Recommendations for the registration of agents used in the prevention and treatment of glucocorticoid-induced osteoporosis.
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Animals↗
Biomedical subjects
J M Kaufman
Publications and source records attributed to J M Kaufman.
Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis.
To determine the effects of long-term daily oral alendronate sodium (ALN) on bone mass in postmenopausal women with osteoporosis, 19 centers enrolled 516 postmenopausal women aged 45-80 years with spine bone mineral density (BMD) at least 2.5 SD below the mean for young premenopausal women in a 3-year, double-blind, placebo-controlled study. Subjects were randomly allocated to one of four treatment groups: placebo; alendronate, 5 or 10 mg/day for 3 years; or alendronate, 20 mg/day for 2 years followed by 5 mg/day for the 3rd year. All patients received 500 mg/day of supplemental calcium to ensure adequate calcium intake. BMD was measured by dual-energy X-ray absorptiometry at several skeletal sites. Nonsignificant mean decreases in BMD of the spine, femoral neck, and trochanter of 0.6, 0.7, and 0.4%, respectively, occurred in the placebo group at 3 years. Relative to placebo-treated patients, spine BMD increased by 5.4%, 7.4%, and 8.4% in the 5, 10, and 20/5 mg ALN groups, respectively. Increases at the femoral neck were 3.5%, 5.5%, and 4.3%, and those at the trochanter were 5.1%, 7.2%, and 7.2%, respectively. Thus, efficacy of 10 and 20/5 mg ALN was similar, whereas the 5 mg dose was less effective. BMD continued to increase over the entire 3-year study duration in the ALN-treated groups and, compared with the other dosage groups, 10 mg ALN produced the largest gains in BMD during the 3rd year. Changes in biochemical markers of bone turnover and mineral homeostasis confirmed the effect of ALN to decrease bone turnover to a new steady-state level. The safety and tolerability of ALN were comparable with those of placebo. In summary, 10 mg daily oral ALN given for 3 years significantly and progressively increases bone mass and is a generally well-tolerated treatment for osteoporosis in postmenopausal women.
Administration, Oral↗
Whole-body bone scan findings in X-linked hypophosphatemia.
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Adult↗
The N-methyl-D-aspartate-mediated inhibitory control of gonadotropin-releasing hormone release in the hypothalamus of the adult male guinea pig is expressed through opioidergic systems.
Previously, we reported on a dual role of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the control of GnRH secretion from the medial basal hypothalamus (MBH) of the adult male guinea pig, with a predominantly inhibitory action in the intact animal, which is reversed to a facilitatory role by orchidectomy. In the present study we examined the hypothesis that endogenous opioids are involved in the NMDA receptor-mediated inhibition of GnRH release. A static incubation system was used to test the effects of excitatory amino acid agonists and an excitatory amino acid antagonist, alone or in the presence of either the opiate agonist morphine or the mu-receptor antagonist naloxone, on in vitro GnRH release from the isolated MBH of intact, orchidectomized, or sham-operated guinea pigs. GnRH output from the MBH of intact guinea pigs was markedly suppressed in the presence of the NMDA-specific receptor agonist, N-methyl-D,L-aspartic acid (NMA; 50 mM), whereas NMDA-specific receptor blockade with D,L-amino-5-phosphonovaleric acid (AP-5; 1 mM) resulted in a pronounced facilitation of GnRH release, as did exposure to the non-NMDA-specific receptor agonist, kainic acid (50 mM). Opioidergic blockade with naloxone (1 mM) caused a reversal of the responses to NMA and AP-5, with exposure to these compounds this time resulting in clear facilitation and inhibition, respectively. The stimulatory action of kainic acid, on the other hand, remained unaffected by the presence of naloxone. Morphine inhibited basal GnRH output and also annulled the stimulatory effect of AP-5 on GnRH secretion. The results obtained from MBHs of sham-operated guinea pigs were identical to those seen for the intact animals, with naloxone effectively increasing baseline GnRH release and reversing the inhibitory effect of NMA and stimulatory action of AP-5 on GnRH secretion to a facilitation and inhibition, respectively. On the other hand, NMA caused a marked stimulation, whereas AP-5 produced a significant inhibition of GnRH release from the MBHs of orchidectomized guinea pigs; neither of these effects was altered by the presence of naloxone, which, moreover, had only a marginal effect on basal GnRH output in this group of animals. In conclusion, our present data provide evidence to support the view that the primary inhibitory action of NMDA receptor-mediated neurotransmission on GnRH release in the MBH of the intact male guinea pig is the result of activation of opioidergic systems and that a marked reduction of opioid tone after orchidectomy brings a facilitatory NMDA receptor-mediated system to the fore. On the other hand, non-NMDA-specific kainate receptor-mediated facilitation of GnRH, previously shown to be unaffected by gonadal status, appears to be also independent from opioidergic modulation.
