Clinical Evidences

So far, several lines of evidence from different physicians and clinics indicate that the concept of Term Oocyte Maturation is correct. A case report is a report on a single case. However, everything in medicine, including the discovery of vaccines and antibiotics, begins with a case report. 

Case report (with Albert Ichmelyan, MD, PhD).  Patient 35 years old. G-o, P-0

This case is of particular interest because it demonstrates that not only Term Stimulation™ achieves better results than conventional stimulation, but also that it seems to be improving oocyte quality compared to the natural cycle. Curiously, the husband’s sperm, in this case, was also a suspect.

Cycle 1. Long protocol, follicles-4, MII-5, 2PN-1, arrest on day 3 with a high rate of fragmentation

Cycle 2. Natural. MII-1, 2PN-0

Cycle 3. Natural. MII-1, 2PN-0

Cycle 4. Natural. MII-1, 2PN-0

Cycle 5. Natural. MII-1, 2PN-1, arrested at 2 cells

Cycle 6. Term StimulationTM , follicles -7, MII-5, MI (matured in vitro to MII)-2, IVF – MII-2 with donor sperm 2PN-0. ICSI – MII-5 with husband sperm – 2PN-4. Blastocysts – 2 (from oocytes injected with husband’s sperm). The patient delivered a healthy boy, 9.5 lb, 22.4″ at 40 weeks.

Case report. (with Dr. Tralik, MD, PhD and Michael Allon, MD). Patient 34 years, G-0, P-0. 

Clomid, Timed intercourse. The patient’s medication was identical in Cycle 1 and 2.

Cycle 1. The follicular phase was 12 days. Three follicles developed. A single fetal sack was seen on ultrasound at 10 weeks, small for gestational age. The pregnancy ended in miscarriage at 12 weeks.

Cycle 2. Term Stimulation™  The duration of the follicular phase was extended under the protection of diclofenac (for the last 3 days) to 14 days. Three follicles were recruited and three fetal sacks were seen on the ultrasound at 10 weeks. Two had the adequate size for gestational age. Pregnancy spontaneously reduced to twins, which were delivered at 37 weeks by c-section.    

Cycle 1. Ultrasound at 10 Weeks

Cycle 2. Ultrasound at 10 Weeks

Case report. Patient 31 years old. G-0, P-0. IVF. Two identical ovarian stimulation regimens two months apart.

Cycle1. Stimulation – 11 days (effective follicular phase – 13 days). From 13 fertilized oocytes developed only 3 blastocysts.

Cycle2. Term Stimulation™ Exactly the same stimulation protocol as in her first cycle with the only difference that it was started 5 days later so that the effective follicular phase became 18 days as opposed to 13 in the first cycle. In the second retrieval, the patient had 19 fertilized oocytes, 13 developed into excellent quality blastocysts and all of them, except 1 were chromosomally normal.  

Retrospective analysis 

An infertility clinic reached out to me for advice. The IVF program manager felt that there is a problem in the laboratory causing embryos development failure to the blastocyst stage. However, a thorough investigation showed that the dramatic increase in embryo development was due to two physicians (#1 and #3) reducing duration of stimulations by 1 day. One physician (#2) has not changed the duration of stimulation and her results were unchanged. Once two physicians increased the duration of stimulation, the problem with failed embryo development had resolved (the smaller number of cycles in 2018 relative to 2017 was due to the incomplete year by the time of the analysis). 

Retrospective analysis (the data are provided by Maria Zarova, MD).

The table below compares pregnancy rates for patients who had less than 13 days of stimulation (less than 15 days of the follicular phase) with those who had 13 days or more (follicular cycle 15 days or more). Although the numbers in the number of patients in the longer stimulation is small, the difference in pregnancy rate is statistically significant. 

Term Maturation explains why very young  patients and patients with PCOS have poor quality oocytes in IVF

A new theory must explain at least one paradox, which does not have a satisfactory explanation under the current paradigm. One of such paradoxes is the unexplainably low oocyte quality in very young IVF patients, despite their excellent response to ovarian stimulation. The phenomenon has been puzzling physicians for many years.

The concept of term maturation provides a simple and very plausible explanation for this paradox. Young patients have a lot of follicles at the start of the follicular phase and respond to hormonal stimulation with most of them recruited into the cycle. Because of an unusually large number of growing follicles, estradiol is rising at a higher pace and the follicles reach ovulatory size earlier than in the natural cycle. This makes it necessary to trigger these patients early before oocytes would be expected to reach term maturation. As the result, they do not produce good quality embryos, creating a false impression that they were intrinsically poor quality. In truth, they were probably perfectly good oocytes, which simply did not get enough time to acquire full development potential. The same reasoning applies to PCOS  patients with high AMH.     

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