Management of Women With an Unexpected Low Ovarian Response to Gonadotropin

Alessandro Conforti, Sandro C Esteves, Danilo Cimadomo, Alberto Vaiarelli, Francesca Di Rella, Filippo Maria Ubaldi, Fulvio Zullo, Giuseppe De Placido, Carlo Alviggi, Alessandro Conforti, Sandro C Esteves, Danilo Cimadomo, Alberto Vaiarelli, Francesca Di Rella, Filippo Maria Ubaldi, Fulvio Zullo, Giuseppe De Placido, Carlo Alviggi

Abstract

POSEIDON groups 1 and 2 patients respond poorly (<4 oocytes retrieved) or sub-optimally (4-9 oocytes retrieved) to gonadotropin stimulation despite the presence of adequate ovarian parameters, which negatively affect their cumulative chances of delivering a baby using Assisted Reproductive Technology. A polygenic trait involving gonadotropins and/or their receptors seems to be the primary pathophysiology mechanism explaining this phenomenon. The clinical management is mainly focused on maximizing oocyte yield as to increase the likelihood of having at least one euploid embryo for transfer. Indices such as FORT (follicle output rate) and FOI (follicle-to-oocyte index) may be used to determine if the ovarian reserve was properly explored during a previous ovarian stimulation. Testing for the presence of common polymorphisms affecting gonadotropins and/or their receptors can also be considered to identify patients at risk of hypo-response. An individualized estimation of the minimum number of oocytes needed to obtain at least one euploid embryo can assist counseling and treatment planning. Among currently existing pharmacological interventions, use of recombinant FSH in preference over urinary gonadotropin preparations, FSH dosage increase, and use of rLH supplementation may be considered -alone or combined- for optimally managing POSEIDON's groups 1 and 2 patients. However, given the recent introduction of the POSEIDON criteria, there is still a lack of studies examining the role of interventions specifically to patients classified as groups 1 and 2, thus making it an area for open research.

Keywords: ART calculator; Assisted Reproductive Technology; POSEIDON criteria; follicle-to-oocyte index; hypo-response; ovarian reserve; ovarian stimulation; suboptimal response.

Figures

Figure 1
Figure 1
Poseidon criteria of low prognosis patients in ART. Four distinct groups of low prognosis patients can be established based on quantitative and qualitative parameters, namely: 1. The age of the patient and the expected embryo aneuploidy rate; 2. Ovarian biomarkers (antral follicle count [AFC] and/or anti-Müllerian hormone [AMH]), and 3. The ovarian response of the patient in terms of oocyte quantity provided a previous cycle of stimulation was carried out. Art drawing by Chloé Xilinas, EXCEMED, Rome, Italy. Adapted from Esteves et al. (10).
Figure 2
Figure 2
Ovarian resistance using the follicle-to-oocyte index (FOI). Reprint from Alviggi et al. (17).
Figure 3
Figure 3
Pathogenesis of low follicle-to-oocyte index (FOI). Reprint from Alviggi et al. (17).
Figure 4
Figure 4
Suggested management of Poseidon groups 1 and 2 patients.

