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Biomedical subjects

D J Handelsman

Publications and source records attributed to D J Handelsman.

At least 109 records · Page 6Linked to original sources
PubMed1989

Pregnancy outcome in luteinizing hormone-releasing hormone induced cycles: a multicentre study.

In a retrospective international study 223 pregnancies induced with pulsatile hormone-releasing hormone (LH-RH) were evaluated. In patients with hypothalamic amenorrhea (HA) and polycystic ovarian disease (PCOD) the abortion rate was similar (10% vs 8.7%). The premature delivery rate was significantly higher, however, in the patients with HA, but this could be explained by the higher incidence of multiple pregnancies in this group. Thirty multiple pregnancies were observed in the HA group (n = 174) compared with none in the PCOD group (n = 24; p less than 0.05). The incidence of multiple pregnancies in the HA group correlated to the pulse dose (p less than 0.05). The 1st treatment cycle resulted in more multiple pregnancies than did subsequent cycles (p less than 0.05). Difference in pulse interval did not affect the incidence of multiple pregnancies, nor did the route of administration (intravenous or subcutaneous). The incidence of congenital anomalies was comparable to that with spontaneously achieved pregnancies.

Adult↗
PubMed1988

Randomized clinical trial of testosterone replacement therapy in hypogonadal men.

We have compared the pharmacokinetics and pharmacodynamics of the three commonly used testosterone formulations in a prospective, randomized cross-over clinical trial. Plasma free and total testosterone and their ratio (proportion of unbound testosterone), sex hormone-binding globulin (SHBG), oestradiol, LH and FSH were measured in 15 hypogonadal men (nine hyper- and six hypogonadotrophic) who underwent, in a randomized sequence, three treatment periods each separated by an intervening washout period. The treatments were: (i) intramuscular injection of 250 mg mixed testosterone esters at 2-weekly intervals, (ii) oral testosterone undecanoate 120 mg bd, and (iii) subcutaneous testosterone pellets (6 x 100 mg). Pellet implantation gave the most prolonged effect with free and total testosterone levels being elevated for up to 4 months. This was accompanied by prompt and sustained suppression of plasma LH and FSH, an increase in plasma levels of oestradiol but no change in SHBG levels. In contrast, intramuscular injections induced marked but reproducible week-to-week fluctuations in free and total testosterone, which resulted in a small decrease in plasma SHBG levels, less marked suppression of LH and FSH and a smaller increase in plasma levels of oestradiol. Oral testosterone undecanoate produced the most variable plasma levels of free and total testosterone with a peak in the first treatment week and a fall thereafter and, despite maintenance of testosterone levels within the physiological range, there was no significant suppression of plasma levels of LH and FSH, and oestradiol levels were unchanged but levels of SHBG and total cholesterol were decreased. Free testosterone levels were increased disproportionately during testosterone treatment as the proportion of unbound testosterone was increased by all three treatments. All three testosterone preparations lowered plasma levels of urea and all were without biochemical or haematological toxicity. Reported sexual function was better maintained and side-effects were fewer with parenteral compared with oral treatments. The marked decrease in SHBG and cholesterol levels during oral testosterone undecanoate, when compared with parenteral treatments, occurred despite lesser androgenic effects (suppression of gonadotrophin levels and reported sexual function), which suggests that the liver is exposed to excessive androgenic load via the portal vein during oral treatment with testosterone esters. It is concluded that testosterone pellets give the closest approximation to zero-order (steady-state) delivery conditions for up to 4 months after a single insertion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1988

Effects of gonadotropin-releasing hormone analogs on cis-platinum-induced spermatogenic damage.

