Cycle science: Genetic evidence for PMDD

By Maegan Boutot, Science Writer for Clue

People experience positive and negative changes over the course of their menstrual cycle. Physical, mental and emotional changes are caused by the natural fluctuations of hormones during the cycle, particularly estrogen (estradiol) and progesterone. These hormones are at high levels during the second half of the menstrual cycle, known as the luteal phase (1–3).

People with severe premenstrual symptoms (symptoms that interfere with daily life) may be diagnosed with premenstrual dysphoric disorder (PMDD) (1–3). PMDD differs from other psychiatric conditions, such as generalized anxiety disorder, in that symptoms are linked directly to the fluctuations of reproductive hormones, and a diagnosis usually requires that people experience these symptoms predominantly during the late luteal phase (1–3). Treatment options for PMDD are limited to drugs that either change hormone release, such as ovulation inhibitors, or treat symptoms, such as antidepressants (2,3). In a broad sense, PMDD is associated with a sensitivity to reproductive hormones, but why this sensitivity exists and whether it is the root cause of PMDD is not understood (2,3).

In January 2017, the journal Nature published the article The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. In this study, researchers investigated how the cells of participants with PMDD and without PMDD (i.e. control participants) responded to estradiol and progesterone exposure (4).

In short, these researchers found the cells of participants with PMDD reacted differently than those of control participants when exposed to estradiol and progesterone (4). This is exciting, as it supports the idea that PMDD is linked to observable genetic behavior within cells.

In more detail, the researchers tested whether the amount of mRNA and the amount of protein expression were different in diagnosed participants as compared to controls. mRNA is a molecule that is used to carry information from your DNA in the nucleus to other parts of the cell in order to make proteins. Researchers can learn which genes are being read from DNA by studying mRNA. Sometimes, when a gene is being read in high amounts, this can mean there is a high amount of protein expression. Sometimes, the opposite happens, and low amounts of protein expression can occur despite genes being read (4).

In this study, researchers mapped about 13,000 genes per group of participants. They found cells exposed to estradiol had over 1,300 differentially expressed genes and those exposed to progesterone had 643 differentially expressed genes (4, Supplemental figures).

Researchers were particularly interested in a group of 13 genes (i.e. gene complex) called extra sex combs and Enhancer of zeste (ESC/E(Z)). The ESC/E(Z) is important because it is associated with the important brain regions related to mood, the neurotransmitters gamma-Aminobutyric acid (GABA) and serotonin, sleep, mood regulation and stress (4).

Here, researchers found levels of mRNA for ESC/E(Z) genes were significantly higher for between 2 and 4 genes. The majority of genes had non-significantly higher rates of expression in participants with PMDD than in controls (4). Although one would expect that these high levels of mRNA would mean that participants with PMDD would have higher levels of protein, the opposite happened, and there were fewer proteins created from these genes (4).

Additionally, gene expression some ESC/E(Z) genes differed in cells from participants with PMDD and control participants when exposed to progesterone and estradiol (4). Control participant cells experienced a significant increase in the expression of 3 ESC/E(Z) genes when exposed to progesterone, whereas expression of these 3 genes in cells of participants with PMDD did not change significantly under the same conditions. When participants’ cells were exposed to estradiol, expression of one ESC/E(Z) gene decreased significantly in the cells from PMDD participants but increased non-significantly in cells of control participants (4). Other differences between levels of gene expression differed regardless of stimulation to reproductive hormones (4).

The researchers also performed an analysis called pathway analysis. Pathway analysis helps identify groups of genes related to a biological process or event, such as a disease (5). Using pathway analysis, researches in this study found that the processes of ESC/E(Z) genes are highly linked with those of estradiol and progesterone. The specific ESC/E(Z) gene HDAC2 was identified as particularly important, in that it is connected to both reproductive hormones and the majority if ESC/E(Z) genes. More research is needed to see if malfunction of HDAC2 is directly associated with the causal mechanisms of PMDD, as it might be a major link between PMDD symptoms and reproductive hormones (4).

Although the results from this study are exciting, they are not definitive and more studies are needed to confirm these findings. One major issue with the study design was the type of cells used by the research team are not the type found in the brain (4). The sample size was also small, and many experiments were run on the same cells, so it is possible that the findings are statistical accidents (4).

Other reasons to perform future analysis would be to see if the changes that exist between participants with PMDD and controls cause PMDD, or are caused by PMDD. Also, it would be interesting to see how other variables, such as smoking or diet, affect this relationship, particularly given how stress and inflammation are linked to PMDD (2–4).

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References

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th edn. American Psychiatric Association: Arlington, VA, USA, 2013.
  2. Ryu A, Kim TH. Premenstrual syndrome: A mini review. Maturitas. 2015 Dec 31;82(4):436–40.
  3. Hantsoo L, Epperson CN. Premenstrual dysphoric disorder: epidemiology and treatment. Current Psychiatry Reports. 2015 Nov 1;17(11):87.
  4. Dubey N, Hoffman JF, Schuebel K, Yuan Q, Martinez PE, Nieman LK, Rubinow DR, Schmidt PJ, Goldman D. The ESC/E (Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Molecular Psychiatry. 2017 Jan 3.
  5. Khatri P, Sirota M, Butte AJ. Ten years of pathway analysis: current approaches and outstanding challenges. PLoS Comput Biol. 2012 Feb 23;8(2):e1002375.
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