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Biomedical subjects

K M Barnes

Publications and source records attributed to K M Barnes.

49 records · Page 3Linked to original sources
PubMed1988

Premature thelarche and central precocious puberty: the relationship between clinical presentation and the gonadotropin response to luteinizing hormone-releasing hormone.

Premature thelarche is a benign condition that affects young girls. In contrast, central precocious puberty is considered a more serious disorder that causes progressive secondary sexual development, accelerated growth and skeletal maturation, early epiphyseal fusion, and short adult stature. Differentiation between these 2 conditions is important, but may be difficult on clinical grounds, since patients with both disorders may present initially as isolated breast development. To examine the potential usefulness of gonadotropin measurements in distinguishing early central precocious puberty from premature thelarche, we measured basal and LHRH-stimulated plasma gonadotropin levels in 58 girls with idiopathic premature breast development. The girls were divided into six clinically distinct groups, based on the severity of clinical presentation, ranging from isolated breast development (group A) to complete secondary sexual development and accelerated growth and skeletal maturation (group F). The mean basal plasma LH levels and the peak LH response to LHRH stimulation were significantly less in girls with isolated thelarche (group A) than in girls with complete sexual development (group F). The mean basal plasma FSH levels did not differ between these groups, but the peak FSH response to LHRH was greater in girls with isolated thelarche than in girls with complete sexual development. Thus, girls with isolated premature thelarche had a FSH-predominant response to LHRH [mean ratio of peak LH to peak FSH, 0.29 +/- 0.10 (+/- SD)], while girls with complete sexual development had a LH-predominant response (peak LH/FSH, 4.16 +/- 1.80). All girls with isolated thelarche had peak LH/FSH ratios less than 1, and all girls with complete sexual development had a ratio greater than 1. Girls with early or intermediate manifestations of central precocious puberty, who had features of puberty in addition to breast development but lacked all of the features of group F, comprised groups B-E. These girls also had intermediate peak LH/FSH ratios, ranging from 0.29 +/- 0.10 (group B) to 3.35 +/- 2.66 (group E). We conclude that girls with early central precocious puberty frequently have LH and FSH responses to LHRH that are indistinguishable from the FSH-predominant responses of girls with isolated thelarche. These data are consistent with the hypothesis that premature thelarche and central precocious puberty may represent different positions along a continuum of hypothalamic LHRH neuron activation.

Breast↗
PubMed1988

Two-year comparison of testicular responses to pulsatile gonadotropin-releasing hormone and exogenous gonadotropins from the inception of therapy in men with isolated hypogonadotropic hypogonadism.

Men with the complete form of isolated hypogonadotropic hypogonadism (initial mean testes volume less than 4 mL) require 2 or more yr of exogenous gonadotropin therapy combining hCG and human menopausal gonadotropin (hMG) to achieve maximal, but subnormal, testis size and sperm output. To test whether pulsatile GnRH therapy, which more closely mimics normal hormonal stimulation, would accelerate or further augment testicular growth, hasten the onset of sperm production, and/or increase sperm output more than occurs during conventional exogenous gonadotropin therapy, we administered either hCG/hMG or GnRH from the inception of therapy to 2 comparable groups of men with complete IHH (initial testicular volume, less than 4 mL) and compared their testicular responses during the first 2 hr of therapy. Five men were treated with pulsatile GnRH in doses of 143-714 ng/kg every 2 h, sc, while 11 other men received hCG (2000 IU) and hMG (75 IU FSH and 75 IU LH) im 3 times/week. In the GnRH-treated men, the mean plasma total and free testosterone levels during therapy rose to within the normal range, but were significantly lower (P less than 0.01 and P less than 0.02, respectively) than those in the hCG/hMG-treated men. The mean plasma estradiol concentrations during therapy were within the high normal range and were similar in the two groups. The mean plasma FSH levels achieved in the GnRH-treated men were significantly (P less than 0.01) and 1.3- to 3.2-fold higher than those in the hCG/hMG-treated men. The mean testicular size achieved in the GnRH-treated men was not significantly different from that in the hCG/hMG-treated men (P = 0.08); the mean testicular volumes after 2 yr were 4.8- and 4.3-fold the pretreatment values in the GnRH and hCG/hMG groups, respectively. After 12 months of therapy, sperm production had occurred in one man in the GnRH group and in no subject in the hCG/hMG group. After 24 months, two men in the GnRH group and eight men in the hCG/hMG group produced sperm. Thus, 40% of the GnRH-treated men and 80% of the hCG/hMG-treated men (P = NS) produced sperm after 2 yr of therapy. The sperm concentrations in all men were below 5 million/mL and were comparable in the two groups (P = NS). These results suggest that pulsatile sc GnRH therapy for the first 2 yr does not accelerate or enhance testicular growth, hasten the onset of sperm production, or increase sperm output significantly compared to hCG/hMG.

