FIG 1 - uploaded by Shalender Bhasin
Content may be subject to copyright.
A, Total testosterone in young and older men from baseline (d 21 and 14) to the treatment phase (d 84 and 113). B, Free testosterone in younger and older men from baseline to d 84 and 113 of the treatment phase. Steady-state levels were reached by d 84, the 12th week of treatment with im TE.
Source publication
Recently we found that testosterone levels are higher in older men than young men receiving exogenous testosterone. We hypothesized that older men have lower apparent testosterone metabolic clearance rates (aMCR-T) that contribute to higher testosterone levels.
The objective of the study was to compare aMCR-T in older and young men and identify pre...
Context in source publication
Context 1
... total and free T levels were steady state by treat- ment d 84 (Fig. 1). Serum levels were not significantly dif- ferent between d 84 and 113. Total and free T levels from d 84 and 113 were averaged for the purpose of calculating percent change from baseline. Serum free and total T levels increased in a dose-dependent manner in both young and older men (Fig. 2). Older men in the 125-, 300-, and 600-mg dose ...
Similar publications
The current increase of life expectancy is associated with the presence of endocrine diseases in the elderly. The management of hypopituitarism in this group of patients is a challenging task. A correct diagnosis, which represents an essential requisite for an appropriate medical treatment, can be difficult because of the physiological changes occu...
Patients with primary amenorrhea, sexual infantilism and elevated pituitary gonadotropins are frequently diagnosed with hypogonadism hypergonadotropic and suspected ovarian failure, secondary to a chromosomal abnormality, intrinsic ovarian failure or altered receptors for gonadotropins, mainly FSH (ovarian resistance). We report the case of a 16-ye...
Context
A novel formulation of oral testosterone (T) undecanoate (TU) was evaluated in a phase 3 clinical trial.
Objective
Determine efficacy, short-term safety, and alignment of new oral TU formulation with current U. S. approval standards for T replacement therapy.
Design
Randomized, active-controlled, open-label study.
Setting and Patients
Ac...
Fracture frequency was studied in 107 hypopituitary patients with GH deficiency (GHD) (69 men, mean age 53 years, range 18-74 and 38 women, mean age 54 years, range 31-73). Routine hormonal replacement therapy was given, except GH. Five male patients and 15 female patients with untreated hypogonadism were allocated to a separate group. The mean dur...
This study aimed to investigate the effects of testosterone replacement therapy (TRT) on lower urinary tract symptoms (LUTS) in men with late-onset hypogonadism (LOH) and to identify parameters predicting the efficacy of TRT in improving LUTS. This study included 60 consecutive Japanese men who were diagnosed with LOH and subsequently received TRT...
Citations
... In addition to increased production of androgens, decreased androgen clearance results in increased serum androgen levels. Conditions associated with decreased androgen clearance include oestrogen treatment [4,11], barbiturate treatment [4,12], hyperthyroidism [4,13], hypogonadism [4,14], and ageing [15]. ...
Endometrial receptivity is a state of the endometrium defined by its readiness for embryo implantation. When the receptivity of the endometrium is impaired due to hyperandrogenism or androgen excess, this condition can lead to pregnancy loss or infertility. Hyperandrogenism encompasses a wide range of clinical manifestations, including polycystic ovary syndrome (PCOS), idiopathic hirsutism, hirsutism and hyperandrogaenemia, non-classical congenital adrenal hyperplasia, hyperandrogenism, insulin resistance, acanthosis nigricans (HAIR-AN), ovarian or adrenal androgen-secreting neoplasms, Cushing’s syndrome, and hyperprolactinaemia. Recurrent miscarriages have been shown to be closely related to elevated testosterone levels, which alter the endometrial milieu so that it is less favourable for embryo implantation. There are mechanisms for endometrial receptivity that are affected by excess androgen. The HOXA gene, aVβ3 integrin, CDK signalling pathway, MECA-79, and MAGEA-11 were the genes and proteins affect endometrial receptivity in the presence of a hyperandrogenic state. In this review, we would like to explore the other manifestations of androgen excess focusing on causes other than PCOS and learn possible mechanisms of endometrial receptivity behind androgen excess leading to pregnancy loss or infertility.