In order to test the hypothesis that pretreatment with gonadotropin-releasing hormone (GnRH) analogs might ameliorate cytotoxic drug-induced testicular damage, mature male Wistar rats were pretreated for 2 weeks with a GnRH superactive agonist or a pure GnRH antagonist prior to, and for 1 week after, a 5 mg/kg intraperitoneal dose of cis-platinum. Despite inhibition of testicular function by both GnRH analogs prior to cis-platinum administration, there was no evidence of protection or enhanced recovery of spermatogenesis at 6 and 12 weeks after cis-platinum treatment, and spermatogenesis was significantly further depressed at both time-points by both GnRH agonist and antagonist pretreatment. This suggests that pretreatment with GnRH analogs in the rat does not protect spermatogenesis from cis-platinum-induced testicular damage within up to two spermatogenic cycles and that hypogonadism at the time of cytotoxic drug treatments may aggravate testicular damage.

Animals↗
PubMed1988

Pharmacodynamics of gonadotropin-releasing hormone. 1. Effects of gonadotropin-releasing hormone pulse contour on pituitary luteinizing hormone secretion in vivo in sheep.

The gonadotropin-releasing hormone (GnRH) waveform arrives at the pituitary gonadotropes via the pituitary portal blood and provides the immediate suprapituitary stimulus to luteinizing hormone (LH) secretion. Despite their importance, nature and influence of the physiological GnRH waveform in vivo have been difficult to study. Recent pharmacological and in vitro studies have suggested the potential importance of the wave contour as a specific and independent factor in the pharmacodynamic effects of GnRH on pituitary gonadotrope LH secretion in vivo, and it has been hypothesized that the steepness of the rising edge of the GnRH wave contour is a specific determinant of pituitary LH secretion. In order to investigate the pharmacodynamic influence of GnRH pulse wave contour on pituitary LH secretion in vivo, variations in plasma LH responses to alterations in GnRH wave contour were measured in chronic ovariectomized, hypothalamopituitary-disconnected sheep undergoing physiological pulsatile GnRH maintenance regimen at a fixed dose (250 ng/pulse) and frequency (interpulse interval 120 min). Variable wave contours were then generated by administration of the same total GnRH pulse dose over various lengths of time from near-instantaneous bolus to increasing lengths of constant-rate infusion time up to 8 min. This model allowed specific examination of pulse wave contour in the absence of concurrent changes in endogenous GnRH or sex steroid secretion and holding constant GnRH pulse dose, frequency, and route of administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Pharmacodynamics of gonadotropin-releasing hormone (GnRH). II. Pattern of GnRH delivery alters pituitary luteinizing hormone secretion in women.

The pulse frequency, amplitude, and mode of administration of GnRH all influence gonadotropin secretion and, ultimately, pituitary-gonadal function. We studied plasma LH responses to repetitive iv administration of GnRH given hourly for 5 h as a 2-microgram rapid (less than 15 s) bolus dose or a 2-microgram dose infused for 15 min of each hour in seven women deficient in endogenous GnRH and sex steroids. Plasma LH levels, measured at 10-min intervals throughout the 5-h period, rose more briskly (pattern X time course interactions: F = 3.33; P less than 0.0001) to higher levels overall (F = 11.7; P = 0.014) after rapid bolus GnRH administration than after GnRH infusion. Plasma FSH levels increased during both modes of delivery, with higher responses to rapid bolus GnRH administration (P = 0.005). Plasma estradiol levels did not change during either 5-h study. We conclude that the pattern of delivery of GnRH is a determinant of pituitary LH and FSH secretion in untreated hypogonadotropic women, and therefore, that alterations in the GnRH wave form and/or peak plasma GnRH concentrations consequent upon different rates of GnRH entry into the blood-stream may explain the different responses that occur when GnRH is given by different routes.

Adult↗
PubMed1988

Comparison of inhibin immunological and in vitro biological activities in human serum.

