The luteal phase during gonadotropin therapy: effects of two human chorionic gonadotropin regimens

OBJECTIVE: Luteal phase abnormalities are known to complicate ovulation induction with gonadotropins. This study was performed to test the effect of a modified human chorionic gonadotropin (hCG) regimen on the luteal phase during gonadotropin treatment. DESIGN: Fifteen women from a private practice setting volunteered to be studied during each of two nonconception, gonadotropin-stimulated cycles. After ovarian stimulation with human menopausal gonadotropins (hMG), hCG was administered either as a single dose of 10,000 IU (single dose) or in two divided doses of 5,000 IU given 1 week apart (split dose). MAIN OUTCOME MEASURES: Early, midluteal, and late luteal estradiol (E2) and progesterone (P) levels and luteal phase lengths were measured, and their median values and intraquartile ranges (IQR) compared using nonparametric analysis. RESULTS: Early and midluteal E2 and P levels were similar regardless of which hCG regimen was administered. The median late luteal E2 level was 1,146.0 pg/mL (the IQR ranged from 633 to 1,650, IQR = 1,017) with the split-dose regimen and 240.0 pg/mL (the IQR ranged from 150 to 460, IQR = 310) with the single-dose regimen. The median late luteal P level was 108.0 ng/mL (the IQR ranged from 58.5 to 129, IQR = 70.5) with the split-dose regimen and 4.2 ng/mL (the IQR ranged from 1.9 to 11.7, IQR = 9.8) with the single-dose regimen. Median luteal phase lengths were 16 days (the IQR ranged from 15 to 17, IQR = 2) for the split-dose regimen and 11 days (the IQR ranged from 10 to 12, IQR = 2) for the single-dose regimen. CONCLUSION: In hMG-stimulated cycles, a second dose of hCG given during the midluteal phase significantly increases late luteal E2 and P levels and consistently lengthens the luteal phase.     

Ovulation induction with subcutaneous pulsatile gonadotropin-releasing hormone: the role of supplemental human chorionic gonadotropin in the luteal phase

Four subjects with hypothalamic amenorrhea were administered subcutaneous pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction. GnRH was discontinued at the time of presumed ovulation in all cases. In the first two patients the luteal phase was supported with human chorionic gonadotropin in the initial cycle but not in the second cycle. In patient 3, the reverse was true. Patient 4 had only one cycle on GnRH, and it was unsupported. Daily blood samples were obtained for luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone (P); and frequent pelvic ultrasound examinations were performed. Presumed ovulation as determined by ultrasound occurred in all seven cycles. The first three patients had short luteal phases with poor P production in the unsupported cycles. However, the fourth patient, who had shown pituitary response in GnRH testing, had a normal luteal phase with good P production without human chorionic gonadotropin support. These data support the notion that subcutaneous pulsatile GnRH can be used for the induction of ovulation. However, if the luteal phase is not supported, an inadequate corpus luteum may result.     

Luteal phase defects in assisted reproduction: the role of luteal phase supplementation.

Data from literature show that whereas in non-GnRH-a controlled ovarian hyperstimulation cycles luteal phase supplementation is not crucial, its use in GnRH-a/gonadotropins protocols seems to lead to a definite reduction of the negative effects of such drugs. The most important side effect of the hCG use as luteal support is the increased rate of the ovarian hyperstimulation syndrome (OHSS). Therefore its use should be reserved for very selected patients, for those subjects with preovulatory levels of E2 < 2500 pg/ml. As regard the use of progesterone, most authors agree that it has less efficacy than hCG but this depends on the administration route.     

Use of recombinant human chorionic gonadotropin in ovulation induction

To review the use of hCG and to describe the clinical benefit of recombinant hCG (r-hCG) based on the published results of prospective, randomized studies.Review of published articles.Tertiary infertility care center.None.None.Oocyte number and quality, luteal phase progesterone, pregnancy and OHSS rate, and local tolerability.The published data consistently show that single doses of 250 microg r-hCG and 5,000 IU urinary (u)-hCG produce similar clinical outcomes when used in infertility treatment cycles for timed intercourse, IUI, and IVF in terms of the number of oocytes retrieved, number of mature oocytes harvested, and fertilization and pregnancy rates attained. Single doses of 10,000 IU u-hCG also gave results comparable to single doses of 250 microg r-hCG. P levels in the midluteal phase were significantly higher with the use of r-hCG compared with u-hCG, and local injection site adverse effects were significantly less frequent, demonstrating the higher purity of the recombinant product. A single 500-microg dose of r-hCG led to a higher rate of ovarian hyperstimulation syndrome compared with a 250-microg dose, with no significant improvement in pregnancy rates.A single dose of 250 microg r-hCG was at least as effective as single doses of 5,000 or 10,000 IU u-hCG but offered the advantages associated with use of a recombinant product: local injection site adverse effects were significantly less frequent with r-hCG than with u-hCG.     

