Months Of Testosterone Treatment Research Articles

Androgen treatment effects on neurocognition in female-to-male transgender adolescents.

It has been hypothesized that cognitive and memory-related brain function in transgender during cross-sex hormonal treatment might be activated towards that of the subjective gender. However, research on this topic has produced inconsistent results, and to the best of our knowledge no studies have investigated neurocognitive changes in androgen-treated female-to-male (FM) transgender adolescents. A total of 15 FM transgender adolescents (14-17 years) underwent neuropsychological testing in order to examine the effects of androgen on visuo-spacial abilities, verbal memory language, processing speed and executive functions. We used a longitudinal design in which 10 participants were tested twice, before and after receiving 12 months of testosterone treatment. This group was also compared with 5 FM transgender adolescents off-androgen treatment. Participants tested before and after 12 months of androgen treatment improved significantly on processing speed in a visuo-spatial (Rey-Osterrieth complex figure test) and in a visuo-oral task (Stroop), their performance on a verbal memory task (TAVEC) and on interference (Stroop) and they exhibited lower impulsivity control (CARAS-R). On-androgen treatment adolescents exhibited worse cognitive impulsivity control than off-androgen treatment adolescents. The results indicate that androgen has an influence on immediate verbal memory, cognitive interference, impulsivity control and processing speed.

PMON264 TESTOSTERONE IMPROVES QUALITY OF LIFE, SEXUAL FUNCTION AND DELAYED VERBAL RECALL- RANDOMISED PLACEBO-CONTROLLED STUDY IN HYPOGONADAL MEN WITH UNCONTROLLED TYPE 2 DIABETES – STRIDE STUDY

Abstract Objective The objective of the study was to assess the effect of long-acting intra-muscular testosterone on Quality of Life (QoL), sexual symptoms, memory and constitutional symptoms in men with hypogonadism and poorly-controlled type 2 diabetes. Research design and methods: This is a randomised double-blinded placebo-controlled add-on trial of intramuscular testosterone undecanoate (Nebido®) administered every 12 weeks in 65 hypogonadal men with poorly-controlled diabetes. Phase 1 patients were randomly assigned to either treatment or placebo arm for 6 months of TRT. Phase 2 was an open-labelled phase for 6 months and patients on placebo moved on to the treatment group wherein patients in the treatment group continued. Outcomes (AMS, SF-36, IIEF-5 questionnaires, MMSE (Mini-Mental State Examination), BDHQ (Barnsley Diabetes Hypogonadism Questionnaire) and NERI questionnaire) were assessed at baseline and every 3 months. Results Mean age of the cohort was 59(42-77) years. Baseline characteristics were comparable between active/placebo groups. Phase 1 - Our study is the first RCT to show a significant reduction in the mean total AMS score from baseline of 48.34±13.13 to 37.72±12.25 at 6 months after testosterone treatment compared to placebo (p<0.05). The proportions of patients with severe symptoms moving to a less severe category (low/mild/moderate severity) was 46% in the active vs only 28% in placebo group(p=0.0024). There was no significant difference in either the SF-36 scores, MMSE scores, BDHQ, NERI or IIEF-5 scores or its domains at baseline and after 6 months of testosterone treatment. In phase 2 of the trial questionnaires were performed at 0,3,6,9,12 months on the testosterone and data presented here as significance between 0 and 12 months. The AMS total score (p=001) and all its subscales (Physical p=0.01), Psychological (p=0.026) and Sexual (p<0.001) with improvement in Libido (p<0.001) showed significant improvement. The BDHQ found significant improvement in two domains - Sexual wellbeing (p=0.002) and Emotional wellbeing (p=0.011) respectively) with the Total score p=0.07. SF-36 QoL score had improvement in the mean scores of physical health domain (p=0.019) and health change domain (0.019). MMSE found a highly significant improvement in Delayed Verbal Recall (p=0.0004). No significant difference to NERI or IIEF-5 scores were found. Conclusions Our trial is the first RCT to show a significant improvement in sexual symptoms, libido, symptom severity, delayed verbal recall (an important Symptom of Dementia) and constitutional symptoms with TRT in a cohort with poorly-controlled type 2 diabetes and hypogonadism. This study demonstrates that symptoms of hypogonadism can continue to improve up to 12 months. It is important to recognize that men with type 2 diabetes have obesity, complications of diabetes, co-morbidities, erectile dysfunction which all compromise their QoL. An improvement in their QoL and other parameters found in this study represent major improvements in health and life situation. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

