Testosterone-induced Changes Research Articles

Effect of long-term testosterone therapy on molecular regulators of skeletal muscle mass and fibre-type distribution in aging men with subnormal testosterone

BackgroundLong-term testosterone replacement therapy (TRT) increases muscle mass in elderly men with subnormal testosterone levels. However, the molecular mechanisms underlying this effect of TRT on protein balance in human skeletal muscle in vivo remain to be established. MethodsHere, we examined skeletal muscle biopsies obtained before and 24-h after the last dose of treatment with either testosterone gel (n = 12) or placebo (n = 13) for 6 months in aging men with subnormal bioavailable testosterone levels. The placebo-controlled, testosterone-induced changes (β-coefficients) in mRNA levels, protein expression and phosphorylation were examined by quantitative real-time PCR and western blotting. ResultsLong-term TRT increased muscle mass by β = 1.6 kg (p = 0.01) but had no significant effect on mRNA levels of genes involved in myostatin/activin/SMAD or IGF1/FOXO3 signalling, muscle-specific E3-ubiquitin ligases, upstream transcription factors (MEF2C, PPARGC1A-4) or myogenic factors. However, TRT caused a sustained decrease in protein expression of SMAD2 (β = −36%, p = 0.004) and SMAD3 (β = −32%, p = 0.001), which was accompanied by reduced protein expression of the muscle-specific E3-ubiquitin ligases, MuRF1 (β = −26%, p = 0.004) and Atrogin-1/MAFbx (β = −20%, p = 0.04), but with no changes in FOXO3 signalling. Importantly, TRT did not affect muscle fibre type distribution between slow-oxidative (type 1), fast-oxidative (type 2a) and fast-glycolytic (type 2×) muscle fibres. ConclusionsOur results indicate that long-term TRT of elderly men with subnormal testosterone levels increases muscle mass, at least in part, by decreasing protein breakdown through the ubiquitin proteasome pathway mediated by a sustained suppression of SMAD-signalling and muscle-specific E3-ubiquitin ligases.

Developmental programming: Prenatal testosterone-induced changes in epigenetic modulators and gene expression in metabolic tissues of female sheep

Prenatal testosterone (T)-treated female sheep manifest peripheral insulin resistance and tissue-specific changes in insulin sensitivity with liver and muscle manifesting insulin resistance accompanied by inflammatory, oxidative and lipotoxic state. In contrast, visceral (VAT) and subcutaneous (SAT) adipose tissues are insulin sensitive in spite of VAT manifesting changes in inflammatory and oxidative state. We hypothesized that prenatal T-induced changes in tissue-specific insulin resistance arise from disrupted lipid storage and metabolism gene expression driven by changes in DNA and histone modifying enzymes. Changes in gene expression were assessed in liver, muscle and 4 adipose (VAT, SAT, epicardiac [ECAT] and perirenal [PRAT]) depots collected from control and prenatal T-treated female sheep. Prenatal T-treatment increased lipid droplet and metabolism genes PPARA and PLIN1 in liver, SREBF and PLIN1 in muscle and showed a trend for decrease in PLIN2 in PRAT. Among epigenetic modifying enzymes, prenatal T-treatment increased expression of 1) DNMT1 in liver and DNMT3A in VAT, PRAT, muscle and liver; 2) HDAC1 in ECAT, HDAC2 in muscle with decrease in HDAC3 in VAT; 3) EP300 in VAT and ECAT; and 4) KDM1A in VAT with increases in liver histone acetylation. Increased lipid storage and metabolism genes in liver and muscle are consistent with lipotoxicity in these tissues with increased histone acetylation likely contributing to increased liver PPARA. These findings are suggestive that metabolic defects in prenatal T-treated sheep may arise from changes in key genes mediated, in part, by tissue-specific changes in epigenetic-modifying enzymes.

Cytomorphologic findings of cervical Pap smears from female-to-male transgender patients on testosterone therapy.

