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In this study, we used novel synthetic conditions of precipitation polymerization to obtain nanosized cyproterone molecularly imprinted polymers for application in the design of new drug delivery systems. The scanning electron microscopy images and Brunauer-Emmett-Teller analysis showed that molecularly imprinted polymer (MIP) prepared by acetonitrile exhibited particles at the nanoscale with a high degree of monodispersity, specific surface area of 246 m(2) g(-1), and pore volume of 1.24 cm(3) g(-1). In addition, drug release, binding properties, and dynamic light scattering of molecularly imprinted polymers were studied. Selectivity of MIPs was evaluated by comparing several substances with similar molecular structures to that of cyproterone. Controlled release of cyproterone from nanoparticles was investigated through in vitro dissolution tests and by measuring the absorbance by HPLC-UV. The pH dissolution media employed in controlled release studies were 1.0 at 37 °C for 5 h and then at pH 6.8 using the pH change method. Results show that MIPs have a better ability to control the cyproterone release in a physiological medium compared to the non molecularly imprinted polymers (NMIPs).

Progesterone plays a central role in the mechanisms of parturition in many species. Despite remarkable advances in our understanding of this hormone's mechanism of action, its roles in human pregnancy maintenance and parturition are not fully appreciated. Proper scientific hypothesis testing of progestins to prevent preterm birth has been limited because of the issues that can plague interventional trials in obstetrics, including patient selection, choice of outcome and power. The largest studies enrolling patients with a history of prior preterm birth alone to prevent recurrence appear contradictory. In contrast, consistent evidence from one multinational trial and a secondary analysis of another suggests cervical length may serve to identify potential responders to this therapy. Finally, the safety of progestin administration is a legitimate concern and a meta-analysis justifies the need for further investigation of safety issues. This review presents recent findings regarding progestin therapy from both clinical and laboratory data and considers unresolved issues for use of these agents.

The aim of this study was to enhance the transdermal absorption of the highly active progestin gestodene from matrix type transdermal delivery systems (TDDS) by formation of prodrugs with improved matrix solubility.Gestodene esters were synthesized via acylation of the drug with the respective carboxylic anhydrides. Subsequently TDDS were produced using the solvent cast method. Selected formulations were examined with in vitro diffusion experiments using skin of nude mice.One prodrug, gestodene caproate proved to be an oil at ambient temperature and showed a very high solubilty of over 10.5% in the TDDS matrix. Within in vitro penetration studies using those systems the prodrug exhibited a significantly higher transdermal penetration rate than gestodene from reference systems. Furthermore, the prodrug was hydrolyzed to the parent drug to a high extent during the passage of the skin.Designing prodrugs to the requirements of matrix TDDS is an efficient way of enhancing the transdermal drug flux rate.

In the development of the obstructive symptomatology of benign prostatic hypertrophy (BPH), two components may be identified, mechanical and dynamic. In the mechanical component, the interaction of a stromal and a epithelial compartment determines prostatic mass growth. The dynamic component involves smooth muscle tone in the prostate and urethra. The consideration that prostatic disease is not only epithelial in origin, but also stromal, leads to the association of an antiandrogen (which acts on the epithelial component) and an antiestrogen (active on the stromal component) in the medical therapy of BPH. In 1985 we carried out a randomized study on 256 BPH patients treated with Cyproterone acetate (CPA) plus Tamoxifen (TAM). Recently, we performed a multicenter double blind study on BPH patients treated with the association CPA plus Serenoa Repens. A statistically significant difference in prostate volume reduction between the groups treated with the combinations and those with the monotherapies was observed. The development of new compounds, such as 5 alpha reductase and aromatase inhibitors, consents to introduce a combination therapy with less side effects. A second pharmacological association may be obtained with drugs acting on the mechanical and others acting on the dynamic (alpha blockers) component of BPH. This combination may associate the early symptomatic effect of alpha blockers with the long term results of a 5 alpha reductase inhibitor, antiestrogen or aromatase inhibitor.

Various non-surgical therapeutic modalities such as balloon dilation of the prostatic urethra, hyperthermia of the prostate and medication with antiandrogens and/or adrenergic blockade have been attempted for the patients with benign prostatic hyperplasia (BPH) especially in an early stage or in a poor operative risk. The observation that androgen deprivation induces shrinkage of the hyperplastic prostate represents the basis for the treatment of BPH with antiandrogen. Although several antiandrogens are now in clinical use in our country, there still remain problems to be solved. We reviewed the mechanism of action and the clinical results of antiandrogens in the treatment of BPH. The improvement following antiandrogen therapy occurred among the patients with symptomatic BPH, in 50-80% subjectively and in 40-50% objectively. The therapy appeared to be more effective in an early stage of the disease. However, the limitation of the duration of the effects and unfavorable side effects should also be noticed. The progestational agents such as gestonorone caproate, chlormadinone acetate and allylestrenol suppress more or less sexual function by interference of the pituitary-gonadal axis. Besides, coincidental prostate cancer must be excluded since antiandrogen therapy might hinder the natural course of the cancer.

