Direct action of melatonin in human granulosa-luteal cells
The direct involvement of melatonin in modulation of ovarian steroidogenesis, the high levels of melatonin found in human follicular fluid, and the presence of melatonin binding sites in the ovary led us to hypothesize that melatonin acts as a modulator of ovarian function. In contrast to the hypoth...
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Published in | The journal of clinical endocrinology and metabolism Vol. 86; no. 10; pp. 4789 - 4797 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
Endocrine Society
01.10.2001
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Subjects | |
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Abstract | The direct involvement of melatonin in modulation of ovarian steroidogenesis, the high levels of melatonin found in human follicular fluid, and the presence of melatonin binding sites in the ovary led us to hypothesize that melatonin acts as a modulator of ovarian function. In contrast to the hypothalamus and pituitary, the mechanism of melatonin action at the level of the ovary is still poorly understood. In the present study, we investigated the gene expression of the two different forms of melatonin receptors in human granulosa-luteal cells, using RT-PCR. PCR products corresponding to the expected sizes of the melatonin receptor subtypes, mt(1)-R and MT(2)-R, were obtained from granulosa-luteal cells, and the authenticity of the PCR products was confirmed by Southern blot hybridization with cDNA probes. Subsequent cloning and sequence analysis revealed that the ovarian mt(1)-R and MT(2)-R cDNAs are identical to their brain counterparts. Because gonadotropins and GnRH acting through specific receptors in the human ovary regulate cellular functions, we investigated the role of melatonin in the regulation of FSH receptor, LH receptor, GnRH, and GnRH receptor levels. Treatment with melatonin (10 pM-100 nM) significantly increased LH receptor mRNA levels without altering the expression of the FSH receptor gene. Both GnRH and GnRH receptor mRNA levels were significantly decreased, to 61% and 45% of control levels, respectively, after melatonin treatment. Melatonin treatment alone had no effect on basal progesterone production but enhanced the effects of human CG-stimulated progesterone production. Because MAPKs are activated in response to a diverse array of extracellular stimuli leading to the regulation of cell growth, division, and differentiation, and because melatonin has been shown to modulate cellular proliferation and differentiation, in this study, we demonstrated that melatonin activated MAPK in a dose- and time-dependent manner. In summary, our studies demonstrate, for the first time, that melatonin can regulate progesterone production, LH receptor, GnRH, and GnRH receptor gene expression through melatonin receptors in human granulosa-luteal cells, which may be mediated via the MAPK pathway and activation of Elk-1. Our results support the notion that melatonin plays a direct role in regulating ovarian function. |
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AbstractList | The direct involvement of melatonin in modulation of ovarian steroidogenesis, the high levels of melatonin found in human follicular fluid, and the presence of melatonin binding sites in the ovary led us to hypothesize that melatonin acts as a modulator of ovarian function. In contrast to the hypothalamus and pituitary, the mechanism of melatonin action at the level of the ovary is still poorly understood. In the present study, we investigated the gene expression of the two different forms of melatonin receptors in human granulosa-luteal cells, using RT-PCR. PCR products corresponding to the expected sizes of the melatonin receptor subtypes, mt(1)-R and MT(2)-R, were obtained from granulosa-luteal cells, and the authenticity of the PCR products was confirmed by Southern blot hybridization with cDNA probes. Subsequent cloning and sequence analysis revealed that the ovarian mt(1)-R and MT(2)-R cDNAs are identical to their brain counterparts. Because gonadotropins and GnRH acting through specific receptors in the human ovary regulate cellular functions, we investigated the role of melatonin in the regulation of FSH receptor, LH receptor, GnRH, and GnRH receptor levels. Treatment with melatonin (10 pM-100 nM) significantly increased LH receptor mRNA levels without altering the expression of the FSH receptor gene. Both GnRH and GnRH receptor mRNA levels were significantly decreased, to 61% and 45% of control levels, respectively, after melatonin treatment. Melatonin treatment alone had no effect on basal progesterone production but enhanced the effects of human CG-stimulated progesterone production. Because MAPKs are activated in response to a diverse array of extracellular stimuli leading to the regulation of cell growth, division, and differentiation, and because melatonin has been shown to modulate cellular proliferation and differentiation, in this study, we demonstrated that melatonin activated MAPK in a dose- and time-dependent manner. In summary, our studies demonstrate, for the first time, that melatonin can regulate progesterone production, LH receptor, GnRH, and GnRH receptor gene expression through melatonin receptors in human granulosa-luteal cells, which may be mediated via the MAPK pathway and activation of Elk-1. Our results support the notion that melatonin plays a direct role in regulating ovarian function. |
Author | SUNG KEUN KANG WOO, Michelle M. M NATHWANI, Parimal S SHIU FUN PANG TAI, Chen-Jei LEUNG, Peter C. K |
Author_xml | – sequence: 1 givenname: Michelle M. M surname: WOO fullname: WOO, Michelle M. M organization: Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, V6H 3V5, Canada – sequence: 2 givenname: Chen-Jei surname: TAI fullname: TAI, Chen-Jei organization: Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, V6H 3V5, Canada – sequence: 3 surname: SUNG KEUN KANG fullname: SUNG KEUN KANG organization: Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, V6H 3V5, Canada – sequence: 4 givenname: Parimal S surname: NATHWANI fullname: NATHWANI, Parimal S organization: Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, V6H 3V5, Canada – sequence: 5 surname: SHIU FUN PANG fullname: SHIU FUN PANG organization: Department of Physiology, University of Hong Kong, Hong-Kong – sequence: 6 givenname: Peter C. K surname: LEUNG fullname: LEUNG, Peter C. K organization: Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, V6H 3V5, Canada |
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Keywords | Human Melatonin Gonadotropin RH Gonadotropin Gene expression In vitro Ovarian hormone Progestagen Endocrine secretion Hypothalamic hormone Polymerase chain reaction Ovary Granulosa cell Adenohypophyseal hormone Luteal cell Hormonal regulation Female Progesterone Molecular biology Hormone releasing factor Sex steroid hormone Pineal hormone Follicle stimulating hormone Hormonal receptor |
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SubjectTerms | Biological and medical sciences Cells, Cultured DNA-Binding Proteins ets-Domain Protein Elk-1 Female Fundamental and applied biological sciences. Psychology Gonadotropin-Releasing Hormone - analysis Gonadotropin-Releasing Hormone - genetics Granulosa Cells - drug effects Granulosa Cells - metabolism Hormone metabolism and regulation Humans Mammalian female genital system Melatonin - pharmacology Mitogen-Activated Protein Kinases - metabolism Phosphorylation Polymerase Chain Reaction Progesterone - biosynthesis Proto-Oncogene Proteins - metabolism Receptors, Cell Surface - genetics Receptors, Cytoplasmic and Nuclear - genetics Receptors, FSH - analysis Receptors, FSH - genetics Receptors, LH - analysis Receptors, LH - genetics Receptors, LHRH - analysis Receptors, LHRH - genetics Receptors, Melatonin RNA, Messenger - analysis Signal Transduction Transcription Factors Vertebrates: reproduction |
Title | Direct action of melatonin in human granulosa-luteal cells |
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