2-Amino-5-phosphonovalerate↗
Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males.
Several aspects of the regulation of androgen secretion and plasma levels in males remain controversial. Among these, we cite the problem of whether the age-related decrease in testosterone (T) levels is an intrinsic aging phenomenon or is a sequel of previous illness, the mechanisms underlying the increase in sex hormone-binding globulin (SHBG)-binding capacity in aging men and the supranormal capacity observed immediately after a weight-reducing diet, and the role of insulin in the age-associated decrease in dehydroepiandrosterone (sulfate) [DHEA (DHEAS)] levels. To gain further insight into these issues, we investigated the influence of age, smoking, body mass index (BMI), serum albumin, insulin, GH, and insulin-like growth factor I (IGF-I) levels, respectively, on androgen levels and SHBG-binding capacity in a nonobese healthy population (n = 250) as well as in an obese population (n = 50) before and after weight loss. The influence of GH supplementation on SHBG, DHEAS, DHEA, and insulin levels was studied in a small group of men (n = 8) with isolated GH deficiency. In nonobese healthy men, age was inversely correlated with serum levels of all androgens studied (although total T levels stayed relatively stable until age 55 yr) as well as with albumin, GH, and IGF-I levels and positively correlated with BMI, insulin levels, and SHBG-binding capacity. Nevertheless, SHBG levels were significantly negatively correlated with insulin levels (P < 0.001) as well as with mean 24-h GH and IGF-I levels. Among possible confounding factors affecting (free) T [(FT)] levels in healthy men, smoking appeared to be accompanied by higher (F)T levels than those in nonsmokers. BMI increased with age, but although BMI was negatively correlated with T, FT, and SHBG, respectively, the age-dependent decrease in T levels persisted after correction for BMI. Data not corrected for BMI may, nevertheless, overestimate the age-associated decrease in T levels. The albumin concentration decreased with age, and if FT is the feedback regulator of plasma T levels, albumin concentration might be a codeterminant (although, evidently, less important than SHBG) of T levels and contribute to the age-associated decrease in T levels. In any case, albumin concentration is a codeterminant of DHEAS concentration. T, DHEA, and DHEAS levels were significantly correlated, but this correlation disappeared after controlling for age; hence, there is no evidence for an adrenal-gonadal interaction in men. In obese men, T, FT, and SHBG levels were significantly lower than those in the nonobese men and inversely correlated with BMI; DHEAS levels were slightly lower than those in the nonobese controls, but no significant correlation between DHEA or DHEAS, and insulin levels was observed. After a weight-reducing, protein-rich diet, resulting in a mean weight loss of +/- 15 kg, SHBG-binding capacity increased to normal values notwithstanding the fact that the subjects were still obese and that the insulin levels remained higher than those in the nonobese controls. Considering that after weight loss, GH and IGF-I levels remained lower than those in the nonobese controls, that adult men with isolated GH deficiency presented with higher SHBG levels than normal controls, which decreased to normal levels during GH substitution, and that elderly men have elevated SHBG levels notwithstanding high insulin levels, we suggest that the low GH and/or IGF-I levels might play a role in the elevated SHBG levels observed in both elderly males and obese men after a weight-reducing diet. As weight loss did not influence DHEAS levels notwithstanding an important decrease in insulin levels, our data do not support a role of insulin in the regulation of plasma DHEAS levels.
Adult↗
Influence of the arterial blood pressure and nonhemodynamic factors on regional arterial wall properties in moderate essential hypertension.
