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Invited Article
2021
:2;
16
doi:
10.25259/JRHM_39_2020

Management of ovarian functions by melatonin

Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
Corresponding author: Prof. Chandana Haldar, Department of Zoology, Banaras Hindu University, Ajagara, Varanasi - 221005, Uttar Pradesh, India. chaldar2001@yahoo.com
Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Haldar C, Chowdhury JP. Management of ovarian functions by melatonin. J Reprod Healthc Med 2021;2:16.

Abstract

Extensive research has unraveled a niche for melatonin that is of great significance for the female reproductive physiology. The potency of melatonin as an antioxidant, anti-inflammatory, and anti-apoptotic agent is being utilized to benefit female reproductive anomalies. Melatonin receptors have been localized in the Supra Chaismatic Nucleus (SCN), pars tuberalis (PT), and the gonads suggesting the regulation of reproduction by melatonin not only at a higher level but also on the gonads through complex interrelated mechanisms. Melatonin secreted by the pineal gland acts on the hypothalamus to regulate gonadotropin-releasing hormone and subsequently gonadotropin (FSH/LH) release from the PT. However, the de novo synthesis of this indoleamine reported in the gonads gave rise to the idea of a more localized action. The mammalian ovary has all the molecular machinery required for the biosynthesis of melatonin and interestingly concentration of melatonin in the follicular fluid of pre-ovulatory follicles is much higher than circulatory melatonin even in humans. This locally produced melatonin has been shown to modulate various pathways governing ovarian steroidogenesis. Further, melatonin and its receptors play a significant role in antioxidant defense mechanism of ovary for follicular growth and maturation. Exposure to stress strongly influences hypothalamic-pituitary-adrenal axis and elevated glucocorticoid levels suppress various ovarian functions including implantation thereby pregnancy. Melatonin acts antagonistically with glucocorticoids, making it crucial for the management of the female reproductive functions/dysfunctions. Usage of melatonin during in vitro fertilization (IVF) procedures has been found to improve oocyte quality, survival, and fecundity. Therefore, in future, melatonin can be implicated as preferable therapeutic especially in IVF and assisted reproductive techniques.

Keywords

Ovary
Steroidogenesis
Oxidative stress
Melatonin
Oocyte quality

INTRODUCTION

Following the discovery of melatonin by Lerner et al., in 1958,[1] there has been a considerable change in the understanding of the various functional aspects of melatonin. Apart from pineal, several extra pineal sites of melatonin biosynthesis in mammals have been identified including skin, retina, gut, ovary, and testis.[2-5] Today, the most pertinent physiological actions of melatonin have been established to be in

  1. Regulation of biological rhythms[6] and reproduction in seasonal breeders,[7]

  2. Enhancing immune responses,[8,9]

  3. Prevention of carcinogenesis, and[10]

  4. As an endogenous antioxidant.[11]

Regulation of seasonal reproduction is one of the initially established functions of melatonin. Within the environmental light dark cycle, circulatory melatonin peaks at night and decreases during the day. Hence, there is a significantly higher concentration of melatonin in blood during the longer nights of winter and vice versa in summer months.[12] Endogenously released melatonin resulting from changes in day length modulates reproduction[13] acts on the hypothalamic-pituitary-gonadal axis[14] by activation of its receptors in hypothalamic gonadotropin-releasing hormone (GnRH) releasing neurons, pars tuberalis, gonadotrophs of pars distalis, testes, and ovaries.[7,15] Melatonin regulates the pulsatile secretion of GnRH from the hypothalamus.[15,16] Although the exact mechanism is still not clearly understood, it is believed not to be a direct effect on GnRH neurons considering there is no change in responsiveness to GnRH with changing photoperiods.[17] It is predicted that two complementary mechanisms[18] regulate seasonal GnRH secretion – a change in the steroid negative feedback on GnRH release[19,20] and a direct modulation of GnRH secretion[6,15,21] that is steroid-independent.

Cases of idiopathic infertility amongst women who have undergone pinealectomy[22] and follicular atresia observed in pinealectomized rodents[23] suggest a direct relationship between melatonin and the female reproductive system. Being lipophilic, melatonin can cross cellular barriers and scavenge free radicals directly and more effectively than any other dietary antioxidant. The downstream metabolites of melatonin generated in process also act as free radical scavengers,[4] a property that is unique to melatonin. Although the foremost, the antioxidant effect of melatonin is just one aspect of the several impacts the molecule has on ovarian function.

