Eugonadal Subjects Research Articles

FRI-466 - Efficacy and safety of LPCN 1144 in hypogonadal and eugonadal subjects for the treatment of non-alcoholic steatohepatitis (NASH) with fibrosis

FRI-466 - Efficacy and safety of LPCN 1144 in hypogonadal and eugonadal subjects for the treatment of non-alcoholic steatohepatitis (NASH) with fibrosis

Very low-calorie ketogenic diet rapidly augments testosterone levels in non-diabetic obese subjects.

The very low-calorie ketogenic diet (VLCKD) represents an opportunity to attain clinically relevant weight loss in obese patients. Functional hypogonadism represents a frequent hormonal disorder associated with obesity and visceral fat accumulation characterised by low testosterone levels and subnormal luteinising hormone (LH) levels. To evaluate the early effects of VLCKD on serum total testosterone (TT) levels in non-diabetic obese patients. Twenty-two obese male patients (mean age 39.3±11.7 years, mean body mass index (BMI) 38.2±6.4kg/m2 ) were enrolled and treated for 28 days with VLCKD. Anthropometric and hormonal variables were assessed before, during and after diet intervention. After 7 and 28 days on a VLCKD, a significant and persistent reduction in body weight, BMI, fat mass, blood glucose, insulin and homeostasis model assessment index was observed compared with baseline. TT significantly increased after 7 days (+35±64ng/dl) and 28 days (+74±97ng/dl) on a VLCKD. In addition to TT, a significant increase in serum sex hormone-binding globulin levels was observed after 7 (+2.1±4.1) and 28 days (+7.7±10.0). However, both calculated free testosterone and LH did not change after 7 or 28 days of VLCKD. Following cessation of VLCKD, hypogonadal subjects achieved a higher percentage of total weight loss (8.5%±1.5%), a greater reduction in weight (-9.94±1.66kg), fat mass (-7±2.1kg) and waist circumference (-6.31±2.65cm) and a greater improvement in glycaemia (-8.75±10.92mg/dl) as compared with eugonadal subjects. Furthermore, hypogonadal subjects exhibited a trend of higher TT increase (+98.12±71.51ng/dl) as compared with eugonadal subjects. VLCKD results in rapid improvements in TT levels associated with weight loss in male obese non-diabetic subjects, particularly in the presence of obesity-related hypogonadism.

Efficacy and Safety of 5-Aminolevulinic Acid for Patients with Symptoms of Late-Onset Hypogonadism: A Preliminary Study.

PurposeAs the concept of late-onset hypogonadism (LOH) has gained increased attention, the treatment of eugonadal patients with LOH symptom has become a clinical problem. Previous studies have shown the possible benefits of 5-aminolevulinic acid (5-ALA) on the somatic, psychological and sexual functions. We therefore conducted this randomized, double-blind, placebo-controlled study to confirm the efficacy and safety of 5-ALA for LOH symptoms.Materials and MethodsThirty-two eugonadal subjects with LOH symptoms were randomly divided into a 5-ALA group (n=15) and a placebo group (n=17). Treatment was continued for 8 weeks. The change of the Aging Males’ Symptoms (AMS) scale score and several biochemical and endocrinological variables during treatment were compared between the groups.ResultsAfter treatment, the change in the total AMS in the 5-ALA group was significantly greater than that in the placebo group (-7.4±4.7 vs. -4.9±4.9, p=0.029). However, the differences between the groups in the change of the somatic, psychological, and sexual sub-scores of the AMS did not reach the statistical significance, although these changes in the 5-ALA group were greater than those in the placebo group. Furthermore, the change in the biochemical and endocrinological variables in the two groups did not differ to a statistically significant extent. During the 8-week treatment period, no patients discontinued 5-ALA due to treatment-emergent adverse events (TEAEs).ConclusionsThe intake of 5-ALA for 8 weeks was beneficial for eugonadal patients with symptoms of LOH and no severe TEAEs was experienced. 5-ALA should be considered as an option for those patients.

Low-intensity shockwave treatment (LISWT) improves penile rigidity in eugonadal subjects with erectile dysfunction: a pilot study.

