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PubMed1989

Progestins and androgens stimulate lipid accumulation in T47D breast cancer cells via their own receptors.

Using electron microscopy, in the human breast cancer cell line T47D, the synthetic progestin R5020, and 5 alpha-dihydrotestosterone were shown to increase significantly the number of lipid droplets per cell section compared to control cells or estradiol- and dexamethasone-treated cells. Lipid accumulation, as measured by Oil Red O dying and by [2-14C]acetate incorporation, was observed at concentrations as low as 10 pM R5020 and 1 nM 5 alpha-dihydrotestosterone, and was always more abundant after progestin treatment. The progestin antagonist RU486 inhibited, in a dose-dependent manner, lipid accumulation initiated by the two hormones, whereas the androgen antagonist flutamide inhibited only the effect initiated by 5 alpha-dihydrotestosterone. Cytoplasmic lipid droplets accumulation was not observed in the BT20 breast cancer cell line, which contains neither progesterone nor androgen receptors. These results indicate that progestins and androgens increase lipid accumulation by interacting with their own receptor. Chromatographic analysis of [2-14C]acetate labeled lipids showed that R5020 and 5 alpha-dihydrotestosterone enhanced the accumulation of cellular triglycerides at least in part by increasing their synthesis and decreased the quantity of lipids released into the medium. To conclude, we have shown that progestins and androgens, via their own receptor, can induce the same triglyceride accumulation in T47D cells. This effect follows fatty acid synthetase induction and precedes cell growth inhibition, two responses also triggered by progestin and androgen in these cells.

Acetates↗

PubMed1986

Hypothalamic nuclear progestin receptors and the duration of sexual receptivity in ovariectomized and ovariectomized-hysterectomized rats.

In order to determine if the enhancement of sexual behavior in hysterectomized rats is associated with an increased level of hypothalamic nuclear progestin receptors, ovariectomized (OVX) and ovariectomized-hysterectomized (OVHX) rats were injected with 2 micrograms estradiol benzoate. Twenty-four hr later, animals were injected with 0.5 mg progesterone and were tested for sexual receptivity every 4 hr. Hysterectomy had an overall facilitatory effect on lordosis and increased the duration of the period of sexual receptivity by about 4 hr. In a second experiment, similarly-treated animals were killed 4, 8, or 12 hr after progesterone injection, and hypothalamic nuclear progestin receptor levels were measured. In contrast to what has been reported for guinea pigs, nuclear progestin receptor levels decreased to baseline 8-12 hr before the termination of sexual receptivity. Nuclear progestin receptor concentrations were higher in OVHX rats than in OVX rats at 4 hr after progesterone injection, and there was a trend toward higher receptor concentrations in OVHX rats at 8 hr. These results demonstrate that hysterectomy-induced facilitation of sexual receptivity is associated with an increased level of hypothalamic nuclear progestin receptors. Furthermore, they suggest a fundamental difference in the regulation of nuclear progestin receptor retention between rats and guinea pigs.

Animals↗

PubMed1989

Intrahypothalamic injection of RU486 antagonizes the lordosis induced by ring A-reduced progestins.

We explored the possibility that ring A-reduced progestins facilitate lordosis in estrogen primed rats through their interaction with an intracellular progestin receptor (PR) by using RU486. This drug binds with high affinity to the PR, thus preventing the action of progesterone (P). Ovariectomized estrogen-primed rats (2 micrograms estradiol benzoate 40 hr earlier) were bilaterally injected into the ventromedial hypothalamic nucleus (VMHN) with 1 microgram of: P, 5 alpha-pregnanedione or 3 beta,5 beta-pregnanolone in 1 microliter oil. All three progestins effectively facilitated lordosis, tested at four and eight hours after intrahypothalamic injections. The ability of RU486 to counteract progestin-induced lordosis was assessed by infusing 10 micrograms of this agent into the VMHN along with any of the progestins. RU486 antagonized the lordosis induced not only by P (67% reduction) but also that induced by 5 alpha-pregnanedione and by 3 beta,5 beta-pregnanolone (47% and 93% reductions, respectively). Results suggest that ring A-reduced progestins may act through the PR mechanism to facilitate lordosis, i.e., in a fashion similar to P.

