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PubMedDate not supplied

Clinical experience with transdermal estradiol in the treatment of the climacteric.

Results of clinical studies have revealed that the transdermal therapeutic system of estrogen administration (Estraderm, Ciba Pharmaceutical Co., Summit, New Jersey) is both effective and well tolerated. Relief of hot flushes and vaginal atrophy has been shown to equal oral administration of conjugated equine estrogens and early experience suggests that the bone sparing effect is maintained. The patch has no effect on certain liver proteins; safety variables have shown no adverse biochemical changes. Moderate bleeding has occurred in some patients with an intact uterus but can be controlled by the addition of a progestogen. The incidence of endometrial hyperplasia and breast tenderness has been relatively low, and minor side effects (such as fluid retention) have been limited. Several investigators have evaluated skin irritation resulting from the systems. Some erythema has been reported but serious ulcerations or sloughing did not occur. A survey of patient attitudes comparing oral administration and transdermal systems indicated a preference for the transdermal method.

Administration, Cutaneous↗
PubMed1999

Biological effects of progestins in breast cancer.

Developments in the synthesis of different progestins have opened up new possibilities for the biological effects and therapeutic uses of these compounds. The actions of progestins are a function of their structure, affinity to the progesterone receptor or to other steroid receptors, the target tissue considered, the biological response, the experimental conditions, dose, and metabolic transformation. Data on the action of progestins in breast cancer patients are very limited. A positive response with the progestins medroxyprogesterone acetate and megestrol acetate has been obtained in postmenopausal patients with advanced breast cancer. However, extensive information on the effect of progestins was obtained in in vitro studies using hormone-dependent and hormone-independent human mammary cancer cell lines. It was demonstrated that in hormone-dependent breast cancer cells, various progestins (nomegestrol acetate, medrogestone, promegestone) as well as tibolone, are potent sulfatase-inhibitory agents. Progestins may also be involved in the inhibition of the mRNA of this enzyme. In another series of studies, it was also demonstrated that various progestins are very active in inhibiting the 17 beta-hydroxysteroid dehydrogenase for the conversion of estrone to estradiol. More recently, it has been observed that promegestone or medrogestone stimulates the sulfotransferase for the formation of estrogen sulfates. Clinical trials of these enzymatic effects on the formation and transformation of estradiol in breast cancer patients could be the next step to investigate new therapeutic possibilities for this disease.

17-Hydroxysteroid Dehydrogenases↗
PubMed1992

Effects of tamoxifen adjuvant therapy and a low-fat diet on serum binding proteins and estradiol bioavailability in postmenopausal breast cancer patients.

Serum was collected at intervals from postmenopausal breast cancer patients to determine the effects of tamoxifen adjuvant therapy and a low-fat dietary intervention, alone and in combination, on sex hormone-binding globulin (SHBG) concentrations and circulating estradiol bioavailability. Serum corticosteroid-binding globulin and follicle-stimulating hormone were also assayed as indicators of patient compliance to tamoxifen therapy. The immunoreactive SHBG concentration was higher (P less than 0.001) in 22 patients who had been treated with tamoxifen for 6-36 weeks when first sampled, compared with 27 who were not receiving tamoxifen therapy. Tamoxifen also produced a reduction in the percentage non-protein-bound estradiol (P less than 0.001) and percentage albumin-bound estradiol (P less than 0.01), the two biologically available fractions, and a corresponding increase in the percentage SHBG-bound estradiol (P less than 0.01). A longitudinal study of 7 patients showed significant reductions in the percentage of albumin-bound estradiol and an increased percentage of SHBG-bound estradiol, after 3-6 months of tamoxifen; after 12-18 months there was also a significant decrease in the non-protein-bound estradiol fraction. We conclude that in postmenopausal breast cancer patients the redistribution of circulating estradiol, with reduced bioavailability, provides an additional mechanism to those demonstrated previously for the therapeutic activity of tamoxifen. Another 12 patients receiving tamoxifen and 8 who were not were followed for 6-12 months on a low-fat diet (fat comprised 20% of the total calories). The dietary intervention had no effect on the serum SHBG concentration or the estradiol distribution. Although tamoxifen increased the serum corticosteroid-binding globulin and partially suppressed the follicle-stimulating hormone concentrations, the responses obtained were less consistent compared with those of the SHBG levels.

Biological Availability↗
PubMedDate not supplied

Cutaneous estradiol permeation, penetration and metabolism in pig and man.

