We examined whether treatment with minimum-dose stimulation (MS) protocol enhances clinical pregnancy rates compared to high-dose stimulation (HS) protocol. A retrospective cohort study was performed comparing IVF and pregnancy outcomes between MS and HS gonadotropin-antagonist protocol for patients with poor ovarian reserve (POR). Inclusion criteria included patients with an anti-Müllerian hormone (AMH) ≤8？pmol/L and/or antral follicle count (AFC) ≤5 on days 2-3 of the cycle. Patients from 2008 exclusively had a HS protocol treatment, while patients in 2010 had treatment with a MS protocol exclusively. The MS protocol involved letrozole at 2.5？mg over 5 days, starting from day 2, overlapping with gonadotropins, starting from the third day of letrozole at 150 units daily. GnRH antagonist was introduced once one or more follicles reached 14？mm or larger. The HS group received gonadotropins (≥300？IU/day) throughout their antagonist cycle. Clinical pregnancy rate was significantly higher in the MS protocol compared to the HS protocol (). Furthermore, the live birth rate was significantly higher in the MS group compare to the HS group (). In conclusion, the MS IVF protocol is less expensive (lower gonadotropin dosage) and resulted in a higher clinical pregnancy rate and live birth rate than a HS protocol for poor responders. 1. Introduction Patients with poor ovarian response (POR) are both challenging to treat and represent a large proportion of patients presenting with infertility [1, 2]. Patients with POR, who are often of advanced maternal age, have a high cycle cancellation rate, higher miscarriage rate, and significantly reduced live birth rate per cycle. To date, there is no universally accepted definition for POR. These patients generally have one or more of the following characteristics: advanced maternal age, low AMH levels, high FSH in the early follicular phase (~day 3) (≥10？mIU/mL), low early follicular phase antral follicle count (AFC) (3–7) [3, 4], low number of mature retrieved oocytes (<4) after superovulation with a moderate to high-dose protocol, low peak E2 levels (<3300？pmol/L), and prior cycle cancellation(s) due to poor response [5–7]. The European Society of Human Reproduction and Embryology (ESHRE) attempted to standardize the definition of POR in 2010 and this resulted in a consensus definition called the Bologna criteria. At least two of the following three features must be present: (1) advanced maternal age (≥40 years) or any other risk factors for POR, (2) a previous POR (≤3 oocytes) with a conventional stimulation protocol,
References
[1]
D. Kyrou, E. M. Kolibianakis, C. A. Venetis, E. G. Papanikolaou, J. Bontis, and B. C. Tarlatzis, “How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis,” Fertility and Sterility, vol. 91, no. 3, pp. 749–766, 2009.
[2]
B. Vollenhoven, T. Osianlis, and J. Catt, “Is there an ideal stimulation regimen for IVF for poor responders and does it change with age?” Journal of Assisted Reproduction and Genetics, vol. 25, no. 11-12, pp. 523–529, 2008.
[3]
E. R. Klinkert, F. J. M. Broekmans, C. W. N. Looman, J. D. F. Habbema, and E. R. te Velde, “Expected poor responders on the basis of an antral follicle count do not benefit from a higher starting dose of gonadotrophins in IVF treatment: a randomized controlled trial,” Human Reproduction, vol. 20, no. 3, pp. 611–615, 2005.
[4]
M. F. Mutlu, M. Erdem, A. Erdem et al., “Antral follicle count determines poor ovarian response better than anti-müllerian hormone but age is the only predictor for live birth in in vitro fertilization cycles,” Journal of Assisted Reproduction & Genetics, vol. 30, no. 5, pp. 657–665, 2013.
[5]
S. M. Zarek and S. J. Muasher, “Mild/minimal stimulation for in vitro fertilization: an old idea that needs to be revisited,” Fertility & Sterility, vol. 95, no. 8, pp. 2449–2455, 2011.
[6]
E. R. Klinkert, F. J. M. Broekmans, C. W. N. Looman, and E. R. Te Velde, “A poor response in the first in vitro fertilization cycle is not necessarily related to a poor prognosis in subsequent cycles,” Fertility and Sterility, vol. 81, no. 5, pp. 1247–1253, 2004.
