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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that estrogen (E) likely plays a dominant role in inhibiting bone resorption in normal elderly men. Because both E and T inhibit osteoclast development and activity, stimulate osteoclast apoptosis, and inhibit osteoblast production of IL-6, it is unclear why T is less potent than E in inhibiting bone resorption in vivo. Osteoprotegerin (OPG) binds to and inactivates RANKL, the final mediator of osteoclastogenesis. In vitro, OPG production is stimulated by E, and preliminary data suggest that T has the opposite effect. Thus, we analyzed serum for OPG levels from a study in which 59 elderly men (mean age, 68 yr) were made acutely hypogonadal using a GnRH agonist and were also placed on an aromatase inhibitor to block conversion of androgens to estrogens. They were studied first under conditions of physiologic E and T replacement, and then randomized to no replacement, replacement with E alone, T alone, or both E and T. E alone resulted in an 18.6 +/- 7.9% (mean +/- SEM) increase in serum OPG levels (P < 0.05), whereas T alone tended to decrease OPG levels (by 10.0 +/- 8.5%; P < 0.05 compared with E alone). Using a two-factor ANOVA model, there was a highly significant T effect (P = 0.006) on decreasing serum OPG levels. Serum TNF-alpha, IL-6, and IL-6 soluble receptor levels increased significantly in the men who had both E and T withdrawn, and the increases in TNF-alpha and IL-6sR were absent in the men treated with either E or T. However, due to the variability in these cytokine measurements, the ANOVA models were not significant for E or T effects. Taken together, these data suggest that in vivo, T decreases OPG levels, whereas E tends to have the opposite effect. These differential effects of E vs. T on OPG production may explain, at least in part, why T has weaker effects than E on inhibiting bone resorption in vivo in humans.
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PMID:Effect of estrogen versus testosterone on circulating osteoprotegerin and other cytokine levels in normal elderly men. 1216 54

Ovarian function in adult human and nonhuman primates is dependent on events that take place during fetal development, including the envelopment of oocytes by granulosa (i.e., folliculogenesis). However, our understanding of fetal ovarian folliculogenesis is incomplete. During baboon pregnancy, placental production and secretion of estradiol into the fetus increases with advancing gestation, and the fetal ovary expresses estrogen receptors alpha and beta in mesenchymal-epithelial cells (i.e., pregranulosa) as early as midgestation. Therefore, the current study determined whether estrogen regulates fetal ovarian follicular development. Pregnant baboons were untreated or treated with the aromatase inhibitor CGS 20267, or with CGS 20267 plus estradiol benzoate administered s.c. to the mother on Days 100-164 (term = Day 184). On Day 165, baboon fetuses were delivered by cesarean section and the number of total follicles and interfollicular nests consisting of oocytes and mesenchymal-epithelial cells in areas (0.33 mm(2)) of the outer and inner cortices of each fetal ovary were quantified using image analysis. Maternal and umbilical serum estradiol levels were decreased by >95% with CGS 20267. Treatment with CGS 20267 and estrogen restored maternal estradiol to normal and fetal estradiol to 30% of normal. Although fetal ovarian weight was unaltered, the mean number of follicles +/- SEM/0.33 mm(2) in the inner (59.0 +/- 1.7) and outer (95.3 +/- 2.4) cortical regions of fetal ovaries in untreated animals was 35%-50% lower (P < 0.01) in estrogen-depleted baboons (25.9 +/- 1.4, inner cortex; 62.5 +/- 2.7, outer cortex) and was restored to normal by treatment with CGS 20267 and estrogen. In contrast, the number of interfollicular nests was 2-fold greater (P < 0.01) in fetal ovaries of estrogen-suppressed animals, a change that was prevented by treatment with estrogen. In summary, fetal ovarian follicular development was significantly altered in baboons in which estrogen was depleted during the second half of gestation and restored to normal by estradiol. We propose that estrogen plays an integral role in regulating, and perhaps programming, primate fetal ovarian development.
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PMID:Developmental regulation of baboon fetal ovarian maturation by estrogen. 1229 30

We recently demonstrated that the number of primordial follicles was significantly reduced in the ovaries of near-term baboon fetuses deprived of estrogen in utero and restored to normal in animals administered estradiol. Although the baboon fetal ovary expressed estrogen receptors alpha and beta, the mechanism(s) of estrogen action remains to be determined. It is well established that inhibin and activins function as autocrine/paracrine factors that impact adult ovarian function. However, our understanding of the expression of these factors in the primate fetal ovary is incomplete. Therefore, we determined the expression of alpha-inhibin, activin beta(A), activin beta(B), and activin receptors in fetal ovaries obtained at mid and late gestation from untreated baboons and at late gestation from animals in which fetal estrogen levels were reduced by >95% by maternal administration of the aromatase inhibitor CGS 20267 or restored to 30% of normal by treatment with CGS 20267 and estradiol benzoate. Immunocytochemical expression of alpha-inhibin was minimal to nondetectable in fetal ovaries from untreated baboons. In contrast, in baboons depleted of estrogen, alpha-inhibin was abundantly expressed in pregranulosa cells of interfollicular nests and granulosa cells of primordial follicles. Thus, the number (mean +/- SEM) per 0.08 mm2 of fetal ovarian cells expressing alpha-inhibin, determined by image analysis, was similar at mid and late gestation and increased approximately 8-fold (P < 0.01) near term in baboons treated with CGS 20267 and was restored (P < 0.01) to normal in baboons treated with CGS 20267 plus estradiol. Activin beta(A) was detected in oocytes and pregranulosa cells at midgestation and in oocytes and granulosa cells of primordial follicles at late gestation. Activin beta(B) was also expressed in pregranulosa cells and granulosa cells at mid and late gestation, respectively, but was not detected in oocytes. Neither the pattern nor the apparent level of expression of activin beta(A) or beta(B) were altered in fetal ovaries of baboons treated with CGS 20267 or CGS 20267 and estrogen. Activin receptors IA, IB, IIA, and IIB were detected by Western blot analysis in fetal ovaries at mid and late gestation, and expression was not altered by treatment with CGS 20267 or CGS 20267 and estrogen. Activin receptors IB and IIA were localized to oocytes and pregranulosa cells at midgestation and to granulosa cells and oocytes of primordial follicles at late gestation. Thus, the decrease in the number of follicles in the primate fetal ovary of baboons deprived of estrogen in utero was associated with increased expression of alpha-inhibin. Therefore, we propose that estrogen regulates fetal ovarian follicular development by controlling alpha-inhibin expression and, thus, the intraovarian inhibin:activin ratio.
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PMID:Up-regulation of alpha-inhibin expression in the fetal ovary of estrogen-suppressed baboons is associated with impaired fetal ovarian folliculogenesis. 1260 24

In the adult ovary, pituitary FSH via interaction with its receptor (FSHR) is required for follicular maturation and granulosa cell development. In humans and nonhuman primates, the pool of follicles available for adult ovarian function is established in utero. However, our understanding of the ontogeny and developmental regulation of FSHR in the ovary of the primate fetus is incomplete. Our goal was to determine whether the baboon fetal ovary expresses the full-length FSHR mRNA transcript and whether levels are developmentally regulated. Fetal ovaries were obtained at mid (Day 100) and late (Day 165) gestation (term = Day 184) from untreated baboons and on Day 165 from baboons in which fetal estrogen levels were either decreased by >95% by treatment with the aromatase inhibitor CGS 20267 or restored to 30% of normal by treatment with CGS 20267 plus estradiol benzoate administered s.c. to the mother on Days 100-164. The full-length 2088-base pair FSHR mRNA transcript was expressed in ovaries of adult and fetal baboons untreated or treated with CGS 20267 or CGS 20267 and estrogen. Mean (+/-SEM) FSHR mRNA levels (ratio of FSHR mRNA:18S rRNA), quantified by reverse transcription polymerase chain reaction, were increased (P < 0.05) 2-fold between mid (0.34 +/- 0.06) and late gestation (0.76 +/- 0.07), an increase prevented (P < 0.05) in estrogen-depleted baboons (0.44 +/- 0.10) and partially restored by treatment with CGS 20267 and estrogen (0.58 +/- 0.16). We previously showed that the number of follicles/0.33 mm2 in fetal ovaries of untreated baboons in late gestation was reduced 50% by treatment with CGS 20267 and restored to normal in baboons treated with CGS 20267 and estrogen. Thus, when corrected for the number of follicles/0.33 mm2, FSHR mRNA levels were similar in baboon fetal ovaries untreated (0.010 +/- 0.001) or treated with CGS 20267 (0.009 +/- 0.002) or CGS 20267 and estrogen (0.007 +/- 0.003). We conclude that estrogen plays a major role in regulating ovarian FSHR mRNA expression in the primate fetus, and that the developmental increase in FSHR mRNA levels reflects the estrogen-dependent increase in folliculogenesis (i.e., increased number of granulosa cells and oocytes).
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PMID:Developmental regulation of follicle-stimulating hormone receptor messenger RNA expression in the baboon fetal ovary. 1260 56

Cytochrome P450 aromatase activity (AA) was measured in different tissues of the sea bass (Dicentrarchus labrax L.) using a tritiated water release assay that was previously optimized and validated for this species. In adult fish entering the reproductive season, AA was highest on a per mg protein basis, in the brain (2.04+/-0.4 pmol/mg prot/h; mean+/-SEM), followed by the ovary (0.59+/-0.1) and was detectable in visceral fat (0.21+/-0.05), liver (0.08+/-0.009), and head kidney (0.03+/-0.004). However, AA was negligible in the rest of the tissues tested: heart, testis, muscle, and spleen. Consistent with results obtained in other species, dissection of the brain into its major constitutive parts revealed that AA was concentrated in areas implicated in the control of reproduction, including the olfactory bulb, telencephalon, and hypothalamus (range: 2.6-16.2 pmol/mg prot/h), as well as the pituitary gland (6.2-9.3 pmol/mg prot/h). Lower AA was noted in the optic bulb, cerebellum, and medulla. However, in contrast to some previously published reports concerning the content and distribution of neural aromatase in fish, males consistently exhibited higher AA than females. In one-year-old juvenile fish completing the process of gonadal sex differentiation, brain AA (0.63 pmol/mg prot/h) was similar in both sexes and ten times lower than that measured in the brain of first time spawners (6.52 pmol/mg prot/h), in this case with males showing an overall higher (24%) activity than females. When surveyed throughout the year, brain AA dramatically changed during the reproductive cycle. Maximum average values of approximately 7 pmol/mg prot/h were obtained that coincided with the spawning season. The peak in brain AA was preceded by two and one months by the peak of plasma testosterone and the peak of the gonadosomatic index, respectively. This is the first measurement of the distribution of the activity of a steroidogenic enzyme in the sea bass, an established model in comparative endocrinology. Together, these results demonstrate sex- and seasonally-related variations in AA and establish the basis for further comparative studies of certain androgen-mediated actions through locally formed estrogen in both central and peripheral targets.
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PMID:Aromatase activity in the European sea bass (Dicentrarchus labrax L.) brain. Distribution and changes in relation to age, sex, and the annual reproductive cycle. 1281 69

Exemestane (EXE) is an irreversible aromatase inactivator used for the treatment of advanced postmenopausal breast cancer. EXE is orally active but its bioavailability is about 5% due to its low solubility in water and the extensive first pass effect. It is known that cyclodextrin (CD) complexation enhances solubility and oral bioavailability of poorly soluble drugs. Thus, it was aimed to design and develop cyclodextrin complexes in powder and tablet forms containing EXE to improve aqueous solubility and in vitro permeability. In this study, inclusion complexes of EXE were prepared with three different CD derivatives (methyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin) and by two different preparation methods (kneading and colyophilization) and the complexes were characterized with (1)H NMR, FT-IR, SEM, X-ray and DSC analyses. Both inclusion complexes and tablet formulations prepared using EXE:CD inclusion complexes showed significant improvement in the dissolution profile of this oral antiestrogen drug. Furthermore, Caco-2 cell permeation studies revealed that apparent permeability constant for EXE was increased by 3-fold via cyclodextrin complexation. In conclusion, complexation of EXE with cyclodextrin derivatives, randomly methylated-beta-cyclodextrin in particular, results in a more efficient tablet formulation with improved dissolution and better permeation suggesting an enhancement in oral bioavailability of the drug.
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PMID:Alternative oral exemestane formulation: improved dissolution and permeation. 2067 61

Chitosan nanoparticles (CNPs) have been proven considerable delivery agents due to their remarkable physicochemical properties. Present study reports the fabrication of CNPs by ionic gelation process and their characterization by different approaches. The constructed nanoparticles were successfully conjugated with eurycomanone with significant entrapment efficiency. Particle size of chitosan and chitosan conjugated eurycomanone nanoparticles were 126.2nm and 130nm respectively. Scanning electron microscopy showed that the particles were spherical in shape and well dispersed. Cross-linking between CNPs and eurycomanone (CENPs) were confirmed by Fourier-transform infrared (FTIR) spectroscopy. Fluorescent nanoparticles were prepared by using Rhodamine-6G dye, characterised by SEM and confirmed for conjugation by FTIR. Biodistribution of CENPs showed the presence of fluorescent nanoparticles in liver, kidney, testes and brain of C. magur. The toxicity of CENPs was evaluated by comparing the histological sections of catfish testes collected from treated and control group. No signs of toxicity were seen in testes after the delivery of CENPs. Molecular docking study revealed high spontaneous binding ability of chitosan with eurycomanone and aromatase enzyme. The study reports that CNPs can act as a stabilizing agent for eurycomanone formulation and could be a promising approach to increase the reproductive performance of the fishes.
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PMID:Fabrication and characterization of chitosan conjugated eurycomanone nanoparticles: In vivo evaluation of the biodistribution and toxicity in fish. 2944 67


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