A Lucky Opportunity: First-ever Confirmation of Highly Individualized Egg Retrieval (HIER) in a Natural Conception Cycle

A Lucky Opportunity: First-ever Confirmation of Highly Individualized Egg Retrieval (HIER) in a Natural Conception Cycle | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A Lucky Opportunity: First-ever Confirmation of Highly Individualized Egg Retrieval (HIER) in a Natural Conception Cycle Sonia Gayete-Lafuente This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5843322/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract To prevent oocyte-toxic premature luteinization of follicles during IVF cycles, which occurs earlier and earlier with advancing female age, our center has learned to advance oocyte retrieval appropriately over the last decade, a process we have given the acronym HIER (Highly Individualized Egg Retrieval). In principle, for practical reasons, the HIER concept was only applicable in IVF cycles. However, as a consequence of several lucky coincidences, we recently had the opportunity to apply HIER to a spontaneous conception. We here report this case to demonstrate that the HIER approach appears to be applicable independent of whether ovaries are exogenously stimulated or not. This case report expands utilization of HIER beyond IVF to practically all treatment cycles in infertility, in the process contradicting two long-held dogmas in worldwide infertility practice. Health sciences/Medical research/Outcomes research Health sciences/Signs and symptoms/Reproductive signs and symptoms Natural cycle ovulation monitoring ovulation trigger ovarian aging Introduction Ovarian reserve (OR) diminishes with advancing female age, while FSH levels concomitantly rise and AMH levels decline, leading to accelerating follicle recruitment and premature follicle luteinization, in the process progressively shortening cycle length. Luteinization of follicles is, moreover, toxic to oocytes. Trying to overcome this challenge, and often unable to pharmacologically prevent premature luteinization effectively in older women, since 2014 our clinic has learned to adjust the timing of ovulation triggers during in vitro fertilization (IVF) at progressively smaller lead-follicle sizes with advancing female age, 1 , 2 a process we have given the acronym HIER (Highly Individualized Egg Retrieval). Our fertility center serves the by-far oldest patient population among U.S. IVF clinics (2023 median age 44 years vs. 36 years for all in the U.S. reported IVF cycles). In fact, early ovulation trigger at lead follicle sizes as small as 9–10 mm, mostly in women above age 45, has become routine. This sharply contrasts with the long-standing dogma in IVF, where trigger sizes have traditionally been set at 18-23mm for lead follicles invariably across all age groups, which we still maintain in women under age 40 with normal functional ovarian reserve. Introducing HIER in practice enabled our center to achieve the current 10% ongoing pregnancy rate for women over 44 years old, a significant improvement compared to the national average, 3 and to report the oldest IVF birth conceived with autologous oocytes in the literature in a 48-year-old woman who was triggered at lead-follicle size 12mm. 4 Our experience with HIER until recently was, however, restricted to only IVF cycles. Whether the HIER concept was also applicable to unstimulated cycles had not been reported before, although based on follicular physiology, seemed likely. We here report such a case which, due to alignment of several unplanned circumstances, ended up offering an almost ideal model for spontaneous conception. Case Report A 42.5-year-old female G2P1 presented to our center after elsewhere having been advised that her very diminished functional OR (with cycle day-2 FSH: 34.0–39.0 mIU/mL; and AMH undetectable) would allow conception only through third-party egg-donation. However, because she demonstrated an antral follicle count of 6, we advised her that she still might have a small chance with her own eggs, as an alternative option with significantly lower chances of success. While balancing her options, a few months later, she informed us that she had conceived spontaneously and already was under the care of her obstetrician. But after showing a positive fetal heartbeat on ultrasound, she spontaneously miscarried. Following a curettage, she decided to attempt for three months spontaneous conception with timed intercourse before moving to IVF. Because of marginally low peripheral androgen levels and mildly elevated sex hormone binding globulin, we also recommended supplementation with dehydroepiandrosterone (25mg BID) at that time. 5 After failing