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Objective: Despite having normal thyroid-stimulating hormone levels, many hypothyroid patients are dissatisfied with the treatment. The primary aim of this study was to evaluate the effect of twice-daily, combination therapy with levothyroxine (LT4) and liothyronine (LT3), at doses adapted according to TSH-level, on peripheral tissues as reflected by sex hormone binding globulin (SHBG) levels in totally thyroidectomized patients. Changes in other tissue markers and quality of life considering DIO2-rs225014 and MCT10-rs17606253 genetic variants were also assessed., Design: Double-blind, randomized, placebo-controlled., Methods: One hundred and forty-one subjects were randomized to LT4 + LT3 group (LT4 + LT3 in the morning and LT3 in the evening; n = 70) or placebo group (LT4 in the morning and placebo in the evening; n = 71). Pituitary-thyroid axis compensation was assessed after 6, 12, and 24 weeks. Clinical parameters, quality of life, and tissue markers (sex hormone binding globulin, serum lipids, bone markers) were evaluated at 12 and 24 weeks. DIO2 and MCT10 single nucleotide polymorphisms were genotyped., Results: The LT4 + LT3 group was treated with mean daily LT3 doses of 5.00 µg, with a mean daily LT4 reduction of 15 µg. After 6 months of treatment, neither SHBG and other tissue markers nor quality of life differed significantly between groups. Combination treatment required greater dose adjustments than placebo (25% vs 54%, P < .001), due to thyroid-stimulating hormone reduction, without hyperthyroidism signs or symptoms. At the end of treatment, the LT4 + placebo group had significantly lower fT3/fT4 compared to the LT4 + LT3 group (0.26 ± 0.05 vs 0.32 ± 0.08, P < .001). No preference for combination therapy was found. Genetic variants did not influence any outcomes., Conclusions: Six months of combination therapy with twice-daily LT3 dose adapted according to TSH-level do not significantly change peripheral tissue response or quality of life, despite an increase in the fT3/fT4 ratio., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Hypogonadism is common in HIV-infected men. The relationship between health status, sex steroids and body composition is poorly known in HIV. The aim was to investigate the association between health status (comorbidities/frailty), body composition, and gonadal function in young-to-middle-aged HIV-infected men., Design: Prospective, cross-sectional, observational study., Methods: HIV-infected men aged <50 years and ongoing Highly Active Antiretroviral Therapy were enrolled. Serum total testosterone (TT), estradiol (E2), estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, LH and FSH by immunoassay. Free testosterone (cFT) was calculated by Vermeulen equation. Body composition was assessed by dual-energy X-ray absorptiometry and abdominal CT scan. Multimorbidity (MM) and frailty were defined as ≥3 comorbidities and by a 37-item index, respectively., Results: A total of 316 HIV-infected men aged 45.3 ± 5.3 years were enrolled. Body fat parameters were inversely related to cFT and TT, and directly related to E1 and E2/testosterone (TS) ratio. Patients with MM had lower cFT (P < 0.0001) and TT (P = 0.036), and higher E1 (P < 0.0001) and E2/TS ratio (P = 0.002). Frailty was inversely related to cFT (R2 = 0.057, P < 0.0001) and TT (R2 = 0.013, P = 0.043), and directly related to E1 (R2 = 0.171, P < 0.0001), E2 (R2 = 0.041, P = 0.004) and E2/TS ratio (R2 = 0.104, P < 0.0001)., Conclusions: Lower TT and cFT, higher E1, E2/TS ratio and visceral fat were independently associated to poor health status and frailty, being possible hallmarks of unhealthy conditions in adult HIV-infected men. Overall, MM, frailty and body fat mass are strictly associated to each other and to sex steroids, concurring together to functional male hypogonadism in HIV.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform., Aims: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD., Design: On-line survey in endocrine centres throughout Europe., Patients and Methods: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018., Results: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved., Conclusion: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.