Structural and functional abnormalities may occur at the left ventricle and in different large arteries in essential hypertension. Noninvasive high resolution pulsed doppler echo-tracking technique allows calculation of regional arterial wall properties, which might be determined by either hemodynamic or non-hemodynamic factors. Therefore we aimed to study regional arterial wall properties in three different vascular territories and examined whether hemodynamic and non-hemodynamic parameters were significantly associated to a specific vascular territory. In 30 patients (mean age 47 +/- 2 years) with newly diagnosed and untreated essential arterial hypertension, arterial wall properties were determined at the carotid (common, external and internal), femoral, and brachial artery using a noninvasive ultrasound wall movement detector system. The study parameters were arterial diameter, relative diameter change, arterial distensibility (DC) and cross-sectional compliance (CC) coefficient. On the day of the experiments office blood pressure (BP) was measured as well as an ambulatory 24 h BP profile performed on an outpatient basis. Blood samples were taken on the day of the vascular examination for the determination of plasma renin activity (PRA), aldosterone, intact (1-84) parathyroid hormone (PTH), insulin and plasma noradrenaline and adrenaline. Among the studied vascular territories, only DC and CC of the common carotid artery were significantly (P < 0.01) correlated with office and ambulatory systolic BP. Intact PTH was significantly correlated with the diameter (r = 0.61, P = 0.005) and DC (r = -0.53, P = 0.01) of the internal carotid artery. Noradrenaline was inversely correlated with DC of the femoral artery (r = - 0.55, P < 0.01). All correlations remained significant after adjustment for age and body mass index as confounding variables. In conclusion, in mild to moderate arterial essential hypertension there is a heterogeneity of vascular wall properties and their relationship to BP and humoral factors between brachial, femoral and carotid (common, external and internal) arteries. Our findings might renew interest in the old concept of the 'circulatory paradox'.
Adult↗
Recommendations for the registration of new chemical entities used in the prevention and treatment of osteoporosis.
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Animals↗
Role of calcium and vitamin D in the prevention and the treatment of postmenopausal osteoporosis: an overview.
When discussing the use of calcium and vitamin D in the prevention and the treatment of osteoporosis one can make a distinction between the use as dietary supplementation to correct or prevent deficiencies, and the pharmacologic use of higher doses, whether or not in association with other drugs. However, in practical terms it is not always possible to clearly make this distinction. Available evidence suggests that increasing the calcium intake can favourably affect the build-up of bone mass in adolescence. In this population, the daily consumption of calcium in the diet should, optimally, be at least 1200 mg/day. In view of the lack of data pertaining to the effect on the final peak bone mass, there is at present time no basis for the systematic administration of calcium supplements to healthy children and adolescents. Calcium supplementation, aiming at a total calcium intake of at least 1500 mg/day, has a partial protective effect on postmenopausal bone loss, this effect being documented mainly in women more than 5 years after menopause. In the present state of our knowledge, there is no established role for vitamin D supplementation in the prevention of postmenopausal osteoporosis, except in elderly patients presenting with a higher risk for relative vitamin D deficiency and with low calcium intake. The results of a controlled trial suggest that in institutionalised elderly patients, systematic administration of calcium and vitamin D supplements can substantially reduce the risk of hip fracture. In the treatment of established postmenopausal osteoporosis, calcium supplementation has only a role as a general adjuvant therapeutic measure and as a specific complement to the treatment with other active compounds. There are indications that treatment alpha-calcidol or calcitriol has a positive effect on the evolution of bone mass, but awaiting further confirmation of a favourable effect on the incidence of osteoporotic fractures, treatment with these drugs remains experimental.
Adolescent↗
Renin-angiotensin-aldosterone system, RR interval, and blood pressure variability during postural changes in borderline arterial hypertension.