Summary. Guanosine 3′:5′-phosphate (cyclic GMP) in urine has been used to monitor the response of patients with ovarian cancer to treatment. Changes in the cyclic GMP level appear to correlate well with clinical status in that the disappearance of clinically detectable tumour is associated with a drop in the level whereas a tumour recurrence is associated with an elevation. Serially measured cyclic GMP is valuable for detecting a recurrence of tumour growth in patients in clinical remission and can predate any clinical signs by as much as 10 months. In patients who show no response to treatment, cyclic GMP levels in urine are elevated in the majority of specimens collected.

Ten female patients with a history of recurrent aphthous lesions for at least 5 years with the lesions occurring regularly in the latter half at the menstrual cycle were treated with progestogen in the form of an intramuscular depot injection. Medroxyprogesterone acetate and gestronol hexanoate was used. All 10 patients were satisfied with the treatment; the side effects were few.

SummaryA study was carried out in 30 male patients with benign prostate hyperplasia to assess the effectiveness of treatment with a progestational agent, gestonorone caproate (200 mg), given intramuscularly every 7 days over a period of 2 to 3 months. The results showed definite subjective and objective improvement after treatment. Residual urine determination diminished significantly after therapy in 78% of the 28 cases completing the study; uroflometry also showed improvement. There appeared to be some reduction in the degree of occlusion of the urethral lumen in at least 13 (65 %) out of20 patients given follow-up cystopanendoscopy after 6 months. This result was further supported by improvement in urinary flow rates and uroflometrograms in the same patients. The only adverse effect of treatment noted was the development ofimpotency in 21 patients.

Fifty-four patients with advanced cystadenocarcinoma of the ovary were treated with gestronol (Depostat), 200 mg/week, by intramuscular injection and continuous oral cyclophosphamide, the dose of the latter being varied to maintain the patient's white cell count at about 1.5 x 10(9)/l. A combined partial and complete remission rate of 76 per cent was obtained. The length of survival depended upon the type of remission and the type of remission was markedly affected by the amount of tumour removed at initial laparotomy.

A placebo-controlled study with progesterone compound, 17-alphahydroxyprogesterone 17-n-caproate (Primostat), in 39 patients with benign enlargement of the prostate is reported. Statistical analysis of the results showed no evidence of significant improvement in patients receiving hydroxyprogesterone-caproate. No evidence of an effect as compared with the placebo was found when the residual urine, prostatic size, and histologic and ultrastructural changes of the removed prostatic gland in 6 of the patients, and in the luteinizing hormone, follicle-stimulating hormone, and estrogen urine levels in 21 patients were examined. Subjective effects, when carefully analyzed, provided some beneficial evidence, however not substantiated, when the patients' mode of voiding was carefully watched. The reported beneficial subjective improvement might be attributed to the enhancement of the beta-adrenergic response by the progesterone compound of the adrenergic receptors in the posterior urethra and bladder, presumably causing relaxation of its smooth muscle. The problems associated with the choice and measurement of parameters to be used in this type of investigation are discussed, and the absolute necessity of proper controls, statistical analysis, and close follow-up of the patients is pointed out.

Summary. Fifty-nine patients with proven stage I adenocarcinoma of the uterine corpus were treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by gestronal hexanoate intramuscularly for 3 months and then medroxyprogesterone acetate orally for a prolonged period. In the 7-year period of study, there were no vaginal recurrences, but one patient suffered a recurrence in the inguinal lymph nodes and pelvis. Undesirable side effects did not occur. These results compare favourably with other reported studies in which surgery and radiotherapy were used.

Summary In twenty patients, Stage I endometrial carcinoma was diagnosed by curettage and treated with gestonorone caproate given systemically, prior to hysterectomy. The histological appearances of the tumours before and after treatment were compared and were related to the total dose of progestogen given. In general, regression of the tumour was noted together with increase in differentiation, particularly of tumours initially showing some degree of differentiation. The future of progestogens in the treatment of endometrial carcinoma is discussed.