A comparison of serum inhibin levels in men and women was undertaken using a sensitive sheep pituitary cell in vitro bioassay and a newly developed heterologous RIA. The RIA was based on an antiserum raised to bovine 31K inhibin using [125I]31K inhibin as tracer. Bovine inhibin alpha- and beta-subunits, bovine activin-A, transforming growth factor-beta, and Mullerian inhibitory substance did not cross-react in the RIA. In both assays, dilutions of serum gave response lines parallel to that of the partially purified human follicular fluid inhibin preparation used as standard. Negligible levels of both bio (B)- and immuno (I) activities were found in serum from women with premature ovarian failure or castrated men. In ovulation-induced cycles, serum B inhibin levels increased progressively from the early to the late follicular phase and remained at the late follicular phase level during the early and midluteal phases. Serum I inhibin levels also rose during the follicular phase, but declined during the early luteal phase before increasing again in the midluteal phase. As a consequence, inhibin B:I ratios varied during the treatment cycle, with high ratios in early follicular (2.86) and early luteal (2.25) phases and a low ratio in the midluteal phase (1.09). Similar changes in serum B:I ratios also occurred during the midcycle and midluteal phases of normal cycles. The B:I ratio was lower (0.35) in normal men. We conclude that the largely similar pattern of inhibin biological and immunological activities in serum obtained during a variety of physiological conditions support the validity of the RIA procedure, and the B:I ratio of serum inhibin varies during the follicular and luteal phases of the cycle and is low in men. Potential reasons for these changes in B:I ratio include the presence of interfering substances in either the bioassay or the RIA, the presence of inhibin isoforms, and/or modulation of secreted forms by sex steroids.

Adult↗
PubMed1988

Comparison of different models of diabetes care on compliance with self-monitoring of blood glucose by memory glucometer.

The modern management of diabetes relies heavily on self-monitoring of blood glucose (SMBG), and therefore SMBG records are an important source of clinical data for management decision making. The development of a memory Glucometer has provided the opportunity to verify the validity of glucose records thus generated and observe the effects of different educational approaches on compliance with SMBG. Thirty-four patients without previous experience of SMBG were randomized into one of the following experimental groups differing in the model of diabetes care: mutual decision making, didactic, and authoritarian. Patients, unaware of the memory capacity of the glucose meter, were required to perform four glucose measurements per day over a 14-day observation period. Patient-generated blood glucose records were then compared with objective records stored in the glucose-meter memory. Patients with gestational diabetes mellitus recorded a lower proportion of correct results (63 vs. 79%, P = .049) and exhibited a tendency to invent results with lower blood glucose levels (5.3 vs. 7.5 mM, P less than .0001) than the results omitted compared with patients with non-insulin-dependent diabetes mellitus. Predictors of greater validity of records were perceived intelligence of the subject (chi 2 = 4.56, P less than .02) and private health-insurance status (chi 2 = 4.52, P less than .04), whereas the experimental group assignment was not significant. These findings reflect potential motivational and sociodemographic limitations in the validity of SMBG recordings within the management and education of patients with gestational and nongestational diabetes.

Blood Glucose Self-Monitoring↗
PubMed1987

Pulsatile intravenous gonadotropin-releasing hormone for ovulation-induction in infertile women. I. Safety and effectiveness with outpatient therapy.

Pulsatile intravenous gonadotropin-releasing hormone (IV-GnRH) was used in 36 infertile patients with primary amenorrhea (n = 5), secondary amenorrhea due to hypothalamic chronic anovulation (HCA) (n = 22), hyperprolactinemia (n = 1) or polycystic ovary syndrome (PCOS) (n = 5), and oligomenorrhea (n = 3). Treatment was commonly initiated in the hospital but was then continued outside, with patients and local physicians accepting responsibility for maintaining IV-GnRH delivery systems. Twenty-eight of 113 treatment cycles (24.8%) resulted in pregnancy, with four spontaneous abortions (14.3%) and four twin pregnancies (16.7%) among 24 births. Probability of pregnancy per treatment cycle was significantly higher for primary amenorrhea (0.30) and for HCA (0.33) than for PCOS (0.07; P less than 0.05) and for oligomenorrhea (no conceptions; P = 0.01). Ovulatory cycles were not achieved in five patients (primary amenorrhea, n = 1; PCOS, n = 3; oligomenorrhea, n = 1). There were no serious complications; six patients recorded eight febrile episodes, which responded quickly to antibiotic therapy and cannula change. The authors conclude that outpatient IV-GnRH is safe, practical, and effective for follicular stimulation and ovulation induction in women presumed to have GnRH deficiency and in whom clomiphene therapy fails, and that less intensive monitoring is needed compared with gonadotropin ovulation induction therapy.