5-alpha-Dihydroprogesterone↗

PubMed1988

Benefits and risks of menopausal estrogen and/or progestin hormone use.

Current evidence is reviewed here on risks and benefits of estrogen and progestin use by peri- and postmenopausal women in relation to the following conditions: endometrial cancer, breast cancer, osteoporosis, and coronary artery disease (CAD). On balance, estrogen therapy appears to be beneficial for menopausal women, as it probably reduces the risks of CAD and osteoporosis, two of the major causes of mortality and morbidity. Although unopposed estrogen therapy increases the risk of endometrial cancer, that cancer is relatively rare and is not fatal in the vast majority of cases associated with estrogen use. Definitive conclusions about the relation of menopausal estrogens to breast cancer cannot be drawn due to inconsistent evidence to date. Although evidence from randomized controlled trials is lacking, biochemical and clinical evidence suggest that progestin supplementation is associated with a reduction in endometrial cancer risk in women taking menopausal estrogens. Progestin supplementation also may augment the beneficial effects of estrogens in providing protection against osteoporosis, although this effect is not yet well established. There is little direct evidence bearing on the relation of menopausal progestins to breast cancer. Although studies of CAD per se are lacking at present, progestins probably unfavorably alter lipoprotein profiles, thereby increasing a user's risk of CAD. Given the relatively high incidence and mortality of CAD in postmenopausal women, any negative effects on CAD risk could potentially counterbalance beneficial effects on other causes. We conclude that estrogen replacement therapy is of potential benefit to postmenopausal women, but that the question of progestin supplementation requires further study, particularly for CAD risk.

Breast Neoplasms↗

PubMed1992

Apparent resistance in human endometrial carcinoma during combination treatment with tamoxifen and progestin may result from desensitization following downregulation of tumor progesterone receptor.

Combined treatment with tamoxifen and progestin effectively controlled human endometrial tumor growth in the nude mouse model. However, after an initial response the tumors became 'resistant' to continuous progestin administration. Tumors excised during the growth arrest or regrowth phases, showed return of the typical growth characteristics of EnCa-101, upon serial transplantation. The characteristic progesterone receptor proteins were observed by Western blot analysis in tamoxifen treated tumors, while tumors treated with both tamoxifen and progestin were devoid of receptor, beginning at 7 days after initiation of progestin therapy. Thus, downregulation of endometrial tumor PR resulting from continuous progestin administration presumably leads to desensitization to progestin, after an initial growth inhibitory response.

Animals↗

PubMed2003

Prevalence of estrogen or estrogen-progestin hormone therapy use.

OBJECTIVE: To use nationally representative data to produce prevalence estimates of combination estrogen-progestin therapy and estrogen-only therapy by covariates, and to evaluate differences between current use of short duration (less than 5 years) and current long-term use. METHODS: We analyzed data from female respondents 40 years of age and older (n = 9400) who were interviewed in the 1999 National Health Interview Survey. Hormone therapy use was categorized into four types: current estrogen-progestin therapy use, current estrogen-only therapy use, former hormone therapy use, and never use. We calculated the prevalence of hormone therapy by different levels of previously identified covariates of hormone therapy, as well as overall prevalence of hormone therapy use by length of use. RESULTS: Approximately 24% of women aged 40 years or older were current hormone users. Of these, 30% were taking estrogen-progestin therapy, and 70% were taking estrogen-only therapy. The prevalence of hormone use differed dramatically by hysterectomy status and age, and less so by many demographic, health-risk behavior, medical access, and medical history variables. Among women with no hysterectomy, the associations with many of the covariates were stronger for estrogen-progestin therapy use than for estrogen-only therapy use. Only 3% of women were estimated to be current estrogen-progestin therapy users for 5 or more years, whereas 10% were current estrogen-only therapy users for 5 or more years. CONCLUSION: Although many women at midlife and older were current hormone users, very few were long-term users of estrogen-progestin therapy.

