Breast cancer risk is increased by elevated testosterone

A paper published in the journal Breast Cancer Research presents evidence that elevated testosterone levels in premenopausal females are a risk factor for breast cancer.The authors note:

"Most breast tumors are estrogen dependent, and postmenopausal women with elevated serum estrogens are at an increased risk of developing breast cancer. Estrogens are synthesized from androgens in the premenopausal ovary and in extraovarian tissues, and postmenopausal women with elevated serum androgens are similarly at an increased risk of breast cancer...Evidence also is accumulating from prospective cohort studies on associations of circulating estrogens and androgens with premenopausal breast cancer risk.'

So they set out to investigate...

"...whether estradiol and testosterone levels in serum collected before menopause are associated with subsequent breast cancer risk."

They examined hormone levels for 266 subjects who were not using exogenous hormones at the time of blood collection and matched the data of 98 breast cancer cases to controls considering age, date, menstrual cycle day, and time of day of blood collection. They also measured sex hormone-binding globulin (SHBG) to calculate the non-SHBG bound hormone fractions (bioactive free fractions). What did the data show?

"Serum testosterone was strongly and significantly associated with breast cancer risk. The relative odds (OR) for increasing quartiles of total testosterone were 1.0, 2.1, 1.5 , and 3.3. Comparable ORs for the non-SHBG bound fraction of testosterone that is bioavailable were 1.0, 1.7, 1.7, and 4.2."

In other words, the subjects with the highest levels of free fraction testosterone exhibited a 320% increase in breast cancer. Interestingly--and this makes sense to those of us who test estrogen and progesterone levels throughout the menstrual cycle...

"Total and non-SHBG-bound estradiol were not associated with breast cancer, but extreme variation in levels across the menstrual cycle coupled with relatively small numbers, particularly for analyses stratified by cycle phase, limited the power to detect associations."

This highlights the importance of seeing the total picture of free fraction estradiol throughout the menstrual cycle in relation to free fraction progesterone.The authors of a subsequent study also published in Breast Cancer Research sought to build on this evidence implicating elevated testosterone as a risk factor for breast cancer. They note:

"Prospective epidemiologic studies have consistently shown that levels of circulating androgens in postmenopausal women are positively associated with breast cancer risk. However, data in premenopausal women are limited."

They investigated the role of premenopausal levels of testosterone by examining data for 356 cases of breast cancer matched to 683 controls according to age and date, phase, and day of menstrual cycle at blood donation. They measured testosterone, androstenedione, dehydroandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) directly and calculated free testosterone. Were the findings consistent with the previous study?

"Premenopausal serum testosterone and free testosterone concentrations were positively associated with breast cancer risk. A marginally significant positive association was observed with androstenedione, but no association with DHEAS or SHBG. Results were consistent in analyses stratified by tumor type (invasive, in situ), estrogen receptor status, age at blood donation, and menopausal status at diagnosis."

In this study there was an 80% increase, almost double, in risk of breast cancer for both free and bound testosterone. The authors conclude:

"Premenopausal concentrations of testosterone and free testosterone are associated with breast cancer risk. Testosterone and free testosterone measurements are also highly reliable (that is, a single measurement is reflective of a woman's average level over time). Results from other prospective studies are consistent with our results...Improving risk prediction models for this age group could help decision making regarding both screening and chemoprevention of breast cancer."

Personally I see elevated levels of testosterone in both pre- and postmenopausal women too often that are driven by the upregulation of the testosterone-producing enzyme by elevated insulin. No assessment of hormone regulation for health and risk factor assessment, to say nothing of the contemplation of testosterone supplementation in post-menopausal women, is complete without a comprehensive assay.