Dr. Weeks’ Comment: Melatonin is a naturally occurring biological hormone secreted by the pineal gland in the brain and typically recommended at 3-10mg to aid sleep. However, melatonin is far more than a sleep aid. In fact, the melatonin is a very powerful fat, soluble antioxidant highly beneficial for preserving neurological function and cognitive function. Concerned about your memory or balance, use melatonin at higher doses: 60-180mg a day. Cancer patients are using this also.
What about fertility? Can melatonin play a role in aiding fertility in this post-COVID age where fertility is plummeting? The answer is “Yes”. See below what the peer-reviewed scientific literature teaches us…
If you want to understand the role of melatonin study the work of my teacher and mentor Russ Reiter whose research is referenced below
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Antioxidants (Basel). 2023 Mar 11;12(3):695.
doi: 10.3390/antiox12030695.
Aging-Related Ovarian Failure and Infertility: Melatonin to the Rescue
Russel J Reiter 1, Ramaswamy Sharma 1, Alejandro Romero 2, Walter Manucha 3, Dun-Xian Tan 1, Debora Aparecida Pires de Campos Zuccari 4, Luiz Gustavo de Almeida Chuffa 5
Abstract
Aging has a major detrimental effect on the optimal function of the ovary with changes in this organ preceding the age-related deterioration in other tissues, with the middle-aged shutdown leading to infertility. Reduced fertility and consequent inability to conceive by women in present-day societies who choose to have children later in life leads to increased frustration. Melatonin is known to have anti-aging properties related to its antioxidant and anti-inflammatory actions. Its higher follicular fluid levels relative to blood concentrations and its likely synthesis in the oocyte, granulosa, and luteal cells suggest that it is optimally positioned to interfere with age-associated deterioration of the ovary. Additionally, the end of the female reproductive span coincides with a significant reduction in endogenous melatonin levels. Thus, the aims are to review the literature indicating melatonin production in mitochondria of oocytes, granulosa cells, and luteal cells, identify the multiple processes underlying changes in the ovary, especially late in the cessation of the reproductive life span, summarize the physiological and molecular actions of melatonin in the maintenance of normal ovaries and in the aging ovaries, and integrate the acquired information into an explanation for considering melatonin in the treatment of age-related infertility. Use of supplemental melatonin may help preserve fertility later in life and alleviate frustration in women delaying childbearing age, reduce the necessity of in vitro fertilization-embryo transfer (IVF-ET) procedures, and help solve the progressively increasing problem of non-aging-related infertility in women throughout their reproductive life span. While additional research is needed to fully understand the effects of melatonin supplementation on potentially enhancing fertility, studies published to date suggest it may be a promising option for those struggling with infertility.
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Theriogenology. 2014 Oct 15;82(7):925-32.
doi: 10.1016/j.theriogenology.2014.07.011. Epub 2014 Jul 15.
Essential actions of melatonin in protecting the ovary from oxidative damage
M H C Cruz 1, C L V Leal 2, J F Cruz 3, D X Tan 4, R J Reiter 4
Abstract
Free radicals and other reactive species are involved in normal ovarian physiology. However, they are also highly reactive with complex cellular molecules (proteins, lipids, and DNA) and alter their functions leading to oxidative stress. Oxidative damage may play a prominent role in the development of disorders that considerably influence female fertility. Melatonin, because of its amphiphilic nature that allows for crossing morphophysiological barriers, is an effective antioxidant for protecting macromolecules against oxidative stress caused by reactive species. The balance between reactive oxygen species and antioxidants within the follicle seems to be critical to the function of the oocyte and granulosa cells and evidence has accumulated showing that melatonin is involved in the protection of these cells. Melatonin appears to have varied functions at different stages of follicle development, oocyte maturation, and luteal stage. Melatonin concentration in the growing follicle may be an important factor in avoiding atresia, because melatonin in the follicular fluid reduces apoptosis of critical cells. Melatonin also has protective actions during oocyte maturation reducing intrafollicular oxidative damage. An association between melatonin concentrations in follicular fluid and oocyte quality has been reported; this would allow a preovulatory follicle to fully develop and provide a competent oocyte for fertilization. The functional role of reactive species and the cytoprotective properties of melatonin on the ovary from oxidative damage are summarized in this brief review.
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J Pineal Res. 2017 Mar;62(2).
doi: 10.1111/jpi.12381. Epub 2017 Jan 23.
