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The effects of long-term testosterone treatment on endocrine parameters in hypogonadal men: 12- year data from a prospective controlled registry study (2022)
Aksam Yassin, Farid Saad, Mustafa Alwani, Omar M. Aboumarzouk, Raed M. Al-Zoubi, Joanne Nettleship, Daniel Kelly & Abdulla Al-Ansari
ABSTRACT
Testosterone therapy (TTh) is the primary treatment for aging men with functional hypogonadism. Whilst the benefits of testosterone (T) replacement are well-evidenced, the long-term data for TTh on metabolic and endocrine parameters is limited. Here we present the effect of TTh on endocrine parameters in hypogonadal men at a 12-year follow-up. In this single-center, cumulative, prospective, registry study, 321 hypogonadal men (mean age: 58.9 years) received testosterone undecanoate injections in 12-week intervals for up to 12 years. Blood samples were taken at every other visit to measure levels of total T (TT), calculated free T, sex hormone-binding globulin (SHBG), estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone and prolactin. We observed an increase in TT of 15.5 nmol/L (p < 0.0001), a reduction in SHBG of 10.5 nmol/L (p < 0.0001) and an increase in calculated free T of 383.04 pmol/L (p < 0.0001) over the study period. This was accompanied by an increase in estradiol levels by 14.9 pmol/L (p < 0.0001), and decreases in progesterone (0.2 ng/mL, p < 0.0001), LH (10.4U/L, p < 0.0001) and FSH (8.4 U/L, p < 0.0001) were demonstrated at 12-years. The levels of prolactin remained unchanged. Long-term TTh altered hormonal parameters to predictably modify the endocrine system. These effects were sustained during the entire observation time of 12 years.
Introduction
The age-associated decline in total testosterone (TT) is a well-established phenomenon in men and is termed functional hypogonadism when symptomatic [1–3]. According to the Baltimore Longitudinal Study of Aging (BLSA), nearly 12% of men in their 50s are hypogonadal, which increases to 20% and 30% for those in their 60s and 70s respectively [1]. Increased life expectancy and the rising prevalence of obesity and type II diabetes, especially in western society, are expected to further increase the prevalence of hypogonadism in coming years [4].
Hypogonadism, or T deficiency, is characterized by impaired libido, fatigue, infertility, and increased risk of depression and therefore can have a significant impact on quality of life (QoL) [5,6]. Furthermore, an increase in all-cause and cardiovascular mortality consistently correlated with low T in large population studies [7,8]. Metabolic syndrome (MetS) which encompasses obesity and its associated comorbidities such as hypertension, dyslipidemia, insulin resistance, dysregulation of glucose metabolism, and decrease in muscle mass also correlates with lower TT levels [9] and thereby contributes to its association with cardiovascular disease.
T deficiency and its associated symptoms are potentially reversible and testosterone therapy (TTh) remains the primary treatment option. Indeed, several long-term studies have reported improved sexual function, body composition and reduced risk of CVD following TTh in hypogonadal men [10–16]. Whilst the immediate beneficial effects of TTh are well evidenced, the long-term effects of exogenous T on physiological parameters remain limited. In a previous report, we described the long-term effects of TTh on anthropometric and metabolic parameters in hypogonadal men at a 10-year follow-up [12], and here we present an update on the endocrine parameters at 12 years in our patient cohort.
*The present study has limitations. This was an observational study with no placebo-controlled group and thus does not allow direct effects of treatment versus non-treatment to be compared therefore limiting the scope of interpretation of the presented findings. Furthermore, a cohort of 147 patients had TTh interrupted due to reimbursement issues and/or diagnosis of prostate cancer. Whilst this may skew the data presented here, especially for years 6–8, we have observed both here and previously [11], that with the recommencement of TTh the hormone concentrations return to pre-interruption levels. Thus, it is unlikely that the interruption affected the circulating levels of the hormones measured at the final 12-year follow-up.
In conclusion, this study provides comprehensive data on the long-term effects of TTh on endocrine parameters in hypogonadal mainly elderly men. The data suggest that TTh affects the hormonal parameters as expected by increasing TT, increasing estradiol but within the reference range, suppressing LH and FSH as part of the HPG feedback loop, decreasing progesterone, and having no effect on prolactin. Importantly, these effects are sustained during the entire observation time of 12 years.
