The treatment of severe premenstrual syndrome with goserelin with and without 'add-back' estrogen therapy: a placebo-controlled study.

The study aimed to determine if the addition of daily low-dose oral estrogen with a cyclical progestogen given to young women using a depot gonadotropin-releasing hormone (GnRH) analog implant for the treatment of their premenstrual syndrome (PMS) would affect the clinical outcome. In a double-blind placebo-controlled study in a specialist premenstrual syndrome clinic setting, 60 women aged between 20 and 45 years were randomized to one of three treatment groups: Group A (placebo implant four weekly + placebo tablets daily), Group B (goserelin 3.6 mg implant four weekly + estradiol valerate 2 mg daily with norethisterone 5 mg from days 21-28 of a 28-day cycle) or Group C (goserelin 3.6 mg implant four weekly + placebo tablets daily). Differences between PMS scores at 2, 4 and 6 months were compared with pretreatment values. There was a significant improvement in PMS scores in Group C (Zoladex + placebo) after 2, 4 and 6 months of treatment when compared to pretreatment values and Group A (placebo + placebo). The addition of a low-dose oral estrogen with a cyclical progestogen to GnRH analog treatment (Group B) resulted in a less dramatic response when compared to pretreatment values and no significant improvement when compared to Group A (placebo + placebo) at 2, 4 and 6 months of treatment. The addition of a low-dose oral estrogen with a cyclical progestogen to depot GnRH analog therapy in the treatment of PMS reduces the clinical response.     

The treatment of severe premenstrual syndrome with goserelin with and without ‘add-back’ estrogen therapy: A placebo-controlled study

The study aimed to determine if the addition of daily low-dose oral estrogen with a cyclical progestogen given to young women using a depot gonadotropin-releasing hormone (GnRH) analog implant for the treatment of their premenstrual syndrome (PMS) would affect the clinical outcome. In a double-blind placebo-controlled study in a specialist premenstrual syndrome clinic setting ,60 women aged between 20 and 45 years were randomized to one of three treatment groups: Group A (placebo implant four weekly + placebo tablets daily) ,Group B (goserelin 3.6 mg implant four weekly + estradiol valerate 2 mg daily with norethisterone 5 mg from days 21-28 of a 28-day cycle) or Group C (goserelin 3.6 mg implant four weekly + placebo tablets daily). Differences between PMS scores at 2 ,4 and 6 months were compared with pretreatment values. There was a significant improvement in PMS scores in Group C (Zoladex + placebo) after 2 ,4 and 6 months of treatment when compared to pretreatment values and Group A (placebo + placebo). The addition of a low-dose oral estrogen with a cyclical progestogen to GnRH analog treatment (Group B) resulted in a less dramatic response when compared to pretreatment values and no significant improvement when compared to Group A (placebo + placebo) at 2 ,4 and 6 months of treatment. The addition of a low-dose oral estrogen with a cyclical progestogen to depot GnRH analog therapy in the treatment of PMS reduces the clinical response.     

Placebo-controlled comparison of danazol and high-dose medroxypro-gesterone acetate in the treatment of endometriosis after conservative surgery

To evaluate the clinical value of postoperative hormone therapy in endometriosis, 60 patients with advanced disease were randomized to receive in a double-blind study danazol (200 mg, 3 times daily), medroxyprogesterone acetate (MPA) (100 mg daily) or placebo post-operatively for 6 months. Treatment efficacy was evaluated clinically and at laparoscopy 6 months after medication.

In relation to placebo, danazol and high-dose MPA treatments, which did not differ from each other in efficacy, significantly alleviated pelvic pain. In addition, the peritoneal endometriosis lesions found at 6-months laparoscopy were significantly smaller in the MPA and danazol groups than in the placebo group. Breakthrough bleeding, weight gain and acne complicated danazol treatment but only breakthrough bleeding complicated MPA treatment. These data suggest that postoperative treatment of advanced endometriosis with high-dose MPA or danazol is clinically beneficial.     

Placebo-controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis after conservative surgery

To evaluate the clinical value of postoperative hormone therapy in endometriosis, 60 patients with advanced disease were randomized to receive in a double-blind study danazol (200 mg, 3 times daily), medroxyprogesterone acetate (MPA) (100 mg daily) or placebo post-operatively for 6 months. Treatment efficacy was evaluated clinically and at laparoscopy 6 months after medication. In relation to placebo, danazol and high-dose MPA treatments, which did not differ from each other in efficacy, significantly alleviated pelvic pain. In addition, the peritoneal endometriosis lesions found at 6-months laparoscopy were significantly smaller in the MPA and danazol groups than in the placebo group. Breakthrough bleeding, weight gain and acne complicated danazol treatment but only breakthrough bleeding complicated MPA treatment. These data suggest that postoperative treatment of advanced endometriosis with high-dose MPA or danazol is clinically beneficial.     

A clinical trial using danazol for the treatment of premenstrual tension

Summary. Forty women with premenstrual tension received either placebo, 100, 200 or 400 mg danazol daily for 3 months in a pilot study arranged as a double-blind trial. Thirteen patients withdrew by the third month usually because they complained of no improvement. They had significantly higher pretrial symptom scores than those who continued. In patients treated with danazol, symptom scores for breast pain during the second and third months and for irritability, anxiety and lethargy during the third month were significantly ( P <0.05) lower than scores in those given placebo. Most symptoms improved on placebo in the first month but by the third month only three remained improved. In contrast eight symptoms were improved on 200 mg danazol by the third month. By the end of the trial more than 75% of patients who were still taking danazol were essentially free of breast pain, lethargy, anxiety and increased appetite, but results for other common symptoms were no better than with placebo.     

Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial

OBJECTIVE: To assess the effect of low-dose mifepristone on quality of life, pain, bleeding, and uterine size among women with symptomatic leiomyomata. METHODS: Forty-two women with symptomatic uterine leiomyomata and uterine volume of 160 mL or more were randomized to mifepristone, 5 mg daily, or placebo for 26 weeks. Quality of life (Uterine Fibroid Symptoms Quality of Life Questionnaire and Medical Outcomes Study 36-Item Short Form survey) and uterine and leiomyoma size (ultrasonography) were assessed at baseline, and at 1 month, 3 months, and 6 months of treatment. Bleeding (daily logs and pictorial charts) and pain (McGill Pain Questionnaire) were assessed monthly. Endometrial pathology was assessed at baseline and 6 months. RESULTS: Forty-two women were randomized; 37 women completed all 6 months. Women randomized to mifepristone showed an improvement in leiomyoma-specific quality of life. Forty-one percent became amenorrheic, rates of anemia improved, and adjusted uterine size was reduced by 47%. Compared with the placebo group, improvements in these outcomes in the treatment group were significantly greater (P<.05 to .001). There were no significant differences in adverse effects between the groups. No endometrial hyperplasia was noted in any participant. CONCLUSION: Low-dose mifepristone improves leiomyoma-specific quality of life and reduces leiomyoma size among women with symptomatic leiomyomata. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov www.clinicaltrials.gov NCT00133705 LEVEL OF EVIDENCE: I.     

A clinical trial using danazol for the treatment of premenstrual tension

Forty women with premenstrual tension received either placebo, 100, 200 or 400 mg danazol daily for 3 months in a pilot study arranged as a double-blind trial. Thirteen patients withdrew by the third month usually because they complained of no improvement. They had significantly higher pretrial symptom scores than those who continued. In patients treated with danazol, symptom scores for breast pain during the second and third months and for irritability, anxiety and lethargy during the third month were significantly (P less than 0.05) lower than scores in those given placebo. Most symptoms improved on placebo in the first month but by the third month only three remained improved. In contrast eight symptoms were improved on 200 mg danazol by the third month. By the end of the trial more than 75% of patients who were still taking danazol were essentially free of breast pain, lethargy, anxiety and increased appetite, but results for other common symptoms were no better than with placebo.     

A comparison of nafarelin acetate and danazol in the treatment of endometriosis

Nafarelin 400 micrograms daily and danazol 600 mg daily were compared in a double-blind randomized study. Eighty-two patients with endometriosis were treated for 6 months after an initial laparoscopy and 74 had a second laparoscopy. Twenty-two (30%) patients had complete disease regression, 42 (57%) patients had a partial regression, and in 10 (13%) patients disease was unchanged or worse. Both treatments led to significant regression of active disease but not of adhesions. At 3 months follow-up, 34 (64%) patients reported their symptoms were improved, 15 (28%) reported no change, and 4 (8%) were worse. Nafarelin was associated with more hot flushes and headaches, and danazol with more weight gain. No significant differences, however, were noted in treatment efficacy between the two groups.     

