A novel delayed start protocol with gonadotropin releasing hormone antagonist improves outcomes in poor responders

The delayed-start protocol improves ovarian response in poor responders by enhancing, promoting, and synchronizing follicle development.

Hakan Cakmak, M.D., Nam D. Tran, M.D. Ph.D., A. Musa Zamah, M.D. Ph.D., Marcelle I. Cedars, M.D., Mitchell P. Rosen, M.D.

Volume 101, Issue 5, Pages 1308–1314


To investigate whether delaying the start of ovarian stimulation with GnRH antagonist improves ovarian response in poor responders.

Retrospective study.

Academic medical center.

Thirty patients, who responded poorly and did not get pregnant with conventional estrogen priming antagonist IVF protocol.

Delayed-start antagonist protocol (estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation).

Main Outcome Measure(s):
Number of dominant follicles and mature oocytes retrieved, mature oocyte yield, and fertilization rate.

The number of patients who met the criteria to proceed to oocyte retrieval was significantly higher in the delayed-start protocol [21/30 (70%)] compared with the previous conventional estrogen priming antagonist cycle [11/30 (36.7%)]. The number of dominant follicles was significantly higher in the delayed-start (4.2 ± 2.7) compared with conventional (2.4 ± 1.3) protocol. In patients who had oocyte retrieval after both protocols (n = 9), the delayed start resulted in shorter ovarian stimulation (9.4 ± 1.4 days vs. 11.1 ± 2.0 days), higher number of mature oocytes retrieved (4.9 ± 2.0 vs. 2.2 ± 1.1), and a trend toward increased fertilization rates with intracytoplasmic sperm injection (ICSI; 86 ± 17% vs. 69 ± 21%) compared with conventional protocol. After delayed start, the average number of embryos transferred was 2.8 ± 1.4 with implantation rate of 9.8% and clinical pregnancy rate of 23.8%.

The delayed-start protocol improves ovarian response in poor responders by promoting and synchronizing follicle development without impairing oocyte developmental competence.

  • muratseval

    Murat SONMEZER, MD¹; Mehmet Murat SEVAL, MD¹; Tolga ECEMIS, MD2.

    ¹Ankara University Medical Faculty, Department of Obstetrics and Gynecology, Ankara, Turkey
    2Ankara Medicana Hospital, IVF unit, Ankara, Turkey

    Corresponding Author:
    Murat Sönmezer, MD.
    Address: Ankara University Medical Faculty, Department of Obstetrics and Gynecology, Cebeci Hospital, 06620, Mamak, Ankara, Turkey
    Phone: +90 312 5957027
    Fax: +90 312 3103553
    e-mail: msonmezer@gmail.com

    We read with great interest the eloquent paper by Cakmak et al. describing a novel delayed start protocol in poor responder patients (1). In their study not only the number of dominant follicles (4.2±2.7 vs. 2.4± 1.3) and mature oocytes (4.9 ±2.0 vs. 2.2 ±1.1) were higher in delayed start protocol compared to conventional stimulation protocol, increased fertilization rates were observed as well (86±17% vs. 69±21%).
    Poor response to ovarian stimulation is in fact, an indirect assessment of diminished primordial follicle reserve. Despite various modifications in stimulation protocols or embryo culture systems no definitive success has been achieved in these patients yet. The follicular phase is generally shortened in patients with diminished ovarian reserve due to accelerated follicular growth. The rising FSH concentrations during the period of luteofollicular transition stimulate earlier follicle development, which is associated with advanced follicular maturation and estradiol rise (2,3). We previously demonstrated that prematurely developing antral follicles are healthy and pregnancy can be achieved using these follicles in poor responder patients (4). However, due to heterogeneity of antral follicle responsiveness to gonadotropins, it is not unusual to see an asynchronous follicular growth in these patients. Even though luteal phase estradiol priming that lowers late luteal FSH rise may in part avoid this unwanted situation, asynchronous follicle growth frequently precludes retrieval of optimal number of mature oocytes following ovarian stimulation.

