The study revealed:
- Estrogen-only HT was associated with a slightly increased risk of breast cancer, compared with what was seen in women who had never used hormones (relative risk, 1.28; 95% CI, 0.98–1.69)
- The type of progestin used in combination HT influenced the observed risk of breast cancer (TABLE); for example, progesterone therapy was associated with a lower risk of breast cancer than was norethindrone acetate therapy or medroxyprogesterone therapy.
Note that, in France, most women who use progesterone therapy receive transdermal, not oral, estrogen. In contrast, most women in France who take norethindrone acetate or medroxyprogesterone acetate use oral estrogen. It is possible that some of the differences observed are an effect of the dosage or route of estrogen, or both.
Search for answers, and inspiration for a new vehicle to deliver hormone
It’s not likely that any investigator will conduct a randomized study large enough to detect a difference between the effects of progesterone and those of medroxyprogesterone acetate or norethindrone acetate on breast cancer or cardiovascular risk in symptomatic postmenopausal women. Without such high-quality data from clinical trials, we’ll need to use epidemiologic evidence and data from small trials, with intermediate markers, to guide treatment choices. Preliminary data suggest that progesterone may be associated with a lower risk of breast cancer than 19-nor progestins appear to be.
When used in a combination HT regimen, oral progesterone can be prescribed as either:
- 100 mg nightly in a continuous regimen
- 200 mg nightly for 12 or more nights each month in a cyclic regimen.
Clinicians have proposed developing an intrauterine progestin-releasing device to fit in the small postmenopausal uterus, to reduce the risk of endometrial hyperplasia and minimize the systemic effect of progestin. In the United States, available intrauterine progestin-releasing systems are large, relative to the endometrial area of the average postmenopausal uterus; a frameless5 or small progestin-releasing device designed to fit in the average postmenopausal uterus6 will, once it is developed and approved, make this approach more practical.
TABLE
The relative risk of invasive breast Ca among HT users varies by type of progestin
| Progestin | Route of administration of estrogen | Person-years of data | Relative risk* of invasive breast Ca | 95% confidence interval |
|---|---|---|---|---|
| Progesterone | Transdermal | 35,513 | 1.08 | 0.89–1.31 |
| Medroxyprogesterone acetate | Oral | 7,035 | 1.48 | 1.02–2.16 |
| Norethindrone acetate | Oral | 7,401 | 2.11 | 1.56–2.86 |
| Dydrogesterone | Transdermal | 25,405 | 1.18 | 0.95–1.48 |
| Nomegestrol acetate | Transdermal | 18,826 | 1.60 | 1.28–2.01 |
| Promegestone | Transdermal | 14,910 | 1.52 | 1.19–1.96 |
| * Compared with risk in women who never used HT. | ||||
| Adapted from Fournier A et al., 2008.4 | ||||
Is your answer in line with current thinking?
The preliminary new evidence reviewed here suggests that, for a postmenopausal woman beginning combination HT, progesterone be given consideration as the progestin component. Only the oral route of progesterone (answer #2) is FDA-approved for endometrial protection in menopausal women receiving estrogen. To repeat my beginning question: What do you prescribe?