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Differences in sex hormone recovery profile after cessation of 12-week gonadotropin-releasing hormone antagonist versus agonist therapy.
Sasaki, H, Miki, K, Tashiro, K, Mori, K, Urabe, F, Fukuokaya, W, Kimura, T, Sato, S, Takahashi, H, Aoki, M, et al
Andrology. 2022;(2):270-278
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Abstract
BACKGROUND Pharmacobiological behavior differs between gonadotropin-releasing hormone (GnRH) antagonists and GnRH agonists. However, reliable evidence clarifying the difference between them is limited. OBJECTIVES We aimed to elucidate the difference in recovery profile between GnRH antagonist (degarelix) and GnRH agonist (leuprorelin acetate or goserelin acetate) as short-term (12 weeks) neoadjuvant androgen deprivation therapy (ADT) prior to 125I-transperineal prostate brachytherapy (TPPB) for localized prostate cancer. MATERIALS AND METHODS This study was initially designed as a single-center, prospective, open-label, randomized controlled trial. The primary endpoint was a serum testosterone level above the castration range (>50 ng/dl) after the cessation of 12-week neoadjuvant ADT (GnRH antagonist or GnRH agonists). All patients underwent 12 weeks of neoadjuvant ADT. The recovery profiles of hormones, prostate-specific antigen, total prostate volume (TPV), bone mineral density, and quality of life scores were investigated. RESULTS Testosterone recovery duration after the last injection was significantly longer in the GnRH antagonist arm than in the GnRH agonist arm (median, 27.3 vs. 4.8 weeks, p < 0.001). The serum levels of luteinizing hormone and follicle-stimulating hormone in the GnRH antagonist arm also remained significantly lower than those in the GnRH agonist arm between 16 and 24 weeks (p < 0.01). Meanwhile, reduction in TPV at the time of TPPB was comparable between both arms (p = 0.128). There were also no significant between-arm differences in the International Prostate Symptom Score and the International Index of Erectile Function scores. DISCUSSION AND CONCLUSION The recovery patterns of hormonal profiles after short-term (12 weeks) neoadjuvant ADT differ between GnRH antagonists and GnRH agonists. The choice between these drugs matters and may have a clinical impact depending on the primary objective of ADT.
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Clamping Cortisol and Testosterone Mitigates the Development of Insulin Resistance during Sleep Restriction in Men.
Liu, PY, Lawrence-Sidebottom, D, Piotrowska, K, Zhang, W, Iranmanesh, A, Auchus, RJ, Veldhuis, JD, Van Dongen, HPA
The Journal of clinical endocrinology and metabolism. 2021;(9):e3436-e3448
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Abstract
CONTEXT Sleep loss in men increases cortisol and decreases testosterone, and sleep restriction by 3 to 4 hours/night induces insulin resistance. OBJECTIVE We clamped cortisol and testosterone and determined the effect on insulin resistance. METHODS This was a randomized double-blind, in-laboratory crossover study in which 34 healthy young men underwent 4 nights of sleep restriction of 4 hours/night under 2 treatment conditions in random order: dual hormone clamp (cortisol and testosterone fixed), or matching placebo (cortisol and testosterone not fixed). Fasting blood samples, and an additional 23 samples for a 3-hour oral glucose tolerance test (OGTT), were collected before and after sleep restriction under both treatment conditions. Cytokines and hormones were measured from the fasting samples. Overall insulin sensitivity was determined from the OGTT by combining complementary measures: homeostasis model assessment of insulin resistance of the fasting state; Matsuda index of the absorptive state; and minimal model of both fasting and absorptive states. RESULTS Sleep restriction alone induced hyperinsulinemia, hyperglycemia, and overall insulin resistance (P < 0.001 for each). Clamping cortisol and testosterone alleviated the development of overall insulin resistance (P = 0.046) and hyperinsulinemia (P = 0.014) by 50%. Interleukin-6, high-sensitivity C-reactive protein, peptide YY, and ghrelin did not change, whereas tumor necrosis factor-α and leptin changed in directions that would have mitigated insulin resistance with sleep restriction alone. CONCLUSION Fixing cortisol-testosterone exposure mitigates the development of insulin resistance and hyperinsulinemia, but not hyperglycemia, from sustained sleep restriction in men. The interplay between cortisol and testosterone may be important as a mechanism by which sleep restriction impairs metabolic health.
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Testosterone Replacement Therapy Added to Intensive Lifestyle Intervention in Older Men With Obesity and Hypogonadism.
Barnouin, Y, Armamento-Villareal, R, Celli, A, Jiang, B, Paudyal, A, Nambi, V, Bryant, MS, Marcelli, M, Garcia, JM, Qualls, C, et al
The Journal of clinical endocrinology and metabolism. 2021;(3):e1096-e1110
Abstract
BACKGROUND Obesity and hypogonadism additively contribute to frailty in older men; however, appropriate treatment remains controversial. OBJECTIVE Determine whether testosterone replacement augments the effect of lifestyle therapy on physical function in older men with obesity and hypogonadism. DESIGN Randomized, double-blind, placebo-controlled trial. SETTING VA Medical Center. PARTICIPANTS 83 older (age ≥65 years) men with obesity (body mass index ≥30 kg/m2) and persistently low am testosterone (<10.4 nmol/L) associated with frailty. INTERVENTIONS Participants were randomized to lifestyle therapy (weight management and exercise training) plus either testosterone (LT+Test) or placebo (LT+Pbo) for 6 months. OUTCOME MEASURES Primary outcome was change in Physical Performance Test (PPT) score. Secondary outcomes included other frailty measures, body composition, hip bone mineral density (BMD), physical functions, hematocrit, prostate specific antigen (PSA), and sex hormones. RESULTS PPT score increased similarly in LT+Test and LT+Pbo group (17% vs. 16%; P = 0.58). VO2peak increased more in LT+Test than LT+Pbo (23% vs. 16%; P = 0.03). Despite similar -9% weight loss, lean body mass and thigh muscle volume decreased less in LT+Test than LT+Pbo (-2% vs. -3%; P = 0.01 and -2% vs -4%; P = 0.04). Hip BMD was preserved in LT+Test compared with LT+Pbo (0.5% vs -1.1%; P = 0.003). Strength increased similarly in LT+Test and LT+Pbo (23% vs 22%; P = 0.94). Hematocrit but not PSA increased more in LT+Test than LT+Pbo (5% vs 1%; P < 0.001). Testosterone levels increased more in LT+Test than LT+Pbo (167% vs 27%; P < 0.001). CONCLUSION In older, obese hypogonadal men, adding testosterone for 6 months to lifestyle therapy does not further improve overall physical function. However, our findings suggest that testosterone may attenuate the weight loss-induced reduction in muscle mass and hip BMD and may further improve aerobic capacity.
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Effects of calorie restricted low carbohydrate high fat ketogenic vs. non-ketogenic diet on strength, body-composition, hormonal and lipid profile in trained middle-aged men.
Vidić, V, Ilić, V, Toskić, L, Janković, N, Ugarković, D
Clinical nutrition (Edinburgh, Scotland). 2021;(4):1495-1502
Abstract
BACKGROUND & AIMS The aim of this paper was to investigate and compare the effects of two iso-energetic hypo-caloric ketogenic hyper-ketonemic and non-ketogenic low carbohydrate high fat high cholesterol diets on body-composition, muscle strength and hormonal profile in experienced resistance-trained middle-aged men. METHODS Twenty non-competitive experienced resistance-trained middle-aged men were on the supervised calorie maintenance western diet and resistance-training regimen for 4 weeks and then divided into ketogenic and non-ketogenic groups for 8 weeks period. Keto bodies (β-hydroxybutyrate) levels were measured weekly, testosterone and insulin biweekly, strength and body-composition monthly, lipid profile and blood sugar level at the beginning and at the end of the study. RESULTS Both groups lost a similar amount of lean body mass and fat tissue (from F = 248.665, p < 0.001 to F = 21.943, p = 0.001), but preserved maximal upper and lower body strength (from F = 1.772, p = 0.238 to F = 0.595, p = 0.577). Basal testosterone and free testosterone increased (from F = 37.267, p = 0.001 to F = 16.261, p = 0.005) and insulin levels decreased significantly in both groups (F = 27.609, p = 0.001; F = 54.256, p < 0.001, respectively). No differences in lipid profile and blood sugar level were found (from F = 4.174, p = 0.058, to F = 0.065, p = 0.802). CONCLUSIONS Ketogenic diet with sustained hyper-ketonemia above 1 mol/l has the same impact as low carbohydrate non-ketogenic diet on muscle strength, body-composition, and hormonal and lipid profile in hypo-caloric dietary conditions in strength-trained middle-aged men.
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Serum Testosterone Levels Are Not Modified by Vitamin D Supplementation in Dialysis Patients and Healthy Subjects.
