Robert P. Kelch

Gonadotropin-Releasing Hormone: Role of Pulsatile Secretion in the Regulation of Reproduction

Reproductive function in humans changes markedly during life and is usually divided into four stages. During the initial stage, which begins early in fetal life and ends in infancy, gonadotropins a...

Insulin and blood pressure during weight loss in obese adolescents.

The role of insulin in the regulation of blood pressure was evaluated in 50 obese adolescents before and after a 20-week weight loss program. When compared with 10 nonobese adolescents, the obese subjects had significantly higher systolic, diastolic, and mean arterial pressures (p = 0.005), an elevated 24-hour urinary sodium excretion (p = 0.002), an elevated fasting insulin concentration (p = 0.001), and an abnormal insulin response to an oral glucose tolerance test (sum of the insulins at 0, 1, and 2 hours post-oral glucose load; p = 0.001). We also observed a significant correlation between systolic and diastolic blood pressure (age and sex normalized) and body weight (r = 0.57, p less than 0.01 and r = 0.7, p less than 0.01), fasting insulin (r = 0.49, p less than 0.01 and r = 0.54, p less than 0.01), and sum of insulins (r = 0.42, p less than 0.01 and r = 0.46, p less than 0.01). To study the effect of weight loss on the relationship between blood pressure and insulin, the obese subjects were randomly assigned to three groups: 15 to a diet and behavior change group, 18 to a diet, behavior change, and exercise group, and 17 to an obese control group. Compared with the obese control group, the two weight loss groups each experienced a significant decrease in insulin (p less than 0.01), sum of the insulins (p less than 0.01), and blood pressure (p less than 0.01). The decrease in blood pressure during the weight loss program significantly correlated with the change in both insulin and body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Gonadotropin-Releasing Hormone Pulses: Regulators of Gonadotropin Synthesis and Ovulatory Cycles

The data reviewed present evidence that the pattern of GnRH secretion is an important factor in the regulation of gonadotropin subunit gene expression, gonadotropin synthesis, and secretion. The information on regulation of mRNA expression by GnRH pulses should be considered with some caution, as the experiments were performed in male rats and may not accurately reflect events in female primates or humans. However, an overall pattern emerges which suggests that common factors may be involved in all mammalian species. If current evidence is correct, and only a single gonadotropin-releasing hormone exists, then mechanisms to differentially regulate the three gonadotropin genes may involve changes in GnRH secretion. Alterations in GnRH pulse frequency and amplitude are recognized by the pituitary gonadotrope cell and could be the mechanism used to effect differential expression of the gonadotropin subunit genes. Differential regulation of subunit gene expression would be expected to be critically important in the establishment of pubertal maturation, and subsequently in the maintenance of ovulatory cycles in women. Our hypotheses, proposing a major role of pulsatile GnRH secretion in the regulation of human reproduction, are summarized in schematic form in Fig. 14 for men and Fig. 15 for women. In utero and during the first few months of life, GnRH is secreted at a relatively fast frequency (approximately 1 pulse/hour). During the first year, GnRH secretion is inhibited and both the amplitude and apparent frequency of pulsatile release is markedly reduced. The mechanisms involved in inhibiting GnRH release remain unclear in humans. Similarly, the mechanisms involved in the disinhibition of GnRH secretion, which first occurs during sleep at the initiation of puberty, are unclear, but in humans do not appear to involve opiates. In males, the increased frequency and amplitude of GnRH secretion favor LH synthesis and release, which in turn stimulates testosterone secretion (Fig. 14). Testosterone acts at the hypothalamus, perhaps through opioid mechanisms, to inhibit GnRH pulse frequency and to maintain a regular pattern of pulses occurring approximately every 90-110 min in adult males. In females, the mechanisms involving alterations in the patterns of GnRH secretion to regulate reproduction appear more complex. This may reflect the need to differentially synthesize and secrete FSH and LH at different times during reproductive cycles to allow orderly follicular maturation and ovulation. As shown in Fig. 15, we hypothesize that the events during the first decade of life and through the initiation of nocturnal GnRH secretion at puberty are similar in both sexes.(ABSTRACT TRUNCATED AT 400 WORDS)

Sexual precocity in association with septo-optic dysplasia and hypothalamic hypopituitarism.