... In a study of different dosage regimens of weekly intramuscular testosterone enanthate, apparent testosterone clearance was calculated based on the amount of testosterone delivered weekly, trough testosterone concentrations and correction by absorption kinetics. The mean clearance was ~25% lower in the older group (ages 60-75 years) than the younger group (ages 19-35 years) [41]. There is indirect evidence of increased, organ-specific, androgen sensitivity in aging men. ...
In men > ~35 years, aging is associated with perturbations in the hypothalamus-pituitary–testicular axis and declining serum testosterone concentrations. The major changes are decreased gonadotropin-releasing hormone (GnRH) outflow and decreased Leydig cell responsivity to stimulation by luteinizing hormone (LH). These physiologic changes increase the prevalence of biochemical secondary hypogonadism—a low serum testosterone concentration without an elevated serum LH concentration. Obesity, medications such as opioids or corticosteroids, and systemic disease further reduce GnRH and LH secretion and might result in biochemical or clinical secondary hypogonadism. Biochemical secondary hypogonadism related to aging often remits with weight reduction and avoidance or treatment of other factors that suppress GnRH and LH secretion. Starting at age ~65–70, progressive Leydig cell dysfunction increases the prevalence of biochemical primary hypogonadism—a low serum testosterone concentration with an elevated serum LH concentration. Unlike biochemical secondary hypogonadism in older men, biochemical primary hypogonadism is generally irreversible. The evaluation of low serum testosterone concentrations in older men requires a careful assessment for symptoms, signs and causes of male hypogonadism. In older men with a body mass index (BMI) ≥ 30, biochemical secondary hypogonadism and without an identifiable cause of hypothalamus or pituitary pathology, weight reduction and improvement of overall health might reverse biochemical hypogonadism. For older men with biochemical primary hypogonadism, testosterone replacement therapy might be beneficial. Because aging is associated with decreased metabolism of testosterone and increased tissue-specific androgen sensitivity, lower dosages of testosterone replacement therapy are often effective and safer in older men.
... Hypogonadism is defined as the failure of the testis to produce physiological amounts of testosterone and/or a normal number of spermatozoa due to abnormalities at one or more levels of the hypothalamic-pituitary-testicular (HPT) axis. 8,9 The term late-onset hypogonadism refers to a cluster of symptoms and signs in older men in association with the age-related decline in testosterone levels similar to those observed in young men with hypogonadism. 1 Many cross-sectional and epidemiological studies agree that total and free testosterone concentrations decline with increasing age in men; 12-14 the trajectory of age-related decline in free testosterone concentrations is greater than that of total testosterone concentrations because SHBG levels increase with advancing age 12,14 . The magnitude and the rate of age-related decline in total and free testosterone levels is affected by obesity and chronic disease. ...
... Testosterone concentrations decrease more in men who have greater adiposity, weight gain, and comorbid diseases. 12,14,15 (6) Along with these, LH and SHBG levels increase with aging. ...
... Age-related decline in circulating testosterone levels is caused primarily by reduced testosterone production by the testes 5,18,34-37 . Testosterone clearance is lower in older men than in young men (14). Reduced testosterone production rates in older men are caused by changes affecting all levels of the hypothalamic-pituitary-testicular (HPT) axis. ...
Total and free testosterone levels decline in men with advancing age due to defects at all levels of the hypothalamic-pituitary-testicular axis. Testosterone treatment of older men with low testosterone levels is associated with improvements in sexual activity, sexual desire, and erectile function; lean body mass, muscle strength, and stair climbing power, and self-reported mobility; areal and volumetric bone mineral density, and estimated bone strength; depressive symptoms; and anemia. Long-term risks of cardiovascular events and prostate cancer during testosterone treatment remain unknown. Testosterone treatment may be offered on an individualized basis to older men with unequivocally low testosterone levels and symptoms or conditions associated with testosterone deficiency after consideration of potential benefits and risks, burden of symptoms, and patient's values.
... Although various physical, psychological or sexual dysfunction symptoms may occur in LOH syndrome, TRT is considered the first treatment, as androgen deficiency is the essence of the condition (5). However, it has also been indicated that an increase in the blood testosterone concentration due to testosterone administration is caused by aging (33). ...
