Estradiol/progesterone substitution in the luteal phase improves pregnancy rates in stimulated cycles--but only in younger women

Innumerable studies have attempted to demonstrate that hormonal support of the luteal phase during ovulation induction cycles improves pregnancy rates. None has, however, so far been able to confirm the validity of such treatment conclusively, possibly because most studies only utilized progesterone substitution. Since luteal phase endometrium also requires estradiol support, this study attempted to investigate whether hormone substitution with progesterone and estradiol would be more successful in improving pregnancy rates. Amongst approximately 7500 consecutive ovulation induction cycles were identified prospectively which were characterized by a precipitous drop of luteal phase serum estradiol levels by more than 50% over a 48 hour period within 10 days from hCG administration. Those cycles were prospectively randomized to oral micronized estradiol substitution (Group I) or not (Group II), while both groups received routine progesterone substitution of the luteal phase. Cycles were then evaluated in regards to the occurrence of chemical, ectopic and clinical pregnancies. One hundred sixty-three Group I cycles resulted in 34 pregnancies (20.9%), which compared favorably to 21 pregnancies in 167 Group II patients (12.6%) (x2[1] = 4.06; p < 0.04). The advantage for Group I cycles (29/95 pregnancies, 31%) vs. Group II cycles (16/105, 15%) became even more pronounced when only women up to age 35 years were evaluated. Estradiol substitution maintained a significant advantage until age 38 (x2 [1] = 6.87; p < 0.009). While gravidity did not affect pregnancy success, estradiol substitution in Group I benefited nulliparous (23% pregnancy rate) over multiparous women (12% pregnancy rate) (x2 [2] = 6.86; p< 0.03). This association was, however, age-dependent. A combined estradiol and progesterone substitution of the luteal phase of ovulation induction cycles increases the overall pregnancy rate. Since estradiol substitution was initiated in this study only once a precipitous drop in serum estradiol levels had already taken place, an even larger improvement in pregnancy rates could conceivably be possible if earlier estradiol substitution of the luteal phase is initiated. A further expansion of investigations of similar protocols for routine ovulation induction and in vitro fertilization (IVF) cycles may be indicated, especially in women below age 38 years and in nulliparous females.