What is the cause of PCOS? 

According to a 2021 study PCOS is Transmitted via a Transgenerational Epigenetic Process, the exposure to an altered hormonal profile in utero (in the womb) plays a significant role in whether the offspring of biological mothers with PCOS will manifest the condition.  

An individual is 5x more likely to have PCOS if their biological mother has the condition.[1]  You have a 60-70% chance of having PCOS if your biological mother has the condition[2] and a 50% chance if your biological sister has the condition.[3] This article explores the link between PCOS and Epigenetics.

The underlying cause of PCOS is a result of a complex interaction of genetic, epigenetic and environmental factors.[4] Genetic factors relate to how individual or groups of genes are implicated in health and disease.[5] Epigenetic factors relate to how genes are expressed or function, in response to the environmental factors within the womb or later in life.[6] Environmental factors include lifestyle, diet, stress / trauma and exposure to endocrine-disruptors,[7] natural or man-made chemicals that may mimic, block or interfere with the body’s hormones.[8]

PCOS is believed to be passed on from biological mother to offspring (and subsequent generations) via an epigenetic process:[9]

• Individuals with PCOS have an excess of androgen and anti-Müllerian hormone (AMH);

• Within the uterus, their offspring are exposed to these elevated levels of hormones;

• These elevated hormone levels suppress the methylation, the addition of a methyl (CH3) group to deoxyribonucleic acid (DNA) molecules;[10],[11] 

  
  

Due to the decreased methylation, the function of a number of specific genes are down-regulated (and are therefore less active), relating to:[12]

• DNA repair, the normal processes to reverse or remove damage to DNA within the cell;[13]

• Cell-cycle arrest, the process by which cell maturation is halted;[14]

• Negative regulation of phosphorylation, the addition of a phosphoryl (PO3) group to a molecule, a reaction vital for storage and transfer of energy;[15] 

• Negative regulation of cell proliferation, the process that results from an increase in the number of cells.[16]

Due to the decreased methylation, the function of a number of specific genes are up-regulated (and therefore more active) across the forkhead box O (FoxO) signaling pathway[17] relating to:[18]

• Cell-cycle and control of quiescence[19] of primordial follicles, the process by which the majority of ovarian egg follicles that are formed around the time of birth are preserved in a dormant state to provide eggs for later reproductive life;[20],[21]

• Steroidogenesis in ovarian granulosa cells, the process by which granulosa cells convert androgens produced by theca cells into estrogens;[22]

• Apoptosis, the natural process of cell death to get rid of unneeded or abnormal cells (a process that is often compromised in cancer cells);[23] and

• Insulin signaling, the process of regulating glucose (sugar), lipid (fat) and energy balance by action on the liver, skeletal muscle and adipose tissue (stored fat deposits).[24]

Additionally, the function of a number of specific genes are up-regulated (and therefore more active) across the transforming growth factor-beta (TGF-ß) signaling pathway[25] relating to:[26] 

• Axon guidance, the process by which neurons (nerve cells)[27] send out axons (the single long cable that snakes away from the main part of the nerve cell)[28] to reach the correct targets;[29]

• Fatty acid biosynthesis, the process by which carbohydrates (sugars)[30] are converted into fatty acids (an important component of lipids or fat molecules)[31] in the liver;[32]

• Production of TGF-ß, a family of growth factors that controls a large number of cellular responses, the disruption of which is implicated in a large number of diseases include cancer;[33] and

• Metabolic processes.

  
  

Reviewed by Dr. Elisabet Stener-Victorin, principal investigator of the Reproductive Endocrinology and Metabolism research group at the Department of Physiology and Pharmacology at Karolinska Institutet, Stockholm, Sweden and Chief Scientific Officer of the AE-PCOS Society

Sources

[1] https://www.nature.com/articles/s41591-019-0666-1.epdf

[2] https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00004-8

[3] https://pubmed.ncbi.nlm.nih.gov/11117675/

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883751/

[5] https://www.cdc.gov/genomics/about/basics.htm

[6] https://www.cdc.gov/genomics/disease/epigenetics.htm

[7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9864804/

[8] https://www.niehs.nih.gov/health/topics/agents/endocrine

[9] https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00004-8

[10] https://www.nature.com/articles/npp2012112

[11] https://www.whatisepigenetics.com/dna-methylation/

[12] https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00004-8

[13] https://www.ncbi.nlm.nih.gov/books/NBK9900/

[14] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082019/

[15] https://www.sigmaaldrich.com/CA/en/technical-documents/technical-article/protein-biology/protein-labeling-and-modification/phosphorylation

[16] https://www.nature.com/subjects/cell-proliferation

[17] https://www.cusabio.com/pathway/FoxO-signaling-pathway.html

[18] https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00004-8

[19] https://www.dictionary.com/browse/quiescence

[20] https://pubmed.ncbi.nlm.nih.gov/19843540/.

[21] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011087/

[22] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463655/.

[23] https://www.cancer.gov/publications/dictionaries/cancer-terms/def/apoptosis

[24] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941218/

[25] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175140/

[26] https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00004-8

[27] https://www.ninds.nih.gov/health-information/public-education/brain-basics/brain-basics-life-and-death-neuron

[28] https://qbi.uq.edu.au/brain/brain-anatomy/axons-cable-transmission-neurons

[29] https://reactome.org/content/detail/R-HSA-422475

[30] https://medlineplus.gov/carbohydrates.html

[31] https://www.britannica.com/science/fatty-acid

[32] https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/fatty-acid-synthesis

[33] https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-10-183