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Biomedical subjects

I M Spitz

Publications and source records attributed to I M Spitz.

At least 37 records · Page 2Linked to original sources
PubMed1993

The combination of gonadotrophin-releasing hormone (GnRH) antagonist and pulsatile GnRH normalizes luteinizing hormone secretion in polycystic ovarian disease but fails to induce follicular maturation.

To evaluate the role of altered luteinizing hormone (LH) release in the mechanism of polycystic ovarian disease (PCOD) anovulation, we have co-administered a gonadotrophin-releasing hormone (GnRH) antagonist and pulsatile GnRH therapy to two clomiphene citrate-resistant PCOD patients. The aim was to correct their inappropriate gonadotrophin secretion. Nal-Glu was administered s.c. every 72 h to both subjects for 3 weeks. On day 7 after commencing the study, intravenous pulsatile GnRH therapy was initiated (10 micrograms/pulse) every 90 min for 15 days to both subjects. In one subject, Nal-Glu treatment was continued and the GnRH dose was increased to 20 micrograms/pulse for 10 additional days. Prior to Nal-Glu, mean serum LH levels were 10.4 +/- 1.6 and 9.3 +/- 1.3 mIU/ml (mean +/- SEM) and mean interpulse intervals were 67.1 and 60 min in patients 1 and 2, respectively. Mean serum FSH levels were 4.9 +/- 0.4 and 4.2 +/- 0.2 mIU/ml for patients 1 and 2, respectively. LH pulsatility was abolished following Nal-Glu, mean serum LH decreased to 1.1 +/- 0.1 and 1.3 +/- 0.5 mIU/ml and mean FSH to 1.8 +/- 0.1 and 2 +/- 0.1 mIU/ml in the two subjects. On the 4th day of the combined therapy, mean serum LH increased to 5.4 +/- 1.3 and 3.9 +/- 0.9 mIU/ml with a mean interpulse interval of 72 and 80 min, respectively. Mean FSH levels increased to 3 +/- 0.1 and 2.8 +/- 0.1 mIU/ml, respectively and to 5.5 +/- 0.2 mIU/ml after the GnRH dose was increased in patient 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

The divergent effect of RU 486 on adrenal function in the dog is related to differences in its pharmacokinetics.

This study has evaluated the relationship between the antiglucocorticoid effect of RU 486 and its pharmacokinetics in seven female mongrel dogs (weight 21-30 kg), all of which had appropriate responses to insulin-induced hypoglycemia and metyrapone. They were given RU 486 (50 mg.kg-1.d-1) for ten days. Three dogs (responders) demonstrated increased secretion of ACTH and cortisol which reached a maximum at the termination of RU 486 administration and returned to baseline by days 22 and 18, respectively. The remaining four dogs (non-responders) showed only transient non-sustained increases in ACTH and cortisol. Serum concentrations of RU 486 and its monodemethylated and di-demethylated (but not its hydroxylated) metabolites were significantly higher in the responder dogs. The ratios of the hydroxylated metabolite to RU 486 and its demethylated derivatives were higher in the non-responders, whereas the ratio of the di-demethylated to monodemethylated compound was higher in the responders. Since variations in the hydroxylation and reductive catabolism of steroids have been well documented in different strains of a species, it is possible that the differences in levels of RU 486 and its metabolites in the two groups are accounted for by variations in RU 486 metabolism. In the responder group the metabolism of RU 486 is directed to demethylation, and in the non-responder group to hydroxylation. Thus, differences in pharmacokinetics of RU 486 in the two groups of dogs may explain the variable biological response to this antiglucocorticoid.

Administration, Oral↗
PubMed1993

Response to intermittent RU486 in women.

