Adjuvant growth hormone therapy in poor responders to in-vitro fertilization: a prospective randomized placebo-controlled double-blind study. Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response: a prospective, randomized, clinical trial. [The effect of co-administration of low dosage growth hormone and gonadotropin for ovarian hyperstimulation in vitro fertilization and embryo transfer]. Effect of growth hormone on follicular fluid androgen levels in patients treated with gonadotropins before in vitro fertilization. Lack of effects of recombinant growth hormone on muscle function in patients requiring prolonged mechanical ventilation: a prospective, randomized, controlled study. Growth parameters and predictors of growth in short children with and without growth hormone (GH) deficiency treated with human GH: a randomized controlled study. Increased mortality associated with growth hormone treatment in critically ill adults. Exogenous luteinizing hormone in controlled ovarian hyperstimulation for assisted reproduction techniques. The effect of growth hormone supplementation on in vitro fertilization outcome: a prospective randomized placebo-controlled double-blind study.
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. 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. 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. 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. To evaluate the benefit of recombinant human growth hormone administration on muscle strength and duration of weaning in critically ill patients undergoing prolonged mechanical ventilation.
                Prospective, randomized, controlled, single-blind study.
                Intensive care unit. Patients: Twenty patients requiring > or = 7 days of mechanical ventilation for acute respiratory failure.
                Random assignment to receive either 0.43 IU (approximately 0.14 mg) recombinant growth hormone/kg body weight/day (treated group), or saline (nontreated group) for 12 days.
                Nutritional support was guided by indirect calorimetry. Cumulative nitrogen balance was positive throughout the study period in the treated group 17.3 (44.9 +/- 17.3[SEM] g/12 days) vs. the nontreated group (-65.8 +/- 11.8 g/12 days) (p<.0001). Despite similar initial plasma concentrations, recombinant growth hormone supplementation resulted in marked increases in growth hormone, insulin like growth factor-1, and insulin concentrations (p<.05, .02, and .0001, respectively, vs. nontreated group). Body impedance determined net fat-free mass increased in the treated group (0.8 +/- 0.6 kg) vs. the nontreated group (-1.1 +/- O.5 kg) (p<.03). Initial peripheral muscle function, assessed by computer-controlled electrical stimulation of the adductor pollicis, was similarly lower in treated and nontreated groups than sex and age-matched normal controls, and decreased further during the study period. Arterial blood gases, cumulative total mechanical ventilation time, and number of hrs/day of mechanical ventilation during weaning were similar in both patient groups. Only three of the ten patients in each group were weaned from mechanical ventilation by day 12.
                Daily administration of recombinant growth hormone in mechanically ventilated patients with acute respiratory failure promotes a marked nitrogen retention. However, this reaction is accompanied neither by an improvement in muscle strength nor by a shorter duration of ventilatory supports. Seventy-seven prepubertal short children with heights below the third centile for age and gender were divided into three groups according to their peak GH response to clonidine and insulin provocation. Group (I) included 30 children with peak GH response < 7 micrograms/l, group (II) included 19 children, with GH peak response between 7 and 10 micrograms/l, and group (III) included 24 children with GH peak > 10 micrograms/l. Each group was divided into two subgroups, a and b. Subgroups (I)b, (II)a and (III)b were treated daily for 1 year with subcutaneous recombinant human growth hormone (GH) 15 U/m2/week, and group (I)a was treated with GH (30 U/m2/week). Before initiation of treatment, the chronological age, the height standard deviation score (HtSDS), and the bone age delay did not differ among the study subgroups. The height growth velocity (GV) and insulin-like growth factor-I concentrations were significantly higher in group (III), with normal GH response to provocation, compared to those for group (I) with GH deficiency. All the children had normal thyroid function and normal glucose tolerance. CT examination of the hypothalamic-pituitary area revealed a picture of empty sella (either partial or complete) in 35 per cent of the children in group (I) and 21 per cent of children in group (II). After 1 year of GH therapy, the