SEARCH · PubMed Health

Results for “Progestins”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources

PubMed2004

Pharmacological profile of progestins.

The synthetic progestins used so far for contraception and menopausal hormone therapy are derived either from testosterone (19-nortestosterone derivatives) or from progesterone (17-OH progesterone derivatives and 19-norprogesterone derivatives). Among the 19-nortestosterone derivatives, the estrane group include norethisterone (NET) and its metabolites, and the gonane group include levonorgestrel (LNG) and its derivatives. The later, including desogestrel (DSG) and its derivative etonogestrel, gestodene (GES) and norgestimate (norelgestromin), have been referred to as third-generation progestins. Several new progestins have been synthesized in the last decade and may be considered as a fourth-generation of progestins. Dienogest is referred to as a hybrid progestin being derived from the estrane group with a 17alpha-cyanomethyl group, and drospirenone derives from spirolactone. These two progestins have no androgenic effect but a partial antiandrogenic effect. The later exerts anti-mineralocorticoid effects. This property leads to a decreased salt and water retention and a lowering in blood pressure in users of pills containing this progestin. The 19-norprogesterone derivatives appear more specifically progestational and do not possess any androgenic, estrogenic or glucocorticoid activity. They are referred to as "pure" progestational molecules as they bind almost exclusively to the progesterone receptor (PR) and do not interfere with the other steroid receptor. This category includes, trimegestone, nomegestrol acetate and Nestorone is not active orally but proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel. Non-androgenic progestins would appear neutral on metabolic factors and on the vessels and would have the advantage of avoiding acnea. Progestins with antiandrogenic properties may also be used for the treatment of women with preexisting androgen related conditions. The progestins available for therapy exhibit profound differences according to their structure or metabolites and it is inappropriate to consider the various effects of the old and new molecules as class-effects.

Estrogen Replacement Therapy↗

PubMed2003

All progestins are not created equal.

A variety of progestins are available for therapeutic use. It is convenient to classify them into those related in chemical structure to progesterone or testosterone. Progestins related to progesterone can be subdivided into pregnanes and 19-norpregnanes, whereas those related to testosterone can be subdivided into those with and without a 17-ethinyl group. 17-Ethinylated progestins consist of the families of norethindrone (estranes) and levonorgestrel (13-ethylgonanes). Progestins administered orally undergo extensive hepatic first pass metabolism primarily by reduction and conjugation, and in most instances, relatively high progestin doses are required for therapeutic use. There are limited reliable data on the pharmacokinetics of most progestins. Some progestins are prodrugs, requiring transformation prior to exhibiting progestational activity. Qualitative and quantitative tests utilizing either human or animal species have been used to establish progestin potency. However, profound differences in progestational activity are often observed between human and animal tissues. Also, there is a misconception about androgenicity of progestins due largely to extrapolation of data from rat studies to the human. Progestins differ widely in their chemical structures, structure-function relationships, metabolism, pharmacokinetics, and potencies; they are not created equal.

Animals↗

PubMed2003

Prolonged progestin treatment induces the promoter of CDK inhibitor p21 Cip1,Waf1 through activation of p53 in human breast and endometrial tumor cells.

Progestins are frequently used in the treatment of advanced breast and endometrial cancer. The human breast carcinoma cell line T47D shows a biphasic response to progestins. Short-term progestin treatment leads to enhanced DNA synthesis, while this line is growth inhibited upon prolonged exposure. An important protein involved in growth regulation by progestins in this cell is the CDK inhibitor p21(Cip1,Waf1). We show that after 1 day of progestin treatment in T47D cells, the p21 promoter-proximal region containing Sp1 binding sites is crucial in the induction by progestins. However, after 3 days the activity of the promoter-distal region becomes predominant in T47D cells or the endometrial carcinoma cell line ECC1. This is dependent upon two domains within this region that contain p53 response elements. In ECC1 and T47D cells 3-day progestin treatment induces a reporter containing a p53 response element, but not a mutated version. This induction is due to activation of p53 by progestin, which may be caused by nuclear translocation of p53. These data indicate that upon prolonged exposure, progestins activate p53, in human breast and endometrial tumor cells, which up-regulates the p21(Cip1,Waf1) promoter. This may be an important mechanism involved in progestin-inhibited cellular proliferation in these cells.

