{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T22:07:26Z","timestamp":1788300446365,"version":"build-2803163510"},"reference-count":30,"publisher":"The Endocrine Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,11,1]]},"abstract":"<jats:p>Ovarian hyperstimulation syndrome (OHSS) incidentally occurs in controlled ovarian stimulation protocols and is associated with human chorionic gonadotropin (hCG) administration. OHSS is caused by increased vascular permeability (VP) and thought to be mediated by hypersecretion of vascular endothelial growth factor (VEGF) by granulosa cells. Low molecular weight (LMW)-LH agonists have a similar mode of action but a shorter half-life compared with hCG, which could potentially lead to a clinical benefit in reducing the risk for OHSS in controlled ovarian stimulation protocols. The objective of this study is to investigate the role of an orally active LMW-LH agonist in OHSS induction compared with recombinant LH (rec-LH) and hCG. Immature rats were hyperstimulated with pregnant mare serum gonadotropin, and ovulation was induced by hCG, rec-LH or a LMW-LH agonist. The degree of VP was determined by Evans Blue in the abdominal cavity. Ovaries were weighed, and VEGF concentration in the ovary was determined. Pregnant mare serum gonadotropin stimulation followed by single-dose hCG or rec-LH resulted in clear enlargement of the ovaries and increased VP and VEGF levels. However, ovulation induction with a single dose of the LMW-LH agonist did not result in increased VP and VEGF levels, and even multiple dosing to mimic a longer exposure did not induce OHSS symptoms. In conclusion, we demonstrated that the oral LMW-LH agonist did not induce VP in rat, indicative for OHSS, possibly due to reduced VEGF production. If this is translatable to human, this could potentially represent a clinical benefit in reducing the risk for OHSS when using these compounds in controlled ovarian stimulation protocols.<\/jats:p>","DOI":"10.1210\/en.2011-1077","type":"journal-article","created":{"date-parts":[[2011,9,6]],"date-time":"2011-09-06T22:09:07Z","timestamp":1315346947000},"page":"4350-4357","source":"Crossref","is-referenced-by-count":49,"title":["Prevention of the Onset of Ovarian Hyperstimulation Syndrome (OHSS) in the Rat After Ovulation Induction with a Low Molecular Weight Agonist of the LH Receptor Compared with hCG and rec-LH"],"prefix":"10.1210","volume":"152","author":[{"given":"Ruud","family":"van de Lagemaat","sequence":"first","affiliation":[{"name":"Departments of Women's Health (R.v.d.L., B.C.R., C.M.T., S.M.M.), Merck Research Laboratories, 5340 BH Oss, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. C.","family":"Raafs","sequence":"first","affiliation":[{"name":"Departments of Women's Health (R.v.d.L., B.C.R., C.M.T., S.M.M.), Merck Research Laboratories, 5340 BH Oss, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"van Koppen","sequence":"first","affiliation":[{"name":"Departments of Women's Health (R.v.d.L., B.C.R., C.M.T., S.M.M.), Merck Research Laboratories, 5340 BH Oss, The Netherlands"},{"name":"Molecular Pharmacology (C.v.K.), Merck Research Laboratories, 5340 BH Oss, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. M.","family":"Timmers","sequence":"first","affiliation":[{"name":"Departments of Women's Health (R.v.d.L., B.C.R., C.M.T., S.M.M.), Merck Research Laboratories, 5340 BH Oss, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. M.","family":"Mulders","sequence":"first","affiliation":[{"name":"Departments of Women's Health (R.v.d.L., B.C.R., C.M.T., S.M.M.), Merck Research Laboratories, 5340 BH Oss, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. G. J. M.","family":"Hanssen","sequence":"first","affiliation":[{"name":"Project and Pipeline Management (R.G.J.M.H.), Merck Research Laboratories, 5340 BH Oss, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2011,9,6]]},"reference":[{"key":"2020071612581681600_B1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1055\/s-2001-13906","article-title":"An overview of the past, present, and future of nongonadal LH\/hCG actions in reproductive biology and medicine.","volume":"19","author":"Rao","year":"2001","journal-title":"Semin Reprod Med"},{"key":"2020071612581681600_B2","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0015-0282(16)57717-6","article-title":"The luteinizing hormone surge\u2013the final stage in ovulation induction: modern aspects of ovulation triggering.","volume":"64","author":"Shoham","year":"1995","journal-title":"Fertil Steril"},{"key":"2020071612581681600_B3","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/S0015-0282(16)60906-8","article-title":"Disappearance of exogenously