Melatonin Reduces Androgen Production and Upregulates Heme Oxygenase-1 Expression in Granulosa Cells from PCOS Patients with Hypoestrogenia and Hyperandrogenia

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Abstract

Background/Aims

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by abnormal hormone levels in peripheral blood and poor-quality oocytes. PCOS is a pathophysiological syndrome caused by chronic inflammation and oxidative stress. The aim of this study was to investigate the mechanism of melatonin regulation on androgen production and antioxidative damage in granulosa cells from PCOS patients with hypoestrogenia and hyperandrogenia.

Methods

Cumulus-oocyte complexes were collected from PCOS patients who had low levels of estrogen in follicular fluids.

Results

Melatonin triggered upregulation of cytochrome P450 family 19 subfamily A member 1 (CYP19A1) expression via the extracellular signal-regulated kinase pathway in luteinized granulosa cells. As a result, conversion of androgen to 17 β-estradiol was accelerated. We also found that melatonin significantly reduced the levels of inducible nitric oxide (NO) synthetase and NO in luteinized granulosa cells. Levels of transcripts encoding NF-E2-related factor-2 and its downstream target heme oxygenase-1 were also increased, leading to anti-inflammatory and antioxidant effects. We also found that melatonin could improve oocyte development potential.

Conclusion

Our preliminary results showed that melatonin had a positive impact on oocyte quality in PCOS patients with hypoestrogenia and hyperandrogenia.

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Most cited references 44

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Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence

Jie Qiao, Huai Feng (2010)

BACKGROUND Polycystic ovary syndrome (PCOS) is a common metabolic dysfunction and heterogeneous endocrine disorder in women of reproductive age. Although patients with PCOS are typically characterized by increased numbers of oocytes retrieved during IVF, they are often of poor quality, leading to lower fertilization, cleavage and implantation rates, and a higher miscarriage rate. METHODS For this review, we searched the database MEDLINE (1950 to January 2010) and Google for all full texts and/or abstract articles published in English with content related to oocyte maturation and embryo developmental competence. RESULTS The search showed that alteration of many factors may directly or indirectly impair the competence of maturating oocytes through endocrine and local paracrine/autocrine actions, resulting in a lower pregnancy rate in patients with PCOS. The extra-ovarian factors identified included gonadotrophins, hyperandrogenemia and hyperinsulinemia, although intra-ovarian factors included members of the epidermal, fibroblast, insulin-like and neurotrophin families of growth factors, as well as the cytokines. CONCLUSIONS Any abnormality in the extra- and/or intra-ovarian factors may negatively affect the granulosa cell–oocyte interaction, oocyte maturation and potential embryonic developmental competence, contributing to unsuccessful outcomes for patients with PCOS who are undergoing assisted reproduction.

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The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome.

Manuel Ramirez, Manuel Luque-Ramírez, L Millan … (2005)

The genetic mechanisms underlying functional hyperandrogenism and the polycystic ovary syndrome (PCOS) remain largely unknown. Given the large number of genetic variants found in association with these disorders, the emerging picture is that of a complex multigenic trait in which environmental influences play an important role in the expression of the hyperandrogenic phenotype. Among others, genomic variants in genes related to the regulation of androgen biosynthesis and function, insulin resistance, and the metabolic syndrome, and proinflammatory genotypes may be involved in the genetic predisposition to functional hyperandrogenism and PCOS. The elucidation of the molecular genetic basis of these disorders has been burdened by the heterogeneity in the diagnostic criteria used to define PCOS, the limited sample size of the studies conducted to date, and the lack of precision in the identification of ethnic and environmental factors that trigger the development of hyperandrogenic disorders. Progress in this area requires adequately sized multicenter collaborative studies after standardization of the diagnostic criteria used to classify hyperandrogenic patients, in whom modifying environmental factors such as ethnicity, diet, and lifestyle are identified with precision. In addition to classic molecular genetic techniques such as linkage analysis in the form of a whole-genome scan and large case-control studies, promising genomic and proteomic approaches will be paramount to our understanding of the pathogenesis of functional hyperandrogenism and PCOS, allowing a more precise prevention, diagnosis, and treatment of these prevalent disorders.

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Roles of Oxidative Stress in Polycystic Ovary Syndrome and Cancers

Tao Zuo, Minghui Zhu, WENMING XU (2015)

Oxidative stress (OS) has received extensive attention in the last two decades, because of the discovery that abnormal oxidation status was related to patients with chronic diseases, such as diabetes, cardiovascular, polycystic ovary syndrome (PCOS), cancer, and neurological diseases. OS is considered as a potential inducing factor in the pathogenesis of PCOS, which is one of the most common complex endocrine disorders and a leading cause of female infertility, affecting 4%–12% of women in the world, as OS has close interactions with PCOS characteristics, just as insulin resistance (IR), hyperandrogenemia, and chronic inflammation. It has also been shown that DNA mutations and alterations induced by OS are involved in cancer pathogenesis, tumor cell survival, proliferation, invasion, angiogenesis, and so on. Furthermore, recent studies show that the females with PCOS are reported to have an increasing risk of cancers. As a result, the more serious OS in PCOS is regarded as an important potential incentive for the increasing risk of cancers, and this study aims to analyze the possibility and potential pathogenic mechanism of the above process, providing insightful thoughts and evidences for preventing cancer potentially caused by PCOS in clinic.

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Author and article information

Contributors

Zheng-Xing Lian:

ORCID: https://orcid.org/0000-0001-7360-8832

Song-Guo Xue:

ORCID: https://orcid.org/0000-0002-0221-5043

Shou-Long Deng:

ORCID: https://orcid.org/0000-0003-1187-3037

Journal

Journal ID (nlm-ta): Oxid Med Cell Longev

Journal ID (iso-abbrev): Oxid Med Cell Longev

Journal ID (publisher-id): OMCL

Title: Oxidative Medicine and Cellular Longevity

Publisher: Hindawi

ISSN (Print): 1942-0900

ISSN (Electronic): 1942-0994

Publication date Collection: 2019

Publication date (Electronic): 20 October 2019

Volume: 2019

Electronic Location Identifier: 8218650

Affiliations

¹Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China

²CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, 100101 Beijing, China

³Center for Reproductive Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China

⁴Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China

⁵State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

⁶Beijing Created Biotechnology Co., Ltd., Beijing 100194, China

⁷Oceanic Consluting Center, Beijing 100071, China

Author notes

Academic Editor: Juan C. Mayo

Author information

Kun Yu https://orcid.org/0000-0002-8838-3039

Rong-Xiang Wang https://orcid.org/0000-0001-5843-3026

Meng-Hui Li https://orcid.org/0000-0002-6738-4913

Yi-Wen Zhou https://orcid.org/0000-0002-2750-9443

Yuan-Yuan Li https://orcid.org/0000-0001-9458-6169

Li-Hua Sun https://orcid.org/0000-0002-7254-0474

Bao-Lu Zhang https://orcid.org/0000-0002-6488-0428

Zheng-Xing Lian https://orcid.org/0000-0001-7360-8832

Song-Guo Xue https://orcid.org/0000-0002-0221-5043

Yi-Xun Liu https://orcid.org/0000-0002-1386-8066

Shou-Long Deng https://orcid.org/0000-0003-1187-3037

Article

DOI: 10.1155/2019/8218650

PMC ID: 6854986

PubMed ID: 31772710

SO-VID: c5dbd569-8161-405d-abfa-bb5821eb8a5a

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 1 April 2019

Date revision received : 7 June 2019

Date accepted : 24 August 2019

Funding

Funded by: Science and Technology Commission of Shanghai Municipality

Award ID: 18411964000

Funded by: National Natural Science Foundation of China

Award ID: 31572546

Funded by: National Transgenic Creature Breeding Grand Project

Award ID: 2016ZX08008-005

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Melatonin Reduces Androgen Production and Upregulates Heme Oxygenase-1 Expression in Granulosa Cells from PCOS Patients with Hypoestrogenia and Hyperandrogenia

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Universal stem cells

Most cited references 44

Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence

The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome.

Roles of Oxidative Stress in Polycystic Ovary Syndrome and Cancers

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Cited by 24

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