progesterone cream
Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor.

Quinkler M, Meyer B, Bumke-Vogt C, Grossmann C, Gruber U, Oelkers W, Diederich S, Bahr V.

Department of Endocrinology, Klinikum Benjamin Franklin, Freie Universitat Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. LepeniesQuinkler compuserve.com

OBJECTIVE: Progesterone binds to the human mineralocorticoid receptor (hMR) with nearly the same affinity as do aldosterone and cortisol, but confers only low agonistic activity. It is still unclear how aldosterone can act as a mineralocorticoid in situations with high progesterone concentrations, e.g. pregnancy. One mechanism could be conversion of progesterone to inactive compounds in hMR target tissues. DESIGN: We analyzed the agonist and antagonist activities of 16 progesterone metabolites by their binding characteristics for hMR as well as functional studies assessing transactivation. METHODS: We studied binding affinity using hMR expressed in a T7-coupled rabbit reticulocyte lysate system. We used co-transfection of an hMR expression vector together with a luciferase reporter gene in CV-1 cells to investigate agonistic and antagonistic properties. RESULTS: Progesterone and 11beta-OH-progesterone (11beta-OH-P) showed a slightly higher binding affinity than cortisol, deoxycorticosterone and aldosterone. 20alpha-dihydro(DH)-P, 5alpha-DH-P and 17alpha-OH-P had a 3- to 10-fold lower binding potency. All other progesterone metabolites showed a weak affinity for hMR. 20alpha-DH-P exhibited the strongest agonistic potency among the metabolites tested, reaching 11.5% of aldosterone transactivation. The agonistic activity of 11beta-OH-P, 11alpha-OH-P and 17alpha-OH-P was 9, 5.1 and 4.1% respectively. At a concentration of 100 nmol/l, progesterone, 17alpha-OH-P and 20alpha-DH-P inhibit nearly 75, 40 and 35% of the transactivation by aldosterone respectively. All other progesterone metabolites tested demonstrate weaker affinity, and agonistic and antagonistic potency. CONCLUSIONS: The binding affinity for hMR and the agonistic and antagonistic activity diminish with increasing reduction of the progesterone molecule at C20, C17 and at ring A. We assume that progesterone metabolism to these compounds is a possible protective mechanism for hMR. 17alpha-OH-P is a strong hMR antagonist and could exacerbate mineralocorticoid deficiency in patients with congenital adrenal hyperplasia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12039699&dopt=Abstract progesterone, progesterone cream



progesterone cream
Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium.

Mesiano S, Chan EC, Fitter JT, Kwek K, Yeo G, Smith R.

Mothers and Babies Research Center, John Hunter Hospital, Newcastle, New South Wales 2310, Australia. smesiano mail.newcastle.edu.au

In human parturition, progesterone withdrawal and estrogen activation are not mediated by changes in progesterone and estrogen levels. Instead, these events could be facilitated by changes in the responsiveness of the myometrium to progesterone and estrogens via changes in PR and ER expression. We hypothesized that functional progesterone withdrawal occurs by increased expression of the type A PR (PR-A), which suppresses progesterone responsiveness, and that functional estrogen activation occurs by increased myometrial expression of ERalpha and/or ERbeta. To test this hypothesis we compared the abundance of mRNAs (assessed by quantitative RT-PCR) encoding PR-A, PR-B, ERalpha, and ERbeta in nonlaboring (n = 12) and laboring (n = 12) term human myometrium. PR-A, PR-B, the PR-A/PR-B mRNA ratio, and ERalpha mRNA were significantly increased in laboring myometrium, whereas ERbeta mRNA was low and unchanged. The PR-A/PR-B mRNA ratio correlated positively with ERalpha mRNA levels in nonlaboring myometrium and with HOXA10 mRNA levels in laboring myometrium. Because progesterone inhibits ERalpha and HOXA10 expression, these findings indicate that myometrial progesterone responsiveness is inversely related to the extent of expression of PR-A relative to PR-B. ERalpha mRNA levels correlated positively with cyclooxygenase type 2 and oxytocin receptor mRNA levels in nonlaboring myometrium, indicating that the increase in ERalpha expression is directly associated with the activation of contraction-associated genes and estrogen responsiveness. These data indicate that in the term human myometrium, responsiveness to progesterone is controlled by the expression of PR-A relative to PR-B and that a significant increase in this ratio underlies functional progesterone withdrawal. Our data also indicate that functional estrogen activation occurs by increased expression of ERalpha and is linked to functional progesterone withdrawal. Interaction between the PR and ER systems in the human myometrium may be critical for the control of human parturition and the coordination of progesterone withdrawal and estrogen activation required for parturition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12050275&dopt=Abstract progesterone, progesterone cream



progesterone cream
Nitric oxide and fusion with prostasomes increase cytosolic calcium in progesterone-stimulated sperm.