Placebo-controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis

A prospective, double-blind, placebo-controlled study was designed to evaluate the clinical efficacy and tolerance of danazol and high-dose medroxyprogesterone acetate (MPA) in the treatment of mild-moderate endometriosis. After laparoscopical confirmation of endometriosis, 59 patients were randomized to receive danazol (200 mg 3 times daily), MPA (100 mg daily) or placebo for 6 months. Clinical examinations were done before and 1, 3, 6 and 12 months after the beginning of the study, and a 2nd laparoscopy 6 months after termination of the medication. Eighteen patients in the danazol group, 16 in the MPA group and 17 in the placebo group completed the trial. Total or partial resolution of peritoneal implants was observed in 60% of the patients receiving danazol and in 63% of the patients receiving MPA. In the placebo group, resolution was observed in 18%, while the size of the implants was estimated to be increased in 23% of the patients. In relation to placebo, danazol and MPA significantly alleviated endometriosis-associated pelvic pain, lower back pain and defecation pain, but they did not differ from each other in these actions. The appearance of acne, muscle cramps, edema, weight gain and spotting bleeding complicated MPA treatment. The present results indicate that because of good efficacy and tolerance, high-dose MPA is a useful alternative in the hormonal treatment of endometriosis.     

Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women

OBJECTIVE: To assess the endometrial effects of bazedoxifene acetate in healthy postmenopausal women. METHODS: The endometrial effects of bazedoxifene 2.5, 5.0, 10, 20, 30, and 40 mg/d were evaluated in a 2-part, 6-month, double-blind, randomized, active- and placebo-controlled study among a total of 497 healthy postmenopausal women. Conjugated estrogens (0.625 mg)/medroxyprogesterone acetate (2.5 mg) served as the active control. Patients underwent transvaginal ultrasonography to measure double-wall endometrial thickness and endometrial biopsy at baseline and at 6 months of treatment. The incidence of amenorrhea was assessed from self-reported daily diaries. RESULTS: Bazedoxifene treatment at 2.5-20 mg/d resulted in mean changes from baseline in endometrial thickness that were no different than those seen with placebo treatment. Changes in endometrial thickness for the bazedoxifene 30 and 40 mg groups were significantly smaller than for placebo. The change from baseline in endometrial thickness was significantly and inversely related to dose (P < or = .001). None of the endometrial biopsy specimens demonstrated endometrial hyperplasia. Subjects in the 2.5-20 mg bazedoxifene groups experienced amenorrhea rates of 57-74%, comparable with the 59% seen in placebo. Over 90% of subjects treated with bazedoxifene 30 or 40 mg/d were amenorrheic at 6 months. CONCLUSION: Bazedoxifene at dosages up to 40 mg/d was well tolerated and did not stimulate the endometrium. The significant decreases in endometrial thickness and decreased uterine bleeding observed with doses of 30 and 40 mg/d as compared with placebo suggest endometrial antagonism, representing a novel characteristic not previously associated with any selective estrogen receptor modulator.     

Increase in serum leptin concentrations among women with endometriosis during danazol and leuprolide depot treatments

OBJECTIVE: This study was undertaken to evaluate serum leptin concentrations in women with endometriosis during treatment with danazol and with leuprolide depot.Study Design: Twenty patients aged 18 to 42 years with regular menses and documented pelvic endometriosis were recruited from a university hospital setting. Treatment was 200 mg danazol 3 times daily for 6 months or 3.75 mg leuprolide depot every 28 days for 6 months. Serum leptin concentrations were measured before, during, and after treatment. A single blood sample was taken from each of 10 control women without endometriosis for comparison. Serum leptin level was measured with a radioimmunoassay kit with human leptin, and analysis of variance and paired t tests were used for statistical analysis. RESULTS: Serum leptin levels were almost the same among women with endometriosis as in the control group. Leptin levels were higher among women with endometriosis during treatment with danazol and leuprolide(P <.001). Three months after treatment, leptin values remained moderately higher than before treatment. CONCLUSION: Danazol and leuprolide increased serum leptin levels. The mechanism of leptin increase is unclear. Further studies are needed to determine whether an adipogonadal axis exists.     