Early pregnancy wastage: the role of repetitive human chorionic gonadotropin supplementation during the first 8 weeks of gestation.

OBJECTIVE: To determine if repetitive administration of hCG causes decreased pregnancy wastage rates in patients who are at a high risk of luteal inadequacy. DESIGN: Ovulation induction using human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) or clomiphene citrate (CC) is associated with luteal phase defects that may cause increased pregnancy wastage. An increased risk of abortion exists also in pregnancies in patients with previous repeated miscarriage, women older than 37 years, and various causes of infertility such as hyperprolactinemia. Because the presumed common denominator to the increased rate of pregnancy wastage in all these cases is luteal dysfunction, repetitive hCG administration, 2,500 U two times weekly, was carried out between the 4th and 8th week of gestation in 249 cases of ovulation induction and/or previous abortions, whereas 198 gestations served as controls (no hCG administration). RESULTS: In the hCG treatment group, 43 ended in miscarriage (17.3%) versus 97 abortions in the control group (49%, P less than 0.01). In 160 cases of hMG/hCG generated gestations, 94 received hCG and 66 did not. The pregnancy wastage rates were 21.3% and 42.4%, respectively (P less than 0.05). In 144 cases of CC/hCG-induced pregnancies, 95 received hCG and 49 served as controls. The respective abortion rates were 15.8% and 44.8% (P less than 0.01). The remaining 143 spontaneous conceptions occurred in infertile patients with previous repeated abortions. In 60 of these conceptions, hCG was administered during the first 4 weeks of gestation and 83 cases served as control. The pregnancy wastage rates were 13.3% versus 56.6%, respectively (P less than 0.001). CONCLUSION: Repetitive administration of hCG during the early gestation in cases that are at high risk of luteal inadequacy may significantly decrease the pregnancy wastage rate.     

Influence of weight in the induction of ovulation with human menopausal gonadotropin and human chorionic gonadotropin

Patients failing to ovulate and conceive on clomiphene citrate (CC) or CC plus human chorionic gonadotropin (hCG) or patients with pituitary gonadotropin deficiency are candidates for human menopausal gonadotropin (hMG) plus hCG therapy. The duration and number of ampules needed to stimulate ovarian response leading to ovulation and/or pregnancy vary individually. Seventy-one patients who had complete follow-up evaluation and accurately documented body weights at the time of therapy were considered for the study. Of these 71 patients, 41 (57.3%) conceived in 293 cycles. The average number of ampules of hMG used by patients with 10% to 20% below ideal body weight (IBW) was 13.9 +/- 6.3 (mean +/- standard deviation [SD]). The average number of ampules used by patients with normal +/- 10% IBW was 14.2 +/- 3.5. Patients who were overweight by 10% to 25% used 15.3 +/- 5.4 ampules, and patients overweight by greater than or equal to 25% used 20.9 +/- 5.6 ampules of hMG. Eleven patients with severe hypothalamic chronic anovulation needed an average of 20.6 +/- 6.2 ampules. The data reveal a direct relationship between IBW and the amount of hMG needed to induce ovulation and/or pregnancy; however, in the presence of chronic hypoestrogenic conditions, it is expected that these patients will need higher amounts of hMG, regardless of body weight.     

The luteal phase in polycystic ovary syndrome during ovulation induction with human menopausal gonadotropin with and without leuprolide acetate

Little data exist on the effects of adjunctive therapy with leuprolide acetate (LA) in the luteal phase of women with polycystic ovary syndrome (PCOS) undergoing ovulation induction with human menopausal gonadotropin (hMG). Additionally, it is not known whether gonadal steroid concentrations in the luteal phase of induced cycles in PCOS are predictive of pregnancy. In this prospective, randomized study comparing cycles using hMG alone (n = 26) with cycles using hMG with LA (n = 33), no differences were noted between treatment groups in progesterone (P), estradiol (E2), and P:E2 ratios on luteal days 3, 6, and 9. When all treatment cycles were pooled, there were no differences in P, E2, or P:E2 ratios, comparing conception and nonconception cycles. We conclude that adjunctive therapy with LA in PCOS patients undergoing ovulation induction with hMG does not alter the luteal phase concentrations of P, E2, and P:E2. Furthermore, no correlation was found between the serum concentrations of these luteal phase steroids and cycle fecundity.     

Vital initiation of pregnancy (VIP) using human menopausal gonadotropin and human chorionic gonadotropin ovulation induction: phase II--1981

In a program for in vitro fertilization, laparoscopies for oocyte aspiration were performed on 24 patients receiving human menopausal gonadotropin and human chorionic gonadotropin. Of the 40 preovulatory oocytes that were recovered from these patients, 33 (83%) were fertilized and 30 (75%) cleaved and were transferred. Ten immature oocytes were collected, and attempts were made to mature these in vitro prior to insemination. All ten oocytes (100%) did fertilize, and seven (70%) cleaved and were transferred. Morphologic variation was noted between cleaving conceptuses, even in those conceptuses responsible for establishing pregnancies. Five pregnancies resulted from 19 embryo transfers (26%).     

