chemical formula of estrogen on a blackboard

Estrogen and Choline Deficiency

Given the connection between low lipids and choline deficiency, it would be tempting to think that as long as someone has enough cholesterol and TG that they will be protected from choline deficiency.  Unfortunately this is not the case.  Having adequate lipids does indeed help support healthy choline levels, but it does not guarantee a person will avoid choline deficiency.  The truth is that choline deficiency can come from more than one source.  Both sex hormone levels and genetic SNPs may lead to a choline deficiency by influencing the PEMT enzyme – the enzyme responsible for synthesis of choline inside the body.  Recent research now confirms how hormones and genetic polymorphisms play a major role in choline deficiency.

The body can make choline only one way; that is by methylating a molecule of phosphatidylethanolamine (PE) into a molecule of phosphatidylcholine (PC).  The body’s only method for accomplishing this is via the enzyme PEMT (phosphatidylethanolamine N-methyltransferase) which is found in the liver, brain, muscle, fat and other tissues.1,2    As with other well-known methylation enzymes like MTHFR and COMT, the PEMT enzyme can have genetic SNPs that slow it down.  When this enzyme slows down the body cannot make choline in high amounts and choline deficiency is more likely.  But there is more to the story of PEMT than just polymorphisms.  In addition to being slowed by SNPs, PEMT is also dependent upon the hormone estrogen for activation. 1, 3  What this means is that the PEMT enzyme, the body’s only method of synthesizing choline, has not one but two Achilles heals.  The PEMT pathway and how it relates to phosphatidylcholine production is shown in Figure 1.3 below.

Communicating Vessels4-PEMT

Figure 1.3 – PEMT is shown as the rate-limiting reaction in the production of phosphatidylcholine inside the human body.  Due to genetic and hormonal variances, most people have a PEMT enzyme working too slow and are susceptible to choline deficiency when there is not enough choline in the diet.  ACoA – Acetyl-CoA; TG – Triglycerides; PE – phosphatidylethanolamine; PC – phosphatidylecholine; PEMT – phosphatidylethanolamine N-methyltransferase.

As mentioned above, the sex hormone estrogen is intimately linked with the production of choline.  Women have a biological advantage here as the premenopausal female body has much higher levels of estrogen than does the male body.  When a woman becomes pregnant this advantage is taken to an extreme, as pregnancy increases estrogen levels over 30 times normal.4  A successful pregnancy requires high amounts of nutrients delivered to the growing baby, esp. choline.  Since the mother’s body is building a human being from scratch, there is an added burden on her biology to provide enough nutrition to her growing baby.  Viewed from this perspective, the high estrogen levels during pregnancy can be seen to act like a biochemical insurance policy.  Since the PEMT enzyme requires estrogen to function, pregnancy allows a woman to make extra choline for her developing child.  Furthermore, the nervous system is the first system to form in utero and is a tissue that requires high levels of choline for proper development.5, 6  Choline plays such an important role in cell membranes, myelin sheaths, and nervous system tissue that the high estrogen levels during pregnancy help make sure the growing brain and nervous system is nourished.  It is a genius system that assures the health and survival of the child.

Even though Nature has conferred an advantage to females by providing them with higher estrogen levels, esp. during pregnancy, this alone cannot protect against a lack of choline in the diet.  All the estrogen in the world will not save a woman from choline deficiency if the gene responsible for producing choline is slowed down by a polymorphism.  Genetic research has shown that the gene responsible for synthesizing choline, the PEMT gene, is susceptible to common polymorphisms which alter its function by slowing it down.  In a recent study looking at a population in North Carolina, men and women of various ages were placed on a choline-deficient diet.  They were followed closely for up to 42 days on a low choline diet consisting of less than 50mg choline per day.  Throughout the study, the participants’ liver function was continuously assessed for any sign of fatty liver and damage.  After eating a choline deficient diet for just six weeks, 63% of participants developed liver dysfunction and choline blood levels dropped 30% in every single participant, including premenopausal females.7  During this six week trial of low dietary choline the odds of developing liver dysfunction were 77% for men, 80% for postmenopausal women and just 44% for premenopausal women.7  Based on what has been discussed so far about estrogen and choline, it makes sense that men and postmenopausal women would be more susceptible to developing fatty liver since they don’t have high estrogen levels.  And based on the fact that estrogen levels drive choline production, premenopausal women should have been protected from fatty liver since they make higher amounts of choline – but that was not the case.

