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PubMed1995

Ring A reduced progestins potently stimulate estrous behavior in rats: paradoxical effect through the progesterone receptor.

The effect of ring A reductions at C5 and C3 on the capacity of the progesterone (P) molecule to stimulate estrous behavior was studied in ovariectomized estrogen primed rats (5 micrograms estradiol benzoate, EB, 40 h before progestin administration). Dose-response curves (dose range: 0.75-200 micrograms) for the lordosis quotient (LQ), lordosis score (LS), and proceptivity were constructed for P and all its ring A reduced metabolites: 5 alpha-pregnanedione (alpha DHP), 5 beta-pregnanedione (beta DHP), 3 alpha,5 alpha-pregnanolone (3 alpha,5 alpha-Pgl), 3 alpha,5 beta-pregnanolone (3 alpha,5 beta-Pgl), 3 beta,5 alpha-pregnanolone (3 beta,5 alpha-Pgl), and 3 beta,5 beta-pregnanolone (3 beta,5 beta-Pgl). Progestins were dissolved in propylene glycol and IV injected through an indwelling jugular catheter. Tests for lordosis and proceptivity were made at 5, 30, and 120 min after progestin injection. Weak, though significant lordosis behavior was observed at 5 min following the injection of some of the progestins, particularly the pregnanolones. Maximal responses were obtained at 120 min postinjection for all progestins. Dose response curves of the LQ, LS, and proceptivity were dualistic for alpha DHP and both 3 alpha pregnanolones, smaller responses being observed with high doses. Relative potency analysis revealed that alpha DHP, 3 alpha,5 beta-Pgl, 3 beta,5 alpha-Pgl, and 3 alpha,5 alpha-Pgl were considerably more potent for eliciting lordosis than P (14, 13.7, 9, and 4-fold, respectively). The same order of relative potencies was found for both LS and proceptivity. 3 beta,5 beta-Pgl and beta DHP were only slightly more potent than P (2 and 1.5-fold, respectively). In a second study, the antiprogestin RU486 (5 mg, SC), injected 60 min before one of four selected progestins (alpha DHP, 3 alpha,5 alpha-Pgl, 3 alpha,5 beta-Pgl, and 3 beta,5 beta-Pgl), significantly inhibited their action on estrous behavior (lordosis and proceptivity) when tested at 60 and 120 min postinjection. On the other hand, RU486 failed to inhibit early lordotic responses obtained at 5 and 30 min following 3 alpha,5 alpha-Pgl and 3 alpha,5 beta-Pgl. Similarly RU486 was ineffective in inhibiting lordosis in ovariectomized rats treated only with estradiol (3 micrograms of EB/day for 7 days). Data suggest that: (i) ring A reduction of the P molecule plays an important role in the normal facilitation of estrous behavior in the rat; and (ii) ring A reduced progestins provoke this effect by acting, at least partially, through the progesterone receptor.

Animals↗

PubMed1990

Progesterone modulation of gonadotropin secretion by dispersed rat pituitary cells in culture. II. Intracellular metabolism and progestin receptors.

Dispersed, estradiol (E2)-treated, rat pituitary cell cultures were used to examine the intracellular processing of progesterone (P) associated with its modulation of gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) secretion. Enhancement and suppression of LH release was only observed with acute and chronic exposures to P or other naturally occurring and synthetic progestins avidly bound by pituitary progestin receptors; such responses were inhibited by cotreatment with the antiprogestin RU486 but not with the antiandrogen flutamide, illustrating the importance of the P + receptor interactions. However, cotreatment with a 100-fold molar excess of the 5 alpha-reductase inhibitor 17 beta-N,N-diethyl-carbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA) had no effect on the expression of P's modulatory actions. Additional studies using different E2 pretreatments revealed that P enhanced LH release when progestin receptor levels were elevated. Moreover, the magnitude and duration of P's influences on LH release increased in cells with higher receptor levels. However, there were several instances in which progestin receptor level and P modulation of LH release did not correlate. In several instances E2-induced progestin receptor levels stabilized at a maximal level whereas P enhancement of LH secretion continued to increase in size and duration. These findings underscore the importance of progestin receptors for P-induced modulation of LH secretion and illustrate that 5 alpha-reduction and further metabolism of P is not obligatory for the expression of these responses. In addition, our data demonstrate that the important cellular mechanisms underlying E2 priming of gonadotroph responsiveness to P entail the induction of progestin receptor levels and other as yet unidentified cellular processes.