Melatonin is established to promote luteinisation and progesterone synthesis.[24] In buffalo granulosa cell cultures, melatonin, when added at a dose of 100 nM significantly increased luteinizing hormone (LH) receptor mRNA.[25] Melatonin upregulates Steroidogenic Acute Regulatory protein (StAR) expression in primary cultures of human granulosa-lutein cells obtained from women undergoing in vitro fertilization (IVF).[26] The stimulatory effect of melatonin on StAR expression mediated through both MT1 and MT2 melatonin receptors was demonstrated by use of pharmacological inhibitors. Further, melatonin exposure activates the PI3K/AKT signaling pathway and its inhibition attenuates the stimulatory effect of melatonin on StAR expression.[27] There is no substantial evidence to support the capacity of melatonin to regulate follicular steroidogenesis before ovulation, but the fact that the melatonin content in the follicle increases as the cycle progresses cannot be ignored and is believed to be involved in granulosa cell proliferation which inadvertently influences steroid production.

MELATONIN AND SEASONALITY

Seasonal regulation of reproduction is one of the earliest observations in regard to effects of melatonin on mammalian physiology. Governed by photoperiodic changes, it is an outcome of the interactions between melatonin and several neural and neuroendocrine pathways in the hypothalamus. Daily changes in photic signals are relayed to the GnRH neurons through direct axonal projections of vasoactive intestinal peptide-expressing neurons of Supra Chaismatic Nucleus (SCN),[28,29] and SCN arginine vasopressin-expressing neurons to kisspeptin neurons in the pre-optic area, while the RFRP-3/(Arg)(Phe) related peptide-3 (gonadotropin inhibitory hormone) neurons in the mediobasal hypothalamus receive both.[30,31] Therefore, it can be said that the SCN neurons control the activity of GnRH neurons directly and indirectly by regulating the activity of POA kisspeptin neurons and DMH RFRP-3 neurons.

Since melatonin is the chemical relay of photic information between the environment and the SCN, it is the primary mediator of seasonal information that is integrated by these neuromodulators. Kisspeptins have a stimulatory effect on the reproductive axis while RFRP-3 is inhibitory in its pathway of action. Thus, melatonin is neither anti-gonadal nor pro-gonadal as previously believed[12] but a chemical link between the environment and mammalian reproductive axis.

INTERACTIONS OF THE FEMALE REPRODUCTIVE SYSTEM WITH THE HYPOTHALAMO-PITUITARY-ADRENAL (HPA) AXIS: ROLE OF THE STRESS RESPONSE

The neuroendocrine axis of reproduction is sensitive toward changes in the environment, both external and physiological. In face of challenges, psychological, physical, or physiological,[32,33] the body initiates a “stress response” that serves as an adaptive mechanism for the organism to return to the steady state. In mammals, reports suggest that there is a significant amount of cross-talk between the different components of the HPA axis with the center of reproduction that is typically antagonistic in nature.[34,35] Interestingly, there is a strong sexual dimorphism in the stress response where the response in females is more pronounced due to the presence of estrogen responsive elements in the CRH gene as seen in case of humans,[36,37] making females more vulnerable toward stress induced disruptive changes. The activation of the stress response has been found to decrease the pulsatile release of both GnRH and LH[38,39] while glucocorticoids modulate levels of circulating gonadotropins by acting on hypothalamus and pituitary, affecting the follicular development in ovary.[40,41] Glucocorticoid can also modulate levels of metabolic hormones and growth factors [42,43] that may lead to a decrease in estrogen production.[25] Elevated levels of glucocorticoid seen during a stress response may inhibit progesterone synthesis[44] and luteolysis by decreasing uterine prostaglandin F2α synthesis.[45]

Generation of free radicals, especially reactive oxygen species (ROS), is another possible mechanism of glucocorticoid mediated inhibition of ovarian axis. Both acute and chronic elevation of glucocorticoid levels have been shown to cause oxidative stress.[46-48] Moreover, the presence of glucocorticoid receptors in mitochondria suggests that they may play a role in the stress response[49] by influencing both ATP and ROS production.[50] Glucocorticoids have also been shown to increase both mitochondrial and non-mitochondrial sources of ROS production[51] thereby making generation of ROS an important by-stander effect of the stress response.

