Endometrial carcinoma: Steroid receptors and response to medroxyprogesterone acetate

The steroid receptor content of the primary endometrial cancer of 22 patients who were treated for recurrent or advanced disease has been measured and correlated with response to medroxyprogesterone acetate. No patient with a progesterone receptor (PR)-negative tumor responded and only 2 patients with PR-positive tumors responded, perhaps related to the low levels of PR in the tumors. It waits to be assessed whether receptor status is as good a guide to response to hormone therapy as tumor differentiation, site of recurrence, or disease-free interval.     

Successful pregnancy in a patient with endometrial carcinoma treated with medroxyprogesterone acetate

A 32-year infertile Japanese woman suffered from endometrial cancer, which was treated with repeated endometrial curettage and medroxyprogesterone acetate for 6 months. The patient then became pregnant and was delivered of a live-born male infant at 37 weeks gestation by cesarean section for placenta previa. At cesarean section there were no abnormal findings in the uterine cavity or other pelvic organs.     

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.     

Changes in apolipoprotein AI after treatment with high-dose medroxyprogesterone acetate

21 women (mean age 60 years, range 48-72) were given depot medroxyprogesterone acetate (DMPA), 1,000 mg/week parenterally for 6 months, as part of the treatment for endometrial carcinoma in either clinical stage I or II. Before treatment and after 1, 3 and 6 months of treatment serum apolipoprotein AI was analyzed by electroimmunoassay. There was a significant decrease in apolipoprotein AI after the administration of DMPA, compared to the value before treatment. A low level of apolipoprotein AI is considered a risk factor for the development of atherosclerosis and cardiovascular disease. Such a risk might therefore be anticipated if the period of treatment was extended to several years.     

The medroxyprogesterone acetate serum level following various medroxyprogesterone acetate dose schedules in gynecologic oncology

Medroxyprogesterone acetate (MPA) is used as an adjuvant hormonal medication in patients with different kinds of carcinomas. Since adequate serum levels are thought to be essential we determined the individual, postoperative MPA levels in 36 patients with endometrial carcinoma over a period of 12 weeks. The patients received either an oral dose of 3 X 100 mg MPA or a weekly changing scheme with 2 X 10 mg Tamoxifen and 3 X 100 mg MPA. An additional small group of 4 patients with ovarian carcinoma was enrolled receiving an oral dose of 1000 mg MPA daily. The peripheral serum levels of MPA exhibit enormous inter- and intraindividuell variations and only the high dosage schemes yield levels above 90 ng/ml which are claimed necessary by some authors. The cortisol concentration measured at the same time were within the normal range and did not correlate with the MPA values.     

Improved fertility following conservative surgical treatment of ectopic pregnancy

Objective To evaluate fertility after salpingectomy or tubotomy for ectopic pregnancy.
Design Retrospective cohort study.
Setting Clinical University Center, Hvidovre Hospital, Copenhagen.
Population Two hundred and seventy-six women undergoing salpingectomy or tubotomy for their first ectopic pregnancy between January 1992 and January 1999 and who actively attempted to conceive were followed for a minimum of 18 months.
Methods Retrospective cohort study combined with questionnaire to compare reproductive outcome following salpingectomy or tubotomy for ectopic pregnancy. Cummulative probabilities of pregnancy for each group were calculated by the Kaplan-Meier estimator and compared by Cox regression analysis to control for potential confounders.
Main outcome measures Intrauterine pregnancy rates and recurrence rates of ectopic pregnancy after surgery for ectopic pregnancy.
Results The cumulative intrauterine pregnancy rate was significantly higher after tubotomy (88%) than after salpingectomy (66%) (log rank   P < 0.05  ) after correction for confounding factors. No difference was found in the recurrence rate of ectopic pregnancy between the treatments (16% vs 17%). In patients with contralateral tubal pathology, the chance of pregnancy was poor (hazard ratio 0.463) and the risk of recurrence was high (hazard ratio 2.25), assessed with Cox regression. The rate of persistent ectopic pregnancy was 8%.
Conclusion Conservative surgery is superior to radical surgery at preserving fertility. Conservative surgery is not followed by an increased risk of repeat ectopic pregnancy, but by the risk of persistent ectopic pregnancy, which should be taken into account when deciding on the operative procedure. Management in case of contralateral tubal pathology is disputed and should ideally be addressed in a randomised clinical trial.     