Sexual precocity in association with abnormalities of the central nervous system is well known, but its occurrence with hypothalamic hypopituitarism is most unusual. We report five females with septo-optic dysplasia, blindness, and multiple pituitary tropic hormone deficiencies: all were growth hormone and adrenocorticotropic hormone deficient; two had diabetes insipidus; one had sexual precocity, and one had early pubertal maturation, whereas three were prepubertal and responded to administration of synthetic gonadotropin-releasing hormone. These children retained ability to secrete gonadotropins despite the presence of anterior hypothalamic disease. Experimental data from primates plus our observations on these patients raise questions about the role of the anterior hypothalamus in gonadotropin secretion in man.

FSH Stimulation of Leydig Cell Function in the Hypophysectomized Immature Rat

Summary FSH treatment of hypophysec-tomized immature rats increased testicular weight, increased the number of LH receptors per testis, and increased the in vitro testicular testosterone production in response to LH. The increase observed in all three parameters was related to the duration of FSH treatment. The testicular response to LH was enhanced to a greater extent than the number of LH receptors. The specificity of the FSH effect was indicated by the observation that administration of LH had no effect on testicular weight or number of LH receptors. LH administration did not increase the in vitro testicular response to LH, but appeared to prevent the decrease in this response observed in saline-injected controls. We thank Carol Craig for expert technical assistance. We also thank Dr. A. F. Parlow for the rat LH, NIAMDD-Rat LH-I-3, and NIAMDD for supplying the NIH-FSH-S11 and NIH-LH-S19. This study was supported by NIH Grant No. HD-08358.

Maintaining the Public Trust in Clinical Research

Financial conflicts of interest are present in many types of medical research. Until recently there has been no unified effort to address the many problems that arise because of such conflicts. The Association of American Medical Colleges recently approved guidelines for dealing with individual, as opposed to institutional, conflicts of interest. In this Sounding Board article, Kelch outlines the many features of the guidelines and urges their widespread adoption.

Estimation of GnRH Pulse Amplitude during Pubertal Development

Summary: Fourteen children between 2.5 and 16 years of age were studied to provide a quantitative estimate of the changes in gonadotropin-releasing hormone (GnRH) pulse amplitude in hypophysial portal plasma during puberty. Responses to physiologic doses of synthetic GnRH were measured [induced luteinizing hormone (ΔLH) and induced follicle-stimulating hormone (ΔFSH)] and compared with spontaneous fluctuations in gonadotropins [spontaneous luteinizing hormone (ΔaLH) and spontaneous follicle-stimulating hormone (ΔaFSH)]. One to four low-dose (0.0125 or 0.025 μg/kg IV) pulses of GnRH were given every 2 hr between 0800 and 1600 or 2200 and 0400 hr. Maximal peripheral plasma concentrations of GnRH one mm after pulses averaged 107 ± 25 pg/ml (S.E.) (0.0125 μg/kg dose) and 218 ± 33 pg/ml (0.025 μg/kg dose). In early pubertal children, the maximal ΔLH was similar to or less than the maximal nocturnal ΔaLH (maximum, ΔLH 7.0 ± 0.2 versus maximum ΔaLH 7.0 ± 1.3 mIU/ml in boys, 7.0 ± 1.2 versus 16.0 ± 3.0 mIU/ml in girls). Luteinizing hormone (LH) responses were low or undetectable in children whose bone ages were less than 10 years. When discernible, LH pulse frequency was similar during daytime and nighttime sampling periods in early pubertal boys. However, two hourly injections of GnRH given during the day did not simulate the initial nocturnal rise in LH. Overall mean ΔFSH and ΔaFSH were similar in three prepubertal female patients (3.0 ± 0.2 versus 2.8 ± 0.2 mIU/ml). ΔFSH was greater than ΔaFSH in two patients with gonadal dysgenesis (bone ages, 2.5 and 5 years) and in one prepubertal girl. The gonadotropin responses seen in early pubertal children suggest that the amplitude of nocturnal GnRH pulses is equal to or greater than that previously reported in normal men.Speculation: Direct measurement of hypophysial portal plasma concentrations of GnRH in human beings is unpractical. Nevertheless, detailed comparison of spontaneous fluctuations in plasma follicle-stimulating and luteinizing hormones with gonadotropin responses induced by a known concentration of exogenous gonadotropin-releasing hormone (GnRH) should provide reasonable estimates of GnRH pulse amplitude. The current studies suggest that: (1) in early pubertal children, the amplitude of nocturnal GnRH pulses equals or exceeds that of normal men; (2) the initial nocturnal rise in plasma LH characteristically noted in early pubertal boys is the result of a transient increase in the frequency of GnRH secretion; and (3) if GnRH is secreted episodically before puberty, GnRH pulse amplitude is low.