With dietary choline restricted to just 50 mg/day, approximately half of the premenopausal group also suffered liver dysfunction, suggesting that a choline deficient diet can even harm women with higher estrogen levels.  In addition, blood tests revealed that premenopausal female experienced a 30% loss of choline on a low choline diet right along with everyone else.   Despite the fact that higher estrogen levels allow fertile women to make more choline, many were not able to make enough to avoid problems.  A PEMT gene polymorphism is the only mechanism that can explain how women with high estrogen levels are still susceptible to choline deficiency when placed on a low choline diet.

Just like many individuals in the population, some of the premenopausal women inherited one or two copies of the PEMT gene which slows down the production of choline.   This study showed that fatty liver occurred in 80% of the premenopausal women with two copies of PEMT and in 43% with only one copy of PEMT.8  What this means is that a premenopausal woman with two copies of the slowed PEMT gene has exactly the same risk of fatty liver as a postmenopausal woman.  It is as if inheriting two copies of the PEMT gene effectively shuts off all estrogen-related choline production in the body.  If a woman only has a single copy of the slowed PEMT gene, she will still have a roughly 50% chance of liver dysfunction on a low choline diet.  Thus a single copy of the gene is only slightly better than two copies, as at least some estrogen-related choline production is preserved.

If having a PEMT gene can put one at risk for choline-related diseases like fatty liver, then it is important to know how common these genes are in population.  We know that 74% of all women in the study had a SNP in the PEMT that made their PEMT enzyme unresponsive to estrogen.9  This means that only 26% of women can make enough choline on a low choline diet; and that ability depends on whether the woman is still fertile or has entered menopause.  In this way genetics can take away the biological advantage that high estrogen levels usually offer to premenopausal females.  Women with these PEMT genes will be at risk for choline deficiency and liver damage just like all men and post-menopausal women – two groups who don’t have enough estrogen to make choline regardless of their genes.  Due to all the interference from the PEMT gene, dietary choline levels must be optimized for the vast majority of our population.

Summary of PEMT and Choline Deficiency:

  • In humans, choline is only made by the PEMT enzyme
  • Estrogen is required for the PEMT enzyme to activate and function normally
  • Men and postmenopausal women have an elevated risk of choline deficiency due to low estrogen levels.
  • The PEMT enzyme is commonly slowed down by polymorphisms, making it unresponsive to estrogen levels
    • 74% of women have at least one copy of a slowed PEMT
    • Homozygous carriers of PEMT have much higher risk of choline deficiency
    • Men, postmenopausal women, and premenopausal women with PEMT SNPs need to increase choline intake in the diet to offset elevated risk of liver dysfunction

The take away here is that studies have recently shown that because of common genetic polymorphisms, choline deficiency is a widespread problem.  Normally the hormone estrogen allows the body to make choline from scratch.  However, genetic variation in the PEMT enzyme, estrogen levels and gender differences prevent most people from making adequate choline.  Realistically then the only group in our population who is protected from choline deficiency are premenopausal females without a single copy of the slowed PEMT gene.   Every single male, every single postmenopausal woman, and 74% of premenopausal woman all require daily intake of approx. 500 mg of choline to prevent fatty liver, organ damage, and the associated health problems.7  If the body is already depleted, then levels that simply prevent deficiency won’t be enough to replete the body.  In these cases, higher daily doses of at least 1 gram or more are needed to replenish the tissues.  Choline it seems must be absorbed from the diet in just about everyone except for the few young women who have a normal PEMT gene and can synthesize choline regardless of dietary intake.


1 Resseguie ME, da Costa KA, Galanko JA, et al. Aberrant estrogen regulation of PEMT results in choline deficiency-associated liver dysfunction. J Biol Chem. 2011 Jan 14;286(2):1649-58.

2 Tehlivets O. Homocysteine as a risk factor for atherosclerosis: is its conversion to s-adenosyl-L-homocysteine the key to deregulated lipid metabolism? J Lipids. 2011;2011:702853. Epub 2011 Aug 1.

3 Wallace JM, McCormack JM, McNulty H, et al. Choline supplementation and measures of choline and betaine status: a randomised, controlled trial in postmenopausal women. Br J Nutr. 2012 Oct;108(7):1264-71. Epub 2011 Dec 15.

