Growth hormone and A. L.
Ogilvy-Stuart
puberty
and S. M. Shalet
a child, puberty encompasses a series of events which include the completion of growth and the maturing of the reproductive system. One of the common hormonal links between these two processes is growth hormone (GH) and, although it has been known for some time that the reproductive axis influences GH secretion and growth, increasing interest is developing in the alternative possibility of GH modifying reproductive processes. In the normal child, there is an increase in GH secretion from mid-childhood with a shift in periodicity and an increase in pulse amplitude (Hindmarsh, Mathews & Brook, 1988). The two- to threefold rise in GH secretion during puberty is a product of the increase in pulse amplitude over the prepubertal value (Martha, Rogol, Veldhuis et al. 1989; Delemarre-van de Waal, Wennink & Odink, 1991). GH pulse amplitude is increased during early puberty in girls and at a later stage in boys, corresponding to the different timing of the pubertal growth spurt in the two sexes (Edge, Dünger, Matthews et al. 1990). In hormone replacement studies the critical contribution of both GH and testosterone to the male pubertal growth spurt has been demonstrated in boys with testosterone deficiency, GH deficiency, or combined deficiencies (Aynsley-Green, Zachmann & Prader, 1976). Avail¬ able evidence suggests that the growth-promoting action of testosterone is, at least in part, mediated by an amplitude-modulated increase in GH secretion. On the other hand, clinical observations have implied that GH modifies the activity of the pituitarygonadal axis. Many children with isolated GH defici¬ ency (IGHD) or GH insensitivity exhibit a marked delay in the onset of puberty which in the child with IGHD is modified by GH therapy. Exactly how and where GH interacts with the reproductive axis remains the subject of intensive study. GH has been shown to increase insulin-like growth factor-I (IGF-I) levels in both the ovary and the testis but it is possible that the GH-mediated increase in circulating IGF-I concentration contributes to the action on the gonad.
In
In in-vitro
systems IGF-I increased gonadotrophininduced testosterone production by the Leydig cells. Alternatively there is evidence that the GH effect is a direct one and not mediated via IGF-I production. In adults, GH appears to facilitate ovulation induc¬ tion with gonadotrophins in women previously resist¬ ant to
gonadotrophin
treatment
(Homburg, Eshel,
Abdalla & Jacobs, 1988; Homburg, West, Torresani & Jacobs, 1990). Co-administration of GH, even in a single dose of 24 IU results in a substantial lowering in total dose of exogenous gonadotrophin required for ovulation induction. Furthermore it has been sug¬ gested that the 'gonadotrophin-sparing' action of GH
persists
subsequent exogenous gonadotrophin cycles (Burger, Kovacs, Poison et al. 1991). There is a significant rise in circulating IGF-I levels after 5 days of treatment (Homburg et al. 1990) and it over
treatment
has been shown that the response of cultured ovarian granulosa cells to stimulation by follicle-stimulat¬ ing hormone (FSH) could be augmented by coincubation with IGF-I, through a potentiation of aro¬ matase activity (Adashi, Resnick, Svoboda & Van Wyk, 1985). It remains unknown, however, if IGF-I mediates the 'gonadotrophin-sparing' effects, as studies by Mason, Martikainen, Beard et al. (.1990) indicate that GH itself has a potent and direct effect on oestradiol secretion by ovarian granulosa cells independent of either FSH or IGF-I. The evidence of an impact of GH on the reproduc¬ tive axis in the adult male is less substantial. Sper¬ matogenesis in adult males with IGHD shows only minor variations from normal; whilst a significant effect of GH on spermatogenesis in males with iso¬ lated gonadotrophin deficiency undergoing gonado¬ trophin treatment remains to be established (Shoham, Lahlou, Conway et al. 1992). Ironically, during puberty it has been suggested that the effect of GH on the reproductive axis is counter¬ productive as far as growth itself is concerned! In children with IGHD, not only is the onset of puberty delayed, but it has been suggested that in those receiv¬ ing GH therapy the duration of puberty is shorter
by approximately 6 months than that seen in normal children, thereby reducing the amount of time for growth to take place. No correlation was found between the dose of GH and either the age at pubertal onset or the duration of puberty. Age at onset was not correlated with duration of puberty, nor was
