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Biomedical subjects

R B Jaffe

Publications and source records attributed to R B Jaffe.

At least 145 records · Page 8Linked to original sources
PubMed1986

Treatment of hirsutism with a gonadotropin-releasing hormone agonist (nafarelin).

GnRH analogs inhibit the secretion of gonadotropins and, therefore, that of estrogens and androgens of ovarian origin. The purpose of this study was to investigate the use of one superactive agonistic GnRH analog, nafarelin, in the treatment of hirsutism. Six hirsute women were treated with nafarelin (1 000 micrograms/day) for 6 months. An acute rise in serum gonadotropin levels occurred in response to nafarelin administration initially, but it lasted less than 2 weeks. Serum gonadotropin, testosterone, free testosterone, and androstenedione concentrations decreased significantly during treatment. Mean serum LH levels decreased from 17.9 +/- 4.6 (+/- SE) to 5.0 +/- 0.5 mIU/ml (P less than 0.01), and FSH decreased from 9.3 +/- 0.7 to 7.2 +/- 0.9 mIU/ml (P less than 0.05) after 1 month of treatment. The total testosterone concentration fell from 0.77 +/- 0.10 to 0.40 +/- 0.14 ng/ml (P less than 0.01) after 1 month of therapy, and free testosterone decreased from 10.7 +/- 2.7 to 4.1 +/- 1.6 pg/ml (P less than 0.01) after 3 months. Androstenedione levels decreased from 2.4 +/- 0.4 to 1.2 +/- 0.2 ng/ml (P less than 0.01) after 1 month of treatment. The mean concentrations of all of the above hormones remained suppressed throughout treatment. Serum 5 alpha-androstane-3 alpha,17 beta-diol glucuronide levels did not decrease significantly during treatment, nor did dehydroepiandrosterone sulfate levels. The mean estradiol concentration during treatment was 34.8 +/- 3.1 pg/ml. The clinical response was very good; hair growth was slower, and new hair was less coarse compared to the pretreatment period. Hirsutism scores (determined by Ferriman-Gallwey assessment of extent and quality of body hair) improved in four of the six patients. In the six patients, the mean score decreased significantly from 19.3 +/- 3.3 to 13.2 +/- 2.8 (P less than 0.05) at the end of treatment. These data demonstrate that by suppressing ovarian androgen production, nafarelin may be useful for the treatment of hirsutism associated with either increased ovarian androgen production or increased sensitivity of the hair follicle to normal concentrations of circulating androgens.

Adolescent↗
PubMed1986

Ontogeny of enkephalin and catecholamine-synthesizing enzymes in the primate fetal adrenal medulla.

Adrenal medullary cells in adult primates contain catecholamines and several neuropeptides. Among these peptides are several products of the three opiate precursor proteins: proenkephalin, prodynorphin, and proopiomelanocortin. We used immunocytochemistry to study the ontogeny of leu-enkephalin and the catecholamine-synthesizing enzymes dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase in adjacent sections of 14 fetal rhesus and 31 fetal human adrenal glands. The adrenal medulla of a 24-week-old human fetus as well as medullas of 11 134- to 172-day-old rhesus fetuses were immunopositive with all 3 antisera employed. Furthermore, in thin serial sections of these glands, dopamine beta-hydroxylase, phenylethanolamine N-methyltransferase, and leu-enkephalin appeared to be colocalized in the same cells of the adrenal medulla. Twenty-six adrenals from fetuses 15-26 weeks stained lightly with one or more of the antisera. Dopamine beta-hydroxylase could be detected at 15 weeks, followed by leu-enkephalin and phenylethanolamine N-methyltransferase at 18-19 weeks. The role of the enkephalins during fetal life or in the adaptation to extrauterine life is not yet clear. In adults, enkephalins are cosecreted with catecholamines in response to stress. Our results suggest that the fetal adrenal may be capable of cosecretion of catecholamines and enkephalins, at least by the end of the second trimester of gestation.

Adrenal Medulla↗
PubMed1986

Dose-dependent inhibition of pituitary-ovarian function during administration of a gonadotropin-releasing hormone agonistic analog (nafarelin).

