ABSTRACT
This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.
Subject(s)
Gonadotropin-Releasing Hormone/therapeutic use , Puberty, Precocious , Adolescent , Child , Female , Humans , Male , Puberty, Precocious/diagnosis , Puberty, Precocious/drug therapy , Puberty, Precocious/pathology , Puberty, Precocious/physiopathologyABSTRACT
CONTEXT: The long-term effects of pure 17ß-estradiol (E2) depending on route of administration have not been well characterized. OBJECTIVE: Our objective was to assess metabolic effects of oral vs transdermal (TD) 17ß-E2 replacement using estrogen concentration-based dosing in girls with Turner syndrome (TS). PATIENTS: Forty girls with TS, mean age 16.7 ± 1.7 years, were recruited. DESIGN: Subjects were randomized to 17ß-E2 orally or TD. Doses were titrated using mean E2 concentrations of normally menstruating girls as therapeutic target. E2, estrone (E1), and E1 sulfate (E1S) were measured by liquid chromatography tandem mass spectrometry and a recombinant cell bioassay; metabolites were measured, and dual-energy x-ray absorptiometry scan and indirect calorimetry were performed. MAIN OUTCOME: Changes in body composition and lipid oxidation were evaluated. RESULTS: E2 concentrations were titrated to normal range in both groups; mean oral dose was 2 mg, and TD dose was 0.1 mg. After 6 and 12 months, fat-free mass and percent fat mass, bone mineral density accrual, lipid oxidation, and resting energy expenditure rates were similar between groups. IGF-1 concentrations were lower on oral 17ß-E2, but suppression of gonadotropins was comparable with no significant changes in lipids, glucose, osteocalcin, or highly sensitive C-reactive protein between groups. However, E1, E1S, SHBG, and bioestrogen concentrations were significantly higher in the oral group. CONCLUSIONS: When E2 concentrations are titrated to the normal range, the route of delivery of 17ß-E2 does not affect differentially body composition, lipid oxidation, and lipid concentrations in hypogonadal girls with TS. However, total estrogen exposure (E1, E1S, and total bioestrogen) is significantly higher after oral 17ß-E2. TD 17ß-E2 results in a more physiological estrogen milieu than oral 17ß-E2 administration in girls with TS.
Subject(s)
Energy Metabolism/drug effects , Estradiol/administration & dosage , Estrogen Replacement Therapy , Turner Syndrome/drug therapy , Administration, Oral , Adolescent , Adult , Basal Metabolism/drug effects , Biotransformation , Body Composition/drug effects , Bone Density/drug effects , Drug Monitoring , Estradiol/blood , Estradiol/pharmacokinetics , Estradiol/therapeutic use , Estrone/analogs & derivatives , Estrone/blood , Feasibility Studies , Female , Humans , Lipid Metabolism/drug effects , Transdermal Patch , Turner Syndrome/blood , Turner Syndrome/metabolism , Young AdultSubject(s)
Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/therapeutic use , Puberty, Precocious/drug therapy , Adolescent , Body Mass Index , Child , Epilepsy , Female , Follicle Stimulating Hormone/blood , Follow-Up Studies , Gonadal Steroid Hormones/blood , Humans , Luteinizing Hormone/blood , Male , Obesity , Ovary/pathology , Ovary/physiopathology , Puberty, Precocious/pathology , Puberty, Precocious/physiopathology , Puberty, Precocious/psychology , Testis/pathology , Testis/physiopathology , Triptorelin Pamoate/analogs & derivativesABSTRACT
We report 98 children who have reached final adult height in a long-term trial of LHRH agonist treatment. These children were 5.3 +/- 2.1 yr old at the start of treatment and were treated with either deslorelin (4 microg/kg.d sc) or histrelin (4-10 microg/kg.d) for an average of 6.1 +/- 2.5 yr. Final height averaged 159.8 +/- 7.6 cm in the 80 girls, which was significantly greater than pretreatment predicted height (149.3 +/- 9.6 cm) but still significantly less than midparental height (MPH) (163.7 +/- 5.6). Final height averaged 171.1 +/- 8.7 cm in the 18 boys, which was significantly greater than pretreatment predicted height (156.1 +/- 14.2 cm) but still significantly less than MPH (178.3 +/- 5.2 cm). However, the average adult height of the 54 children who had less than a 2-yr delay in the onset of treatment was not significantly different from their MPH, and 21 children exceeded MPH. Final height SD score correlated positively with duration of treatment (P < 0.01), midparental height (P < 0.001), predicted height at the start of treatment (P < 0.001), and growth velocity during the last year of treatment (P < 0.001) and correlated inversely with delay in the onset of treatment (P < 0.001), age at