Adult↗
PubMed1987

Dissociation of adrenarche and gonadarche in precocious puberty and in isolated hypogonadotropic hypogonadism.

Adrenarche is a developmental change of the adrenal gland that results in increased secretion of adrenal androgens. This maturational process generally begins several years before activation of the hypothalamic-pituitary-gonadal axis (gonadarche). To study further the relationship between adrenarche and gonadarche, we examined adrenarche in patients with precocious puberty and in patients with isolated hypogonadotropic hypogonadism. Plasma dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and cortisol were measured basally and during an infusion of ACTH in 50 children with precocious puberty, 5 patients with isolated hypogonadotropic hypogonadism, 7 preadrenarchal children with constitutional short stature, 44 normal pubertal children, and 40 normal adults. Children with precocious puberty did not have a corresponding advance in the timing of adrenarche. Their basal and ACTH-stimulated adrenal androgen levels were markedly lower than those of normal children matched for pubertal stage (P less than 0.05) and were only slightly greater than those reported for normal children of the same age. Similarly, patients with isolated hypogonadotropic hypogonadism and delayed puberty had no corresponding delay of adrenarche. Their adrenal androgen levels were appropriate for chronological age. Thus, these data provide further support for the hypothesis that adrenarche and gonadarche are independent maturational events controlled by separate mechanisms.

Adolescent↗
PubMed1986

Luteinizing hormone releasing hormone analogue therapy for central precocious puberty. Long-term effect on somatic growth, bone maturation, and predicted height.

The long-acting analogue of luteinizing hormone releasing hormone, D-Trp6-Pro9-NEt-LHRH (LHRHa), is effective in the short-term treatment of central precocious puberty. We report the results of two to four years of LHRHa therapy in 27 children with this disorder. Secondary sex characteristics regressed in most patients. Sex steroid levels and basal and LHRH-stimulated gonadotropin levels remained suppressed compared with pretreatment values. Linear growth rates decreased from 11.0 +/- 0.8 (SEM) cm/yr before treatment to 5.7 +/- 0.4 cm/yr at two years of treatment and 3.7 +/- 0.7 cm/yr at four years of treatment. Predicted heights by the Bayley-Pinneau method increased from 156.4 +/- 2.0 cm before treatment to 162.3 +/- 2.3 cm at two years and 163.4 +/- 2.4 cm at three years. Five patients treated for four years had a mean increase in predicted height of 5.5 cm. To date no adverse effects have been observed. However, the ultimate safety of this analogue is not known. We conclude that LHRHa appears to be an effective long-term therapy for central precocious puberty.

Body Height↗
PubMed1985

Evidence that synthetic 31-amino acid inhibin-like peptide lacks inhibin activity.

We studied the biological activity of a recently characterized 31-amino acid inhibin-like peptide (ILP) using a synthetic preparation. While the material yielded a single component on chromatography, amino acid sequence analysis suggested that only 30% of the molecules possess the complete structure. Bioactivity was tested in vitro using whole pituitaries from 25 day-old male Sprague-Dawley rats. Pituitaries were incubated with 500 ng/ml of the ILP preparation or vehicle alone for 60 min, followed by a 3 h exposure to 2 ng/ml of luteinizing hormone releasing hormone (LHRH) or its diluent. In the ILP-incubated pituitary media, no significant suppression of basal FSH and LH release or stimulated FSH release was observed, while a significant increase in stimulated LH release was seen (p less than 0.05). An in vivo bioassay study was performed on 38 day-old male Sprague-Dawley rats. Test animals were injected with 0.1, 1, 10 or 20 mcg of ILP immediately after castration, and 10 and 24 h later. Control animals received bovine serum albumin or vehicle alone. There were no statistically significant differences in serum LH or FSH concentrations taken at 30 h after castration between the ILP-treated rats and controls. Possible reasons for our inability to demonstrate inhibin bioactivity (selective FSH suppression) with this ILP preparation include: Only about 30% of the peptides had the complete amino acid sequence. Other peptides with deletions might have acted as antagonists, thus obscuring the inhibin bioactivity. The 31-amino acid ILP may not be the authentic inhibin molecule. We suggest that further studies are needed to determine the true identity of inhibin.

Animals↗
PubMed1984

A comparison of two methods for detecting hormone peaks: the effect of sampling interval on gonadotropin peak frequency.