To determine if treatment with the GnRH agonistic analog nafarelin could reliably block ovulation while only partially disrupting ovarian estrogen production, three degrees of pituitary-ovarian inhibition were investigated. Thirty-two women with ovulatory menstrual cycles were given 125 micrograms (group (Gp) I), 250 micrograms (Gp II), or 1000 micrograms (Gp III) nafarelin daily by intranasal spray. Twenty-seven women completed 6 months of treatment. Basal serum FSH concentrations decreased (P less than 0.01) in all groups. Suppression of serum LH was dose dependent and significant (P less than 0.01) only in Gps II and III. Pituitary desensitization to nafarelin developed in all groups. Peak LH responses to nafarelin decreased by about 70% (Gps I and II) and 95% (Gp III). Basal serum estradiol levels after 1 month of treatment were approximately 70 pg/ml (Gp I) and 25 pg/ml (Gps II and III). Serum estradiol levels increased acutely in Gps I and II, but not in Gp III, in response to each dose of nafarelin. Thus, average daily estradiol levels in Gp II were higher than those in Gp III. Serum testosterone and androstenedione levels decreased slightly (P less than 0.05; Gp II) or by 50% (P less than 0.01; Gp III) during treatment. The effects of nafarelin on ovulatory function also were dose-dependent. In Gp I there were four ovulations (progesterone, greater than 4 ng/ml) and seven instances of luteinization (progesterone, 2-4 ng/ml) during 73 months of nafarelin administration. In contrast, there were no ovulations during 58 and 44 months in Gps II and III, respectively. After discontinuance of nafarelin, ovulatory menstrual function returned rapidly in all women. In summary, inhibition of pituitary-ovarian function by daily intranasal nafarelin administration is dose dependent. Gonadotroph sensitivity to 125 micrograms is variable, and there is inconsistent inhibition of ovulation. Daily doses of 250 or 1000 micrograms analog reliably inhibit ovulation, but are associated with either moderate (Gp II) or marked (Gp III) reduction of ovarian estradiol secretion. The effects of these reduced levels of circulating estradiol on bone are not known. Further investigation, with dosage adjusted according to individual patient sensitivity, may lead to the development of a clinically acceptable contraceptive which consistently inhibits ovulation while maintaining serum estradiol levels sufficient to prevent osteoporosis.

Administration, Intranasal↗
PubMed1986

Trampoline fracture of the proximal tibia in children.

Seven children (aged 2-5 years) sustained fractures of the proximal tibial metaphysis while jumping on a trampoline with a heavier child or adult. Most impaction fractures were transverse and neither angulated nor displaced. None of the children developed permanent disability or impairment. Parents and physicians should be aware of the possible danger to small children while tandem jumping on a trampoline with a heavier partner.

Athletic Injuries↗
PubMed1985

Ablation of folliculogenesis in women by a single dose of gonadotropin-releasing hormone agonist: significance of time in cycle.

Effects of single subcutaneous doses (1, 5, 20, and 100 micrograms) of nafarelin, a potent gonadotropin-releasing hormone agonist, on the physiologic events of the human menstrual cycle were studied in 28 normal women. Nafarelin entered the circulation rapidly after injection. Peak concentrations were observed within 1 hour, and the plasma half-life was 4 to 5 hours. Maximal concentrations of luteinizing hormone and follicle-stimulating hormone were reached 3 to 4 hours after nafarelin administration. The magnitude of the gonadotropin responses depended both on the phase of the menstrual cycle (smallest responses during the early follicular phase) and the dose of nafarelin. Nafarelin administration during the early follicular phase delayed ovulation by 4.6 +/- 1.7 (standard deviation) days and prolonged the duration of the menstrual cycle from a pretreatment length of 29.2 +/- 2.1 days to 33.4 +/- 4.0 days (P less than 0.001). When nafarelin was administered shortly before or after ovulation, cycle length was not altered consistently. Administration 5 to 10 days after ovulation resulted in a truncated luteal phase. These observations suggest that the hormonal events triggered by nafarelin during the early follicular phase temporarily arrest the process of selection of the dominant follicle. Repeated intermittent administration of nafarelin or other gonadotropin-releasing hormone agonists in the early follicular phase may prevent follicular maturation and ovulation and may be a practical approach to contraceptive development.

