Endogenous luteinizing hormone release using human menopausal gonadotropins for in vitro fertilization

This study demonstrates that luteinizing hormone (LH) release may occur despite sustained elevations of estradiol E₂ in women receiving human menopausal gonadotropin. Mean levels of E₂ did not correlate with the LH surge, however, the follicle number and a rapid rise in E₂ did. Therefore, it appears that the protective influence of inhibitory proteins secreted by multiple follicles can be overridden, allowing spontaneous LH release.     

Small increases in circulating luteinizing hormone (LH) concentrations shortly before human chorionic gonadotropin (hCG) are associated with reduced in vitro fertilization (IVF) pregnancy rate

The effects of slight elevations in serum LH just before hCG administration on IVF cycle outcome were studied in 219 women undergoing retrieval. One hundred seven patients were stimulated using human menopausal gonadotropin (hMG), and 112 received clomiphene citrate and hMG. Serum LH, estradiol (E₂), and progesterone concentrations were measured before and during controlled ovarian stimulation. Retrospectively the women were subdivided into three groups based on serum LH before hCG: Group I, <50% LH rise from baseline (BL) value (mean of day 2 and day 7); Group II, LH rise 50% but <2×BL; and, Group III, LH rise 2×BL. The fertilization and cleavage rates were similar in all groups. However, a 50% rise in serum LH before hCG was associated with a significantly reduced IVF pregnancy rate.Presented in part at the VI World Congress on in Vitro Fertilization and Alternate Assisted Reproduction, 1989.     

Preimplantation development following in vitro fertilization of mouse oocytes: Effects of timing of superovulation and preincubation in vitro

The early embryonic development of in vitro fertilized oocytes was assessed following superovulation in F₁ hybrid C57BL/6×CBA/Ca mice. Decreasing the time interval between the administration of constant doses of pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) resulted in decreases in the frequency of development to the blastocyst stage but had no significant effect on development to the two-cell stage. Preincubation of postovulatory oocytes in vitro prior to insemination did not compensate for the reduced preovulatory development in vivo but resulted in decreases in the frequency of development to the blastocyst stage. The results indicate that inadequate preovulatory development of superovulated mouse oocytes can adversely affect the preimplantation development of in vitro fertilized embryos in the absence of a visible inhibitory effect on development to the two-cell stage and also that preincubation of postovulatory oocytes in vitro prior to fertilization reduces subsequent developmental capacity.     

Relationship among serum levels of luteinizing hormone,estradiol, and progesterone during follicle stimulation and results of in vitro fertilization and embryo transfer (IVF-ET)

Eighty-eight IVF-ET cycles were classified into four groups according to the results of IVF-ET (Group A—conceptional cycles, 10 cycles; Group B—cycles with cleaved oocytes, 58 cycles; Group C—cycles with fertilized oocytes, 9 cycles; Group D—cycles without fertilization, 11 cycles). Serum luteinizing hormone (LH), estradiol (E ₂ ), and progesterone (P) levels during follicle stimulation were studied in these groups. Patients participated in our IVF-ET program due to irreparable tubal damage. Follicle development was stimulated with a clomiphene—human menopausal gonadotropin (hMG)—human chorionic gonadotropin (hCG) regimen. Group C showed a low E ₂ response to follicle stimulation. Groups B and D showed significantly higher serum P levels on day 0 (the day of hCG injection) than Group A (Group A, 0.73 ± 0.11, vs Groups B and D, 1.43 ± 0.15 and 2.17 ± 0.42 ng/ml; P <0.01). The effects of serum P and LH levels on the fertilization and pregnancy rates were studied. The pregnancy rate was not affected by the serum LH level but was only 2.7% in cycles in which serum P was 1.2 ng/ml on day 0, which was significantly lower than that in cycles in which serum P was <1.2 ng/ml on day 0 (19.1%) (P <0.05). The fertilization rate was significantly lower in the cycles with higher levels of serum P and/or LH than in cycles in which serum P was <1.2 ng/ml and serum LH was normal (50.5 vs 78.8%; P <0.01). These findings suggest that the serum P level, but not the LH level, during follicle stimulation is closely related to the achievement of pregnancy.     

