Luteal dysfunction in ovulation induction: the role of repetitive human chorionic gonadotropin supplementation during the luteal phase

Several studies have indicated that ovulation induction with human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) or clomiphene citrate (CC) is associated with luteal phase defect. To assess the efficiency of luteal support by hCG to an infertile population undergoing ovulation induction, with CC/hCG or hMG/hCG, we have randomly administered 2500 IU hCG intramuscularly on days 3, 6, and 9 after ovulation induction by 10,000 IU of hCG to 74 patients on 265 treatment cycles. As controls served 357 ovulation induction cycles in the same 74 patients. The treatment cycles were randomly alternated with control cycles so that each patient served as her own control. However, the mean +/- standard deviation (SD) midluteal P was 38.1 +/- 10.8 ng/ml in the study group versus 15.7 +/- 10.5 ng/ml in the control group (P less than 0.001). Luteal phase length was 15.4 +/- 1.5 days in the treatment group versus 12.1 +/- 1.7 in the control group (P less than 0.01). In the treatment group, 64.8% of the patients achieved pregnancy (27% pregnancies/treatment cycle) versus 47.3% in the control group (11.5% pregnancies/control cycle) (P less than 0.01). The pregnancy wastage rates (including abortions and "chemical" pregnancies) were 30.6% in the treatment group versus 56% in the control group (P less than 0.01). We conclude that repetitive hCG administration may be an efficient luteal support in infertile patients undergoing ovulation induction.     

Endometrial inadequacy after treatment with human menopausal gonadotropin/human chorionic gonadotropin

The incidence of abnormal endometrial histology in patients undergoing human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG) treatment during cycles of in vitro fertilization (IVF) or gamete intrafallopian transfer has been reported to be 52% to 91%. The incidence of endometrial inadequacy, as judged by a single late luteal endometrial biopsy, has not been studied in hMG/hCG non-IVF cycles. In the current study, 30 patients (30 cycles) undergoing hMG/hCG treatment were evaluated by an endometrial biopsy. The incidence of endometrial inadequacy was found to be 27%. No preovulatory predictors for endometrial inadequacy could be identified. Therefore, luteal support for patients undergoing non-IVF hMG/hCG cycles should be considered.     

The importance of human chorionic gonadotropin support of the corpus luteum during human gonadotropin therapy in women with anovulatory infertility

One hundred ten women with anovulatory infertility (World Health Organization [WHO] group I n = 50, WHO group II n = 60) were given 341 treatment courses with human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG). Additional hCG was given as single or repeated injections during the luteal phase in 205 ovulatory cycles. In WHO group I, the incidence of luteal phase defects was lower and the pregnancy rate higher in cycles with extra hCG administration during the luteal phase than in cycles with no extra hCG. In WHO group II, there was no such difference after supplemental hCG. The abortion rate was the same after cycles with or without extra hCG administration. It is suggested that during ovulation induction with hMG/hCG in anovulatory women with no evidence of endogenous estrogen activity, the luteal phase should be supplemented with additional hCG.     

The predictive value of hCG beta subunit levels in pregnancies achieved by in vitro fertilization and embryo transfer: an international collaborative study

Serial human chorionic gonadotropin (hCG) beta subunit measurements of 300 pregnancies achieved by in vitro fertilization (IVF) were obtained by 15 IVF centers worldwide. Hormonal curves were established for 164 normal singleton pregnancies, 25 normal multiple gestations, 60 chemical pregnancies, 41 first-trimester spontaneous abortions, and 10 ectopic pregnancies. In comparison to the normal singleton pregnancy curve, chemical pregnancies and spontaneous abortions showed statistically lower hCG levels. hCG levels of ectopic pregnancies, compared with normal singleton gestations, were lower from days 7 to 14. It is concluded that beta-hCG determinations of in vitro fertilized pregnancies allow pregnancy diagnosis as early as 7 to 9 days after embryo transfer (ET) and will permit early discrimination between normal and abnormal IVF pregnancies. A single beta-hCG determination on day 9 after ET may discriminate chemical, ectopic pregnancy or impending miscarriage from a normal gestation. An hCG determination on day 17 will predict early normal development of an IVF pregnancy.     

