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Proliferative effects of combination estrogen and progesterone replacement therapy on the normal postmenopausal mammary gland in a murine model.

Raafat AM, Hofseth LJ, Haslam SZ.

Department of Physiology, Michigan State University, East Lansing, USA.

OBJECTIVE: The aim of the study was to analyze the proliferative response of the normal mammary gland to combination hormone replacement therapy with estrogen and progesterone in a murine model of early versus late postmenopausal states. STUDY DESIGN: Ovariectomized mice were injected daily for up to 56 days with estrogen plus progesterone, starting at either 1 or 5 weeks after ovariectomy to simulate early and late menopausal periods, respectively. At various times after treatment, proliferation was analyzed by deoxyribonucleic acid histoautoradiography and whole-mount preparations. The induction of progesterone receptor by estrogen was also analyzed. To distinguish between estrogen- and progesterone-specific responses, we tested the effects of the antiprogesterone mifepristone (RU 486) and the antiestrogen ICI 182,780. RESULTS: The acute response to estrogen-progesterone therapy in the early postmenopausal period resulted in duct-end enlargement, ductal side branching, alveolar bud formation, and a 100-fold increase in epithelial cell proliferation. This was caused by the dominant effect of progesterone acting through the progesterone receptor. In the late postmenopausal period the acute response produced only duct-end enlargement; the 100-fold increase in epithelial cell proliferation resulted from the dominant effect of estrogen. After long-term treatment, both early and late postmenopausal glands exhibited similar morphologic features and a 9-fold higher steady-state proliferation rate than was found in control-treated groups. CONCLUSIONS: Starting combined estrogen and progesterone hormone replacement therapy in either early or late postmenopause produced a persistent, steady-state 9-fold increase in epithelial cell proliferation, which could be a contributing factor to increased breast cancer risk. The acute response in the late postmenopausal period mimics the hormonal response of the pubertal mammary gland, which in rodents is the stage most susceptible to carcinogen-induced mammary tumorigenesis. These observations raise questions about increased susceptibility of the late postmenopausal gland to carcinogenesis and a role for hormone replacement therapy in the promotion of tumorigenesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11228484&dopt=Abstract progesterone, progesterone cream



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Effects of steroid hormones on calcitonin gene-related peptide receptors in cultured human myometrium.

Dong YL, Wimalawansa S, Yallampalli C.

Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston 77555, USA.

OBJECTIVE: This study was designed to examine whether, with the use of human myometrial explants in culture, calcitonin gene-related peptide B receptors are regulated by steroid hormones. STUDY DESIGN: Myometrial tissues were obtained from the lower uterine segments from women in a nonpregnant state and pregnant women who were not in labor undergoing cesarean delivery (39.1 +/- 0.2 weeks of gestation). Tissues were incubated in Dulbecco's modified Eagle's medium without phenol red, with either 17beta-estradiol (10(-9), 10(-8), 10(-7) mol/L), progesterone (10(-8), 10(-7), 10(-6) mol/L), or in a combination of 17beta-estradiol (10(-8) mol/L) and progesterone (10(-7) mol/L). Reverse transcriptase-polymerase chain reaction was performed to examine the expression of estrogen receptor-alpha, progesterone receptor, and Western blotting was used for calcitonin gene-related peptide B receptor protein measurement in the myometrium. RESULTS: We found that (1) messenger RNA expression for both estrogen receptor-alpha and progesterone receptor in nonpregnant myometrium significantly declined within 48 hours explant culture; (2) estrogen receptor-alpha messenger RNA levels in the pregnant myometrium were 98.6%, 95.3%, and 89.8% at 12, 24, and 48 hours of incubation, respectively; (3) the levels of messenger RNA for progesterone receptor in the pregnant myometrium were 96.2%, 93.3%, 90.1%, at 12, 24, and 48 hours of incubation, respectively; (4) the 17beta-estradiol dose dependently inhibited calcitonin gene-related peptide B receptor protein in pregnant myometrium explant culture; (5) the progesterone dose dependently increased calcitonin gene-related peptide B receptor expression in pregnant myometrium explant culture; (6) the combined treatment with 17beta-estradiol (10(-8) mol/L) and progesterone (10(-7) mol/L) further enhanced myometrial calcitonin gene-related peptide B receptor protein expression. CONCLUSION: We conclude from this study that (1) the messenger RNA expression of estrogen receptor-alpha and progesterone receptor in pregnant myometrium were maintained at relatively high levels (>89%) within 48 hours incubation and that this may be useful for in vitro studies that are designed to evaluate the effects of sex steroids on the human myometrium during pregnancy and that (2) estrogen inhibits and progesterone stimulates the expression of calcitonin gene-related peptide B receptors in cultured pregnant myometrial explants. We suggest that steroid hormone-regulated calcitonin gene-related peptide B receptor expression could underlie differential myometrial sensitivity to calcitonin gene-related peptide-induced relaxation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12592257&dopt=Abstract progesterone, progesterone cream



progesterone cream
Induction of the acrosome reaction in dog sperm cells is dependent on epididymal maturation: the generation of a functional progesterone receptor is involved.