Ulrich, C, Trojanowicz, B, Fiedler, R, Kraus, FB, Stangl, GI, Girndt, M, Seibert, E
Nephron. 2021;(5):481-485
Abstract
INTRODUCTION Low serum testosterone is related to increased mortality in male dialysis patients. An association of vitamin D status with serum androgen levels with concordant seasonal variation has been described, but it is undecided whether vitamin D supplementation improves testosterone levels. METHODS In a randomized, placebo-controlled, and double-blind manner, we investigated the effects of an oral vitamin D supplementation in healthy subjects and hemodialysis patients on testosterone levels. One hundred three healthy individuals received cholecalciferol 800 IE/day (n = 52) or placebo (n = 51) for 12 weeks. Thirty-three hemodialysis patients received cholecalciferol adapted to their serum levels following current guidelines (n = 15) or placebo (n = 18) for 12 weeks. RESULTS In healthy individuals, 25(OH)D3 levels rose significantly in the verum group (38.1 ± 13.7 vs. 72.5 ± 15.4 nmol/L, p < 0.001), whereas in the placebo group, levels dropped (37.7 ± 14.7 vs. 31.9 ± 13.1, p < 0.001). Testosterone levels did not change significantly (verum, males: 20.9 ± 6.6 vs. 20.5 ± 7.9 nmol/L, p = 0.6; verum, females: 0.9 ± 0.5 vs. 0.92 ± 0.5, p = 0.4; placebo, males: 18.5 ± 10.2 vs. 21.8 ± 16.5, p = 0.07, placebo, females: 1.6 ± 4.2 vs. 1.6 ± 4.9, p = 0.6). In dialysis patients, the mean cholecalciferol level was only 32.3 ± 17.8 nmol/L, with only 2% of the values being within the normal range. Cholecalciferol levels normalized in the verum group (29.4 ± 11.2 vs. 87.8 ± 22.3, p < 0.001), whereas levels dropped further in the placebo group (33.6 ± 16.6 vs. 24.6 ± 8.0 nmol/L, p < 0.001). Testosterone levels did not change significantly (verum, males: 8.0 ± 3.7 vs. 7.8 ± 3.8, p = 0.8; verum, females: 1.3 ± 1.0 vs. 1.2 ± 1.0 nmol/L, p = 0.5; placebo, males: 11.9 ± 5.0 vs. 11.6 ± 4.0 nmol/L, p = 0.6; placebo, females: 0.8 ± 0.5 vs. 0.7 ± 0.4 nmol/L, p = 0.8). CONCLUSION Serum testosterone levels in hemodialysis patients and healthy individuals are independent from vitamin D status and cannot be significantly increased by cholecalciferol supplementation.
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Impact of Clomiphene Citrate on the Steroid Profile in Dysmetabolic Men with Low Testosterone Levels.
Pelusi, C, Fanelli, F, Baccini, M, De Pergola, G, Triggiani, V, Mezzullo, M, Fazzini, A, Di Dalmazi, G, Petrovic, B, Paterini, P, et al
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2021;(8):520-528
Abstract
Clomiphene citrate (CC) in male hypogonadism increases testosterone (T) and estrogen levels by stimulating pituitary gonadotropin release. Our group confirmed these hormonal changes in a randomized, cross-over, double-blind trial of CC versus placebo in addition to metformin, conducted in 21 obese dysmetabolic men with low T levels. However, we hypothesize that based on its mechanism of action, CC may directly or indirectly affect adrenal steroidogenesis. The aim of this sub-study was to better understand the changes in steroid levels and metabolism induced by CC treatment. We assessed 17α-hydroxypregnelone (17αOH-P5), dehydroepiandrosterone (DHEA), progesterone (P4), 17α-hydroxyprogesterone (17αOH-P4), androstenedione (A), T, dihydrotestosterone (DHT), estrone (E1), 17β-estradiol (E2), 11-deoxycortisol (11 S), cortisol (F), and cortisone (E) by LC-MS/MS, and corticosteroid binding globulin (CBG) by ELISA, before and after each treatment. In addition, free-F and steroid product/precursor ratios were calculated. We observed a significant change in serum levels induced by CC compared with placebo for 17αOH-P4, DHT, T, E2, E1, F, E, and CBG, but not free-F. In addition, compared to placebo, CC induced higher 17αOH-P4/P4, E2/E1, 17αOH-P4/17αOH-P5, A/17αOH-P4, T/A, E1/A, F/11 S, and F/E ratios. Therefore, besides the CC stimulating effect on testis steroidogenesis, our study showed increased F, E, but not free-F, levels, indicating changes in steroid metabolism rather than adrenal secretion stimulation. The steroid profiling also revealed the CC stimulation of the Δ5 rather than the Δ4 pathway, thus indicating considerable testicular involvement in the increased androgen secretion.
