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PubMedDate not supplied

[Results of low-dose treatment of oligozoospermia with clomiphene citrate].

30 oligozoospermia patients from the andrologic outpatient service of the University-Hospital for Gynecology and Obstetrics, Graz, Austria, received a treatment with clomiphene-citrate. A doses of 25 mg daily was given for 25 days, followed by a break of 5 days. This treatment cycle was repeated three times, providing a total of 4 months of therapy. Rigid criteria of selection were applied for the patients in this trial, pretreatment serum levels of FSH, LH, testosterone, prolactin and estradiol had to be in normal or low-normal range. After treatment FSH, LH and testosterone were re-evaluated and a semen analysis was performed. Six to eight weeks afterwards another spermiogram was done. A significant raise of sperm density was observed immediately after treatment and at the control 6-8 weeks after therapy. Motility and morphologic quality remained unchanged after the therapeutic course. Fructose content of seminal plasma raised significantly 6-8 weeks after therapy. FSH, LH and testosterone increased also on a significant level. 6 pregnancies could be achieved, no negative side effects of treatment had to be registered.

Clomiphene↗
PubMed2006

Inhibition of androgen-independent prostate cancer by estrogenic compounds is associated with increased expression of immune-related genes.

The clinical utility of estrogens for treating prostate cancer (CaP) was established in the 1940s by Huggins. The classic model of the anti-CaP activity of estrogens postulates an indirect mechanism involving the suppression of androgen production. However, clinical and preclinical studies have shown that estrogens exert growth-inhibitory effects on CaP under low-androgen conditions, suggesting additional modes whereby estrogens affect CaP cells and/or the microenvironment. Here we have investigated the activity of 17beta estradiol (E2) against androgen-independent CaP and identified molecular alterations in tumors exposed to E2. E2 treatment inhibited the growth of all four androgen-independent CaP xenografts studied (LuCaP 35V, LuCaP 23.1AI, LuCaP 49, and LuCaP 58) in castrated male mice. The molecular basis of growth suppression was studied by cDNA microarray analysis, which indicated that multiple pathways are altered by E2 treatment. Of particular interest are changes in transcripts encoding proteins that mediate immune responses and regulate androgen receptor signaling. In conclusion, our data show that estrogens have powerful inhibitory effects on CaP in vivo in androgen-depleted environments and suggest novel mechanisms of estrogen-mediated antitumor activity. These results indicate that incorporating estrogens into CaP treatment protocols could enhance therapeutic efficacy even in cases of advanced disease.

Animals↗
PubMed1996

Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta.

Postmenopausal osteoporosis, the most common bone disease in the developed world, is associated with estrogen deficiency. This deficiency induces increased generation and activity of osteoclasts, which perforate bone trabeculae, thus reducing their strength and increasing fracture risk. Estrogen replacement prevents these effects, indicating that estrogen negatively regulates osteoclast formation and function, but how it does this is unclear. Because functional osteoclast life span and thus the amount of bone that osteoclasts resorb could also be enhanced following estrogen deficiency, and since sex steroids regulate apoptosis in other target tissues, we investigated whether estrogen may affect osteoclast function by promoting apoptosis. 17 beta-Estradiol promoted apoptosis of murine osteoclasts in vitro and in vivo by two- to threefold. Tamoxifen, which has estrogenic effects on bone resorption, and transforming growth factor-beta 1 (TGF-beta), whose production by osteoblasts is increased by estrogen, had similar effects in vitro. Anti-TGF-beta antibody inhibited TGF-beta-, estrogen- and tamoxifen-induced osteoclast apoptosis, indicating that TGF-beta might mediate this effect. These findings suggest that estrogen may prevent excessive bone loss before and after the menopause by limiting osteoclast life span through promotion of apoptosis. The development of analogues to promote this mechanism specifically could be a useful and novel therapeutic approach to prevent postmenopausal osteoporosis.

Animals↗
PubMed2000

A prospective randomized study comparing endocrinological and clinical effects of two types of GnRH agonists in cases of uterine leiomyomas or endometriosis.

