Effect of growth hormone on follicular fluid androgen levels in patients treated with gonadotropins before in vitro fertilization. Adjuvant growth hormone therapy in poor responders to in-vitro fertilization: a prospective randomized placebo-controlled double-blind study. Improvement of delivery and live birth rates after ICSI in women aged >40 years by ovarian co-stimulation with growth hormone. Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response: a prospective, randomized, clinical trial. Effect of growth hormone administration on human ovarian function and steroidogenic gene expression in granulosa-luteal cells. The effect of growth hormone supplementation on in vitro fertilization outcome: a prospective randomized placebo-controlled double-blind study. [The effect of co-administration of low dosage growth hormone and gonadotropin for ovarian hyperstimulation in vitro fertilization and embryo transfer]. Growth hormone and ovulation: is there an indication for treatment of infertile women with growth hormone?
Forty normally ovulating women aged 25-38 years from one private and two university in vitro fertilization (IVF) centres were used in this randomized, double-blind, parallel, placebo-controlled study to explore the effect of recombinant human growth hormone (GH) on follicular fluid (FF) levels of steroid hormones, particularly androgens. All the women had tubal factor infertility and were classified as poor responders with at least two previously performed and failed IVF treatments in which less than five oocytes had been retrieved following ovarian hyperstimulation. Growth hormone (GH 0.1 IU/kg body wt per day) or placebo was given as pretreatment during down-regulation with gonadotropin-releasing hormone agonist and during stimulation with human menopausal gonadotropin (hMG) according to the randomized protocol. Follicular fluid concentrations of steroids were measured and changes related to the levels of insulin-like growth factor I (IGF-I) and IGF binding proteins 1 and 3 and to the mode of GH administration. Pretreatment with GH, i.e. administration of GH before hMG stimulation only, caused significantly elevated follicular fluid concentrations of estrone, testosterone and dehydroepiandrosterone (DHEA) and higher values for markers of aromatase activity (ratios between estrone and androstenedione and between estradiol-17 beta and androstenedione) than in the placebo group, as well as in the two groups receiving GH during hMG stimulation. The highest values for markers of steroid sulfatase activity (ratios between DHA and DHEA sulfate and between unconjugated and conjugated estrone) were found in the patients pretreated with GH. Positive correlations were found between follicular fluid IGF-I and IGF binding protein 3 on the one hand and androgens on the other. This study showed that the administration of adjuvant GH to women who were poor responders to gonadotropins alters the endocrine/paracrine ovarian response to gonadotropins. The objective of the study was to assess the effect of growth hormone (GH) supplementation to a combined gonadotrophin-releasing hormone agonist/human menopausal gonadotrophin (GnRHa/HMG) treatment protocol on ovarian response in 'poor responders' undergoing in-vitro fertilization (IVF). GH or a placebo were administered in a prospective randomized double-blind manner. A total of 14 poor-responder patients (oestradiol < 500 pg/ml, less than three oocytes retrieved in two previous IVF cycles) were randomly allocated to a combined treatment of either GnRHa/HMG/GH (18 IU on alternate days, total dose 72 IU) or GnRHa/HMG placebo. No difference was found between the study and control groups in the number of HMG ampoules used, the number of follicles (> 14 mm) and serum oestradiol concentrations on the day of administration of human chorionic gonadotrophin (HCG), the number of oocytes retrieved and fertilized, and the number of embryos transferred. The GH group (n = 7) did not show a better ovulatory response in the study cycles; mean +/- SD serum oestradiol on day of HCG 411 +/- 124 versus 493 +/- 291 pg/ml, aspirated oocytes 2.2 +/- 1.5 versus 1.9 +/- 2.0. Interestingly, when the above results for the placebo group were compared with their previous cycles (serum oestradiol 403 +/- 231 pg/ml; 0.4 +/- 0.5 aspirated oocytes), a non-specific effect was found. Follicular recruitment, oestradiol secretion by mature follicles and the number of oocytes retrieved in poor responders were not improved by GH supplementation. Growth hormone (GH) is required for ovarian follicular development, and its administration during ovarian stimulation improves pregnancy rate in cow and sheep. Data on the use of exogenous GH in human assisted reproduction treatment are inconsistent. This prospective randomized study evaluates the usefulness of GH administration in women of >40 years undergoing ovarian stimulation for assisted reproduction treatment.
                One hundred women of >40 years undergoing assisted reproduction treatment were randomized between a GH treatment group and a placebo group. Assisted reproduction treatment outcomes were evaluated.