Androgen Antagonists↗

PubMedDate not supplied

A comparison of the action of progestins and estrogen on the growth and differentiation of normal adult human osteoblast-like cells in vitro.

Estrogen/gestagen replacement therapy prevents excess bone loss in postmenopausal women. The mode of action by which these sex steroids exert their anabolic effects on bone has not been completely clarified yet. In this study, 17 beta-estradiol (E2), as well as progestins progesterone (P), dydrogesterone (DD), 20 alpha-dihydroxydydrogesterone (DHD), medroxyprogesterone acetate (MPA), and cyproterone acetate (CPA) were able to stimulate the mitogenesis and differentiation of normal adult human osteoblast-like (HOB) cells harvested from female trabecular bone explants. The different progestins exerted a more pronounced stimulatory effect on HOB proliferation than E2 did. The combination of E2 with P, DD, or DHD did not result in a statistically significant further increase of HOB proliferation, as compared with the progestins alone. In general, E2 showed a stronger differentiation-inducing effect than the progestins, as measured by histochemical staining of the HOB cells for alkaline phosphatase activity. Combining E2 and the progestins did not result in a further increase of the number of alkaline phosphatase positive cells, compared with E2 alone. The different progestins proved to be equally potent in stimulating HOB proliferation and differentiation. In conclusion, progestins as well as E2 exerted anabolic but differential effects on normal adult human osteoblasts in vitro.

Aged↗

PubMed2003

Differential effects of progestins on the circulating IGF-I system.

OBJECTIVE: Circulating insulin-like growth factor-I (IGF-I) is mainly produced by the liver under GH stimulation and is influenced by nutrition and insulin. IGF-I bioavailability is regulated by interactions with specific binding proteins (IGFBPs). The objective of this paper is to review available data on modifications of the IGF-I system in menopausal women during HRT, with particular attention on the differential effects of progestins. METHOD: All available reports on the effects of different forms of HRT have been taken into account. RESULTS: Available data suggest that different kinds of HRT have different effect on the IGF-I system, depending on route of administration, oestrogen dose, basal IGF-I values and type of progestin. Oestrogen administration (oestrogen replacement therapy (ERT)) reduces circulating IGF-I mainly through a hepatocellular effect. The decrease is sharper when oral ERT is used (first pass hepatic effect) and in women with higher basal IGF-I levels. The progestins endowed with androgenic effects--the 19-nortestosterone derivatives and, to a lesser extent, medroxyprogesterone acetate (MPA)--tend to reverse the IGF-I decrease induced by oral oestrogens. In contrast, progestins devoid of androgen-like hepatocellular and metabolic actions (e.g. dydrogesterone) do not interfere with the IGF-I decrease induced by oral oestrogens. Data on the effect of ERT on IGFBP-3 level are not consistent. Oral ERT, via hepatocellular actions (amplified by the first pass hepatic effect) causes a two to three-fold increase in IGFBP-1 levels. Androgenic progestins oppose the IGFBP-1 increase induced by oral oestrogens. Data on the effect of ERT and different progestins on the level of free IGF-I are scant and inconsistent. CONCLUSION: Even if some aspects need clarification, available data demonstrate that different progestins have differential effects on the circulating IGF-I system.

Estrogen Replacement Therapy↗

PubMed1985

Progestin regulation of progesterone biosynthetic enzymes in cultured rat granulosa cells.

