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PubMed2003

[High concentrations of serum estradiol in assisted reproduction].

OBJECTIVES: To analyze the influence of the levels of estradiol on the day of HCG in the pregnancy rate (PR) of ICSI and oocyte donation. STUDY DESIGN: Retrospective, comparative. MATERIAL AND METHODS: 333 patients underwent ICSI and 66 in oocyte donation were included dividing them according to the level of estradiol: a) < 1,000 pg/mL, b) 1,001-3,000 pg/mL and c) > 3,000 pg/mL. Therapeutic protocol: Down regulation with acetate leuprolide in late luteal phase, COH with FSHr and/or HMG, ultrasonographic monitoring and estradiol blood levels, HCG application with > 3 follicles > 18 mm, oocyte retrieval 34 hours later. We analyzed: PR, age (including receptors), FSH and LH. Number, mature grade and fertilized oocytes; luteal support, transfer quality and type of catheter. Statistical analysis (SPSS 11) with chi square, ANOVA and Kruskall-Wallis. RESULTS: ICSI: Older patients in group A (p < 0.001), but without difference between B and C groups (p = 0.08). Statistical difference in number of follicles, number of oocytes, fertilized oocytes and transferred embryos being less in the A group (p < 0.001). Statistical difference in PR 21.7, 35.6 and 25.7% in A, B and C groups respectively (p = 0.032). Oocyte donation: Group A has younger patients (p = 0.005), FSH and LH were similiar among groups. Major number of follicles were observed to increase estradiol levels, but major quantity of metaphase II and fertilized oocytes were observed in group B (p = 0.05). PR without significant differences: 50, 51.5 and 52.3% in groups A, B and C (p = 0.977). Without statistical difference in the age of receptors; transferred embryos, type of catheter and quality on ICSI and oocyte donation groups. CONCLUSION: High estradiol levels at the day of HCG application affect the PR in patients submitted to ICSI. The best results were obtained with estradiol levels between 1,000 and 3,000 pg/mL. In oocyte donation the high concentrations of estradiol do not affect the PR of the receptors.

Adult↗
PubMedDate not supplied

[Responses of somatotropin to stimuli after brief administration of estradiol in short children].

Ethinyl estradiol has been administered orally, 100 micrograms per day during three days, to enhance the growth hormone (GH) response to usual pharmacological stimuli. 102 prepubertal short patients aged 2 to 17 years with height between 2 to 6 SD below the mean, were studied. Human growth hormone (hGH) treatment was given only to those patients whose GH response was still below 10 ng/ml after estradiol. Under hGH treatment, their growth rate increased twofold, as much in patients with partial GH deficiency as in those with complete GH deficiency. It is concluded that the lack of GH response after estradiol priming contributes to the assessment of the indication for treatment with hGH. However, since it has not been possible to give this treatment to very short children whose GH response became normal after priming, this study does not allow to preclude the effect of hGH in such conditions. Thus estradiol priming must not be included among the practical criteria leading to therapeutic decision in doubtful cases.

Adolescent↗
PubMed1984

Inhibition of human placental progesterone synthesis by danazol in vivo.

In vivo, a single dose of 1000 mg danazol was given orally to pregnant volunteers (n = 8) prior to a therapeutic abortion (8th-12th week of gestation). Changes in serum progesterone and estradiol were evaluated both by analysis of percentage values related to initial concentrations or statistically by a Kruskal-Wallis test comparing absolute steroid concentrations. Following treatment (n = 8), a significant decrease in mean plasma progesterone of about 20% was observed within 2-4 hours; progesterone levels varied between 80-120% during 24 hours in controls (n = 10); individual serum estradiol decreased up to 30% of control values 2 hours after danazol application. Changes in estradiol in controls versus tests were not statistically significant (p less than 0.05) when absolute estradiol concentrations were compared. Only a slight (10-20%) decrease in mean serum DHAS was found between 2 to 6 hours following danazol treatment. This study demonstrates the inhibitory activity of danazol on the human maternal and fetal steroidogenesis in vivo. The possible sites of action of danazol are discussed.

Abortion, Therapeutic↗
PubMed1995

The bone-specific estrogen centchroman inhibits osteoclastic bone resorption in vitro.

