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Progestogens and mammary tumours in the beagle bitch.

Progesterone administration induces specific cytosol receptors for progesterone in the mammary glands and uterus of adult beagle bitches but not in the mammary tissues or uterus of adult female rats. The specifiity of the progesterone receptor of dog myometrium is unlike that of human myometrium and is significantly different from progesterone receptors in tissues of th guinea pig. A spontaneous mammary benign mixed adenoma from an old beagle bitch was shown to contain specific progesterone receptors of similar affinity for progestogens as the dog uterine receptor. It is proposed that chronic toxicity tests of progestogens in the bitch cannot predict potential adverse human side effects because the regulatory mechanism for progesterone receptors is so different in the dog and major species differences exist in cytosol receptor affinity for particular progestational compounds.

Adenoma↗

Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial.

CONTEXT: Standard therapy for hot flashes has been hormone replacement with estradiol or progestational agents, but recent data suggest that antidepressants inhibiting serotonin reuptake may also be effective. OBJECTIVE: To evaluate a selective serotonin reuptake inhibitor (paroxetine controlled release [CR]) in treating the vasomotor symptoms displayed by a general cross-section of menopausal women. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled, parallel group study conducted across 17 US sites, including urban, suburban, and rural clinics. PATIENTS: A total of 165 menopausal women aged 18 years or older experiencing at least 2 to 3 daily hot flashes and must have discontinued any hormone replacement therapy for at least 6 weeks. Women were excluded if they had any signs of active cancer or were undergoing chemotherapy or radiation therapy. INTERVENTION: After a 1-week placebo run-in phase, study participants were randomized to receive placebo or receive 12.5 mg/d or 25.0 mg/d of paroxetine CR (in a 1:1:1 ratio) for 6 weeks. MAIN OUTCOME MEASURES: Mean change from baseline to week 6 in the daily hot flash composite score (frequency x severity). RESULTS: Fifty-six participants were randomly assigned to receive placebo and 51 to receive 12.5 mg/d and 58 to receive 25.0 mg/d of paroxetine CR. The mean reductions in the hot flash frequency composite score from baseline to week 6 were statistically significantly greater for those receiving paroxetine CR than for those receiving placebo. By week 6, the mean daily hot flash frequency went from 7.1 to 3.8 (mean reduction, 3.3) for those in the 12.5-mg/d and from 6.4 to 3.2 (mean reduction, 3.2) for those in the 25-mg/d paroxetine CR groups and from 6.6 to 4.8 (mean reduction, 1.8) for those in the placebo group. Mean placebo-adjusted reduction in hot flash composite scores were -4.7 (95% confidence interval, - 8.1 to -1.3; P =.007) comparing 12.5-mg/d paroxetine CR with placebo; and -3.6 (95% confidence interval, -6.8 to -0.4; P =.03) comparing 25.0-mg/d paroxetine CR with placebo. This corresponded to median reductions of 62.2% for those in the 12.5-mg/d and 64.6% for those in the 25.0-mg/d paroxetine CR groups compared with 37.8% for those in the placebo group. CONCLUSION: Paroxetine CR may be an effective and acceptable alternative to hormone replacement and other therapies in treating menopausal hot flash symptoms.

Adult↗

[Mechanisms of the antitumor action of gestagens on endometrial cancer].

An attempt was made to elucidate the relationship between the progestational activities and antitumor effects of various steroid hormones in vitro and in vivo. The established cell line (Ishikawa cells) of a human endometrial adenocarcinoma bearing estrogen and progesterone receptors was used in this study. Sixteen kinds of steroid hormones including progesterone, medroxyprogesterone acetate (MPA) and danazol were used in vitro. Each hormone was administered at 20 micrograms/ml continuously from the 4th day of culture and the growth curve was evaluated. The effects of progesterone, MPA and danazol at a dosage of 24 mg/kg/day for 53 days on the tumor induced in athymic nude mice with Ishikawa cells were also evaluated. Three kinds of hormones, progesterone, 16 alpha-methylprogesterone and danazol revealed cytocidal effects on the cells in vitro. There was no relationship between the progestational activity and cytocidal effect of each steroid hormone. On the other hand, no significant tumor regression was observed in vivo, but progesterone and danazol showed a tendency to suppress the growth of the tumor. These results suggest that the cytotoxic properties of progesterone may play a more important role than progestational action the cytocidal effect in vitro. It has been known that MPA had antitumor effects on DMBA-induced mammary cancer in rat and human endometrial cancer. However, MPA did not show a significant antitumor effect either in vitro or against the transplanted tumor in this study. Therefore, it was suggested that the antitumor effect of MPA is not direct action on the tumor cells, but indirect action through the interstitial cells of the target organ.