Progestins have recently been shown to augment gonadotropin-stimulated progesterone and 20 alpha-hydroxypregn-4-en-3-one (20 alpha-OH-P) biosynthesis in cultured rat granulosa cells. The mechanism by which progestins autoregulate ovarian progestin biosynthesis was investigated by studying the modulation of pregnenolone biosynthesis as well as the activities of the enzymes 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) and 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSD). Granulosa cells obtained from immature hypophysectomized, estrogen-treated rats were cultured with FSH and/or progestins. Pregnenolone production was measured in the presence of cyanoketone (10(-6) M) to inhibit 3 beta-HSD activity. Enzymatic activities of 3 beta-HSD and 20 alpha-HSD were determined in cell homogenates by direct enzyme assays. FSH stimulated pregnenolone production, while treatment with progesterone or R5020 alone was ineffective. Concomitant treatment with the progestins further enhanced FSH-stimulated pregnenolone production in a dose-dependent manner with minimal effective doses of 10(-8) and 10(-7) M for R5020 and progesterone, respectively. In FSH-primed cells, LH increased pregnenolone accumulation, and concomitant treatment with R5020 also enhanced the LH action. Furthermore, the gonadotropins stimulated the activity of 3 beta-HSD, and this effect was further enhanced by concomitant treatment with either R5020 or progesterone in a dose-dependent manner. In addition, the 20 alpha-HSD activities were enhanced by progestins in cells treated with FSH but not with LH. Thus, both natural and synthetic progestins stimulate the gonadotropin-induced progesterone production in cultured granulosa cells via enhancing the 3 beta-HSD enzyme as well as pregnenolone biosynthesis.

20-Hydroxysteroid Dehydrogenases↗

PubMed2005

[Propause survey: profile of patients treated with progestins in perimenopause].

UNLABELLED: Progestins are widely used in France for treatment of perimenopause. OBJECTIVES: To evaluate the real use of progestins in daily practice. MATERIAL AND METHODS: A transverse epidemiological survey conducted between May and June 1998, by 284 gynecologists representative of French private practitioner gynecologists, who selected the first 4 patients treated with progestins for perimenopause. RESULTS: For 887 observations collected, the most frequent indications of prescription were: functional disorders of perimenopause (57%), mastalgia (47%), premenstruel syndrome (38%), endometrial pathology (29%) and ovulation inhibition (28%). Multiple reasons were present in 81% of patients: when progestin was prescribed more than 10 days per cycle, breast pathologies were the most frequent indication and the length of treatment was more than one year; when progestin was prescribed 10 days per cycle, isolated menstrual irregularities (without breast or endometrium pathology) predominated and the length of treatment was one year or less. The most widely used progestin classes were pregnanes and norpregnanes; there was an estrogene co-prescription in 17% of cases, more frequently in women with perimenopause disorders. CONCLUSION: We found the following pattern for progestin prescription in perimenopause: 10-day prescription for one-third of the women, 11 to 15 days for one-third, and 20 days per cycle for one-third. We thus observe some differences with recommended use. This difference is observed either with the initial prescription or with symptom-related dose adaptation.

Drug Prescriptions↗

PubMed2001

Rat uterine complement C3 expression as a model for progesterone receptor modulators: characterization of the new progestin trimegestone.

Progestins have a wide variety of activities in female reproduction. There are also pharmacological applications for progestins, including hormone replacement therapy and contraception. Here we report the development and characterization of the rat uterine complement component C3 mRNA as a molecular target for the evaluation of the antiestrogenic activity of progestins in the uterus. In this assay, ethinyl estradiol (EE) is used to stimulate C3 expression and progestins are then evaluated for their ability to inhibit this expression. The three reference progestins, progesterone (P4), levonorgestrel (LNG), and medroxyprogesterone acetate (MPA) blocked the increase in C3 mRNA levels induced by EE. Dexamethasone (DEX) and 17alpha-methyl testosterone did not inhibit the estrogen induced C3 mRNA levels; in fact, DEX caused a further increase in C3 mRNA levels. Finally, the antiprogestin RU486 was able to block the MPA inhibition of C3 message. RU486, like DEX, caused an increase in C3 mRNA levels above that of estrogen treatment alone. The model was also used to evaluate trimegestone (TMG), a new steroidal progestin, that has been shown to be a potent and selective progesterone receptor agonist. The activity of TMG in the rat uterine decidualization and ovulation inhibition assays was similar to MPA. However, in the C3 model, TMG caused a dose-dependent inhibition of the EE induced C3 message and was approximately five-fold more potent in this model than MPA (EC(50) of 4.7 microg/kg and 26.5 microg/kg, respectively). Therefore, TMG was a more potent antagonist of estrogenic activity in the uterine endometrium than any of the reference progestins tested and therefore may be more effective in protecting the endometrium in hormone replacement therapy.