Luteal phase hyperprolactinemia during ovulation induction with human menopausal gonadotropins: incidence, recurrence, and effect on pregnancy rates

Hyperprolactinemia may develop during ovulation induction with human menopausal gonadotropins and hCG (hMG/hCG). Because elevated serum prolactin (PRL) has several adverse effects on female reproductive function, this event has been implicated as a factor to explain the difference between ovulation and pregnancy rates in hMG/hCG treatment cycles. The incidence and severity of hyperprolactinemia in the luteal phase of hMG/hCG-stimulated cycles was investigated in a large series of patients. We analyzed 240 consecutive, ovulatory hMG/hCG cycles in 96 women from July 1984 to January 1986. All women had failed to conceive with clomiphene citrate, and had normal luteal phase PRL levels during unstimulated cycles. Daily serum total estrogens were determined during hMG administration. Serum progesterone and PRL were determined in the mid-luteal phase (7 days post-hCG administration). In 7.5% of the cycles, luteal phase PRL elevations were greater than 25 ng/mL. Only 2.5% of cycles had levels of PRL greater than 35 ng/mL. Hyperprolactinemia infrequently recurred in different cycles of the same patient (two of 16 patients, 12.5%). Cycles with hyperprolactinemia were found to have significantly higher preovulatory estrogen levels. Serum progesterone levels were not significantly decreased in cycles with elevated PRL. Pregnancy rates in cycles with and without hyperprolactinemia were similar (7.7 versus 11.1%, respectively; P greater than .05). We conclude that the development of luteal phase hyperprolactinemia during ovulation induction with hMG/hCG is an isolated event. High preovulatory estrogen levels may predispose to its development. Because hyperprolactinemia is uncommon and is usually mild, other factors must be responsible for the difference between ovulation and pregnancy rates using hMG/hCG.     

Delaying human chorionic gonadotropin administration in human menopausal gonadotropin-induced cycles decreases successful in vitro fertilization of human oocytes

Correct timing of human chorionic gonadotropin (hCG) administration in induced cycles for in vitro fertilization is of crucial importance to oocyte maturation and normal luteal function. The purpose of this work was to compare the effect of hCG timing on follicular development, oocyte maturation, and fertilization in vitro, as well as on the pattern of luteal phase hormone secretion. Ovulation was induced in 32 normally cycling women by human menopausal gonadotropin (hMG)/hCG administration. In the first group (17 women) 10,000 IU hCG was administered 24 hours after the last injection of hMG and in the second group (15 women) 48 to 72 hours after the last hMG injection. Serum estradiol levels prior to oocyte aspiration were similar in both groups, as were the numbers of large follicles on the day of hCG administration (4.5 +/- 2.3 versus 4.1 +/- 1.9 follicles/woman, respectively). The distribution of oocyte-corona-cumulus complexes was similar in both groups and was comprised of 11% immature, 43% intermediate, and 45% mature complexes. The fertilization rate, however, was significantly (P less than 0.001) reduced in the group treated by delayed hCG injection (57% versus 84%), and the percentage of degenerated oocytes was increased (9% versus 1%). Luteal phase length as well as progesterone and estradiol levels were comparable in both groups. It is concluded that an interval longer than 24 hours between the last injection of hMG and the administration of an ovulatory dose of hCG does not affect follicular and luteal phase serum steroid patterns but may result in a decreased oocyte fertilization rate, possibly due to atretic changes in the follicles.     

Luteal function following ovarian stimulation in rhesus monkeys for in vitro fertilization: atypical response to human chorionic gonadotropin treatment simulating early pregnancy

