Melatonin, a possible promising panacea for premature ovarian failure

Premature ovarian failure (POF) indicates a consecutive menstrual disorder, e.g. menopause, abnormal amount of menstruation, and aberrant endometrorrhagia for over 4 months. In the meantime, serum level of follicle-stimulating hormone reaches menopausal threshold, namely ≥ 40 mIU/ml. Such terminology has been questioned recently for being insolent and inconclusive of the prognosis, and is proposed to be named as primary ovarian insufficiency (POI) in lieu. In the present review, we still describe the disease as POF in accordance with most of the literature. The incidence of POF varies from 1 : 10 000 at the age of 20, to 1 : 1000 at 30, and eventually up to 1 : 100 in the forties with a tendency of increasing yearly [1]. Consequences of POF are distinctive yet severe, including sterility, osteoporosis and increased risk of cardiovascular events etc. Whereas the mechanism of POF onset remains majorly unclear resulting in inefficient treatments which are mostly symptom-based, it is of note that several causes are more disposed to cause POF on observation, including chemo- and radio-therapy and deranged autoimmune status. In the survey of possible treatment of POF, we notice melatonin (MLT), an endogenous pluripotent factor exerting various effects in regulating reproduction, oxidative stress and immunologic homeostasis. Interestingly, such regulations cover almost every aspect of the impairment POF brings about, which validates MLT as a possible cure for the disease.

Features of melatonin

Melatonin was first extracted and recognized by Lerner et al. in 1958. It belongs to indoleamine hormones with a chemical structure of N-acetyl-5-methoxytryptamine [2]. Though mainly synthesized in the pituitary gland, MLT is also distributed in the gastrointestinal system, skin etc. It is of note that the secretion of MLT in pituitary gland and iris presents a rhythmic pattern, which is elevated at night and is decreased in the daytime. Metabolism of MLT can also be influenced by drugs that interfere with 5-hydroxytryptamine (5-HT), the precursor of MLT. Receptors of MLT are extensively distributed in the skin, liver, kidney, brain and reproductive systems and can be sorted into MT-1, -2 and -3;

the former two are family members of 7-G protein coupling receptors. Studies on MLT have vastly revealed its beneficial aspects mainly in anti-oxidation, anti-carcinogenesis, autoimmune regulation and reproductive modulation [3].

Melatonin in the ovary

In 1987, Brzezinski et al. detected the existence of MLT in pre-ovulatory follicle fluid in humans, which was at higher concentration in contrast to serum level [4]. It was at first thought to be an active intake of MLT by the ovaries from the circulation until Itoh et al. identified several requisite enzymes for MLT synthesis in the ovary and inferred that MLT could also be secreted by the ovarian granulocytes [5]. Niles et al. further reported identification of MTs on the cytomembrane of granulosa cells and assumed that MLT may exert direct effects on the ovary [6]. It has been reported that MLT level is decreased in post-menopausal and POF population, explicable for the impaired sleeping quality of such people [7]. Nonetheless, investigation on the direct linkage between MLT and POF remains unexplored. Below, we review the current experience that offer us

a sound postulation that MLT may become a therapy of POF, and in the meantime, we propose where studies can further be done.

Melatonin and oxidation

One of the important causes of POF is chemo- and radio- therapy. Among teenagers with malignant ovarian diseases, the storage function of ovary is often impaired after such treatments which, in turn, increase the risk of POF development. The primary follicle amount is in negative correlation with radiation intensity [8]. Chemotherapy, as well as the ionizing radiation induced by radiotherapy may cause the release of large amounts of reactive oxygen species (ROS). Aside from exogenous ROS, ovulation itself is recognized as an inflammatory reaction which produces notable amounts of endogenous ROS. Zhang et al. have reported that ROS can induce apoptosis of quiescent stage oocyte in vitro. Gupta et al. have pointed out that oxidation and lack of antioxidase (SOD, GPx, etc.) can lead to atresia of antral follicle. Such evidence indicates that oxidation plays a pivotal role in the process of POF.

It has been assumed that POF is not but simple premature menopause, yet a manifestation of decrepitude [9]. MLT, however, can resist the apoptosis and decrepitude caused by oxidative stress. As the scavenger of ROS, MLT has been proven in a number studies to exert anti-oxidation effect extensively [10]. MLT may directly capture free radicals and transform them into molecules with less toxicity, or, indirectly resist ROS by elevating the antioxidase level. Not limited with MLT

itself, the metabolic products thereof also possess potent activity of anti-oxidation [11]. Lissoni et al. have applied MLT in the process of chemotherapy performed on patients with solid malignant tumours and have reported reduction of adverse events caused by oxidative stress e.g. thrombocytopenia, cardio- and neuro- toxicity [12]. Similar functions of MLT have additionally been reported in breast cancer and prostate cancer where MLT also acts as an anti-tumourigenic factor [13]. Furthermore, in IVF-ET patients, MLT is detected to be negatively correlated with 8-OHdG, a sort of ROS, whose concentration is in close relation to follicular degeneration [14]. The above-mentioned evidence indicates that MLT and POF can possibly be connected with regard to oxidation and this is a field where studies should be done.

