Theoretical Backgrounds of the Natural Cycle and Other Minimal Stimulation Cycles: From Follicle Observation to Embryo Transfer

Minimal Simulation and Natural Cycle In Vitro Fertilization, Allahbadia, G and Nitzschke, M, 2015

Theoretical Backgrounds of the Natural Cycle and Other Minimal Stimulation Cycles: From Follicle Observation to Embryo Transfer (Teramoto, S)

 

Dr Daiter of Central New Jersey Low Cost IVF mini and natural cycle ivf provides a summary of this research article on low cost ivf
In cycles where in vitro maturation (IVM) of eggs is desired, protocols that allow for the retrieval of viable immature eggs from follicles attempt to retrieve the eggs when the lead follicle is less than 13mm diameter (prior to the development of the dominant follicle and the atresia of the remaining follicles).

In natural cycle IVF, no drugs are used except for a GnRH agonist to trigger ovulation and time oocyte (egg) retrieval.  In their protocol, cycle day (CD) 3 monitoring with an ultrasound (determine the antral follicle count to decide whether to proceed on this cycle) and serum evaluation of E2 + P4 + LH + FSH + AMH; CD 10 with repeat ultrasound for follicular growth and serum evaluation of  E2 + P4 + LH + FSH (with possible trigger of ovulation or immediate egg retrieval); then additional monitoring as needed with decisions based on blood work:

 

  1. LH/basal LH <1.25 with dominant follicle >16mm with E2 >250 pg/mL per follicle >16mm… then administer GnRH agonist trigger at 2200 and retrieve eggs 34-35 hours later
  2. LH/basal LH 1.25-3.0 then administer GnRH antagonist immediately and trigger with GnRH agonist at 2200 and retrieve eggs 34 hours later
  3. LH/basal LH >3.0 with FSH/basal FSH <2 then administer GnRH agonist immediately and retrieve eggs 24-28 hours later (emergency)
  4. LH/basal LH >3.0 with FSH/basal FSL >2 then immediately retrieve eggs

These protocol differences attempt to identify the stage of the LH surge, where it can be delayed with a GnRH antagonist is near the beginning, it is difficult to delay if the LH/basal LH >3, and the LH surge is near the end if the FSH/basal FSH is >2.

Egg maturation is thought to be maximal when the E2 is 264-268 pg/mL and the follicular diameter is >16mm, with the E2 level taking priority over follicle size.  This center performed roughly 1,000 natural cycle IVF cases a year over the two years study and they were able to retrieve eggs from follicles >11mm 56% of the time (and from follicles <11mm 37% of the time), the rate of retrieval of MII (mature) eggs from follicles >11mm was 81% (and from follicles <11mm was 24%), the percentage of embryos to blastocyst was 38% from follicles >11mm (and 7% from smaller follicles), and the rate of ongoing pregnancy to 22 weeks or longer was 13% per cycle start (36% from follicles smaller than 11mm.

Femara (an aromatase inhibitor) inhibits estrogen synthesis within follicles to thereby increase GnRH release (by decreasing the negative feedback of estrogen on GnRH), increase FSH action on the ovaries, and increase follicular development.  Additionally, the androgen concentration in the follicular fluid is thought to increase, and this is thought to increase follicular sensitivity to FSH to promote follicular development.  However, Femara (with a half life of 69 +/- 37 hours) makes it impossible to follow E2 as an indicator of follicular maturity so protocols are developed that limit the duration of use of Femara (in this center it is only used from CD 3-5).  In Femara cycles, the LH surge tends to advance more rapidly and at a lower E2 when compared to a drug free natural cycle.  In the author’s IVF center, about 1260 cases were performed in 2 years using Femara, with an average age for the women being 38 years old (30-45 year range), the AMH was 13 pM (0.0-136 pM range), the FSH was 8 IU/L (0.5-41 IU/L range), the average number of days from from cycle start to egg retrieval was 13.8 +/- 2.4 days, premature ovulation of the dominant follicle occurred in 7% of cases, and the ongoing pregnancy rate was 16% (40% of which were from follicles smaller than 11mm).