This study determined if corpora lutea of hyperstimulated cycles in rhesus monkeys could be "rescued" by the pregnancy signal, chorionic gonadotropin (CG), given at the typical time of implantation. At menses, female monkeys received human follicle-stimulating hormone (hFSH, 60 IU, days 1 to 6) followed by human menopausal gonadotropin (hMG, 60 IU hFSH/60 IU luteinizing hormone [hLH], days 7 to 9). On day 10, human chorionic gonadotropin (hCG) was given to mimic the LH surge. Nine days later, a regimen of daily increasing doses of hCG (15 to 360 IU twice a day) was initiated to simulate rescue of the corpus luteum in early pregnancy. Serum levels of progesterone (P) increased through day 5 of the luteal phase but then declined. Circulating levels of bioactive LH were significantly less on days 7 to 9 of the luteal phase than at this stage in the natural cycle. The hCG regimen extended (P less than 0.05) the luteal phase in five of six animals. The hCG treatment elicited a persistent increase (P less than 0.05) in circulating P levels, rather than a transient rise typical of normal or simulated pregnancy in natural cycles. The authors conclude that (1) corpora lutea of hyperstimulated cycles can respond to CG, but (2) there are differences in luteal function during both the luteal phase and simulated early pregnancy that may be due to inadequate luteal development or the abnormal gonadotropin milieu existing after ovulation or both.     

Preclinical abortions: incidence and significance in the Norfolk in vitro fertilization program

Clinical and prognostic significance of preclinical abortions in assisted reproduction is ill defined. Strict diagnostic criteria include a transient and synchronous elevation of serum beta-human chorionic gonadotropin (hCG), estradiol, and progesterone levels 13 days after hCG administration, ending in a bleeding episode no more than 14 days after the missed period. The preclinical abortion study group (54 patients, 178 cycles) was compared with matched control groups A (54 patients, 132 cycles) and B (54 patients, 155 cycles), representing normal term pregnancies and all outcomes, respectively. Control group C included the overall population during the study period. The abortion rate per transfer (preclinical abortion and total miscarriage rates) and total pregnancy wastage in the study group were significantly higher; the ongoing pregnancy rate was significantly lower. Preclinical abortion should be considered as a true reproductive failure with similar implications.     

促性腺激素释放激素激动剂超短方案在超促排卵中的应用

目的：探讨促性腺激素释放激素激动剂（ＧｎＲＨ－ａ）超短方案在促排卵中的作用。方法：以采用克罗米芬联合人绒毛膜促性腺激素（ＣＣ／ｈＣＧ组，５０个周期、３１例），及克罗米芬联合人绝经期促性腺激素、绒毛膜促性腺激素（ＣＣ／ｈＭＧ／ｈＣＧ组，１６个周期、１６例）方案者为对照，对比ＧｎＲＨ－ａ超短方案联合人绝经期促性腺激素、绒毛膜促性腺激素方案者（ＧｎＲＨ－ａ超短方案／ｈＭＧ／ｈＣＧ组，１５个周期、１５例）ｈＣＧ注射日激素水平、优势卵泡个数、子宫内膜厚度、宫颈评分及妊娠率。ＧｎＲＨ－ａ超短方案／ｈＭＧ／ｈＣＧ组全部来自采用ＣＣ助孕失败或采用ＣＣ／ｈＭＧ／ｈＣＧ方案显示卵巢反应性差的患者。结果：ＣＣ／ｈＭＧ／ｈＣＧ组有３例（１８．８％）发生过早黄素化。ＧｎＲＨ－ａ超短方案／ｈＭＧ／ｈＣＧ组ｈＣＧ注射日血清黄体生成素（ＬＨ）水平明显低于对照组，其优势卵泡个数、子宫内膜厚度及宫颈评分都明显高于对照组，差异均具有显著性（Ｐ＜０．０５）。３组周期妊娠率相近。结论：ＧｎＲＨ－ａ超短方案／ｈＭＧ／ｈＣＧ方案为一种较好的促超排卵方案，对ＣＣ助孕失败及ＣＣ／ｈＭＧ／ｈＣＧ方案卵巢反应性差的患者仍有较好的效果。     

Buserelin suppression of endogenous gonadotropin secretion in infertile women with ovarian feedback disorders given human menopausal/human chorionic gonadotropin treatment

Fifty infertile women with oligomenorrhea, anovulation, or luteal phase defects were selected for a combined therapy consisting of a gonadotropin-releasing hormone analog (Buserelin Hoechst AG, Frankfurt/Main, FRG) and human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG). Serving as their own controls, these women had been subjected to a total of 238 hMG/hCG treatment cycles with no pregnancy observed (average, 4.7 cycles; range 2 to 14). Of these 238 hMG/hCG cycles, only 98 (41.1%) appeared normal, while the others showed symptoms consistent with inadequate follicle maturation, luteal phase defects, and premature luteinization. In contrast, 89 cycles from 133 combined buserelin/hMG/hCG treatment cycles (66.9%) appeared to be normal, with no evidence of premature luteinization, and 21 patients became pregnant. These data indicate that the likelihood of group II World Health Organization (WHO) patients becoming pregnant with hMG/hCG therapy may be enhanced when endogenous gonadotropin secretion is suppressed at the same time.     

