0021-972X/92/7506-1550$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society
The Natural Adrenarche, Independent
Vol. 75, No. 6 Printed in U.S.A.
History of Autonomous Gonadal Function, and Central Puberty in GonadotropinPrecocious Puberty*
PAUL A. BOEPPLE, LAUREN S. FRISCH, WILLIAM H. HOFFMAN+, AND WILLIAM Pediatric
and Reproductive
Endocrine
MARGARET F. CROWLEY,
Units, Massachusetts
General
ABSTRACT
E. WIERMAN”r, JR. Hospital,
Boston, Massachusetts
02114
manners despite long term pubertal levels of gonadal sex steroid secretion. After the development of central puberty, as documented by the appearance of pulsatile gonadotropin secretion, we sought to determine whether the potential for gonadal autonomy persisted. Despite complete pituitary desensitization induced by administration of a GnRH agonist, both patients studied demonstrated an ongoing capacity to secrete pubertal levels of gonadal steroids. Our study suggests that the timing of adrenarche and central puberty in these subjects with GIP was apparently unaltered by prolonged exposure to gonadal steroids. Subsequent to the development of central puberty, pulsatile gonadotropin secretion may override and, thus, mask the underlying defect(s) in adolescents and adults with histories of GIP. (J Clin Endocrinol Metub 75: 1550-1555,1992)
Gonadotropin-independent precocity (GIP) is a syndrome marked by precocious pubertal development in the absence of pubertal levels of gonadotropins. To investigate the discrete patterns of central nervous system, gonadal, adrenal, and skeletal maturation in this syndrome, we conducted longitudinal studies spanning up to 10 yr in two such affected individuals. A cross-sectional analysis of adrenal androgen secretion was performed in nine additional patients to assess further the time course of adrenarche in GIP. Serial evaluations revealed progression of secondary sexual characteristics, statural growth, and skeletal maturation, all consistent with ongoing exposure to pubertal gonadal steroid levels. On the other hand, adrenarche (n = 11) and spontaneous and GnRH-stimulated gonadotropin secretion (n = 2) progressed in chronological age-appropriate
T
HE SYNDROME of gonadotropin-independent precocity (GIP) is marked by pubertal development in the absence of pubertal levels of gonadotropin secretion. This unique mode of sexual maturation has been described in both girls with the McCune-Albright syndrome and boys in whom there is often a family history of precocious puberty in male relatives (l-3). Gonadal steroid hormone secretion in both males and females with GIP is unaltered by the administration of potent long-acting GnRH agonists (1, 3, 4), providing additional evidence that their early gonadal maturation is independent of pituitary gonadotropin stimulation. While the development of pubertal pituitary responsivenessto exogenous GnRH has been documented in patients with GIP (5, 6), little is known about the longitudinal neuroendocrine development and gonadal maturation in this syndrome. A similar paucity of data exists regarding the natural history of adrenal androgen secretion and skeletal maturation in GIP. Consequently, we sought to investigate the discrete patterns of central nervous system, gonadal, adrenal, and skeletal Received March 5, 1992. Address all correspondence and requests for reprints to: Paul A. Boepple, M.D., Reproductive Endocrine Unit, Bartlett Hall Extension 5, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114. * This work was supported in part by NIH Grants HD-18169 and RR-01066. t Present address: Division of Endocrinology, University of Colorado, Denver, Colorado 80262. $ Present address: Department of Pediatrics, Medical College of Georgia, Augusta, Georgia 30912.
maturation in this syndrome through a longitudinal study of two affected individuals. To further elucidate the natural history of adrenal androgen secretion in GIP, a cross-sectional study of adrenal androgen secretion was carried out in an additional nine affected children. After the development of central puberty in two patients, pituitary desensitization was employed to determine if the capacity for autonomous gonadal function persisted. Subjects and Methods Patient
population
In all patients, the diagnosis of GIP was made on the basis of precocious secondary sexual development, pubertal levels of gonadal sex steroids (testosterone or estradiol), and prepubertal or undetectable basal and GnRH-stimulated levels of LH and FSH. In the first six patients studied, the failure of a long-acting suprapotent GnRH agonist (GnRHa) to induce suppression of gonadal steroidogenesis was also used to document GIP (1). Two patients underwent serial observations over 610 yr. GIP in the boy occurred in the absence of relevant family history. GIP in the girl occurred in association with cafe au lait skin hyperpigmentation consistent with McCune-Albright syndrome (7). An additional nine patients, whose serial evaluations were not sufficiently long to document the transition from gonadotropin-independent to central puberty, permitted a cross-sectional study of adrenal androgen secretion, This cohort included three girls with McCune-Albright syndrome and six boys with GIP (three familial and three isolated). None of the patients had evidence of adrenal or central nervous system pathology.