The clinical therapeutic window for luteinizing hormone in controlled ovarian stimulation

Objective: To discuss the clinical therapeutic window for LH during the follicular phase.

Design: Review of selected papers that were retrieved through a Medline search and a review of clinical trials, the results of which are in the process of publication.

Patient(s): Women undergoing infertility treatment.

Intervention(s): Recombinant human LH (r-hLH) was administered SC as a supplement to FSH during controlled ovarian hyperstimulation.

Main Outcome Measure(s): Follicular development, E₂ production, and endometrial thickness.

Result(s): Optimal follicular maturation is the result of both FSH and LH stimulation. In patients with hypogonadotropic hypogonadism, 75 IU of r-hLH and 150 IU of FSH per day resulted in more follicles and provided sufficient E₂ for optimal endometrial proliferation. Additional r-hLH (>250 IU/day), in patients with either hypogonadotropic hypogonadism or polycystic ovary disease, may precipitate a series of deleterious physiological actions leading to atresia of developing follicles. Adding r-hLH to FSH in women treated with GnRH agonist showed no benefits in terms of number of mature oocytes, fertilization, and cleavage. However, those who experience profound pituitary desensitization may benefit from adding LH to the stimulation protocol. No obvious clinical criteria have been established to define this group of patients.

Conclusion(s): A “threshold” and “ceiling” level for LH (therapeutic window) is proposed, below which E₂ production is not adequate and above which LH may be detrimental to follicular development.     

Recombinant luteinizing hormone priming in multiple follicular stimulation for in-vitro fertilization in downregulated patients

Follicle development is controlled amongst other factors by pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) that act in synergy in completing follicle maturation. Exogenous gonadotropins, combined with gonadotropin-releasing hormone agonists, have been successfully used in patients with ovulatory disorders undergoing assisted reproduction. There is some evidence of a beneficial role of androgens or LH administration before FSH stimulation. This study was designed to verify whether the addition of LH in the early follicular phase, in downregulated patients undergoing follicular stimulation for assisted reproduction, would add benefits in terms of general outcomes and pregnancy rates. We compared two groups of patients one of which was treated with recombinant FSH (rFSH) alone and the other with rFSH plus recombinant LH (rLH), in the early follicular phase only. The number of eggs recovered was higher in the group treated with FSH only; however, the number of embryos available at transfer was similar in the two groups and, more importantly, the number of Grades I and II embryos was higher in the group pretreated with LH. Similarly, although biochemical pregnancy rate and clinical pregnancy rates were similar in both groups, a beneficial role of LH priming was demonstrated by the higher implantation rate achieved in these patients.     

Atypical response to luteinizing hormone-releasing hormone (LH-RH) agonist (Suprefact nasal) in induction of ovulation in in vitro fertilization (IVF)

Animal and human research has indicated the presence of receptors to luteinizing hormone-releasing hormone (LH-RH) in the ovaries. However, the role of these receptors is not yet clear. Forty-five patients were treated with Suprefact (d-Serg-Des-Gly10-GnRGH), starting in the midluteal phase of a nonstimulatory menstrual cycle. The Suprefact (300 g t.i.d.) was administered as a nasal spray until the administration of human chorionic gonadotropin (hCG). On the third to fifth day of the following menstrual cycle, the patients were treated with a high dose of human menopausal gonadotropin (hMG). hCG was administered when at least two follicles reached a mean diameter of 18 mm. Five of these patients who ovulated spontaneously and had normal menstrual cycles did not respond to the stimulation with hMG. Treatment was stopped after 12 days of hMG administration. During the following cycle of the five patients, levels of gonadotropins were found to be in the normal range, and all of them responded as expected to hMG administered for 3 days only (hMG test). These findings suggest that LH-RH agonist may interfere with ovarian steroidogenesis.     

