Bradford A. Kolb

The luteal phase of cycles utilizing controlled ovarian hyperstimulation and the possible impact of this hyperstimulation on embryo implantation.

OBJECTIVE Our purpose was to evaluate the early luteal phase of assisted reproductive cycles utilizing controlled ovarian hyperstimulation and to compare these results with those obtained in unstimulated cycles. STUDY DESIGN We undertook a descriptive study analyzing luteal phase serum progesterone levels, endometrial histologic features, and endometrial surface ultrastructure by scanning electron microscopy of cycles utilizing controlled ovarian hyperstimulation. Study samples were obtained from 7 oocyte donors undergoing controlled ovarian hyperstimulation for the purpose of follicle aspiration in oocyte donation. Control (unstimulated) serum progesterone samples were obtained from 19 patients undergoing in vitro fertilization in unstimulated cycles. Prospective recipients of oocyte donation (n = 20) undergoing mock cycles of exogenous estradiol and progesterone acted as controls for the endometrial biopsies. RESULTS Serum progesterone levels on the day of human chorionic gonadotropin administration were twofold higher in the study group than in the unstimulated group (1.1 +/- 0.6 vs 0.5 +/- 0.2 ng/ml, mean +/- SD, p < 0.01). On the day of follicle aspiration, progesterone levels were much higher in the study group (8.5 +/- 2.2 vs 0.5 +/- 0.1 ng/ml, p < 0.001). Histologic dating of endometrial biopsies revealed that the study group was advanced by nearly 2 days as compared with the group having artificial cycles. Pinopods, ultrastructural markers of the implantation window, were present in only one of seven study cycles as compared with all of the four artificial cycles. CONCLUSIONS The early luteal phase of cycles undergoing controlled ovarian hyperstimulation is characterized by markedly elevated serum progesterone levels during the periovulatory period, advanced endometrial histologic features, and an absence of endometrial pinopods at the time of embryo implantation. We speculate that these high levels of progesterone in the early luteal phase cause premature endometrial luteinization and a premature appearance of the implantation window, thus providing an explanation for the observed decrease in endometrial receptivity.

Ultrastructural characteristics of the luteal phase endometrium in patients undergoing controlled ovarian hyperstimulation

OBJECTIVE To provide a descriptive analysis of the ultrastructure of the endometrial surface epithelium during the luteal phase from patients undergoing controlled ovarian hyperstimulation (COH). DESIGN Prospective, observational study. SETTING Tertiary care academic IVF center. PATIENT(S) Twelve oocyte donors undergoing COH. INTERVENTION(S) After oocyte aspiration, patients underwent two endometrial biopsies 2 to 7 days after hCG administration. MAIN OUTCOME MEASURE(S) Appearance of the endometrial epithelial surface as evaluated by scanning electron microscopy. RESULT(S) Endometrial maturation proceeded in an orderly manner. The ciliated cells remained unchanged, both in regards to cell density, cilia density, and ratio of ciliated cells to nonciliated cells. The microvilli became more uniformly distributed as the luteal phase progressed. The central aspect of the cells also appeared to protrude more into the endometrial lumen as the cycle progressed. Elongation the glandular orifices also was noted with progression of the luteal phase. Apical protrusions, pinopods, were noted to develop and regress during a short period during the midluteal phase spanning days 4 to 7 after hCG administration. Initial pinopod development began in the region of the glandular orifices, with substantially fewer occurring outside this region. CONCLUSION(S) Although the development of the endometrial ultrastructural characteristics during the luteal phase progresses in an orderly manner that is comparable to that of endometrium obtained in unstimulated cycles, pinopod expression was noted at an earlier phase of endometrial maturation. This advanced development may result in an alteration the window of implantation and affect pregnancy rates in women undergoing COH.

Serum inhibin B levels in males with gonadal dysfunction.

OBJECTIVE To determine whether inhibin B levels are reflective of the etiology of gonadal dysfunction. DESIGN Institutional study. SETTING A tertiary care university-affiliated infertility clinic. PATIENT(S) Forty-four men: 16 with primary testicular failure, 10 with partial idiopathic hypogonadotropic hypogonadism (IHH), 8 with primary germ cell failure, one with iatrogenic hypogonadotropic hypogonadism, one with untreated Kallmanns syndrome, and 8 healthy fertile controls. INTERVENTION(S) Three individuals (one each with IHH, hypogonadotropic hypogonadism [HH], and Kallmanns syndrome) underwent treatment with human chorionic gonadotropin. MAIN OUTCOME MEASURE(S) Baseline serum inhibin B, FSH, LH, total testosterone and estradiol levels, and sperm concentrations were measured. RESULT(S) Serum inhibin B concentrations were significantly higher in fertile controls (255 +/- 59 pg/mL) than in men presenting with primary testicular failure (75 +/- 46 pg/mL, P<.0001) or in those presenting with primary germ cell failure (73 +/- 31 pg/mL, P<.0001). Inhibin B levels were also lower in males with partial IHH (187 +/- 112 pg/mL, P<.05). The patient with iatrogenic HH had a level of 184 pg/mL, whereas the patient with Kallmanns syndrome had nondetectable levels (<10 pg/mL). Serum inhibin B levels correlated positively with sperm concentration (P=.0001), and negatively with FSH levels (P=.01) and LH levels (P<.05). Human chorionic gonadotropin therapy altered inhibin B levels. CONCLUSION(S) Inhibin B plays an important role as an endocrine regulator of FSH secretion, whereas gonadotropins are involved in the regulation of inhibin B secretion.

Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation

OBJECTIVE To assess the efficacy and safety of a vaginal progesterone (P(4)) insert (Endometrin) for luteal support for assisted reproductive technology (ART). DESIGN Multicenter, randomized, open-label (assessor-blinded) phase III clinical trial. SETTING Twenty-five U.S. ART centers. PATIENT(S) A total of 1,211 ART patients randomized to three groups: Endometrin 100 mg twice daily (n = 404), Endometrin 100 mg three times daily (n = 404), and P(4) 90 mg 8% gel daily (n = 403). INTERVENTION(S) In vitro fertilization and ET were performed according to site-specific protocols. The day after oocyte retrieval, Endometrin or vaginal P(4) gel was begun for luteal support and continued for up to 10 weeks of pregnancy. MAIN OUTCOME MEASURE(S) Biochemical, clinical, and ongoing pregnancy and live birth rates. RESULT(S) Pregnancy rates were high and similar in all treatment groups, with biochemical rates exceeding 50%, clinical and ongoing rates >or=40%, and live birth rates at 35%-38%. The adverse event profiles were similar across groups. CONCLUSION(S) Pregnancy rates and live birth rates for Endometrin (twice daily and three times daily) were high and similar to those for P(4) gel. The adverse event profiles for both were similar to that for P(4) gel and primarily due to IVF stimulation and oocyte retrieval. Endometrin was safe and well tolerated.