Distribution volume, metabolic clearance and plasma half disappearance time of exogenous luteinizing hormone releasing hormone in normal women and women with obesity and anorexia nervosa

Abstract

Synthetic LRH was infused into normal women and women with obesity and anorexia nervosa to determine the distribution volume (DV), metabolic clearance rate (MCR) and half disappearance time (t\m=1/2\)of plasma LRH.In normal women, the DV of LRH was 12.1 \m=+-\0.9 (mean \ m=+-\se) 1, the MCR was 1478.9 \m=+-\39.8 ml/min (28.5 \m=+-\1.2 ml/min/kg body weight) and the initial t \ m=1/ 2\ was 5.6 \m=+-\0.4 min.In obese patients the DV (20.6 \ m=+-\ 1.5 1) was significantly higher than that in normal subjects (P < 0.005), but the MCR and t\m=1/2\were not significantly different from those in normal subjects.In patients with anorexia nervosa the DV and MCR were 6.5 \m=+-\1.1 l and 621.8 \m=+-\110.5 ml/min (17.9 \ m=+-\2.4 ml/ min/kg body weight), respectively, which were both significantly lower than those in normal subjects (P < 0.02), while the t\m=1/2\(7.3 \m=+-\0.1 min) was longer than in normal subjects (P < 0.02).These data suggest that 1) the abnormal responses of some hormones to provocation tests observed in obese patients and patients with anorexia nervosa should be evaluated in consideration of changes in the DV and metabolic clearance of hormones in these conditions, and 2) in patients with anorexia nervosa changes in MCR and t \ m=1/ 2\ may reflect low metabolism of LRH.Various endocrine and metabolic abnormalities have been found in obese subjects (Beck et al. 1964;Copinschi et al. 1967) and underweight subjects (Frankel & Jenkins 1975). As we previously reported, the release of some pituitary hormones in response to various stimuli is impaired in obese patients (Chikamori 1976), and elevation of the plasma growth hormone (GH) level and decrease in luteinizing hormone (LH) secretion are noted in many patients with anorexia nervosa (Nishimura et al. 1979). These abnormalities in hormone secre¬ tion have been considered as secondary changes due to change in the body weight or dysfunction of the hypothalamo-pituitary axis. However, the plasma concentration of a hormone reflects a ba¬ lance between the rates of its secretion and meta¬ bolism, and thus endocrine function should be evaluated on the basis not only of the plasma concentration but also of metabolic clearance of the hormone released from the endocrine gland.For investigation of this problem, it is necessary to study changes in the distribution volume (DV) and metabolic clearance rate of hypothalamic or pituitary hormones in patients with obesity and anorexia nervosa. At present few purified pituitary hormones are available for iv injection into hu¬ mans, but hypothalamic releasing hormone is read¬ ily available.The metabolic clearance of synthetic luteinizing hormone releasing hormone (LRH) in normal sub¬ jects has been studied (Miyachi et al. 1973;Keye et al. 1973), but litüe is known about changes in metabolic clearance of LRH in diseased states (Pimstone et al. 1977). Therefore, we studied the DV, metabolic clearance rate (MCR) and half disap-

Pharmacokinetics of Gonadotropin-Releasing Hormone and Its Analogs

“…The decline of MCR across puberty suggests that it is the rate of hypothalamic GnRH secretion rather than ambient sex steroid levels that determines MCR (15) which is also consistent with the lack of influence of androgen (44) or estrogen (18) on MCR in males, although the effects of estrogen treatment on GnRH MCR in hypogonadal women remain inconclusive (47). These effects of age and physiology on GnRH MCR may influence choice of appropriate GnRH and analog doses.…”

“…The first phase is a rapid (ti/ 2 2-8 min) composite of mixing throughout the vascular and extracellular fluid spaces with rapid clearance. When the mixing phase is eliminated in postinfusion studies of plasma disappearance (13)(14)(15)(16)(17), the initial half-lives are slightly longer (5-8 min). The second phase is a slower clearance component (half-times of 15-60 min) the physical interpretation of which remains unclear.…”

“…Many early studies measured GnRH in unextracted plasma or serum (13,(44)(45)(46) explaining the artefactually high apparent basal endogenous GnRH immunoreactivity (19). More recent studies (14,15,24,26,27,(47)(48)(49) have used extraction (usually acid-alcohol) methods before GnRH assays to remove blank effects due to tracer proteolysis, nonspecific binding, and possibly other mechanisms (19). Since these effects occur capriciously between samples, they cannot be overcome by the addition of noninterfering serum to the standard curve (19,45,46).…”

“…Pharmacokinetic studies of GnRH during steady state iv continuous infusions indicate slower MCR (49) and postinfusion plasma halftimes (13)(14)(15)(16)(17) compared with iv bolus studies presumably due to the superimposition of extracellular fluid space mixing on initial clearance rates that are estimated as a composite clearance during bolus iv studies.…”

“…Undernutrition in hypogonadotropic women with weight loss-related hypogonadism or patients with malignancy might reduce sc adiposity and alter thermoregulatory control of cutaneous blood vessels. Similarly, obesity, anorexia nervosa (15), or the supervention of chronic renal failure may alter the whole body pharmacokinetics of GnRH (13,104) or analogs (55).…”