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Effect of cotreatment with growth hormone on ovarian stimulation in poor responders to in vitro fertilization

2003; Elsevier BV; Volume: 79; Issue: 5 Linguagem: Inglês

10.1016/s0015-0282(02)04959-2

1556-5653

Susumu Sugaya, Mina Suzuki, Kazuyuki Fujita, Takumi Kurabayashi, Kenichi Tanaka,

Growth Hormone and Insulin-like Growth Factors

In ovarian follicles, growth hormone (GH) is thought to act directly on thecal granulosa cells or through the insulin-like growth factor-I (IGF-I) and IGF binding protein system (1Christman G.M. Halme J.K. Growth hormone reviewed.Fertil Steril. 1992; 57: 12-14Abstract Full Text PDF PubMed Scopus (11) Google Scholar). Several studies have examined the effect of GH cotreatment for ovulation induction. Poor responders to IVF with conventional GnRH agonist/hMG therapy have been reported to have a mixed response to adjunctive GH therapy. While some authors have reported beneficial clinical effects of this therapy (2Ibrahim Z.H. Matson P.L. Buck P. Lieberman B.A. The use of biosynthetic human growth hormone to augment ovulation induction with buserelin acetate/human menopausal gonadotropin in women with a poor ovarian response.Fertil Steril. 1991; 55: 202-204Abstract Full Text PDF PubMed Google Scholar, 3Owen E.J. Shoham Z. Mason B.A. Ostergaard H. Jacobs H.S. Cotreatment with growth hormone, after pituitary suppression, for ovarian stimulation in in vitro fertilization a randomized, double-blind, placebo-control trial.Fertil Steril. 1991; 56: 1104-1110Abstract Full Text PDF PubMed Google Scholar), others have found no effect (4Hughes S.M. Huang Z.H. Morris I.D. Matson P.L. Buck P. Lieberman B.A. A double-blind cross-over controlled study to evaluate the effect of human biosynthetic growth hormone on ovarian stimulation in previous poor responders to in-vitro fertilization.Hum Reprod. 1994; 9: 13-18PubMed Google Scholar, 5Suikkari A. MacLachlan V. Koistinen R. Seppala M. Healy D. Double-blind placebo controlled study human biosynthetic growth hormone for assisted reproductive technology.Fertil Steril. 1996; 65: 800-805PubMed Google Scholar). Recently, Schoolcraft et al. (6Schoolcraft W. Schlenker T. Gee M. Stevens J. Wagley L. Improved controlled ovarian hyperstimulation in poor responder in vitro fertilization patients with a microdose follicle-stimulating hormone flare, growth hormone protocol.Fertil Steril. 1997; 67: 93-97Abstract Full Text PDF PubMed Scopus (172) Google Scholar) described a novel approach to poor responders by using a microdose GnRH agonist flare, FSH, and GH protocol. They found that this protocol was superior to a standard luteal GnRH agonist, FSH, and GH protocol. We investigated whether a controlled ovarian hyperstimulation (COH) protocol together with GH cotreatment would improve ovarian response in poor responders undergoing IVF-ET. In our protocol, GnRH agonist administration ended with the onset of menses, and GH/high-dose gonadotropins were then administered. We also investigated the role of IGF and IGF binding protein in follicular development. Nine poor responders who underwent IVF-ET at Niigata University Hospital between January and December 2000 were recruited for this study. The study was approved by our hospital’s institutional review board. Poor responders were defined as patients in which fewer than three follicles 14 mm or larger in diameter developed with previous COH, which combined GnRH agonist down-regulation, stopping of GnRH agonist therapy with the onset of menses, and initiation of high-dose gonadotropins (hMG, 450 IU) on cycle day 3. The mean (±SD) age was 38.1 ± 2.0 years (range, 35–40 years), and the mean number of prior IVF attempts was 5.4 ± 2.0 (range, 2–9). The indication for IVF-ET was tubal factor in one patient, endometriosis in four patients, and male factor in four patients. The mean basal FSH level was 8.5 ± 2.8 mIU/mL (range, 6.8–10.2 mIU/mL). Informed consent was obtained from all patients. The patients received 900 μg of buserelin acetate (Suprecur; Aventis Farma Inc., Tokyo, Japan) daily, starting at the