Protocol All investigations were preceded by obtaining informed consent from parents and were carried out at the General Clinical Research Center of 1550
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 08 December 2014. at 06:14 For personal use only. No other uses without permission. . All rights reserved.
NATURAL
HISTORY
the Massachusetts General Hospital. After initial periods of GnRHa administration (o-Trp6-Pro’-NEt-GnRH; 4-8 Fcg/kg day, SC), during which gonadal sex steroid levels were not effectively suppressed (l), two patients (male patient 5 and the female patient reported in Ref. 1) were evaluated at 6- to 12-month intervals for 5-6 yr according to the protocol previously described (8). Briefly, blood samples for the determination of LH and FSH levels were drawn at lo- to 20.min intervals for 8-16 h between 2200-1400 h the following afternoon, at which time the response to exogenous GnRH (2.5 &kg) was assessed. Once a clearly pubertal pattern of gonadotropin secretion had been documented, both patients were again administered GnRHa (8 rg/kg.day, SC) for 6 months. Monitoring consisted of serial evaluations, as described above, after 3 and 6 months of pituitary desensitization with GnRHa. Dehydroepiandrosterone sulfate (DHEA-S) was measured as an index of adrenal androgen secretion in all patients.
Laboratory
methods
Skeletal age, estradiol, testosterone, DHEA-S, LH, and FSH were measured as previously reported (S-10). The RIAs for LH and FSH were characterized by sensitivities of 0.8 W/L Second International Reference Prepartaion of human menopausal gonadotropin, inter- and intraassay coefficients of variation that averaged 7%, and cross-reactivities with free a-subunit of less than 5% and 0.03%, respectively. LH pulses were identified using a previously reported modification of the method of Santen and Bardin (10, 11). Pulse identification required a minimum amplitude of 2 IU/L, representing a 20% or greater rise from nadir to peak, corresponding to approximately 3 times the intrassay coefficient of variation.
Results Transition from gonadotropin-independent mediated puberty
to centrally
Secondary sexual development was first noted in our male patient at 4 yr of age. After a diagnosis of GIP, his serial evaluations chronicled growth and skeletal maturation (Fig. 1A) during his progression from prepubertal gonadotropin secretion (Fig. 2, A and B) through an early to midpubertal pattern of secretion with marked diurnal variation (Fig. 2, C and D), to an adult mode of secretion in which night/day differences were no longer apparent (Fig. 2E). At a chronological age of 12.3 yr, the LH interpulse interval (137 min) and mean LH pulse amplitude (7.9 & 2.8 IU/L) were within the normal range for adult men (10) (Fig. 2E). Our female patient with GIP displayed a similar progression during her serial evaluations. After the onset of menses and breast development at 3 yr of age, she displayed accel-
2 1 6 8 101214161820 A(;1
FIG. 1. Growth GIP (A, male; height us. bone
(years)
2 4 6 8 101214161820 ACF
OF GIP
1551
erated skeletal growth and maturation (Fig. 1B). Longitudinal studies revealed recurrent cycles of ovarian follicular growth and involution associatedwith waxing and waning estradiol levels and irregular menses,all occurring against the backdrop of low and apulsatile gonadotropin secretion (Fig. 2, F and G). It is of note that gonadotropin levels monitored in the face of active gonadal steroid production (Fig. 2G) were suppressedrelative to the already low levels present during a period of relative ovarian quiescence (Fig. 2F). At chronological age 15.8 yr, studies revealed a pattern of LH secretion characterized by an interpulse interval (75 min) and mean pulse amplitude (4.2 f 1.3 IU/L) within normal limits for adult women in the midfollicular phase (12) (Fig. 21). However, mensescontinued to be irregular and frequent (every 2 weeks), and pelvic ultrasound revealed four ovarian follicles 1-2 cm in diameter, rather than a single dominant follicle. The gonadotropin responsesto exogenous GnRH matured in both patients with GIP coincident with their patterns of spontaneous gonadotropin secretion (i.e. prepubertal to pubertal to adult; Fig. 3). Cyclic gonadal function appeared to influence the levels of gonadotropins in our female patient during the gonadotropin-independent phase. The FSH-predominant response, typical of prepubertal girls, was evident when gonadal function was relatively quiescent [chronological age, 7.3 yr; estradiol, ~73.4 pmol/L ((20 pg/mL)], but was suppressedduring an active period of ovarian secretion [chronological age, 7.7 yr; estradiol, 407.5 pmol/L (111 pg/