There is considerable interest in identifying bone-specific estrogen-like compounds with beneficial activities on bone and the cardiovascular system, but lacking side effects on the reproductive system. Two such compounds are currently under clinical investigation -raloxifene (Lilly) and centchroman (Novo-Nordisk). There is evidence suggesting that 17 beta-estradiol can inhibit osteoclastic bone resorption although this is somewhat controversial. Therefore, we examined the effect of centchroman and raloxifene, as well as 17 beta-estradiol, in the in vitro bone slice assay, where the direct effect of compounds on osteoclast activity can be assessed. Centchroman (0.001 - 1 microM) dose-dependently inhibited osteoclastic bone resorption up to 70% at 1 microM (p = 0.007) with an IC50 = 0.1 microM, while in contrast, raloxifene had no significant effect on bone resorption over the same dose range. 17 beta-estradiol (0.0001 - 1 microM) had a modest but significant inhibitory effect on resorption (40%, p < 0.05) at 1 microM, but no effect at lower physiological/therapeutic concentrations. Centchroman (1 microM) inhibited osteoclast cytoplasmic spreading by 32%, while raloxifene and 17 beta-estradiol were without effect. These results show that centchroman at therapeutic concentrations (ED50 approximately 1 mg/kg in animal models) is a potent inhibitor of osteoclastic bone resorption in vitro, suggesting that bone-specific estrogen-like molecules may have different mechanisms of action.

Animals↗
PubMed2003

A beta-lactamase-dependent Gal4-estrogen receptor beta transactivation assay for the ultra-high throughput screening of estrogen receptor beta agonists in a 3456-well format.

Estrogen action is mediated via two estrogen receptor (ER) subtypes, ERalpha and ERbeta. Selective ER modulators with balanced high affinity for ERalpha and ERbeta have been developed as therapeutics for the treatment of a variety of diseases, including hormone-responsive breast cancer and osteoporosis. Recent data based primarily on the evaluation of ER-knockout mice have revealed that ERalpha and ERbeta may regulate separate and distinct biological processes. The identification of ERbeta specific ligands could further enhance our understanding of ERbeta biology. In addition, compounds targeting ERbeta may prove useful as therapeutic agents with activity profiles distinguishable from that of estradiol. To discover novel selective ligands for ERbeta, we developed and characterized a cell-based Gal4-ERbeta beta-lactamase reporter gene assay (GERTA) in CHO cells for the ligand-induced activation of the human ERbeta. The sensitivity and selectivity of this assay were found to be comparable to those of an ER ligand-binding assay. The assay was optimized for screening in an ultra high throughput 3456-well nanoplate format and was successfully used to screen a large compound collection for ERbeta agonists. Compounds identified in a primary screen were tested in an in vitro ligand-binding assay to characterize further the selectivity and potency for ERbeta.

Animals↗
PubMed1984

Estramustine phosphate sodium.

Estramustine phosphate is approved by the Food and Drug Administration for oral use in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a conjugate of 17 beta-estradiol and the carbamate of nitrogen mustard. Although its therapeutic efficacy has been demonstrated, it is not clear to what extent each constituent contributes to estramustine's effectiveness. Estramustine phosphate therapy achieves objective response rates of 60-90 percent in advanced stage D prostatic cancer patients with no prior hormonal therapy. These results are consistent with those obtained with conventional hormonal therapy in similar patient populations. Therapeutic efficacy does not appear to increase when estramustine is used concurrently with other cytotoxic chemotherapeutic agents. An objective response rate of 20-30 percent can be anticipated in patients refractory to conventional hormonal therapy. It is in this group, the estrogen-resistant patients, that estramustine shows the most promise. Adverse effects of estramustine are similar to those of diethylstilbestrol. Gastrointestinal and cardiovascular side effects appear to be the most important and may be severe enough to require discontinuation of therapy.

Animals↗
PubMedDate not supplied

Breast cancer and HRT--what are the data?

Breast cancer remains one of women's greatest concerns. When asked regarding the likelihood of contracting a specific disease, most women believe their greatest risk of death is from breast cancer. Interestingly, we have gone from a time when estrogen was utilized as a treatment regimen in advanced breast cancer, to the current question of hormone replacement therapy increasing the risk of breast cancer. When one searches earlier data, it is noted that estrogen in several different forms, including ethinyl estradiol, as well as DES, was used as a therapeutic agent in the management of advanced breast cancer. Indeed, some of the original trials evaluating tamoxifen for adjunctive treatment of breast cancer used estrogen as the "gold-standard" treatment arm. Numerous publications have attempted to address the relationship between hormone replacement therapy and breast cancer. In the last quarter of a century, at least 50 epidemiological studies have been published, with some studies demonstrating slight increases in patients who used hormone replacement therapy for an extended time, while others demonstrated no evidence of a change in incidence. The "Nurses' Health Study" suggested that current users of hormone replacement therapy of 5 or more years' duration have a relative risk of greater than 1.4. While a well-performed and conceived trial, it suffers from limitations like all other studies. In the same time period, multiple additional studies have cast doubt on the likelihood of hormone replacement therapy markedly increasing the risk of breast cancer. When the multitude of studies is combined, the evidence seems to demonstrate that in ever-use of hormone replacement therapy the increase in relative risk is small. It is interesting that, in almost all studies published (even those demonstrating increases such as the "Nurses' Health Study") discontinuation of 2 to 5 years evaporates the increased risk. This seems biologically implausible, given the prior exposure. A recent study by Sellers et al evaluated over 41,000 patients in a prospective cohort. In this study, they closely evaluated patients who were at a higher risk of breast cancer based on a positive family history in first-degree relatives. Interestingly, they, like others, found that HRT was not associated with a significantly increased incidence of breast cancer, but did note a significantly reduced total mortality rate. When one evaluates the sum total data in the world literature regarding hormone replacement therapy and breast cancer, it is difficult to ascertain that any substantial clinical risk exists with the use of hormone replacement therapy and breast cancer. Multiple ongoing trials, including the Women's Health Initiative-a Prospective Protocol, will help to define better if any appreciable risk exists.

Breast Neoplasms↗
PubMed1997

[Effects on bone mass of oral alendronate, hormone replacement therapy and combined regimes in post-menopausal women: preliminary report on a comparative study].

The results of a prospective study that compared the short term effects on skeletal bone of oral alendronate, transdermal hormone replacement therapy (HRT) and two combined regimens with both medications are reported. Ninety six posmenopausal women with osteopenia (WHO classification) in lumbar spine or femoral neck measured by DEXA (table 1) were included in 4 therapeutic groups: Group I (n:19): 17 beta-Estradiol 50 micrograms daily transdermally/medroxiprogesterone 2.5 mg orally per day; Group II (n:42): alendronate 10 mg/day orally; Group III (n:15): HRT + alendronate 10 mg/day and Group IV (n:20): HTR + alendronate 5 mg/day. After 12 month treatment, lumbar bone mineral density (BMD) significantly increased to 3.6%; 4.1%; 6.5% y 3.1% in group I to IV, respectively (p < 0.01; figure 1). Differences among groups do not reached statistical significance. The percentage of responders to medication in each group was of 68.8%; 92%; 90% y 83%, respectively. Bone mineral density in femoral neck (FN) increased with all regimens, though mean values did not surpass method variation coefficient. Differences from baseline were statistically significant in group I (p < 0.05). The percentage of responders in this region was 58.8%; 60%; 62.5% y 45.5%, respectively. Biochemical bone markers (table 2), especially urinary pyridinoline and serum osteocalcin, showed a trend in bone metabolism inhibition that was more sustained in group III, as show mainly by the bone markers pyridinolines and osteocalcin. It is concluded that either single therapy with alendronate or estrogen or their combination halted bone loss in most patients leading to bone mass gain mainly in lumbar spine in the short term. However, bone effects with hormone replacement therapy in association with alendronate 10 mg were comparatively major, indicating the potential benefits of this regimen in the long term.

Aged↗
PubMed1988

[Chemotherapeutic characterization of new nitrosourea compounds].

The development of new nitrosoureas is described using selected examples. Results obtained with water-soluble analogs and with compounds linked to biomolecules as for instance amino acids, oligopeptides and steroids, are presented. The pronounced antineoplastic effect of some water-soluble analogs is paralleled by an increased rate of DNA-interstrand cross-links and by an increased suppression of hematopoietic stem cells. The suppression of bone marrow stem cells is followed by their rapid regeneration. Water-soluble nitrosoureas induce significant less inhibition of glutathione reductase as compared with established compounds. With regard to long-term toxicity and carcinogenicity water-soluble are superior to established compounds as for instance BCNU. Linking of the nitrosourea moiety to amino acids and oligopeptides led to some analogs with outstanding therapeutic ratio. Out of a group of steroid-linked nitrosoureas, CNC-L-alanine-estradiol-17-ester (CNC-ala-17-E2) is chosen to demonstrate the possibility of reducing bone marrow toxicity despite unchanged or increased therapeutic activity by attachment of the nitrosourea moiety to a steroid. Results of a comparative interspecies in vitro evaluation of CNC-ala-17-E2 in transplanted MXT mammary carcinoma of the mouse, MNU-induced autochthonous rat mammary carcinoma and primary human mammary carcinomas are presented and the question is discussed to what extent in vitro activity of such receptor agents using the tumor stem cell assay reflects their in vivo activity.

Animals↗
PubMed2005

Effects of estradiol and dihydrotestosterone on osteoblast gene expression in osteopenic ovariectomized rats.

Because androgens increase bone formation and estrogens inhibit bone resorption, there is a potential therapeutic use for a combined treatment of these hormones to preserve bone. We investigated the effect of dihydrotestosterone (DHT) and estradiol, alone and in combination, on the mRNA levels of genes expressed during osteoblast development in osteopenic ovariectomized (ovx) rats: 40 animals were ovx and administered vehicle or 80 mg/kg body weight DHT at 15 weeks postovariectomy. At 19 weeks postovariectomy, the rats were administered vehicle or 20 mg/kg body weight estradiol for 1 week. The treatment groups were as follows: (1) vehicle + vehicle, (2) DHT + vehicle, (3) vehicle + estradiol, and (4) DHT + estradiol. Fasting blood and urine samples were collected at 15, 17, 19, and 20 weeks postovariectomy for bone biochemical analyses. On completion of both procedures, the long bones were removed and total RNA extracted. Combined DHT and estradiol treatment increased the mRNA (P < 0.001) and serum levels of alkaline phosphatase (ALP) (P < 0.01) compared to control rats. These data suggest that combined DHT and estradiol treatment stimulates osteoblasts at an early stage of their development when ALP is expressed.

Animals↗
PubMed1982

Endocrine and therapeutic effects of aminoglutethimide in premenopausal patients with breast cancer.

Aminoglutethimide in combination with hydrocortisone provides an effective therapy in postmenopausal advanced breast cancer patients, with response rates of 37.5--50% having been found. Treatment with aminoglutethimide of only four premenopausal breast cancer patients has been reported in which two patients responded. The clinical and endocrine effects of 1000 mg aminoglutethimide daily and 20 mg hydrocortisone twice daily were studied in 18 premenopausal patients with breast cancer. Eight patients developed menstrual abnormalities, but there were no objective tumor responses in the 14 patients with assessable disease. Adrenal suppression was produced in all patients, with dehydroepiandrosterone sulfate levels suppressed to 20% of baseline values. Estrone and estradiol levels were not suppressed into the postmenopausal range. However, the therapeutic regime resulted in suppression of estrogen peaks after Pergonal administration, thus demonstrating a partial block of ovarian estrogen synthesis.

Adult↗
PubMed2006

Solid-phase organic synthesis (SPOS) of modulators of estrogenic and androgenic action.

Estrogens and androgens are key growing factors involved in a large series of disorders. Two main strategies are possible for controlling their undesirable agonist effects: (1) blocking their biosynthesis by using selective enzyme inhibitors, and (2) antagonizing their hormonal action on a receptor with an antiestrogen or an antiandrogen. In this review, we will briefly discuss the identification of a series of important therapeutic targets, through the study of steroidogenesis of potent estrogens, estrone and estradiol, and potent androgens, testosterone and dihydrotestosterone, as well as of their nuclear receptors. We will next review the solid-phase synthesis of steroidogenic enzyme (steroid sulfatase and 17beta-hydroxysteroid dehydrogenases) inhibitors and steroid (estrogen and androgen) receptor modulators, all being potential therapeutic agents for the treatment of hormone-sensitive diseases.

17-Hydroxysteroid Dehydrogenases↗
PubMed2002

Extending the postpartum anovulatory period in dairy cattle with estradiol cypionate.

