Controlled Ovarian Stimulation Using Medroxyprogesterone Acetate and hMG in Patients With Polycystic Ovary Syndrome Treated for IVF: A Double-Blind Randomized Crossover Clinical Trial

Yun Wang, Qiuju Chen, NingLing Wang, Hong Chen, Qifeng Lyu, Yanping Kuang, Yun Wang, Qiuju Chen, NingLing Wang, Hong Chen, Qifeng Lyu, Yanping Kuang

Abstract

Ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation is a current challenge for patients with polycystic ovarian syndrome (PCOS). Our previous studies indicated that progestin can prevent premature luteinizing hormone (LH) surge or moderate/severe OHSS in the general subfertile population, both in the follicular-phase and luteal-phase ovarian stimulation but it is unclear if this is true for patients with PCOS. The aim of the article was to analyze cycle characteristics and endocrinological profiles using human menopausal gonadotropin (hMG) in combination with medroxyprogesterone acetate (MPA) for PCOS patients who are undergoing IVF/intracytoplasmic sperm injection (ICSI) treatments and investigate the subsequently pregnancy outcomes of frozen embryo transfer (FET). In the randomized prospective controlled study, 120 PCOS patients undergoing IVF/ICSI were recruited and randomly classified into 2 groups according to the ovarian stimulation protocols: hMG and MPA (group A, n = 60) or short protocol (group B, n = 60). In the study group, hMG (150-225IU) and MPA (10 mg/d) were administered simultaneously beginning on cycle day 3. Ovulation was cotriggered by a gonadotropinreleasing hormone (GnRH) agonist (0.1 mg) and hCG (1000IU) when dominant follicles matured. A short protocol was used as a control. The primary end-point was the ongoing pregnancy rate per transfer and incidence of OHSS. Doses of hMG administrated in group A are significantly higher than those in the controls. LH suppression persisted during ovarian stimulation and no incidence of premature LH surge was seen in both groups. The fertilization rate and the ongoing pregnant rate in the study group were higher than that in the control. The number of oocytes retrieved, mature oocytes, clinical pregnancy rates per transfer, implantation rates, and cumulative pregnancy rates per patient were comparable between the 2 groups. The incidence of OHSS was low between the 2 groups, with no significant difference. The study showed that MPA has the advantages of an oral administration route, easy access, more control over LH levels. A possible reduction in the incidence of moderate or severe OHSS with the MPA protocol should be viewed with caution as the data is small. Large randomized trials with adequate sample size remain necessary.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

FIGURE 1
FIGURE 1
Study flow chart.
FIGURE 2
FIGURE 2
Serum hormone profiles present during ovarian stimulation in the 2 regimens. The green line refers to the MPA group and the red line stands for the control group. The asterisk (∗) represents P < 0.05 at the time point. MPA = medroxyprogesterone acetate.

