Initiation of ovarian stimulation independent of the menstrual cycle: a case–control study

Purpose In the GnRH-antagonist protocol, ovarian stimulation with gonadotropins typically commences on cycle day 2 or 3. Initiation of ovarian stimulation with a spontaneously occurring menstruation, however, poses significant organizational challenges for treatment centres and patients alike. It ha...

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Veröffentlicht in:Archives of gynecology and obstetrics 2013-10, Vol.288 (4), p.901-904
Hauptverfasser: Buendgen, Nana Kristin, Schultze-Mosgau, Askan, Cordes, Tim, Diedrich, Klaus, Griesinger, Georg
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container_issue 4
container_start_page 901
container_title Archives of gynecology and obstetrics
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creator Buendgen, Nana Kristin
Schultze-Mosgau, Askan
Cordes, Tim
Diedrich, Klaus
Griesinger, Georg
description Purpose In the GnRH-antagonist protocol, ovarian stimulation with gonadotropins typically commences on cycle day 2 or 3. Initiation of ovarian stimulation with a spontaneously occurring menstruation, however, poses significant organizational challenges for treatment centres and patients alike. It has previously been demonstrated in the context of fertility preservation that initiation of stimulation in the luteal phase is feasible in terms of retrieval of mature oocytes for cryopreservation. Herein, we report the extension of this concept to a routine IVF setting with the aim of establishing an ovarian stimulation protocol, which can be utilized independent of menstruation. Because of asynchrony of endometrium and embryo in such a setting, all fertilized oocytes have to be cryopreserved for a later transfer. Methods This was a prospective, case–control study (trial registration: NCT00795041) on the feasibility of starting ovarian stimulation in a GnRH-antagonist protocol in the luteal phase. Inclusion criteria were: IVF or ICSI; 18–36 years; ≤3 previous IVF/ICSI attempts; BMI 20–30 kg/m 2 ; regular cycle (28–35 days); luteal phase progesterone >7 ng/ml at initiation of stimulation. Exclusion criteria were: PCOS, endometriosis ≥AFS III°, unilateral ovary, expected poor response. Stimulation was performed with highly purified uFSH (Bravelle ® ) 300 IU/day and 0.25 mg/day GnRH-antagonist starting on cycle day 19–21 of a spontaneous menstrual cycle and commencing until hCG administration when three follicles ≥17 mm were present. All 2PN stage oocytes were vitrified for later transfers in programmed cycles. Feasibility was defined as the achievement of ongoing pregnancies progressing beyond the 12th gestational week in at least 2/10 study subjects (primary outcome). Secondary outcomes were gonadotropin consumption per oocyte obtained, stimulation duration, and fertilization rates. Study subjects were matched in a 1:3 ratio with concomitantly treated control cases of similar age, BMI, and duration of infertility who were treated in a conventional GnRH-antagonist protocol with 150–225 rFSH or HP-HMG/day. Results The study group consisted of ten subjects, mean age 31.4 years, BMI 25.4 kg/m 2 , of which one had fertilization failure. Mean stimulation duration was 11.7 (SD 1.6) vs. 9.1 (SD 1.3) days, mean cumulative FSH dose was 3,495.0 (SD 447.5) vs. 2,040.5 (SD 576.2) IU, and mean number of oocytes was 8.8 (SD 5.0) vs. 10.0 (SD 5.4) in study vs. control group, res
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Initiation of ovarian stimulation with a spontaneously occurring menstruation, however, poses significant organizational challenges for treatment centres and patients alike. It has previously been demonstrated in the context of fertility preservation that initiation of stimulation in the luteal phase is feasible in terms of retrieval of mature oocytes for cryopreservation. Herein, we report the extension of this concept to a routine IVF setting with the aim of establishing an ovarian stimulation protocol, which can be utilized independent of menstruation. Because of asynchrony of endometrium and embryo in such a setting, all fertilized oocytes have to be cryopreserved for a later transfer. Methods This was a prospective, case–control study (trial