Congenital adrenal hypoplasia and isolated gonadotropin deficiency

Abstract Congenital adrenal hypoplasia with gonadotropin deficiency is a rare X-linked recessive disorder that usually manifests with symptoms of adrenal insufficiency early in infancy. Adequate replacement therapy with glucocorticoids, mineralocorticoids, and salt has resulted in an increased survival. Slow growth and failure to undergo sexual maturation during the adolescent years usually ensues, secondary to hypogonadotropic hypogonadism. The X-linked congenital adrenal hypoplasia locus has been mapped to region Xp21.3-p21.2. Interstitial deletions of the X chromosome overlapping this region have been observed to cause complex clinical problems, with adrenal hypoplasia as a prominent component. Within a family segregating the disease, there is a 50% risk of having an affected male and a 50% risk of having a carrier female; considerations of genetic heterogeneity, possible chromosomal abnormalities, and prenatal diagnostic studies warrant medical genetic evaluations. The following case presentations illustrate the clinical spectrum of this condition.

Selective inhibition of follicle-stimulating hormone secretion by estradiol. Mechanism for modulation of gonadotropin responses to low dose pulses of gonadotropin-releasing hormone.

Prepubertal girls and gonadotropin-releasing hormone (GnRH)-deficient females secrete follicle-stimulating hormone (FSH) preferentially in response to intravenous GnRH. With continued pulsatile GnRH stimulation, FSH secretion is reduced when plasma estradiol (E2) is increasing. To delineate the mechanisms involved in these changing gonadotropin responses, e studied the effect of low dose (0.025 micrograms/kg) pulsatile injections of GnRH in females with varying degrees and/or duration of endogenous GnRH deficiency (idiopathic panhypopituitarism, PHP; isolated growth hormone deficiency, IGHD; isolated gonadotropin deficiency, IGD; and anorexia nervosa, AN; both at low body weight and after weight regain). In patients presumed to have the most severe GnRH deficiency (PHP), responses of both FSH and luteinizing hormone (LH) were small and delayed, and no increase in plasma estradiol occurred during the 5 d of GnRH injections. In patients previously exposed to prepubertal or adult levels of endogenous GnRH secretion (IGHD, IGD, AN at low body weight), a rapid initial FSH response occurred that subsequently declined when plasma estradiol rose to concentrations greater than 40-50 pg/ml. Prior therapy with estrogen (micronized estradiol, Estrace) abolished FSH responses but LH responses were only slightly impaired. The degree of FSH response was dependent upon the time of initiation of estrogen relative to the onset of GnRH injections. Administration of estrogen after the first GnRH injection inhibited gonadotropin responses, whereas later estrogen therapy (after 1 d of GnRH pulses) blunted the GnRH induced FSH secretion without significantly impairing the LH response. In weight-regained anorexic patients who had spontaneous pulsatile LH secretion and a mean basal plasma estradiol concentration of 53 +/- 15 pg/ml, administration of GnRH pulses did not change plasma LH and a minimal FSH response was seen. The data indicate that the pattern of gonadotropin responses to low dose GnRH injections depends upon the degree of previous exposure of the pituitary to endogenous GnRH. Furthermore, estradiol selectively inhibits FSH secretion by a direct action on the pituitary gland. This action of estradiol provides an explanation for the selective reduction in FSH responses to GnRH seen during pubertal maturation in girls and during the mid-follicular stage of the menstrual cycle.

Hypocalcemia, Hypomagnesemia, and Transient Hypoparathyroidism During Therapy with Potassium Phosphate in Diabetic Ketoacidosis

The effects of intravenous administration of potassium phosphate in the treatment of diabetic ketoacidosis were studied in nine children, ages 99/12 to 1710/12 yr. During phosphate infusion (20–40 meq/L of fluid), all children maintained normal serum concentrations of phosphorus. Transient hypocalcemia occurred in six and transient hypomagnesemia in five patients. One child developed carpopedal spasms refractory to intravenous infusion of calcium gluconate but responsive to intramuscular injection of magnesium sulfate. In three patients, serum levels of intact parathyroid hormone were low at the time of hypocalcemia, an observation that suggests transient hypoparathyroidism. This study indicates that the use of potassium phosphate as the sole source of potassium replacement might potentiate ketoacidosis-induced hypocalcemia through multiple mechanisms.