FERTILITY AND STERILITY
Vol. 57, No.1, January 1992
Printed on acid-free paper in U.S.A.
Copyright © 1992 The American Fertility Society
Growth hormone: revisited
Gregory M. Christman, M.D. Clinical Instructor
Jouko K. Halme, M.D., Ph.D. Associate Professor Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Fertility, University of North Carolina, Chapel Hill, North Carolina
Received November 11, 1991. Reprint requests: Gregory M. Christman, M.D., Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, CB #7570, Old Clinic Building, Chapel Hill, North Carolina 27599-7570.
12
Christman and Halme
The recent availability of recombinant human growth hormone (G H) and reports of its ability to augment ovulation induction by exogenous gonadotropins (1-3) have caused a re-examination of the role GH plays in reproductive physiology. Included in this month's issue are two articles that further define the role of G H in reproduction. The article by Lanzone et al. (4) shows increasing evidence for local ovarian actions of G H by demonstrating the ability of human G H to enhance progesterone (P) production by human luteal cells in vitro. In the article by Ovesen et al. (5), a relationship between anovulatory dysfunction and a diminished G H secretory capacity was demonstrated. These articles and articles to come undoubtedly will help to clarify how G H facilitates ovulation by either a combination of direct effects on the ovary and/or the increased hepatic production of insulin -like growth factor-I (lGF-I). It has been observed for many years that delayed puberty, as associated with isolated G H deficiency in humans, is readvanced with G H therapy (6, 7), suggesting a role of G H in gonadal differentiation and the promotion of normal menstrual cycles. The interplay of G H and the hypothalamic-pituitary-ovarian axis is also evident in the ability of estradiol (E 2 ) to stimulate G H release and conversely inhibit the GH-mediated hepatic secretion of IGF-I. In the study by Ovesen et al. (5), GH secretory capacity of infertile women with anovulation or diminished luteal phase P production was compared with normal cycling controls matched for E2 levels, age, and body composition. To assess G H secretion, an arginine infusion was utilized as a stimulus for G H release on the basis of its ability to inhibit somatostatin release from the hypothalmus. Although the basal levels of G H did not differ between the two groups, stimulated G H release was blunted in the anovulatory women. IGF-I levels, however, were not different between the groups either before or after stimulation, suggesting that the defect in GH secretion must represent a relative deficiency rather than a significant deficit in G H availability or action. This well-controlled study substantiates previous observations linking GH secretion to ovulation. One of these is the work of Menashe et al. (8), in which the dose of human menopausal gonadotropins required for ovulation induction could be correlated to the amount of G H release after clonidine challenge. In the study by Lanzone et al. (4), cultures of human luteal cells obtained in the early midluteal phase (days 3 to 6 after ovulation) were incubated with or without human chorionic gonadotropin (heG) and/ or human GH at differing concentrations. The authors demonstrate in this system the ability of human G H alone to augment P pro-
Editor's corner
Fertility and Sterility
duction in a dose-dependent fashion and to interact with hCG in a synergistic manner. However, supraphysiological concentrations of GH alone (> 1,000 ng/mL) were required to stimulate P production, whereas only modest GH levels were required to augment hCG-stimulated P production. This study complements the work of Mason et al. (9), in which cultures of human granulosa cells showed increased production of E 2 in response to low levels of human GH (1 or 10 ng/mL) and demonstrated a significant additive effect of human GH and human follicle-stimulating hormone (hFSH) on granulosa cell E 2 production. These demonstrations, that human G H can have a local effect on E 2 and P production in the human ovary, are logical extensions of previous animal studies in which GH had been shown to augment FSH -stimulated differentiation and luteinizing hormone