A prospective randomized comparison between long and discontinuous-long protocols of gonadotropin-releasing hormone agonist for in vitro fertilization

Objective: To investigate the efficacy of a discontinuous-long protocol in an IVF program.

Design: Prospective randomized study.

Setting: University hospital.

Patient(s): One hundred thirty-seven IVF cycles of 92 patients in an outpatient IVF program from April 1995 to December 1995.

Intervention(s): In the discontinuous-long protocol group (n = 68), GnRH agonist (GnRH-a) was administered from the luteal phase until cycle day 7, when pure FSH administration was begun. In the long protocol group (n = 69), GnRH-a was administered until the day before hCG administration.

Main Outcome Measure(s): Serum LH and ovarian steroid hormone levels, and IVF outcome.

Result(s): The period and the total dosage of hMG were increased in the discontinuous-long protocol group. Although the fertilization rate was similar under both protocols, the number of embryos transferred was smaller and the cancellation rate was higher in the discontinuouslong protocol group because of the greater failure of oocyte retrieval and fertilization. Serum E₂ levels in the late follicular phase were lower in the discontinuous-long protocol group.

Conclusion(s): Early discontinuation of GnRH-a is not beneficial because of its adverse effects on follicular development.     

Short-term use of gonadotropin-releasing hormone agonist (Leuprolide) for in vitro fertilization

A common problem encountered by in vitro fertilization (IVF) programs is the premature occurrence of the spontaneous lutenizing hormone (LH) surge during ovarian stimulation cycles. Administration of gonadotropin-releasing hormone agonists (GnRH-a) for 2 to 3 weeks produces a state of hypogonadotropic hypogonadism, thus allowing ovarian stimulation to proceed uncomplicated by a spontaneous LH surge. We have elected to treat seven patients with GnRH-a in a short-term protocol, with GnRH-a initiated on cycle day 3 along with exogenous gonadotropins. In this series, we found that the spontaneous LH surge was abolished, while ovarian responsiveness seemed to be improved. These results suggest that the initial surge of gonadotropins elicited by GnRH-a administration may enhance ovarian stimulation and that spontaneous LH surge is blocked when GnRH-a and exogenous gonadotropins are initiated concomitantly.     

In vitro fertilization outcomes in patients experiencing a premature rise in luteinizing hormone during a gonadotropin-releasing hormone antagonist cycle

Patients undergoing controlled ovarian hyperstimulation and pituitary suppression with a GnRH antagonist who experienced a transient premature rise in LH were compared with those who did not have an early surge. Those experiencing a premature LH surge had equivalent clinical and ongoing pregnancy rates per ET.     

Basal serum pituitary hormone levels and outcome of in vitro fertilization utilizing a flare nasal gonadotropin releasing hormone agonist and fixed low-dose follicle-stimulating hormone/human menopausal gonadotropin regimen

Day 2 serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are prognostic indicators in treatment with in vitro fertilization (IVF) and FSH is especially useful in predicting the ovarian response to superovulation.     

Follicular-phase response in two clomiphene-human menopausal gonadotropin regimes for an in vitro fertilization program