Since low-intensity shockwave treatment (LISWT) has putative effects on penile hemodynamics remodeling, the aim of this study was to evaluate any improvement of penile vascular flows after LISWT treatment in patients with erectile dysfunction (ED) and poor response to PDE5i. Twenty-one eugonadal patients with different ED severity underwent 6 weekly LISWT sessions (1500-4000 pulses) after 2 weeks withdrawal from PDE5i assumption. Once daily Tadalafil (2.5 mg daily) was reintroduced 4 weeks apart from LISWT termination and patients were evaluated at 1, 2 and 6 months follow-up (T1, T2, T6) by the International Index of Erectile Function-15 items questionnaire (IIEF-15) erectile function (EF) domain, Erection Hardness Score (EHS) and Global Assessment Questionnaires (GAQ). Basal Penile Color-Doppler Ultrasound parameters in the flaccid state (B-PCDU) were evaluated before, during and after interventional protocol. Mean EHS score improved in 35% of patients at T1, and in up to 50% of patients at T2 and T6 follow-up visits (P<0.05). We found 25% improvement of EF scores at T1 session, 43.75% at T2 and 62.5% at T6, respectively (P<0.05). No statistically significant differences in flow parameters, EF-domain and testosterone levels were found when baseline and last observation carried forward (LOCF) parameters were compared. The GAQ questionnaire scored higher satisfaction rates either at the end of the treatment (100%), or at LOCF (92.5%). Despite the study limitations with respect to B-PCDU in this setting, our results confirm a trend toward improvement of erectile questionnaire scores after LISWT with higher overall satisfaction rates among patients with ED. We conclude that LISWT may be an effective option in some difficult-to-treat patients with ED by improving the erectile response to PDE5i.

Controversial aspects of testosterone in the regulation of sexual function in late-onset hypogonadism.

Testosterone (T) plays a pivotal role in coordinating a series of psychological, cognitive and physical events that might (or might not) culminate in male sexual activity. In fact, T deficiency is associated, in a statistically significant way, with several sexual dysfunctions including erectile dysfunction (ED), reduction of spontaneous erection and hypoactive sexual desire (HSD). Although these associations are statistically significant, there is debate if they are also clinically meaningful. In addition, sexual dysfunctions are present also in several metabolic conditions - such as type 2 diabetes mellitus and obesity - that often associate with low T. In particular, this is the case of ED, but not of HSD, that, therefore, should be considered a more genuine correlate of T deficiency in adulthood and aging (late-onset hypogonadism, LOH). The aim of this review is to scrutinize evidence from our and other studies on sexual effects of T replacement therapy (TRT) in LOH. We will use preclinical and clinical data coming from our and other laboratories and meta-analyses. Intervention studies in clinical trials involving subjects with LOH, and their meta-analyses, indicate that TRT is able to ameliorate HSD, spontaneous erection and ED. However, the relative improvement of ED by TRT is marginal [2-3 points of International Index of Erectile Function-erectile function domain (IIEF-EFD)] and significantly smoothed in subjects with the aforementioned metabolic conditions. In LOH, positive effects of TRT on other domains of sexual activity, such as orgasm and sexual satisfaction, are also apparent in the different meta-analyses. Hence, TRT is a reasonable treatment for restoring sexual drive in LOH, with some additional positive effects also on erection (spontaneous and sexual-related) and on orgasm. In contrast, preclinical and clinical studies indicate that T administration to eugonadal subjects does not improve male sexual activity.

Insulin Sensitivity and Testicular Function in a Cohort of Adult Males Suspected of Being Insulin-Resistant.