Estradiol cypionate (ECP), a long-acting estrogen, has been used therapeutically in early postpartum (PP) dairy cows. In experiment 1, effects of ECP on circulating reproductive hormones, cyclicity, and ovarian function in early PP dairy cows were investigated. Lactating Holsteins received 10 mg of ECP (ECP; n = 17) or placebo (CON; n = 16) on d 7 PP. Serum and ultrasound data were acquired from 5 to 90 d of lactation. Compared to CON, ECP cows had greater serum estradiol for 10 d and lower serum FSH for 15 d posttreatment. After ECP, the appearance of follicles > or = 10 mm and time to first ovulation were delayed. Nevertheless, by 90 d PP, normal estrous cycles were found in only 50% of CON versus 88% of ECP cows. Primiparous, but not multiparous, cows receiving ECP had higher milk yields. Experiment 2 investigated effects of ECP on reproduction and milk production on a commercial dairy. Cows were blocked by parity and randomized to three treatments: 0 (n = 85), 4 (n = 85), or 10 (n = 86) mg of ECP on d 5 to 8 PP. Data included cycling status (two ultrasound examinations at 30 to 33 d PP and 7 d later), individual reproduction records, and daily milk yields from 10 to 90 d PP. In primiparous cows, ECP had no significant effects on ovulatory status or milk yields. By 40 d PP, a greater percentage of multiparous cows receiving 10 mg of ECP remained anovulatory compared with those receiving 0 or 4 mg. Milk yields were highest for multiparous cows receiving 4 mg of ECP, intermediate for the 10-mg dose, and lowest for controls. Lower conception was observed in multiparous cows receiving 4 mg of ECP. In summary, ECP delayed time to first ovulation particularly in multiparous cows, an effect associated with observed inhibition of circulating FSH. Milk yield responses to ECP were inconsistent within parity groups across the two experiments.

Animals↗
PubMed1989

Bioequivalence of two oral contraceptive drugs containing norethindrone and ethinyl estradiol.

Two oral contraceptive drugs, Formulation A and Formulation B, both of similar hormonal content, were compared with each other to determine if they were bioequivalent. Both drugs contain 1 mg of norethindrone (NET) and 0.035 mg of ethinyl estradiol (EE). Application of an interval test for the ratio of the computed parameter means demonstrated equivalence for the two formulations with respect to the 0-24 hour area under the plasma level versus time curve (AUC24), the total area under the curve (AUCtot) and for the maximum plasma concentration (Cmax) for both ethinyl estradiol and norethindrone. The data support the hypothesis for bioequivalence of the two formulations with respect to total absorption.

Adult↗
PubMedDate not supplied

Compounded percutaneous testosterone gel: use and effects in hypogonadal men.

BACKGROUND: Current methods of testosterone replacement therapy are limited to fixed-dosage patches and depot injections. Neither of these methods provides ideal therapy because of the inflexibility of dosing and other nuisance problems associated with the patches and nonphysiologic hormone levels when depot injections are used. Testosterone gels offer the potential for convenience and ease of administration, as well as flexible dosing regimens, by means of a simple topical application. METHODS: Ten hypogonadal men were selected from the author's general practice, ranging in age from 44 to 77 years. Four of these men had newly diagnosed and 6 had preexisting hypogonadism. Patients were withdrawn from their previous hormone therapy (where applicable), and baseline laboratory studies were obtained for total testosterone, free testosterone, dihydrotestosterone, estradiol, luteinizing hormone, follicle-stimulating hormone, complete blood counts, lipid panels, and chemistry panels. The patients then started taking increasing dosages of the testosterone gel until physiologic levels of testosterone were realized or until the study period (6 weeks) was concluded. There was no blinding, and each patient served as his own control. Testosterone and free testosterone levels were monitored weekly, and estradiol and dihydrotestosterone less frequently. At the conclusion of the study, all the baseline laboratory tests were repeated. A questionnaire evaluating the psychosexual well-being of the patients was administered before and after the treatment period. RESULTS: The average total testosterone level rose from 136 ng/dL to 442.9 ng/dL (P < .001). Average free testosterone levels rose from 34.2 pg/mL to 120.3 pg/mL (P < .001). Average dihydrotestosterone levels rose from 20.5 to 199.2 ng/dL (P = .006). Average estradiol levels rose only slightly from 34.1 pg/mL to 40.0 pg/mL P = .191). Average total androgens (testosterone plus dihydrotestosterone) rose in all patients to therapeutic levels, from 149.3 ng/dL to 642.1 ng/dL (P = .001). The ratio of total androgen to estradiol rose from 5.1 to 17.1 (P < .002). Luteinizing hormone was suppressed in the 6 patients for whom meaningful data were available, and decreased on average from 5.66 to 1.10 mIU/mL (P = .005) Lipid effects were measured, and a 15% drop in all cholesterol fractions was noted (P < .005). Evaluation of the questionnaire showed considerable improvements in sexual function and overall well-being in all but 1 patient. No adverse effects or nuisance-problems were detected during the duration of the study. CONCLUSION: Topically applied testosterone gels are an effective and convenient means of hormone replacement in hypogonadal men.

Administration, Cutaneous↗