This study aimed to examine the changes in RR interval and blood pressure (BP) variability and humoral factors during postural changes in borderline arterial hypertension. Twenty-nine patients (44 +/- 3 year; BP, 145 +/- 3/84 +/- 3 mm Hg) with borderline hypertension and a control group of 38 subjects (35 +/- 2 year; BP, 123 +/- 3/70 +/- 2 mm Hg) underwent power spectrum analysis of RR interval and BP (low frequency (LF), 0.05 to 0.15 Hz; high frequency (HF), 0.15 to 0.40 Hz) in the supine and standing positions. Concentrations of plasma renin activity, angiotensin II, and aldosterone in supine and standing positions had been determined in the hypertensive group. Borderline hypertensives are characterized by higher oscillations of systolic and diastolic BP, but not of RR interval in the supine position versus the control group. Low frequency and HF components of systolic and diastolic BP expressed as absolute data are also significantly higher in borderline hypertensives. Moreover, standing tended to increase the LF/HF ratio of both RR interval and BP variability compared to controls. The standing position was able to further activate the LF but not the HF component of BP variability. In borderline hypertension renin release during postural changes correlated well with the decrease in the power of the HF vagal component of RR interval variability (r = -0.70, P < .001) and with the increase of the LF component of diastolic blood pressure variability (r = 0.43, P = .03). In conclusion, our results indicate that in borderline arterial hypertension, LF and HF oscillations of BP are already significantly increased at rest.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Renin-angiotensin-aldosterone system, RR-interval and blood pressure variability during postural changes after myocardial infarction.
Low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.40 Hz) components of heart rate variability have been used to evaluate the autonomic nervous system. The sympathico-vagal balance as well as the renin-angiotensin-aldosterone (RAA) axis are disturbed in the post-acute phase of acute myocardial infarction (AMI). This study examined the relationship between the RAA-axis and spectral indices of the RR-interval and blood pressure (BP) variabilities during postural manoeuvres in the post-AMI period. Power spectral analysis of the RR-interval and BP variability was computed from non-invasive beat-to-beat BP measurements 10-12 days post-AMI, using Fast-Fourier transforms. Concomitantly, hormonal changes of the RAA-axis were determined and data were further correlated with the left ventricular ejection fraction. When the patient moved from the lying to the supine position all RAA-axis parameters significantly increased. Both LF and HF components of total RR-interval variability decreased upon standing, while the LF component of systolic and diastolic BP variability increased and HF components remained constant. In the upright position, plasma renin activity (P<0.01) and angiotensin II (borderline) were inversely related with the LF component of systolic BP. The aldosterone level was dissociated from plasma renin activity and angiotensin II. The left ventricular ejection fraction was inversely correlated (P<0.05) with systolic and diastolic BP variabilities and their LF and HF powers. These results suggest that the renin-angiotensin II system in the post-acute phase of AMI patients treated with aspirin and beta-blocking agents is correlated with cardiovascular autoregulation during postural manoeuvres.
Autonomic Nervous System↗
Ageing of the hypothalamo-pituitary-testicular axis in men.
In distinction to the course of reproductive ageing in women, men do not experience a rapid decline of Leydig cell function or irreversible arrest of reproductive capacity in old age. Hence, strictu sensu, the andropause does not exist. Nevertheless, both spermatogenesis and fertility as well as Leydig cell function do decline with age, as shown by a decrease of +/- 35% of total and of 50% of free testosterone levels between the age of 20 and 80 years. The origin of this decline of Leydig cell function resides on the one hand in the testes, and is essentially characterized by a decreased number of Leydig (and Sertoli) cells and on the other hand in the hypothalamo-pituitary complex characterized by a decreased luteinzing hormone (LH) pulse amplitude, LH pulse frequency being maintained. As the responsiveness of the gonadotrophs to gonadotropin-releasing hormone (GnRH) remains unimpaired, one may assume that the amount of GnRH released at each pulse is also reduced, possibly as the consequence of a reduction of the cellular mass of GnRH neurones. Plasma levels of testosterone below the lower normal limit occur, however, only in a minority of elderly men from 7% in the age group 40-60, to 20% in the age group 60-80 and 35% in the age group over 80 years old. Factors influencing testosterone levels in elderly men are multiple: hereditary, environmental (obesity, stress), psychosocial (depression, smoking, drugs) or socioeconomical (diet, hygiene). Whether these elderly men should be substituted with androgens remains controversial.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Involvement of neuroexcitatory amino acids in the control of gonadotropin-releasing hormone release from the hypothalamus of the adult male guinea pig: predominantly inhibitory action of N-methyl-D-aspartate-mediated neurotransmission and its reversal after orchidectomy.
