Lars Rönnberg

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.

Estrogen and progestin receptors in endometriosis lesions: Comparison with endometrial tissue

Cytosol estrogen (ER) and progestin (PR) receptors were quantified in 47 endometriosis lesions from 41 patients and compared with receptor measurements in the endometrial tissue of nine of these patients. Half of the specimens of endometriosis tissue contained PR only, in concentrations that were significantly lower than in the endometrium. Only 30% of the specimens of endometriosis tissue contained the two receptors simultaneously, and levels of ER were very low compared with those in the endometrium. Levels of PR in the specimens of endometriosis tissue were highest at the periovulatory period, whereas concentrations of ER tended to be highest at the beginning and close to the end of the cycle. These results suggest that regulation of these receptors is dissimilar in endometriosis lesions and endometrium. It remains to be seen whether differences in receptor distribution in the lesions of individual patients could explain differences in the course of this disease, and have therapeutic implications. The presence of PR in the majority of the endometriosis lesions is in accord with the favorable therapeutic response often obtained with progestin treatment of this disease.

Steroidal regulation of endometriosis tissue: lack of induction of 17β-hydroxysteroid dehydrogenase activity by progesterone, medroxyprogesterone acetate, or danazol

Cytosol and nuclear estrogen receptors were detected in 73% and 89% of untreated endometriosis specimens, respectively. The corresponding figures for cytosol and nuclear progestin receptors were 94% and 100%, respectively. Compared with the endometrium, the concentrations in endometriosis tissue were low. The anatomic site, the severity of the disease, and the phase of the menstrual cycle had no significant influence on receptor concentrations in endometriosis tissue. The activities of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) did not increase during the luteal phase. Danazol for 1, 3, 7 to 11, and 18 to 30 days, or medroxyprogesterone acetate for 5 days, had no effect on receptor concentrations or 17 beta-HSD activity in endometriosis tissue. The frequent presence of the receptors suggests that endometriosis lesions are under the control of steroid hormones. The lack of effect by progesterone and progestins on 17 beta-HSD shows that this regulation is different in endometriosis tissue and in the endometrium.

LH(hCG) Receptor in Benign and Malignant Tumors of Human Ovary

LH(hCG) receptors were identified with [125I]hCG in 38 benign and 26 malignant ovarian tumors of the human ovary. Eighteen per cent of all the benign and 27% of all the malignant tumors were LH(hCG) receptor‐positive. Four of 12 benign serous tumors and 3 of 17 benign mucinous tumors displayed definitive binding of [125I]hCG. Two Brenner tumors failed to bind [125I]hCG. Six of 21 malignant epithelial tumors displayed definitive binding of [125I]hCG. Only one out of 4 malignant granulosa cell tumors bound [125I]hCG, while the other sex cord stromal tumors as well as one dysgerminoma failed to bind [125I]hCG. LH(hCG) receptor content in the benign and malignant receptor‐positive tumors was low compared with the normal ovarian tissue. The presence of LH(hCG) receptors in certain benign and malignant ovarian tumors may be a sign of the gonadotropic control of these tumors. The possible applications of these findings for the diagnosis and treatment of human ovarian tumors is discussed.

Measurement of the Ovarian Follicle by Ultrasound in Ovulation Induction

Ultrasonic monitoring of ovarian follicles and estimation of serum estradiol were carried out in 12 patients with clomiphene therapy, in 5 patients with gonadotropin therapy, and in 7 normal controls. The average diameter of preovulatory follicles in normal controls was 12,8 mm; in ovulation induction groups it was 2 to 4 mm greater. The level of serum estradiol was also higher in ovulation induction groups than in normal controls. The combined use of these two methods is recommended: ultrasonic monitoring to minimize the risk of multiple pregnancies and estrogen level monitoring to minimize the risk of hyperstimulation. Ultrasound is also safe and practical in following the size of hyperstimulated ovaries.

Elevated serum levels of endometrial secretory protein PP14 in patients with advanced endometriosis: Suppression by treatment with danazol and high-dose medroxyprogesterone acetate

The circulating concentration of endometrial protein PP14 varied during the menstrual cycle in patients with endometriosis. The highest levels were found on days 1 to 4 of the cycle (176 +/- 123 micrograms/L; mean +/- SD), and the lowest on days 5 to 20 (44.1 +/- 29.7 micrograms/L). Rising levels were observed on days 21 to 30 (58.3 +/- 62.6 micrograms/L). On days 5 to 20 (i.e., during period of the lowest levels) patients with advanced endometriosis had higher PP14 levels (63.9 +/- 39.0 micrograms/L) than those with mild endometriosis (29.3 +/- 18.2 micrograms/L; p less than 0.01). Patients with mild endometriosis had slightly higher serum PP14 levels than apparently healthy control subjects (p less than 0.05), but overlapping of values between the two groups is remarkable. Conservative surgical elimination of endometriosis significantly decreased the serum PP14 levels. Treatment with danazol (600 mg/day), or with medroxyprogesterone acetate (100 mg/day) after laparoscopy also resulted in significant decreases in the serum PP14 concentration. After 6 months of treatment, conservative surgery in combination with danazol or with medroxyprogesterone acetate, yielded more pronounced declines in serum PP14 level than conservative surgery plus placebo. No significant difference was observed between the effects of danazol and medroxyprogesterone acetate. We conclude that endometriosis tissue contributes to the circulating PP14 level, and the decline in PP14 level during danazol and medroxyprogesterone acetate treatments reflects regression of intrauterine and ectopic endometrial tissues.

