Male sex hormones, aging, and inflammation

[madman]

Male sex hormones, aging, and inflammation (2023)
Justin M. Ketchem · Elizabeth J. Bowman · Carlos M. Isales


Abstract

Adequate levels of androgens (eugonadism), and specifically testosterone, are vital compounds for male quality of life, longevity, and positive health outcomes. Testosterone exerts its effects by binding to the androgen receptor, which is expressed in numerous tissues throughout the body. Significant research has been conducted on the impact of this steroid hormone on skeletal, muscle, and adipose tissues and on the cardiovascular, immune, and nervous systems. Testosterone levels have also been studied in relation to the impact of diseases, aging, nutrition, and the environment on its circulating levels. Conversely, the impact of testosterone on health has also been evaluated with respect to its cardiac and vascular protective effects, body composition, autoimmunity, and all-cause mortality. The male aging process results in decreasing testosterone levels over time. The exact mechanisms and impact of these changes in testosterone levels with age on health- and lifespan are still not completely clear. Further research is needed to determine the optimal testosterone and androgen levels to protect from chronic age-related conditions such as frailty and osteoporosis.




Introduction

In the aging male, there is a loss of overall efficiency and function of many body systems. These functions include changes in overall metabolism, strength, blood pressure, heart rate, appetite, body temperature, sleep/wake cycle, and sexual function. Perhaps the most essential organ system that declines in capacity over time is the endocrine system. The male sex hormones, testosterone, and its derivatives regulate and modulate almost all bodily functions directly or indirectly. Aging has been consistently shown to correlate with marked declines in androgen levels (Harman et al. 2001), which is associated with the development of many chronic and wasting diseases. This review explores current findings regarding androgens, aging, and inflammation. A literature search of PubMed was performed using the following keywords: testosterone, androgens, aging, sarcopenia, osteopenia, and inflammation. Additional searches using the same criteria were performed in the Mendeley and Google Scholar databases. The search was conducted in June and July 2022.




*Production and regulation of testosterone


*Testosterone effects on organ systems
-Skeleton
-Skeletal muscle
-Adipose tissue
-Cardiovascular/hematopoietic
-Immune system
-Nervous system


*Testosterone effects on illness/disease
-Body composition
-Fighting infection
-Cardiac and vascular protection
-Metabolic syndrome
-Autoimmune diseases
-All-cause mortality


Inflammation and androgens
-Aging and inflammation
-Sarcopenia
-Osteopenia


*Aging and androgens




Discussion

Testosterone and its derivatives have been shown to interact with the AR to activate genomic and nongenomic pathways that affect a wide variety of body tissues. The evidence presented in this review indicates a variety of conditions that may be correlated with and possibly caused by low levels of androgens. Healthy levels of androgens, or eugonadism, have been demonstrated to correlate with a higher quality of life, better longevity, and positive health outcomes. Androgen levels have also been shown to consistently decline in the aging male. Hypogonadism is of greater importance in older men, and this subject has been receiving increasing research attention in recent years. TRT may be a promising treatment option for hypogonadal men, older men, and patients at risk of viral infection or wasting diseases. Some contraindications and side effects may limit the application of TRT in clinical settings, including increased hair loss (Dallob et al. 1994), infertility (Crosnoe et al. 2013), as well as some conflicting evidence on the development of CVD (Corona et al. 2011). These risks must be evaluated on an individual basis and weighed against the potential benefits to the quality of life and longevity of the patient.

Additionally, the role of androgens is complex due to crosstalk with multiple organ systems, cellular processes, and metabolism into various bioactive compounds. One of the more promising aspects of androgen action is interaction with the body’s inflammatory system. Testosterone and its metabolites may modulate various aspects of the inflammatory cascade, apoptosis, and cellular aging. Current literature provides evidence that androgens may play a significant role in decreasing multiple pro-inflammatory markers while also increasing several anti-inflammatory markers. These effects may explain why healthy androgen levels seem to attenuate disease of many organ systems and correlate with lower all-cause mortality. The impacts of aging must also be considered in this context. The process of aging has been shown to correlate with higher levels of inflammation, ROS, harmful microbiota, and senescent cells. Androgens have been shown to improve these markers, which may explain why eugonadal older men have better health outcomes and quality of life. These findings may also support the use of androgen replacement in hypogonadal older men.

Two critical features of age-related wasting are sarcopenia and osteopenia. Both conditions result in progressive loss of strength, movement ability, and quality of life. In a clinical context, these conditions lead to an increased risk of immobility, dependence, and injury from daily activity. Older men with healthy androgen levels are significantly less likely to exhibit symptoms of muscular or skeletal wasting, which further supports the conclusion that TRT may be beneficial to treat and prevent cachexia in older men. Inflammation has also been shown to be a key contributor to the development of sarcopenia and osteopenia. The findings that T and DHT lead to a downstream anti-inflammatory response provide further evidence that androgen replacement could be a valuable tool to combat age-related wasting for older hypogonadal men.

