterone treatment, 20 out of the 29 patients demonstrated marked improvement in erectile function domain, as assessed by the IIEF-5. This was also associated with diminution of venous leakage. We suggest that, in hypogonadal men with ED, testosterone therapy improves erectile function in patients with ED and venous leakage.

7α‐Methyl‐19‐Nortestosterone (MENT) vs Testosterone in Combination With Etonogestrel Implants for Spermatogenic Suppression in Healthy Men

Testosterone with a progestogen can suppress spermatogenesis for contraception. The synthetic androgen 7alpha-methyl-19-nortestosterone (MENT) may offer advantages because it is resistant to 5alpha-reduction and is therefore less active at the prostate. This study aimed to investigate MENT implants in combination with etonogestrel on spermatogenesis, gonadotropins, and androgen-dependent tissues in comparison with a testosterone/etonogestrel regimen. Healthy men (n = 29) were recruited and randomized to receive 2 etonogestrel implants with either 600-mg testosterone pellets repeated every 12 weeks or 2 MENT implants for up to 48 weeks. Testosterone concentrations in the testosterone group remained in the normal range. Subjects with 2 MENT implants showed peak MENT levels at 4 weeks with testosterone concentrations of 2 nmol/L. Sperm concentrations fell rapidly to less than 1 x 10(6)/mL at 12 weeks in 8 of 10 subjects in the MENT group and 13 of 16 subjects in the testosterone group with equally suppressed gonadotropins. Thereafter, suppression was not maintained in the MENT group, and 6 men noted loss of libido. Fourteen men completed 48 weeks of testosterone treatment, and all became azoospermic. Hemoglobin concentrations rose, and high density lipoprotein-cholesterol (HDL-C) fell in both groups. The MENT group showed a fall in prostate-specific antigen with no change in bone mass. MENT with a progestogen can achieve rapid suppression of spermatogenesis similar to testosterone, but this promising result was not sustained due to a decline in MENT release from the implants. This dose of testosterone, compared with previous studies using a lower dose with a higher dose of etonogestrel, had nonreproductive side effects without any increase in spermatogenic suppression. These data indicate the importance of the doses of progestogen and testosterone for optimum spermatogenic suppression while minimizing side effects.

Sensitivity as outcome measure of androgen replacement: the AMS scale

BackgroundThe capacity of the AMS scale as clinical utility and as outcome measure still needs validation.MethodsAn open post-marketing study was performed by office-based physicians in Germany in 2004. We analysed data of 1670 androgen-deficient males who were treated with testosterone gel. The AMS scale was applied prior to and after 3 months treatment.ResultsThe improvement of complaints under treatment relative to the baseline score was 30.7% (total score), 27.3% (psychological domain), 30.5% (somatic domain), and 30.7% (sexual domain), respectively. Patients with little or no symptoms before therapy improved by 9%, those with mild complaints at entry by 24%, with moderate by 32%, and with severe symptoms by 39% – compared with the baseline score. We showed that the distribution of complaints of testosterone deficient men before therapy almost returned to norm values after 12 weeks of testosterone treatment. Age, BMI, and total testosterone level at baseline did not modify the positive effect of androgen therapy. We also demonstrated that the AMS results can predict the independent (physician's) opinion about the individual treatment effect. Both, sensitivity (correct prediction of a positive assessment by the physician) and specificity (correct prediction of a negative assessment by the physician) were over 70%, if about 22% improvement of the AMS total score was used as cut-off point.ConclusionThe AMS scale showed a convincing ability to measure treatment effects on quality of life across the full range of severity of complaints. Effect modification by other variables at baseline was not observed. In addition, results of the scale can predict the subjective clinical expert opinion on the treatment efficiency.

Safety and Efficacy of Testosterone Gel 1% Augmentation in Depressed Men With Partial Response to Antidepressant Therapy

The current study evaluates the efficacy and safety of testosterone (T) gel 1% augmentation on depressive symptoms and quality of life in treatment-resistant, depressed, hypogonadal men older than 50 years of age who are receiving antidepressants. The authors hypothesized that T augmentation would improve depressive symptoms and quality of life. Eighteen hypogonadal men entered the study who had had an adequate trial of antidepressant therapy and had significant depressive symptoms. Participants were continued on their antidepressant and were randomized to receive either placebo or active T gel (5 g) to be applied once a day. Participants were tested on 6 occasions: screening visit, an initial session (pretreatment), at 6 and 12 weeks during the first treatment condition, and at 18 and 24 weeks during the crossover condition. The authors found a significant improvement in depressive symptoms from baseline to 12 weeks of testosterone treatment. However, a statistical difference between placebo and testosterone treatment phases was not demonstrated. The limitations of the study, including the chronicity and severity of patients' depression, variability in T levels, and a small sample size, probably influenced the ability to detect a discernable difference. Nevertheless, the study shows that T gel augmentation may be helpful in hypogonadal males with depression.