registration: NCT00795041) on the feasibility of starting ovarian stimulation in a GnRH-antagonist protocol in the luteal phase. Inclusion criteria were: IVF or ICSI; 18–36 years; ≤3 previous IVF/ICSI attempts; BMI 20–30 kg/m 2 ; regular cycle (28–35 days); luteal phase progesterone &gt;7 ng/ml at initiation of stimulation. Exclusion criteria were: PCOS, endometriosis ≥AFS III°, unilateral ovary, expected poor response. Stimulation was performed with highly purified uFSH (Bravelle ® ) 300 IU/day and 0.25 mg/day GnRH-antagonist starting on cycle day 19–21 of a spontaneous menstrual cycle and commencing until hCG administration when three follicles ≥17 mm were present. All 2PN stage oocytes were vitrified for later transfers in programmed cycles. Feasibility was defined as the achievement of ongoing pregnancies progressing beyond the 12th gestational week in at least 2/10 study subjects (primary outcome). Secondary outcomes were gonadotropin consumption per oocyte obtained, stimulation duration, and fertilization rates. Study subjects were matched in a 1:3 ratio with concomitantly treated control cases of similar age, BMI, and duration of infertility who were treated in a conventional GnRH-antagonist protocol with 150–225 rFSH or HP-HMG/day. Results The study group consisted of ten subjects, mean age 31.4 years, BMI 25.4 kg/m 2 , of which one had fertilization failure. Mean stimulation duration was 11.7 (SD 1.6) vs. 9.1 (SD 1.3) days, mean cumulative FSH dose was 3,495.0 (SD 447.5) vs. 2,040.5 (SD 576.2) IU, and mean number of oocytes was 8.8 (SD 5.0) vs. 10.0 (SD 5.4) in study vs. control group, respectively. Per follicle ≥10 mm, the cumulative FSH dose was 274.5 (SD 130.8) IU vs. 245.2 (SD 232.3) IU in study and control groups, respectively. Cumulative ongoing pregnancy rates were 1/10 (10 %) and 6/30 (20.0 %) in study and control group, respectively (difference: 10 %, 95 % confidence interval of the difference: −29.2–22.2 %, p  = 0.47). Fertilization rate was similar between groups, with 63.5 % (SD 32.9) in the study and 61.3 % (SD 26.7) in the control group, respectively. Serum estradiol levels were significantly lower on the day of triggering final oocyte maturation with 1,005.3 (SD 336.2) vs. 1,977.4 pg/ml (SD 1,106.5) in study and control group, respectively. Similarly, peak estradiol biosynthesis per growing follicle ≥10 mm was lower in the study group (134 pg/ml, SD 158.4 vs. 186.7 pg/ml, SD 84.7). Conclusions Per retrieved oocyte, a nearly threefold higher dose of FSH had to be administered when ovarian stimulation had been initiated in the luteal phase. Furthermore, the present study casts doubt on the efficacy of initiating ovarian stimulation in the luteal phase in terms of pregnancy achievement. Thus, this concept is currently not feasible for routine use, and it should also be explored further before using it at larger scale in the context of emergency stimulation for fertility preservation.</description><identifier>ISSN: 0932-0067</identifier><identifier>EISSN: 1432-0711</identifier><identifier>DOI: 10.1007/s00404-013-2794-z</identifier><identifier>PMID: 23545834</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adolescent ; Adult ; Drug Administration Schedule ; Drug Therapy, Combination ; Endocrinology ; Feasibility Studies ; Female ; Fertilization in Vitro - methods ; Gonadotropin-Releasing Hormone - antagonists &amp; inhibitors ; Gynecology ; Human Genetics ; Humans ; Infertility ; Infertility, Female - therapy ; Luteal Phase ; Medicine ; Medicine &amp; Public Health ; Menstruation ; Obstetrics/Perinatology/Midwifery ; Oocyte Retrieval ; Ovulation Induction - methods ; Pregnancy ; Pregnancy Rate ; Prospective Studies ; Reproductive Medicine ; Treatment Outcome ; Urofollitropin - administration &amp; dosage ; Young Adult</subject><ispartof>Archives of gynecology and obstetrics, 2013-10, Vol.288 (4), p.901-904</ispartof><rights>Springer-Verlag Berlin Heidelberg 2013</rights><rights>Archives of Gynecology and Obstetrics is a copyright of Springer, (2013). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-dbff8500eaad677d31d1191056079ca07c06a809708b4f1f8e30cb7688f3a07b3</citedby><cites>FETCH-LOGICAL-c372t-dbff8500eaad677d31d1191056079ca07c06a809708b4f1f8e30cb7688f3a07b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00404-013-2794-z$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00404-013-2794-z$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23545834$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Buendgen, Nana Kristin</creatorcontrib><creatorcontrib>Schultze-Mosgau, Askan</creatorcontrib><creatorcontrib>Cordes, Tim</creatorcontrib><creatorcontrib>Diedrich, Klaus</creatorcontrib><creatorcontrib>Griesinger, Georg</creatorcontrib><title>Initiation of ovarian stimulation independent of the menstrual cycle: a case–control study</title><title>Archives of gynecology and obstetrics</title><addtitle>Arch Gynecol Obstet</addtitle><addtitle>Arch Gynecol Obstet</addtitle><description>Purpose In the GnRH-antagonist protocol, ovarian stimulation with gonadotropins typically commences on cycle day 2 or 3. Initiation of ovarian stimulation with a spontaneously occurring menstruation, however, poses significant organizational challenges for treatment centres and patients alike. It has previously been demonstrated in the context of fertility preservation that initiation of stimulation in the luteal phase is feasible in terms of retrieval of mature oocytes for cryopreservation. Herein, we report the extension of this concept to a routine IVF setting with the aim of establishing an ovarian stimulation protocol, which can be utilized independent of menstruation. Because of asynchrony of endometrium and embryo in such a setting, all fertilized oocytes have to be cryopreserved for a later transfer. Methods This was a prospective, case–control study (trial registration: NCT00795041) on the feasibility of starting ovarian stimulation in a GnRH-antagonist protocol in the luteal phase. Inclusion criteria were: IVF or ICSI; 18–36 years; ≤3 previous IVF/ICSI attempts; BMI 20–30 kg/m 2 ; regular cycle (28–35 days); luteal phase progesterone &gt;7 ng/ml at initiation of stimulation. Exclusion criteria were: PCOS, endometriosis ≥AFS III°, unilateral ovary, expected poor response. Stimulation was performed with highly purified uFSH (Bravelle ® ) 300 IU/day and 0.25 mg/day GnRH-antagonist starting on cycle day 19–21 of a spontaneous menstrual cycle and commencing until hCG administration when three follicles ≥17 mm were present. All 2PN stage oocytes were vitrified for later transfers in programmed cycles. Feasibility was defined as the achievement of ongoing pregnancies progressing beyond the 12th gestational week in at least 2/10 study subjects (primary outcome). Secondary outcomes were gonadotropin consumption per oocyte obtained, stimulation duration, and fertilization rates. Study subjects were matched in a 1:3 ratio with concomitantly treated control cases of similar age, BMI, and duration of infertility who were treated in a conventional GnRH-antagonist protocol with 150–225 rFSH or HP-HMG/day. Results The study group consisted of ten subjects, mean age 31.4 years, BMI 25.4 kg/m 2 , of which one had fertilization failure. Mean stimulation duration was 11.7 (SD 1.6) vs. 9.1 (SD 1.3) days, mean cumulative FSH dose was 3,495.0 (SD 447.5) vs. 2,040.5 (SD 576.2) IU, and mean number of oocytes was 8.8 (SD 5.0) vs. 10.0 (SD 5.4) in study vs. control group, respectively. Per follicle ≥10 mm, the cumulative FSH dose was 274.5 (SD 130.8) IU vs. 245.2 (SD 232.3) IU in study and control groups, respectively. Cumulative ongoing pregnancy rates were 1/10 (10 %) and 6/30 (20.0 %) in study and control group, respectively (difference: 10 %, 95 % confidence interval of the difference: −29.2–22.2 %, p  = 0.47). Fertilization rate was similar between groups, with 63.5 % (SD 32.9) in the study and 61.3 % (SD 26.7) in the control group, respectively. Serum estradiol levels were significantly lower on the day of triggering final oocyte maturation with 1,005.3 (SD 336.2) vs. 1,977.4 pg/ml (SD 1,106.5) in study and control group, respectively. Similarly, peak estradiol biosynthesis per growing follicle ≥10 mm was lower in the study group (134 pg/ml, SD 158.4 vs. 186.7 pg/ml, SD 84.7). Conclusions Per retrieved oocyte, a nearly threefold higher dose of FSH had to be administered when ovarian stimulation had been initiated in the luteal phase. Furthermore, the present study casts doubt on the efficacy of initiating ovarian stimulation in the luteal phase in terms of pregnancy achievement. Thus, this concept is currently not feasible for routine use, and it should also be explored further before using it at larger scale in the context of emergency stimulation for fertility preservation.