Understanding PMDD
Premenstrual Dysphoric Disorder (PMDD) affects millions of individuals worldwide, causing significant distress during the luteal phase (second half) of the menstrual cycle. Characterized by severe mood swings, irritability, and physical symptoms, PMDD can significantly impact daily life. Approximately 5% of women and gender diverse individuals assigned female at birth are diagnosed with PMDD (1).
The diagnostic criteria for PMDD include at least one of four mood symptoms (depressed mood, anxiety, irritability, mood swings) and at least one of seven mind and body symptoms (difficulty concentrating, feeling overwhelmed, decreased interest in usual activities, lack of energy, change in appetite, change in sleep, physical symptoms like breast tenderness, joint pain, and bloating) during the luteal phase, adding up to a total of at least five symptoms. In addition, the person should be nearly asymptomatic during the follicular phase (first half) of the menstrual cycle, and the symptoms must cause significant distress for at least two months. PMDD is strongly associated with thoughts of suicide (2).
The luteal phase of the menstrual cycle is marked by higher progesterone levels in the blood, thus leading many to believe that PMDD is a symptom of high progesterone. Alternately, symptoms may be due in part to the decreased estrogen levels during this time, or the drop in both estrogen and progesterone at the end of the luteal phase. People with PMDD do not have significantly different ovarian hormone levels than the general population (1). People with PMDD show an altered conversion to, and response to, the neurosteroid allopregnanolone, a metabolite of progesterone, which spikes in the late luteal phase and in turn impacts GABA levels in the brain (1,3).
PMDD is thought to involve dysregulation of the serotonin system in the brain (1). Selective serotonin reuptake inhibitor antidepressants are the mainstay of treatment for PMDD, because they modulate both serotonin and allopregnanolone levels in the brain and tend to work well whether cycled or used continuously (1). However, not everyone can tolerate these medications or finds them effective.
Hormonal Changes During the Menstrual Cycle with vs. without Selective Progesterone Receptor Modulators:
Source: Sundström-Poromaa I, Comasco E. New Pharmacological Approaches to the Management of Premenstrual Dysphoric Disorder. CNS Drugs. 2023 May;37(5):371-379. doi: 10.1007/s40263-023-01004-9. Epub 2023 May 12. PMID: 37171547; PMCID: PMC10212816.
Can You Treat PMDD With Hormones?
Although antidepressants are considered the first-line treatment for PMDD, there are two main, and opposing, hormonal strategies to tackling PMDD symptoms: either by supplementing circulating hormone levels, or decreasing them.
1. Hormone Supplementation
Ethinyl estradiol and drospirenone: Oral contraceptives provide an unnaturally high, steady level of estrogens and progestogens in order to suppress ovulation. Drospirenone is a synthetic progesterone derivative with antiandrogenic properties. In randomized controlled trials, combination pills containing these hormones have proven effective in treating PMDD. Brands like Yaz, Ocella, and Beyaz fall into this category. Yaz is the only oral contraceptive approved by the U.S. Food and Drug Administration (FDA) specifically for PMDD symptom management (2). Similar results were found whether ethinyl estradiol/drospirenone contraceptives were given cyclically or continuously (2).
Estrogen +/- Progestogen: A 2015 Cochrane review did find evidence to support continuous transdermal estrogen with a progestogen to treat PMS symptoms, however the evidence was of low quality. Based on 11 studies, unopposed luteal-phase estrogen is probably ineffective and possibly detrimental for controlling PMS. Moreover, uncertainty remains regarding the safety of unopposed estrogen in premenopausal individuals (4).
Drosperinone: Slynd is the sole drosperinone-only birth control option currently available on the market. One study of postpartum women receiving Slynd showed a decrease in depressive scores at week 12 compared with control (5). Further study is needed in PMDD.
Progesterone: One 2017 open-label study of women given micronized progesterone sublingually on days 11 to 25 of their cycle showed significant improvement in severe PMS symptoms over placebo, with 86.5% of participants having a full regression of symptoms. The authors suggested that the sublingual (beneath the tongue) route may have been absorbed more effectively than typical oral progesterone, leading to improved results compared with prior studies (6). Previously, a 2012 Cochrane review had found no evidence to recommend progesterone for PMS (7). These contradictory findings may be due to the theory that it's not sustained high levels of progesterone that trigger PMDD symptoms, but rather abrupt changes in progesterone concentration (3).