OBJECTIVE: In order to assess the endocrinological changes associated with 2 types of low-dose GnRH agonists depot as well as their clinical efficacy, we performed a randomized prospective comparison study of patients having uterine leiomyomas or endometriosis. METHODS: A prospective randomized study involving 67 patients with uterine leiomyomas or endometriosis was carried out. These patients were randomly administered either buserelin MP 1.8 mg (Group B, n = 34) or leuprolide 1.88 mg (Group L, n = 33). In each group we evaluated the symptoms of genital bleeding and hot flashes during GnRHa treatment, as well as the levels of serum LH, FSH, and estradiol 8 weeks after the start of treatment. In addition, the endometrial thickness was measured by transvaginal ultrasonography, and changes in the volume of the uterine leiomyoma or endometrial cyst at the end of treatment. The GnRHa depot was administered from 3 to 8 times, 28 days apart, in both groups. RESULTS: The incidence of menstruation-like genital bleeding 8 weeks after treatment was significantly (p < 0.01) higher in Group B. However this difference disappeared by 12 weeks after treatment. The climacteric symptom of hot flashes was found to be significantly (p < 0.01) more severe in Group L, and this tendency continued until 20 weeks after treatment. The 2 groups did not differ significantly with regard to the levels of the serum LH, FSH, and estradiol at 8 weeks after treatment or in the endometrial thickness at the end of the GnRHa treatment. In both groups, the volumes of the uterine leiomyomas were significantly (p < 0.01) lower after the treatment. In contrast, the volumes of the endometrial cysts did not decrease after administration of GnRHa in both groups. CONCLUSION: Leuprolide 1.88 induced pituitary down regulation more rapidly than buserelin MP. However the hypoestrogenic symptoms such as hot flashes were more severe in cases treated with leuprolide 1.88 than in those treated with buserelin MP. Our data confirm that the therapeutic efficacy of buserelin MP and leuprolide 1.88 are similar, with both being sufficient to treat uterine leiomyomas and endometriosis.

Adult↗
PubMed2001

Inhibition of volume-regulated anion channels in cultured endothelial cells by the anti-oestrogens clomiphene and nafoxidine.

1. We have used the whole-cell patch clamp technique to study the effect of the partial anti-oestrogens clomiphene and nafoxidine, the pure anti-oestrogens ICI 182,780 and RU 58,668 and the oestrogen ss-estradiol, on the volume-regulated anion channel (VRAC) in cultured pulmonary artery endothelial (CPAE) cells. 2. In contrast to the pure anti-oestrogens and ss-estradiol, clomiphene and nafoxidine potently inhibited the volume-sensitive chloride current, I(Cl,swell), activated by challenging CPAE cells with a 25% hypotonic solution. For clomiphene, the estimated IC(50) and Hill coefficient were 1.03+/-0.14 microM and 1.40+/-0.21 respectively. In the case of nafoxidine, these values were 1.61+/-0.29 microM and 1.24+/-0.19. 3. The inhibition induced by the pure enantiomers of clomiphene, zuclomiphene and enclomiphene, was not different from that of the racemic mixture, indicating that the interaction between clomiphene and VRAC is not stereoselective. 4. Clomiphene and nafoxidine inhibited proliferation of CPAE cells. Half-maximal inhibition was found at 1.98+/-0.17 and 1.66+/-0.21 microM respectively, concentrations similar to those for half-maximal block of VRAC. 5. In conclusion, the nonsteroidal partial anti-oestrogens nafoxidine and clomiphene are potent inhibitors of volume-regulated anion channels. The inhibition by clomiphene is not stereoselective and occurs at concentrations close to therapeutically relevant concentrations. Finally, both drugs inhibit the proliferation of endothelial cells.

Cell Division↗
PubMed2004

Estrogen-mediated protection against HIV Tat protein-induced inflammatory pathways in human vascular endothelial cells.