A cohort of 141 males (18–80 yo, 42.9 ± 12.9) strongly suspected of being Insulin Resistant (IR) was prospectively studied by determining their insulin sensitivity (Pancreatic Suppression Test, PST) and testicular function (total testosterone and SHBG). The subjects were labeled as IR when the Steady State Plasma Glucose (SSPG) was ≥150 mg/dL and Non-Insulin Resistant (NIR) when SSPG was <150 mg/dl; similarly, the subjects were labeled as Hypogonadal (HYPOG) when total testosterone was ≤3.0 ng/mL and Eugonadal (EUG) when total testosterone was >3.0 ng/mL. Two out of three subjects turned out to be IR, while around one in four subjects were HYPOG. Contingency analysis indicated a significant interdependence between insulin resistance and hypogonadism (chi-square was 4.69, p = 0.0303). Age (>43 yo) predicted hypogonadism (AUROC 0.606, p = 0.0308). Twice as many HYPOG subjects were IR as compared with EUG subjects. Also, HYPOG subjects exhibited higher SSPG values as compared with EUG subjects. Statistically, neither Weight nor BMI predicted hypogonadism, while Waist Circumference (>110 cm) was only a mediocre predictor (AUROC 0.640, p = 0.009). SSPG (>224 mg/dL) on the other hand, was the best predictor of hypogonadism (AUROC 0.709, p = 0.002), outperforming Waist Circumference (half of the subjects with an SSPG >224 mg/dL were HYPOG). Age did not predict insulin resistance, while Weight (>99 kg), BMI (>29), and especially, Waist Circumference (>99 cm, AUROC 0.812, p < 0.0001) were all predictors of insulin resistance. Almost 90% of the subjects with a waist circumference >99 cm was IR. As a logical consequence of the selection criteria (various clues suggesting insulin resistance), most subjects with normal weight in this cohort were IR (53.3%) while 20% were HYPOG. On the other hand, 13.6% of the obese subjects were NIR, and 2 out of 3 of them were both NIR and EUG. In conclusion, Waist Circumference predicted both insulin resistance (>99 cm) and hypogonadism (>110 cm), suggesting that the first hit of abdominal obesity is insulin resistance and the second hit is male hypogonadism. Normal weight did not protect from IR, while a relevant proportion of obese subjects were NIR (with 2/3 being also EUG).

Clinical and biochemical correlates of male hypogonadism in type 2 diabetes.

The origin of hypogonadism, a condition including both symptoms and biochemical criteria of androgen deficiency, in type 2 diabetes is poorly known. In a cross-sectional study of 267 unselected patients, we analyzed the potential correlation of several clinical and biochemical variables as well as chronic micro- and macrovascular diabetic complications with hypogonadism. Hypogonadism was present in 46 patients (17.2%) using a cutoff of total testosterone 10.4nmol/L and in 31 (11.6%) with a cutoff of 8nmol/L. Among these patients, hypogonadotropic hypogonadism was the most prevalent form (82.6%). Compared to eugonadal subjects, hypogonadal men had significantly lower glomerular filtration rate (67.1±23.4 vs. 78.4±24.6mL/min/1.73 m2 , p=0.005) and higher prevalence of chronic kidney disease (43.5% vs. 20.4%, p=0.002), abnormal liver function tests (26.7% vs. 12%, p=0.019), and psychiatric treatment (23.9% vs. 10.4%, p=0.025). Total testosterone levels correlated inversely with age (R=-0.164, p=0.007), fasting blood glucose (R=-0.127, p=0.037), and triglycerides (R=-0.134, p=0.029) and directly with glomerular filtration rate (R=0.148, p=0.015). Calculated free testosterone and bioavailable testosterone correlated directly with hemoglobin (R=0.171, p=0.015 and R=0.234, p=0.001, respectively). Multivariate logistic regression analysis, after adjusting for relevant confounding variables, showed that age >60years (OR=3.58, CI 95%=1.48-8.69, p=0.005), body mass index >27kg/m2 (OR=2.85, CI 95%=1.14-7.11, p=0.025), hypertriglyceridemia (OR=2.16, CI 95%=1.05-4.41, p=0.035), glomerular filtration rate <60mL/min/1.73m2 (OR=2.51, CI 95%=1.19-5.29, p=0.015), and abnormal liver function tests (OR=3.57, CI 95%=1.48-8.60, p=0.005) were independently associated with male hypogonadism. Although older age, body mass index, and hypertriglyceridemia have been previously related to hypogonadism, our results describe that chronic kidney disease and abnormal liver function tests are independently correlated with hypogonadism in type 2 diabetic men.

Testicular responses to hCG stimulation at varying doses in men with spinal cord injury.

Study designProspectiveObjectivesTo test whether provocative stimulation of the testes identifies men with chronic spinal cord injury (SCI), a population in which serum testosterone concentrations are often depressed, possibility due to gonadal dysfunction. To accomplish this objective, conventional and lower than the conventional doses of human chorionic gonadotropin (hCG) were administered.MethodsThirty men with chronic SCI [duration of injury >1 year; 18 and 65 years old; 16 eugonadal (>12.1 nmol/l) and 14 hypogonadal (≤12.1 nmol/l)] or able-bodied (AB) men [11 eugonadal and 27 hypogonadal] were recruited for the study. Stimulation tests were performed to quantify testicular responses to the intramuscular administration of hCG at three dose concentrations (i.e., 400 IU, 2000 IU, and 4000 IU). The hCG was administered on two consecutive days and blood was collected for serum testosterone in the early morning prior to each of two injections; subjects returned on day 3 for a final blood sample collection.ResultsThe average gonadal response in the SCI and AB groups to each dose of hCG was not significantly different in the hypogonadal or eugonadal subjects, with the mean serum testosterone concentrations in all groups demonstrating an adequate response.ConclusionsThis work confirmed the absence of primary testicular dysfunction without additional benefit demonstrated of provocative stimulation of the testes with lower than conventional doses of hCG. Our findings support prior work that suggested a secondary testicular dysfunction occurs in a majority of those with SCI and depressed serum testosterone concentrations.