OVULATION: THE ROLE OF GOOD ROS

ROS production is inevitable within the biological system as all metabolic organs produce high amount of free radicals. The ovary is no exception and association of ROS in maintaining the follicular fluid environment, folliculogenesis, and steroidogenesis is one of the benefits of endogenous ROS.[52] Locally produced ROS is essential for follicle rupture and acts as second messengers, to modulate expression of genes involved in oocyte maturation.[53-55] However, ROS in excess can lead to oxidative stress that can inflict damages to the oocyte and granulosa cells within a follicle. While ROS mediated oxidative damage to primordial follicles is ambiguous, antral follicles have been reported to be highly sensitive to oxidative stress-induced apoptosis of granulosa cells. As the recruited follicles enter the gonadotropin dependent stage, there is a marked increase in metabolic function of granulosa cells, especially the production of steroids through enhanced activity of cytochrome P450 enzymes.[56] The electron transport associated with the P450 enzymes is a primary site of free-radical generation, suggesting that differentiation and functional activity of granulosa cells within the follicle experiences a surge in ROS production with a concomitant augmentation of prooxidants. The Graafian follicle is also a potential source of ROS due to the presence of large numbers of infiltrative macrophages, neutrophils, and metabolically active granulosa cells. The ROS produced within the pre-ovulatory follicle are essential for induction of ovulation. Interestingly, in dominant follicles an increase in ROS initiates the resumption of meiosis I of oocytes that have been found to be inhibited by antioxidants. The progression of meiosis II, on the other hand, is promoted by antioxidants,[57] suggesting that there is a delicate balance between ROS and antioxidants in the ovary.[58] Besides maintaining oocyte function ROS play an important role during luteolysis. Several antioxidants including melatonin are found in follicular fluid[59-62] which protect oocytes from ROS-induced damage as its generation is an inevitable aspect of ovarian function.

ROLE OF ROS IN FEMALE INFERTILITY

Detailed understanding of the implications of ROS in female infertility is an area of great significance. The presence of oxidative and antioxidant systems in various female reproductive tissues suggests that infertility associated pathological conditions such as endometriosis and hydrosalpinx may be caused, at least in part, by oxidative stress.[63-67] The potential negative effects of very high ROS concentrations are always a matter of concern, no matter what the benefits are.[68] Oxidatively modified substances in peritoneal fluid and ectopic endometrial tissue have been found to be higher in case of patients with endometriosis[69] which further supports the theory that ROS plays a major role in female reproductive pathophysiology.

MELATONIN AS AN ANTIOXIDANT IN THE OVARY

Melatonin reduces tissue oxidative stress by direct free-radical scavenging, in a non-receptor mediated manner as well as by upregulating the expression of genes coding for antioxidants such as SOD, catalase, and glutathione peroxidase. The gradual rise in melatonin concentration in ovarian follicles with a maximum at the prevoulatory stage[70] is suggestive of the possible role of locally synthesized melatonin in maintenance of the pro-oxidant-antioxidant balance which protects the oocyte from peri-ovulatory increase in ovarian ROS. Accumulation of free radicals in the ovary has also been found to occur during activation of the stress response[32] and due to exposure to chemicals and xenobiotics. Melatonin has been found to counteract the toxic effects of the herbicide, fenoxaprop-ethyl on the cytoskeletal integrity of oocytes during meiotic maturation[71] caused due to oxidative stress. The chemical not only disrupted spindle assembly by affecting actin filaments but also increased ROS accumulation in the oocyte that led to apoptosis. Oxidative stress is a key role player in ovarian ageing[72] and melatonin administration over a period from 10 to 43 weeks of age in mice was found to elevate 77 genes that decreased with age.[73] Based on the results of pathway analysis, half of these genes were involved in ribosomal function and maintenance of the accuracy of protein synthesis suggesting that melatonin maintains ribosomal function, accuracies of gene translation, and protein synthesis, thereby slowing the processes of aging. Other genes identified by the authors to be regulated by melatonin include those involved in DNA repair and checkpoint functions. Melatonin also suppresses autophagy-related protein by enhancing intracellular pathways and had a stimulatory effect on antioxidative mechanisms. Moreover, the telomere length, which typically decreases during aging, and expressions of the sirtuin longevity genes (SIRT1 and SIRT3) were significantly higher in the melatonin-treated animals compared to the control mice. Collectively, the results suggest that, through various mechanisms, melatonin reduces at least some aging processes in the ovaries and oocytes. Another characteristic of ovarian ageing is the loss of integrity of the surface epithelium and a gradual decrease in the number of ovarian surface epithelial cells Melatonin has antagonistic effects against the oncogene-induced senescence of human ovarian surface epithelium cells by inhibiting the ROS-YTHDF2-MAPK-NF-kB pathway.[74] A deeper understanding of the various pathways regulated by melatonin may provide key insights into the potential avenues for preventing and treating ovarian aging.