OBJECTIVE: It has been proposed that human immunodeficiency virus (HIV) infection-induced inflammatory environment may contribute to the pathogenesis of cardiovascular diseases. Recent studies have also demonstrated the potential role of estrogen as therapeutic agents in the prevention or treatment of cardiovascular diseases. In the present study, we assessed the hypothesis that estrogen may attenuate the HIV Tat protein-induced inflammatory pathways in human vascular endothelium. METHODS: Expression of inflammatory mediators in human endothelial cells was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Electrophoretic mobility shift assay (EMSA) also was performed to investigate the DNA-binding activities of several transcription factors, which are known to regulate expression of these inflammatory genes. RESULTS: Acute exposure of human endothelial cells to Tat markedly induced the mRNA and protein expression of IL-1beta, MCP-1, VCAM-1, and E-selectin. Tat also stimulated the adherence of inflammatory cells to endothelial cell monolayers. Significant and dose-dependent increases in NF-kappaB DNA-binding activity were observed in human endothelial cells treated with Tat. However, Tat did not affect DNA-binding activities of AP-1, CREB, and STAT1. Pretreatment with 17beta-estradiol dramatically blocked the activation of NF-kappaB in human endothelial cells exposed to Tat. In addition, 17beta-estradiol selectively inhibited the Tat-induced expression of IL-1beta. CONCLUSION: Our results suggest that estrogen may protect against Tat-induced inflammatory reactions in human vascular endothelium via blocking the NF-kappaB-mediated molecular signaling pathways. These data may contribute to understanding the pathogenesis of cardiovascular complications and development of therapeutic strategies for HIV-infected patients.

Cell Adhesion↗
PubMed1979

Iodoestrogens, syntheses, and interaction with uterine receptors.

The rationale for undertaking the present study was to evaluate the utility of iodoestradiol analogs made highly radioactive with iodine isotopes in (a) the non-invasive differentiation of estrogen-dependent from estrogen-independent breast tumors, (b) spread of metastases containing estrogen receptors, and (c) potential application in therapeutic irradiation of target tissues. In the present paper, the model syntheses of a number of nonradioactive 127I-estrogen analogs are described. The analogs were tested for their ability to displace (compete with) [3H]estradiol from receptor sites. The most active compounds, 16beta-iodoestra-1,3,5(10)-triene-3,17 beta-diol (17) and 6-iodoestra-1,3,5(10),6-tetraene-3,17 beta-diol (10b), showed a relative binding affinity of 0.57 and 0.49, respectively.

Animals↗
PubMed1984

Clinical, biochemical and histological results of a double-blind trial with 1,25-dihydroxyvitamin D3, estradiol and placebo in post-menopausal osteoporosis.

Twenty-eight women with postmenopausal osteoporosis were studied in a double-blind trial aimed to compare the effects of a one-year treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), estradiol valerate (E2) and placebo. Patients were divided into 4 groups: group 1 was given 1,25(OH)2D3 alone, group 2 was given E2 alone, group 3 was given 1,25(OH)2D3 + E2, group 4 received a placebo. The evaluation of the effects of the treatments included clinical examination of patients, the measurement of a number of biochemical parameters, such as plasma and urinary calcium and phosphate, urinary hydroxyproline, serum alkaline phosphatase, the measurement of intestinal calcium absorption and bone mineral content (BMC) and a histomorphometric study of bone biopsies from the iliac crest. The best clinical results were obtained in the patients who were given 1,25(OH)2D3 alone; appreciable results were also noticed in the patients who were given E2 alone or in combination with 1,25(OH)2D3, while patients in the placebo group worsened. BMC decreased in the placebo group and increased, although non significantly, in the patients treated with 1,25(OH)2D3 or E2 or both. The histomorphometric study showed a significant increase in the mean trabecular diameter in patients treated with 1,25(OH)2D3 alone or in combination with E2. Changes in the volume density of trabecular bone paralleled those in BMC. The results of the trial indicate that 1,25(OH)2D3 is an effective therapeutic agent in postmenopausal osteoporosis.