mL)l. Autonomous
gonadal
function
persists after central puberty
After the documentation of pubertal gonadotropin secretion, both patients were treated with a GnRHa regimen that consistently suppressespituitary-gonadal function in patients with central precocious puberty (CPP) (1, 8, 9). The complete nature of pituitary desensitization was verified by the low and apulsatile spontaneous LH secretion as well as the suppressed responsesof LH to GnRH (100 pg) and GnRHa (8 pg/kg; Fig. 4, A and B, upper panels). As had been the case during earlier periods of GnRHa administration, gonadotropin-independent gonadal steroid secretion remained evident in both patients after central puberty (Fig. 4, A and B, lower panels). In our female patient, mensespersisted,and estradiol levels fluctuated in the pubertal range despite effective pituitary suppression. In our male patient, the testosterone level decreased from pretreatment levels, but remained between 1.46 nmol/L (42 ng/dL) and 6.93 nmol/L (200 ng/dL) during GnRHa administration. Thus, both patients exhibited gonadal steroid secretion at levels clearly in excess of the maximal concentrations [estradiol, ~73.4 pmol/L (
The Natural Adrenarche, Independent
Vol. 75, No. 6 Printed in U.S.A.
History of Autonomous Gonadal Function, and Central Puberty in GonadotropinPrecocious Puberty*
PAUL A. BOEPPLE, LAUREN S. FRISCH, WILLIAM H. HOFFMAN+, AND WILLIAM Pediatric
and Reproductive
Endocrine
MARGARET F. CROWLEY,
Units, Massachusetts
General
ABSTRACT
E. WIERMAN”r, JR. Hospital,
Boston, Massachusetts
02114
manners despite long term pubertal levels of gonadal sex steroid secretion. After the development of central puberty, as documented by the appearance of pulsatile gonadotropin secretion, we sought to determine whether the potential for gonadal autonomy persisted. Despite complete pituitary desensitization induced by administration of a GnRH agonist, both patients studied demonstrated an ongoing capacity to secrete pubertal levels of gonadal steroids. Our study suggests that the timing of adrenarche and central puberty in these subjects with GIP was apparently unaltered by prolonged exposure to gonadal steroids. Subsequent to the development of central puberty, pulsatile gonadotropin secretion may override and, thus, mask the underlying defect(s) in adolescents and adults with histories of GIP. (J Clin Endocrinol Metub 75: 1550-1555,1992)
Gonadotropin-independent precocity (GIP) is a syndrome marked by precocious pubertal development in the absence of pubertal levels of gonadotropins. To investigate the discrete patterns of central nervous system, gonadal, adrenal, and skeletal maturation in this syndrome, we conducted longitudinal studies spanning up to 10 yr in two such affected individuals. A cross-sectional analysis of adrenal androgen secretion was performed in nine additional patients to assess further the time course of adrenarche in GIP. Serial evaluations revealed progression of secondary sexual characteristics, statural growth, and skeletal maturation, all consistent with ongoing exposure to pubertal gonadal steroid levels. On the other hand, adrenarche (n = 11) and spontaneous and GnRH-stimulated gonadotropin secretion (n = 2) progressed in chronological age-appropriate
T