to conceive over 3 months, she went through an IVF cycle with HIER trigger timing at 13mm lead follicle size. One mature MII oocyte was retrieved, fertilized via intracytoplasmic sperm injection, and a cleavage-stage (day-3) 8B3 embryo was transferred fresh with the endometrial lining of 7mm. Although she did not conceive, the cycle confirmed that through ovulation trigger at 13mm she could still produce a mature oocyte of good quality. Following the failed IVF cycle, the couple returned to the clinic after 6 months of no further treatments for advice. At that time, a random vaginal ultrasound on day 12 of a natural cycle revealed 2 follicles of 13 and 9 mm, respectively. The patient’s estradiol level was 159 pg/mL and her endometrial thickness was 6 mm. An hCG (250 mcg/0.5 mL) I.M. trigger (Ovidrel ® , Merck Global, Darmstadt, Germany) was administered, followed by timed intercourse and luteal support with micronized progesterone 200 mg vaginally BID, starting three days after trigger. In June of 2024, the patient’s recorded a positive pregnancy test. By August 2024, ultrasound confirmed a normally progressing intrauterine singleton pregnancy with nuchal translucency (NT) of 1.5mm, crown-rump length (CRL) of 6.28mm, and normal fetal heart rate at 157 bpm. Her NIPT at 11 weeks 6 days was normal, indicating a male fetus. She is currently 33 weeks pregnant, and her pregnancy has been uneventful so far. Discussion We here presented a patient of advanced maternal age and with very low functional ovarian reserve who naturally conceived after timed intercourse following an ovulation trigger at lead follicle size 13mm. She in a preceding IVF cycle – coincidentally with identical timing– had produced a mature MII oocyte which, in turn, had produced a very good-quality day-3 embryo. Though at our IVF center HIER has been routine practice for almost 10 years, only a very small number of IVF clinics worldwide have so-far followed in this practice. In fact, the overwhelming number of IVF clinics around the world still automatically trigger ovulation at lead follicle sizes of 18-23mm in all IVF cycles independently of female age. This case, along with extensive research from our group, calls for reevaluation of this dogma. In fact, only very recently, for the first time, a study published in Nature Communications by a team of British researchers using artificial intelligence (AI) showed that follicle sizes at trigger and retrieval times are important not just for older patients, but for IVF patients of all ages, strongly supporting all of our previous findings. 6 Moreover, we recently reported that not only appropriate follicle sizes for trigger change with advancing female age, but also oocyte ability to produce good quality embryos. While mature MII oocytes significantly decline in their competence, MI oocytes remain relatively stable, but GV oocytes -paradoxically and surprisingly - greatly improve with advancing female age. 7 In the oldest patients (in our study women above age 45 and into early 50s), the majority of GV oocytes, which most IVF clinics almost routinely still discard without any efforts at rescue maturation, mature overnight and via ICSI produce transferrable embryos by day-3. These findings provided further evidence that ovarian aging significantly favors earlier and earlier ovulation triggers and retrievals. As HIER has broken the IVF practice dogma of over 40 years that ovulation-induction should be universally triggered at 18–23 mm lead follicle size, this more recent observation 7 broke with another even older IVF dogma that oocyte maturity grades maintain the same clinical relevance at all ages. Combined, both these refuted dogmas communicate the same highly important message: as ovaries age, metabolic processes within follicles speed up, demanding highly personalized IVF practice, which usually means earlier and earlier ovulation rigger timing to prevent the exposure of oocytes to follicular luteinization or – as we explain it to patients – retrievals of “hard-boiled” in place of “soft-boiled” eggs. The here presented case report offered the unique opportunity to expand our understanding of HIER from IVF to unstimulated cycles and confirmed the suspected universality of the HIER concept. The practice of individualization of ovulation trigger timing, therefore, should be expanded from IVF to ovulation induction cycles with either timed intercourse or intrauterine inseminations and even natural cycles. As practically almost all cycle managements in infertility practice utilize ovulation triggers, this case report has major implications for daily worldwide infertility practice. Declarations The patient