Luteinizing hormone receptor disorder in endometriosis

Luteinizing hormone (LH) receptor concentrations in ovarian follicles and corpora lutea were measured in 51 patients with histologically proven endometriosis and in 41 control patients. The LH receptor concentrations in cases of endometriosis were lower during the early (0.43 +/- 0.11 [mean +/- standard error] versus 1.31 +/- 0.27 fmol/mg protein; P less than 0.001) and late (0.48 +/- 0.10 versus 1.59 +/- 0.22 fmol/mg protein; P less than 0.001) follicular phase, and during the late luteal phase (2.62 +/- 0.55 versus 4.62 +/- 0.65 fmol/mg protein; P less than 0.05) of the cycle than in control patients. In contrast to the control patients, the LH receptor concentration during the follicular phase remained constant in endometriosis, being lower in patients with extensive or severe disease than in patients with moderate or mild disease (0.28 +/- 0.07 versus 0.61 +/- 0.21 fmol/mg protein; P less than 0.05). Endometriosis-associated infertility might be a consequence of a defect in the mechanism mediating LH action in the ovaries.

Hypoprolactinemia and ovarian function.

Thirty-two patients with ovarian hyperstimulation were randomized to receive bromocriptine or placebo from cycle day 5 onward. Bromocriptine decreased serum and follicular fluid prolactin (PRL), accelerated ovarian follicle growth, increased serum and follicular fluid estradiol, lowered luteal phase progesterone, and shortened the luteal phase length of the cycle. The maximal luteal phase estradiol and progesterone concentrations correlated with each other in the placebo group, but not in the bromocriptine group. These findings indicate that hypoprolactinemia interferes with ovarian function. The unchanged concentrations of gonadotropic hormones and pattern of luteinizing hormone pulsation during bromocriptine suggest direct ovarian effects of hypoprolactinemia. Because PRL suppression enhanced follicular responses and inhibited corpus luteum formation and function, the follicular and corpus luteum actions of PRL may be different.

Placebo-controlled study on serum concentrations of CA-125 before and after treatment of endometriosis with danazol or high-dose medroxyprogesterone acetate alone or after surgery

Serum concentrations of CA-125 were determined in association with 6-month medical (n = 48) or surgical and medical therapy (n = 40) of endometriosis. The concentration of CA-125 was significantly higher in stages III + IV (66.6 +/- 22.0 [standard deviation] U/ml) than in stage I (20.9 +/- 2.3 U/ml) or II (28.4 +/- 2.8 U/ml); in stage II, the concentration was higher than in stage I. Surgical elimination of endometriosis significantly decreased the level of CA-125, as did danazol, but not medroxyprogesterone acetate (MPA), although these drugs were equal in clinical efficacy. The CA-125 changes during hormonal treatment did not correlate with the clinical response. Postoperatively, CA-125 responses to danazol, MPA, or placebo did not differ significantly from each other. During the 6-month follow-up after medication, the CA-125 concentrations tended to increase, especially in danazol-treated women. The determination of CA-125 is useful in estimating the extent of the disease, but it is less valuable in monitoring the treatment effect. The ability of danazol to suppress CA-125 expression emphasizes the specific properties of this drug.

Medroxyprogesterone acetate supplementation diminishes the hypoestrogenic side effects of gonadotropin-releasing hormone agonist without changing its efficacy in endometriosis

OBJECTIVE To examine the effects of concomitant use of goserelin and medroxyprogesterone acetate (MPA) in the treatment of endometriosis. DESIGN Thirty-eight women with laparoscopically confirmed endometriosis were treated with once-a-month s.c. injections of goserelin acetate 3.6 mg (Zoladex depot; Zeneca Pharmaceutics, Cheshire, United Kingdom) randomly combined with either MPA (100 mg daily; n = 19) or a placebo (one tablet daily; n = 19) in a double-blind trial. Symptoms and side effects were monitored for a treatment period of 6 months and a follow-up period of 6 months. Blood and urine samples were collected for the assessment of endocrine and biochemical parameters. A second-look laparoscopy was performed 6 months after the treatment in 29 women. RESULTS The extent of endometriosis was diminished similarly in both treatment groups, as were pelvic symptoms. Fewer women in the MPA group had hot flushes and sweating at 3 and 6 months of treatment. Sex hormone-binding globulin decreased in the MPA group but not in the placebo group. Consequently, the E2 index (E2/SHBG X 100), reflecting the free fraction of E2, fell more in the placebo group than it did in the MPA group. The increased urinary excretion of calcium observed during placebo treatment was prevented by MPA. CONCLUSION High-dose MPA combined with a GnRH agonist (GnRH-A) diminished some antiestrogenic effects of the agonist. A reduction in hypoestrogenic side effects and a possible bone-sparing effect can be regarded as beneficial, especially as the good effect of the GnRH-a on endometriotic implants and pelvic symptoms prevailed.