Breast Neoplasms↗

PubMed1998

Progestins and breast cancer.

In the last years there has been an extraordinary development in the synthesis of new progestins. These compounds are classified, in agreement with their structure, in various groups which include progesterone, retroprogesterones, 17alpha-hydroxyprogesterones, 19-norprogesterones, 17alpha-hydroxyprogesterone derivatives, androstane and estrane derivatives. The action of progestins is a function of many factors: its structure, affinity to the progesterone receptor or to other steroid receptors, the target tissue considered, the biological response, the experimental conditions, dose, and metabolic transformation. The information on the action of progestins in breast cancer patients is very limited. Positive response with the progestins: medroxyprogesterone acetate and megestrol acetate was obtained in post-menopausal patients with advanced breast cancer. However, extensive information on the effect of progestins was obtained in in vitro studies using hormone-dependent and hormone-independent human mammary cancer cell lines. It was demonstrated that in the hormone-dependent breast cancer cells, various progestins (nomegestrol acetate, tibolone, medrogestone, promegestone) are potent sulfatase inhibitory agents. The progestins can also involve the inhibition of mRNA of this enzyme. In another series of studies it was also demonstrated that various progestins are very active in inhibiting the 17beta-hydroxysteroid dehydrogenase for the conversion of estrone to estradiol. More recently it was observed that the progestins promegestone or medrogestone stimulate the sulfotransferase for the formation of estrogen sulfates. Consequently, the blockage in the formation of estradiol via sulfatase, or the stimulatory effect on sulfotransferase activity, by progestins can open interesting and new possibilities in clinical applications in breast cancer.

17-Hydroxysteroid Dehydrogenases↗

PubMed2001

Molecular tools to reestablish progestin control of endometrial cancer cell proliferation.

OBJECTIVE: Endometrial cancers often arise in a setting of estrogen stimulation unopposed by the differentiating effects of progesterone. Our laboratory and others have previously shown that progesterone receptor down-regulation or perturbation of progesterone receptor isoform A or B expression is associated with the development of poorly differentiated endometrial cancers that are not growth inhibited by progestins. The purpose of these studies was to reestablish high progesterone receptor isoform A and B gene expressions in such endometrial cancer cells and to examine the effects of progestin treatment on cell growth and metastatic potential after this transformation. STUDY DESIGN: To induce high levels of expression of the progesterone receptor isoforms in KLE and Hec50 endometrial cancer cells, adenoviral vectors encoding the genes for progesterone receptor isoforms A and B were created. The characteristic ability of cancer cells to grow independently of anchorage to the surrounding solid matrix was measured by counting colony formation on soft agar for 8 to 14 days. Cell proliferation in response to a time course of progestin treatment was tested with flow cytometry. RESULTS: After treatment with a control vector without a progesterone receptor--encoding insert, no effect of progestin treatment on cell proliferation was found; after treatment with vectors encoding progesterone receptor isoform A or B, however, progestin treatment resulted in significant inhibition of cell growth. The anchorage-independent cell growth on soft agar assay showed that by 8 to 14 days the number of cell colonies was reduced by 50% relative to control preparations in the presence of progesterone receptor isoform A plus progestin (P <.0001, both Hec50 and KLE cell lines) and by 90% in the presence of progesterone receptor isoform B plus progestin (P <.0001, both Hec50 and KLE cell lines). Progestin treatment also resulted in a time-dependent reduction in cell proliferation as measured by flow cytometry. Although transfection with both progesterone receptor isoforms A and B reduced cell proliferation according to our assays, progesterone receptor isoform B caused a much more dramatic decrease in cell growth (P =.001, Hec50 cells; P <.0001, KLE cells). CONCLUSION: In poorly differentiated endometrial cancer cells that are resistant to progestin therapy, adenovirus-induced expressions of progesterone receptors A and B reestablish progestin control of endometrial cancer cell proliferation.