Excitatory amino acids (EAA) have been implicated in the control of LH secretion through facilitation of GnRH release, although disparate findings of an inhibitory effect of EAA on LH secretion in several species after gonadectomy have been reported. Using a static incubation system, we studied the effects of EAA receptor agonists and antagonists on in vitro GnRH release from the isolated medial basal hypothalamus (MBH) of the male guinea pig. In the presence of 0.4 mM glycine, the N-methyl-D-aspartate (NMDA)-specific receptor agonist N-methyl-D,L-aspartic acid (NMA) exerted a dose-dependent inhibition of GnRH output from the MBH of intact guinea pigs, which was significant (P < or = 0.01) at concentrations of 1 and 50 mM. The NMDA-specific receptor antagonist D,L-2-amino-5-phosphonovaleric acid (AP-5) significantly stimulated GnRH release at 10(-3) and 1 mM (P < or = 0.001) and was ineffective at 10(-6) mM. NMA (50 mM) and AP-5 (1 mM) produced similar effects when tested at a lower glycine concentration of 10 nM. The presence of the two compounds together resulted in overall unchanged GnRH output. The inhibitory effect of 50 mM NMA was also effectively blocked in the presence of 2 mM Mg2+ at both high and low glycine concentrations. When, for comparative purposes, isolated MBHs of 50-day-old intact male rats were exposed to 50 mM NMA, a response opposite to that seen in the intact guinea pig was observed, with a marked increase in GnRH output (P < or = 0.001). When tested at 10 nM glycine, 50 mM kainic acid, a non-NMDA-specific receptor agonist, on the other hand, had a marked stimulatory effect on GnRH output (P < or = 0.01) from intact guinea pig MBHs, an action that was prevented in the presence of the kainate/quisqualate receptor antagonist 6,7-dinitro-quinoxaline-2,3-dione (0.1 mM); 6,7-dinitro-quinoxaline-2,3-dione alone inhibited GnRH release (P < or = 0.01). In a separate series of experiments, the effects of EAA (in the presence of 10 nM glycine) on GnRH release from the MBHs of long term orchidectomized and sham-operated guinea pigs were compared. Orchidectomy led to a dramatic reversal of the NMDA-mediated inhibition of GnRH secretion observed in MBHs of sham-operated animals, with 50 mM NMA producing a marked increase (P < or = 0.0001) and 1 mM AP-5 resulting in a clear inhibition (P < or = 0.0001) of GnRH release. Kainic acid (50 mM), on the other hand, had a similar stimulatory action on GnRH release from the MBHs of both orchidectomized (P < or = 0.0001) and sham-castrated (P < or = 0.001) guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hypothalamic multiunit activity and pulsatile luteinizing hormone release in the castrated male rat.
Using chronically implanted microelectrodes, multiunit electrical activity (MUA) was recorded from the arcuate nucleus of freely moving gonadectomized male rats. Intermittent increases in MUA activity (MUA volleys) closely associated with luteinizing hormone pulses measured in the peripheral circulation were observed, which confirms that this experimental approach can be used for monitoring the activity of the gonadotropin-releasing hormone-associated hypothalamic pulse generator in the male rat. The mean MUA volley frequency was 22.2 min (range 13-38 min), whereas the mean MUA volley duration was 2.7 +/- 0.8 min (standard deviation). In addition to a large inter-individual variability. MUA volley intervals also showed an important intra-individual variability. This observation suggests that, beside the mean frequency of pulse generator activation, the degree of variability in gonadotropin-releasing hormone-associated pulse generator activity might be an additional relevant parameter in the characterization of the reproductive function in the male rat.
Animals↗
Deep dorsal vein arterialization in arteriogenic impotence: use of the dorsal artery as a neoarterial source.
