Avoiding OHSS: Controlled Ovarian Low-Dose Stimulation in Women with PCOS

Abstract

The polycystic ovary syndrome is a common endocrine disorder which influences outcome and potential risks involved with controlled ovarian stimulation for artificial reproductive techniques (ART). Concrete practical recommendations for the dosage of gonadotropins, the preferred protocol and preventive methods to avoid ovarian hyperstimulation syndrome (OHSS) are lacking. We present retrospective data of 235 individually calculated gonadotropin low-dose stimulations for ART in a single center from 2012 to 2014. Clinical data and outcome parameter of patients diagnosed with PCOS according to Rotterdam criteria (n = 39) were compared with patients without PCOS (n = 196). The starting dose of gonadotropins was individually calculated depending on patientsʼ age, BMI, ovarian reserve, ovarian response in previous cycles, and diagnostic criteria of PCOS. Mean age and duration of infertility did not differ between the groups, whereas mean BMI (p = 0.007) and AMH (p < 0.001) were higher in the PCOS-group. A lower mean FSH-starting and maximum dose was administered to women with PCOS (p < 0.001). The biochemical pregnancy rate of 42.4 % and the clinical pregnancy rate of 32.2 % for PCOS-patients did not differ from those of the control group (42.2 % and 34.4 % respectively). Neither mild, nor moderate or severe manifestation of OHSS occurred significantly more often in patients with PCOS. Our study supports the use of a calculated low-dose FSH-stimulation strategy in ART for patients with PCOS. Further randomized clinical trials should confirm this strategy and lead to define individual risk factors for OHSS, which can be used for recommendation of safer ART-techniques like in vitro maturation.

Zusammenfassung

Das polyzystische Ovarsyndrom (PCOS) ist eine häufige endokrinologische Störung der Frau, die erhebliche Auswirkungen auf Erfolg und potenzielle Risiken einer Gonadotropinstimulation bei künstlicher Befruchtung hat. Klare praktische Empfehlungen für die FSH-Dosierung und das optimale Stimulationsprotokoll zur Vermeidung eines OHSS fehlen weitgehend. Retrospektiv wurden Zyklen von 235 Patientinnen, die von 2012 bis 2014 für eine IVF/ICSI kontrolliert stimuliert wurden, analysiert. Klinische Daten der PCOS-Patientinnen (n = 39) wurden mit denen ohne PCOS (n = 196) verglichen. Die Gonadotropin-Startdosierung orientierte sich am Alter der Patientinnen, dem BMI, der ovariellen Reserve, Stimulationsverläufen in Vorzyklen und diagnostischen Kriterien des PCOS. Durchschnittliches Alter und Dauer der Infertilität unterschieden sich nicht signifikant zwischen den beiden Gruppen. Der durchschnittliche BMI (p = 0,007) und basale AMH-Wert (p < 0,001) lag bei Frauen mit PCOS höher. Bei ihnen fand sich eine signifikant niedrigere FSH-Start- und Maximaldosis (p < 0,001). Die Gesamtdosis verwendeter Gonadotropineinheiten sowie der maximale Östradiolspiegel jedoch unterschieden sich nicht. Auch die biochemischen und klinischen Schwangerschaftsraten von 42,2 und 32,2 % bei PCOS-Patientinnen wichen nicht signifikant von den Ergebnissen der Kontrollgruppe ab (42,2 und 34,4 %). Weder leichte noch moderate oder schwere Ausprägungen des OHSS kamen häufiger in einer der beiden Gruppen vor. Unsere Studie schlägt eine kalkulierte, niedrigdosierte Stimulationsstrategie mit Dosissteigerung in kleinen Schritten vor. Durch weitere randomisierte, kontrollierte klinische Studie sollte diese Strategie überprüft werden und individuelle Risikofaktoren erkannt werden, die in Einzelfällen als Indikation zu anderen sicheren Methoden der ART wie der In-vitro-Maturation genutzt werden können.

