North American Menopause Society

North American Menopause Society

October 12, 2017
4 min read

Progestin/estrogen HT comes with caveats for some menopausal women

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James Liu
James Liu

PHILADELPHIA — Combination estrogen and progestin hormone therapy can serve as a “necessary evil” for endometrial protection, but its use comes with caveats for some menopausal women, according to a speaker here.

Progestins in clinical use, including progesterone, medroxyprogesterone (MPA) and norethindrone, prevent overgrowth in the uterine lining in postmenopausal women receiving estrogen HT, and can decrease the risk of endometrial hyperplasia progression. But combination estrogen/progestin use comes with several risks — albeit some small — including an increased incidence of breast cancer and dementia diagnoses in women prescribed combination therapy vs. estrogen alone, and a diminishing cardiovascular benefit in older women when compared with women aged 65 years and younger prescribed the same therapy.

“As you all know, progestins are given to women with a uterus for endometrial protection, so as clinicians, we all feel that progestins are a necessary evil,” James Liu, MD, chairman of the department of obstetrics and gynecology at UH Cleveland Medical Center, said during a plenary symposium on HT at the North American Menopause Society Annual Meeting. “Some of my patients come to me and say, ‘That progesterone, it is evil.’ “

Progesterone, MPA and norethindrone have somewhat different structures, Liu said. Compared to natural progesterone, both MPA and norethindrone have greater binding properties and will displace native progesterone if used concurrently.

Oral progesterone, after it is absorbed in the gut, it is subject to a “first pass” effect, Liu said. In the liver, hydroxy reductases convert the progesterone to a different molecule with different properties other than progesterone. One of them, 3 alpha hydroxyprogesterone, leads to a decrease in breast cell activity, Liu said.

“The other you may realize is the conversion to 20 alpha hydroxyprogesterone, which is responsible for the brain sedation or sleepiness that some patients report,” Liu said.

Another metabolite, 5 alpha reductase, an enzyme present in men and women, stimulates breast cell mitoses and may be responsible for some of the actions observed in breast tissue in several studies, Liu said.

Undesired effects on the breast

There are some major differences with how breast tissue in premenopausal women behaves vs. the endometrium, Liu said. In a premenopausal woman, in the face of high progestin exposure, there is a major drop of mitoses in endometrial cells. In contrast, breast tissue in the luteal phase, in similar premenopausal women, has high mitotic activity, Liu said.


“I think the conclusion from these observations are progesterone stimulates mitosis in estrogen-primed breast tissue, at least in premenopausal women, and perhaps, the same thing holds true in postmenopausal women,” Liu said.

Combinations of estrogen and progestins appear to increase risk of breast cancer by 20% to 30%, however the absolute risk is quite low — less than 1 in 1,000, Liu noted. Evidence does not suggest a difference in cancer rates among the various synthetic progestins, and there is very little information about natural progestins, he said.

One of the therapies used in the active treatment group of the Women’s Health Initiative (WHI) trial was conjugated equine estrogens (CEE) plus MPA on a continuous basis, said Liu, also a former WHI principal investigator. The data with regards to breast tissue, he said, are powerful.

“What we find is there is almost always an immediate response in breast tissue within 1 year, relative to placebo, including abnormalities in breast density and cysts,” Liu said, referring to the active treatment group.

Overall, this difference persisted over 5.5 years, he said.

Looking at the overall trial including follow-up, the accumulated invasive breast cancer diagnosis was made more frequently in the active treatment group compared to the placebo group, Liu said. In contrast, the estrogen alone group did not see a difference in breast cancer occurrence, whereas the placebo group saw a slightly increased risk for breast cancer, Liu said.

“If we look at the characteristics of what we found, there was an increase in tumor size and increased incidence of positive lymph nodes [in the combination group]; however, there was no difference in terms of staging or overall morphology of the tumors,” Liu said. “So, regarding the WHI, estrogen alone for 7 years did not appear to increase risk for breast cancer, whereas the combination of MPA and estrogen was associated with a small increased risk of breast cancer without a prior hysterectomy. I think that’s the take home message with regards to MPA in a randomized trial of women, and it’s pretty powerful.”

Other smaller trials with similar formulations, like HER and HER2, showed a similar trend, Liu said.

Cognition effects

When looking at progestin’s possible effects on cognition and dementia risk, things become “more muddy,” Liu said, because as a woman ages, memory, attention span and coordination may all decrease naturally.

“The caveat is everyone with dementia has cognitive impairment, but not everyone with cognitive impairment has dementia,” Liu said. “For a diagnosis [of dementia], you need not only a decline in memory but ... it is affecting your occupational or social function.”

In an analysis of women aged at least 65 years in the WHI, findings suggested that the estrogen/MPA group had a greater number of dementia diagnoses, whereas dementia diagnoses in the estrogen-alone group, although slightly higher than placebo, was not statistically significant, Liu said. There was no evidence of a significant increase in mild cognitive impairment with the estrogen/MPA combination, and Alzheimer’s disease incidence wasn’t evaluated, he said

“In those individuals over age 65 [years], the estrogen/progestin combinations, if you start them, can increase the risk for dementia, and the cardioprotective effect of estrogen/progestin combinations in women under [age] 60 [years] appears to be beneficial, but this benefit may diminish in older women.” – by Regina Schaffer


Liu J. Selecting progestogens: Breast, cardiovascular, endometrial and cognitive outcomes. Presented at: Annual Meeting of the North American Menopause Society; Oct. 11-14, 2017; Philadelphia.

Disclosures: Liu reports he receives advisory or consulting fees from Allergan, Bayer, Pfizer and Therapeutics MD.