References

    1. ACOG Committee opinion no 671: perinatal risks associated with assisted reproductive technology. Obstet Gynecol. (2016) 128:e61–8. 10.1097/AOG.0000000000001643
    1. Practice Committee of Society for Assisted Reproductive T, Practice Committee of American Society for Reproductive M. Elective single-embryo transfer. Fertil Steril. (2012) 97:835–42. 10.1016/j.fertnstert.2011.11.050
    1. ACOG ACOG Practice bulletin no. 144: multifetal gestations: twin, triplet, and higher-order multifetal pregnancies. Obstet Gynecol. (2014) 123:1118–32. 10.1097/01.AOG.0000446856.51061.3e
    1. Alviggi C, Conforti A, Carbone IF, Borrelli R, de Placido G, Guerriero S. Influence of cryopreservation on perinatal outcome after blastocyst- vs cleavage-stage embryo transfer: systematic review and meta-analysis. Ultrasound Obstetr. Gynecol. (2018) 51:54–63. 10.1002/uog.18942
    1. Verhaak CM, Smeenk JM, van Minnen A, Kremer JA, Kraaimaat FW. A longitudinal, prospective study on emotional adjustment before, during and after consecutive fertility treatment cycles. Hum Reprod. (2005) 20:2253–60. 10.1093/humrep/dei015
    1. Slade P, Emery J, Lieberman BA. A prospective, longitudinal study of emotions and relationships in in-vitro fertilization treatment. Human Reprod. (1997) 12:183–90. 10.1093/humrep/12.1.183
    1. Verberg MF, Eijkemans MJ, Heijnen EM, Broekmans FJ, de Klerk C, Fauser BC, et al. . Why do couples drop-out from IVF treatment? A prospective cohort study. Hum Reprod. (2008) 23:2050–5. 10.1093/humrep/den219
    1. Practice Committee of the American Society for Reproductive Medicine. Electronic address Aao, Practice Committee of the American Society for Reproductive M. Fertility drugs and cancer: a guideline. Fertil Steril. (2016) 106:1617–26. 10.1016/j.fertnstert.2016.08.035
    1. Humaidan P, Alviggi C, Fischer R, Esteves SC. The novel POSEIDON stratification of “Low prognosis patients in Assisted Reproductive Technology” and its proposed marker of successful outcome. F1000Res. (2016) 5:2911 10.12688/f1000research.10382.1
    1. Esteves SC, Roque M, Bedoschi GM, Conforti A, Humaidan P, Alviggi C. Defining low prognosis patients undergoing assisted reproductive technology: POSEIDON criteria-the why. Front Endocrinol. (2018) 9:461. 10.3389/fendo.2018.00461
    1. Alviggi C, Andersen CY, Buehler K, Conforti A, De Placido G, Esteves SC, et al. . A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril. (2016) 105:1452–3. 10.1016/j.fertnstert.2016.02.005
    1. Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H, et al. . Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod. (2016) 31:370–6. 10.1093/humrep/dev316
    1. Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. (2011) 26:1768–74. 10.1093/humrep/der106
    1. Polyzos NP, Drakopoulos P, Parra J, Pellicer A, Santos-Ribeiro S, Tournaye H, et al. . Cumulative live birth rates according to the number of oocytes retrieved after the first ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection: a multicenter multinational analysis including approximately 15,000 women. Fertil Steril. (2018) 110:661–70.e1. 10.1016/j.fertnstert.2018.04.039
    1. Gallot V, Berwanger da Silva AL, Genro V, Grynberg M, Frydman N, Fanchin R. Antral follicle responsiveness to follicle-stimulating hormone administration assessed by the Follicular Output RaTe (FORT) may predict in vitro fertilization-embryo transfer outcome. Hum Reprod. (2012) 27:1066–72. 10.1093/humrep/der479
    1. Genro VK, Grynberg M, Scheffer JB, Roux I, Frydman R, Fanchin R. Serum anti-Mullerian hormone levels are negatively related to Follicular Output RaTe (FORT) in normo-cycling women undergoing controlled ovarian hyperstimulation. Hum Reprod. (2011) 26:671–7. 10.1093/humrep/deq361
    1. Alviggi C, Conforti A, Esteves SC, Vallone R, Venturella R, Staiano S, et al. . Understanding ovarian hypo-response to exogenous gonadotropin in ovarian stimulation and its new proposed marker—the follicle-To-Oocyte. (FOI) index. Front Endocrinol. (2018) 9:589. 10.3389/fendo.2018.00589
