A C TA Obstetricia et Gynecologica
AOGS LE TT E R TO THE EDIT O R
Maternal age and serum concentration of human chorionic gonadotropin in early pregnancy: influence of gonadotropinreleasing hormone
Sir Progesterone is a critical hormone for the maintenance of pregnancy. The corpus luteum (during early pregnancy) and the syncytiotrophoblast (after 7–9 weeks of gestation) play roles in progesterone secretion (1). Human chorionic gonadotropin (hCG), which is secreted by the syncytiotrophoblast, stimulates progesterone production by rescuing corpus luteum regression (1). Hence, hCG plays an important role in the maintenance of pregnancy during the early stages of pregnancy (1). Gonadotropin-releasing hormone (GnRH) is synthesized in the human placenta. GnRH-I, GnRH-II, and gonadotropin-releasing hormone receptor (GnRHR)-I have been identified in decidua and trophoblasts during pregnancy (2). GnRH-I and GnRH-II were reported to induce the production of hCG in trophoblasts, HTR-8/SV neo cells, and choriocarcinoma cells (2,3). We previously reported that GnRH/GnRHR signaling at the maternal–fetal interface increased hCG production in a dose-dependent manner that was independent of GnRH-I or GnRH-II stimulation (3). Hence, it is possible that GnRH/GnRHR signaling may contribute to the maintenance of pregnancy. Haavaldsen et al. reported that serum concentrations of hCG in very early pregnancy decrease with increasing maternal age (4). They also reported that the lower hCG levels found in women of advanced age may reflect functional impairment or delayed proliferation of trophoblasts in early pregnancy in these women (4). We agree with this finding and suggest a mechanism that might be responsible for the decreased expression of hCG that is observed with aging. Female reproductive senescence in rodents is associated with a decrease in the ability of the hypothalamic–pituitary axis to respond to positive estradiol feedback (5). This could cause a decrease in the activation of GnRH neurons, a decrease in GnRH release, and an abnormal luteinizing hormone (LH) surge, even though the GnRH peptide level is unchanged or may even be increased (5). Similar to rodents, perimenopausal and middle-aged women exhibit attenuated LH release characterized by the failure of positive estrogen feedback to induce an LH surge (5). b-hCG, LH, and follicle-stimulating hormone share a common a subunit, although they have distinct b subunits. Therefore, it is likely that the mechanism by which GnRH stimulates b-hCG transcription is similar to the mechanism by which it stimulates LH transcription (2). This finding is supported by previous reports that GnRH increased hCG production at the maternal–fetal interface (2,3). One study reported that estradiol downregulated the expression of the GnRH gene in human cytotrophoblasts in a dose-depen-
dent manner (6). Additionally, negative and positive estrogen response elements were identified in an upstream promoter in the placental JEG-3 cells (7). Therefore, we postulated that there might be negative and positive estrogen feedback at the maternal–fetal interface. In conclusion, we suggest that a progressive decrease in GnRH release might develop via estrogenrelated mechanisms, such as the failure of positive estrogen feedback due to aging in pregnant women, and is followed by a gradual decrease in the secretion of hCG by trophoblasts. This hypothesis will need to be tested in well-designed studies.
Banghyun Lee1, Tae Chul Park2 and Hee Joong Lee2,* Department of Obstetrics & Gynecology, Seoul National University Bundang Hospital, Seoul National University, Seoul, and 2Department of Obstetrics & Gynecology, The Catholic University of Korea, Seoul, Korea 1
*Corresponding Author: Hee Joong Lee E-mail: [email protected] DOI: 10.1111/aogs.12573
References 1. Nakajima ST, Nason FG, Badger GJ, Gibson M. Progesterone production in early pregnancy. Fertil Steril. 1991;55:516–21. 2. Sasaki K, Norwitz ER. Gonadotropin-releasing hormone/ gonadotropin-releasing hormone receptor signaling in the placenta. Curr Opin Endocrinol Diabetes Obes. 2011;18:401–8. 3. Lee HJ, Snegovskikh VV, Park JS, Foyouzi N, Han KT, Hodgson EJ, et al. Role of GnRH-GnRH receptor signaling at the maternal-fetal interface. Fertil Steril. 2010;94:2680–7. 4. Haavaldsen C, Fedorcsak P, Tanbo T, Eskild A. Maternal age and serum concentration of human chorionic gonadotropin in early pregnancy. Acta Obstet Gynecol Scand. 2014;93:1290–4. 5. Neal-Perry G, Nejat E, Dicken C. The neuroendocrine physiology of female reproductive aging: an update. Maturitas. 2010;67:34–8.