Sirivaidyapong S, Bevers MM, Gadella BM, Colenbrander B.

Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Yalelaan 7, 3584 CL Utrecht, The Netherlands.

In the current study we investigated the progesterone receptor exposure on the sperm from the testis and different parts of the epididymis, the relation to the sperm maturation stage, the functionality of the progesterone receptor and the capacity of sperm to undergo acrosome reaction. Exposed progesterone receptors on spermatozoa were detected using Progesterone-BSA conjugate labeled with fluorescein isothiocyanate (P-BSA-FITC) or a monoclonal antibody against progesterone receptor, C-262. Either progesterone or calcium ionophore was used to induce acrosome reaction. A high percentage (69 +/- 8%; mean +/- SD) of spermatozoa from the cauda epididymis showed P-BSA-FITC labeling at the onset of incubation, whereas only 0.1 +/- 1 and 4 +/- 2%, of spermatozoa from the testes, caput, and corpus epididymis, respectively, were labeled. There was no significant increase in P-BSA-FITC binding during the course of a 6 hr incubation. Treatment with either 10 microM progesterone or 5 microM calcium ionophore induced acrosome reaction in cauda epididymal sperm but not in testicular sperm, caput or corpus epipidymal sperm. It is concluded that the matured sperm of the dog from cauda epididymis and freshly ejaculated sperm demonstrate a functional membrane-bound progesterone receptor while less matured spermatozoa from the testicle, caput, and corpus epididymis fail to demonstrate such a receptor. Acrosome reaction of dog sperm can be induced using either progesterone or calcium ionophore; however, the maturation stages of spermatozoa influence this occurrence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11241783&dopt=Abstract progesterone, progesterone cream



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In vivo modulation of the splenocyte yield and composition by female sex steroid hormones.

Obradovic S, Vidic-Dankovic B, Pejcic-Karapetrovic B, Kosec D, Leposavic G.

Immunology Research Center Branislav Jankovic, Belgrade, Yugoslavia.

The study was designed to shed more light on the controversial role of the two main ovarian steroid hormones (i.e. estradiol and progesterone) in shaping the size and phenotypic characteristics of the splenic lymphocyte pool. For this purpose ovariectomized adult rats (OVX) were treated for 14 subsequent days with either estradiol or progesterone (to attain physiological concentrations of the hormones). Afterwards, the splenocyte yield, and overall number of splenocytes bearing TCR alpha beta receptor, CD4 and CD8 coreceptor were evaluated. Fourteen-day-long ovarian hormone deprivation produced an increase in the splenic weight and splenocyte yield (on the account of a rise in the number of TCR alpha beta- cells), although the number of TCR alpha beta+ cells was reduced as a result of a decrease in the size of the CD4+ cell subpopulation. Replacement of either estradiol or progesterone prevented the increase in splenic weight and reduced the splenocyte yield to values significantly lower than that in sham-OVX rats. Both the treatments completely abolished the effect of ovariectomy on the size of TCR alpha beta- cell population, but had differential effects on that of TCR alpha beta+ cell population; estradiol did not affect its size, while progesterone caused a reduction on the account of a decrease in the numbers of both CD4+ and CD8+ cells. The results suggest that: a) estradiol and progesterone have similar effects on the size of the splenic B cell population and that replacement of either estradiol or progesterone can prevent the effects of ovariectomy on the size of this population and b) estradiol does not affect while progesterone reduces the size of splenic T cell population. Thus, replacement of none of them is able to compensate the removal of gonads.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11265591&dopt=Abstract progesterone, progesterone cream



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Effects of indomethacin, luteinizing hormone (LH), prostaglandin E(2) (PGE(2)), trilostane, mifepristone, ethamoxytriphetol (MER-25) on secretion of prostaglandin E (PGE), prostaglandin F(2alpha) (PGF(2alpha)) and progesterone by ovine corpora lutea of pregnancy or the estrous cycle.

Kim L, Weems YS, Bridges PJ, LeaMaster BR, Ching L, Vincent DL, Weems CW.

Dept. of Animal Science, University of Hawaii, 96822, Honolulu, HI, USA

Two experiments were conducted to determine the luteotropin of pregnancy in sheep and to examine autocrine and paracrine roles of progesterone and estradiol-17 beta on progesterone secretion by the ovine corpus luteum (CL). Secretion of progesterone per unit mass by day-8 or day-11 CL of the estrous cycle was similar to day-90 CL of pregnancy (P >/= 0.05). In experiment 1, secretion of progesterone in vitro by slices of CL from ewes on day-8 of the estrous cycle was increased (P </= 0.05) by LH or PGE(2). Secretion of progesterone in vitro by CL slices from day-90 pregnant ewes was not affected by LH (P >/= 0.05) while PGE(2) increased (P </= 0.05) secretion of progesterone. Day 8 ovine CL of the estrous cycle did not secrete (P >/= 0.05) detectable quantities of PGF(2alpha) or PGE while day-90 ovine CL of pregnancy secreted PGE (P </= 0.05) but not PGF(2alpha). Secretion of progesterone and PGE in vitro by day-90 CL of pregnancy was decreased (P </= 0.05) by indomethacin. The addition of PGE(2), but not LH, in combination with indomethacin overcame the decreases in progesterone by indomethacin (P </= 0.05).In experiment 2, secretion of progesterone in vitro by day-11 CL of the estrous cycle was increased at 4-h (P </= 0.05) in the absence of treatments. Both day-11 CL of the estrous cycle and day-90 CL of pregnancy secreted detectable quantities of PGE and PGF(2alpha) (P </= 0.05). In experiment 1, PGF(2alpha) secretion by day-8 CL of the estrous cycle and day-90 ovine CL of pregnancy was undetectable, but was detectable in experiment 2 by day-90 CL. Day 90 ovine CL of pregnancy also secreted more PGE than day-11 CL of the estrous cycle (P </= 0.05), whereas day-8 CL of the estrous cycle did not secrete detectable quantities of PGE (P >/= 0.05). Trilostane, mifepristone, or MER-25 did not affect secretion of progesterone, PGE, or PGF(2alpha) by day-11 CL of the estrous cycle or day-90 CL of pregnancy (P >/= 0.05). It is concluded that PGE(2), not LH, is the luteotropin at day-90 of pregnancy in sheep and that progesterone does not modify the response to luteotropins. Thus, we found no evidence for an autocrine or paracrine role for progesterone or estradiol-17 36 on luteal secretion of progesterone, PGE or PGF(2alpha).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11278017&dopt=Abstract progesterone, progesterone cream



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Progesterone stimulates adipocyte determination and differentiation 1/sterol regulatory element-binding protein 1c gene expression. potential mechanism for the lipogenic effect of progesterone in adipose tissue.

Lacasa D, Le Liepvre X, Ferre P, Dugail I.

Laboratoire de Biochimie et Biologie Moleculaire, Faculte de Medecine Paris Ouest, Universite Rene Descartes, 75270 Paris, France.

Fatty acid synthase (FAS), a nutritionally regulated lipogenic enzyme, is transcriptionally controlled by ADD1/SREBP1c (adipocyte determination and differentiation 1/sterol regulatory element-binding protein 1c), through insulin-mediated stimulation of ADD1/SREBP1c expression. Progesterone exerts lipogenic effects on adipocytes, and FAS is highly induced in breast tumor cell lines upon progesterone treatment. We show here that progesterone up-regulates ADD1/SREBP1c expression in the MCF7 breast cancer cell line and the primary cultured preadipocyte from rat parametrial adipose tissue. In MCF7, progesterone induced ADD1/SREBP1c and Metallothionein II (a well known progesterone-regulated gene) mRNAs, with comparable potency. In preadipocytes, progesterone increased ADD1/SREBP1c mRNA dose-dependently, but not SREBP1a or SREBP2. Run-on experiments demonstrated that progesterone action on ADD1/SREBP1c was primarily at the transcriptional level. The membrane-bound and mature nuclear forms of ADD1/SREBP1 protein accumulated in preadipocytes cultured with progesterone, and FAS induction could be abolished by adenovirus-mediated overexpression of a dominant negative form of ADD1/SREBP1 in these cells. Finally, in the presence of insulin, progesterone was unable to up-regulate ADD1/SREBP1c mRNA in preadipocytes, whereas its effect was restored after 24 h of insulin deprivation. Together these results demonstrate that ADD1/SREBP1c is controlled by progesterone, which, like insulin, acts by increasing ADD1/SREBP1c gene transcription. This provides a potential mechanism for the lipogenic actions of progesterone on adipose tissue.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11278421&dopt=Abstract progesterone, progesterone cream



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Developmental changes in progesterone biosynthesis and metabolism in the quail brain.

Ukena K, Honda Y, Lea RW, Tsutsui K.

Laboratory of Brain Science, Faculty of Integrated Arts and Sciences, Hiroshima University, 739-8521, Higashi-Hiroshima, Japan.

We have recently demonstrated that the quail brain possesses the cholesterol side-chain cleavage enzyme (cytochrome P450scc) and 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4-isomerase (3beta-HSD) and produces pregnenolone, pregnenolone sulfate and progesterone from cholesterol. To elucidate the developmental changes in progesterone biosynthesis and its metabolism in the quail brain, we examined the expression and activity of 3beta-HSD and progesterone metabolite(s) during embryonic and post-hatched ages. Both the progesterone concentration and 3beta-HSD mRNA expression in the brain were almost constant during embryonic and post-hatched ages. The conversion of pregnenolone to progesterone (net 3beta-HSD enzymatic activity) was also constant during development and at maturity. However, without radioinert progesterone, the production of progesterone was drastically reduced in the embryonic brain, indicating active progesterone metabolism at the embryonic stage. Biochemical analysis together with HPLC and TLC revealed that only the embryonic brain actively produced 5beta-dihydroprogesterone from progesterone. Thus, progesterone production may be constant during embryonic and post-hatched development and in adulthood, whereas 5beta-dihydroprogesterone may be produced actively only in embryonic life due to 5beta-reductase.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11292466&dopt=Abstract progesterone, progesterone cream