Prediagnostic Circulating Levels of Sex Steroid Hormones and SHBG in Relation to Risk of Ductal Carcinoma In Situ of the Breast among UK Women

Abstract

Background: Sex steroid hormones and sex hormone-binding globulin (SHBG) have been implicated in the etiology of invasive breast cancer, but their associations with risk of the precursor lesion, ductal carcinoma in situ (DCIS) of the breast, remain unclear.Methods: We used Cox proportional hazards regression models to estimate the associations of serum levels of estradiol (premenopausal women only), testosterone, and/or SHBG with DCIS risk among 182,935 women. After a median follow-up of 7.1 years, 186 and 531 DCIS cases were ascertained in premenopausal and postmenopausal women, respectively.Results: Total and free estradiol were positively associated with risk of DCIS among premenopausal women. The HRs for the highest versus the lowest tertiles were 1.54 (1.06-2.23) and 1.72 [95% confidence interval (CI), 1.15-2.57], respectively. Among postmenopausal women, elevated levels of free testosterone (FT), and to a lesser extent, total testosterone, were positively associated with DCIS risk. The HRs for the highest versus the lowest quartiles were 1.42 (95% CI, 1.09-1.85) and 1.16 (95% CI, 0.91-1.48), respectively. Serum SHBG levels were inversely associated with risk of DCIS among postmenopausal women (HR q4 vs. q1 : 0.75; 95% CI, 0.56-0.99).Conclusions: This study suggests that elevated levels of estradiol are associated with increased risk of DCIS among premenopausal women, and that among postmenopausal women, elevated levels of testosterone, and particularly those of FT, are associated with increased DCIS risk, while elevated levels of SHBG are associated with reduced risk.Impact: These findings may be helpful in developing prevention strategies aimed at reducing breast cancer risk among premenopausal and postmenopausal women.

Definition, Prevalence, and Risk Factors of Low Sex Hormone-Binding Globulin in US Adults

“…To my knowledge, there are no prior studies reporting the definition of low SHBG for US adults. This deficiency becomes more problematic given that accumulating studies have shown that a lower level of SHBG, which was treated as a continuous variable or a multilevel categorical variable, is associated with many diseases including cardiovascular diseases ( 3-7 ), cancer ( 8 , 9 ), liver disease ( 12 ), arthritis ( 11 ), and polycystic ovarian syndrome ( 10 ). Therefore, the availability of the definition of low SHBG, provided by the current study, could facilitate future research to investigate the role of low SHBG in the pathogenesis of other diseases as well as the suitability of using low SHBG as a potential therapeutic target.…”

“…Recent studies indicate that SHBG may be involved in many diseases. In particular, lower levels of SHBG are reported to be associated with higher prevalence or incidence of hypertension ( 4 ), arterial stiffness ( 5 ), insulin resistance ( 3 ), type 2 diabetes ( 3 ), coronary heart disease ( 6 ), stroke ( 7 ), cancer ( 8 , 9 ), polycystic ovarian syndrome ( 10 ), arthritis ( 11 ), liver disease ( 12 ), and inflammation ( 13 ), highlighting the importance of investigating the condition of low SHBG. The mechanisms by which lower SHBG levels are related to an increased risk of these diseases are not well understood.…”

Polymorphic locus rs8023580 NR2F2-AS1 is associated with breast cancer risk in residents of Central Russia

“…Согласно имеющимся литературным данным, SHBG имеет первостепенное значение в детерминации уровня «активного» (биодоступного) тестостерона в женском организме [8,13], роль которого в развитии РМЖ доказана в масштабных эпидемиологических исследованиях [6,14]. В исследовании S. Tin Tin и соавт., основанном на изучении сывороточного уровня тестостерона у 30 565 пременопаузальных (из них 527 имели РМЖ) и 133 294 постменопаузальных женщин (из них 2 997 имели РМЖ), показано рисковое значение как общего (HR = 1,18; 95% CI : 1,14-1,23), так и свободного (HR = 1,31; 95% CI : 1,23-1,40) тестостерона для РМЖ у постменопаузальных женщин и отсутствие его связи с заболеванием у пременопаузальных женщин [6].…”

“…В патофизиологии РМЖ большое значение имеют половые гормоны (эстрадиол, тестостерон и др. ), высокие концентрации которых обусловливают и более высокий риск возникновения заболевания [6][7][8]. Биологические эффекты половых гормонов, значимые для РМЖ, напрямую зависят от содержания SHBG, который связывает / транспортирует их и таким образом является важнейшим «регулятором» уровня биодоступных (так называемых биологически активных) форм этих половых гормонов [8].…”

“…), высокие концентрации которых обусловливают и более высокий риск возникновения заболевания [6][7][8]. Биологические эффекты половых гормонов, значимые для РМЖ, напрямую зависят от содержания SHBG, который связывает / транспортирует их и таким образом является важнейшим «регулятором» уровня биодоступных (так называемых биологически активных) форм этих половых гормонов [8]. Концентрация циркулирующего SHBG в организме более чем на 50% определяется наследственными факторами, и к настоящему времени известен ряд GWAS-значимых локусов, ассоциированных с уровнем SHBG [9].…”