the start of treatment (P < 0.001), bone age at the start of treatment (P < 0.001), bone age at the end of treatment (P < 0.001), breast stage at the start of treatment (P = 0.02), and bone age minus chronological age at the start of treatment (P = 0.001). We conclude that LHRH agonist treatment improves the final height for children with rapidly progressing precocious puberty treated before the age of 8 yr for girls or 9 yr for boys. Less delay in the onset of treatment, longer duration of treatment, and lower chronological and bone age at the onset of treatment all lead to greater final height. All children with onset of pubertal symptoms before age 8 in girls and age 9 in boys should be evaluated for possible treatment. Treatment is appropriate in children with rapidly progressing puberty, accelerated bone maturation, and compromise of adult height prediction, regardless of bone age or chronological age at time of evaluation. However, once treatment is considered appropriate, it should be initiated quickly, because longer delays lead to shorter final height. In addition, the longer the treatment is continued, the greater is the final height outcome.
Subject(s)
Body Height/drug effects , Gonadotropin-Releasing Hormone/therapeutic use , Age Factors , Child , Child, Preschool , Female , Gonadotropin-Releasing Hormone/analogs & derivatives , Humans , Infant , Male , Puberty, Precocious/drug therapy , Triptorelin Pamoate/analogs & derivativesABSTRACT
We have shown that testosterone (T) deficiency per se is associated with marked catabolic effects on protein, calcium metabolism, and body composition in men independent of changes in GH or insulin-like growth factor I production. It is not clear,,however, whether estrogens have a major role in whole body anabolism in males. We investigated the metabolic effects of selective estrogen suppression in the male using a potent aromatase inhibitor, Arimidex (Anastrozole). First, a dose-response study of 12 males (mean age, 16.1 +/- 0.3 yr) was conducted, and blood withdrawn at baseline and after 10 days of oral Arimidex given as two different doses (either 0.5 or 1 mg) in random order with a 14-day washout in between. A sensitive estradiol (E2) assay showed an approximately 50% decrease in E2 concentrations with either of the two doses; hence, a 1-mg dose was selected for other studies. Subsequently, eight males (aged 15-22 yr; four adults and four late pubertal) had isotopic infusions of [(13)C]leucine and (42)Ca/(44)Ca, indirect calorimetry, dual energy x-ray absorptiometry, isokinetic dynamometry, and growth factors measurements performed before and after 10 weeks of daily doses of Arimidex. Contrary to the effects of T withdrawal, there were no significant changes in body composition (body mass index, fat mass, and fat-free mass) after estrogen suppression or in rates of protein synthesis or degradation; carbohydrate, lipid, or protein oxidation; muscle strength; calcium kinetics; or bone growth factors concentrations. However, E2 concentrations decreased 48% (P = 0.006), with no significant change in mean and peak GH concentrations, but with an 18% decrease in plasma insulin-like growth factor I concentrations. There was a 58% increase in serum T (P = 0.0001), sex hormone-binding globulin did not change, whereas LH and FSH concentrations increased (P < 0.02, both). Serum bone markers, osteocalcin and bone alkaline phosphatase concentrations, and rates of bone calcium deposition and resorption did not change. In conclusion, these data suggest that in the male 1) estrogens do not contribute significantly to the changes in body composition and protein synthesis observed with changing androgen levels; 2) estrogen is a main regulator of the gonadal-pituitary feedback for the gonadotropin axis; and 3) this level of aromatase inhibition does not negatively impact either kinetically measured rates of bone calcium turnover or indirect markers of bone calcium turnover, at least in the short term. Further studies will provide valuable information on whether timed aromatase inhibition can be useful in increasing the height potential of pubertal boys with profound growth retardation without the confounding negative effects of gonadal androgen suppression.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Estrogen Antagonists/pharmacology , Nitriles/pharmacology , Triazoles/pharmacology , Adolescent , Adult , Anastrozole , Antineoplastic Agents, Hormonal/adverse effects , Body Composition/drug effects , Body Composition/physiology , Bone and Bones/metabolism , Calcium/metabolism , Estradiol/blood , Estrogen Antagonists/adverse effects , Growth Substances/blood , Hormones/blood , Human Growth Hormone/blood , Humans , Keto Acids/blood , Kinetics , Leuprolide/pharmacology , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Nitriles/adverse effects , Proteins/metabolism , Triazoles/adverse effectsABSTRACT