Adult↗

PubMed1977

High inhibitory activity of R 5020, a pure progestin, at the hypothalamic-adenohypophyseal level on gonadotropin secretion.

Synthetic "progestins" currently used in the contraceptive pill inhibited the luteinizing hormone (LH) responsiveness to LH-releasing hormone in cells in culture in a way undistinguishable from that of androgens. Moreover, they competed for binding of the 3H-labeled androgen R 1881 to the rat prostate androgen receptor and stimulated seminal vesicle and prostate weight in castrated rats. R 5020, a pure progestin, was without effect on the above-mentioned parameters. However, a complete inhibition of the LH surge measured in the afternoon of expected proestrus was obtained at a dose of R 5020 similar to that of D-norgestrel. The synthetic progestin was also found to inhibit ovulation and to delay vaginal cornification. The present data show that the synthetic "progestins" commonly used in the pill possess intrinsic androgenic activity which could well be responsible, to an unknown extent, for their effectiveness as contraceptive agents. R 5020, a synthetic progestin devoid of androgenic activity, is at least as potent as the most potent 19-nortestosterone derivative, D-norgestrel, in inhibiting gonadotropin secretion and other parameters of the estrous cycle in the rat. The availability of a pure progestin devoid of androgenic activity but highly effective as an inhibitor of gonadotropin secretion could be of great interest for the development of an improved contraceptive.

Animals↗

PubMed1984

Zinc concentration and progestin receptor in human benign hyperplastic prostate.

The effect of cationic zinc on the specific binding of the synthetic progestin, promegestone (17 alpha-21-dimethyl-19-nor-pregna-4,9-diene-3,20-dione, R5020), has been investigated in cytosols from human benign hyperplastic prostate. Zinc was analyzed using flameless atomic absorption spectrometry. Progestin specific binding was assayed using sucrose density gradient centrifugation in a vertical tube rotor. The concentration of endogenous zinc in benign hyperplastic prostate cytosols was 0.53 mM +/- 0.26 (range 0.15 mM to 0.88 mM). No significant relationship was observed between zinc concentration in cytosols and the amount of progestin specific binding in the 7-8S peak in sucrose density gradients. Addition of excess zinc to cytosols (1.6 mM) in the presence or absence of monothioglycerol had no effect on the total amount of 7-8S progestin specific binding observed. Removal of free zinc by gel filtration of cytosols on Sephadex G-25 did not change the amount of 7-8S cytosolic receptor binding observed. The addition of the chelating agents, 2,2',2''-tripyridine, 9,10-phenanthroline or EGTA, after the gel filtration step had no apparent effect on the 7-8S progestin specific binding. The anionic chelator, EDTA, inhibited the 7-8S specific binding in a dose dependent manner. However, this inhibition was not reversed by the addition of excess zinc (6 mM) and was observed at very high concentrations of EDTA. This suggests that the effect of EDTA was due to its anionic effect rather than to its effect as a chelator. We conclude that cationic zinc in concentrations up to 2 mM does not change the amount of 7-8S progestin specific receptor binding in cytosols from BPH tissue.

Chelating Agents↗

PubMedDate not supplied

Progestin, estrogen, and insulin-like growth factor-I stimulate the prolactin receptor mRNA in human endometrial stromal cells.