receptor formation in rat granulosa cells (10) and to increase local IGF-1 and P production in porcine granulosa cells (11). What remains to be answered are the mechanisms by which G H mediates these local actions in the human ovary. Possibilities include a direct action of G H after binding to its receptor or the intermediate local production of IGF-1 with subsequent autocrine or paracrine actions on granulosa cell function. Human granulosa cells have been shown to contain receptors for IGF-1 (12), andiGF-1 has been shown to increase both aromatase activity (13, 14) and P production (15) in human granulosa cells, making the second alternative attractive. However, critical evidence for GH-mediated regulation of IGF-1 messenger ribonucleic acid in human granulosa cells is still lacking (16). Future studies will need to address the regulation of the GH receptor in the human ovary and the effects of G H action on steroidogenic and follicular enzymes, IGF binding proteins, growth factors, and gonadotropin receptors to completely define the local actions of this hormone. When recombinant human GH was first used in clinical trials, its preliminary use seemed justified on the basis of prior animal studies and of the strong evidence of the positive interaction of IGF-1 and gonadotropins in ovulation. Indeed, an initial report demonstrated a 30% reduction in the requirement for menopausal gonadotropins in women receiving human GH undergoing superovulation (1). However, noting the high current cost of recombinant human GH, this study has little immediate clinical relevance other than to confirm a positive therapeutic effect of human GH. A subsequent study by Ibrahim et al. (3) focused on a clinical trial of human GH in 10 patients with a previous poor response to Vol. 57, No. 1, January 1992
gonadotropins in an in vitro fertilization (IVF) program. They found a reduction in the requirement for menopausal gonadotropins with human GH cotreatment and found that, despite a lack of improvement in peak serum E 2 and the number of follicles ~ 14 mm, the number of oocytes, and embryos replaced had increased and 6 of 10 of these women later became pregnant. All of these patients had FSH values < 10 IU/mL. This group may represent a small but clinically important subset of IVF patients where the usual methods of gonadotropin administration result in minimal follicular response resulting either in cancellation of IVF cycles or ·poor oocyte retrieval rates with diminished success. Such a group appears to be a much more logical and cost-effective target population for human GH therapy, and it will be interesting in the future to see if any selection criteria can be determined to beet identify appropriate candidates for this therapy. In addition to the highlighted local actions of GH on ovarian function, administration of recombinant human GH also has the anticipated effect of increasing circulating levels of IGF-1 by hepatic production. The relative physiological importance of increased hepatic production and circulating levels of IGF-1 and the local ovarian actions of human GH is unclear. Studies have shown increased concentrations of IGF-1 in the follicular fluid of women given human GH, and although in vitro evidence for local IGF-1 production in response to human GH is lacking, further in vivo studies may resolve this issue. The articles reported by Lanzone et al. (4) and Ovesen et al. (5) truly broaden our understanding of the role of GH in reproductive physiology. Their work illustrates that human GH has local effects on the human ovary and that a patient population exists where a relative deficiency in GH secretion coexists with ovulatory dysfunction and infertility. As recombinant human GH will be applied for augmentation of ovulation induction in the future, we also look forward to a re-examination and further study into the role of GH in the physiology of follicular development and ovulation. A more detailed understanding of GH action in the ovary hopefully will enhance our ability to use human GH to the patient's best advantage. REFERENCES 1. Homburg R, West C, Toressani T, Jacobs HS. Cotreatment with growth hormone and gonadotropins for induction of ovulation: a controlled clinical trial. Fertil Steril1990;53:25460.