Influence of Androgen Receptor Gene CAG and GGC Polymorphisms on Male Sexual Function: A Cross-Sectional Study.

Background. No study has assessed the possible involvement of GGC androgen receptor (AR) polymorphism in sexual function. Our aim is to evaluate the association between CAG and GGC AR polymorphisms in this function. Methods. We retrospectively examined eighty-five outpatients. Clinical, biochemical, and genetic parameters were considered. Sexual assessment was performed using the International Index of Erectile Function (IIEF) which evaluates erectile function (EF), orgasmic function (OF), sexual desire (SD), intercourse satisfaction (IS), and overall satisfaction (OS). Results. In the whole sample, CAG repeats were inversely correlated with EF, OF, and total IIEF-15 score, whereas GGC tracts did not show any significant correlation with sexual function. CAG relationship with IIEF items retained significance only in the eugonadal but not in the hypogonadal cohort. On the other hand, GGC tracts were not found to be significantly correlated with IIEF variables in either eugonadal or hypogonadal subjects. In eugonadal subjects, logistic regression pointed out that a higher number of CAG triplets were associated with lower values of EF, OF, SD, OS, and total IIEF independently from other confounders. Conclusions. GGC polymorphism seems not to exert any influence on sexual function, whereas CAG polymorphism appears to affect sexual parameters only in eugonadal subjects.

Low testosterone syndrome protects subjects with high cardiovascular risk burden from major adverse cardiovascular events.

The role of testosterone (T) in the cardiovascular (CV) health of men is controversial. Some data suggest that hypogonadism is associated with CV mortality but not morbidity, however, recent evidence shows that hypogonadal subjects treated with T replacement therapy have a higher incidence of new CV events. The aim of this study is to analyse whether gonadal status might predict new CV event incidence according to a patient's previous history of CV events, in a cohort of subjects complaining of sexual dysfunction. A consecutive series of 1687 patients was followed-up for a mean time of 4.3 ± 2.6 years for new occurrence of CV events, detecting 139 events. Hypogonadism (total T < 12 nmol/L) was not associated with an increased incidence of new CV events in the entire cohort. However, when considering patients with a previous history of CV events, hypogonadism was associated with a reduced risk of new CV events, even after adjusting for confounders (hazard ratios - HR = 0.498 [0.240; 0.996]; p = 0.049), whereas no relationship was observed in subjects free of previous CV events. Similar results were observed when reduced testis volume (TV) was considered as a predictor of new CV events in subjects with previous CV events (HR = 0.486 [0.257; 0.920]; p = 0.027). In patients with a history of previous CV events, but not in those without previous CV events, having both low T and low TV was associated with a lower incidence of new CV events as compared with subjects with only one or none of these conditions, even after adjusting for confounders (HR = 0.514 [0.306; 0.864]; p for trend < 0.02). Notably, CV risk estimated with risk engines based on traditional risk factors was not different between hypogonadal and eugonadal subjects. In conclusion, hypogonadism could be interpreted as a protective mechanism in unhealthy conditions, such as previous CV events, to avoid fatherhood and spare energy.

Lean tissue mass and energy expenditure are retained in hypogonadal men with spinal cord injury after discontinuation of testosterone replacement therapy

