Operation, hormone therapy and recovery of the patients with severe forms of adenomyosis.

Endometriosis is among the prevalent gynecological diseases and diagnosed in 10% of women of reproductive age. Endometriosis/adenomyosis is becoming increasingly a health-social problem, which is associated with severe clinical manifestations and recurrent disease which has a negative effect on quality of life, women ability to work and her reproductive function. This article presents modern approaches of drug therapy to treat severe forms of adenomyosis. We have reviewed recent major studies in the field of surgical treatment of this disease, analyzed the main stages of disease progress and the results of our surgeries. Here, we are presenting our own results of long-term post-operative hormonal therapy and complex medical treatment.

A pilot study to determine whether progestogen supplementation using dydrogesterone during the first trimester will reduce the incidence of gestational hypertension in primigravidae.

BACKGROUND: Gestational hypertension (GH) remains one of the main causes of high maternal and perinatal morbidity and mortality worldwide with the highest incidence among primigravidae of about 10%-15%. However, it was noted that the incidence of GH in primigravidae who conceived following assisted reproductive technique (ART) or intrauterine insemination (IUI) supplemented with dydrogesterone during the first trimester was low. AIM: To determine whether dydrogesterone supplementation during the first trimester can reduce the incidence of GH among primigravidae. METHOD: A prospective cross-sectional comparative study was undertaken in 2010 on 116 primigravidae (study group) who conceived following ART or IUI and supplemented with dydrogesterone up to 16 weeks gestation. They were matched for age and race at 16 weeks gestation with a control patient from the early pregnancy clinic who were primigravidae (n = 116) who conceived spontaneously without dydrogesterone supplementation. FINDINGS: The incidence of GH in the study group was significantly lower than the control group (1.7% versus 12.9%, p = 0.001). The incidence of fetal distress was also significantly lower in the study group compared to the control group (4.3% versus 18.1%, p = 0.001). INTERPRETATION: Dydrogesterone supplementation during the first trimester significantly reduced the incidence of GH and fetal distress in primigravidae.

Implementation of certified endometriosis centers: 5-year experience in German-speaking Europe.

The idea of quality improvement in the management of endometriosis has been brought to attention throughout Europe. This - first and foremost - includes the implementation of centers specialized in treating endometriosis. This leads to qualification of both physicians and other medical staff, enforcement of research efforts, and informing the patients, the public, politicians, healthcare providers, and industry. Given limited budgets, focusing on the existing national commitment may be the first step.

Non-contraceptive benefits of hormonal contraceptives.

Besides the contraceptive effect of the various hormonal contraceptives, it is intended to demonstrate the non-contraceptive health benefits for treatment and prevention of bleeding problems, menstruation-related pain and other disorders, such as premenstrual syndrome and signs of androgenization. The effectiveness can be improved by choosing the proper progestogen with antiandrogenic action. Treatment but also prevention can be achieved with hormonal contraceptives in benign proliferative diseases of women, such as ovarian cysts, endometriosis, adenomyosis, endometrial hyperplasia, myoma and benign breast disease. Furthermore, hormonal contraceptives such as estrogen/progestogen combinations reduce pelvic inflammatory disease, rheumatoid arthritis, asthma symptoms and preserve bone density. In addition, a major impact in oncological prevention seems to be possible for ovarian, endometrial and colon cancer and these positive preventive effects seem to persist also after discontinuation of hormonal contraceptives. In addition, practical concepts for hormonal contraceptive selection will be outlined.

Progestogens and immunology.

Fifty percent of fetal antigens are of paternal origin. These are recognized by the maternal immune system, thereby resulting in lymphocyte activation and the induction of progesterone receptors (PRs) in immune cells. Upon binding of progesterone to PRs on lymphocytes, a downstream mediator called progesterone-induced blocking factor (PIBF) is produced. The full-length PIBF is a 90 kDa protein; however, because of alternative splicing, several smaller isoforms are also produced. While the 90 kDa molecule plays a role in cell cycle regulation, the small isoforms are localized in the cytoplasm, and after secretion, they bind to their receptors on other cells and act in a cytokine-like manner. The communication between the embryo and the maternal immune system is established through PIBF-containing extracellular vesicles. PIBF induces an increased production of Th2 cytokines and inhibits degranulation of NK cells, and by regulating the maternal immune response, it contributes to successful implantation and maintenance of pregnancy.