Aged↗
PubMed2005

Membrane 5alpha-pregnane-3,20-dione (5alphaP) receptors in MCF-7 and MCF-10A breast cancer cells are up-regulated by estradiol and 5alphaP and down-regulated by the progesterone metabolites, 3alpha-dihydroprogesterone and 20alpha-dihydroprogesterone, with associated changes in cell proliferation and detachment.

Previous studies have shown that the progesterone metabolite, 5alpha-pregnane-3,20-dione (5alphaP), exhibits mitogenic and metastatic activity in breast cell lines and that specific, high affinity receptors for 5alphaP are located in the plasma membrane fractions of tumorigenic (ER/PR-positive) MCF-7 cells. The aim of this study was to determine the effects of the mitogenic (estradiol; 5alphaP) and anti-mitogenic (3alpha-hydroxy-4-pregnen-20-one, 3alphaHP; 20alpha-hydroxy-4-pregnen-3-one, 20alphaHP) endogenous steroid hormones on 5alphaP receptor (5alphaP-R) numbers and on cell proliferation and adhesion of MCF-7 and MCF-10A cells. Exposure of MCF-7 cells for 24h to estradiol or 5alphaP resulted in significant (p < 0.05-0.001) dose-dependent increases in 5alphaP-R levels. Conversely, treatment with 3alphaHP or 20alphaHP resulted in significant (p < 0.05-0.01) dose-dependent decreases in 5alphaP-R levels. Treatment with one mitogenic and one anti-mitogenic hormone resulted in inhibition of the mitogen-induced increases, whereas treatment with two mitogenic or two anti-mitogenic hormones resulted in additive effects on 5alphaP-R numbers. Treatments with cycloheximide and actinomycin D indicate that changes in 5alphaP-R levels depend upon transcription and translation. The non-tumorigenic breast cell line, MCF-10A, was also shown to posses specific, high affinity plasma membrane receptors for 5alphaP that were up-regulated by estradiol and 5alphaP and down-regulated by 3alphaHP. Estradiol binding was demonstrated in MCF-10A cell membrane fractions and may explain the estradiol action in these cells that lack intracellular ER. In both MCF-7 and MCF-10A cells, the increases in 5alphaP-R due to estradiol or 5alphaP, and decreases due to 3alphaHP or 20alphaHP correlate with respective increases and decreases in cell proliferation as well as detachment. These results show distribution of 5alphaP-R in several cell types and they provide further evidence of the significance of progesterone metabolites and their novel membrane-associated receptors in breast cancer stimulation and control. The findings that 3alphaHP and 20alphaHP down-regulate 5alphaP-R and suppress mitogenic and metastatic activity suggest that these endogenous anti-mitogenic progesterone metabolites deserve considerations in designing new breast cancer therapeutic agents.

20-alpha-Dihydroprogesterone↗
PubMed1999

Endocrine, neuroendocrine and behavioral effects of oral dehydroepiandrosterone sulfate supplementation in postmenopausal women.

