Role of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) for prognosis in endometrial cancer.

BACKGROUND: Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) contribute to the invasiveness of many carcinomas. Here, we studied a possible association between cytosolic uPA and PA-1 concentrations in tumor tissue with prognosis in patients with endometrial cancer. METHODS: Cytosolic concentrations of uPA and PAI-1 were determined in 69 primary endothelial adenocarcinomas using an enzyme-linked immunoassay (ELISA). A possible influence of uPA and PAI-1 was studied by multivariate Cox regression adjusting for the established clinical prognostic factors FIGO-stage, grading, depth of invasion, diabetes mellitus and age. RESULTS: Both uPA (p=0.011) and PAI-1 (p=0.003) were associated with relapse free time using the multivariate proportional hazards model. Association with overall survival was less pronounced with p=0.021 for uPA and p=0.358 for PAI-1. Concentrations of PAI-1 increased with FIGO stage (p=0.003) and with histological grading (p=0.005). Both uPA and PAI-1 concentrations were negatively correlated with estrogen and progesterone receptor levels. CONCLUSION: The combination of high cytosolic concentrations of uPA (>5 ng/mg total protein) and high PAI-1 (>20 ng/mg total protein) may reveal a group of patients with increased risk of progression.

The rheological changes after cesarean section: The influence of low molecular weight or unfractionated heparin on the rheological properties of blood.

Thromboembolic complications remain an important cause of maternal mortality. The present recommendations favour for prophylaxis unfractionated (UFH) and low molecular weight heparin (LMWH). We investigated 150 pregnant women before and after cesarean section in three randomized groups. Fifty women received no prophylaxis (group I), 50 women UFH two times 5000 IU/day (group III) and 50 women Dalteparin 5000 U/day (group II). We determined the blood count, the rheological parameters and cholesterol, triglycerides, D-dimer, fibrinogen and the anti-Xa-level. We found a classical hemodilution, with increase of erythrocyte aggregation and plasma viscosity postoperatively. The fibrinogen turnover and D-dimer concentration were elevated. The patients with Dalteparin prophylaxis showed lower thrombin activation, minor changes in the cholesterol and triglycerides level and an improvement of red cell deformability in low shear regions. Our results demonstrated an influence of Dalteparin on the rheological parameters post surgery. The DVT incidence was 1.33% generally and occurred only in the Control group and in women with unfractionated heparin. We observed no side effects such as major bleeding, osteopenia or allergy.

[Severe virilization in a postmenopausal woman: a case report]. / Ausgeprägte Virilisierung in der Postmenopause -- eine Falldarstellung.

Severe postmenopausal virilization is a rare event in clinical practice. To evaluate ovarian or adrenal hyperandrogenism endocrine tests and imaging are useful diagnostic tools. We report a case of a postmenopausal woman with hirsutism and androgenetic alopecia. A malignant cause for the present disorder could be excluded by imaging. Selective venous sampling was administered with increased testosterone level of the right adrenal vein. Right adrenalectomy and right oophorctomy was recommended.

[Perinatal outcome of premature infants weighing less than 1500 g]. / Untersuchungen des perinatalen Zustandes bei frühgeborenen Kindern mit weniger als 1500 g.

BACKGROUND: Prematurity is a main issue in modern obstetrical care. The purpose of the present study was to evaluate the perinatal outcome of premature infants weighing less than 1500 g according to the mode of delivery. PATIENTS AND METHODS: 122 patients with infants weighing less than 1500 g were enrolled in this retrospective study (26 to 32 weeks of gestation). The perinatal outcomes of 26 infants born by vaginal delivery were compared to 96 infants delivered by caesarean section. RESULTS: The rates of rupture of membranes, preterm labour and intravenous tocolysis were significantly increased in patients after vaginal delivery. Preeclampsia and pathological cardiotocograms were increased in patients after caesarean section. Infants born by vaginal delivery showed a significant increase of peri- and intraventricular haemorrhage grade III, periventricular leukomalacia, C-reactive protein 24 hours postpartum and mortality until the seventh day of life. However, the rate of bronchopulmonary dysplasia was significantly increased in infants born by caesarean section (p < 0.05). CONCLUSIONS: These data suggest that the mode of delivery affects the perinatal outcome of infants weighing less than 1500 g. Based on the results of the present study, it appears unclear which mode of delivery should be preferred, depending on particular material and fetal factors.

[Inhibins and Activin A in hypertensive Disorders of Pregnancy and HELLP-Syndrome]. / Inhibine und Aktivin A bei hypertensiven Schwangerschaftserkrankungen und HELLP-Syndrom.

OBJECTIVE: Are serum concentrations of the ovarian glycoproteins inhibin A, inhibin B, pro-alpha-C and activin A different in normotensive, chronical hypertensive or pregancies complicated by preeclampsia or HELLP-syndrome? What are the clinical consequences? METHODS: Serum concentrations of inhibin A, inhibin B, pro-alpha-C, and activin A of 99 women (37 normotensive patients, 23 patients with chronical hypertension, 25 women with preeclampsia and 14 patients with HELLP-syndrome) at different stages of pregnancy were determined by high specific ELISAS. RESULTS: During pregnancy serum levels of all parameters increased continually and fell rapidly within parturition. Activin A and inhibin B levels showed significant higher serum concentrations in patients with preeclampsia and - even more pronounced - in patients with HELLP-syndrome. Normotensive and chronically hypertensive patients were not different. CONCLUSION: Activin A and inhibin A appear to be viable candidates as laboratory parameters for detection of pregnancy induced hypertension. Maybe furthermore both parameters will allow the discrimination between chronic hypertension and hypertension induced by pregnancy.

Early postpartum hyponatremia in a patient with transient Sheehan's syndrome.

In modern day health care, Sheehan's syndrome is a rare disorder affecting the postpartum period. We present a case of a 33-year-old woman with atonic hemorrhage developing a transient Sheehan's syndrome associated with hyponatremia six days postpartum. Evaluation of cranial computer tomography and magnetic resonance imaging of the pituitary demonstrated normal finding. Immediate replacement therapy using sodium, chloride, hydrocortisone, fludrocortisone and levothyroxine revealed regression of the Sheehan's syndrome to complete recovery. The present report shows that Sheehan's syndrome can be associated with hyponatremia and illustrates the need to include hyponatremia as an initial symptom in the differential diagnosis of Sheehan's syndrome.

Concentrations of inhibins and activin in women undergoing stimulation with recombinant follicle-stimulating hormone for in vitro fertilization treatment.

OBJECTIVE: To investigate the influence of human recombinant follicle-stimulating hormone (FSH) on circulating serum concentrations of the ovarian proteohormones inhibin A, inhibin B, pro alpha-C, and activin A and serum levels of estradiol after down-regulation with GnRH analogue. DESIGN: Serum concentrations of ovarian proteohormones and estradiol. SETTING: Academic clinical practice. PATIENT(S): 30 women who underwent assisted reproductive techniques. INTERVENTION(S): Blood samples were analyzed for inhibin A, inhibin B, pro alpha-C, activin A, and estradiol during IVF treatment at points coinciding with pituitary down-regulation, stimulation with recombinant FSH, ovulatory triggering, and the luteal phase of the cycle. RESULT(S): Activin A levels did not change with recombinant FSH stimulation. In women with a sonographically detected leading follicle >17 mm in diameter, levels of inhibin A, pro alpha-C, and estradiol increased significantly (P<.05). The increase in inhibin B level was not statistically significant. In patients without adequate follicle development during FSH stimulation, serum levels of inhibins remained low and did not significantly deviate from values measured before stimulation. CONCLUSION(S): Inhibin A and pro alpha-C are effective markers of follicular development and may be effective additions to estradiol as a marker.

Inverse correlation between baseline inhibin B and FSH after stimulation with GnRH: a study of serum levels of inhibin A and B, pro alpha-C and activin A in women with ovulatory disturbances before and after stimulation with GnRH.