Deep dorsal vein (DDV) arterialization has developed as a treatment option for patients with arteriogenic impotence, especially in situations where artery-to-artery bypass is not feasible. The inferior epigastric artery (IEA), harvested through a lower abdominal incision, has usually served as the neoarterial source. Using dynamic infusion cavernosometry and cavernosography (DICC) to evaluate arterial and venous erection factors and pudendal arteriography to define arterial anatomy, we have identified 16 patients with cavernosal artery (CA) obstruction and a normal dorsal artery (DA) to serve as the neoarterial source. All patients were less than 50 years old (mean 34.8 +/- 8.6 years). During DICC, the gradient between systemic and CA systolic occlusion pressures averaged 38.7 mmHg. Two patients showed moderate and two minimal corporal veno-occlusive dysfunction (CVOD). From 1991-94, all 16 underwent microscopic DA-DDV arterialization. Four of these patients also underwent venous ligation procedures and three had IEA bypass to the other DA. With adequate follow-up in 15 men, the results for six are considered excellent or normal (40%); eight improved (53.3%) and one was unchanged. In the improved group are three men who did not respond adequately to maximum penile injection therapy before surgery but used small doses afterward with success. Of the three smokers in the series, two were improved and one unchanged. Excellent results were found in four of five men (80%) under age 30 but only one of five (20%) over age 40. Complications included two instances of penile shortening and one of glans hyperemia requiring reoperation. By avoiding an abdominal approach, operative times, morbidity and recovery were substantially shortened. This operative approach can provide an excellent treatment for nonsmokers with CA obstruction and a normal DA.
Adult↗
In vitro GnRH release from the isolated medial basal hypothalamus of the male guinea pig: evidence for the existence of two pools of releasable GnRH.
We studied in vitro GnRH output from the isolated medial basal hypothalamus (MBH) of the adult intact male guinea pig. Both basal release and the response to veratridine (V), which exerts a depolarizing action by increasing Na+ permeability, were assessed using a static incubation system. Spontaneous GnRH release from single MBHs was pulsatile, with mean pulse frequency ('Ultra' program; 3 CV threshold) of 0.86 +/- 0.17 pulse/h (range: 0.17-1.75) for 7.5 min fractions collected over a 240 to 360 min observation period (n = 10). Exposure to 20 microM V for a 15-60 min period resulted in increased GnRH output characterized by a consistently biphasic pattern of release, with an immediate response, and a secondary increase usually observed with a delay of 30 to 60 min relative to the introduction of V. This characteristic pattern of response was seen for tested V concentrations ranging between 0.1 and 50 microM. The Na+ channel blocker tetrodotoxin (TTX, 3 microM), the calcium chelator EGTA (20 mM) and the calcium channel blocker verapamil (1 mM) significantly suppressed basal GnRH release and effectively prevented the GnRH response to V when added simultaneously with V. The secondary response to V could not be blocked selectively by tetrodotoxin introduced following V or from the last 7.5 min of v exposure onwards. In contrast, this secondary response could be selectively suppressed with either EGTA or verapamil. We conclude that the secondary component of the GnRH response to V is the result of delayed, calcium dependent secretory events triggered by the initial depolarizing action of V. These findings indicate the presence of two distinct pools of releasable GnRH in the MBH of the adult male guinea pig. The relevance of this finding to the pulsatile mode of GnRH release remains to be established. When, for purposes of comparison, isolated MBHs from 50-day-old male rats were studied, a clearly different, monophasic pattern of response to V was observed. Whether this observation is related to the known differences in distribution of hypothalamic GnRH between the rat and the guinea pig, still needs to be elucidated.
Animals↗
Bone mineral status in paraplegic patients who do or do not perform standing.
Bone mineral density (BMD) was assessed by dual-photon X-ray absorptiometry at the lumbar spine (L3, L4), the proximal femur and the femoral shaft, and by single-photon absorptiometry at the forearm in 53 patients with complete traumatic paraplegia of at least 1 year's duration and in age- and sex-matched healthy controls. The patients did (n = 38) or did not (n = 15) regularly perform passive weightbearing standing with the aid of a standing device. Compared with the controls, the BMD of paraplegic patients was preserved in the lumbar spine and was markedly decreased in the proximal femur (33%) and the femoral shaft (25%). When considering all patients performing standing, they had a better-preserved BMD at the femoral shaft (p = 0.009), but not at the proximal femur, than patients not performing standing. BMD at the lumbar spine (L3, L4) was marginally higher in the standing group (significant only for L3; p = 0.040). A subgroup of patients performing standing with use of long leg braces had a significantly higher BMD at the proximal femur than patients using a standing frame or a standing wheelchair (p = 0.030). The present results suggest that passive mechanical loading can have a beneficial effect on the preservation of bone mass in osteoporosis found in paraplegics.