OBJECTIVE: To identify the expression of the prolactin receptor (PRL-R) mRNA in human endometrial stromal and glandular epithelial cells in order to ascertain the autocrine/paracrine actions of PRL and to determine the effect of steroid hormones and growth factor on PRL-R mRNA during decidualization. METHODS: Human endometrial stromal cells and glandular epithelial cells were isolated from tissue fragments by collagenase digestion and total RNA was isolated. Stromal cells were cultured with or without progesterone (P) or medroxyprogesterone acetate (MPA) for various periods of time. Prolactin receptor and its mRNA were determined by Western blot analysis and solution hybridization/ribonuclease protection assay. The effects of estrogen, insulin-like growth factor (IGF)-I, and PRL on PRL-R mRNA were also studied. RESULTS: Both types of endometrial cells expressed PRL-R mRNA. Prolactin receptor mRNA content in glandular cells was consistently much less than that in stromal cells (1 versus 5-12). Progesterone or MPA stimulated the PRL-R mRNA expression two- to greater than ten-fold in the stromal cells of eight endometrial specimens. Stimulation by progestin was concentration dependent and required at least 1-2 days' incubation. A high level of PRL-R mRNA was maintained in stromal cells beyond 10 days' incubation with progestin. The stimulatory effect of progestin was inhibited by RU 486 and by cycloheximide, suggesting that progestin-receptor interaction and de novo protein synthesis mediate the up-regulation. In addition, estradiol and IGF-I stimulated PRL-R mRNA. Western blot analysis showed that progestin increased the PRL-R protein. A 90-kd band previously identified as PRL-R was ubiquitously distributed in the soluble and particulate fractions of the stromal cells. CONCLUSION: This study demonstrated that PRL-R mRNA is expressed in both types of endometrial cells and that PRL-R mRNA and its protein are up-regulated by progestin, estrogen, and IGF-I during decidualization of endometrial stromal cells.

Cells, Cultured↗

PubMed1978

Interaction of progestins with steroid receptors in human uterus.

Norethindrone (17beta-hydroxy-19-nor-17alpha-pregn-4-en-20-yn-3-one) and norethindrone acetate (17beta-acetoxy-19-nor-17alpha-pregn-4-en-20-yn-3-one) interfered to a varying degree, by competitive inhibition, with the binding of progesterone and oestradiol to respective cytoplasmic receptors in the human uterus. Progesterone binding to 4S macromolecule was saturable and co-specific for progestins. Competitors like norgestrel (17beta-hydroxy-18-methyl-19-nor-17alpha-pregn-4-en-20-yn-3-one), 19-norprogesterone, medroxyprogesterone acetate (17alpha-acetoxy-6alpha-methylpregn-4-ene-3,20-dione) and compound R(5020) (17,21-dimethyl-19-norpregna-4,9-diene-3,20-dione) possessed higher binding affinities for the progestin receptor. The dissociation constant (K(d)) for the progesterone-receptor interaction was 0.6-1.6nm and the receptor concentration ranged between 6600 and 8200 sites/cell. Norethindrone and norethindrone acetate competed for the progesterone receptor with inhibition constants (K(i)) of 6.8 and 72nm respectively. Gradient displacement and competitive-receptor assays indicated that norethindrone acetate-binding affinity for progestin receptor was approximately one-tenth that of norethindrone and progesterone. The progestins also inhibited oestradiol binding to 4.6S oestrogenic receptor by 8-12%, involving interaction at the oestradiol-binding site with a calculated K(i) value of 0.5-0.8mum. The competitive interaction of progestins with steroid receptors may be of putative importance in explaining the progestin action at the target site.

Acetates↗

PubMed2006

Both GnRH agonist and continuous oral progestin treatments reduce the expression of the tyrosine kinase receptor B and mu-opioid receptor in deep infiltrating endometriosis.

BACKGROUND: Deep infiltrating endometriosis (DIE) is commonly associated with severe pain. The pain can be managed successfully with GnRH agonists or continuous progestins. The precise molecular mechanism by which DIE causes pain or why hormonal treatment is effective, however, remains unclear. We recently identified three potential candidate genes that might be involved in DIE pain pathways: tyrosine kinase receptor B (TrKB), mu-opioid receptor (MOR) and serotonin transporter (5HTT). We hypothesized that if these three genes were involved in DIE-associated pain, their expression levels would probably be modulated by GnRH agonist or progestin. In this study, we compared mRNA expression levels of TrKB, MOR and 5HTT in DIE among patients pre-operatively treated with GnRH agonist, progestin or without pre-operative medical treatments. METHODS: The expression levels of TrKB, MOR and 5HTT mRNA in DIE were determined using laser capture microdissection and real-time RT-PCR techniques. RESULTS: The expression levels of TrKB in epithelial cells and MOR in stromal cells from DIE were significantly decreased in patients with pre-operative GnRH agonist or progestin. There was no significant difference in 5HTT expression levels among untreated, GnRH agonist- and progestin-treated patients. CONCLUSION: The expression levels of TrKB and MOR genes in DIE appeared to be modulated by GnRH agonist or progestin. However, the functional roles of TrKB and MOR in DIE remain to be clarified.

