Uncovering the Possible Causes and Genetics of PMDD

black woman hugging her knees
JGI/Jamie Grill / Getty Images

Most women will experience some unpleasant symptoms in the days before their period. These symptoms might include mild mood changes or just feeling a little off.

But, if you suffer from severe mood changes that always occur in the 7 to 14 days before your period and then completely go away during the first few days of bleeding chances are you have premenstrual dysphoric disorder (PMDD)

PMDD Is a Mood Disorder

A mood disorder is thought to be the result of disturbances that alter your brain's neurochemistry and communication circuits. We may not completely understand how your mood is controlled, but we do know that the control of your mood is in your brain. Research has shown that your mood is the result of complex interactions between brain structures, brain circuits, and your brain chemicals or neurotransmitters.

What triggers the brain changes that lead to a mood disorder is an area of active investigation. The results of current studies suggest several possible causes of mood disorders, including:

  • Genetic causes
  • Stress
  • Medication
  • Chronic medical conditions

If you are suffering from PMDD, the cause of your mood disorder has an added layer of complexity: your reproductive hormones.

What We Know About the Cause of PMDD

Your reproductive hormones, namely estrogen, and progesterone, interact with your brain chemicals and can influence certain functions in your brain, including your mood. Estrogen and progesterone are produced by your ovaries and the levels of these hormones fluctuate during a regular menstrual cycle.

These are normal hormonal changes that all women experience, but not all women suffer from PMDD. So, something different is going on in the 3 to 8 percent of women who have PMDD.

If you have PMDD you do not have a hormonal imbalance or deficiency. Instead, it is thought that you may be more sensitive to the normal hormone changes of your menstrual cycle.

What we don't yet fully understand is what causes that sensitivity.


The major diagnostic criteria for PMDD is that your symptoms are limited to the luteal phase of your menstrual cycle. The luteal phase is the time between ovulation and the first day of your period. In a regular 28 day menstrual cycle this corresponds to cycle days 14 to 28.

At ovulation, your ovaries begin to increase their production of progesterone. Progesterone is then converted into another hormone called allopregnanolone (ALLO). Progesterone and ALLO levels continue to rise until you start your period, at which point they rapidly drop. One thought is that if you have PMDD you are more sensitive to this progesterone withdrawal.

Another thought is that ALLO is more responsible for your symptoms because it interacts with the GABA receptors in your brain. GABA is a normal brain chemical or neurotransmitter that, when bound to its receptors in your brain, controls agitation and anxiety. In fact, the reason why alcohol and benzodiazepines are anxiolytic and sedating is that they bind to the GABA receptors in your brain and act like your brain's own GABA. Normally, ALLO works in your brain just like alcohol and benzodiazepines.

But in women with PMDD it is thought that something is different with the normal function of ALLO. One possibility is that there is a change in the GABA receptor sensitivity to ALLO in the luteal phase. Or, perhaps there is a defect in the luteal phase production of ALLO. This dysfunction of ALLO could cause the increased anxiety, irritability, and agitation of PMDD.


Again, when trying to uncover the possible causes of PMDD, it is important to remember that PMDD only occurs during the luteal phase of your menstrual cycle. After ovulation, when progesterone levels rise, your estrogen levels fall. This rapid decrease in your estrogen level is another possible cause of PMDD.

We know that estrogen interacts with several brain chemicals that control your mood. One of these brain chemicals is called serotonin. Serotonin plays a powerful role in your body by maintaining your sense of well-being. Serotonin is involved in regulating many functions, including your mood, sleep, and appetite. Serotonin also influences your cognition, or how you acquire, process, and perceive information from your environment.

Estrogen promotes the positive effects of serotonin. It is thought that if you have PMDD, your serotonin system may be more sensitive to the normal decrease in estrogen during the luteal phase of your cycle. In other words, if you have PMDD the normal drop in estrogen during the luteal phase of your menstrual cycle can result in an exaggerated drop in the serotonin levels in your brain. Low serotonin levels are associated with the depressed mood, food cravings, and impaired cognitive functioning of PMDD. This finding supports the use of the selective serotonin receptor inhibitors (SSRIs) to treat PMDD.


If you have PMDD it is possible that you have a personal history of childhood physical, emotional, or sexual abuse. Some, but not all, women with PMDD have a history of significant stress exposure.

Researchers are looking at how this history of stress can lead to PMDD. One pathway that looks promising is the relationship between your stress response and ALLO. Normally, ALLO increases at times of acute stress, exerting its normal calming and sedative effect. Experimental studies have shown that the ALLO response to acute stress is decreased when exposed to chronic stress.

Understanding how stress may lead to or worsen the symptoms of PMDD is currently an area of active investigation. Certainly, the possibility of a connection between your stress response and PMDD supports the common sense first line treatment interventions for PMDD, including lifestyle modifications and stress reduction.

Immune Activation/Inflammation

There is a well-established relationship between depression and the functioning of your immune system. Although PMDD is a different diagnosis than major depressive disorder (MDD), there may be some role that your immune response may contribute to PMDD.

Because of the normal changes in immune and inflammatory response factors during a normal menstrual cycle, women with certain inflammatory conditions like gingivitis and inflammatory bowel disease may see a worsening of their symptoms in the luteal phase.

Early research in this area suggests that women with more significant premenstrual symptoms may have an increased inflammatory response in the luteal phase compared to women with minimal symptoms.


Mood disorders are known to run in families. Your susceptibility to developing a mood disorder in your lifetime is inherited from your parents through your genes. Just like physical traits like height and eye color are inherited, so are certain disease susceptibilities, including cancer and depression. Until recently, no such genetic basis for PMDD had been established.

Women with PMDD are more sensitive to the normal hormone changes in the luteal phase of their menstrual cycle. NIH researchers searched for the reason why. What they discovered is that women with PMDD have changes in one of the gene complexes that control how they respond to estrogen and progesterone. In other words, there is a genetic basis for the hormonal sensitivities seen in women with PMDD.

This discovery is extremely validating if you have PMDD. It gives concrete scientific evidence that something biological and beyond your control is causing your mood changes. It confirms that PMDD is not just a behavioral choice.

But these findings are not the whole story. The success of this research does, however, encourage further studies and opens the door to finding new treatment options for PMDD.

A Word From Verywell

Likely, there are multiple factors that influence the development of PMDD, but one thing that's certain is that PMDD is a real condition and not just something that's your doing or that you can wish away. Perhaps more than one pathway exists between your cyclic hormone changes and PMDD.

The possibility that there are variable causes of PMDD could help explain why some treatments work well for you but not for others, and vice versa. It is important to keep this in mind as you and your doctor are exploring the various treatment options to help you live very well with PMDD.

View Article Sources
  • Hantsoo L.& Epperson C.N. (2015) Premenstrual Dysphoric Disorder: Epidemiology and Treatment. Curr Psychiatry Rep.,17(11)87. doi:10.1007/s1920-015-0628-3
  • Dubey N, Hoffman JF, Schuebel K, Yuan Q, Martinez PE, Nieman LK, Rubinow DR, Schmidt PJ, Goldman D. The ESC/E(Z) complex, an intrinsic cellular molecular pathway differentially responsive to ovarian steroids in Premenstrual Dysphoric Disorder, Molecular Psychiatry, January 3, 2016, doi:10.1038/mp.2016.229.