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PubMed2005

The effects of the neurosteroids: pregnenolone, progesterone and dehydroepiandrosterone on muscarinic receptor-induced responses in Xenopus oocytes expressing M1 and M3 receptors.

The neurosteroids pregnenolone, progesterone, and dehydroepiandrosterone (DHEA) occur naturally in the nervous system. They act on neural tissues, participate in neuronal signaling, and are reported to alter neuronal excitability via nongenomic mechanisms. Muscarinic receptors have important roles in neuronal functions in the brain and autonomic nervous system. In this study, we investigated the effects of pregnenolone, progesterone, and DHEA on M(1) and M(3) muscarinic receptors using the Xenopus oocyte expression system. Pregnenolone and progesterone inhibited the acetylcholine (ACh)-mediated responses of M(1) and M(3) receptors expressed in Xenopus oocytes, whereas DHEA did not. The half-maximal inhibitory concentrations (IC(50)) for pregnenolone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 11.4 and 6.0 microM respectively; the IC(50) values for progesterone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 2.5 and 3.0 microM respectively. The selective protein kinase C (PKC) inhibitor GF109203X had little effect on the pregnenolone or progesterone inhibition of the ACh-induced currents in Xenopus oocytes expressing M(1) or M(3) receptors. The inhibitory effects of pregnenolone and progesterone were overcome at higher concentrations of ACh. Pregnenolone and progesterone inhibited the [(3)H]quinuclidinyl benzilate (QNB) binding to M(1) and M(3) receptor expressed in Xenopus oocytes, and Scatchard plot analysis of [(3)H]QNB binding revealed that pregnenolone and progesterone altered the K(d) value and the B(max), indicating noncompetitive inhibition. In conclusion, pregnenolone and progesterone inhibited M(1) and M(3) receptor functions noncompetitively by the mechanism independent of PKC and by interfering with ACh binding to the receptors.

Acetylcholine↗
PubMed1999

Assessment of neuroleptic-like properties of progesterone.

There is considerable evidence from epidemiological studies that the onset of psychiatric disorders may be related to changes in the secretion of gonadal hormones. For example, the postpartum period appears to be a vulnerable phase for the occurrence of psychiatric disturbances such as dysphoric mood and even severe psychotic disturbances. It has been suggested that a sudden drop in progesterone concentrations may contribute to the development of such disorders. Because the administration of this steroid might be of therapeutic value in psychiatric disturbances, we investigated the behavioral properties of progesterone in the rat to assess putative neuroleptic-like properties of this steroid. Progesterone administration dose-dependently increased the EEG activity during wakefulness in the 10- to 30-Hz frequency bands and decreased locomotor activity. While no anxiolytic activity could be detected in the plus maze, the highest dose of progesterone (90 mg/kg) exerted an inhibitory effect on the conditioned avoidance response. In contrast to haloperidol (0.5 mg/kg), progesterone neither produced catalepsy nor antagonized amphetamine-induced stereotypy. However, both progesterone (10, 30 and 90 mg/kg) and haloperidol (0.1 mg/kg) effectively restored the disruption of the prepulse inhibition (PPI) of the acoustic startle response (ASR) that was evoked by apomorphine (2 mg/kg). In contrast, allopregnanolone (10 mg/kg), one of the main metabolites of progesterone, did not significantly antagonize the effect of apomorphine on the PPI. This behavioral profile of progesterone is compatible with the sedative properties of its metabolite allopregnanolone via the GABAA receptor, but also with the possibility that progesterone itself shares some properties with atypical antipsychotics, which may be relevant for the development and treatment of psychotic disturbances.

Animals↗
PubMed2000

Effects of estrogen and progesterone on tibia histomorphometry in growing rats.

The present study was performed to evaluate possible interactions between estrogen and progesterone on peak cancellous bone mass. Ovariectomized (OVX) growing rats were treated with 17beta-estradiol (4.8 microg/day), progesterone (4.8 mg/day), a combination of the two sex steroids, or with vehicle for 14 days beginning 7 days after OVX. The tibiae were removed for histomorphometric analysis of the proximal metaphysis. OVX and growth each resulted in net resorption of cancellous bone at a sampling site adjusted for longitudinal bone growth. Estradiol and progesterone treatment each antagonized bone loss by inhibiting the decrease in trabecular number. Estradiol increased but progesterone had no effect on trabecular thickness. Progesterone did not influence either osteoclast number or the resorption of the pretreatment fluorochrome label. Estradiol reduced osteoclast number and inhibited label resorption, the latter change being accentuated by combination treatment. Estradiol reduced and progesterone enhanced the mineral apposition and bone formation rates. The results indicate that estradiol and progesterone have independent activities on cancellous bone turnover during growth. Whereas estradiol reduced bone turnover, progesterone had a stimulatory effect on bone formation. These findings suggest that progesterone has a role in establishing and maintaining peak cancellous bone volume during growth.