OBJECTIVE: To determine the effects of intermittent administration of the antiprogestin RU486 on ovarian function. DESIGN: Three different regimens of RU486 were tested. PARTICIPANTS: Nine healthy regularly menstruating volunteers protected by an intrauterine device or surgical sterilization. INTERVENTIONS: Two groups of three women each received 10 mg or 50 mg RU486 at weekly intervals for 5 weeks. Another three women received 50 mg RU486 for 3 consecutive days at 10-day intervals for 80 days. MAIN OUTCOME MEASURES: Serum E2, P and RU486 levels. Ovarian ultrasound (US) and serum LH and FSH in select subjects. RESULTS: The predominant effect was partial inhibition of E2 secretion and suppressed P levels. During a total aggregate of 16 treatment months, there were seven episodes of elevated P levels; however, US did not always indicate the occurrence of normal ovulation. CONCLUSION: Intermittent RU486 administration can interfere with normal follicular development and function, but its clinical application may require a more effective dose and/or timing of administration.

Administration, Oral↗
PubMed1992

Spontaneous luteinizing hormone surges can be reliably prevented by the timely administration of a gonadotrophin releasing hormone antagonist (Nal-Glu) during the late follicular phase.

A new gonadotrophin releasing hormone antagonist (Nal-Glu) was used during the late follicular phase of the natural cycle in order to prevent spontaneous surges of luteinizing hormone (LH). Eight regularly ovulating women (group 1) received two injections of Nal-Glu (5 mg) administered 48 h apart when plasma oestradiol levels exceeded 125 pg/ml. Human menopausal gonadotrophin (HMG, 225 IU) was administered simultaneously with Nal-Glu and repeated every 12 h thereafter until either a spontaneous LH surge occurred or human chorionic gonadotrophin (HCG, 5000 IU) was administered. HCG was arbitrarily administered 48 h after the second Nal-Glu injection. Six other women (group 2) receiving only HMG served as controls. In seven of the eight women in group 1, LH and progesterone remained low for 96 h following Nal-Glu, i.e. until HCG administration. In the remaining woman in this group, LH started to rise 12 h before HCG injection. In this group, Nal-Glu did not interfere with follicular development or the plasma profile of oestradiol. All women developed one single dominant follicle with the exception of one subject who had already spontaneously developed two dominant follicles prior to administration of Nal-Glu and HMG. In group 2, LH rose spontaneously in all women before the planned HCG injection. The luteal phase was apparently not altered by Nal-Glu. These results suggest that Nal-Glu administration during the late follicular phase of natural cycles supported by HMG, can prevent the spontaneous LH surge while not interfering with follicular growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Prevention of premature luteinizing hormone and progesterone rise with a gonadotropin-releasing hormone antagonist, Nal-Glu, in controlled ovarian hyperstimulation.

OBJECTIVE: To report a preliminary study on the efficacy of a gonadotropin-releasing hormone antagonist (Nal-Glu) for preventing premature luteinizing hormone (LH) and progesterone (P) rise in controlled ovarian hyperstimulation using clomiphene citrate (CC) and human menopausal gonadotropin (hMG). DESIGN: Participants in the study formed two groups. Both groups received CC-hMG and Nal-Glu. Group II differs from group I for receiving human chorionic gonadotropin (hCG) and blood samples for 10 days after the second Nal-Glu injection. SETTING: Centre de Fecondation in Vitro, Hôpital Antoine Béclère. PATIENTS: Eleven women 25 to 34 years of age and having normal menstrual cycles using barrier method of contraception not attempting pregnancies participated in the study. INTERVENTION: Daily blood samples, pelvic ultrasound, and CC-hMG/Nal-Glu/hCG administration. MAIN OUTCOME MEASURES: (1) Spontaneous LH surge and P rise, follicular growth, and plasma E2 levels in cycles with CC-hMG/Nal-Glu administration and (2) luteal phase after hCG injection in subjects previously treated with CC-hMG/Nal-Glu. RESULTS: Plasma E2 level increased from 983 +/- 80 pg/mL (mean +/- SEM) on the day of the first Nal-Glu administration to 1,159 +/- 102 and 1,610 +/- 114 pg/mL (mean +/- SEM) 24 and 48 hours later. In 10 women, LH and P remained low for at least 96 hours after the first Nal-Glu administration. In one subject, plasma LH was already elevated at the time of the first Nal-Glu injection. In women who received hCG, plasma E2 and P reached a maximum of 1,258 +/- 313 pg/mL and 50.3 +/- 12.8 ng/mL (mean +/- SEM), respectively, on the 6th day of the luteal phase. CONCLUSION: Our results suggest that timely Nal-Glu injections can prevent LH and P rise for at least 96 hours, in spite of increasing levels of plasma E2. Moreover, Nal-Glu had no adverse effect on the kinetic of E2 rise, the follicular growth, or on the post-hCG hormonal profile.