duration of treatment with GH before the onset of puberty (Darendelilier, Hindmarsh, Preece et al. 1990). In a preliminary report of a prospective study of boys with isolated idiopathic GH deficiency, the effect of two different doses of GH on the duration of puberty has been studied by Stanhope, Uruena, Hindmarsh et al. (1991). One group continued with the conventional prepubertal dose of 15IU/m2 per week, and at the onset of puberty the other group received a doubling of the dose to 30 IU/m2 per week. The boys receiving the higher dose appeared to go through puberty more quickly, but the numbers were small and the results not completely analysed. In both the above studies, the total growth during puberty and final height attained are unknown; even if the duration of puberty is reduced in GH-treated GH-deficient children the exact impact on growth is not clear. It would appear that whilst GH has a fundamental role in the growth process, the action of GH on the reproductive axis is more akin to 'fine tuning' than that of a 'major player'. It is contradictory, however, that under normal circumstances GH secretion increases threefold during puberty and yet it has been suggested that an increase in GH dosage in a pubertal child might be unhelpful by reducing the duration of puberty and thus the 'window' in which growth might take place. Presumably, however, the unphysiological manner in which GH therapy is administered, i.e. by a daily subcutaneous injection, is so far removed from the normal situation, in which a GH pulse is secreted approximately every 3 h, that the above irony is apparent rather than real. As far as clinical practice is concerned, however, it is possible that an increase in GH dosage might optimize pubertal growth in a GH-deficient child but equally in a 'normal short child' in whom endogenous GH secretion is intact, larger doses of GH during puberty might negate any height gained during prepubertal life. REFERENCES
Adashi, E. Y., Resnick, C. E., Svoboda, M. E. & Van Wyk, J. J. (1985). Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocrine Reviews 6, 400-420.
Aynsley-Green, ., Zachmann, M, & Prader, A, (1976). Interrela¬ tion of the therapeutic effects of growth hormone and testos¬ terone on growth in hypopituitarism. Journal of Pediatrics 89, 992-999.
Burger, H. G., Kovacs, G. T., Poison, D. M., McDonald, J., McCloud, P. I., Harrop, ML, Colman, P. & Healy, D. L. (1991). Ovarian sensitization to gonadotrophins by human growth hormone. Persistence of the effect beyond the treated cycle. Clinical Endocrinology 35, 119-122. Darendelilier, F., Hindmarsh, P. C, Preece, . ., Cox, L. & Brook, C. G. D. (1990). Growth hormone increases rate of pubertal maturation. Ada Endocrinologica 122, 414 416.
Delemarre-van de Waal, . ., Wennink, J. M. B. & Odink, R. J. H. (1991). Gonadotrophin and growth hormone secretion throughout puberty. Ada Paediatrica Scandinavica (Suppl.) 372, 26-31. Edge, J. ., Dunger, D. ., Matthews, D. R., Gilbert, J. P. & Smith, C. (1990). Increased overnight growth hormone release in diabetics compared with normal adolescents. Journal of Clinical Endocrinology and Metabolism 71, 1356-1362. Hindmarsh, P. C, Mathews, D. R. & Brook, C. G. D. (1988). Growth hormone secretion in children determined by time series analysis. Clinical Endocrinology 29, 35 44. Homburg, R., Eshel, ., Abdalla, H. I. & Jacobs, H. S. (1988). Growth hormone facilitates ovulation induction by gonado¬ trophins. Clinical Endocrinology 29, 113-117. Homburg, R., West, C, Torresani, T. & Jacobs, H. S. (1990). A comparative study of single-dose growth hormone therapy as an adjuvant to gonadotrophin treatment for ovulation induction. Clinical Endocrinology 32, 781-785. Martha, P. M„ Rogol, A. D., Veldhuis, J. D., Kerrigan, J. R., Goodman, D. W. & Blizzard, R. M. (1989). Alterations in the pulsatile properties of circulating growth hormone concentra¬ tions during puberty in boys. Journal of Clinical Endocrinology and Metabolism 69, 563-570. Mason, H. D., Martikainen, H., Beard, R. W., Anyaoku, V. & Franks, S. (1990). Direct gonadotrophic effect of growth hormone on oestradiol in human granulosa cells in vitro. Journal of Endocrinology 126, R1-R4. Shoham, Z., Lahlou, N., Conway, G. S., Bouchard, P., Ostergaard, H. & Jacobs, H. S. (1992). Cotreatment with growth hormone for induction of spermatogenesis in patients with hypogonadotrophic hypogonadism. Fertility and Sterility 57, 1044-1051. Stanhope, R., Uruena, M., Hindmarsh, P., Leiper, A. D. & Brook, C. G D. (1991). Management of growth hormone deficiency through puberty. Ada Paediatrica Scandinavica (Suppl.) 371, 47-52.
Department of Endocrinology, Christie Hospital and Holt Radium Institute, Wilmslow Road, Manchester M20 9BX, U.K.