Blotting, Western↗

PubMed1999

Progestins and cancer.

The role of progestins in breast tissue is less well defined than in the endometrium. Although in vitro studies have shown that progestins induce a similar decrease in both estrogen and progesterone receptors and an increase in 17beta-estradiol dehydrogenase in the breast as in the endometrium, epidemiologic studies have suggested that progestins prevent endometrial cancer, but do not reverse the estrogen-related increase in breast cancer risk in long-term hormone-replacement therapy (HRT). Other studies have also suggested a protective effect for progestins on breast tissue. The dual effect of progesterone and progestins on the cell cycle has been demonstrated, suggesting that according to the duration of administration, the same steroid can induce cells to enter the multiplication phase or to enter a resting state. Progestins exert different effects according to the steroid from which they are derived, e.g. pregnanes derived from progesterone, estranes or gonanes derived from testosterone. Some estrane derivatives are able to stimulate breast cell multiplication in vitro through an estrogen receptor-mediated pathway. Most pregnanes do not exert such an effect. Also, some pregnane derivatives stimulate apoptosis, leading to cell death. However, it is well established that high doses of progestins have been successfully used in the treatment of advanced breast cancer as second-line endocrine therapy. Finally, striking differences have been observed in progestin use in Europe and in the USA. In France, where the rate of progestin use per head is higher than in the USA, the rate of breast cancer has not increased as sharply as observed in North America. Although cancer genesis is multifactorial, it may be concluded that progestins do protect endometrial tissue against the proliferative action of estrogen and if they do not protect breast tissue, at least they do not stimulate its proliferation. Also, they are useful agents as a second-line therapy for breast cancer, when used at high doses.

Animals↗

PubMed2002

Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk.

BACKGROUND: Oral contraceptive (OC) use is associated with a reduced risk of developing ovarian cancer, but the mechanism for the risk reduction has not been well defined. In this study, we investigate the relationship between the progestin and estrogen potency in combination OCs and the risk of developing ovarian cancer. METHODS: The study included 390 case subjects with epithelial ovarian cancer and 2865 control subjects, between 20 and 54 years of age, identified from the Cancer and Steroid Hormone Study. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between ovarian cancer risk and combination OC formulations while controlling for potential confounders. All statistical tests were two-sided. RESULTS: With users of high-progestin/high-estrogen potency OC as the referent group, users of low-progestin/high-estrogen potency formulations (adjusted OR = 2.1; 95% CI = 1.2 to 3.7) and low-progestin/low-estrogen potency formulations (adjusted OR = 1.6; 95% CI = 0.9 to 3.0) had a higher risk of ovarian cancer than users of high-progestin/high-estrogen potency formulation. Low-progestin potency OC formulations were associated with a statistically significant higher risk than high-progestin potency formulations (adjusted OR = 2.2; 95% CI = 1.3 to 3.9). This association was seen even among users of short duration. CONCLUSION: The combination OC formulations with high-progestin potency appear to be associated with a greater reduction in ovarian cancer risk than those with low-progestin potency. Mechanisms underlying this reduction may include inhibition of ovulation and/or some direct biologic effects of the progestin.

Adult↗

PubMed2004

Transition from estrogen-progestin to raloxifene in postmenopausal women: effect on vasomotor symptoms.

OBJECTIVE: To compare vasomotor symptoms after transition from estrogen-progestin therapy to raloxifene 60 mg/d with and without a placebo washout. METHODS: Postmenopausal women currently taking continuous combined estrogen-progestin therapy (conjugated equine estrogen, 0.625 mg/medroxyprogesterone acetate, 2.5 or 5 mg) daily for 5 or more months were enrolled. Women were randomized to 1 of 4 blinded regimens: 1) 12 weeks estrogen-progestin; 2) 12 weeks placebo; 3) 4 weeks placebo, then 8 weeks raloxifene; or 4) 12 weeks raloxifene. For the final 36 weeks, all subjects received raloxifene. Vasomotor symptoms were assessed by patient diaries. RESULTS: A total of 266 women (mean age 57.5) were enrolled. Mean hot flush frequency at baseline was approximately 1 per week in the entire population, with 16% of women reporting hot flushes. Mean frequency and severity of hot flushes during the first 12 weeks of the study were statistically greater in the 3 groups transitioned off estrogen-progestin (range of hot flushes per week: 4 weeks, 11-12; 8 weeks, 18-24; 12 weeks, 13-16), as compared with those continuing estrogen-progestin, with no difference between these 3 groups (P> or =.1). Approximately 50-70% of these women reported hot flushes, generally rated as mild to moderate by participants, after estrogen-progestin discontinuation. CONCLUSION: A large proportion of women discontinuing estrogen-progestin experience hot flushes. Raloxifene does not appear to increase the frequency or severity of vasomotor symptoms in women discontinuing estrogen-progestin more than that observed with placebo treatment after estrogen-progestin discontinuation. Transition from estrogen-progestin to raloxifene with no washout period therefore may be acceptable. LEVEL OF EVIDENCE: I

Administration, Oral↗

PubMed1985

Progestin modulation of estrogen-dependent marker protein synthesis in the endometrium.

While it is well known that progestins have significant effects on estrogen-dependent processes in the uterus, very little is known about the molecular details of these effects. To understand these processes we have developed an immunocytochemical staining technique to help clarify the progestin regulation of estrogen receptor (ER), and we have also studied the effects of progestins on estrogen-dependent specific protein synthesis and secretion in the immature rat uterus. The immunocytochemical method for identifying estrogen receptor in tissue sections uses biotinylated monoclonal antibody to the estrogen receptor protein and shows a largely nuclear localization of the receptor protein in the rat uterine endometrium and myometrium. This method can be used to explore changes in the intercellular and intracellular localization of the uterine ER during progestin action. In an effort to correlate these changes with specific biological responses in the uterus we have been studying the effects of the administration of estrogens and progestins in vivo on the synthesis of specific proteins in uterine target cells in vitro. We previously reported that one-dimensional SDS-PAGE analysis of labeled secreted uterine proteins and cellular proteins extracted from the luminal epithelium and from the stroma plus myometrial fractions of the uterus revealed that estradiol-17 beta preferentially stimulated the synthesis of 110,000, 74,000, and 66,000 dalton secreted proteins, and 180,000 and 110,000 dalton epithelial proteins. We found that while progestins administered alone in vivo did not have any stimulatory effect on the synthesis of these secreted or cellular uterine proteins, concomitant administration of either progesterone or megestrol acetate and estradiol in vivo substantially reduced the estrogen-stimulated increase in labeling of the 110,000, 74,000, and 66,000 dalton secreted uterine proteins in vitro. In animals first primed with the progestin prior to combined estrogen/progestin treatment, the progestins were even more effective antagonists of estrogen. In addition, progestins alone given 24 hours after estradiol substantially inhibited the estrogen-stimulated synthesis of these proteins. These results suggest that progestins can both modulate the initial level of estrogen stimulation of synthesis of specific proteins and selectively terminate their synthesis, by affecting the continued transcription of their estrogen-regulated genes, altering the processing, half-life, or translation of their mRNAs, or by modulating the translation or the posttranslational processing of the nascent peptide chains.

Animals↗

PubMed1995

The role of TGF-beta production in growth inhibition of breast-tumor cells by progestins.

