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Newsletter No. 19
  1. Treatment of acne in hyperandrogenemia
  2. Ultra-long protocol of GnRH agonist administration in ART of women with endometriosis
  3. Follow-up in breast cancer I
  4. Follow-up in breast cancer II
  5. Mammographic density and breast cancer
  6. New insights into the pathophysiology of pre-eclampsia

1.Treatment of acne in hyperandrogenic women.

The relative effectiveness of two newer antiandrogens (flutamide and finasteride) with cyproterone acetate (CPA) was compared, at both low and high doses in the treatment of moderate to severe acne in hyperandrogenic women. Forty-eight hyperandrogenic women were prospectively randomized to the following treatments for 1 year: CPA 2 mg with 35 micro g ethinylestradiol; CPA 50 mg with 25 micro g ethinylestradiol (reverse sequential regimen); flutamide 250 mg daily; and finasteride 5 mg daily. Assessment of Cook scores was the primary end-point of the trial. Blood for androgens was obtained at baseline in these women and 30 ovulatory age-matched controls. Serum androgens were elevated in all 48 women and was similar in each of the four treatment groups. Cook scores were significantly and equally decreased (59-71%) with flutamide and both low and high doses of CPA (P < 0.01). The decrease with finasteride (-36 +/- 2%) was statistically significant but lower than that obtained with the other agents. All treatments were well tolerated. The study showed that low and high doses of CPA with ethinylestradiol were equally effective and were comparable to the effects of a low dose of flutamide. Finasteride was less beneficial.

Carmina E, Lobo RA. A comparison of the relative efficacy of antiandrogens for the treatment of acne in hyperandrogenic womenClin Endocrinol (Oxf). 2002 Aug;57(2):231-4.

2.Prolonged gonadotropin-releasing hormone agonist therapy for in vitro fertilization-embryo transfer in patients with endometriosis.

In cases of endometriosis a prolonged administration of agonistic GnRH analogues prior to initiation of IVF/ICSI treatment resulted in an increase in pregnancy rates over controls. In one of the studies the GnRH analogue was administered over a period of three months and in the other study over a period of six months. The latter study revealed that the increase in pregnancy rates was only significant in cases of severe endometriosis (grades III and IV) and not in lower grades (grade II). Prolonged administration of the GnRH-agonist did not have deleterious on ovarian reserve.

Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB. Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis. Fertil Steril. 2002 Oct;78(4):699-704.

Rickes D, Nickel I, Kropf S, Kleinstein J. Increased pregnancy rates after ultralong postoperative therapy with gonadotropin-releasing hormone analogs in patients with endometriosis. Fertil Steril. 2002 Oct;78(4):757-62.

3. Follow-up of breast cancer I

The Veronesi group in Milano, Italy, conducted 20 years of follow-up of women enrolled in a randomized trial to compare the efficacy of radical (Halsted) mastectomy with that of breast-conserving surgery. From 1973 to 1980, 701 women with breast cancers measuring no more than 2 cm in diameter were randomly assigned to undergo radical mastectomy (349 patients) or breast-conserving surgery (quadrantectomy) followed by radiotherapy to the ipsilateral mammary tissue (352 patients). After 1976, patients in both groups who had positive axillary nodes also received adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. Thirty women in the group that underwent breast-conserving therapy had a recurrence of tumor in the same breast, whereas eight women in the radical-mastectomy group had local recurrences (P<0.001). The crude cumulative incidence of these events was 8.8 percent and 2.3 percent, respectively, after 20 years. In contrast, there was no significant difference between the two groups in the rates of contralateral-breast carcinomas, distant metastases, or second primary cancers. After a median follow-up of 20 years, the rate of death from all causes was 41.7 percent in the group that underwent breast-conserving surgery and 41.2 percent in the radical-mastectomy group. The respective rates of death from breast cancer were 26.1 percent and 24.3 percent (P=0.8). Thus, the long-term survival rate among women who undergo breast-conserving surgery is the same as that among women who undergo radical mastectomy. Breast-conserving surgery is therefore the treatment of choice for women with relatively small breast cancers.

Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, Aguilar M, Marubini E. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002 Oct 17;347(16):1227-32.

