The effect of growth hormone supplementation on in vitro fertilization outcome: a prospective randomized placebo-controlled double-blind study.

OBJECTIVE: To determine the effect of growth hormone (GH) supplementation to a long gonadotropin-releasing hormone agonist (GnRH-a)/human menopausal gonadotropin (hMG) treatment protocol, on ovarian response, embryo quality, and clinical outcome in in vitro fertilization (IVF). DESIGN: Growth hormone or placebo were administered in a prospective randomized double-blind manner. PATIENTS: Forty-two normal ovulatory, women who were 38 years of age or less with mechanical factor infertility and a normal male factor were selected for this study. INTERVENTIONS: Gonadotropin-releasing hormone agonist, 0.5 mg/d, was initiated in the midluteal phase of the preceding cycle and continued until the day of human chorionic gonadotropin (hCG) administration. Ovulation induction with hMG was started 14 days after pituitary down regulation (17 beta-estradiol [E2] serum level less than 30 pg/mL). Growth hormone (12 IU/d) or placebo were administered on days 1, 3, 5, and 7 of hMG treatment. RESULTS: Breaking the code at the completion of the study revealed that 20 women received GH and 22 placebo. The age and duration of infertility did not differ between the two groups. Follicular phase duration, hMG ampules used, serum E2, and number of follicles (greater than or equal to 14 mm) on day of hCG as well as number of oocytes and embryos achieved were similar in both groups. Embryo morphology and rate of cleavage were also similar. Insulin-like growth factor-I (IGF-I) serum levels did not change after pituitary down regulation and increased significantly both after GH/hMG and placebo/hMG ovulation induction treatment. Clinical pregnancy rate (PR) per embryo transfer and implantation rate were 40% versus 32% and 17.9% versus 11.3% in the GH and placebo groups, respectively, and were not statistically different. CONCLUSIONS: In normo-ovulatory women undergoing ovulation induction for IVF, GH supplementation to hMG after GnRH-a pituitary down regulation does not seem to augment ovarian response or improve embryo quality. The effect of this regimen on actual PRs and implantation rates needs further clarification.     

Cotreatment with growth hormone for induction of spermatogenesis in patients with hypogonadotropic hypogonadism.

OBJECTIVE: To induce spermatogenesis by cotreatment with growth hormone (GH) and gonadotropin therapy in patients with hypogonadotropic hypogonadism who had failed to respond adequately to conventional treatment. DESIGN: Cotreatment with GH (4 IU) and human menopausal gonadotropin, 150 IU of follicle-stimulating hormone and 150 IU of luteinizing hormone (LH), three times a week, and human chorionic gonadotropin, 2,500 IU, two times a week for 24 weeks after unsuccessful treatment for 12 weeks with either pulsatile LH-releasing hormone or gonadotropins. SETTING: Specialist Reproductive Endocrine Unit. PATIENTS, PARTICIPANTS: Seven patients, four of whom had failed to respond adequately to the conventional treatment. MAIN OUTCOME MEASURES: Serum testosterone (T), estradiol, and sperm production, testicular and semen volume, and serum insulin-like growth factor-I and inhibin concentrations. RESULTS: Of the four patients who received cotreatment with GH, three increased T secretion (greater than 11 nmol/L) within a relatively short period of time, two produced adequate amount of sperm (13 and 12 x 10(6)/mL), and one of them impregnated his wife. One patient did not respond. CONCLUSION: The results offer a new approach to the problem of induction of spermatogenesis in patients who respond poorly to conventional treatment because cotreatment with GH enhanced T secretion and sperm production in a relatively short period of time.     

Successful pregnancy and birth after sequential cotreatment with growth hormone and gonadotropins in a woman with panhypopituitarism: a new treatment protocol

Objective: To report a successful pregnancy in a woman with panhypopituitarism who received 3 months of pretreatment with growth hormone (GH) before ovulation induction. Prior attempts at ovulation induction had failed for this patient.

Design: Case report.

Setting: Department of Endocrinology.

Patient(s): A 32-year-old woman with panhypopituitarism and secondary infertility.

