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PubMedDate not supplied

Solid-phase synthesis of phenolic steroids: from optimization studies to a convenient procedure for combinatorial synthesis of biologically relevant estradiol derivatives.

During the course of our studies on therapeutic agents for the treatment of breast cancer, we became interested in the solid-phase combinatorial synthesis of estradiol derivatives that contain a functionalized side chain at either position 16 beta or 7 alpha. Both types of compounds have already demonstrated inhibitory activity toward both biosynthesis and action of estradiol. As a first step, two versatile precursors bearing an azidoalkyl side chain at either position 16 beta or 7 alpha of estradiol were synthesized using standard solution-phase methods. Afterward, the effectiveness of five linkers to attach the phenolic function of these estradiol derivatives to a polystyrene resin was investigated; they were benzylic ether (Merrifield), 4-alkoxy-benzylic ethers (Wang, Sheppard), tetrahydropyranyl ether (Ellman), benzoic ester, and o-nitrobenzyl ether. To test the linker in a synthetic context, a short sequence of reactions, including reduction of the azide and acylation of the corresponding amine, was performed on the polymer-bound estradiol derivative. While all of the tested linkers proved effective in attaching the phenol functionality of the precursor, only the o-nitrobenzyl ether photolabile linker enabled the release of the final products in acceptable purities. Consequently, this linker was used to perform successfully the solid-phase synthesis of four different classes of estradiol derivatives in acceptable yields and excellent purities. This study was preliminary to the combinatorial synthesis of larger libraries of biologically relevant estradiol derivatives.

Estradiol↗
PubMed1977

The influence of combined cyproterone acetate-ethinyl oestradiol therapy on serum levels of dehydroepiandrosterone, androstenedione, and testosterone in hirsute women.

Serum levels of dehydroepiandrosterone, androstenedione, and testosterone in hirsute women suffering from either idiopathic hirsutism or the polycystic ovary syndrome were determined before and during treatment with cyproterone acetate combined with ethinyl oestradiol. During this treatment the hirsutism decreased markedly. In untreated hirsute women serum dehydroepiandrosterone levels do not differ from those in normal women and do not change during therapy; androstenedione levels are higher than normal and decrease markedly during treatment, and the testosterone levels are elevated compared to normals, with a considerable overlap, and show only a tendency to decrease. There is no correlation between dehydroepiandrosterone and androstenedione levels or between androstenedione and testosterone levels in the serum of untreated hirsute women. After 12-14 months of cyproterone acetate-ethinyl oestradiol therapy a linear correlation is found between dehydroepiandrosterone and androstenedione levels. This can be explained by the relatively higher contribution of the peripheral conversion of dehydroepiandrosterone to androstenedione to the occurrence of lower androstenedione levels. The linear correlation between androstenedione and testosterone after treatment, also found in normal women, indicates the restoration of the role of androstenedione as the major peripheral precursor of testosterone.

Adolescent↗
PubMedDate not supplied

Treatment of hirsutism related to micropolycystic ovary syndrome (MPCO) with two low-dose oestrogen oral contraceptives: a comparative randomized evaluation.

In order to evaluate the clinical and endocrinological efficacy of two low-dose oral contraceptives (OC) containing 30 micrograms Ethinylestradiol (EE) and 150 micrograms Desogestrel (DG) and 75 micrograms Gestodene (GD), respectively, an open randomized study was carried out in 34 young hirsute women, matched for body mass index and age. All of them met endocrine and ultrasonic criteria for Micropolycystic Ovary Syndrome (MPCO). The participants were randomly assigned to one of two pill groups (each of 17). The serum values for Total Testosterone (TT), Free Testosterone (FT), Androstenedione (A), Dehydroepiandrosterone (DHEA), Dehydroepiandrosterone Sulphate (DHEAS), 17-Hydroxyprogesterone (17Pg), Sex Hormone Binding Globulin (SHBG), Ceruloplasmin (CP), as well as Ferriman-Gallwey Index (FGI) and Free Androgen Index (FAI) were evaluated prior to and after EE-DG and EE-GD 6 cycle treatment. A significant decrease in TT, FT, A, 17Pg, DHEA, DHEAS, FGI, FAI was observed, SHRG and CP increased significantly. There were no significant differences between the two OC. Our results seem to indicate that both OC are equipotent as far as their pharmacological profile and residual androgenic activity are concerned. Therefore, these OC may represent a highly effective and suitable alternative to the treatment of hyperandrogenism related to MPCO.

17-alpha-Hydroxyprogesterone↗
PubMed1982

Cyproterone acetate in the treatment of acne vulgaris in adult females.

22 adult females with therapy-resistant acne vulgaris were treated for 12 months with Diane, a drug containing cyproterone acetate and ethinylestradiol. Treatment was withdrawn in 7 patients because of side-effects of lack of of effect. In the remaining 15 patients, the treatment had extremely promising results, from 70 to 90% improvement of the acne. In a remarkably high number of patients, the androgen production, measured by the urinary excretion of fractional 17-ketosteroids, was elevated. None of these patients had signs of endocrinological diseases, in particular no cases of hirsutism of Stein-Leventhal syndrome were found. The current concept of the course of acne is that the conversion in the skin of testosterone to dehydrotestosterone is increased. The finding of an elevated urinary excretion of androgenic substances in this group of acne patients indicates that the pathogenesis is far more complicated.

17-Ketosteroids↗
PubMed2000

[Specific modulators of estrogen action].

Selective estradiol receptor modulators (SERMs) are specific modulators of estradiol action. They are used in therapeutics to obtain an estrogenic effect on certain cells and an antiestrogenic effect on other cells. Recent progress in the knowledge of the mechanism of action of estradiols implies that new molecules could be designed. This progress involves the cloning of a new estradiol receptor, ER beta, the discovery of co-activators and the elucidation of their molecular mechanism of action, and the crystallization of the ligand binding domain in the presence of an agonist or an antagonist.

Animals↗
PubMed1991

Transdermal estradiol substitution therapy for the induction of puberty in female hypogonadism.

Fifteen patients aged 14.5-27.3 years (mean +/- SE 18.8 +/- 0.9) with pubertal development failure underwent replacement therapy with estradiol (E2) using a transdermal therapeutic system (TTS). Fourteen of them were affected by hypogonadotropic hypogonadism (11 with thalassemia major, 3 with multiple pituitary hormone deficiency), the 15th patient had an asymmetric gonadal dysgenesis (karyotype 45, X 0/46, XY). Two sizes (5 and 10 cm2) of E2 TTS, delivering respectively 25 and 50 micrograms of E2 a day for 3 1/2 days, were used in this study. All patients were initially given the lower dose of 25 micrograms, twice weekly for 3 weeks each month; 6 months after starting therapy, 5-10 mg oral medroxyprogesterone acetate (MPA) daily was added during the third week. Later, the following sequence was used: 25 micrograms E2 TTS (twice weekly), on days 1 through 14, and 50 micrograms E2 TTS (twice weekly), on days 15 through 25 of each month. On days 15 through 25, 5 mg daily of MPA were administered orally. The period of treatment ranged from 0.5 to 3 years. Breast development was obtained in all cases. The vaginal maturation index rose. Ultrasonography showed an increase of uterine size and uterine shape became of pubertal type. Withdrawal bleeding occurred in all patients. Plasma E2 levels rose to normal levels, estrone (E1) levels increased slightly. No change in plasma SHBG levels was observed. Urinary E2, E1 and estriol rose to maximum levels the 3rd day after the application of each system. Neither systemic side effects nor adverse metabolic effects were observed except for an increased sensitivity to the platelet aggregating agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMedDate not supplied

A comparative study of the effects of an estradiol-releasing vaginal ring combined with an oral gestagen versus transdermal estrogen combined with a levonorgestrel-releasing IUD: clinical findings and endometrial response.

OBJECTIVE: Our purpose was to compare the effects of a new estradiol-releasing vaginal ring with an oral progestin versus the efficacy, safety and acceptability of an intrauterine device releasing levonorgestrel combined with estradiol, delivered transdermally from a patch. Climacteric symptoms, bleeding pattern, and endometrial histologic features were studied. MATERIALS AND METHODS: Fifty-six parous, postmenopausal women with urogenital symptoms were allocated to two groups for 1 year" 28 women receiving estradiol by a vaginal ring (2 mg/3 months) and an oral progestin for 7 days every month and 28 women receiving a continuous transdermal daily dose of 50 micrograms of estradiol with a levonorgestrel-releasing (20 micrograms/day) intrauterine device inserted. All the patients were subjected to vaginosonographic examination followed by thorough pathological examination of uterine curetting samples. RESULTS: A mean endometrial thickness (double layer) of 2.9 and 3.0 mm, respectively, was found to be predictive of normal endometrium. Both treatment regimens effectively relieved urogenital symptoms. Endometrial proliferation was not observed. CONCLUSIONS: Treatment of urogenital symptoms in postmenopausal women with these two forms of hormone replacement therapy was shown to be an effective and safe method, exhibiting possible advantages over other methods of treatment.

