Biomedical subjects

D J Handelsman

Publications and source records attributed to D J Handelsman.

At least 73 records · Page 4Linked to original sources

PubMed1995

Density adjustment of software settings minimizes bias in automated sperm motility estimation.

To minimize overestimation of motility, it is recommended that fresh semen be diluted with seminal plasma prior to automated analysis. However, for glycerolated or cryopreserved semen this is impractical, and alternative methods are needed to minimize automated motility bias. In the present study, the proportion of motile spermatozoa was determined in fresh, diluted and cryopreserved semen (n = 25 ejaculates) using visual and automated methods. The effect of software settings on motility was investigated by assessing samples at a range of modified settings. At standard settings, automated motility was biased in fresh semen (+7.2%) after dilution with cryopreservative (-2.9%) and after cryopreservation (-7.8%) (P < 0.0001 versus visual). Automated motility was inversely related to the minimum number of frames for motility sampling (P < 0.0001), with mean estimates of 41.0, 46.1, 52.0 and 58.2% generated at settings of 8, 4, 2 and 1 frame(s) respectively (n = 15 fresh, diluted and cryopreserved samples). Based on an arbitrary ordinal scale, a method was developed whereby motility sampling was adjusted prior to analysis according to sperm density. Analysis of an independent set of semen samples with density-adjusted software settings reduced bias in automated estimates (n = 30) before and after freezing (P < 0.0001). In addition, bias was no longer related to sperm density. In conclusion, modification of software settings is an effective alternative to dilution to minimize bias in automated motility estimates in fresh, diluted and cryopreserved human semen.

Autoanalysis↗

PubMed1995

Tolerability of intramuscular injections of testosterone ester in oil vehicle.

We undertook a prospective survey of the tolerability of deep i.m. injections of testosterone enanthate in a castor oil vehicle, the most widely used form of androgen replacement therapy. Over a period of 8 months, 26 men received 551 weekly injections into the gluteal, deltoid or thigh muscle and side-effects were recorded immediately and 1 week after each injection by the same nurse using a standardized questionnaire. Most injections caused no complaints [389/551, 70.6% (95% confidence interval 66.6-74.4%)] but minor local side-effects, mostly pain and bleeding, were common [162/551, 29.4% (25.6-33.4%)]; no serious side-effects were observed. Considering all side-effects, the gluteal site had fewer complaints and was less prone to bleeding but was painful more often than deltoid or thigh injection sites. The laterality of injection at any site had no significant effect on side-effects. The only systemic side-effect was episodes of sudden-onset, non-productive cough associated with faintness following eight injections [1.5% (0.6-2.9%)] which we speculate may have been due to pulmonary oil microembolism. We conclude that, when administered by an experienced nurse, deep i.m. injection of testosterone enanthate in a castor oil vehicle is generally safe and well tolerated but causes relatively frequent minor side-effects, including pain and bleeding. An improved depot form of testosterone would be highly desirable for androgen replacement therapy and hormonal male contraception.

Adult↗

PubMed1995

Hypothalamic-pituitary-testicular function in end-stage non-alcoholic liver disease before and after liver transplantation.

OBJECTIVE: Gonadal dysfunction is common in chronic liver disease, but most of the previous studies have been restricted to men with alcohol-induced liver disease. We have evaluated hypothalamic-pituitary-testicular function in patients with end-stage non-alcoholic liver disease before and at 6 and 12 months after hepatic transplantation. DESIGN: A prospective study of hypothalamic-pituitary-testicular endocrine function before and after cadaveric hepatic transplantation. PATIENTS: Fifty four consecutive patients with end-stage, non-alcoholic liver disease were evaluated before and after liver transplantation. MEASUREMENTS: Hypothalamic-pituitary-testicular (HPT) axis function was evaluated under basal conditions by single morning measurements of plasma total and free testosterone, sex hormone-binding globulin and by plasma LH and FSH responses to 100 micrograms i.v. GnRH. RESULTS: Men with chronic non-alcoholic liver disease had reduced levels of total and free testosterone and increased levels of SHBG compared with controls with normal liver function. Total and free testosterone were positively correlated with basal and stimulated LH (but not FSH) concentrations. Gonadotrophin responses to GnRH were preserved but delayed compared with healthy controls consistent with a predominantly hypothalamic defect in regulation of pituitary-testicular function. Increasing severity of underlying liver disease was associated with declining total and free testosterone as well as peak GnRH-stimulated LH concentrations. Spironolactone treatment was associated with decreased circulating testosterone levels only in men with liver disease of intermediate severity (Child-Pugh class B). Following hepatic transplantation, total and free testosterone and SHBG concentrations returned progressively towards eugonadal control levels over the first 12 months but total and free testosterone levels remained subnormal. CONCLUSIONS: Hypothalamic-pituitary regulation of testicular function is impaired in end-stage non-alcoholic liver disease in proportion to the severity of underlying liver disease. Spironolactone reduces circulating testosterone but only among men with Child-Pugh B liver cirrhosis. Gonadal function improves, but is not normalized, over the first year following successful liver transplantation.