midluteal phase and ending with the onset of menses. Cotreatment with GH was started on day 3 of the treatment cycle. The patients received 450 IU of hMG (HMG Nikken; Nikken Chemicals Co., Ltd., Tokyo, Japan) and 4 IU of GH (Norditropin; Novo Nordisk Pharma Ltd., Tokyo, Japan) daily until the day before the administration of 10,000 IU of hCG (HCG Mochida; Mochida Pharmaceutical Co., Ltd., Tokyo, Japan). Human chorionic gonadotropin was administered when at least two follicles reached a diameter of 18 mm or larger. Transvaginal follicular aspiration was performed approximately 34 hours after hCG injection. Conventional insemination was performed in all patients. Embryo transfer was performed on day 2 of culture. The quality of all embryos was evaluated as one of five grades according to Veeck’s classification (7Veeck L.L. Atlas of the human oocyte and early conceptus. Williams & Wilkins, Baltimore1986Google Scholar). We considered embryos classified as grades 1 or 2 to be good-quality embryos. Assisted hatching with use of a piezo-micromanipulator was performed before embryo transfer in two patients (8Nakayama T. Fujiwara H. Tatsumi K. Fujita K. Higuchi T. Mori T. A new assisted hatching technique using a piezo-micromanipulator.Fertil Steril. 1998; 69: 784-788Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). Serum samples were obtained on day 3 of the pretreatment cycle, on day 3 of the GH treatment cycle, and on the day of hCG administration. The serum E2 concentration was measured by radioimmunoassay (DPC, Los Angeles, CA). The serum FSH, IGF-I, and IGF binding protein-3 concentrations were measured by immunoradiometric assays (TFB, Inc., Tokyo, Japan). Statistical analyses were performed by using the Wilcoxon signed-rank test or the Mann–Whitney U test, as appropriate. Results are expressed as means (±SD). P<.05 was considered significant. In one patient, the treatment cycle was abandoned before oocyte retrieval because of no follicular growth. The remaining eight patients had follicular growth. When we compared the previous IVF cycle and GH cotreatment cycle, there were no significant differences in the duration of hMG administration (9.5 ± 3.3 days vs. 10.0 ± 0.8 days), the total dose of hMG (4,031.3 ± 1,368.8 IU vs. 4,350.0 ± 551.1 IU), serum E2 concentration on the day of hCG administration (325.0 ± 74.0 pg/mL vs. 704.5 ± 423.8 pg/mL), and number of follicles 14 mm or larger in diameter (1.6 ± 1.3 vs. 5.4 ± 3.1). A significantly higher number of oocytes were retrieved and significantly more fertilized oocytes were obtained in the GH cotreatment cycle than the previous cycle (4.4 ± 2.8 and 3.3 ± 1.8 vs. 1.3 ± 1.0 and 1.0 ± 0.9, respectively; P<.05). The fertilization rate did not differ significantly between the previous cycle and the GH cotreatment cycle (77.8 ± 40.4% vs. 78.8 ± 23.9%). The number of embryos transferred and the number of good quality embryos were also significantly increased in the GH cotreatment cycle compared with the previous IVF cycle (2.4 ± 0.7 and 2.0 ± 0.8 vs. 1.0 ± 0.9 and 0.9 ± 0.8, respectively; P<.05). The serum IGF-I concentration was significantly higher on the day of hCG administration than on day 3 of the COH cycle during GH cotreatment (363.1 ± 135.4 ng/mL vs. 217.4 ± 80.4 ng/mL; P<.05). The serum IGF binding protein-3 level remained unchanged between day 3 and the day of hCG injection in GH cotreatment cycle (3.32 ± 0.63 μg/mL vs. 3.62 ± 0.67 μg/mL). No patient became pregnant after the GH cotreatment, and no adverse effects to GH were observed. We performed GH cotreatment on patients in whom fewer than three follicles 14 mm or larger in diameter developed in the previous COH cycle. The mean serum E2 concentration on the day of hCG administration was 325.0 pg/mL (range, 211–399 pg/mL) in the previous COH cycle. Table 1 shows that more than four follicles 14 mm or larger in diameter developed in five patients (patients 1–5). The serum E2 concentrations of these patients ranged from 631 to 1,240 pg/mL. However, three patients did not have improvement in ovarian response (patients 6–8), and one patient had the