Animals↗

PubMed1999

Progestins' rapid facilitation of lordosis when applied to the ventral tegmentum corresponds to efficacy at enhancing GABA(A)receptor activity.

Progestins may have actions in the midbrain though gamma-aminobutyric acid (GABA)A/benzodiazepine receptor complexes (GBRs) that are relevant for sexual receptivity. The efficacy and time course of various progestins to enhance lordosis when applied to the ventral tegmental area (VTA), following progesterone to the ventral medial hypothalamus (VMH) was investigated. Ovariectomized, oestrogen-primed rats and hamsters with contralateral VMH/VTA cannulae were tested for lordosis before and after implants of P to the VMH and progestins to the VTA. The progestins were P, 5alpha-pregnan-3,20-dione (DHP), 5alpha-pregnan-3alpha-ol-20-one(3alpha,5alpha-TH P), 5alpha-pregnan-3alpha,21-diol-20-one (THDOC), 5beta-pregnan-3alpha-ol-20-one(3alpha,5beta-THP) , 17alpha-ol-6-methyl-4,6-pregnadiene-3,20-dione-17-acetate (megestrol acetate, MA), and 6-chloro-17-ol-4,6-pregnadiene-3, 20-dione-17-acetate (chlormadinone acetate, CA). Progestins' effects on GABA-mediated chloride influx and SR 95531 binding in cortical and midbrain tissue, respectively, were examined in rats and hamsters. 3alpha,5alpha-THP and THDOC implants to the VTA were the most effective at immediately facilitating lordosis of rats and hamsters. Two hours later all other progestins, except MA and CA, increased lordosis in rats; only P, 3alpha,5alpha-THP, and THDOC were effective in hamsters. The progestins' effectiveness at facilitating lordosis were similar to their effects on GABA-stimulated chloride influx and SR 95531 receptor binding (3alpha,5alpha-THP and THDOC>P>DHP>3alpha, 5beta-THP>MA and CA). These findings suggest that progesterone lordosis enhancing effects in the rodent VTA may be via GBRs.

Animals↗

PubMed1999

Opposing effects of estrogen and progestins on LDL oxidation and vascular wall cytotoxicity: implications for atherogenesis.

Estrogens are widely regarded as beneficial to arterial wall health. Among the mechanisms of this benefit are antioxidant effects on LDL and the arterial wall. Because progestins oppose the effect of estrogen in several systems, we asked if progestins oppose the antioxidant effect of estrogen. To study this question, LDL and various female sex hormones were incubated alone and combined in the absence or presence of bovine aortic endothelial cells, placental trophoblast, or macrophages, and LDL oxidation and cytotoxicity were quantitated. In the absence of cells, LDL incubated with copper in phosphate-buffered saline enhanced the oxidation of LDL. When 17beta-estradiol was added to this system, an antioxidant effect was observed. Progestins inhibited this protective estrogenic effect. In endothelial cell culture, progestins also opposed the antioxidant effect of estrogen, with the strongest antiestrogenic effect seen with the synthetic progestins, levonorgestrel and medroxyprogesterone acetate (MPA). Endothelial cell cytotoxicity was proportional to the enhanced lipid peroxide formation observed with progestins or estrogen. Similar opposing effects were seen when estrogen and progesterone were added to primary cultures of placental trophoblast or macrophages. Thus, three cell culture systems modeling circulating arterial blood contact with cell surfaces demonstrated opposing effects of estrogens and progestins on LDL oxidation and cell cytotoxicity. These studies are in keeping with published reports that female sex steroids influence LDL oxidation in vivo and consequent arterial wall injury.

Arteriosclerosis↗

PubMed2000

Progestins abrogate estrogen-induced changes in the insulin-like growth factor axis.

OBJECTIVE: We sought to investigate the effect of oral progestins on estrogen-mediated changes in the insulin-like growth factor axis in the peripheral circulation. STUDY DESIGN: Oral conjugated equine estrogen alone or in combination with medroxyprogesterone acetate, desogestrel, or norethindrone was given in a randomized triple-crossover fashion to 10 healthy postmenopausal women, and the effects on the insulin-like growth factor axis were determined. RESULTS: Baseline circulating insulin-like growth factor I levels were significantly reduced by conjugated equine estrogen (359 +/- 54 vs 225 +/- 44 ng/mL; P =.0001). This effect was reversed by progestins (medroxyprogesterone acetate, 254 +/- 44 ng/mL; desogestrel, 266 +/- 50 ng/mL; norethindrone, 286 +/- 48 ng/mL; F = 12.2; P =.0015). Free insulin-like growth factor I was reduced by conjugated equine estrogen (1.00 +/- 0.15 ng/mL vs 2.10 +/- 0.39 ng/mL; P =.004), but addition of progestogens had no further effect. Insulin-like growth factor II and insulin levels were unaffected by conjugated equine estrogen or progestins. Plasma insulin-like growth factor binding protein 1 concentration increased significantly from baseline with conjugated equine estrogen alone (44.1 +/- 6.0 vs 154 +/- 30 microg/L; P =.003). This rise was opposed by progestins of increasing androgenicity (medroxyprogesterone acetate, 130 +/- 26 microg/L; desogestrel, 100 +/- 16 microg/L; norethindrone, 78.0 +/- 12 microg/L; F = 12.5; P =.0015). Insulin-like growth factor binding protein 3 levels fell with conjugated equine estrogen, and this was reversed by progestins (conjugated equine estrogen, 2.17 +/- 0.13 mg/L; vs norethindrone and conjugated equine estrogen, 2.41 +/- 0.12 mg/L; F = 7.6; P =.01). Insulin-like growth factor binding protein 4 levels increased with conjugated equine estrogen with or without progestins, whereas insulin-like growth factor binding protein 2 levels were unchanged. CONCLUSIONS: Coadministration of androgenic progestins abrogates estrogen-related changes in circulating insulin-like growth factor I, insulin-like growth factor binding protein 1, and insulin-like growth factor binding protein 3. Such hormone replacement therapy-induced changes may have significant consequences for the development of cardiovascular disease and osteoporosis and implications for the use of insulin-like growth factor I in monitoring growth hormone replacement.

Cross-Over Studies↗

PubMed1997

Novel progesterone target genes identified by an improved differential display technique suggest that progestin-induced growth inhibition of breast cancer cells coincides with enhancement of differentiation.

Progesterone is an important regulator of normal and malignant breast epithelial cells. In addition to stimulating development of normal mammary epithelium, it can be used to treat hormone-dependent breast tumors. However, the mechanism of growth inhibition by progestins is poorly understood, and only a limited number of progesterone target genes are known so far. We therefore decided to clone such target genes by means of differential display polymerase chain reaction. In this paper, we describe an improved differential display strategy that eliminates false positives, along with the identification of nine positive (TSC-22, CD-9, Na+/K+-ATPase alpha1, desmoplakin, CD-59, FKBP51, and three unknown genes) and one negative progesterone target genes (annexin-VI) from the mammary carcinoma cell line T47D, which is growth-inhibited by progestins. None of these genes have been reported before to be progesterone targets. Regulation of desmoplakin, CD-9, CD-59, Na+/K+-ATPase alpha1, and annexin-VI by the progestin suggests that progesterone induces T47D cells to differentiate. Three of these genes were repressed by estradiol and up-regulated by the progestin. Estradiol treatment of T47D cells also leads to formation of lamellipodia and delocalization of two cell adhesion proteins, E-cadherin and alpha-catenin. All these effects were reversed by the progestin. These data suggest that estradiol dedifferentiates T47D cells, while progestins have the opposite effect. This may be linked to the capacity of progestins to inhibit tumor growth.

Base Sequence↗

PubMed2004

Clinical profile of contraceptive progestins.