To evaluate the changes in calcium and bone mineral metabolism associated with early pubertal development, we performed longitudinal measurements of calcium absorption, calcium kinetics, bone mineral content, and hormonal markers related to puberty in a multiethnic group of girls beginning when they were 7 or 8 yr old. Girls were Tanner stage 1 (breast) at the start of the study. They were placed on a 1200 mg/day dietary calcium intake and studied at approximately 6-month intervals until they reached Tanner stage 2 (breast). Results at that time point (PUB) were compared to values obtained approximately 1 yr earlier (LatePRE) and those 1 yr before that (EarlyPRE). We found an increase in calcium absorption comparing PUB to LatePRE (n = 34; 36.6 +/- 8.7% vs. 30.7 +/- 9.9%; P = 0.002). Using whole body, dual energy, x-ray absorptiometry scanning, we found an increase in calcium gain during the LatePRE to PUB period compared with that during the EarlyPRE to LatePRE period (135 +/- 53 vs. 110 +/- 45 mg/day; P = 0.04). Calcium kinetic studies showed a significant increase in the bone calcium deposition rate (Vo+) during the PUB compared to the LatePRE period. Hormonal and biochemical markers of bone development were also significantly increased at PUB compared to LatePRE. Hormonal activity, as evidenced by the unstimulated LH level, was significantly correlated with calcium gain between the LatePRE and PUB studies and the bone calcium deposition rate in the PUB study. These data demonstrate, using multiple independent methods, an increase in calcium utilization associated with the earliest physical signs of puberty.
Subject(s)
Bone Density , Calcium, Dietary , Calcium/metabolism , Puberty/physiology , Black People , Calcium/urine , Child , Estradiol/blood , Female , Follicle Stimulating Hormone/blood , Hispanic or Latino , Humans , Insulin-Like Growth Factor I/metabolism , Intestinal Absorption , Kinetics , Longitudinal Studies , Luteinizing Hormone/blood , Osteocalcin/blood , United States , White PeopleABSTRACT
We studied the time frame of suppression and recovery of estradiol after injection with leuprolide acetate utilizing an ultrasensitive recombinant cell bioassay for estradiol in eight normal premenopausal women. Previous studies have shown suppression of gonadotropins and estradiol at 4 weeks after the depot injection, but no studies have shown the weekly time course of estradiol suppression or recovery. Four women received one 3.75 mg i.m. injection of leuprolide acetate and four received two 3.75 mg doses of leuprolide acetate 4 weeks apart. Estradiol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were measured weekly for 8 to 12 weeks. Estradiol was significantly suppressed to 26.6 +/- 19.3% of baseline values by week 3 after the initial dose of leuprolide acetate and suppressed to 2.7 +/- 3.1% of baseline values by week 4 (p < 0.01 versus baseline). The actual values were less than 14.7 pmol/l (4 pg/ml) in all women by week 4. Estradiol remained suppressed for 8 weeks after one dose of leuprolide acetate and remained suppressed for 6 weeks after a second dose administered 4 weeks later. LH and FSH followed a similar pattern, but only remained suppressed for 7 weeks after one dose of leuprolide acetate and for 6 weeks after two doses. Estradiol levels at baseline were significantly correlated with body mass index (BMI). We also studied one postmenopausal woman. Her baseline estradiol levels were 10.3 pmol/l (2.8 pg/ml) and were suppressed to 3.9 pmol/l (1.1 pg/ml) by 2 weeks after leuprolide acetate. In conclusion, estradiol was suppressed to postmenopausal levels by the end of the first month of treatment with leuprolide acetate, as determined by an ultrasensitive bioassay. Higher doses would need to be tested to determine whether greater suppression can be achieved. The hypothalamic-pituitary-gonadal axis begins to recover 7 weeks after one dose and 6 weeks after a second dose of leuprolide acetate. This confirms the adequacy of 4-week dosing to maintain estradiol and gonadotropin suppression in adult women treated with leuprolide acetate, but raises the question whether less frequent dosing may be possible in some situations, or whether higher doses may be needed in some situations for an even greater degree of estradiol suppression.
