Combined Administration Of Testosterone Research Articles

How Does Testosterone Augment the Anabolic Response to Exercise in Frail Older Adults?

Testosterone treatment increases muscle mass, strength, and leg power in menopausal women, hypogonadal men, older men with mobility limitation, COPD and ESRD. Testosterone's effects on muscle mass and strength are augmented by exercise training and growth hormone. Testosterone treatment improves some measures of physical performance, such as stair climbing power and aerobic capacity; the improvements in gait speed have been modest. Testosterone increases muscle mass by inducing the hypertrophy of type 1 and 2 muscle fibers, and by increasing satellite cell number. Testosterone promotes the differentiation of mesenchymal progenitor cells into myogenic lineage and inhibits their differentiation into adipogenic lineage by activating Wnt-target genes, including follistatin that plays an important role in mediating testosterone's effects on the muscle. Testosterone also increases polyamine synthesis in the muscle. Combined administration of testosterone plus multi-component exercise intervention that includes functional training may be needed to improve function and mobility in older adults.

Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate‐sparing anabolic therapy

Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone’s adverse effects on prostate have inspired efforts to develop strategies that selectively increase muscle mass while sparing the prostate. Testosterone’s promyogenic effects are mediated through upregulation of follistatin. We show here that the administration of recombinant follistatin (rFst) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of rFst administration, follistatin transgenic mice with constitutively elevated follistatin levels displayed greater muscle mass than controls, but had similar prostate weights. To elucidate signaling pathways regulated differentially by testosterone and rFst in prostate and muscle, we performed microarray analysis of mRNAs from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or rFst. Testosterone and rFst shared the regulation of many transcripts in levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testosterone treatment, while rFst showed a negligible effect with only 9 transcripts differentially expressed. Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine biosynthesis, as a testosterone-responsive gene that is unresponsive to rFst. Accordingly, we administered testosterone with and without α-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice. DFMO selectively blocked testosterone’s effects on prostate, but did not affect testosterone’s anabolic effects on muscle. Co-administration of testosterone and Odc1 inhibitor presents a novel therapeutic strategy for prostate-sparing anabolic therapy.

Role of the bed nucleus of the stria terminalis in cardiovascular changes following chronic treatment with cocaine and testosterone: A role beyond drug seeking in addiction?

Neural plasticity has been observed in the bed nucleus of the stria terminalis (BNST) following exposure to both cocaine and androgenic–anabolic steroids. Here we investigated the involvement of the BNST on changes in cardiovascular function and baroreflex activity following either single or combined administration of cocaine and testosterone for 10 consecutive days in rats. Single administration of testosterone increased values of arterial pressure, evoked rest bradycardia and reduced baroreflex-mediated bradycardia. These effects of testosterone were not affected by BNST inactivation caused by local bilateral microinjections of the nonselective synaptic blocker CoCl2. The single administration of cocaine as well as the combined treatment with testosterone and cocaine increased both bradycardiac and tachycardiac responses of the baroreflex. Cocaine-evoked baroreflex changes were totally reversed after BNST inactivation. However, BNST inhibition in animals subjected to combined treatment with cocaine and testosterone reversed only the increase in reflex tachycardia, whereas facilitation of reflex bradycardia was not affected by local BNST treatment with CoCl2. In conclusion, the present study provides the first direct evidence that the BNST play a role in cardiovascular changes associated with drug abuse. Our findings suggest that alterations in cardiovascular function following subchronic exposure to cocaine are mediated by neural plasticity in the BNST. The single treatment with cocaine and the combined administration of testosterone and cocaine had similar effects on baroreflex activity, however the association with testosterone inhibited cocaine-induced changes in the BNST control of reflex bradycardia. Testosterone-induced cardiovascular changes seem to be independent of the BNST.

Influence of the single or combined administration of cocaine and testosterone in autonomic and neuroendocrine responses to acute restraint stress

Abuse of cocaine and androgenic-anabolic steroids (AASs) has become a serious public health problem. Despite reports of an increase in the incidence of simultaneous abuse of these substances, potential toxic interactions between cocaine and AASs are poorly known. In the present study, we investigated the effects of either single or combined administration of testosterone and cocaine for one or 10 consecutive days on autonomic (arterial pressure, heart rate and tail cutaneous temperature) and neuroendocrine (plasma corticosterone) responses induced by acute restraint stress in rats. Combined administration of testosterone and cocaine for 10 days reduced the increase in heart rate and plasma corticosterone level, as well as the fall in tail skin temperature induced by restraint stress. Furthermore, repeated administration of cocaine inhibited the increase in arterial pressure observed during restraint, and this effect was not affected by coadministration of testosterone. Ten-day combined administration of testosterone and cocaine increased basal values of arterial pressure. Moreover, chronic administration of testosterone induced rest bradycardia and elevated basal level of plasma corticosterone. One-day single or combined administration of the drugs did not affect any parameter investigated. In conclusion, the present study demonstrated that combined administration of testosterone and cocaine changed the autonomic and neuroendocrine responses to acute restraint stress. These findings suggest that interaction between AASs and cocaine may affect the ability to cope with stressful events.