Femara and Clomiphene citrate can be used in combination during stimulation, and the protocol in this IVF center uses Femara on CD 3-5 and Clomiphene (12.5 mg/day) on CD 6 until the day that ovulation is triggered.  The author’s IVF center performed 1456 cycles of Femara/Clomiphene in two years, the rate of increase of E2 in these Femara Clomiphene cycles is generally more stable and higher than in natural cycles or Femara only cycles, the average age of the woman was 38 years old (30-45 years range), the day 3 AMH was 15 pM (0-126 pM range), the FSH was 7.6 IU/L (1-20 IU/L range), the average days from CD1 to egg retrieval was 14 +/- 3 days, 3.7% of cycles had premature ovulation of the dominant follicle, and the ongoing pregnancy rate was 19% (38% of those were achieved from eggs retrieved from small follicles <11mm).

Clomiphene citrate can be used in combination with FSH (or HMG) in an attempt to retain the FSH level at 7.5 IU/L or greater (the equivalent of CD 3 level) since Clomiphene can reduce FSH as the E2 rises.  Exogenous FSH has an accumulative effect so that a dose of 75 IU of FSH daily reaches a level of about 5 IU/L on the 3rd day of administration and keeps a plateau level of about 6-7 IU/L.  Since there is some endogenous FSH production, a dosage of about 37.5-50 IU/day is thought to be required.  This IVF center generally used a base dose of 37.5 IU/day until the E2 was high enough to further suppress FSH and a greater add back dose was given.  Clomiphene citrate was administered as 25 mg/day from CD 3 until the day prior to ovulation trigger.  Ovulation was triggered using a GnRH agonist when the E2 per dominant follicle was 200 pg/mL or more.  In this IVF center 1705 cases of Clomiphene/FSH cycles were performed over a 2 year period, the average age of the woman was 36 years old (30-45 range), the CD 3 AMH was 27 pM (1.6-113.8 pM), the CD3 FSH was 8 IU/L (0.1-23 IU/L range), the average days from CD1to retrieval was 16 +/- 2 days, the average dosage of FSH was 472 +/- 192 IU, the average number of eggs retrieved was 4.5, and the rate of ongoing pregnancy was 37.5%.  In these cycles, the patients were given OCPs the cycle prior to starting in an attempt to synchronize antral follicle sizes at the onset of treatment (note that the OCPs reduce FSH to reduce the number of follicles to reduce the CD3 AMH by about 30%- so this protocol excluded women with an AMH of less than 15 pM to start).  Of note, due to the success of Clomiphene with Femara cycles the author discontinued this protocol since 2012.

The author makes a special point in his conclusions that he retrieves eggs from small follicles measuring 2-6 mm diameter (with a custom made catheter) 40% of the time and more than 30% of these eggs are MII (mature) with development to blastocyst similar to dominant follicles.  He also notes that the combination of Femara and Clomiphene allows for a very inexpensive cycle with more eggs retrieved than a natural cycle and good success rates in terms of pregnancy.

 

​Dr. Daiter’s review of this chapter
Dr. S. Teramoto is one of the pioneers recognized as a leading authority on minimal stimulation IVF and natural cycle IVF.  He is working at the Shinbashi Yume Clinic in Japan at the time that this article was published in 2015.

Dr. Teramoto provides valuable guidelines for assessing hormone concentrations at around the time of an expected LH surge, which can be used to guide clinicians regarding administration of medications to trigger ovulation and the timing of an egg retrieval.

Dr. Teramoto’s considerable experience with different mild stimulation protocols using Femara, Clomiphene citrate and/or FSH/HMG in IVF cycles provides a great deal of value to his insights and suggestions.

Dr. Teramoto’s aspiration of very small follicles in order to mature the retrieved eggs in vitro is also quite interesting.

 

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