Background: Men with Klinefelter syndrome (KS) show hypergonadotropic hypogonadism, but the pathogenesis of hypotestosteronemia remains unclear. Testicular steroidogenesis in KS men was evaluated over three decades ago after human chorionic gonadotropin (hCG) stimulation, but inconclusive results were obtained. Intriguingly, some recent studies show increased intratesticular testosterone concentrations in men with KS., Objective: To analyze serum steroid profile, as a proxy of testicular steroidogenesis, after hCG stimulation in KS compared with control men., Design: A prospective, longitudinal, case-control, clinical trial., Methods: Thirteen KS patients (36±9 years) not receiving testosterone (TS) replacement therapy and 12 eugonadic controls (32±8 years) were enrolled. Serum steroids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline and for five consecutive days after intramuscular injection of 5000IU hCG., Results: Progesterone (P), 17-hydroxyprogesterone (17OHP), TS, and estradiol (E2) showed a significant increase (P<0.001) after hCG stimulation in both groups. On the contrary, androstenedione (AS) and dehydroepiandrosterone did not increase after hCG stimulation. The 17OHP/P ratio increased in both groups (P<0.001), the TS/AS ratio (17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) activity) did not increase after hCG in any group, and the E2/TS ratio (aromatase activity) increased significantly in both groups (P=0.009 in KS and P<0.001 in controls). Luteinizing hormone decreased after hCG in both groups (P=0.014 in KS and P<0.001 in controls), whereas follicle-stimulating hormone decreased only in control men (P<0.001)., Conclusion: This study demonstrates for the first time using LC-MS/MS that Leydig cells of KS men are able to respond to hCG stimulation and that the first steps of steroidogenesis are fully functional. However, the TS production in KS men is impaired, possibly related to reduced hydroxysteroid deydrogenase activity due to an unfavorable intratesticular metabolic state., (© 2016 European Society of Endocrinology.)

Objective: Type 2 diabetes mellitus (T2DM) is associated with endothelial dysfunction, characterized by a reduction of nitric oxide (NO)-mediated relaxation. Phosphodiesterase type 5 inhibitors (PDE5i) improve NO levels. The aim of the study was to investigate whether long-term, chronic treatment with the PDE5i vardenafil improves systemic endothelial function in diabetic men., Design: A prospective, investigator-initiated, randomized, placebo-controlled, double-blind, clinical trial was conducted., Methods: In total, 54 male patients affected by T2DM, diagnosed within the last 5 years, and erectile dysfunction were enrolled, regardless of testosterone levels. In all, 26 and 28 patients were assigned to verum and placebo groups respectively. The study consisted of an enrollment phase, a treatment phase (24 weeks) (vardenafil/placebo 10  mg twice in a day) and a follow-up phase (24 weeks). Parameters evaluated were as follows: International Index of Erectile Function 15 (IIEF-15), flow-mediated dilation (FMD), serum interleukin 6 (IL6), endothelin 1 (ET-1), gonadotropins and testosterone (measured by liquid chromatography/tandem mass spectrometry)., Results: IIEF-15 erectile function improved during the treatment (P<0.001). At the end of the treatment both FMD (P=0.040) and IL6 (P=0.019) significantly improved. FMD correlated with serum testosterone levels (R(2)=0.299; P<0.001). Testosterone increased significantly under vardenafil treatment and returned in the eugonadal range only in hypogonadal men (n=13), without changes in gonadotropins. Chronic vardenafil treatment did not result in relevant side effects., Conclusion: This is the first double-blind, placebo-controlled clinical trial designed to evaluate the effects of chronic treatment of vardenafil on endothelial health-related parameters and sexual hormones in patients affected by a chronic disease. Chronically administered vardenafil is effective and improves endothelial parameters in T2DM patient. Moreover, chronic vardenafil therapy improves hypogonadism in diabetic, hypogonadal men., (© 2016 European Society of Endocrinology.)