Adult↗
PubMed1987

Pulsatile intravenous gonadotropin-releasing hormone for ovulation-induction in infertile women. II. Analysis of follicular and luteal phase responses.

Pulsatile intravenous gonadotropin releasing hormone (IV-GnRH) was used in 36 infertile patients with primary amenorrhea (n = 5), secondary amenorrhea due to hypothalamic chronic anovulation (HCA) (n = 22), hyperprolactinemia (n = 1) or polycystic ovary syndrome (PCOS) (n = 5), and oligomenorrhea (n = 3), using several dosage and timing regimens. Early follicular phase responses showed four patterns: type 1 consisted of a delayed follicle-stimulating hormone (FSH) peak and was seen with severe hypothalamic suppression (n = 4); type 2 consisted of a brisk and dominant FSH peak on the first day of treatment, and occurred with mild to moderate hypothalamic suppression (n = 19); type 3, which consisted of an FSH peak accompanied by an immediate and exaggerated luteinizing hormone (LH) rise, occurred with mild PCOS and some cases of HCA (n = 5); and type 4, in which LH levels were high to begin with and neither FSH nor LH levels rose with GnRH, occurred with severe PCOS (n = 2). Exaggerated estradiol responses within 24 hours of therapy were seen in eight cycles: in four cases no ovarian abnormality was apparent; in three cases a dominant follicle was already present; and in one case ovarian hyperstimulation was diagnosed ultrasonographically. With standard human chorionic gonadotropin luteal phase support, luteal phase defects were rare with HCA but common with PCOS.

Estradiol↗
PubMed1987

Diet composition and lipoprotein lipase (EC 3.1.1.34) activity in human obesity.

1. Adipose tissue lipoprotein lipase (EC 3.1.1.34; AT-LPL), a rate-limiting enzyme in triglyceride storage in adipose tissue, is hormonally regulated and may be important in the maintenance of obesity. 2. In twelve obese women, AT-LPL activity was measured before weight loss, during weight loss and after 1 and 2 weeks of weight maintenance on either a high-carbohydrate or a high-protein diet. 3. When related to tissue weight, AT-LPL activity during the 2 weeks of weight maintenance was higher than the initial AT-LPL activity; there was no difference when activity was expressed per cell. 4. Changes in AT-LPL activity were not affected by diet composition. AT-LPL activity correlated with insulin levels and a change in insulin sensitivity of AT-LPL was observed after weight loss.

Adipose Tissue↗
PubMed1987

Hormonal regulation of the peripubertal surge of insulin-like growth factor-I in the rat.

The marked increase in circulating insulin-like growth factor-I (IGF-I) levels during puberty observed in primates indicates an important functional relationship between hypothalamic-pituitary gonadal function and hormonal regulation of peripubertal circulating IGF-I levels. Recent studies demonstrating local production and secretion of gonadal peptides including IGF-I suggest that increased circulating IGF-I levels during puberty might be due to direct gonadal secretion of IGF-I or alternatively to indirect effects of increased gonadal steroid secretion on nongonadal tissues including the hypothalamus, pituitary, and liver. We therefore studied the effects of prepubertal castration on the pubertal IGF-I surge and demonstrate that castration provokes a further increase rather than ablation of the pubertal IGF-I surge in the rat. Furthermore, neonatal treatment with monosodium glutamate, a hypothalamic neurotoxin, abolishes the pubertal IGF-I surge when commenced on postnatal day 1 but not on day 5, whereas treatment with a GnRH antagonist commencing within 12 h of birth significantly reduces but does not abolish the pubertal IGF-I surge. We therefore propose that the pubertal IGF-I surge in the rat is not due to direct gonadal secretion of IGF-I or other gonadal hormones during puberty but may involve hypothalamic and/or hepatic programming by events during prenatal or very early postnatal life.

Animals↗
PubMed1987

Short-term exposure to insulin-like growth factors stimulates testosterone production by testicular interstitial cells.