Prevention and treatment of pregnancy-induced hypertension (preeclampsia) with progestogens.

Available data indicate that progesterone is able to treat pregnancy-induced hypertension (preeclampsia). Dydrogesterone and 17alpha-hydroxyprogesterone caproate might also be used for this purpose. Prevention of hypertensive disorders in preeclampsia also seems possible, but studies are needed to confirm this.

Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies.

A Phase I dose escalation and pharmacokinetic study of the alkylating cytotoxic agent treosulfan was conducted to evaluate the maximum tolerated dose and the dose-limiting toxicities in patients with advanced malignancies rescued by autologous peripheral blood stem cell transplantation. Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 h at escalating doses from 20 to 56 g/m2, and pharmacokinetic parameters were analyzed. At 56 g/m2, three of six patients experienced dose-limiting toxicities: diarrhea grade III/IV in three patients; mucositis/stomatitis grade III in one patient; toxic epidermal necrolysis in one patient; and grade III acidosis in one patient. Other low-grade side effects, including erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patients died within 4 weeks after treatment because of rapid tumor progression and fungal infection, respectively. Plasma half-life, distribution volume, and renal elimination of treosulfan were independent of dose, whereas the increase in area under the curve was linear up to 56 g/m2 treosulfan. The maximum tolerated dose of high-dose treosulfan is 47 g/m2. A split-dose or continuous infusion regimen is recommended for future high-dose trials. In consideration of antineoplastic activity and limited organ toxicity, inclusion of high-dose treosulfan in combination protocols with autologous peripheral blood stem cell transplantation seems worthwhile.

WITHDRAWN: The safety of synthetic paclitaxel by intralesional delivery with OncoGeltrade mark into skin breast cancer metastases: method and results of a clinical pilot trial.

Ahead of Print article withdrawn by publisher

Human pituitary gonadotropin index. I. Standardized LRH test criteria for evaluation of functional amenorrhea.

LRH test were carried out by giving 339 amenorrheic women and 74 normally menstruating volunteers an intravenous injection of 25 mug LRH (Hoe 471). Plasma LH and FSH were measured by RIA in two laboratories (Tuebingen and Ulm) using two standard reference preparations: LER 907 and 2nd IRP-HMG. The average conversion factors between the two standard preparations were calculated at 5.0 for LH and 25.0 for FSH. Furthermore, the estradiol-17beta levels were measured in 139 out of the 339 patients immediately before and 60 minutes after LRH injection. Taking the episodic and cyclic plasma gonadotropin fluctuations into consideration a shorthand system classifying the gonadotropin baseline (BI-BIV) and LH responses to 25 mug LRH (R0-R2) has been established and is referred to as Human Pituitary Gonadotropin Index (HPGI). It is possible to achieve reproducible gonadotropin results in two different laboratories using two different standard reference preparations. Two separate, randomly selected groups of amenorrheic women were found to have the same percent distribution of the HPGI. A correlation coefficient of r equal 0.67 between basal and LRH stimulated plasma LH levels does not sufficiently characterize the individual LH response behavior. A significant increase of plasma LH and FSH within the test period (60') reveals that the iv administration of 25 mug LRH represents an adequate dose for the LRH test in women. The HPGI which characterizes the functional state of gonadostat, may become a useful diagnostic index for evaluating women with anovulatory disease before, during, and after therapy.

A summary of two clinical studies on tumor cell dissemination in primary and metastatic breast cancer: methods, prognostic significance and implication for alternative treatment protocols (Review).