Sequential clomiphene citrate-menotropin therapy for induction or enhancement of ovulation

Either to induce ovulation in anovulatory infertility patients or to enhance ovulation in patients with mild endometriosis or luteal phase inadequacy, we utilized a sequential regimen of low-dose clomiphene citrate (CC) followed by human menopausal gonadotropin (hMG) injections on alternate days; duration and dosage of menotropin therapy was individualized by using serum estradiol levels for monitoring until the time of administration of human chorionic gonadotropins. Previous therapeutic efforts without menotropins had been unsuccessful in all patients. One third of 70 treated patients conceived during 156 treatment cycles. The pregnancy rate was 44% in anovulatory patients (n = 34), and 26% in patients with ovulation dysfunction (n = 23). Pregnancy rates declined with patient's age. Four of the 23 patients that conceived had a spontaneous abortion (17%). The multiple gestation rate was 10.5%. A relative inhibition of cervical mucus development was noted and shown to be caused by CC. Hyperstimulation occurred in three patients. The discussed CC-hMG regimen approaches the effectiveness of standard hMG therapy; but compared with standard hMG therapy, it has significant economic advantages and seems to have a markedly lower rate of multiple gestation. However, like standard hMG therapy, CC-hMG therapy requires careful monitoring specifically, because hyperstimulation may occur.     

Progesterone levels on the day of human chorionic gonadotropin administration in cycles with gonadotropin-releasing hormone agonist suppression are not predictive of pregnancy outcome

In in vitro fertilization (IVF) cycles using gonadotropin-releasing hormone agonist (GnRH-a) suppression, we investigated whether an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration indicates premature luteinization and is associated with a lower pregnancy rate. We retrospectively studied 101 patients treated with the GnRH-a leuprolide acetate, begun in the luteal phase of the prior menstrual cycle and continued until the day of hCG administration. On the day of hCG, 72 patients had P less than 0.9 ng/mL and 29 had less than or equal to 0.9 ng/mL. Patients in the high P group had a significantly greater estradiol level on the day of hCG. No significant difference in clinical pregnancy rates or ongoing pregnancy rates occurred between the low P and high P groups. We conclude that in IVF cycles pretreated with GnRH-a, P levels on the day of hCG are not predictive of conceiving in that cycle.     

Altered follicular development in clomiphene citrate versus human menopausal gonadotropin-stimulated cycles for in vitro fertilization

The pattern of periovulatory and luteal phase serum estradiol (E2) and progesterone (P) as well as follicular fluid (FF) E2, P, androgen, gonadotropin, and prolactin concentrations of eight women undergoing clomiphene citrate (CC)/human chorionic gonadotropin (hCG) stimulation and eight women undergoing human menopausal gonadotropin (hMG)/hCG stimulation of follicular development for the purpose of in vitro fertilization were compared. Ovulation was induced with either a 5-day course of CC (100 mg/day beginning on day 5 of the cycle) or an individualized hMG regimen, and laparoscopy was performed 36 hours after hCG administration. The length of the luteal phase was significantly longer (P less than 0.05) in the CC-treated group as compared with the hMG-treated group. The pattern of serum E2 levels differed significantly (P less than 0.01) in that E2 levels were lower in the early and midluteal phase in CC-stimulated cycles; in addition, a delayed second E2 peak was observed in the late luteal phase in these women. Serum P levels, however, were lower in the hMG-stimulated group. Analysis of FF hormone concentrations revealed significantly (P less than 0.05) higher concentrations of E2 and androsterone in the FF of hMG-treated patients. It is concluded that follicular development in CC-stimulated cycles differs markedly from that in hMG-stimulated cycles. These differences may reflect either an altered follicular maturational process or may represent a direct inhibitory effect of CC on follicular steroidogenesis.     