We have studied the influence of synthetic progestins on the estrogen-induced proliferation and type-beta transforming-growth-factor (TGF-beta) production of 3 breast-tumor cell lines. In long-term growth experiments, progestins inhibited proliferation of T47D cells, while a specific T47D variant and MCF7 cells were not affected, despite the presence of functional progesterone receptors. The effect of progestins was biphasic, since an initial stimulation of proliferation was followed by a prolonged inhibition. This response suggests the involvement of a progestin-induced negative growth regulator. We show here that TGF-beta s do not fulfill this role since (i) the progestin-induced T47D cells are not sensitive to TGF-beta 1, -beta 2 or -beta 3, (ii) secretion of TGF-beta s is decreased by progestins in all 3 cell lines, and (iii) TGF-beta neutralizing antibodies do not reverse progestin-induced growth inhibition. Furthermore, evidence was obtained that medium conditioned by T47D cells does not contain any other growth inhibitor to which this cell line responds in a negative autocrine manner. In contrast, MCF7 cells are growth-inhibited by all 3 TGF-beta isoforms, but are not growth-inhibited by progestins, suggesting that there is no correlation between growth inhibition by progestins and responsiveness to and production of TGF-beta in vitro. Although TGF-beta is a strong growth inhibitor of normal mammary tissue, recent evidence suggests that, in malignant tissue, enhanced TGF-beta secretion correlates with increased malignancy. Therefore, a progestin-induced decrease in TGF-beta production, as observed here, may lead to enhanced proliferation of normal but not malignant mammary epithelium.

Breast Neoplasms↗

PubMed1979

Cytoplasmic progestin-receptors in guinea pig brain: characteristics and relationship to the induction of sexual behavior.

The synthetic progestin, R 5020, was used to measure cytoplasmic progestin receptors in the brain and pituitary gland of ovariectomized guinea pigs. Progestin receptors with a dissociation constant of 0.1--0.3 nM were measured by gel filtration in all brain regions studied, pituitary gland and the uterus. The receptor is progestin-specific; biologically potent progestins compete well against [3H]R 5020 for binding, but androgens, glucocorticoids and estrogens do not. The concentration of the cytoplasmic progestin receptor in hypothalamus-preoptic area-septum and midbrain is decreased in vivo by behaviorally effective doses of progesterone. In the pituitary gland, hypothalamus, preoptic area-septum and midbrain, but not other brain regions, the concentration of progestin receptors increases after estradiol benzoate-priming. The increase in the concentration of cytoplasmic progestin receptors in hypothalamus-preoptic area-septum is dependent on the dose of estradiol benzoate injected. After a single injection of a dose of estradiol benzoate routinely used to facilitate the display of sexual receptivity (1.6 microgram estradiol benzoate/animal), the latency to an increase and subsequent decrease in cytoplasmic progestin receptors in the hypothalamus-preoptic area-septum correlates well with the previously reported time course for progesterone's facilitation of sexual receptivity after estradiol benzoate injection. The experiments are consistent with the notion that brain progestin receptors mediate at least some of the behavioral effects of progesterone.

20-alpha-Dihydroprogesterone↗

PubMed1985

Loss of hypothalamic nuclear-bound progestin receptors: factors involved and the relationship to heat termination in female guinea pigs.

