Helicobacter pylori is associated with lower androgen activity among men in NHANES III

To the editor

Chen et al., using a nationally representative sample of the US population from the National Health and Nutrition Examination Survey III (NHANES III), intriguingly suggest infection with Helicobacter (H.) pylori may have positive health effects in addition to a causal role in gastric cancer.[1] H. pylori has a long history of co-existence with humans. Research on the human microbiome has also highlighted the symbiotic relation of gut microorganisms with their hosts. Animal biology suggests immune defense trades-off against reproductive success, such that infections suppresses androgens.[2] Correspondingly, changing the gut microbial environment in mice changes mice testosterone levels.[3] The same mechanisms may also apply to humans, particularly at older ages when the immune system is less effective. H. pylori could modulate androgen production and thereby affect health, because androgens, and similarly endocrine disruptors, may play a role in chronic diseases.

Two androgen biomarkers (serum testosterone and androstanediol glucuronide (3-alpha-diol-G) (AAG)) were assayed for a male sub-sample (12+ years) from NHANES III, who attended a morning examination session (n=2205) in phase 1 (1988–91) and had surplus sera available,[4] using a competitive electrochemiluminescence immunoassay for serum testosterone and an enzyme immunoassay for AAG.[4] H. pylori antibodies, assayed using ELISA, and antigens to cagA positive H. pylori strains were also obtained from surplus sera.[1] NHANES III was approved by the US Centers for Disease Control and Prevention’s Institutional Review Board and all participants provided written informed consent.

Of 1445 men (18+ years) with an androgen and clearly negative or positive H. pylori status, 50.9% were H. pylori positive. H. pylori was associated with older age, less education, other than non-Hispanic white ethnicity and higher body mass index (BMI).[1] H. pylori was negatively associated with AAG, adjusted for age, race/ethnicity, education, BMI and smoking (model 2) using linear regression adjusted for the complex sample and weighted back to the US population (Table 1). Somewhat similar associations occurred for joint H pylori/cagA status among men aged 20+ years, where the associations did not appear to differ for cagA⁺ (Table 1). The association of H. pylori with AAG, but not with testosterone, varied with age, such that H. pylori was more strongly associated with lower AAG among older men (Figure 1).

Table 1.

Adjusted association of H. pylori and joint H. pylori and cagA status with serum testosterone and AAG using multivariable linear regression models among 1,435 men from NHANES III phase 1 (1988–1991).

	mean (standard deviation)	Model	H. pylori positive compared with H. pylori negative				Joint status of H. pylori and cagA compared to H. pylori− cagA−
			n	b	95% CI	Difference by age p-value*	H. pylori+ cagA−			H. pylori+ cagA+ †		Difference by age p-value*
							n	b	95% CI	b	95% CI
Testosterone (ng/mL)	5.3	1	1425	−0.08	−0.50 to 0.33	0.18	1399	−0.24	−0.62 to −0.14	−0.12	−0.47 to 0.22	0.05
	(2.04)	2	1416	−0.18	−0.50 to 0.13	0.08	1390	−0.40	−0.65 to −0.14	−0.16	−0.47 to 0.15	0.02
Androstanediol glucuronide (ng/mL)	13.3	1	1435	−1.85	−3.22 to −0.48	0.04	1409	−2.46	−4.28 to −0.64	−1.53	−3.35 to 0.29	0.06
	(11.6)	2	1427	−1.66	−3.13 to −0.20	0.03	1401	−2.28	−4.06 to −0.50	−1.45	−3.43 to 0.52	0.08

Model 1 adjusted for age (continuous) and race/ethnicity (Non-Hispanic white, Non-Hispanic black, Mexican-American and other)

Model 2 additionally adjusted for educational attainment (years), body mass index (<25,>25, missing) and smoking (never, past, current)

^*p-value for the interaction of H. pylori status with age

^†as previous publications H pylori⁺ cagA⁺ includes anyone cagA⁺ regardless of the results of the H. pylori assay, [1] including those with equivocal H. pylori status [1]

Figure 1.

Association of H. pylori (positive men compared to negative) with AAG by age-group using a multivariable linear regression model among 1,427 men from NHANES III phase 1 (1988–1991), adjusted for age (continuous), race/ethnicity, educational attainment, body mass index and smoking.

H. pylori was most clearly associated with lower AAG, although testosterone had non-significant associations in the same direction. AAG was weakly positively correlated with testosterone (0.13), which may not capture all androgen activity,[5] consistent with anti-androgens treating prostate cancer effectively at castrate levels of serum testosterone.[5;6] AAG also had the biologically expected positive association of an androgen with higher hemoglobin (0.06 g/L per ng/ml/L AAG, 95% confidence interval (CI) 0.002 to 0.12 in model 2) whereas testosterone did not (0.22 g/L per ng/mL testosterone, 95% CI −0.17 to 0.62 in model 2).

These findings are consistent with some ecological observations. Some populations with high levels of stomach cancer, such as in China,[7] also have lower androgen related parameters, such as testicular weight,[8] than Caucasians, and lower rates of prostate cancer.[7] The association of H. pylori with lower androgens may also shed light on other observations. H. pylori is positively associated with type 2 diabetes;[9] lower androgens is a possible mechanism, as androgen deprivation increases vulnerability to diabetes. Antibiotic use is associated with prostate cancer,[10] for which raising androgens by eliminating H. pylori is a speculative mechanism. Clearly, these findings need to be confirmed or refuted in other study designs capable of establishing causality. H. pylori is currently very common; ongoing eradication could have widespread health consequences, particularly for older men, via altered androgens, such as increasing hormonally modulated cancers or affecting other chronic diseases.