ObjectiveTo determine whether favorable changes to lean tissue mass (LTM), resting energy expenditure (REE), and testosterone (T) that occurred with 12 months of physiological testosterone replacement therapy (TRT) were retained 6 months after discontinuing treatment.DesignProspective, open-label, controlled drug intervention trial.SettingMetropolitan area hospitals.SubjectsEugonadal (n = 11) and hypogonadal (n = 13) men with chronic spinal cord injury (SCI).InterventionsHypogonadal subjects received a 5 or 10 mg transdermal T patch daily for 12 months, with adjustment of the dose to normalize the serum T concentration; TRT was discontinued after 12 months (TRT-12M) and subjects were followed for an additional 6 months and re-evaluated (Post-TRT). Total body dual energy X-ray absorptiometry and blood draws were performed at baseline (BL) prior to TRT, TRT-12M, and Post-TRT. Eugonadal subjects did not receive treatment and were evaluated at comparable time points.ResultsThere were no significant differences between groups prior to TRT at BL for any of the study endpoints. In the hypogonadal group, a significant increase in LTM was observed from BL to TRT-12M (50.2 ± 7.4 vs. 52.9 ± 6.8 kg, P < 0.01), which persisted Post-TRT compared to BL (52.2 ± 7.8 kg, P < 0.05). The increase in REE from BL to TRT-12M (1283 ± 246 vs. 1410 ± 250 kcal/day) was also retained at Post-TRT (1393 ± 220 kcal/day). These sustained improvements in LTM and REE after termination of anabolic hormonal therapy may be associated with persistent beneficial effects on health and physical function of hypogonadal men with chronic SCI.

Male and female hypogonadism are highly prevalent in South Africans with Addison's disease.

Hypogonadism may complicate Addison's disease (primary hypoadrenalism), but prevalence and metabolic sequelae of hypogonadism in Addison's disease are poorly described. We recruited patients from the South African Addison's disease national registry who received stable replacement doses of hydrocortisone and had no acute illness. Male biochemical testosterone deficiency was defined as an early morning basal testosterone<9.9 nmol/l and premature ovarian failure (POF) when menopause occurred before 40 years of age. Cardiometabolic risk variables were measured in males only. Male hypogonadism prevalence was 33% (14/42), and 10 patients had newly diagnosed hypogonadism. Two untreated patients had elevated FSH or LH (>10 or 12 IU/l). Testosterone deficiency did not correlate with age, disease duration or hydrocortisone dose. Untreated male hypogonadal subjects had a higher (mean ± standard deviation) BMI compared to eugonadal subjects 29.2 ± 4.9 kg/m(2) vs. 24.7 ± 3.4 kg/m(2) (p=0.01) and a higher median (interquartile range) high-sensitive-CRP 6.4 (2.5-14.0) mg/l vs. 1.45 (0.6-2.8) mg/l (p=0.002). There were no differences between the 2 groups in lipids, lipoproteins and fasting glucose. The median (interquartile range) DHEAS was lower in the hypogonadal 0.31 (0.27-0.37) μmol/l, compared with the eugonadal group 0.75 (0.50-1.51) μmol/l (p=0.005). POF was documented in 11% of female patients. Male testosterone deficiency was highly prevalent in this cohort and was primarily due to secondary hypogonadism. Only BMI and hs-CRP were increased in untreated male hypogonadal subjects. Male and female hypogonadism appears to be a common complication of Addison's disease and may contribute to its morbidity.

Clinical and biologic evaluation of ovarian function in women treated by bone marrow transplantation for various indications during childhood or adolescence

To evaluate which factors determine premature ovarian failure after bone marrow transplantation (BMT) during childhood and adolescence. Cross-sectional study. Academic teaching hospital. Thirty-five women with previous allogeneic (n = 19) or autologous (n = 16) BMT for benign (n = 12) or malignant disease (n = 23). Mean age at BMT was 9.8 ± 5.2 years. Eighteen patients had received total body irradiation (TBI). Twenty-three (66%) were premenarchal at the time of BMT. Evaluation of ovarian function. Retrospective analysis of gynecologic history and hormone measurements (FSH, E(2), and antimüllerian hormone [AMH]) in relation to initial pathology, treatment protocols, age, and menarchal status at the time of BMT and time elapsed since BMT. Clinical evidence of persistent ovarian function after BMT was found in 46% of patients (16/35), but low AMH concentrations (<1.2 μg/L) were observed in 85% of patients, including a large subset (2/3) of clinically eugonadal subjects. Age ≤10 years at the time of BMT and absence of TBI were significantly and independently associated with higher rates of clinically proven persistent ovarian function at the time of evaluation. After BMT, ovarian function is impaired in the majority of women, even without clinical signs of premature ovarian failure. This impairment is mostly related to older age at the time of treatment and conditioning treatment with TBI.

Androgens in the feedback regulation of gonadotropin secretion in men: effects of administration of dihydrotestosterone to eugonadal and agonadal subjects and of spironolactone to eugonadal subjects.