Aromatase inhibitor “letrozole” versus progestin “norethisterone” in women with simple endometrial hyperplasia without atypia: A prospective cohort trial

ObjectiveTo evaluate the effectiveness of the aromataze inhibitor “letrozole” to progestin “norethisterone” for women with simple endometrial hyperplasia without atypia.Subjects and methodsOne hundred women with a histo-pathological diagnosis of simple endometrial hyperplasia without atypia were divided into two groups: Groups A and B. Group A included 50 patients who received a daily 5 mg dose of letrozole for three successive months. Group B included the other 50 patients who received norethisterone 10 mg daily by non-stop regimen for 3 months. All patients in both groups were reevaluated after treatment. Women diagnosed with progressive or persistent endometrial hyperplasia at the second curettage were asked to continue on the same medication for another 3 months. Transvaginal sonography as well as serum estradiol level measurement were performed before the start of treatment and 3 months after treatment.ResultsDespite that there was no statistically significant difference between the two groups as regards the proportion of women whose endometrial sample revealed resolution, regressing or persistence after 3 months of treatment. However, endometrial thickness was significantly thinner in women who received letrazole than in women who received norethisterone (mean difference 0.12 mm, 95% CI: 0.22–0.01, P = 0.02). Serum E2 level was significantly lower in the Group A compared to Group B (mean difference 9.1 pg, 95% CI: 13.74–4.45, P < 0.001).ConclusionLetrozole is as effective as norethisterone for women with abnormal uterine bleeding due to endometrial hyperplasia without atypia.     

A randomized, prospective study of endometrial resection to prevent recurrent endometrial polyps in women with breast cancer receiving tamoxifen.

STUDY OBJECTIVE: To assess the role of endometrial resection in preventing recurrence of tamoxifen-associated endometrial polyps in women with breast cancer. DESIGN: Randomized, prospective study (Canadian Task Force classification I). SETTING: Tertiary university-affiliated medical center. PATIENTS: Twenty consecutive women (age range 43-61 yrs). INTERVENTIONS: Hysteroscopic removal of tamoxifen-associated endometrial polyps with or without simultaneous resection of the endometrium. MEASUREMENTS AND MAIN RESULTS: Patients were randomized to undergo (10 women) or not undergo (10) concomitant endometrial resection. They were followed for at least 18 months (range 18-24 mo), including transvaginal ultrasonography every 6 months and hysteroscopy when endometrial irregularity was noted. The main outcome variable was recurrence of endometrial polyps; occurrence of uterine bleeding was also noted. In women who underwent endometrial resection, only one had a 1 x 1-cm endometrial polyp diagnosed and removed during follow-up. Seven women remained amenorrheic, and three experienced spotting for a few days every month. In the control group, six women had recurrent endometrial polyps requiring hysteroscopic removal (two-tail Fisher's exact test p <0.06). CONCLUSION: Recurrence of endometrial polyps, one of the most common problems in patients with breast cancer receiving long-term treatment with tamoxifen, may be reduced by performing endometrial resection at the time of hysteroscopic removal of polyps. The possible risk of occult endometrial cancer is yet to be determined. (J Am Assoc Gynecol Laparosc 6(3):285-288, 1999)     