There is no consensus on the optimum method to identify gonadotropin pulses in serum. We compared two approaches for detecting gonadotropin peaks. The first employed the conventional criterion of an increment from nadir to peak of 3 times the intraassay coefficient of variation (3 CV). The second identified peaks by Student's t test to quadruplicate measurements at each time point. We obtained blood samples every 5 min for 6 h from four women in the follicular phase. We also constructed control or noise series by subdividing single serum pools into consecutively labeled aliquots. Any variations in hormone concentration in the noise series that were identified as peaks were, by definition, false positive peaks. We evaluated the effect of sampling interval on gonadotropin peak detection by omitting data to simulate sampling every 10, 15, or 20 min. The 3 CV approach identified numerous false positive peaks in the noise series and detected as many peaks in the noise series as it did in the patient series. Increasing the sampling frequency from every 20 to every 5 min nearly doubled the apparent peak frequencies in both the patient and the noise series (P less than 0.025). By contrast, the t test method detected far fewer false positive peaks and significantly more peaks in the patient series than in the noise series. Increasing the sampling frequency from every 20 to every 5 min resulted in a 50-75% increase in peak frequency by the t test method. This increase in peak frequency appeared to result from improved detection of small peaks, because samples were obtained nearer the true peaks and nadirs. The resulting increase in the nadir to peak increment made it more likely that a small peak would achieve statistical significance. We conclude that increasingly stringent criteria for pulse detection should be applied as one increase the sampling frequency, and that the t test approach is a more valid method than the 3 CV approach because it yields significantly fewer false positive peaks.

Adolescent↗
PubMed1981

Developmental changes in rabbit and dog adrenal function: a possible homologue of adrenarche in the dog.

Histologic, hormonal, and enzymatic studies were performed in the rabbit and dog to identify maturational changes similar to human adrenarche. Development of an adrenal reticular zone was observed in both the rabbit and dog, analogous to the change in the man. Plasma dehydroepiandrosterone (DHA) and androstenedione (delta 4-A) increased significantly in postpubertal compared to prepubertal male rabbits and dogs, but the increases were much smaller than those reported in man. Orchiectomy reduced plasma DHA and delta 4-A of adult rabbit and dog to near undetectable levels, suggesting a primarily testicular origin. The activities of adrenal microsomal 17-hydroxylase and 17,20-desmolase in the orchiectomized rabbit and dog were subsequently measured to explain this apparent low adrenal contribution to DHA and delta 4-A. Adrenal 17-hydroxylase activity in the rabbit ad 17,20-desmolase activity in both the rabbit and dog were significantly lower than in an adrenal androgen-secreting primate (cynomolgus macaque). Adrenal 17-hydroxylase activity in the dog, measured 1 wk after castration, doubled after sexual maturation (P less than 0.001). This change was paralleled by a significant rise in basal and ACTH-stimulated plasma 17-hydroxyprogesterone in the intact dog (P less than 0.05). Because adrenal 17-hydroxylase activity has been shown to increase during adrenarche in man, this change may be homologous to human adrenarche.

Adrenal Glands↗
PubMedDate not supplied

Recovery of reproductive function in rats treated with the aromatase inhibitor fadrozole.

The aromatase inhibitor, fadrozole hydrochloride (CGS 16949A), was developed for the treatment of breast cancer, and has not been available for pediatric use because of the lack of information about potential reproductive toxicology. To determine the effect of fadrozole on subsequent fertility and reproductive performance in rats, peripubertal male and female Sprague-Dawley rats (10/group) were given fadrozole by oral gavage once a day for 60 consecutive days (age 21 through 80 d) at a dose of 0, 1200, or 6000 micrograms/kg/d (dose range in women with breast cancer: 60 to 240 micrograms/kg/d). Following a 30-d recovery period (days 81 through 111 of age), cohabitation with untreated rats of the opposite sex was accomplished for 30 d or until positive evidence of mating was obtained (daily vaginal smears). The nonfadrozole-treated males used for cohabitation were proven fertile breeders; the females were virgin with proven 4-d estrous cycles. The duration of pregnancy, number, sex, condition, and body weight of pups were determined. Pregnant rats were weighed on gestational days 7, 14, and 20. There was a profound decrease in the number of estrous cycles at both dose levels of fadrozole compared to the control (P < 0.001). During the 30-d recovery period, estrous cycles were reestablished within a few days in the treated rats and the number and length of estrous cycles were not statistically different between fadrozole-treated and control rats. The gestational body weights of fadrozole-treated and untreated females did not differ significantly. There were no statistically significant differences in the number of matings/number of pairings, gestational length, mean live pups/litter, % pups born alive/litter, and % male pups/litter in the three groups (vehicle-, low-, and high-dose fadrozole-treated females, cohabited with untreated males and fadrozole-treated males, cohabited with untreated females). Thus, young male and female rats treated for 60 d with large doses of fadrozole had no detectable adverse effect on subsequent reproductive function.

Administration, Oral↗