Two clomiphene-human menopausal gonadotropin regimes were assessed for our in vitro fertilization and embryo replacement (IVF and ER) program since September 1983. Clomiphene, 50 mg bd, was taken from day 2 for 5 days. Human menopausal gonadotropin (hMG) was given from day 6; for the first regime, 75 IU/day was given for the first 3 days, and for the second, 150 IU/day. The subsequent dosages were dependent on the estradiol response. There were 9 cases for the first regime and 10 cases for the second. The mean number of hMG ampoules given was 16.5 and 19.25, respectively. The number of follicles seen on ultrasound was 3.0±0.5 and 3.4±1.2 (mean±SD), respectively. There was no statistical difference in the estradiol response up to the day of laparoscopic ova recovery for the two regimes. However, a spontaneous luteinizing hormone (LH) surge was observed in 4 of 9 cases in the first group and 6 of 10 cases in the second group. When a comparison was made between cases that had a spontaneous LH surge and cases that were given human chorionic gonadotropin (hCG), there was a higher estradiol level on the day of the laparoscopy in the hCG group with the lower hMG regime (P<0.05). There were no other differences. Our small series shows a 52.6% incidence of spontaneous LH surge with clomiphene-hMG. Hence such stimulated regimes can result in a high proportion of spontaneous LH surges; this may be an index of satisfactory endocrinological control in spite of an increase in the number of follicles.     

Ovarian stimulation for in vitro fertilization using pure follicle-stimulating hormone with and without gonadotropin-releasing hormone agonist in high-responder patients

There is a distinct pattern of response to gonadotropin stimulation in some patients marked by high peak estradiol (E₂) levels, multifollicular ovarians response, and elevated basal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratios. We reviewed the stimulation profiles of five such high-responder patients who failed to conceive during in vitro fertilization with ovarian stimulation using pure FSH. All patients had baseline LH/FSH >1.5 and peak E₂>800 pg/ml. One cycle was canceled prior to hCG administration because of marked ovarian response (E₂>2500 pg/ml, multiple small follicles). In a subsequent cycle, all patients were pretreated with the gonadotropin releasing-hormone agonist (GnRHa) leuprolide acetete for 10–14 days prior to initiation of FSH for ovarian stimulation. Leuprolide was continued until the day of hCG administration. During cycles using GnRHa, there was a statistically significant decrease (P <0.05) in serum FSH on day 3 (<5 vs 8.3 mIU/ml), serum E₂ on day 3 (14.6 vs 34.6 pg/ml), and peak serum E₂ (1197.6 vs 1923.0 pg/ml). Patients during cycles with GnRHa had a greater number of preovulatory (8.6 vs 3.0) and total (12.4 vs 6.0) oocytes retrieved (P<0.05). The fertilization rate of preovulatory oocytes was also higher during cycles using GnRHa (83 vs 64%). Two pregnancies occurred in the cycles pretreated with GnRHa. These preliminary data indicate that in high-responder patients, a combination of GnRHa and pure FSH results in lower E₂ levels during the stimulation cycle and a greater number of total and mature oocytes retrieved and fertilized.     

Effectiveness of short pituitary suppression with gonadotropin-releasing hormone agonist leuprolide during induction of ovulation for in vitro fertilization

A short suppression regimen with daily 0.5 mg leuprolide commencing the first day of in vitro fertilization (IVF) cycles was evaluated in 10 women who previously underwent similar IVF cycle without suppression. Induction of ovulation, oocyte retrieval, incubation, and embryo transfer were similar in all the cycles. Assessment included the amount of human menopausal gonadotrpin (hMG) used, length of stimulation, serum estradiol and luteinizing hormone (LH) levels, number of oocytes retrieved and their quality, cleavage rate, and number of embryos. The results showed that when leuprolide was used, no endogenous LH surge was detected, and there was a significant increase in hMG injected, from 19.0±5.8 to 34.4±17 ampoules, and in estradiol, levels, from 1276±470 to 2618±1084 pg/ml (mean ± SD). In addition, there was an increase in the total oocytes retrieved from 54 to 94, their cleavage rate from 59 to 86%, and the number of embryos from 24 to 70 in the suppressed cycle. No deleterious effects were observed and there were two pregnancies in this group.     

Serum luteinizing hormone level on the third day after ovarian stimulation in GnRH agonist short protocol is predictive of outcome in poor responders but not in normal responders

Objectives: To identify whether prognostic value of LH measurement in normal responders (NR) is different from poor responders (POR).