Adenocarcinoma↗

Pathogenesis and medical treatment of benign prostatic hyperplasia.

Tissue concentrations of dihydrotestosterone (DHT) and the enzymes that regulate its level, such as 5 alpha-reductase, appear to play a major role in the pathogenesis of benign prostatic hyperplasia (BPH). This argument is strongly supported by the objective decreases in prostate size and improvement in symptoms of prostatism that occur following androgen withdrawal. A variety of androgen-withdrawal therapies for BPH have been reported since the early 1900s. Although success in the treatment of BPH has been claimed for all of them, including surgical castration, medical castration with progestational antiandrogens, gonadotropin-releasing hormone (GNRH)-agonist castration, or androgen-receptor blockade with pure antiandrogens such as flutamide, very few studies, until recently, have provided convincing objective evidence for therapeutic efficacy in BPH. Recently, magnetic resonance imaging (MRI) scanning and ultrasound have become available to quantify objective changes in prostate volume and have indisputably demonstrated that androgen withdrawal does significantly decrease prostate size. The consequences of this on clinical symptoms of prostatism are currently under study. Studies of the effect of 5 alpha-reductase inhibitors on prostatism are in progress. They hold promise for future treatment of BPH since they may decrease prostate size and DHT concentration without any effect on sexual function.

Adrenergic alpha-Antagonists↗

Pathophysiology of endometrial bleeding.

OBJECTIVES: To review the morphological and molecular events responsible for uterine bleeding in health and disease. METHODS: Review of pertinent literature focusing on the histology and pathophysiology of normal and abnormal uterine bleeding (AUB). RESULTS: The seat of normal menstrual bleeding is located in the upper two-thirds of the endometrial mucosa and is recognized by tissue necrosis, disruption of microvasculature, migratory leukocytes and platelet/fibrin thrombi in microvessels. The molecular events responsible for tissue and vascular breakdown are related to the release of proteolytic lysosomal enzymes of endometrial cell and inflammatory cell origin. In cases of AUB, tissue breakdown is located in the superficial layer (subsurface) of the endometrium. It is either focal (breakthrough bleeding) or diffuse (withdrawal bleeding). It is initiated by either chronic endometritis and/or microerosions or vascular fragility due to structural abnormalities of microvessels. Endometritis and microerosions occur in otherwise normal endometrium, polyps, submucosal leiomyomata, atrophy and cancer (organic causes). Primary vascular alterations are found in hyperestrogenic-type endometria, i.e. anovulatory dysfunctional uterine bleeding (DUB) and progestational-type endometrium, i.e. progestational contraceptives and combined, continuous hormonal replacement therapy (HRT) (non-organic causes). Ovulatory DUB and coagulation disorders are not appreciated histologically. These are related to impaired vasoconstriction and fibrinolysis and impaired coagulation factors, respectively. CONCLUSIONS: Histology may contribute to better understanding of the mechanisms of action that initiate, regulate and lead to AUB. Better insight may trigger in the development of therapeutic procedures that could either prevent or control vascular breakdown which results in unexpected uterine bleeding.

Endometrium↗

Renal cell carcinoma: analysis of 31 cases with assessment of endocrine therapy.

Thirty-one patients with locally extensive and metastatic renal cell carcinoma were observed over an eight year period. At onset of the disease, symptoms due to metastatic deposits were the most frequent mode of presentation, followed by manifestation of local tumor growth (hematuria, flank pain or palpable mass) and paraneoplastic syndromes. Hormonal therapy with testosterone propionate, a progestational agent or both was assessed in 21 cases. Five instances of tumor regression, two involving recalcification of lytic osseous metastases, were documented. Endocrine studies to elucidate possible mechanisms of hormonal effectiveness were carried out in seven cases. Median survival from diagnosis was ten months. Following the rapid early mortality, a very gradual decrease in survival occurred, with 25% alive at ten years. Factors influencing survival include the duration of the interval between diagnosis of the primary tumor and appearance of metastases and the association of certain paraneoplastic syndromes.

Adenocarcinoma↗

[Prevention and treatment of postmenopausal osteoporosis in women treated for cancer].