The term progestogen has been widely utilized to indicate the general class of agents that includes both progesterone and its synthetic analogs, whereas the term progestin refers only to synthetic progestational steroids. The development of progestins has been influenced in a major way by the search for orally active hormonal contraceptives, since it is likely that hormonal contraceptives will continue to utilize a progestin, the only possible alternative being represented by the utilization of antiprogestins. Synthetic progestogens in clinical use today belong to three main chemical families: progesterone derivatives (progesterone, retro-progesterone, 19-norprogesterone and 17alpha-hydroxyprogesterone); gonane and 19-nortestosterone derivatives (norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate); a spironolactone derivative. Biological potency of progestogens varies depending on the end-point measured, usually ovulation inhibition and endometrial transformation; with both these tests, the most active compounds are all gonane derivatives, with a potency over a 100 times that of the natural hormone. When administered in adequate doses, a progestin inhibits fertility by inhibiting ovulation. This action is mainly exerted at the hypothalamic level where, physiologically, progesterone decreases the number of LH pulses. When progestogens are delivered directly to the uterine cavity, their action seems to be purely local. It has been amply proven that--even when administered in doses that do not constantly inhibit ovulation--a progestin can still remain effective as a contraceptive by acting at the level of the cervical mucus and, at least in part, of the endometrium. Progestogens utilized today differ largely in their pharmacokinetics. In general, after intake, these compounds are rapidly absorbed and distributed so that peak serum concentrations are reached between 1 and 4 h. Third-generation progestins (desogestrel, gestodene, norgestimate) have common characteristics: a higher affinity for progesterone receptors than their predecessors, a lower affinity for androgen receptors, a higher selectivity of action, a higher central inhibitory activity, a higher potency at the level of the endometrium, and an overall metabolic neutrality, in terms of effects on lipid and carbohydrate metabolism. In general, progestins can induce two types of adverse effects: changes in lipid metabolism and bleeding irregularities. Whereas the newer compounds seem to have overcome the first of these adverse effects, the second remains untouched: to this day, proper cycle control can only be achieved with combined hormonal contraceptives.

Contraceptive Agents↗

PubMed1997

Concentrations of progesterone and the 5 alpha-reduced progestins, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnan-20-one, in luteal tissue and circulating blood and their relationship to luteal function in the African elephant, Loxodonta africana.

The 5 alpha-reduced metabolites 5 alpha-pregnane-3,20-dione (5 alpha-DHP) and 3 alpha-hydroxy-5 alpha-pregnan-20-one (5 alpha-P-3 alpha-OH) are the principal progestins biosynthesized by the African elephant corpus luteum. The aim of the present study was to determine luteal and circulating concentrations of these 5 alpha-reduced progestins in relation to progesterone (P4) and to examine whether their measurement reflects corpus luteum function. Ovarian (luteal) tissue (30 corpora lutea and 3 corpora rubra from 8 animals) and plasma samples (30 animals) were collected from pregnant and nonpregnant adult elephants shot in the Kruger National Park. Specific immunological measurement for both 5 alpha-reduced progestins and P4 was achieved by enzymeimmunoassay of tissue and plasma extracts following purification by HPLC. Mean (+/- SEM) luteal concentrations of 5 alpha-DHP and 5 alpha-P-3 alpha-OH were 79.5 +/- 9.4 micrograms/g and 196.5 +/- 24.8 micrograms/g, respectively, approximately 2-3 orders of magnitude higher than those of P4 (mean +/- SEM, 0.16 +/- 0.01 microgram/g). Whereas 5 alpha-reduced progestin concentrations tended to be lower in corpora lutea from late pregnancy compared with earlier stages and were lowest in corpora rubra, P4 levels were similar in all tissues/stages examined. The 5 alpha-reduced progestins also predominated over P4 in plasma (mean 5 alpha-DHP:P4 and 5 alpha-P-3 alpha-OH:P4 ratios 20.3 and 13.4, respectively). Similar to results for luteal tissue, plasma concentrations of 5 alpha-reduced progestins, but not of P4, were lower in late pregnancy than in earlier gestation stages and in nonpregnant animals. Moreover, plasma levels of both 5 alpha-reduced metabolites were negatively correlated with gestation age, whereas those of P4 were not. Levels of 5 alpha-reduced metabolites (without chromatography) were also measured in weekly blood samples throughout two complete ovarian cycles in one captive female. Both measurements showed a cyclic profile (similar to that of P4) with a luteal-phase elevation of 10- to 15-fold. The results indicate that 5 alpha-reduced compounds are the predominant progestins contained within and secreted by the corpus luteum of the African elephant, both during the ovarian cycle and throughout pregnancy. They also provide preliminary evidence to suggest that measurements of 5 alpha-reduced metabolites may reflect corpus luteum function more closely than those of P4.

