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