The purpose of this literature review is to understand the symptoms, potential causes, populations affected, and solutions for Premenstrual Dysphoric Disorder (PMDD).  It is reported by the Committee on Gynecologic Practice of the American College of Obstetricians and Gynecologists that up to 80 percent of menstruating women experience changes, whether emotional, cognitive or physical during the luteal phase of their cycles (Bhatia & Bhatia, 2002). 

What is PMDD?

PMDD can affect menstruating women ages 13 to 60 years of age and symptoms are only present in the second half of the menstrual cycle, the luteal phase and disappear when a woman completes menopause.  To understand PMDD, one must first understand the menstrual cycle. 

The menstrual cycle typically lasts anywhere from 28-40 days.  The first half of the cycle is known as the follicular phase, starting at the first day of bleeding up to ovulation.  The second half of the cycle then is the luteal phase, starting just after ovulation until the first day of bleeding (Draper et al., 2018).  It is during this second phase of the menstrual cycle that many women experience either premenstrual symptoms (PMS) or PMDD.  Menstrual cycle hormones differ with PMDD as compared to those without PMDD.  According to Yen (2019), individuals with PMDD experience an early luteal phase increase in progesterone and a lower level of estrogen in the early luteal phase compared to those without PMDD.

Symptoms associated with PMDD are different than those seen in premenstrual syndrome (PMS) as well and are usually more severe (Bhatia & Bhatia, 2002).  PMDD symptoms are categorized by physical symptoms as well as psychological.  Some of the physical symptoms experienced are dizziness, palpitations, headaches, edema, carbohydrate cravings, breast pain or tenderness, and abdominal pains.  The psychological symptoms experienced with PMDD are aggression, depressive feelings, anxiety, and agitation (Verkaik, Kamperman, van Westrhenen, & Schulte, 2017).  To be diagnosed with PMDD, one must present with five out of eleven symptoms seen in the luteal phase only that are then minimized or disappear once menstruation has begun (Zamani, Neghab, & Torabian, 2012).

What causes PMDD?

The direct causes of PMDD are not yet fully understood, but there are several theories.  In a recent study, researchers saw abnormalities in prefrontal cortex functioning where gonadal hormones such as estrogen target the brain (Verkaik et al., 2017).  Additional areas of research looked into for causes relating to PMDD are hypoglycemia, hyperprolactinemia, neurotransmitter serotonin, and excess levels of aldosterone (Verkaik et al., 2017).  Additional research indicates, however, that women with PMDD experience an imbalance of estrogen to progesterone in the early and late luteal phase of the menstrual cycle, which suggests hormone levels play a part in PMDD symptoms (Atmaca, Kumru, & Tezcan, 2003).  

Is PMDD treatable?

Several treatments and remedies have been researched over the years to try and minimize the PMDD symptoms, and some work well for physical symptoms while others work better for psychological aspects of PMDD.  Researchers have looked into herbal remedies, supplements (Vitamin B6, magnesium), prescriptions (selective serotonin reuptake inhibitors) and lifestyle changes such as, regular exercise, adequate sleep, minimizing alcohol, caffeine and smoking, as well as minimizing processed sugar intake and opting for complex carbohydrates (Verkaik et al., 2017).  When Vitamin B6 (also known as pyridoxal) supplementation was compared to that of Vitex agnus castus (VAC, also known as chaste tree berry), no differences were found in one study (Zamani et al., 2012).

What is VAC and why is it so promising?

Within the area of research on herbal remedies and supplements to treat PMDD symptoms, much research has looked into VAC (Verkaik et al., 2017).  VAC is a small shrub containing berries from the Mediterranean area.  The research theory is that VAC components are able to bind to dopamine receptors in the brain as well as opioid and beta estrogen receptors (Verkaik et al., 2017).  This is because VAC naturally contains the compounds apigenin and linoleic acid that can alter how androgens are made into estrogen by binding to estrogen receptors turning on estrogen inducing genes.  Therefore, taking VAC may help increase estrogen levels in the early luteal phase of the menstrual cycle to mitigate symptoms of low levels of estrogen experienced by women with PMDD (Ahangarpour, Najimi, & Farbood, 2016). 