To study the role of androgens in the feedback regulation of gonadotropin secretion, we measured the effects of administration of dihydrotestosterone undecanoate (DHTU) and of spironolactone. Basal and LRH stimulated LH/FSH levels were determined in: Six eugonadal men, before and after six weeks' DHTU 120 mg/day. Six agonadal subjects after 12 weeks' DHTU 120 mg/day. The results of B were compared to those of Six agonadal subjects without sex steroid treatment. Six eugonadal subjects were studied before and after six weeks' administration of spironolactone. In the two groups of eugonadal subjects, administration of either dihydrotestosterone or spironolactone had no effect on basal and LRH-stimulated gonadotropin levels. A clear but modest suppression was observed in agonadal subjects. Possibly DHT exerts some suppressive effect on gonadotropin secretion in the absence of other testicular products (estradiol, testosterone, inhibin), known to play a role in the negative feedback regulation. From these data it seems unlikely that in the eugonadal male circulating DHT has an important role in the feedback regulation of gonadotropin secretion.

Estrogens in the feedback regulation of gonadotropin secretion in men: effects of administration of estrogen to agonadal subjects and the antiestrogen tamoxifen and the aromatase inhibitor delta'-testolactone to eugonadal subjects.

To elucidate the specific role of estrogens in the feedback regulation of gonadotropin secretion in men, basal and LRH-stimulated gonadotropin levels were studied in: Six agonadal subjects Six agonadal subjects continuously treated with 50 micrograms ethinylestradiol Six eugonadal subjects, treated with the aromatase inhibitor delta'-testolactone, which induced a reduction of estrogen levels, independently of testosterone. Further, to determine whether estrogens exert differential effects in time on LH and FSH secretion, the anti-estrogen tamoxifen was administered to: Six eugonadal subjects for two weeks and Six eugonadal subjects for six weeks. It was found that estrogens have a strong suppressive effect on both LH and FSH secretion. However, changes in estrogen levels and blocking of estrogen receptors are followed more rapidly by FSH than LH. Estrogens affect LRH-induced LH release more than basal LH levels; basal and LRH-stimulated FSH are approximately equally influenced. Basal and LRH-induced LH secretion are known to be more dependent upon previous LRH stimulation than FSH secretion. Since FSH followed changes of estrogens more rapidly than LH did, we postulate that the negative feedback action of estrogens on: LH secretion is predominantly exerted at the level of the hypothalamus, through inhibition of LRH secretion FSH secretion predominantly at the level of the pituitary through a direct action on the gonadotroph.

Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis: A model for compartment-specific androgen action in the skeleton

Androgens are anabolic hormones that affect many tissues, including bone. However, an anabolic effect of androgen treatment on bone in eugonadal subjects has not been observed and clinical trials have been disappointing. The androgen receptor (AR) mediates biological responses to androgens. In bone tissue, both AR and the estrogen receptor (ER) are expressed. Since androgens can be converted into estrogen, the specific role of the AR in maintenance of skeletal homoeostasis remains controversial. The goal of this study was to use skeletally targeted overexpression of AR in differentiated osteoblasts as a means of elucidating the specific role(s) for AR transactivation in the mature bone compartment. Transgenic mice overexpressing AR under the control of the 2.3-kb α1(I)-collagen promoter fragment showed no difference in body composition, testosterone, or 17ß-estradiol levels. However, transgenic males have reduced serum osteocalcin, CTx and TRAPC5b levels, and a bone phenotype was observed. In cortical bone, high-resolution micro-computed tomography revealed no difference in periosteal perimeter but a significant reduction in cortical bone area due to an enlarged marrow cavity. Endocortical bone formation rate was also significantly inhibited. Biomechanical analyses showed decreased whole bone strength and quality, with significant reductions in all parameters tested. Trabecular morphology was altered, with increased bone volume comprised of more trabeculae that were closer together but not thicker. Expression of genes involved in bone formation and bone resorption was significantly reduced. The consequences of androgen action are compartment-specific; anabolic effects are exhibited exclusively at periosteal surfaces, but in mature osteoblasts androgens inhibited osteogenesis with detrimental effects on matrix quality, bone fragility and whole bone strength. Thus, the present data demonstrate that enhanced androgen signaling targeted to bone results in low bone turnover and inhibition of bone formation by differentiated osteoblasts. These results indicate that direct androgen action in mature osteoblasts is not anabolic, and raise concerns regarding anabolic steroid abuse in the developing skeleton or high-dose treatment in eugonadal adults.

Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy.

Adiponectin is an adipocyte-specific secretory protein which exhibits antiatherogenic, anti-inflammatory and antidiabetic properties. We hypothesized that testosterone plays an important role in the regulation of its secretion in humans, as adiponectin concentrations are higher in women than in men and as testosterone administration is accompanied by a reduction in serum adiponectin in animals and by reduced protein secretion in cultured adipocytes. This study aimed to evaluate adiponectin levels in hypogonadal men prior to and during testosterone replacement therapy. In a retrospective study, adiponectin, total and free testosterone, oestradiol, SHBG, total cholesterol and triglyceride levels were evaluated in 31 hypogonadal men [HM; age, mean +/- SEM: 36.5 +/- 2.4 years; body mass index (BMI) 24.6 +/- 0.8 kg/m2] and 29 weight-matched eugonadal men (EM; age 30.8 +/- 1.5 years; BMI 23.4 +/- 0.6 kg/m2). In 13 HM (age 33.9 +/- 3.2 years; BMI 24.2 +/- 0.9 kg/m2) the same parameters were also evaluated after 6 months of testosterone replacement therapy. Correlation analysis between adiponectin and hormonal, biochemical and anthropometric parameters was performed in all subjects. Testosterone, free testosterone and oestradiol concentrations were significantly lower in HM than in EM (4.4 +/- 0.4 nmol/l, 78.4 +/- 10.9 pmol/l and 36.1 +/- 3.0 pmol/l, respectively, in HM vs. 21.9 +/- 0.7 nmol/l, 507.9 +/- 13.8 pmol/l and 65.2 +/- 1.8 pmol/l, respectively, in EM, P < 0.0001), while SHBG levels in HM were higher than in EM (54.4 +/- 7.5 vs. 30.9 +/- 2.2 nmol/l, P < 0.005). Serum adiponectin levels in HM were significantly higher than in EM (9.53 +/- 0.73 vs. 6.80 +/- 0.55 microg/ml, P < 0.01). Calculation of the Pearson coefficient showed that adiponectin levels in HM were not correlated with any of the anthropometric and hormonal parameters examined, but showed a significant negative correlation with serum triglycerides (r = -0.38, P < 0.05). Serum adiponectin levels were negatively correlated with body weight (r = -0.41, P < 0.05) in EM but not with other anthropometric, hormonal or biochemical parameters. Six months after initiation of testosterone replacement therapy, which increased testosterone and free testosterone levels to the normal range, adiponectin levels were significantly reduced in HM (6.37 +/- 0.93 vs. 9.26 +/- 1.01 microg/ml, P < 0.01) and similar to those recorded in EM. Compared to eugonadal subjects, hypogonadal men show higher adiponectin levels which are reduced by testosterone replacement therapy. This study indicates that testosterone exerts a regulatory role on adiponectin secretion in humans.

Andropause and psychopathology: minor symptoms rather than pathological ones

This study examined the psychological symptomatology of men diagnosed with andropause and the association between calculated free testosterone (T) and depressed mood, anxiety and quality of life. Subjects were 153 men, aged 50–70 years, who participated in a screening of andropause. Total testosterone, FSH, LH and SHBG levels were measured. Depressed mood was assessed with the Carroll Rating Scale, anxiety with the “anxiety-insomnia” dimension of the General Health Questionnaire, and quality of life with the World Health Organisation Quality of Life questionnaire. The results showed that levels of free T decreased with age, whereas FSH and LH increased. Carroll Rating Scale scores were higher among hypogonadal subjects, but the mean score was low and not pathological. A negative correlation was observed between severity of depression as assessed by the Carroll Rating Scale and free T levels. However, subjects with a significant score on this scale did not exhibit different free T levels compared to subjects with a non-significant depressive score. Anxiety and quality of life did not differ between hypogonadal and eugonadal subjects. The present study therefore suggests that andropause is not characterised by specific psychological symptoms, but may be associated with “depressive symptoms” that are not considered as pathological.