consented to case review and publication. Author Contributions: The HIER concept was developed by D.H.B, D.F.A, and N.G. Here presented case was managed by all authors. A first draft of the report was written by S.G-L. The final version of the manuscript was written by N.G., with all authors’ contribution and final consent. Competing Interest Statement: D.H.B. and N.G. are co-owners of several already awarded and still pending U.S. patents, some claiming benefits from androgens, including DHEA, supplementation in women with low functional ovarian reserve, other infertility conditions, and perimenopausal hypo-androgenism-induced sexual dysfunction. Other patents relate to diagnostic and potential therapeutic benefits of AMH. N.G. is also a shareholder in Fertility Nutraceuticals LLC and D.H.B as well as N.G. receive patent royalties from Fertility Nutraceuticals, LLC. N.G. also received research support, travel funding and lecture fees from several Pharma companies, none, however, in any way related to matters discussed in this manuscript. All other authors report no potential competing interests. Classification: Reproductive Medicine, Reproductive Endocrinology, Infertility. Acknowledgments: This article was supported by intramural salary support from the Center for Human Reproduction (CHR) and continuous research funding by the Foundation for Reproductive Medicine. References YG Wu, DH Barad, VA Kushnir, E Lazzaroni, Q Wang, DF Albertini, N Gleicher. Aging-related premature luteinization of granulosa cells is avoided by early oocyte retrieval. J Endocrinol. 2015 Sep;226(3):167-80. doi: 10.1530/JOE-15-0246. Epub 2015 Aug 11. PMID: 26264981. YG Wu, DH Barad, VA Kushnir, Q Wang, L Zhang, SK Darmon, DF Albertini, N Gleicher. With low ovarian reserve, Highly Individualized Egg Retrieval (HIER) improves IVF results by avoiding premature luteinization. J Ovarian Res. 2018 Mar 16;11(1):23. doi: 10.1186/s13048-018-0398-8. PMID: 29548330; PMCID: PMC5857093. Society for Assisted reproduction (SART). 2022 Annual Report. Accessed on Jan 12th, 2025: https://www.sartcorsonline.com/EmbryoOutcome/PublicSARTOutcomeTables. N Gleicher, VA Kushnir, S Darmon, DF Albertini, DH Barad. Older women using their own eggs? Issue framed with two oldest reported IVF pregnancies and a live birth. Reprod Biomed Online. 2018 Aug;37(2):172-177. doi: 10.1016/j.rbmo.2018.05.010. Epub 2018 May 24. PMID: 29936089. DH Barad, N Gleicher. Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril. 2005 Sep;84(3):756. doi: 10.1016/j.fertnstert.2005.02.049. PMID: 16169414. Hanassab S, Nelson SM, Akbarov A, Yeung AC, Hramyka A, Alhamwi T, et al. Explainable artificial intelligence to identify follicles that optimize clinical outcomes during assisted conception. Nat Commun 2025;16:296. C Nicholas, S Darmon, P Patrizio, DF Albertini, DH Barad, N Gleicher. Changing clinical significance of oocyte maturity grades with advancing female age advances precision medicine in IVF. iScience. 2023 Jul 11;26(8):107308. doi: 10.1016/j.isci.2023.107308. PMID: 37539038; PMCID: PMC10393729, Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5843322","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":412254319,"identity":"1840b73d-4f68-4fe4-b594-50b64cd69b25","order_by":0,"name":"Sonia Gayete-Lafuente","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIiWNgGAWjYBADOQYJBgZmEjQkMBjzkKwlsYdoLfL9i59JfPxhk75fuvng58I9DPL8YgfwazG48cxMckZCWm6PzLFk6RnPGAxnzk4goEXigJk0T8Lh3B6JHDNmngMMCQa3CWiRn3H8m/SfhP/pPBL534jTwnC+x0yaIeFAAo9EDhtxWgxu8BRb9qQlG/bcSDOW5jkgQdgv8v3HN974YWMnzz4j+eFnngM28vzShBwmkcAigcwloBwE+A8wfyBC2SgYBaNgFIxkAADHOT/gBtLf7QAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-7375-5848","institution":"The Center for Human Reproduction","correspondingAuthor":true,"prefix":"","firstName":"Sonia","middleName":"","lastName":"Gayete-Lafuente","suffix":""}],"badges":[],"createdAt":"2025-01-16 15:56:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5843322/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5843322/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":77362268,"identity":"fdb4f7ab-4b94-4916-978a-b1d3e5e84e5a","added_by":"auto","created_at":"2025-02-27 20:18:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":200651,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5843322/v1/1215e1b1-e1d1-474c-9561-021e8d2c4075.