PMS, Genetics, and Solutions

A lot of women know the moodiness and brain fog that comes with premenstrual syndrome (PMS).  It can range from simply feeling irritable and icky to being something that really interferes with our lives.

What role do genes play in PMS?  It has been shown in the past few years that there is a genetic component, especially for a severe form of PMS called premenstrual dysphoric disorder (PMDD). PMS is thought to affect about 30-40% of women, while PMDD is rarer and affects only 3-8%.[ref] One 2011 study of twins estimated that heritability of PMS was around 95%.[ref]

Neurotransmitters cause some of the symptoms of PMS and PMDD. Serotonin is an important neurotransmitter involved in mood stability. Estrogen is a serotonin agonist, and fluctuations in estrogen levels also affect serotonin levels. GABA, another neurotransmitter, is also involved in PMS symptoms for some.

Genes involved in PMS and PMDD

HTR1A Serotonin Receptor Gene:
The HTR1A gene codes for a serotonin receptor. rs6295 is a fairly common genetic variant of the serotonin receptor gene. One study found that the variant (C/C for 23andMe) reduces serotonin neurotransmission and is “associated with impaired WM [working memory] in the premenstrual phase and premenstrual decline of cognitive function.”

Check your 23andMe results for rs6295 (plus orientation, v4, v5):

  • G/G : normal/ wildtype
  • C/G: increased risk of PMDD
  • C/C: Impaired working memory in premenstrual phase[ref] increased risk of PMDD[ref]

Note that on for rs6295, studies will usually use the minus orientation.  So to switch to the 23andMe (plus) orientation, you will need to mentally switch the C and G when reading the studies.

ESR1 Estrogen Receptor 1 gene:
ESR1 mediates estrogen activity in the brain and has been studied as a risk for diseases such as breast cancer, osteoporosis, and endometriosis as well as severe PMS. ESR1 has also been studied in relation to cognitive impairment and Alzheimer’s Disease.[ref]  (There are lots and lots of studies on this gene – worth looking into if you are homozygous for the variant.)

Check your 23andMe results for rs9340799 (v4, v5):

  • G/G : 8x higher risk for severe PMS [ref][ref]
  • A/G:   normal risk of PMS
  • A/A: normal risk of PMS

One study showed that the ESR1 polymorphisms are most associated with PMDD for those with a COMT (catechol-o-methyl transferase) polymorphism.  [ref] Also known as COMT Val158Met (rs4680), this is a well-studied polymorphism that is involved in dopamine activity.

Check your 23andMe results for COMT rs4680 (v4, v5):

  • G/G: higher risk of PMDD (combined with ESR1 polymorphism) [ref]
  • A/G: normal risk of PMS
  • A/A: normal risk of PMS


While genes seem to play a bigger role in PMDD, for most of us, we may need to look further for solutions to  PMS woes.

Histamine intolerance is tied to PMS, especially for menstrual cramps.  You can read up on the genes involved in histamine intolerance here and here – as well as Googling histamine intolerance.  If the symptoms of histamine intolerance seem to fit you, a diet lower in histamines may help your PMS.  Foods that are high in histamines (avoid for low histamine diet) include anything fermented (soy sauce, vinegar, wine, kombucha), lunch meats, tomatoes, oranges, strawberries, chocolate, and fish that is not completely fresh.

GABA is a neurotransmitter that has been found to be low in some women with PMDD and PMS.  This may be due to low levels of allopregnanolone, a metabolite of the hormone progesterone, which modulates GABA.[ref]  Nutrients that increase GABA levels include theanine (found in tea), magnesium, chamomile, potassium, and glycine (found in gelatin). [ref]  When you think about it, the age-old remedy of chicken soup (made with homemade chicken stock) and a cup of hot tea may be just the thing for raising your GABA levels.   Follow this with a nice soak in the bathtub with some Epsom salt to raise your magnesium levels… Sounds like a good plan to me.

Zinc sulfate supplementation (50mg) was found in a study to decrease the symptoms of PMS.[ref]

Vitex agnus castus (Chasteberry) has been shown in quite a few studies to help with premenstrual syndrome. [ref]  About half of the women who tried it in one study had a positive response. If you want to give it a try, here is an inexpensive organic option on Amazon, or you can also probably find Chasteberry at your local health food store.

Vitamin B6 has been studied in placebo-controlled studies and was found to help decrease PMS symptoms.[ref]  The active form of vitamin B6 is pyridoxal-5-phosphate (P5P) and can be found in better quality supplements. Interestingly, P5P is a co-factor for diamine oxidase, which is the enzyme that breaks down histamine.  P5P is also involved in many, many other enzymatic reactions.  Food sources of vitamin B6 include raw meat, cheese, and milk as well as beef liver, sunflower seeds, and pistachios.  Here is a great article on B6 helping with PMS:

A study of teenage girls with very low vitamin D levels (<10ng/mL) found that supplementing with vitamin D helped their PMS irritability and anxiety.[ref] Other studies show varying results, but if you are deficient in vitamin D, a supplement or getting more sunshine may help.

What doesn’t seem to work? 
Antioxidants – specifically vitamins A, E, and C – were studied and found to have no effect on PMS symptoms.[ref]

Shockingly (not!), a study found that women with PMDD tend to eat more right before their period. [ref]

Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between scientific research and the lay person's ability to utilize that information. To contact Debbie, visit the contact page.

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