Intervention(s): GH (1 IU/day) alone for 3 months; during the next cycle, 1 IU/day of GH; 3 ampules of hMG per day during days 1–21; 1 ampule of hCG on day 21. GH was discontinued on day 35 when a pregnancy test was positive.

Main Outcome Measure(s): Pregnancy and delivery.

Results: Pregnancy and birth of a normal child after a single ovulation stimulation using GH and gonadotropins.

Conclusion(s): This case report suggests interest in a new protocol for follicular stimulation in women with hypopituitarism who are responding poorly to gonadotropin therapy.     

Effect of growth hormone administration on human ovarian function and steroidogenic gene expression in granulosa-luteal cells.

OBJECTIVE: To study the effect of growth hormone (GH) in combination with an ultrashort-term gonadotropin-releasing hormone analogue/human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) regimen in ovarian hyperstimulation for in vitro fertilization (IVF). DESIGN: Prospective randomized placebo-controlled study. SETTING: University-based IVF program. PATIENTS: Fifty-four normally cycling women (27 control and 27 GH-treated) participated in this study. INTERVENTIONS: Human recombinant GH (24 IU)/placebo was given intramuscularly on alternate days starting on cycle day 4 until the day of last hMG injection. RESULTS: Serum estradiol (E2) and progesterone (P) concentrations were slightly lower in the GH group than in the placebo group on the day of hCG injection and 1 day thereafter (P < 0.01 to 0.001). Serum luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone (T), and sex hormone-binding globulin did not differ between the groups. The follicular fluid (FF) concentration of T was higher in the GH group than in the placebo group (15.9 +/- 6.0 nmol/L versus 10.2 +/- 4.9 nmol/L, P < 0.005), and no differences were observed in the FF concentrations of E2, P, and insulin-like growth factor I between the groups. In granulosa cells isolated from patients who received GH treatment, the levels of 3 beta-hydroxysteroid dehydrogenase and aromatase messenger ribonucleic acid were significantly higher than in the patients receiving placebo. The number of hMG ampules needed for follicular development and the number of follicles and oocytes recovered were similar in both groups. CONCLUSIONS: These results indicate that GH administration modifies ovarian steroidogenic response to gonadotropins in IVF patients, suggesting a role for GH in the regulation of human ovarian function.     

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.     

Induction of ovulation with pulsatile subcutaneous administration of human menopausal gonadotropin in anovulatory infertile women

Pulsatile administration of human menopausal gonadotropin (hMG) via the subcutaneous route was evaluated in 15 patients with various ovulatory disorders. Administration of hMG was started at a dose of 4.6875 IU (75 IU/day) or 9.375 IU (150 IU/day) per pulse every 90 minutes. Ovulation was observed in 26 (92.9%) of 28 treatment cycles, and two singleton pregnancies were confirmed. Ovarian hyperstimulation was observed in 1 to 26 ovulatory cycles; however, no other side effects were observed during treatment. A regimen of 75 IU/day resulted in a significant increase (P less than 0.0001) of the total dose and prolongation of the treatment period for induction of ovulation, as compared with that of 150 IU/day. Shortened luteal phases occurred in ovulatory cycles induced by pulsatile subcutaneous treatment. Human chorionic gonadotropin administration given every other day until the midluteal phase significantly prolonged the duration of the luteal phase (P less than 0.05). This treatment in patients with the polycystic ovary syndrome was followed by a normalization of luteinizing hormone/follicle-stimulating hormone ratio and resulted in a successful induction of ovulation in 8 to 10 cycles. The present data demonstrated that pulsatile subcutaneous administration of hMG was effective in inducing follicular maturation and ovulation in patients with various types of anovulatory infertility.     

生长激素在多囊卵巢综合征促排卵中的作用

目的　探讨生长激素(GH)在多囊卵巢综合征(PCOS)患者促排卵中的作用。方法　测定130例PCOS患者(PCOS组)及107例正常妇女(对照组)的血中生殖激素及GH和胰岛素样生长因子Ⅱ(IGF-Ⅱ)的基础水平，并应用GH辅助促排卵方案治疗7例对人绝经期促性腺激素(hMG)反应不良的PCOS患者，观察疗效。结果　PCOS患者血中GH水平明显降低，肥胖者更为明显，非肥胖与肥胖者分别为(2.50±1.33)μg/L及(1.04±0.47)μg/L,而对照组肥胖与非肥胖者分别为(2.95±1.49)μg/L、（5.30±2.26）μg/L（P均<0.05）;PCOS组肥胖者IGF-Ⅱ水平为（136±27）nmol/L，高于非肥胖者的（123±20）nmol/L，两者比较，差异有显著性（P<0.05）。应用GH辅助促排卵治疗，可以明显减少hMG用量1～12支，缩短hMG刺激时间3～12d，增加优势卵泡的数量。结论　PCOS患者存在GH分泌障碍，应用GH辅助促排卵可以提高排卵率。     