2. Hormone Suppression
Selective progesterone receptor modulators (SPRMs): Fibristal (ulipristal 5 mg) is a selective progesterone receptor modulator that reduces progesterone levels and is used to treat fibroids. One randomized controlled trial found a significant improvement in PMDD symptoms after one month (1). Neuroimaging studies have shown enhanced activity in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex with SPRMs (1). More studies are needed to clarify its long-term effects, with special attention to liver function (2).
Dutasteride: This synthetic 4-azasteroid selectively inhibits 5α-reductase, preventing metabolism of progesterone to allopregnanolone. One small study found significant improvement in PMDD with 2.5 mg dutasteride daily. Dutasteride is pregnancy category X, which must be considered in this population (2).
Sepranolone (isoallopregnanolone): Isoallopregnanolone is an antagonist of allopregnanolone that does not act on GABA receptors. As a novel strategy to reduce allopregnannolone's affect on GABA receptors during the luteal phase, initial studies show promising results (2).
Gonadotropin-Releasing Hormone (GnRH) Analogues: These injections induce temporary menopause by suppressing ovarian function. However, early induced menopause has significant implications for cardiovascular and bone health. While not a first-line treatment, these can be helpful when other options fail (2).
Surgery: Bilateral salpingo-oopherectomy, or sugical menopause, is a last resort for treatment-resistant PMDD. Circulating levels of estrogen and progesterone will be permanently decreased after this surgery (1).
Could a Glaucoma Medication Cure PMDD?
Likely no, but an exciting series of case studies was published in 2014.
Acetazolamide: This carbonic anhydrase inhibitor, typically used for glaucoma and altitude sickness, potentiates GABAergic transmission. Experimenters provided eight women with treatment-resistant PMDD acetazolamide for 7 to 10 days prior to menstruation each month, with 100% achieving remission at one year (8). Although this study is 10 years old, no further studies on acetazolamide for PMDD have been published to date, suggesting that these findings likely have not been replicated.
Are There Medication-Free Options to Treat PMDD?
Yes, several supplements, cognitive therapies, and mindfulness practices have been shown to significantly improve PMDD.
1. Supplements
Chasteberry Extract: A meta-analysis showed that chasteberry extract users were 2.57 times more likely to achieve PMDD remission than placebo users (2).
Lemon Balm: Several small studies have shown a moderate improvement in PMS symptoms with lemon balm (9).
Swedish Pollen Extract: One study showed that this supplement can be helpful for PMS symptoms, particularly for those with irritability as a major factor (10).
Vitamin B6 (pyridoxine): An important cofactor in the synthesis of GABA, a 2016 meta-analysis found vitamin B6 to be more effective than placebo in treating PMS symptoms (2).
Vitamin B1 (thiamine), Calcium, and Vitamin B2 (riboflavin): Supplement or dietary intake has been shown to improve PMS in small studies, but these supplements seem to work best in combination, especially in addition to vitamin B6 (2).
Vitamin D: Supplementation may be helpful in those with a vitamin D deficiency (2).
Zinc, Magnesium, Omega 3s: Small studies have shown improvement in PMS symptoms (2).
2. Cognitive Therapies
Cognitive behavioral therapy (CBT): This is the best-studied psychotherapeutic treatment for PMDD, and several studies have shown improvements in depression, anxiety, and stress (2). The effect size of CBT is considered similar to that of antidepressants, and two studies have found efficacy of CBT even when provided online (2, 3).
Hypnotherapy: People with PMDD show altered reactivity in the brain, specifically in the anterior cingulate cortex, amygdala, and insula (1). These areas are all implicated in diminished emotional control and increased negative mood symptoms (1). These are also the same areas that are the most impacted by hypnotherapy. Much like selective progesterone receptor modulators, hypnotherapy increases activity in the anterior cingulate cortex and improves top-down emotional regulation. Therefore, there is a strong potential mechanism for hypnotherapy to improve PMDD. That said, there have been few studies on this topic. One 2021 randomized controlled trial of 60 women showed significant improvements in pain and psychological distress due to PMDD with hypnotherapy vs. no intervention (11). Although more research is needed, there is little potential downside to hypnotherapy.
3. Yoga & Meditation
Several studies have shown an improvement in both the physical and psychological aspects of PMDD with yoga (3). In fact, yoga can increase brain-derived neurotrophic factor (BDNF), much like antidepressants (3).
Stimulation of the prefrontal cortex during meditation can decrease pain and depression while increasing immune function (3). Mindfulness can also help with the secretion of melatonin, which is important for sleep (3).
Considerations and Caution
Individualized Approach: PMDD treatment should be tailored to each patient’s unique needs.