Although only less than 10% of women with primary breast cancer have clinicopathologic signs of overt metastases, metastatic relapse occurs in about half of the cases with apparently localized tumors within five years after surgery. In 23% of the patients, bone marrow metastases are detectable at first relapse and this rate even increases in patients with metastatic breast cancer. However, hematogeneous or lymphatic spread of occult tumor cells can arise before diagnosis at an early stage of primary tumor growth and is regularly underestimated by currently available clinical and pathologic staging procedures. We studied cytokeratin-positive (CK+) cells in the bone marrow (BM) and tumor markers in the blood of 128 patients with primary breast cancer in order to obtain an early diagnosis of residual disease. In a second study, we monitored cytokeratin (CK)/17-1A positive cells in the BM and peripheral blood stem cells (PBSC) to evaluate whether dose intensive or high-dose (HD)-chemotherapy can eliminate micrometastases in high-risk breast cancer patients. The overall CK+ rate was 34% (44/128 patients), 29% (15/51) for patients with T1 tumors, 33% (28/84) for N0 patients and 31% (26/82) for patients with G1-2 breast carcinoma. Interestingly, 67% of CK+ patients were only positive in one of the two BM aspirates studied. At least one tumor marker including carcinoembryonic antigen, carbohydrate antigen 15-3 and tissue polypeptide antigen, was increased in 58/128 (45%) patients [21/58 (36%) were CK+ in the BM]. Surprisingly, levels for the extracellular domain of Her-2/neu in serum samples were within the normal range in every patient studied. After a 2-year follow-up, 7/128 patients relapsed (3/7 CK+/TM-; 2/7 CK-/TM+; 2/7 CK-/TM-). We concluded that studying two BM aspirates for CK+ cells by immunocytochemistry in combination with tumor marker determination is useful for identifying patients with a higher risk for relapse. A tumor cell enrichment technique, applied in 70 patients prior to immunocytochemistry using dynabeads directly coupled to an antibody (BerEp4) targeting the 17-1A antigen, did not enhance the detection rate of disseminated tumor cells in this patient group. We monitored CK+/17-1A+ cells in the BM and PBSC and studied Her-2/neu serum levels of patients with locally advanced (n=13, group 1) and metastatic breast cancer (n=30, group 2). CK+ cells were found in the BM of 3/13 (23%) group 1 patients before but not after chemotherapy resulting in an overall survival (OS) of 92% after a median follow-up of 33 months. Contamination of PBSC in 2/9 (22%) patients was not associated with decreased survival. In group 2 patients, the CK+ rate was 60% (18/30 patients) before and 40% (4/10 patients) after therapy with an OS rate of 43% after 29 months. PBSC samples were positive in 7/24 (29%) patients. CK+ BM and PBSC led to a rapid progress and short OS whereas tumor cell free BM and PBSC resulted in a mean OS of 30 months. The antigen 17-1A was detected on most CK+ cells in both patient groups before therapy, on all CK+ PBSC and on CK+ cells in group 2 patients after therapy. Increased Her-2/neu levels were found in group 2 patients before chemotherapy. In conclusion, micrometastatic cells are present in blood and PBSC grafts of high-risk breast cancer patients and can survive even HD-chemotherapy. Immunotherapeutic target antigens on the cell surface of these cells support the idea that a combined chemoimmunotherapy might be successful in eliminating minimal residual disease.

High-dose chemotherapy with peripheral blood stem cell transplantation for patients with advanced ovarian cancer.

PURPOSE: We report the results of high-dose chemotherapy (HDC) with peripheral blood stem cell transplantation in twenty-one patients with primarily advanced or relapsed ovarian cancer. METHODS: Twenty-five women underwent stem cell collection, and 21 were finally treated with different regimens of HDC containing cyclophosphamide, etoposide, carboplatin, and treosulfan. The patients received cyclophosphamide +/- cisplatin and cisplatin + paclitaxel, respectively, followed by G-CSF (n = 24) or GM-CSF (n = 1) for stem cell mobilization. RESULTS: A mean of 7.2 +/- 6.1 x 10(6) CD34+ cells per kg bw were collected. Thirteen patients received double transplants and one patient received a triple transplant. The median age was 47 years (range 24-61 years) and the mean number of prior regimens was three (range 1-8). Engraftment occurred on time in all patients and there was one treatment-related death resulting in an overall mortality rate of 4.8% among the 21 patients treated with HDC. The response rate was 72% (48% CR, 24% PR) and the mean time to progression and overall survival after HDC were 7 and 32 months, respectively. CONCLUSION: HDC could be performed safely in patients with advanced ovarian cancer. However, even with a high response rate, the duration of response is short, warranting new treatment approaches to further improve the outcome of this population of patients with unfavorable prognosis.

Influence on hormone levels, lipid metabolism and reversibility of endocrinological changes after leuprorelin acetate depot therapy.

The effect of leuprorelin acetate depot on the endocrine system and on lipid metabolism was evaluated in a multicentre, noncomparative study. During the first month of treatment, suppression of serum oestradiol levels to below 20 pg/ml was achieved and luteinising hormone and follicle-stimulating hormone levels were reduced to less than 50% of pretreatment values. A negative influence on lipid metabolism was not recorded. The high-density lipoprotein/low-density lipoprotein ratio did not change during therapy. Resumption of menstruation occurred within a mean period of 3 months after the last leuprorelin acetate depot injection.