OBJECTIVE: Interest has focused recently on the influences of the polypeptide factors inhibin and activin on the selective regulation of the pituitary secretion of gonadotropins. DESIGN: Measurement of the concentrations of inhibin-related proteins in relation to the changes in pituitary gonadotropin (FSH, LH) parameters, after GnRH stimulation with a bolus injection of 100 microg gonadorelin, in 19 women with ovulatory disturbances. METHODS: Serum levels of inhibin A and B, activin A, and pro alpha-C were measured using sensitive ELISA kits. RESULTS: Within 60 min after GnRH stimulation, FSH values doubled from 5 to 10 mU/ml (P < 0.001). LH increased 12-fold from 2 to 24 mU/ml (P < 0.001). Activin A showed a significant decrease from 0.47 to 0.36 ng/ml (P < 0.001), whereas pro alpha-C increased from 127 to 156 pg/ml (P = 0.039). The median inhibin A concentration did not show a significant change between baseline and the 60 min value, whereas inhibin B was characterized by a minor, but not significant, increase in the median from 168 to 179 pg/ml (P = 0.408). A significant inverse correlation (P = 0.014) with a mean coefficient of correlation of 0.5516 was found, demonstrating a strong relationship between high inhibin B baseline levels and a small increase of FSH after 60 min. CONCLUSION: Our results show an interesting correlation between the baseline inhibin B and the change in FSH before and after GnRH stimulation. A high baseline inhibin B implies only a minor increase of FSH after 60 min.

[P53-status in primary ovarian carcinomas, ovarian metastases of neoplasms in other sites and benign ovarian tumors: predictive value in comparison to histopathological parameters]. / P53-Status in primären Ovarialkarzinomen, Ovarialmetastasen von Fremdtumoren und benignen Ovarialtumoren: Wertigkeit als Prognosefaktor im Vergleich zu histopathologischen Parametern.

OBJECTIVE: The purpose of this study was to determine whether the tumor suppressor gene p53 can be used as a prognosis factor to assess individual patient risk in primary ovarian carcinoma. MATERIALS AND METHODS: The concentration of the mutated, as well as the wild type p53 was examined in 98 cases of ovarian carcinoma. Among 98 ovarian tumors examined, 77 were primary carcinomas, 14 tumors were metastasis of foreign tumors, and 7 were benign ovarian tumors. The pan-53 ELISA from Fa. Dianova was used to test for the p53 protein. RESULTS: The p53 protein concentration exhibited a wide range in the different tissue samples. Benign tumors contained significantly lower p53 concentrations than malignant tumors. After the data was analyzed using Kaplan-Meier, a p53 concentration of 507.1 pg/ml was established as cut-off point for assessing cancer prognosis as good or poor. Patients exhibiting p53 concentrations over 507.1 pg/ml had a median life expectancy of 20 months, and patients exhibiting lower tumor concentrations of p53 had a life expectancy of over 70 months. A significant relationship between patient life expectancy could also be shown for tumor stage and type, whereas not for tumor grading. CONCLUSIONS: Based on the results of this study, the routine measurement of p53 may allow for a better prognostic assessment of life expectancy of patients with primary ovarian carcinoma.

[Needle biopsy vs. conventional surgical biopsy - biochemical analysis of various prognostic factors]. / Vergleich der biochemischen Analyse verschiedener Prognosefaktoren zwischen Stanzbiopsie und intraoperativ gewonnenem Tumormaterial beim Mammakarzinom.

OBJECTIVE: In which way is the biochemical analysis of fine needle biopsy comparable to the biochemical analysis of conventional surgical biopsy samples in the examination of prognosis factors in mammary carcinomas. MATERIAL AND METHODS: Conventional surgical biopsy and fine needle biopsy were performed on 63 mammary carcinomas. The results from the biochemical analysis of tissue samples, from each form of biopsy, with respect to estradiol and progesterone receptor, UPA and PAI-1, as well as Kathepsin D and the EGF receptor, were compared and statistically analyzed. RESULTS: When compared to conventional tissue biopsy samples, the sensitivity and specificity of the measured prognosis factors in fine needle biopsy tissue were variable for each parameter, but fell within the statistically safe margin of 86 to 100%. CONCLUSIONS: The biochemical analysis of the prognosis factors found in fine needle biopsy samples showed that fine needle biopsy is a viable alternative to intraoperative conventional surgical biopsy.

[Value of p53, urokinase plasminogen activator, PAI-1 and Ki-67 in vulvar carcinoma]. / Untersuchungen zu p53, UPA, PAI-1 und Ki-67 beim Vulvakarzinom.