MELATONIN AND OOCYTE QUALITY

Apart from the known causes, there are many idiopathic cases of infertility wherein the exact cause cannot be determined and free-radical mediated injury might be an aspect that is often overlooked. The oocyte and the surrounding granulosa cells and feeder cells need significant care and protection from such damages. Melatonin, from the circulation or produced locally within the ovary and melatonin receptors in both the theca and granulosa cells[72] perhaps preserves the oocyte from free-radical damages. Melatonin has been reported to improve the survival rate of mouse and goat preantral follicles cultured in vitro. In caprine oocytegranulosa cell complexes, melatonin upregulated expression of 75 genes, 12 of which have been identified to be potential regulators of metabolic pathways indicating that melatonin improves developmental competence of porcine oocytegranulosa cell complexes.[73]

Oral administration of melatonin in mice reinstated oocyte meiotic maturation and fertilization ability of oocytes exposed to BPA that compromises the first polar body extrusion by disrupting normal spindle assembly, chromosome alignment, and kinetochore microtubule attachment and impairs oocyte quality. In the same study, BPA was also found to decrease the fertilization rate of oocytes by affecting interaction of the sperm with the zona pellucida proteins such as ovastacin and Juno, the sperm receptor on the egg membrane. Melatonin restored the above defects of fertilization proteins and events, improving oocyte quality through reduction of ROS levels and inhibition of apoptosis.[74] In another study melatonin protected mouse oocytes from DNA damage induced by double strand breaks during prophase arrest[75] and subsequently improved oocyte quality. It is suggested that DNA damage during meiotic prophase arrest prevented further maturation and deteriorated oocyte quality due to increase in chromosome fragmentation, spindle abnormality, mitochondrial aggregation, and oxidative stress. Melatonin treatment at this stage inhibited the accumulation of DNA damage by reducing the levels of phosphorylated histone, γλ H2AX. The authors have predicted that melatonin enhanced DNA repair through non-homologous end-joining pathway instead of directly downregulating kinases.

The oocyte is one of the sources of follicular melatonin biosynthesis. One study revealed that oocyte mitochondria are the major sites for melatonin production, contributing to the bulk of melatonin that is locally available during their maturation and promotes oocyte development.[75] The study further explored that exogenous melatonin addition to oocyte cultures improved mitochondrial function by increasing copy of mitochondrial DNA, mitochondrial membrane potential, distribution, and ATP production. Further, melatonin enhanced the meiotic spindle assembly and inhibited 8-oxo-deoxyguanosine formation, thereby preventing potential DNA mutation from oxidative damage resulting in an improvement in oocyte quality. Such findings not only widen the scope of exogenous melatonin use especially in assisted reproductive techniques but also open a new horizon to explore the applications of endogenous or locally produced melatonin, especially with regard to female reproduction.

MELATONIN: AN ASSISTANT IN FEMALE REPRODUCTION

Oral supplementation of melatonin during ovarian stimulation of IVF cycle has been shown to reduce intrafollicular oxidative stress and increase fertilization rates and embryo quality.[76] Women with sleep disturbances undergoing IVF when treated with 3 mg of oral melatonin at night till administration human chorionic gonadotropin (hCG) had increased number of metaphase II (MII) oocytes and percentage of Grade I embryos.[77] Melatonin supplementation from the time of hCG trigger throughout the luteal phase increased progesterone levels in patients undergoing IVF-ET.[64] Melatonin has also been observed to increase serum progesterone levels in patients with luteal phase defect.[78]

Studies have demonstrated that low concentrations of melatonin in IVF culture media improved nuclear maturation rate of immature MI oocytes,[79] implantation rate and an insignificant increase in clinical pregnancy rate in humans.[80]

Daily melatonin intake at a dose of 3 mg/day along with Vitamin E (600 mg/day) has been found effective in yielding proper and good quality oocytes for IVF.[64] The optimal melatonin concentration for human oocyte maturation in vitro was found to be 10−11 M.[81] The MII stage oocytes obtained from such treatments had a significantly higher fertilization rate and blastocyst formation rate compared to controls with greatly enhanced clathrin mediated endocytosis (CME) and decreased intra oocyte cAMP levels.[82] Dynasore, an inhibitor of endocytosis increased intra oocyte cAMP level and blocked oocyte maturation, and melatonin were found to partially rescue oocyte maturation and significantly elevate the expression of clathrin and AP2 in the presence of dynasore suggesting that melatonin could promote human oocyte maturation and early embryo development through enhancing CME. Therefore, melatonin might be the future choice of medicine for IVF especially for women who undergo repeated failures due to poor oocyte quality.