Plasmatic haemostasis in gonadotrophin-releasing hormone analogue therapy: effects of leuprorelin acetate depot on coagulatory and fibrinolytic activities.

The plasmatic parameters of coagulatory and fibrinolytic activity were studied in 15 patients with biopsy-proven endometriosis treated with leuprorelin acetate for 6 months. Bleeding time remained constant, indicating the absence of increased bleeding tendencies. The activity of the main inhibitor of the fibrinolytic response, plasminogen activator inhibitor, was reduced by 25%, suggesting an improvement in fibrinolytic reactivity. Plasma levels of fibrin degradation fragments were reduced by 35%, suggesting a marked reduction in the rate of fibrin generation and degradation. A simultaneous reduction in thrombin-antithrombin III complexes and prothrombin fragment 1 + 2 (-10%) indicated that this effect was induced by reduced procoagulant activity, ie, thrombin generation. These data indicate that in gonadotrophin-releasing hormone (Gn-RH) analogue therapy the basal rate of coagulatory processes is reduced. The frequency and extent of fibrin-generating and degrading processes are reduced, suggesting a beneficial effect of Gn-RH analogues on the risk of thromboembolic disease.

Treatment of endometriosis with leuprorelin acetate depot: a German multicentre study.

During the past decade, the development of various gonadotrophin-releasing hormone (Gn-RH) agonists, which induce reversible hypo-oestrogenism has opened a new area in the medical management of endometriosis. In an open, multicentre phase III study, the efficacy, tolerance and safety of the Gn-RH agonist leuprorelin acetate were tested. The preliminary results of 104 women treated in seven German centres are presented. Pelvic endometriosis was diagnosed by laparoscopy and classified according to the American Fertility Society scoring system: 33% of patients had minimal, 22% mild, 28% moderate and 8% severe endometriosis and in 9% no pathological results were obtained. The patients' mean age was 30 +/- 6 years and 66 had infertility problems. Treatment was started within the first 3 days of the menstrual cycle and consisted of a subcutaneous injection of leuprorelin acetate 3.75 mg, repeated once monthly over 24 weeks. A follow-up period of 12 months after the last injection has been completed in 70 patients, including a second laparoscopy. At all visits, symptoms were evaluated, physical examinations performed, and blood samples collected for haematological screening, serum chemistry determinations and measurement of the gonadotrophins oestradiol and progesterone and leuprorelin acetate. The median score at laparoscopy fell from 12 before operation to 8 after operation and 2 after treatment with leuprorelin acetate. Of the total number of patients, 89% had improvements in their endometriosis, 8% a deterioration and 3% no change. Patients reported improvement in the following: dysmenorrhoea 93%, dyspareunia 62% and pelvic pain 70%. However, all women complained of at least one of the following symptoms: hot flushes 86%, sleep disturbance 62%, sweating 61%, headache 41%, nausea 32% and depression 20%. Fifty-five percent of patients reported additional side effects such as vaginal dryness, fatigue and lower abdominal pain. After the third injection, amenorrhoea persisted in 94% of the women. Four weeks after the first leuprorelin acetate injection median concentrations of oestradiol fell from 45 pg/ml to 11 pg/ml, follicle-stimulating hormone from 7 U/L to 3 U/L and luteinising hormone from 5 U/L to 1 U/L and remained almost unchanged over the observation period. During the 6 months' treatment, laboratory parameters showed no significant deviations from normal; only total cholesterol, high-density lipoprotein cholesterol and alkaline phosphatase increased. Treatment results were judged as good and satisfactory in 82% and 11% of cases, respectively. On the basis of this study, it can be concluded that leuprorelin acetate treatment is safe, well tolerated and effective in the medical management of endometriosis and endometriosis-related complaints.

Experience with leuprorelin acetate depot in the treatment of fibroids: a German multicentre study.