The cervical cancer screening recommendation for transgender female-to-male (FTM) patients is the same as that for cisgender females. A lack of literature on testosterone-induced changes in cervical cytology in these patients may result in interpretation errors, especially without a proper clinical history. The aim of this study was to delineate the Papanicolaou (Pap) test findings in this patient population. A pathology laboratory information system was used to obtain a cohort of FTM transgender patients on testosterone therapy (2009-2019). A cohort of age-matched, atrophic, control cisgender female patients (postpartum or menopausal) was selected. A retrospective review of the cytomorphologic findings on cervical Pap smears, pertinent follow-up, and human papillomavirus (HPV) test results was performed. Fourteen transgender patients (age range, 21-64years; mean age, 42.5years) receiving testosterone therapy with 17 Pap smears were identified. One of the 5 available HPV tests was positive for HPV, and 4 were negative. A Pap smear review revealed the following: negative for intraepithelial lesion (NILM; 82.4%), unsatisfactory (5.9%), atypical squamous cells of undetermined significance (ASCUS; 5.9%), and low-grade squamous intraepithelial lesion (5.9%). The Pap smears of the atrophic cisgender cohort (102 patients) revealed the following: NILM (92.5%), unsatisfactory (0.9%), ASCUS (5.6%), and high-grade squamous intraepithelial lesion (0.9%). The difference between the rates of epithelial cell abnormality in the 2 cohorts was not statistically significant. Although atrophy was noted in both groups, cytomorphologic findings of transitional cell metaplasia (TCM; 88.2%) and "small cells" (82.4%) were characteristic of the testosterone-treated transgender cohort. Histologic correlates of TCM and small cells were noted in hysterectomy specimens from 6 patients. Small cells and TCM are common cytomorphologic findings in Pap smears of testosterone-treated transgender (FTM) patients. On the basis of histologic follow-up, small cells most likely represent atrophic parabasal cells of cervical-vaginal epithelium.

The effect of testosterone on thyroid autoimmunity in euthyroid men with Hashimoto's thyroiditis and low testosterone levels.

Thyroid autoimmune diseases occur much more frequently in women than men. Unfortunately, no previous study has determined whether sex hormones produce any effect on thyroid antibody titres. The primary study aim was to assess whether exogenous testosterone affects thyroid autoimmunity in men with Hashimoto's thyroiditis and low testosterone levels. The study population consisted of 34 euthyroid men with autoimmune thyroiditis and testosterone deficiency. On the basis of patient preference, these patients were either treated with oral testosterone undecanoate (120mg daily; n=16) or remained untreated (n=18). Circulating levels of thyrotropin, free thyroxine, free triiodothyronine, prolactin and total testosterone, as well as serum titres of thyroid peroxidase and thyroglobulin antibodies, were measured at the beginning of the study and 6months later. Thestructure parameters of thyroid homeostasis(Jostel's thyrotropin index, SPINA-GT and SPINA-GD) were also calculated. Moreover, semen analyses were performed in eight patients in each group. In testosterone-naïve men, serum hormone levels and antibody titres remained at the similar levels throughout the study. Apart from increasing serum testosterone levels, testosterone undecanoate reduced titres of thyroid peroxidase and thyroglobulin antibodies and increased SPINA-GT. The drug produced a neutral effect on circulating levels of thyrotropin, free thyroid hormones, prolactin and testosterone, Jostel's thyrotropin index, SPINA-GD and semen parameters. Testosterone-induced changes in antibody titres correlated with the effect of treatment on SPINA-GT and with serum testosterone levels. This study is the first one to have shown that exogenous testosterone may have a protective effect on thyroid autoimmunity in men with Hashimoto's thyroiditis and testosterone deficiency.