4. Follow-up of breast cancer II

In 1976, the NSABP initiated a randomized trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer. A total of 1851 women for whom follow-up data were available and nodal status was known underwent randomly assigned treatment consisting of total mastectomy, lumpectomy alone, or lumpectomy and breast irradiation. Kaplan-Meier and cumulative-incidence estimates of the outcome were obtained. The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3 percent in the women who underwent lumpectomy and breast irradiation, as compared with 39.2 percent in the women who underwent lumpectomy without irradiation (P<0.001). No significant differences were observed among the three groups of women with respect to disease-free survival, distant-disease-free survival, or overall survival. The hazard ratio for death among the women who underwent lumpectomy alone, as compared with those who underwent total mastectomy, was 1.05 (95 percent confidence interval, 0.90 to 1.23; P=0.51). The hazard ratio for death among the women who underwent lumpectomy followed by breast irradiation, as compared with those who underwent total mastectomy, was 0.97 (95 percent confidence interval, 0.83 to 1.14; P=0.74). Among the lumpectomy-treated women whose surgical specimens had tumor-free margins, the hazard ratio for death among the women who underwent postoperative breast irradiation, as compared with those who did not, was 0.91 (95 percent confidence interval, 0.77 to 1.06; P=0.23). Radiation therapy was associated with a marginally significant decrease in deaths due to breast cancer. This decrease was partially offset by an increase in deaths from other causes. It is concluded that lumpectomy followed by breast irradiation continues to be appropriate therapy for women with breast cancer, provided that the margins of resected specimens are free of tumor and an acceptable cosmetic result can be obtained.

Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, Jeong JH, Wolmark N. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002 Oct 17;347(16):1233-41.

5. Mammographic density and breast cancer

Women with extensive dense breast tissue visible on a mammogram have a risk of breast cancer that is 1.8 to 6.0 times that of women of the same age with little or no density. Mammographic densitiy appears to have a strong hereditary component. The biological basis for this association of mammographic density and increased risk of breast cancer is unknown. The authors have examined the association of circulating levels of hormones and growth factors with mammographic density. A total of 382 subjects, 193 premenopausal and 189 postmenopausal, without previous breast cancer or current hormone use, were selected in each of five categories of breast density from mammography units. Risk factor information, anthropometric measures, and blood samples were obtained, and oestradiol, progesterone, sex hormone binding globulin, growth hormone, insulin-like growth factor-I and its principal binding protein, and prolactin measured. Mammograms were digitised and measured using a computer-assisted method. After adjustment for other risk factors, we found in premenopausal women that serum insulin-like growth factor-I levels, and in postmenopausal women, serum levels of prolactin, were both significantly and positively associated with per cent density. Total oestradiol and progesterone levels were unrelated to per cent density in both groups. In postmenopausal women, free oestradiol (negatively), and sex hormone binding globulin (positively), were significantly related to per cent density. These data show an association between blood levels of breast mitogens and mammographic density, and suggest a biological basis for the associated risk of breast cancer.

Boyd NF, Dite GS, Stone J, Gunasekara A, English DR, McCredie MR, Giles GG, Tritchler D, Chiarelli A, Yaffe MJ, Hopper JL. Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med. 2002 Sep 19;347(12):886-94.

Boyd NF, Stone J, Martin LJ, Jong R, Fishell E, Yaffe M, Hammond G, Minkin S. The association of breast mitogens with mammographic densities. Br J Cancer. 2002 Oct 7;87(8):876-82.

6. New insights into the pathophysiology of pre-eclampsia

The examination of fetal cells, specifically erythroblasts, and cell-free fetal DNA from the blood of pregnant women is currently the subject of intense research with the aim of developing new risk-free methods for prenatal diagnosis. An unexpected finding made during these studies was that the traffic of fetal erythroblasts into the maternal peripheral circulation was enhanced in pre-eclampsia. Independent prospective studies examining samples collected in the second trimester indicated that this perturbation in fetal cell trafficking occurs early in pregnancy, well before the onset of pre-eclampsia symptoms. The quantitative analysis of cell-free fetal and maternal DNA levels indicated that these concentrations were elevated in a co-ordinate manner in manifest pre-eclampsia, and that these elevations corresponded to disease severity. On the other hand, analysis of prospectively collected samples indicated that only cell-free fetal but not maternal DNA levels were elevated before onset of symptoms in pregnancies which subsequently developed pre-eclampsia. These data support hypotheses suggesting that pre-eclampsia is a multi-step disorder, initiated by a placental lesion that occurs early in pregnancy and which subsequently leads to a systemic maternal inflammatory response and associated endothelial cell damage.

Hahn S, Holzgreve W. Fetal cells and cell-free fetal DNA in maternal blood: new insights into pre-eclampsia. Hum Reprod Update. 2002 Nov-Dec;8(6):501-8.

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Gerhard Leyendecker