The effect of Depostat has been evaluated by the aid of cystotono-sphincterotonometry in 30 subjects with prostatic adenoma of early and advanced stages. The objective clinical benefits provided by the drug result from an increase in detrusor tonicity, a reduction in the opening pressure of the neck of the bladder and from a regulatory influence on the disturbed coordination of the detrusor-sphincter system.

A clinical evaluation of nor progesterone caproate (Primostat) suggests that this drug has a limited place in the treatment of bladder neck obstruction due to benign prostatic hyperplasia.

Summary. Women with ovarian adenocarcinoma who were treated with high dose progestogens showed subjective and objective improvements during treatment.

A comparative study was conducted to assess the effects of estrogen or progestogen therapy on bone loss in postmenopausal women. 35 women who were suffering from menopausal symptoms and having had no period for at least 6 months were randomly assigned to receive estrogen progestogen or placebo therapy. Mestranol was the estrogen used in the test; gestronol hexanoate was the progestogen. The placebo-treated patients lost a significant among of bone during the year of the study. Bone mineral loss seems to have been prevented by both the estrogen and the progestogen therapy. The estrogen seems to work by reducing bone resorption while the progestogen works by increasing bone formation. This suggests that the ideal preparation to prevent bone loss might be a combination of the 2 hormones. This suggestion needs further research however. It would have to be determined whether there is any interaction between the effects of the 2 when given in combination.

A pilot study with adjuvant hormone therapy in FIGO stage I endometrial carcinoma with myometrial invasion was carried out. All patients received total abdominal hysterectomy and bilateral salpingo-oophorectomy plus complementary radium therapy on the vaginal stump. After the conventional treatment, patients were randomly allocated to adjuvant hormone therapy or no further treatment. Hormone therapy consisted of gestonorone caproate (17α-hydroxy-19-norpregn-4-en 3,20 dione caproate) administered i.m. at the dose of 200 mg/week for 1 year. Of the 62 patients who entered the study, 51 were considered evaluable (24 with adjuvant hormone therapy and 27 with no further treatment). Five patients had a relapse: four of these were in the group with no further treatment. Actuarial relapse-free survival analysis at 5 years was 95.7% in the group of adjuvant-treated patients and 82.8% in the control group. Although there is no statistical significance, adjuvant therapy appears to result in an increase in relapse-free survival in the group of patients with deep myometrial invasion and undifferentiated carcinoma. Further studies are necessary to assess the effectiveness of hormone adjuvant treatment in FIGO stage I endometrial carcinoma with myometrial invasion.

Six human endometrial cancers in different clinical stages were xenotransplanted into thymusaplastic nude mice. Estrogen and progesterone receptors in the tumor tissue were determined in each case. Two carcinomas with both estrogen and progesterone receptors showed a better clinical course and grew more slowly in nude mice than the four carcinomas with no receptors at all. Treatment with the antiestrogen Tamoxifen in the carcinoma with positive estrogen receptors showed a significant growth retardation compared with the control group. Estrogen treatment gave accelerated growth, whereas gestagen treatment showed no significant effect. The progesterone receptor content of the receptor-positive tumor tissue might have been too small. None of the four receptor-negative carcinomas showed any influence of tumor growth during endocrine therapy. The results demonstrate the importance of receptor determination as a prognostic sign and, further, allow the endocrine therapy of endometrial carcinomas to be complemented with Tamoxifen in estrogen-receptor-positive tumor tissue.

Selective uptake of H3-testosterone in human benign prostatic hypertrophy (BPH) has been demonstrated by in vitro and in vivo studies. 5α-dihydrotcstosteronc and 5α,3α-androstanediol are by far the major metabolites of testosterone. Progesterone and gestonorone capronate are competitive inhibitors of testosterone metabolism in BPH. These progestagens are taken up in preference to testosterone into prostatic cells. The subsequent formation of dihydrotestostcronc is inhibited, whereas cyproterone acetate does not influence the reduction of testosterone. Animal studies support the concept that this antiandrogcn acts by interfering with the binding of dihydrotestosterone to an intranuclear receptor.

Glucose tolerance test (oral standard glucose tolerance test) was carried out--before starting radiotherapy--in 99 female patients suffering from inoperable cancer of the genitals. 47 of these patients were administered gestonoroncapronate (600 mg/week) during radiotherapy. Glucose tolerance was tested anew after the last irradiation. During the first hour after the second glucose tolerance test, an improvement of glucose tolerance was stated in the patients' group treated with gestonoroncapronate, whereas during the second hour a deterioration of glucose tolerance was found. The patients' collective treated without gestonoroncapronate demonstrated an improved glucose tolerance during the entire second course of the test. A decrease of capacity of the islet cell organ, induced by gestonoroncapronate, is discussed.

