The human menopausal gonadotropin (hMG) dose in in vitro fertilization (IVF): What is the optimal dose?

Conclusion Evaluating clinical studies on ovarian response, the initial hMG dose should be 150 IU hMG/day in IVF programs without GnRH cotreatment and 225 IU hMG/day in IVF programs with cotreatment with GnRH-a. Age (>35 years), basal FSH level, and body weight are variables known to affect ovarian response and, therefore, reasons to consider an increase in the initial hMG dose. In addition to a good ovarian response, ovarian stimulation with 150 IU/hMG may restrict possible adverse effects of high-dose hMG treatment on the endometrium and on the oocyte (1,12,13). Let us hope that in the future prospective randomized studies will be available to answer questions on the optimal hMG dose in different stimulation protocols.     

Clinical characteristics of ovulation induction with human menopausal gonadotropins with and without leuprolide acetate in polycystic ovary syndrome

Ovulation induction in polycystic ovary syndrome (PCOS) with human menopausal gonadotropins (hMG) results in suboptimal cycle fecundity and frequently is complicated by ovarian hyperstimulation. The use of a gonadotropin releasing-hormone agonist (Gn-RH-a) with hMG induction of ovulation may improve the therapeutic outcome. In this prospective, randomized trial, 27 women with PCOS underwent a total of 25 cycles of hMG alone and 33 cycles with adjunctive GnRH-a (leuprolide) treatment. Premature luteinization was seen less frequently in the leuprolide-treated cycles than in cycles treated with hMG alone. There were no differences between the treatments in ovarian sensitivity to hMG. Cycle fecundity was 0.16 for hMG alone cycles, and 0.27 for leuprolide with hMG cycles, which were not statistically different. We conclude that the sensitivity of the PCOS ovary to hMG is not affected by 4 weeks of leuprolide pretreatment.     

The response of patients with polycystic ovarian disease to human menopausal gonadotropin therapy after ovarian electrocautery or a luteinizing hormone-releasing hormone agonist.

OBJECTIVE: To compare the effect of ovarian electrocautery versus an intranasal (IN) luteinizing hormone-releasing hormone agonist (LH-RH-a) in the response of patients with polycystic ovarian disease (PCOD) to human menopausal gonadotropin (hMG) therapy. DESIGN: A prospective study with serial randomization of patients in two groups for treatment with ovarian electrocautery + hMG or LH-RH-a + hMG. SETTING: A teaching hospital reproductive endocrinology clinic. PATIENTS: Thirty-three women with PCOD who failed to conceive after six treatment cycles with hMG. MAIN OUTCOME MEASURES: Midcycle and luteal phase endocrinology, ovulation, pregnancy rates (PRs), and miscarriage rates. RESULTS: There was no difference in the ovulation or PRs between the two groups. However, the number of cycles with multiple dominant follicles, the luteal phase serum testosterone, and the miscarriage rate were lower in the group pretreated with ovarian electrocautery. CONCLUSIONS: Pretreatment of patients with PCOD with ovarian electrocautery may be a better alternative to IN LH-RH-a therapy for induction of ovulation with hMG.     

Delayed ovarian response in oligomenorrheic women using gonadotropin-releasing hormone agonist.

Ovarian response to human menopausal gonadotropins (hMG) was studied in the presence or absence of prior ovarian suppression using gonadotropin-releasing hormone agonist in the same oligomenorrheic women. Delayed response, with higher hMG requirements, was observed in cycles with prior ovarian suppression.     

The relative success of gonadotropin-releasing hormone analogue, clomiphene citrate, and gonadotropin in 1,099 cycles of in vitro fertilization.

OBJECTIVES: To evaluate the effectiveness of and analyze the factors influencing the outcome of three ovarian stimulation protocols used during in vitro fertilization (IVF) in a large population. DESIGN: Retrospective file review. SETTING: In vitro fertilization program in one center during the years 1985 to 1990. PATIENTS AND PROTOCOLS: Three hundred forty-one patients received clomiphene citrate (CC) and human menopausal gonadotropin (hMG), 365 received hMG alone, and 393 received gonadotropin-releasing hormone analogue (GnRH-a) for pituitary suppression followed by hMG stimulation. MAIN OUTCOME MEASURE: Rates of cancellation, total pregnancies, and ongoing pregnancies, with breakdown by age of patients. RESULTS: The cancellation rate because of early luteinization following GnRH-a/hMG was significantly reduced compared with the other two protocols: 3.6% versus 9.4% and 13.7% for CC/hMG and hMG, respectively. However, in women over 40 years of age, GnRH-a/hMG resulted in the highest rate of poor ovarian response. Significantly more oocytes were retrieved, fertilized, and cleaved after the use of GnRH-a/hMG compared with the other two protocols. Despite this, clinical pregnancy rate (PR) was the highest with CC/hMG compared with GnRH-a/hMG and hMG:31.4% versus 16.9% and 15.7%, respectively. Ongoing PRs were 20.5%, 9.7%, and 11.6%, respectively. CONCLUSIONS: Although the use of GnRH-a for pituitary suppression before ovarian stimulation for IVF reduced the cancellation rate and increased the number of retrieved oocytes, it was not found to result in higher PRs than those achieved by stimulation with CC/hMG. This suggests that treatment by GnRH-a/hMG should be reserved mainly for the prevention of early luteinization.     