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Effects of testosterone administration on fMRI responses to executive function, aggressive behavior, and emotion processing tasks during severe exercise- and diet-induced energy deficit.
Carmichael, OT, Pillai, SR, Murray, K, Shankapal, P, Caldwell, J, Vartanian, O, Berryman, CE, Karl, JP, Harris, M, Rood, JC, et al
NeuroImage. 2021;:118496
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Abstract
BACKGROUND Clinical administration of testosterone is widely used due to a variety of claimed physical and cognitive benefits. Testosterone administration is associated with enhanced brain and cognitive function, as well as mood, in energy-balanced males, although such relationships are controversial. However, the effects of testosterone administration on the brains of energy-deficient males, whose testosterone concentrations are likely to be well below normal, have not been investigated. METHODS This study collected functional magnetic resonance imaging (fMRI) data from 50 non-obese young men before (PRE) and shortly after (POST) 28 days of severe exercise-and-diet-induced energy deficit during which testosterone (200 mg testosterone enanthate per week in sesame oil, TEST) or placebo (sesame seed oil only, PLA) were administered. Scans were also collected after a post-energy-deficit weight regain period (REC). Participants completed five fMRI tasks that assessed aspects of: 1) executive function (Attention Network Task or ANT; Multi-Source Interference Task or MSIT; AXE Continuous Processing Task or AXCPT); 2) aggressive behavior (Provoked Aggression Task or AGG); and 3) latent emotion processing (Emotional Face Processing or EMO). RESULTS Changes over time in task-related fMRI activation in a priori defined task-critical brain regions during performance of 2 out of 5 tasks were significantly different between TEST and PLA, with TEST showing greater levels of activation during ANT in the right anterior cingulate gyrus at POST and during MSIT in several brain regions at REC. Changes over time in objective task performance were not statistically significant; testosterone-treated volunteers had greater self-reported anger during AGG at POST. CONCLUSIONS Testosterone administration can alter some aspects of brain function during severe energy deficit and increase levels of anger.
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Cognitive response to testosterone replacement added to intensive lifestyle intervention in older men with obesity and hypogonadism: prespecified secondary analyses of a randomized clinical trial.
Gregori, G, Celli, A, Barnouin, Y, Paudyal, A, Armamento-Villareal, R, Napoli, N, Qualls, C, Villareal, DT
The American journal of clinical nutrition. 2021;(5):1590-1599
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BACKGROUND Both obesity and hypogonadism are common in older men which could additively exacerbate age-related declines in cognitive function. However, little is known about the effects of lifestyle intervention plus testosterone replacement therapy in this population. OBJECTIVES In this secondary analysis of the LITROS (Lifestyle Intervention and Testosterone Replacement in Obese Seniors) trial, we examined whether testosterone replacement therapy would improve cognitive function when added to intensive lifestyle intervention in older men with obesity and hypogonadism. METHODS Eighty-three older, obese hypogonadal men with frailty were randomly assigned to lifestyle therapy (weight management and exercise training) plus testosterone (LT + Test) or lifestyle therapy plus placebo (LT + Pbo) for 6 mo. For this report, the primary outcome was change in the global cognition composite z score. Secondary outcomes included changes in z score subcomponents: attention/information processing, memory, executive function, and language. Changes between groups were analyzed using mixed-model repeated-measures ANCOVAs following the intention-to-treat principle. RESULTS Global cognition z score increased more in the LT + Test than in the LT + Pbo group (mean change: 0.49 compared with 0.21; between-group difference: -0.28; 95% CI: -0.45, -0.11; Cohen's d = 0.74). Moreover, attention/information z score and memory z score increased more in the LT + Test than in the LT + Pbo group (mean change: 0.55 compared with 0.23; between-group difference: -0.32; 95% CI: -0.55, -0.09; Cohen's d = 0.49 and mean change: 0.90 compared with 0.37; between-group difference: -0.53; 95% CI: -0.93, -0.13; Cohen's d = 1.43, respectively). Multiple regression analyses showed that changes in peak oxygen consumption, strength, total testosterone, and luteinizing hormone were independent predictors of the improvement in global cognition (R2 = 0.38; P < 0.001). CONCLUSIONS These findings suggest that in the high-risk population of older men with obesity and hypogonadism, testosterone replacement may improve cognitive function with lifestyle behaviors controlled via lifestyle intervention therapy.This trial was registered at clinicaltrials.gov as NCT02367105.
