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The effects of hormone replacement therapy on sleep-disordered breathing in postmenopausal women: a pilot study.

Manber R, Kuo TF, Cataldo N, Colrain IM.

Department of Psychiatry and Behavioral Sciences, Stanford University, CA, USA. rmanber stanford.edu

STUDY OBJECTIVES: To evaluate the impact of estrogen and estrogen plus progesterone hormone-replacement therapy (HRT) on mild-to-moderate sleep-disordered breathing (SDB) in postmenopausal women. DESIGN AND SETTING: Within-subjects, progesterone placebo-controlled prospective HRT trial in a clinical laboratory. PARTICIPANTS: Six postmenopausal women, diagnosed with mild-moderate SDB. INTERVENTION: Transdermal estradiol and oral micronized progesterone. MEASUREMENTS AND RESULTS: Subjects underwent polysomnography (PSG) on four occasions: a screening/adaptation night; a baseline night on no HRT; and two nights on HRT: one night after 7 to 12 days on estrogen plus placebo followed by a second night after 7-13 days on estrogen plus progesterone. The PSG was performed with a Sandman computerized PSG system using a standard clinical montage. Modified sleep diaries were used in the baseline week and throughout the study period. Mood was measured with the 20-item version of the Positive and Negalive Affect Schedule (PANAS). Estrogen monotherapy was associated with a significant reduction in the overall apnea-hypopnea index (AHI) (from a mean of 22.7 events per hour at baseline to a mean of 12.2 events per hour), but the AHI reduction on estradiol plus progesterone relative to baseline was not statistically significant (AHI=16.2 events per hour). Similar results were found for the percentages of total sleep time and of total non-rapid eye movement sleep time with oxygen saturation less than 90%. Estrogen, neither alone nor in combination with progesterone, significantly altered PSG- or diary-based measures of total sleep time, time to sleep onset, or time awake after sleep onset. CONCLUSIONS: While the data are preliminary and based on a small number of subjects, estrogen appeared to have a substantial beneficial effect on measures of SDB in postmenopausal women. Overall, no additional benefit was seen with the addition of progesterone. In fact, progesterone attenuated the beneficial effects of estrogen in 4 out of the 6 participants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12683475&dopt=Abstract progesterone, progesterone cream



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Fungal metabolites, PF1092 compounds and their derivatives, are nonsteroidal and selective progesterone receptor modulators.

Tabata Y, Iizuka Y, Kashiwa J, Masuda NT, Shinei R, Kurihara K, Okonogi T, Hoshiko S, Kurata Y.

Drug Discovery, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Yokohama, 222-8567, Kohoku, Japan. yuji_tabata meiji.co.jp

The potential of new nonsteroidal progesterone receptor ligands, the derivatives of PF1092C ((4aR,5R,6R,7S)-6,7-dihydroxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) discovered from fungal metabolites, was evaluated. PF1092A ((4aR,5R,6R,7S)-6-acetoxy-7-hydroxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) showed good and moderate affinity for porcine and human progesterone receptors in in vitro receptor binding assays, respectively, and partial agonist activity for the progesterone receptor, as determined in assays of two types of progesterone-dependent enzymes in human mammary carcinoma T47D cells. The derivative of PF1092C, CP8481, ((4aR,5R,6R,7S)-6-(2-furancarbonyloxy)-7-hydroxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) possessed better affinity for both progesterone receptors and showed less cross-reactivity for other steroid receptors, such as rat androgen receptor, human glucocorticoid receptor, and human estrogen receptor, and was a more potent modulator of the progesterone receptor than PF1092A. CP8400 ((4aR,5R,6R,7S)-6,7-diacetoxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) and CP8401 ((4aR,5R,6R,7S)-6,7-dipropionyloxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one), other derivatives, were indicated to be progesterone receptor antagonists. These results suggest that PF1092 compounds can serve as a new pharmacophore for potent and specific nonsteroidal progesterone receptor modulators.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11711027&dopt=Abstract progesterone, progesterone cream



progesterone cream
Role of endogenous opioid peptides in mediating progesterone-induced disruption of the activation and transmission stages of the GnRH surge induction process.

Richter TA, Spackman DS, Robinson JE, Dye S, Harris TG, Skinner DC, Evans NP.

Laboratory of Neuroendocrinology, The Babraham Institute, Cambridge CB2 4AT, United Kingdom. trichter primate.wisc.edu

How progesterone blocks the E2-induced GnRH surge in females is not known. In this study we assessed whether the endogenous opioid peptides (EOPs) that mediate progesterone negative feedback on pulsatile GnRH secretion also mediate the blockade of the GnRH surge. We treated ovariectomized ewes with physiological levels of E2 and progesterone to stimulate and block the GnRH surge, respectively, using LH secretion as an index of GnRH release. A pilot study confirmed that blocking opioidergic neurotransmission with the opioid receptor antagonist, naloxone (NAL; 1 mg/kg.h, i.v.), could prevent the suppression of pulsatile LH secretion by progesterone in our model. By contrast, antagonizing EOP receptors with NAL did not restore LH surges in ewes in which the E2-induced GnRH surge was blocked by progesterone treatment during the E2-dependent activation stage (Exp 1) of the GnRH surge induction process. However, in ewes treated with progesterone during the E2-independent transmission stage (Exp 2), NAL partially restored blocked LH surges, as indicated by increased fluctuations in LH that, in some cases, resembled LH surges. We conclude, therefore, that the EOPs that mediate progesterone negative feedback on pulsatile GnRH secretion are not involved in blockade of activation of the E2-induced GnRH surge by progesterone, but do appear to be part of the mechanism by which progesterone disrupts the transmission stage.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11713217&dopt=Abstract progesterone, progesterone cream



progesterone cream
Implications of progesterone metabolism in MA-10 cells for accurate measurement of the rate of steroidogenesis.

Rommerts FF, King SR, Span PN.

Department of Endocrinology and Reproduction, Erasmus University, 3000 DR Rotterdam, The Netherlands. rommerts endov.fgg.eur.nl

In virtually all studies with MA-10 cells, progesterone RIAs have been used to measure steroid synthesis. To test whether progesterone is a stable end product, we investigated the metabolism of added tritiated progesterone and pregnenolone in MA-10 cells over a period of 3 h. Steroids were then extracted, separated by HPLC, and identified by GC/MS. We found that more than 70% of radiolabeled steroids were converted to at least five different metabolites. A major metabolite (40%) was 5 alpha-pregnan-3 alpha or 3 beta-ol-20one. Similar studies, using radiolabeled T, demonstrated conversion to dihydrotestosterone and two forms of 5 alpha-androstane-diols. These data indicate the presence of active 5 alpha-reductase and 3 alpha- and/or 3 beta-hydroxysteroid dehydrogenase activities in MA-10 cells. Because these results suggest that progesterone is an unstable end product, to gauge the level of active metabolism, we incubated cells in the presence of inhibitors of pregnenolone metabolism and assessed pregnenolone levels by RIA. We discovered that basal levels of steroidogenesis in MA-10 cells were considerably higher than previously estimated. Moreover, dibutyryl cAMP-stimulated steroid production was linear over more than 13 h, in contrast to previous findings that measured progesterone levels. Other consequences of inaccurate assessment of steroidogenic activity in MA-10 cells because of the application of the progesterone assay are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11713220&dopt=Abstract progesterone, progesterone cream



progesterone cream
Progesterone receptor in patients with hepatolithiasis.

Sheen-Chen SM, Ho HT, Chen WJ, Sheen CW, Eng HL, Chou FF.

Division of General Surgery, Chang Gung Memorial Hospital, Kaohsiung, College of Medicine, Chang Gung University, Taiwan.

Altered gallbladder motility by progesterone has been recognized as an important factor in the development of gallstones. There are two types of hepatolithiasis, that occurs de novo in the intrahepatic ducts with an intact gallbladder (primary hepatolithiasis) and that which originates in the gallbladder and the stones migrate into the intrahepatic duct (secondary hepatolithiasis). This study was designed to evaluate the possible role of the progesterone receptor of gallbladder in the pathogenesis of hepatolithiasis. Eighty-four patients with hepatolithiasis (34 patients had primary hepatolithiasis and the other 50 patients secondary hepatolithiasis) were included. Paraffin-embedded specimens of gallbladder were processed to have an immunohistochemical staining for progesterone receptor. Positivity for progesterone receptor of gallbladder specimens was noted in eight patients (23.5%) with primary hepatolithiasis and in 23 patients (46%) with secondary hepatolithiasis. There is significant difference (P = 0.031) in positive rate for progesterone receptor between the primary hepatolithiasis and secondary hepatolithiasis groups. In conclusion, many more patients (46%) with secondary hepatolithiasis show positivity for progesterone receptor of gallbladder specimens than patients with primary hepatolithiasis (23.5%) (P = 0.031). This phenomenon is intriguing and should be of further evaluation and elucidated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11713938&dopt=Abstract progesterone, progesterone cream



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Estrogen-inducible progesterone receptors in the rat lumbar spinal cord: regulation by ovarian steroids and fluctuation across the estrous cycle.

Monks DA, Arciszewska G, Watson NV.

Department of Psychology, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, V5A 1S6, Canada.

Ovarian hormones influence the physiology of the spinal cord through incompletely understood cellular mechanisms. To date, there has been little compelling evidence for progesterone receptors in spinal cord neurons. Using two antibodies specific for progesterone receptors in an immunohistochemical investigation, we now report the presence of estrogen-inducible progesterone receptors in the spinal cord. Estrogen-inducible progesterone receptors were observed in the neurons of lamina X and the interomedialateral cell column, which are also known to express estrogen receptors. Estrogen-inducible progesterone receptors similar to those observed in females were also apparent in lamina X and interomediolateral cell column neurons in the spinal cords of males treated with estradiol. Furthermore, the density of progesterone receptors in lamina X was observed to fluctuate across the estrous cycle in female rats, with the highest progesterone receptor expression levels occurring late in proestrus, following the estradiol surge and coincident with high circulating progesterone levels. The lowest progesterone receptor expression levels were observed late in estrus following the progesterone surge. Together, these results demonstrate that estrogen-sensitive progestin targets exist in the spinal cord, and their possible role in the nervous control of reproduction and ovarian steroid modulation of nociception is discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11716578&dopt=Abstract progesterone, progesterone cream



progesterone cream
Inhibitory effects of flavonoids on the reduction of progesterone to 20alpha-hydroxyprogesterone in rat liver.

Shimada H, Uchida M, Okawara T, Abe S, Imamura Y.

Faculty of Education, Kumamoto University, 2-40-1, Kurokami, Kumamoto 860-8555, Japan.

The first aim of this study is to characterize the reduction of progesterone in rat liver. Progesterone was mainly reduced to 20alpha-hydroxyprogesterone in the cytosolic fraction of rat liver. The amount of 20alpha-hydroxyprogesterone formed from progesterone in the cytosolic fraction was significantly larger in the males than in the females and this enzyme reaction proceeded not only in the presence of NADPH, but also in the presence of NADH. Furthermore, we attempted to evaluate the inhibitory effects of 15 flavonoids on the NADPH-dependent reduction of progesterone to 20alpha-hydroxyprogesterone in liver cytosol of male rats. The order of the inhibitory potencies was luteolin>apigenin>quercetin>myricetin=fisetin=kaempferol. Other flavonoids exhibited lower inhibitory potencies. Energy-minimized molecular models demonstrated that a planar benzopyrone ring (A and C rings) with a coplanar phenyl ring (B ring) is a structural characteristic determining the inhibitory effects of flavonoids other than isoflavones.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15748835&dopt=Abstract progesterone, progesterone cream