References

    1. Homburg R, Berkowitz D, Levy T, et al. In vitro fertilization and embryo transfer for the treatment of infertility associated with polycystic ovary syndrome. Fertil Steril 1993; 60:858–863.
    1. Delvigne A, Demoulin A, Smitz J, et al. The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study. I. Clinical and biological features. Hum Reprod 1993; 8:1353–1360.
    1. Pundir J, Sunkara SK, El-Toukhy T, et al. Meta-analysis of GnRH antagonist protocols: do they reduce the risk of OHSS in PCOS? Reprod Biomed Online 2012; 24:6–22.
    1. Heijnen EM, Eijkemans MJ, Hughs EG, et al. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update 2006; 12:13–21.
    1. Kuang YP, Hong QQ, Chen QJ, et al. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril 2014; 101:105–111.
    1. Kuang YP, Chen QJ, Fu YL, et al. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril 2015; 104:62–70.
    1. Evans J, Hannan NJ, Edgell TA, et al. Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence. Hum Reprod Update 2014; 20:808–821.
    1. Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum Reprod 2011; 26:2593–2597.
    1. Wong KM, Mastenbroek S, Repping S. Cryopreservation of human embryos and its contribution to in vitro fertilization success rates. Fertil Steril 2014; 102:19–26.
    1. Doody KJ. Cryopreservation and delayed embryo transfer-assisted reproductive technology registry and reporting implications. Fertil Steril 2014; 102:27–31.
    1. Sitruk-Ware R, Nath A, Mishell DR., Jr Contraception technology: past, present and future. Contraception 2013; 87:319–330.
    1. Kolibianakis E, Zikopoulos K, Albano C, et al. Reproductive outcome of polycystic ovarian syndrome patients treated with GnRH antagonists and recombinant FSH for IVF/ICSI. Reprod Biomed Online 2003; 7:313–318.
    1. Cummins JM, Breen TM, Harrison KL, et al. A formula for scoring human embryo growth rates in in vitro fertilization: its value in predicting pregnancy and in comparison with visual estimates of embryo quality. J In Vitro Fert Embryo Transf 1986; 3:284–295.
    1. Schmidt DW, Maier DB, Nulsen JC, et al. Reducing the dose of human chorionic gonadotropin in high responders does not affect the outcomes of in vitro fertilization. Fertil Steril 2004; 82:841–846.
    1. Liu XY, Xue SG, Jin W, et al. Impact of incubation time of vitrification-warming embryos on frozen-thawed embryo transfer outcomes (Chinese). J Reprod Med 2010; 19:104–107.
    1. Balaban B, Urrman B, Ata B, et al. A randomized controlled study of human Day 3 embryo cryopreservation by slow freezing or vitrification: vitrification is associated with higher survival, metabolism and blastocyst formation. Hum Reprod 2008; 23:1976–1982.
    1. Griesinger G, Venetis CA, Marx T, et al. Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists for IVF: a systematic review and meta-analysis. Fertil Steril 2008; 90:1055–1063.
    1. Borman SM, Chaffin CL, Schwinof KM, et al. Progestin promotes oocytes maturation, but not ovulation, in nonhuman primate follicles without a gonadotropin surge. Biol Reprod 2004; 71:366–373.
    1. Morrison T, Waggoner L, Whitworth-Langley L, et al. Nongenomic action of progesterone: activation of Xenopus oocyte phospholipase C through a plasma membrane-associated tyrosine kinase. Endocrinology 2000; 141:2145–2152.
    1. Salehnia M, Zavareh S. The effects of progesteron on oocyte maturation and embryo development. Int J Fertil Steril 2013; 7:74–81.
    1. Morgan PM, Boatman DE, Bavister BD. Relationships between follicular fluid steroid hormone concentrations, oocyte maturity, in vitro fertilization and embryonic development in the rhesus monkey. Mol Reprod Dev 1990; 27:145–151.
    1. Richter TA, Robinson JE, Evans NP. Progestin blocks the estradiol-stimulated luteinizing hormone surge by disrupting activation in response to a stimulatory estradiol signal in the ewe. Biol Reprod 2002; 67:119–125.
    1. Wikström A, Green B, Johansson ED. The plasma concentration of medroxyprogesterone acetate and ovarian function during treatment with medroxyprogesterone acetate in 5 and 10 mg doses. Acta Obstet Gynecol Scand 1984; 63:163–168.
    1. Soules MR, Steiner RA, Clifton DK, et al. Progestin modulation of pulsatile luteinizing hormone secretion in normal women. J Clin Endocrinol Metab 1984; 58:378–383.
    1. Pohl CR, Richardson DW, Marshall G, et al. Mode of action of progestin in the blockade of gonadotropin surges in the rhesus monkey. Endocrinology 1982; 110:1454–1455.
    1. Richter TA, Robinson JE, Evans NP. Progestin treatment that either blocks or augments the etradiol-induced gonadotropin-releasing hormone surge is associated with different patterns of hypothalamic neural activation. Neuroendocrinology 2001; 73:378–386.
    1. Ruiz de Galarreta CM, Fanjul LF, Hsueh AJ. Progestin regulation of progestin biosynthetic enzymes in cultured rat granulosa cells. Steroids 1985; 46:987–1002.
    1. Fanjul LF, Ruiz de Galarreta CM, Hsueh AJ. Progestin augmentation of gonadotropin-stimulated progestin production by cultured rat granulosa cells. Endocrinology 1983; 112:405–407.
    1. Fanjul LF, Ruiz de Galarreta CM, Hsueh AJ. Estrogen regulation of progestin biosynthetic enzymes in cultured rat granulosa cells. Biol Reprod 1984; 30:903–912.
    1. Orvieto R, Nahum R, Meltcer S, et al. Ovarian stimulation in polycystic ovary syndrome patients: the role of body mass index. Reprod Biomed Online 2009; 18:333–336.
    1. Trifon G, Lainas, Ioannis A, et al. Flexible GnRH antagonist protocol versus GnRH agonist long protocol in patients with polycystic ovary syndrome treated for IVF: a prospective randomised controlled trial (RCT). Hum Reprod 2010; 25:683–689.
    1. Hong Chen, Yun Wang, Qifeng Lyu, et al. Comparison of live-birth defects after luteal-phase ovarian stimulation vs. conventional ovarian stimulation for in vitro fertilization and vitrified embryo transfer cycles. Fertil Steril 2015; 103:1194–1201.
    1. Bo Huang, Dan Hu, Kun Qian, et al. Is frozen embryo transfer cycle associated with a significantly lower incidence of ectopic pregnancy? An analysis of more than 30000 cycles. Fertil Steril 2014; 102:1345–1349.
    1. Roque M, Lattes K, Serra S, et al. Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. Fertil Steril 2013; 99:156–162.
    1. Pinborg A, Henningsen AA, Loft A, et al. Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique? Hum Reprod 2014; 29:618–627.
    1. Young LE, Sinclair KD, Wilmut I. Large offspring syndrome in cattle and sheep. Rev Reprod 1998; 3:155–163.
    1. Sinclair KD, Young LE, Wilmut I, et al. In-utero overgrowth in ruminants following embryo culture: lessons from mice and a warning to men. Hum Reprod 2000; 15:68–86.
    1. Grace KS, Sinclair KD. Assisted reproductive technology, epigenetics, and long-term health: a developmental time bomb still ticking. Semin Reprod Med 2009; 27:409–416.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren