Article
Hyperhomocysteinemia in polycystic ovary syndrome: decreased betaine-homocysteine methyltransferase and cystathionine β-synthase-mediated homocysteine metabolism

https://doi.org/10.1016/j.rbmo.2018.05.008Get rights and content

Abstract

Research question

What are the metabolic characteristics of homocysteine in polycystic ovary syndrome (PCOS)?

Design

Homocysteine concentrations were determined in serum samples from non-obese and obese control subjects and PCOS patients. Homocysteine metabolism was studied in a rat model of PCOS established using dehydroepiandrosterone (DHEA) or DHEA in combination with a high-fat diet (HFD).

Results

It was shown that (i) serum homocysteine concentrations were greater in PCOS patients than in control subjects in the obese group (P < 0.05) and serum homocysteine concentrations were significantly higher in the obese group than in the non-obese group, regardless of PCOS status (both P < 0.05); (ii) serum homocysteine concentrations were significantly increased in DHEA + HFD-induced rats compared with controls (P < 0.05); (iii) when compared with the control group, mRNA concentrations of homocysteine metabolic enzymes Bhmt and Cbs were significantly reduced in the liver tissues of DHEA + HFD-induced rats (both P < 0.0001); (iv) when compared with the control group, there was a significant decrease in the methylation concentrations of the Cbs (P < 0.05) and Bhmt (P < 0.05 and P < 0.0001) promoter in the DHEA + HFD group. The methylation patterns, together with previous data, indicate that hypomethylated promoter-mediated transcriptional activation of Bhmt and Cbs might be a defence mechanism against PCOS-related hyperhomocysteinemia.

Conclusions

These findings indicate that decreased liver Bhmt and Cbs-mediated homocysteine metabolism might have a role in hyperhomocysteinemia in PCOS and provides further evidence for a potential role of decreased liver function in PCOS.

Introduction

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting approximately 10% of the female population of reproductive age (Goodarzi et al., 2011), with significant and diverse reproductive, metabolic and psychological features (Li et al, 2015, Teede et al, 2010). In addition to a genetic predisposition, environmental and lifestyle factors contribute to the pathogenesis of PCOS (Insenser et al., 2013).

Homocysteine is a toxic sulphur-containing amino acid formed during the methionine cycle (Lehotsky et al., 2016). Recently, emerging evidence has suggested an important link between elevated homocysteine concentrations and PCOS (Qi et al., 2017). Elevated concentrations of homocysteine are a recognized risk factor for reproductive dysfunction (Aitken et al., 2016), metabolic disorders (Schalinske and Smazal, 2012), reduced prenatal brain growth and neurodevelopmental delays (Ars et al., 2016). Furthermore, genetic, dietary and other lifestyle factors are independent factors affecting homocysteine metabolism (Saw et al., 2001), and elevated homocysteine concentrations are associated with almost all of the symptoms of PCOS. For example, hyperhomocysteinemia is a risk factor for obesity (Tabassum et al., 2012), and homocysteine concentrations are positively correlated with plasma triglyceride content (Fulghesu et al., 2010). Women with PCOS display significantly elevated homocysteine concentrations (Toulis et al., 2011), and this elevation is associated with their serum insulin concentration (Yilmaz et al., 2008). Notably, homocysteine concentration is worsened by increasing insulin resistance, dyslipidaemia and poor glucose control (Ala et al., 2017). However, to date, little is known about the regulatory mechanism for homocysteine accumulation in PCOS.

Homocysteine may be remethylated to methionine via the betaine-dependent pathway utilizing betaine-homocysteine methyltransferase (BHMT), or the folate-dependent pathway utilizing methionine synthase (MTR), or converted to cystathionine by cystathionine β-synthase (CBS) in the liver (Li et al, 2013, Zhou et al, 2011). To further elucidate the relationship between homocysteine metabolism and PCOS, this study examined homocysteine concentrations in serum samples from non-obese and obese control subjects and PCOS patients; and investigated Mtr, Bhmt and Cbs-mediated homocysteine metabolism in a dehydroepiandrosterone (DHEA) and DHEA + high-fat diet (HFD)-induced rat model of PCOS. DHEA can induce PCOS phenotypes through the hypothalamus–pituitary–ovarian axis, whereas the addition of a HFD exaggerates endocrine and metabolic dysfunction of the PCOS model (Zhang et al., 2016).

Section snippets

Ethical statement

The study was conducted in accordance with ethical standards and the Helsinki Declaration of 1975.

Participants

This study was approved by the Institutional Review Board at the China Medical University on 28 February 2015 (reference number 2015PS108K). All participants provided written informed consent. A total of 201 control subjects and 348 PCOS patients were recruited. A female body mass index (BMI) ≥ 23 kg/m2 was used as the diagnostic criterion for overweight and obesity in Asians (World Health

Differences in serum homocysteine concentrations between non-obese and obese control subjects and PCOS patients

BMI, serum triglyceride and homocysteine concentrations were significantly higher in the obese group than in the non-obese group, regardless of PCOS status (all P < 0.05; Figures 1A–C). It is interesting to note that serum homocysteine concentrations were greater in PCOS patients than in control subjects in the obese group (P < 0.05; Figure 1C). Serum testosterone concentrations were significantly higher in PCOS patients than control subjects, regardless of obesity (both P < 0.05; Figure 1D).

DHEA + HFD-treated rats exhibit high serum homocysteine concentrations

Discussion

The present study confirmed that serum homocysteine concentrations are significantly increased in obese PCOS patients. Serum homocysteine concentrations are determined by the remethylation of homocysteine to methionine and the conversion of homocysteine to cystathionine in the liver (Li et al, 2013, Zhou et al, 2011). Our data also indicate that decreased Bhmt and Cbs-mediated homocysteine metabolism in the liver might play a potential role in increased serum homocysteine concentrations in PCOS.

Acknowledgement

This work was supported by the National Natural Science Foundation of China (grant numbers 81472438, 81671423, 81602918, 81402130); the Fok Ying Tung Education Foundation (grant number 151039); the Campus Research Fund of China Medical University (grant number YQ20160004); and the Distinguished Talent Program of ShengJing Hospital (grant number ME76).

Da Li is an Associate Professor at the Center for Reproductive Medicine, ShengJing Hospital of China Medical University. His main research is on PCOS and infertility. He has published over 40 peer-reviewed articles, served on the editorial board of five SCI journals, and as a reviewer for 23 peer-reviewed journals.

Key message

Serum homocysteine concentrations are significantly increased in obese PCOS patients. Decreased Bhmt and Cbs-mediated homocysteine metabolism in the liver may

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  • Cited by (0)

    Da Li is an Associate Professor at the Center for Reproductive Medicine, ShengJing Hospital of China Medical University. His main research is on PCOS and infertility. He has published over 40 peer-reviewed articles, served on the editorial board of five SCI journals, and as a reviewer for 23 peer-reviewed journals.

    Key message

    Serum homocysteine concentrations are significantly increased in obese PCOS patients. Decreased Bhmt and Cbs-mediated homocysteine metabolism in the liver may be responsible for hyperhomocysteinemia in PCOS.

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