[7]
E. S. Surrey and W. B. Schoolcraft, “Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques,” Fertility and Sterility, vol. 73, no. 4, pp. 667–676, 2000.
[8]
M. F. M. Mitwally and R. F. Casper, “Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate,” Fertility and Sterility, vol. 75, no. 2, pp. 305–309, 2001.
[9]
H. Yarali, I. Esinler, M. Polat, G. Bozdag, and B. Tiras, “Antagonist/letrozole protocol in poor ovarian responders for intracytoplasmic sperm injection: a comparative study with the microdose flare-up protocol,” Fertility & Sterility, vol. 92, no. 1, pp. 231–235, 2009.
[10]
S. Healey, S. L. Tan, T. Tulandi, and M. M. Biljan, “Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination,” Fertility and Sterility, vol. 80, no. 6, pp. 1325–1329, 2003.
[11]
R. F. Casper and M. F. M. Mitwally, “Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome,” Clinical Obstetrics and Gynecology, vol. 54, no. 4, pp. 685–695, 2011.
[12]
A. P. Ferraretti, A. La Marca, B. C. J. M. Fauser, B. Tarlatzis, G. Nargund, and L. Gianaroli, “ESHRE consensus on the definition of 'poor response to ovarian stimulation for in vitro fertilization: the Bologna criteria,” Human Reproduction, vol. 26, no. 7, pp. 1616–1624, 2011.
[13]
V. A. Akande, C. F. Fleming, L. P. Hunt, S. D. Keay, and J. M. Jenkins, “Biological versus chronological ageing of oocytes, distinguishable by raised FSH levels in relation to the success of IVF treatment,” Human Reproduction, vol. 17, no. 8, pp. 2003–2008, 2002.
[14]
G. Nargund, W. C. Cheng, and J. Parsons, “The impact of ovarian cystectomy on ovarian response to stimulation during in-vitro fertilization cycles,” Human Reproduction, vol. 11, no. 1, pp. 81–83, 1996.
[15]
S. D. Keay, N. H. Liversedge, and J. M. Jenkins, “Could ovarian infection impair ovarian response to gonadotrophin stimulation?” British Journal of Obstetrics & Gynaecology, vol. 105, no. 3, pp. 252–254, 1998.
[16]
D. Nikolaou and A. Templeton, “Early ovarian ageing: a hypothesis: detection and clinical relevance,” Human Reproduction, vol. 18, no. 6, pp. 1137–1139, 2003.
[17]
J. A. Garcia-Velasco, L. Moreno, A. Pacheco et al., “The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study,” Fertility and Sterility, vol. 84, no. 1, pp. 82–87, 2005.
[18]
S. G. Hillier, “Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in folliculogenesis,” Human Reproduction, vol. 9, no. 2, pp. 188–191, 1994.
[19]
S. Weil, K. Vendola, J. Zhou, and C. A. Bondy, “Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 8, pp. 2951–2956, 1999.
[20]
N. Gleicher and D. H. Barad, “Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR),” Reproductive Biology and Endocrinology, vol. 9, article 67, 2011.
[21]
R. S. Corfman, M. P. Milad, T. L. Bellavance, S. J. Ory, L. D. Erickson, and G. D. Ball, “A novel ovarian stimulation protocol for use with the assisted reproductive technologies,” Fertility and Sterility, vol. 60, no. 5, pp. 864–870, 1993.
[22]
H. Al-Fozan, M. Al-Khadouri, S. L. Tan, and T. Tulandi, “A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation,” Fertility and Sterility, vol. 82, no. 6, pp. 1561–1563, 2004.
[23]
I. A. Mohsen and R. E. El Din, “Minimal stimulation protocol using letrozole versus microdose flare up GnRH agonist protocol in women with poor ovarian response undergoing ICSI,” Gynecological Endocrinology, vol. 29, no. 2, pp. 105–108, 2013.