The hypothesis that the termination of sexual receptivity (heat) in female guinea pigs results from loss of progestin receptors from hypothalamic cell nuclei was tested. First, we attempted to find an optimal dose of progesterone that would result in a prolonged period of sexual receptivity. Ovariectomized guinea pigs were implanted with 10% estradiol capsules. Forty hours later, each received one of several sized progesterone capsules before being tested hourly for lordosis. Surprisingly, none of the progesterone doses resulted in delayed heat termination. In order to determine whether elevated levels of estradiol and progesterone maintain elevated levels of nuclear progestin receptors despite the lack of effect on heat duration, animals were treated as described above except that only one size progesterone capsule (3.0 cm) or an empty capsule was implanted. Despite elevated serum progesterone concentrations, nuclear progestin receptor levels decreased gradually and approached control levels at about the same time as heat termination had occurred in similarly-treated animals. Cytosol progestin receptor levels decreased following progesterone treatment and remained lowered at all times measured. In order to further investigate the relationship between blood progesterone concentrations and retention of nuclear progestin receptors we decreased blood progesterone concentrations by removing progesterone capsules 2 h following insertion. Nuclear progestin receptor levels declined gradually concurrent with a decline in serum progesterone levels in animals exposed to progesterone capsules for only 2 h. In animals exposed to capsules continuously, nuclear progestin receptor levels again decreased but at a slightly slower rate. In order to test the effect of progesterone capsule removal on female sexual behavior, ovariectomized guinea pigs were treated as described and tested hourly for lordosis. Fewer animals in the group exposed to progesterone capsules for 2 h became sexually receptive as compared to animals continuously-exposed to progesterone capsules. Of those animals that did respond, heat termination had occurred by the same time that nuclear progestin receptor levels had returned to control levels in similarly-treated animals. These experiments support the hypothesis that heat termination results from the loss of progestin receptors from hypothalamic cell nuclei. In addition, they demonstrate that circulating progesterone levels play a role in regulating nuclear progestin receptor retention.

Animals↗

PubMed2005

p53-dependent inhibition of progestin-induced VEGF expression in human breast cancer cells.

VEGF, a potent angiogenic growth factor, is up-regulated in many tumors including human breast tumors and stimulates growth of vascular networks that support tumor growth and metastasis. We previously reported that natural and synthetic progestins (P) increased VEGF mRNA and protein levels in progesterone receptor (PR) containing T47-D human breast cancer cells in a PR dependent manner, but not in PR positive ZR-75 and MCF-7, or in PR negative MDA-MB-231 cells. This indicated that factors beside PR are involved in progesterone-dependent VEGF regulation. We, therefore, tested additional tumor cell lines reported to contain PR for progestin-dependent VEGF induction. Out of nine PR-positive breast tumor cell lines, progestins induced VEGF in three cell lines that lack wild-type p53 (T47-D, BT-474, and HCC-1428) but not in cell lines that contained the wild-type p53 protein. The T47-D and BT-474 cells express mutant p53, while the p53 protein is absent HCC-1428 cells. The anti-progestin RU-486 blocked progestin-dependent induction of VEGF in T47-D and BT-474 cells but not in HCC-1428 cells. However, RU-486 partially blocked medroxyprogesterone acetate-dependent induction of VEGF in HCC-1428 cells. Estrogen receptor (ER) and PR agonists and antagonists also induce VEGF in HCC-1428 cells and this effect was partially blocked by anti-estrogen ICI-182, 780. Progestin-dependent VEGF induction was completely inhibited by PRIMA-1-activated p53 in all cell-types, but progestin-dependent transcription of a progesterone-regulated minimal promoter was only partially inhibited. PRIMA-1 induced activation of p53 in tumor cell lines was confirmed with a p53-responsive p21 reporter plasmid and by detecting increased levels of p21 proteins in cell lysates. PRIMA-1 induced p53 protein in the HCC-1428 cells while levels of mutant p53 protein in T47-D and BT-474 remained unaltered. Progestin-dependent induction of VEGF was also inhibited by stable transfection of wild-type p53 in T47-D cells. These results are consistent with the hypothesis that wild-type p53 blocks progestin-dependent induction of VEGF in breast cancer cells and this may be a novel anti-angiogenic mechanism for controlling the growth of progestin-dependent tumors.

Base Sequence↗

PubMed2002

Progestin receptor immunoreactivity within steroid-responsive vasopressin-immunoreactive cells in the male and female rat brain.