    1. Alviggi C, Guadagni R, Conforti A, Coppola G, Picarelli S, De Rosa P, et al. . Association between intrafollicular concentration of benzene and outcome of controlled ovarian stimulation in IVF/ICSI cycles: a pilot study. J Ovar Res. (2014) 7:12. 10.1186/1757-2215-7-67
    1. Mahalingaiah S, Missmer SA, Maity A, Williams PL, Meeker JD, Berry K, et al. . Association of hexachlorobenzene. (HCB), dichlorodiphenyltrichloroethane. (DDT), and dichlorodiphenyldichloroethylene. (DDE) with in vitro fertilization. (IVF) outcomes. Environ Health Perspect. (2012) 120:316–20. 10.1289/ehp.1103696
    1. Conforti A, Mascia M, Cioffi G, De Angelis C, Coppola G, De Rosa P, et al. Air pollution and female fertility: a systematic review of literature. Reprod Biol Endocrinol. (2018) 16:117 10.1186/s12958-018-0433-z
    1. Conforti A, Cariati F, Vallone R, Alviggi C, de Placido G. Individualization of treatment in controlled ovarian stimulation: myth or reality? Biochim Clin. (2017) 41:294–305. 10.19186/BC_2017.051
    1. Alviggi C, Conforti A, Santi D, Esteves SC, Andersen CY, Humaidan P, et al. . Clinical relevance of genetic variants of gonadotrophins and their receptors in controlled ovarian stimulation: a systematic review and meta-analysis. Human Reprod Update. (2018) 24:1–16. 10.1093/humupd/dmy019
    1. Alviggi C, Conforti A, Esteves SC. Impact of mutations and polymorphisms of gonadotrophins and their receptors on the outcome of controlled ovarian stimulation. Princ Pract Contr Ovar Stimul ART. (2015) 147–56. 10.1007/978-81-322-1686-5_14
    1. Alviggi C, Conforti A, Caprio F, Gizzo S, Noventa M, Strina I, et al. . In estimated good prognosis patients could unexpected “hyporesponse” to controlled ovarian stimulation be related to genetic polymorphisms of FSH receptor? Reprod Sci. (2016) 23:1103–8. 10.1177/1933719116630419
    1. Achrekar SK, Modi DN, Desai SK, Mangoli VS, Mangoli RV, Mahale SD. Follicle-stimulating hormone receptor polymorphism. (Thr307Ala) is associated with variable ovarian response and ovarian hyperstimulation syndrome in Indian women. Fertil Steril. (2009) 91:432–9. 10.1016/j.fertnstert.2007.11.093
    1. La Marca A, Papaleo E, Alviggi C, Ruvolo G, De Placido G, Candiani M, et al. . The combination of genetic variants of the FSHB and FSHR genes affects serum FSH in women of reproductive age. Hum Reprod. (2013) 28:1369–74. 10.1093/humrep/det061
    1. Desai SS, Achrekar SK, Pathak BR, Desai SK, Mangoli VS, Mangoli RV, et al. . Follicle-stimulating hormone receptor polymorphism. (G-29A) is associated with altered level of receptor expression in Granulosa cells. J Clin Endocrinol Metab. (2011) 96:2805–12. 10.1210/jc.2011-1064
    1. Tohlob D, Abo Hashem E, Ghareeb N, Ghanem M, Elfarahaty R, Byers H, et al. . Association of a promoter polymorphism in FSHR with ovarian reserve and response to ovarian stimulation in women undergoing assisted reproductive treatment. Reprod Biomed Online. (2016) 33:391–7. 10.1016/j.rbmo.2016.06.001
    1. Simoni M, Gromoll J, Hoppner W, Kamischke A, Krafft T, Stahle D, et al. . Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms. J Clin Endocrinol Metab. (1999) 84:751–5. 10.1210/jcem.84.2.5500
    1. Alviggi C, Humaidan P, Ezcurra D. Hormonal, functional and genetic biomarkers in controlled ovarian stimulation: tools for matching patients and protocols. Reprod Biol Endocrinol. (2012) 10:9. 10.1186/1477-7827-10-9
    1. Overbeek A, Kuijper EA, Hendriks ML, Blankenstein MA, Ketel IJ, Twisk JW, et al. . Clomiphene citrate resistance in relation to follicle-stimulating hormone receptor Ser680Ser-polymorphism in polycystic ovary syndrome. Hum Reprod. (2009) 24:2007–13. 10.1093/humrep/dep114
    1. Achrekar SK, Modi DN, Desai SK, Mangoli VS, Mangoli RV, Mahale SD. Poor ovarian response to gonadotrophin stimulation is associated with FSH receptor polymorphism. Reprod Biomed Online. (2009) 18:509–15. 10.1016/S1472-6483(10)60127-7
    1. Rull K, Grigorova M, Ehrenberg A, Vaas P, Sekavin A, Nommemees D, et al. . FSHB−211 G>T is a major genetic modulator of reproductive physiology and health in childbearing age women. Hum Reprod. (2018) 33:954–66. 10.1093/humrep/dey057
    1. Ferlin A, Vinanzi C, Selice R, Garolla A, Frigo AC, Foresta C. Toward a pharmacogenetic approach to male infertility: polymorphism of follicle-stimulating hormone beta-subunit promoter. Fertil Steril. (2011) 96:1344–9.e2. 10.1016/j.fertnstert.2011.09.034
    1. Grigorova M, Punab M, Poolamets O, Kelgo P, Ausmees K, Korrovits P, et al. . Increased prevalance of the−211 T allele of follicle stimulating hormone (FSH) β subunit promoter polymorphism and lower serum FSH in infertile men. J Clin Endocrinol Metab. (2010) 95:100–8. 10.1210/jc.2009-1010
    1. Alviggi C, Pettersson K, Longobardi S, Andersen CY, Conforti A, De Rosa P, et al. . A common polymorphic allele of the LH beta-subunit gene is associated with higher exogenous FSH consumption during controlled ovarian stimulation for assisted reproductive technology. Reprod Biol Endocrinol. (2013) 11:51. 10.1186/1477-7827-11-51
    1. Drakopoulos P, Santos-Ribeiro S, Bosch E, Garcia-Velasco J, Blockeel C, Romito A, et al. . The effect of dose adjustments in a subsequent cycle of women with suboptimal response following conventional ovarian stimulation. Front Endocrinol. (2018) 9:361. 10.3389/fendo.2018.00361
    1. Conforti A, Esteves SC, Strina I, Picarelli S, Iorio G, Rania E, et al. Novel approaches for diagnosis and management of low prognosis patients in ART: the POSEIDON concept. Panminerva Med. (2018) 61:24–9. 10.23736/S0031-0808.18.03511-5
    1. van Tilborg TC, Oudshoorn SC, Eijkemans MJC, Mochtar MH, van Golde RJT, Hoek A, et al. . Individualized FSH dosing based on ovarian reserve testing in women starting IVF/ICSI: a multicentre trial and cost-effectiveness analysis. Hum Reprod. (2017) 32:2485–95. 10.1093/humrep/dex321
    1. Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature. (2015) 526:343–50. 10.1038/nature15817
    1. Alviggi C, Conforti A, Fabozzi F, De Placido G. Ovarian stimulation for IVF/ICSI cycles: A pharmacogenomic approach. Med Therap Med Reprod Gynecol Endocrinol. (2009) 11:271–7. 10.1684/mte.2009.0255
    1. Conforti A, Alfano S, De Rosa P, Alviggi C, De Placido G. The role of gonadotropin polymorphisms and their receptors in assisted reproductive technologies and controlled ovarian stimulation: a prospective observational study. Ital J Gynaecol Obstetr. (2017) 29:15–21. 10.14660/2385-0868-67
    1. Simoni M, Casarini L. Mechanisms in endocrinology: genetics of FSH action: a 2014-and-beyond view. Eur J Endocrinol. (2014) 170:R91–107. 10.1530/EJE-13-0624
    1. Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, et al. . In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. (2013) 100:100–7.e1. 10.1016/j.fertnstert.2013.02.056
    1. Ata B, Kaplan B, Danzer H, Glassner M, Opsahl M, Tan SL, et al. Array CGH analysis shows that aneuploidy is not related to the number of embryos generated. Reprod Biomed Online. (2012) 24:614–20. 10.1016/j.rbmo.2012.02.009
    1. Esteves SC, Carvalho JF, Martinhago CD, Melo AA, Bento FC, Humaidan P, et al. . Estimation of age-dependent decrease in blastocyst euploidy by next generation sequencing: development of a novel prediction model. Panminerva Med. (2018) 61:3–10. 10.23736/S0031-0808.18.03507-3
    1. Devroey P, Pellicer A, Nyboe Andersen A, Arce JC. A randomized assessor-blind trial comparing highly purified hMG and recombinant FSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer. Fertil Steril. (2012) 97:561–71. 10.1016/j.fertnstert.2011.12.016