Regulation of ovarian follicular and luteal function during treatment with exogenous gonadotropins in anovulatory infertility

The dosage, duration of treatment, and plasma hormone levels were analyzed statistically between and within groups of treatment cycles with (n = 46) and without (n = 10) ovulation. A significant difference was observed in the dosage of human menopausal gonadotropins (hMG) over various days of treatment, but not in the mean dosage of hMG and human chorionic gonadotropin (hCG) administered per cycle. Follicle-stimulating hormone (FSH):luteinizing hormone (LH) ratios, prolactin (PRL) levels, and the magnitude and the duration of the estradiol response were greater in the ovulatory cycles. Additionally, in the ovulatory cycles, the dose of hMG correlated with the plasma levels of estradiol, FSH, and LH, while in the anovulatory cycles, hMG dosage correlated only with the LH concentrations. After administration of hCG, the mean plasma concentrations of its beta subunit peaked within 1 day and remained detectable for up to 10 days thereafter. In the ovulatory cycles, the mean progesterone level was maximal 6 days following hCG administration. In these cycles, luteal phase progesterone levels correlated positively with the preovulatory estradiol and inversely with concentrations of the beta subunit of hCG. The data demonstrate that, in contrast to anovulatory follicles, ovulatory follicles were exposed to a relative "dominance" of FSH over LH, with higher concentrations of estradiol and PRL for several days before hCG was administered. Apart from hMG dosage, the endogenous discharge of LH appeared to be an important determinant of the ovarian response. A single 10,000 IU dose of hCG was adequate for inducing ovulation and maintaining luteal function.     

Human menopausal gonadotropin/human chorionic gonadotropin follicular maturation for oocyte aspiration: phase I, 1981

Thirty-one human menopausal gonadotropin and human chorionic gonadotropin (hMG/hCG) ovulation induction cycles from 25 normally ovulating patients who applied to a program for the Vital Initiation of Pregnancy (VIP) are discussed. Three different categories of serum estradiol (E2) response were found. Serum E2 and progesterone responses were inversely related to the amount of hMG, indicating a patient sensitivity rather than a dosage relationship. Luteinizing hormone levels were suppressed by gonadotropins. Daily evaluation of vaginal smear, cervical mucus, serum E2 determinations, and pelvic ultrasound are necessary for an optimum ovulation induction with gonadotropins. Two successful pregnancies are reported.     

Successful induction of ovulation and conception with pulsatile intravenous administration of human menopausal gonadotropins in anovulatory infertile women resistant to clomiphene and pulsatile gonadotropin-releasing hormone therapy

Gonadotropins are released in a pulsatile fashion at a frequency of between 1 and 2 hours in the follicular phase of the menstrual cycle. Human menopausal gonadotropins are usually administered intramuscularly. We evaluated the gonadal response to intravenous human menopausal gonadotropins administered in a pulsatile fashion over nine treatment cycles in three anovulatory infertile women. Human menopausal gonadotropin pulses in doses up to 12 IU follicle-stimulating hormone at frequencies between 2 to 3 hours over 3 to 17 days resulted in ovulation in five cycles with one pregnancy being conceived. In the ovulatory cycles (5,000 to 10,000 IU of human chorionic gonadotropin was used to induce ovulation), the 17 beta-plasma estradiol level was 961 +/- 128 versus 326 +/- 95 pg/ml (mean +/- SEM) in the anovulatory cycles (p = 0.015). The dose of human menopausal gonadotropins (in ampules of Pergonal, 75 IU of follicle-stimulating hormone and 75 IU of luteinizing hormone) in the intravenous cycles needed to induce ovulation was 12.3 +/- 1.4 versus 20.4 +/- 0.9 for intramuscular cycles (n = 80 in 23 women, p = 0.008). Treatment was well tolerated and without complications. We are continuing to explore the use of this apparently more efficient mode of administering human menopausal gonadotropins to anovulatory patients resistant to other techniques of ovulation induction therapy.     