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 443–444
443
Letter to the Editor
6. Wong BC, Wang X, Oehninger S, Gibbons WE, Dong KW. Estrogen down-regulates GnRH gene expression in human placental cytotrophoblast cells. Mol Cell Endocrinol. 2004;213:199–210.
7. Chen Z, Zheng H, Dong KW. Identification of negative and positive estrogen response elements in human GnRH upstream promoter in the placental JEG-3 cells. Mol Cell Endocrinol. 2001;184:125–34.
Reply to Bang Hyun Lee et al.: Maternal age and human chorionic gonadotropin in early pregnancy: influence of gonadotropin-releasing hormone
Sir, We appreciate the interest of Professor Lee and co-workers in our study on maternal age and early serum concentration of hCG in IVF pregnancies (1). Unfortunately, and as pointed out by Lee and co-workers, our study cannot explain why hCG in early pregnancy declines with increasing maternal age. In pregnancy, hCG exists in at least two biologically active forms, synthesized in different types of trophoblast cells and with different functions (2). In our study, we studied all hCG types together. However, normoglycosylated hCG is synthesized in syncytiotrophoblast. It functions through binding to an LH receptor-like molecule and stimulates progesterone synthesis in the corpus luteum. Hyperglycosylated hCG, on the other hand, is produced in the cytotrophoblasts. It binds to the transforming growth factor (TGF)b-receptor and stimulates trophoblast invasion and proliferation, but it has no stimulatory effect on the corpus luteum. Hyperglycosylated hCG is the dominant hCG form during the early weeks of pregnancy, but this hCG type almost disappears after the first trimester (3–5). We therefore believe that the regulation of hCG synthesis/secretion, whether through estradiol feedback, hypothalamic or placental GnRH secretion, or through other mechanisms, should be tested for these two hCG molecules separately. It could be that the regulation of the synthesis of the different types of hCG molecules differs by maternal age.
Camilla Haavaldsen1,2,*, Peter Fedorcsak3, Tom Tanbo2,3 and Anne Eskild1,2 1 Department of Gynecology and Obstetrics, Akershus University Hospital, Lørenskog, Norway, 2Institute of Clinical Medicine, University of Oslo, and 3Section for Reproductive Medicine,
444
Department of Gynecology, Oslo University Hospital, Rikshospitalet, Oslo, Norway *Corresponding Author: Camilla Haavaldsen E-mail: [email protected] DOI: 10.1111/aogs.12583
References 1. Haavaldsen C, Fedorcsak P, Tanbo T, Eskild A. Maternal age and serum concentration of human chorionic gonadotropin in early pregnancy. Acta Obstet Gynecol Scand. 2014;93:1290–4. 2. Cole LA. hCG, five independent molecules. Clin Chim Acta. 2012;413:48–65. 3. Guibourdenche J, Handschuh K, Tsatsaris V, Gerbaud P, Leguy MC, Muller F, et al. Hyperglycosylated hCG is a marker of early human trophoblast invasion. J Clin Endocrinol Metab. 2010;95:E240–4. 4. Crochet JR, Shah AA, Schomberg DW, Price TM. Hyperglycosylated human chorionic gonadotropin does not increase progesterone production by luteinized granulosa cells. J Clin Endocrinol Metab. 2012;97:E1741–4. 5. Berndt S, Blacher S, Munaut C, Detilleux J, Perrier d’Hauterive S, Huhtaniemi I, et al. Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-b receptor activation. FASEB J. 2013;27:1309– 21.