Key words

PCOS - IVF/ICSI - ART - ovarian hyperstimulation syndrome (OHSS) - gonadotropins

Schlüsselwörter

PCOS - IVF/ICSI - künstliche Befruchtung - ovarielles Überstimulationssyndrom (OHSS) - Gonadotropin

• References

• 1 Tan S. Endokrionologie. Minimaldiagnostik und Therapieansätze beim PCOS. Geburtsh Frauenheilk 2012; 72: 696-700
• 2 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19-25
• 3 Geisthövel F. [Functional hyperandrogenism—classification, etiology, diagnosis and therapy]. Ther Umsch 2002; 59: 163-173
• 4 Cupisti S. Komplikation bei Ovulationsinduktion. Das ovarielle Überstimulationssyndrom. Geburtsh Frauenheilk 2012; 72: 798-801
• 5 Binder H, Cupisti S, Dittrich R et al. Ovarielles Überstimulationssyndrom-update – Teil 2. Geburtsh Frauenheilk 2004; 64: R77-R100
• 6 Nelson SM, Yates RW, Lyall H et al. Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod 2009; 24: 867-875
• 7 Lee TH, Liu CH, Huang CC et al. Serum anti-Mullerian hormone and estradiol levels as predictors of ovarian hyperstimulation syndrome in assisted reproduction technology cycles. Hum Reprod 2008; 23: 160-167
• 8 World Health Organisation. WHO laboratory Manual for the Examination and Processing of human Semen. 5th ed. Geneva: World Health Organisation; 2010: 271
• 9 Aboulghar MA, Mansour RT. Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures. Hum Reprod Update 2003; 9: 275-289
• 10 Heijnen EM, Eijkemans MJ, Hughes EG et al. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update 2006; 12: 13-21
• 11 Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 2008; 89: 505-522
• 12 Swanton A, Storey L, McVeigh E et al. IVF outcome in women with PCOS, PCO and normal ovarian morphology. Eur J Obstet Gynecol Reprod Biol 2010; 149: 68-71
• 13 Rittenberg V, Seshadri S, Sunkara SK et al. Effect of body mass index on IVF treatment outcome: an updated systematic review and meta-analysis. Reprod Biomed Online 2011; 23: 421-439
• 14 Bailey AP, Hawkins LK, Missmer SA et al. Effect of body mass index on in vitro fertilization outcomes in women with polycystic ovary syndrome. Am J Obstet Gynecol 2014; 211: 163.e1-163.e6
• 15 Figen Turkcapar A, Seckin B, Onalan G et al. Human menopausal gonadotropin versus recombinant FSH in polycystic ovary syndrome patients undergoing in vitro fertilization. Int J Fertil Steril 2013; 6: 238-243
• 16 Steward RG, Lan L, Shah AA et al. Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles. Fertil Steril 2014; 101: 967-973
• 17 Practice Committee of American Society for Reproductive Medicine. Ovarian hyperstimulation syndrome. Fertil Steril 2008; 90: S188-S193
• 18 Teede HJ, Joham AE, Paul E et al. Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women. Obesity 2013; 21: 1526-1532
• 19 Beydoun HA, Stadtmauer L, Zhao Y et al. Impact of polycystic ovary syndrome on selected indicators of in vitro fertilization and intracytoplasmic sperm injection treatment success. J Womens Health (Larchmt) 2009; 18: 717-723
• 20 Liu L, Tong X, Jiang L et al. A comparison of the miscarriage rate between women with and without polycystic ovarian syndrome undergoing IVF treatment. Eur J Obstet Gynecol Reprod Biol 2014; 176: 178-182
• 21 Wang JX, Davies MJ, Norman RJ. Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment. Hum Reprod 2001; 16: 2606-2609