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.     

Ovulation induction in a poor responder with panhypopituitarism: a case report and review of the literature.

BACKGROUND: Most women with panhypopituitarism will undergo successful ovulation induction with gonadotropin therapy. Few proven treatment options exist for those who respond poorly to such therapy. A poor response may indicate diminished ovarian reserve, or reflect a deficiency of other key components for ovarian function. CASE: A 31-year-old female with panhypopituitarism and a poor response to gonadotropin therapy took growth hormone (GH) replacement for 4 months prior to restarting gonadotropins. When the serum level of insulin-like growth factor-I normalized, she began ovulation induction with gonadotropins with transdermal estradiol. After 63 days of gonadotropin therapy, she had a leading follicle of 18 mm, followed by follicles of 16.5 mm and 15.5 mm. The serum estradiol was 796 pg/ml, and human chorionic gonadotropin was administered. The patient conceived with timed intercourse. A prior attempt at ovulation induction with gonadotropins alone failed to produce follicular development. CONCLUSION: Prolonged gonadotropin treatment may be necessary to achieve ovulation and avoid the misdiagnosis of ovarian failure. Co-treatment with GH and estrogen may improve the follicular response in a poor responder with panhypopituitarism.     

胰岛素样生长因子-Ⅰ辅助促排卵的实验研究

目的探讨胰岛素样生长因子Ⅰ（ＩＧＦⅠ）辅助促排卵的作用。方法建立小白鼠排卵障碍动物模型,将排卵障碍性小白鼠分为３组,分别于每只小白鼠腹腔内一次性注射ＩＧＦⅠ１μｇ加人绝经期促性腺激素（ｈＭＧ）５ＩＵ（ＩＧＦⅠ加ｈＭＧ组）、ＩＧＦⅠ２μｇ（ＩＧＦⅠ组）和ｈＭＧ１０ＩＵ（ｈＭＧ组）,观察阴道脱落细胞涂片的周期性变化和输卵管内卵母细胞数。结果ＩＧＦⅠ加ｈＭＧ组、ＩＧＦⅠ组和ｈＭＧ组阴道脱落细胞涂片呈周期性变化者分别为８０％、２０％和６０％,ＩＧＦⅠ加ｈＭＧ组高于ＩＧＦⅠ组和ｈＭＧ组（Ｐ＜０．０１和Ｐ＜０．０５）,ＩＧＦⅠ组与ｈＭＧ组比较,差异无显著性（Ｐ＞０．０５）。输卵管内卵母细胞数,ＩＧＦⅠ加ｈＭＧ组平均为１２．３个,ｈＭＧ组平均为９．２个,两组比较,差异有显著性（Ｐ＜０．０５）。ＩＧＦⅠ组阴道脱落细胞呈周期性变化的小白鼠,输卵管内未见卵母细胞。结论ＩＧＦⅠ可作为辅助促排卵剂。     

Ovulation induction with a combination of LHRH analogue and hMG pulsatile subcutaneous administration in PCO patients

The pulsatile subcutaneous administration of hMG (hMG therapy) and treatment with a combination of luteinizing hormone releasing hormone analogue (Buserelin) and hMG (combined therapy) were used to induce ovulation in 9 patients with polycystic ovary syndrome (PCO). Ovulation was observed in all twelve treatment cycles in the combined therapy, and two cases (delivery at term, and abortion) of pregnancy were confirmed. In the hMG therapy, ovulation occurred in 22 cycles of 26 treatment cycles. Ovarian hyperstimulation occurred in one cycle in the combined therapy and in 5 cycles (3 ovulated patients) in the 26 hMG therapy. The total dose per cycle of hMG required to induce ovulation in the combined therapy (1,700 +/- 203IU) was significantly lower than in the hMG therapy (2,344 +/- 223IU). In response to Buserelin administration, LH and FSH increased transiently and then declined to the normal range observed in the early follicular phase. The reduced LH level was sustained throughout the hMG administration. The concentration of FSH increased in response to hMG administration, resulting in a change in the LH/FSH ratio. The LH/FSH ratio in the combined therapy was significantly lower than in the hMG therapy. The present data demonstrated that pulsatile subcutaneous administration of hMG associated with Buserelin was effective in inducing ovulation in patients with PCO with a low incidence of serious side effects.     