The Aging Males' Symptoms scale (AMS) as outcome measure for treatment of androgen deficiency.

No clinical study data in which the AMS scale was applied as outcome measure has been reported until today. An open post-marketing study was performed by office-based urologists in Germany in 2000/01. We analysed data of 1174 androgen-deficient males who were treated with testosterone enanthate. The AMS scale was applied prior to and after 12 weeks treatment. The improvement of complaints during treatment relative to the baseline score was 32% on average. Patients with little or no symptoms before therapy improved by 11%, those with mild complaints at entry by 24%, with moderate by 31%, and with severe symptoms by 39% compared with the baseline score. We showed that the distribution of complaints of testosterone-deficient men before therapy almost returned to norm values after 12 weeks of testosterone treatment. We also demonstrated that the AMS results can predict the independent (physician's) opinion about the individual treatment effect. The positive predictive value was 89%, the negative predictive value 59%, sensitivity (correct prediction of a positive assessment by the urologist) 96%, however, the specificity (correct prediction of a negative assessment by the physician) was only 30%. The AMS scale showed a convincing ability to measure treatment effects on quality of life across the full range of severity of complaints. In addition, results of the scale can predict the subjective clinical expert opinion on the treatment efficiency.

Temporal gene expression is restored concomitantly with germ cells in the experimentally regressed rat testis

The present study was designed to examine the effect of hypophysectomy and subsequent testosterone administration on germ cell numbers and germ cell- and Sertoli cell-specific mRNA levels in adult rats. Rats were hypophysectomized and 4 weeks later received 24-cm testosterone-containing polydimethylsiloxane (PDS) implants. Sham-hypophysectomized rats received an empty PDS implant. At 0 and 3 days, and at 1, 2, 4, and 8 weeks, rats were killed. One testis from each rat (n = 4/group) was used to prepare total RNA; the other testis was used to enumerate stage VII-VIII germ cells. cDNA probes for germ cell and Sertoli cell products were used to monitor germ cell- and Sertoli cell-specific mRNAs on Northern blots. Four weeks after hypophysectomy (0 days), preleptotene and pachytene spermatocytes and round and elongating spermatids were reduced in number to 54%, 12%, 1%, and 0%, respectively, of the control values. Testosterone administration caused a time-dependent increase in germ cell numbers; after 8 weeks of testosterone treatment, preleptotene and pachytene spermatocytes and round and elongating spermatids were 75%, 79%, 74%, and 22%, respectively, of control values. Lactate dehydrogenase-C, phosphoglycerate kinase-2, protamine-1, and sulfated glycoprotein-2 mRNA levels (on a per micrograms RNA basis) were 34%, 34%, less than 1%, and 580% of control values, respectively, 4 weeks after hypophysectomy and 79%, 87%, 61%, and 192% of control values, respectively, after 8 weeks of testosterone treatment. Pachytene spermatocyte and round spermatid numbers increased, while Sertoli cell sulfated glycoprotein-2 mRNA levels decreased, with respect to 4 week hypophysectomy values, as early as 3 days after implantation of testosterone capsules. In contrast, germ cell (lactate dehydrogenase-C, phosphoglycerate kinase-2, and protamine-1) mRNA levels increased to the greatest extent between 1-4 weeks after the start of testosterone treatment and, after a short lag period, reflected increases in germ cell type and number. The results indicate that cell-specific mRNAs appear concomitantly with germ cell reappearance in a time-dependent manner in the testes of testosterone-treated hypophysectomized adult rats.

Temporal gene expression is restored concomitantly with germ cells in the experimentally regressed rat testis.