CONCLUSION

The synergism of melatonin and the various factors governing female reproductive physiology has widened the scope of therapeutic approach to sustain the reproductive axis. The beneficial properties of melatonin are being used for the yield of good quality oocytes both in vitro and in vitro. The intervention of melatonin as an antioxidant to prevent ROS production during gamete/embryo handling and preservation, optimization of gamete quality, and viability has strengthened the ground for the use of melatonin in maintenance of normal outcome of assisted reproduction, beginning with quality of gametes, implantation, and maintenance of pregnancy, finally fetal development and parturition. Along with its oncostatic properties[11] melatonin is also significantly helpful in counteracting reproductive carcinogenesis.

It was the year 1958, when melatonin was revealed with a plethora of biological functions and after 6 decades of its discovery, it is still emerging as a promising molecule that can benefit mankind in many ways.

Acknowledgment

Authors are grateful to University Grants Commission, New Delhi for UGC BSR Faculty Fellowship (award no F.18-1/2011 [BSR] 04-Jan-2017) to CH and Indian Council of Medical Research, New Delhi for ICMR Senior Research Fellowship award (RBMH/FW/2018/6) to JPC.

Declaration of patient consent

Patient’s consent not required as there are no patients in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

Prof. Chandana Halder is on the editorial board of this journal. She has no conflict of interest.