Abstract
In the present study, the initial treatment efficiency of combination therapy using testosterone replacement therapy (TRT), herbal medicine and phosphodiesterase 5 inhibitors (PDE5i) in male patients with late-onset hypogonadism (LOH) were assessed. A total of 21 patients were enrolled and after 12 weeks, the clinical efficacy was evaluated based on improvement of LOH symptoms via laboratory parameters and several questionnaires, including the Ageing Males' Symptoms (AMS) scale. The overall AMS scores, as well as the psychological, physical and sexual AMS factors prior to and after treatment in the TRT, testosterone enanthate (T enanthate) monotherapy and T enanthate + PDE5i treatment groups were significantly improved. In the herbal medicine group, only the AMS physiological factors were significantly improved after treatment compared with the baseline. The improvement of the overall AMS scores, as well as the physiological and sexual AMS factors, were significantly negatively correlated with the free testosterone (FT) value prior to treatment. In conclusion, treatment with combination therapy using TRT, herbal medicine and PDE5i improved AMS scores in patients with LOH syndrome. Particularly in patients with LOH syndrome and low FT, the symptoms were significantly improved following combination therapy.
... 15 SHBG has a high affinity for testosterone, and increasing levels of SHBG can restrict the availability of circulating testosterone for hepatic extraction. 16,17 Consistent with its physiologic role, SHBG was found to be a significant covariate on CL/F in the current population PK model (ie, lower SHBG levels were associated with increased CL/F). Given that testosterone undecanoate is administered IM, it was hypothesized that the rate of absorption of the depot IM injection could be dependent on body weight (ie, muscle mass). ...
Intramuscular testosterone undecanoate is indicated as testosterone replacement in adult males with a deficiency in or absence of endogenous testosterone (hypogonadism). Intramuscular testosterone undecanoate 750 mg is approved to be administered at initiation and at 4 weeks, followed by a maintenance dose every 10 weeks. However, a more frequent maintenance regimen may improve symptom management of low testosterone at the end of each dosing interval. The current objective was to develop a population pharmacokinetic (PK) model for intramuscular testosterone undecanoate 750 mg and to perform PK simulations to assess the impact of an 8‐week maintenance regimen on testosterone exposure. A 1‐compartment model with first‐order absorption and first‐order elimination best described the PK of testosterone undecanoate. The model included time‐dependent suppression and gradual recovery of endogenous testosterone production during testosterone undecanoate administration. Significant covariates included body weight and sex hormone binding globulin level. With the final PK model, simulations were performed to evaluate the impact of an 8‐week versus a 10‐week maintenance regimen on testosterone exposure. The 8‐week testosterone undecanoate regimen had a predicted 11% increase in Cavg and Ctrough and a 5% increase in Cmax. This translated into an ≈10% increase in the percentage of patients predicted to have Ctrough >300 ng/dL, minimal change in the percentage of patients with Cavg in the normal range, and a low likelihood of Cmax >2500 ng/dL. These simulations suggest that more frequent administration of intramuscular testosterone undecanoate may be beneficial in some patients. Further clinical evaluation of an 8‐week dose regimen is warranted. This article is protected by copyright. All rights reserved
... Comorbidity and adiposity are the major contributors to testosterone deficiency in older men. plasma clearance of testosterone is lower in older men than in young men (8). Several mechanisms contribute to the age-related decline in testosterone levels; with aging, the secretion of gonadotropin-releasing hormone is attenuated; pituitary luteinizing hormone (LH) secretion becomes more disorderly and asynchronous; and the Leydig cell's response to LH stimulation is diminished (9)(10)(11)(12)(13). ...
... Older men may be at increased risk of the adverse effects of testosterone treatment for several reasons. The plasma clearance rates of testosterone are lower in older men; consequently, serum testosterone levels are higher in testosterone-treated older hypogonadal men than in young men, after adjusting for age (8). Older men also exhibit greater increments in hemoglobin and hematocrit in response to testosterone administration than young men (43). ...