Objective: Gender influence on GH secretion in human immunodeficiency virus (HIV)-infected patients is poorly known., Design and Methods: To determine the effect of gender, we compared GH response to GH-releasing hormone plus arginine (GHRH+Arg), and body composition in 103 men and 97 women with HIV and lipodystrophy. The main outcomes were IGF1, basal GH, GH peak and area under the curve (AUC) after GHRH+Arg, body composition, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT)., Results: Men had lower GH peak and AUC than women (P<0.001). Of the study population, 21% of women and 37% of men had biochemical GH deficiency (GHD; GH peak <7.5 μg/l). VAT-to-SAT ratio was higher in men than in women with GHD (P<0.05). Unlike women, VAT, SAT, and trunk fat were greater in men with GHD than in men without GHD. IGF1 was significantly lower in women with GHD than in women without GHD, but not in men. At univariate analysis, BMI, trunk fat mass, VAT, and total adipose tissue were associated with GH peak and AUC in both sexes (P<0.05). BMI was the most significant predictive factor of GH peak, and AUC at multiregression analysis. Overall, abdominal fat had a less pronounced effect on GH in females than in males., Conclusions: These data demonstrate that GH response to GHRH+Arg is significantly lower in HIV-infected males than females, resulting in a higher percentage of GHD in men. Adipose tissue distribution more than fat mass per se seems to account for GH gender differences and for the alteration of GH-IGF1 status in these patients.

Objective: GH secretion is impaired in lipodystrophic human immunodeficiency virus (HIV) patients and inversely related to lipodystrophy-related fat redistribution in men. Less is known about the underlying mechanisms involved in reduced GH secretion in HIV-infected women., Design: A case-control, cross-sectional study comparing GH/IGF1 status, body composition, and metabolic parameters in 92 nonobese women with HIV-related lipodystrophy and 63 healthy controls matched for age, ethnicity, sex, and body mass index (BMI)., Methods: GH, IGF1, IGF binding protein 3 (IGFBP3), GH after GHRH plus arginine (GHRH+Arg), several metabolic variables, and body composition were evaluated., Results: GH response to GHRH+Arg was lower in HIV-infected females than in controls. Using a cutoff of peak GH ≤ 7.5 μg/l, 20.6% of HIV-infected females demonstrated reduced peak GH response after GHRH+Arg. In contrast, none of the control subjects demonstrated a peak GH response ≤ 7.5 μg/l. Bone mineral density (BMD), quality of life, IGF1, and IGFBP3 were lowest in the HIV-infected females with a GH peak ≤ 7.5 μg/l. BMI was the main predictive factor of GH peak in stepwise multiregression analysis followed by age, with a less significant effect of visceral fat in the HIV-infected females., Conclusions: This study establishes that i) GH response to GHRH+Arg is lower in lipoatrophic HIV-infected women than in healthy matched controls, ii) BMI more than visceral adipose tissue or trunk fat influences GH peak in this population, and iii) HIV-infected women with a GH peak below or equal to 7.5 μg/l demonstrate reduced IGF1, IGFBP3, BMD, and quality of life.