• 22 Ozgun MT, Uludag S, Oner G et al. The influence of obesity on ICSI outcomes in women with polycystic ovary syndrome. J Obstet Gynaecol 2011; 31: 245-249
• 23 Esinler I, Bayar U, Bozdag G et al. Outcome of intracytoplasmic sperm injection in patients with polycystic ovary syndrome or isolated polycystic ovaries. Fertil Steril 2005; 84: 932-937
• 24 Sahu B, Ozturk O, Ranierri M et al. Comparison of oocyte quality and intracytoplasmic sperm injection outcome in women with isolated polycystic ovaries or polycystic ovarian syndrome. Arch Gynecol Obstet 2008; 277: 239-244
• 25 McCormick B, Thomas M, Maxwell R et al. Effects of polycystic ovarian syndrome on in vitro fertilization-embryo transfer outcomes are influenced by body mass index. 2008. Fertil Steril 2008; 90: 2304-2309
• 26 Swanton A, Storey L, McVeigh E et al. IVF outcome in women with PCOS, PCO and normal ovarian morphology. Eur J Obstet Gynecol Reprod Biol 2010; 149: 68-71
• 27 Hamdine O, Eijkemans MJ, Lentjes EW et al. Ovarian response prediction in GnRH antagonist treatment for IVF using anti-mullerian hormone. Hum Reprod 2015; 30: 170-178
• 28 Fauser BC, Nargund G, Andersen AN et al. Mild ovarian stimulation for IVF: 10 years later. Hum Reprod 2010; 25: 2678-2684
• 29 Yates AP, Rustamov O, Roberts SA et al. Anti-mullerian hormone-tailored stimulation protocols improve outcomes whilst reducing adverse effects and costs of IVF. Hum Reprod 2011; 26: 2353-2362
• 30 Gera PS, Tatpati LL, Allemand MC et al. Ovarian hyperstimulation syndrome: Steps to maximize success and minimize effect for assisted reproductive outcome. Fertil Steril 2010; 94: 173-178
• 31 Humaidan P, Polyzos NP, Alsbjerg B et al. GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients. Hum Reprod 2013; 28: 2511-2521
• 32 Humaidan P, Engmann L, Benadiva C. Luteal phase supplementation after gonadotropin-releasing hormone agonist trigger in fresh embryo transfer: The American versus European approaches. Fertil Steril 2015; 103: 879-885
• 33 Seyhan A, Ata B, Polat M et al. Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG. Hum Reprod 2013; 28: 2522-2528
• 34 von Wolff M, Eberhardt I, Strowitzki T. In-vitro-Maturation – Indikationen, Risiken und Chancen einer neuen assistierten Reproduktionstechnik. Geburtsh Frauenheilk 2009; 67: 734-741
• 35 Fatemi HM, Popovic-Todorovic B, Humaidan P et al. Severe ovarian hyperstimulation syndrome after gonadotropin-releasing hormone (GnRH) agonist trigger and “freeze-all” approach in GnRH antagonist protocol. Fertil Steril 2014; 101: 1008-1011
• 36 Gurbuz AS, Gode F, Ozcimen N et al. Gonadotrophin-releasing hormone agonist trigger and freeze-all strategy does not prevent severe ovarian hyperstimulation syndrome: a report of three cases. Reprod Biomed Online 2014; 29: 541-544
• 37 Ling LP, Phoon JW, Lau MS et al. GnRH agonist trigger and ovarian hyperstimulation syndrome: Relook at ‘freeze-all strategy’. Reprod Biomed Online 2014; 29: 392-394
• 38 von Otte S, Griesinger G, Schultze-Mosgau A et al. Die Etablierung der In-vitro-Maturation als neue Variante der assistierten Reproduktion – Erfahrungen der Lübecker Arbeitsgruppe. Geburtsh Frauenheilk 2007; 67: 1009-1017
• 39 Roesner S, von Wolff M, Eberhardt I et al. In vitro maturation: a five-year experience. Acta Obstet Gynecol Scand 2012; 91: 22-27