Subject(s)
Estradiol/blood , Fertility Agents, Female/pharmacology , Leuprolide/pharmacology , Adult , Biological Assay/methods , Female , Fertility Agents, Female/administration & dosage , Follicle Stimulating Hormone/blood , Humans , Leuprolide/administration & dosage , Luteinizing Hormone/blood , Middle Aged , Multivariate Analysis , Pilot Projects , Postmenopause/blood , Premenopause/bloodABSTRACT
OBJECTIVE: Estradiol levels in girls with premature thelarche have not previously been well defined because of the lack of adequate sensitivity of previously available estradiol assays. The ultrasensitive recombinant cell bioassay for estradiol has made the study of estradiol levels in premature thelarche possible. We hypothesized that girls with premature thelarche have higher estradiol levels than normal prepubertal girls. STUDY DESIGN: We used an ultrasensitive recombinant cell bioassay to study estradiol levels in 20 girls with premature thelarche and 15 normal prepubertal girls less than 3 years of age. The 2 groups were compared by Student t test. RESULTS: Estradiol levels were significantly greater in the girls with premature thelarche (8.4 4. 5 pmol/L estradiol equivalents) than in the normal prepubertal girls (3.3 3.5 pmol/L estradiol equivalents; P <.01). The estradiol level was not significantly correlated with age, height, weight, body mass index, age at onset of thelarche, or the presence or absence of ovarian cysts. CONCLUSION: Girls with premature thelarche have significantly higher estradiol levels than normal prepubertal girls. This is consistent with the hypothesis that the mechanism of premature thelarche involves increased estradiol levels rather than increased sensitivity of breast tissue to normal estradiol levels.
Subject(s)
Breast/growth & development , Estradiol/blood , Puberty, Precocious/blood , Biological Assay , Female , Humans , InfantABSTRACT
OBJECTIVE: This study was designed to test the hypothesis that hypothalamic hamartoma causes precocious puberty through a different neuroendocrine mechanism than that of normal puberty or of idiopathic precocious puberty. DESIGN AND PATIENTS: We compared the pattern of gonadotrophin secretion among 4 girls with precocious puberty due to hypothalamic hamartoma, 27 girls with idiopathic precocious puberty, and 14 girls with normal puberty. All subjects were breast stage 3 or 4. Blood samples were obtained every 20 min for 4 h during the day (1.000 hours to 1400 h) and night (22.00 hours to 0200 h). MEASUREMENTS: LH, FSH, and prolactin were measured in each blood sample. Girls also underwent LHRH-stimulation with measurement of LH and FSH before and after stimulation. RESULTS: There were no significant differences in mean LH level, LH peak amplitude, or LH or FSH peak frequency during either the day or the night among the three diagnostic groups. However, the mean +/- SD LHRH-stimulated peak LH levels were greater in girls with hypothalamic hamartoma than in girls with normal puberty or with idiopathic precocious puberty (194 +/- 142 vs 85 +/- 60 or 66 +/- 54 IU/l, respectively, P < 0.05). The LHRH-stimulated peak FSH level in girls with hypothalamic hamartoma exceeded the level for the normal pubertal girls (31 +/- 19 vs 17 +/- 7 IU/l, P < 0.05), but not the level for the girls with idiopathic precocious puberty (25 + 12 IU/l). The peak LH to peak FSH ratio in the girls with hypothalamic hamartoma exceeded the ratio for the girls with idiopathic precocious puberty (7.3 +/- 3.9 vs 2.6 +/- 3.0 IU/l, P < 0.05), but not the ratio for the normal pubertal girls (5.0 + 2.9). There were no significant differences in mean prolactin level, peak amplitude or frequency, or in the ratio of mean night to mean day prolactin, among the 3 diagnostic groups. CONCLUSIONS: We conclude that spontaneous gonadotrophin and prolactin secretion are similar among girls with hypothalamic hamartoma, idiopathic precocious puberty, or normal puberty. However, the increased LHRH-stimulated peak LH in the girls with hypothalamic hamartoma suggests subtle differences in neuroendocrine regulation that may underlie their more rapid pubertal maturation.