The substantial increase in life expectancy of men has focused growing attention on quality-of-life issues associated with reproductive aging. Serum total and free testosterone levels in men, after reaching a peak in the second and third decade of life, decline gradually with advancing age. The trajectory of age-related decline is affected by comorbid conditions, adiposity, medications, and genetic factors. Testosterone treatment of older men with low testosterone levels improves overall sexual activity, sexual desire, and erectile function; improves areal and volumetric bone density, as well as estimated bone strength in the spine and the hip; corrects unexplained anemia of aging; increases skeletal muscle mass, strength and power, self-reported mobility, and some measures of physical function; and modestly improves depressive symptoms. The long-term effects of testosterone on major cardiovascular events and prostate cancer risk remain unclear. The Endocrine Society recommends against testosterone therapy of all older men with low testosterone levels but suggests consideration of treatment on an individualized basis in men who have consistently low testosterone levels and symptoms or conditions suggestive of testosterone deficiency.
Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... Previous dose-response studies demonstrate that a given T dose results in greater serum T elevations in older (60-75 years) versus younger (18-35 years) eugonadal males, but the greater increases in serum T in older males did not result in greater increases in FFM [22,23]. The higher serum T concentrations following a given T dose observed in older males [22,23] are thought to be partially attributed to agerelated decreases in T clearance rates [51]. Although these findings contradict ours, such that increases in serum T were the smallest in OLD and largest in YNG, the magnitude of the effects of TA on serum T and FFM may be dependent on participant characteristics and T formulations. ...
Testosterone (T) administration (TA) increases serum T and fat-free mass (FFM). Although TA-mediated increases in FFM may enhance physical performance, the data are largely equivocal, which may be due to differences in study populations, the magnitude of change in serum T and FFM, or the performance metrics. This meta-analysis explored effects of TA on serum T, FFM, and performance. Association between increases in serum T and FFM were assessed, and if changes in serum T or FFM, study population, or the performance metrics affected performance was determined. A systematic review of double-blind randomized trials comparing TA versus placebo on serum T, FFM, and performance was performed. Data were extracted from 20 manuscripts. Effect sizes (ES) were assessed using Hedge’s g and a random effects model. Data are presented as ES (95% CI). No significant correlation between changes in serum T and FFM was observed (p=0.167). Greater increases in serum T, but not FFM, resulted in larger effects on performance. Larger increases in testosterone [7.26(0.76,13.75)] and FFM [0.80(0.20,1.41)] were observed in young males, but performance only improved in diseased [0.16(0.05,0.28)] and older males [0.19(0.10,0.29)]. TA increased lower body [0.12(0.07,0.18)], upper body [0.26(0.11,0.40)], and handgrip [0.13(0.04,0.22)] strength, lower body muscular endurance [0.38(0.09,0.68)], and functional performance [0.20(0.00,0.41)], but not lower body power or aerobic endurance. TA elicits increases in serum T and FFM in younger, older and diseased males; however, the performance-enhancing effects of TA across studies were small, observed mostly in muscular strength and endurance, and only in older and diseased males.
... 1,[6][7][8][9][10] However, for several reasons, older men can be at a higher risk of experiencing adverse events during testosterone therapy when compared with young men. The plasma clearance of testosterone is lower in men aged 59 years than in young men (aged 19-35 years), 11 resulting in higher testosterone levels in older men at any testosterone dose. ...
Testosterone levels decline gradually with advancing age. At this point, testosterone administration as a therapy has been largely used to improve different outcomes. However, testosterone induces dose-dependent negative effects on the structure and function of the liver across age. Therefore, the present study aimed to carry out a systematic review of the effects of testosterone administration on the hepatic structure of adult and aged animals. We have searched the PubMed, Google Scholar, Science Direct, Scielo and Lilacs databases for animal experimental studies on the effects of testosterone administration on the hepatic structure across age. After applying the inclusion and exclusion criteria, we included two articles in a systematic review and meta-analysis (regarding adult/aged rats). We have shown through a systematic review with meta-analysis that testosterone may cause chronic hepatic congestion. However, the present review had a small number of studies, which was considered a limitation. At this point, we encourage the development of more studies to elucidate the cellular and molecular mechanisms involved in hepatic injuries, as well as the hepatic metabolism of exogenous testosterone across age.
... However, the correlation between Sal-T and U-T was weaker and with large inter-individual variations. U-T concentrations are influenced by numerous variations in biotransformation and renal excretion that may contribute to the inter-individual variations (Coviello et al., 2006;Anizan & Huestis, 2014). We suggest that Sal-T has potential as a tool in clinical assessment and might add information for optimal dosing of long-acting testosterone injections to HG men and GD FtM. ...