Adolescent↗

PubMed1995

Hormonal male contraception: progress and prospects for the 21st century.

During the second half of the 20th century, progress in developing novel, practical contraceptive methods for men has lagged significantly behind developments for women. Despite the lack of reliable, reversible methods, men throughout the world continue to be strongly involved in family planning but a greater involvement will require more attractive and reliable contraceptive options for men. The closest to fruition are hormonal methods the features of which are reviewed. Landmark WHO contraceptive efficacy studies have established that hormonally-induced azoospermia provides highly effective and reversible contraception for at least 12 months with minimal short-term side effects. Even among the small subgroup of men who remain oligozoospermic during hormonal suppression, good contraceptive efficacy is achieved. The present goals are to develop improved second generation hormonal regimens which provide more uniform azoospermia to obviate the need for monitoring of sperm output and to develop long-acting depot testosterone formulations used alone or with additional gonadotrophin suppressive agents such as progestins or GnRH antagonists. Significant obstacles to progress are the flight of industry from contraceptive R&D dur to the financial deterrent posed by the product liability crisis as well as the low priority accorded male reproductive health. Together those will determine whether the range of contraceptive options available to our children in the 21st century will improve, or whether the historically recent unbalanced increase in reliance on women for family planning will continue.

Animals↗

PubMed1995

Induction of spermatogenesis by androgens in gonadotropin-deficient (hpg) mice.

Using a new experimental model for studying the hormonal induction of spermatogenesis, the hpg mouse, which has congenital functional gonadotropin deficiency due to a major deletion in the GnRH gene, we investigated the roles of testosterone (T) and dihydrotestosterone (DHT) in the initiation of spermatogenesis. Weanling homozygous hpg male mice were implanted subdermally with SILASTIC brand implants of varying lengths (0-2 cm) filled with T or DHT, using phenotypically normal (N/N or N/hpg) and untreated hpg/hpg mice as positive and negative controls. After 8 weeks, both T and DHT equally stimulated (approximately 14-fold) testis size and induced qualitatively complete spermatogenesis despite low intratesticular androgen levels and undetectable circulating FSH. Stereological quantitation of Sertoli and germ cells demonstrated a dose-dependent rise in the absolute numbers of all germ cell types induced by both T and DHT. At maximal androgen doses, germ cell numbers expressed per Sertoli cell and homogenization-resistant elongated spermatids expressed per mg testis were increased to more than 80% of non-hpg control values. An in vitro fertilization assay confirmed that both T and DHT induced quantitatively normal fertilizing capacity of the sperm in hpg males. We conclude that androgens, acting through the androgen receptor without need for aromatization, initiate qualitatively complete spermatogenesis in the mouse, including fertile sperm despite low intratesticular androgen levels and the absence of blood FSH levels. The hpg mouse model is a useful new paradigm to study the molecular basis of the hormonal induction of spermatogenesis.

Androgens↗

PubMed1995

Androgens rapidly increase the cytosolic calcium concentration in Sertoli cells.

We demonstrate that androgens rapidly and specifically increase intracellular calcium in Sertoli cells, investigate the mechanism, and suggest the unifying hypothesis that calcium might be a common intracellular molecular effector to explain the known synergism between FSH and testosterone (T) action on Sertoli cells in support of spermatogenesis. In freshly isolated Sertoli cells, T and its 5 alpha-reduced metabolite dihydrotestosterone increased intracellular calcium from 83 +/- 4 to 147 +/- 8 and 167 +/- 29 nM, respectively, whereas estradiol had minor (117 +/- 9 nM) and progesterone no (80 +/- 6 nM) effect. The effect of T was rapid (20-40 sec) and inhibited by 1) preincubation with either a pure nonsteroidal antiandrogen (hydroxyflutamide) or a 5 alpha-reductase inhibitor (finasteride) or 2) removal of extracellular calcium (47 +/- 4 nM) or pharmacological blockade of voltage-activated (62 +/- 5 nM) or voltage-independent (55 +/- 14 nM) membrane calcium channels. These findings suggest that the T-induced rise in Sertoli cell cytosolic calcium involves sequential 5 alpha-reduction, binding to a classical androgen receptor, and activation of transmembrane influx of extracellular calcium. Immobilization of T by conjugation to a large carrier molecule (BSA) to prevent steroid entry into Sertoli cells also resulted in a rapid increase in cytosolic calcium to a similar magnitude as unconjugated T, consistent with a plasma membrane site of action. This finding together with the rapid cytosolic calcium rise caused by T argues for the possible existence of a short term, nongenomic effects in hormonal regulation of Sertoli cell function in addition to the well known, slower genomic response.

Androgen Antagonists↗

PubMed1995

Pharmacokinetics of human follicle-stimulating hormone in gonadotropin-deficient men.

Gonadotropin treatment of hypogonadotropic infertile men usually requires regular im administration of human urinary FSH (uFSH); however, testicular function is rarely normalized despite years of treatment. As the pharmacokinetics of standard FSH doses (75 IU, two or three times weekly) in gonadotropin-deficient men are poorly characterized, we studied 10 gonadotropin-deficient men by measuring plasma FSH levels with an ultrasensitive fluoroimmunoassay (Delfia, Pharmacia) in single dose and multidose studies. The single dose studies involved blood samples taken 15 min before and 0, 1, 2, 4, 6, 8, 10, 12, 15, 18, 21, 24, 48, 72, and 96 h after the injection of 75 IU uFSH in 1 mL diluent, either sc under the abdominal wall skin or im into the deltoid muscle, in a random sequence, cross-over design (n = 7 men) and after the injection of 150 IU, sc, with additional blood sampling at 120 and 168 h (n = 7 men). The multidose studies used a fixed ascending dose sequence, with blood sampled at 24-h intervals posttreatment after at least 1 month of regular administration of either 75 or 150 IU uFSH, sc, at injection intervals of 72, 48, and 24 h (n = 6 men). From the single dose studies, pharmacokinetic variables were estimated from a one-compartment open model fitted by a weighted polyexponential curve fit of plasma FSH over time. The bioavailability of uFSH via the sc route was high (mean area under the curve, 90% for 75 IU and 143% for 150 IU vs. 75 IU, im). Peak plasma FSH levels were later (21.1 vs. 7.1 h; P < 0.001) and lower (2.0 vs. 2.7 IU/L; P < 0.001) after sc compared with im administration of 75 IU due to a slower absorption half-time (6.1 h vs. 1.4 h; P < 0.001), whereas mean residence times and clearance half-times were similar. The pharmacokinetic features of the 150- and 75-IU doses sc were essentially identical, apart from expected dose-dependent increases in peak plasma FSH level (2.8 vs. 2.0 IU/L; P < 0.001) and area under the curve (206 vs. 129 IU.h/L; P < 0.05). Multidose simulations based on the single dose pharmacokinetic models predicted that during chronic sc administration of standard FSH doses, plasma FSH levels would be in the lower half of the eugonadal range and fluctuate less than with im administration. The multidose study confirmed empirically these predictions. These studies form a pharmacological basis for a more flexible, cost-effective, and convenient self-administered sc regimen.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1995

Factors in nonuniform induction of azoospermia by testosterone enanthate in normal men. World Health Organization Task Force on Methods for the Regulation of Male Fertility.

OBJECTIVE: To identify factors differentiating men becoming azoospermic from those remaining oligozoospermic within 6 months of T treatment. DESIGN: Prospective, open, noncomparative contraceptive efficacy study. SETTING: International multicenter study of 271 men in 10 centers in seven countries. PATIENTS: Data from 157 achieving azoospermia and 68 remaining oligozoospermic after 6 months of treatment were analyzed. The remaining 46 men were excluded as having unclassifiable suppression status due to discontinuation before completion of suppression. INTERVENTIONS: Weekly IM injections of 200 mg T enanthate. MAIN OUTCOME MEASURES: Anthropometric, seminal, hormonal, and biochemical data obtained before, during, and after treatment as potential predictors of consistent azoospermia. RESULTS: Azoospermic men had [1] faster rates of fall in sperm output and, after a delay of 75 +/- 4 days (mean +/- SE) for sperm to reappear in the ejaculate, exhibited a faster rate of recovery of sperm output; [2] higher pretreatment levels of FSH (mean +/- SE; 3.7 +/- 0.3 versus 2.7 +/- 0.4 mIU/mL [conversion factor to SI units, 1.00]); and [3] (if treated for > 15 months) a prolonged after treatment rebound in gonadotropins compared with nonazoospermic men. There were no other differences in pretreatment variables or plasma T levels and changes in androgen-sensitive markers during treatment. None of the variables explained the higher rates of azoospermia among men in Chinese (91%, n = 3) compared with non-Chinese centers (60%, n = 7). CONCLUSION: Nonuniformity of T-induced azoospermia among healthy fertile men is not due to anthropometric or ethnic differences, to variations in androgen effects, or to poor compliance with treatment. The heterogeneity in individual susceptibility to T-induced azoospermia is most consistent with quantitative differences in the hormonal regulation of spermatogenesis and is likely to be evident with other hormonal methods for male contraception.

Adult↗

PubMed1994

Androgen receptor function during undernutrition.

Hypothalamo-pituitary inhibition of reproductive function during undernutrition is well known, however, the physiological mechanisms leading to suppression of gonadotrophin secretion are not clear. A variety of studies have indicated that testicular negative feedback on LH secretion is enhanced during food restriction. To evaluate directly the suppression by endogenous androgens on hypothalamic GnRH pulse generator activity during food restriction and examine the mechanism underlying the increased testicular steroidal feedback, we examined (1) circulating bioactive LH (bLH) levels in response to selective cerebral androgen blockade by intraventricular administration of an androgen receptor antagonist (hydroxyflutamide, SCH 16423) and (2) the binding capacity and affinity of androgen receptors in medio-basal hypothalamus, pituitary and prostate during undernutrition of intact mature male rats. Hydroxyflutamide (20 micrograms in 10 microliters vehicle), but not vehicle alone, markedly increased bLH levels in both food restricted and ad-lib fed rats. However, the faster (geometric mean 11.4 vs 27.7 min) and greater (47.2 vs 21.9 ng/ml) increase in bLH level in food restricted compared with ad-lib fed controls demonstrates an enhanced sensitivity to blockade of androgenic negative feedback during undernutrition. Food restriction increased androgen receptor binding capacity in pituitary (3.36 vs 0.77 fmol/mg protein) but not in medio-basal hypothalamus or prostate while binding affinity was unchanged by undernutrition in all 3 tissues. These studies reveal that undernutrition both enhances tonic, androgen receptor-mediated feedback suppression of GnRH secretion and increases in pituitary (but not hypothalamic) androgen receptor numbers to cause inhibition of LH secretion.

Androgen Receptor Antagonists↗

PubMed1994

The relationship between 3',5'-cyclic adenosine monophosphate and calcium in mediating follicle-stimulating hormone signal transduction in Sertoli cells.

FSH signal transduction in Sertoli cells involves the generation of cAMP and calcium as second messengers; however, the relationship between these two signals is not clear. In order to determine whether these were serial or parallel signals, we studied cytosolic calcium levels in freshly isolated rat Sertoli cells using maneuvers to dissociate generation of endogenous cAMP from cytosolic calcium. Pretreatment with 1 mM MDL 12,330A, an adenylate cyclase inhibitor, reduced by greater than 90% increases in cytosolic calcium induced by FSH (97 +/- 6 vs. 213 +/- 16 nM), whereas, despite adenylate cyclase blockade, 1 mM (Bu)2cAMP continued to elevate cytosolic calcium (from 87 +/- 6 to 182 +/- 23 nM), indicating the involvement of adenylate cyclase in the FSH-induced rise of cytosolic calcium. A cAMP antagonist, 1 mM Rp-cAMP, reduced by 75% the FSH-induced rise of cytosolic calcium (115 +/- 14 vs. 213 +/- 16 nM), suggesting that endogenous cAMP levels generated by FSH are sufficient to activate the cytosolic calcium response to FSH. Pretreatment with pertussis toxin (1 mg/liter) to dissociate the FSH-receptor interaction from its G-protein-mediated linkage to adenylate cyclase also suppressed the FSH-induced rise in cytosolic calcium (97 +/- 11 vs. 213 +/- 16 nM). Sertoli cells preincubated with 1 mM staurosporine, an inhibitor of protein kinases, exhibited a reduced calcium response to FSH (125 +/- 14 vs. 213 +/- 16 nM), suggesting that FSH-induced calcium flux might be mediated by protein kinase, presumably cAMP-dependent protein kinase A. The present findings therefore strengthen the premise that the cytosolic calcium response to FSH in Sertoli cells is predominantly attributable to serial signaling after the generation of endogenous cAMP.

Adenylate Cyclase Toxin↗

PubMed1994

Effect of undernutrition on pulsatile luteinizing hormone (LH) secretion in castrate and intact male rats using an ultrasensitive immunofluorometric LH assay.

The recent development of an ultrasensitive immunofluorometric rat LH assay makes possible evaluation of pulsatile LH secretion in intact male rats under physiological conditions of minimal volume blood sampling without requiring orchidectomy. Specifically, we applied this assay to determine the effect of macronutrient restriction on pulsatile LH secretion in the presence or absence of testes. In testes-intact rats, halving of food intake for 7 days while maintaining micronutrient supply caused a reduction of mean, maximal, and basal LH levels and LH pulse amplitude (all P < 0.05) compared with those in ad libitum fed controls. The loss of body weight was positively correlated with decreases in mean LH level, pulse amplitude, and area under the curve (all P < 0.009). In contrast, the same food restriction in castrated rats caused an increase in pulse length and area under the curve and a decrease in pulse frequency, but did not change mean, maximal, and basal LH levels or LH pulse amplitude compared to castrated ad libitum fed controls (all P < 0.02). The observed positive correlations between body weight and the LH secretion parameters in intact rats were absent or reversed in castrated rats. This study demonstrates qualitatively different effects of macronutrient restriction on pulsatile LH secretion in castrated and intact rats, indicating that it is not necessary valid to extrapolate consequences of undernutrition on LH secretion from castrate to intact male rats. We conclude that undernutrition-induced inhibition of LH secretion involves both an indirect suppression of LH secretion via amplification of endogenous testicular negative feedback as well as more direct suppression of GnRH release.

Animal Nutritional Physiological Phenomena↗

PubMed1994

Recombinant growth hormone and insulin-like growth factor I do not alter gonadotrophin stimulation of the baboon testis in vivo.

In vitro studies indicate a physiological role for insulin-like growth factor I (IGF-I) in paracrine regulation of testicular function and recent clinical studies suggest a potential role for growth hormone (GH) and/or IGF-I in the treatment of hypogonadotrophic states in males. This study aimed to examine the effects of pretreatment with recombinant human GH (rhGH) or rhIGF-I on the response to gonadotrophins of the non-human primate testis in vivo. Using a balanced Latin square design with repeated measures, six prepubertal male hamadryas baboons (Papio hamadryas hamadryas) were treated in a cross-over sequence for periods of 18 days with daily im injections of rhGH (0.4 IU.kg-1.day-1), rhIGF-I (0.1 mg.kg-1.day-1) or saline with a 2-week washout period between each treatment. A single im injection of hCG (1500 IU) increased serum testosterone (p = 0.0002) but neither rhGH nor rhIGF-I influenced the timing or magnitude of this response (p > 0.5). A single im dose of FSH (75 IU) stimulated immunoreactive inhibin (p = 0.01) but also was unaffected in magnitude or timing by pretreatment with rhGH or rhIGF-I (p > 0.2). Circulating IGF-I levels were increased independently by hCG (p = 0.01) and FSH (p < 0.0001) administration. These findings indicate that neither GH nor IGF-I pre-treatment enhance acute gonadal responses to gonadotrophin stimulation of the prepubertal non-human primate testis in vivo. These findings suggest that GH or IGF-I treatment of hypogonadotrophic men without somatotrophin deficiency is unlikely to be beneficial.

Animals↗

PubMed1994

Growth hormone (GH) regulation of circulating insulin-like growth factor-I levels during sexual maturation of the GH-deficient dwarf (dw/dw) male rat.

In many mammalian species, circulating levels of insulin-like growth factor-I (IGF-I) rise during puberty. Previous studies manipulating testosterone levels in rats with normal GH secretion suggested that the pubertal IGF-I rise is regulated by an interaction between GH and sex steroids. Therefore, in a reciprocal study, IGF-I levels were examined during sexual maturation of the GH-deficient dwarf (dw/dw) rat which has a selective genetic deficiency of GH but normal sex steroid levels. Male dw/dw rats were treated with daily injections of recombinant human GH (200 micrograms/100 g body weight) or saline vehicle, from 28 to 70 days of age. Sexual maturation was determined to occur primarily between 42 and 63 days of age based on testis and seminal vesicle growth and plasma testosterone levels. GH treatment had no effect on seminal vesicle weights, plasma testosterone or gonadotrophins. GH administration resulted in a 7% increase in absolute testes weight (P < 0.05), but a 50% increase in body weight (P < 0.0001). These results supported previous findings that the reproductive development of dw/dw rats is essentially normal. Untreated dw/dw rats had no rise in IGF-I levels during sexual maturation. In contrast, treatment with GH produced a marked sustained rise in IGF-I levels (P < 0.0001). LIgand blots demonstrated GH induction of IGF-binding protein-3 (IGFBP-3) and an IGFBP cluster at 32 kDa. The initially high immunoreactive IGFBP-1 levels (> 600 ng/ml) decreased by 49 days of age after which untreated dw/dw rats had significantly higher IGFBP-1 levels than GH-treated dw/dw rats (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Testicular dysfunction in systemic disease.

The testis is the most accessible endocrine organ to clinical examination and is highly responsive to environmental factors, including systemic illness. The clinical management of any disorder warrants consideration of the effects of illness and its treatment of male reproductive function. Testicular physiology and clinical evaluation are reviewed, as are the mechanisms of reproductive disruption by systemic disease. Specific diseases and disorders, including renal, liver, respiratory, neurologic, and gastrointestinal diseases, and their effects on the testes are discussed also.

Endocrine System Diseases↗

PubMed1993

Requirement for transmembrane sodium flux in maintenance of cytosolic calcium levels in rat Sertoli cells.

The prompt rise in cytosolic calcium induced by follicle-stimulating hormone (FSH) in rat Sertoli cells suggests a role for calcium in FSH signal transduction. To evaluate the requirement for sodium in transmembrane calcium fluxes in Sertoli cells, we measured intracellular calcium concentration under sodium-free conditions and during stimulation by monensin and veratridine, used to elevate cytosolic sodium. Cytosolic calcium levels were measured by dual-wavelength spectrofluorimetry using freshly isolated cells loaded with fura-2 acetoxymethyl ester. Whereas, removal of extracellular sodium lowered cytosolic calcium in unstimulated cells from 89 +/- 4 to 75 +/- 8 nM, treatment with monensin and veratridine increased cytosolic calcium to 142 +/- 19 and 126 +/- 13 nM, respectively. Without extracellular calcium, monensin still produced 47% of the rise in cytosolic calcium observed in the presence of extracellular calcium, indicating approximately equal contributions of calcium from intracellular and extracellular sources. Blockade of voltage-sensitive or/and voltage-insensitive calcium channels by verapamil and ruthenium red was unable to completely prevent the monensin-induced elevation of cytosolic calcium. In addition tetrodotoxin failed to block the FSH-induced rise in cytosolic calcium. These observations, together with the considerable reduction in monensin-induced rise in cytosolic calcium under extracellular sodium-free condition, support the hypothesis that sodium-calcium exchange rather than the specific calcium or sodium channels regulate basal and monensin-induced transmembrane sodium and calcium fluxes in Sertoli cells.