Side Effects: Any treatment for PMDD may have risks and benefits. Discuss these with your healthcare provider.
Monitoring: Regular follow-ups are essential to assess effectiveness and adjust treatment as needed.
Personalized care and evidence-based approaches are key to managing PMDD effectively.
Disclaimer: This blog provides general information and should not replace individualized medical advice. Always consult with a qualified healthcare provider for personalized recommendations.
Sources:
Sundström-Poromaa I, Comasco E. New Pharmacological Approaches to the Management of Premenstrual Dysphoric Disorder. CNS Drugs. 2023 May;37(5):371-379. doi: 10.1007/s40263-023-01004-9. Epub 2023 May 12. PMID: 37171547; PMCID: PMC10212816.
Carlini SV, Lanza di Scalea T, McNally ST, Lester J, Deligiannidis KM. Management of Premenstrual Dysphoric Disorder: A Scoping Review. Int J Womens Health. 2022 Dec 21;14:1783-1801. doi: 10.2147/IJWH.S297062. PMID: 36575726; PMCID: PMC9790166.
Modzelewski S, Oracz A, Żukow X, Iłendo K, Śledzikowka Z, Waszkiewicz N. Premenstrual syndrome: new insights into etiology and review of treatment methods. Front Psychiatry. 2024 Apr 23;15:1363875. doi: 10.3389/fpsyt.2024.1363875. PMID: 38716118; PMCID: PMC11075635.
Naheed B, Kuiper JH, Uthman OA, O’Mahony F, O’Brien PMS. Non-contraceptive oestrogen-containing preparations for controlling symptoms of premenstrual syndrome. Cochrane Database Syst Rev. 2017;2017(3). doi: 10.1002/14651858.CD010503.pub2
Caruso S, Caruso G, Bruno MT, Minona P, Di Guardo F, Palumbo M. Effects of Drospirenone only pill contraception on postpartum mood disorders: A prospective, comparative pilot study. Eur J Obstet Gynecol Reprod Biol. 2023 Sep;288:73-77. doi: 10.1016/j.ejogrb.2023.06.026. Epub 2023 Jul 6. PMID: 37453345.
Horbatiuk O, Binkovska A, Herych O, et al. Using micronized progesterone for treatment of premenopausal age women suffering from severe premenstrual syndrome. Curr Issues Pharm Med Sci. 2017;30(3):138–141. doi: 10.1515/cipms-2017-0025
Ford O, Lethaby A, Roberts H, Mol BWJ. Progesterone for premenstrual syndrome. Cochrane Database Syst Rev. 2012;2012(3). doi: 10.1002/14651858.CD003415.pub4
Sani G, Kotzalidis GD, Panaccione I, Simonetti A, De Chiara L, Del Casale A, Ambrosi E, Napoletano F, Janiri D, Danese E, Girardi N, Rapinesi C, Serata D, Manfredi G, Koukopoulos AE, Angeletti G, Nicoletti F, Girardi P. Low-dose acetazolamide in the treatment of premenstrual dysphoric disorder: a case series. Psychiatry Investig. 2014 Jan;11(1):95-101. doi: 10.4306/pi.2014.11.1.95. Epub 2014 Jan 21. PMID: 24605130; PMCID: PMC3942558.
Alimoradi, Z., Jafari, E., Abdi, F., & Griffiths, M. D. (2023). Therapeutic applications of lemon balm (Melissa officinalis) for obstetrics and gynecological health issues: A systematic review. Journal of Herbal Medicine, 42, 100751. doi:10.1016/j.hermed.2023.100751
Kaj Winther, Joan Campbell-Tofte, Alzahraa M. Motawei, Frank Pedersen, Signe Barfod Roos, Anne Sophie Vinther Hansen, Gitte Gleerup Fornitz, Marianne Killi, Gerhardt Gerhardsen,
A double-blinded, randomized, placebo controlled, parallel study of pollen pistil extract (Sèrèlys) on women reporting irritability as predominant PMS symptom,
Journal of Herbal Medicine, Volume 12, 2018, Pages 23-32, ISSN 2210-8033, https://doi.org/10.1016/j.hermed.2018.02.002.
Abazari, Nader & Heydarinasab, Leila & Yaghubi, Hamid & Farahani, Hojjatollah. (2021). Efficacy of hypnotherapy on pain intensity and psychological distress among women with premenstrual dysphoric disorder, applicability of suggestions focused on cognitive flexibility and ego strength. 10.21203/rs.3.rs-835578/v1.