Detrimental effect of endometrial biopsies on pregnancy rate following human menopausal gonadotropin/human chorionic gonadotropin-induced ovulation

The effect of luteal phase endometrial biopsy was studied in 33 anovulatory women treated with human menopausal gonadotropins (hMG) to induce ovulation and pregnancy. Over-all, 33 of 85 ovulatory cycles resulted in pregnancy (39%). Of 50 nonbiopsied cycles, 26 resulted in pregnancy (52%) whereas only 7 of 35 biopsied cycles resulted in pregnancy (20() (P less than 0.01). Four pregnancies terminated in spontaneous first-trimester abortions, 12% in the nonbiopsied group and 14% in the biopsied group. Luteal phase endometrial biopsy significantly lowers pregnancy rates in hMG-induced ovulatory cycles, but does not change abortion rates.     

Combined use of progesterone and human chorionic gonadotropin determinations for differential diagnosis of very early pregnancy

Progesterone (P) level and daily change in human chorionic gonadotropin (hCG) were determined in the serum of 307 patients with suspected ectopic pregnancy (EP). Of the viable intrauterine pregnancies (IUP), 99% had P values above 30 nmol/L, whereas 75% of the EP and 81% of the spontaneous abortions had P values less than 30 nmol/L. Among the viable IUP, 95% had normal hCG increases, whereas 89% of the EP and 99% of the spontaneous abortions had abnormal hCG increases. A P value less than 30 nmol/L combined with an abnormal hCG increase had a positive predictive value for pathological pregnancy of 1.0. Consequently, in such cases, further invasive diagnostic or therapeutic measures can be taken with a low risk of jeopardizing a viable IUP.     

Luteal phase support with hCG does not improve fecundity rate in human menopausal gonadotropin-stimulated cycles.

The luteal phase of cycles stimulated with human menopausal gonadotropins (hMG) may be characterized by aberrant hormone levels, altered endometrial development, and shortened length. Luteal phase support with supplemental progesterone or hCG has been recommended to help correct these problems and thus improve pregnancy rates, but the efficacy of such regimens is controversial. Therefore, a randomized cross-over study was performed to evaluate the effects of luteal phase hCG administration on pregnancy rates during ovulation induction with hMG. Sixty-seven infertile women were randomly assigned to either group A (N = 33) or group B (N = 34). Non-treatment cycles (no luteal phase support) were alternated with treatment cycles, in which patients received 2500 IU hCG on the third, sixth, and ninth days after the ovulatory dose of 10,000 IU hCG. Patients in group A received supplemental hCG in odd-numbered cycles, whereas group B was given luteal support in even-numbered cycles. The mean number of cycles per patient was 2.2 and 2.3 for groups A and B, respectively. Analysis of 151 cycles revealed a cycle fecundity of 0.15 for 72 hCG-supported cycles, versus 0.13 for 79 nonsupported cycles (P = not significant). Midluteal progesterone levels were significantly higher in supported (45.6 ng/mL) versus unsupported cycles (31.9 ng/mL) (P less than .001). There were no significant differences in the mean peak estradiol levels in hCG-supported versus -unsupported cycles. We conclude that hCG support of the luteal phase is not routinely warranted in hMG-stimulated cycles.     

The effect of the day of initiation of ovarian stimulation in the day of luteinizing hormone surge and outcome of in vitro fertilization

It was hypothesized that the day of initiation of ovarian stimulation may influence the day of the luteinizing hormone (LH) surge onset and follicular development. Two groups of 52 patients were randomly selected to commence ovarian stimulation on either day 2 or day 4. The mean +/- standard deviation day of the LH surge was 11.0 +/- 0.9 for day 2 and 12.2 +/- 0.9 for day 4 (P less than 0.001), and the day of human chorionic gonadotropin (hCG) administration was 10.7 +/- 1.2 for day 2 and 11.4 +/- 0.9 for day 4 (P less than 0.02). The two groups also differed significantly in the mean number of days of human menopausal gonadotropin (hMG) administration (day 2, 7.4 +/- 2.7, versus day 4, 6.3 +/- 2.5), and the mean number of vials of hMG administered (day 2, 10.4 +/- 3.2, versus day 4, 8.1 +/- 2.9). However, the mean estradiol level on the day of the LH surge or hCG administration, the number of oocytes collected and fertilized, the number of embryos transferred, and the pregnancy rates were not significantly different. In conclusion, the day of the LH surge or hCG administration can be influenced by the day of initiation of ovarian stimulation, and the initiation of ovarian stimulation around day 4 of the menstrual cycle is clinically more efficient than initiation of follicular development early in the follicular phase.     