Aging in women and men is characterized by a progressive decline of circulating dehydroepiandrosterone (DHEA) levels and its sulfate ester (DHEAS). The improvement of wellbeing described in postmenopausal women treated with DHEA suggests that this steroid may exert specific actions on the central nervous system (CNS). The postmenopausal period is associated with several neuroendocrine modifications. The decrease of circulating levels of beta-endorphin is considered a hormonal marker of those changes. The aim of the present study was to investigate neuroendocrine and behavioral effects of three months of DHEAS supplementation in postmenopausal women. Postmenopausal women (n = 22) were divided in three groups: the first group was treated with oral DHEAS (n = 8) (50 mg/day), the second treated with the same dose of oral DHEAS + transdermal estradiol (n = 8) (DHEAS) 50 mg/day, estradiol 50 micrograms/patch) and the third with transdermal estradiol alone (n = 6) (50 micrograms/day). Before and after 1, 2 and 3 months of therapy, the following circulating steroid and protein hormone levels were evaluated: DHEA, DHEAS, androstenedione, testosterone, estrone, estradiol, 17-hydroxyprogesterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinizing hormone (LH), beta-endorphin, growth hormone (GH) and cortisol, and a Kupperman score was performed. Before and after treatments, plasma beta-endorphin levels were evaluated in response to three neuroendocrine tests: (a) clonidine, an alpha 2-presynaptic adrenergic agonist (1.25 mg i.v.) (b) naloxone, an opioid receptor antagonist (4 mg i.v.) and (c) fluoxetine, a serotonin selective reuptake inhibitor (30 mg p.o.). In both groups of women treated with DHEAS, mean basal serum DHEA, DHEAS, androstenedione, and testosterone levels significantly increased after treatment, while no changes were shown in the group receiving estradiol alone. Serum estradiol, estrone, GH and plasma beta-endorphin levels significantly increased progressively for the three months of treatment, with higher levels for estrone and estradiol in subjects receiving estradiol alone or plus DHEAS. Serum SHBG, cortisol, and 17-hydroxyprogesterone did not show significant variations under any treatment. Serum LH and FSH levels showed a significant decrease in groups treated with estradiol alone or plus DHEAS at the second and third months. The Kupperman score showed that all treatments were associated with similar and progressive improvement. Before therapy clonidine, naloxone and fluoxetine stimuli failed to modify circulating beta-endorphin levels. After each of the treatments, the beta-endorphin response was completely restored and was similar, independent of the kind of therapy. Restoration of the beta-endorphin response to specific stimuli suggests that DHEAS and/or its active metabolites modulates the neuroendocrine control of pituitary beta-endorphin secretion, which may support the therapeutic efficacy of the DHEAS on behavioral symptoms.

Administration, Oral↗
PubMed2001

Tamoxifen inhibits nerve growth factor-induced proliferation of the human breast cancerous cell line MCF-7.

An array of polypeptide growth factors contribute to the development of breast cancer, the most common tumor-related cause of death in women of Western countries. Therefore, breast cancer therapy should be aimed at inhibition of growth factor-dependent breast cancerous cell proliferation. However, the relative contribution of each individual factor in the development and maintenance of the transformed phenotype is largely unknown. Here we report for the first time that the proliferative effects of nerve growth factor, (NGF) a typical neurotrophin, are similar to those of epidermal growth factor (EGF) and insulin-like growth factor II, and are enhanced by 17beta-estradiol in the human breast cancer cell line MCF-7. The effect of NGF appeared to be mediated by its trkA receptors (trkA(NGFR)), as suggested by the potent inhibition of both MCF-7 cell proliferation and trkA(NGFR) phosphorylation occurring upon treatment of cultures with the selective trkA(NGFR) inhibitor K252a. Surprisingly, the antiestrogen drug tamoxifen (TAM) inhibited NGF-induced MCF-7 cell proliferation and trkA(NGFR) phosphorylation in a concentration-related fashion. The effect of TAM seemed to be estrogen receptor-independent, because the pure estrogen receptor antagonist ICI 182.780 was unable to block NGF-induced trkA(NGFR) phosphorylation. Our data underline the new emerging role of trkA(NGFR) in breast tumor growth, and suggest a related novel therapeutic use of TAM in breast cancer.

Animals↗
PubMed2000

Low areal bone mineral density values in adolescents and young adult turner syndrome patients increase after long-term transdermal estradiol therapy.