Adult↗
PubMed1991

Treatment of unresectable meningiomas with the antiprogesterone agent mifepristone.

The possibility that meningioma growth may be related to female sex hormone levels is suggested by several lines of evidence. Meningiomas are twice as common in women as in men, have been observed to wax and wane with pregnancy, and are positively associated with breast cancer. A physiological explanation for these phenomena is provided by the finding of steroid hormone receptors in meningiomas. However, unlike breast cancer, meningiomas are much more commonly positive for progesterone receptors than for estrogen receptors. The authors initiated a study on long-term oral therapy of unresectable meningiomas with the antiprogesterone mifepristone (RU486). Fourteen patients received mifepristone in daily doses of 200 mg for periods ranging from 2 to 31+ months (greater than or equal to 6 months in 12 patients). Five patients have shown signs of objective response (reduced tumor measurement on computerized tomography scan or magnetic resonance image, or improved visual field examination). Three have also experienced subjective improvement (improved extraocular muscle function or relief from headache). The side effects of long-term mifepristone therapy have been mild. Fatigue was noted in 11 of the 14 patients. Other side effects included hot flashes in five patients, gynecomastia in three, partial alopecia in two, and cessation of menses in two. Long-term therapy with mifepristone is a new therapeutic option that may have efficacy in cases of unresectable benign meningioma.

Adult↗
PubMed1990

Antiprogestin treatment decreases midluteal luteinizing hormone pulse amplitude and primarily exerts a pituitary inhibition.

Mifepristone (RU 486), a synthetic steroid with antiprogesterone receptor activity, was given with and without naloxone hydrochloride to six women in the midluteal phase to investigate the role of progesterone in the modulation of endogenous opioid activity and the secretion of luteinizing hormone and cortisol. Subjects were evaluated during four sequential monthly admissions during which multiple blood samples were obtained every 15 minutes for 8 hours. Patients were studied during a baseline cycle, after administration of RU 486 alone (100 mg/day), naloxone with RU 486, and naloxone alone. After administration of RU 486 there was a significant decline in total luteinizing hormone secretion (p less than 0.01) and luteinizing hormone pulse amplitude (p less than 0.05), but compared with baseline there was no significant change in luteinizing hormone pulse frequency. After infusion of naloxone there was a significant increase in mean luteinizing hormone values (p less than 0.05) and luteinizing hormone pulse frequency (p less than 0.01) but no change in pulse amplitude. There was no significant difference in mean luteinizing hormone values or luteinizing hormone pulse amplitude and frequency between administration of RU 486 and naloxone plus RU 486. Administration of naloxone alone, RU 486 alone, and RU 486 plus naloxone caused a significant increase in cortisol as compared with baseline cycles (p less than 0.05). These data further support the notion that progesterone is important in the control of luteinizing hormone secretion and suggest that progesterone may primarily influence luteinizing hormone pulse amplitude and pituitary release of luteinizing hormone during the luteal phase.

Adult↗
PubMed1990

Gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists do not alter endogenous GnRH secretion in short-term castrated rams.