Summary 18 patients with obstructive benign prostatic hypertrophy were studied. A 5-day treatment with gestonorone caproate (200 mg daily and 200 mg on alternate days) and cyproterone acetate (300 mg daily) suppressed the plasma LH and serum LH levels. Subsequently, H3-testosterone was injected intravenously and its elimination from plasma and uptake and metabolism in the BPH tissue studied. The elimination of total radioactivity and H3-testosterone from plasma was not altered after the 3 treatment regimens as compared to the control group. The uptake of total radioactivity into BPH tissue and its intraprostatic metabolism particularly to dihydrotestosterone was significantly suppressed in the patients with daily injections of gestonorone. Cyproterone acetate and gestonorone caproate on alternate days did not cause this effect. Supported by the Helmut Horten Foundation.

58 women with raised serum prolactin levels and normal hypophyseal X-ray parameters were subdivided into three groups according to the serum prolactin level (16 to 40, 41 to 80, greater than 80 ng/ml). In addition to the determination of LH, FSH, oestradiol, progesterone and testosterone in the serum and thyroid diagnostic procedures the following hormonal tests were performed: 1. response to gestagen; 2. response to clomiphene; 3. Gn-RH-test for hypophyseal function; 4. ovarian response to administered gonadotropins (only in cases with prolactin levels administered gonadotropins (only in cases with prolactin levels greater than 80 ng/ml). The grade of menstrual cycle disorders depends on the severity of the observed hyperprolactinaemia. Slight disorders like luteal phase insufficiency, anovulatory cycle and oligomenorrhoea are associated with low- or medium-grade hyperprolactinaemia. Mainly secondary, but also primary amenorrhoea is found in cases with higher serum prolactin levels (greater than 80 ng/ml). In these cases the hypophyseal response to Gn-RH is frequently found (61%) to be negative and, moreover, the ovarian response to administered gonadotropins seems to be diminished. Increasing HPRL levels often appear to be associated with a negative response to the other above-mentioned tests.

The mechanism of action of weight reduction of the ventral prostate by gestonorone caproate (GC) in rats was studied. GC was subcutaneously injected (100 mg/week/rat) for 3 weeks in normal rats, castrated rats, castrated rats treated with testosterone propionate (TP, 0.03–0.24 mg/2 days/rat) and hypophysectomized rats treated with human chorionic gonadotropin (hCG, 4 IU/day/rat). The following results were obtained. In normal rats, weights of the prostates and seminal vesicles and serum levels of testosterone (T) were decreased significantly by treatment with GC (about half of the non-treated controls), whereas the weights of testes, spermatogenesis and 5α-dihydrotestosterone (DHT) receptor in the cytosol of the prostate remained unchanged. In castrated rats without TP treatment, weights of prostates and serum luteinizing hormone (LH) levels were similar in both groups of rats, whether treated with GC or not. In castrated rats treated with TP, weights of prostates and seminal vesicles showed no significant decrease under treatment with GC but serum LH levels decreased significantly. In hypophysectomized rats treated with hCG, prostate weights and serum T levels were similar in both groups. In addition, GC did not compete for [ 3 H]-DHT binding sites in cytosol from rat prostate. From these results it can be concluded that the decrease of prostate weight by GC treatment is due mainly to the reduction of LH and testosterone secretion, but not to a direct inhibitory effect of GC on target cells for gonadotropins and androgens.

Early results of a prospective, randomized trial of active, specific immunotherapy adjunctive to nephrectomy in all stages of RCC are presented. Forty-three patients with median followup of 30 m, who were randomly allocated to either immuno-hormonotherapy arm (IMT), or hormonotherapy alone (HT), are evaluated in terms of progression-free interval (PFI) and overall survival by life table method. Immunotherapy consisted of autologous irradiated tumor cells (AITC), admixed with bacillus Calmette-Guérin (Glaxo) administered by the intradermal and endolymphatic route. Clinical results of this study show only a trend for advantage of the experimental (IMT) arm over the control (HT) arm, this trend did not reach statistical significance level: prolongation of disease free period in stages I-III with localized disease (p less than 0.1) and prolongation of survival in patients with metastatic disease (p less than 0.07). A correlation was established between induction of cutaneous delayed hypersensitivity (DTH) to AITC and prolonged PFI and survival: patients with positive DTH had a significantly better course of disease than those who could not be converted to positivity after repeated immunizations. Positive in vitro leukocyte migration inhibition against autologous tumor preparations correlates well with positive in vivo cutaneous DTH. Some immunological aspects of active immunization with autologous tumor cells are discussed.