HtSDS, GV, and IGF-I concentrations increased significantly in the four subgroups treated with GH compared to their pretreatment values and to their controls. All the children in group (I) were responders (increment in GV of 2 cm2/year above the pretreatment GV), of the nine subjects treated in group (II)a, one child was a non-responder and of the 12 children in group (III)a three children were non-responders. GV was non-significantly higher in group (I)a (30 U/m2/week) v. group (I)b (15 U/m2/week). GV of children in groups (I)b, with abnormal GH response to provocation, was significantly higher than GV of children in group (III)a. Bone age advanced by less than 1 year in the treated groups (0.84 +/- 0.14 years) v. the untreated groups (0.73 +/- 0.3 years). None of the children had impaired glucose tolerance or abnormal thyroid function after 1 year of GH therapy. In all the treated children, GV after 1 year of GH treatment was correlated significantly with the pretreatment GV (r = -0.63, P < 0.01), peak GH response to provocation (r = -0.59, P < 0.01), IGF-I concentration (r = -0.54, P < 0.01), and positively with the GH dose (r = 0.589, P < 0.01). In group (III) children, with normal GH reserve, GV correlated significantly with the pretreatment GV (r = -0.48, P < 0.01) and negatively with the GH peak response to provocation (r = -0.25, P < 0.05). In conclusion, GH therapy improved GV of children growing along or parallel to the 3rd centile, irrespective of their GH response to provocation, without untoward effect on skeletal maturation, thyroid function or glucose tolerance. The administration of growth hormone can attenuate the catabolic response to injury, surgery, and sepsis. However, the effect of high doses of growth hormone on the length of stay in intensive care and in the hospital, the duration of mechanical ventilation, and the outcome in critically ill adults who are hospitalized for long periods is not known.
                We carried out two prospective, multicenter, double-blind, randomized, placebo-controlled trials in parallel involving 247 Finnish patients and 285 patients in other European countries who had been in an intensive care unit for 5 to 7 days and who were expected to require intensive care for at least 10 days. The patients had had cardiac surgery, abdominal surgery, multiple trauma, or acute respiratory failure. The patients received either growth hormone (mean [+/-SD] daily dose, 0.10 +/- 0.02 mg per kilogram of body weight) or placebo until discharge from intensive care or for a maximum of 21 days.
                The in-hospital mortality rate was higher in the patients who received growth hormone than in those who did not (P<0.001 for both studies). In the Finnish study, the mortality rate was 39 percent in the growth hormone group, as compared with 20 percent in the placebo group. The respective rates in the multinational study were 44 percent and 18 percent. The relative risk of death for patients receiving growth hormone was 1.9 (95 percent confidence interval, 1.3 to 2.9) in the Finnish study and 2.4 (95 percent confidence interval, 1.6 to 3.5) in the multinational study. Among the survivors, the length of stay in intensive care and in the hospital and the duration of mechanical ventilation were prolonged in the growth hormone group.
                In patients with prolonged critical illness, high doses of growth hormone are associated with increased morbidity and mortality. To investigate the role of exogenous LH in controlled ovarian hyperstimulation for assisted reproductive technologies.
                Prospective randomized study.
                SISMER fertility unit.
                Women showing a hyporesponsiveness to FSH under GnRH agonist down-regulation were randomized into three groups: group A (n = 54) received an increased dosage of FSH; group B (n = 54) was administered recombinant LH in addition to the increased dose of FSH; group C (n = 22) was given additional FSH and LH using hMG as a combined drug. Fifty-four age-matched women with no need to increase the FSH dose were included as a control group (D).
                None.
                Implantation and live birth rate per started cycles.
                In group B, the pregnancy and implantation rates were statistically higher when compared with groups A and C and did not differ from the control group for normal response. The live birth rate was similar in groups B and D but was half as high in groups A and C.
                Hyporesponsiveness to FSH could be related to iatrogenic LH deficiency that, in turn, could affect oocyte competence. Addition of a small amount of recombinant LH is able to rescue oocyte competence to produce viable embryos. 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.
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.