Subject(s)
Gonadotropins, Pituitary/metabolism , Hamartoma/blood , Hypothalamic Diseases/blood , Puberty, Precocious/blood , Puberty/blood , Adolescent , Analysis of Variance , Child , Child, Preschool , Female , Follicle Stimulating Hormone/blood , Gonadotropin-Releasing Hormone , Gonadotropins, Pituitary/blood , Hamartoma/complications , Hamartoma/physiopathology , Humans , Hypothalamic Diseases/complications , Hypothalamic Diseases/physiopathology , Hypothalamus/drug effects , Hypothalamus/metabolism , Luteinizing Hormone/blood , Prolactin/blood , Puberty, Precocious/etiology , Puberty, Precocious/physiopathology , Secretory Rate/drug effectsABSTRACT
The purpose of this study was to investigate 24-h estradiol and leptin levels in obese and nonobese children to further understand the roles of estradiol and leptin in obesity and puberty. We measured serum estradiol, leptin, insulin, glucose, and GH levels every hour for 24 h in 18 obese (12 females and 6 males) and 30 nonobese (11 females and 19 males) prepubertal and early pubertal (stages 1-2) children. Bone age and dual energy x-ray absortiometry (DEXA) were obtained upon completion of the 24-h study. Obese children were significantly younger than nonobese children, with no difference in pubertal stage, height, or bone age between the 2 groups. Obese children had greater bone age to chronological age ratios than nonobese children, indicating a more advanced rate of bone maturation. Mean 24-h estradiol levels correlated significantly with chronological age and bone age as well as with insulin-like growth factor I, insulin-like growth factor-binding protein-3, dehydroepiandrosterone sulfate, mean 24-h GH, and lean body mass. Mean 24-h estradiol levels did not differ between obese and nonobese children [1.65+/-1.47 us. 2.75+/-3.30 pmol/L (0.45+/-0.40 vs. 0.75+/-0.90 pg/mL), respectively]. Similar mean 24-h estradiol levels in obese and nonobese children are consistent with the increased bone maturation of the obese children. Estradiol did not correlate significantly with DEXA fat mass, body mass index, or arm fat measures of adiposity. Obese children had higher 24-h mean leptin concentrations than nonobese children (28.6+/-17.4 vs. 6.8+/-7.1 ng/mL; P < 0.001). Leptin concentrations positively correlated with DEXA fat mass, body mass index, and arm fat measurement of adiposity. Girls had higher 24-h mean leptin levels than boys when controlling for adiposity. Estradiol and leptin concentrations fluctuated over a 24-h period in both groups, with all children having higher leptin concentrations at night and higher estradiol concentrations in the morning. This diurnal rhythm was of a similar pattern, but at higher levels for leptin and lower levels for estradiol in the obese children compared to nonobese children. There was no significant correlation between estradiol and leptin levels. Bone mineral density, as measured by DEXA, did not differ between obese and nonobese children. Similar bone mineral density values in obese and nonobese children are consistent with the increased bone maturation of the obese children. Bone mineral density was not correlated with estradiol or leptin level in these children. In conclusion, obese children had similar estradiol levels and equivalent bone ages at a younger chronological age than nonobese children. Leptin was higher in these obese children, but did not correlate with estradiol level or bone age. These findings suggest that the role of leptin in both obesity and pubertal development is not directly correlated with the estradiol level.
Subject(s)
Bone Density/physiology , Bone Development/physiology , Child Development/physiology , Estradiol/blood , Obesity/metabolism , Proteins/analysis , Child , Circadian Rhythm/physiology , Female , Humans , Leptin , Male , Obesity/blood , Obesity/physiopathology , Osmolar Concentration , Reference ValuesABSTRACT
For more than 60 years, soy-based infant formulas have been fed to millions of infants worldwide and studied in controlled clinical research. These products provide essential nutrients required for normal growth and development. The safety of isoflavones in soy-based products, including infant formulas, has been questioned recently owing to reports of possible endocrine effects in animals and in cultured cells. The literature offers no evidence of endocrine effects in humans from infant consumption of modern soy-based formulas. Growth is normal and no changes in the timing of puberty or in fertility rates have been reported in humans who consumed soy formulas as infants. Consequently, soy-based infant formulas continue to be a safe, nutritionally complete feeding option for most infants.
