PMDD: Genetic clues may lead to improved treatment

 

“This is a big moment for women’s health,” says researcher Dr. David Goldman, of the NIH’s National Institute on Alcohol Abuse and Alcoholism. Goldman and his colleagues discovered a gene complex in women with premenstrual dysphoric disorder (PMDD). In their research, this gene complex was associated with a genetically disordered cellular response after being exposed to estrogen and progestin. Goldman hopes that what they learn about the genetic response could one day lead to improved, targeted treatment for PMDD and related disorders.

Nearly every woman with menstrual cycles has experienced premenstrual symptoms of PMS (premenstrual syndrome), but some suffer more extreme symptoms of PMDD. Early  research investigating premenstrual symptoms in twins suggested that PMS has a heritability of 30% to 80%.[1]^,[2]  This research was performed prior to PMDD being designated as a separate DSM category. Between 2% to 5% endure the extreme anxiety or depression of PMDD.

In a 2007 preliminary study, researchers identified a variant in a gene that affects how estrogen and dopamine are metabolized in PMDD sufferers.[3] The gene variant was not present in controls. Building on that discovery, Goldman and colleagues more carefully examined how the genes expressed themselves differently in women with PMDD compared with women without PMDD. They began by conducting a case-control study of women: 34 reported having PMDD and 33 reported no similar symptoms. First the researchers administered hormone blockers to determine the effect on the women’s moods. This confirmed the diagnoses: women who said they suffered PMDD reported a marked improvement in their symptoms, while the controls reported no change.

In the next phase of the study, the researchers drew blood and tested the white blood cells to make sure the WBCs expressed sex receptor genes. Then they sequenced the mRNA from the white blood cells. Compared with the cells from women without PMDD,  the cells from women with PMDD had more genes switched on. Then the researchers exposed all the women to estrogen and progestin. With the women having been exposed to the hormones for 24 hours, the researchers drew more blood from the women and sequenced the mRNA from the white blood cells. What the researchers found were differences in the intrinsic cellular response to exposure to estrogen and progesterone, with the ‘on’ genes in women with PMDD turning ‘off, and vice versa in women without PMDD. These differences occurred in the ESC/E(Z) gene complex (an ovarian steroid-regulated gene silencing complex, explain Goldman, et al.).

According to Goldman, it is apparent that women with PMDD have an intrinsic difference in their response to sex hormones—not just emotional behaviors they should be able to voluntarily control. They are not simply having a “bad day.” With these findings, researchers now have information about what takes place on a cellular level when women are exposed to estrogen and progesterone. It appears that there is a clear physiologic trigger for PMDD, which may offer a target for treating the disorder more directly. Antidepressants and hormone treatments can help some women, but not all women can take these treatments. These treatments can have side effects, too. And they can be contraindicated for women with certain conditions or who are trying to get pregnant.

The next step will be to take a deeper look into the genes’ role in the brain, using cutting-edge methods called ‘disease-in-a-dish’ technology. In this new technology, neural stem cells and precursor cells are generated from cells sampled from a patient and grown in a petri dish. The researchers believe that ESC/E(Z) gene complex may be relevant to other reproductive endocrine-related disorders, including postpartum depression. Improved understanding can lead to improved treatment.

[1] Treloar, SA, Heath AC, and Martin NG. Genetic and environ- mental influences on premenstrual symptoms in an Australian twin sample. Psychological Medicine 2002;32:25–38.

[2] Kendler, KS, Karkowski LM, Corey,LA, and Neale MC. Longitudinal population-based twin study of retrospectively reported pre-menstrual symptoms and lifetime major depression. American Journal of Psychiatry 1998;155:1234–1240.

[3] Huo L, Straaub RE, Schmidt PJ, et al. Risk for premenstrual dysphoric disorder is associated with genetic variation in ESR1, the estrogen receptor alpha gene. Bio Psych 2007;62:935-33.