The prevalence of PCOS in women of reproductive age varies but has been reported to be around 6%-19% of this population. This condition’s etiology relies on the presence of multiple signs and symptoms like hyperandrogenism, chronic oligo-/anovulation, and insulin resistance. Nevertheless, these alterations’ presentation converges with the complexity of the patient’s genetic predisposition and the interactions with the environment.

A woman’s genetic predisposition combined with environmental factors such as a sedentary lifestyle and a diet constituted by high carbohydrate load, industrialized foods, and high saturated fat content is considered the triggers of this dysregulation. The initial androgen overproduction leads to reduced sized ovarian follicles, which results in an oligo-/anovulation problem. The lack of progesterone peaks modifies the GnRH dynamic, leading to a higher LH secretion, which stimulates the ovaries’ androgen synthesis. Furthermore, the ingestion of an unbalanced diet increased body weight, and insulin resistance leads to increased insulin secretion and a low-grade inflammatory milieu.

Genetic studies and anthropology:

To understand how scientists discovered genetic information that ties PCOS and insulin resistance with human evolution is essential to look at what we were doing in prehistoric times.

The similarity of PCOS’s prevalence between different human populations shows that the genetic risk factors were present since our ancestors migrated from Africa. Furthermore, the human species come from an evolutionary path that can be traced back to chimpanzees, around 6 million years ago. Nevertheless, 50,000 years ago, anthropologists reported several human anatomy changes, describing them and a more modern, lean-bodied individual. In addition to these anatomical findings, brain size, body shape, increased fat storage, muscle, bone strength, new communication skills, and tools can be associated with a shift in diet and, therefore, metabolic changes. These findings are linked to the environmental conditions reported with a hunter-gatherer lifestyle.

If we fast forward to 40,000-10,000 years ago, we would observe a different environment. It has been reported that our ancestors went through another shift that accompanied a major dispersal of humans out of Africa and new stone-tools that allowed them to inhabit different geographic areas. Nevertheless, this was a harsh time for this population; child mortality was high; women died before turning 40 and were encouraged to have additional children at early ages. This wouldn’t last long after the hunter-gatherer approach came the agricultural period (10,000 years ago) along with a sedentary lifestyle. In fact, this would have an impact on women. Better nutrition and more food availability would result in early menarche and a longer period of fertility, fewer miscarriages, and lower child mortality.

Nowadays, the genome-wide association study (GWAS) provided the first PCOS research made in Chinese women, resulting in the identification of 3 susceptibility loci in the genes LHCGR, THADA, and DENND1A. Shortly after that, 8 new loci were found, and single-nucleotide polymorphisms (SNPs) in different genes code for hormones and growth. Conversely, these genes were similar to the ones related to type 2 diabetes. In fact, the effects of these loci have been found in women of European ancestry. This last finding shows that the genetic susceptibility of PCOS can be represented with the same loci and that the same PCOS genetic profile could be found across different ethnic groups.

GWAS

Genes	Loci
LHCGR   THADA DENND1A C9orf3 FSHR INSR HMAGA2 YAP1 RAB2B/SOUX TOX3 SUMO1P1	2p16.3   2p21 9q33.1 9q22.32 11q22.1 12q13.2 12q14.3 16q12.1 19p13.3 20q13.2

Hyperandrogenemia and its protective effects:

The presence of high levels of androgens secreted by the adrenals in prehistoric women seems to point to the most common autosomal recessive genetic disorder, the nonclassic congenital adrenal hyperplasia (NCAH). This particular condition could be associated with early puberty and masculinization, protecting the women and their children given the cruel setting in which they lived. Also, women would have increased bone density, muscular strength, and mass, which would result in a feature for evolutionary matters.

On the other hand, cortisol might have had an additional resource for survival. It has been demonstrated that the secretion of cortisol in CYP21A heterozygote carriers of 21-hidroxylase deficiency could be protective against exacerbated immune responses and could improve homeostasis restoration in an inflammatory setting.

Insulin Resistance:

INSR codes for the insulin receptor have an important role in regulating insulin functions and have a tight association with PCOS genetic etiology. In fact, this gene has been passed through evolutionary phases. It is believed that the organization of insulin action/resistance is adapted from the famine and feast phases of our ancestors, from the hunter-gatherer era. During prolonged starvation, insulin resistance’s role is to minimize protein losses by reducing the necessity to utilize amino acid carbon skeletons to produce glucose.

Know your genes, know your treatment.

Studies in PCOS have shown that the loci and genes have not changed over 50 000 years. It is a fact that it has taken a toll on our feminine population. If we look into history, we could see that it was the body trying to protect us and ensure the race’s survival. Nevertheless, it is safe to say that what has changed is our lifestyle. I don’t know if you notice, but if these genes have been on our code for so long, our environment and lifestyle are the only things to modify.

Your daily methylation smoothie:

To ensure my daily fiber and veggie intake, I like to start strong. Most of the days, this is my favorite smoothie to have as part of my breakfast.

Ginger Greens Juice Servings: 1

• 1 cup pineapple cubes ( I cut mine in advance)

• 1/2 frozen blackberries or strawberries

• 1-inch knob of ginger, rinsed, peeled, and chopped

• 3 cups kale, rinsed and roughly chopped or ripped or nopal (which I love. It makes everything sticky. Add more water).

-Ana Paola Rodríguez Arciniega. Master in Clinical Nutrition

References

Ünlütürk, U?ur, Efe Sezgin, and Bulent Okan Yildiz. “Evolutionary determinants of polycystic ovary syndrome: part 1.” Fertility and sterility 106.1 (2016): 33-41.

Dr. Alex Jimenez’s Blog Post

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