As previously reported, ovarian epithelial carcinomas may respond to endocrine therapy. We examined the direct effect of progesterone, medroxyprogesteroneacetate, gestoneron, 17-beta-estradiol, tamoxifen, 4-OH-tamoxifen, or N-desmethyltamoxifen on the proliferative capacity of ovarian carcinoma cells by means of the colony assay described by Hamburger and Salmon. The growth rate of 25 tested tumors (ascitic fluid, primary tumor, metastases) was 68%. The plating efficiency was 0.078%. Beside the drug testing estrogen and progesterone receptor levels were determined. The inhibition of colony survival was slightest with 17-beta-estradiol, more pronounced with medroxyprogesteroneacetate, gestoneron, N-desmethyltamoxifen, and progesterone, and greatest with 4-OH-tamoxifen and tamoxifen. Significant and dose-dependent inhibition of greater than 70% was observed with tamoxifen and 4-OH-tamoxifen in 80% of the tested tumors. There was no significant correlation between the in vitro responsiveness and the level of hormonal act not only via an estrogen receptor but also via an antiestrogen-binding site.

96 patients with benign hyperplasia of the prostate and dysuric complaints in stage I and beginning stage II were treated conservatively and medicamentously up to 12 months. In the collective of patients subdivided into 4 groups the conservative therapy was carried out in 3 groups with different phyto-preparations and in one group with gestonorone capromate. The voiding of the bladder was examined by means of uroflowmetry in intervals of four weeks before and after therapy. A clear success of the effect appeared only in the group of patients treated with gestonorone capromate. With phyto-preparations uroflowmetrically no significant effect on the disturbed voiding of the bladder could be established. The conservative treatment of the benign hyperplasia of the prostate should be carried out under uroflowmetrical control, in order not to miss the time of a necessary operative intervention.

To investigate the effect of gestagens on renal cell carcinoma 300-mg slices of normal, human kidney, renal cell carcinoma (RCC), and preoperatively irradiated RCC were subjected to a short term incubation with 200 pmoles of 3H-testosterone and 1 and 2 mug of gestonorone caproate. In the normal kidney 61.4 per cent of the testosterone added was metabolized, the oxidation products androstenedione and epitestosterone outweighing by 6:1 the reduction products 5alpha-dihydrotestosterone and androstanediol. In RCC only 22 per cent of the testosterone was metabolized, with 8.5 per cent being converted to 5alpha-androstanes. Gestonorone caproate essentially did not influence testosterone turnover. This can be explained by its action as an inhibitor of the reductive pathway of the testosterone metabolism only, which is insignificant in these tissues.

Depostat® treatment was found to reduce plasma testosterone and to have a gonadotrophin suppressive effect in males. In our study the clinical effect on prostatic cancer was, however, disappointing when compared to the well established effect of orchiectomy. The therapeutic failure of Depostat® might be related to the incomplete suppression of plasma testosterone compared to that observed after orchiectomy.

Clinical trials with gestonorone led to favourable results in 65% of the patients. The drug is recommended particularly to patients in stage I or II of prostatic adenoma. It is justified to prescribe this treatment to high risk patients who cannot be operated because of their serious conditions. An objective assessment of the effect of the drug was possible by means of urodynamic and ultrasound tests which detected also fewer latent changes suggesting a continuation or repetition of the treatment.

The human tumor colony forming assay was used to evaluate the response of ovarian carcinoma cells from primary tumors, ascitic fluids and metastasis to hormonal treatment. In 12/35 patients a sufficient colony formation (greater than 30 colonies/dish) was obtained in order to perform a simultaneous drug testing. The plating efficiency of the metastatic samples (0.12%) was significantly higher (P less than 0.053) than those from the primary tumor (0.076%) or those that were derived from the ascitic fluid (0.082%). Colonies from the metastatic tissues could be evaluated 2-4 days earlier than those from primary tumors. These discrepancies may be due to a heterogeneity in the clonable tumor cell compartment of primary tumor and metastasis. The antiproliferative properties of the antiestrogen tamoxifen and the progestin gestoneron were studied. In 9/12 cases a significant, dose-dependent reduction of colony formation (greater than 70-90% of the controls) was observed after continuous exposure to 1 mumole tamoxifen. No correlation between the dose response and the content of steroid receptors was found. Even estrogen receptor negative tumor samples showed a maximal antiproliferative effect of tamoxifen.