Long-term melatonin treatment delays ovarian aging
Hiroshi Tamura 1, Mai Kawamoto 1, Shun Sato 1, Isao Tamura 1, Ryo Maekawa 1, Toshiaki Taketani 1, Hiromi Aasada 1, Eiichi Takaki 2, Akira Nakai 2, Russel J Reiter 3, Norihiro Sugino 1
Abstract
Ovarian aging is characterized by gradual declines in oocyte quantity and quality. Melatonin is considered an anti-aging agent due to its cytoprotective actions as an antioxidant. This study examined whether long-term melatonin treatment would delay ovarian aging in mice. Female ICR mice (10 weeks old) were given melatonin-containing water (100 μg/mL; melatonin) or water only until 43 weeks of age. Their oocytes were recovered from the oviduct, and in vitro fertilization was performed. The ovaries were used for a histological analysis of the number of follicles. The mRNA expression of the aging-related sirtuin genes (SIRT1, SIRT3) and the autophagy-related gene (LC3) and the telomere length of the ovarian chromosomes were analyzed. Transcriptome changes in the ovaries were also characterized using microarray. The number of ovulated oocytes decreased with age; however, it was greater in melatonin-treated mice than that from control animals. The decreased fertilization rate and blastocyst rate during aging also were higher in the melatonin-treated mice than in the controls, as were the numbers of primordial, primary, and antral follicles. The mRNA expression of SIRT1 and LC3 and telomere length were enhanced due to melatonin treatment. Seventy-eight genes that were downregulated during aging and upregulated by melatonin were identified by a microarray analysis. Forty of these 78 genes were ribosome-related genes, and a free radical scavenging network was identified. The present results indicate that melatonin delays ovarian aging by multiple mechanisms including antioxidant action, maintaining telomeres, stimulating SIRT expression and ribosome function, and by reducing autophagy.
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J Pineal Res. 2017 Oct;63(3).
doi: 10.1111/jpi.12431. Epub 2017 Jul 18.
Longsen Han 1, Haichao Wang 1, Ling Li 1, Xiaoyan Li 1 2, Juan Ge 1, Russel J Reiter 3, Qiang Wang 1
Abstract
Maternal obesity in humans is associated with poor outcomes across the reproductive spectrum. Emerging evidence indicates that these defects are likely attributed to factors within the oocyte. Although various molecules and pathways may contribute to impaired oocyte quality, prevention of fertility issues associated with maternal obesity is a challenge. Using mice fed a high-fat diet (HFD) as an obesity model, we document spindle disorganization, chromosome misalignment, and elevated reactive oxygen species (ROS) levels in oocytes from obese mice. Oral administration of melatonin to HFD mice not only reduces ROS generation, but also prevents spindle/chromosome anomalies in oocytes, consequently promoting the developmental potential of early embryos. Consistent with this finding, we find that melatonin supplement during in vitro maturation also markedly attenuates oxidative stress and meiotic defects in HFD oocytes. Finally, by performing morpholino knockdown and acetylation-mimetic mutant overexpression assays, we reveal that melatonin ameliorates maternal obesity-induced defective phenotypes in oocytes through the SIRT3-SOD2-dependent mechanism. In sum, our data uncover the marked beneficial effects of melatonin on oocyte quality from obese females; this opens a new area for optimizing culture system as well as fertility management.
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J Pineal Res. 2018 Sep;65(2):e12497.
doi: 10.1111/jpi.12497. Epub 2018 Apr 30.
Teng Zhang 1 2, Yang Zhou 1 3, Lan Li 1, Yong Zhao 1, Massimo De Felici 4, Russel J Reiter 5, Wei Shen 1
Abstract
A growing number of couples experience fertility issues with almost half being due to malefactors. The exposure to toxic environmental contaminants, such as endocrine disruptors (EDs), has been shown to negatively affect male fertility. EDs are present in the environment, and exposure to these toxins results in the failure of spermatogenesis. The deleterious effects of EDs on spermatogenesis have been well documented, whereas improvement of infertility associated with spermatogenesis defects remains a great challenge. Herein, we report that in vitro exposure of prepuberal mouse testes to two well-known endocrine disruptors (EDs), bisphenol A (BPA) or diethylhexyl phthalate (DEHP), impairs spermatogenesis with perturbing self-renewal, spermatogonia activity, and meiosis. Evidence indicates that such effects are likely due, at least in part, to decreased G9a-dependent H3K9 di-methylation. Of note, we found that melatonin (MLT) protected the testis from the negative ED impacts with preserving spermatogonia stem and meiotic cells, along with maintaining normal H3K9 di-methylation in these cells. Taken together, this work documents that BPA and EDHP adversely affect prepuberal spermatogenesis and perturb crucial epigenetic activities in male germ cells and highlight the protective ability of MLT.
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Ecotoxicol Environ Saf. 2021 Dec 15:226:112878.
doi: 10.1016/j.ecoenv.2021.112878. Epub 2021 Oct 8.
Massimo Venditti 1, Mariem Ben Rhouma 2, Maria Zelinda Romano 3, Imed Messaoudi 4, Russel J Reiter 5, Sergio Minucci 6
Free article
Abstract
Herein, we further document the protective action of melatonin (MLT) in mitigating cadmium (Cd) effects on adult rat testis. Cd treatment provoked testicular injury, that was documented by histological and biomolecular alterations, i.e., decrease of serum and testicular testosterone concentration and modified sperm parameters. Mainly, both the cytoarchitecture of the blood-testis barrier (BTB) and germ cell morphology were perturbed, as highlighted by impairment in structural (OCN, VANGL, Cx43) and regulative (Src and FAK) protein levels and/or activation. The study focused on the involvement of the autophagy pathway, that was enhanced especially in the Sertoli cells, probably in response to the disorganization of the BTB. Results obtained with the MLT co-treatment demonstrated that its administration decreased the level of oxidative damage caused by Cd, with reversal of all the observed changes. Moreover, the beneficial effects of MLT alone were evidenced by an increase of sperm quality, in term of motility and DNA integrity. The combined results, obtained in rat, strongly encourage to consider a role for MLT in improving also human testicular health, not only in men exposed to Cd, but also in those having fertility disorders, to ameliorate sperm quality and, consequently, reproductive success.