Ogilvy-Stuart
puberty
and S. M. Shalet
a child, puberty encompasses a series of events which include the completion of growth and the maturing of the reproductive system. One of the common hormonal links between these two processes is growth hormone (GH) and, although it has been known for some time that the reproductive axis influences GH secretion and growth, increasing interest is developing in the alternative possibility of GH modifying reproductive processes. In the normal child, there is an increase in GH secretion from mid-childhood with a shift in periodicity and an increase in pulse amplitude (Hindmarsh, Mathews & Brook, 1988). The two- to threefold rise in GH secretion during puberty is a product of the increase in pulse amplitude over the prepubertal value (Martha, Rogol, Veldhuis et al. 1989; Delemarre-van de Waal, Wennink & Odink, 1991). GH pulse amplitude is increased during early puberty in girls and at a later stage in boys, corresponding to the different timing of the pubertal growth spurt in the two sexes (Edge, Dünger, Matthews et al. 1990). In hormone replacement studies the critical contribution of both GH and testosterone to the male pubertal growth spurt has been demonstrated in boys with testosterone deficiency, GH deficiency, or combined deficiencies (Aynsley-Green, Zachmann & Prader, 1976). Avail¬ able evidence suggests that the growth-promoting action of testosterone is, at least in part, mediated by an amplitude-modulated increase in GH secretion. On the other hand, clinical observations have implied that GH modifies the activity of the pituitarygonadal axis. Many children with isolated GH defici¬ ency (IGHD) or GH insensitivity exhibit a marked delay in the onset of puberty which in the child with IGHD is modified by GH therapy. Exactly how and where GH interacts with the reproductive axis remains the subject of intensive study. GH has been shown to increase insulin-like growth factor-I (IGF-I) levels in both the ovary and the testis but it is possible that the GH-mediated increase in circulating IGF-I concentration contributes to the action on the gonad.
In
In in-vitro
systems IGF-I increased gonadotrophininduced testosterone production by the Leydig cells. Alternatively there is evidence that the GH effect is a direct one and not mediated via IGF-I production. In adults, GH appears to facilitate ovulation induc¬ tion with gonadotrophins in women previously resist¬ ant to
gonadotrophin
treatment
(Homburg, Eshel,
Abdalla & Jacobs, 1988; Homburg, West, Torresani & Jacobs, 1990). Co-administration of GH, even in a single dose of 24 IU results in a substantial lowering in total dose of exogenous gonadotrophin required for ovulation induction. Furthermore it has been sug¬ gested that the 'gonadotrophin-sparing' action of GH
persists
subsequent exogenous gonadotrophin cycles (Burger, Kovacs, Poison et al. 1991). There is a significant rise in circulating IGF-I levels after 5 days of treatment (Homburg et al. 1990) and it over
treatment
has been shown that the response of cultured ovarian granulosa cells to stimulation by follicle-stimulat¬ ing hormone (FSH) could be augmented by coincubation with IGF-I, through a potentiation of aro¬ matase activity (Adashi, Resnick, Svoboda & Van Wyk, 1985). It remains unknown, however, if IGF-I mediates the 'gonadotrophin-sparing' effects, as studies by Mason, Martikainen, Beard et al. (.1990) indicate that GH itself has a potent and direct effect on oestradiol secretion by ovarian granulosa cells independent of either FSH or IGF-I. The evidence of an impact of GH on the reproduc¬ tive axis in the adult male is less substantial. Sper¬ matogenesis in adult males with IGHD shows only minor variations from normal; whilst a significant effect of GH on spermatogenesis in males with iso¬ lated gonadotrophin deficiency undergoing gonado¬ trophin treatment remains to be established (Shoham, Lahlou, Conway et al. 1992). Ironically, during puberty it has been suggested that the effect of GH on the reproductive axis is counter¬ productive as far as growth itself is concerned! In children with IGHD, not only is the onset of puberty delayed, but it has been suggested that in those receiv¬ ing GH therapy the duration of puberty is shorter
by approximately 6 months than that seen in normal children, thereby reducing the amount of time for growth to take place. No correlation was found between the dose of GH and either the age at pubertal onset or the duration of puberty. Age at onset was not correlated with duration of puberty, nor was