RF34 | PMON263 Study of Testosterone Replacement in Hypogonadal Men With Uncontrolled Type 2 Diabetes – a Randomised Double Blinded Placebo Controlled Trial (STRIDE Study)

Abstract Objective This RCT set out to test the effect of testosterone on glycaemic control, parameters of metabolic control and quality of life(QoL) in a cohort of people with poorly-controlled type 2 diabetes and hypogonadism. Research design and methods: This is a randomised double-blinded placebo-controlled add-on trial of intramuscular testosterone undecanoate (Nebido®) administered every 12 weeks in 65 hypogonadal men with poorly-controlled type 2 diabetes. Phase 1 patients were randomly assigned to either treatment or placebo arm for 6 months of TRT. Phase 2 was an open-labelled phase for 6 months and patients on placebo moved on to the treatment group wherein patients in the treatment group continued. Anthropometric measurements, questionnaires and biochemical parameters were recorded at baseline and every three months for a year. Results Mean age of the cohort was 59±8.98 years(mean±SD). Mean duration since diagnosis of diabetes was 8.6 years. 17(26%) were on insulin. Baseline cohorts were comparable. There was no improvement in mean HbA1c or fasting plasma glucose(FBG) between the active and placebo groups after 6 months of TRT. No difference was found in HbA1c or FBG at 12 months compared to baseline in the active group either. Our study also showed a significant decrease in serum triglycerides (-0.497±0.213mmol/l, p=0.023) and improvement in left hand grip strength (p=0.025) at 6 months post treatment in the active group compared to placebo group. There was no significant difference in the mean weight, BMI, WC, WHR, fat mass, fat percentage or fat free mass between the groups. Our study is the first ever RCT to show a significant improvement in total AMS (aging male symptom) scores from baseline after 6 months of TU treatment compared to placebo group (p<0.05) in a cohort with poorly-controlled type 2 diabetes and hypogonadism. Another key finding from our study substantiating the clinical argument of treatment of patients with hypogonadism in diabetes cohort is that the proportion of patients with severe symptoms moving to a less severe category (low/mild/moderate severity) was 46% in the active vs only 28% in placebo group(p=0.0024). Conclusions Our study concludes that testosterone therapy did not have a significant improvement in glycaemic control at 6 months between the active and placebo groups and at 12 months within the in the active group and may need longer duration to see the positive effects especially in cohort of people who have had long duration of diabetes. There was a significant reduction in triglyceride levels and increase muscular strength after 6 months of TRT. STRIDE study is the first ever RCT to show a significant improvement in clinical symptoms and symptom severity following testosterone treatment in patients with hypogonadism and type 2 diabetes after 6 months of testosterone treatment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:42 p.m. - 12:47 p.m.

Metabolic effects of estradiol versus testosterone in complete androgen insensitivity syndrome

PurposeTo study differences in metabolic outcomes between testosterone and estradiol replacement in probands with complete androgen insensitivity syndrome (CAIS).MethodsIn this multicentre, double-blind, randomized crossover trial, 26 women with CAIS were included of whom 17 completed the study. After a two-months run in phase with estradiol, probands either received transdermal estradiol followed by crossover to transdermal testosterone or vice versa. After six months, differences in lipids, fasting glucose, insulin, hematocrit, liver parameters and blood pressure between the treatment phases were investigated.ResultsLinear mixed models adjusted for period and sequence did not reveal major group differences according to treatment for the investigated outcomes. In each treatment group, there were however significant uniform changes in BMI and cholesterol. BMI increased significantly, following six months of estradiol ( + 2.7%; p = 0.036) as well as testosterone treatment ( + 2.8%; p = 0.036). There was also a significant increase in total ( + 10.4%; p = 0.001) and LDL-cholesterol ( + 29.2%; p = 0.049) and a decrease in HDL-cholesterol (−15.8%; p < 0.001) following six months of estradiol as well as six months of testosterone treatment (total cholesterol: + 14.6%; p = 0.008; LDL-cholesterol: + 39.1%; p = 0.005, HDL-cholesterol: −15.8%; p = 0.004). Other parameters remained unchanged.ConclusionTransdermal estradiol as well as testosterone treatment in women with CAIS results in worsening in lipid profiles. Given the relatively small sample size, subtle group differences in other metabolic parameters may have remained undetected.

