Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats
Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we...
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| Veröffentlicht in: | International journal of molecular sciences 2023-12, Vol.24 (23), p.16618 |
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| creator | Derkach, Kira V Lebedev, Ivan A Morina, Irina Yu Bakhtyukov, Andrey A Pechalnova, Alena S Sorokoumov, Viktor N Kuznetsova, Veronica S Romanova, Irina V Shpakov, Alexander O |
| description | Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active when administered orally. The aim was to study the effectiveness of TP4/2 (orally, 40 mg/kg) as an ovulation inducer in FSH-stimulated immature female rats, compared with hCG (s.c., 15 IU/rat). TP4/2 stimulated progesterone production and corpus luteum formation; time-dependently increased the ovarian expression of steroidogenic genes (
,
,
) and genes involved in ovulation regulation (
,
,
,
); and increased the content of metalloproteinase ADAMTS-1 in the ovaries. These effects were similar to those of hCG, although in some cases they were less pronounced. TP4/2, in contrast to hCG, maintained normal LH levels and increased the ovarian expression of the LH/hCG receptor gene, indicating preservation of ovarian sensitivity to LH, and did not cause a sustained increase in expression of vascular endothelial growth factor-A involved in OHSS. Thus, TP4/2 is an effective ovulation inducer that, unlike hCG, has a lower risk of OHSS and ovarian LH resistance due to its moderate stimulating effect on steroidogenesis. |
| doi_str_mv | 10.3390/ijms242316618 |
| format | Article |
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,
,
) and genes involved in ovulation regulation (
,
,
,
); and increased the content of metalloproteinase ADAMTS-1 in the ovaries. These effects were similar to those of hCG, although in some cases they were less pronounced. TP4/2, in contrast to hCG, maintained normal LH levels and increased the ovarian expression of the LH/hCG receptor gene, indicating preservation of ovarian sensitivity to LH, and did not cause a sustained increase in expression of vascular endothelial growth factor-A involved in OHSS. Thus, TP4/2 is an effective ovulation inducer that, unlike hCG, has a lower risk of OHSS and ovarian LH resistance due to its moderate stimulating effect on steroidogenesis.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms242316618</identifier><identifier>PMID: 38068943</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Animals ; Chorionic gonadotropin ; Chorionic Gonadotropin - pharmacology ; Chorionic Gonadotropin - therapeutic use ; Female ; Females ; Genes ; Glycoproteins ; Gonadal Steroid Hormones - pharmacology ; Hormones ; Humans ; Kinases ; Luteinizing Hormone - metabolism ; Ovarian Hyperstimulation Syndrome - drug therapy ; Ovarian Hyperstimulation Syndrome - metabolism ; Ovaries ; Ovulation ; Progesterone ; Proteins ; Rats ; Receptors, LH - metabolism ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - metabolism</subject><ispartof>International journal of molecular sciences, 2023-12, Vol.24 (23), p.16618</ispartof><rights>COPYRIGHT 2023 MDPI AG</rights><rights>2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c383t-332a3a36fdddaa7efa5f53f6c8005638e4af9e0e651be83ecf63feff874e769d3</cites><orcidid>0000-0002-4917-2175 ; 0000-0002-0348-0631 ; 0009-0003-0668-2110 ; 0000-0002-4293-3162 ; 0009-0002-4240-4604 ; 0000-0001-6555-9540 ; 0000-0002-2060-2020 ; 0000-0002-2252-0088</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38068943$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Derkach, Kira V</creatorcontrib><creatorcontrib>Lebedev, Ivan A</creatorcontrib><creatorcontrib>Morina, Irina Yu</creatorcontrib><creatorcontrib>Bakhtyukov, Andrey A</creatorcontrib><creatorcontrib>Pechalnova, Alena S</creatorcontrib><creatorcontrib>Sorokoumov, Viktor N</creatorcontrib><creatorcontrib>Kuznetsova, Veronica S</creatorcontrib><creatorcontrib>Romanova, Irina V</creatorcontrib><creatorcontrib>Shpakov, Alexander O</creatorcontrib><title>Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active when administered orally. The aim was to study the effectiveness of TP4/2 (orally, 40 mg/kg) as an ovulation inducer in FSH-stimulated immature female rats, compared with hCG (s.c., 15 IU/rat). TP4/2 stimulated progesterone production and corpus luteum formation; time-dependently increased the ovarian expression of steroidogenic genes (
,
,
) and genes involved in ovulation regulation (
,
,
,
); and increased the content of metalloproteinase ADAMTS-1 in the ovaries. These effects were similar to those of hCG, although in some cases they were less pronounced. TP4/2, in contrast to hCG, maintained normal LH levels and increased the ovarian expression of the LH/hCG receptor gene, indicating preservation of ovarian sensitivity to LH, and did not cause a sustained increase in expression of vascular endothelial growth factor-A involved in OHSS. Thus, TP4/2 is an effective ovulation inducer that, unlike hCG, has a lower risk of OHSS and ovarian LH resistance due to its moderate stimulating effect on steroidogenesis.</description><subject>Animals</subject><subject>Chorionic gonadotropin</subject><subject>Chorionic Gonadotropin - pharmacology</subject><subject>Chorionic Gonadotropin - therapeutic use</subject><subject>Female</subject><subject>Females</subject><subject>Genes</subject><subject>Glycoproteins</subject><subject>Gonadal Steroid Hormones - pharmacology</subject><subject>Hormones</subject><subject>Humans</subject><subject>Kinases</subject><subject>Luteinizing Hormone - metabolism</subject><subject>Ovarian Hyperstimulation Syndrome - drug therapy</subject><subject>Ovarian Hyperstimulation Syndrome - metabolism</subject><subject>Ovaries</subject><subject>Ovulation</subject><subject>Progesterone</subject><subject>Proteins</subject><subject>Rats</subject><subject>Receptors, LH - metabolism</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptkk9r3DAQxU1padK0x16LoZdenMgaW5aPy5I_CwsLaXs2ijTaaLEkV5ID7afqR6yW3SRNKTpoRvzeY0a8ovhYk3OAnlyYnY20oVAzVvNXxWndUFoRwrrXf9UnxbsYd4RQoG3_tjgBThjvGzgtfi-9nUQw0bvS6_JrwuCN8lt0RpbCqXLzMI8iGe-qlVOzNG5bXmqNMsU9vwnp3scsOtKLcXxsF1vvTDxg6zmhcebXXn3jg_UOL5b3PmTbTF57J5RPwU_GlbcocUo-lLleWSvSHLC8QitGLG9Fiu-LN1qMET8c77Pi-9Xlt-VNtd5cr5aLdSWBQ6oAqAABTCulhOhQi1a3oJnkhLQMODZC90iQtfUdckCpGWjUmncNdqxXcFZ8OfhOwf-YMabBmihxHIVDP8eB9oT2DKDtMvr5H3Tn5-DydAPlfd80nND2mdrmVQbjdN5YyL3psOi6lmcSSKbO_0Plo9Aamf9Nm_z-QlAdBDL4GAPqYQrGivBzqMmwT8jwIiGZ_3Qcdr6zqJ7ox0jAH716uiI</recordid><startdate>20231201</startdate><enddate>20231201</enddate><creator>Derkach, Kira V</creator><creator>Lebedev, Ivan A</creator><creator>Morina, Irina Yu</creator><creator>Bakhtyukov, Andrey A</creator><creator>Pechalnova, Alena S</creator><creator>Sorokoumov, Viktor N</creator><creator>Kuznetsova, Veronica S</creator><creator>Romanova, Irina V</creator><creator>Shpakov, Alexander O</creator><general>MDPI AG</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4917-2175</orcidid><orcidid>https://orcid.org/0000-0002-0348-0631</orcidid><orcidid>https://orcid.org/0009-0003-0668-2110</orcidid><orcidid>https://orcid.org/0000-0002-4293-3162</orcidid><orcidid>https://orcid.org/0009-0002-4240-4604</orcidid><orcidid>https://orcid.org/0000-0001-6555-9540</orcidid><orcidid>https://orcid.org/0000-0002-2060-2020</orcidid><orcidid>https://orcid.org/0000-0002-2252-0088</orcidid></search><sort><creationdate>20231201</creationdate><title>Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats</title><author>Derkach, Kira V ; Lebedev, Ivan A ; Morina, Irina Yu ; Bakhtyukov, Andrey A ; Pechalnova, Alena S ; Sorokoumov, Viktor N ; Kuznetsova, Veronica S ; Romanova, Irina V ; Shpakov, Alexander O</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c383t-332a3a36fdddaa7efa5f53f6c8005638e4af9e0e651be83ecf63feff874e769d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Chorionic gonadotropin</topic><topic>Chorionic Gonadotropin - pharmacology</topic><topic>Chorionic Gonadotropin - therapeutic use</topic><topic>Female</topic><topic>Females</topic><topic>Genes</topic><topic>Glycoproteins</topic><topic>Gonadal Steroid Hormones - pharmacology</topic><topic>Hormones</topic><topic>Humans</topic><topic>Kinases</topic><topic>Luteinizing Hormone - metabolism</topic><topic>Ovarian Hyperstimulation Syndrome - drug therapy</topic><topic>Ovarian Hyperstimulation Syndrome - metabolism</topic><topic>Ovaries</topic><topic>Ovulation</topic><topic>Progesterone</topic><topic>Proteins</topic><topic>Rats</topic><topic>Receptors, LH - metabolism</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Derkach, Kira V</creatorcontrib><creatorcontrib>Lebedev, Ivan A</creatorcontrib><creatorcontrib>Morina, Irina Yu</creatorcontrib><creatorcontrib>Bakhtyukov, Andrey A</creatorcontrib><creatorcontrib>Pechalnova, Alena S</creatorcontrib><creatorcontrib>Sorokoumov, Viktor N</creatorcontrib><creatorcontrib>Kuznetsova, Veronica S</creatorcontrib><creatorcontrib>Romanova, Irina V</creatorcontrib><creatorcontrib>Shpakov, Alexander O</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Derkach, Kira V</au><au>Lebedev, Ivan A</au><au>Morina, Irina Yu</au><au>Bakhtyukov, Andrey A</au><au>Pechalnova, Alena S</au><au>Sorokoumov, Viktor N</au><au>Kuznetsova, Veronica S</au><au>Romanova, Irina V</au><au>Shpakov, Alexander O</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2023-12-01</date><risdate>2023</risdate><volume>24</volume><issue>23</issue><spage>16618</spage><pages>16618-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active when administered orally. The aim was to study the effectiveness of TP4/2 (orally, 40 mg/kg) as an ovulation inducer in FSH-stimulated immature female rats, compared with hCG (s.c., 15 IU/rat). TP4/2 stimulated progesterone production and corpus luteum formation; time-dependently increased the ovarian expression of steroidogenic genes (
,
,
) and genes involved in ovulation regulation (
,
,
,
); and increased the content of metalloproteinase ADAMTS-1 in the ovaries. These effects were similar to those of hCG, although in some cases they were less pronounced. TP4/2, in contrast to hCG, maintained normal LH levels and increased the ovarian expression of the LH/hCG receptor gene, indicating preservation of ovarian sensitivity to LH, and did not cause a sustained increase in expression of vascular endothelial growth factor-A involved in OHSS. Thus, TP4/2 is an effective ovulation inducer that, unlike hCG, has a lower risk of OHSS and ovarian LH resistance due to its moderate stimulating effect on steroidogenesis.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>38068943</pmid><doi>10.3390/ijms242316618</doi><orcidid>https://orcid.org/0000-0002-4917-2175</orcidid><orcidid>https://orcid.org/0000-0002-0348-0631</orcidid><orcidid>https://orcid.org/0009-0003-0668-2110</orcidid><orcidid>https://orcid.org/0000-0002-4293-3162</orcidid><orcidid>https://orcid.org/0009-0002-4240-4604</orcidid><orcidid>https://orcid.org/0000-0001-6555-9540</orcidid><orcidid>https://orcid.org/0000-0002-2060-2020</orcidid><orcidid>https://orcid.org/0000-0002-2252-0088</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of molecular sciences, 2023-12, Vol.24 (23), p.16618 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central |
| subjects | Animals Chorionic gonadotropin Chorionic Gonadotropin - pharmacology Chorionic Gonadotropin - therapeutic use Female Females Genes Glycoproteins Gonadal Steroid Hormones - pharmacology Hormones Humans Kinases Luteinizing Hormone - metabolism Ovarian Hyperstimulation Syndrome - drug therapy Ovarian Hyperstimulation Syndrome - metabolism Ovaries Ovulation Progesterone Proteins Rats Receptors, LH - metabolism Vascular endothelial growth factor Vascular Endothelial Growth Factor A - metabolism |
| title | Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats |
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