Ahangarpour et al. (2016) performed a 45-day study, using seventy-two female mice by administering 600mg/kg VAC to see how VAC affected their sex hormones as well as the aging changes of the uterus and resulting sex hormones.  The scientists induced aging by injecting d-galactose into the mice.  D-galactose is a sugar that when reduced can become aldehydes or hydrogen peroxide which increases oxidative stress in mice by elevating malondialdehyde while decreasing superoxide dismutase and catalase enzyme activity (Ahangarpour et al., 2016). With the injection of d-galactose, follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in mice increased and estrogen decreased.  With elevated levels of FSH and LH, reproductive signs of aging can occur as well as a thinning of the endometrium lining.  When these mice were treated with VAC, they saw decreased LH, FSH and an elevation in estrogen (Ahangarpour et al., 2016).  Although researchers could not obviously ask the mice how their PMDD symptoms changed, but results of this study contributes to the research supporting VAC in affecting estrogen production.  

Furthermore, other research studies have also indicated that VAC may reduce PMDD symptoms.  Zamani et al.’s (2012) randomized, placebo-controlled, double blind study on 134 women suffering from PMS and PMDD reported that the four symptoms (depression, anxiety, desire for sweets and water blockage/retention) were decreased with use of VAC in 85% of their study participants.  

Similar to Zamani, Schellenberg studied the use of VAC over three menstrual cycles and reported that VAC use improved 6 symptoms (headache, mood change, breast pain, nervousness, restlessness and tympani) compared to placebo (Schellenberg, 2001). 

In yet another study on VAC treatment, Chopin Lucks (2003) examined 52 women throughout a large age range (38 – 73 years old) with some being perimenopausal and others being post-menopausal.  This group of women were also followed for 3 months, using 2.5mL of VAC oil applied dermally once per day for 5-7 days per week.  The researchers noted that 33 percent of participants reported major improvements, 36 percent reported mild to moderate improvement while 23.5 percent reported worse symptoms (Chopin Lucks, 2003).  These research studies indicate that VAC supplementation can help some women of all age ranges minimize their PMDD symptoms.

What about other prescriptions?

Prescriptions have also been looked into for the treatment of PMDD symptoms to help with the depression component, specifically selective serotonin reuptake inhibitors (SSRIs).  This is because many of the reported symptoms of PMDD such as irritability, depressed mood, anger and carbohydrate cravings are thought to be controlled by the serotonergic neurotransmission (Atmaca et al., 2003).  Because PMDD symptoms are only seen in the second phase of the menstrual cycle, the luteal phase, there is the question as to whether or not SSRIs taken during the luteal phase only may work for those suffering with PMDD symptoms. 

In a study by Atmaca et al. (2003), the researchers compared 20-40mg/d of VAC to the SSRI, fluoxetine, at 20-40mg/d in an 8-week randomized, single blind, rater-blinded, prospective trial.  Both groups saw improvements.  The group taking the SSRI saw a 50 percent improvement in symptoms, specifically depression, irritability, insomnia, nervous tension, breast tenderness, and feeling out of control; whereas the VAC group saw 50 percent or more improvement in food cravings, swelling, breast tenderness, irritability, and cramps (Atmaca et al., 2003).  Although both groups saw improvement in their PMDD symptoms, it was noted that the SSRI seemed to help improve the psychological symptoms associated with PMDD, whereas VAC helped more with the physical aspects associated with PMDD (Atmaca et al., 2003). 

According to the research there are several approaches that can help minimize PMDD symptoms to some degree, which vary from Vitamin B6, magnesium, VAC to SSRI’s.   The severity of ones PMDD symptoms will determine the prescribing approach.  Depending on the SSRI prescribed, there can also be several side effects such as nausea, headache, anxiety, insomnia, sexual dysfunction, weight gain, anorexia or intestinal bleeding (Verkaik et al., 2017).  Because of these side effects, the use of SSRI’s is suggested for more moderate to severe symptoms of PMDD where daily life activities are greatly affected by PMDD symptoms. 

Finally, the gonadotropin releasing hormone (GnRH) has been looked into as a treatment option for symptoms of PMDD, but as it has a negative impact on bone density, it is only suggested as a last resort (Verkaik et al., 2017).

So, what did we learn?

In conclusion, with so many varying symptoms and levels of severity resulting in the diagnosis of PMDD, more research needs to be done on those with PMDD to identify the cause and, in turn, find a solution.  Studying and identifying more specifically the differences between the levels of severity of PMDD could also inform how and with what the individual is treated. 

