Role of androgens in energy metabolism affecting on body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity: lessons from a meta-analysis and rodent studies

Figures & data

Figure 1. Testosterone surges in a human male. Three testosterone surges–fetal, neonatal, and pubertal surges, are indicated. Testosterone levels among men (in Western countries) decline with age. G, gestation; mo, month; wk, week; y, year.

Table 1. Summary of meta-analyses and a large-cohort studies of testosterone and metabolic disorders.

Study [reference]	Type of data	Treatment	Adjustment	Findings
Araujo et al. 2011 [25]	Prospective longitudinal cohort study			Low TT: all-cause mortality ↑, CV mortality ↗
Corona et al. 2011 [26]	Cross-sectional study		Age, BMI, diabetes, and hypertension	Low TT in CV patients
	Prospective longitudinal cohort study			Low TT: all-cause mortality↑, CV mortality↑, CV morbidity →
Ruige et al. 2011 [27]	Prospective longitudinal cohort study			Low TT: CV morbidity (< 70 y) →, CV morbidity (> 70 y)↑
Isidori et al. 2005 [29]	RCT	TRT		TRT: body fat↓, fat-free mass↑, body weight →, total chol↓, LDL →
Elliott et al. 2017 [30]	RCT and non-randomized studies	TRT		TRT: CV mortality →
Corona et al. 2014 [34]	RCT (placebo-controlled)	TRT		TRT: CV morbidity → TRT: CV morbidity (in subjects with metabolic derangements)↓
Corona et al. 2015 [35]	RCT	TRT		TRT: CV mordibity →
	Cohort study			Low TT: CV mortality ↗
Fernandez-Balsells et al. 2010 [36]	Randomized and non-randomized trial	TRT		TRT: all-cause mortality →, CV morbidity →, HDL ↓
Calof et al. 2005 [37]	RCT (placebo-controlled)	TRT		TRT: CV morbidity →
Haddad et al. 2007 [38]	RCT (placebo-controlled)	TRT		TRT: CV morbidity (odds ratio, 1.82; CI, 0.78–4.23) →, total chol ↓
Xu et al. 2013 [39]	RCT (placebo-controlled)	TRT		TRT: CV morbidity (studies not funded by the pharmaceutical industry)↑ TRT: CV morbidity (studies funded by the pharmaceutical industry) →
Borst et al. 2014 [40]	RCT (placebo-controlled)	TRT		TRT: CV morbidity (oral treatment)↑ TRT: CV morbidity (injected or transdermal treatment) →
Corona et al. 2016 [45]	RCT	TRT		TRT: body weight →, BMI →, waist circumstance →, fat mass ↓, lean mass ↑, fasting glucose ↓, HOMA-IR ↓, triglyceride ↘, total chol ↘, HDL →, blood pressure →
Sharma et al. 2015 [46]	RCT (not meta-analysis but large longitudinal cohort study)	TRT		TRT: all-cause mortality↓, CV morbidity↓, stroke↓
Corona et al. 2011 [50]	Cross-sectional study		No adjustment	Low TT, low free T, and low SHBG in MetS patients
	Cross-sectional study		Age and BMI	Low TT in T2DM and Low TT in MetS
	Prospective longitudinal cohort study			Low TT: MetS↑
	RCT	TRT		TRT (in MetS patients): fasting glucose↓, HOMA-index↓, triglyceride↓, waist circumference↓, HDL↑, total chol →, blood pressure →, BMI →
Brand et al. 2014 [51]	Cross-sectional study		Age, lifestyle, BMI, or HOMA-IR	Low TT, low free T, and low SHBG in MetS patients
	Prospective longitudinal cohort study		Age, lifestyle, BMI, or HOMA-IR	Low TT: MetS (all case)↑; high SHBG: MetS (all case)↑ Low free T: MetS (Age, lifestyle, HOMA-IR)↑, MetS (BMI) →
	Cross-sectional study		Age and lifestyle	Decreased TT, free T, and SHBG are associated with an increased number or prevalence of MetS components.
	Prospective longitudinal cohort study		Without adjusting	Low TT: abdominal obesity↑, triglyceride↑, hyperglycemia↑, HDL↓, hypertension↑ Low freeT: abdominal obesity↑, triglyceride↑, hyperglycemia↑, HDL↓, hypertension↑ Low SHBG: abdominal obesity↑, triglyceride↑, hyperglycemia↑, HDL↓, hypertension↑
	Prospective longitudinal cohort study		Age and lifestyle	Low TT: abdominal obesity↑, triglyceride↑, hyperglycemia ↑, HDL↓, hypertension↑ Low freeT: abdominal obesity↑, triglyceride →, hyperglycemia↑, HDL →, hypertension → Low SHBG: abdominal obesity↑, triglyceride↑, hyperglycemia↑, HDL↓, hypertension↑
Brand et al. 2011 [52]	Cross-sectional and longitudinal study		Age and BMI	Low TT, low free T, and low SHBG in MetS patients Higher TT and higher SHBG reduced MetS risk
Corona et al. 2013 [53]	Cross-sectional study		Age	CV morbidity↑, obesity↑, T2DM↑, MetS↑, waist circumstance↑, triglyceride↑, glycemia↑, HDL↓ in LOH patients
	RCT	TRT		TRT (in MetS patients): fasting glycemia↓, HOMA index↓, triglyceride↓, waist circumstance↓
	RCT	TRT		TRT (in T2DM patients): fasting glycemia↓, HbA1c↓, triglyceride↓
Ding et al. 2006 [54]	Cross-sectional study			Low TT in T2DM patients
	Prospective longitudinal cohort study			Low TT: T2DM↑
Corona et al. 2011 [55]	Cross-sectional study		No adjustment	Low TT, low free T, low SHBG in T2DM patients
	Cross-sectional study		Age and BMI	Low TT in T2DM patients
	Prospective longitudinal cohort study			Low TT: T2DM↑
	RCT	TRT		TRT (in T2DM patients): fasting plasma gluocse↓, HbA1c↓, fat mass↓, triglyceride↓, HDL →, blood pressure →, BMI →
Whitsel et al. 2001 [57]	RCT and quasiexperimental study	TRT		TRT: total chol↓, LDL↓, HDL ↘
Cai et al. 2014 [58]	RCT	TRT		TRT (in T2DM patients): fasting glucose↓, fasting insulin↓, HbA1c↓, triglyceride levels↓, total chol →, HDL →, LDL →, body fat →
Grossmann et al. 2015 [59]	RCT (placebo-controlled)	TRT		TRT (in MetS and/or T2DM patients): insulin sensitivity (HOMA1-IR↑, HOMA2-IR →), HbA1c →
Corona et al. 2016 [60]	Observational study	TRT		TRT: body weight (2 y treatment)↓, waist circumference(2 y treatment)↓, fat mass↓, lean mass↑, fasting glycemia↓, HOMA-IR↓, triglyceride↓, total chol↓, HDL cholesterol↑, blood pressure↓
Nguyen et al. 2011 [63]	RCT	ADT		ADT: all-cause mortality↓, CV mortality →
Zhao et al. 2014 [64]	Population-based observational study	ADT		ADT: CV mortality↑, CV morbidity ↗
Bosco et al. 2015 [65]	Observational study	ADT		ADT: CV morbidity↑
Meng et al. 2016 [66]	Cohort and nested case-control study	ADT		ADT: stroke↑
Haseen et al. 2010 [67]	Cohort study and RCT	ADT		ADT: body weight↑, BMI↑, fat mass↑, lean mass↓
Wang et al. 2016 [68]	Observational study	ADT		ADT: diabetes↑
Bosco et al. 2015 [69]	Cross-sectional and cohort study	ADT		ADT: MetS↑, diabetes↑
Corona et al. 2013 [83]	RCT and cohort study	low calorie diet or bariatric surgery		Increase of TT by low calorie diet or bariatric surgery

ADT, androgen deprivation therapy; BMI, body-mass inde; chol, cholesterol; CV, cardiovascular; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; LDL, low-density lipoprotein; LOH, late-onset hypogonadism; MetS, metabolic syndrome; RCT, randomized controlled trial; SHBG, sex hormone binding globlin; T, testosterone; TRT, testosterone replacement; TT, total testosterone; T2DM, type 2 diabetes mellitus

↑, significant increase; ↓, significant decrease; →, no change;↗, tendency to increase; ↘, tendency to decrease

Table 2. Summary of the metabolic changes in androgen receptor knockout male mice.

Study [reference]	Tissue/Cre (background)	Deletion (floxed mice)	Findings
Kato and Yanase’s group Sato et al. [124] Fan et al. [126]	Global (C57BL/6/CD-1)	exon 1 (Ar^tm1Ska)	SD: body weight (late-onset, after 12 wk)↑, food consumption →, visceral (infrarenal↑, intraperitoneal↑, and epididymal→) fat ↑, subcutaneous fat↑, oxygen consumption↓, blood glucose (GTT) →, insulin sensitivity →, fatty liver →, adiponectin↑
Chang’s group Lin et al. [125]	Global/ACTB-Cre (C57BL/6/129Sv/FVB)	exon 2 (Ar^tm1Chc)	SD: body weight (late-onset, after 22 wk)↑, visceral (gonadal) fat↑, blood glucose (each fasting, fed, or GTT)↑, insulin sensitivity↓, liver triglyceride↑, adiponectin↓
Zajac and MacLean’s group Rana et al. [127] Notini et al. [130] MacLean et al. [131]	Global/CMV-Cre (C57BL/6)	exon 3 (Ar^tm1Jdz)	SD: body weight (until 25 wk↓and at 52 wk →), visceral fat (until 24 wk →, at 52 wk↑), subcutaneous fat↑, food intake↓, oxygen consumption →, blood glucose (fasting) →, insulin sensitivity →, adiponectin↑, inferior limb (each gastrocnemius, soleus, EDL, or TA) mass↓, muscle strength↓, muscle fatigue resistance↑ HFD (from 12 wk): body weight (at 24 wk) →, visceral fat →, subcutaneous fat↑, food intake →, blood glucose (fasting) →, insulin sensitivity →, adiponectin↑
Claessens’s group Dubois et al. [128]	Global/PGK-Cre (C57BL/6)	exon 2 (Ar^tm1Vheh)	SD: body weight (at 10–20 wk)↓, food consumption↓, subcutaneous fat →, lean mass →, blood glucose (fasting and GTT) →, insulin sensitivity → HFD (from 10 wk): body weight (at 20 wk) →, food consumption↓, visceral (perigonadal↓ and perirenal →) fat, subcutaneous fat↑, lean mass↓, blood glucose (fasting → and GTT↑), insulin sensitivity↓, liver triglyceride↑
Vanderschueren’s group Ophoff et al. [129] Challewaert et al. [154]	Global/PGK-Cre (C57BL/6N) or Global (C57BL/6)	exon 2 (Ar^tm1Vheh)	SD: body weight (at 6–16 wk)↓, food consumption↓, lean mass↓, muscle (quadriceps) mass↓, total fat mass →
Iseki’s group Adthapanyawanich et al. [132]	Global/CAG-Cre (C57BL/6)	exon 1 (Ar^tm2Ska)	SD: body weight (at 10 wk) ↓
Chang’s group Yu et al. [96]	Adipocytes/aP2-Cre (C57BL/6)	exon 2 (Ar^tm1Chc)	SD: body weight (at 20 wk) →, body fat →, blood glucose (fasting) →
McInnes’s group McInnes et al. [97]	Adipocytes/aP2-Cre (C57BL/6)	exon 2 (Ar^tm1Vheh)	SD: body weight (at 3 mo↓, 6 and 12 mo →), visceral (mesenteric: both 3 and 12 mo →; perigonadal: at 3 mo↓ and 12 mo →) fat, subcutaneous fat (3 and 12 mo) →, blood glucose (GTT at 6 mo↑and at 3, 9, and 12 mo →), liver triglyceride → HFD (for 24 wk): body weight →, visceral (both mesenteric and omental↑, gonadal →) fat, subcutaneous fat →, blood glucose (GTT, for 6 and 12 wk →, 24 wk↑), liver triglyceride →
