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Hormone replacement therapy after menopause is the poster child for irrational exuberance in the medical profession. Rarely has a therapy that made so much sense from a physiologic point of view led to so many conflicting conclusions when rigorously tested. This week, another notch in the “pro” column for post-menopausal hormone replacement therapy with results from the KEEPS study, which evaluated the effect of HRT on sexual function after menopause.

Broadly speaking, this was a positive, study. Of the 670 women who were randomized, either to oral estrogen, transdermal estrogen, or placebo, those who got the estrogen tended to have better scores on the Female Sexual Function Inventory – a validated survey which looks at sexual domains including desire, arousal, lubrication, orgasm, satisfaction and pain. You can see here the scores over time. I’m highlighting the transdermal estrogen group here because overall the effects were larger than in the oral formulation.

That’s actually a pretty interesting finding. Oral estrogen undergoes first-pass metabolism in the liver, which increases the synthesis of sex hormone binding globulin in response. Transdermal estrogen doesn’t do this. You can see the profound difference in SHBG levels in this figure.

SHBG binds testosterone, which you definitely don’t want to do if you are worried about improving sexual function, so this study provides good evidence that the transdermal approach for treatment makes sense.

But let’s not get too excited. There are some big caveats here.

First off, it’s clear these researchers had taken to heart the potential risks of HRT. You couldn’t get into this trial unless you were, first, within 3 years of your last menstrual period, and second, free from even the vaguest cardiovascular risk. Women with higher coronary artery calcium, smoking, obesity, elevated lipids, hypertension, or diabetes were all excluded. In fact, around 60% of women screened for this study were excluded.

And overall, the effect was pretty small, 2.6 points on the female sexual function inventory. 75% of women had low sexual function at baseline, this number decreased to 67% with transdermal estrogen treatment, that’s a significant improvement but it also means that you would need to treat about 15 women with transdermal estrogen to get one person to respond.

In fact, subgroup analysis showed that the only women who saw benefit were the group that had low sexual function at baseline. That said, they were in the majority.

So we have clear, if modest, results from this trial. What is unclear is whether patients start to see estrogen as a legitimate treatment for low sexual function, or the sexual benefits of estrogen as simply a pleasant side-effect.