Methods: A retrospective, single-center study was conducted among patients who underwent ovarian stimulation with short protocol, with 300 NR and 101 POR, according to Bologna Consensus criteria. LH was measured on 3rd and 5th day after stimulation and HCG administration day.

Results: There was significant difference in the clinical pregnancy rate per cycle initiated among those with LH level on the third day after stimulation (a) below the 25 centile (b) between the 25 and 75 centile and (c) above the 75 centile in women with POR (7.7%, 15.1% vs. 36.4%, p?=?0.02) but not in NR. There was significant correlation between LH ranks and clinical pregnancy rate in POR (p?=?0.02) but not in NR. Factors associated with clinical pregnancy rate in POR were age and LH on the third of stimulation, while factors in NR were age, AFC and FSH.

Conclusion: LH level on the 3rd day of stimulation was predictive of clinical pregnancy in POR but not in NR.     

Efficacy of the urinary hemagglutination test (Higonavis) and enzyme immunoassay (Ovustick) in detection of the spontaneous luteinizing hormone surge in an in vitro fertilization/gamete intrafallopian transfer (IVF/GIFT) program

Fifty-eight treatment cycles in an in vitro fertilization/gamete intrafallopian transfer (IVF/GIFT) program were studied to compare the efficacy of two urinary methods, hemagglutination test (Higonavis) and enzyme immunoassay (Ovustick), in detection of spontaneous luteinizing hormone (LH) surge. If an isolated rise in urinary LH level was taken as indicative of LH surge, the false-positive rate was 36.7% for Higonavis and 10.2% for Ovustick. The difference was statistically significant (P<0.001). If only a sustained rise in urinary LH was taken to indicate LH surge, the false-positive rate was 6.1% for Higonavis and 0% for Ovustick. In the seven cycles with a spontaneous plasma LH surge, there was a positive correlation between the plasma LH levels and the two urinary assay methods in six cycles (85.7%). Compared to plasma LH, there was a mean delay of 17.4 hr by the Higonavis test and 15.6 hr by the Ovustick test. If a sustained rise in urinary LH levels was taken as indicative of LH surge, both methods are quite accurate but the Ovustick appeared to be more specific.     

Clinical aspects with regard to the occurrence of an endogenous luteinizing hormone surge in gonadotropin-induced normal menstrual cycles

A decline in serum E₂ the day before laparoscopy indicated that ovulation had occurred in 16 cycles stimulated with exogenous gonadotropins for the purpose of in vitro fertilization (IVF). In contrast to 18 control cycles with rising E₂ values after human chorionic gonadotropin (hCG) administration and without evidence of ovulation, the onset of the endogenous luteinizing hormone (LH) surge had been initiated. From this study, it is believed that the onset of an endogenous LH surge can be identified by the terminal preovulatory E₂ pattern. Further, the incidence of an endogenous LH surge in gonadotropin-induced menstrual cycles and the present clinical approach of the Norfolk IVF program to this phenomenon are discussed.     

Ovarian stimulation for in vitro fertilization in low-responder patients using pulsatile intravenous follicle stimulating hormone

There is a subset of patients who fail to respond adequately to exogenous gonadotropin stimulation for in vitro fertilization (IVF). In this study, six such low-responder patients who had inadequate stimulations with high-dose intramuscular (im) follicle stimulating hormone (FSH) were treated in a subsequent cycle with pulsatile intravenous (iv) FSH. A paired analysis was performed to compare the cycles using high-dose im FSH with those using pulsatile iv FSH. Trough serum FSH levels were significantly higher with pulsatile iv FSH. No significant difference was noted in the stimulation characteristics or the number or quality of oocytes retrieved and embryos transferred. No pregnancies occurred in either group. While pulsatile iv administration of gonadotropin increases serum FSH levels, it does not appear to have a major impact on follicular stimulation or outcome in low-responder patients undergoing IVF.