administered human chorionic gonadotropin.","volume":"52","author":"Damewood","year":"1989","journal-title":"Fertil Steril"},{"key":"2020071612581681600_B4","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1093\/humrep\/13.6.1461","article-title":"A randomized three-way cross-over study in healthy pituitary-suppressed women to compare the bioavailability of human chorionic gonadotrophin (Pregnyl) after intramuscular and subcutaneous administration.","volume":"13","author":"Mannaerts","year":"1998","journal-title":"Hum Reprod"},{"key":"2020071612581681600_B5","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1210\/jcem-57-4-792","article-title":"Hormonal dynamics at midcycle: a reevaluation.","volume":"57","author":"Hoff","year":"1983","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612581681600_B6","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0015-0282(16)54474-4","article-title":"Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist.","volume":"56","author":"Itskovitz","year":"1991","journal-title":"Fertil Steril"},{"key":"2020071612581681600_B7","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1093\/humupd\/8.6.559","article-title":"Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review.","volume":"8","author":"Delvigne","year":"2002","journal-title":"Hum Reprod Update"},{"key":"2020071612581681600_B8","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1055\/s-0030-1265669","article-title":"Ovarian hyperstimulation syndrome: definition, incidence, and classification.","volume":"28","author":"Zivi","year":"2010","journal-title":"Semin Reprod Med"},{"key":"2020071612581681600_B9","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s10815-010-9387-6","article-title":"Ovarian hyperstimulation syndrome: pathophysiology and prevention.","volume":"27","author":"Nastri","year":"2010","journal-title":"J Assist Reprod Genet"},{"key":"2020071612581681600_B10","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1093\/humrep\/deh638","article-title":"Early and late ovarian hyperstimulation syndrome: early pregnancy outcome and profile.","volume":"20","author":"Papanikolaou","year":"2005","journal-title":"Hum Reprod"},{"key":"2020071612581681600_B11","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1093\/humrep\/den412","article-title":"Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor.","volume":"24","author":"van de Lagemaat","year":"2009","journal-title":"Hum Reprod"},{"key":"2020071612581681600_B12","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s00210-008-0318-3","article-title":"A signaling-selective, nanomolar potent allosteric low molecular weight agonist for the human luteinizing hormone receptor.","volume":"378","author":"van Koppen","year":"2008","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"2020071612581681600_B13","doi-asserted-by":"crossref","first-page":"4339","DOI":"10.1210\/en.2002-220204","article-title":"Vascular endothelial growth factor receptor-2 activation induces vascular permeability in hyperstimulated rats, and this effect is prevented by receptor blockade.","volume":"143","author":"G\u00f3mez","year":"2002","journal-title":"Endocrinology"},{"key":"2020071612581681600_B14","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1095\/biolreprod.102.010801","article-title":"Administration of moderate and high doses of gonadotropins to female rats increases ovarian vascular endothelial growth factor (VEGF) and VEGF receptor-2 expression that is associated to vascular hyperpermeability.","volume":"68","author":"G\u00f3mez","year":"2003","journal-title":"Biol Reprod"},{"key":"2020071612581681600_B15","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1530\/rep.1.00129","article-title":"Administration of low-dose LH induces ovulation and prevents vascular hyperpermeability and vascular endothelial growth factor expression in superovulated rats.","volume":"127","author":"G\u00f3mez","year":"2004","journal-title":"Reproduction"},{"key":"2020071612581681600_B16","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1093\/humrep\/deg116","article-title":"Bilateral partial oophorectomy in the management of severe ovarian hyperstimulation syndrome. An aggressive, but perhaps life-saving procedure.","volume":"18","author":"Amarin","year":"2003","journal-title":"Hum Reprod"},{"key":"2020071612581681600_B17","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1159\/000010306","article-title":"Use of intramuscular progesterone versus intravenous albumin for the prevention of ovarian hyperstimulation syndrome.","volume":"50","author":"Costabile","year":"2000","journal-title":"Gynecol Obstet