References

  1. , , . Isolation of melatonin, a pineal factor that lightens melanocytes. J Am Chem Soc. 1958;80:2057-8.
    [CrossRef] [Google Scholar]
  2. , , , , , . International union of basic and clinical pharmacology. LXXV, Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev. 2010;62:343-80.
    [CrossRef] [PubMed] [Google Scholar]
  3. , , , , , , et al. Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem. 1994;269:28531-4.
    [CrossRef] [Google Scholar]
  4. , , , , , , et al. Melatonin: A hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J Pineal Res. 2003;34:75-8.
    [CrossRef] [PubMed] [Google Scholar]
  5. , , , , , , et al. Serotoninergic and melatoninergic systems are fully expressed in human skin. FASEB J. 2002;16:896-8.
    [CrossRef] [PubMed] [Google Scholar]
  6. , , , . Circadian control of kisspeptin and a gated GnRH response mediate the preovulatory luteinizing hormone surge. Endocrinology. 2011;152:595-606.
    [CrossRef] [PubMed] [Google Scholar]
  7. , , , , , . Direct effect of melatonin on Syrian hamster testes: Melatonin subtype 1A receptors, inhibition of androgen production, and interaction with the local corticotropin-releasing hormone system. Endocrinology. 2005;146:1541-52.
    [CrossRef] [PubMed] [Google Scholar]
  8. , , , , . Bidirectional communication between the pineal gland and the immune system. Can J Physiol Pharmacol. 2003;81:342-9.
    [CrossRef] [PubMed] [Google Scholar]
  9. , . Photoperiodic regulation of MT1 and MT2 melatonin receptor expression in spleen and thymus of a tropical rodent Funambulus pennanti during reproductively active and inactive phases. Chronobiol Int. 2010;27:446-62.
    [CrossRef] [PubMed] [Google Scholar]
  10. , , . Antiestrogens modulate MT1 melatonin receptor expression in breast and ovarian cancer cell lines. Oncol Rep. 2006;15:231-5.
    [CrossRef] [PubMed] [Google Scholar]
  11. , , , , . One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res. 2007;42:28-42.
    [CrossRef] [PubMed] [Google Scholar]
  12. . The pineal and its hormones in the control of reproduction in mammals. Endocr Rev. 1980;1:109-31.
    [CrossRef] [PubMed] [Google Scholar]
  13. , , , . Effect of melatonin on the reproductive systems of male and female Syrian hamsters: A diurnal rhythm in sensitivity to melatonin. Endocrinology. 1976;99:1534-41.
    [CrossRef] [PubMed] [Google Scholar]
  14. , , , . Melatonin influences on the neuroendocrine-reproductive axis. Ann N Y Acad Sci. 2005;1057:337-64.
    [CrossRef] [PubMed] [Google Scholar]
  15. , , , , . Cyclical regulation of GnRH gene expression in GT1-7 GnRH-secreting neurons by melatonin. Endocrinology. 2001;142:4711-20.
    [CrossRef] [PubMed] [Google Scholar]
  16. , , , , , . Pineal melatonin mediates photoperiodic control of pulsatile luteinizing hormone secretion in the ewe. Neuroendocrinology. 1985;40:409-18.
    [CrossRef] [PubMed] [Google Scholar]
  17. , , , , , , et al. Kisspeptin: A key link to seasonal breeding. Rev Endocr Metab Disord. 2007;8:57-65.
    [CrossRef] [PubMed] [Google Scholar]
  18. , , , . Biology of mammalian photoperiodism and the critical role of the pineal gland and melatonin. J Biol Rhythms. 2001;16:336-47.
    [CrossRef] [PubMed] [Google Scholar]
  19. , , , , , . Melatonin inhibition and pinealectomy enhancement of 7, 12-dimethylbenz (a) anthracene-induced mammary tumors in the rat. Cancer Res. 1981;41:4432-6.
    [Google Scholar]
  20. , , , . Alterations in the control of luteinizing hormone pulse frequency underlie the seasonal variation in estradiol negative feedback in the ewe. Biol Reprod. 1982;27:580-9.
    [CrossRef] [PubMed] [Google Scholar]
  21. . The circadian timing system and reproduction in mammals. Steroids. 1999;64:679-85.
    [CrossRef] [Google Scholar]
  22. , , , . Selenium dependent glutathione peroxidase activity in human follicular fluid. Clin Chim Acta. 1995;236:173-80.
    [CrossRef] [Google Scholar]
  23. , , , , , . Pinealectomy changes rat ovarian interstitial cell morphology and decreases progesterone receptor expression. Gynecol Endocrinol. 2003;17:115-23.
    [CrossRef] [Google Scholar]
  24. , , , , , , et al. Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res. 2008;44:280-7.
    [CrossRef] [PubMed] [Google Scholar]
  25. , , , , . Effect of melatonin on regulation of apoptosis and steroidogenesis in cultured buffalo granulosa cells. Anim Sci J. 2019;90:473-80.
    [CrossRef] [PubMed] [Google Scholar]
  26. , , , , , , et al. Melatonin induces progesterone production in human granulosa-lutein cells through upregulation of StAR expression. Aging (Albany NY). 2019;11:9013-24.
    [CrossRef] [PubMed] [Google Scholar]
  27. , , , , , . Melatonin stimulates STAR expression and progesterone production via activation of the PI3K/AKT pathway in bovine theca cells. Int J Biol Sci. 2019;15:404-15.