HE SYNDROME of gonadotropin-independent precocity (GIP) is marked by pubertal development in the absence of pubertal levels of gonadotropin secretion. This unique mode of sexual maturation has been described in both girls with the McCune-Albright syndrome and boys in whom there is often a family history of precocious puberty in male relatives (l-3). Gonadal steroid hormone secretion in both males and females with GIP is unaltered by the administration of potent long-acting GnRH agonists (1, 3, 4), providing additional evidence that their early gonadal maturation is independent of pituitary gonadotropin stimulation. While the development of pubertal pituitary responsivenessto exogenous GnRH has been documented in patients with GIP (5, 6), little is known about the longitudinal neuroendocrine development and gonadal maturation in this syndrome. A similar paucity of data exists regarding the natural history of adrenal androgen secretion and skeletal maturation in GIP. Consequently, we sought to investigate the discrete patterns of central nervous system, gonadal, adrenal, and skeletal Received March 5, 1992. Address all correspondence and requests for reprints to: Paul A. Boepple, M.D., Reproductive Endocrine Unit, Bartlett Hall Extension 5, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114. * This work was supported in part by NIH Grants HD-18169 and RR-01066. t Present address: Division of Endocrinology, University of Colorado, Denver, Colorado 80262. $ Present address: Department of Pediatrics, Medical College of Georgia, Augusta, Georgia 30912.
maturation in this syndrome through a longitudinal study of two affected individuals. To further elucidate the natural history of adrenal androgen secretion in GIP, a cross-sectional study of adrenal androgen secretion was carried out in an additional nine affected children. After the development of central puberty in two patients, pituitary desensitization was employed to determine if the capacity for autonomous gonadal function persisted. Subjects and Methods Patient
population
In all patients, the diagnosis of GIP was made on the basis of precocious secondary sexual development, pubertal levels of gonadal sex steroids (testosterone or estradiol), and prepubertal or undetectable basal and GnRH-stimulated levels of LH and FSH. In the first six patients studied, the failure of a long-acting suprapotent GnRH agonist (GnRHa) to induce suppression of gonadal steroidogenesis was also used to document GIP (1). Two patients underwent serial observations over 610 yr. GIP in the boy occurred in the absence of relevant family history. GIP in the girl occurred in association with cafe au lait skin hyperpigmentation consistent with McCune-Albright syndrome (7). An additional nine patients, whose serial evaluations were not sufficiently long to document the transition from gonadotropin-independent to central puberty, permitted a cross-sectional study of adrenal androgen secretion, This cohort included three girls with McCune-Albright syndrome and six boys with GIP (three familial and three isolated). None of the patients had evidence of adrenal or central nervous system pathology.
Protocol All investigations were preceded by obtaining informed consent from parents and were carried out at the General Clinical Research Center of 1550
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 08 December 2014. at 06:14 For personal use only. No other uses without permission. . All rights reserved.
NATURAL
HISTORY
the Massachusetts General Hospital. After initial periods of GnRHa administration (o-Trp6-Pro’-NEt-GnRH; 4-8 Fcg/kg day, SC), during which gonadal sex steroid levels were not effectively suppressed (l), two patients (male patient 5 and the female patient reported in Ref. 1) were evaluated at 6- to 12-month intervals for 5-6 yr according to the protocol previously described (8). Briefly, blood samples for the determination of LH and FSH levels were drawn at lo- to 20.min intervals for 8-16 h between 2200-1400 h the following afternoon, at which time the response to exogenous GnRH (2.5 &kg) was assessed. Once a clearly pubertal pattern of gonadotropin secretion had been documented, both patients were again administered GnRHa (8 rg/kg.day, SC) for 6 months. Monitoring consisted of serial evaluations, as described above, after 3 and 6 months of pituitary desensitization with GnRHa. Dehydroepiandrosterone sulfate (DHEA-S) was measured as an index of adrenal androgen secretion in all patients.