Adult↗
PubMed1985

Effect on corpus luteum function of luteal phase administration of a potent gonadotropin-releasing hormone analog (nafarelin).

Fourteen women with ovulatory menstrual cycles were treated with a superactive agonistic analog of gonadotropin-releasing hormone (6-D-[2-naphthyl]-alanyl)-GnRH (nafarelin). Eight of the women received a single subcutaneous injection of nafarelin during the luteal phase at a dosage of 2, 5, or 100 micrograms for determination of the dose-response and pharmacokinetic characteristics of the drug. All doses stimulated the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Maximal release was obtained with the 5-micrograms dose (mean +/- standard deviation: delta LH = 297 +/- 75 mIU/ml; delta FSH = 29 +/- 7 mIU/ml), and there was no greater release of gonadotropin with the 100-micrograms dose. To investigate the contraceptive potential of nafarelin as a luteolytic agent, six of the women were treated with 100 micrograms of analog by daily injection for 10 days, beginning either 2 to 3 days or 5 to 7 days after ovulation. Gonadotroph desensitization or down-regulation developed within 24 hours, but serum concentrations of LH and FSH did not fall below normal values during treatment. There were no significant changes in mean estradiol or progesterone concentrations. There also was no change in mean length of the luteal phase (13.7 +/- 2.1 days [control] versus 13.6 +/- 1.4 days). Thus, nafarelin, like other superactive analogs of GnRH, does not appear to be clinically useful as a luteolytic agent in contraceptive development.

Corpus Luteum↗
PubMed1985

Characterization of dopamine and alpha-adrenergic receptors in human prolactin-secreting adenomas with [3H]-dihydroergocryptine.

One tenable hypothesis for the etiology of the development of prolactin-secreting adenomas is that a decrease in inhibitory dopaminergic regulation leads to increased lactotroph proliferation. Dopamine receptors have been repeatedly characterized on prolactin-secreting adenomas using labelled antagonists as ligands; however, no data are available on characterization of the receptor with a dopaminergic agonist. An agonist was utilized as the radioligand in the present study to permit the direct comparison of the pharmacological characteristics of the binding site with the biological response, the inhibition of prolactin secretion. This comparison has never been reported in tissues from the same species. Binding of the dopamine agonist and alpha-adrenergic antagonist [3H]-dihydroergocryptine ([3H]-DHE) to particulate fractions of surgically resected human prolactin-secreting adenomas was high affinity, monophasic, and saturable. Careful characterization of the [3H]-DHE binding by competitions with a large number of dopaminergic and alpha-adrenergic agents revealed the presence of both dopaminergic and alpha-adrenergic binding sites. The presence of a saturable, high affinity alpha-adrenergic binding site was confirmed with the specific alpha-adrenergic antagonist [3H]-WB4101 as a radioligand. Although the rank order of potency for dopaminergic compounds to compete for [3H]-DHE binding was consistent with an interaction with a dopamine receptor, the inhibitory constants (Ki) calculated from the competitions were higher than expected at an anterior pituitary dopamine receptor. This appeared to be due to the lower affinity of these agents at the alpha-adrenergic sites. The observed potency of dopaminergic compounds was inversely related to the number of alpha-adrenergic sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed1985

Leydig cell desensitization by human chorionic gonadotropin does not occur in the human fetal testis.