    [CrossRef] [PubMed] [Google Scholar]
  28. , , , , . Lesions of the suprachiasmatic nucleus indicate the presence of a direct vasoactive intestinal polypeptide-containing projection to gonadotrophin-releasing hormone neurons in the female rat. J Neuroendocrinol. 1993;5:137-44.
    [CrossRef] [PubMed] [Google Scholar]
  29. , , , , , , et al. Circadian control of the female reproductive axis through gated responsiveness of the RFRP-3 system to VIP signaling. Endocrinology. 2015;156:2608-18.
    [CrossRef] [PubMed] [Google Scholar]
  30. , , , , , , et al. Evidence for suprachiasmatic vasopressin neurones innervating kisspeptin neurones in the rostral periventricular area of the mouse brain: Regulation by oestrogen. J Neuroendocrinol. 2010;22:1032-9.
    [CrossRef] [PubMed] [Google Scholar]
  31. , , . Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: Clinical implications. Ann Intern Med. 1998;129:229-40.
    [CrossRef] [PubMed] [Google Scholar]
  32. , , , . Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress. Front Neurosci. 2014;8:456.
    [CrossRef] [PubMed] [Google Scholar]
  33. . Actions of glucocorticoid and their regulatory mechanisms in the ovary. Anim Sci J. 2007;78:112-20.
    [CrossRef] [Google Scholar]
  34. , . Glucocorticoids, stress, and fertility. Minerva Endocrinol. 2010;35:109-25.
    [Google Scholar]
  35. , . Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction. J Clin Invest. 1993;92:1896-902.
    [CrossRef] [PubMed] [Google Scholar]
  36. , . Structural organization of the 5' flanking region of the human corticotropin releasing hormone gene. DNA Seq. 1993;4:197-206.
    [CrossRef] [PubMed] [Google Scholar]
  37. , , , . Corticotropin-releasing factor decreases plasma luteinizing hormone levels in female rats by inhibiting gonadotropin-releasing hormone release into hypophysial-portal circulation. Endocrinology. 1987;120:1083-8.
    [CrossRef] [PubMed] [Google Scholar]
  38. , . Corticotropin-releasing hormone inhibits gonadotropin secretion in the ovariectomized rhesus monkey. J Clin Endocrinol Metab. 1987;65:262-7.
    [CrossRef] [PubMed] [Google Scholar]
  39. , , . Suppression of the hypothalamic-pituitary-ovarian axis in normal women by glucocorticoids. Biol Reprod. 1993;49:1270-6.
    [CrossRef] [PubMed] [Google Scholar]
  40. , , , . Maintenance of gonadotropin secretion by glucocorticoids under stress conditions through the inhibition of prostaglandin synthesis in the brain. Endocrinology. 2006;147:1087-93.
    [CrossRef] [PubMed] [Google Scholar]
  41. , . Growth hormone secretion: The role of glucocorticoids. Life Sci. 1994;55:1083-99.
    [CrossRef] [Google Scholar]
  42. , , , . Dexamethasone decreases serum and liver IGF-I and maintains liver IGF-I mRNA in parenterally fed rats. Am J Physiol Regul Integr Comp Physiol. 2002;282:R528-36.
    [CrossRef] [PubMed] [Google Scholar]
  43. . Environment, human reproduction, menopause, and andropause. Environ Health Perspect. 1993;101:91-100.
    [CrossRef] [PubMed] [Google Scholar]
  44. , , . Immunosuppressive levels of glucocorticoid block extrauterine luteolysins in the rat. Biol Reprod. 1993;49:66-73.
    [CrossRef] [PubMed] [Google Scholar]
  45. , . Predation risk induces stress proteins and reduces antioxidant defense. Funct Ecol. 2008;22:637-42.
    [CrossRef] [Google Scholar]
  46. , . Modulation of in vivo oxidative status by exogenous corticosterone and restraint stress in rats. Stress. 2009;12:167-77.
    [CrossRef] [PubMed] [Google Scholar]
  47. , , . A meta-analysis of glucocorticoids as modulators of oxidative stress in vertebrates. J Comp Physiol B. 2011;181:447-56.
    [CrossRef] [PubMed] [Google Scholar]
  48. , , , , , . Localization of glucocorticoid hormone receptors in mitochondria of human cells. Eur J Cell Biol. 2000;79:299-307.
    [CrossRef] [Google Scholar]
  49. , , . Mitochondrial allostatic load puts the 'gluc' back in glucocorticoids. Nat Rev Endocrinol. 2014;10:303-10.
    [CrossRef] [PubMed] [Google Scholar]
  50. , , , , , , et al. Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circ Res. 2003;92:81-7.
    [CrossRef] [PubMed] [Google Scholar]
  51. . Reactive oxygen species in ovarian physiology. Reprod Med Biol. 2005;4:31-44.
    [CrossRef] [PubMed] [Google Scholar]
  52. , , , , . Reactive oxygen species, cell signaling, and cell injury. Free Radic Biol Med. 2000;28:1456-62.
    [CrossRef] [Google Scholar]
  53. . Free radicals in the physiological control of cell function. Physiol Rev. 2002;82:47-95.
    [CrossRef] [PubMed] [Google Scholar]
  54. . Hormonal control of gene expression in the ovary. Endocr Rev. 1994;15:725-51.
    [CrossRef] [PubMed] [Google Scholar]