The effect of short-term exposure to the insulin-like growth factors (IGF-I and IGF-II) on testosterone production by rat testicular interstitial cells in primary culture has been examined. Both peptides, when present during a 1-h pre-incubation period, increased human chorionic gonadotropin (hCG)-stimulated testosterone release over the following 16-h period. The effect of exposure to IGFs was most marked on maximally hCG-stimulated testosterone release. Maximal stimulation following IGF exposure was 80-85% above that seen without IGFs, and the IGF effect was half-maximal at 1.5-2 micrograms/l of IGF-I or IGF-II. Pre-incubation with IGFs did not alter the concentration of hCG (0.1 microgram/l) at which half-maximal stimulation of testosterone release was seen. Increasing cell density had a marked effect on the testosterone production rate per 10(5) cells, and the stimulatory effect of IGFs was only seen at relatively high cell density (2.8 X 10(5) cells/ml). Varying the period of pre-incubation with IGFs between 0.5 and 16 h, it was found that a 1-h period gave maximal stimulation. We conclude that a short exposure to IGFs is capable of increasing hCG-stimulated steroidogenesis in Leydig cells, and postulate that this effect may be part of an intratesticular paracrine control mechanism.

Animals↗
PubMed1986

Hormonal therapy of cryptorchidism. A randomized, double-blind study comparing human chorionic gonadotropin and gonadotropin-releasing hormone.

We conducted a randomized, double-blind study comparing intranasal gonadotropin-releasing hormone (1.2 mg per day for 28 days) with parenteral human chorionic gonadotropin (3300 IU per week for four weeks) in the treatment of cryptorchidism in 33 boys one to five years old (29 with unilateral and 4 with bilateral cryptorchidism). Testicular descent into the scrotum occurred in 3 of the 16 patients (19 percent) treated with gonadotropin-releasing hormone and in 1 of the 17 (6 percent) treated with human chorionic gonadotropin (P = 0.23). The mean luteinizing hormone and testosterone levels were similar in both groups before treatment. During treatment, the testosterone levels were significantly increased in both groups, but higher levels occurred in the group treated with human chorionic gonadotropin (P less than 0.05). In a parallel (but uncontrolled) study of five boys with retractile testes (defined as a nonscrotal testis that could be manipulated into the bottom of the scrotum) who were originally excluded from the main protocol but were treated with the same regimen of human chorionic gonadotropin, descent into the scrotum occurred in all patients. We conclude that hormonal therapy with either gonadotropin-releasing hormone or human chorionic gonadotropin is, in most cases, ineffective in promoting testicular descent of true cryptorchid testes. However, short-term treatment with human chorionic gonadotropin is very effective in producing descent of retractile testes. These results suggest that the wide discrepancies in apparent efficacy in previous trials of hormonal therapy of cryptorchidism may have been due to inclusion in those studies of various proportions of patients with retractile testes.

Administration, Intranasal↗
PubMed1986

Luteinizing hormone and follicle-stimulating hormone responses to intransal gonadotropin-releasing hormone.

For determination of the dose-response relationships of plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to the intranasal administration of gonadotropin-releasing hormone (GnRH), normal adult men were administered doses of 100, 200, 400, and 800 micrograms of GnRH on separate days, and plasma LH and FSH were measured before and after nasal insufflation of GnRH. Plasma LH was increased after a minimum dose of 200 micrograms GnRH. Median peak plasma LH levels occurred 30 minutes after intranasal GnRH and followed a log-dose relationship. When compared with intravenous GnRH, the biopotency of intranasal GnRH at the 200-, 400-, and 800-microgram doses was 1.1%, 2.3%, and 6.2%, respectively. Plasma FSH levels rose significantly only after the highest (800-micrograms) intranasal GnRH dose. From these data, we conclude that in eugonadal adult men the minimal effective dose of intranasal GnRH to elicit a significant pituitary (LH) response is 200 micrograms and that the relative efficacy of intranasal GnRH increases with the dose. In spite of the apparently low biopotency for intranasal GnRH, this route of administration may be considered as an alternative to the parenteral mode of GnRH delivery, and the lower biopotency can be partly overcome by increasing the dose.