The present study was designed to examine the effect of hypophysectomy and subsequent testosterone administration on germ cell numbers and germ cell- and Sertoli cell-specific mRNA levels in adult rats. Rats were hypophysectomized and 4 weeks later received 24-cm testosterone-containing polydimethylsiloxane (PDS) implants. Sham-hypophysectomized rats received an empty PDS implant. At 0 and 3 days, and at 1, 2, 4, and 8 weeks, rats were killed. One testis from each rat (n = 4/group) was used to prepare total RNA; the other testis was used to enumerate stage VII-VIII germ cells. cDNA probes for germ cell and Sertoli cell products were used to monitor germ cell- and Sertoli cell-specific mRNAs on Northern blots. Four weeks after hypophysectomy (0 days), preleptotene and pachytene spermatocytes and round and elongating spermatids were reduced in number to 54%, 12%, 1%, and 0%, respectively, of the control values. Testosterone administration caused a time-dependent increase in germ cell numbers; after 8 weeks of testosterone treatment, preleptotene and pachytene spermatocytes and round and elongating spermatids were 75%, 79%, 74%, and 22%, respectively, of control values. Lactate dehydrogenase-C, phosphoglycerate kinase-2, protamine-1, and sulfated glycoprotein-2 mRNA levels (on a per micrograms RNA basis) were 34%, 34%, less than 1%, and 580% of control values, respectively, 4 weeks after hypophysectomy and 79%, 87%, 61%, and 192% of control values, respectively, after 8 weeks of testosterone treatment. Pachytene spermatocyte and round spermatid numbers increased, while Sertoli cell sulfated glycoprotein-2 mRNA levels decreased, with respect to 4 week hypophysectomy values, as early as 3 days after implantation of testosterone capsules. In contrast, germ cell (lactate dehydrogenase-C, phosphoglycerate kinase-2, and protamine-1) mRNA levels increased to the greatest extent between 1-4 weeks after the start of testosterone treatment and, after a short lag period, reflected increases in germ cell type and number. The results indicate that cell-specific mRNAs appear concomitantly with germ cell reappearance in a time-dependent manner in the testes of testosterone-treated hypophysectomized adult rats.

Temporal constraints on androgen directed laryngeal masculinization in Xenopus laevis

Temporal constraints on androgen regulated masculinization of three sexually dimorphic laryngeal properties--tension, fiber type, and fiber recruitment--were examined in Xenopus laevis frogs. Endocrine state was manipulated at PM0 when the larynx is similar in males and females, at PM2 when the larynx begins sexual differentiation, and at PM6 when sexual differentiation is complete. Removing the testes in developing males (PM0 or PM2) completely arrests laryngeal masculinization. Masculinization resumes when testosterone is replaced later in development (PM2 or PM6, respectively). Thus, testicular secretions, in particular androgens, are required for laryngeal masculinization. The ability of androgens to masculinize tension, fiber type, and fiber recruitment in developing and adult larynges was also determined. Five weeks of testosterone treatment in PM0 or PM2 males and females completely masculinizes laryngeal tension and fiber type, but only partially masculinizes fiber recruitment. However, fiber recruitment can be fully masculinized in PM6 males castrated at PM2. We conclude that androgen induced masculinization of tension and fiber type are not temporally constrained but that androgen induced masculinization of fiber recruitment is. Prolonged androgen treatment can override the temporal constraints on masculinization of the larynx. Testosterone treatment for more than 6 months fully masculinizes fiber recruitment in developing (PM0 or PM2) females. In addition, prolonged treatment (greater than 9 months) completely masculinizes tension, fiber type, and fiber recruitment in adult females; these properties were not fully masculinized by shorter (1-3 months) treatments in adult females. Testosterone induced masculinization in females is maintained for up to 8 months following testosterone removal; thus androgen effects are long lasting and possibly permanent.

The effect of 6 weeks of testosterone treatment on pulsatile luteinizing hormone secretion in eugonadal female-to-male transsexuals

Polycystic ovary disease generally is associated with elevated androgen levels and elevated luteinizing hormone (LH) levels, whereas follicle-stimulating hormone (FSH) levels are (sub)normal. To assess the role of androgens on gonadotropin secretion, we investigated the effect of 6 weeks of testosterone (T) undecanoate, 120 to 160 mg/d orally, on the parameters of the pulsatile secretion of LH in a group of six eugonadal female-to-male transsexuals with normal menstrual cycles. The treatment suppressed menstrual activity in all patients. Serum T and estrone were significantly elevated after treatment with oral T undecanoate. The parameters of the pulsatile secretion of LH were not affected by androgen administration. Levels of FSH, estradiol, and progesterone also did not change significantly.

To What Extent Can Spermatogenesis Be Maintained in the Hypophysectomized Adult Rat Testis with Exogenously Administered Testosterone?*

In a previous study it was demonstrated that spermatogenesis can be maintained quantitatively with exogenously administered testosterone in adult intact rats that lack LH. The studies described herein were designed to examine the extent to which spermatogenesis can be maintained quantitatively with exogenously administered testosterone in adult rats that lack all pituitary hormones. Adult male rats were hypophysectomized and testosterone was administered at the time of hypophysectomy via sustained release polydimethylsiloxane (PDS) capsules of increasing lengths. We used the PDS capsules to clamp testosterone at defined concentrations within the seminiferous tubule fluid over a 2- to 3-month treatment period. Mean testis weights and advanced spermatid numbers per testis stabilized by 8 weeks of testosterone treatment regardless of testosterone dose. Both testis weight and advanced spermatid number responded to testosterone dose, reaching plateaus of 1.2 g and 170 x 10(6) per testis, respectively. These values were 60% of, and significantly less than, the respective control values. This result was in striking contrast to the results of our previous study of LH-suppressed intact rats, in which exogenously administered testosterone resulted in testis weights and advanced spermatid numbers that plateaued at values not significantly different from those in controls. These different effects of testosterone in intact and hypophysectomized rats occurred despite the fact that the seminiferous tubule fluid testosterone concentrations achieved in the hypophysectomized rats (up to 25 ng/ml) were greater than the minimal testosterone concentration found previously to be required to maintain spermatogenesis quantitatively in LH-suppressed intact rats (13 ng/ml). Taken together, these results demonstrate clearly that intratesticular testosterone doses that are as high as or higher than those that maintain spermatogenesis quantitatively in intact rats lacking LH fail to maintain spermatogenesis quantitatively in rats lacking all pituitary hormones.