The observed decline in androgen levels with age may be due to several contributing factors, including increased SHBG levels, dysfunction of the hypothalamus and anterior pituitary glands, and loss of testicular secretion. As a result, the decline in androgen levels in the aging male requires further examination and research due to its importance in a variety of diseases, as well as the quality of life. Future studies should focus on clarifying the causes and effects of male hypogonadism and its impact on health. The current androgen replacement therapy protocol also requires further investigation into benefits, contraindications, and long-term safety profiles.

 

[madman]

Fig. 1 Regulation and metabolism of testosterone. Testosterone production begins in the hypothalamus when GnRH is released into the hypophyseal portal system and acts upon the anterior pituitary causing the release of FSH and LH (Plant and Marshall 2001). FSH acts on the Sertoli cells of the testes to stimulate spermatogenesis (Grinspon et al. 2018). LH acts on the Leydig cells of the testes causing the release of Testosterone (Choi and Smitz 2014). Testosterone is metabolized into DHT by the action of 5α-reductase (Randall 1994). Both testosterone and DHT act on the AR with DHT exerting more potent effects (Marchetti and Barth 2013). Aromatase converts testosterone into estradiol (Stocco 2012) which regulates many bodily processes (Schulster et al. 2016)

 

[madman]

Fig. 2 Androgen effects on organ systems. Testosterone and its derivatives have been shown to result in increased muscle protein synthesis (Griggs et al. 1989), amino acid utilization (Shefeld-Moore et al. 1999), and maximum skeletal muscle strength (Bhasin et al. 2001). Androgens have been shown to increase EPO and hematocrit with their effects on CVD still under debate (Shores and Matsumoto 2014). Testosterone increases BMD and osteoblast growth (Nakano et al. 1994) while concurrently decreasing the apoptosis of osteocytes (Kousteni et al. 2001). Testosterone increases T cell maturation (Viselli et al. 1995a, b), decreases the proliferation of autoantibodies (Rettew et al. 2008), as well as signaling involving TLR4, TNF-α, and IL-1β (Corcoran et al. 2010). Androgens decrease the activity of LPL and ACS (Santosa et al. 2017), resulting in a decline in lipogenesis (Weimar et al. 2002). The nervous system responds to testosterone by increasing ant-inflammatory markers including IL-10 (Dalal et al. 1997), remyelination of neurons (Palaszynski et al. 2004), and increasing cognitive and spatial function (Azad et al. 2003; Barrett-Connor et al. 1999; Janowsky et al. 1994). Androgens also decrease the concentration of ROS (Ahlbom et al. 2001) and Aβ plaques in the nervous system (Pike 2001)

 

[madman]

Fig. 3 Androgen effects on inflammation. The androgens have been shown to decrease concentrations of infammatory markers including TNFα, IFN-γ, IL-6, IL-2 (Fijak et al. 2011), NF-κB, AP-1 (Chen et al. 2017a, b), TLR4 (Rettew et al. 2008), ILC2 (Cephus et al. 2017), IL-1β (Mohamad et al. 2019), IL-12. Androgens also increase the concentration of the anti-inflammatory cytokine IL-10 (Liva and Voskuhl 2001)

 

[madman]

Fig. 4 Causes of chronic inflammation. Chronic inflammation has multiple components including a buildup of cellular debris and antibodies (Sanada et al. 2018), elevated levels of ROS (Vigneron and Vousden 2010), increased circulating inflammatory cytokines (Sarkar and Fisher 2006), cellular aging and telomere shortening (Sanada et al. 2009), as well as decreased microbiome diversity (Kinross and Nicholson 2012; Claesson et al. 2011)

 

[madman]

Fig. 5 Causes of Decline in Androgen Levels with Age. Androgen levels decline with age due to many factors including decreased StAR protein (Manna et al. 2016) and secretion of GnRH (Keenan et al. 2006). Levels of SHBG have been observed to increase at a dramatic rate in older men (Feldman et al. 2002). Other contributing factors include a decline in Leydig cell number and function (Korenman et al. 1990), as well as LH levels (Veldhuis et al. 1999). Androgen levels also decline with the occurrence of varicocele (Tanrikut et al. 2011), negative feedback on the HPG axis (Pincus et al. 1997), a decline in the concentration of AR (Haji et al. 1981), decreased testicular volume (Mahmoud et al. 2003), and increased estrogen levels (Ferrini and Barrett-Connor 1998)

 

[Nelson Vergel]

Excellent paper! @madman

 

[Nelson Vergel]

The Association between Inflammation, Testosterone and SHBG in men: A cross-sectional Multi-Ethnic Study of Atherosclerosis - PubMed

Our results indicate that inflammatory markers have independent associations with levels of testosterone (total and bioavailable) and furthermore, appear to associate differently with SHBG levels.

pubmed.ncbi.nlm.nih.gov