Subject(s)
Endocrine Glands/physiology , Infant Food , Isoflavones , Soybean Proteins , Animals , Growth , Humans , Infant , Infant Nutritional Physiological Phenomena , Isoflavones/adverse effects , Milk , Milk, Human , Soybean Proteins/adverse effectsABSTRACT
Although treatment of girls with precocious puberty should ideally restore estradiol levels to the normal prepubertal range, treatment effectiveness has usually been monitored by gonadotropin levels because estradiol RIAs have lacked sufficient sensitivity to monitor treatment effectiveness. We hypothesized that a recently developed ultrasensitive recombinant cell bioassay for estradiol would have sufficient sensitivity to demonstrate a dose-dependent suppression of estradiol during LH-releasing hormone agonist treatment and to determine whether currently used doses are able to suppress estradiol levels to the normal prepubertal range. Twenty girls with central precocious puberty were assigned randomly to receive deslorelin for 9 months at a dose of 1, 2, or 4 micrograms/ kg.day. A significant dose-response relationship was observed, with mean +/- SD estradiol levels of 16.7 +/- 6.1, 7.9 +/- 1.6, and 6.5 +/- 0.7 pmol/L at the doses of 1, 2, and 4 micrograms/kg.day, respectively (P < 0.01). The highest dose suppressed estradiol levels to just above the 95% confidence limits for normal prepubertal girls (< 0.07-6.3 pmol/L). We conclude that the ultrasensitive bioassay for estradiol has sufficient sensitivity for monitoring the response to LH-releasing hormone agonist treatment of central precocious puberty. Additionally, the observation that the deslorelin dose of 4 micrograms/kg.day did not fully restore estradiol levels to the normal prepubertal range suggests that some girls with precocious puberty may require higher doses to receive the maximal benefit of treatment. We suggest that restoration of estradiol levels to the normal prepubertal range should be the ultimate biochemical measure of efficacy, as estradiol is the key hormone that accelerates growth rate, bone maturation rate, and breast development in girls with precocious puberty.
Subject(s)
Estradiol/blood , Puberty, Precocious/drug therapy , Receptors, LHRH/agonists , Biological Assay , Child , Dose-Response Relationship, Drug , Female , Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/therapeutic use , Humans , Puberty, Precocious/blood , Sensitivity and Specificity , Triptorelin Pamoate/analogs & derivativesABSTRACT
A limited number of reports of estrogen levels in prepubertal and early pubertal boys have been published because previous estrogen assays have lacked adequate sensitivity to quantitate circulating estrogen concentrations. Development of a new ultrasensitive assay has permitted measurement of estrogen levels in 23 normally growing boys progressing through puberty. Concentrations were measured at approximately 4-month intervals over a 5- to 8-yr period. The levels increased with maturation in all and correlated directly with chronological age, bone age, weight, height, pubertal stage, and testosterone and insulin-like growth factor-I levels. Of these factors, the level of testosterone had the greatest influence on the estrogen concentration. The time from peak growth velocity also significantly correlated with estrogen level. The estrogen level correlated positively with growth velocity before the time of peak growth velocity and negatively after peak growth velocity. The estrogen levels first increased significantly an average of 3 yr after pubertal onset and reached a peak by 5 yr after pubertal onset. Peak growth velocity was attained an average of 3 yr after pubertal onset. The greatest increase in the rate of rise of the estrogen level was an 11-fold rise during the year in which puberty began. The next most significant increase was a 4.8-fold rise 3 yr after pubertal onset. With respect to pubertal stage, the greatest absolute change occurred from stage 4 to stage 5 and the greatest fold change occurred from stage 1 to stage 2. The estrogen level did not significantly correlate with the 24-h GH level. In conclusion, circulating estrogen levels are very low in all boys prepubertally and rise steadily during adolescent development. The estrogen level is closely related to testosterone concentration and to the time of peak growth velocity. These findings are consistent with the hypothesis that estrogen at low levels augments skeletal growth and maturation in boys (as well as girls). They are also consistent with the hypothesis that continued exposure to estrogen leads to epiphyseal fusion. Further studies are required to define the separate and combined roles of estrogen, GH, and testosterone, as well as other factors, on growth and sexual development at puberty.