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"A Lucky Opportunity: First-ever Confirmation of Highly Individualized Egg Retrieval (HIER) in a Natural Conception Cycle","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOvarian reserve (OR) diminishes with advancing female age, while FSH levels concomitantly rise and AMH levels decline, leading to accelerating follicle recruitment and premature follicle luteinization, in the process progressively shortening cycle length. Luteinization of follicles is, moreover, toxic to oocytes. Trying to overcome this challenge, and often unable to pharmacologically prevent premature luteinization effectively in older women, since 2014 our clinic has learned to adjust the timing of ovulation triggers during in vitro fertilization (IVF) at progressively smaller lead-follicle sizes with advancing female age,\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e a process we have given the acronym HIER (Highly Individualized Egg Retrieval).\u003c/p\u003e \u003cp\u003eOur fertility center serves the by-far oldest patient population among U.S. IVF clinics (2023 median age 44 years vs. 36 years for all in the U.S. reported IVF cycles). In fact, early ovulation trigger at lead follicle sizes as small as 9\u0026ndash;10 mm, mostly in women above age 45, has become routine. This sharply contrasts with the long-standing dogma in IVF, where trigger sizes have traditionally been set at 18-23mm for lead follicles invariably across all age groups, which we still maintain in women under age 40 with normal functional ovarian reserve. Introducing HIER in practice enabled our center to achieve the current 10% ongoing pregnancy rate for women over 44 years old, a significant improvement compared to the national average,\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e and to report the oldest IVF birth conceived with autologous oocytes in the literature in a 48-year-old woman who was triggered at lead-follicle size 12mm.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur experience with HIER until recently was, however, restricted to only IVF cycles. Whether the HIER concept was also applicable to unstimulated cycles had not been reported before, although based on follicular physiology, seemed likely. We here report such a case which, due to alignment of several unplanned circumstances, ended up offering an almost ideal model for spontaneous conception.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 42.5-year-old female G2P1 presented to our center after elsewhere having been advised that her very diminished functional OR (with cycle day-2 FSH: 34.0\u0026ndash;39.0 mIU/mL; and AMH undetectable) would allow conception only through third-party egg-donation. However, because she demonstrated an antral follicle count of 6, we advised her that she still might have a small chance with her own eggs, as an alternative option with significantly lower chances of success. While balancing her options, a few months later, she informed us that she had conceived spontaneously and already was under the care of her obstetrician. But after showing a positive fetal heartbeat on ultrasound, she spontaneously miscarried.\u003c/p\u003e \u003cp\u003eFollowing a curettage, she decided to attempt for three months spontaneous conception with timed intercourse before moving to IVF. Because of marginally low peripheral androgen levels and mildly elevated sex hormone binding globulin, we also recommended supplementation with dehydroepiandrosterone (25mg BID) at that time.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAfter failing to conceive over 3 months, she went through an IVF cycle with HIER trigger timing at 13mm lead follicle size. One mature MII oocyte was retrieved, fertilized via intracytoplasmic sperm injection, and a cleavage-stage (day-3) 8B3 embryo was transferred fresh with the endometrial lining of 7mm. Although she did not conceive, the cycle confirmed that through ovulation trigger at 13mm she could still produce a mature oocyte of good quality.\u003c/p\u003e \u003cp\u003eFollowing the failed IVF cycle, the couple returned to the clinic after 6 months of no further treatments for advice. At that time, a random vaginal ultrasound on day 12 of a natural cycle revealed 2 follicles of 13 and 9 mm, respectively. The patient\u0026rsquo;s estradiol level was 159 pg/mL and her endometrial thickness was 6 mm. An hCG (250 mcg/0.5 mL) I.M. trigger (Ovidrel\u003csup\u003e\u0026reg;\u003c/sup\u003e, Merck Global, Darmstadt, Germany) was administered, followed by timed intercourse and luteal support with micronized progesterone 200 mg vaginally BID, starting three days after trigger.\u003c/p\u003e \u003cp\u003eIn June of 2024, the patient\u0026rsquo;s recorded a positive pregnancy test. By August 2024, ultrasound confirmed a normally progressing intrauterine singleton pregnancy with nuchal translucency (NT) of 1.5mm, crown-rump length (CRL) of 6.28mm, and normal fetal heart rate at 157 bpm. Her NIPT at 11 weeks 6 days was normal, indicating a male fetus. She is currently 33 weeks pregnant, and her pregnancy has been uneventful so far.