The administration of GnRH agonists and antagonists suppresses pituitary LH secretion. However little is known about their effects on endogenous GnRH secretion. To determine if GnRH analogs act on GnRH secretion through a short or ultrashort loop feedback mechanism, experiments were performed to analyze GnRH secretion in hypophyseal portal blood of conscious short-term castrated rams under both agonist or antagonist treatment. In Study 1, six rams were castrated and surgically prepared for portal blood collection on day -7. Portal and peripheral blood were collected simultaneously every 10 min for 14-15 h on day 0. Five hours after the beginning of the portal blood collection, animals were injected im with 5 mg potent GnRH antagonist (Nal-Glu). In Study 2, six rams were treated daily from day -11 to day 0 with the GnRH agonist D-Trp6 GnRH (0.5 mg im). Castration and surgical preparation for portal blood collection were performed on day -7. On day 0 portal and peripheral blood were collected simultaneously every 10 min for 10-11 h. In both studies, to determine whether an increase in GnRH concentration in hypophyseal portal blood can overcome the inhibitory effect of the GnRH analogs, between 5 and 5.5 h after the injection of the analogs, endogenous GnRH secretion was stimulated by Naloxone administration (3 x 100 mg, iv, at 30-min intervals) followed by a bolus of exogenous GnRH (2 x 10 micrograms, iv at 30-min intervals). In Study 1, Nal-Glu administration led to a rapid cessation of pulsatile LH secretion for the duration of blood collection while GnRH pulse frequency and amplitude were not affected. GnRH and LH pulse frequency before and after Nal-Glu administration were, 6.2 +/- 0.6 vs. 5.7 +/- 0.8 (NS) and 5.3 +/- 0.3 vs. 0.3 +/- 0.2 pulses/6 h (P less than 0.001) respectively. In Study 2, peripheral LH secretion was completely suppressed while GnRH secretion (portal blood) remained pulsatile. GnRH pulses frequency and pulse amplitude were 4.3 +/- 0.3 pulses/6 h and 43.0 +/- 4.7 pg/ml, respectively. In both experiments, neither stimulation of endogenous GnRH secretion by naloxone nor administration of exogenous GnRH allowed reinitiation of LH secretion. However, additional studies in two animals of each treatment group (study-III) showed that this was clearly a dose related effect in antagonist treated but not in agonist-treated animals since higher doses of exogenous GnRH (i.e. 100 micrograms or 1000 micrograms) can increase significantly LH levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Changes in gonadotropin and alpha-subunit secretion after a single administration of gonadotropin-releasing hormone antagonist in adult males.

The suppressive effect of the gonadotropin-releasing hormone (GnRH) antagonist Nal-Glu ([Ac-D2Nal1, D4ClPhe2, D3Pal3, Arg5, D-4-p-methoxybenzoyl-2-aminobutyric acid6, DAla10]-GnRH), injected intramuscularly with 5 mg, was studied in six men. Testosterone decreased by 87 +/- 2.3%, whereas the mean drops were 50 +/- 10%, 43 +/- 6.6%, and 39 +/- 5.6% for radioimmunoassayable luteinizing hormone (LH), follicle-stimulating hormone, and free alpha-subunit, respectively (mean +/- SEM). Immunological characteristics of plasma LH were modified during the inhibition and recovery phases as evidenced by comparison between polyclonal and monoclonal assays. In two additional subjects sampled every 10 minutes, both LH and alpha-subunit pulses were suppressed by NalGlu injection and restored by pulsatile GnRH infusion. However, a nonpulsatile and possibly non-GnRH-dependent alpha-subunit secretion was maintained after NalGlu administration.

Adult↗
PubMed1990

A gonadotropin releasing hormone analogue prevents cyclical attacks of porphyria.