Progestin receptor immunoreactivity is found in the same regions of the bed nucleus of stria terminalis (BST) and centromedial amygdala (CMA) as steroid-responsive vasopressin immunoreactive (AVP-ir) cells. To test whether AVP-ir cells express progestin receptors, brains of male rats were stained immunocytochemically for arginine vasopressin as well as progestin receptors. In BST and CMA, over 95% of AVP-ir cells contained progestin receptor immunoreactivity. In contrast, none of the AVP-ir cells in the suprachiasmatic, supraoptic and paraventricular nuclei expressed progestin receptor immunoreactivity. To study whether progestin receptor expression in AVP-ir cells in the BST and CMA is responsive to gonadal steroids, male and female rats were castrated and implanted with either empty capsules or capsules filled with testosterone or oestradiol, respectively. Ten days later, brains were processed for AVP and progestin receptor immunoreactivity. Although there was no effect of hormonal status on the percentage of colocalized cells, the level of progestin receptor immunoreactivity was higher in rats that received gonadal steroids than those that did not. The presence of progestin receptor immunoreactivity in steroid responsive AVP-ir cells, and the responsiveness of this expression to gonadal hormones, is consistent with the possibility that the effects of gonadal steroids on AVP-ir expression in the BST and CMA may be mediated at least in part by progestin receptors.

Amygdala↗

PubMed1991

Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor alpha, epidermal growth factor receptor, c-fos, and c-myc genes.

This study documents a biphasic change in the rate of cell cycle progression and proliferation of T-47D human breast cancer cells treated with synthetic progestins, consisting of an initial transient acceleration in transit through G1, followed by cell cycle arrest and growth inhibition. Both components of the response were mediated via the progesterone receptor. The data are consistent with a model in which the action of progestins is to accelerate cells already progressing through G1, which are then arrested early in G1 after completing a round of replication, as are cells initially in other phases of the cell cycle. Such acceleration implies that progestins act on genes or gene products which are rate limiting for cell cycle progression. Increased production of epidermal growth factor and transforming growth factor alpha, putative autocrine growth factors in breast cancer cells, does not appear to account for the initial response to progestins, since although the mRNA abundance for these growth factors is rapidly induced by progestins, cells treated with epidermal growth factor or transforming growth factor alpha did not enter S phase until 5 to 6 h later than those stimulated by progestin. The proto-oncogenes c-fos and c-myc were rapidly but transiently induced by progestin treatment, paralleling the well-known response of these genes to mitogenic signals in other cell types. The progestin antagonist RU 486 inhibited progestin regulation of both cell cycle progression and c-myc expression, suggesting that this proto-oncogene may participate in growth modulation by progestins.

Blotting, Northern↗

PubMed1991

Progestin receptor cells in the 8-day-old male and female mouse cerebral cortex: autoradiographic evidence for a sexual dimorphism in target cell number.

The present study examined the number and distribution of progestin receptor cells in the 8-day-old male and female cortex and compared cortical labeling with that in the preoptic area and central hypothalamus. Eight-day postnatal mice (four males and four females), treated with estradiol, were each sc injected with 0.32 micrograms/100 g BW [125I]progestin (SA, 2200 Ci/mM). Brains were frozen 2 h after injection of [125I]progestin, sectioned, and processed for thaw-mount autoradiography. Cells with a nuclear concentration of radioactivity were localized in lamina VI of the lateral cortical regions of the male and female brain, while only a few cortical cells were seen in laminae II, III, and V of the suprarhinal, lateral, and cingulate/paracingulate regions. Comparison of the number of labeled cells revealed that the female cortex contained significantly more labeled cells than the male at three of the four levels investigated. Similarly, the number of target cells was higher in the female medial preoptic nucleus, but not in the arcuate nucleus and ventromedial hypothalamic nucleus, while the distributions of labeled cells in the male and female preoptic/hypothalamic regions were comparable. Injection of unlabeled progesterone or R5020 1 h before [125I]progestin reduced the nuclear concentration of radioactivity in all target regions and verified the specificity of [125I]progestin for the progestin receptor. The results of these studies indicate that mouse 8-day-old cortex and preoptic area in the female animal have more progestin receptor cells than those in the male and demonstrate that progestin receptor cells are localized in a region of the cortex known to contain few estrogen target cells. These results further suggest that a sexual dimorphism in progestin cell number may result in a differential effect of progestin on the cortex and preoptic area of the mouse, perhaps establishing a dimorphism in development and function.

