Effects of SR 49059, an orally active V1a vasopressin receptor antagonist, on vasopressin-induced uterine contractions.

OBJECTIVE: To test the effect of SR 49059, an orally active, nonpeptide, selective and specific antagonist of the vasopressin V1a receptors in humans. DESIGN: A placebo-controlled, double-blind, cross-over trial. SETTING: The Department of Obstetrics and Gynaecology, Lund University Hospital, Sweden. PARTICIPANTS: Twelve healthy women, who had previously been sterilised by tubal ligation. INTERVENTIONS: The women participated on days 1, 2 or 3 of two menstrual cycles, with intrauterine pressure recordings and intravenous bolus injections of 10 pmol/kg body weight of lysine vasopressin given 1 h before and at 1, 2 and 3 h after oral administration of 300 mg of the study drug or of placebo. MAIN OUTCOME MEASURE: The area between the recording curve and zero level of pressure. Vital signs, safety parameters and drug plasma concentrations were also measured. RESULTS: The spontaneous uterine activity as well as the response to lysine vasopressin injections before administration of the test drugs were almost identical at the two experiments. Following intake of SR 49059 the area under the recording curve (0-10 min) after the second, third, and fourth injection of lysine vasopressin were reduced by 57, 42, and 66%, respectively, compared with placebo. Trough plasma concentrations of lysine vasopressin were markedly higher and systolic blood pressure slightly lower after antagonist administration than after placebo, whereas no significant difference between treatments was observed in diastolic pressure, heart rate or plasma osmolality. CONCLUSIONS: This study demonstrates for the first time a biological effect of an orally active vasopressin V1a antagonist in humans in vivo and the results support the importance of vasopressin in uterine activation. The differences between study drug and placebo treatments in lysine vasopressin levels and systolic blood pressure, but lack of difference in osmolality indicate that SR 49059 antagonises the effect of lysine vasopressin on the vasopressin V1a receptor, but not that on the vasopressin V2 one. It is suggested that SR 49059 be explored therapeutically in dysmenorrhoea.

Recurrent tension headache in adolescents treated with self-help relaxation training and a muscle relaxant drug.

Forty-eight adolescents suffering from recurrent tension headache participated in a controlled trial conducted in a high school setting. During the first treatment phase self-help relaxation training was compared with a waiting-list group. Following this phase a pharmacological regimen consisting of a muscle relaxant (chlormezanone) and placebo was superimposed on relaxation therapy in a double-blind crossover design. Each treatment phase encompassed a 5-week period. In addition to the evaluation of headache complaints, psychological distress among students was measured with respect to their experience of somatic complaints, depressive, anxiety and stress symptoms. Although self-help relaxation training significantly decreased the severity and annoyance of adolescents' headache besides their somatic complaints, the clinical improvement of headache was modest. The addition of chlormezanone did not help those who were nonresponders to self-help relaxation training. Finally, a set of pretreatment variables consisting of baseline headache severity and annoyance, experience of anxiety and daily life stress among adolescents could predict outcome of self-help relaxation therapy.

Danazol concentrations in human ovarian follicular fluid and their relationship to simultaneous serum concentrations.

Danazol concentrations in follicular fluid and serum were studied in eight women scheduled for laparoscopy because of suspected endometriosis. In order to obtain some variation in follicular maturity, danazol administration was started 2 to 7 days before the expected day of ovulation. A total of nine doses were given, i.e., 200 mg four times daily for 2 days; the last 200-mg dose was given 3 hours before the laparoscopy during which the follicular fluid from the dominant follicle was aspirated. Peripheral venous blood samples were drawn before, during, and after laparoscopy. Danazol concentrations were assayed by means of a high-performance liquid chromatography method. At the time of follicular aspiration, the mean concentration of danazol was estimated at 96 ng/ml in serum and at 71 ng/ml in follicular fluid, i.e., an average of 73% of the simultaneous serum concentration. The data suggest that even short-term therapy with danazol is likely to produce intrafollicular drug concentrations that have a direct inhibitory effect on follicular steroidogenesis.

Inhibition of steroid sulfatase activity by danazol.

The hydrolysis of dehydroepiandrosterone sulfate (DHAS) by human liver cells in culture and the hydrolysis of and formation of estradiol-17 beta (E2) from estrone sulfate (E1S) by human breast tumor preparations in vitro were studies in the presence and absence of danazol. In the latter tissue the effects of medroxyprogesterone acetate (MPA), trilostane, aminoglutethimide (AG) and tamoxifen were tested for comparison. Danazol at concentrations of 10(-6) - 1.4 X 10(-4) M strongly inhibited the hydrolysis of DHAS as well as the hydrolysis of and formation of E2 from E1S. With the exception of a slight inhibitory effect of trilostane upon E1S hydrolysis, the other four drugs did not inhibit the metabolism of E1S. Danazol, at concentrations corresponding to those occurring in vivo during therapy, is a potent inhibitor of steroid sulfatase activity. This may be one of the ways in which the drug affects peripheral and target tissue levels of steroid hormones.