A comparison of clomiphene/menotropins and D-Trp6-LH-RH/menotropins cycles of IVF-ET in the same patients.

Pituitary suppression by long-acting D-Trp6-LH-RH and concomitant hMG ovarian stimulation for in vitro fertilization and embryo transfer (ET) has been used in 19 patients who previously failed to conceive, following ovarian stimulation by clomiphene citrate and hMG. When available, up to five embryos were transferred. Compared with the previous CC/hMG cycles, D-Trp6-LH-RH/hMG cycles were associated with significantly more embryos (P less than .002), lower follicular-phase basal LH levels (P less than .05), and a higher early luteal progesterone level (P less than .05). Following D-Trp6-LH-RH/hMG cycles, 11 patients had a clinical pregnancy. The multiple pregnancy rate was 18% and the abortion rate, 18%. Thirty percent of the cycles (6/20) were associated with the ovarian hyperstimulation syndrome. These promising results warrant a further trial of D-Trp6-LH-RH-hMG stimulation.     

The effect of gonadotropin suppression on the induction of ovulation in premature ovarian failure patients

Ovulation induction in patients with hypergonadotropic premature ovarian failure is rarely successful. The authors have attempted to reproduce the results of recent case reports that suggest that ovulation and pregnancy can be successfully achieved when estrogen therapy precedes or coincides with ovarian stimulation with human menopausal gonadotropins (hMG). Fourteen patients with idiopathic premature ovarian failure underwent gonadotropin suppression and attempted ovulation induction with at least one of three regimens, which were as follows: 1) Group A: estrogen-induced suppression followed by hMG stimulation (n = 4). 2) Group B: estrogen-induced suppression followed by hMG stimulation with concomitant estrogen therapy (n = 10). 3) Group C: gonadotropin-releasing hormone agonist-induced gonadotropin suppression followed by concomitant hMG stimulation (n = 6). Despite complete gonadotropin suppression and high-dose hMG therapy in all three groups, ovulation occurred in only a single patient in group C. Pregnancy did not ensue. These data fail to corroborate previous case reports.     

Can growth hormone increase, after clonidine administration, predict the dose of human menopausal hormone needed for induction of ovulation?

Recent observations claimed that growth hormone (GH) administration increased the sensitivity of the ovary to gonadotropin stimulation. These findings prompted us to assess whether ovarian response to human menopausal gonadotropin (hMG) is correlated to GH reserve. Before hMG administration, 25 patients were tested for GH reserve by administration of clonidine. Of the 25 patients, 8 showed a significant increase in GH (9.2 +/- 4.5 ng/mL) and needed a significantly lower dose of hMG/human chorionic gonadotropin to elicit a good ovarian response than the 17 patients who did not respond to clonidine administration may help to estimate the initial dose range of hMG necessary for induction of ovulation.     

Ovarian hyporesponsiveness in combined gonadotropin-releasing hormone agonist and menotropin therapy is associated with low serum follicle-stimulating hormone levels.

The study was designed to evaluate if ovarian hyporesponsiveness, which is associated with combined gonadotropin-releasing hormone agonist (GnRH-a) and human menopausal gonadotropin (hMG) therapy is because of suboptimal serum follicle-stimulating hormone (FSH) levels. Two groups of 12 patients each were suppressed with GnRH-a and stimulation with a fixed dose of hMG. The control group (n = 10) received equal doses of hMG only. The follicular phase and the number of hMG ampules was significantly higher in the study group. Basal FSH levels and FSH levels during hMG treatment were significantly lower in patients treated with GnRH-a. Peak estradiol levels and the outcome of in vitro fertilization treatment were similar in the three groups. We suggest that the delay in ovarian response in patients treated with a combination of GnRH-a and hMG is because of lack of endogenous contribution of FSH, resulting in low circulating levels of FSH. An increase of serum FSH levels by administration of higher doses of hMG can reverse this effect.     