OBJECTIVE: To study the effects of long-term estradiol therapy on areal bone mineral density (aBMD) values in young adult Turner syndrome patients. METHODS: The effects of 2-year transdermal estradiol administration on lumbar, L2-L4, aBMD values were evaluated in 12 Turner syndrome patients, 15.41-21.85 years old, who had reached adult height and had low aBMD values. Puberty was induced in all at a chronological age above 12 years and menarche appeared between 13.82 and 15.40 years. The patients were on oral estrogen/gestagen therapy from then until the start of the study. Adhesive patches of 17-beta-estradiol designed to be worn for 72 h and deliver 100 microg of estradiol per day, which results in a steady mean serum estradiol level of 75 pg/ml, were used for 21 days. From day 11 to day 21, 10 mg of oral didrogesterone were also added. Nutritional and physical activity habits were evaluated at the beginning, after 1 year and at the end of the study. RESULTS: aBMD values significantly increased from 0.910 +/- 0.065 to 1.005 +/- 0.086 g/cm2 (10.06 +/- 3.37%) and the z-score from -2.38 +/- 0.63 to -1.54 +/- 0.71 (0.81 +/- 0.30 z-score). No significant differences were observed in body mass index, calcium intake and physical activity habits at the start, during and at the end of the study. CONCLUSION: In summary, our results underline the importance of estrogens for bone mass peaking and suggest that this therapeutic protocol may be useful in the therapy of Turner syndrome patients with low bone mass.

Adolescent↗
PubMed2001

Serum concentrations of 17beta-estradiol and estrone after multiple-dose administration of percutaneous estradiol gel in symptomatic menopausal women.

In two multicenter phase III efficacy studies, blood samples were obtained to evaluate the serum concentrations of 17beta-estradiol (E2) and unconjugated estrone (E1) after administration of a percutaneous gel or transdermal patch containing estradiol. In postmenopausal women, normal laboratory E2 and E1 serum concentrations range from 10-30 pg/mL and 20-40 pg/mL, respectively. Study subjects were healthy postmenopausal women with moderate to severe hot flushes occurring at least seven times daily or 60 times per week. Study 1 was a randomized, double-blind, multicenter study of percutaneous E2 gel 1.25 or 2.5 g (0.75 and 1.5 mg E2, respectively) versus placebo gel. Study 2 was a double-blind (blinded to E2 gel dose), randomized, active-controlled, multicenter, 12-week phase 3 study of E2 gel 0.625, 1.25, or 2.5 g (0.375, 0.75, or 1.5 mg E2, respectively) versus a transdermal E2 patch delivering 0.05 mg E2 per day. Serum E2 and E1 concentrations were evaluated at baseline and at week 12 for study 1 and at baseline and weeks 4, 8, and 12 for study 2 using radioimmunoassay. Median serum concentrations of E2 after 1.25- and 2.5-g gel administration appeared to be dose-proportional throughout both studies. In study 1, the median serum concentrations of E2 at week 12 were 33.5 and 65.0 pg/mL for 1.25- and 2.5-g gel dose, respectively. The corresponding E1 values were 49.0 and 58.0 pg/mL. In study 2, both E2 and E1 concentrations were relatively stable at weeks 4, 8, and 12. E2 values at week 12 for 0.625-, 1.25-, and 2.5-g gel doses and E2 patch were 25.0, 32.0, 60.0, and 38.5 pg/mL, respectively. The corresponding E1 values were 39.0, 41.0, 62.5, and 40.0 pg/mL. Application of the 1.25-g gel dose and a transdermal patch delivering 50 microg per day of E2 resulted in comparable median E2 and E1 concentrations. However, the 0.625-g gel dose did not produce E2 levels in a range expected to be consistently therapeutic in most postmenopausal women.

Administration, Topical↗
PubMed1978

Testosterone metabolism in patients with advanced carcinoma of the prostate: a comparative in vivo study of the effects of oestrogen and antiprolactin.

In the light of the high incidence of cardiovascular side effects with oestrogen therapy in patients with prostatic cancer, other medications altering androgen metabolism are under investigation. The influence of the anti-prolactin bromocriptin (CB157) on plasma kinetics of testosterone and on endogenous hormones was studied and compared with the effect of ethinyl oestradiol in 25 patients with prostatic carcinoma. Bromocriptine significantly suppressed both prolactin and testosterone, inhibited the transfer of androgen from the inner pool into the deep compartment and favoured its degradation. Ethinyl oestradiol decreased testosterone, LH and FSH, and prolonged the biological half-life of testosterone. The effects of bromocriptine on androgen metabolism might be of therapeutic value in patients with prostatic carcinoma.