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.     

The effect of the dose of human chorionic gonadotropin and the type of gonadotropin stimulation on oocyte recovery rates in an in vitro fertilization program

The effect of the dose of human chorionic gonadotropin (hCG) on oocyte retrieval in an in vitro fertilization (IVF) program was studied. Following ovulation induction using clomiphene citrate and either pure follicle-stimulating hormone (FSH) or human menopausal gonadotropin (hMG), hCG was administered at a dose of 2000 IU (n = 88), 5000 IU (n = 110), and 10,000 IU (n = 104). There was a significantly lower successful oocyte recovery in patients who received 2000 IU of hCG (77.3%) compared with patients who received either 5000 IU of hCG (95.5%) or 10,000 IU of hCG (98.1%; P less than 0.001). There was no significant difference between 5000 or 10,000 IU of hCG. In patients who received 2000 IU of hCG, successful oocyte recovery was significantly lower when pure FSH was used (60%) compared with those who received hMG (84.1%; P less than 0.03). Patients have different thresholds for follicular response to hCG and the recommended minimum dose of hCG should be at least 5000 IU.     

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.     

Induction of ovulation with luprolide acetate and human menopausal gonadotropin

Four women with unexplained infertility and two anovulatory oligomenorrheic women who experienced repeated premature luteinization when treated with human menopausal gonadotropin (hMG) or gonadotropin-releasing hormone (GnRH) were given the gonadotropin-releasing hormone agonist (GnRHa), luprolide acetate, in order to effect medical hypophysectomy. This was followed by hMG for induction of ovulation. Four of the six patients had hMG-only cycles, which were compared with the luprolide acetate/hMG cycles. The luprolide acetate/hMG cycles resulted in normal folliculogenesis with presumptive ovulation. In luprolide/hMG cycles, significantly more hMG was needed for induction of ovulation than in hMG-only cycles. Premature luteinization was abolished with luprolide acetate treatment.     

促排卵治疗对多囊卵巢综合征患者子宫内膜整合素αv,β3表？…

目的 了解促排卵药物对多囊卵巢综合征（ＰＣＯＳ）患者黄体中期子宫内膜整合素αｖ、β３表达的影响。方法 应用单克隆抗体,采用免疫组织化学技术对２２例正常妇女、４０例无排卵ＰＣＯＳ患者促排卵治疗后黄体中期的子宫内膜整合素αｖ、β３进行测定。结果正常妇女子宫内膜整合素αｖ、β３表达在“着床窗口期”呈现强阳性;而氯米芬（ＣＣ）及绝经期促性腺激素（ｈＭＧ）抑制αｖ、βｂ的表达,使其表达呈弱阳性;而促性腺素释     

A randomized prospective study on the effect of short and long Buserelin treatment in women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response

Fifty four women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response to stimulation with human menopausal gonadotropins (hMG) participated in this study. They were randomized to receive either gonadotropin releasing hormone agonist (GNRHa), Buserelin, prior to and during induction of ovulation by hMG (Group I—long protocol), or GnRHa starting on the first day of the cycle together with induction of ovulation by hMG (Group II—short protocol). Mean follicular phase serum luteinizing hormone (LH) and progesterone (P) levels were significantly lower in Group I than in Group II (P<0.01). Cancellation rate was significantly lower in Group I than in Group II (P<0.01). The long GNRHa protocol resulted in statistically significant lower cancellation rates, more oocytes per pickup (OPU), more embryos trans-ferred per patient, and a higher pregnancy rate. Significantly more hMG ampoules and more treatments days were required in the long GNRHa protocol. Our data demonstrate that the use of GNRHa prior to and during ovarian stimulation with hMG offers a very good alternative for patients with repetitive unsuccessful IVF cycles due to inadequate response.