In addition, one limitation of the majority of the research was that studies only looked at one month of a menstrual cycle at a minimum and no more than 2 – 3 menstrual cycle experiences (Atmaca et al., 2003; Schellenberg, 2001).  Longer studies over more menstrual cycles may accurately track changes and monitor improvements in order to provide even more reliable results and treatment options for those struggling with PMDD.  

PMDD affects 8% of all women (Cerqueira, Frey, Leclerc, & Brietzke, 2017), and because it is a more severe form of PMS, it affects an individual’s daily life functioning several days out of every month, which is quite impactful.  If physical pain and/or psychological aspects can be improved for those affected by PMDD whether that is by proven research supporting VAC, SSRI, Vitamin B6, magnesium or Gonadotropin releasing hormone use they can improve their quality of life.

Because of the side effects experienced with SSRIs and GnRH and insufficient research on Vitamin B6, many if not most women affected by PMDD still suffer from symptoms that impact their daily functioning and quality of life. Future research on treating symptoms with VAC, for example, could look at larger sample sizes, follow more than 3 menstrual cycles, and use human studies, instead of mice, to determine the most successful dose and treatments for women.

References

1. Ahangarpour, A., Najimi, S. A., & Farbood, Y. (2016). Effects of Vitex agnus-castus fruit on sex hormones and antioxidant indices in a d-galactose-induced aging female mouse model. Journal of the Chinese Medical Association, 79(11), 589–596. https://doi.org/10.1016/j.jcma.2016.05.006
2. Atmaca, M., Kumru, S., & Tezcan, E. (2003). Fluoxetine versus Vitex agnus castus extract in the treatment of premenstrual dysphoric disorder. Human Psychopharmacology: Clinical and Experimental, 18(3), 191–195. https://doi.org/10.1002/hup.470
3. Bhatia, S. C., & Bhatia, S. K. (2002). Diagnosis and treatment of Premenstrual Dysphoric Disorder. American Family Physician, 66(7), 1239–1248. Retrieved from https://www-ncbi-nlm-nih-gov.bigbrother.logan.edu:2443/pubmed/12387436
4. Cerqueira, R. O., Frey, B. N., Leclerc, E., & Brietzke, E. (2017). Vitex agnus castus for premenstrual syndrome and Premenstrual Dysphoric Disorder: A systematic review. Archives of Women’s Mental Health, 20(6), 713–719. https://doi.org/10.1007/s00737-017-0791-0
5. Chopin Lucks, B. (2003). Vitex agnus castus essential oil and menopausal balance: A research update [Complementary Therapies in Nursing and Midwifery 8 (2003) 148–154]. Complementary Therapies in Nursing and Midwifery, 9(3), 157–160. https://doi.org/10.1016/s1353-6117(03)00020-9
6. Draper, C. F., Duisters, K., Weger, B., Chakrabarti, A., Harms, A. C., Brennan, L., … van der Greef, J. (2018). Menstrual cycle rhythmicity: Metabolic patterns in healthy women. Scientific Reports, 8(1). https://doi.org/10.1038/s41598-018-32647-0
7. Schellenberg, R. (2001). Treatment for the premenstrual syndrome with agnus castus fruit extract: Prospective, randomised, placebo controlled study. BMJ, 322(7279), 134–137. https://doi.org/10.1136/bmj.322.7279.134
8. Verkaik, S., Kamperman, A. M., van Westrhenen, R., & Schulte, P. F. J. (2017). The treatment of premenstrual syndrome with preparations of Vitex agnus castus: A systematic review and meta-analysis. American Journal of Obstetrics and Gynecology, 217(2), 150–166. https://doi.org/10.1016/j.ajog.2017.02.028
9. Yen, Lin, Lin, Liu, Long, & Ko. (2019). Early- and late-luteal-phase estrogen and progesterone levels of women with Premenstrual Dysphoric Disorder. International Journal of Environmental Research and Public Health, 16(22), 4352. https://doi.org/10.3390/ijerph16224352
10. Zamani, M., Neghab, N., & Torabian, S. (2012). Therapeutic Effect of Vitex Agnus Castus in patients with premenstrual syndrome. Acta Medica Iranica, 50(2), 101–106. Retrieved from http://acta.tums.ac.ir/index.php/acta/article/view/3866