Arienti G, Carlini E, Saccardi C, Palmerini CA.

Laboratorio di Biochimica, Dipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.

Spermatozoa must undergo a number of reactions before they are able to fertilize the oocyte. Among these is the acrosome reaction, which is related to an increase in cytosolic Ca2+ concentration ([Ca2+]i). It has been reported in the literature that progesterone may achieve this effect through the intervention of extragenomic receptors. Nitric oxide (NO) has been reported to affect spermatozoa; the nature of the effect depends on the concentration of the radical. In a previous paper, we reported that the fusion of spermatozoa with prostasomes may also produce a transient increase in spermatozoa [Ca2+]i; in addition, this phenomenon causes a long-lasting effect that influences the action of progesterone. In this paper, we test the effects of a NO donor (CysNO) and of fusion of the prostasome to spermatozoa on progesterone-induced [Ca2+]i increase. No effect at all was noticed in the absence of progesterone stimulation. In the presence of the hormone, both CysNO and fusion increased the progesterone effect. This phenomenon was much more evident if the two treatments were used together. We conclude that both NO and fusion with prostasomes act on the progesterone-dependent pathway additively. Probably the effects are independent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12051671&dopt=Abstract progesterone, progesterone cream



progesterone cream
Estrogen increases endothelial nitric oxide synthase via estrogen receptors in rat cerebral blood vessels: effect preserved after concurrent treatment with medroxyprogesterone acetate or progesterone.

McNeill AM, Zhang C, Stanczyk FZ, Duckles SP, Krause DN.

Department of Pharmacology, College of Medicine, University of California at Irvine, CA 92697-4625, USA.

BACKGROUND AND PURPOSE: In vivo and in vitro rat models of hormone therapy were used to test the following hypotheses: (1) estrogen acts directly on cerebrovascular estrogen receptors to increase endothelial nitric oxide synthase (eNOS); (2) increased protein correlates with higher NOS activity; and (3) effects of estrogen on eNOS are altered by concurrent treatment with either medroxyprogesterone acetate (MPA) or progesterone. METHODS: Blood vessels were isolated from brains of ovariectomized female rats; some were treated for 1 month with estrogen, estrogen and progesterone, or estrogen and MPA. Isolated cerebral vessels were also treated in vitro with estrogen in the absence and presence of progesterone, MPA, tamoxifen, and the estrogen receptor antagonist ICI 182 780. Levels of eNOS were measured by Western blot, and NOS activity was measured by [14C]arginine-[14C]citrulline conversion. RESULTS: Chronic hormone treatment in vivo resulted in plasma levels of 17beta-estradiol, progesterone, and MPA in the range of values found in humans. Estrogen treatment resulted in higher levels of cerebrovascular NOS activity that paralleled increases in eNOS protein. In vitro estrogen treatment for 18 hours also resulted in a concentration-dependent increase in eNOS protein (EC50 approximately 300 pmol/L) that was completely prevented by estrogen receptor antagonists tamoxifen or ICI 182 780. However, cotreatment with progesterone or MPA, either in vivo or in vitro, did not alter the effect of estrogen on eNOS protein. CONCLUSIONS: Estrogen receptor activation in cerebrovascular tissue results in increased eNOS activity and protein levels. The latter effect persists in the presence of either progesterone or MPA. Thus, increased NO production by eNOS may contribute to the neuroprotective effects of estrogen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12053012&dopt=Abstract progesterone, progesterone cream



progesterone cream
Relation between progesterone concentrations during the early luteal phase and follicular dynamics in goats.

Menchaca A, Rubianes E.

Faculty of Veterinary Medicine, Department of Physiology, Montevideo, Uruguay.

We studied the relationship between progesterone (P4) concentrations early in the estrus cycle and follicular dynamics in dairy goats. We used seven untreated goats (control group) and six progesterone treated goats (P group) with a controlled internal drug release device from Days 0 to 5 (Day 0: day of ovulation). We performed daily ultrasonograph during the interovulatory interval to determine ovarian change and took daily blood samples to determine serum estradiol 17beta (E2) and P4 concentrations by RIA. We divided the control goats into 3- (n = 4) and 4-wave goats (n = 3), according to the number of follicular waves recorded during the ovulatory cycle. Mean progesterone concentrations between Days I and 5 were higher and mean estradiol concentrations between Days 3 and 5 were lower in 4-wave goats (P4: 3.8+/-0.2 ng/ml; E2: 1.6+/-0.2 pg/ml) than in 3-wave goats (P4: 2.0+/-0.5 ng/ml, P < 0.05; E2: 4.4+/-0.9 pg/ml, P < 0.05). Wave 2 emerged earlier in 4-wave (Day 4.2+/-0.3) than in 3-wave goats (Day 7.3+/-0.3, P < 0.05). Three out of six of the progesterone-treated goats had short cycles (mean 8.0+/-0.0 days) and ovulated from Wave 1. The other three goats had shorter cycles (mean 18.3+/-0.3 days) than the control group (20.0+/-0.2 days; P < 0.05), although they were within the normal range of control cycles (shortened cycles). In the three treated goats with shortened cycles (two with four waves, one with three waves), mean progesterone concentrations between Days I and 5 were higher (4.7+/-0.6 ng/ml) than in the 3-wave control goats. In these goats, Wave 2 emerged at Day 4.3+/-0.3, similar to the time observed in 4-wave goats but earlier (P < or = 0.05) than in 3-wave control goats. Overall results confirm a relationship between the progesterone levels and the follicular wave turnover during the early luteal phase in the goat. Higher progesterone concentrations may accelerate follicular turnover probably by an early decline of the negative feedback action of the largest follicle of Wave 1. This is followed by an early emergence of Wave 2.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12054200&dopt=Abstract progesterone, progesterone cream



progesterone cream
[The stability of progesterone in feces of different wild animal species kept in a zoological garden]

[Article in German]

Neumann G, Gottschalk J, Eulenberger K, Grun E.

Veterinar-Physiologisch-Chemisches Institut, Leipzig. vet99kzw studserv.uni-leipzig.de

Methodical investigations were carried out to monitor especially in what respect external factors (dry mass of faeces, time point of freezing, duration of storage of the frozen samples, multiple defrosting of the samples) influence the progesterone concentration of the faeces of several wild animal species (Baringo giraffe, Black rhinoceros, Dama gazelle, Mountain goat) living in a zoological garden. With reference to one animal species the dry mass of the faeces showed only small variations. Therefore, it is possible to estimate comparable progesterone levels in several faecal samples of the same animal species without drying the samples. In all cases the progesterone concentration was increased after 24 and 48 hour storage of the faecal samples at room temperature compared with samples frozen directly (significant differences for giraffes and rhinoceroses). Samples of rhinoceroses and gazelles showed no significant changes of their progesterone concentration after a long time of storage (one and three months) in the freezing state (-20 degrees C). On the other hand, in faeces of giraffes with high progesterone levels a significant decrease of the initial level was pointed out. In comparison of single and multiple defrosting of the faecal samples, the latter caused a decrease of the progesterone concentration of the faeces of all animal species investigated (significant differences for rhinoceroses and gazelles).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12073499&dopt=Abstract progesterone, progesterone cream



progesterone cream
[Species and tissue distribution specificity of proteins binding 16alpha,17alpha-cycloalkane derivatives of progesterone]

[Article in Russian]

Smirnov AN, Pokrovskaia EV, Shevchenko VP, Nagaev IIu, Miasoedov NF, Levina IS, Kulikova LE, Kamernitskii AV.

Biological Faculty, Moscow State University, Vorob'evy gory, Moscow, 119899 Russia. smirnov_an mail.ru

The binding of [3H]progesterone and [3H] 16 alpha,17 alpha-cycloalkanoprogesterones to proteins from rat, rabbit, and human uteri and other organs was studied. We found that 16 alpha,17 alpha-cycloalkanoprogesterone derivatives display affinities for the uterine progesterone receptors comparable with that of the natural hormone and no substantial species differences in the affinity. Rabbit uterus was found to have no proteins distinct from the progesterone receptor that specifically bind [3H] 16 alpha,17 alpha-cycloalkanoprogesterones. At the same time, in the human uterus, we found another protein that binds some of these progesterone derivatives; it turned out to be similar to the protein from rat uterus. A similar protein with the same selectivity and affinity for steroids was also found in rat and human kidneys. Blood serum, liver, lung, and a number of other tissues were found to contain a protein of the third type that binds the same 16 alpha,17 alpha-cycloalkanoprogesterones and exhibits submicromolar Kd values for these steroids and a very low affinity for progesterone. We speculated that the introduction of a bulky substituent adjacently to the 17 beta-side chain of progesterone could result in a change in the general biodynamics of the derivative including its transport, uptake, and accumulation in tissues, which may determine the selectivity of its effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12077851&dopt=Abstract progesterone, progesterone cream