Low-dose Testosterone Treatment Research Articles

Diagnostic utility of testosterone priming prior to dynamic tests to differentiate constitutional delay in puberty from isolated hypogonadotropic hypogonadism in boys

BackgroundDifferentiation between isolated hypogonadotropic hypogonadism (IHH) and constitutional delay in puberty (CDP) throughout adolescence can be challenging for doctors. This study examines the withdrawal effects of short-term, low-dose testosterone treatment (testosterone priming) on the ability of dynamic testing to distinguish between CDP and IHH based on activation of the hypothalamo-pituitary–testicular axis.MethodsA case–control study included 20 boys with delayed puberty (group A) and 20 patients with IHH (group B). Both groups underwent Triptorelin and human chorionic gonadotropin (hCG) stimulation tests before and 2 months after testosterone injections (100 mg) intramuscularly every 4 weekly for 3 months.ResultsThe triptorelin-stimulated 4-h LH with a cutoff of 2.4 IU/L and the hCG-stimulated testosterone with a cutoff of 1.160 ng/mL had sensitivities of 65% each, and specificities of 90% and 95%, respectively, to diagnose CDP. After testosterone withdrawal, the cut-off values for 4-h LH were 8.850 IU/L and 3.190 ng/mL for hCG-stimulated testosterone. Basal inhibin B > 88.25 pg/ml was found to be a differentiating factor in diagnosing CDP after testosterone withdrawal.Conclusionsfollowing the withdrawal of testosterone therapy, Inhibin B levels or 4-h stimulated LH are the most effective discriminant assays to distinguish CDP from IHH.

Recovery of hypothalamic-pituitary-gonadal function with low dose testosterone treatment in a male with idiopathic hypogonadotropic hypogonadism

Recovery of hypothalamic-pituitary-gonadal function with low dose testosterone treatment in a male with idiopathic hypogonadotropic hypogonadism

Menopause, androgens, and cardiovascular ageing: a narrative review.

Cardiovascular disease is the leading cause of death worldwide; however, women tend to be less affected than men during their reproductive years. The female cardiovascular risk increases significantly around the time of the menopausal transition. The loss of the protective action of ovarian oestrogens and the circulating androgens has been implicated in possibly inducing subclinical and overt changes in the cardiovascular system after the menopausal transition. In vitro studies performed in human or animal cell lines demonstrate an adverse effect of testosterone on endothelial cell function and nitric oxide bioavailability. Cohort studies evaluating associations between testosterone and/or dehydroepiandrosterone and subclinical vascular disease and clinical cardiovascular events show an increased risk for women with more pronounced androgenicity. However, a mediating effect of insulin resistance is possible. Data on cardiovascular implications following low-dose testosterone treatment in middle-aged women or high-dose testosterone supplementation for gender affirmatory purposes remain primarily inconsistent. It is prudent to consider the possible adverse association between testosterone and endothelial function during the decision-making process of the most appropriate treatment for a postmenopausal woman.

Exercise and Testosterone Countermeasures to Mitigate Metabolic Changes during Bed Rest