Background: In men, the feedback of gonadotropins is regulated by estrogens that come from the aromatization of testosterone, but the relative contribution to the inhibition of LH and FSH secretion by the amount of locally produced estrogens within the hypothalamus and/or the pituitary, and the amount of circulating estrogens still remains unknown., Objective: In order to evaluate the effect of regulation induced by estradiol on the hypothalamic-pituitary-gonadal (HPG) axis, we studied the pulsatility of LH and FSH in two aromatase-deficient men (called subject 1 and subject 2), in which the production rate of estrogen (both local and circulating) is completely, or at least severely, impaired., Design: FSH and LH were evaluated in terms of their pulsated secretion and as GnRH-stimulated secretion in two phases: phase 1, before estrogen treatment; and phase 2, during estrogen treatment with 25 microg transdermal estradiol twice weekly., Methods: Blood samples were taken during phase 1 and phase 2 at 0800 h for basal measurements of LH, FSH, inhibin B, testosterone, and estradiol. The analysis of the pulsatility of LH and FSH was performed by sampling every 10 min for 8 h in the two phases. Gonadotropin response to GnRH-stimulation test was studied by serial standard sampling after 100 microg GnRH i.v. bolus in phases 1 and 2., Results: Estrogen treatment led to a significant reduction in both LH-pulsated frequency (7.5 +/- 0.7 in phase 1, 4.5 +/- 0.7 in phase 2) and amplitudes (3.5 +/- 0.006 in phase 1, 1.9 +/- 0.4 in phase 2) of peaks, whereas FSH showed only a conspicuous reduction in serum levels and a trend towards the reduction of the amplitudes of its peaks without modification of the frequency of the pulses. Both testosterone and gonadotropins decreased during phase 2, whereas estradiol reached the normal range in both subjects. Transdermal estradiol treatment significantly lowered the peaks of both serum LH and FSH after GnRH as well as the incremental area under the curve after GnRH administration in both subjects. Basal serum inhibin B levels were slightly higher before transdermal estradiol treatment (phase 1) than during estrogen treatment (phase 2) in both subjects., Conclusions: The administration of estrogen to aromatase-deficient men discloses the effects of circulating estrogens on LH secretion, exerted both at pituitary level, as shown by the decrease of basal and GnRH-stimulated secretion of LH and the LH pulsed amplitude, and at hypothalamic level as shown by the reduction of the frequency of LH pulses. The present study, coupling the outcomes of basal, GnRH-stimulated and the pulsatile evaluation of LH and FSH secretion in two aromatase-deficient men, demonstrates that circulating estrogens play an inhibitory role in LH secretion by acting on the hypothalamus and the pituitary gland of men. The discrepancy among testosterone levels, the arrest of spermatogenesis and a slightly inappropriate respective increase of serum FSH (lower than expected) suggests a possible role of estrogens in the priming and the maturation of HPG axis in men, an event that has never occurred in these two subjects as a consequence of chronic estrogen deprivation.

Objective: Aromatase, the key enzyme involved in estrogen synthesis, is expressed in a variety of cells and tissues including human peripheral blood leukocytes (PBLs). The present study was designed to evaluate PBL aromatase gene expression in male and female subjects of different age groups. In addition, differences in gene expression during the follicular and luteal phase of the menstrual cycle in women, and before and after testosterone administration in men, were estimated., Design: Aromatase mRNA and protein were measured in PBLs obtained from young (n = 10) and postmenopausal women (n = 10), men (n = 15), and prepubertal children (n = 10). Aromatase mRNA and protein were also measured during the follicular and luteal phases of the menstrual cycle in women, and before and after the intramuscular administration of 250 mg testosterone enanthate in men., Methods and Results: Aromatase mRNA measured by real-time PCR in PBLs from women during the follicular phase was significantly higher than during the luteal phase of the menstrual cycle (P < 0.05). In men, PBL aromatase mRNA values increased significantly following testosterone administration (P < 0.05). PBL mRNA aromatase levels in women during the follicular phase and men after testosterone administration were significantly higher (one-way ANOVA; P < 0.05) than in any other group. Children, postmenopausal women, and women during the luteal phase showed the lowest aromatase mRNA expression. The results of the immunoblot analysis confirmed the data obtained by real-time PCR. A positive correlation between PBL aromatase mRNA values and plasma estradiol and estrone levels during the follicular phase of the menstrual cycle was observed in the group of adult women. No other correlations were found., Conclusions: The aromatase gene is differentially expressed in PBLs from women, men, and prepubertal children, indicating a sexual dimorphism in the enzyme expression and an important role of sex steroids in the modulation of aromatase gene expression.

Male age-related bone loss is caused, at least in part, by hypogonadism that occurs with advancing age. The study of the effects of sex steroids on bone physiology in men has recently highlighted the central role of estrogens on bone pathophysiology. This review focuses on particular aspects of bone physiology and pathophysiology in aging men, noting both the similarities to and the differences from female counterparts. In particular, the role of sex steroids on bone sexual dimorphism in health and disease has been analyzed.