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe here presented a patient of advanced maternal age and with very low functional ovarian reserve who naturally conceived after timed intercourse following an ovulation trigger at lead follicle size 13mm. She in a preceding IVF cycle \u0026ndash; coincidentally with identical timing\u0026ndash; had produced a mature MII oocyte which, in turn, had produced a very good-quality day-3 embryo.\u003c/p\u003e \u003cp\u003eThough at our IVF center HIER has been routine practice for almost 10 years, only a very small number of IVF clinics worldwide have so-far followed in this practice. In fact, the overwhelming number of IVF clinics around the world still automatically trigger ovulation at lead follicle sizes of 18-23mm in all IVF cycles independently of female age. This case, along with extensive research from our group, calls for reevaluation of this dogma. In fact, only very recently, for the first time, a study published in Nature Communications by a team of British researchers using artificial intelligence (AI) showed that follicle sizes at trigger and retrieval times are important not just for older patients, but for IVF patients of all ages, strongly supporting all of our previous findings.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Moreover, we recently reported that not only appropriate follicle sizes for trigger change with advancing female age, but also oocyte ability to produce good quality embryos. While mature MII oocytes significantly decline in their competence, MI oocytes remain relatively stable, but GV oocytes -paradoxically and surprisingly - greatly improve with advancing female age.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e In the oldest patients (in our study women above age 45 and into early 50s), the majority of GV oocytes, which most IVF clinics almost routinely still discard without any efforts at rescue maturation, mature overnight and via ICSI produce transferrable embryos by day-3. These findings provided further evidence that ovarian aging significantly favors earlier and earlier ovulation triggers and retrievals.\u003c/p\u003e \u003cp\u003eAs HIER has broken the IVF practice dogma of over 40 years that ovulation-induction should be universally triggered at 18\u0026ndash;23 mm lead follicle size, this more recent observation\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e broke with another even older IVF dogma that oocyte maturity grades maintain the same clinical relevance at all ages. Combined, both these refuted dogmas communicate the same highly important message: as ovaries age, metabolic processes within follicles speed up, demanding highly personalized IVF practice, which usually means earlier and earlier ovulation rigger timing to prevent the exposure of oocytes to follicular luteinization or \u0026ndash; as we explain it to patients \u0026ndash; retrievals of \u0026ldquo;hard-boiled\u0026rdquo; in place of \u0026ldquo;soft-boiled\u0026rdquo; eggs.\u003c/p\u003e \u003cp\u003eThe here presented case report offered the unique opportunity to expand our understanding of HIER from IVF to unstimulated cycles and confirmed the suspected universality of the HIER concept. The practice of individualization of ovulation trigger timing, therefore, should be expanded from IVF to ovulation induction cycles with either timed intercourse or intrauterine inseminations and even natural cycles. As practically almost all cycle managements in infertility practice utilize ovulation triggers, this case report has major implications for daily worldwide infertility practice.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe patient consented to case review and publication.\u003c/p\u003e\n\u003cp\u003eAuthor Contributions: The HIER concept was developed by D.H.B, D.F.A, and N.G. Here presented case was managed by all authors. A first draft of the report was written by S.G-L. The final version of the manuscript was written by N.G., with all authors\u0026rsquo; contribution and final consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting Interest Statement:\u0026nbsp;D.H.B. and N.G. are co-owners of several already awarded and still pending U.S. patents, some claiming benefits from androgens, including DHEA, supplementation in women with low functional ovarian reserve, other infertility conditions, and perimenopausal hypo-androgenism-induced sexual dysfunction. Other patents relate to diagnostic and potential therapeutic benefits of AMH. N.G. is also a shareholder in Fertility Nutraceuticals LLC and D.H.B as well as N.G. receive patent royalties from Fertility Nutraceuticals, LLC. N.G. also received research support, travel funding and lecture fees from several Pharma companies, none, however, in any way related to matters discussed in this manuscript. All other authors report no potential competing interests.\u003c/p\u003e\n\u003cp\u003eClassification: Reproductive Medicine, Reproductive Endocrinology, Infertility.\u003c/p\u003e\n\u003cp\u003eAcknowledgments:\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThis article was supported by intramural salary support from the Center for Human Reproduction (CHR) and continuous research funding by the Foundation for Reproductive Medicine.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eYG Wu, DH Barad, VA Kushnir, E Lazzaroni, Q Wang, DF Albertini, N Gleicher. Aging-related premature luteinization of granulosa cells is avoided by early oocyte retrieval. J Endocrinol. 2015 Sep;226(3):167-80. doi: 10.1530/JOE-15-0246. Epub 2015 Aug 11. PMID: 26264981.\u003c/li\u003e\n \u003cli\u003eYG Wu, DH Barad, VA Kushnir, Q Wang, L Zhang, SK Darmon, DF Albertini, N Gleicher. With low ovarian reserve, Highly Individualized Egg Retrieval (HIER) improves IVF results by avoiding premature luteinization. J Ovarian Res. 2018 Mar 16;11(1):23. doi: 10.1186/s13048-018-0398-8. PMID: 29548330; PMCID: PMC5857093.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSociety for Assisted reproduction (SART). 2022 Annual Report. Accessed on Jan 12th, 2025: https://www.sartcorsonline.com/EmbryoOutcome/PublicSARTOutcomeTables. \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eN Gleicher, VA Kushnir, S Darmon, DF Albertini, DH Barad. Older women using their own eggs? Issue framed with two oldest reported IVF pregnancies and a live birth. Reprod Biomed Online. 2018 Aug;37(2):172-177. doi: 10.1016/j.rbmo.2018.05.010. Epub 2018 May 24. PMID: 29936089.\u003c/li\u003e\n \u003cli\u003eDH Barad, N Gleicher. Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril. 2005 Sep;84(3):756. doi: 10.1016/j.fertnstert.2005.02.049. PMID: 16169414.\u003c/li\u003e\n \u003cli\u003eHanassab S, Nelson SM, Akbarov A, Yeung AC, Hramyka A, Alhamwi T, et al. Explainable artificial intelligence to identify follicles that optimize clinical outcomes during assisted conception. Nat Commun 2025;16:296.\u003c/li\u003e\n \u003cli\u003eC Nicholas, S Darmon, P Patrizio, DF Albertini, DH Barad, N Gleicher. Changing clinical significance of oocyte maturity grades with advancing female age advances precision medicine in IVF. iScience. 2023 Jul 11;26(8):107308. doi: 10.1016/j.isci.2023.107308. PMID: 37539038; PMCID: PMC10393729,\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Natural cycle, ovulation monitoring, ovulation trigger, ovarian aging","lastPublishedDoi":"10.21203/rs.3.rs-5843322/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5843322/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTo prevent oocyte-toxic premature luteinization of follicles during IVF cycles, which occurs earlier and earlier with advancing female age, our center has learned to advance oocyte retrieval appropriately over the last decade, a process we have given the acronym HIER (Highly Individualized Egg Retrieval). In principle, for practical reasons, the HIER concept was only applicable in IVF cycles. However, as a consequence of several lucky coincidences, we recently had the opportunity to apply HIER to a spontaneous conception. We here report this case to demonstrate that the HIER approach appears to be applicable independent of whether ovaries are exogenously stimulated or not. This case report expands utilization of HIER beyond IVF to practically all treatment cycles in infertility, in the process contradicting two long-held dogmas in worldwide infertility practice.\u003c/p\u003e","manuscriptTitle":"A Lucky Opportunity: First-ever Confirmation of Highly Individualized Egg Retrieval (HIER) in a Natural Conception Cycle","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-13 04:33:57","doi":"10.21203/rs.3.rs-5843322/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5f7a4d54-d371-4fc4-9851-37733ee882b0","owner":[],"postedDate":"February 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":43963455,"name":"Health sciences/Medical research/Outcomes research"},{"id":43963456,"name":"Health sciences/Signs and symptoms/Reproductive signs and symptoms"}],"tags":[],"updatedAt":"2025-02-27T20:10:22+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-13 04:33:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5843322","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5843322","identity":"rs-5843322","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}