5-alpha-Dihydroprogesterone↗

PubMed2006

Effects of hormone replacement therapy regimens on mammographic breast density: the role of progestins.

AIM: To evaluate the effects of different regimens of hormone replacement therapy (HRT) on mammographic breast density. METHODS: Mammograms of 113 healthy postmenopausal women who were on different HRT regimens were evaluated retrospectively. All women had a baseline mammography and at least one mammogram after at least 12 months of HRT. Four parenchymal patterns were considered mammographically. Quantification of density changes that occurred on follow-up mammograms was done qualitatively and with reference to densities on baseline mammograms. RESULTS: Sixty women were treated with a continuous estrogen-progestin combination; 16 with a cyclic estrogen-progestin combination and 37 were with estrogen only. Twenty-six women had increased mammographic density after HRT. Mammographic density increase was detected in 23 women (38.3%) of the continuous estrogen-progestin combination group, two women (12.5%) of the cyclic estrogen-progestin combination group and one woman (2.7%) of the estrogen-only group. Mammographic density increase was more common among women in the continuous estrogen-progestin combination group than the other groups and this difference was found to be statistically significant (P < 0.001). Breast density increase was observed in 18 of 30 women (60%) with higher doses of progestin compared to 5 of 30 women (16.7%) with lower dose (P < 0.05). CONCLUSIONS: Postmenopausal HRT may increase mammographic breast density. Breast density appears to be mostly affected by higher doses and continuous administration of progestin.

Breast↗

PubMed1975

The effect of progestins on submaxillary gland epidermal growth factor: demonstration of androgenic, synandrogenic and antiandrogenic actions.

The effects of progestins (0.1, 1.0, 6-10 mg/day) alone and in combination with testosterone (0.1 mg/day) on immunoreactive epidermal growth factor (EGF) concentrations in submaxillary glands from normal and androgen-insensitive (tfm/y) mice were studied. Since androgens are known to stimulate increased EGF levels, the responses to progestins were interpreted as androgenic, synandrogenic or antiandrogenic if they simulated, potentiated or inhibited androgen response, respectively. Of the progestins studied, medroxyprogesterone acetate (MPA) caused the greatest androgenic response when given alone; 10 mg produced a greater than 40-fold increase of EGF over control values. Lesser responses were achieved when progesterone or megestrol acetate (Meg Ac) were given alone. Cyproterone acetate (Cyp Ac) had no androgenic activity when administered alone and acted as a potent antiandrogen at all doses used. Progesterone and Meg Ac had weak antiandrogenic activity. The only synandrogenic response elicited was with a high dose (10 mg) of progesterone caproate. Neither MPA nor progesterone alone had any effect on EGF levels in tfm/y mice. These patterns of response differ from those seen in mouse kidney. The data indicate that progestins as a class are capable of androgenic, synandrogenic and antiandrogenic action in the mouse submaxillary gland, but that no single progestin is capable of all three actions. Since tfm/y mice lack a functional androgen receptor, the absence of EGF response in these mice to progestins as well as androgens suggest that the action of progestins may be mediated by the androgen receptor in the submaxillary gland.

Androgens↗

PubMed1991

Progestins induce down-regulation of insulin-like growth factor-I (IGF-I) receptors in human breast cancer cells: potential autocrine role of IGF-II.

Insulin-like growth factor-I (IGF-I) receptors are present in breast cancer cells and may play a role in breast cancer cell growth. We have studied the effect of progestins on IGF-I receptors in T47D human breast cancer cells. T47D cells constitutively express high levels of progesterone receptors and are a model for studying the regulation of cellular functions by progestins. Treatment of T47D cells with either progesterone or the synthetic progestin promegestone (R5020) decreased IGF-I receptor content by approximately 50%, as measured by Scatchard analysis and receptor biosynthesis studies. In contrast to progestins, estradiol, dexamethasone, and dihydrotestosterone did not influence IGF-I receptor content. No effect of R5020 was seen after 12 h of incubation, a near-maximal effect was seen after 24 h, and greatest effects were seen after 72 h. R5020 decreased IGF-I receptor mRNA abundance, indicating that progestins acted at the level of gene expression. However, progestins also increased the secretion of IGF-II, a ligand for the IGF-I receptor. In contrast to IGF-II, T47D cells did not express IGF-I. The addition of exogenous IGF-II to T47D cells down-regulated both IGF-I receptor binding and IGF-I receptor mRNA abundance. This study indicates, therefore, that progestins regulate IGF-I receptors in breast cancer cells and suggests that this regulation occurs via an autocrine pathway involving enhanced IGF-II secretion.

Breast Neoplasms↗

PubMed2003

Cytoskeletal responsiveness to progestins is dependent on progesterone receptor A levels.

Changes in the cell cytoskeleton occur in cell transformation and recent data suggest the involvement of ovarian hormones, which are implicated in cancer development and progression. In human breast and endometrial tumors, there is disrupted expression of progesterone receptor (PR) isoforms and predominance of one isoform, usually PRA. PRA predominance is an early event in carcinogenesis, and in cancers is associated with poor clinical features. Overexpression of PRA in vitro causes altered progestin regulation of cell morphology, suggesting that PRA overexpression may provoke deleterious changes in cell functioning. This study aimed to identify pathways of cytoskeleton regulation responsive to progestins and to determine whether these are perturbed when PRA is overexpressed to the levels seen in cancers. Progestin treatment of PR-positive breast cancer cells caused increased cell surface area whereas after induction of a stably integrated PRA construct, cells became rounded and the cell surface was decreased. The effect of PRA induction on cell rounding was reversed by the anti-progestin RU38486. Altered tropomyosin (Tm) isoforms were implicated in these morphological differences, as there was a PRA-mediated alteration in Tm5 isoform levels, and transfection of Tm5a mimicked progestin-mediated cell rounding in PRA-overexpressing cells. Ezrin was redistributed from the membrane to cytoplasmic locations in the presence of progestin, and discrete focal localization was evident in cells with PRA predominance. Progestin effects on the cytoskeleton in PRA-overexpressing cells provide evidence for novel endocrine regulation of aspects of actin microfilament composition, suggesting that changes in the cytoskeleton known to be associated with cancer development and progression may be regulated in part by altered PRA expression which develops early in carcinogenesis.

Actin Cytoskeleton↗

PubMed1983

Modulation of progestin binding activity in cultured human breast carcinoma cells: the effect of serum type and concentration.

Progesterone receptor levels in MCF-7 human breast cancer cells increase as a specific response to estrogen and to some nonsteroidal antiestrogens. In the present study we demonstrate that the type and quantity of serum present during culture of these cells modifies the level of progestin binding activity, but not the level of estradiol binding activity. MCF-7 cells maintained in media supplemented with 5% charcoal-dextran treated calf serum (CDCS) contain 0.3 - 0.4 pmol of cytosol progesterone receptor (PRc) per mg DNA. When cells previously maintained in 5% CDCS-media are shifted to media containing 5% charcoal-dextran treated fetal calf serum (CDFCS), the level of progestin binding increases after day 16, and stabilizes at 2 - 3 pmol/mg DNA at days 30 to 40. Shifting these cells back to 5% CDCS-media, reduces PRc to 0.2 - 0.4 pmol/mg DNA within 3 days. This reduction is dose dependent with a half-optimal decrease at 1% CDCS, and a full decrease at 2% CDCS (4d incubation). Nuclear progestin binding was uniformly low (0.2 - 0.4 pmol/mg DNA) and unaffected by type or concentration of serum, and no consistent change in cytosol or nuclear estrogen receptor levels was observed. These cytoplasmic progestin binding sites are translocated to the nucleus by progesterone, and are similar to estradiol (E2) induced sites by Scatchard binding and sucrose gradient analysis. Similar serum-dependent changes are also observed in the T47D human breast cancer cell line where growth in CDFCS-media results in 4-fold higher progestin binding levels than observed in CDCS-media. Our findings suggest the presence of non-dialyzable stimulatory factor(s) in CDFCS that influence the progestin receptor level and highlight the fact that serum components can alter dramatically the cellular progestin binding activity.

Binding Sites↗