Christman and Halme Editor's corner
13
2. Blumenfeld Z, Lunenfeld B. The potentiating effects of growth hormone on follicle stimulation with human menopausal gonadotropin in a panhypopituitary patient. Fertil Steril 1989;52:328-31. 3. Ibrahim ZHZ, Matson PL, Buck P, Lieberman BA. The use of a biosynthetic human growth hormone to augment ovulation induction with buserelin acetate/human menopausal gonadotropin in women with a poor ovarian response. Fertil Steril 1991;55:202-4. 4. Lanzone A, DiSimone N, Castellani R, Fulghesu AM, Caruso A, Mancuso S. Human growth hormone enhances progesterone production by human luteal cells in vitro: evidence of a synergistic effect with human chorionic gonadotropin. Fertil Steril 1992;57:92-6. 5. Ovesen P, Moller J, Moller N, Christiansen JS, Jorgenson JOL, Orskov H. Growth hormone secretory capacity and serum insulin-like growth factor I levels in primary infertile, anovulatory women with regular menses. Fertil Steril1992;57: 97-101. 6. Sheikholislam BM, Stempel RS. Hereditary isolated somatotropin deficiency: effects of human growth hormone administration. Pediatrics 1972;49:362-74. 7. Ramalay JA, Phares CK. Delay of puberty onset in females due to suppression of growth hormone. Endocrinology 1980;106:1989-93. 8. Menashe Y, Lunenfeld B, Pariente C, Frenkel Y, Mashiach S. Can growth hormone increase, after clonidine administration, predict the dose of human menopausal hormone
14
Christman and Halme Editor's corner
needed for induction of ovulation? Fertil Steril1990;53:4325. 9. Mason HD, Martikainen H, Beard RW, Anyaoku V, Franks S. Direct gonadotropic effect of growth hormone on oestradiol production by human granulosa cells in vitro. J Endocrinol 1990;126:R1-4. 10. Jia X, Kalmijn J, Hsueh AJW. Growth hormone enhances follicle stimulating hormone-induced differentiation of cultured rat granulosa cells. Endocrinology 1896;118:1401-9. 11. Hsu CJ, Hammond JM. Concominant effects of growth hormone on secretion of insulin-like growth factor I and progesterone by cultured porcine granulosa cells. Endocrinology 1987;121:1343-8. 12. Poretsky L, Kalin MF. The gonadotropic function of insulin. Endocr Rev 1987;8:132-41. 13. Erickson GF, Garzo VG, Magoffin DA. Insulin-like growth factor-I regulates aromatase activity in human granulosa cells and granulosa luteal cells. J Clin Endocrinol Metab 1989;69: 716-24. 14. Christman GM, Randolph JF Jr, Peegel H, Menon KM. Differential responsiveness of luteinized granulosa cells to gonadotropins and insulin-like growth factor- I for induction of aromatase activity. Fertil Steril1991;55:1099-1105. 15. Bergh C, Olsson JH, Hillensjo T. Effect of insulin-like growth factor I on steroidogenesis in cultured human granulosa cells. Acta Endocrinol (Copenh) 1991;125:177-85. 16. Ramasharma K, Li CH. Human pituitary and placental hormones control human insulin-like growth factor II secretion in human granulosa cells. Proc Natl Acad Sci USA 1987;84: 2643-7.
Fertility and Sterility
Vol. 57, No.1, January 1992
Printed on acid-free paper in U.S.A.
Copyright © 1992 The American Fertility Society
Growth hormone: revisited
Gregory M. Christman, M.D. Clinical Instructor
Jouko K. Halme, M.D., Ph.D. Associate Professor Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Fertility, University of North Carolina, Chapel Hill, North Carolina
Received November 11, 1991. Reprint requests: Gregory M. Christman, M.D., Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, CB #7570, Old Clinic Building, Chapel Hill, North Carolina 27599-7570.
12
Christman and Halme
The recent availability of recombinant human growth hormone (G H) and reports of its ability to augment ovulation induction by exogenous gonadotropins (1-3) have caused a re-examination of the role GH plays in reproductive physiology. Included in this month's issue are two articles that further define the role of G H in reproduction. The article by Lanzone et al. (4) shows increasing evidence for local ovarian actions of G H by demonstrating the ability of human G H to enhance progesterone (P) production by human luteal cells in vitro. In the article by Ovesen et al. (5), a relationship between anovulatory dysfunction and a diminished G H secretory capacity was demonstrated. These articles and articles to come undoubtedly will help to clarify how G H facilitates ovulation by either a combination of direct effects on the ovary and/or the increased hepatic production of insulin -like growth factor-I (lGF-I). It has been observed for many years that delayed puberty, as associated with isolated G H deficiency in humans, is readvanced with G H therapy (6, 7), suggesting a role of G H in gonadal differentiation and the promotion of normal menstrual cycles. The interplay of G H and the hypothalamic-pituitary-ovarian axis is also evident in the ability of estradiol (E 2 ) to stimulate G H release and conversely inhibit the GH-mediated hepatic secretion of IGF-I. In the study by Ovesen et al. (5), GH secretory capacity of infertile women with anovulation or diminished luteal phase P production was compared with normal cycling controls matched for E2 levels, age, and body composition. To assess G H secretion, an arginine infusion was utilized as a stimulus for G H release on the basis of its ability to inhibit somatostatin release from the hypothalmus. Although the basal levels of G H did not differ between the two groups, stimulated G H release was blunted in the anovulatory women. IGF-I levels, however, were not different between the groups either before or after stimulation, suggesting that the defect in GH secretion must represent a relative deficiency rather than a significant deficit in G H availability or action. This well-controlled study substantiates previous observations linking GH secretion to ovulation. One of these is the work of Menashe et al. (8), in which the dose of human menopausal gonadotropins required for ovulation induction could be correlated to the amount of G H release after clonidine challenge. In the study by Lanzone et al. (4), cultures of human luteal cells obtained in the early midluteal phase (days 3 to 6 after ovulation) were incubated with or without human chorionic gonadotropin (heG) and/ or human GH at differing concentrations. The authors demonstrate in this system the ability of human G H alone to augment P pro-