Administration, Cutaneous↗
PubMed2005

Estrogen and raloxifene, a selective estrogen receptor modulator, ameliorate renal damage in db/db mice.

Despite the potentially protective effects of estrogen on bone and cardiovascular tissue as well as against kidney diseases, its effects on diabetic nephropathy are unknown. Here, we examined the therapeutic effectiveness of 17beta-estradiol and raloxifene, a selective estrogen receptor modulator, for preventing functional and histological alterations in the kidneys of db/db mice, a model of type 2 diabetes. In the first experiment, ovariectomized female db/db mice were treated with 17beta-estradiol for 8 weeks. The treatment significantly ameliorated albuminuria, attenuated weight gain, and reduced hyperglycemia in diabetic ovariectomized db/db mice. Histologically, the increases in mesangial area and the accumulation of fibronectin were significantly inhibited by 17beta-estradiol. In the second experiment, mice were administered vehicle or raloxifene hydrochloride (3 mg/kg/day) for 8 weeks. Raloxifene significantly reduced mesangial expansion and fibronectin accumulation in db/db mice, but in contrast to 17beta-estradiol, it failed to affect body weight or hyperglycemia. An in vitro experiment further demonstrated that raloxifene inhibited transforming growth factor beta-1-induced fibronectin transcription and AP-1 activity. Thus, our findings suggest that raloxifene, which lacks the harmful effects of estrogen, is useful for the treatment of diabetic nephropathy.

Animals↗
PubMed2000

Effect of estrogen replacement on temporomandibular joint remodeling in ovariectomized rats.

PURPOSE: The investigation was performed to elucidate the effect of estrogen on the temporomandibular joint (TMJ) and to evaluate the therapeutic effect of 17beta-estradiol replacement in growing rats. MATERIALS AND METHODS: Thirty 4-week-old female albino Wistar rats were divided into 3 groups. Ten rats were ovariectomized followed by intramuscular administration of 17beta-estradiol for hormone replacement (OVX + E2), 10 were sham operated (CTL), and 10 were ovariectomized without hormone replacement (OVX). Five rats from each group were killed at 1 and 2 weeks postoperatively, and the serum estrogen was determined to verify the adequacy of replacement. The temporomandibular joints of the age-matched sham-operated control and ovariectomized groups were histomorphometrically evaluated at the same periods. RESULTS: In OVX animals, the thickness of the articular soft tissue was increased by a concomitant increase of the transitional and cartilage zones in the anterior and posterior portions at 1 and 2 weeks postoperatively. However, the bone volume was decreased in the anterior and posterior portions at 2 weeks after the surgery and the condyle was flattened. Replacement with 17beta-estradiol restored most of the histomorphometric parameters. The thickness of articular soft tissue was increased in the anterior portion by an increase in the cartilage zone in the OVX + E2 group at 2 weeks postoperatively. Increase of bone volume was found at 2 weeks after hormone replacement with a corresponding increased osteoid surface and decreased quiescent surface in the central portion at 1 week postoperatively. A flattened condyle was still noted at 2 weeks postoperatively in the OVX + E2 animals despite the hormone replacement. CONCLUSIONS: Estrogen in a physiologic concentration may play an important role in TMJ remodeling. Progesterone may be indispensable for remodeling, particularly contributing to morphogenesis.

Animals↗
PubMed1989

A review of contact dermatitis associated with transdermal therapeutic systems.

The literature is reviewed for contact dermatitis associated with transdermal therapeutic systems. Clonidine, nitroglycerin, scopolamine, estradiol and testosterone are utilized in such applications, and fentanyl is under investigation. Most cutaneous reactions are limited to localized dermatitis; however, generalized systemic effects may occur. Investigators are reporting skin-related side-effects in up to 50% of patients using transdermal clonidine; however, with the other agents, this is demonstrated much less frequently. Reactivation of the dermatitis via oral medication, following sensitization to the patch, is noted in rare instances.

Administration, Cutaneous↗
PubMed1999

Differential effects of sex hormones and phytoestrogens on peak and steady state contractions in isolated rabbit detrusor.

PURPOSE: Recent evidence suggests that sex steroids may produce rapid inhibition of voltage operated Ca2+ channels (VOCCs). Detrusor smooth muscle is highly dependent upon Ca2+ influx for receptor-activated contractions. Thus, we examined the relative effectiveness of a select group of sex steroids and dietary phytoestrogens to relax detrusor contracted with the muscarinic receptor agonist, bethanechol (BE) and the purinergic P2X receptor agonist, alpha,beta-methylene ATP (alpha,beta-MeATP). MATERIALS AND METHODS: Isolated strips of rabbit detrusor were secured to isometric force transducers in a tissue bath and length-adjusted until maximum contractions were achieved. Peak (P) contractile responses were recorded for alpha,beta-MeATP (P(ATP)) and BE (P(BE)) and steady-state (SS) responses were recorded for BE (SS(BE)) in the presence and absence of selected sex steroids and phytoestrogens (10 microM, unless indicated). RESULTS: The L-type VOCC inhibitor, nifedipine (1 to 10 microM), completely inhibited P(ATP) but reduced SS(BE) by approximately 50%, whereas the VOCC and non-VOCC inhibitor, SKF 96365, inhibited SS(BE) by approximately 95%, suggesting that P(ATP) was entirely dependent on L-type VOCCs, but (BE)-induced contractions depended also on activation of non-VOCCs. 17Beta-estradiol (estradiol) and progesterone inhibited P(ATP) by approximately 60% and 20%, respectively, and 32 microM estradiol and ethinyl estradiol inhibited SS(BE) by approximately 80 and 95%, respectively. Inhibition by estradiol was potentiated, rather than blocked, by the nuclear estrogen receptor antagonist, tamoxifen. Moreover, tamoxifen alone nearly completely relaxed SS(BE). The inactive metabolite of estradiol, 17alpha-estradiol, inhibited both P(ATP) and P(BE) by approximately 40%. Testosterone had no effect on P(ATP) and P(BE). The phytoestrogen and tyrosine kinase inhibitor, genistein, inhibited SS(BE) by 44%, whereas daidzein, a phytoestrogen without tyrosine kinase inhibitory activity, produced only a 7% inhibition. None of the phytoestrogens examined inhibited P(BE), whereas all inhibited P(ATP) by approximately 20 to 35%. A comparison of inhibition of (BE) and alpha,beta-MeATP-induced contractions by selected estrogen isomers showed some distinct differences. For example, estrone did not inhibit P(BE) or SS(BE), but inhibited P(ATP) by approximately 20%, whereas DES inhibited SS(BE) by nearly 90%, but P(ATP) by a lesser degree (approximately 70%). CONCLUSIONS: Our data support the hypothesis that 17beta-estradiol, ethinyl estradiol, DES, tamoxifen and genistein may relax detrusor contractions by inhibition of both VOCCs and non-VOCCs. Moreover, our data show that genistein, a dietary phytoestrogen with tyrosine kinase inhibitory activity, selectively reduced alpha,beta-MeATP-induced peak and BE-induced steady-state contractions, sparing the maximum response to BE. Lastly, the inactive isomer, 17alpha-estradiol, inhibited both BE- and alpha,beta-MeATP-induced contractions. These data suggest that certain dietary phytoestrogens (for example, genistein) or sex steroids, especially those with weak activity at the nuclear steroid site (for example, 17alpha-estradiol), or tamoxifen may prove therapeutically useful in treating overactive bladder caused by elevated muscarinic and purinergic receptor activation.

Animals↗
PubMed1996

Oestrogen treatment for increased bleeding in Norplant users: preliminary results.

A clinical study was conducted to assess the effects of oestrogen in controlling increased endometrial bleeding problems in the first year of Norplant use. Three treatment groups were studied: (i) 50 micrograms ethinyl oestradiol (EE); (ii) a combined pill containing 30 micrograms EE and 150 micrograms levonorgestrel (LNG); and (iii) placebo. Based on menstrual diary records, women with prolonged, frequent or irregular bleeding, as defined by World Health Organization criteria, were randomly allocated to one treatment for 21 days. A first endometrial biopsy was taken before commencing treatment and a second biopsy at either day 14 or 21 of treatment. Following treatment, all subjects kept a menstrual diary card for 90 days. In this preliminary study, 48 subjects had completed the full 90 day post-treatment record. Within 21 days of EE treatment, the number of bleeding/spotting days was reduced significantly (P < 0.02). In the 90 days following treatment, the administration of EE and EE + LNG significantly decreased the number of bleeding/spotting days (P < 0.05). There was no reduction in the number of bleeding/spotting episodes in the EE and EE + LNG groups, but the length of each bleeding/spotting episode was significantly shorter (P < 0.05). Histopathological findings of endometrium on day 0 revealed consistent progestogenic effects, and there was no apparent change in response by day 14 or 21 of EE or EE + LNG treatment. The results of this study confirm the clinical effectiveness of EE and EE + LNG for the treatment of irregular, frequent and prolonged bleeding in Norplant users.

Adult↗