Acute intermittent porphyria is a genetic disease in which endogenous hormones affect clinical expression. Premenstrual exacerbations can occur, sometimes often, in women with this disease. Gonadotropin releasing hormone analogues can prevent ovulation by reducing secretion of luteinizing hormone and follicle-stimulating hormone. In six patients with well-documented acute intermittent porphyria and frequent cyclical exacerbations, daily administration of an agonistic gonadotropin releasing hormone analogue, ([ImBzl]-D-His6,Pro9-NET)gonadotropin releasing hormone, intranasally or subcutaneously for as long as 26 months reduced or eliminated premenstrual attacks and caused only minor side effects. Adjustments in dosage or route of administration were sometimes needed. We conclude that endocrine manipulation by treatment with a gonadotropin releasing hormone agonist will prevent neurovisceral attacks of acute intermittent porphyria due to cyclical changes in endogenous hormones and is a safe alternative to exogenous steroids, which may induce attacks of this disease.

Adult↗
PubMed1989

Variable effects of RU 486 on endometrial maintenance in the luteal phase extended by exogenous hCG.

This study was designed to assess the features and conditions for endometrial bleeding induction with the synthetic antiprogestin and antiglucocorticoid RU 486 during hCG-induced prolongation of the luteal phase. Eighteen healthy, surgically sterilized women and another five women with an intrauterine contraceptive device (IUD) participated. All subjects received hCG which was injected daily in increasing doses (500 to 15,000 IU) from day 9 to day 15 of the luteal phase. Ten subjects received hCG alone, and groups of three to 16 subjects received hCG combined with RU 486 (25, 50, 100, 200 or 400 mg/day). RU 486 administration was commenced on day 12 following the LH surge and given either for 1, 4 or 7 consecutive days. In certain cycles, tamoxifen (20 mg/day) was given for 4 consecutive days with hCG, or with hCG and RU 486. All treatment cycles were separated by one or two resting cycles. Frequent blood samples were taken to monitor the endocrine response. Treatment with hCG alone or with the various combinations of RU 486 produced similar serum levels of oestradiol and progesterone which were equivalent to those observed during early pregnancy. With hCG alone, the onset of bleeding was on day 21-24 after the LH surge, coinciding with the drop in oestradiol and progesterone. With RU 486 doses of 50 mg/day or more, an early bleeding episode almost invariably occurred on day 14-17 after the LH surge in the presence of high circulating steroid levels. In contrast, 25 mg/day RU 486 for 4 days failed to induce this early onset of bleeding in three out of six cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Response to the antiprogestagen RU 486 (mifepristone) during early pregnancy and the menstrual cycle in women.

RU 486 has wide potential utility as an abortifacient drug when used within the first 6 weeks of pregnancy and has the ability to induce an abortion in about 80% of subjects. Administration of low doses of prostaglandins together with RU 486 increases the success rate. It is possible that alterations in metabolism of RU 486 may explain non-responsiveness to the drug in some women. Mid-luteal phase administration of RU 486 produces bleeding within 72 h and in one-third of subjects there was luteolysis with decrease in serum FSH, oestradiol and progesterone concentrations. Administration of RU 486 in the late luteal phase does not disturb menstrual cycle length, bleeding patterns, ovulation, or hormonal parameters in treatment or posttreatment cycles. However, the drug alone cannot be used as a 'menses regulator' or 'once monthly pill' since some pregnancies do continue. Possibly the efficacy of RU 486 may be enhanced when it is combined with prostaglandins or other agents. Administration of RU 486 in the follicular phase blocks ovulation, delays the LH surge, and is associated with low concentrations of oestradiol. This is presumably the result of gonadotrophin inhibition.

Abortion, Induced↗
PubMed1988

Effects of the antiglucocorticoid RU 486 on adrenal function in dogs.