AIM AND METHODS: Drug development in dermatotherapy and also development of transdermal therapeutic systems (TTS) demand high-predictive in vitro models to estimate drug levels in skin and systemic uptake. Here we compare three ready-to-use models, reconstructed human epidermis, split porcine skin and the perfused porcine forelimb. 17beta-Estradiol (E(2)), which is highly metabolized by skin cells, serves as model drug since E(2) application is of high relevance in hormone replacement therapy while topical E(2) may promote wound healing. E(2) TTS, gel and an ethanolic solution were investigated for cutaneous penetration, permeation and metabolism. RESULTS: E(2) TTS enabled an E(2) uptake of 42.9% of the applied dose accompanied by a high percentage of E(2) metabolism (30% of the penetrated dose) in the perfused porcine forelimb. In Franz cell experiments with reconstructed human epidermis and split porcine skin, the gel allowed an E(2) uptake of 41.7 and 22.9% of the applied dose accompanied by a high E(2) metabolism (42.6 and 28.6% of the penetrated dose). Due to toxic effects of the vehicle, this was not true with an ethanolic solution, then E(2) permeation and metabolism were clearly diminished. Most importantly, the in vitro models proved to be predictive with respect to the E(2)/estrone ratio in female plasma under transdermal hormone replacement therapy. CONCLUSION: In vitro tests should reduce the need for both animal and human studies for cutaneous uptake and metabolism in the future.

Administration, Cutaneous↗
PubMed2004

Estrogenic restoration of functional pancreatic islet cytoarchitecture in diabetes (db/db) mutant C57BL/KsJ mice: relationship to estradiol localization, systemic glycemia, and persistent hyperinsulinemia.

The diabetes (db/db) genotype mutation induces a hyperglycemic-hyperinsulinemic endometabolic state in C57BL/KsJ mice, manifesting a type 2 NIDDM diabetes-obesity syndrome (DOS) in this hyperphagic, leptin receptor (lf) defective model. The severity of the DOS induced by the single gene, homozygous-recessive mutation may be therapeutically moderated by gonadal steroids and pre-steroidal metabolites. The current studies define the estradiol (E2)-modulated phenotypic, systemic, cytochemical, and cellular metabolic responses to db/db mutation expression as compared to littermate control (+/?) indices. The db/db mutation induced dramatic age- and DOS severity-related increases in body weights, blood glucose, and serum insulin concentrations relative to +/? indices between 4-week-old (i.e., initial onset stage of DOS phenotype) and 16-week-old (i.e., chronic stage of DOS) groups. Chronic, low-dose (0.1 microg/3.5 days) E2 treatment (E2-HRx) significantly reduced the obesity mass and blood glucose levels of db/db mutants relative to oil-HRx groups. Similarly, E2-HRx maintained pancreatic glucose utilization rates and pancreatic tissue weights in db/db mutants to near +/? indices. Concurrent amelioration of db/db-enhanced pancreatic lipogenesis and islet hypercytolipidemia occurred following E2-HRx. Pancreatic islet lipo-deposition was markedly reduced in db/db mutants following E2-HRx, and the restoration of islet size and cellular insulin concentrations correlated with beta-cell cytoplasmic regranulation of insulin secretory vesicles. In chronic E2-HRx db/db groups, autoradiographic localization of (3)H-E2 was demonstrated in the nuclear compartments of regranulated, nonhypertrophic islet cell populations, including insulin-containing beta-cells. In chronic E2-HRx db/db mutants, beta-cell insulin granulation was prominent in mildly hypertrophic pancreatic islets, with cytodistribution patterns and concentrations comparable to normal +/? indices. In contrast, E2-HRx maintained the systemic hyperinsulinemia characteristic of oil-HRx db/db mutants. The results of these studies indicate that the severity of the type 2 NIDDM endometabolic syndrome induced by the db/db genotypic mutation may be influenced by E2-HRx, including reduction of the islet hypercytolipidemia and hypertrophic atrophy which are indicators of impending pancreatic involution in this mutant model. The hypercytolipidemia-induced demise of beta-cell cytoarchitecture was reduced by E2-HRx, including the reestablishment of islet beta-cell cytogranulation. These data suggest that the severity of genomic db/db-mutation expression may be modified by E2-HRx, with the gonadal steroid probably acting as a nuclear-specific stimulatory transcriptional modulator of cellular glucometabolic cascades in the absence of leptin-directed homeostatic influences.

Acetyl-CoA Carboxylase↗
PubMed1985

Cyproterone acetate in the treatment of metastatic cancer of the male breast.