OBJECTIVE: The present study was to measure new prognostic factors including the plasminogen activator urokinase and the plasminogen inhibitor PAI-1, as well as p53 and Ki-67, a marker of proliferation and to compare the clinical value of these in relation to the classic histopathological prognostic factors. MATERIAL AND METHODS: The patient collective included 45 patients with vulvar carcinoma, both primary tumors and recurrences. RESULTS: Highly significant correlations were found for tumor diameter and thickness. According to Kaplan-Meier estimations, the influence of thickness on the prognosis had a p-value of 0.048, while the influence of diameter had a p-value of 0.029. The variable grading was also significantly associated to the probability of survival (p = 0.01). There was no statistically significant correlation between p53 and the parameters grading, degree of keratinization and Ki-67 color index. The correlation between p53 and PAI-1 as well as between UPA and PAI-1 was highly significant. According to the Kaplan-Meier estimations, Ki-67, UPA and PAI-1 had no influence on survival in our group of patients. CONCLUSIONS: For p53, the median value could be used as a divider with the median survival of patients with a p53 below 122 pg/mg protein being 151 months and with a p53 above 122 pg/mg being only 61 months. The corresponding p-value was significant at 0.0201.

Urokinase and plasminogen activator-inhibitor (PAI-1) status in primary ovarian carcinomas and ovarian metastases compared to benign ovarian tumors as a function of histopathological parameters.

Ninety-eight patients with histologically confirmed ovarian tumors (77 primary ovarian carcinomas of stages T1 to T3 according to the postoperative histopathological classification pTNM classification, 14 ovarian metastases of various origins and seven benign ovarian tumors) were investigated with regard to the concentration of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) in membrane extracts of tumors. The results were correlated with the clinical course and with histopathological findings. With more advanced stage of primary ovarian carcinomas, there was a highly significant rise in the membrane concentrations of both uPA and PAI-1. However, increasing dedifferentiation of the tumors correlated only with uPA, but not with PAI-1. There was no correlation between the number of steroid receptors for estradiol and progesterone and the content of uPA or PAI-1 in the primary ovarian carcinomas. In the 14 ovarian metastases of different origins incluced in the study, the contents of uPA and PAI-1 were comparable to those of primary ovarian carcinomas. Compared with the malignant ovarian tumors, the median uPA and PAI-1 concentrations in the membrane fraction were 2.5-6 fold lower (highly significant) in the group of seven benign tumors. A cut-off value of 4.8ng/mg pellet protein for a prognostically favorable (< 4.8) or unfavorable course (> 4.8) could be determined for uPA (p = 0.0392) but not for PAI-1 on the basis of the Kaplan and Meier survival curves in the malignant primary ovarian carcinomas.

Chemotherapy and thrombosis in gynecologic malignancy.

Thromboembolism is a severe and frequent problem in gynecologic malignancy. The average DVT incidence during chemotherapy of 5% might represent the lower range of incidence because < 55% of thrombotic complication manifest clinical signs. However, it seems likely that in addition to chemotherapy other risk factors such as menopausal status, BMI of patients, or type of preceding surgery must coincide before thrombosis manifests. While monitoring of patients using sophisticated coagulation tests did not identify patients' risk for DVT during chemotherapy, an evaluation of the coagulation status before initiating chemotherapy is recommended. Patients with a venous access device (e.g., indwelling central venous catheter or with port cart) are at a particularly high risk for DVT. This has to be considered when cytoreductive therapy is given. Thrombosis prophylaxis, orally or subcutaneously, should only be considered in a subpopulation of patients who offer a combination of the aforementioned risk factors. Thrombosis prevention trials during chemotherapy found a significant reduction of DVT in patients treated with anticoagulants.

[Circadian blood serotonin and melatonin level in anorexia nervosa patients in comparison with normally menstruating women]. / Zirkadiane Serotonin- und Melatonin-Serumspiegel bei Anorexia-nervosa-Patientinnen im Vergleich zu normal-menstruierenden Frauen.