Adult↗

PubMed1992

Splenic macrophages enhance prolactin-induced progestin secretion from mature rat granulosa cells in vitro.

The effect of splenic macrophages on in vitro progestin secretion (the sum of the progesterone and 4-pregnen-20 alpha-ol-3-one concentrations in the medium) from mature rat granulosa cells was examined by means of co-culture techniques. When splenic macrophages (3.0 x 10(5) cells/ml) obtained from adult female rats on the evening of proestrus (1800 h) were added to granulosa cells (1.5 x 10(5) cells/ml) and co-cultured for 96 h in the absence of prolactin (PRL), progestin secretion from granulosa cells did not change. However, co-culture of granulosa cells with the macrophages in the presence of PRL (2 micrograms/ml) significantly enhanced progestin secretion after 48 h of culture. This stimulatory effect on progestin secretion was observed only when the number of macrophages added was more than twice the number of granulosa cells. On the other hand, splenic macrophages obtained on the evening of diestrus had no effect on progestin secretion from granulosa cells even in the presence of PRL. These results suggest that splenic macrophages can enhance PRL action so as to stimulate progestin secretion from granulosa cells and that this function of splenic macrophages varies during the estrous cycle.

Animals↗

PubMed1996

Progestin-induced puberty and secretion of luteinizing hormone in heifers.

Two experiments were designed to investigate the endocrine mechanisms by which progestin administration induces puberty in heifers. In experiment 1, prepubertal heifers were randomly assigned by age to receive either a single norgestomet implant for 10 days (NORG; n = 15) or to serve as unimplanted controls (CONT; n = 14). Serial blood samples were obtained on Days -0.5, 8.5, and 10.5 (Day 1 = day of implant insertion) and were analyzed for concentrations of LH. On days 9 and 11, 4 heifers in each treatment were slaughtered, and the reproductive tracts were obtained. Weekly progesterone analyses were performed to estimate the day of puberty in heifers not slaughtered. Puberty was induced in 6 of 7 heifers in the NORG treatment, resulting in an earlier (p < 0.05) day of puberty in the NORG than in the CONT treatment. The frequency of LH pulses was higher (p < 0.05) on Days 8.5 and 10.5 in the NORG as compared to the CONT treatment. Although no difference (p > 0.10) was observed between treatments in follicular development, uterine weight was greater (p < 0.05) in NORG than in CONT heifers on Day 11. In experiment 2, prepubertal heifers (n = 47) were administered either 1 (1NORG; n = 16), 3(3NORG; n = 16), or 0 (CONT; n = 15) norgestomet implants for 10 days, and serial blood samples were obtained as described for experiment 1. Transrectal ultrasonography was used to determine the diameter of the largest follicle on Day 9. Plasma samples were obtained after each serial sample collection period and were analyzed for estradiol concentrations. Puberty was induced in 75% (12 of 16) and 81% (13 of 16) of heifers in the 1NORG treatments, respectively. Four heifers in the 1NORG treatment, from which serial blood samples were collected, ovulated before removal of the progestin implant, and the LH data for this treatment were deleted. In the 3NORG treatment, LH pulse frequency was suppressed (p < 0.05) on Day 8.5, but was greater (p < 0.05) 12 h after removal of the progestin (Day 10.5) than in the CONT treatment. We conclude that progestin administration hastens puberty by increasing LH secretion after progestin withdrawal and propose that progestin administration induces puberty by accelerating the peripubertal decrease of estradiol negative feedback on LH secretion.

Animals↗

PubMed2006

Natural and synthetic progestins accelerate 7,12-dimethylbenz[a]anthracene-initiated mammary tumors and increase angiogenesis in Sprague-Dawley rats.

