Epigenetics & Menstrual Cycles
How a mysterious premenstrual disorder could advance epigenetic research
Epigenetics is a fascinating, emerging field of scientific research that opens the door for rapid advancements in healthcare. Epigenetics —the study of how our genes are turned on or off based on environmental factors— has much to offer science and medicine.
The study of epigenetics offers an eloquent explanation for the difference between genes handed down from our ancestors and the genes in use— or expressed—at any given time. We know that just because we have a gene that puts us at risk for a health condition doesn’t mean we will develop the condition.
Epigenetics seeks to explain the underlying biological mechanisms to account for this flexibility in gene expression. What was once thought of as genetic fate is challenged by the idea that gene expression can change rapidly based on environmental factors.
epi from Ancient Greek meaning on top of, over or around
Coined in 1942 by C. H. Waddington, epigenetics was used as a conceptual model to describe how genetic material may interact with its surroundings to create what’s known as a phenotype.
The phenotype, put simply, is DNA turned on. While we have tens of thousands of genes available, the phenotype determines which genes are turned on, or expressed. Sometimes described as software, the phenotype—unlike the underlying genotype— is flexible and can change rapidly based on one’s environment.
Environment in this context means literally everything. Foods, smells, hormones, physical environment, other people’s vibes etc. Any input or data from the internal or external environment may affect which genes are expressed.
phenotype from Ancient Greek to appear, show, shine
It’s common knowledge that lifestyle plays a major role in health and well-being, but the biological mechanism that underlies it wasn’t always well understood. Epigenetics offers an attractive model of genes + environment = health. Simple, yet intuitive, and backed by recent scientific research.
With applications in just about every area of healthcare, epigenetics is an important field of research, particularly with hard to treat conditions that have been shown to have a genetic component like Parkinson’s, ALS, various types of cancer, schizophrenia, post traumatic stress disorder, major depression and premenstrual dysphoric disorder.
Research on premenstrual dysphoric disorder, or PMDD, may help researchers learn more about how epigenetics processes manifest into observable disease or disorder.
Why is a premenstrual disorder important for epigenetic research?
Premenstrual Dysphoric Disorder, or PMDD affects an estimated 5-8% of reproductive aged females and is a chronic condition categorized by severe and debilitating mood symptoms in the one to two weeks before the period starts, also known as the luteal phase of the menstrual cycle.
PMDD symptoms are wide ranging and include a variety of psychological, cognitive and physiological symptoms. Women with PMDD may experience severe depression, suicidal ideation, paranoia, disabling anxiety, dissociation, body dysmorphia, anger, rage, self-isolation, interpersonal relationship problems, memory issues, brain fog, painful periods, acne, headaches and muscle spasms.
In 2017, the National Institute of Health demonstrated that gene expression in a large gene complex differed between PMDD patients and controls. This ESC/E(Z) gene complex is responsible for epigenetic processes related to sex hormones and stressors.
“Notably, this ESC/E(Z) gene complex regulates epigenetic mechanisms that govern the transcription of genes into proteins in response to the environment — including sex hormones and stressors.” - NIH, 2017
The study demonstrates a biologically based, behavioral abnormality to normal levels of ovarian hormones. For most women, the menstrual cycle doesn’t trigger extreme, debilitating mood swings, but in a small percentage of the population—the PMDD phenotype—normal levels of ovarian sex hormones wreaks havoc on quality of life.
“In women with PMDD, experimentally turning off estrogen and progesterone eliminated PMDD symptoms, while experimentally adding back the hormones triggered the re-emergence of symptoms. This confirmed that they had a biologically-based behavioral sensitivity to the hormones that might be reflected in molecular differences detectable in their cells.” NIH, 2017
The cause for this abnormal sensitivity is unknown. However, there are clues from other studies that may help researchers formulate a testable hypothesis. Research suggests that women with PMDD have a history of trauma, much like other mood disorders including PTSD, major depression and generalized anxiety.
Unlike other mood disorders PMDD is categorized by symptoms that present only during the luteal phase of the menstrual cycle and disappear within a few days of the period starting.
Sometimes classified as an endocrine disorder, PMDD patients are often referred to gynecologists for treatment. First line treatments include birth control and SSRIs and the only medically recognized cure is turning off the reproductive cycle completely via surgical or chemical menopause. None of these treatment options account for a history of trauma or the difference in gene expression demonstrated in the 2017 NIH study.
Why would some women develop an abnormal, behavioral response to ovarian hormones?
In a 2018 study performed by the National Institute of Health, research suggests a link between generational trauma and debilitating mood disorders like PTSD and depression. PMDD is almost never included in these types of studies, despite the potential for PMDD to shed light on biologically based mood disturbances.
Generational trauma has been shown to be passed down to offspring through what’s known as inherited phenotypes. This idea opens a whole new can of worms, because it begs the question of whether or not the PMDD phenotype can be reinforced or outright inherited from previous generations that experienced trauma during the luteal phase of the menstrual cycle.
In this context, it’s plausible that PMDD is the result of a defense mechanism or a trauma response directly correlated to the hormones released during this phase of the cycle.
In mice studies, researchers found that fearful memories of traumatic experiences were passed down to two generations of offspring. In the study, mice were negatively conditioned to a particular smell by receiving an electric shock when the smell was introduced to their environment. Over time, the mice developed an association between the electric shock and the smell and reacted negatively to the smell even without the electric shock.
The offspring of those mice exhibited fearful behaviors towards the smell even though they had never been exposed to it during their lifetimes and had never met their parents. What’s even more bizarre is that the offspring of those mice exhibited the same behavior toward the smell without ever being exposed to it, suggesting that phenotypes may be passed down to at least two generations.
“And why, evolutionarily, would a parent pass down such specific information? “So that when the offspring, or descending generations, encounter that environment later in life, they’ll know how to behave appropriately.” — Brian Dias, Postdoctoral Fellow
PMDD offers a clear biological trigger—hormones—that produce mood disturbances.
An epigenetic tag, or map, is an input from the environment that triggers the expression of genes. These epigenetic imprints—or programs— are responsible for both negative and positive aspects of how we respond to our environments. These tags can be helpful in many ways when associated to positive experiences, but maladaptive programs can persist even when the threat from the environment is no longer relevant in one’s life.
With PMDD, it’s plausible that ovarian sex hormones are an epigenetic tag, rather than the root cause. Just like fireworks that trigger a veteran with PTSD, the fireworks evoke the trauma response because of the sound, but the fireworks didn’t cause the PTSD.
PMDD has been shown to progress with age, worsening over time. Every month when the hormones are released, women with PMDD are flooded with epigenetic inputs that may be negatively conditioned to traumatic experiences passed down from previous generations. In this way, the phenotype is being reinforced on a monthly basis when the woman experiences life disrupting symptoms associated to the hormones.
For some women with PMDD—including myself—healing from past traumas is the preferred treatment option. What was once believed to be a strictly emotional aspect of health and well-being is slowly emerging as a scientifically backed, biological process that underlies how and why genes are expressed.
As the field of epigenetic research continues to advance, I’m optimistic that PMDD will be included in future research. PMDD is unique in mental health. It offers a clear biological indicator that triggers behavioral symptoms and is directly linked to a gene complex that regulates epigenetic processes.
Including PMDD in future epigenetic research is a no brainer and in that process, I believe we will learn more about other disorders that may be linked to maladaptive, epigenetic programming.
“DNA neither cares nor knows. DNA just is. And we dance to its music.” - Richard Dawkins
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