Day and night rhythms of melatonin and serotonin were measured in four female anorexia nervosa patients and for comparison in a control group with normal 28-day menstrual cycle. In the anorexia nervosa group the levels of gonadotropins and sexual steroids were distinctly lowered. In the LHRH test the hormonal profile showed pubertal to prepubertal patterns of secretion with an only moderate increase of LH and distinct shifting of the LH/FSH ratio in direction of FSH. For both groups the 24-hour profiles of melatonin and serotonin showed a normal cycle, i.e. melatonin had its maximum by night, whereas serotonin in contrast displayed its highest values by day. However, in the group of patients with anorexia nervosa the maximum of melatonin was on the average 2.1 fold higher than that found in the control group, whereas that of serotonin was 1.4 fold higher. A close functional coherence between the neurotransmitters melatonin and serotonin and the hypothalamic secretion of LHRH is being discussed.

Effects of TNF-alpha and retinoic acid on the proliferation of the clear cell and chromophilic types of human renal cell carcinoma in vitro.

Since no effective therapeutic approach is known so far for metastatic renal cell carcinoma (RCC), we analyzed the anti-proliferative effects of TNF-alpha and retinoic acid (RA), applied either alone or in combination on 7 different RCC cell lines in vitro. In 5 out of 7 cell lines, a significant (p < 0.05) dose-dependent inhibition of tumor cell proliferation became evident after exposure to TNF-alpha, the response being of modest magnitude in 5 cell lines. In 2 cell lines the effects were more pronounced with a reduction of cell viability to 55 +/- 11% of the control. Northern blot analysis revealed no expression of TNF-alpha and p75 TNF-receptor in any cell line. All the cell lines showed p55 TNF-receptor mRNA. Scatchard analysis revealed no correlation between TNF-alpha receptor status and growth inhibitory response to TNF-alpha, the number of TNF-receptors per cell ranging from 0 to 3,976, and the affinity values from Kd = 0.621 nmol/l to Kd = 4.28 nmol/l. Exposure to RA alone resulted in significant (p < 0.05), but modest growth inhibition in 2 out of 7 cell lines with a reduction of cell viability to 83 +/- 1% of the control. In 2 out of 7 cell lines, combination of RA and TNF-alpha was significantly (p < 0.05) more effective than the single application of each compound. Northern blot analysis revealed no transcripts of CRABP I and retinoic acid receptor (RAR)-beta. All the cell lines expressed RAR-alpha mRNA and one cell line additionally expressed RAR-gamma mRNA. A correlation between RAR status and RA response was not seen.

[Hormone receptor determination in breast carcinoma tissue. Comparison of recent immunohistologic techniques with biochemical receptor testing]. / Hormonrezeptorbestimmung am Mammakarzinomgewebe. Vergleich neuer immunhistologischer Techniken mit der biochemischen Rezeptortestung.

For evaluation of the hormone receptor status in breast cancer tissues two methods are mainly used: immunohistochemical detection by monoclonal antibodies on frozen sections (ER-ICA, PgR-ICA) and the biochemical radioligand-binding assay (DCC) of fresh tissue. Using new antibodies makes it possible to evaluate the estrogen and progesterone receptor status in formalin-fixed and paraffin-embedded tissue. In the present retrospective study, tissues from 223 primary breast carcinomas or breast carcinoma recurrences were re-evaluated with the three methods mentioned above and the results were compared. We used antibody 1D5.26 reacting with the estrogen receptor and mPR1 specific for the progesterone receptor in paraffin-embedded tissue. The agreement of positive and negative cases between these two immunohistochemical procedures was 97.8% for the estrogen receptor and 85.7% for the progesterone receptor. Comparison of immunohistochemistry on paraffin-embedded tissue and biochemical evaluation showed an agreement of 74.7% for the estrogen receptor and 68.7% for the progesterone receptor. These results are comparable to the correspondence between ER-ICA and PgR-ICA and the DCC method. This study proves that the prognostically and therapeutically important hormone receptors can be reliably determined in formalin-fixed and paraffin-embedded tissues. These results are not only important for the evaluation of hormone receptors of a small breast carcinoma that is not found in the frozen section, but for the considerable difference in costs among the different methods.

[Synthesis and reactions of 2-methylene-canrenone]. / Darstellung und Reaktionen von 2-methylen-canrenon.

Starting from the Mannich salt 1 of the aldosterone antagonist canrenone or from 2-methylene-canrenone (2) the A-ring annulated hetero- and carbocycles 5, 6, 8-13 were prepared. Receptor (estradiol, progesterone, androgen, gluco- and mineralocorticoid) binding studies and competition studies with the serum proteins SHBG and CBG were carried out using the compounds 2, 3, 4b, 5, 6b, 8 and 12. The relative binding affinities with CBG are below 1%, in all other cases lower than 0.01%.