Bone density in long term users of depot medroxyprogesterone acetate

Objective To identify any adverse effect on bone density in long term users of depot medroxyprogesterone acetate (DMPA) for contraception.
Design Cross-sectional measurement of bone density in users with amenorrhoea of more than one year or any woman using DMPA for more than five years.
Setting Community Family Planning Clinics in Portsmouth and Manchester.
Population One hundred and eighty-five women aged 17–52 years (mean 33.3 years) who had used DMPA for between 1 and 16 years and were attending the clinics for further injections, between August 1994 and August 1996.
Methods Dual energy X-ray measurement of bone density of femoral neck and lumbar spine, and venous blood sample taken just prior to the next injection of DMPA.
Main outcome measures Bone density of femoral neck and lumbar spine and serum oestradiol in relationship to years of DMPA use and duration of amenorrhoea.
Results Most women (   n = 153  ) had serum oestradiol levels < 150 pmol/l. Despite this, the mean bone density of the lumbar spine compared with the population mean for women aged 20–59 years gave a Z score (95% CI) of -0.332 (-0.510 to -0.154). There was no significant difference in the mean density of the femoral neck from the normal population mean.
Conclusion Despite amenorrhoea and low serum oestradiol, this sample of long term DMPA users had bone density only minimally below the normal population mean. We therefore found no clinically important adverse effect on bone density and therefore no reason to recommend bone conserving measures, such as add-back oestrogen.     

Long-term treatment with transcutaneous estradiol and oral medroxyprogesterone acetate.

In an open prospective study with therapeutic monitoring, 34 women with climacteric symptoms, FSH > 40 IU/L and LH > 25 IU/L were treated for 12 months with an estradiol-depot-patch (Estraderm TTS) 50 micrograms twice a week and medroxyprogesterone acetate 10 mg tablets from 12th to 25th day of cycle. During the first months a significant improvement was seen in hot flushes and other climacteric inconveniences in terms of Kupperman's menopause index. During the study period FSH and LH were suppressed and the estrogen values were normalized. The fraction of free estradiol compared to protein bound estradiol remained unchanged during the whole treatment. The serum-lipids and serum-SHBG at inclusion were within normal limits and did not change during 12 months of treatment. Thus from these parameters no sign of any liver induction was seen. Ten patients had short term skin symptoms while four withdrew from the study because of persistent skin symptoms. Nine patients withdrew from the study, in five cases this was related to the therapy while in the other four it was due to other causes. Twenty-five (74%) women wished to continue the treatment after 12 months.     

Lipoprotein changes during treatment of pelvic endometriosis with medroxyprogesterone acetate

Ten women with endometriosis were treated with medroxyprogesterone acetate (MPA), 150 mg intramuscularly every second week. After 2 weeks, there was a significant (8%) decrease in the high-density lipoprotein (HDL) concentration. This reduction became more pronounced after 8 and 24 weeks' medication. The HDL reduction was confined to the HDL2 subfraction, which was decreased by 15%, 33%, and 58% after 2, 8, and 24 weeks, respectively; there was no significant change in the HDL3 concentration. During treatment, there was a continuous increase in the mean MPA plasma level and a strong inverse correlation between this level and the mean HDL and HDL2 cholesterol concentrations. It was concluded that MPA affects HDL metabolism in a dose-dependent way and in the same direction as other progestins.     

Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate.

OBJECTIVE: To determine the endometrial safety of lower doses of continuous combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA). DESIGN: Randomized, double-blind, placebo-controlled study (the Women's Health, Osteoporosis, Progestin, Estrogen study). SETTING: Study centers across the United States. PATIENT(S): Healthy, postmenopausal women (n = 2,673) with an intact uterus. INTERVENTION(S): Patients received CEE 0.625 mg/day, CEE 0.625/MPA 2.5 mg/day, CEE 0.45 mg/day, CEE 0.45/MPA 2.5 mg/day, CEE 0.45/MPA 1.5 mg/day, CEE 0.3 mg/day, CEE 0.3/MPA 1.5 mg/day, or placebo for 1 year. Endometrial biopsies were evaluated at baseline, cycle 6, and year 1 using a centralized protocol.MAIN OUTCOME MEASURE(S): Efficacy of lower doses of CEE/MPA in reducing the incidence of endometrial hyperplasia rates associated with unopposed CEE. RESULT(S): Endometrial hyperplasia rates ranged from 0 to 0.37% for all CEE/MPA doses. Twenty-nine of the 32 cases of endometrial hyperplasia developed in women who were administered CEE 0.625 mg or CEE 0.45 mg. The incidence of endometrial hyperplasia increased with age for patients administered CEE alone. As expected, there were some inconsistencies among pathologists' ratings in the numbers of hyperplasias and incidence rates for the CEE-alone regimens. There were too few cases of hyperplasia in the combination groups to evaluate consistency among pathologists. CONCLUSION(S): One year of treatment with lower doses of CEE/MPA provides endometrial protection comparable to commonly prescribed doses. These regimens may be used by clinicians to individualize hormone replacement therapy in postmenopausal women.     