We studied the antiglucocorticoid effects of RU 486 given orally in doses of 5 (low), 20 (intermediate), and 50 mg/kg (high) daily for 10 days to seven female mongrel dogs. No changes in plasma ACTH or cortisol levels were produced by the 5 mg/kg dose. Plasma ACTH levels increased 3-fold with both intermediate and high dosages. Plasma cortisol levels rose 4-fold (P less than 0.05) within 2 days of commencing the high dose schedule and within 3 days with the intermediate dosage. Plasma aldosterone concentrations increased significantly only with the highest dose schedule. Plasma RU 486 levels rose progressively during the 10 days of RU 486 administration and with the highest dose remained elevated for 7 days after it was stopped. Plasma RU 486 levels measured by RIA and high pressure liquid chromatography were comparable. The monodemethylated metabolite of RU 486 changed in parallel to the parent compound. During the high dose of RU 486, there was a 4% increase in body weight, with a reduction in hematocrit and plasma protein concentration. Plasma electrolyte levels and osmolality did not change. We conclude that in dogs a daily RU 486 dose of 5 mg/kg does not alter adrenal function, whereas higher doses (20 and 50 mg/kg) induce increases in plasma ACTH and cortisol concentrations. Despite the blockade of glucocorticoid receptors by RU 486, the presence of isotonic hypervolemia suggests that there was no functional deficiency of cortisol at the renal tubule or it was overshadowed by augmented mineralocorticoid production and action.

Administration, Oral↗
PubMed1988

Effects of the antiprogestin RU486 on progesterone-dependent uterine development and bioassay of progestational activity in estrogen-primed immature female dogs.

A bioassay for progesterone activity in dogs was established based on uterine weight (mg/kg body weight) in immature beagles administered progesterone for 10 days starting 9 days after priming with estradiol cypionate (50 micrograms/kg, im). Progesterone doses of 0, 0.17, 0.5, 1.5, 13.5 and 40.5 mg/kg per day, im, produced dose-dependent increases in the weights of uterine horns obtained after 5 or 10 days of treatment. The total uterine responses (horn removed at 5 days plus horn and fundus removed at 10 days) to those were (mean +/- SEM) 374 +/- 33, 465 +/- 97, 684 +/- 68, 795 +/- 96, 1005 +/- 38, 1232 +/- 15 mg/kg, respectively. Responses to the 13.5 mg/kg per day dose of progesterone in dogs given the steroid antagonist RU486 at daily oral doses of 5, 20 and 50 mg/kg were reduced to values of 634 +/- 24, 464 +/- 74 and 468 +/- 18 mg/kg, respectively, vs 1005 +/- 38 mg/kg in controls. Mean progesterone levels were 27 +/- 1 micrograms/l. The RU486 did not produce any consistent alterations in serum cortisol levels. The results suggest that, in immature bitches, uterine weight changes can be used to bioassay progestin activity following estrogen priming, RU486 is more potent as an antiprogestin than as an antiglucocorticoid, and RU486 at oral doses of 5 and 20 mg/kg exerts submaximal and maximal antiprogestin activity, respectively, in the presence of physiological levels of progesterone.

Animals↗
PubMed1987

The progesterone antagonist RU 486. A potential new contraceptive agent.

Since progesterone supports endometrial nidation of the fertilized ovum, a progesterone antagonist would theoretically block this process and thus have contraceptive potential. We have explored the ability of RU 486, a newly developed competitive progesterone antagonist, to function as a contraceptive agent. A single oral dose of 10 mg per kilogram of body weight given in the midluteal phase consistently induced menses within 72 hours in women with normal cycles and no risk of pregnancy. Bleeding was not prevented by administration of human chorionic gonadotropin in the midluteal phase. This suggested that giving a single dose of RU 486 late in the menstrual cycle might be an effective contraceptive strategy. This concept was tested in monkeys. When given to rhesus females on day 25 of the cycle, a single intramuscular dose of RU 486 (5 mg per kilogram) prevented pregnancy. The vehicle-treated control animals had a 28 percent pregnancy rate (P less than 0.05 by chi-square analysis). No side effects were noted in women or monkeys. These data suggest that a progesterone antagonist such as RU 486 has the potential to be an effective, safe, and convenient contraceptive agent. Further work will be necessary to assess the safety of long-term monthly administration and to define the optimal dose and time of administration in women.

Adult↗