ApoE4 and PCOS, Metabolic Syndrome, Female-to-Male TS – Part 1

The ε4 allele has been alleged by many to be contributory to a number of Western disease outcomes. Not only that, the differing responses of the human organism having the various alleles of apoE has created, I think, a nightmare of misunderstanding and opportunity for the flourishing of a gaggle of half-baked dietary gurus.  I was surprised to find out that in people of European descent, ε4 is far more prevalent than I had thought: 20% – 25% of us have it. And now, it’s been confirmed that I have it too, although for me, it’s in the less problematic form, E3/E4. So, it’s become greatly interesting to me, and I would think it should be of great interest to just about anyone concerned with health, diet and nutrition.

And so it is that I’m taking a little detour from single-mindedly pursuing whether LDLc causes heart disease, in order to get up to speed on Apolipoprotein E (apoE).

ApoE is one of the lipoproteins that help cart cholesterol around in your bloodstream. The genes that code for apoE have 3 main variants (called alleles): ε2, ε3, ε4, which since you get one from your father and one from your mother, generate 6 genotypes: E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4.

I just read Evelyn AKA CarbSane’s recent book review of PCOS Unlocked by Stefani Ruper  and it’s led me to decide me that looking at whether there might be an association between apoE variants and the basic gender identity mismatch behind FtM might be as good a place as any to start.

Ha! You might well be wondering how I got from PCOS to thinking about FtM issues?

PCOS and FtM

Being an FtM myself, I’ve known for years that there is a strong correlation between PCOS and female-to-male transsexual (FtM) incidence. No need to PubMed research it – somebody already has. And just google “FtM PCOS” – you’ll find pages and pages of relevant hits. So when I see PCOS, I automatically think FtM, forgetting that women without gender identity issues also get PCOS.

The link between the two might be higher than normal androgen levels in bio-women. It’s undisputed that PCOS goes along with elevated androgen. For example, here[1] free testosterone was found to be more than twice as high in PCOS patients vs controls. And, there are a few studies suggesting that maternal exposure to androgens late in female fetal development masculinizes the brain and could account for a male gender identity (see this and this[3]). But for whatever reason, FtM and PCOS are definitely correlated.

PCOS and MetX

The same article[1] above that showed elevated T levels in PCOS patients also documents the high total / LDL-cholesterol and the impaired glucose metabolism associated with MetX problems within the PCOS group:

Cetinkalp et al, J Assist Reprod Genet. 2009 January; 26(1): 1–6.

Cetinkalp et al, J Assist Reprod Genet. 2009 January; 26(1): 1–6.

The middle 2 columns (“Patients” w 129 women and “Controls” w 91 women)  compare lab results of women w PCOS and women not affected by PCOS. The final column, “P”, is the probablity those results would be due to random chance; the lower the P, the more significant the finding. I highlighted the significant differences showing that PCOS is accompanied by a slew of symptoms of a systemic endocrine system disorder, ie, MetX.

ApoE4 and PCOS?

Having shown that a  FtM-PCOS-MetX connection exists, since both MetX and apoE4 have elevated LDLc, the question has to arise in everyone’s mind, could they be genetically related at all? After all, if E4 has elevated cholesterol levels, since the sex hormones are derived from cholesterol, could that not also elevate maternal androgens during pregnancy? Which would link in the FtM connection.

Finch[6] says essentially that we couldn’t have apoE4 today unless there was some positive association with fertility and then, confusingly, goes on to deny it in observation:

Caleb E. Finch (2007) - The Biology of Human Longevity - Inflammation, Nutrition, and Aging, p 369

Caleb E. Finch (2007) – The Biology of Human Longevity – Inflammation, Nutrition, and Aging, p 369

Can a relation between PCOS and apoE can be found?

Dr. B G at Animal Pharm cites Corbo et al[2] saying that in a pre-industrial environment the ApoE4 allele would confer higher fertility and more offspring, but with the E4 carriers’ adverse sensitivity to the “anti-HG diet (e.g. refined, non-ancestral)” of our modern world, the result is:

“the preponderance of small dense, oxidizable LDL and a hyperactive immune system which searches and scars, yes of course, will result in higher rates of infertility, fibroids, ovarian cysts, PCOS and less pregnancies, as countless PubMed articles report.”