Between October 1988 and October 1990 in a noncomparative multicentre study, 114 patients were treated for uterine fibroids with the gonadotrophin-releasing hormone (Gn-RH) agonist, leuprorelin acetate depot. The mean age of the women was 33 years and 55.3% of them had a history of infertility. After confirmation of the diagnosis by ultrasound and/or operation, treatment began between day 1 and 3 of the cycle with leuprorelin acetate depot 3.75 mg subcutaneously. Therapy was carried out for a total of 6 months with one injection every 4 weeks. Treatment was paralleled by measurements of endocrine and metabolic parameters, estimation of myoma and uterine size by ultrasound and self-reporting of the patients of drug-related complaints. Four of the 114 women did not complete the whole treatment, two of them because of general side effects, one because of carcinophobia and unsatisfactory regression of the myoma and the last one for unspecified reasons. During treatment, a mean reduction of the uterine volume of about 67% was observed, in conjunction with shrinkage of the myoma in 92.1% of cases (mean decrease of 56% of the fibroids) with a large interindividual difference. Maximal diminution of uterine and fibroid size had been nearly completely reached within the first 12 weeks of therapy. After 4 weeks of the Gn-RH agonist depot most of the patients had achieved postmenopausal status, which continued throughout the remaining 20 weeks of treatment. In accordance with this finding, the majority of general side effects was due to the hypo-oestrogenic endocrine status. Liver and lipid metabolism was almost unaffected, although increasing calcium and alkaline phosphatase serum levels as well as an increased urinary calcium/creatinine ratio demonstrated an increased metabolic turnover of the bone. Haemoglobin concentrations, however, increased in those cases with fibroid-related anaemia. Thus the slow-release form of leuprorelin acetate is an adjunct to myomectomy especially in those women in whom family planning is not yet completed.

Plasma dehydroepiandrosterone in pregnant and nonpregnant women.

From 157 plasma samples taken randomly throughout normal pregnancy and from 42 plasma samples of nonpregnant women, total plasma dehydroepiandrosterone was measured by a method using Amberlite XAD-2 column chromatography at 45degreesC, enzyme hydrolysis, radioactive internal standard, thin-layer chromatography and gas-liquid chromatography after trimethylsilyl ether derivative formation. The following values for dehydroepiandrosterone were obtained: from individual, nonpregnant samples, (n = 25) 69.6 +/- 10.6 mug/100 ml (S.E.M.); from the pool of nonpregnant samples (n = 17) 67.7 mug/100 ml; from individual samples, 6-12 weeks of gestation (n = 32) 48.5 +/- 5.7 mug/100 ml (S.E.M.); from individual samples, 13-18 weeks of gestation (n = 13) 45.9 +/- 7.7 mug/100 ml (S.E.M.); from individual samples, 19-24 weeks of gestation (n = 20) 42.9 +/- 6.9 mug/100 ml (S.E.M.); from individual samples, 25-30 weeks of gestation (n = 22) 41.7 +/- 6.8 mug/100 ml (S.E.M.); from individual samples, 31-36 weeks of gestation (n = 31) 39.5 +/- 6.1 mug/100 ml (S.E.M.); from individual samples, 37-43 weeks of gestation (n = 29) 37.6 +/- 3.6 mug/100 ml (S.E.M.); and from the pool sample, 37-43 weeks of gestation (n = 10) 25.4 mug/100 ml. This study demonstrates a significant decrease of total plasma dehydroepiandrosterone throughout the course of normal pregnancy in individual and pooled plasma samples, thus confirming previous reports. These plasma hormone changes are discussed in relation to production and utilization of this steroid in pregnancy.

Post-menopausal bleeding: a study of more than 1000 cases.

This paper reports the cause, incidence of malignancies, certain clinical features, and the time lag between the bleeding and the establishment of its cause, in the 1019 cases of post-menopausal bleeding investigated by the Universitäts-Frauenklinik in Tübingen, West Germany, between 1969 and 1972. Although many of the patients had experienced just one post-menopausal bleeding before seeking medical help, and most reported that their bleeding(s) had been "light" and of short duration, a malignancy was found in 48% of the cases. The most common were cervical cancer (228 cases) and endometrial cancer (215). 31% of the cervical cancers and 12% of the endometrial cancers were in an advanced stage of development. A clear link emerged between increased age and the incidence of malignancies, but the paper shows the importance of any type of post-menopausal bleeding, however slight, being thoroughly investigated.

Aspects of progestin activity on the breast. European Progestin Club.

On 9-11 May 1997, the second Meeting of the European Progestin Club was held in Turin, Italy. Aspects of progestin use on the breast were discussed, based on the currently available scientific data. The paper covers topics addressed at the meeting and summarizes the recommendations which could be agreed on by the participants.