Controlled ovarian stimulation with exclusive FSH followed by stimulation with hCG alone, FSH alone or hMG

OBJECTIVE: To assess if low-dose hCG is similar to hMG and to rFSH in the late follicular phase. STUDY DESIGN: In a prospective randomized controlled trial, 51 patients undergoing controlled ovarian stimulation received ovarian priming with rFSH and then received hCG (200 IU/day) (hCG group, n=17), hMG (225 IU/day) (hMG group, n=17) or rFSH (200 IU/day) (FSH group, n=17) in the late stage of follicular development. Parameters of follicular response and serum estradiol, progesterone and testosterone levels were assessed. RESULTS: Pre-ovulatory ovarian follicle occurrence and length of treatment were similar among the three treatment groups. Serum progesterone level on the day of pre-ovulatory hCG was significantly higher in the hCG group than in the hMG or rFSH group. Clinical pregnancy rates were similar for all groups. The total cost of treatment was significantly lower for the hCG group than for the groups supplemented with hMG or rFSH. CONCLUSIONS: LH in the form of low-dose hCG during the late follicular phase induced the same follicular pattern as hMG and rFSH after ovulation induction. The procedure using hCG produced pregnancy rates similar to those obtained using hMG and rFSH, even though the patients showed higher serum progesterone levels on the hCG day.     

GnRH类似物－Buserelin在体外受精与胚胎移植超排卵（长方案）治疗中的作用

从１９９４年４月至１９９５年７月在体外受精与胚胎移植超排卵中，应用ＧｎＲＨ类似物－Ｂｕｓｅｒｅｌｉｎ及ＦＳＨ／ｈＭＧ长方案治疗９例（Ⅰ组）与单独用ＦＳＨ／ｈＭＧ１２例（Ⅱ组）进行比较。结果：Ⅰ组的ＦＳＨ／ｈＭＧ用量大，用药时间长，其受精率、卵裂率及妊娠数均高于Ⅱ组。卵巢过度刺激综合征（ＯＨＳＳ）发生率明显低于Ⅱ组。本文研究显示了Ｂｕｓｅｒｅｌｉｎ长方案治疗能明显提高体外受精与胚胎移植的效果。     

Ovarian suppression with leuprolide acetate: Comparison of luteal,follicular, and flare-up administration in controlled ovarian hyperstimulation for oocyte retrieval

Adjunct use of leuprolide (LA) in patients undergoing controlled ovarian hyperstimulation with human menopausal gonadotropins (hMG) was evaluated by three protocols: Group F(n=24) began LA on day 2 of the cycle and Group L(n=38) began LA on day 23 of the cycle until ovarian suppression, at which time hMG was added. Group FL (n=17) began LA on day 1 and hMG on day 3. Compared to FL, more ova were collected, more ova fertilized, and more pregnancies resulted per initiated cycle in groups achieving suppression before hMG stimulation. Fewer days were necessary to attain suppression for L vs F. After achieving suppression, patients were maintained on either 0.5 mg LA or 0.25 mg LA daily during hMG coadministration with similar results. Lower maintenance doses of LA during hMG did not decrease the amount of hMG needed but retained the benefits of LA. We recommend luteal initiation of LA to achieve suppression before hMG.Presented in part at the 45th Annual Meeting of the American Fertility Society, San Francisco, California, November 1989.     

Comparison of urinary human follicle-stimulating hormone and human menopausal gonadotropin for ovarian stimulation in polycystic ovarian syndrome

A randomized, double-blind, crossover study was carried out to compare purified urinary follicle-stimulating hormone (FSH) and human menopausal gonadotropin (hMG) for ovarian stimulation in polycystic ovarian syndrome (PCOS). Twelve patients were stimulated with FSH and hMG in three alternate cycles. FSH, luteinizing hormone (LH), estradiol, dihydroepiandrosterone sulphate, free and total testosterone, delta 5-androstenedione, sex hormone binding globulin, and ovarian volume were monitored during the stimulation. There was no difference between the dose of FSH and hMG necessary to induce preovulatory follicles in the individual patients. The mean increase of ovarian volume during stimulation with FSH and hMG was 120% and 129% respectively (no significant difference). Two patients became pregnant in the first cycle. Two other patients had delayed bleeding and positive serum-human chorionic gonadotropin. No significant difference was found in the endocrine changes during the two different stimulation methods. The LH/FSH ratio was normalized after a few days of treatment regardless of the type of stimulation. The size of the material does not permit a comparison of the efficacy of the two treatment schedules. Our clinical and ultrasonic observations do not support the theory that treatment of infertility in PCOS with FSH is more safe than with hMG.     