Editor's corner
Fertility and Sterility
duction in a dose-dependent fashion and to interact with hCG in a synergistic manner. However, supraphysiological concentrations of GH alone (> 1,000 ng/mL) were required to stimulate P production, whereas only modest GH levels were required to augment hCG-stimulated P production. This study complements the work of Mason et al. (9), in which cultures of human granulosa cells showed increased production of E 2 in response to low levels of human GH (1 or 10 ng/mL) and demonstrated a significant additive effect of human GH and human follicle-stimulating hormone (hFSH) on granulosa cell E 2 production. These demonstrations, that human G H can have a local effect on E 2 and P production in the human ovary, are logical extensions of previous animal studies in which GH had been shown to augment FSH -stimulated differentiation and luteinizing hormone receptor formation in rat granulosa cells (10) and to increase local IGF-1 and P production in porcine granulosa cells (11). What remains to be answered are the mechanisms by which G H mediates these local actions in the human ovary. Possibilities include a direct action of G H after binding to its receptor or the intermediate local production of IGF-1 with subsequent autocrine or paracrine actions on granulosa cell function. Human granulosa cells have been shown to contain receptors for IGF-1 (12), andiGF-1 has been shown to increase both aromatase activity (13, 14) and P production (15) in human granulosa cells, making the second alternative attractive. However, critical evidence for GH-mediated regulation of IGF-1 messenger ribonucleic acid in human granulosa cells is still lacking (16). Future studies will need to address the regulation of the GH receptor in the human ovary and the effects of G H action on steroidogenic and follicular enzymes, IGF binding proteins, growth factors, and gonadotropin receptors to completely define the local actions of this hormone. When recombinant human GH was first used in clinical trials, its preliminary use seemed justified on the basis of prior animal studies and of the strong evidence of the positive interaction of IGF-1 and gonadotropins in ovulation. Indeed, an initial report demonstrated a 30% reduction in the requirement for menopausal gonadotropins in women receiving human GH undergoing superovulation (1). However, noting the high current cost of recombinant human GH, this study has little immediate clinical relevance other than to confirm a positive therapeutic effect of human GH. A subsequent study by Ibrahim et al. (3) focused on a clinical trial of human GH in 10 patients with a previous poor response to Vol. 57, No. 1, January 1992
gonadotropins in an in vitro fertilization (IVF) program. They found a reduction in the requirement for menopausal gonadotropins with human GH cotreatment and found that, despite a lack of improvement in peak serum E 2 and the number of follicles ~ 14 mm, the number of oocytes, and embryos replaced had increased and 6 of 10 of these women later became pregnant. All of these patients had FSH values < 10 IU/mL. This group may represent a small but clinically important subset of IVF patients where the usual methods of gonadotropin administration result in minimal follicular response resulting either in cancellation of IVF cycles or ·poor oocyte retrieval rates with diminished success. Such a group appears to be a much more logical and cost-effective target population for human GH therapy, and it will be interesting in the future to see if any selection criteria can be determined to beet identify appropriate candidates for this therapy. In addition to the highlighted local actions of GH on ovarian function, administration of recombinant human GH also has the anticipated effect of increasing circulating levels of IGF-1 by hepatic production. The relative physiological importance of increased hepatic production and circulating levels of IGF-1 and the local ovarian actions of human GH is unclear. Studies have shown increased concentrations of IGF-1 in the follicular fluid of women given human GH, and although in vitro evidence for local IGF-1 production in response to human GH is lacking, further in vivo studies may resolve this issue. The articles reported by Lanzone et al. (4) and Ovesen et al. (5) truly broaden our understanding of the role of GH in reproductive physiology. Their work illustrates that human GH has local effects on the human ovary and that a patient population exists where a relative deficiency in GH secretion coexists with ovulatory dysfunction and infertility. As recombinant human GH will be applied for augmentation of ovulation induction in the future, we also look forward to a re-examination and further study into the role of GH in the physiology of follicular development and ovulation. A more detailed understanding of GH action in the ovary hopefully will enhance our ability to use human GH to the patient's best advantage. REFERENCES 1. Homburg R, West C, Toressani T, Jacobs HS. Cotreatment with growth hormone and gonadotropins for induction of ovulation: a controlled clinical trial. Fertil Steril1990;53:25460.