Among 50-year-old women, about 30%, will suffer from osteoporosis resulting in vertebral compression, pain, and possible disablement; this represents a cost of over 4 billion French franco, and therefore necessitates a prevention policy. It has been established that estrogens applied in a dose-dependent manner have a preventive action against bone loss during the treatment period. The action of nor-steroid progestatives and anti-estrogens is likely, although this has not been fully demonstrated. Estrogens, when administered alone, increase the risk of endometrial cancer; however, this risk seems to be reduced by the addition of progestatives over a minimal period of time. Regarding breast cancer, it seems that substitutional hormone treatments for menopause only increase the risk of the above cancer after a prolonged period of over 10 years. The role of progestatives in breast-cancer risk remains uncertain, and is a subject of controversy. It therefore seems justified to prescribe substitutional hormone treatments combining estrogens and progestatives for young women in whom treatment for non hormone-dependent cancers of the cervix, ovary, etc has resulted in castration. For women who have been treated for breast or endometrial cancer, we are of the opinion that the treatment of choice should consist of non-hormonal treatments for prevention of osteoporosis.

Breast Neoplasms↗

Steroids and related products. XLI. (1) the synthesis of 11-oxa steroids. III. (2) 17-acetoxy-11-oxaprogesterone (3).

The synthesis of 17-acetoxy-11-oxaprogesterone, the 11-oxa analogue of the orally active progestational and anti-fertility agent 17-acetoxyprogesterone, is described. An intermediate in the synthesis of 11-oxaprogesterone, 11-oxa-5alpha-pregnane-3,20-dione, available from hecogenin, was used as starting material and the 17-hydroxy function was introduced by a modified Barton oxidation. The new hormone analogue shows only extremely weak progestational activity in the oral Clauberg assay.

Contraceptives, Oral↗

Serum levels of cholesterol and lipoproteins in rhesus monkeys: comparison of the effect of gonadotropin-releasing hormone agonist and the progestin, levonorgestrel.

Levonorgestrel, a progestational steroid, and the more widely used antigonadotropin, danazol have been used in the treatment of endometriosis. Both of these agents decrease serum levels of HDL cholesterol. Recently, GnRH agonists came into use for treatment of endometriosis. Our objective in this study was to compare the effects of levonorgestrel and a GnRH analog on serum cholesterol levels in rhesus monkeys being treated for surgically induced endometriosis. A high dose of levonorgestrel significantly reduced total serum cholesterol and HDL cholesterol during a 12-week treatment period. Levonorgestrel had no significant effects on the concentration of LDL/VLDL cholesterol or the percentage of total cholesterol in the HDL fraction. Conversely, the GnRH agonist had no significant effect on total serum cholesterol, HDL cholesterol, LDL/VLDL cholesterol, or the percentage of HDL cholesterol. Because the concentration of HDL cholesterol is closely correlated with atherosclerotic risk, this factor should be weighed in the overall risk/benefit analysis for the patient with endometriosis.

Animals↗

Medroxyprogesterone acetate (Provera) in the treatment of metastatic renal cancer.

Eighty patients with advanced metastatic renal cancer have been treated with hormones, chiefly medroxyprogesterone acetate (Provera). This progestational compound is remarkably free from side-effects and can be given in high dosage for long periods without serious complications. Ninety per cent of cases had multiple metastases: in 76% more than one organ was involved and nearly 50% were seriously ill or "terminal".Subjective improvement occurred in at least 55%. In 11 patients there was marked improvement in the radiological or clinical signs of tumour within 2 to 6 weeks of commencing treatment or changing to a different hormone. In two further cases improved general health was associated with stationary metastases for 20 months. A significant objective response occurred in 16% of the total series. A favourable response was seen more often in men (21%) than in women (8%). If deaths within 6 weeks are excluded the objective response rate in men is increased to 27%. Although the response of advanced renal cancer to hormonal treatment is usually incomplete and of brief duration, it is possible for such treatment to offer a "new lease of life" to a seriously ill patient, even in old age, for 2 to 3 years.

Abdominal Neoplasms↗

Fluoxymesterone as third line endocrine therapy for advanced breast cancer. A phase II trial of the Piedmont Oncology Association.

The Piedmont Oncology Association conducted a Phase II trial of fluoxymesterone (Halotestin) in 28 patients who failed to respond to prior hormonal therapy with tamoxifen and a progestational agent. Of nine patients who had responded to prior endocrine therapy, one had a partial response (PR) as defined by strict criteria and remains on study at 17 + months for an 11% response rate [95% confidence interval (CI), complete response (CR) + PR, 0-48%]. None of 19 previously unresponsive patients achieved remission (95% CI, CR + PR, 0-18%). Eleven patients' performance status deteriorated during therapy. Five of them had not received prior chemotherapy, and their response to subsequent chemotherapy may have been adversely affected. Third-line hormonal therapy with fluoxymesterone can be recommended only as a temporizing measure in patients with indolent disease who have responded to prior hormonal therapy.

Adult↗