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Drug Administration Schedule</subject><subject>Drug Therapy, Combination</subject><subject>Endocrinology</subject><subject>Feasibility Studies</subject><subject>Female</subject><subject>Fertilization in Vitro - methods</subject><subject>Gonadotropin-Releasing Hormone - antagonists &amp; inhibitors</subject><subject>Gynecology</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Infertility</subject><subject>Infertility, Female - therapy</subject><subject>Luteal Phase</subject><subject>Medicine</subject><subject>Medicine &amp; Public Health</subject><subject>Menstruation</subject><subject>Obstetrics/Perinatology/Midwifery</subject><subject>Oocyte Retrieval</subject><subject>Ovulation Induction - methods</subject><subject>Pregnancy</subject><subject>Pregnancy Rate</subject><subject>Prospective Studies</subject><subject>Reproductive Medicine</subject><subject>Treatment Outcome</subject><subject>Urofollitropin - administration &amp; 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Schultze-Mosgau, Askan ; Cordes, Tim ; Diedrich, Klaus ; Griesinger, Georg</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c372t-dbff8500eaad677d31d1191056079ca07c06a809708b4f1f8e30cb7688f3a07b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Drug Administration Schedule</topic><topic>Drug Therapy, Combination</topic><topic>Endocrinology</topic><topic>Feasibility Studies</topic><topic>Female</topic><topic>Fertilization in Vitro - methods</topic><topic>Gonadotropin-Releasing Hormone - antagonists &amp; inhibitors</topic><topic>Gynecology</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Infertility</topic><topic>Infertility, Female - therapy</topic><topic>Luteal Phase</topic><topic>Medicine</topic><topic>Medicine &amp; Public Health</topic><topic>Menstruation</topic><topic>Obstetrics/Perinatology/Midwifery</topic><topic>Oocyte Retrieval</topic><topic>Ovulation Induction - methods</topic><topic>Pregnancy</topic><topic>Pregnancy Rate</topic><topic>Prospective Studies</topic><topic>Reproductive Medicine</topic><topic>Treatment Outcome</topic><topic>Urofollitropin - administration &amp; dosage</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Buendgen, Nana Kristin</creatorcontrib><creatorcontrib>Schultze-Mosgau, Askan</creatorcontrib><creatorcontrib>Cordes, Tim</creatorcontrib><creatorcontrib>Diedrich, Klaus</creatorcontrib><creatorcontrib>Griesinger, Georg</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 &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Health &amp; Medical Collection (Alumni Edition)</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 China</collection><collection>MEDLINE - Academic</collection><jtitle>Archives of gynecology and obstetrics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Buendgen, Nana Kristin</au><au>Schultze-Mosgau, Askan</au><au>Cordes, Tim</au><au>Diedrich, Klaus</au><au>Griesinger, Georg</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Initiation of ovarian stimulation independent of the menstrual cycle: a case–control study</atitle><jtitle>Archives of gynecology and obstetrics</jtitle><stitle>Arch Gynecol Obstet</stitle><addtitle>Arch Gynecol Obstet</addtitle><date>2013-10-01</date><risdate>2013</risdate><volume>288</volume><issue>4</issue><spage>901</spage><epage>904</epage><pages>901-904</pages><issn>0932-0067</issn><eissn>1432-0711</eissn><abstract>Purpose In the GnRH-antagonist protocol, ovarian stimulation with gonadotropins typically commences on cycle day 2 or 3. Initiation of ovarian stimulation with a spontaneously occurring menstruation, however, poses significant organizational challenges for treatment centres and patients alike. It has previously been demonstrated in the context of fertility preservation that initiation of stimulation in the luteal phase is feasible in terms of retrieval of mature oocytes for cryopreservation. Herein, we report the extension of this concept to a routine IVF setting with the aim of