Subject(s)
Biological Assay/statistics & numerical data , Estrogens/blood , Puberty/physiology , Age Determination by Skeleton , Body Height , Body Weight , Child , Growth Hormone/blood , Humans , Insulin-Like Growth Factor I/metabolism , Longitudinal Studies , Male , Multivariate Analysis , Saccharomyces cerevisiae/drug effects , Sensitivity and Specificity , Testosterone/bloodABSTRACT
The development of well tolerated, potent, specific, and nontoxic aromatase inhibitors for the treatment of postmenopausal women with estrogen-dependent breast cancer has been a major goal of recent studies. The third generation inhibitors now under investigation are nearly 10,000-fold more potent than first generation compounds. Currently available RIAs for plasma estradiol lack sufficient sensitivity to measure levels during aromatase inhibition and, thus, to assess drug potency precisely. The availability of an ultrasensitive bioassay for estradiol provided the opportunity to accurately assess the potency of a new third generation triazole aromatase inhibitor, letrozole (CGS 20267). We used this assay to measure estradiol levels in 14 women with metastatic breast cancer given letrozole at doses of 100 micrograms to 5.0 mg/day over a 12-week period. The lack of differences between doses and sampling times allowed pooling of data. Basal estradiol levels of 7.2 +/- 1.9 pmol/L (mean +/- SEM, 1.95 +/- 0.52 pg/mL) fell to 0.26 +/- 0.11 pmol/L (0.07 +/- 0.03 pg/mL) during the first 6 weeks of therapy and to 0.48 +/- 0.18 pmol/L (0.13 +/- 0.05 pg/mL) during the second 6 weeks of therapy. Although plasma estradiol levels measured by RIA were significantly correlated with levels measured by bioassay (r = 0.79; P < 0.01), the degree of suppression assessed by the bioassay (95 +/- 2% after 6 weeks) was greater than that determined by the RIA (81 +/- 4%), presumably due to improved ability to measure very low estradiol levels. We conclude that plasma estradiol is suppressed by letrozole to lower levels than previously observed, with equivalent suppression at all doses studied. A slight, although not statistically significant, rebound in estradiol levels occurs during the second 6 weeks of therapy compared to the first 6 weeks. Maximum inhibition of aromatase is achieved at letrozole doses as low as 100 micrograms.
Subject(s)
Aromatase Inhibitors , Biological Assay/methods , Breast Neoplasms/blood , Breast Neoplasms/drug therapy , Estradiol/blood , Nitriles/therapeutic use , Triazoles/therapeutic use , Female , Humans , Letrozole , Radioimmunoassay , Recombination, Genetic , Sensitivity and SpecificityABSTRACT
In mammals, longitudinal bone growth results from the precise coupling of chondrogenesis and osteogenesis within the epiphyseal growth plate, a process termed endochondral ossification. The mechanisms coupling chondrogenesis and osteogenesis are unknown. Previous studies have shown that both basic fibroblast growth factor (bFGF) and acidic FGF are expressed by growth plate chondrocytes. Here we show that bFGF, infused directly into the rabbit proximal tibial growth plate, accelerates vascular invasion and ossification of growth plate cartilage. Our results suggest the possibility that bFGF (or a related member of the FGF family) couples osteogenesis to chondrogenesis by attracting vascular and bone cell invasion from the adjacent metaphyseal bone.