Adult↗
Impotence and chronic renal failure: a study of the hemodynamic pathophysiology.
A retrospective multi-institutional study was performed to document and characterize the arterial vascular disease in the hypogastric-cavernous arterial bed and/or veno-occlusive dysfunction of the corpora cavernosa in patients with end stage renal disease. We evaluated 20 impotent patients (mean age 40 +/- 9 years) with chronic renal failure using pharmaco-cavernosometry and pharmacocavernosography (4 also underwent pharmaco-arteriography). Patients were divided into groups based on the treatment (14 with renal transplantation and 6 with hemodialysis or peritoneal dialysis), as well as by history of vascular risk factors (16 with and 4 without risk factors). Of the patients 19 revealed abnormal intracavernous pressure responses to repeated intracavenous injections of vasoactive agents implying vascular disease of the penis. Cavernous artery occlusive disease was found in 78% of the patients. All patients who underwent arteriography had diffuse atherosclerotic disease of the distal penile arteries. Corporeal veno-occlusive dysfunction was found in 90% of the patients, of whom 60% had diffuse pan-cavernous leakage involving the dorsal, cavernous and crural veins, glans penis and corpus spongiosum. This renal failure-associated vascular disease of the penis was found to occur independently of the presence of known systemic atherosclerotic vascular risk factors. Patients who underwent early treatment of the uremia by renal transplantation had vasculogenic impotence only in the case of rejection of the renal transplant, suggesting that early renal transplantation may delay or prevent the development of the penile vasculopathy. The most likely pathophysiology of the vascular impairment includes renal failure-associated atherosclerosis, and renal failure-associated hypoxia changes of the contractile (smooth muscle) and structural (collagen/elastin) components of the erectile tissue. Strategies for future research and clinical therapies are suggested.
Adult↗
Effects of long-term orchidectomy on in vitro pulsatile gonadotropin-releasing hormone release from the medial basal hypothalamus of the adult guinea pig.
There is ample evidence provided by in vivo studies that orchidectomy increases the frequency of episodic GnRH release from the hypothalamus, but the effects on other aspects of pulsatile GnRH secretion are less well defined. We used a continuous superfusion system to study the effects of long term (4 weeks) orchidectomy or sham castration on in vitro release of GnRH from the retrochiasmatic medial basal hypothalamus (MBH) of the adult male guinea pig. RIA of GnRH in 5-min fractions (750 microliters) of superfusion medium collected during a 540-min observation period revealed a clearly episodic pattern (Ultra pulse analysis algorithm) of GnRH secretion for the MBHs of both orchidectomized (n = 15) and sham-operated animals (n = 15). Pulse frequency was significantly higher (P < or = 0.01) after orchidectomy than after sham castration (mean +/- SEM pulse intervals of 32.5 +/- 2.7 and 57.8 +/- 5.1 min, respectively; pulse analysis at 3 coefficient of variation threshold). The mean amplitude of all pulses (15.8 +/- 0.8 vs. 15.2 +/- 1.1 pg/750 microliters) and mean GnRH output (8.2 +/- 1.3 vs. 6.7 +/- 1.3 pg/750 microliters) were not significantly different between the two groups. Exposure for 30 min to 20 microM veratridine, a depolarizing agent, toward the end of the experiment resulted in a significant increase in GnRH output (P < or = 0.01) in both groups. The latter response was somewhat greater for the MBHs of orchidectomized animals (P < or = 0.01 for absolute response; nonsignificant for percent response), notwithstanding a 50% reduction of the total GnRH content of the MBH explants (P < or = 0.0001). The results of the present study provide further support for the view that retardation of the GnRH pulse generator frequency is the major mechanism by which the testicular hormones exert, at the hypothalamic level, their negative feedback action on gonadotropin secretion.
Animals↗