Aksam Yassin, Farid Saad, Mustafa Alwani, Omar M. Aboumarzouk, Raed M. Al-Zoubi, Joanne Nettleship, Daniel Kelly & Abdulla Al-Ansari
ABSTRACT
Testosterone therapy (TTh) is the primary treatment for aging men with functional hypogonadism. Whilst the benefits of testosterone (T) replacement are well-evidenced, the long-term data for TTh on metabolic and endocrine parameters is limited. Here we present the effect of TTh on endocrine parameters in hypogonadal men at a 12-year follow-up. In this single-center, cumulative, prospective, registry study, 321 hypogonadal men (mean age: 58.9 years) received testosterone undecanoate injections in 12-week intervals for up to 12 years. Blood samples were taken at every other visit to measure levels of total T (TT), calculated free T, sex hormone-binding globulin (SHBG), estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone and prolactin. We observed an increase in TT of 15.5 nmol/L (p < 0.0001), a reduction in SHBG of 10.5 nmol/L (p < 0.0001) and an increase in calculated free T of 383.04 pmol/L (p < 0.0001) over the study period. This was accompanied by an increase in estradiol levels by 14.9 pmol/L (p < 0.0001), and decreases in progesterone (0.2 ng/mL, p < 0.0001), LH (10.4U/L, p < 0.0001) and FSH (8.4 U/L, p < 0.0001) were demonstrated at 12-years. The levels of prolactin remained unchanged. Long-term TTh altered hormonal parameters to predictably modify the endocrine system. These effects were sustained during the entire observation time of 12 years.
Introduction
The age-associated decline in total testosterone (TT) is a well-established phenomenon in men and is termed functional hypogonadism when symptomatic [1–3]. According to the Baltimore Longitudinal Study of Aging (BLSA), nearly 12% of men in their 50s are hypogonadal, which increases to 20% and 30% for those in their 60s and 70s respectively [1]. Increased life expectancy and the rising prevalence of obesity and type II diabetes, especially in western society, are expected to further increase the prevalence of hypogonadism in coming years [4].
Hypogonadism, or T deficiency, is characterized by impaired libido, fatigue, infertility, and increased risk of depression and therefore can have a significant impact on quality of life (QoL) [5,6]. Furthermore, an increase in all-cause and cardiovascular mortality consistently correlated with low T in large population studies [7,8]. Metabolic syndrome (MetS) which encompasses obesity and its associated comorbidities such as hypertension, dyslipidemia, insulin resistance, dysregulation of glucose metabolism, and decrease in muscle mass also correlates with lower TT levels [9] and thereby contributes to its association with cardiovascular disease.
T deficiency and its associated symptoms are potentially reversible and testosterone therapy (TTh) remains the primary treatment option. Indeed, several long-term studies have reported improved sexual function, body composition and reduced risk of CVD following TTh in hypogonadal men [10–16]. Whilst the immediate beneficial effects of TTh are well evidenced, the long-term effects of exogenous T on physiological parameters remain limited. In a previous report, we described the long-term effects of TTh on anthropometric and metabolic parameters in hypogonadal men at a 10-year follow-up [12], and here we present an update on the endocrine parameters at 12 years in our patient cohort.
*The present study has limitations. This was an observational study with no placebo-controlled group and thus does not allow direct effects of treatment versus non-treatment to be compared therefore limiting the scope of interpretation of the presented findings. Furthermore, a cohort of 147 patients had TTh interrupted due to reimbursement issues and/or diagnosis of prostate cancer. Whilst this may skew the data presented here, especially for years 6–8, we have observed both here and previously [11], that with the recommencement of TTh the hormone concentrations return to pre-interruption levels. Thus, it is unlikely that the interruption affected the circulating levels of the hormones measured at the final 12-year follow-up.
In conclusion, this study provides comprehensive data on the long-term effects of TTh on endocrine parameters in hypogonadal mainly elderly men. The data suggest that TTh affects the hormonal parameters as expected by increasing TT, increasing estradiol but within the reference range, suppressing LH and FSH as part of the HPG feedback loop, decreasing progesterone, and having no effect on prolactin. Importantly, these effects are sustained during the entire observation time of 12 years.