Melatonin and follicle

Follicular atresia and dysfunction account critically for POF. Current postulations of the detailed mechanism state that gene mutation causes primary ovarian follicle depletion, that mutation in FSH receptor causes disorder in follicle development and ovulatory signalling pathway, and that synthetic derangement of ovarian aromatase induces follicular dysfunction. Those pathologic changes eventually result in luteinized unruptured follicle syndrome (LUFS), even follicular atresia, namely POF [9, 15]. Nakamura et al. found that MLT concentration in pre-ovulatory follicular fluid was 3-fold higher than serum level and that MLT level was higher in larger follicles [16]. Treatment with MLT in sterile females resulted in MLT aggregation in their follicles [14].

Ovulation is a complicated process in which multiple factors e.g. oestrogen, androgen, progesterone and prostaglandin (PG) are co-functioning in a complex pathway [15]. Adriaens et al. report that MLT stimulates ovulation with a better antral follicle amount, follicular size and maturation in vitro. They have also observed that the progesterone and androgen level is elevated after MLT application and the changes are in positive correlation [17]. In the study of oesophagus, MLT is reported to elevate the PGE level [18]. Injection of MLT in goats is revealed to increase the oocyte capability in cleavage and development [19]. Tamura et al. have treated 115 failed IVF patients with MLT and have reported a higher fecundability [14]. Thus, it is reasonable to assume that MLT plays a crucial role in follicle formation and ovulation, where further studies should be conducted in a POF population. Not limited with direct influence on the ovarian function, MLT may also co-effect with distinctive factors whose functions in ovaries are broadly studied. BMP15 belongs to the TGF-β family and acts pivotally in ovulation. A reproductive defect is observed in BMP15 knock-out mouse model and TGF-β activity is increased by MLT stimulation in rats [20-21]. IGF-I is an anti-apoptotic factor in follicular formation and MLT has been proven to stimulate the production of IGF-I in granulocytes [22-23]. To sum up, MLT can possibly possess the anti-apoptotic effect in follicular formation which leaves a broad area of research.

Melatonin and autoimmune

It is reported that 10% to 30% of POF patients also have immune disorders [24]. In subjects with adrenal autoimmunity, autoimmune oophoritis is usually identified in histological exams: vast infiltration of lymphocytes, plasmacytes and macrophage cells. The factors released by these inflammatory cells have impaired the ovarian function and accelerated atresia. In POF patients, various anti-ovary antibodies can still be detected in dearth of histological inflammatory change. One of the important causes is the imbalance between effector T cells and regulatory T cells observed in POF patients [25].

The value of MLT application in several autoimmune diseases has been verified due to its exquisite immunomodulation [26]. MLT can combine with lymphocytes and monocytes via special sites and regulate such function. In the meantime, MLT is capable of affecting T cell related factors such as IL-2, IL-6 and TNF to maintain immune balance (immunostasis) [27]. Voznesenskaya et al. have constructed autoimmune-induced POF mouse model and have discovered that exogenous MLT at 5 mg/kg can relieve autoimmune reaction, improve maturation and elevate follicular survival rate. However, they point out that the injection should be made before the ovarian antigen is introduced [28]. More evidence should be gathered to validate the exact effectiveness of MLT application against POF in which a complete series of autoimmune-related factors should be investigated to outline a detailed signalling pathway.

Prospects

Thus far, there is no research on MLT application in POF while it has been revealed that MLT treatment may bring exciting outcomes. Current opinions concerning MLT have no longer been constrained within circadian rhythms regulation. The pluripotent functions of MLT have gradually converted into therapeutic practice in myocardial and Alzheimer researches [29-30]. It is also noted that the anti-tumourigenic effect of MLT may also contribute to development of novel auxiliary therapies against cancer and bring hope to prevent iatrogenic POF.

References

1. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol 1986; 67: 604-6.

2. Lerner AB, Case JD, Takahashi Y, et al. Isolation of melatonin, a pineal factor that lightens melanocytes. J Am Chem Soc 1958; 80: 2587.

3. Altun A, Ugur-Altun B. Melatonin: therapeutic and clinical utilization. Int J Clin Pract 2007; 61: 835-45.

4. Brzezinski A, Seibel MM, Lynch HJ, et al. Melatonin in human preovulatory follicular fluid. J Clin Endocrinol Metab 1987; 64: 865-7.

5. Itoh MT, Ishizuka B, Kuribayashi Y, et al. Melatonin, its precursors, and synthesizing enzyme activities in the human ovary Mol Hum Reprod. 1999; 5: 402-8.