Effects of chronic testosterone administration on the degree of preference for a high-fat diet and body weight in gonadal-intact and ovariectomized female rats

Energy balance and reproductive functions are closely linked in some species. The sex hormones (estrogens and androgens) are involved in the regulation of appetite, metabolism, body weight (BW), and body composition in mammals. Previously, we showed that the effects of testosterone on BW, appetite, and fat weight were markedly affected by alterations to the gonadal hormonal milieu. In this study, we examined whether testosterone administration changes food preferences and whether these effects of testosterone depend on gonadal status in female rats. We also evaluated the underlying mechanisms responsible for these effects, focusing on hypothalamic inflammation and endoplasmic reticulum (ER) stress. In gonadal-intact (sham) female rats, chronic testosterone administration promoted a preference for a high-fat diet (HFD) and increased BW gain, fat weight, and adipocyte size, whereas no such effects were observed in ovariectomized (OVX) rats. Testosterone administration increased hypothalamic interleukin-1 mRNA expression in the sham rats, but not the OVX rats. On the contrary, testosterone administration decreased the hypothalamic mRNA levels of ER stress-response genes in the OVX rats, but not the sham rats. These testosterone-induced alterations in OVX rats might represent a regulatory mechanism for preventing hypothalamic inflammation and the overconsumption of a HFD. In conclusion, testosterone’s effects on food preferences and the subsequent changes were affected by gonadal status. Testosterone-induced changes in hypothalamic inflammatory cytokine production and ER stress might be related to these findings.

Testosterone supplementation, glucocorticoid milieu and bone homeostasis in the ageing male.

Male ageing is entwined with a continuous fall in free testosterone levels, which contributes to the pathogenesis of bone loss. Glucocorticoid excess, either dependent on the ageing process or iatrogenically induced, was found to additionally impair the bone structure and metabolism. Cautious testosterone supplementation in this respect may positively affect the glucocorticoid milieu and bone homeostasis, while testosterone-induced changes in the glucocorticoid output could serve as a determinant of bone-related therapeutic outcome. Namely, bone mineral content/density, the parameters of trabecular bone structure as well as bone strength are enhanced, serum calcitonin levels tend to increase, while serum osteocalcin, serum parathyroid hormone and urinary calcium decrease, all upon testosterone administration to the ageing male. In parallel, testosterone application decreases glucocorticoid secretion in the animal models of male ageing, while clinical data in this field are still inconsistent. Importantly, a physiological link exists between testosterone-induced changes in glucocorticoid levels and the tendency of bone status improvement in the ageing male. We believe that the assessment of circulating adrenocorticotropic hormone concentrations together with glucocorticoid levels, reflecting the hypothalamic-pituitary-adrenal axis feedback loop operativeness during testosterone supplementation, represents a well-balanced bone-related therapeutic update.

Prolonged in vivo administration of testosterone-enanthate, the widely used and abused anabolic androgenic steroid, disturbs prolactin and cAMP signaling in Leydig cells of adult rats

This study was designed to systematically analyze and define the effects of 1-day, 2-weeks, 10-weeks intramuscular administration of testosterone-enanthate, widely used and abused anabolic androgenic steroid (AAS), on main regulators of steroidogenesis and steroidogenic genes expression in testosterone-producing Leydig cells of adult rats. The results showed that prolonged (10-weeks) intramuscular administration of testosterone-enanthate, in clinically relevant dose, significantly increased prolactin, but decreased Prlr2 and Gnrhr in pituitary of adult rat. The levels of testosterone, Insl3, cAMP and mitochondrial membrane potential of Leydig cells were significantly reduced. This was followed by decreased expression of some steroidogenic enzymes and regulatory proteins such as Lhcgr, Prlr1/2, Tspo, Star, Cyp11a1, Cyp17a1, Dax1. Oppositely, Hsd3b1/2, Hsd3b5, Hsd17b4, Ar, Arr19 increased. In the same cells, transcriptional milieu of cAMP signaling elements was disturbed with remarkable up-regulation of PRKA (the main regulator of steroidogenesis). Increased prolactin together with stimulated transcription of Jak2/Jak3 could account for increased Hsd3b1/2 and Hsd3b5 in Leydig cells following 10-weeks in vivo treatment with testosterone-enanthate. In vitro studies revealed that testosterone is capable to increase level of Prlr1, Prlr2, Hsd3b1/2, Hsd3b5 in Leydig cells. Accordingly, testosterone-induced changes in prolactin receptor signaling together with up-regulation of PRKA, Hsd3b1/2, Hsd3b5, Ar in Leydig cells, could be the possible mechanism that contribute to the establishment of a new adaptive response to maintain homeostasis and prevent loss of steroidogenic function. Presented data provide new molecular insights into the relationship between disturbed testosterone homeostasis and mammalian reproduction and are important in terms of wide use and abuse of AASs and human reproductive health.

Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway.

Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase), breakdown (catechol-O-methyl transferase; monoamine oxygenase), transport [vesicular monoamine transporter (VMAT), dopamine transporter (DAT)] and receptors (DRD1-D5)] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen receptor-driven events as estradiol had minimal effect. We conclude that nigrostriatal responsivity to dopamine may be modulated by testosterone acting via androgen receptors to alter gene expression of molecules involved in dopamine signaling during adolescence.

Effect of exogenous testosterone on oxidative status of the testes in adult male rats

The aim of this study was to investigate the testosterone-induced changes in the oxidative status of testes in adult male rats treated either with testosterone or after blockade of androgen receptors with cyproterone acetate. A total of 40 intact rats were divided into four groups: a control group receiving sterile oil, the testosterone group receiving testosterone isobutyras, the cyproterone group receiving cyproterone acetate and the combination group receiving both testosterone isobutyras and cyproterone acetate. Treatments were carried out for 2days by intramuscular application. Parameters of oxidative stress and the expression levels of the steroidogenic acute regulatory protein (StAR) gene were measured in testes. Significantly increased TBARS and advanced glycation end products (AGEs) levels were found in the testosterone group when compared to the control group. The °1 ferric-reducing ability of the tissue and total antioxidative capacity were lower in the testosterone group in comparison with the control group. Gene expression analysis revealed significant downregulation of the StAR gene in the testes of rats in the testosterone and combination groups with respect to control animals. In conclusion, administration of exogenous testosterone influences the lipid peroxidation and carbonyl stress and decreases the antioxidant defence in the testes. These data might have implications for male fertility in humans.

Evaluation of early biomarkers of muscle anabolic response to testosterone

BackgroundEarly biomarkers of skeletal muscle anabolism will facilitate the development of therapies for sarcopenia and frailty.Methods and resultsWe examined plasma type III collagen N-terminal propeptide (P3NP), skeletal muscle protein fractional synthesis rate, and gene and protein expression profiles to identify testosterone-induced changes in muscle anabolism. Two placebo-controlled studies enrolled community-dwelling men (study 1, 60–75 years; study 2, 18–40 years) with low to normal testosterone levels. Men were randomized to lower dose (study 1, 100 mg; study 2, 200 mg) or higher dose (study 1, 300 mg; study 2, 600 mg) single intramuscular testosterone or saline injection. After 1 week, testosterone acutely increased plasma P3NP levels in a dose-dependent manner and altered the expression of several skeletal muscle transcripts and proteins. Though not statistically significant, mixed muscle protein fractional synthesis rate tended to increase (1.08-fold with 100 mg testosterone, 1.12-fold with 300 mg testosterone). Testosterone exposure also increased skeletal muscle expression of the collagen type III gene that encodes P3NP.ConclusionP3NP is a potentially useful early biomarker for muscle anabolic therapy. Skeletal muscle protein and RNA profiling are useful tools for the discovery of novel muscle anabolic biomarkers.