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Environ Pollu. 2021 Feb 1:270:116056.
doi: 10.1016/j.envpol.2020.116056. Epub 2020 Nov 9.
Safa Kechiche 1, Massimo Venditti 2, Latifa Knani 1, Karolina Jabłońska 3, Piotr Dzięgiel 3, Imed Messaoudi 1, Russel J Reiter 4, Sergio Minucci 5
Abstract
Herein, the first evidence of the ability of melatonin (MLT) to counteract cadmium (Cd) toxic effects on the rat ovary is reported. Cd treatment, enhancing oxidative stress, provoked clear morphological, histological and biomolecular alterations, i.e. in the estrous cycle duration, in the ovarian and serum E2 concentration other than in the steroidogenic and folliculogenic genes expression. Results demonstrated that the use of MLT, in combination with Cd, avoided the changes, strongly suggesting that it is an efficient antioxidant for preventing oxidative stress in the rat ovary. Moreover, to explore the underlying mechanism involved, at molecular level, in the effects of Cd-MLT interaction, the study focused on the mTOR and ERK1/2 pathways. Interestingly, data showed that Cd influenced the phosphorylation status of mTOR, of its downstream effectors and of ERK1/2, inducing autophagy and apoptosis, while cotreatment with MLT nullified these changes. This work highlights the beneficial role exerted by MLT in preventing Cd-induced toxicity in the rat ovary, encouraging further studies to confirm its action on human ovarian health with the aim to use this indolamine to ameliorate oocyte quality in women with fertility disorders.
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Cell Death Dis. 2018 Sep 20;9(10):968.
doi: 10.1038/s41419-018-0956-4.
Zhaoyu Du 1, Shuanshuan Xu 1, Shuxian Hu 1, Hong Yang 1, Zhe Zhou 1, Kuldip Sidhu 2, Yiliang Miao 3, Zhonghua Liu 4, Wei Shen 5, Russel J Reiter 6, Jinlian Hua 7, Sha Peng 8
Abstract
Diabetes mellitus affects a large number of men of reproductive age and it usually leads to serious reproductive disorders. However, the underlying mechanisms and specific therapies still remain largely unknown. We observed Leydig cell loss in the testes of diabetic mice. Continuous high glycemic status of testes stimulated expression of Caspase12, Grp78, and Chop, the three ERS response factors; this might induce cell cycle arrest and apoptosis of Leydig cells in response to ERS. In these diabetic mouse models, melatonin alleviated apoptosis of testicular stromal cell induced by ERS, and promoted SSCs self-renewal by recovering Leydig cells secretion of CSF1 after 8 weeks of treatment. To explore the relationship between CSF-1 and ERS in Leydig cells, we treated Leydig tumor cell line with an activator Tuniamycin and an inhibitor 4-Phenylbutyrate of ERS. Our data showed that the CSF-1 expression in mouse Leydig cell lines decreased six-fold while reversely increasing five-fold in the 4-Phenylbutyrate-treated group. Thus, melatonin likely alleviates the loss of Leydig cells in diabetic testes and provides a healthier niche for SSCs to self-renew and continually provide healthy sperm for male fertility.
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However, the practice of medicine is an art and scientific knowledge must be tailored to the individual patient so dosage and timing of melatonin must be optimized. Let’s remember that only Mae West said: “Too much of a good thing is wonderful.”
J Exp Zool. 1981 Feb;215(2):173-8.
doi: 10.1002/jez.1402150206.
The anovulatory hamster: a comparison of the effects of short photoperiod and daily melatonin injections on the induction and termination of ovarian acyclicity
Abstract
Cyclic female hamsters were rendered anovulatory by daily subcutaneous melatonin injections (25 microgram/0.1 ml oil) in 29 days or by transfer to a short light cycle, LD 6:18 (lights 1000-1600 hrs) in 33 days. Estrous cyclicity was reinitiated in these animals in 44 or 45 days following cessation of melatonin injections or transfer to long light cycles (LD 14:10, lights 0600-2000 hrs), respectively. Exposure of both groups to LD 6:18 after reinitiation of estrous cyclicity caused a second cessation of ovulation in 75 (melatonin group) or 61 (short light cycle group) days. Thus, although both treatments disrupted estrous cyclicity for nearly 6 weeks, this was not sufficient to induce photorefractoriness (failure to respond to short light cycles with continued estrous cyclicity). Rather, every animal responded to LD 6:18 and ceased ovulating. Melatonin-induced anovulatory hamsters showed daily gonadotropin release patterns identical to those reported in hamsters in other anovulatory states (lactating, prepubertal, and photoinduced anovulatory hamsters); that is, peak LH and FSH release at 1700 hrs daily.