Subject(s)
Fibroblast Growth Factor 2/pharmacology , Growth Plate/drug effects , Osteogenesis/drug effects , Animals , Blood Vessels/drug effects , Growth Plate/blood supply , Growth Plate/physiology , Male , Rabbits , Tibia/blood supply , Tibia/drug effectsABSTRACT
We hypothesized that estradiol levels are higher in prepubertal girls than in prepubertal boys and that this greater secretion of estradiol might drive the more rapid epiphyseal development and earlier puberty in girls. Since previous estradiol assays have lacked adequate sensitivity to test the hypothesis of higher estradiol levels in girls, we developed a new ultrasensitive assay to measure estrogen levels. The assay uses a strain of Saccharomyces cerevisiae genetically engineered for extreme sensitivity to estrogen. Yeast were transformed with plasmids encoding the human estrogen receptor and an estrogen-responsive promoter fused to the structural gene for beta-galactosidase. Ether extracts of 0.8 ml of serum were incubated with yeast for 8 h and the beta-galactosidase response was used to determine estrogen bioactivity relative to estradiol standards prepared in charcoal-stripped plasma. The assay was highly specific for estradiol with < 3% cross-reactivity with estrone, estriol, or estradiol metabolites. The detection limit was < 0.02 pg/ml estradiol equivalents (100-fold lower than existing assays). Using this assay, we measured estrogen levels in 23 prepubertal boys (9.4 +/- 2.0 yr) and 21 prepubertal girls (7.7 +/- 1.9 [SD] yr). The estrogen level in girls, 0.6 +/- 0.6 pg/ml estradiol equivalents, was significantly greater than the level in boys, 0.08 +/- 0.2 pg/ml estradiol equivalents (P < 0.05). We conclude that the ultrasensitive recombinant cell bioassay for estrogen is approximately 100-fold more sensitive than previous estradiol assays, that estrogen levels are much lower prepubertally, in both sexes, than reported previously, and that prepubertal girls have 8-fold higher estrogen levels than prepubertal boys.
Subject(s)
Biological Assay/methods , Estrogens/blood , Sex Characteristics , Adolescent , Child , Child, Preschool , Female , Gene Expression Regulation, Fungal , Genetic Engineering , Humans , Male , Puberty , Recombinant Fusion Proteins/biosynthesis , Reproducibility of Results , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Sensitivity and Specificity , beta-Galactosidase/biosynthesis , beta-Galactosidase/geneticsABSTRACT
In humans and other mammals, the release from growth-inhibiting conditions, such as glucocorticoid excess, leads to supranormal linear growth. The prevailing explanation for this catch-up growth involves a central nervous system mechanism that compares actual body size to an age-appropriate set-point and adjusts growth rate accordingly via a circulating factor. Although such a neuroendocrine "sizostat" was hypothesized more than 30 yr ago, its existence has never been confirmed experimentally. Here we show that suppression of growth within a single growth plate by locally administered glucocorticoid is followed by local catch-up growth that is restricted to the affected growth plate. Thus, the catch-up growth cannot be explained by neuroendocrine mechanism but, rather, must arise from a mechanism intrinsic to the growth plate. To explain this finding, we propose that the normal senescent decline in growth plate function depends not on age per se, but on the cumulative number of stem cell divisions, and that glucocorticoid administration, by suppressing stem cell proliferation, delays senescence, resulting in catch-up growth after the growth-inhibiting agent is removed.
Subject(s)
Glucocorticoids/pharmacology , Growth Plate/growth & development , Aging/physiology , Animals , Cell Division/drug effects , Dexamethasone/pharmacology , Dose-Response Relationship, Drug , Femur/cytology , Femur/drug effects , Femur/physiology , Growth Plate/cytology , Growth Plate/drug effects , Male , Rabbits , Tibia/cytology , Tibia/drug effects , Tibia/physiologyABSTRACT
A recent report in Science suggests that human growth occurs in brief bursts, up to 1.65 cm in a single day, separated by extended periods of stasis, lasting up to 63 days. Thus, the organism is proposed to alternate between two states, one with a growth velocity of zero, the other with a mean annualized growth velocity greater than 350 cm/yr. These observations, if correct, suggest the existence of a previously unsuspected hormonal mechanism capable of abruptly switching growth plate cell division on and off and of synchronizing cellular growth not only throughout the growth plate, but presumably throughout all the growth plates in the organism. However, the experimental assessment of short-term growth velocity in the human faces the formidable obstacle of a technical error of measurement that exceeds the mean daily growth rate. Accordingly, we tested the saltatory growth hypothesis by measuring proximal tibial growth in the rabbit, a model in which daily growth rate could be measured more than 15 times more accurately than in the human. The model of saltation and stasis predicts a majority of daily growth velocities clustered around zero, and a minority of high growth velocities, that is, a bimodal distribution. The frequency distribution of observed daily growth velocities instead approximated a single Gaussian distribution, indicating continuous growth. We conclude that linear growth, in the most accurate mammalian system yet studied, is continuous, not saltatory.