In vivo data concerning human fetal testicular testosterone production as well as in vitro findings in fetal and neonatal rats suggest that fetal Leydig cells may be capable of responding to gonadotropins and secreting testosterone at high levels for prolonged periods, in contrast to adult testes which reportedly become desensitized after high dose gonadotropin administration. To evaluate fetal testicular testosterone production during long term, high dose gonadotropic stimulation, we cultured human, rhesus monkey, and rabbit fetal testes in organ and cell cultures. After 24 h of culture with different concentrations of hCG (0-100 ng/ml, physiological fetal concentrations during human gestation), the fetal testes were still able to respond to a second hCG stimulus (no desensitization). The 24-h incubation with hCG (0-100 ng/ml) also increased the capacity of the cultures to secrete testosterone during a second incubation in a dose-dependent manner even in the absence of hCG (steroidogenic enzyme induction). Furthermore, hCG increased thymidine incorporation into DNA by the human fetal testis. The results of this study substantiate the role of hCG in the regulation of fetal Leydig cells. They suggest that long term effects via nuclear mechanisms (RNA and DNA synthesis) may be important aspects of this regulation, and that fetal Leydig cells are able to respond to sustained concentrations of gonadotropin without being desensitized.

Animals↗
PubMed1985

Effects of oestradiol and prolactin on progesterone production by rhesus monkey luteal cells in vitro.

The effects of oestradiol and prolactin (Prl) on progesterone production by dispersed monkey luteal cells were examined. Corpora lutea were recovered from monkeys 5-7 days following ovulation induction during the puerperium. The tissue was dispersed by collagenase and mechanical disruption. The resulting cells were incubated in Dulbecco's modified Eagle's medium, containing the hormones to be tested, for 3 h at 37 degrees C. The medium was removed and assayed for progesterone by RIA. Human luteinizing hormone (hLH) produced a significant, dose-related increase in progesterone secretion that was comparable to that produced by dibutyryl cyclic adenosine monophosphate. Human follicle stimulating hormone (hFSH) had no effect upon progesterone production by the luteal cells. Oestradiol (100-10 000 pg/ml) produced a significant, dose-related decrease in both basal and hLH-stimulated progesterone production. Ovine Prl (oPrl) had neither a stimulatory nor an inhibitory effect upon basal progesterone secretion at doses up to 1000 ng/ml. Further, oPrl did not affect hLH-stimulated progesterone production. We conclude that oestradiol is a potent inhibitor of luteal progesterone secretion in vitro and that Prl does not inhibit progesterone production in the primate corpus luteum under these experimental conditions.

Animals↗
PubMed1985

Treatment of endometriosis with a potent agonist of gonadotropin-releasing hormone (nafarelin).

Administration of superactive agonistic analogs of gonadotropin-releasing hormone (GnRH) has been shown to induce a paradoxic and reversible suppression of gonadotropins, resulting in suppressed gonadal steroid concentrations. Because there currently is no uniformly successful and acceptable medical therapy for endometriosis, we examined the effects of 6 months of nasal administration (500 micrograms every 12 hours) of the agonistic analog of GnRH, nafarelin, on clinical signs and symptoms and hormonal profiles in eight women with endometriosis. All patients had prompt and near-complete relief from their painful symptoms of endometriosis. Laparoscopy or laparotomy, performed both before and after treatment in seven of the women, revealed complete resolution of active endometriotic lesions in five patients and only a single, small cul-de-sac implant in a sixth woman. A large ovarian endometrioma decreased slightly in response to treatment in the seventh woman. Serum luteinizing hormone and follicle-stimulating hormone concentrations, after a transitory stimulation at the onset of treatment, declined and were suppressed (P less than 0.001) during the remainder of treatment. Serum estradiol concentrations fell to approximately menopausal levels (less than 30 pg/ml) after 1 to 4 weeks. Reversibility of drug effect was prompt, with ovulatory menses returning 47 +/- 8 days (+/- standard deviation) after treatment. Thus, nasal administration of agonistic analogs of GnRH may represent a new treatment modality for endometriosis.

Administration, Intranasal↗
PubMed1985

Polycystic ovarian disease.

Polycystic ovarian disease represents a poorly defined spectrum of clinical disorders having oligo-ovulation or anovulation as a common feature. There is no single, universally accepted biochemical or clinical definition. Clinical findings usually include anovulation resulting in irregular uterine bleeding and infertility, androgen excess resulting in hirsutism and acne, and obesity. The patho-physiology involves altered functions of the hypothalamus, pituitary, ovary and adrenal glands, resulting in failure of folliculogenesis to regularly proceed to ovulation. The cause of the initiating event in this disease process remains enigmatic. Therapy for the various abnormalities in polycystic ovarian disease is tailored to a patient's needs and may include preventing endometrial hyperplasia, controlling irregular uterine bleeding, controlling hirsutism and inducing ovulation.