  55. , , , . Oxidative stress and the ovary. J Soc Gynecol Investig. 2001;8:S40-2.
    [CrossRef] [Google Scholar]
  56. , , , , , . The role of antioxidant enzymes in the ovaries. Oxid Med Cell Longev. 2017;2017:4371714.
    [CrossRef] [PubMed] [Google Scholar]
  57. , , , , . Melatonin, its precursors, and synthesizing enzyme activities in the human ovary. Mol Hum Reprod. 1999;5:402-8.
    [CrossRef] [PubMed] [Google Scholar]
  58. , , , . Oxidative stress markers in preovulatory follicular fluid in humans. Mol Hum Reprod. 1999;5:409-13.
    [CrossRef] [PubMed] [Google Scholar]
  59. , , , , , , et al. The effect of follicular fluid reactive oxygen species on the outcome of in vitro fertilization. Int J Fertil Womens Med. 2000;45:314-20.
    [Google Scholar]
  60. , , , , , . Antioxidants and reactive oxygen species in follicular fluid of women undergoing IVF: Relationship to outcome. Hum Reprod. 2003;18:2270-4.
    [CrossRef] [PubMed] [Google Scholar]
  61. , , , , . Macrophage scavenger receptor(s) and oxidatively modified proteins in endometriosis. Fertil Steril. 1998;69:1085-91.
    [CrossRef] [Google Scholar]
  62. , , . Endometriosis: A disease of oxidative stress? Semin Reprod Endocrinol. 1998;16:263-73.
    [CrossRef] [PubMed] [Google Scholar]
  63. , , , , , , et al. Relationship between oxidative stress and embryotoxicity of hydrosalpingeal fluid. Hum Reprod. 2002;17:601-4.
    [CrossRef] [PubMed] [Google Scholar]
  64. , , , , , , et al. Prediction of endometriosis with serum and peritoneal fluid markers: A prospective controlled trial. Hum Reprod. 2002;17:426-31.
    [CrossRef] [PubMed] [Google Scholar]
  65. , , . Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril. 2003;79:829-43.
    [CrossRef] [Google Scholar]
  66. , , . Role of oxidative stress in female reproduction. Reprod Biol Endocrinol. 2005;3:28.
    [CrossRef] [PubMed] [Google Scholar]
  67. , , . Oxidative stress and peritoneal endometriosis. Fertil Steril. 2002;77:861-70.
    [CrossRef] [Google Scholar]
  68. , , , , . Melatonin protects against fenoxaprop-ethyl exposure-induced meiotic defects in mouse oocytes. Toxicology. 2019;425:152241.
    [CrossRef] [PubMed] [Google Scholar]
  69. , , , , . Melatonin as potential targets for delaying ovarian aging. Curr Drug Targets. 2019;20:16-28.
    [CrossRef] [PubMed] [Google Scholar]
  70. , , , , , , et al. Profile of melatonin and its receptors and synthesizing enzymes in cumulus-oocyte complexes of the developing sheep antral follicle-a potential estradiol-mediated mechanism. Reprod Biol Endocrinol. 2019;17:1.
    [CrossRef] [PubMed] [Google Scholar]
  71. , , , , , , et al. Long-term melatonin treatment delays ovarian aging. J Pineal Res. 2017;62:e12381.
    [CrossRef] [PubMed] [Google Scholar]
  72. , , , , , , et al. Melatonin antagonizes ovarian aging via YTHDF2-MAPK-NF-kB pathway In: Genes Dis. In press .
    [CrossRef] [Google Scholar]
  73. , , , , , . Direct action of melatonin in human granulosa-luteal cells. J Clin Endocrinol Metab. 2001;86:4789-97.
    [CrossRef] [PubMed] [Google Scholar]
  74. , , , , , , et al. Melatonin improves developmental competence of oocyte-granulosa cell complexes from porcine preantral follicles. Theriogenology. 2019;133:149-58.
    [CrossRef] [PubMed] [Google Scholar]
  75. , , , , , , et al. Mitochondria synthesize melatonin to ameliorate its function and improve mice oocyte's quality under in vitro conditions. Int J Mol Sci. 2016;17:939.
    [CrossRef] [PubMed] [Google Scholar]
  76. , , , , , , et al. Melatonin protects oocyte quality from bisphenol A-induced deterioration in the mouse. J Pineal Res. 2017;62:e12396.
    [CrossRef] [PubMed] [Google Scholar]
  77. , , , . Melatonin protects mouse oocytes from DNA damage by enhancing nonhomologous end-joining repair. J Pineal Res. 2019;67:e12603.
    [CrossRef] [PubMed] [Google Scholar]
  78. , , , , , , et al. Protective role of melatonin in progesterone production by human luteal cells. J Pineal Res. 2011;51:207-13.
    [CrossRef] [PubMed] [Google Scholar]
  79. , , , , , , et al. Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation. J Clin Endocrinol Metab. 1992;74:108-17.
    [CrossRef] [PubMed] [Google Scholar]
  80. , , , , , , et al. Supplementation with low concentrations of melatonin improves nuclear maturation of human oocytes in vitro. J Assist Reprod Genet. 2013;30:933-8.
    [CrossRef] [PubMed] [Google Scholar]
  81. , . Roadmap to embryo implantation: Clues from mouse models. Nat Rev Genet. 2006;7:185-99.
    [CrossRef] [PubMed] [Google Scholar]
  82. , , , , , , et al. Melatonin promotes human oocyte maturation and early embryo development by enhancing clathrin-mediated endocytosis. J Pineal Res. 2019;67:e12601.
    [CrossRef] [Google Scholar]
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