establishing an ovarian stimulation protocol, which can be utilized independent of menstruation. Because of asynchrony of endometrium and embryo in such a setting, all fertilized oocytes have to be cryopreserved for a later transfer. Methods This was a prospective, case–control study (trial registration: NCT00795041) on the feasibility of starting ovarian stimulation in a GnRH-antagonist protocol in the luteal phase. Inclusion criteria were: IVF or ICSI; 18–36 years; ≤3 previous IVF/ICSI attempts; BMI 20–30 kg/m 2 ; regular cycle (28–35 days); luteal phase progesterone &gt;7 ng/ml at initiation of stimulation. Exclusion criteria were: PCOS, endometriosis ≥AFS III°, unilateral ovary, expected poor response. Stimulation was performed with highly purified uFSH (Bravelle ® ) 300 IU/day and 0.25 mg/day GnRH-antagonist starting on cycle day 19–21 of a spontaneous menstrual cycle and commencing until hCG administration when three follicles ≥17 mm were present. All 2PN stage oocytes were vitrified for later transfers in programmed cycles. Feasibility was defined as the achievement of ongoing pregnancies progressing beyond the 12th gestational week in at least 2/10 study subjects (primary outcome). Secondary outcomes were gonadotropin consumption per oocyte obtained, stimulation duration, and fertilization rates. Study subjects were matched in a 1:3 ratio with concomitantly treated control cases of similar age, BMI, and duration of infertility who were treated in a conventional GnRH-antagonist protocol with 150–225 rFSH or HP-HMG/day. Results The study group consisted of ten subjects, mean age 31.4 years, BMI 25.4 kg/m 2 , of which one had fertilization failure. Mean stimulation duration was 11.7 (SD 1.6) vs. 9.1 (SD 1.3) days, mean cumulative FSH dose was 3,495.0 (SD 447.5) vs. 2,040.5 (SD 576.2) IU, and mean number of oocytes was 8.8 (SD 5.0) vs. 10.0 (SD 5.4) in study vs. control group, respectively. Per follicle ≥10 mm, the cumulative FSH dose was 274.5 (SD 130.8) IU vs. 245.2 (SD 232.3) IU in study and control groups, respectively. Cumulative ongoing pregnancy rates were 1/10 (10 %) and 6/30 (20.0 %) in study and control group, respectively (difference: 10 %, 95 % confidence interval of the difference: −29.2–22.2 %, p  = 0.47). Fertilization rate was similar between groups, with 63.5 % (SD 32.9) in the study and 61.3 % (SD 26.7) in the control group, respectively. Serum estradiol levels were significantly lower on the day of triggering final oocyte maturation with 1,005.3 (SD 336.2) vs. 1,977.4 pg/ml (SD 1,106.5) in study and control group, respectively. Similarly, peak estradiol biosynthesis per growing follicle ≥10 mm was lower in the study group (134 pg/ml, SD 158.4 vs. 186.7 pg/ml, SD 84.7). Conclusions Per retrieved oocyte, a nearly threefold higher dose of FSH had to be administered when ovarian stimulation had been initiated in the luteal phase. Furthermore, the present study casts doubt on the efficacy of initiating ovarian stimulation in the luteal phase in terms of pregnancy achievement. Thus, this concept is currently not feasible for routine use, and it should also be explored further before using it at larger scale in the context of emergency stimulation for fertility preservation.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>23545834</pmid><doi>10.1007/s00404-013-2794-z</doi><tpages>4</tpages></addata></record>
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1432-0711
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source MEDLINE; Springer Nature - Complete Springer Journals
subjects Adolescent
Adult
Drug Administration Schedule
Drug Therapy, Combination
Endocrinology
Feasibility Studies
Female
Fertilization in Vitro - methods
Gonadotropin-Releasing Hormone - antagonists & inhibitors
Gynecology
Human Genetics
Humans
Infertility
Infertility, Female - therapy
Luteal Phase
Medicine
Medicine & Public Health
Menstruation
Obstetrics/Perinatology/Midwifery
Oocyte Retrieval
Ovulation Induction - methods
Pregnancy
Pregnancy Rate
Prospective Studies
Reproductive Medicine
Treatment Outcome
Urofollitropin - administration & dosage
Young Adult
title Initiation of ovarian stimulation independent of the menstrual cycle: a case–control study
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