PURPOSE: Synthetic progestins are widely used therapeutically; however, there is controversy regarding their proliferative effects. We used a rat 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor model to test the hypothesis that progestins increase angiogenesis and as a result decrease the latency period and increase the multiplicity of mammary tumors. EXPERIMENTAL DESIGN: Medroxyprogesterone acetate (MPA) pellets were implanted 2, 4, or 6 weeks after DMBA exposure; RU-486 was given 3 days before MPA. Experiments were concluded 70 days after DMBA administration. RESULTS: MPA exposure 4 or 6 weeks after DMBA reduced the latency period for appearance of tumors in a dose-dependent manner and increased tumor incidence. Administration of MPA 2 weeks after DMBA administration reduced tumor incidence and was protective. Progesterone did not reduce the latency period but significantly increased tumor incidence. RU-486 delayed the latency period and decreased tumor incidence in animals exposed to MPA at 4 weeks after DMBA treatment, indicating that the progesterone receptor may be partially responsible for transmission of proliferative signals. RU-486 also delayed the latency period but failed to reduce overall tumor incidence when animals were exposed to MPA at 6 weeks after DMBA treatment, indicating that other factors may also control MPA-induced acceleration. Whereas MPA-accelerated tumors were both intraductal and tubular, progesterone-accelerated and/or DMBA-induced tumors were tubular. Progestin treatment increased vascular endothelial growth factor expression within tumors in a ligand- and cell type-dependent manner and increased angiogenesis in correlation with vascular endothelial growth factor expression. No mammary tumors or progesterone receptor were detected in DMBA-treated ovariectomized rats regardless of progestin administration. CONCLUSIONS: We propose that progestins can accelerate the development of mammary tumors and that antiangiogenic agents and/or the use of antiprogestins that can reduce tumor incidence might be a viable therapeutic option for treatment of progestin-accelerated tumors. The model described here is a potentially useful preclinical model for rapidly screening such compounds.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1987

Estrogen and progestin receptors in intracranial tumors.

Tissue samples from 17 intracranial tumors were analysed for the cytosolic estrogen and progestin receptor concentration. Three of the four meningiomas were progestin receptor-positive, but all were estrogen receptor-negative. All the four meningioma patients were postmenopausal women. The intracranial metastasis of a mammary carcinoma contained both estrogen and progestin receptors. Low progestin receptor concentration was found in an astrocytoma of a postmenopausal women. In addition, the presence of estrogen and progestin receptors was studied in four prolactinomas, two glioblastomas, two oligodendrogliomas, two mixed-cell carcinomas and one astrocytoma. All these tumors were estrogen and progestin receptor-negative.

Brain Neoplasms↗

PubMed2004

Estrogen plus progestin and the risk of peripheral arterial disease: the Women's Health Initiative.

BACKGROUND: Observational studies have reported less frequent carotid atherosclerosis in healthy women taking postmenopausal hormone therapy. Estrogen with progestin did not reduce peripheral arterial events among women with preexisting coronary heart disease. This analysis evaluates clinical peripheral arterial disease among generally healthy women in the Women's Health Initiative randomized trial of estrogen plus progestin. METHODS AND RESULTS: The Estrogen Plus Progestin trial assigned 16 608 postmenopausal women, mean age 63.3+/-7.1 years, to daily conjugated estrogens (0.625 mg) with medroxyprogesterone acetate (2.5 mg) or placebo and documented health outcomes over an average of 5.6 years of follow-up. Hospitalization for peripheral arterial disease was infrequent, with annualized rates of 0.08%, 0.06%, and 0.02% for carotid disease, lower extremity arterial disease, and abdominal aortic aneurysm, respectively. The incidence of peripheral arterial events did not differ between treatment groups (hazard ratio [HR] 0.89, 95% confidence interval 0.63, 1.25). The risk was slightly greater among women assigned to active estrogen with progestin in years 1 (HR 1.33) and 2 (HR 1.27), and was slightly lower in later years (HR 0.85 and 0.87 in years 5 and > or =6). Among adherent participants, the hazard ratio for peripheral arterial events was 1.23 (95% confidence interval 0.79, 1.91) over the 5.6 years of follow up. Subgroup analysis identified no significant interactions between estrogen with progestin and baseline characteristics with regard to peripheral arterial disease risk. CONCLUSIONS: Among generally healthy postmenopausal women, conjugated estrogens with progestin did not confer protection against peripheral arterial disease.