Long-term testosterone replacement therapy is mainly monitored by trough levels of serum testosterone (S-T), while urinary testosterone (U-T) is used by forensic toxicology to evaluate testosterone doping. Testosterone in saliva (Sal-T) may provide additional information and simplify the sample collection. We aimed to investigate the relationships between testosterone measured in saliva, serum and urine during standard treatment with 1,000 mg testosterone undecanoate (TU) every 12th week during 1 year. This was an observational study. Males with primary and secondary hypogonadism (HG; n = 23), subjects with gender dysphoria (GD FtM; n = 15) and a healthy control group of men (n = 32) were investigated. Sal-T, S-T and U-T were measured before and after TU injections. Sal-T was determined with Salimetrics® enzyme immunoassay, S-T with Roche Elecsys® testosterone II assay and U-T by gas chromatography-mass spectrometry. Sal-T correlated significantly with S-T and calculated free testosterone in both controls and patients (HG men and GD FtM), while Sal-T to U-T showed weaker correlations. Trough values of Sal-T after 12 months were significantly higher in the GD FtM group (0.77 ± 0.35 nmol/L) compared to HG men (0.53 ± 0.22 nmol/L) and controls (0.46 ± 0.15 nmol/L), while no differences between S-T and U-T trough values were found. Markedly elevated concentrations of salivary testosterone, 7–14 days after injection, were observed, especially in the GD FtM group. This study demonstrates that Sal-T might be a useful clinical tool to monitor long-term testosterone replacement therapy and might give additional information in forensic cases.
... The variability in serum testosterone concentrations on a fixed dose of transdermal testosterone could be due to variation in drug absorption into the blood stream or the inter-individual differences in plasma clearance of testosterone. Because the variability has been observed even in men treated with the injectable testosterone esters (Coviello et al., 2006;Swerdloff et al., 2015), for which we assume 100% bioavailability, we infer that differences in circulating levels during testosterone therapy are in part due to genetic differences in plasma clearance of testosterone. Indeed, genetic differences in testosterone metabolism and clearance have been previously suggested (Santner et al., 1998;Wang et al., 2004;Schulze et al., 2008;Eriksson et al., 2009;Sten et al., 2009). ...
... level, and SHBG levels accounted for only a small fraction of the variation in on-treatment testosterone levels. Previous studies using injectable testosterone esters have shown a significant age effect on apparent plasma clearance of testosterone and higher testosterone levels in older men than in young men (Coviello et al., 2006). In the three trials included in this study, age was not strongly correlated with change in testosterone levels from baseline. ...
There is substantial inter-individual variability in serum testosterone levels in hypogonadal men treated with testosterone gels. We aimed to elucidate participant-level factors that contribute to inter-individual variability in testosterone levels during testosterone therapy. An exploratory aim was to determine whether polymorphisms in genes encoding testosterone-metabolizing enzymes could explain the variation in on-treatment testosterone concentrations in men who were randomized to testosterone arm in TOM Trial. We used data from three randomized trials that used 1% transdermal testosterone gels and had testosterone levels measured 2–4 weeks after randomization for dose adjustment: Testosterone in Older Men with Mobility Limitation (TOM), Effects of Testosterone on Pain Perception (TAP), and Effects of Testosterone on Atherosclerosis Progression (TEAAM). Forty-seven percent, 38%, and 9% of participants in TAP, TEAAM, and TOM trials, respectively, failed to raise testosterone levels >400 ng/dL; 6, 8, and 30% of participants had on-treatment testosterone levels >1000 ng/dL. Even after dose adjustment, there was substantial variation in on-treatment levels at subsequent study visits. Baseline characteristics (age, height, weight, baseline testosterone, SHBG, hematocrit, and creatinine) accounted for only a small fraction of the variance (<8%). Polymorphisms in SHBG and AKR1C3 genes were suggestively associated with on-treatment testosterone levels. To conclude, baseline participant characteristics account for only a small fraction of the variance in on-treatment testosterone levels investigated. Multiple dose titrations are needed to maintain on-treatment testosterone levels in the target range. The role of SHBG and AKR3C1 polymorphisms as contributors to variations in on-treatment testosterone levels should be investigated.