Background/Objectives: Exercise is a front-line countermeasure used to maintain astronaut health during long-duration spaceflight; however, reductions in metabolic health still occur. Accordingly, we evaluated serial changes in metabolic parameters in a spaceflight analog and evaluated the efficacy of exercise with or without the addition of low-dose testosterone treatment on mitigating adverse metabolic changes. Subjects/Methods: Healthy young (<55 years) men were randomly assigned to one of three groups during 70-days of strict, diet controlled, 6° head-down bed rest: Control (CON, n=9), exercise plus testosterone countermeasure (TEX, n=8), or exercise countermeasure plus placebo (PEX, n=9). Basal metabolic rate (BMR), glucose tolerance, and insulin sensitivity were measured before, during, and after bed rest. Exercise energy expenditure and excess post-exercise oxygen consumption were measured in TEX and PEX subjects during bed rest. Results: Leptin decreased during bed rest (Pre to BR+0 changed from 6.9 ± 5.1, 5.8 ± 4.2, and 4.7 ± 4.1 to 7.9 ±3.6, 6.5 ± 4.6, and 4.1 ±3.0 ug• L−1 for CON, PEX, and TEX respectively). Bed rest induced a decrease in BMR (Pre to BR57 changed from 1655 ± 212, 1629 ± 108, and 1706 ± 146 to 1476 ± 166, 1668 ± 142, and 1603 ± 132 kcal • day−1 ± 95%CI for CON, PEX, and TEX respectively). Similarly, bed rest negatively affected glucose metabolism assessed by 2hr OGTT glucose (Pre to BR66 changed from 6.29 ± 0.72, 5.13 ± 0.72, and 5.87 ± 0.73 to 6.62 ± 0.72, 5.83 ± 0.72, and 7.08 ± 0.72 mmol • L−1 ± 95%CI). Reambulation following bed rest positively affected glucose tolerance in CON (2hr OGTT glucose at BR+12: 5.3 ± 0.72, 6.42 ± 0.73, and 6.04 ± 0.73 mmol • L−1 ± 95%CI). Testosterone protected against bed rest induced insulin resistance (HOMA-IR from Pre to BR+66 changed from 1.74 ± 0.54, 1.18 ± 0.55, and 1.45 ± 0.56 to 2.24 ± 0.56, 1.47 ± 0.54, and 1.07 ± 0.54). Conclusion: This study confirmed that inactivity during 70 days of head-down bed rest adversely affects metabolic health. The daily exercise countermeasures were beneficial but not completely protective of bed rest induced decrements in metabolic health. Supplementary countermeasures such as testosterone may provide additional benefits not provided by exercise alone.

USO DE TESTOSTERONA EM MULHERES COM DIMINUIÇÃO OU PERDA DE INTERESSE/EXCITAÇÃO SEXUAL

Disfunções Sexuais Femininas (DSF) são problemas comuns que atingem, em alguma fase da vida,mais de 1/3 das mulheres. Os androgênios são importantes moduladores da função sexual feminina. Baixosníveis de testosterona total e livre, androstenediona e S-DHEA estão associados a um menor desejo sexualautorrelatado e há evidências de que o tratamento com baixas doses de testosterona é eficaz em mulherescom Desejo Sexual Hipoativo (DSH) e deficiência androgênica. O objetivo deste trabalho foi rever as indicações de uso da testosterona por mulheres com disfunção sexual, doses, vias de administração e efeitoscolaterais mais comuns do medicamento. Trata-se de revisão da literatura, com artigos publicados entreos anos 2000 e 2019, nas bases de dados da SciELO, LILACS e PubMed. As indicações do uso de androgêniosem mulheres são restritas. O tratamento é off-label e deve ser, preferencialmente, realizado com géis, cremes ou adesivos transdérmicos de testosterona. Não há segurança estabelecida em tratamentos por períodos maiores que 24 semanas. Pacientes com sintomas da deficiência androgênica e com indicação de tratamento devem ser submetidas à revisão laboratorial regularmente de modo a avaliar os eventuais efeitos adversos do excesso de androgênios.

Efficacy of Testosterone plus NASA Exercise Countermeasures during Head-Down Bed Rest.

Prolonged confinement to head-down bed rest (HDBR) results in musculoskeletal losses similar to those observed during long-duration space flight. Exercise countermeasures by themselves have not completely prevented the deleterious losses in muscle mass or function in HDBR or space flight. The objective was to investigate the safety and efficacy of intermittent, low-dose testosterone treatment in conjunction with NASA exercise (SPRINT) countermeasures during 70 d of 6° HDBR. Healthy men (35 ± 8 yr) were randomized into one of three groups that remained inactive (CON) or performed exercise 6 d·wk in addition to receiving either placebo (PEX) or testosterone treatment (TEX, 100 mg·wk). Testosterone/placebo injections were administered once a week for 2 wk, followed by 2 wk off and so on, during HDBR. Total, leg, and trunk lean body mass (LBM) consistently decreased in CON, increased in TEX, and had little or no changes in PEX. Total, leg, and trunk fat mass consistently increased in CON and PEX and decreased in TEX. Leg strength decreased in CON, whereas PEX and TEX were protected against loss in strength. Changes in leg LBM correlated positively with changes in leg muscle strength. Addition of a testosterone countermeasure enhanced the preventative actions of exercise against body composition changes during long-term HDBR in healthy eugonadal men. This is the first report to demonstrate that cycled, low-dose testosterone treatment increases LBM under conditions of strict exercise control. These results are clinically relevant to the development of safe and effective therapies against muscle atrophy during long-term bed rest, aging, and disease where loss of muscle mass and strength is a risk. The potential space flight applications of such countermeasure combinations deserve further investigations.

Low-dose testosterone alleviates vascular damage caused by castration in male rats in puberty via modulation of the PI3K/AKT signaling pathway.

The aim of the present study was to investigate the effect of testosterone on glucolipid metabolism and vascular injury in male rats, and examine the underlying molecular mechanisms. A total of 40 male Sprague-Dawley rats were divided into a control group (n=10), high-fat-diet + castration group (n=10), high-fat-diet + castration + low dose testosterone group (n=10), and high-fat-diet + castration + high dose testosterone group (n=10). Hematoxylin and eosin staining was performed to evaluate the morphology of the thoracic aortic tissues. Immunohistochemical staining was used to detect biomarkers of the phosphoinositide 3-kinase (PI3K) signaling pathway. The mRNA and protein expression levels of PI3K, AKT, insulin receptor substrate-1 (IRS-1), glucose transporter type 4 (GLUT-4), nuclear factor (NF)-κB and tumor necrosis factor (TNF)-α in the aortas were determined using quantitative polymerase chain reaction and Western blot analyses, respectively. Apoptosis in the aortic tissues was detected using a TUNEL assay. Castration induced apoptosis in the animals fed a high-fat-diet, whereas low dose testosterone replacement ameliorated the apoptosis in the aorta. However, the levels of apoptosis was more severe following high-dose testosterone treatment. Low-dose testosterone induced upregulation in the levels of IRS-1, AKT, GLUT-4 protein, NF-κB, TNF-α and PI3K, compared with those in the animals fed a high-fat diet following castration. A high dose of testosterone resulted in a significant decrease in the levels of IRS-1, AKT, GLUT-4, NF-κB, TNF-α and PI3K. Compared with the rats in the high-fat diet + castration group, a low dose of testosterone induced upregulation in the mRNA levels of IRS-1, AKT and GLUT-4, and downregulation of the mRNA levels of NF-κB, TNF-α and PI3K. A high dose of testosterone resulted in a significant decrease in the levels of IRS-1, AKT and GLUT-4, and marked increases in the mRNA levels of NF-κB, TNF-α and PI3K, compared with the low dose group. Castration induced marked disorders of glucolipid metabolism and vascular injuries in the pubescent male rats. Low-dose testosterone treatment was found to ameliorate the vascular damage caused by castration via the PI3K/AKT signaling pathway.

Low-dose testosterone treatment decreases oxidative damage in TM3 Leydig cells

Testosterone replacement therapy has benefits for aging men and those with hypogonadism. However, the effects of exogenous testosterone on Leydig cells are still unclear and need to be clarified. In this report, we demonstrate that testosterone supplementation can reduce oxidative damage in Leydig cells. The TM3 Leydig cell line was used as an in vitro cell model in this study. Cytoprotective effects were identified with 100-nmol l⁻¹ testosterone treatment, but cytotoxic effects were found with ≥ 500-nmol l⁻¹ testosterone supplementation. Significantly reduced reactive oxygen species (ROS) generation, lipid peroxide contents and hypoxia induction factor (HIF)-1α stabilization and activation were found with 100-nmol l⁻¹ testosterone treatment. There was a 1.72-fold increase in ROS generation in the 500-nmol l⁻¹ compared to the 100-nmol l⁻¹ testosterone treatment. A 1.58-fold increase in steroidogenic acute regulatory protein (StAR) expression was found in 50-nmol l⁻¹ testosterone-treated cells (P < 0.01). Chemically induced hypoxia was attenuated by testosterone supplementation. Leydig cells treated with low-dose testosterone supplementation showed cytoprotection by decreasing ROS and lipid peroxides, increasing StAR expression and relieving hypoxia stress as demonstrated by HIF-1α stabilization. Increased oxidative damage was found with ≥ 500-nmol l⁻¹ testosterone manipulation. The mechanism governing the differential dose effects of testosterone on Leydig cells needs further investigation in order to shed light on testosterone replacement therapy.

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.

Novel treatment of short stature with aromatase inhibitors

Estrogens have an essential role in the regulation of bone maturation and importantly in the closure of growth plates in both sexes. This prospective, randomized, placebo-controlled study was undertaken to evaluate whether suppression of estrogen synthesis in pubertal boys delays bone maturation and ultimately results in increased adult height. A total of 23 boys with constitutional delay of puberty (CDP) received a conventional, low-dose testosterone treatment for inducing progression of puberty. Eleven of these 23 boys were randomized to receive a specific and potent P450-aromatase inhibitor, letrozole, for suppression of estrogen action, and 12 boys were randomized to receive placebo. Estradiol concentrations in the letrozole-treated boys remained at the pretreatment level during the administration of letrozole, whereas the concentrations increased during the treatment with testosterone alone and during spontaneous progression of puberty. Testosterone concentrations increased in all groups, but during the letrozole treatment, the increase was more than fivefold higher than in the group treated with testosterone alone. The inhibition of estrogen synthesis delayed bone maturation. The slower bone maturation in the boys treated with testosterone and letrozole, despite higher androgen concentrations, than in the boys treated with testosterone indicate that estrogens are more important than androgens in regulation of bone maturation in pubertal boys. During the 18 months follow-up, an increase of 5.1 cm in predicted adult height was observed in the boys who received testosterone and letrozole, but no change was seen in the boys who received testosterone alone or in the untreated boys. This finding indicates that an increase in adult height can be attained in growing adolescent boys by inhibiting of estrogen action.

Testosterone Treatment in Adolescent Boys with Constitutional Delay in Growth and Development

The administration of androgens to adolescent boys with constitutional delay in growth has been highly controversial because of the possibility of premature epiphyseal closure and reduced final height. We have treated 15 such boys with a mean (+/- SD) age of 14.1 +/- 1.0 years and a mean initial height of 142.2 +/- 8.6 cm (range, 127.1 to 156.2). The boys received monthly intramuscular injections of testosterone enanthate (50 mg) for 1.2 +/- 0.3 years. The mean height velocity rose from the 3rd percentile for mean skeletal age to above the 90th percentile, where it remained throughout treatment. Although skeletal maturation accelerated initially in the seven boys with a skeletal age under the pretreatment group mean of 11.3 years, it advanced normally in the others. The concomitant increase in stature was sufficient to offset the advancement in skeletal age in most boys, so that the mean predicted adult height was essentially unaffected. Sexual maturation also progressed; testicular volume increased from 5.9 +/- 2.7 to 11.3 +/- 2.7 ml. After treatment, the skeletal age advanced normally and sexual development continued. Eight of the boys are now 18.1 +/- 0.5 years of age and have stopped growing; their present mean height (167.6 +/- 4.7 cm) is very close to their pretreatment predicted height of 168.0 +/- 5.6 cm. We conclude that low-dose testosterone treatment is effective in adolescent boys with delayed growth and development and that it does not appear to compromise final adult height.

Supportive testosterone treatment in surgical repair of hypospadias

Hypoplastic development of the phallus renders repair of hypospadias more difficult and very often limits functional and cosmetic results. We therefore tried to simplify surgery and to improve results by perioperative low-dose intramuscular testosterone treatment. 9 children with hypospadias of varying degree were treated with testosterone enantate 25-250 mg x 3 (2 injections at 3 weeks intervals preop. and 1 injection postop). Bone age, growth and phallic development were followed up to 2 years. While there was a reliable degree of phallic growth in most of the boys, in only 3 of the children we observed a slight transitory acceleration of skeletal development, in 7 a transitory increase of growth rate. No signs of virilisation were noted. We believe that in selected cases of hypospadias a short-term low-dose testosterone treatment may be an acceptable means to simplify and improve repair.