cycle cancelled because of no follicular growth (patient 9). We thus classified five patients (patients 1–5) as having improved ovarian response and four patients (patients 6–9) as having poor ovarian response.TABLE 1Ovarian response and serum concentrations of IGF-1 and IGF binding protein-3 with growth hormone cotreatment.PatientDuration of hMG administration (d)E2 level on the day of hCG administration (pg/mL)No. of follicles ≥14 mm in diameterNo. of oocytes retrievedIGF-I level (ng/mL)IGF binding protein-3 level (μg/mL)Day 3 of COHDay of hCGDay 3 of COHDay of hCG19631981152722.382.97210957991602292.892.643101,240851152893.003.19410912542885013.664.005111,160632602673.003.15610205221703933.314.21711354223054473.703.8589177223216203.313.919aThe treatment cycle was abandoned on day 10 of COH owing to no follicular growth. Serum samples were collected on day 3 and day 10 of COH. Sugaya. Cotreatment with GH in IVF poor responders. Fertil Steril 2003.————2232504.604.70Note: COH = controlled ovarian hyperstimulation; IGF = insulin-like growth factor.a The treatment cycle was abandoned on day 10 of COH owing to no follicular growth. Serum samples were collected on day 3 and day 10 of COH.Sugaya. Cotreatment with GH in IVF poor responders. Fertil Steril 2003. Open table in a new tab Note: COH = controlled ovarian hyperstimulation; IGF = insulin-like growth factor. We compared serum levels of IGF-I and IGF binding protein-3 between the improved and poor responders. The mean age, mean basal FSH level, and mean number of prior IVF attempts did not statistically differ between the two groups (data not shown). No significant difference was observed in serum concentration of IGF-I on day 3 of the COH cycle between the improved response group and the poor response group (187.6 ± 81.6 ng/mL vs. 254.8 ± 71.0 ng/mL). On the day of hCG administration, no significant difference was noted between the two groups in IGF-I level (311.6 ± 108.1 ng/mL vs. 427.5 ± 152.9 ng/mL). In contrast, the serum concentration of IGF binding protein-3 on day 3 of the COH cycle was significantly higher in the poor response group than the improved response group (3.73 ± 0.61 μg/mL vs. 2.99 ± 0.46 μg/mL; P<.05). The serum concentration of IGF binding protein-3 on the day of hCG administration did not differ between the groups (3.19 ± 0.50 μg/mL vs. 4.17 ± 0.39 μg/mL; P=.05). Use of GnRH agonist offers synchronized follicular development and eliminates the LH surge. However, Furger et al. (9Furger C. Bourrie N. Cedard L. Ferre F. Zorn J.R. Gonadotrophin-releasing hormone and triptorelin inhibit the follicle stimulating hormone-induced response in human primary cultured granulosa-lutein cells.Mol Hum Reprod. 1996; 2: 259-264Crossref PubMed Scopus (18) Google Scholar) found that GnRH agonist inhibited FSH-mediated function in human granulosa lutein cells in culture and suggested that such inhibition might cause the low follicular development observed in patients treated with GnRH agonist and gonadotropins. In an attempt to maximize ovarian response without loss of these advantages of GnRH agonist, a COH protocol has been developed for patients who respond poorly or not at all to ovarian stimulation (10Faber B.M. Mayer J. Cox B. Jones D. Toner J.P. Oehninger S. et al.Cessation of gonadotropin-releasing hormone agonist therapy combined with high-dose gonadotropin stimulation yields favorable pregnancy results in low responders.Fertil Steril. 1998; 69: 826-830Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). In this protocol, GnRH agonist therapy is terminated with the onset of menses and is followed by high-dose gonadotropins administration. The investigators reported a favorable outcome in low IVF responders. In our study, GnRH agonist therapy was initiated in the midluteal phase and ceased with the onset of menses. From day 3 of the COH cycle, GH and high-dose gonadotropins were administrated daily until hCG injection. The number of oocytes retrieved, number of embryos transferred, and number of good-quality embryos were significantly increased in the GH cotreatment cycle compared with