The plasma concentration of medroxyprogesterone acetate and ovarian function during treatment with medroxyprogesterone acetate in 5 and 10 mg doses

Peripheral plasma levels of medroxyprogesterone acetate (MPA) were determined by radioimmunoassay in 5 women after oral administration of 5 and 10 mg medroxyprogesterone acetate daily. Peak levels of MPA in plasma were recorded within 1 - 3 hours of taking the tablet, which indicates a rapid absorption from the gastro-intestinal tract. The levels of medroxyprogesterone acetate 12 hours after taking of the 5 mg tablet remained constant throughout the 8 weeks of study. Peripheral plasma levels of estradiol and progesterone were determined throughout treatment. The estradiol levels indicated development of follicles in 7 out of 10 treatment months in the 5 mg group, and in 3 of the subjects treated with 10 mg MPA. The progesterone levels in those women treated with 5 mg MPA showed normal luteal concentration values in 2 out of 10 treatment months. No woman treated with 10 mg MPA had an increase in progesterone during the 21-day period of treatment. The results obtained in this study suggest that 10 mg MPA daily will inhibit ovulation but 5 mg is not sufficient to inhibit ovulation in all women.     

Epidermal growth factor receptor signaling enhanced by long-term medroxyprogesterone acetate treatment in endometrial carcinoma

OBJECTIVE: Progestin is an effective endocrine treatment for patients with atypical hyperplasia or with endometrial carcinoma that is estrogen receptor (ER) positive and progesterone receptor (PR) positive. However, long-term progestin treatment may lead to resistance. We have studied the progestin resistance phenotype that frequently develops in endometrial carcinoma. METHODS: Ishikawa endometrial carcinoma cells were cultured for a long period (10 months) in the presence of the synthetic progestin medroxyprogesterone acetate (MPA), thereby generating a subline refractory to the growth-suppressive effects of MPA. RESULTS: The MPA-resistant subline showed growth stimulation rather than inhibition after MPA treatment. Immunocytochemical analysis showed reduced ER alpha and PR-B expression and increased ER beta expression in this subline compared with parental Ishikawa cells. Progestin-resistant Ishikawa cells also showed increased expression of transforming growth factor alpha (TGFalpha), the epidermal growth factor receptor (EGFR), and EGFR tyrosine kinase (EGFR-TK); MPA treatment further stimulated the expression of TGFalpha in these cells. Additionally, progestin-resistant Ishikawa cells were highly sensitive to growth stimulation by TGFalpha and to growth inhibition by the EGFR-TK-specific inhibitor AG1478, and they showed increased dependence on TGFalpha-EGFR signaling. CONCLUSIONS: Our results suggest that prolonged treatment of endometrial carcinoma cells with MPA induces resistance to the growth-suppressive effects of MPA and enhances cancer cell proliferation. The downregulation of ER alpha and PR-B, the upregulation of ER beta, and highly activated TGF-EGFR signaling are thus likely to contribute to progestin resistance in endometrial carcinoma. Therefore, an EGFR-TK-specific inhibitor might be useful in the treatment of progestin-resistant endometrial carcinoma.     

Subsequent pregnancy outcome after conservative treatment of a previous cesarean scar pregnancy

BACKGROUND: To assess pregnancy course and outcome after conservative treatment of a cesarean scar pregnancy. METHODS: During an 8-year period, 15 cases of cesarean scar pregnancies were diagnosed at our institution. Seven of the 14 patients for whom we successfully preserved the uterus became pregnant within 3 years after termination of the scar pregnancy. The year of diagnosis, conservative method and gestational age for these five patients were recorded. Delivery method, time interval between the scar pregnancy and subsequent pregnancy, and maternal and neonatal outcome were evaluated. RESULTS: Seven pregnancies (eight live and one dead baby) were noted. The mean interval between the ectopic pregnancy and subsequent pregnancy was 13.3 months (range 0-34 months). One patient, who became pregnant 3 months after the scar pregnancy was found, suffered uterine rupture at 38.3 weeks' gestational age. Two patients with placental accrete, and one of them who continued the existing intrauterine twin pregnancy after transvaginal sono-guided aspiration of the scar pregnancy received a cesarean hysterectomy at 32 weeks of gestation. The remaining four pregnancies were uneventful, followed by early cesarean sections at 36 weeks. CONCLUSION: The results of this first series of seven subsequent pregnancies after conservative treatment of scar pregnancies are promising. An early cesarean section before over-extension of the uterus and spontaneous labor can help to prevent uterine rupture. Placenta accrete is another severe morbidity of these patients in addition to uterine rupture. Thus a cesarean hysterectomy may be the choice of treatment.     

Persistent ectopic pregnancy following conservative surgery for tubal pregnancy

Objective To audit the incidence and management of persistent ectopic pregnancy following conservative tubal surgery performed at laparotomy and via the laparoscope.
Design A retrospective analysis of the case records. Setting The Birmingham and Midland Hospital for Women.
Participants Two hundred and fourteen women who received surgical treatment for ectopic pregnancy between October 1991 and December 1994.
Results Of the 85 women who underwent conservative tubal surgery, nine were diagnosed as having persistent ectopic pregnancy on the basis of hCG values. The incidence after laparoscopy was no higher than after laparotomy. A second surgical procedure was indicated in only four cases.
Conclusions Post-operative surveillance of serum hCG remains mandatory. Patients who remain symptom free may be managed conservatively The threshold for a second-look laparoscopy should be relatively high and be based on the presence of symptoms rather than changes in hCG values.