duration of treatment with GH before the onset of puberty (Darendelilier, Hindmarsh, Preece et al. 1990). In a preliminary report of a prospective study of boys with isolated idiopathic GH deficiency, the effect of two different doses of GH on the duration of puberty has been studied by Stanhope, Uruena, Hindmarsh et al. (1991). One group continued with the conventional prepubertal dose of 15IU/m2 per week, and at the onset of puberty the other group received a doubling of the dose to 30 IU/m2 per week. The boys receiving the higher dose appeared to go through puberty more quickly, but the numbers were small and the results not completely analysed. In both the above studies, the total growth during puberty and final height attained are unknown; even if the duration of puberty is reduced in GH-treated GH-deficient children the exact impact on growth is not clear. It would appear that whilst GH has a fundamental role in the growth process, the action of GH on the reproductive axis is more akin to 'fine tuning' than that of a 'major player'. It is contradictory, however, that under normal circumstances GH secretion increases threefold during puberty and yet it has been suggested that an increase in GH dosage in a pubertal child might be unhelpful by reducing the duration of puberty and thus the 'window' in which growth might take place. Presumably, however, the unphysiological manner in which GH therapy is administered, i.e. by a daily subcutaneous injection, is so far removed from the normal situation, in which a GH pulse is secreted approximately every 3 h, that the above irony is apparent rather than real. As far as clinical practice is concerned, however, it is possible that an increase in GH dosage might optimize pubertal growth in a GH-deficient child but equally in a 'normal short child' in whom endogenous GH secretion is intact, larger doses of GH during puberty might negate any height gained during prepubertal life. REFERENCES
Adashi, E. Y., Resnick, C. E., Svoboda, M. E. & Van Wyk, J. J. (1985). Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocrine Reviews 6, 400-420.
Aynsley-Green, ., Zachmann, M, & Prader, A, (1976). Interrela¬ tion of the therapeutic effects of growth hormone and testos¬ terone on growth in hypopituitarism. Journal of Pediatrics 89, 992-999.
Burger, H. G., Kovacs, G. T., Poison, D. M., McDonald, J., McCloud, P. I., Harrop, ML, Colman, P. & Healy, D. L. (1991). Ovarian sensitization to gonadotrophins by human growth hormone. Persistence of the effect beyond the treated cycle. Clinical Endocrinology 35, 119-122. Darendelilier, F., Hindmarsh, P. C, Preece, . ., Cox, L. & Brook, C. G. D. (1990). Growth hormone increases rate of pubertal maturation. Ada Endocrinologica 122, 414 416.
Delemarre-van de Waal, . ., Wennink, J. M. B. & Odink, R. J. H. (1991). Gonadotrophin and growth hormone secretion throughout puberty. Ada Paediatrica Scandinavica (Suppl.) 372, 26-31. Edge, J. ., Dunger, D. ., Matthews, D. R., Gilbert, J. P. & Smith, C. (1990). Increased overnight growth hormone release in diabetics compared with normal adolescents. Journal of Clinical Endocrinology and Metabolism 71, 1356-1362. Hindmarsh, P. C, Mathews, D. R. & Brook, C. G. D. (1988). Growth hormone secretion in children determined by time series analysis. Clinical Endocrinology 29, 35 44. Homburg, R., Eshel, ., Abdalla, H. I. & Jacobs, H. S. (1988). Growth hormone facilitates ovulation induction by gonado¬ trophins. Clinical Endocrinology 29, 113-117. Homburg, R., West, C, Torresani, T. & Jacobs, H. S. (1990). A comparative study of single-dose growth hormone therapy as an adjuvant to gonadotrophin treatment for ovulation induction. Clinical Endocrinology 32, 781-785. Martha, P. M„ Rogol, A. D., Veldhuis, J. D., Kerrigan, J. R., Goodman, D. W. & Blizzard, R. M. (1989). Alterations in the pulsatile properties of circulating growth hormone concentra¬ tions during puberty in boys. Journal of Clinical Endocrinology and Metabolism 69, 563-570. Mason, H. D., Martikainen, H., Beard, R. W., Anyaoku, V. & Franks, S. (1990). Direct gonadotrophic effect of growth hormone on oestradiol in human granulosa cells in vitro. Journal of Endocrinology 126, R1-R4. Shoham, Z., Lahlou, N., Conway, G. S., Bouchard, P., Ostergaard, H. & Jacobs, H. S. (1992). Cotreatment with growth hormone for induction of spermatogenesis in patients with hypogonadotrophic hypogonadism. Fertility and Sterility 57, 1044-1051. Stanhope, R., Uruena, M., Hindmarsh, P., Leiper, A. D. & Brook, C. G D. (1991). Management of growth hormone deficiency through puberty. Ada Paediatrica Scandinavica (Suppl.) 371, 47-52.
Department of Endocrinology, Christie Hospital and Holt Radium Institute, Wilmslow Road, Manchester M20 9BX, U.K.
