Study: Suppressing ovaries with hormone add-back
A 2025 study in The American Journal of Psychiatry offers a detailed look at how women with PMDD respond to ovarian suppression plus hormone addback. The study replicated and extended earlier NIH research using leuprolide, commonly known as Lupron, to suppress ovarian hormone production, followed by addback of estradiol and progesterone.
In the study, forty nine women with PMDD were given the GnRH against Lupron. For 34 of them - 69% - “medical menopause” worked. Their PMDD symptoms disappeared when their ovarian cycling was suppressed.
The key issue for Lupron or any GnRH agonist has always been the long term risks and side effects. The drug puts you into menopause immediately and this means hot flashes, brain fog and all the other delightful symptoms menopausal and perimenopausal women know so well. It also puts you at an elevated risk of osteoporosis, dementia, and early death.
The way to mitigate all these risks and side effects is Hormone Replacement Therapy - the “add-back” of the estrogen and progesterone lost when your ovaries stop working. Unfortunately, doctors wouldn’t prescribe HRT for decades because of the FDA’s black box label on HRT based on a flawed study connecting them with cancer. Luckily for us, that prohibition was lifted in 2025. This makes the use of Lupron in concert with HRT far safer and freer from menopausal symptoms.
Unfortunately, as this study shows, not all women can tolerate the hormone add-back.
Among the 34 women who responded well to Lupron:
38% had symptoms return with both estradiol and progesterone
21% had symptoms return only with progesterone
12% had symptoms return only with estradiol
29% tolerated HRT add-back with no or mild side effects
The clinical implications are significant but bounded. The study supports the usefulness of ovarian suppression as a treatment model for a subset of women with PMDD and shows that hormone-addback responses are not uniform. Some women were more progesterone-sensitive, some were more estradiol-sensitive, some were sensitive to both, and some didn’t have any symptoms when they re-introduced either progesterone or estradiol. This could eventually help clinicians better match treatments to biological response patterns.
But the limits are important. The key addback analysis included only 34 women with PMDD, a small and highly selected group. Participants were medically healthy, medication-free, regularly menstruating, and excluded if they had current psychiatric disorders or significant follicular-phase mood symptoms. That makes the findings cleaner scientifically, but less representative of many real-world PMDD patients.
The addback periods were also short: estradiol and progesterone were each tested for several weeks, with the main comparisons focused on the first four weeks.The study does not answer whether women who did well on Lupron plus addback would remain well over months or years. Finally, the study tested estradiol and progesterone separately. It did not test the combined effect of estrogen and progesterone together, as they typically occur in clinical HRT regimens or across the natural menstrual cycle.
The bottom line: this study helps divide PMDD patients into meaningful hormone-response categories, but it should be read as a mechanistic study, not a definitive guide to long-term treatment outcomes.
READ THE STUDY: Wei SM, Wakim P, Martinez PE, Nieman LK, Rubinow DR, Schmidt PJ. “Differential Effects of Ovarian Steroids in Women With and Without Premenstrual Dysphoric Disorder: A Replication and Extension of Findings.” Am J Psychiatry. 2025 Oct 1;182(10):922-934. doi: 10.1176/appi.ajp.20240596. PMID: 41030005.