Peripheral levels of dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, and testosterone following different doses of danazol.

Peripheral serum levels of dehydroepiandrosterone sulfate (DHAS), dehydroepiandrosterone (DHA), androstenedione (A4) and testosterone (T) were measured in two groups of premenopausal women with fibrocystic breast disease, given 200 and 400 mg of danazol a day respectively for 6 months. During treatment, DHAS levels increased and DHA, DHA/DHAS ratio, A4, and T decreased. A tendency towards dose dependency was observed. The changes in DHAS, DHA and DHA/DHAS ratio were interpreted as resulting from inhibition of liver sulfatase activity by danazol. The decreased A4 and T levels probably reflect a suppression of ovarian steroidogenesis due to enzyme inhibition by danazol, and for the latter steroid also and increased metabolism due to interaction of the drug with sex hormone-binding globulin.

Regression of endometriosis following shorter treatment with, or lower dose of danazol. Comparison of pre- and post-treatment laparoscopic findings in the Scandinavian multi-center study.

One hundred and sixteen patients with laparoscopically confirmed primary or recurrent endometriosis were treated with danazol, either 600 mg daily for 4 months (group A, n = 76) or 600 mg daily for the first 2 months, followed by 400 mg daily for an additional 4 months (group B, n = 40). The only surgery performed before treatment was biopsies, resection of endometriomas greater than or equal to 3 cm and/or adhesiolysis. The extent of endometriosis before and after treatment was established laparoscopically and recorded by means of a modified AFSrecord as mean additive diameter of implants (mean ADI) in millimeters. This provided a uniform and reproducible quantitative registration for each type and location of endometriotic implant. Both treatment schemes resulted in a highly significant (p less than 0.001) reduction of endometriosis, by 79 and 89% in groups A and B, respectively. However, the reduction in mean ADI was significantly greater (p less than 0.025) in group B which had been treated for a longer period. Moreover, the proportion of patients with extensive pre-treatment lesions (mean ADI greater than or equal to 40 mm) was significantly greater in this group. Active residual endometriosis was found in 21 and 17.5% in groups A and B, respectively. These patients had significantly more extensive endometriosis before treatment. The regression of endometriotic implants was independent of type and/or location, i.e. superficial or scarred; peritoneal, ovarian, or tubal. There was no apparent correlation between the quantitative reduction of endometriosis and amenorrhea versus occasional spotting and/or irregular menstruations.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in the SHBG concentration during danazol treatment.

Serum levels of sex hormone binding globulin (SHBG) were measured by radioelectro-immunoassay before and during administration of danazol in daily doses varying between 200 and 800 mg for a period of 1-6 months. The patients consisted of different groups of regularly menstruating women (n = 76) and of postmenopausal women (n = 12). A rapid proportional decrease in SHBG was seen at all dose levels in both pre- and postmenopausal women, starting within the first 24 hours and reaching statistical significance by 48 hours. The fractional rate of fall appeared to be determined by the metabolic half-life of the protein itself. Plotting log concentrations of SHBG versus time and using the slope of the linear regression for calculations, the half-life of SHBG appeared to be 15 +/- 5.7 (SD) days. After approximately one month of treatment, the SHBG concentrations began to approach a new steady state at a level of approximately 20-30% of the original concentration, depending on the dose of danazol. The proportional suppression of SHBG was significantly greater following 600 or 800 mg of danazol daily than following 200 or 400 mg. However, with all doses the SHBG levels after one month of treatment were well below the levels normally found in healthy males. The mean proportional reduction following a certain dose was almost identical in premenopausal and postmenopausal women. The findings of the present investigation suggest that danazol exerts a direct inhibitory effect on the hepatic synthesis of SHBG, which is dependent of the dose of danazol, independent of estrogen concentration, but possibly accentuated by endogenous androgens.

Danazol treatment of severely symptomatic fibrocystic breast disease and long-term follow-up--the Hjørring project.