Aged↗

PubMed1983

Progestin receptors in female rat brain and hypophysis in the development from fetal to postnatal stages.

The fetal and postnatal development of the progestin receptors in the intact female rat brain was investigated by means of the in vitro cytosol binding and the nuclear exchange assay using 3H-R5020 ([17 alpha-methyl-3H] 17 alpha-,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione). A large 7S peak of progestin binding in the cerebral cortical cytosols was observed at days 7-14 with less evident binding in the hypothalamus-preoptic area (HPOA). The cortical cytosol receptors, first detectable at day 0, rapidly increased at days 1-7, reaching a maximum at day 10, then gradually declined thereafter. The receptors in the HPOA and other brain areas appeared at day 1, increased during the first week, then remained constant at days 10-28. Hypophysial cytosol receptors, first detectable at day 10, increased at day 28. Nuclear progestin binding was low in the HPOA and cortex of the neonates at days 1-3. Interestingly, despite the low level of serum progesterone, the cortical nuclear binding suddenly increased at days 7-10, then remained high at days 14-21. A similar, though less pronounced, pattern was seen in the HPOA. Diethylstilbestrol injection caused an increase in the cytosol binding capacities in the HPOA, but did not in the cortex. These results suggest the appearance of the brain progestin receptor system immediately after birth, and differential patterns of their postnatal development in the intact female rat. The onset of increased nuclear translocation of endogenous progestin-receptor complex may occur in the cortex, and possibly HPOA, at around days 7-10. Progestin receptors in the postnatal rat HPOA are estrogen inducible, but not in the cortex.

Animals↗

PubMed1990

Comparison of age- and sex-related changes in cell nuclear estrogen-binding capacity and progestin receptor induction in the rat brain.

Previous studies have suggested parallels between the mechanisms underlying sexual differentiation and age-related loss of reproductive cyclicity in the female rat. Both appear to involve the actions of estrogen on the brain and are associated with a reduction in hypothalamic estrogen sensitivity. In this study the effects of sex and aging on cell nuclear estrogen receptor-binding capacity and cytosol progestin receptor induction in the pituitary gland, periventricular preoptic area (PVP), medial preoptic area (mPO), bed nucleus of the stria terminalis, arcuate median eminence region (ARC), ventromedial nucleus (VMN), and corticomedial amygdala were directly compared. Young (2.5 months old) and middle-aged (8-10 months old) male and female and old (19 months old) female rats were gonadectomized 14 days before adrenalectomy (ADX). For comparison of cell nuclear estrogen receptor-binding capacity, animals received a saturating dose of estradiol (36.0 micrograms/kg BW) 3 days after ADX and 1 h before death. Cell nuclear estrogen binding was measured by an in vitro exchange assay. For comparison of estrogen-induced progestin receptors, animals received a sc placed Silastic capsule containing 10% 17 beta-estradiol at the time of ADX and were killed 3 days later. Cytosol progestin binding was measured by an in vitro binding assay. Cell nuclear estrogen-binding capacities and cytosol progestin receptor induction were lower in the PVP, mPO, and VMN of the young male than in the young female. In the female, the level of progestin receptor induction in the pituitary and brain was unaffected by age; however, cell nuclear estrogen-binding capacity in the mPO, VMN, ARC, and pituitary gland was lower in old than in middle-aged females. These results demonstrate that the effects of sexual differentiation and aging on the hypothalamus involve similar, but not identical, region-specific reductions in cell nuclear estrogen receptor-binding capacity. The consequences of these reduced estrogen receptor binding levels in terms of the induction of progestin receptor in response to estrogen exposure are, however, very different in the male compared to those in old female rats.

Adrenalectomy↗