So, how do the cited study authors rationalize the enhanced fertility among the apoE4 group for pre-industrial women, but decreased fertility relative to E3 now? And can I find PubMed documentation of this more recent decreased fertility relative to E3 in industrialized regions? Answering the first question, Corbo et al says:

A possible explanation for this inconsistency could be due to genotype–environment interactions. Most pre-industrial populations have lower plasma cholesterol levels than those observed in western countries. In these populations individuals carrying e*3 and the hypercholesterolaemic e*4 allele would be favoured because this allele could help in rebalancing cholesterol  levels which would otherwise be too low

BTW, as an aside, this explanation doesn’t sound too supportive of Plant Positive’s thesis in his How Much LDL? video that LDLc can never be too low. Apparently, fertility is negatively impacted by low LDLc.

For the second question, here’s the start my PubMed mini-review:

  1. Apolipoprotein E alleles in women with polycystic ovary syndrome[4] (2001) – The study results: “The frequency of the apo ϵ4 allele was 17.2% among women with polycystic ovary syndrome and was 18.7% among healthy fertile women, which is close to the rate in the general population in our area (19%). …  ϵ4 was not associated with the clinical disease.” The area in question was Kuopio, Finland.
  2. Functional genetic polymorphisms and female reproductive disorders …[5] – This was a review that located 139 publications involving genetics and PCOS up until Aug 2007 and found only the one I found (above) relating apoE and PCOS. No genetic association of any kind w PCOS was reported.
  3. Apolipoprotein E gene polymorphism and polycystic ovary syndrome …[1] – This 2009 study of a Turkish population found a highly significant protective effect of E2/E3 for PCOS and a surprising susceptibility of E3/E3 towards PCOS; E3/E4 didn’t quite reach significance and was also in the unexpected direction!

ApoE3 and PCOS?

The 2009 study took me by surprise. So much so that I stopped my PubMed search to look at it in depth. What’s up with E3 and PCOS? This is the exact opposite from what Dr. B G at Animal Pharm said I would find in PubMed. Here’s  the raw study numbers (circled):

Cetinkalp et al, J Assist Reprod Genet. 2009 January; 26(1): 1–6.

Cetinkalp et al, J Assist Reprod Genet. 2009 January; 26(1): 1–6.

To explain, the patient group (129 women – in red) has PCOS, the control group (91 women – in blue) does not. This is again that very same study that sourced the “Table 1” above. Here’s little graph I made to visualize the two distributions; again the PCOS group is in red, behind the healthy women in blue:

Population Distributions, PCOS vs Healthy

The differences in the distributions of the apoE variants between the women w PCOS and the women without PCOS is striking! The apoE4 appears to be somewhat protective; the apoE2 highly protective. The study numbers say it is highly unlikely that this difference would be due to chance.

What to make of this? This is just one study and of a Turkish population, so it would be unwise to give it too much weight. But it is highly significant and it does seem to put a damper on Dr. B G’s thought that there’s a need for apoE4’s to eat low-carb Paleo in order to protect themselves from PCOS.

But is there another way to interpret this study? … To be continued in part 2.


  1. Cetinkalp et al (2008) – Apolipoprotein E gene polymorphism and polycystic ovary syndrome patients in Western Anatolia, Turkey, J Assist Reprod Genet. 2009 January; 26(1): 1–6.
  2. Corbo et al (2004) – Apolipoprotein E polymorphism and fertility: a study in pre-industrial populations, Mol Hum Reprod. 2004 Aug;10(8):617-20.
  3. Meyer-Bahlburg HF et al – Prenatal androgenization affects gender-related behavior …, Arch Sex Behav. 2004 Apr;33(2):97-104.
  4. Heinonen et al (2001) – Apolipoprotein E alleles in women with polycystic ovary syndrome, Fertil Steril. 2001;75:878–880.
  5. M. Simoni et al (2007) – Functional genetic polymorphisms and female reproductive disorders …, Hum Reprod Update. 2008 Sep-Oct; 14(5): 459–484.
  6. Finch, Caleb E (2007) – The Biology of Human Longevity:: Inflammation, Nutrition, and Aging, Academic Press, Amsterdam, p 369

About Dan Hunter

Retired software engineer wading through the obfuscation, confusion and contradiction that corporate and political funding of medical research along with ego over science has created.
This entry was posted in ApoE4, FtM, PCOS, Personal and tagged , , , , , , . Bookmark the permalink.

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