The effect of gender-affirming hormone treatment on serum creatinine in transgender and gender-diverse youth: implications for estimating GFR.

Equations for estimated glomerular filtration rate (eGFR) based on serum creatinine include terms for sex/gender. For transgender and gender-diverse (TGD) youth, gender-affirming hormone (GAH) treatment may affect serum creatinine and in turn eGFR. TGD youth were recruited for this prospective, longitudinal, observational study prior to starting GAH treatment. Data collected as part of routine clinical care were abstracted from the medical record. For participants designated male at birth (DMAB, N = 92), serum creatinine decreased within 6months of estradiol treatment (mean ± SD 0.83 ± 0.12mg/dL to 0.76 ± 0.12mg/dL, p < 0.001); for participants designated female at birth (DFAB, n = 194), serum creatinine increased within 6months of testosterone treatment (0.68 ± 0.10mg/dL to 0.79 ± 0.11mg/dL, p < 0.001). Participants DFAB treated with testosterone had serum creatinine similar to that of participants DMAB at baseline, whereas even after estradiol treatment, serum creatinine in participants DMAB remained higher than that of participants DFAB at baseline. Compared to reference groups drawn from the National Health and Nutritional Examination Survey, serum creatinine after 12months of GAH was more similar when compared by gender identity than by designated sex. GAH treatment leads to changes in serum creatinine within 6months of treatment. Clinicians should consider a patient's hormonal exposure when estimating kidney function via eGFR and use other methods to estimate GFR if eGFR based on serum creatinine is concerning.

Relation of Testosterone, Dihydrotestosterone, and Estradiol With Changes in Outcomes Measures in the Testosterone Trials.

Many effects of testosterone are mediated through dihydrotestosterone (DHT) and estradiol. To determine the relative contributions of each hormone to the observed effects of testosterone treatment in older men with hypogonadism. Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and DHT levels over 12 months of testosterone treatment with hemoglobin, high-density lipoprotein (HDL) cholesterol, volumetric bone mineral density (vBMD) of lumbar spine, sexual desire, and prostate-specific antigen (PSA). We used random forests to model the associations of predicted mean changes in outcomes with change in each hormone at low, mean, or high change in the other 2 hormones. Stepwise regression models were run to confirm the findings of random forests. Predicted increases in hemoglobin and sexual desire were greater with larger increases in estradiol and were larger with high change in DHT compared with low change in DHT. Greater increases in estradiol were associated with larger decreases in HDL cholesterol; this association did not vary according to changes in DHT or testosterone. Change in vBMD was most robustly associated with change in estradiol and was greater with high change in testosterone and DHT. There was no consistent relation between change in PSA and change in any hormone. Change in estradiol level was the best predictor not only of the change in vBMD and sexual desire but also of the changes in hemoglobin and HDL cholesterol. Consideration of testosterone, estradiol, and DHT together offers a superior prediction of treatment response in older hypogonadal men than testosterone alone.

Physical changes, laboratory parameters, and bone mineral density during testosterone treatment in adolescents with gender dysphoria

IntroductionCurrent treatment guidelines for adolescents with gender dysphoria recommend therapy with gonadotropin-releasing hormone agonists (GnRHa) and testosterone in transgender males. However, most evidence on the safety and efficacy of testosterone is based on studies in adults. AimThis study aimed to investigate the efficacy and safety of testosterone treatment in transgender adolescents. MethodsThe study included 62 adolescents diagnosed with gender dysphoria who had started GnRHa treatment and had subsequently received testosterone treatment for more than 6 months. Main Outcome MeasureVirilization, anthropometry, laboratory parameters, and bone mineral density (BMD) were analyzed. ResultsAdolescents were treated with testosterone for a median duration of 12 months. Voice deepening began within 3 months in 85% of adolescents. Increased hair growth was first reported on the extremities, followed by an increase of facial hair. Acne was most prevalent between 6 and 12 months of testosterone therapy. Most adolescents had already completed linear growth; body mass index and systolic blood pressure increased but diastolic blood pressure did not change. High-density lipoprotein (HDL) cholesterol and sex hormone binding globulin significantly decreased, but hematocrit, hemoglobin, prolactin, androstenedione, and dehydroepiandrosterone sulfate significantly increased, although not all changes were clinically significant. Other lipids and HbA1c did not change. Vitamin D deficiency was seen in 32–54% throughout treatment. BMD z-scores after 12 to 24 months of testosterone treatment remained below z-scores before the start of GnRHa treatment. Clinical ImplicationsAdolescents need to be counseled about side effects with potential longer term implications such as increased hematocrit and decreased HDL cholesterol and decreased BMD z-scores. They should be advised on diet, including adequate calcium and vitamin D intake; physical exercise; and the use of tobacco and alcohol to avoid additional risk factors for cardiovascular disease and osteoporosis. Strengths & LimitationsStrengths are the standardized treatment regimen and extensive set of safety parameters investigated. Limitations are the limited duration of follow-up and lack of a control group so some of the observed changes may be due to normal maturation rather than to treatment. ConclusionTestosterone effectively induced virilization beginning within 3 months in the majority of adolescents. Acne was a common side effect, but no short-term safety issues were observed. The increased hematocrit, decreased HDL cholesterol, and decreased BMD z-scores are in line with previous studies. Further follow-up studies will need to establish if the observed changes result in adverse outcomes in the long term.Stoffers IE, de Vries MC, Hannema SE. Physical Changes, Laboratory Parameters, and Bone Mineral Density During Testosterone Treatment in Adolescents with Gender Dysphoria. J Sex Med 2019;16:1459–1468.

Testosterone treatment and risk of venous thromboembolism: population based case-control study

Objective To determine the risk of venous thromboembolism associated with use of testosterone treatment in men, focusing particularly on the timing of the risk.Design Population based case-control studySetting 370 general...

Male-typical visuospatial functioning in gynephilic girls with gender dysphoria - organizational and activational effects of testosterone.

Sex differences in performance and regional brain activity during mental rotation have been reported repeatedly and reflect organizational and activational effects of sex hormones. We investigated whether adolescent girls with gender dysphoria (GD), before and after 10 months of testosterone treatment, showed male-typical brain activity during a mental rotation task (MRT). Girls with GD underwent fMRI while performing the MRT twice: when receiving medication to suppress their endogenous sex hormones before onset of testosterone treatment, and 10 months later during testosterone treatment. Two age-matched control groups participated twice as well. We included 21 girls with GD, 20 male controls and 21 female controls in our study. In the absence of any group differences in performance, control girls showed significantly increased activation in frontal brain areas compared with control boys (pFWE = 0.012). Girls with GD before testosterone treatment differed significantly in frontal brain activation from the control girls (pFWE = 0.034), suggesting a masculinization of brain structures associated with visuospatial cognitive functions. After 10 months of testosterone treatment, girls with GD, similar to the control boys, showed increases in brain activation in areas implicated in mental rotation. Since all girls with GD identified as gynephilic, their resemblance in spatial cognition with the control boys, who were also gynephilic, may have been related to their shared sexual orientation rather than their shared gender identity. We did not account for menstrual cycle phase or contraceptive use in our analyses. Our findings suggest atypical sexual differentiation of the brain in natal girls with GD and provide new evidence for organizational and activational effects of testosterone on visuospatial cognitive functioning.

Testosterone treatment and MMPI-2 improvement in transgender men: a prospective controlled study.

Most transgender men desire to receive testosterone treatment in order to masculinize their bodies. In this study, we aimed to investigate the short-term effects of testosterone treatment on psychological functioning in transgender men. This is the 1st controlled prospective follow-up study to examine such effects. We examined a sample of transgender men (n = 48) and nontransgender male (n = 53) and female (n = 62) matched controls (mean age = 26.6 years; 74% White). We asked participants to complete the Minnesota Multiphasic Personality Inventory (2nd ed., or MMPI-2; Butcher, Graham, Tellegen, Dahlstrom, & Kaemmer, 2001) to assess psychological functioning at baseline and at the acute posttreatment follow-up (3 months after testosterone initiation). Regression models tested (a) Gender × Time interaction effects comparing divergent mean response profiles across measurements by gender identity; (b) changes in psychological functioning scores for acute postintervention measurements, adjusting for baseline measures, comparing transgender men with their matched nontransgender male and female controls and adjusting for baseline scores; and (c) changes in meeting clinical psychopathological thresholds. Statistically significant changes in MMPI-2 scale scores were found at 3-month follow-up after initiating testosterone treatment relative to baseline for transgender men compared with female controls (female template): reductions in Hypochondria (p < .05), Depression (p < .05), Hysteria (p < .05), and Paranoia (p < .01); and increases in Masculinity-Femininity scores (p < .01). Gender × Time interaction effects were found for Hysteria (p < .05) and Paranoia (p < .01) relative to female controls (female template) and for Hypochondria (p < .05), Depression (p < .01), Hysteria (p < .01), Psychopathic Deviate (p < .05), Paranoia (p < .01), Psychasthenia (p < .01), and Schizophrenia (p < .01) compared with male controls (male template). In addition, the proportion of transgender men presenting with co-occurring psychopathology significantly decreased from baseline compared with 3-month follow-up relative to controls (p < .05). Findings suggest that testosterone treatment resulted in increased levels of psychological functioning on multiple domains in transgender men relative to nontransgender controls. These findings differed in comparisons of transgender men with female controls using the female template and with male controls using the male template. No iatrogenic effects of testosterone were found. These findings suggest a direct positive effect of 3 months of testosterone treatment on psychological functioning in transgender men.

Metabolic syndrome and the effect of testosterone treatment in young men with congenital hypogonadotropic hypogonadism

The relationship between metabolic syndrome (MS) and hypogonadism has always been investigated in study groups confounded with aging, obesity or chronic metabolic disorders. So far, there has been no data about the presence of MS in young hypogonadal patients. Also, there is controversial data about the metabolic effects of testosterone replacement therapy. We investigated the frequency of MS in treatment-naïve, young men with congenital hypogonadal hypogonadism (CHH). We also searched for the effect of testosterone replacement on the metabolic profiles of this specific patient group. Retrospective analysis. A total of 332 patients (age 21.68 ± 2.09 years) were enrolled. The control group included 395 age- and body mass index (BMI)-matched healthy young men (age 21.39 ± 1.49 years). Standard regimen of testosterone esters (250 mg/3 weeks) was given to 208 patients. MS was more prevalent in CHH (P<0.001) according to healthy controls. The patients had higher arterial blood pressure, waist circumference (WC), triglyceride (P<0.001 for all), fasting glucose (P=0.02), fasting insulin (P=0.004), homeostatic model assessment of insulin resistance (HOMA-IR) (P=0.002) and lower high density lipoprotein (HDL) cholesterol (P<0.001) levels. After 5.63±2.6 months of testosterone treatment, the BMI, WC (P<0.001 for both), systolic blood pressure (P=0.002) and triglyceride level (P=0.04) were increased and the total and HDL cholesterol levels were decreased (P=0.02 and P<0.001 respectively). This study shows increased prevalence of MS and unfavorable effects of testosterone replacement in young patients with CHH. Long-term follow-up studies are warranted to investigate the cardiovascular safety of testosterone treatment in this specific population.

Androgen treatment effects on memory in female-to-male transsexuals

It has been hypothesized that cognitive and memory-related brain function in transsexuals during cross-sex hormonal treatment might be activated towards that of the subjective gender. However, research on this topic has produced inconsistent results, and to the best of our knowledge no studies have investigated memory changes in androgen-treated female-to-male (FM) transsexuals. A total of 33 FM transsexuals underwent neuropsychological testing in order to examine the effects of androgen on memory. We used a longitudinal design in which 14 FM transsexuals were tested twice, before and after receiving 6 months of testosterone treatment. In addition, a cross-sectional design was used to compare 10 individuals off treatment versus 9 individuals on testosterone treatment for at least 6 months. Participants tested before and after 6 months of androgen treatment improved significantly their performance on a visual memory task (visual paired associates, immediate recall, WMS-R). The cross-sectional design confirmed that patients on androgen treatment for at least 6 months performed better than subjects off treatment on the same task and also on another visual memory task (Rey-Osterrieth complex figure test, ROCF; copy and delayed recall). No differences were found in any verbal memory test for either design. The results indicate that androgen has an influence on visual memory, but not on verbal memory. Therefore, for FM transsexuals the data support an activating effect for androgens on visual memory, a domain that generally tends to favour males.

Effect of Testosterone on Insulin Sensitivity in Men with Idiopathic Hypogonadotropic Hypogonadism

To assess the presence of insulin resistance (IR) among a homogeneous cohort of male patients with idiopathic hypogonadotropic hypogonadism (IHH) and to investigate the effects of testosterone therapy on IR in this specific group. Twenty-four male patients with untreated IHH and 20 age-, sex-, and weight-matched eugonadal healthy control subjects were recruited for the study. Plasma glucose, plasma insulin, total and free testosterone, follicle-stimulating hormone, luteinizing hormone, estradiol, and sex hormone-binding globulin levels were measured in fasting blood samples, and biochemical and hormonal analyses were performed for all study participants. IR was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) formula and the quantitative insulin sensitivity check index (QUICKI). Body mass index was calculated by weighing and measuring the heights of all study participants at the beginning of the investigation. Body fat mass and body lean mass were calculated as percentages of body weight by bioelectrical impedance analysis of body composition. Sustanon 250 (a combination of 4 testosterones) was administered intramuscularly once every 3 weeks for 6 months to male patients with IHH after a basal anthropometric, biochemical, and hormonal evaluation. The response to therapy was monitored by regular clinical examinations and serum testosterone measurements. After 6 months of testosterone treatment, the entire anthropometric, biochemical, and hormonal evaluation was repeated 14 days after the last injection of testosterone. Before treatment, male patients with IHH had higher fasting plasma glucose concentrations, higher fasting plasma insulin levels, a higher HOMA-IR score, and a lower QUICKI when compared with the control group. After testosterone treatment in the patient group, the HOMA-IR score decreased dramatically to the level in the control group. The high body fat mass of the male patients with IHH was reduced significantly after testosterone treatment, concomitant with significant increases in body mass index and body lean mass. Insulin sensitivity improves and body fat mass decreases with long-term testosterone replacement therapy.

Drug Insight: recent advances in male hormonal contraception

As there are limitations to current methods of male contraception, research has been undertaken to develop hormonal contraceptives for men, analogous to the methods for women based on estrogen and progestogens. When testosterone is administered to a man, it functions as a contraceptive by suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. Since these hormones are the main stimulatory signals for spermatogenesis, low levels of LH and FSH markedly impair sperm production. After 3-4 months of testosterone treatment, 60-70% of men no longer have sperm in their ejaculate, and most other men exhibit markedly diminished sperm counts. Male hormonal contraception is well tolerated, free of serious adverse side effects, and 95% effective in the prevention of pregnancy. Importantly, male hormonal contraception is reversible, with sperm counts usually recovering within 4 months of the discontinuation of hormone treatment. Because exogenous testosterone administration alone does not completely suppress sperm production in all men, researchers have combined testosterone with second agents, such as progestogens or gonadotropin-releasing-hormone antagonists, to further suppress secretion of LH and FSH and improve suppression of spermatogenesis. Recent trials have used combinations of long-acting injectable or implantable forms of testosterone with progestogens, which can be administered orally, by injection or by a long-acting implant. Such combinations suppress spermatogenesis to zero without severe side effects in 80-90% of men, with near-complete suppression in the remainder of individuals. One of these testosterone and progestogen combination regimens might soon bring the promise of male hormonal contraception to fruition.