    1. Lehert P, Schertz JC, Ezcurra D. Recombinant human follicle-stimulating hormone produces more oocytes with a lower total dose per cycle in assisted reproductive technologies compared with highly purified human menopausal gonadotrophin: a meta-analysis. Reprod Biol Endocrinol. (2010) 8:112. 10.1186/1477-7827-8-112
    1. Hompes PG, Broekmans FJ, Hoozemans DA, Schats R. Effectiveness of highly purified human menopausal gonadotropin vs. recombinant follicle-stimulating hormone in first-cycle in vitro fertilization-intracytoplasmic sperm injection patients. Fertil Steril. (2008) 89:1685–93. 10.1016/j.fertnstert.2007.05.039
    1. Platteau P, Andersen AN, Balen A, Devroey P, Sorensen P, Helmgaard L, et al. . Similar ovulation rates, but different follicular development with highly purified menotrophin compared with recombinant FSH in WHO Group II anovulatory infertility: a randomized controlled study. Hum Reprod. (2006) 21:1798–804. 10.1093/humrep/del085
    1. Behre HM, Greb RR, Mempel A, Sonntag B, Kiesel L, Kaltwasser P, et al. . Significance of a common single nucleotide polymorphism in exon 10 of the follicle-stimulating hormone (FSH) receptor gene for the ovarian response to FSH: a pharmacogenetic approach to controlled ovarian hyperstimulation. Pharm Genom. (2005) 15:451–6. 10.1097/01.fpc.0000167330.92786.5e
    1. Genro VK, Matte U, De Conto E, Cunha-Filho JS, Fanchin R. Frequent polymorphisms of FSH receptor do not influence antral follicle responsiveness to follicle-stimulating hormone administration as assessed by the Follicular Output RaTe (FORT). J Assist Reprod Genet. (2012) 29:657–63. 10.1007/s10815-012-9761-7
    1. Lisi F, Rinaldi L, Fishel S, Lisi R, Pepe GP, Picconeri MG, et al. . Use of recombinant LH in a group of unselected IVF patients. Reprod Biomed Online. (2002) 5:104–8. 10.1016/S1472-6483(10)61610-0
    1. Ferraretti AP, Gianaroli L, Magli MC, D'Angelo A, Farfalli V, Montanaro N. Exogenous luteinizing hormone in controlled ovarian hyperstimulation for assisted reproduction techniques. Fertil Steril. (2004) 82:1521–6. 10.1016/j.fertnstert.2004.06.041
    1. De Placido G, Alviggi C, Perino A, Strina I, Lisi F, Fasolino A, et al. . Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial. Hum Reprod. (2005) 20:390–6. 10.1093/humrep/deh625
    1. Ruvolo G, Bosco L, Pane A, Morici G, Cittadini E, Roccheri MC. Lower apoptosis rate in human cumulus cells after administration of recombinant luteinizing hormone to women undergoing ovarian stimulation for in vitro fertilization procedures. Fertil Steril. (2007) 87:542–6. 10.1016/j.fertnstert.2006.06.059
    1. Alviggi C, Conforti A, Esteves SC, Andersen CY, Bosch E, Buhler K, et al. . Recombinant luteinizing hormone supplementation in assisted reproductive technology: a systematic review. Fertil Steril. (2018) 109:644–64. 10.1016/j.fertnstert.2018.01.003
    1. Alviggi C, Mollo A, Clarizia R, De Placido G. Exploiting LH in ovarian stimulation. Reprod Biomed Online. (2006) 12:221–33. 10.1016/S1472-6483(10)60865-6
    1. De Placido G, Alviggi C, Mollo A, Strina I, Ranieri A, Alviggi E, et al. . Effects of recombinant LH (rLH) supplementation during controlled ovarian hyperstimulation (COH) in normogonadotrophic women with an initial inadequate response to recombinant FSH (rFSH) after pituitary downregulation. Clin Endocrinol. (2004) 60:637–43. 10.1111/j.1365-2265.2004.02027.x
    1. Yilmaz FY, Görkemli H, Çolakoglu MC, Aktan M, Gezginç K. The evaluation of recombinant LH supplementation in patients with suboptimal response to recombinant FSH undergoing IVF treatment with GnRH agonist down-regulation. Gynecol Endocrinol. (2015) 31:141–4. 10.3109/09513590.2014.965675
    1. Pezzuto A, Ferrari B, Coppola F, Nardelli GB. LH supplementation in down-regulated women undergoing assisted reproduction with baseline low serum LH levels. Gynecol Endocrinol. (2010) 26:118–24. 10.3109/09513590903215516
    1. Pettersson KS, Söderholm JR. Individual differences in lutropin immunoreactivity revealed by monoclonal antibodies. Clin Chem. (1991) 37:333–40.