Christman and Halme Editor's corner
13
2. Blumenfeld Z, Lunenfeld B. The potentiating effects of growth hormone on follicle stimulation with human menopausal gonadotropin in a panhypopituitary patient. Fertil Steril 1989;52:328-31. 3. Ibrahim ZHZ, Matson PL, Buck P, Lieberman BA. The use of a biosynthetic human growth hormone to augment ovulation induction with buserelin acetate/human menopausal gonadotropin in women with a poor ovarian response. Fertil Steril 1991;55:202-4. 4. Lanzone A, DiSimone N, Castellani R, Fulghesu AM, Caruso A, Mancuso S. Human growth hormone enhances progesterone production by human luteal cells in vitro: evidence of a synergistic effect with human chorionic gonadotropin. Fertil Steril 1992;57:92-6. 5. Ovesen P, Moller J, Moller N, Christiansen JS, Jorgenson JOL, Orskov H. Growth hormone secretory capacity and serum insulin-like growth factor I levels in primary infertile, anovulatory women with regular menses. Fertil Steril1992;57: 97-101. 6. Sheikholislam BM, Stempel RS. Hereditary isolated somatotropin deficiency: effects of human growth hormone administration. Pediatrics 1972;49:362-74. 7. Ramalay JA, Phares CK. Delay of puberty onset in females due to suppression of growth hormone. Endocrinology 1980;106:1989-93. 8. Menashe Y, Lunenfeld B, Pariente C, Frenkel Y, Mashiach S. Can growth hormone increase, after clonidine administration, predict the dose of human menopausal hormone
14
Christman and Halme Editor's corner
needed for induction of ovulation? Fertil Steril1990;53:4325. 9. Mason HD, Martikainen H, Beard RW, Anyaoku V, Franks S. Direct gonadotropic effect of growth hormone on oestradiol production by human granulosa cells in vitro. J Endocrinol 1990;126:R1-4. 10. Jia X, Kalmijn J, Hsueh AJW. Growth hormone enhances follicle stimulating hormone-induced differentiation of cultured rat granulosa cells. Endocrinology 1896;118:1401-9. 11. Hsu CJ, Hammond JM. Concominant effects of growth hormone on secretion of insulin-like growth factor I and progesterone by cultured porcine granulosa cells. Endocrinology 1987;121:1343-8. 12. Poretsky L, Kalin MF. The gonadotropic function of insulin. Endocr Rev 1987;8:132-41. 13. Erickson GF, Garzo VG, Magoffin DA. Insulin-like growth factor-I regulates aromatase activity in human granulosa cells and granulosa luteal cells. J Clin Endocrinol Metab 1989;69: 716-24. 14. Christman GM, Randolph JF Jr, Peegel H, Menon KM. Differential responsiveness of luteinized granulosa cells to gonadotropins and insulin-like growth factor- I for induction of aromatase activity. Fertil Steril1991;55:1099-1105. 15. Bergh C, Olsson JH, Hillensjo T. Effect of insulin-like growth factor I on steroidogenesis in cultured human granulosa cells. Acta Endocrinol (Copenh) 1991;125:177-85. 16. Ramasharma K, Li CH. Human pituitary and placental hormones control human insulin-like growth factor II secretion in human granulosa cells. Proc Natl Acad Sci USA 1987;84: 2643-7.
Fertility and Sterility