Influence of human menopausal gonadotropin on the recruitment of human ovarian follicles

Human menopausal gonadotropin (hMG) was administered once (225 IU) to 16 women during different phases of the menstrual cycle: either late-luteal, early-follicular, midfollicular, or late-follicular phases before surgical ovarian resection or ablation. The mitotic index (MI) of follicular granulosa cells and the proportion of recruitable healthy follicles were analyzed 4 to 5 days after hMG injection, the findings being compared with those in unstimulated ovaries from 22 normally cycling patients. The percentages of healthy recruitable follicles greater than or equal to 2 mm in diameter was not altered by hMG as compared with controls. The granulosa cell MI was highly stimulated by hMG when administered in late-luteal or early-follicular phases; however, no granulosa cell MI stimulation was noted when hMG was administered in the midfollicular or late-follicular phases. The progressive abolition of the ability of hMG to stimulate follicular growth as ovulation approaches supports the existence of an inhibitory activity (possibly ovarian) designed to suppress the selection and the maturation of the less developed antral follicles from the midfollicular phase of the spontaneous human menstrual cycle.     

Comparison of ovarian stimulation regimens for in vitro fertilization (IVF) with and without a gonadotropin-releasing hormone (GnRH) agonist: Results of a randomized study

In order to diminish the cancellation rate due to a premature endogeneous LH surge and/or to a poor ovarian response and thus increasing the pregnancy rate, a GnRH agonist (Buserelin) was applied in patients starting their first ovarian stimulation with gonadotropins for IVF. All patients suffered from tubal infertility and were not older than 40 years. Each woman was allocated randomly to one of three groups: the conventional treatment with hMG alone (group I), patients from group II started the hMG treatment shortly after the LH rise caused by the GnRH agonist and patients in group III commenced the hMG treatment when an hypogonadotropic state was achieved after a long treatment of Buserelin. All male partners had a normal spermiogram. A reduction of poor responders to the superovulation is seen in the short-term group (6%), compared with the other two groups (14%). In some cases from group III ovarian cyst formation led to the cancellation of the treatment. The long-term group differs significantly from the other two in the duration of the gonadotropin stimulation and the number of ampoules hMG used. A severe ovarian overstimulation syndrome was not observed. There is no difference in the number of retrieved oocytes and the fertilization rate among the three groups. The pregnancy rate per cycle or per patients in the group with a short-term GnRH-agonist regimen is significantly higher compared to that of the group using the conventional hMG treatment.     

Ovarian stimulation protocol for in vitro fertilization with gonadotropin-releasing hormone agonist widens the implantation window

Pregnancy rates vary considerably with the type of ovarian stimulation used for in vitro fertilization and embryo transfer (IVF-ET). The window of implantation may represent one of the rate-limiting steps in IVF success. We therefore investigated estimated implantation times of 10 consecutive IVF singleton pregnancies, achieved using pituitary suppression with gonadotropin-releasing hormone agonist (GnRH-a) before and during ovarian stimulation with human menopausal gonadotropins (hMG), and compared those with 9 consecutive IVF pregnancies achieved by hMG stimulation only. Estimated implantation times were calculated by regression analysis of serial human chorionic gonadotropin (hCG) measurements between days 7 and 16 after ET. The GnRH-a/hMG pregnancies implanted between days 7 and 11, whereas hMG pregnancies implanted between days 7 and 9 after ET. The hCG regression curve for the GnRH-a/hMG pregnancies revealed a delay of 1.5 days in estimated implantation time compared with the hMG only group. There were no significant differences in pretransfer in vitro embryos development between the two groups. Thus, the delay in hCG rise probably reflects a delay in embryo implantation. We therefore conclude that a GnRH-a/hMG stimulation protocol appears to widen the implantation window in comparison with a hMG only protocol. This observation may at least in part explain the improved IVF pregnancy success with GnRH-a/hMG stimulation protocols.     