Ten male patients with advanced cancer of the breast were treated with cyproterone acetate, an anti-androgenic compound with additional progestational properties. Seven patients achieved a response, for a median duration of 8 months. Plasma testosterone and estradiol levels fell significantly during therapy, but quantitatively this drop was not related to the therapeutic response. Cyproterone acetate is an effective and well-tolerated treatment for metastatic male breast cancer.

Aged↗
PubMed1982

An intrauterine progesterone contraceptive system (52 mg) used in pre- and peri-menopausal patients with endometrial hyperplasia.

An intrauterine progesterone contraceptive system (IPCS) (52 mg) was inserted in 25 women with cystic endometrial hyperplasia. Among these women, 11 complained of heavy climacteric symptoms and also received an oestrogen replacement therapy consisting of conjugated oestrogens (0.625 mg/day) administered cyclically for 3 out of 4 wk. Prior to the therapy and after 6 mth of treatment, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), oestrone (E1) and oestradiol (E2) plasma levels were measured and endometrial histology was evaluated. In the women receiving IPCS treatment alone, there were no significant changes in FSH, LH, PRL, E1 and E2 plasma levels. However, there were remarkable changes found in their endometrial histology. In the remaining women receiving both treatments there was a sharp decrease in FSH and LH plasma levels and an increase in E1 and E2 plasma levels, while the prolactin levels remained unchanged. With the exception of two of these women, the endometrial histology changed remarkably. The endometrial morphology of the two exceptions remained unchanged. All climacteric symptoms disappeared after the administration of both IPCS and the oestrogen replacement therapy. The remarkable changes which did occur in the endometrial histology resulted in a less active glandular epithelium and stromal decidual formation, thus proving a useful effect of treatment.

Adult↗
PubMed2003

[The influence of hormonal replacement therapy on bone density in postmenopausal women depending on polymorphism of vitamin D receptor (VDR) and estrogen receptor (ER) genes].

Osteoporosis is still an important health problem in modern societies. The densitometric criterion for the diagnosis of this condition established by WHO in 1994 is bone mass density (BMD) lower than 2.5 standard deviation (SD) from the mean value for young healthy individuals of the same sex. Between 60 and 90% of bone density (quantity of bone tissue in the human skeleton) at the time when growth is terminated is genetically determined. For this reason, genes predisposing to osteoporosis and mechanisms of their activity remain the object of investigations. Among them are genes coding for vitamin D receptor (VDR), estrogen receptor (ER), type I collagen, TGF-beta and IL-6. Diminishing bone density past the age of thirty is a physiologic process. Bone loss averages 0.3-0.6% per year. Acceleration of this process to 1.2-6% per year in postmenopausal women has been attributed to constantly decreasing estrogen concentration. Hence, the gold standard in osteoporosis prevention and treatment includes estrogen-progestagen therapy enriched with vitamin D analogues, calcium-rich diet and regular physical exercises. Treatment of osteoporosis can be long and expensive. The condition may lead to disability. Osteoporotic fractures and their complications may be fatal. For these reasons, the chief priority in osteoporosis is prevention. Unfortunately, current diagnostic methods (for detection of osteoporosis and monitoring of treatment) remain unsatisfactory. Molecular techniques offer a promising approach to diagnosis and monitoring of therapy. Additionally, the risk of osteoporosis in 1st degree relatives can be assessed and early prevention can be started. The present study addressed the following questions: 1. Are there differences in spine BMD in untreated women with postmenopausal osteoporosis depending on polymorphism of VDR and ER genes? 2. Does efficacy of treatment (increase in spine BMD) in women with postmenopausal osteoporosis depend on polymorphism of VDR and ER genes? 3. What estrogen concentration is necessary to protect bone tissue depending on the polymorphism of VDR and ER genes? The study group included 44 postmenopausal women aged 44-75 years with primary osteoporosis on cyclic HRT (hormonal replacement therapy). Two hormonal preparations were administered: Systen 50 (Jansen Cilag) transdermal system twice per week between day 1 and 21 of the cycle; Provera (Upjohn) 5 mg tablets daily between day 16 and 27 of the cycle. This therapy was supplemented with vitamin D analogue (Alphacalcidolum, Glaxo-Poznan) orally at 0.25 microg per day, calcium-enriched (1200 mg daily) diet and regular physical exercise. Patients were qualified to the study on the basis of a questionnaire. Women with secondary osteoporosis were excluded. TSH, FT3, and FT4 concentrations, as well as fasting glucose were measured. 24 h glycemia was established in women with elevated glucose levels. Polymorphism of the ER gene was studied with Xba I and Pvu II restrictases. Polymorphism of the VDR gene was studied with Bsm I restrictase. Age and BMI were recorded. Spine BMD was determined with DEXA (Dual Energy X-ray Absorptiometry (Lunar instrument) before treatment and after 12 months of HRT. Serum estradiol concentrations were measured before treatment and after 2 months of HTR. The following conclusions were drawn: 1. There is no connection between VDR and ER gene polymorphism and degree of osteoporosis before treatment. 2. XX, PP and Bb markers or X, P, B alleles are associated with a significant decrease in therapeutic efficacy. Nevertheless, satisfactory results were achieved in each woman with primary osteoporosis. 3. Estradiol concentration in serum before and during HRT does not depend on the polymorphism of VDR and ER genes.

