- Recent studies have increased our understanding of how hormone levels can affect symptoms.
- Changing levels of progesterone and estrogen and their metabolites may exert different effects in women with PMDD.
- A healthy diet and regular exercise may improve symptoms, but further treatment may be necessary.
Throughout history, women who have described physical and psychological symptoms before their periods may have been dismissed as “crazy” or found their experiences invalidated. However, we now understand some of the biological drivers of these experiences.
Let’s Start With the Female Menstrual Cycle
After puberty, biological females experience a monthly cycle of changing hormone levels, primarily estrogen and progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), leading to menstruation. In the absence of external influence, such as birth control pills or intrauterine devices (IUDs), these cycles last an average of 28 days, though they can range from 21 to 25 days.
The first day of the menstrual cycle is defined as the first day of menstruation or menses. At this time, if no pregnancy occurs, the uterus sheds its lining. Following menses, the next 1-2 weeks is the follicular phase, when the estrogen level rises, causing the uterine lining to grow and thicken. Also, FSH does just what you would think, stimulating the growth of follicles in the ovaries, one of which may go on to form a mature egg (ovum.)
The next step is ovulation when the ovaries are stimulated to release this egg by a luteinizing hormone (LH) surge. After ovulation, the luteal phase begins, and the egg begins its journey through the fallopian tubes to the prepared uterus. During this phase, a rise in progesterone continues to ready the uterus for a fertilized egg. If no fertilized egg implants, i.e., no pregnancy occurs, the levels of estrogen and progesterone drop quickly, and the uterine lining is again shed during menses.
All of these steps are repeated throughout a female’s reproductive lifetime, between puberty and menopause.
How Do Women with PMDD Differ?
Recent studies have investigated the potential cause of premenstrual dysphoric disorder (PMDD) and premenstrual symptoms (PMS). We have identified some potential culprits by comparing women with these experiences to those who do not have significant premenstrual worsening of mood, anxiety, or physical sensations.
One key finding has been the importance of one of progesterone’s metabolites, or break-down products, allopregnanolone. This hormone is known to act on the GABAA receptor in the brain. Notably, this type of receptor is also involved in our response to alcohol and benzodiazepines such as Ativan or Xanax, so, understandably, this would affect anxiety levels.
Although studies have been mixed about a difference in allopregnanolone levels, what seems to be fairly clear is that women with PMDD have an altered sensitivity to this hormone and possibly a difference in how quickly their levels drop just prior to menstruation. They may also have differences in how changing estrogen levels, which also drop just before menstruation, affect the activity of serotonin, a neurotransmitter involved in the regulation of mood and anxiety.
Current Recommendations for Treatment
After a diagnosis of premenstrual dysphoric disorder (PMDD), the next step is to consider options for treatment. Typically, women are counseled to increase the frequency of exercise, increase their intake of anti-inflammatory foods including fruits and vegetables, nuts, legumes, fish, and olive oil, eat multiple small meals to limit bloating, and limit their intake of caffeine and alcohol, particularly during the days just prior to menses (the luteal phase). Data are mixed on herbal remedies for PMDD symptoms, but there is support for supplementation with 1,200mg of calcium daily in treating PMS.
These options can help but may not provide a robust improvement in symptoms. An attempt to optimize diet, exercise, and sleep can be attempted, but often women express interest in further treatment. For some, a trial of cognitive-behavioral therapy (CBT) can benefit symptoms such as anxiety, mood lability, and irritability.
Typically, our first-line medication for PMDD is one of the selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft) or fluoxetine (Prozac). Interestingly, we can dose SSRIs differently than we might in cases of depression or anxiety without PMDD. For example, women may receive benefits from lower doses of these agents.
Additionally, due to a difference in the mechanism of action (back to the allopregnanolone again), these medications can either be dosed daily or intermittently. We mean that women can take the medication only during the luteal phase and the first several days of menses and then stop it. This is unique because we typically counsel patients that SSRIs can take several weeks to begin helping anxiety and depression, but in PMDD, they can work almost immediately.
After a trial of an SSRI, perhaps followed by a second trial if the first is ineffective, the next steps tend to involve a discussion with their gynecologist to see if oral contraceptive pills would be beneficial to modulate their cycle. Birth control pills seem to be more helpful for the physical symptoms of PMDD but can still be considered for general treatment.
In rare cases, women may take gonadotropin-releasing hormone agonists (GnRH agonists). However, these create a chemical menopause, causing their own symptoms such as hot flashes and night sweats, and should only be considered if other options have failed.
Some New Opportunities for Treatment
Research on progesterone, estrogen, and their metabolites has been crucial in identifying a recent treatment for severe postpartum depression, Brexanolone, marketed as Zulresso, a medication structurally identical to allopregnanolone. This medication is FDA-approved as a 60-hour infusion to rapidly treat postpartum depression.
An isomer (same chemical formula, but arranged differently, creating different properties) of allopregnanolone called isoallopregnanolone has also recently been studied for the treatment of PMDD. This agent, Sepranolone (UC1010), is thought to block the effects of allopregnanolone and help decrease the sensitivity to this hormone in women suffering from PMDD symptoms. This experimental agent is still being studied, and interest may be limited due to its injectable delivery, but it is encouraging to see new options created for this disorder.
In summary, healthy lifestyles are certainly important for all women, but the symptoms of PMDD may require medical intervention to improve significantly. We have recently learned about the hormone interactions and differences in women with PMDD, and awareness of this cyclical mood disorder is growing.
If you are struggling with these symptoms each month, speak with your health care provider about the treatment options listed above. You deserve to get off of the roller coaster that PMDD can create in your life. Be well, friends.
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Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet 2018 Sept 22-28;392(10152):1058-1070.
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