Animals↗

PubMed1993

LH pulsatility, biopotency, and clearance during undernutrition in orchidectomized mature rats.

The effect of food restriction on circulating luteinizing hormone (LH) levels in orchidectomized rats is controversial. The present study demonstrates that decreasing food intake by 50% for 3-10 days in orchidectomized rats increases LH pulse amplitude, length, area under pulse curve, and mean levels but decreases LH pulse frequency compared with ad-lib fed, orchidectomized controls. The effects on pulsatile LH secretion of food reduction by 50% with or without dilution by cellulose to maintain food volume in orchidectomized rats were also examined. Food volume influences pulsatile LH secretion independent of macronutrient effect after 3 days of food restriction, but subsequently macronutrient deprivation predominates. The exaggerated increase in LH levels in orchidectomized rats subject to food restriction for 7 days was not due to immunochemical or chromatographic heterogeneity or alteration in biopotency of circulating LH molecules. Intravenously injected 125I-labeled rat LH analyzed by noncompartmental modeling revealed that neither LH clearance nor mean residence time was reduced by food restriction. We conclude that during food restriction in orchidectomized rats, increases in LH pulse amplitude exceed and precede the decreases in LH pulse frequency, although the early changes in pulse amplitude are predominantly due to reduced food volume rather than macronutrient deprivation.

Aging↗

PubMed1993

Androgen regulation of circulating insulin-like growth factor-I during puberty in male hypogonadal mice.

This study aimed at determining the relationship of sex steroids, particularly in the perinatal period, to the pubertal insulin-like growth factor-I (IGF-I) surge in male mice. We used hypogonadal (hpg) mice, which have a major deletion in the gonadotrophin-releasing hormone (GnRH) gene, in order to have a model lacking all GnRH-induced gonadotrophin and sex steroid secretion throughout pre- and postnatal life. Cross-sectional data on body weights and weights of testes, seminal vesicles, kidneys, liver and spleen from 9 to 77 days of age were obtained in male hpg, heterozygous (Hz) and homozygous normal (N/N) littermates (n = 75-78/group). These data did not reveal any difference between Hz and N/N mice. Hpg mice had decreased body weights which by 70-77 days of age were approximately 18% less than normal controls. Testes and seminal vesicles of hpg mice did not demonstrate any significant postnatal growth. Relative to body weight, kidney weights were also markedly reduced in hpg mice (P < 0.0001), deviating significantly from normal by 28-35 days of age, reflecting the impact of androgen deficiency on a non-reproductive organ. From the cross-sectional data it was concluded that puberty commenced soon after weaning (21 days) in the male and that maturity was achieved within 4-5 weeks. Longitudinal study showed that, compared with normal controls, untreated hpg mice had an exaggerated pubertal IGF-I surge (P < 0.005) which peaked in mid-puberty.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗

PubMed1993

Hypothalamo-pituitary gonadal axis in chronic renal failure.

Chronic renal failure causes extensive neuroendocrine disturbance, including marked hypothalamo-pituitary dysfunction which is reversed by renal transplantation but not dialysis. Gonadal dysfunction in uremia is manifest as delayed puberty in adolescents; as testicular atrophy, hypospermatogenesis, infertility, impotence in men; and as anovulation, infertility, and menstrual disturbance in women. Gonadal steroidogenesis and gametogenesis are impaired and gonadotropin levels are increased. In addition to evidence of defects in pituitary and gonadal function, increasing evidence indicates the importance of alterations in hypothalamic regulation of pituitary-gonadal function in the pathogenesis of uremic hypogonadism. Experimental uremia induced by subtotal nephrectomy in mature rats causes gonadal dysfunction, which is principally due to aberrant neuroendocrine regulation of GnRH secretion involving inhibition of GnRH secretion, hypersensitivity to negative testicular feedback, and resistance to naloxone, a triad of features termed ontogenic regression.

Female↗