[Heterocyclic annulated steroids from 2-hydroxymethylene-canrenone]. / Heterocyclisch anellierte Steroide aus 2-Hydroxymethylen-canrenon.

A-ring annulated heterocycles, the isoxazole 6, the pyrazoles 8 and the pyrimidines 9 are prepared starting from 2-hydroxymethylene canrenone 1. Binding studies were carried out with the compounds 1 and 6-8 using estrogen, progesterone, androgen, gluco- and mineralocorticoid receptors as well as the serum proteins SHBG and CBG: the substances were inactive on the receptor level. 1, 7 and 8a show weak binding affinity to CBG.

Immunohistochemical detection of hormone receptors in breast carcinomas (ER-ICA, PgR-ICA): prognostic usefulness and comparison with the biochemical radioactive-ligand-binding assay (DCC).

In a prospective study conducted since 1983, the hormone-receptor status of primary breast carcinomas was investigated using immunohistochemical (ER-ICA, PgR-ICA) and biochemical (DCC) methods. The degree of immunohistochemical staining was evaluated according to the immunoreactive score (IRS) devised by Remmele and Stegner [Frauenarzt 28, 41-43 (1987)]. The findings obtained using the biochemical radioactive-ligand-binding assay (cutoff level, 20 fmol/mg) and those obtained using qualitative immunohistochemical methods were in agreement in 72.5% (ER-ICA) and 72.2% (PgR-ICA) of cases. For the 789 cases of primary breast carcinoma examined, postoperative data were available for a mean follow-up period of 48 months. Using the statistical procedure of Kaplan-Meyer to analyze the probability of disease-free and overall survival, it emerged that ER-ICA- and PgR-ICA-positive breast carcinomas exhibited the most favorable course of disease. Breast carcinomas with negative immunohistochemical findings for both types of receptor were found to have a significantly less favorable disease course. Semiquantitative evaluations of the staining results using the IRS failed to yield significant differences among the 12 IRS groups. Neither the percentage of positive tumor cells nor the immunohistochemical staining intensity proved to be prognostically useful parameters for predicting the course of disease. In comparison to the established biochemical method for the demonstration of hormone receptors, however, the immunohistochemical procedure was found to be superior with respect to prognostic meaningfulness, particularly in the group with conflicting biochemical and immunohistochemical findings with respect to hormone-receptor status. Using Cox analysis, the prognostic usefulness of the immunohistochemical test was compared with that of certain established prognosis parameters (pT, pN, grading, Ki-67), from which it became apparent that PgR-ICA has the greatest prognostic value, with the most lasting influence on the course of disease. The results of the present study demonstrate that, with respect to the prognostic value of its findings, the immunohistochemical test for hormone receptors is superior to the biochemical procedure.

Receptor binding of norgestimate--a new orally active synthetic progestational compound.

Binding of the new progestagen, norgestimate (D-(-)-13 beta-ethyl-17 beta-acetoxy-17-ethinyl-4-gonen-3-one-oxime), and its metabolites (levonorgestrel-3-oxime, levonorgestrel-17-acetate and levonorgestrel) to the progesterone receptor was investigated by competition experiments using cytosol from human myometrial tissue. Compared to R5020, a highly potent synthetic ligand for progesterone receptor analysis, the L-isomer of norgestimate shows only a weak specific behaviour with regard to binding to the progesterone receptor from uterine cytosol with an RBA value of 0.8%, whereas the D-isomer of this compound is characterized by a lack of binding activity to the progesterone receptor. Levonorgestrel-3-oxime, one of the possible metabolites of norgestimate, binds to the progesterone receptor with an RBA value of 8%, whereas levonorgestrel-17-acetate, the other possible metabolite of norgestimate, binds with a binding affinity of 110% which is in the same order of magnitude as levonorgestrel itself. The competition experiments suggest that norgestimate is a prodrug and that the metabolites, levonorgestrel and levonorgestrel-17-acetate, which actively bind to the progesterone receptor, must first be formed from the parent drug via metabolic processes in vivo. These are the actual biologically active compounds which are responsible for the gestagenic potency.