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The effects of three types of exercise training on steroid hormones in physically inactive middle-aged adults: a randomized controlled trial.
Dote-Montero, M, De-la-O, A, Jurado-Fasoli, L, Ruiz, JR, Castillo, MJ, Amaro-Gahete, FJ
European journal of applied physiology. 2021;(8):2193-2206
Abstract
PURPOSE Physical inactivity and ageing are associated with imbalances in anabolic/catabolic steroid hormones, jeopardizing health. We investigated the effects of three types of training on plasma steroid hormone levels in physically inactive, middle-aged adults. METHODS A 12-week randomized controlled trial was performed with a parallel-group design. A total of 67 (36 women) middle-aged adults (45-65 years old) were randomly assigned to (1) no exercise (control), (2) concurrent training based on the international physical activity recommendations (PAR), (3) high-intensity interval training (HIIT), or (4) HIIT plus whole-body electromyostimulation (HIIT + EMS). The training volume in the PAR group was 150 min/week at 60-65% of the heart rate reserve for aerobic training and ~ 60 min/week at 40-50% of the one-repetition maximum for resistance training. The training volume in the HIIT and HIIT + EMS groups was 40-65 min/week at > 95% of the maximum oxygen uptake in long interval sessions, and > 120% of the maximum oxygen uptake in short interval sessions. RESULTS Compared to the control group, dehydroepiandrosterone sulfate increased in the PAR, HIIT, and HIIT + EMS groups (~ 14%, ~ 14%, and ~ 20%, respectively; all P < 0.01). Cortisol decreased in the PAR, HIIT, and HIIT + EMS groups (~ - 17%, ~ - 10%, and ~ - 23%, respectively; all P ≤ 0.05). Testosterone increased in the HIIT and HIIT + EMS groups (~ 28%, and ~ 16%, respectively; all P ≤ 0.01). Free testosterone increased in the HIIT and HIIT + EMS groups (~ 30% and ~ 18% respectively; all P ≤ 0.01). No significant increase in sex hormone-binding globulin was observed (P = 0.869). CONCLUSION Our findings suggest that HIIT, with or without whole-body EMS, can significantly enhance steroid hormones status in previously physically inactive middle-aged adults. The PAR program led to slight improvements than the HIIT and HIIT + EMS groups despite the application of a higher training volume. CLINICAL TRIAL REGISTRY NCT03334357 (ClinicalTrials.gov). November 7, 2017 retrospectively registered.
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The effects of Elaeagnus angustifolia L. whole fruit on the sex hormone profile in menopausal women: A double-blind, randomized, placebo-controlled study.
Emaminia, F, Rezaei, A, Badehnoosh, B, Ramezani, R, Shabani, M
Journal of ethnopharmacology. 2020;:112229
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Menopause is a product of interrupted ovarian activity and decrease in its estradiol production. Herbal medicines as an alternative to hormone therapy are increasingly used by menopausal women. Elaeagnus angustifolia L. (Senjed in Persian) is a well-known herbal remedy with various therapeutic effects according to Iranian traditional medicine which is recommended to relieve the menopausal side effects. The aim of present study was to evaluate the effects of oral intake of whole fruit powder of E. angustifolia on the sex hormones profile in menopausal women. MATERIALS AND METHODS In present double-blind randomized placebo-controlled trial, 58 eligible women who were referred to Kamali Women Hospital (Karaj, Iran, 2017) were randomly assigned into herbal medicine (15 g E. angustifolia) and placebo (7.5 g cornstarch +7.5 g isomalt) groups. Initially and after 10 weeks of the treatment, serum levels of estradiol, progesterone, testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) hormones were measured. RESULTS According to between-group analyses, the changes in the studied parameters were not significant between herbal medicine and placebo groups, except for joint pain that improved significantly in herbal medicine group. However, by within-group analysis the levels of FSH and FSH to testosterone showed a significant increase, whereas the level of progesterone decreased significantly after 10 weeks of E. angustifolia consumption. CONCLUSIONS The improvement of the sex hormone profile was not in a full accordance with Iranian folklore after E. angustifolia consumption in the present menopausal participants. However, considering a strong belief on the beneficial effects of E. angustifolia in Iranian folklore, a long-term studies of larger group participants are needed to evaluate the efficacy.