Animals↗

PubMed1992

Progestin target cell distribution in forebrain and midbrain regions of the 8-day postnatal mouse brain.

The present study investigated the anatomical distribution of progestin target cells throughout the forebrain and midbrain regions of the 8-day postnatal female mouse. Female ICR mice were sc injected with 100 micrograms/100 g BW estradiol valerate on postnatal day 5 (birth = day 0). On postnatal day 8, treated mice were sc injected with 0.32 micrograms/100 g BW (Z)-17 beta-hydroxy-17 alpha-(2-[125I]iodovinyl)4-estren-3-one ([125I] progestin). For competition, additional estrogen-treated mice were each injected with 320 micrograms R5020 (17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione; a potent synthetic progestin), 320 micrograms dihydrotestosterone, or 32, 160, or 320 micrograms corticosterone 1 h before [125I]progestin to show the specificity of [125I]progestin for the progestin receptor. Two hours after injection of [125I]progestin, the brains were removed, frozen, and processed for high resolution thaw-mount autoradiography. After 8-60 days of exposure, nuclear uptake and retention of [125I]progestin were detected in many brain regions, including the septum; bed nucleus of the stria terminalis; and preoptic area, periventricular nucleus, ventromedial nucleus, arcuate nucleus, and dorsomedial nucleus of the hypothalamus. In addition, labeling was seen in the cerebral cortex, caudate putamen, hippocampus, amygdala, and substantia nigra. Competition studies showed that excess R5020 prevented nuclear concentration of ligand, while dihydrotestosterone and corticosterone did not. The results indicate that the distribution of progestin target cells in extrahypothalamic regions of the developing brain is more extensive than that in the adult, while a similar topography was seen in the preoptic area and hypothalamus. The results further suggest that progestin action during brain development may influence the growth and development of target cells not only in the hypothalamus but also in regions of the brain previously not considered to be sites of hormone action.

Animals↗

PubMed2003

Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy.

Previous studies have indicated that the addition of progestins during sequential hormonal replacement therapy (HRT) causes negative mood and physical symptoms. History of premenstrual syndrome, type of progestin, and dose of progestin have thus far been shown to influence the progestin-induced adverse mood symptoms during HRT. The aim of this study was to compare adverse mood effects of two different doses of estradiol, in combination with a progestin, during postmenopausal HRT. Twenty-eight perimenopausal women were included in this randomized, double-blind, crossover study comparing 2- or 3-mg continuous estradiol, with an addition of 10 mg medroxyprogesterone acetate on d 17-28 during each treatment cycle. The main outcome measures were mood and physical symptoms kept on a daily rating scale. Together with the progestin, the higher dose of estrogen caused significantly more negative mood symptoms than the lower dose. Tension, irritability, and depressed mood were all significantly augmented during the progestin phase of cycles with 3 mg estradiol (P < 0.001). Physical symptoms also increased during the progestin phase of 3-mg estradiol cycles (P < 0.001), whereas positive mood symptoms were less affected. The only positive mood that changed with estrogen dose was friendliness, which decreased during the progestin phase of high estradiol cycles compared with cycles with lower estradiol (P < 0.05). Our conclusion is that an increase of the estrogen dose accentuates negative mood and physical symptoms during the progestin phase of sequential hormonal therapy.

Adult↗