    A previous intriguing study by Baerwald et al. indicated that there are multiple major follicle recruitment waves during a normal menstrual cycle, and therefore the concept of a narrow window of opportunity for follicle recruitment may not be accurate (5). Given the current availability of GnRH antagonists, the utility of these multiple recruitment waves throughout the menstrual cycle can be feasible especially in the fertility preservation setting where endometrial development is irrelevant. As was clearly demonstrated in fertility preservation studies, ovarian stimulation can be started safely and effectively at any day of the menstrual cycle with favorable fertilization rates (6). This concept was then dubbed by us as “random start controlled ovarian hyperstimulation – RSCOH”. In RSCOH protocol GnRH antagonists are started similar to conventional GnRH antagonist protocols when serum estradiol is over 350 pg/ml or when the leading follicle is >13mm. As stated by authors, we think that by administering GnRH antagonist from the start of menstrual cycle and delaying gonadotropin stimulation by 7 days, more than one major follicular wave can be utilized in one menstrual cycle, which in turn can increase the success of index cycle. However it may be noted that the long-term impact of delaying follicular growth by GnRH antagonists during follicular selection and utilizing follicles that do not belong to the primary wave is obscure. With accumulating scientific data, babies born after delayed start protocol or RS-COH protocol employed for emergency fertility preservation should be followed up to assess long term safety.

    1. Cakmak H, Tran ND, Zamah AM, Cedars MI, Rosen MP. A novel “delayed start” protocol with gonadotropin-releasing hormone antagonist improves outcomes in poor responders. Fertil Steril [Internet] 2014 [cited 2014 Jun 3];101(5):1308–14.

    2. Klein NA, Harper AJ, Houmard BS, Sluss PM, Soules MR. Is the short follicular phase in older women secondary to advanced or accelerated dominant follicle development? J Clin Endocrinol Metab [Internet] 2002 [cited 2014 Jun 30];87(12):5746–50.

    3. Van Zonneveld P, Scheffer GJ, Broekmans FJM, Blankenstein MA, de Jong FH, Looman CWN, et al. Do cycle disturbances explain the age-related decline of female fertility? Cycle characteristics of women aged over 40 years compared with a reference population of young women. Hum Reprod [Internet] 2003 [cited 2014 Jun 30];18(3):495–501.

    4. Sönmezer M, Cil AP, Oktay K. Ongoing pregnancies from early retrieval of prematurely developing antral follicles after DHEA supplementation. Reprod Biomed Online [Internet] 2009 [cited 2014 Jun 30];19(6):816–9.

    5. Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril [Internet] 2003 [cited 2014 Jun 30];80(1):116–22.

    6. Sönmezer M, Türkçüoğlu I, Coşkun U, Oktay K. Random-start controlled ovarian hyperstimulation for emergency fertility preservation in letrozole cycles. Fertil Steril [Internet] 2011 [cited 2014 May 26];95(6):2125.e9–11.

  • Lauren Johnson

    Congratulations to Hakan and colleagues on publication of your paper. The “delayed start” protocol that you describe may be a promising treatment option for poor responders. As the authors acknowledge, this study should be interpreted cautiously as the study is small, retrospective, and subject to selection bias. Nonetheless, the findings are encouraging and warrant further consideration in randomized trials. Do the authors have any plans to study this protocol further in the setting of a randomized trial?

    • Micah Hill

      I echo Lauren’s comments, this paper was very intriguing to me and clearly many others (top viewed article in the journal last month!). As Lauren mentions, the interpretation should be cautious, given the design of the retrospective study hazards the risk for improvement in outcome due to regression to the mean. I also hope the authors and others will examine this hypothesis with a randomized
      trial! I wonder if given the lack of prospective data, did the authors have another comparison group who met the Bologna criteria in the first cycle and then had some other adjustment to their protocol in the next cycle (change in pituitary protocol or gonadotropin dosing)? Such a design would still have limitations, but might avoid regression to the mean.

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