Aging and sex hormones in males

Figures & data

Figure 1. Serum levels of both testosterone (T) (solid lines) and estradiol (E₂)* (broken lines) across the lifespan in men (blue lines) and women (pink lines). Data used for plotting age-related sex steroids changes in both sexes have been derived from Kaufman & Vermeulen 2005⁵, Zmuda et al. 1997⁶ (for men), and from Al-Safi et al. 2000² and Veldhuis 2013 (for women). serum E₂ levels of premenopausal women are represented as the mean of E2 measured during the different phases of the menstrual cycle; T: testosterone; E₂: estradiol.

Table 1. Risk factors involved in serum T decline in aging men.

Risk factors and predictors of T deficiency:

General factors: Age, ethnicity, poor health status and frailty, progressive decrease of number and function of Leydig cells.

Metabolic and and anthropometric factors: BMI, weight, waist circumference, visceral adiposity.

Life-style habits: excessive alcohol intake, cigarette smoking, sedentary lifestyle.

Comorbidities: hypertension, metabolic syndrome.

Chronic Diseases: moderate to severe chronic obstructive pulmonary disease, HIV, chronic liver diseases, chronic renal failure (especially end-stage and hemodyalisis), type 2 diabetes, hypopituitarism, reumatoid arthritis, Hodgkin disease.

Critical Acute illness

Pharmacological and other treatments: opiates, glucocorticoids, inhibitors of T synthesis (e.g., mitotane, ketoconazole), chemotherapy, testicular irradiation, GnRH analogs

Note. T: testosterone; BMI: body mass index; GnRH: gonadotropin-releasing hormone.

Table 2. Main characteristics of large cohort studies investigating sex steroids and aging.

Study	Period (yrs)	Study Design	Sex M, F	Subjects (N)^*	Age	Span (yrs)	T assay^**	Sex Steroids as Main Aim	Primary End Point^ˆ  ˆ	Country
BLSA	1958-	PLOC-B	M,F	n.a.	>20	58	IAs	no	General overview on aging	Baltimore (USA)
MMAS	1987–2004	PLOC-B	M	1709	40–70	17	IAs	yes	Hormone levels and ED	Boston (USA)
MrOS	2000–2006	MC-PLOC-B	M	∼11000	>65	6	LC-MS/MS	no	Fracture risk factors	USA, Sweden, Hong-Kong
EMAS	2003–2010	MC-PLOC-B	M	3369	40–79	7	LC-MS/MS IAs	yes	Anabolic hormones changes and health outcomes	Some EU Countries^ˆ
RBS	1972-	PLOC-B	M,F	1094	>30	44	IAs	no	Heart disease risk factors	Southern California (USA)
InCHIANTI	1998-	PLOC-B	M,F	601	>65	18	IAs	no	Physical function in aging	Tuscany (Italy)
Tromsø	1974–2008	PLOC-B	M,F	6595	n.d.	34	IAs	no	CV-related mortality	Tromsø (Norway)
CHAMP	2005-	PLOC-B	M	1705	>70	11	LC-MS/MS	no	Major geriatric syndromes	Sydney (Australia)
HIMS	1996–2004	P-BRT	M	12203	>65	8	IAs	no	Aortic aneurysm in aging	Perth (Australia)

Notes. M: males; F: females;

* Number of male participants at the beginning of the study;

** For some studies methods for T assay varied overtime during the long period of study protocol;

ˆ  UK, Italy, Belgium, Poland, Sweden, Spain, Hungary, Estonia; EU: European;

ˆ  ˆ The main end point to be investigated in relation to aging; PLOC-B: Prospective, Longitudinal, Observational, Community-Based Study; MC-PLOC-B: MultiCenter, Prospective, Longitudinal, Observational, Community-Based Study; P-BRT: Population-Based, Randomized, Trial; n.d.: not detectable at any analysis; CV: cardiovascular; ED: erectile dysfunction.

Table 3. Main outcomes from large cohort studies investigating sex steroid changes occurring in aging.

Outcomes	BLSA	MMAS	MrOS	EMAS	RBS	In CHIANTI	Tromsø	CHAMP	HIMS
Total T decline (per year)	Yes (3.2 ng/dl)	Yes (1.6%)	n.a.	Yes	Yes (1.9 pg/ml)	n.a.	Yes	Yes (2% per year)	No
T-free/bioavailable decline (per year)	Yes	Yes (2–3%)	Yes	Yes	Yes (18.5 pg/ml)	n.a.	Yes	Yes	Yes
SHBG increase	Yes	Yes	Yes	Yes	Yes	n.a.	n.a.	Yes	Yes
E2 decline (per year)	n.a.	n.a.	Yes	Yes	n.a.	n.a.	n.a.	No (↑3%)	n.a.
Sexual desire decline	n.a.	Associated to ↓TT and ↓fT	n.a.	n.a.	n.a.	n.a.	n.a.	Associated to ↓TT and ↓fT	n.a.
Erectile function decline	n.a.	Associated to ↓TT and ↓fT^*	n.a.	Associated to ↓fT	n.a.	n.a.	n.a.	No association with TT and fT	n.a.
BMD impairment	n.a.	n.a.	Associated to ↓E2; conflicting data about T	Associated to ↓E2 but not to T	Associated to ↓bioavailable E2 and T	n.a.	Associated to ↑SHBG, but not with T and E2	Associated to ↑SHBG, but not with T and E2	n.a.
Increased fracture risk	n.a.	n.a.	Associated to↓ E2 and ↓ T and ↑SHBG	n.a.	n.a.	n.a.	Not associated to TT, fT, E2	Not associated to sex steroids	n.a.
Lean mass and muscle strength decline	Associated to ↓fTˆ	n.a.	Associated to ↓fT	Associated to ↓fT	n.a.	Associated to ↓TT	n.a.	Associated to ↓fT and ↓TT	n.a.
Physical performance decline	Associated to ↓fT	Associated (weakly) to ↓TT	n.a.	Associated to ↓fT	n.a.	n.a.	n.a.	n.a.	n.a.
Frailty increase	n.a.	n.a.	Associated to ↓TT	n.a.	n.a.	n.a.	n.a.	Associated to ↓TT, ↓fT, ↓E2, not to SHBG	Associated to ↓TT, ↓fT
Overweight and obesity increase	n.a.	Associated to ↓TT and ↓SHBG	n.a.	Associated to ↓TT, ↓fT, and ↓SHBG	n.a.	n.a.	Associated to ↓TT, ↓fT, ↓SHBG, and ↑E2	n.a.	Associated to ↓TT (if BMI>25)
Metabolic Syndrome risk	Associated to ↓TT and ↓SHBG	Associated to ↓TT and ↓SHBG	n.a.	n.a.	n.a.	Associated to ↓TT and ↓SHBG, and ↑E2, not to ↓fT	n.a.	Associated to ↓SHBG, not to ↓TT	Associated to ↓TT, ↓fT, ↓SHBG
Diabetes risk	n.a.	Associated to ↓TT and ↓SHBG	n.a.	n.a.	Associated to ↓TT, ↓fT	n.a.	↑TT and ↑SHBG are protective	n.a.	n.a.
CV risk increase	Arterial stifness associated to ↓TT	n.a.	Atherosclerosis associated to ↓TT	Hypertension associated to ↓TT	Hypertension associated to ↓TT	Artery disease associated to ↑SHBG, not to T and E2	Hypertension and carotid atherosclerosis associated to ↓TT	n.a.	n.a.
Low T association with poor health status and unhealthy habits	Alcohol intake associated to ↓TT	n.a.	n.a.	n.a.	n.a.	n.a.	Smoking associated to ↑TT, ↑fT, ↑SHBG	Self-reported poor status associated to ↓TT, ↓fT,	n.a.
Low T associated to reduced hemoglobin	n.a.	n.a.	n.a.	yes	n.a.	yes	n.a.	n.a.	n.a.
Low T associated to dyslipidemia	n.a.	n.a.	n.a.	yes	yes	n.a.	yes	n.a.	n.a.
Increase of all-cause mortality risk with low T	no	Weak association	yes	yes	yes	yes^ˆ  ˆ	yes	yes^ˆ ˆ ˆ	yes
CV mortality risk increase associated to low T	n.a	n.a.	n.a.	n.a.	yes	n.a.	No	Associated to↓E2	Associated to ↓fT
Cognitive function decline	Associated to ↓fT	Not associated to T	Associated to ↑SHBG	n.a.	n.a.	n.a.	n.a.	No associated to E2, T, and SHBG levels	Not associated to T
Depressive mood increase	Not associated to T	n.a.	n.a.	n.a.	Associated to↓bioavailable T	n.a	n.a.	n.a.	Associated to ↓TT