Variable effects of danazol on endometriosis at 4 low-dose levels

Danazol was administered in a daily dose of 100, 200, 400, or 600 mg for 6 months in a double-blind fashion to 27 women with pelvic endometriosis. Symptoms and pelvic findings were observed and recorded monthly. Laparoscopy and laparoscopic biopsies were performed before and on the last day of treatment to evaluate the extent of endometriosis and the effect of the drug. The findings were documented with drawings and photography. The degree of clinical improvement varied with the daily dose used, from just over 50% on a regimen of 100 mg/day to 83% on a regimen of 600 mg/day. Laparoscopic improvement in the extent of endometriosis was noted in all patients but residual disease was common. The degree of laparoscopic improvement appeared to be related to the dose of danazol and to the effect of the drug on the menstrual cycle. The highest, 81%, laparoscopic improvement was observed in patients who developed amenorrhea during the study. After the completion of treatment, 6 patients required operation for residual endometriosis or for its early recurrence. The recurrence of endometriosis during 24 months of follow-up was observed in 29% of patients. Six of 15 infertile patients conceived spontaneously within 6 months after treatment in spite of mild (5) or moderate (1) residual disease. There was no difference in the extent of endometriosis between infertile patients who did or did not conceive. There was, however, a statistically significant difference in the adhesion score between these 2 groups. The authors conclude that danazol may be less effective in doses lower than the standard 800 mg/day. However, downward adjustment of the individual dose may be attempted on the basis of the development of amenorrhea and clinical improvement.     

A Comparative Treatment Trial of Endometriosis Using the Gonadotrophin-releasing Hormone Agonist, Nafarelin, and the Synthetic Steroid, Danazol

A randomized and double-blind trial was carried out comparing intranasal nafarelin acetate (400 micrograms daily) and oral danazol (600 mg daily), given over 6 months, in the treatment of 49 patients with laparoscopically proven endometriosis. Both drugs produced a highly significant and similar reduction (of 60 to 70%) in objective American Fertility Society scoring, even in severe disease. No effect was seen on adhesions. Both drugs suppressed oestradiol levels to a similar extent, although nafarelin caused a substantial rise in the first 2 weeks after the initiation of therapy. Nafarelin suppressed LH substantially and FSH, testosterone and prolactin to a small degree, whereas FSH and LH increased slightly during danazol. Pregnancies occurred in 12 of 22 infertile women in the 12 months following nafarelin, and in 6 of 14 in the danazol group. Side-effects were reported at a similar rate with both drugs, but the pattern was different. Hot flushes were the predominant side effect with nafarelin, although oestradiol levels were not suppressed to the extent expected. Small amounts of spotting or light bleeding were experienced with both drugs, but these tended to decrease with time with nafarelin and increase with danazol.     

Evidence of similar increases in bone turnover during nafarelin and danazol use in women with endometriosis

Medical 'oophorectomy' by GnRH agonist or danazol is an effective treatment for endometriosis. Since increased bone loss is a potential risk of hypoestrogenism, we compared the effect of nafarelin and danazol treatment on bone metabolism. Twelve patients with laparoscopically confirmed endometriosis received nafarelin (400 micrograms day intranasally) and six patients danazol (600 mg day orally) for 6 months. Both treatments had already led to hypoestrogenism (E2 less than 21.6 pg/ml) after 3 months. They both were accompanied by an approximately 50% rise in 24-h urinary hydroxyproline output, suggesting accelerated bone resorption at 6 months; yet urinary calcium output did not change significantly. Serum osteocalcin rose by 80-120% and bone alkaline phosphatase activity by 34-40%, suggesting stimulated bone formation at the same time. No detectable changes ensued in cortical bone mineral content in the distal radius or in serum levels of calcium, calcitonin, parathyroid hormone, or aminoterminal propeptide of type III collagen. Three months after treatment, hydroxyproline output, serum osteocalcin and bone alkaline phosphatase were still elevated in women taking nafarelin, whereas only serum osteocalcin was elevated in women taking danazol. Our data thus suggest that bone turnover was increased during nafarelin and danazol therapy and that this effect was reversible.     

Hot flashes in postmenopausal women ameliorated by danazol

Six postmenopausal women with hot flashes were studed for two 8-week periods during which they received low-dose danazol (100 mg/24 hours) for one time interval and placebo for the other in a randomized double-blind manner. The patients recorded the number and severity of their hot flashes daily. On the last day of each period the patients were admitted to the research center overnight for an 8-hour monitoring of forehead skin temperatures and for continuous withdrawal of blood to determine 20-minute integrated levels of luteinizing hormone. Three of the six patients responded to danazol with a mean reduction of 88% in the number of hot flashes and a 53% decrease in the severity of hot flashes. Responders differed from nonresponders in that on treatment the frequency of nocturnal pulses of luteinizing hormone was reduced more (36.1% versus 14.4%), the increase in amplitude of the pulses was greater (+30.7% versus -11.8%), and the fall in the mean level of luteinizing hormone was more marked (19.0% versus 10.5%). The findings suggest that danazol may be a reasonable alternative to estrogen in the treatment of postmenopausal women with severe vasomotor symptoms.     