4 Guyton AC, Hall JE. Textbook of Medical Physiology, 11th ed.  Philadelphia, PA: Elsevier, 2006, p. 1033.

5 Sadler, TW. Medical Embryology, 10th ed. Baltimore, MD: Lippincott Williams & Wilkins, 2006, p. 86.

6 Steinfeld R, Grapp M, Kraetzner R, et al. Folate Receptor Alpha Defect Causes Cerebral Folate Transport Deficiency: A Treatable Neurodegenerative Disorder Associated with Disturbed Myelin Metabolism. Am J Hum Genet. 2009 September 11; 85(3): 354–363.

7 da Costa KA, Kozyreva OG, Song J, et al. Common genetic polymorphisms affect the human requirement for the nutrient choline. FASEB J. 2006 Jul;20(9):1336-44.

8 Fischer LM, da Costa KA, Kwock L, et al. Dietary choline requirements of women: effects of estrogen and genetic variation. Am J Clin Nutr. 2010 Nov;92(5):1113-9. Epub 2010 Sep 22.

9 Zeisel SH. Nutritional genomics: defining the dietary requirement and effects of choline. J Nutr. 2011 Mar;141(3):531-4. Epub 2011 Jan 26.


  • March 12, 2014 Reply


    Fantastic Article Dr Rostenberg. If you’d would like to generate your 23andMe Raw Data report with your results on PEMT SNPs, click on this link and your LiveWello will generate your Variance Report:

  • October 26, 2014 Reply


    I was taking 1 gram of choline and 1 gram of inositol daily; I cut the dose in half and noticed near-constant tiny muscle cramps in my hands and feet. Is there a connection? I am pre-menopausal, had four children in five years and believed I was choline-deficient due to pregnancies, breastfeeding and my diet, which is why I started taking it. I hate the idea that I may have created a dependency on the choline by taking 1 gram daily, unless my body’s needs and hormone shifts are requiring that to keep a balance. I changed nothing else in my diet or supplements other than halve the dose of choline/inositol, and these weird little cramps in my hands and feet began. Is there a possible correlation between muscle cramps, or calcium or magnesium levels in the body, and bioavailable choline?

    • October 27, 2014 Reply


      I’m not sure of a direct correlation except that cramping is absolutely related to electrolyte concentrations. You won’t create a choline dependency, its a normal, healthy part of our diet. It is interesting that you are feeling symptoms from the lack of choline and inositol. It may be that choline is required by your body to help the gb produce enough quality bile. This bile is required for absorption of calcium in the diet. Lack of choline = lack of bile flow = lack of calcium uptake into gut = muscle cramps. While that is not a 1:1 relationship, it may be one way you are being impacted. If you would like more of my help, please feel free to reach out. Contact my office at 208-322-7755 or and I can help you get better results, in less time. In Health, Dr. Rostenberg

  • December 24, 2014 Reply

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  • May 2, 2016 Reply


    What is a good test to assess if you’re making enough bile acid or choline? A complete digestive stool analysis?

    • May 4, 2016 Reply


      Hi Bee,

      Thanks for your comment. Yes, CDSA will show you if there are excessive fats in the stool, which indicates poor bile and gallbladder function. You can also look at whether or not stool floats, changes color from light tan to dark, you are unable to tolerate fatty foods, hiccups and burps, etc.

      In Health,

      Dr. Rostenberg

  • May 28, 2016 Reply


    Should one be using the choline/inositol combo if they don’t have a gallbladder? Mine was removed 20 years ago. I am waiting for my stool analysis test. My doc wants me start inositol at night to help me sleep as I am tapering nuerontin. I am also concerned about this… “Inositol can cause too much intracellular calcium which can be responsible of muscle spasms and twitches”. From what I know about tapering neurontion, less of the medication leaves the calcium ion channels sort of unprotective causing excititory nerves. I feel this would make things worse during a taper. I am having such a grotty time tapering, having to go so slow otherwise I have extreme withdrawals! I know my doc is trying to help, but I don’t think this will.

  • July 10, 2016 Reply


    Another great article. The cytochrome p450 ( cyp3A4 ) plays a role in bile acid detoxification.
    All the best,

    Ramzy Haddad

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