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Link between hormone replacement therapy and mammographic density

The review concluded that the highest increase in MD is among current users of HRT, particularly those taking continuous estrogen plus progestin (CEP).

A significant positive association exists between hormone replacement therapy (HRT) and mammographic density (MD), according to a systematic literature review in the journal Breast Cancer Research and Treatment.

The review concluded that the highest increase in MD is among current users of HRT, particularly those taking continuous estrogen plus progestin (CEP).

“HRT has been used as an effective treatment for alleviating the climacteric symptoms of menopause, such as hot flushes, sleeping disturbance, depressive mood, and muscle and joint pain for many years,” said senior author Shadi Azam, PhD, a breast cancer epidemiologist at Karolinska Institute in Stockholm, Sweden.

Dr. Azam told Contemporary OB/GYN that various papers and reviews have evaluated the effect of different HRT regimes, state of exposure and risk of breast cancer.

“However, ours is the first systematic review to assess the impact of HRT regimens on MD, which is an important risk factor for breast cancer,” she said.

Articles published between 2002 and 2019 from PubMed, Embase and Ovid were reviewed. Among the 22 studies that met the inclusion criteria, six studies showed that using estrogen plus progestin (E + P) HRT was associated with higher MD than estrogen alone.

Four studies reported that CEP was connected to higher MD than sequential estrogen plus progestin (SEP) or estrogen alone, but two studies showed that SEP caused slightly higher MD than CEP or estrogen alone.

“The review showed that MD significantly increases in women who have ever used HRT, compared to never users, with the highest increase in MD among current HRT users,” Dr. Azam said. “CPP users also have the highest increase in MD, followed by SEP users and estrogen alone users.”

Dr. Azam is not surprised by any of the findings. “Epidemiological evidence is rather consistent, suggesting that there is a positive association between HRT and MD,” she said.

However, it is unclear why HRT causes increasing MD, although one established hypothesis is based on the breast cell proliferation theory.

In menstruating women, it has been observed that breast epithelial cell proliferation is increased due to high levels of estrogen and progestin.

Study findings can be helpful in primary prevention of breast cancer and secondary prevention of false-negative diagnosis of small tumors, according to Dr. Azam.

“From the primary prevention perspective, our results indicate that HRT should be minimized at the lowest doses needed for as short of time as possible,” she said, “And from the secondary prevention perspective, women who currently use HRT and for whom an increase in MD is detected by mammography screening may require additional screening procedures, shorter screening intervals and the use of advanced imaging techniques such as magnetic resonance imaging/ultrasound for detecting small tumors.”

Dr. Azam emphasized that MD is one of the strongest risk factors for breast cancer.

“At a given age and body mass index (BMI), women with very dense breasts (more than 75% dense) have a four- to six-times greater risk of breast cancer compared with women with less dense tissue (occupying less than 5% of the breast),” she said.

To prevent breast cancer, “HRT should be given with caution and consideration.” Dr. Azam said.


Dr. Azam reports no relevant financial disclosures.


  1. Azam S, Jacobsen KK, Aro AR, et al. Hormone replacement therapy and mammographic density: a systematic literature review. Breast Cancer Res Treat. 2020;183(2):555-759. doi:10.1007/s10549-020-05744-w