Bromocriptine↗
PubMed2006

Association of CD45(dim)VLA-4 (+) cells with the NKT cell lineage and their selective expression of IL-13, IP-15, and CCR3 transcripts.

INTRODUCTION: Estrogen (E2) was shown to prevent experimental autoimmune encephalomyelitis (EAE) and to produce a novel population of regulatory CD45(dim)VLA-4(+) cells. Although their appearance was dependent upon an elevated hormonal level, E2 was not required for their production, as they also were induced by immunization with Mycobacterium tuberculosis as a component of complete Freund's adjuvant. MATERIALS AND METHODS: Molecular techniques, including ribonuclease protection assays and quantitative RT-PCR, were used to provide further characterization of CD45(dim)VLA-4(+) cells. Moreover, we determined the developmental requirements of the CD45(dim)VLA-4(+) cells using genetically modified mice and extensive flow cytometry analysis. RESULTS: Characterization of CD45(dim)VLA-4(+) mRNA profile revealed highly elevated levels of CD16, CD44, CCR3, IP-15, and IL-13 transcripts compared with their CD45(high)VLA-4(+) counterparts. Furthermore, we found up-regulation of anti-apoptotic bcl-w and bcl-xl genes and transcripts encoding the TCRalpha and CD8alpha homodimer. The production of CD45(dim)VLA-4(+) cells was evident in nude mice and in MHC class II- and beta2-microglobulin, but not in CD1-deficient mice, suggesting a crucial role for CD1 in their induction. CONCLUSIONS: These findings suggest that CD45(dim)VLA-4(+) cells might resemble natural killer T cells and imply possible roles for IL-13 and IP-15 in the protective function of CD45(dim)VLA-4(+) cells. A better understanding of how these cells, also occurring naturally during pregnancy, suppress the harmful immune response of EAE may lead to novel therapeutic approaches to combat multiple sclerosis and other autoimmune diseases.

Animals↗
PubMed2006

The effect of opiates on the activity of human placental aromatase/CYP19.

Aromatase, cytochrome P450 19, is a key enzyme in the biosynthesis of estrogens by the human placenta. It is also the major placental enzyme that metabolizes the opiates L-acetylmethadol (LAAM), methadone, and buprenorphine (BUP). Methadone and BUP are used in treatment of the opiate addict and are competitive inhibitors of testosterone conversion to estradiol (E(2)) and 16alpha-hydroxytestosterone (16-OHT) to estriol (E(3)) by aromatase. The aim of this investigation is to determine the effect of 20 opiates, which can be administered to pregnant patients for therapeutic indications or abused, on E(2) and E(3) formation by placental aromatase. Data obtained indicated that the opiates increased, inhibited, or had no effect on aromatase activity. Their effect on E(3) formation was more pronounced than that on E(2) due to the lower affinity of 16-OHT than testosterone to aromatase. The K(i) values for the opiates that inhibited E(3) formation were sufentanil, 7 +/- 1 microM; LAAM, 13 +/- 8 microM; fentanyl, 25 +/- 5 microM; oxycodone, 92 +/- 22 microM; codeine, 218 +/- 69 microM; (+)-pentazocine, 225 +/- 73 microM. The agonists morphine, heroin, hydromorphone, oxymorphone, hydrocodone, propoxyphene, meperidine, levorphanol, dextrorphan, and (-)-pentazocine and the antagonists naloxone and naltrexone caused an increase in E(3) formation by 124-160% of control but had no effect on E(2) formation. Moreover, oxycodone and codeine did not inhibit E(2) formation and the IC(50) values for fentanyl, sufentanil, and (+)-pentazocine were >1000 microM. It is unlikely that the acute administration of the opiates that inhibit estrogen formation would affect maternal and/or neonatal outcome. However, the effects of abusing any of them during the entire pregnancy are unclear at this time.

Aromatase↗
PubMed1995

Hormonal and pregnancy relationships to rheumatoid arthritis: convergent effects with immunologic and microvascular systems.

OBJECTIVE: To review sex hormones and rheumatoid arthritis (RA) and the interrelationships between hormonal, immunological, and vascular systems. DATA SOURCES: Publications detailing serum sex hormone levels and their HLA interactions, steroidogenesis, pregnancy, and therapeutic uses of sex hormones in RA. STUDY SELECTION: Controlled studies of sex hormone levels in RA patients not previously treated with glucocorticoids. DATA EXTRACTION: Mean (+/- SD) serum levels of dehydroepiandrosterone sulfate (DHEAS), testosterone (T), and estradiol (E2). DATA SYNTHESIS: Mean (+/- SD) levels were collated into tables for women with pre-versus postmenopausal onsets of disease and men. Data were also ordered across all study groups by increasing mean levels of the control subjects. Pooled data were summarized statistically, and major sources of variation between the studies were identified. CONCLUSIONS: Serum DHEAS, an adrenal androgen, was impressively decreased among women with premenopausal onset of RA. One study showed such deficiency years before disease onset. Serum T was somewhat decreased in the premenopausal onset group, but could be explained by decreased peripheral conversion of the lower levels of adrenal androgens. Women with postmenopausal onset of RA had modestly decreased serum DHEAS levels overall, but no difference in serum T, compared with controls. Male RA cases had consistently decreased serum levels of T, but not of DHEAS. Serum E2 was comparable in all RA versus control groups. The complex biology of pregnancy was interpreted as an example of vital interactions between hormonal, immunological, and vascular systems, as they may relate to the physiopathology of RA. The major age, sex, and hereditable determinants of RA were compared within a composite table of estimated relative risks. Elucidation of the interacting risk factors offers promising avenues of research in this complex disease.

Adrenal Cortex Hormones↗
PubMed2000

Parenteral estrogen versus total androgen ablation in the treatment of advanced prostate carcinoma: effects on overall survival and cardiovascular mortality. The Scandinavian Prostatic Cancer Group (SPCG)-5 Trial Study.

OBJECTIVES: To compare the effect on overall survival of total androgen ablation (TAA) with that of parenteral estrogen and to pay special attention to cardiovascular mortality. TAA (orchiectomy or a luteinizing hormone-releasing hormone analogue combined with an antiandrogen) has been proposed as superior to other endocrine treatments for patients with prostate carcinoma. Recently, the use of parenteral estrogen has been suggested to reduce or even negate the well-known cardiovascular side effects of oral estrogens. METHODS: Nine hundred fifteen patients were randomized to intramuscular injections of 240 mg polyestradiol phosphate (PEP) every second week for the first 8 weeks (5 doses) followed by a maintenance dose of 240 mg every month (n = 458) or to bilateral orchiectomy or triptorelin 3.75 mg every month combined with the antiandrogen flutamide 250 mg three times daily. The choice between orchiectomy and triptorelin was at the discretion of the clinician and patient. Patients were stratified according to performance status, presence of cardiovascular disease, and alkaline phosphatase level. An observer totally unaware of the treatment given classified all deceased patients. RESULTS: At a median follow-up of 18.5 months, no signs of a difference in overall survival were found between TAA and PEP (P <0.001). Of 458 patients, 266 (58.1%) had died in the PEP group compared with 269 (58.9%) of 457 patients in the TAA group. Within the TAA group, no difference in overall survival existed between patients who had undergone orchiectomy or who were given triptorelin. Furthermore, no differences in cardiovascular mortality were found (3.5% in the PEP group and 3.1% in the TAA group). CONCLUSIONS: The current parenteral estrogen regimen seems to be of comparable efficacy and cardiovascular safety as TAA in terms of overall survival. PEP has by far the lowest drug cost and also the lowest cumulative direct costs and thus has the highest cost-effectiveness. We suggest that parenteral estrogen be included as a therapeutic option in the endocrine management of prostate carcinoma.

Aged↗