Effects of testosterone on morphology, performance and muscle mass in a lizard

Because sexual selection pressures are high in sexually dimorphic organisms, morphological, physiological and performance traits are often studied in a sexual selection context. The proximate mechanisms underlying evolutionary change in these traits, however, remain largely unstudied. Here, we examined the role of steroids in shaping morphology and physiological performance in males of a sexually dimorphic lizard (Gallotia galloti). We compared morphology and physiological performance of males with experimentally elevated testosterone levels to sham-operated males. Before surgery, inter-individual variation in plasma testosterone levels correlated positively with bite force capacity. Administration of exogenous testosterone resulted in an increase of the mass of both jaw closing and locomotory muscles compared with sham-operated individuals, but the responsiveness varied considerably among muscle groups. In contrast to our expectations, the dramatic testosterone-induced changes in muscle masses did not result in concordant changes in bite force performance or sprint speed.

Testosterone-induced changes in testicular antioxidant system.

In order to investigate the role of testosterone propionate (TP) on the antioxidant system of the rat testis, lipid peroxidation (LPX) and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) of the testis of testosterone-treated and control rats were compared. The results indicate that TP administration to intact adult rats resulted in a significant decline in protein content of various subcellular fractions. This is accompanied with significant elevation in LPX levels of various subcellular fractions suggesting induction of oxidative stress. Activities of three enzymes related to the metabolism of superoxide radical (SOD) and hydrogen peroxide (CAT and GPx) of testis, were found to be significantly decreased in response to TP treatment. The role of testosterone in regulating testicular spermatogenesis through oxidative stress is discussed.

Distinct Effects of Testosterone on Plasma and Cerebrospinal Fluid Amyloid-β Levels

The effect of testosterone on the levels of the Alzheimer's disease amyloid-beta peptide (Abeta) was investigated in guinea pigs. Castrated guinea pigs (GPX) were administered testosterone at two different dosages, following which plasma and cerebrospinal fluid (CSF) Abeta_{40} levels were measured. Plasma Abeta_{40} levels were reduced in GPX in the early stages of low-dose testosterone treatment, whereas CSF Abeta_{40} levels were only reduced by the time circulating testosterone had returned to untreated GPX levels. The supraphysiological testosterone dose did not reduce CSF Abeta_{40} levels significantly until circulating testosterone was back to uncastrated levels, whereas plasma Abeta_{40} levels significantly increased over time in these animals. These results indicate that the extent of testosterone-induced changes to Abeta_{40} levels and their response rates depend on both the tissue examined and testosterone dosage.

Testosterone Increases Amygdala Reactivity in Middle-Aged Women to a Young Adulthood Level

Testosterone modulates mood and sexual function in women. However, androgen levels decline with age, which may relate to the age-associated change in sexual functioning and the prevalence of mood and anxiety disorders. These effects of testosterone are potentially mediated by the amygdala. In the present study, we investigated whether the age-related decline in androgen levels is associated with reduced amygdala activity, and whether exogenous testosterone can restore amygdala activity. Healthy young and middle-aged women participated during the early follicular phase of the menstrual cycle, and amygdala responses to biologically salient stimuli were measured with functional magnetic resonance imaging (fMRI). Androgen levels were lower in middle-aged than young women, which was associated with decreased amygdala reactivity. Endogenous testosterone levels correlated positively with amygdala reactivity across the young and middle-aged women. The middle-aged women received a single nasal dose of testosterone in a double-blind, placebo-controlled, crossover manner, which rapidly increased amygdala reactivity to a level comparable to the young women. The enhanced testosterone levels correlated positively with superior frontal cortex responses and negatively with orbitofrontal cortex responses across individuals, which may reflect testosterone-induced changes in amygdala regulation. These results show that testosterone modulates amygdala reactivity in women, and suggest that the age-related decline in androgen levels contribute to the decrease in amygdala reactivity.

Steroid Hormones Act Transsynaptically within the Forebrain to Regulate Neuronal Phenotype and Song Stereotypy

Steroid sex hormones induce dramatic seasonal changes in reproductive related behaviors and their underlying neural substrates in seasonally breeding vertebrates. For example, in adult white-crowned sparrows, increased Spring photoperiod raises circulating testosterone, causing morphological and electrophysiological changes in song-control nuclei, which modify song behavior for the breeding season. We investigated how photoperiod and steroid hormones induce these changes in morphology, electrophysiology, and behavior. Neurons in a song premotor nucleus, the robust nucleus of the arcopallium (RA), show increased intrinsic spontaneous firing rate and soma size when birds are in breeding condition. Using combinations of systemic and unilateral local intracerebral hormonal manipulations, we show that long-day photoperiod accelerates the effects of systemic testosterone on RA neurons via the estradiol-synthesizing enzyme aromatase (CYP19A1); these changes require inputs from the afferent song control nucleus HVC (used as a proper name) and steroid receptor activation within HVC; local coactivation of androgen and estrogen receptors (ARs and ERs, respectively) within HVC, but not RA, is sufficient to cause neuronal changes in RA; activation of ARs in RA is also permissive. Using bilateral local intracerebral hormone-receptor blockade, we found that ARs and ERs in the song-control nucleus HVC mediate systemic testosterone-induced changes in song stereotypy but not rate. This novel transsynaptic effect of gonadal steroids on activity and morphology of RA neurons is part of a concerted change in key premotor nuclei, enabling stereotyped song.

Steroid hormones alter neuroanatomy and aggression independently in the tree lizard

Steroid hormones effect changes in both neuroanatomy and aggressive behavior in animals of various taxa. However, whether changes in neuroanatomy directly underlie changes in aggression is unknown. We investigate this relationship among steroid hormones, neuroanatomy, and aggression in a free-living vertebrate with a relatively simple nervous system, the tree lizard ( Urosaurus ornatus). Weiss and Moore [1] manipulated testosterone and progesterone levels in adult male tree lizards and found that both hormones facilitated aggressive behavior toward a conspecific. In this study, we examined the brains of a subset of these animals to determine whether changes in limbic morphology were associated with hormone-induced changes in aggressive behavior. Specifically, we tested the hypothesis that testosterone and/or progesterone cause changes in neural morphology that are necessary for the expression of testosterone's effects on aggressive behavior. We found that both hormones increased aggression; however, only testosterone induced changes in neuroanatomy. Testosterone increased the size of both the amygdala and nucleus sphericus. However, we could detect no individual correlations between neuroanatomy and aggression levels suggesting that the observed large-scale changes in neuroanatomy are not precisely reflective of changes in mechanisms underlying aggression.

Effects of testosterone and estrogen treatment on lipolysis signaling pathways in subcutaneous adipose tissue of postmenopausal women

The aim of this study was to investigate the treatment effects of testosterone and estrogen on the expression of proteins and genes involved in adipocyte signal transduction to lipolysis in abdominal subcutaneous adipose tissue of postmenopausal women. An open, randomized clinical study with parallel group comparison. Women's health clinical research unit and a research laboratory at a university hospital. Thirty-six healthy naturally postmenopausal women. The participants were randomly given testosterone undecanoate (40 mg every second day) or estradiol valerate (2 mg daily) for 3 months. Expression of proteins and genes involved in adipocyte signal transduction to lipolysis in abdominal subcutaneous adipose tissue, determined by quantitative real-time polymerase chain reaction and Western blot, respectively, and related to plasma glycerol before or during a euglycemic hyperinsulinemic clamp. Testosterone treatment decreased the expression of hormone-sensitive lipase and increased the expression of phosphodiesterase-3B, whereas no effect of estrogen was observed. Testosterone-induced changes in hormone-sensitive lipase expression correlated positively with corresponding changes in basal or clamp-induced plasma glycerol concentrations. Treatment with testosterone in postmenopausal women down-regulates hormone-sensitive lipase and up-regulates phosphodiesterase-3B expressions in abdominal subcutaneous adipose tissue in relation to changes in vivo of lipolytic activity, which may promote the accumulation of fat.

Testosterone responsiveness of spleen and liver in female lymphotoxin β receptor-deficient mice resistant to blood-stage malaria

Disrupted signaling through lymphotoxin β receptor (LTβR) results in severe defects of the spleen and even loss of all other secondary lymphoid tissues, making mice susceptible to diverse infectious agents. Surprisingly, however, we find that female LTβR-deficient mice are even more resistant to blood stages of Plasmodium chabaudi malaria than wild-type C57BL/6 mice. Higher resistance of LTβR-deficient mice correlates with an earlier onset of reticulocytosis, and the period of anemia is shorter. After surviving fulminant parasitemias of about 35%, mice develop long-lasting protective immunity against homologous rechallenge, with both spleen and liver acting as anti-malaria effectors. Testosterone suppresses resistance, i.e. all mice succumb to infections during or shortly after peak parasitemia. At peak parasitemia, testosterone does not essentially affect cellularity and apoptosis in the spleen, but aggravates liver pathology in terms of increased cell swelling, numbers of apoptotic and binucleated cells and reduced serum alkaline phosphatase levels, and conversely, reduces inflammatory lymphocytic infiltrates in the liver. In the spleen, hybridization of cDNA arrays identified only a few testosterone-induced changes in gene expression, in particular upregulation of INFγ and IFN-regulated genes. By contrast, a much larger number of testosterone-affectable genes was observed in the liver, including genes involved in regulation of the extracellular matrix, in chemokine and cytokine signaling, and in cell cycle control. Collectively, our data suggest that testosterone dysregulates the inflammatory response in spleen and liver during their differentiation to anti-malaria effectors in malaria-resistant female LTβR-deficient mice, thus contributing to the testosterone-induced lethal outcome of malaria.

The mechanisms of androgen effects on body composition: mesenchymal pluripotent cell as the target of androgen action.

Testosterone supplementation increases muscle mass primarily by inducing muscle fiber hypertrophy; however, the mechanisms by which testosterone exerts its anabolic effects on the muscle are poorly understood. The prevalent view is that testosterone improves net muscle protein balance by stimulating muscle protein synthesis, decreasing muscle protein degradation, and improving the reutilization of amino acids. However, the muscle protein synthesis hypothesis does not adequately explain testosterone-induced changes in fat mass, myonuclear number, and satellite cell number. We postulate that testosterone promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into the adipogenic lineage. The hypothesis that the primary site of androgen action is the pluripotent stem cell provides a unifying explanation for the observed reciprocal effects of testosterone on muscle and fat mass.

Both estrogen receptors and androgen receptors contribute to testosterone-induced changes in the morphology of the medial amygdala and sexual arousal in male rats

In male rats, a steroid-sensitive circuit in the forebrain regulates mating behavior. The masculine phenotype in one component of the circuit, the posterodorsal nucleus of the medial amygdala (MePD), depends on the level of circulating androgens in the adult. To investigate which gonadal steroid receptor(s) mediate sexual arousal and MePD plasticity, adult male rats were castrated and given Silastic capsules containing the nonaromatizable androgen 5α-dihydrotestosterone (DHT), 17β-estradiol (E2), both steroids, or nothing. A fifth group was sham-castrated and treated with blank capsules. DHT treatment was necessary and sufficient to maintain the expression of noncontact penile erections and ultrasonic vocalizations in castrates. E2 had no significant effect on these measures. Both DHT and E2 increased olfactory investigation (“nosepokes”) during the noncontact penile erection test. E2, but not DHT, maintained intromission patterns, while either steroid, alone or in combination, maintained ejaculatory behavior. Regional volume and cell soma size of the MePD both decreased following castration. Additionally, MePD cell size was lateralized, with left hemisphere neurons larger than those on the right, an effect that appeared independent of steroid manipulations. DHT and E2 each maintained neuronal soma size. E2 maintained MePD regional volume more effectively in the left MePD than in the right, which may have been due to a greater sensitivity of the left to both castration and hormone treatment. Thus, both androgen receptors and estrogen receptors appear to participate in sexual behaviors that may be mediated by the MePD in adult rats, and both receptors contribute to the steroid-regulated structural plasticity in this brain region.