Lower pregnancy rate with premature luteinization during pituitary suppression with leuprolide acetate

The relationship of the circulating level of progesterone (P) on the day of human chorionic gonadotropin (hCG) injection to occurrence of clinical pregnancy was examined in 133 leuprolide acetate human menopausal gonadotropin (hMG) in vitro fertilization cycles in women having at least three embryos transferred. Progesterone concentrations greater than 0.5 ng/mL were associated with a significantly lower rate of pregnancy (12/59, 20%) compared with less than 0.5 ng/mL (40/74, 54%, P less than 0.005). The higher P cycles were associated with greater patient age and hMG dose, although these relationships appeared to be indirect. Luteinizing hormone (LH) concentrations remained suppressed. Ovarian stimulation may cause excessive luteinization and an adverse cycle outcome even in the presence of low LH levels. Prospective use of P levels may be helpful to determine optimal hCG timing.     

Clinical experience in the induction of ovulation and pregnancy with pulsatile subcutaneous administration of human menopausal gonadotropin: a low incidence of multiple pregnancy

The pulsatile subcutaneous administration of human menopausal gonadotropin (hMG) or follicle-stimulating hormone (FSH) was used for induction of ovulation in 26 patients with hypothalamic/pituitary amenorrhea or polycystic ovary syndrome (PCO). Ovulation was observed in 116 (90.6%) of 128 treatment cycles, and 15 (16 treatment cycles) of 26 patients became pregnant. All 14 fetuses, excluding two pregnancies interrupted spontaneously at weeks 6 and 9, were singleton conceptions. Ovarian hyperstimulation was observed in 15.6% of treatment cycles. Five patients with PCO who failed to conceive on the hMG regimen also received pulsatile FSH administration. Although ovulation rates in PCO patients did not differ significantly between the hMG (88.1%) and FSH (88.2%) regimens, a significant reduction in the average dose of FSH (P less than 0.05) was observed with pulsatile FSH administration. Furthermore, the number of patients who conceived during the FSH regimen was significantly greater than that found with hMG treatment. The present data demonstrate that pulsatile subcutaneous administration of hMG or FSH is effective in induction of successful ovulation and establishment of singleton pregnancy in patients with various types of anovulatory infertility.     

Dose of human menopausal gonadotropin influences the outcome of an in vitro fertilization program

This study compares outcomes of in vitro fertilization (IVF) in two groups of 57 patients when either 2 (group 1) or 3 (group 2) ampules of human menopausal gonadotropin (hMG) were administered daily. Treatment began on day 3 of the cycle and was discontinued when at least 2 follicles attained diameters greater than or equal to 1.5 cm. Human chorionic gonadotropin (hCG) was given either 24 or 48 hours after the last dose of hMG. Although serum estradiol levels were lower in group 1, the average number of oocytes retrieved (3.2 versus 2.9), fertilized (1.9 versus 2.0), and cleaved (1.7 versus 1.8) per completed cycle did not differ between groups 1 and 2. Likewise, the number of oocytes that fertilized abnormally was similar in both groups (0.5 versus 0.3/cycle). However, the number of atretic oocytes (0.03 versus 0.5/cycle) and the percent of oocytes recovered from the cul-de-sac (0 versus 7.2%) were significantly (P less than 0.05) lower in group 1. In group 1, administration of hCG 48 hours after the last dose of hMG was associated with a higher number of cleaving embryos (2.1 versus 1.5/cycle) and a higher pregnancy rate (34.8 versus 14.7%; P less than 0.05) when compared with injection at 24 hours. In group 2, the interval between hMG and hCG did not influence these results. Together, the associations between fewer oocytes that were atretic or recovered from the cul-de-sac, and a trend toward a higher pregnancy rate, suggest that follicular recruitment with 2 ampules of hMG is more appropriate than 3 ampules in an IVF program.