Minimal ovarian stimulation with clomiphene citrate: a large-scale retrospective study

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Minimal ovarian stimulation with clomiphene citrate: a large-scale retrospective study Teramoto, S  Reprod Biomed Online 2007

Target: A retrospective examination of 43,433 IVF cycles at Kato Ladies Clinic in Tokyo Japan from 2001-2005, including women aged 27-47 years old

Purpose:   Evaluate the efficacy of the minimal ovarian stimulation method with the use of clomiphene citrate.

Historically, methods of controlling an IVF patient’s spontaneous LH surge (event that triggers ovulation) that might result in premature ovulation have included the use of (1) GnRH agonists in long and short (flare) protocols and (2) GnRH antagonist protocols.  However, these medication protocols had some undesirable effects on the follicles and/or endometrium and they added tremendous expense to the IVF cycles with additional expensive medication and/or monitoring.

Clomiphene citrate can result in the induction of ovulation stimulation + suppression of ovulation.  The minimal ovarian stimulation method attempts to take advantage of these characteristics.

Protocol:  The minimal ovarian stimulation method protocol:

  1. Clomiphene citrate (50mg/day) was initiated on cycle day (CD) 3 and was continued until the day prior to ovulation trigger,
  2. An ultrasound examination was performed on CD 8 (generally continued every other day until ovulation was triggered) and when (1) only one follicle was seen developing then follicular development was monitored until ovulation was triggered with GnRH agonist (when the follicle was at least 18mm diameter and the serum estradiol was at least 300 pg/mL) or (2) when multiple follicles appeared to be developing then urinary HMG (150 IU every other day) or recombinant FSH (150 IU every other day) was started on CD 8 and continued to the day prior to ovulation trigger with GnRH agonist (when the lead follicle was at least 18mm diameter and the serum estradiol was at least 300 pg/mL per mature follicle).
  3. The serum LH concentration was determined on the day of ovulation trigger and when the LH/basal LH concentration at the time of an 18mm follicle was <1.5 then GnRH agonist was given at 2400 (midnight) and eggs were retrieved 32-35 hours later.  If the LH/basal LH concentration at the time of a 18mm follicle was 1.5 or greater then a variety of “emergency egg retrieval” protocols were initiated base on the exact ratio found.
  4. Luteal phase support was provided with dydrogesterone (30 mg/day) and serum progesterone concentrations on (1) day 0 (day of embryo transfer) + day 6-8 + day 12 (for 4 cell stage embryo transfers) or (2) day 0 (day of embryo transfer) + day 3-5 + day 7 for blastocyst transfer were measured. If the mean value of progesterone was dropping then 125 mg of progesterone depot was provided.

Conclusions: Of the 43,433 initiated IVF cycles, the rate of egg retrieval and embryo cleavage was 83% and 64% respectively, the mean number of eggs retrieved was 2.2, the rates of live births, spontaneous pregnancy loss and ectopic pregnancy “per initiated cycle” was 11.1%, 3.4% and 0.2% respectively.  This protocol is far less expensive than conventional IVF protocols, it improves the ability for patients to pursue their usual daily activities since there is far less monitoring, and it has a reasonable success rate.  It is noted that for patients 38 years old and younger that there was a cumulative live birth rate of 53% per patient after 2-3 cycles.

Dr. Daiter reviews this research article
The author is a renowned expert on mild stimulation IVF from one of the world’s largest IVF centers located in Japan, providing their experience with over 43,000 IVF cycles
This classic article supports the use of minimal stimulation IVF as a reasonable alternative to the much more expensive forms of conventional IVF, with a cumulative live birth rate of 53% per patient after 2-3 cycles.

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