Effect of Testosterone Replacement on Trabecular Architecture in Hypogonadal Men

We evaluated the effect of testosterone treatment on trabecular architecture by microMRI in 10 untreated severely hypogonadal men. After 2 years, microMRI parameters of trabecular connectivity improved significantly, suggesting the possibility that testosterone improves trabecular architecture. Osteoporosis, characterized by low BMD and diminished bone quality, is a significant public health problem in men. Hypogonadal men have decreased BMD and deteriorated trabecular architecture compared with eugonadal men, and testosterone treatment improves their BMD. We tested the hypothesis that testosterone replacement in hypogonadal men would also improve their trabecular architecture. We selected 10 untreated severely hypogonadal men and treated them with a testosterone gel for 24 months to maintain their serum testosterone concentrations within the normal range. Each subject was assessed before and after 6, 12, and 24 months of testosterone treatment by magnetic resonance microimaging (microMRI) of the distal tibia and by DXA of the spine and hip. The microMRI parameters reflect the integrity of the trabecular network and include the ratio of all surface voxels (representing plates) to curve voxels (representing rods) and the topological erosion index, a ratio of topological parameters expected to increase on trabecular deterioration to those expected to decrease. The higher the surface-to-curve ratio and the lower the topological erosion index, the more intact the trabecular network. Serum testosterone concentrations increased to midnormal after 3 months of treatment and remained normal thereafter. After 24 months of testosterone treatment, BMD of the spine increased 7.4% (p<0.001), and of the total hip increased 3.8% (p=0.008). Architectural parameters assessed by microMRI also changed: the surface-to-curve ratio increased 11% (p=0.004) and the topological erosion index decreased 7.5% (p=0.004). These results suggest the possibility that testosterone replacement of hypogonadal men improves trabecular architecture.

Testosterone treatment alters melatonin concentrations in male patients with gonadotropin-releasing hormone deficiency.

Recently, we demonstrated that melatonin secretion is increased in untreated male patients with GnRH deficiency. As testosterone (T) can be aromatized to estradiol (E2), and both T and E2 increase during T enanthate treatment, we were interested in determining whether T treatment (when T and E2 levels were well matched with pubertal control values) has an effect on melatonin levels in these patients. We measured nocturnal serum melatonin levels during the administration of 250 mg testosterone enantale/month for 4 months in 12 male patients with idiopathic hypogonadotropic hypogonadism (IGD; n = 6) and delayed puberty (DP; n = 6). Serum samples for melatonin and LH determinations were obtained every 15 min from 1900-0700 h in a controlled light-dark environment. The results of melatonin profiles were compared with the pretreatment values in each group and with values obtained in six normal pubertal male controls. After 4 months of testosterone treatment, all patients attained normal serum testosterone (19.5 +/- 3.7 in IGD vs. 20.8 +/- 4.1 nmol/L in DP) and E2 levels (83 +/- 12 in IGD vs. 84 +/- 9 pmol/L in DP). Serum LH levels were suppressed in all patients during T treatment (0.12 +/- 0.1 in IGD vs. 0.12 +/- 0.2 IU/L in DP). Before T treatment, patient melatonin levels were greater than those in age-matched pubertal controls. Melatonin levels were equal in patients and controls when T and E2 levels were well matched. Mean (+/- SD) dark-time melatonin levels decreased from 286 +/- 23 to 157 +/- 36 pmol/L in IGD and from 217 +/- 32 to 133 +/- 47 pmol/L in DP (vs. 183 +/- 64 pmol/L in controls). The integrated melatonin values decreased to normal (from 184 +/- 16 to 102 +/- 21 in IGD and from 142 +/- 19 to 90 +/- 26 pmol/min.L x 10(3) in DP vs. 119 +/- 61 pmol/min.L x 10(3) in controls). The intraindividual variations in melatonin levels ranged from 7.2-14.5%. These data indicate that male patients with GnRH deficiency have increased nocturnal melatonin secretion. T treatment decreased melatonin secretion to normal levels. The results suggest that in GnRH-deficient male patients, sex steroids, rather than LH, modulate pineal melatonin in a reverse fashion.

