PCOS Overview

Highlights

• PCOS patients present with at least two of the following: (1) infrequent or non-ovulation, (2) clinically or biologically evident hyperandrogenism, and (3) polycystic ovaries on ultrasound.
• Insulin resistance is common in women with PCOS, accompanied by elevated plasma levels of insulin and homocysteine. ¹
• The ovarian follicular fluid in PCOS women have elevated levels of homocysteine in comparison to women without PCOS. ²
• High levels of homocysteine are present in the follicular fluid of PCOS patients undergoing ART, and are negatively correlated with vitamin B₁₂, E₂ and oocyte and embryo quality. ³
• In a porcine model of PCOS, high levels of homocysteine were present in the follicular fluid of ovaries, and retrieved oocytes exhibited decreased cleavage and blastocyst rates in association with reduced expression of mitochondrial DNA encoded genes and mitochondrial dysfunction. ⁴
• Decreased methionine synthase (MTR) genetic expression was observed in granulosa cells from hyperandrogenic PCOS patients, along with reductions in serum S-adenosylmethionine (SAM). ⁵ Similar changes were seen in prenatally androgenized (PNA) mice.

Discussion

Elevated levels of homocysteine are present in the blood and follicular fluid of women with PCOS, accompanied by a corresponding reduction in serum levels of SAM, suggesting a perturbation in 1C metabolism that is related to the observed reduction in oocyte and embryo quality. ^1,2,3  Recent studies have begun to clarify the relationship between these epiphenomena and changes occurring in oocytes and their microenvironment that adversely affect reproductive performance.

Lei et al ⁵ have shown that expression of methionine synthase (MTR) in granulosa cells from hyperandrogenic PCOS patients is reduced in comparison to normal control patients. Since MTR is responsible for re-methylating homocysteine to methionine, the likely outcome is homocysteine accumulation, which is consistent with other studies of PCOS patients, and with the decrease in serum SAM observed by Lei and colleagues. This observation was also confirmed in an animal model of PCOS, and the authors have suggested that folate supplementation my benefit PCOS patients by compensating for decreased expression of MTR. Indeed, Kazerooni et al ⁶ and Schiuma et al ⁷ have demonstrated that three months of treatment with either folic acid or micronutrients supporting 1C metabolism reduced homocysteine levels in women with PCOS. In this latter study, treated PCOS women exhibited a significant decline in homocysteine blood levels (11.9 → 8.1 µM/L, p = 0.003), with homocysteine slightly increasing in the untreated controls (11.4 → 12.1, p = 0.498). ⁷ Although the clinical relevance of these findings is uncertain at the present time, homocysteine control may very well be important for the reproductive health of PCOS patients.

Because of the significant energy requirements of oocytes during the maturation/insemination process, and ultimately embryonic development, normal mitochondrial function is undoubtedly an important aspect of successful reproductive outcomes following both natural conception and ART cycles. Jia et al ⁴ found polycystic oocytes exhibit significant reductions in cleavage and blastocysts rates, accompanied by mitochondrial anomalies, which included abnormal distribution, deformed structure, and diminished membrane potential. In addition, mitochondrial DNA (mtDNA) copy number and expression of mtDNA-encoded genes were significantly lower in polycystic ovaries, while there was a coincident upregulation of enzymes involved in 1C metabolism, including betaine homocysteine methyltransferase (BHMT) and glycine N-methyl transferase (GNMT), and the DNA methylation enzyme, DNA methyltransferase (DNmt1). These observations suggest that high homocysteine is associated with dysregulated 1C metabolism and DNA methylation in the polycystic ovary, thus highlighting the importance of controlling homocysteine levels.

Conclusion

PCOS is a condition that leads to poor reproductive health outcomes for affected women; and there is evidence that women with PCOS have elevated levels of homocysteine and a corresponding reduction in SAM, thus indicating dysfunctional 1C metabolism. In support of this idea, recent studies have shown that several months of supplementation with 1C metabolism micronutrients lower homocysteine levels in PCOS women.

References

1.  Schachter M, Raziel A, Friedler S, et al. Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine. Human Reproduction. 2003;18:721-727.
2. Eskandari Z, Sadrkhanlou RA, Nejati V, et al. PCOS women show significantly higher homocysteine level, independent to glucose and E2 level. Int J Reprod BioMed. 2016;14:495-500,
3. Berker B, Kaya C, Aytac R, et al. Homocysteine concentrations in follicular fluid are associated with poor oocyte and embryo qualities in polycystic ovary syndrome patients undergoing assisted reproduction. Human Reproduction, 2009;24:2293 – 2302.
4. Jia L, Li J, He B, et al. Abnormally activated one-carbon metabolic pathway is associated with mtDNA hypermethylation and mitochondrial malfunction in the oocytes of polycystic gilt ovaries. Sci Rep. 2016;6:19436.
5. Lei L, Ding L, Su J, et al. Attenuated expression of MTR in both prenatally androgenized mice and women with the hyperandrogenic phenotype of PCOS. PLOS ONE. 2017;12: e0187427.
6. Kazerooni T, Asadi N, Dehbashi S, Zolghadri J. Effect of folic acid in women with and without insulin resistance who have hyperhomocysteinemic polycystic ovary syndrome. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2008;101(2):156–60. pmid:18313674.
7. Schiuma N, Costantino A, Bartolotti T, et al. Micronutrients in support to the one carbon cycle for the modulation of fasting homocysteine in PCOS women. J Endocrinol Invest. 2020; 43(6): 779–786.