PMDD or premenstrual dysphoric disorder has always been a bit of mystery.  We explain that PMDD is triggered by changes in reproductive hormone levels, but when you look at hormone levels in women with PMDD, they do not differ significantly from the hormone levels of women without PMDD.  Another question is why some women develop PMDD later in their reproductive lives.  PMDD most commonly has its onset not at menarche but in the 20’s, and some women do not experience PMDD until they enter into the perimenopause.

The elegant studies of Peter Schmidt and David Rubinow have helped us to better understand  what causes PMDD.  In 1998, they reported that ovarian suppression using treatment with the gonadotropin releasing hormone (GnRH) agonist, leuprolide (Lupron), eliminated premenstrual symptoms in women with PMDD.  However, when they reintroduced estrogen and progesterone to the leuprolide-treated women, those with histories of PMDD experienced a recurrence of their symptoms.  On the other hand, women with no history of PMDD experienced no change in symptoms after reintroduction of estrogen and progesterone.    

Their most recent study on PMDD included 22 women with PMDD, between the ages of 30 and 50 years. Ovarian function was suppressed using treatment with the GnRH agonist, leuprolide (Lupron).  Twelve women who experienced remission of their symptoms after 2-3 months of leuprolide treatment then received one month of placebo followed by 3 months of continuous combined estradiol/progesterone.

Similar to the study discussed above, premenstrual symptoms increased during the first month of treatment with estradiol/progesterone compared with the last month of treatment with leuprolide alone.  However, the symptoms appeared to improve over time.  Premenstrual symptoms during the second and third months of estradiol/progesterone treatment did not significantly differ from symptoms on leuprolide alone.

They conclude that it is the changing levels of estrogen and progesterone which trigger premenstrual symptoms after ovarian suppression, but that when levels of these hormones reach stable levels, the symptoms subside.

What are Clinical Implications?

This is such an interesting study because it so elegantly confirms what we have suspected — that shifting hormone levels can elicit symptoms in a certain vulnerable subset of women — but it also suggests that we might have some new options for the management of PMDD.  

When we consider pharmacologic treatment for PMDD, our first line of treatment consists of the selective serotonin reuptake inhibitors (SSRIs).  While this approach can be highly effective, some women do not respond to or cannot tolerate the side effects of SSRIs.  In addition, there are some women, such as those with a history of bipolar disorder, where we might want to avoid using SSRIs because antidepressants may negatively affect mood stability.

Oral contraceptives are frequently used for the treatment of PMDD; however, data regarding the effectiveness of oral contraceptives for the management of PMDD have been somewhat mixed.  Most of the studies showing a beneficial effect of oral contraceptives (OCs) for premenstrual symptoms have studied OCs containing the novel progestin drospirenone (YaZ and Yasmin).  The current study suggests that maybe it’s not the progestin that is important for the treatment of PMDD but instead that continuous (as opposed to interrupted) exposure to hormones could be an effective treatment for some women with PMDD.  If we do use OCs in this setting, we would have to inform patients that they might experience recurrent symptoms during the first phase of treatment but that these symptoms will eventually subside.

We might also consider ovarian suppression using a GnRH agonist.  Based on the earlier findings of Schmidt and Rubinow, we have typically avoided hormone replacement in this population because of the concern that estrogen and progesterone addback might retrigger premenstrual symptoms.  We rarely choose this approach because in a young woman, long-term ovarian suppression (without hormone replacement) would mean subjecting her to the negative effects of early menopause, including bone loss and increased cardiovascular risk.  The current study indicates that ovarian suppression with leuprolide may actually be a viable and effective long-term treatment option for women with PMDD and that estrogen and progesterone addback may, despite some increased symptoms during the early phases of treatment, be well-tolerated over a longer course of treatment.  

Ruta Nonacs, MD PhD


Premenstrual Dysphoric Disorder Symptoms Following Ovarian Suppression: Triggered by Change in Ovarian Steroid Levels But Not Continuous Stable Levels.

Schmidt PJ, Martinez PE, Nieman LK, Koziol DE, Thompson KD, Schenkel L, Wakim PG, Rubinow DR.  Am J Psychiatry. 2017 Apr 21

Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome.

Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR.  N Engl J Med. 1998 Jan 22;338(4):209-16.  Free Article

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