Female↗
PubMed1984

Decreased spinal mineral content in amenorrheic women.

Premenopausal amenorrheic women may be at risk for the development of osteoporosis. In hyperprolactinemia, cortical bone mass is decreased and the magnitude of the decrease correlates with the severity of the estrogen deficiency. However, bone loss in women with amenorrhea from other causes has not been assessed. We have studied women with hypothalamic and hyperprolactinemic amenorrhea and premature ovarian failure. Bone mass in the peripheral cortical bone was only slightly decreased from age-matched controls, but spinal trabecular bone was decreased 20% to 30%. Estradiol levels were 20 to 80 pg/mL in these women, not different from normal early follicular levels. The decrease in bone mass in the spine did not correlate with serum estradiol at these levels. The hypothalamic amenorrhea group was made up of athletes in whom the bone mass decrease was an unexpected finding.

Adolescent↗
PubMed1984

Fluoroscopic removal of ingested alkaline batteries.

The ingestion of small, flat disc batteries by infants and children may be life threatening if the battery leaks or disintegrates resulting in perforation of the gastrointestinal tract. The fluoroscopic removal of six ingested batteries from the stomach using an orogastric tube and magnet and a Foley catheter is described.

Child↗
PubMed1984

Prolactin-secreting adenomas in women. VII. Dopamine regulation of prolactin secretion.

Previous studies demonstrated that high doses of dopamine administered as a constant infusion were capable of suppressing PRL secretion in both normal and hyperprolactinemic individuals. The present study was designed to examine the dose-response relationship of PRL suppression to low doses of dopamine (between 0.06 and 4 micrograms/kg X min) infused in a step-wise fashion. Ten hyperprolactinemic patients with PRL-secreting pituitary adenomas and 10 normally menstruating women in the early follicular phase of a cycle were studied. For hyperprolactinemic women, the mean (+/- SD) serum PRL level (by RIA) was 112 +/- 101 ng/ml, with a range of 26-386 ng/ml, the mean estradiol level (by RIA) was 28 +/- 8 pg/ml, and the mean baseline dopamine level by carboxy-o-methyl transferase assay (COMT) was 357 +/- 237 pg/ml (2.33 +/- 1.54 X 10(-9) M). The normal women had a mean PRL of 8.1 +/- 3.5 ng/ml, a mean estradiol level of 42 +/- 12 pg/ml, and a mean baseline dopamine level of 317 +/- 223 pg/ml (2.07 +/- 1.45 X 10(-9) M). Concentrations of dopamine achieved at the lowest doses infused were less than 10 times baseline levels and were in the nanomolar range. The measured IC50 (the concentration of dopamine required to achieve 50% of maximal suppression) was 6 +/- 3 X 10(-9) M for normal women and 14 +/- 4 X 10(-9) M for hyperprolactinemic patients. The apparent inhibition constant determined by a nonlinear least squares procedure, was 3 +/- 3 X 10(-9) M for normal women and 11 +/- 12 X 10(-9) M for women with hyperprolactinemia. Both groups exhibited dose-dependent suppression of PRL to about 80% of initial values. Under these experimental conditions, the data do not support the hypothesis that there is a marked loss in sensitivity to dopamine in patients with PRL-secreting adenomas.

Adenoma↗
PubMed1983

Biologically active chorionic gonadotropin: synthesis by the human fetus.

The kidney, and to a slight extent the liver, of human fetuses were found to synthesize and secrete the alpha subunit common to glycoprotein hormones. Fetal lung and muscle did not synthesize this protein. Since fetal kidney and liver were previously found to synthesize beta chorionic gonadotropin, their ability to synthesize bioactive chorionic gonadotropin was also determined. The newly synthesized hormone bound to mouse Leydig cells and elicited a biological response: namely, the synthesis of testosterone. These results suggest that the human fetus may participate in metabolic homeostasis during its development.

Animals↗