Effect of testosterone on metabolic rate and body composition in normal men and men with muscular dystrophy.

We have examined the effect of testosterone enanthate injections (3 mg/kg.week, im) on the basal metabolic rate (BMR) estimated by indirect calorimetry and on lean body mass (LBM) estimated by 40K counting in four normal men and nine men with muscular dystrophy. Testosterone treatment increased plasma testosterone levels in all subjects (3-fold mean elevation). BMR increased significantly after 3 months of testosterone treatment (mean, 10%; P less than 0.01; 13% mean increase in the men with muscular dystrophy and 7% mean increase in the normal subjects). BMR remained elevated (mean increase, 9%) after 12 months of testosterone treatment in four men with muscular dystrophy. LBM also was significantly higher after 3 months of treatment (mean, 10%; P less than 0.01) and remained elevated at 12 months. The percent increase in LBM was similar in men with muscular dystrophy (+10%) and normal men (+11%). When BMR was adjusted for the increase in LBM by linear regression, the men with muscular dystrophy had an increase in adjusted BMR after 3 months of testosterone treatment (mean increase, 7%), but not after 12 months. The normal men did not have an increase in adjusted BMR. Testosterone treatment for 12 months slightly reduced body fat, whereas there was an increase in body fat in subjects with muscular dystrophy who were treated with placebo for 12 months. We conclude that there is a significant increase in BMR associated with pharmacological testosterone treatment, which for the most part is explained by the increase in LBM. However, in men with muscular dystrophy, there is a small hypermetabolic effect of testosterone beyond that explained by increased LBM.

Gonadotropin-Producing Pituitary Adenoma in a Man with Long-Standing Primary Hypogonadism*

Pituitary adenomas that secrete gonadotropins are generally believed to arise spontaneously rather than as a response to chronic primary gonadal failure. However, two women who were found to have gonadotroph adenomas several years after ovarian ablation have been reported. We describe a middle-aged man who developed bitemporal hemianopia and was found to have a large pituitary tumor 35 yr after castration. He had never received any replacement therapy. The tumor was considered to be a primary gonadotroph adenoma, rather than secondary gonadotroph hyperplasia, on the basis of its secretory capabilities, its reticulin patterns, and its specific immunostaining for human FSH beta, human LH beta, and alpha-subunit. Furthermore, the tumor did not decrease appreciably in size after 12 months of testosterone treatment, although plasma gonadotropin levels decreased. Unless the association of primary gonadal failure with a gonadotroph adenoma was coincidental, it suggests that some human gonadotroph adenomas may be secondary to failure of the gonads.

The Laurence-Moon-Bardet-Biedl Syndrome: Unresponsiveness to the Action of Testosterone, A Possible Mechanism

The pathogenesis of hypogonadism and hypogenitalism was investigated in a male patient with the complete form of the Laurence-Moon-Bardet-Biedl syndrome. Synthetic gonadotropin-releasing hormone induced an increase in serum luteinizing hormone levels from 16.5 mIU/ml to 19.3 mIU/ml and in follicle-stimulating hormone levels from 18.5 mIU/ml to 25.9 mIU/ml. Serum testosterone levels were normal and did not rise after stimulation with human chorionic gonadotropin. The administration of thyrotropin-releasing hormone resulted in an increase in serum thyrotropin levels from 9.0 microU/ml to 12.0 microU/ml. Serum testoterone/estradiol-binding globulin, adrenocorticotropic hormone, and T3 resin uptake were normal. Serum cortisol showed a normal diurnal variation. The sex chromatin test was negative and the karyotupe revealed a 46,XY chromosome pattern. On biopsy, the left testis lacked germinal cells and the right testis showed spermatogenic arrest. Signs of hypogonadism and hypogenitalism persisted after 11 months of testosterone treatment. In this patient the target-organ unresponsiveness resulted in hypogenitalism and hypogonadism.