While many women experience physical symptoms prior to the onset of their period or premenstrual syndrome (PMS), a smaller subset of women suffer from Premenstrual Dysphoric Disorder (PMDD), a more severe form of premenstrual syndrome.  PMDD is characterized by significant premenstrual mood disturbance, often with prominent mood reactivity, irritability, and depression. Symptoms of PMDD can emerge 1-2 weeks preceding menses and typically resolve with the onset of menses. This mood disturbance results in marked social or occupational impairment, with its most prominent effects noted in interpersonal functioning. 

Serotonergic antidepressants have been established as the first-line treatment option for PMDD; however, some women either do not tolerate or fail to respond to this class of medications.  Some women may benefit from treatment with oral contraceptives; however, a significant proportion of women, especially those with more severe symptoms, may not respond to these interventions.  

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).  However,  other studies suggest that it’s not the type of 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. 

While there are effective treatments for PMDD, we do encounter a fair number of women who have failed to respond or cannot tolerate these treatments.  

What Options are Available for the Treatment of Severe PMDD?

One option is ovarian suppression.  We learned from the elegant studies of Peter Schmidt and David Rubinow (1998) that ovarian suppression can eliminate PMDD symptoms.  When given continuously, gonadotropin releasing hormone (GnRH) agonists, such as leuprolide (Lupron), inhibit the pituitary-gonadal axis, shutting down the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) and thereby suppressing ovulation.  Instead of the cyclical rise and fall of estrogen and progesterone levels which occurs in premenopausal women, the ovaries produce postmenopausal levels of ovarian hormones.  In other words, GnRH agonists can bring about a chemically induced menopause.  

Without this monthly cycling, and without the monthly fluctuations in hormone levels, women with PMDD experience improvement or remission of their premenstrual symptoms.  While GnRH agonists may succeed where other treatments have failed, the long-term use of GnRH agonists is limited.  This dramatic reduction in estrogen levels can lead to long-term consequences of low estrogen levels, including decreased bone mineral density and increased risk for cardiovascular disease.  

 GnRH Agonists with Estrogen Addback

In order to reverse the hypoestrogenic effects of GnRH agonist treatment, Schmidt and colleagues (1998) gave physiologic doses of either estradiol (transdermal 17?-estradiol at a dose of 0.1 mg per day) or progesterone (200 mg twice daily) to women on leuprolide.  However, after addback of either estrogen or progesterone, women with PMDD experienced recurrent premenstrual symptoms.  It was hypothesized that adding back stable levels of hormones — rather than cyclically fluctuating levels — would be tolerable, but that’s not what happened.  

Because treatment with a GnRH agonist in combination with an estrogen and progesterone addback did not appear to improve premenstrual symptoms, we rarely choose this approach for young woman with PMDD, as 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.  

Another Look at Estrogen Addback with GnRH Agonists

In a more recent study of PMDD from Schmidt’s group, they used the same technique to suppress ovarian function using the GnRH agonist, leuprolide (Lupron).  Twelve of the 22 women experienced remission of their symptoms after 2-3 months of leuprolide treatment.  They 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 differ significantly from symptoms on leuprolide alone.

The authors concluded 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.

Is Ovarian Suppression a Viable Treatment Option?

The most recent study from Schmidt and colleagues 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.  The challenge is reassuring women with severe PMDD that, although their symptoms may disappear after treatment with a GnRH agonist,  they may experience an increase in symptoms after adding back estrogen but that these symptoms will eventually subside. 

It should be noted, however, that treatment with a GnRH agonist only works in about  half of the women who receive this treatment.  This is somewhat surprising, as we have hypothesized that turning off the cyclical hormonal fluctuations should eliminate PMDD symptoms.  While we do not understand why some women with PMDD may not respond to ovarian suppression, this finding highlights the importance of broadening our array of effective treatments for women with severe PMDD.  

Ruta Nonacs, MD PhD

Schmidt PJ, Martinez PE, Nieman LK, Koziol DE, Thompson KD, Schenkel L, Wakim PG, Rubinow DR.  Premenstrual Dysphoric Disorder Symptoms Following Ovarian Suppression: Triggered by Change in Ovarian Steroid Levels But Not Continuous Stable Levels.  Am J Psychiatry. 2017 Apr 21

Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR.    Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome.  N Engl J Med. 1998 Jan 22;338(4):209-16.  Free Article

Ovarian Suppression for PMDD: New Study Suggests Long-Term Effectiveness and Tolerability