the previous COH cycle. Growth hormone increases serum IGF-I concentrations by stimulating hepatic production (11Wu M.Y. Chen H.F. Ho H.N. Chen S.U. Chao K.H. Huang S.C. et al.The value of human growth hormone as an adjuvant for ovarian stimulation in a human in vitro fertilization program.J Obstet Gynaecol Res. 1996; 22: 443-450Crossref PubMed Scopus (10) Google Scholar, 12Huang Z.H. Baxter R.C. Hughes S.M. Matson P.L. Lieberman B.A. Morris I.D. Supplementary growth hormone treatment of women with poor ovarian response to exogenous gonadotrophins changes in serum and follicular fluid insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3).Hum Reprod. 1993; 8: 850-857PubMed Google Scholar). However, serum IGF-I levels have been reported to not change during COH without GH administration (11Wu M.Y. Chen H.F. Ho H.N. Chen S.U. Chao K.H. Huang S.C. et al.The value of human growth hormone as an adjuvant for ovarian stimulation in a human in vitro fertilization program.J Obstet Gynaecol Res. 1996; 22: 443-450Crossref PubMed Scopus (10) Google Scholar, 12Huang Z.H. Baxter R.C. Hughes S.M. Matson P.L. Lieberman B.A. Morris I.D. Supplementary growth hormone treatment of women with poor ovarian response to exogenous gonadotrophins changes in serum and follicular fluid insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3).Hum Reprod. 1993; 8: 850-857PubMed Google Scholar). Insulin-like growth factor-I has been shown to amplify the action of FSH on the proliferation and differentiation of granulosa cells (13Adashi E.Y. Resnick C.E. D’Ercole A.J. Svoboda M.E. Van Wyk J.J. Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function.Endocr Rev. 1985; 6: 400-420Crossref PubMed Scopus (843) Google Scholar). In our study, a significant increase in serum IGF-I concentration in GH cotreatment was found on the day of hCG administration compared with day 3 of the COH cycle. Insulin-like growth factor binding protein-3 has a very high affinity for IGF-I and inhibits the bioactivity of IGF-I (14Albiston A.L. Herington A.C. Tissue distribution and regulation of insulin-like growth factor (IGF)-binding protein-3 messenger ribonucleic acid (mRNA) in the rat comparison with IGF-I mRNA expression.Endocrinology. 1992; 130: 497-502Crossref PubMed Scopus (62) Google Scholar, 15Mason H.D. Willis D. Holly J.M. Cwyfan-Hughes S.C. Seppala M. Franks S. Inhibitory effects of insulin-like growth factor-binding proteins on steroidogenesis by human granulosa cells in culture.Mol Cell Endocrinol. 1992; 89: R1-4Crossref PubMed Scopus (62) Google Scholar). Mason et al. (15Mason H.D. Willis D. Holly J.M. Cwyfan-Hughes S.C. Seppala M. Franks S. Inhibitory effects of insulin-like growth factor-binding proteins on steroidogenesis by human granulosa cells in culture.Mol Cell Endocrinol. 1992; 89: R1-4Crossref PubMed Scopus (62) Google Scholar) showed that in the absence of IGF binding protein-3, E2 production in cultured granulosa cells increased in the presence of FSH or IGF-I. However, E2 production in cultured granulosa cells with FSH or IGF-I was significantly reduced in the presence of IGF binding protein-3. Thus, IGF binding protein-3 had an inhibitory effect on the action of IGF-I on granulosa cells. In our study, serum IGF binding protein-3 concentration on day 3 of COH was significantly higher in the poor response group than the improved response group. This result suggests that GH cotreatment does not improve ovarian responsiveness in patients with high serum IGF binding protein-3 concentrations. Several adjuvant GH therapies have been reported. However, poor IVF responders have been shown to a mixed response to GH adjuvant therapy. We found that an adjuvant GnRH agonist regimen significantly increased the number of oocytes retrieved and the number of good-quality embryos in poor IVF responders. In addition, our results suggest that cotreatment with GH has no benefit for patients with high serum IGF binding protein-3 concentrations. However, our sample was small. Studies in a larger number of patients are needed to clarify the effectiveness of this protocol for poor IVF responders.