Laboratory
methods
Skeletal age, estradiol, testosterone, DHEA-S, LH, and FSH were measured as previously reported (S-10). The RIAs for LH and FSH were characterized by sensitivities of 0.8 W/L Second International Reference Prepartaion of human menopausal gonadotropin, inter- and intraassay coefficients of variation that averaged 7%, and cross-reactivities with free a-subunit of less than 5% and 0.03%, respectively. LH pulses were identified using a previously reported modification of the method of Santen and Bardin (10, 11). Pulse identification required a minimum amplitude of 2 IU/L, representing a 20% or greater rise from nadir to peak, corresponding to approximately 3 times the intrassay coefficient of variation.
Results Transition from gonadotropin-independent mediated puberty
to centrally
Secondary sexual development was first noted in our male patient at 4 yr of age. After a diagnosis of GIP, his serial evaluations chronicled growth and skeletal maturation (Fig. 1A) during his progression from prepubertal gonadotropin secretion (Fig. 2, A and B) through an early to midpubertal pattern of secretion with marked diurnal variation (Fig. 2, C and D), to an adult mode of secretion in which night/day differences were no longer apparent (Fig. 2E). At a chronological age of 12.3 yr, the LH interpulse interval (137 min) and mean LH pulse amplitude (7.9 & 2.8 IU/L) were within the normal range for adult men (10) (Fig. 2E). Our female patient with GIP displayed a similar progression during her serial evaluations. After the onset of menses and breast development at 3 yr of age, she displayed accel-
2 1 6 8 101214161820 A(;1
FIG. 1. Growth GIP (A, male; height us. bone
(years)
2 4 6 8 101214161820 ACF
OF GIP
1551
erated skeletal growth and maturation (Fig. 1B). Longitudinal studies revealed recurrent cycles of ovarian follicular growth and involution associatedwith waxing and waning estradiol levels and irregular menses,all occurring against the backdrop of low and apulsatile gonadotropin secretion (Fig. 2, F and G). It is of note that gonadotropin levels monitored in the face of active gonadal steroid production (Fig. 2G) were suppressedrelative to the already low levels present during a period of relative ovarian quiescence (Fig. 2F). At chronological age 15.8 yr, studies revealed a pattern of LH secretion characterized by an interpulse interval (75 min) and mean pulse amplitude (4.2 f 1.3 IU/L) within normal limits for adult women in the midfollicular phase (12) (Fig. 21). However, mensescontinued to be irregular and frequent (every 2 weeks), and pelvic ultrasound revealed four ovarian follicles 1-2 cm in diameter, rather than a single dominant follicle. The gonadotropin responsesto exogenous GnRH matured in both patients with GIP coincident with their patterns of spontaneous gonadotropin secretion (i.e. prepubertal to pubertal to adult; Fig. 3). Cyclic gonadal function appeared to influence the levels of gonadotropins in our female patient during the gonadotropin-independent phase. The FSH-predominant response, typical of prepubertal girls, was evident when gonadal function was relatively quiescent [chronological age, 7.3 yr; estradiol, ~73.4 pmol/L ((20 pg/mL)], but was suppressedduring an active period of ovarian secretion [chronological age, 7.7 yr; estradiol, 407.5 pmol/L (111 pg/
mL)l. Autonomous
gonadal
function
persists after central puberty
After the documentation of pubertal gonadotropin secretion, both patients were treated with a GnRHa regimen that consistently suppressespituitary-gonadal function in patients with central precocious puberty (CPP) (1, 8, 9). The complete nature of pituitary desensitization was verified by the low and apulsatile spontaneous LH secretion as well as the suppressed responsesof LH to GnRH (100 pg) and GnRHa (8 pg/kg; Fig. 4, A and B, upper panels). As had been the case during earlier periods of GnRHa administration, gonadotropin-independent gonadal steroid secretion remained evident in both patients after central puberty (Fig. 4, A and B, lower panels). In our female patient, mensespersisted,and estradiol levels fluctuated in the pubertal range despite effective pituitary suppression. In our male patient, the testosterone level decreased from pretreatment levels, but remained between 1.46 nmol/L (42 ng/dL) and 6.93 nmol/L (200 ng/dL) during GnRHa administration. Thus, both patients exhibited gonadal steroid secretion at levels clearly in excess of the maximal concentrations [estradiol, ~73.4 pmol/L (