    1. Haavisto AM, Pettersson K, Bergendahl M, Virkamaki A, Huhtaniemi I. Occurrence and biological properties of a common genetic variant of luteinizing hormone. J Clin Endocrinol Metab. (1995) 80:1257–63. 10.1210/jcem.80.4.7714098
    1. Lindgren I, Baath M, Uvebrant K, Dejmek A, Kjaer L, Henic E, et al. . Combined assessment of polymorphisms in the LHCGR and FSHR genes predict chance of pregnancy after in vitro fertilization. Hum Reprod. (2016) 31:672–83. 10.1093/humrep/dev342
    1. Alviggi C, Conforti A, Cariati F, Alfano S, Strina I, Huhtaniemi I, et al. Abstracts of the 32nd annual meeting of the european society of human reproduction and embryology. Hum Reprod. (2016) 31(suppl_1):i1–513. 10.1093/humrep/31.Supplement_1.1
    1. Conforti A, Esteves SC, Di Rella F, Strina I, De Rosa P, Fiorenza A, et al. The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: a systematic review and meta-analysis. Reprod Biol Endocrinol. (2019) 17:18 10.1186/s12958-019-0460-4
    1. Yakin K, Urman B. DHEA as a miracle drug in the treatment of poor responders; hype or hope? Hum Reprod. (2011) 26:1941–4. 10.1093/humrep/der150
    1. Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod. (2000) 15:2129–32. 10.1093/humrep/15.10.2129
    1. Nagels HE, Rishworth JR, Siristatidis CS, Kroon B. Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction. Cochrane Database Syst Rev. (2015) 26:Cd009749 10.1002/14651858.CD009749.pub2
    1. Tartagni M, Cicinelli MV, Baldini D, Tartagni MV, Alrasheed H, DeSalvia MA, et al. . Dehydroepiandrosterone decreases the age-related decline of the in vitro fertilization outcome in women younger than 40 years old. Reprod Biol Endocrinol. (2015) 13:18. 10.1186/s12958-015-0014-3
    1. Moawad A, Shaeer M. Long-term androgen priming by use of dehydroepiandrosterone (DHEA) improves IVF outcome in poor-responder patients. A randomized controlled study. Middle East Fertil Soc J. (2012) 17:268–74. 10.1016/j.mefs.2012.11.002
    1. Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab. (2005) 90:3847–53. 10.1210/jc.2005-0212
    1. Welt CK, Jimenez Y, Sluss PM, Smith PC, Hall JE. Control of estradiol secretion in reproductive ageing. Hum Reprod. (2006) 21:2189–93. 10.1093/humrep/del136
    1. Vaiarelli A, Cimadomo D, Ubaldi N, Rienzi L, Ubaldi FM. What is new in the management of poor ovarian response in IVF? Curr Opin Obstet Gynecol. (2018) 30:155–62. 10.1097/gco.0000000000000452
    1. Cimadomo D, Vaiarelli A, Colamaria S, Trabucco E, Alviggi C, Venturella R, et al. . Luteal phase anovulatory follicles result in the production of competent oocytes: intra-patient paired case-control study comparing follicular versus luteal phase stimulations in the same ovarian cycle. Hum Reprod. (2018). 10.1093/humrep/dey217. [Epub ahead of print].
    1. Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colamaria S, Alviggi C, et al. . Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertil Steril. (2016) 105:1488–95.e1. 10.1016/j.fertnstert.2016.03.002
    1. Vaiarelli A, Cimadomo D, Trabucco E, Vallefuoco R, Buffo L, Dusi L, et al. . Double stimulation in the same ovarian cycle (DuoStim) to maximize the number of oocytes retrieved from poor prognosis patients: a multicenter experience and SWOT analysis. Front Endocrinol. (2018) 9:317. 10.3389/fendo.2018.00317

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel