Send Orders for Reprints to reprints@benthamscience.ae Current Drug Targets, 2018, 19, 000-000 1 REVIEW ARTICLE 1389-4501/18 $58.00+.00 ©2018 Bentham Science Publishers Melatonin as Potential Targets for Delaying Ovarian Aging Yanzhou Yang 1,* , Hoi-Hung Cheung 2 , Cheng Zhang 3 , Ji Wu 1,4* and Wai-Yee Chan 2,* 1 Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Ningxia Medical University, Yinchuan, Ningxia, 75004, P.R. China; 2 Chinese University of Hong Kong - Shandong University Joint Laboratory for Reproductive Genetics, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, SAR, Hong Kong; 3 College of Life Science, Capital Normal Univer- sity, Beijing 100048, People's Republic of China; 4 Renji Hospital, Key Laboratory for the Genetics of Developmental & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, School of Medicine, Shanghai Jiao Tong Univer- sity, Shanghai, 200240, China A R T I C L E H I S T O R Y Received: April 14, 2018 Revised: August 02, 2018 Accepted: August 15, 2018 DOI: 10.2174/1389450119666180828144843 Abstract: In previous studies, oxidative stress damage has been solely considered to be the mecha- nism of ovarian aging, and several antioxidants have been used to delay ovarian aging. But recently, more reports have found that endoplasmic reticulum stress, autophagy, sirtuins, mitochondrial dys- function, telomeres, gene mutation, premature ovarian failure, and polycystic ovary syndrome are all closely related to ovarian aging, and these factors all interact with oxidative stress. These novel in- sights on ovarian aging are summarized in this review. Furthermore, as a pleiotropic molecule, mela- tonin is an important antioxidant and used as drugs for several diseases treatment. Melatonin regulates not only oxidative stress, but also the various molecules, and normal and pathological processes inter- act with ovarian functions and aging. Hence, the mechanism of ovarian aging and the extensive role of melatonin in the ovarian aging process are described herein. This systematic review supply new in- sights into ovarian aging and the use of melatonin to delay its onset, further supply a novel drug of melatonin for ovarian aging treatment. Keywords: Melatonin, oxidative stress, endoplasmic reticulum stress, autophagy, ovarian ageing. 1. INTRODUCTION The female reproductive cycle is mainly determined by the ovarian lifespan, and decreased fertility and even infertil- ity is caused by the shortening of the female reproductive cycle, attributed to the ovarian lifespan, particularly ovarian aging. Women suffer a significant reduction in fecundity and an increase in the probability of infertility in their late thirties, accompanied by decreased ovarian functions [1]. The func- tions of the human ovary alternate dynamically with the menopausal period [2]. An increase in fibrous tissues and a decrease in the number of primordial follicles are two obvi- ous characteristics observed histologically in the aged ovary [2], especially after 38 years of age [3]. There is also a grad- ual decline in oocyte quantity and quality [4], accompanied by increased aneuploidy and unfavorable oocyte maturation [5, 6]. A reduction in oocyte quality and diminishing folli- cles and oocytes are main traits of ovarian aging [7, 8]. *Address correspondence to this author at the Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Ningxia Medical University, China; Cell: +86-951-6980172; E-mail: alnord820119@163.com Clinically, ovarian aging is characterized by a diminished ovarian reserve (DOR), accompanied with a decrease in anti- Müllerian hormone, an increase in follicle-stimulating hor- mone (FSH) and a decrease in the antral follicular count (AFC) [9]. The complications of ovarian aging have several causes. Previous studies have suggested that menopause [3], chemotherapy [10], endocrinological disorder, genetic mutation, and micro-environmental factors [11] are associated with and inducers of ovarian aging. The pathology and the mechanism of ovarian aging are complicated and not fully known. Understanding the mechanism of ovarian aging will provide new insights and drugs to delay ovarian aging and improve female fertility. Melatonin (N-acetyl-5-methoxytryptamine) is an en- dogenous hormone produced by the pineal gland and re- leased in a circadian manner; its secretion is exclusively at night and is regulated by light and dark environment [12, 13]. Exogenous melatonin administration has no obvious short- or long-term adverse effects and is well tolerated [13]. Melatonin involves several physiological and pathological processes (Fig. 1). As an anti-cancer agent for the prevention and treatment of cancer [14], melatonin regulates DNA dam- age response and repair pathways. It interacts with DNA damage agents to increase their efficacy in cancer therapy