Invest"},{"key":"2020071612581681600_B18","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1507\/endocrj.50.515","article-title":"Organ-specific production control of vascular endothelial growth factor in ovarian hyperstimulation syndrome model rats.","volume":"50","author":"Ishikawa","year":"2003","journal-title":"Endocr J"},{"key":"2020071612581681600_B19","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1210\/jcem-28-12-1763","article-title":"Disappearance rates of endogenous luteinizing hormone and chorionic gonadotropin in man.","volume":"28","author":"Yen","year":"1968","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612581681600_B20","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0065-230X(08)60716-2","article-title":"Role of VEGF-flt receptor system in normal and tumor angiogenesis.","volume":"67","author":"Shibuya","year":"1995","journal-title":"Adv Cancer Res"},{"key":"2020071612581681600_B21","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1093\/humupd\/dmn008","article-title":"Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome.","volume":"14","author":"Soares","year":"2008","journal-title":"Hum Reprod Update"},{"key":"2020071612581681600_B22","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/nature03987","article-title":"Pathophysiological consequences of VEGF-induced vascular permeability.","volume":"437","author":"Weis","year":"2005","journal-title":"Nature"},{"key":"2020071612581681600_B23","doi-asserted-by":"crossref","first-page":"6076","DOI":"10.1210\/en.2008-0521","article-title":"Vascular endothelial growth factor mediates the estrogen-induced breakdown of tight junctions between and increase in proliferation of microvessel endothelial cells in the baboon endometrium.","volume":"149","author":"Aberdeen","year":"2008","journal-title":"Endocrinology"},{"key":"2020071612581681600_B24","doi-asserted-by":"crossref","first-page":"5400","DOI":"10.1210\/en.2006-0657","article-title":"Low-dose dopamine agonist administration blocks vascular endothelial growth factor (VEGF)-mediated vascular hyperpermeability without altering VEGF receptor 2-dependent luteal angiogenesis in a rat ovarian hyperstimulation model.","volume":"147","author":"Gomez","year":"2006","journal-title":"Endocrinology"},{"key":"2020071612581681600_B25","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1055\/s-0030-1265670","article-title":"Physiology and pathology of ovarian hyperstimulation syndrome.","volume":"28","author":"G\u00f3mez","year":"2010","journal-title":"Semin Reprod Med"},{"key":"2020071612581681600_B26","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/S0015-0282(02)04242-5","article-title":"Concentration of vascular endothelial growth factor released by cultured human luteinized granulosa cells is higher in women with polycystic ovaries than in women with normal ovaries.","volume":"78","author":"Agrawal","year":"2002","journal-title":"Fertil Steril"},{"key":"2020071612581681600_B27","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/humupd\/3.3.255","article-title":"The role of vascular endothelial growth factor and interleukins in the pathogenesis of severe ovarian hyperstimulation syndrome.","volume":"3","author":"Rizk","year":"1997","journal-title":"Hum Reprod Update"},{"key":"2020071612581681600_B28","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1093\/molehr\/8.5.409","article-title":"The role of endothelial cells in the pathogenesis of ovarian hyperstimulation syndrome.","volume":"8","author":"Albert","year":"2002","journal-title":"Mol Hum Reprod"},{"key":"2020071612581681600_B29","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1038\/ncb1486","article-title":"VEGF controls endothelial-cell permeability by promoting the \u03b2-arrestin-dependent endocytosis of VE-cadherin.","volume":"8","author":"Gavard","year":"2006","journal-title":"Nat Cell Biol"},{"key":"2020071612581681600_B30","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1080\/10739680600930347","article-title":"Ca2+ signaling, TRP channels, and endothelial permeability.","volume":"13","author":"Tiruppathi","year":"2006","journal-title":"Microcirculation"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/152\/11\/4350\/9015373\/endo4350.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/152\/11\/4350\/9015373\/endo4350.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T18:33:38Z","timestamp":1594924418000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/152\/11\/4350\/2457091"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,9,6]]},"references-count":30,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2011,11,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2011-1077","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,9,6]]}}}