© 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 443–444
Copyright of Acta Obstetricia et Gynecologica Scandinavica is the property of WileyBlackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
AOGS LE TT E R TO THE EDIT O R
Maternal age and serum concentration of human chorionic gonadotropin in early pregnancy: influence of gonadotropinreleasing hormone
Sir Progesterone is a critical hormone for the maintenance of pregnancy. The corpus luteum (during early pregnancy) and the syncytiotrophoblast (after 7–9 weeks of gestation) play roles in progesterone secretion (1). Human chorionic gonadotropin (hCG), which is secreted by the syncytiotrophoblast, stimulates progesterone production by rescuing corpus luteum regression (1). Hence, hCG plays an important role in the maintenance of pregnancy during the early stages of pregnancy (1). Gonadotropin-releasing hormone (GnRH) is synthesized in the human placenta. GnRH-I, GnRH-II, and gonadotropin-releasing hormone receptor (GnRHR)-I have been identified in decidua and trophoblasts during pregnancy (2). GnRH-I and GnRH-II were reported to induce the production of hCG in trophoblasts, HTR-8/SV neo cells, and choriocarcinoma cells (2,3). We previously reported that GnRH/GnRHR signaling at the maternal–fetal interface increased hCG production in a dose-dependent manner that was independent of GnRH-I or GnRH-II stimulation (3). Hence, it is possible that GnRH/GnRHR signaling may contribute to the maintenance of pregnancy. Haavaldsen et al. reported that serum concentrations of hCG in very early pregnancy decrease with increasing maternal age (4). They also reported that the lower hCG levels found in women of advanced age may reflect functional impairment or delayed proliferation of trophoblasts in early pregnancy in these women (4). We agree with this finding and suggest a mechanism that might be responsible for the decreased expression of hCG that is observed with aging. Female reproductive senescence in rodents is associated with a decrease in the ability of the hypothalamic–pituitary axis to respond to positive estradiol feedback (5). This could cause a decrease in the activation of GnRH neurons, a decrease in GnRH release, and an abnormal luteinizing hormone (LH) surge, even though the GnRH peptide level is unchanged or may even be increased (5). Similar to rodents, perimenopausal and middle-aged women exhibit attenuated LH release characterized by the failure of positive estrogen feedback to induce an LH surge (5). b-hCG, LH, and follicle-stimulating hormone share a common a subunit, although they have distinct b subunits. Therefore, it is likely that the mechanism by which GnRH stimulates b-hCG transcription is similar to the mechanism by which it stimulates LH transcription (2). This finding is supported by previous reports that GnRH increased hCG production at the maternal–fetal interface (2,3). One study reported that estradiol downregulated the expression of the GnRH gene in human cytotrophoblasts in a dose-depen-
dent manner (6). Additionally, negative and positive estrogen response elements were identified in an upstream promoter in the placental JEG-3 cells (7). Therefore, we postulated that there might be negative and positive estrogen feedback at the maternal–fetal interface. In conclusion, we suggest that a progressive decrease in GnRH release might develop via estrogenrelated mechanisms, such as the failure of positive estrogen feedback due to aging in pregnant women, and is followed by a gradual decrease in the secretion of hCG by trophoblasts. This hypothesis will need to be tested in well-designed studies.
Banghyun Lee1, Tae Chul Park2 and Hee Joong Lee2,* Department of Obstetrics & Gynecology, Seoul National University Bundang Hospital, Seoul National University, Seoul, and 2Department of Obstetrics & Gynecology, The Catholic University of Korea, Seoul, Korea 1
*Corresponding Author: Hee Joong Lee E-mail: [email protected] DOI: 10.1111/aogs.12573
References 1. Nakajima ST, Nason FG, Badger GJ, Gibson M. Progesterone production in early pregnancy. Fertil Steril. 1991;55:516–21. 2. Sasaki K, Norwitz ER. Gonadotropin-releasing hormone/ gonadotropin-releasing hormone receptor signaling in the placenta. Curr Opin Endocrinol Diabetes Obes. 2011;18:401–8. 3. Lee HJ, Snegovskikh VV, Park JS, Foyouzi N, Han KT, Hodgson EJ, et al. Role of GnRH-GnRH receptor signaling at the maternal-fetal interface. Fertil Steril. 2010;94:2680–7. 4. Haavaldsen C, Fedorcsak P, Tanbo T, Eskild A. Maternal age and serum concentration of human chorionic gonadotropin in early pregnancy. Acta Obstet Gynecol Scand. 2014;93:1290–4. 5. Neal-Perry G, Nejat E, Dicken C. The neuroendocrine physiology of female reproductive aging: an update. Maturitas. 2010;67:34–8.