Adult↗
PubMed1986

Comparison of the efficacy of subcutaneous and nasal spray buserelin treatment in suppression of testicular steroidogenesis in men with prostate cancer.

The comparative efficacy of subcutaneous injections and intranasal spray in the maintenance of suppression of testicular function in men with advanced prostatic cancer treated with a gonadotropin-releasing hormone (GnRH) agonist, Buserelin, was evaluated in a nonrandomized clinical trial. After a common induction period of 1 week's treatment with 500 micrograms three times daily by subcutaneous injection, patients were allocated into one of two groups for maintenance therapy with either subcutaneous (200 micrograms once daily) or intranasal (400 micrograms nasal spray three times daily) Buserelin therapy. Plasma luteinizing hormone (LH) and sex steroid (testosterone [T], dihydrotestosterone [DHT], and estradiol [E2]) patterns were studied before the start and at days 1, 7, and 14 and months 2, 4, 6, and 12 on maintenance regimens. During the maintenance therapy, age-adjusted T levels were markedly suppressed to near-castrate levels in both treatment groups. Despite this marked suppression, age-adjusted T levels were consistently lower in men treated with the subcutaneous regimen from the 2nd week to the 12th month of treatment in morning pooled specimens as well as in detailed sampling over a 24-hour period after 12 months of continuous treatment. A similar pattern of enhanced suppression by the subcutaneous regimen was also observed for age-adjusted DHT, but not E2, levels during the study. Neither the magnitude nor the time course of T suppression by GnRH analog treatment could be entirely explained by the nature of the decline in plasma LH levels, which fell much less and more gradually over a 12-month period.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗
PubMed1986

Bioactive luteinizing hormone in plasma of uraemic men and men with primary testicular damage.

Elevation of immunoreactive LH and reduced testosterone production are consistent features of Leydig cell dysfunction in uraemic hypogonadism. To investigate further Leydig cell regulation in uraemia, we measured plasma bioactive LH (B-LH) and immunoreactive LH (I-LH), as well as FSH, testosterone, creatinine, urea and albumin in seven uraemic men before and after haemodialysis and compared them to levels both in eugonadal controls (n = 10) and in men with primary testicular damage (n = 10). Plasma B-LH was increased in uraemic men compared with both nonuraemic control groups. Plasma I-LH and FSH were increased and testosterone decreased in uraemic men compared to eugonadal controls. In comparison with nonuraemic men with primary testicular damage, plasma I-LH levels were similar but FSH and testosterone lower in uraemic men. As a consequence, the ratio of B-LH to I-LH (LH:B/I ratio) was decreased in men with primary testicular damage but normal in uraemic men. A single session of haemodialysis decreased creatinine (50.5%) and urea (58.5%) and increased B-LH (47.7%), I-LH (32.9%), FSH (24.4%), testosterone (15.8%) and albumin (17.8%) levels, but the LH:B/I ratio was unchanged. Increases in gonadotrophin levels were greater than could be accounted for by haemoconcentration suggesting that dialysis may also ameliorate uraemic suppression of the hypothalamus and pituitary. Ultrafiltrates of human uraemic plasma (mol wt less than 25 000) had no inhibitory effect on in-vitro steroidogenesis by isolated rat Leydig cells making circulating uraemic 'middle-molecule'-type toxins unlikely to be involved in causing lowered testosterone levels in uraemic men.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effects of aging on the in vitro release of gonadotropin-releasing hormone.

Secretion of GnRH from mediobasal hypothalami (MBH) of old (23 month) and young (2 month) male rats was studied in an in vitro superfusion system. GnRH efflux from both old and young MBH increased in response to stimulation with 20 microM norepinephrine and 40 microM naloxone; however, both basal and stimulated GnRH release were reduced from MBH of old rats despite similar hypothalamic GnRH content. The diminished basal secretion and responsiveness to two major stimuli of the GnRH neuron may be important in the well-known involution of the hypothalamic-pituitary testicular axis in aging male rats.

Aging↗