Chang’s group Lin et al. [95]	Hepatocytes/Alb-Cre (C57BL/6)	exon 2 (Ar^tm1Chc)	SD: body weight (until 24 wk) →, body fat →, blood glucose (fasting and fed) →, insulin sensitivity →, liver triglyceride →, adiponectin↓, HFD (from 8 wk): body weight (late-onset, after 14 wk)↑, body fat ↑, blood glucose (each fasting, fed, or GTT)↑, insulin sensitivity↓, liver triglyceride↑
Chang’s group Yu et al. [140]	Neuronal cells/Syn-Cre (C57BL/6J)	exon 2 (Ar^tm1Chc)	SD: body weight (late-onset, after 28 wk)↑, visceral (retroperitoneal and epididymal) fat↑, liver triglyceride↑, insulin sensitivity↓, blood glucose (fasting↑and fed →) HFD (from 10 wk for 14 d): body weight gain↑, food consumption→
Mhaouty-Kodja’s group Raskin et al. [141]	Neural and glial stem cells/Nes-Cre (C57BL/6J/129SvEv)	exon 2 (Ar^tm1Vheh)	SD: body weight (until 20 wk)↓
Shah’s group Juntti et al. [142]	Neural and glial stem cells/Nes-Cre (C57BL/6J/129Sv)	exon 2 (Ar^tm1Vheh)	SD: body weight (until 20 wk) →
Vanderschueren’s group Ophoff et al. [98]	Skeletal muscle myofibers/MCK-Cre (C57BL/6J/CD-1)	exon 2 (Ar^tm1Vheh)	SD: body weight: (at 8–16 wk)↓, food consumption →, visceral (each mesenteric, perirenal, or perigonadal) fat↓, subcutaneous fat ↓, muscle mass (quadriceps →, gastrocnemius →, soleus →, EDL↘, LA↓)
Chambon and Metzger’s group Chambon et al. [153]	Skeletal muscle myofibers/HSA-Cre	exon 1 (Ar^tm1Ska)	SD: body weight (until 65 wk) →, muscle mass (each quadriceps, gastrocnemius, TA, or soleus at 6, 13, or 40 wk) →, muscle strength↓
Claessens’s group Dubois et al. [155]	Skeletal muscle satellite cells/MyoD-Cre (C57BL/6J)	exon 2 (Ar^tm1Vheh)	SD: body weight→, lean mass→, visceral (each mesenteric, perirenal, or perigonadal) fat→, subcutaneous fat→, muscle mass (each gastrocnemius, EDL, soleus, or TA)→, muscle strength↓
Mauvais-Jarvis’s group Navarro et al. [102]	Pancreatic beta-cells/RIP-Cre (C57BL/6J)	exon 2 (Ar^tm1Vheh)	SD: blood glucose (fasting and fed →, GTT↑), blood insulin↓, beta-cell mass→ HFD (for 9 wk): blood glucose (each fasting, fed, or GTT)↑, blood insulin↓, beta-cell mass→
	Neuronal cells/Syn-Cre (C57BL/6J)	exon 2 (Ar^tm1Vheh)	SD: blood glucose (each fasting, fed, or GTT) →, blood insulin → HFD (for 9 wk): blood glucose (each fasting, fed, or GTT) →, blood insulin →
	Cre-loxP: MIP-Cre ERT (Tam for 5 d) (C57BL/6J)	exon 2 (Ar^tm1Vheh)	HFD (for 9 wk): blood glucose (GTT)↑, blood insulin ↓

d, day; EDL, extensor digitorum longus; GTT, glucose tolerance test; HFD, high-fat diet; mo, month; SD, standard chow diet; TA, tibialis anterior; wk, week

↑, significant increase; ↓, significant decrease; →, no change; ↗, tendency to increase; ↘, tendency to decrease

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