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 443–444
443
Letter to the Editor
6. Wong BC, Wang X, Oehninger S, Gibbons WE, Dong KW. Estrogen down-regulates GnRH gene expression in human placental cytotrophoblast cells. Mol Cell Endocrinol. 2004;213:199–210.
7. Chen Z, Zheng H, Dong KW. Identification of negative and positive estrogen response elements in human GnRH upstream promoter in the placental JEG-3 cells. Mol Cell Endocrinol. 2001;184:125–34.
Reply to Bang Hyun Lee et al.: Maternal age and human chorionic gonadotropin in early pregnancy: influence of gonadotropin-releasing hormone
Sir, We appreciate the interest of Professor Lee and co-workers in our study on maternal age and early serum concentration of hCG in IVF pregnancies (1). Unfortunately, and as pointed out by Lee and co-workers, our study cannot explain why hCG in early pregnancy declines with increasing maternal age. In pregnancy, hCG exists in at least two biologically active forms, synthesized in different types of trophoblast cells and with different functions (2). In our study, we studied all hCG types together. However, normoglycosylated hCG is synthesized in syncytiotrophoblast. It functions through binding to an LH receptor-like molecule and stimulates progesterone synthesis in the corpus luteum. Hyperglycosylated hCG, on the other hand, is produced in the cytotrophoblasts. It binds to the transforming growth factor (TGF)b-receptor and stimulates trophoblast invasion and proliferation, but it has no stimulatory effect on the corpus luteum. Hyperglycosylated hCG is the dominant hCG form during the early weeks of pregnancy, but this hCG type almost disappears after the first trimester (3–5). We therefore believe that the regulation of hCG synthesis/secretion, whether through estradiol feedback, hypothalamic or placental GnRH secretion, or through other mechanisms, should be tested for these two hCG molecules separately. It could be that the regulation of the synthesis of the different types of hCG molecules differs by maternal age.
Camilla Haavaldsen1,2,*, Peter Fedorcsak3, Tom Tanbo2,3 and Anne Eskild1,2 1 Department of Gynecology and Obstetrics, Akershus University Hospital, Lørenskog, Norway, 2Institute of Clinical Medicine, University of Oslo, and 3Section for Reproductive Medicine,
444
Department of Gynecology, Oslo University Hospital, Rikshospitalet, Oslo, Norway *Corresponding Author: Camilla Haavaldsen E-mail: [email protected] DOI: 10.1111/aogs.12583
References 1. Haavaldsen C, Fedorcsak P, Tanbo T, Eskild A. Maternal age and serum concentration of human chorionic gonadotropin in early pregnancy. Acta Obstet Gynecol Scand. 2014;93:1290–4. 2. Cole LA. hCG, five independent molecules. Clin Chim Acta. 2012;413:48–65. 3. Guibourdenche J, Handschuh K, Tsatsaris V, Gerbaud P, Leguy MC, Muller F, et al. Hyperglycosylated hCG is a marker of early human trophoblast invasion. J Clin Endocrinol Metab. 2010;95:E240–4. 4. Crochet JR, Shah AA, Schomberg DW, Price TM. Hyperglycosylated human chorionic gonadotropin does not increase progesterone production by luteinized granulosa cells. J Clin Endocrinol Metab. 2012;97:E1741–4. 5. Berndt S, Blacher S, Munaut C, Detilleux J, Perrier d’Hauterive S, Huhtaniemi I, et al. Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-b receptor activation. FASEB J. 2013;27:1309– 21.
© 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 443–444
Copyright of Acta Obstetricia et Gynecologica Scandinavica is the property of WileyBlackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