                In patients of the GH treatment group, a similar number of oocytes, embryos and pregnancies was achieved as compared with the placebo group. However, the patients treated with GH suffered fewer pregnancy losses, resulting in higher delivery and live birth rates. These patients also showed higher peak serum estradiol concentration and higher concentrations of GH and estradiol in pre-ovulatory follicular fluid as compared with the placebo group.
                Administration of GH during ovarian stimulation alleviates age-related decrease in assisted reproduction treatment efficiency. This effect appears to be mainly due to an improvement of oocyte developmental potential, but GH action on the uterus cannot be excluded. The efficacy of growth hormone co-stimulation to long luteal GnRHa regimen in poor responders to COH for IVF was assessed.
                This prospective, randomized, clinical trial was performed in a private assisted reproduction center. The study involved 61 patients who responded poorly to high dose gonadotropin treatment in their first cycles in the same center. Study group of 31 patients were given growth hormone co-treatment, daily subcutaneous injection of 4 mg from day 21 of preceding cycle along with GnRHa, until the day of hCG. Control group of 30 patients received the same treatment protocol except the growth hormone cotreatment. Primary end-point of the study was the number of oocytes fertilized whereas the pregnancy rate was the secondary end-point.
                Patients' demographic characteristics did not differ significantly between the two groups. 2PNs in growth hormone co-treatment group was significantly higher than the control group (4.4 +/- 1.8 vs 1.5 +/- 0.9, p < 0.001). Although more pregnancies and more clinical pregnancies with fetal heart beat were achieved in growth hormone group (12/31), compared to the control group (6/30), the difference did not reach to statistical significance.
                Poor responder women undergoing repeated assisted reproduction treatment and co-stimulated with GH achieve more oocytes, higher fertilization rate if growth hormone started in the luteal phase of previous cycle, as compared with women of the same status treated with GnRHa long protocol. The study was unable to show that clinical pregnancy rate was increased significantly. 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).
                Prospective randomized placebo-controlled study.
                University-based IVF program.
                Fifty-four normally cycling women (27 control and 27 GH-treated) participated in this study.
                Human recombinant GH (24 IU)/placebo was given intramuscularly on alternate days starting on cycle day 4 until the day of last hMG injection.
                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.
                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. 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).
                Growth hormone or placebo were administered in a prospective randomized double-blind manner.
                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.
                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.
                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.
                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. The co-administration of low dosage growth hormone (GH) and gonadotropin (Gn) to women with suboptimal response to GnRH-a/hMG/hCG hyperstimulation regimen during previous cycles in in vitro fertilization-embryo transfer (IVF-ET) might be beneficial by promoting the maturation of oocytes, improving the fertilization rate and increasing the number of embryos replaced. Our results showed the pregnancy rate increased significantly. However, this protocol neither enhanced ovarian response to Gn, nor reduced Gn dosage required for follicular recruitment. The levels of insulin-like growth factor I (IGF-I) in the co-treatment group increased from 150 +/- 44 micrograms/L to 222 +/- 46 micrograms/L (P < 0.01) during the administration of GH. These increased significantly as compared with the control group. The present study showed that the administration of GH in low doses is effective. We have explored the use of growth hormone (GH) for ovulation induction and ovarian stimulation for in vitro fertilization and embryo transfer (IVF-ET). We first compared the effects of co-treatment with GH and placebo on the dose of gonadotrophins required to induce ovulation. The patients were gonadotrophin deficient and, for the main part, hypopituitary. We found a significant reduction in the dose of gonadotrophins and the duration of treatment needed to induce ovulation. The dose of GH used in these studies was substantial, and we await the results of a multi-centre trial attempting to establish a dose-response relationship. We then explored the role of GH in patients undergoing IVF-ET. The end-point measured was an increase in the number of follicles developing during standard treatment with gonadotrophins. In the first randomized controlled clinical trial we found a suggestion only of an enhanced ovarian response to co-treatment with GH. Specifically selected patients with ultrasound-diagnosed polycystic ovaries were then treated. All were receiving treatment with luteinizing hormone-releasing hormone analogue as part of their ovarian stimulation protocol. The results showed clearly that in this group of patients, co-treatment with GH augmented the ovarian response to treatment with gonadotrophins. We also found an increase in serum and follicular-fluid insulin-like growth factor I (IGF-I) concentrations, but since the serum concentrations always exceeded those in follicular fluid, the results were consistent with the notion that follicular-fluid growth factor was predominantly derived from serum IGF-I rather than being synthesized locally.
Although the use of growth hormone in poor responders has been found to show a significant improvement in live birth rates, we were unable to identify which sub-group of poor responders would benefit the most from adjuvant growth hormone. The result needs to be interpreted with caution, the included trials were few in number and small sample size. Therefore, before recommending growth hormone adjuvant in in-vitro fertilisation further research is necessary to fully define its role.