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。     

不同促排卵方法在卵巢储备功能下降患者中的应用

目的:探讨卵巢储备功能下降患者的促排卵优选方案。方法:GnRH-a/hMG/rFSH(Gn)长方案促排卵(A组)共39个周期,GnRH-a/hMG/rFSH(Gn)短方案促排卵(B组)46个周期,GnRH-A/hMG/rFSH(Gn)促排卵(C组)共35个周期,比较3组临床用药和临床结局情况。结果:A组Gn所用天数(12.4±1.51d)显著高于B组(9.5±1.7d)、C组(10.7±3.2),P<0.05,且Gn(75IU/支)所用支数(41.5±8.6支)也明显多于B组(34.7±9.7支)和C组(33.4±16.2支)(P<0.05)。B组Gn所用天数要少于C组(P<0.05),Gn所用总量与C组间无统计学差异(P>0.05)。hCG注射日的血清LH水平A组(1.20±1.02IU/L)显著低于B组(3.17±1.58IU/L)和C组(2.15±1.8IU/L)(P<0.05),B组与C组之间无统计学差异(P>0.05)。A组与C组注射hCG日的血清E2值(7958±4586pmol/L,6022±7852pmol/L)均低于B组(10145±5503pmol/L)(P<0.05)。3组种植率、临床妊娠率均无显著性差异。3组间hCG注射日内膜厚度、受精率、卵裂率均无统计学差异(P>0.05)。结论:短方案更适合于卵巢功能减退患者的促排卵治疗,长方案与GnRH-A方案促排卵也是可行方法。     

Endocrine evaluation of induction of ovulation with pulsatile and continuous administration of human menopausal gonadotropin (hMG) in anovulatory women

To evaluate the endocrine profiles during induction of ovulation with pulsatile and continuous administration of hMG (Pergonal), 3 patients with polycystic ovarian disease (PCO) and 4 patients with hypothalamic amenorrhea were selected as the subjects. The total dose of hMG per day was 150 IU in each patient. hMG pulse was administered intravenously via a portable infusion pump every 90 min in 4 patients including 3 PCO cases (9.375 IU/pulse) and every 18 min in one patient (1.875 IU/pulse). The remaining 2 patients received continuous subcutaneous infusion of hMG (150 IU/day). Following hMG treatment, 8,000 to 10,000 IU of hCG was used to induce ovulation. All 7 patients ovulated and 4 of them conceived. Pregnancy resulted in 2 patients following pulsatile (every 90 min) administration and in 2 patients after continuous infusion. The duration of hMG treatment needed to induce ovulation was similar among the three modes of administration and within the range of 7 to 10 days. A sustained elevation of circulating FSH levels was observed in all patients and serum estradiol increased more than 3,000 pg/ml in 6 of 7 patients during the course of treatment. Mean (+/- SE) midluteal progesterone level was 107.1 +/- 20.9 ng/ml. Moderate to severe ovarian hyperstimulation occurred in all patients. These results indicate that both pulsatile and continuous administration of hMG are similarly effective in inducing ovulation. They also appear to indicate that the hMG-induced follicular development is profoundly affected by the maintenance of high levels of FSH in the circulation rather than by the mode of administering hMG, whether pulsatile or continuous.     

Interest of growth hormone-releasing hormone administration for improvement of ovarian responsiveness to gonadotropins in poor responder women.

OBJECTIVE: We have investigated the beneficial effect of a somatotroph axis stimulation on ovarian response to gonadotropin. DESIGN: Growth hormone-releasing hormone (GH-RH) was administered in a prospective study in women undergoing an in vitro fertilization protocol. PATIENTS: Twelve patients were selected for their poor ovarian response to previous stimulations using gonadotropin-releasing hormone analog (GnRH-a) and human menopausal gonadotropins (hMG). INTERVENTIONS: Five hundred micrograms of GH-RH1-29 were administered two times daily concomitantly with GnRH-a and hMG from day 2 of the cycle to the time of ovulation. MAIN OUTCOME MEASURES: Stimulation of somatotroph axis was appreciated by measuring over-night urinary growth hormone (GH) output, plasma GH, and insulin-like growth factor I (IGF-I) and follicular fluid (FF) IGF-I. The effects of GH-RH administration on ovarian function were determined by plasma estradiol levels and follicular data. RESULTS: Administration of GH-RH was associated with a significant improvement of urinary (P less than 0.025) and plasma (P less than 0.001) GH concentrations and of the hormonal response to hMG (P less than 0.01). Levels of IGF-I followed a biphasic plasma variation, and a slight increase in recruited follicles, retrieved oocytes, and FF IGF-I content was also observed. CONCLUSIONS: Activation of the somatotroph axis by GH-RH enhances the hormonal ovarian response to hMG and may be an adjunctive therapy to improve follicular maturation.