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PubMed2005

Comparison of the steady-state pharmacokinetics, metabolism, and variability of a transdermal testosterone patch versus a transdermal testosterone gel in hypogonadal men.

AIM: To compare the pharmacokinetics (PK), metabolism, intra- and inter-subject variability of a permeation-enhanced testosterone patch versus a topical testosterone gel. METHODS: 28 hypogonadal men were treated with a testosterone patch (5 mg/day applied at 2200 h) and a 1% testosterone gel (5 g/day applied at 0800 h; nominal delivery 5 mg/day), each for 14 days, in an open-label crossover design. PK profiles of total testosterone (TT) and calculated free testosterone (cFT) were measured on day 7 and day 14 of each treatment, with patches or gel applied to the abdomen; dihydrotestosterone (DHT) and estradiol (E2) profiles were measured on day 14. The time-average (Cavg), maximum (Cmax), time of maximum (Tmax) and minimum concentrations (Cmin) were derived from each profile. The intra- and inter-subject coefficients of variation (CVintra and CVinter) of the TT and cFT parameters were computed by ANOVA. RESULTS: Nightly applications of the patch produced a mean TT profile that mimicked the circadian pattern of healthy men. Morning applications of the gel produced a flatter mean profile; though individual subjects exhibited significant peaks at variable times. For TT, the mean and 90% confidence intervals of the patch/gel ratio of Cavg (1.030; 0.936-1.133; P > 0.05) and Cmax (1.086; 0.974-1.211; P > 0.05) met the criteria for bioequivalence. Cmin was lower for the patch. DHT levels and DHT/T ratios were 2 to 3-fold higher for the gel (P < 0.0001). E2 levels and E2/T ratios were comparable. CVintra and CVinter for Tmax approached 100% for the gel and were 23% and 42%, respectively, for the patch (P < 0.0001). Other variability parameters were generally comparable. Both products were well tolerated, and the patches adhered well. CONCLUSIONS: These findings reflect the different mechanisms of transdermal absorption from the patch and gel and provide new considerations for selecting testosterone replacement therapies in hypogonadal men.

Administration, Cutaneous↗
PubMed2001

Enhancement of splenic-macrophage Fcgamma receptor expression by treatment with estrogens.

Splenic-macrophage Fcgamma receptors (FcgammaRs) participate in the pathophysiologies of immune-complex diseases and in host defense against infection. Modulation of macrophage FcgammaR expression is an immuno-therapeutic target. Glucocorticoids, sex steroids, and dopaminergic drugs modulate macrophage FcgammaR expression. Previous data indicate that estradiol increases macrophage FcgammaR expression. Nevertheless, the effects of clinically used estrogens upon macrophage FcgammaR expression are unknown. We assessed the effects of treatment with commonly used estrogens on the expression of macrophage FcgammaRs using a guinea pig experimental model. Six estrogens have been studied: ethynylestradiol (Et), mestranol (M), chlortianisene (Ct), promestriene, 17-epiestriol, and 17beta-estradiol. Following in vivo treatment of guinea pigs, we determined the clearance of immunoglobulin G (IgG)-sensitized erythrocytes in vivo, the binding of IgG-sensitized erythrocytes by isolated splenic macrophages, and splenic-macrophage FcgammaR cell surface expression. Estrogens enhance the clearance of IgG-sensitized erythrocytes by increasing splenic-macrophage FcgammaR expression. Et, M, and Ct were more effective than the other estrogens. Flow cytometry and fluorescence microscopy with monoclonal antibodies demonstrated that estrogens increase the cell surface expression of FcgammaR1 and -2 more than that of FcgammaR2. These data indicate that treatment with commonly used estrogens enhances the clearance of IgG-sensitized cells by improving splenic-macrophage FcgammaR expression.

Animals↗
PubMed1977

Hormonal control of neutrophil chemotactic activity in the rat vagina.

A sexual-hormone-dependent neutrophil chemotactic factor(s), operative under physiological conditions, is described. Rat vaginal washouts were shown to be both chemotactic and chemokinetic for rat neutrophils in vitro, whereas macrophages were not attracted. Peak activity was observed at the end of estrus and preceded maximal neutrophil infiltration in the vagina. In order to mimic these events, gonadectomized animals were treated with estradiol for a week. They showed a similar peak of chemotactic activity 30-36 h after estradiol withdrawal, accompanied by a massive neutrophil accumulation. These data suggest that a decrease in estradiol level permits the expression of the chemotactic signal. There was no evidence for chemotaxis and/or migration inhibitors before and during estrus or during long-term estradiol treatment of gonadectomized rats. Induced neutrophil accumulation in the peritoneal cavity and chemotactic responsiveness of these cells in vitro were similar in all stages during the estrus cycle. Estradiol, progesterone, testosterone, and hydrocortisone neither promoted nor significantly inhibited the neutrophil migratory behavior over a wide range of concentrations. Our experiments suggest that the periodic neutrophil accumulation in the rat vagina after estrus is triggered by locally expressed chemotactic mechanisms that are controlled by sexual hormones. The data provide the first evidence that hormonal changes can control chemotactic factors and thus indirectly control cell migration.

Animals↗
PubMed2004

Brain steroidogenesis: emerging therapeutic strategies to prevent neurodegeneration.

Decreasing levels of gonadal steroids with aging are associated to an increase in cognitive, neurological and psychiatric disturbances. Estradiol is neuroprotective in animal models of neurodegeneration. However, the effects of hormonal replacement therapy on brain function in postmenopausal women are controversial. A possible alternative to hormonal replacement therapy is to increase local brain steroidogenesis, since experimental studies indicate that local estrogen formation in the brain is neuroprotective.

Animals↗
PubMed2002

Synthesis of chimeric 7alpha-substituted estradiol derivatives linked to cholesterol and cholesterylamine.

We report the synthesis of 7alpha-substituted beta-estradiol derivatives bearing side chains terminated with cholesterol and 3beta-cholesterylamine. These chimeric compounds were designed to exhibit high affinity for estrogen receptors (ERs) and cellular plasma membranes to potentially enable regulated uptake of ERs by mammalian cells. Evaluation with recombinant yeast reporting compound-mediated ER dimerization revealed potencies similar to the antiestrogen ICI 182780. Compounds that efficiently deliver dominant negative ERs into cells may provide novel therapeutics against breast cancers.

Animals↗
PubMed2003

Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells.

Recent clinical studies estimate that 60-70% of human ovarian and breast cancers overexpress the estrogen receptor (ER). However, despite the established mitogenic effects of estrogen in these tumors, proliferative markers of hormone action are limited. In the current study, we report that the growth stimulatory cytokine stromal cell-derived factor 1 (SDF-1) is a bona fide target of estrogen action in ERalpha-positive human ovarian and breast cancer cells. Notably, estradiol treatment of BG-1 (ovarian carcinoma) and MCF-7 (breast carcinoma) cells leads to rapid and robust induction of the SDF-1alpha and beta isoforms. This response is blocked by the pure ER antagonist ICI 182,780 and is not apparent in ER-negative ovarian cells, indicating that SDF-1 regulation is ERalpha mediated. Treatment with the protein synthesis inhibitor cycloheximide had no effect on estradiol induction of induction of SDF-1 mRNA levels mRNA levels, demonstrating that SDF-1 is a direct target of ERalpha. SDF-1 protein levels, although undetectable under basal conditions, were strikingly increased by hormone both intracellularly and in the media of cultured BG-1 and MCF-7 cells. In cell proliferation assays, the mitogenic effects of estradiol were neutralized by addition of an SDF-1 antibody and mimicked by the addition of exogenous SDF-1 protein, indicating that SDF-1 mediates the proliferative actions of hormone. Furthermore, activation of the SDF-1 receptor CXCR4 stimulated BG-1 and MCF-7 cell proliferation in a manner comparable to estradiol. Taken together, these results demonstrate a novel estrogen-mediated paracrine pathway for inducing cancer cell proliferation and suggest that SDF-1 and CXCR4 may represent novel therapeutic targets in ERalpha-positive ovarian and breast tumors.

Breast Neoplasms↗
PubMed1989

Binding of radiolabeled estrogens by human cells in vitro: implications to the development of a new diagnostic and therapeutic modality in the treatment of malignancies with estrogen receptors.

An in vitro technique was employed to demonstrate the binding of Auger electron-emitting nuclide-labeled estrogenic compounds by a variety of human cell types. Human granulosa cells, endometrium, and MCF-7 breast cancer cells were incubated with either 16 alpha-[I125]-iodoestradiol-17 beta or 16 alpha-[I123]-iodoestradiol-17 beta in vitro. Autoradiographic techniques were subsequently utilized and revealed that binding of these estrogenic compounds by all three types of cells did occur and that this binding was inhibited by excess unlabeled estradiol. Histologic examination was not able to demonstrate nuclear-specific binding in all instances, however. These compounds are potentially useful in both diagnostic and therapeutic settings and this study is the first to provide such data from human tissue.

Autoradiography↗
PubMed2001

Norgestimate. From the laboratory to three clinical indications.

This review of preclinical studies and clinical trials of efficacy and safety examines the relation between structure and function in the norgestimate (NGM) molecule, describes the pharmacologic characteristics of NGM and evaluates clinical experience with NGM in oral contraception (OC), treatment of hyperandrogenism in women and hormonal replacement therapy (HRT). NGM is a progestin of the 19-norsteroid series with an oxime group on C-3. In women, only low serum levels of NGM can be detected for five hours after ingestion. NGM is swiftly converted into its main metabolite, the 17-deacetylated norgestimate (norelgestromin), which carries the progestogenic properties of NGM. The metabolite reaches a mean peak concentration of 3,500 pg/mL 1.5 hours after intake and has a half-life of > 24 hours. The progestogenic potency of NGM and its main metabolite is comparable to that of progesterone. The doses of NGM in OCs effectively inhibit ovulation and control uterine bleeding. In the triphasic NGM/ethinyl estradiol (EE) OC, the total monthly load of progestin is only 4.5 mg. NGM has a low androgenic impact and does not interfere with the positive metabolic actions of estrogens, notably the estrogen-induced increase in high-density lipoprotein levels. OCs with NGM and EE increase the serum concentration of sex hormone binding globulin threefold, augmenting the binding of circulating testosterone and reducing free testosterone levels by 50%. Consequently, OCs with NGM are therapeutic for hyperandrogenic symptoms, such as acne. In a new type of HRT three-day dosing with 17 beta-estradiol (E2) alone is followed by three-day dosing with E2 plus NGM. This regimen treats vasomotor symptoms, protects the endometrium from hyperproliferation and is associated with a favorable lipid profile. NGM is a versatile progestin suitable for medical use from adolescence through the reproductive years to menopause.

Contraceptives, Oral, Sequential↗
PubMed2003

The role of aromatase inhibitors in early breast cancer.

The role of hormonal therapy for the treatment of patients with early stage breast cancer has been evaluated in many studies. The results of these studies establish tamoxifen as the gold standard of hormonal therapy for the adjuvant treatment of hormone receptor-positive invasive breast cancer in pre- and postmenopausal women. Studies show tamoxifen reduces the risk of invasive breast cancer in women at increased risk for the disease, including women with ductal carcinoma in situ. Tamoxifen has adverse effects such as hot flashes, increased risk of uterine cancer in postmenopausal women, and rare occurrence of thromboembolic disease. Despite the multiple therapeutic roles of tamoxifen, alternatives are needed. Aromatase inhibitors (AI) are drugs with antiestrogenic activity. AIs function by inhibiting the peripheral conversion of adrenally synthesized androstenedione to estradiol through inhibition of the aromatase enzyme. AIs do not suppress estradiol synthesis by the ovary adequately. Therefore, AIs are effective in reducing circulating estradiol levels in postmenopausal women, but not premenopausal women. Selective nonsteroidal AIs, including anastrozole (Arimidex; AstraZeneca, Wilmington, DE) and letrozole (Femara; Novartis, East Hanover, NJ), and the steroidal AI exemestane (Aromasin; Pharmacia, Peapack, NJ) have been associated with increased specificity and improved therapeutic index compared to nonselective AIs such as aminoglutethamide. Nonsteroidal and steroidal AIs have demonstrated to be superior to megestrol acetate in second-line therapy of postmenopausal women with metastatic breast cancer, and selective nonsteroidal AIs have shown to be superior to tamoxifen in first-line therapy of postmenopausal women with metastatic breast cancer. The ATAC (Arimidex, tamoxifen, alone, or in combination) trial is the only published randomized trial comparing the efficacy of an AI to tamoxifen for the adjuvant treatment of women with early breast cancer. This large study showed that at a median follow-up time of 33 months, anastrozole alone results in significant improvement in disease-free survival rates, reduction in contralateral breast cancers, and increased tolerability, compared to tamoxifen in postmenopausal women. Although the long-term effects of AIs are not known, the early positive results of the ATAC trial led to the approval of anastrozole by the US Food and Drug Administration for use as adjuvant hormonal therapy for postmenopausal women with hormone receptor-positive invasive breast cancer. Thus, there is an alternative to tamoxifen for postmenopausal women with relative/absolute contraindications to tamoxifen use or patients who choose not to take tamoxifen because of its side-effect profile. New AIs may challenge the position of tamoxifen as the gold standard for the treatment of early stage breast cancer in postmenopausal women.

Adult↗
PubMed1992

Steroid sulphotransferase activity in human hormone-independent MDA-MB-468 mammary cancer cells.

The metabolism of various unconjugated oestrogens [oestrone (E1), oestradiol (E2) and oestriol (E3)], in MDA-MB-468 human mammary cancer cells, a cell line characterised by the absence of oestrogen receptor has been investigated. 24 h after incubation of these cells with 5 x 10(-9) mol/l of tritiated E1, E2, or E3, 62-90% of the total radioactivity was localised in the sulphate fraction. Analysis showed that 73-90% of the sulphate fraction corresponds with the oestrogen incubated. The formation of the oestrogen sulphates is rapid and maximum values are found after 3 h incubation. Intense sulphotransferase activity was also found for testosterone, pregnenolone and dehydroepiandrosterone. Thus these cells contained high oestrogen sulphotransferase activity, suggesting that the presence of high levels of oestrogen sulphates in breast cancer can be synthesised in the tumour itself. In addition, the control of this enzymatic activity could open new possibilities in the knowledge of oestrogen responses and of therapeutic applications in breast cancer.

Animals↗
PubMed1980

Studies on ethanol and oral contraceptives: feasibility of a hepatic-gonadal link.

Adult male and female rats were subjected to gonadectomy by means of surgical removal of the gonads. In the male, castration resulted in a significant decrease in both body and liver weights compared to intact controls, which persisted for at least 3 weeks. Conversely, ovariectomy was associated with a significant enhancement in both growth rate and liver weight from intact controls. Castration of male rats resulted in induction of hepatic L-ADH (cytosolic alcohol dehydrogenase) and L-ALDH (cytosolic aldehyde dehydrogenase) as contrasted with inhibition of mitochondrial ALDH which was evident in the enzyme with the apparent high Km. Kinetic studies indicate that there was an increase in apparent Km of L-ADH, and hence reduced affinity to hepatic metabolism of ethanol as a consequence of castration in the male rat. This is compared with few changes occurring in the apparent Km value of L-ALDH. Ovariectomy did not alter endogenous L-ADH or L-ALDH. Short-term administration of a synthetic estrogenic steroid ethinyl estradiol, inhibited liver mitochondrial ALDH in the intact female rat but not in the ovariectomized female. Short-term administration of the same dose of an androgen, testosterone, did not alter specific activities of the liver enzymes measured in the intact or in the castrated male rat. Administration of both components of OCs (oral contraceptives) combined or the estrogen alone in behavioral experiments profoundly reduced ethanol drinking by voluntary intake of diluted ethanol solution by the intact female rat. These results suggest a hepatic-gonadal link may exist and that a toxic interaction between the OCs and alcohol drinking is definitely possible.

Alcohol Drinking↗
PubMed1994

Levels of circulating peptide and steroid hormones in men with lung cancer.

Levels of circulating peptide (FSH, LH, prolactin, ACTH, calcitonin, gastrin and insulin-like growth factor-1 [IGF-1]) and steroid (estradiol, progesterone, DHEA-S and testosterone) hormones were estimated by radioimmunoassay (RIA) and immunoradiometric assay (IRMA) in male patients with lung cancer (n = 37) pre-therapeutically and compared with 25 age matched healthy controls. In this retrospective study, FSH, LH, prolactin, ACTH, calcitonin, gastrin and IGF-1 were significantly higher with concomitant lower levels of DHEA-S and testosterone, while the difference was statistically non-significant for estradiol and progesterone in patients with lung cancer when compared with controls. Early stage patients (Stage II) exhibited higher levels of gastrin as compared to advanced stage patients (Stages III and IV). It is suggested that hormonal imbalance might play an important role in the development and progression in male patients with lung cancer.

Adrenocorticotropic Hormone↗