Administration, Cutaneous↗
PubMed2000

Estradiol exerts neuroprotective effects when administered after ischemic insult.

BACKGROUND AND PURPOSE: 17beta-Estradiol (E2) has been reported to exert neuroprotective effects when administered before an ischemic insult. This study was designed to determine whether E2 treatment after ischemia exerts the same effects and, if so, how long this therapeutic window remains open, and whether the effects are related to changes in cerebral blood flow (CBF). METHODS: Female Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO). In protocol 1, E2 was administered (100 microg/kg IV followed immediately by subcutaneous implantation of crystalline E2 in a silicone elastomer tube) to ovariectomized females (OVX+E2) at 0.5 (n=8), 1 (n=6), 2 (n=7), 3 (n=6), or 4 (n=9) hours after MCAO. Intact (INT; n=6) and ovariectomized females (OVX; n=12) were subjected to MCAO and received vehicle instead of E2. Two days after MCAO the animals were killed, and ischemic lesion volume was determined by 2,3,5-triphenyltetrazolium chloride staining. In protocol 2, CBF was monitored before and at 1, 24, and 48 hours in a group of animals receiving E2 or vehicle 0.5 hour after ischemia induction (INT, n=6; OVX, n=8; OVX+E2, n=6). RESULTS: Lesion volume was 20.9+/-2.2% and 21.8+/-1.2% in the INT and OVX groups, respectively. E2 was found to decrease lesion volume significantly when administered within 3 hours after MCAO. The lesion volumes were 6.3+/-0.5%, 10.3+/-2.1%, 11.8+/-1.8%, 13.5+/-1.6%, and 17.9+/-2.8% when E2 was administered at 0.5, 1, 2, 3, or 4 hours after MCAO, respectively. CBF decreased to 43.1+/-2.2% and 25.4+/-1.0% in the INT and OVX animals, respectively, at 5 minutes after MCAO. In comparison to OVX rats, CBF was not different at 1 hour after E2 administration but was increased significantly in the OVX+E2 group 1 and 2 days after E2 administration. CONCLUSIONS: E2 exerts neuroprotective effects when administered after ischemia, with a therapeutic window in a permanent focal cerebral ischemia model of approximately 3 hours. This effect of estradiol was associated with no immediate change in blood flow but with a delayed increase in CBF.

Animals↗
PubMed1976

Estrogen-androgen levels in aging men and women: therapeutic considerations.

The influence of aging on serum levels of gonadotropins (FSH and LH), testosterone and estradiol was studied in the following groups: 4 normal men (ages 30 to 50), 38 men with symptoms of the male climacteric (ages 51 to 84), 25 men with relative impotence (ages 31 to 50), 10 normal women (ages 24 to 31), and 6 menopausal women (ages 58 to 76). FSH and LH levels began to rise in men in their 40's, and the increase became more conspicuous in the later age decades. The degree of elevation was nowhere comparable to that observed in the aging women. In the male, the serum testosterone levels showed a progressive decrease from the fifth age decade onward, whereas in the female there was an increase after the menopause. Estradiol levels showed no significant change in the aged male, but they were somewhat higher than in the aged female. Exceptions to the low-testosterone and low-gonadotropin relationship were observed in individual cases and might be explained by relatively high estradiol values. Proper replacement therapy by means of estrogens for the postmenopausal female and androgens for the aging male is often of great benefit, physically and emotionally.

Adult↗
PubMed1980

Estramustine phosphate: plasma concentrations of its metabolites following oral administration to man, rat and dog.

Estramustine phosphate, a nitrogen mustard derivative of estradiol used for the treatment of advanced prostatic cancer, was administered orally to man, rat and dog and the plasma concentrations of its unconjugated metabolites were determined by high performance liquid chromatography. In all species the drug was rapidly and completely dephosphorylated prior to reaching the peripheral circulation. In man and the rat, the 17-keto analogue of estramustine (estromustine) was the mamor metabolite found in plasma with considerably lesser amounts of estramustine itself. In the dog, significant concentrations of both estramustine and estromustine were present. Highly elevated levels of both estrone and estradiol, as a result of cleavage of the nitrogen mustard from the steroid, were observed in all species. Chronic administration of therapeutic doses of estramustine phosphate to man did not result in any apparent accumulation of circulating metabolites. The study suggests that the metabolite, estromustine, in addition to estramustine, may play an important role in the therapeutic efficacy of estramustine phosphate.

Administration, Oral↗
PubMedDate not supplied

[Therapeutic systems and drug delivery. 3. Transdermal therapeutic systems].

Following a short review of penetration of drugs through the skin (a bilayer membrane which consists of the stratum corneum and the viable epidermis), transdermal therapeutic systems (TTS) are described. These systems are special pharmaceutical preparations capable of delivery of some drugs (e.g. very potent drugs, with narrow therapeutic index, short biological half-life) via skin under well controlled conditions. After their application drug passes directly into the systemic circulation avoiding the effect of first-pass hepatic metabolism. At the same time, their advantages and disadvantages are presented. Finally, currently existing TTS in the market containing e.g. scopolamine (motion sickness), nitroglycerin (angina pectoris), estradiol (postmenopause), clonidine (hypertension) and systems in the development are briefly reported. These transdermal therapeutic systems are considered as a new approach to improve the usage of drugs in terms of better dosage control, increased safety and easier application.

Administration, Cutaneous↗
PubMed2004

[Clinical observation on treatment of female delayed acne vulgaris with qingre cuochuang tablet].

OBJECTIVE: To observe the clinical therapeutic effect of Qingre Cuochuang tablet (QCT) in treating female delayed acne vulgaris (FDAV, with patients age more than 25 years old), to evaluate objectively the sexual hormone in patients and to assess the effect of QCT on sexual hormone. METHODS: Sixty FDAV patients were randomly divided into the treated group (n = 40) and the control group (n = 20), they were treated with QCT and western medicine (including antisterone, tetracycline and metronidazole) respectively. Besides, 10 healthy female subjects aged > or = 25 years were selected as normal control. Serum levels of testosterone (T) and estradiol (E2) in all patients and healthy subjects as well as the clinical therapeutic effect of the treatments were observed and compared. RESULTS: The total effective rate in the treated group and the control group was 92.5% and 90.0% respectively, comparison between them showed insignificant difference. Serum level of T in the patients before treatment were higher than that in healthy subjects (P < 0.01), and showed no difference between the treated group and the control group. After treatment, it lowered significantly in the treated group (P < 0.01), but unchanged in the control group, E2 level showed no significant change in both groups before and after treatment. CONCLUSION: QCT has definite clinical effect in treating FDAV, it could lower the serum level of T and with few adverse reaction.

Acne Vulgaris↗
PubMed2003

Effects of the novel orally active antiestrogen TZE-5323 on experimental endometriosis.

Danazol and gonadotropin-releasing hormone agonists which are used as therapeutic drugs for endometriosis, develop adverse reactions in association with their long-term use. The efficacy of anti-estrogens for endometriosis, an estrogen-dependent disorder, has not been demonstrated. A novel, orally active anti-estrogen, TZE-5323 ((2-cyclohexy-6-hydroxybenzo[b]thien-3-yl)[4-[2-(1- piperidinyl)ethoxy]phenyl] methanone hydrochloride, CAS 150797-71-0; free salt formula) was developed. TZE-5323 showed strong affinity for human estrogen receptor alpha (hER alpha) and beta (hER beta), and dose-dependently inhibited estradiol-stimulated transcriptional activation via hER alpha and hER beta. Furthermore, TZE-5323 dose-dependently reduced estrogen-increased uterine weight in ovariectomized rats. Tamoxifen showed agonistic activity on hER alpha, while TZE-5323 did not show such activity. In the experimental endometriosis model in rats in which endometrial tissue is autotransplanted into the renal subcapsular space, TZE-5323 dose-dependently reduced the volume of the endometrial implant as did danazol and leuprorelin acetate. Furthermore, the long-term administration of TZE-5323 neither showed a decrease in bone mineral density nor did it affect serum estradiol concentrations in intact rats. Therefore, TZE-5323 suggested its potential as a novel therapeutic drug for endometriosis which is effective also in long-term use.

Animals↗