Addition of human chorionic gonadotropin to clomiphene citrate ovulation induction therapy does not improve pregnancy outcomes and luteal function

In a randomized prospective study, 125 women with World Health Organization class II anovulation received 50 mg of clomiphene citrate alone (group A, n = 65) or 50 mg of clomiphene citrate plus hCG (group B, n = 60) in a total of 125 cycles during natural intercourse-advised cycles. There were no statistically significant differences between groups regarding pregnancy outcomes and midluteal P levels, but luteal phase length was longer in group A.     

Follicular development and induction of ovulation with human chorionic gonadotropin in the pregnant rat

Aims: The number of ovarian follicles and ovulations after human chorionic gonadotrophin (hCG) was given at various doses during pregnancy were investigated in rats.
Methods: On designated days of pregnancy, rats were injected with hCG at 13.00 hours and the number of ova were observed. The same rats were then killed at 13.00 hours the next day. The ovaries were cut into complete sections. All sections were observed and the size of each follicle was measured.
Results: The number of large (≥550 µm), healthy, non-atretic follicles (Graafian follicles) ranged from 1.5 to 11 during pregnancy. Ovulation was induced in rats at any stage of pregnancy with intramuscular injections of 40 or 50 IU hCG, but 10 IU had no effect and 20 or 30 IU had an incomplete effect. The number of ovulations after 40 IU hCG was 2–12 and there was not a significant difference between the number of ovulations and the number of large, healthy follicles at any point in the pregnancy.
Conclusion: Graafian follicles existed through the pregnancy. Results suggest that although hCG induces ovulation in large ovarian follicles (≥550 µm) during pregnancy, the responsiveness to hCG is lower than in recurrent estrus-stage rats. (Reprod Med Biol 2004; 3 : 201–204)     

Advanced endometrial maturation after ovulation induction with human menopausal gonadotropin/human chorionic gonadotropin for in vitro fertilization

Endometrial biopsy was performed between the first and third luteal phase day in 22 normally cycling patients following human menopausal gonadotropin and human chorionic gonadotropin ovulation induction for in vitro fertilization but in whom embryo transfer was not accomplished. Eleven patients showed an "advanced" pattern and 10 an "in-phase" endometrium according to the Noyes criteria. A significant difference in serum progesterone levels on days 16 and 18 was found in these two groups. Serum progesterone levels were significantly higher by day 18 if pregnancy was established. In in vitro fertilization and embryo transfer the embryo arrives 24 to 48 hours earlier than in natural conception in the endometrial cavity. Therefore, the "advanced" endometrium may have some benefit for embryo implantation.     

Controlled ovulation in the marmoset monkey (Callithrix jacchus) with human chorionic gonadotropin following prostaglandin-induced luteal regression

Controlled induction of ovulation in the marmoset monkey was attempted with a single injection of human chorionic gonadotropin (hCG; 50 IU) given on day 7 after prostaglandin-induced luteal regression. Animals given hCG (n = 12) ovulated within a 2-day period (days 9 and 10 after prostaglandin) compared with a 4-day period (days 9 to 12) in the control group (n = 12). The mean interval to ovulation was similar in both groups. There was no difference in the timing of the preovulatory estradiol (E2) peak between groups, although E2 levels on the day of hCG injection were lower than in controls on the day of the onset of the luteinizing hormone surge. All animals given hCG ovulated and 11 of 12 became pregnant. Ten of 11 embryos recovered surgically from six of these animals were normal blastocysts; 5 of the remaining 6 animals carried pregnancies to term. The results are of practical importance for experiments involving follicular and oocyte maturation and the collection and transfer of embryos.     

Vital initiation of pregnancy (VIP) using human menopausal gonadotropin and human chorionic gonadotropin ovulation induction: Phase I--1981

Laparoscopies for oocyte aspiration in 31 cycles were performed on 25 patients receiving human menopausal gonadotropin and human chorionic gonadotropin. Sixty oocytes were aspirated, of which 48 were considered preovulatory. Ninety-seven percent (58 of 60) of the oocytes were found in the original aspirate, and the remaining oocytes were found in either the first or second follicle wash. The fertilization rate per preovulatory oocyte was 33% (16 of 48), whereas on a per cycle basis it was 39% (12 of 31). A total of 15 conceptuses (2-cell = 5; 3-cell = 3; 4-cell = 7) were transferred to 12 patients, and two pregnancies were established. These pregnancies were established by transfers of 3-cell and 4-cell conceptuses at approximately 47 hours after insemination. Both pregnancies resulted in term deliveries of normal infants.