Effect of combined administration of testosterone and cocaine on baroreflex activity in unanesthetized rats

Effect of combined administration of testosterone and cocaine on baroreflex activity in unanesthetized rats

Sexual hormones utilize complex mechanisms to modulate sebocyte differentiation

Sexual hormones are important in the maintenance of human skin. Being the endocrine “brain” of the skin, the sebaceous gland is a major target of sexual hormones. While androgens stimulate sebocyte proliferation, estrogens do not to affect sebaceous gland growth. Regarding differentiation, androgens are expected to stimulate and estrogens to suppress sebaceous lipid synthesis, while estrogens, in vivo, enhance sebaceous lipogenesis in aged skin. The latter results have been disputed by current in vitro data indicating no direct effect of sexual hormones on sebocyte differentiation. To elucidate these contradictions we have investigated possible pathways which may be used by sexual hormones to modulate sebocyte differentiation in vitro. It has been postulated that androgen induction of lipogenesis requires the concomitant presence of peroxisome proliferator‐activated receptor (PPAR) ligands. We found that arachidonic acid (AA), the direct precursor of leukotriene B4, a natural PPARα ligand, and linoleic acid (LA), a natural PPARδ ligand, induce sebocyte enlargement, accumulation of lipid droplets in the cytoplasm, and nuclear fragmentation. The combined administration of testosterone and AA or LA slightly increased sebaceous lipogenesis. In contrast, synthetic PPAR ligands were unable to enhance sebaceous lipogenesis. Interestingly, AA synthesis in human sebocytes was significantly stimulated by the prostaglandins (PG) E2 and Δ15‐J2. On the other hand, PPARγ expression was downregulated by the phytoestrogen genistein. Interestingly, 17β‐estradiol has previously been shown to induce the metabolism of PGD2 to Δ12‐PGJ2, a natural PPARγ ligand. In addition, we found that 17β‐estradiol increases IGF‐I synthesis (+28%) and down‐regulates IGF‐IR expression (−37 to −48%), whereas IGF‐I significantly induces sebaceous lipogenesis. In conclusion, sexual hormones are not directly active but are likely to utilize complex mechanisms, including modified known pro‐inflammatory pathways, to modulate sebocyte differentiation.

Involvement of transforming growth factor alpha (TGFalpha) and epidermal growth factor receptor (EGFR) in sex hormone-induced prostatic dysplasia and the growth of an androgen-independent transplantable carcinoma of the prostate.

We previously reported the induction of dysplasia, a putative precursor of carcinoma, in the dorsolateral prostates (DLPs) of Noble rats by the combined administration of testosterone (T) and estradiol-17beta (E2) for 16 weeks. Additionally, we demonstrated growth of the AIT, a DLP-derived, androgen-independent, transplantable solid tumor, in castrated syngeneic hosts. In this investigation, using Northern blot hybridization, radioimmunoassays and radioligand assays, we showed that transforming growth factor-alpha (TGFalpha) and epidermal growth factor receptor (EGFR) were expressed at close to non-detectable levels in the ventral prostates but at low, but measurable, levels in the DLPs of untreated rats. Enhanced expression of this ligand and its receptor was detected in the DLPs harboring dysplasia and marked overexpression of these molecules was noted in the AIT. In contrast, epidermal growth factor (EGF) expression was found to be constitutively expressed, at high levels, in both normal and dysplastic DLPs, but virtually absent in the AIT. Immunohistochemical data suggested that EGF, TGFalpha and EGFR were aprocine secretory products of the normal DLP, with TGFalpha and EGF localized to the supranuclear complexes and EGFR to the apical membranes of epithelial cells. Alterations in immunostaining patterns for TGFalpha and EGFR were exclusively detected in the dysplastic lesions in the DLPs of T + E2-treated rats. Enhanced intracytoplasmic localization for both peptides were found to accompany the loss of cell polarity in dysplastic foci. Strong intracytoplasmic immunostaining for TGFalpha was observed in some AIT cells whilst staining for EGFR was present in the membranes of tumor cells that formed psuedoacini. Taken together, our findings suggest that autocrine mechanisms may play an important role early in the carcinogenic process and that progression to an androgen-independent neoplastic growth may be modulated by this signaling pathway.

Restoration of testicular transferrin, insulin-like growth factor-1 (IGF-1), and spermatogenesis by exogenously administered purified FSH and testosterone in medically hypophysectomized rats.

To investigate the relation between testicular transferrin and insulin-like growth factor-1 (IGF-1) secreted by Sertoli cells and the differentiation of germ cells in the rat, testosterone and/or purified FSH was administered to rats medically hypophysectomized by an LH-RH agonist. Spermatogenesis was quantitatively analyzed and concentrations of intratesticular transferrin and IGF-1 were measured by radioimmunoassays. The last step of spermatogenesis was quantitatively restored by combined administration of testosterone and purified FSH. Intratesticular IGF-1 concentrations were significantly increased by combined administration of testosterone and purified FSH. From these observations, it is surmised that IGF-1 may have a stimulatory effect on the last step of spermatogenesis.