Notes. TT: Total Testosterone; fT: free Testosterone;

* Conflicting data (association with both total and free low T, but only in more recent analyses);

ˆ muscle strength only, not muscle and lean mass;

ˆ  ˆ no correlation with low T alone, but with low T together with other hormones deficit;

ˆ ˆ ˆ correlation with both total and free low T and with low E₂.

Table 4. Main similarities and differences of large longitudinal, cohort studies.

STRONG DISCREPANCIES	WEAK DISCREPANCIES	WEAK ANALOGIES	STRONG ANALOGIES
Hormonal Trajectories
–	–	↓ serum total and free E2	↓serum total T
		with advancing age	↓↓serum free T
			↓↓bioavailable T
			↑serum SHBG
			with advancing age
Consequences of Hormonal Changes Related to Male Aging
• Association between low T and low BMD.	• Association between T and cognitive functions.	• Association between low T and CV risk factors' increase.	• Serum T is directly related to sexual function, especially libido.
• Association between low T and depression.	• Association between low T and atherosclerosis.	• Association between low T and increased CV risk.	• Association between low T and increased all-causes mortality risk.
• Association between low T and CV-related mortality.	• Relationship between hypogonadism and frailty development.	• Association between low T and poor health status.	• Healthy life-style correlates with higher T levels/prevention of T decline.
• Relationship between T and physical performance.	• Correlation between serum T measured by LC-MS/MS and by AIs.	• Association between low T and low hemoglobin.	• Association between low T and both overweight and obesity.
• Relationship between T and prostate cancer.	• Association between low T and impaired pulmonary function.	• High T correlates with better lean mass, and muscle strength.	• Association between low T and both metabolic syndrome and type 2 diabetes.
	• Association between low T and/or low E2 and frailty.	• Low T correlates with erectile dysfunction.	• Serum E2 correlates with BMD.
		• Serum E2 is inversely related to fracture risk.

Figure 2. Classification of hypogonadism according to its pathogenesis.

Table 5. Serum testosterone (T) cutoffs suggested for the diagnosis of LOH.

Cutoff Provider	Biochemical Hypogonadism	Gray Area (Mild Biochemical Hypogonadism)	Normal T
	Serum total T ng/dL (nmol/L)
Endocrine Society Guidelines	<300 (<10.4)	–	>300 (>10.4)
AACE Guidelines	202(<7)	–	>202 (>7.0)
ISA, ISSAM, EAU, EAA, & ASA Guidelines	<231(<8)	231 < T < 346   (8 < T < 12.0)	>346 (>12.0)
EMAS Study	<317(<11)	–	>317(>11.0)
HIMS Study (<5^th percentile)	<185(<6.4)	–	>185(>6.4)
MMAS Study
40–49 yrs	<251 (<8.7)	–	>251 (>8.7)
50–59 yrs	<216 (<7.5)		>216 (>7.5)
60–69 yrs	<196 (<6.8)		>196 (>6.8)
>70 yrs	<156 (<5.4)		>156 (>5.4)
Australian Clinical Pathology Laboratories	<185 (<6.4)	–	>185 (>6.4)
	Serum free T pg/mL (pmol/L)
ISA, ISSAM, EAU, EAA, & ASA Guidelines	<64.8 (<225)	–	>64.8 (>225)
EMAS Study	<63,4 (<220)	–	>63.4(>220)

https://uroweb.org/guideline/male-hypogonadism/

Notes. T: testosterone; AACE: American Association of Clinical Endocrinologists; ISA: International Society of Andrology; ISSAM: International Society for the Study of the Aging Male; EAU: European Association of Urology, EAA: European Academy of Andrology; ASA: American Society of Andrology; EMAS: The European Male Aging Study; MMAS: The Massachusetts Male Aging Study.

Figure 3. Signs and symptoms of late-onset hypogonadism according to their specificity.