The purpose of the investigation was to study various aspects of danazol treatment in patients with fibrocystic breast disease and pronounced mastodynia. To qualify for inclusion, the patients in this study had to have a mammographically confirmed prominent glandular structure and/or severe cystic breast disease, associated with pronounced cyclical mastodynia lasting at least one week per menstrual cycle for more than 6 months. They also had to be premenopausal and not undergoing hormonal therapy. Of 109 patients with a mean age of 40 +/- 6.2 (SD) years, who completed 6 months' treatment with danazol, 65% had a pre-treatment history of more than 5 years. According to detailed mammographic characterization, only 18% of the patients had no visible cysts. Of the 82% with visible cysts, half presented with both small (less than 1 cm) and large cysts. The patients were treated in two consecutive groups, 55 patients receiving 400 mg a day and 54 patients 200 mg a day. The therapeutic response was similar following both dosages. Mastodynia responded rapidly and total elimination was noted in about 90% of cases. A marked decrease in prominence of palpable structure was observed in virtually all patients. Mammographically, a decrease in the amount of glandular tissue was observed. These changes during treatment were statistically highly significant (p less than 0.001), irrespective of dose or category of patient. Non-cystic nodularities gradually decreased in 85% and resolved completely in 58% of the cases, but the degree of resolution in the groups of patients with no or only small (less than 1 cm) visible cysts was significantly greater (p less than 0.02 or less) than in the group which also had large cysts and which included the most severe and intractable cases. The mammographical visualization of cysts, ductal system, and fibrous tissue increased initially due to the marked regression of obscuring glandular tissue. Thereafter, a decrease in the number and spread of small cysts was observed in a significant proportion of patients and in some cases a reduction in duct diameter could be demonstrated by means of galactography. Nipple discharge also decreased. The extent of fibrosis appeared to be unaffected by therapy. In the 46 patients with large cysts and, in most cases, a documented history of repeated cyst formation, danazol treatment was found to arrest the development of new cysts and to prevent recurrence for a considerable time thereafter.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of recurrent cyclical mastodynia in patients with fibrocystic breast disease. A double-blind placebo-controlled study--the Hjørring project.

Thirty premenopausal women with recurrent, pronounced cyclical mastodynia associated with mammographically confirmed fibrocystic disease were studied. All patients had long-standing symptoms, had undergone one previous course of treatment with danazol, and were recruited during long-term follow-up after original treatment, when cyclical mastodynia had again reached similar severity as before the original treatment (mean interval between treatments 9.5 +/- 3.9 (SD) months). Fifteen patients each were randomly allocated to double-blind treatment with either danazol or placebo. During the first month, 2 capsules a day (each containing danazol 100 mg or placebo) were given, thereafter one capsule a day up to 6 months. Danazol caused a marked and sustained decrease in mastodynia, according to the clinician's assessment and according to each patient's self-rating on a visual analogue scale. The response to danazol was fairly uniform and statistically significant (p less than 0.005 or less), whereas the response to placebo was inconsistent and not statistically significant (p greater than 0.10). Danazol proved significantly more effective than placebo (p less than 0.05 or less). Changes in palpatory and/or mammographic findings were also found more consistently after danazol treatment than after placebo. During treatment, there was a modest weight increase, which was statistically significant in the danazol group (p less than 0.01) but not in the placebo group. A greater frequency in menstrual irregularities was observed in the danazol group than in the placebo group, but not to an extent that would have caused 'unblinding' of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of danazol on serum concentrations of pituitary gonadotropins in postmenopausal women.

The antigonadotropic action of danazol is still a subject of controversy. Danazol does not cause a consistent and significant suppression of basal gonadotropin concentrations in premenopausal women. In order to investigate the possible effects of danazol on circulating gonadotropin levels in the absence of gonadal feedback, postmenopausal women were studied. Twelve healthy women, at least 3 years past the menopause, volunteered. Their mean age was 61.1 +/- 5.5 (SD) years. Danazol in daily doses of 400, 600 or 800 mg was given randomized, to 4 patients each, for 4 weeks. Venous samples were drawn at -1, 0, +1, +2, +4 weeks of medication. FSH and LH in serum were measured by means of double antibody radio-immunoassay. There was no significant difference between any of the pre-treatment means in the three dose groups. After 4 weeks of danazol treatment, FSH had decreased by 18%, 31%, and 32% in the 400, 600 and 800 mg groups, respectively. The corresponding decreases in LH were 14%, 24% and 21%. There was no significant dose response between any of the doses used. In the absence of significant differences between the pre-treatment means and of significant dose response, data for all 12 patients were pooled for statistical evaluation. The mean decrease in FSH was significant only after 4 weeks (-4.8 micrograms/l; p less than 0.001). The mean decrease in LH was significant after 1, 2 and 4 weeks of treatment (-1.0 to -1.13; p less than 0.01 or less).(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral androgen levels in danazol-treated premenopausal women.

Eighteen normally menstruating women with endometriosis were treated with 600 mg of danazol daily for 6 months. Blood samples were taken before and after 2, 4, 8, 12, and 16 weeks of treatment and were analyzed for plasma dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), and testosterone (T) and for serum alanine aminotransferase (ALAT), albumin, creatinine, potassium, and sodium. The basal values of all parameters studied were well within normal reference limits. DHEA-S was significantly increased at 2, 4, and 8 weeks, and DHEA significantly decreased at 8 and 12 weeks of treatment. The ratio between DHEA and DHEA-S was significantly decreased at weeks 4, 8, 12, and 16. T was significantly decreased during the whole period of observation. ALAT was significantly increased at weeks 4, 8, 12, and 16. A slight but significant increase was observed for creatinine and potassium, while no changes were observed for albumin and sodium. Of the two major androgen sources, the adrenal cortex appears to be relatively unaffected; whereas the ovary may be affected to a minor degree. Therefore, it seems likely that the changes observed in DHEA and DHEA-S may be due to minor alterations in renal and hepatic turnover rather than an effect on adrenal steroidogenesis.