Monitoring bone density in hypogonadal men by quantitative phalangeal ultrasound

Monitoring bone density (BMD) in hypogonadal and testosterone (T) substituted men is a major component of andrological therapy and is performed by methods that are cost-intensive and use radiation, such as quantitative computer tomography (QCT). Therefore, we assessed the feasibility of a more practical and inexpensive approach through application of phalangeal quantitative ultrasound (pQUS; IGEA DBM BP Sonic 1200, Sensweiler, Germany) in a cross-sectional study of 521 men, aged 18–91 years (224 healthy controls, 156 newly diagnosed hypogonadal, and 141 T substituted men). The method was compared with QCT of the lumbar spine in the first 80 patients. We evaluated longitudinal changes of amplitude-dependent speed-of-sound (AdSoS) in 54 hypogonadal men from the beginning of T substitution. AdSoS decreased with age ( p < 0.0001) and with declining total T concentration, with a four to fivefold larger reduction in AdSoS for each nanomole-per-liter decrement in total T in the hypogonadal range (<12 nmol/L) compared with the eugonadal range ( p < 0.0001). AdSoS was higher in eugonadal and substituted men than in hypogonadal patients ( p < 0.0001, by analysis of covariance [ANCOVA]). Substituted men <50 years of age showed lower AdSoS than eugonadal men ( p = 0.004) and untreated men with secondary hypogonadism had lower values than men with primary hypogonadism ( p = 0.005). Therapeutic effects were seen regardless of age, diagnosis, or T substitution modality. In the longitudinal approach, AdSoS increased from 1986 ± 93 to 2035 ± 77 m/sec over 237 ± 57 days with the highest gain in those men with initially the lowest values ( p < 0.0001, by ANCOVA for repeated measurements). In comparison to QCT, patients with a lumbar content of hydroxylapatite of <100 mg/cm 3 were reliably identified by pQUS (cutoff level 1965 m/sec, T score −3.5 based on eugonadal subjects; receiver operating characteristics: area under the curve [AUC] 0.94, sensitivity 94.1, specificity 92%, p < 0.0001), but specific values of lumbar BMD could not be predicted by pQUS. pQUS represents a feasible, sensitive, and inexpensive method for assessing bone tissue in hypogonadal men over the full age range and also for monitoring the effects of T substitution.

Sex steroids and pulsatile luteinizing hormone release in men. Studies in estrogen-treated agonadal subjects and eugonadal subjects treated with a novel nonsteroidal antiandrogen.

This study evaluated the effects of estrogens and androgens on LH pulse frequency and amplitude in male subjects. To assess the role of estrogens we compared the serum LH pulse frequency and amplitude between 3 groups: 8 agonadal subjects receiving no steroid treatment; 6 agonadal subjects continuously treated with 50 micrograms ethinylestradiol/day; and 17 eugonadal men. Mean serum LH levels and LH pulse amplitude were significantly lower in the agonadal subjects receiving estrogens (14.8 +/- 5.4 (SD) U/L and 4.1 +/- 1.5 U/L, respectively) than in the group of agonadal subjects not receiving sex steroid treatment (35.7 +/- 8.4 U/L and 7.3 +/- 2.0 U/L, respectively). The mean LH pulse frequency was 7.1 +/- 1.5/7 h in the group not receiving sex steroid treatment and 6.0 +/- 1.4/7 h in the group receiving estrogens (P NS). The LH pulse frequency in the eugonadal men (3.8 +/- 1.3/7 h) was significantly lower than the frequency in both groups of agonadal subjects. The LH pulse amplitude was of the same magnitude in the estrogen-treated agonadal subjects and in eugonadal men (4.1 +/- 1.5 U/L and 3.5 +/- 1.2 U/L, respectively). The role of androgens was studied in 15 eugonadal male subjects (who presented for female role reassignment) by determining the effects of a novel nonsteroidal androgen receptor blocker, Anandron, on basal and LH-releasing hormone (LHRH)-stimulated serum LH/FSH levels; LH pulse frequency and amplitude; sex steroid and sex hormone-binding globulin levels; and serum PRL levels during an 8-week period. Basal and LHRH-stimulated LH levels and testosterone rose progressively during the first 6 weeks and reached a plateau thereafter, while estradiol levels continued to increase somewhat. The LH pulse amplitude and frequency had increased after 6 weeks (3.1 +/- 0.6 vs. 4.5 +/- 1.2 U/L and 4.4 +/- 2.4 vs. 6.6 +/- 1.1 pulses/7 h, respectively). Basal FSH levels were not affected while LHRH-stimulated FSH levels progressively decreased from 2 to 6 weeks, after which they did not change. Along with the rise of estradiol levels an increase of sex hormone-binding globulin and PRL levels occurred.(ABSTRACT TRUNCATED AT 400 WORDS)