Preliminary characterization, androgen-dependence and ontogeny of an abundant protein from mouse vas deferens.

Polyacrylamide gel electrophoresis analysis revealed that the vas deferens of adult mouse contains a major protein. Mouse vas deferens protein is a basic glycoprotein with a molecular weight of 34,800 +/- 300. The protein represents 17 +/- 0.7% and 42 +/- 2.4% of soluble proteins from homogenate and luminal fluid respectively, an estimate based on densitometric scanning of polyacrylamide gels. The protein originated from the vas deferens since it was not detected in blood plasma or in sexual organs and it was still present after ligation of the epididymis. Changes in androgen status of the animal markedly affected the vas deferens protein. After castration a progressive decrease in the protein was observed and its relative percentage dropped to 2 +/- 0.4% after 45 days. The concentration of the protein returned to precastration levels after 2 weeks of testosterone treatment but oestradiol, progesterone and corticosterone were ineffective in this respect. The vas deferens protein was not synthesized in significant amounts until animals were 20 days old and its concentration increased rapidly from 20 to 30 days in concert with the pubertal increase of androgens in the vas deferens.

Aggression in adult female mice: Chronic testosterone treatment induces attack against olfactory bulbectomized male and lactating female mice

Ovariectomized adult female CFW mice were given a series of tests for fighting behavior against olfactory bulbectomized male and lactating female mice prior to (for 2 weeks), and during (for 4 weeks) chronic treatment with testosterone propionate. While ovariectomized, 40% attacked the lactating female and 13.3% attacked the olfactory bulbectomized male. While ovariectomized and testosterone-treated, 73.3% attacked the lactating female and 60% attacked the olfactory bulbectomized male. However, during the initial 2 weeks of testosterone treatment there was an inhibition of attack against the lactating female. This was followed by a facilitation of attack against the olfactory bulbectomized male and the lactating female during the third and fourth weeks of testosterone treatment. When compared with a previous experiment showing that male mice, gonadally-intact or castrated and testosterone-treated, discriminate between these two stimuli (only the bulbectomized male is attacked), the present data do not support the notion that sexual differentiation of mouse aggression is due solely to the development of a limited sensitivity to testosterone in females.

Testosterone-dependent non-copulatory behaviour in male hamsters (Mesocricetus auratus).

Male hamsters (intact, castrated or testosterone-treated) were tested for their response to dioestrous and to oestrous females. Response to the dioestrous female was measured in terms of proximity and olfactory investigation; response to the oestrous female was measured in terms of mounting, intromission and ejaculation. Interest in dioestrous females declined in parallel with copulatory behaviour after castration and was restored by implantation of testosterone. Six weeks of testosterone treatment failed to restore copulatory behaviour to pre-castration levels; in contrast, interest in the dioestrous female was fully restored. Different components of the behaviour towards dioestrous female changed at different rates; some were restored within a week of implantation while others took several weeks to reach pre-castration levels. As found previously, the tendencies of the male to approach and to leave the female varied independently.

Plasma testosterone levels and sexual performance of young obese male Zucker rats

The sexual behavior of obese male Zucker rats was studied at the age of 7, 8, 9, 10, 11, 14, and 16 weeks. Between 12–14 weeks of age, obese rats were treated with 400 μg testosterone propionate daily. Plasma testosterone levels were determined at the age of 10, 14, 16, and 20 weeks. Compared to lean rats, the sexual performance of the obese rats was abnormal at all ages. Plasma testosterone levels of obese rats were significantly lower at the age of 20 weeks but not at the age of 10 and 16 weeks, compared to those of their lean littermates. At the age of 14 weeks, after 2 weeks of testosterone treatment, plasma testosterone concentration rose to levels significantly higher than those of their lean littermates. However, there was no improvement in their sexual behavior following this period of hormone treatment. This study strongly suggests that obese male Zucker rats have abnormal reproductive function at all ages and that testosterone deficiency is not a primary cause of this abnormality.