Recommendations for estrogen and progestin replacement in the climacteric and postmenopause. European Progestin Club.

The diversity of function that sex steroids have proven to have in the female body, gives them a position of central importance in gynaecology. Scientific research demonstrates not only the well known genital functions of sexual steroids, furthermore, various extragenital organs are influenced and modulated by ovarian hormones. Therefore, the general benefit of HRT for the female organism becomes clearer and the clinical management of menopause is developing to a broad new discipline, the gender specific medicine. In clinical practise, phytosteroids are claimed by the patient and therefore, also of high interest for the scientific research. Also, tissue specificity of the endocrine treatment and the biological relevance of different steroid receptors of HRT are discussed, leading to the development of new HrT preparations. Individualisation, the tailoring of HRT, according to the patients needs, and low dose steroids management, will also become an important aspect in the recommendations for estrogen and progestin replacement therapy.

A comparative study of the effects of the hemostatic system of two monophasic gestodene oral contraceptives containing 20 micrograms and 30 micrograms ethinylestradiol.

The effects of two oral contraceptives, containing gestodene and either 20 micrograms or 30 micrograms ethinylestradiol, on hemostatic parameters was investigated in a six-month randomized study involving a total of 40 healthy women between the ages of 18 and 30 years. A large number of hemostatic parameters were measured, which were categorized as either pro-coagulatory, anti-coagulatory, profibrinolytic, anti-fibrinolytic or indicative of fibrin turnover. Additionally, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) were measured before and after venous occlusion and delta and ratio values calculated. Pro-coagulatory factors as well as reaction products reflecting in vivo coagulatory activity (thrombin-antithrombin III complex, prothrombin fragment 1 + 2) were found to increase. Among the anti-coagulatory parameters, only protein S concentration and protein S activity decreased, most notably in the 30 micrograms EE group. There was a corresponding increase in fibrinolytic activity reflected by reaction products of in vivo fibrinolysis (plasmin-antiplasmin 2-complex, fibrin-degradation products). Measurement of t-PA and PAI-1, before and after venous occlusion, revealed that the fibrinolytic response was more pronounced in the 20 micrograms EE group. There was also an increase in the threshold of fibrinolytic inhibition (ratio PAI-1) in both groups, which was less pronounced in the 20 micrograms EE group. Apart from isolated measurements, all parameters remained within their normal ranges and values returned to baseline in the follow-up cycle. It is concluded that both preparations had a balanced effect on the hemostatic system stimulating both pro-coagulant and fibrinolytic activity. No statistically significant differences were observed between the two groups; however, there was a trend towards greater fibrinolytic capacity in the 20 micrograms EE group.

PIP: In Germany, 40 healthy women aged 18-30 with no contraindications to combined oral contraceptives (OCs) participated in a comparative study (2 pre-treatment cycles, 6 treatment cycles, and 1 post-treatment follow-up cycle). It aimed to assess the effect of the new low-dose monophasic OCs containing 20 mcg ethinyl estradiol (EE) and 75 mcg gestodene on the hemostatic system, the effect of reducing the EE dose from 30 mcg to 20 mcg, and the effect of this OC and another combined OC with 30 mcg EE on the fibrinolytic capacity at the vessel wall. Both OCs increased coagulatory and fibrinolytic parameters, except for isolated measurements, which remained within their normal ranges. The effect occurred as early as four days after beginning OC treatment. There was a general trend towards increased change during treatment. Within 14 days after stopping OC treatment, most parameters returned to baseline values. Protein C activity increased somewhat in both groups. Protein S activity was reduced in both groups, but the reduction was less in the 20 mcg EE group than in the 30 mcg EE group. There was a tendency towards greater plasminogen activator activity and lower plasminogen activator inhibitor activity in the 20 mcg EE group than in the 30 mcg EE group, suggesting increased fibrinolytic activity in the 20 mcg EE group. In both groups, an increase in the threshold of fibrinolytic inhibition occurred, but the increase was lower in the 20 mcg EE group. These findings suggest that both OC preparations have a balance effect on hemostasis, stimulating both pro-coagulant, anti-coagulant, and fibrinolytic activity. The 20 mcg EE OC tended to have a greater fibrinolytic activity than the 30 mcg EE OC, however.