6. Niles LP, Wang J, Shen L, et al. Melatonin receptor mRNA expression in human granulosa cells. Mol Cell Endocrinol 1999; 156: 107-10.

7. National Sleep Foundation: Understanding Menopause. Available at: http://www.sleepfoundation.org/site/c.huIXKjMOIxF/b.2419231/k.63B3/understandingmenopause.htm. Accessed on May 8, 2008.

8. Schmidt KT, Larsen EC, Andersen CY, Andersen AN. Risk of ovarian failure and fertility preserving methods in girls and adolescents with

a malignant disease. BJOG 2010; 117: 163-74.

9. Nelson LM, Covington SN, Rebar RW. An update: spontaneous premature ovarian failure is not an early menopause. Fertil Steril 2005; 83: 1327-32.

10. Velkov ZA, Velkov YZh, Galunska BT, et al. Melatonin: Quantum-chemical and biochemical investigation of antioxidant activity. Eur J Med Chem 2009; 44: 2834-9.

11. Tan DX, Manchester LC, Terron MP, et al. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 2007; 42: 28-42.

12. Treeck O, Haldar C, Ortmann O. Antiestrogens modulate MT1 melatonin receptor expression in breast and ovarian cancer cell lines. Oncol Rep 2006; 15: 231-5.

13. Lissoni P, Brivio F, Fumagalli L, Messina G, et al. Neuroimmunomodulation in medical oncology: application of psychoneuroimmunology with subcutaneous low-dose IL-2 and the pineal hormone melatonin in patients with untreatable metastatic solid tumors. Anticancer Res 2008; 28: 1377-81.

14. Tamura H, Takasaki A, Miwa I, 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.

15. Duffy DM, Dozier BL, Seachord CL. Prostaglandin dehydrogenase and prostaglandin levels in periovulatory follicles: implications for control of primate ovulation by prostaglandin E2. J Clin Endocrinol Metab 2005; 90: 1021-7.

16. Nakamura Y, Tamura H, Takayama H, Kato H. Increased endogenous level of melatonin in preovulatory human follicles does not directly influence progesterone production. Fertil Steril 2003; 80: 1012-6.

17. Adriaens I, Jacquet P, Cortvrindt R, et al. Melatonin has dose-dependent effects on folliculogenesis, oocyte maturation capacity and steroidogenesis. Toxicology 2006; 228: 333-43.

18. Konturek SJ, Zayachkivska O, Havryluk XO, et al. Protective influence of melatonin against acute esophageal lesions involves prostaglandins, nitric oxide and sensory nerves. J Physiol Pharmacol 2007; 58: 361-77.

19. Berlinguer F, Leoni GG, Succu S, et al. Exogenous melatonin positively influences follicular dynamics, oocyte developmental competence and blastocyst output in a goat model. J Pineal Res 2009; 46: 383-91.

20. Yan C, Wang P, DeMayo J, et al. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function. Mol Endocrinol 2001; 15: 854-66.

21. Turgut M, Oktem G, Uslu S, et al. The effect of exogenous melatonin administration on trabecular width, ligament thickness and TGF-beta(1) expression in degenerated intervertebral disk tissue in the rat. J Clin Neurosci 2006; 13: 357-63.

22. Hastie PM, Haresign W. Expression of mRNAs encoding insulin-like growth factor (IGF) ligands, IGF receptors and IGF binding proteins during follicular growth and atresia in the ovine ovary throughout the oestrous cycle. Anim Reprod Sci 2006; 92: 284-99.

23. Picinato MC, Hirata AE, Cipolla-Neto J, et al. Activation of insulin and IGF-1 signaling pathways by melatonin through MT1 receptor in isolated rat pancreatic islets. J Pineal Res 2008; 44: 88-94.

24. Bakalov VK, Anasti JN, Calis KA, et al. Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure. Fertil Steril 2005; 84: 958-65.

25. Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat Rev Endocrinol 2010; 6: 270-7.

26. Cutolo M, Maestroni GJ. The melatonin-cytokine connection in rheumatoid arthritis. Ann Rheum Dis 2005; 64: 1109-11.

27. Carrillo-Vico A, Lardone PJ, Fernández-Santos JM, et al. Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system. J Clin Endocrinol Metab 2005; 90: 992-1000.

28. Voznesenskaya T, Makogon N, Bryzgina T, et al. Melatonin protects against experimental immune ovarian failure in mice. Reprod Biol 2007; 7: 207-20.

29. Dominguez-Rodriguez A, Abreu-Gonzalez P, Sanchez-Sanchez JJ, et al. Melatonin and circadian biology in human cardiovascular disease.

J Pineal Res 2010; 49: 14-22.

30. Sánchez-Barceló EJ, Mediavilla MD, Tan DX, Reiter RJ. Clinical uses of melatonin: evaluation of human trials. Curr Med Chem 2010; 17: 2070-95.