Studies on estrogen replacement therapy with conjugated estrogens by histological evaluation of the endometrium of 205 women

205 postmenopausal women, who received 0.625mg of conjugated equine estrogen (CEE) daily for 2-12 years, were evaluated by endometrial histopathology in three treatment schedules. Group I received CEE for 3 weeks followed by a pause for 1 week in each course. Group II took norethindrone, 10mg daily for 1 week, between CEE and the one week pause. Group III received CEE on calendar days 1 to 21 and norethindrone, 10mg daily, together from day 15 to day 21, and no drug from day 22 every month. The endometrial biopsy was done before and 3 months after the start of the treatment, and every twelve months thereafter. In Group I (73 cases, 4,327 courses), 2 cystic hyperplasias and 8 adenomatous hyperplasias, and in Group II (70 cases, 3,936 courses), 2 cystic hyperplasias, 14 adenomatous hyperplasias, and 2 atypical hyperplasias were developed. In contrast, in Group III (62 cases, 2,765 courses), only 2 adenomatous hyperplasias appeared. Accordingly the incidence of endometrial hyperplasia was 1 for 433, 219, and 1,383 courses respectively. These hyperplasias rapidly disappeared after the cessation of estrogen administration. No endometrial carcinomas were detected throughout the treatment. From these results the treatment schedule for Group III was judged to be superior to the others.     

Effects of danazol on the endometrium during peri-menopausal meno-metrorrhagia

Perimenopausal abnormal bleeding is one of the most common gynecological problems. We have assessed the effectiveness of danazol 200 mg daily for 3 months in 42 patients with perimenopausal abnormal bleeding without any previous treatment and in 23 patients previously treated with norethisterone or medroxyprogesterone acetate but with a recurrence of bleeding 2 months after the end of the treatment. In the overall population treated by danazol at the end of treatment we had: bleeding normalized in 88.2% and hysteroscopic patterns, showing regression of hyperplasia in 95% of cases. The endometrial effects were maintained 2 months after the end of treatment with an increase of the hyperplastic pictures at 4 (26%) and up to 12 months (60%). We had amenorrhea in 10% of patients at the end of treatment and in 2 cases only treatment was discontinued for severe side effects. The comparison of these better results with those obtained by progesterone agents and with those of a preliminary experience with GnRH agonists had led us to consider the importance of an additional endometrial effects exerted by danazol. Particularly the immunosuppressive properties of this drug, as we have shown in "in vitro" conditions, can determine a decreased secretion of growth factors by local immune cells which in turn can further explain the endometrial antiproliferative action of this drug.     

Comparison of cyproterone acetate and danazol in the treatment of pelvic pain associated with endometriosis

Twenty-three patients with laparoscopically diagnosed endometriosis and pelvic pain were allocated randomly to treatment with cyproterone acetate 27 mg plus ethinyl estradiol 0.035 mg/day (11 patients) or danazol 600 mg/day (12 patients). All women received treatment for 6 months, except for one in the cyproterone group who suspended treatment for nonmedical reasons and was excluded from analysis of the results. The clinical condition and pain symptoms were monitored in all patients for 1 year after treatment suspension. The intensity of pelvic pain at diagnosis, during treatment, and at follow-up was evaluated by a multidimensional verbal score and an analogue scale. At the end of treatment, a repeat laparoscopy was performed in those patients who agreed (four in the cyproterone group, five in the danazol group); the results showed a partial regression of endometriotic lesions in both groups, with no significant differences between them. Dysmenorrhea disappeared in all patients during treatment. At 6 months after suspension, dysmenorrhea recurred in 66% of the cyproterone group and 58% of the danazol group, and at 1 year in 89 and 92%, respectively. Intermenstrual pelvic pain improved markedly during treatment in both groups; 6 months after treatment withdrawal it was present in four cyproterone subjects and four danazol group patients, whereas after 1 year, only one woman in the danazol group did not have this symptom. Deep dyspareunia was less affected by treatment, and 6 months later had recurred in all the women.(ABSTRACT TRUNCATED AT 250 WORDS)