The Uncertain Etiology of PMS and a Link to Infectious Disease

Student guest post by Anne Dressler

Ninety percent of menstruating women experience some kind of premenstrual symptoms during the luteal phase of the menstrual cycle, with 20-30% experiencing moderate to severe symptoms. With an even more severe collection of symptoms, is premenstrual dysphoric disorder (PMDD). 3-8% of menstruating women report symptoms severe enough to be considered suffering from PMDD. Yet another designation, premenstrual magnification (PMM), is used to describe women who are symptomatic the entire cycle but have a premenstrual exacerbation of a diagnosed psychiatric, medical, or gynecological condition.

With a large number of wide-ranging symptoms and the difficulty involved in making a diagnosis, it is not surprising that the various theories advanced to explain premenstrual syndrome (PMS) have yet to been proven. One problem is that PMS is a diagnosis of exclusion, meaning there could be a variety of poorly understood conditions responsible for these symptoms. Several theories attribute PMS to fluctuations in sex hormones and neurotransmitters. The observation that symptoms disappear when a women has a menstrual cycle during which she does not ovulate and a corpus luteum is not formed, led to the theory that sex steroids, estrogen and progesterone, produced by the corpus luteum are responsible. In addition, the neurotransmitters serotonin and gamma amino butyric acid (GABA) have been implicated in various pathways. The list of other hormones and their modes of action that are suspected to be involved is long and confusing, making it no wonder that there is still no known etiology.

One distinctly different hypothesis is that PMS is due to a broad set of persistent infectious illnesses that are exacerbated by cyclic changes in immunosuppression due to the fluctuating levels of progesterone and estrogen. In general, there have been studies looking at two major categories of causation- genetic and environmental and have found moderate correlations at the best. Infectious causation has been overlooked for the most part, with almost no empirical support in published literature. I don't think this means there is no value to the theory, simply that it is a very hard one to test. One very convincing article by Doyle et. al explains how this possibility of infectious causation is integrated with the cyclic changes in hormone levels that have been observed and are generally thought to be involved in PMS.

As the article explains, immune function varies across the menstrual cycle. During the luteal phase, cell-mediated immunity is suppressed and humoral immunity is amplified. This appears to be related to higher levels of progesterone that enhances humoral immunity by promoting the development of type 2 helper T cells. In addition, progesterone is involved in suppressing type 1 helper T cells, which is associated with inhibition of natural killer cells and phagocytosis. This leads to less effective control of various fungi, viruses, and intracellular bacteria. Estrogen also seems to suppress cell-mediated immunity. These hormone driven changes to the immune system provide the possibility that persistent infections may be less well controlled during the luteal phase, leading to the symptoms that make up PMS.

Supporting evidence for this theory is a long list of infections, compiled by Doyle et. al, that are normally controlled by cell-mediated immunity but are exacerbated premenstrually. These include, increased proliferation of Candida albicans, increased proliferation of cytomegalovirus in the cervix, increased number of lesions from human herpes simplex virus-1, and exacerbated peptic ulcers from Helicobacter pylori among others. There are also chronic diseases that have infectious causes or are suspected to have infectious causes that are exacerbated premenstrually. A few examples are, Crohn's disease, lupus, multiple sclerosis, rheumatoid arthritis, asthma, and chronic fatigue syndrome. The pathogens that are suspected causes for these diseases are also controlled by cellular immunity.

Finally, one group performed a double blind, randomized clinical trial to determine the effects of the antibiotic doxycycline on PMS. Compared to the placebo group, individuals taking the antibiotic had significantly decreased symptoms. Subsequently, the placebo group was also given the antibiotic and experienced similar symptom reduction. This reduction in symptoms was steady during a six-month follow-up period. The investigators also found a high percentage of endometrial biopsy cultures positive for Mycoplasma species, Chlamydia trachomatis, and anaerobic bacteria.

This theory seems to be strongly biologically plausible, but lacks any of the other criteria for causality due to the lack of published studies on the topic. It is not in disagreement with the currently accepted idea that sex hormones fluctuate during the menstrual cycle and are involved in symptom manifestation. However, Doyle et. al advance this idea by explaining how it is may not be the direct effects of the hormones, rather a hormone-driven suppression of cellular immunity that could lead to poor control of persistent infections causing symptoms. This is certainly an interesting theory, yet one that would be difficult to study. Practical applications of findings from studies on this subject could be to consider control of PMS symptoms with antibiotics.

References:

Backstrom, T., et al. The Role of Hormones and Hormonal Treatments in Premenstrual Syndrome." CNS drugs 17.5 (2003): 325-42.

Doyle, C., H. A. Ewald, and P. W. Ewald. "Premenstrual Syndrome: An Evolutionary Perspective on its Causes and Treatment." Perspectives in biology and medicine 50.2 (2007): 181-202.

Korzekwa, M. I., and M. Steiner. "Premenstrual Syndromes." Clinical obstetrics and gynecology 40.3 (1997): 564-76.

Pinkerton, J. V., C. J. Guico-Pabia, and H. S. Taylor. "Menstrual Cycle-Related Exacerbation of Disease." American Journal of Obstetrics and Gynecology 202.3 (2010): 221-31.

Silberstein, S. D., and G. R. Merriam. "Physiology of the Menstrual Cycle." Cephalalgia : an international journal of headache 20.3 (2000): 148-54.

Toth, A., et al. "Effect of Doxycycline on Pre-Menstrual Syndrome: A Double-Blind Randomized Clinical Trial." The Journal of international medical research 16.4 (1988): 270-9.