Progestins and mood

Schiff: Based on your studies and your experience, you all seem to feel that estrogen has a positive effect on mood. What happens when you add the progestin component?

Berga: It’s not always predictable. Some women do well and some do terribly. Most feel “a little less good.”

Sarrel: We know that the choice of the progestin can have very important effects on mood. What is being looked at in psychiatry now is the effect of progestins in inducing irritability and depression, as well as their major effects on brain blood flow.

Nachtigall: Progestins definitely can affect mood. It’s been my experience that about 10% of women cannot tolerate progestins of any type at any level because of the depression, anxiety, and other side effects progestins can induce. In addition, there are the 10% to 20% of women who have no problems with progestins of any kind. Everyone else is in the middle. They may or may not have problems.

Schiff: What do you do for those few women who can’t tolerate any progestin, Dr. Nachtigall?

Nachtigall: Usually I give them estrogen alone and monitor them annually for endometrial proliferation. I have used vaginal progesterone successfully in some cases, since it is absorbed only locally.

Berga: I use the levonorgestrel IUD in that situation for the same reason.** The effects are confined to the uterus.

Schiff: If the woman has an adverse symptom with one oral progestin, do you also try changing progestins or are all progestins the same?

Berga: All progestins are not the same, so it’s a trial-and-error process. For the very sensitive individual—the woman who’s tried different products, hasn’t done well, and is in your office as a last resort—we usually stop the progestin and try different estrogens until we find a dose and product that agree with her. Then we try adding progestins until we find the best combination. There are many progestins to consider, and I do find that some women feel better on one than another.

Nachtigall: I agree. For example, I’ve found that many women who couldn’t tolerate medroxyprogesterone acetate [MPA] could tolerate norethindrone acetate [NETA], which is available for postmenopausal women now both separately and in combination with estrogen. A lot of women do quite well on this progestin. Among other things, NETA seems to improve libido, and many women find that appealing.

Schiff: What dose do you prescribe?

Nachtigall: I give 5 mg for 12 days per month in a cyclic regimen as a test. If the woman likes it, I consider switching her to a continuous combined regimen containing NETA, such as the combination of 1 mg of estradiol plus 0.5 mg of NETA. Bleeding is usually minimal with that combination [Figure 1], and I think it benefits mood as well as libido.

Schiff: Is your experience similar, Dr. Berga?

Berga: I don’t know that MPA is statistically more likely than other progestins to cause problems, but we do see many women who have been put on MPA by other doctors and have not done well with it. The point is that if you give women something that makes them feel bad, they’re unlikely to remain with you and unlikely to continue therapy. When a woman is having problems with MPA, I ask her if she used oral contraceptives and if she liked them. If she says yes, then she’s probably going to like one of the norethindrone-based HRT products. I agree that vaginal progesterone is also worth trying in women who can’t tolerate MPA, if the woman is interested in that form of administration.

Schiff: Dr. Sarrel, what’s your approach to progestins?

Sarrel: I have a preference for using an androgenic progestin. In my experience, I’ve seen potent progestational progestins such as MPA induce depression. In contrast, androgenic progestins such as norethindrone and NETA appear to have mood-elevating effects.¹⁶

** Indicated for contraceptive use. No other uses are currently FDA-approved.