Animals↗
PubMed1989

Increased placental progesterone may cause decreased placental prostacyclin production in preeclampsia.

UNLABELLED: Placentas obtained from women with preeclampsia produce more thromboxane and less prostacyclin than normal. They also produce more progesterone than normal. This study tested whether a progesterone concentration equivalent to that in the medium after in vitro incubation of placentas from women with preeclampsia (greater than or equal to 1.5 x 10(-5) mol/L) could cause an imbalance of increased thromboxane and decreased prostacyclin production by normal placentas. Fresh term placental tissues were incubated for 48 hours in the absence or presence of various concentrations of progesterone and/or estradiol. Prostacyclin and thromboxane were determined by radioimmunoassay of their stable metabolites, 6-keto-prostaglandin F1 alpha and thromboxane B2. A progesterone concentration of 1.5 x 10(-5) mol/L significantly (p less than 0.001) inhibited prostacyclin production, compared with control, but lower concentrations did not. Estradiol at concentrations present in the medium after incubation of either normal or preeclamptic placental tissue did not significantly affect prostacyclin production, nor did it prevent progesterone at 1.5 x 10(-5) mol/L from inhibiting prostacyclin. Thromboxane production was not affected by either progesterone or estradiol. CONCLUSION: In vitro addition of progesterone at a concentration equivalent to that in the medium after incubation of preeclamptic placentas inhibited prostacyclin production by normal placentas to a rate characteristic of preeclampsia. However, it did not increase thromboxane. SPECULATION: Increased trophoblast progesterone in preeclampsia may act by a paracrine mechanism to inhibit prostacyclin synthesis in placental vasculature. Progesterone's selective inhibition of prostacyclin without affecting thromboxane may be due to the compartmentalization of thromboxane production to trophoblast and stroma and prostacyclin production to placental vasculature.

Dose-Response Relationship, Drug↗
PubMed1990

A progesterone-induced blocking factor corrects high resorption rates in mice treated with antiprogesterone.

Earlier we showed that because of the presence of functional progesterone receptors, lymphocytes of healthy pregnant women produced an immunomodulatory protein in the presence of progesterone, whereas those of nonpregnant persons did not. Progesterone-treated murine pregnancy lymphocytes release a similar factor. The present study reveals the biologic significance of this finding. Treatment of BALB/c mice that were 8 days pregnant with a progesterone receptor blocker (RU 486) resulted in 100% resorption of the fetuses. Simultaneous administration of the supernatant from progesterone-treated murine pregnancy spleen cells restored the resorption rate to the original 6% observed in untreated control animals. These data suggest that functional lymphocytic progesterone binding sites are needed for the maintenance of normal pregnancy. Because of the blockage of progesterone receptors and the consequent inability of the lymphocytes to produce the progesterone-induced blocking factor, abortion is initiated by immune factors. The fact that administration of the preformed blocking factor counteracted the effect of antiprogesterone treatment suggests that progesterone-mediated immunosuppression is needed for the maintenance of normal gestation.

Abortion, Induced↗
PubMed1983

Rat uterine progesterone receptor: stabilization of hormone-binding components for biochemical analyses.

A method was developed for quantitative recovery of the labile rat uterine progesterone receptor hormone-binding components. Initial conditions were established by the sucrose gradient procedure. Upon centrifugation through low-salt 5-20% sucrose gradients prepared in 10% glycerol, the well-known 6-8 S progesterone receptor components were observed either when cytosol was prelabeled with [3H]17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione [( 3H]R5020) or when prelabeled with [3H]progesterone followed by postlabeling the fractions collected after centrifugation with either [3H]progesterone or [3H]R5020. Recovery of progesterone receptor binding was improved by prelabeling with [3H]R5020, by adding 1.5 mM ethylene glycol bis(beta-aminoethylether)N,N'-tetraacetic acid (EGTA) to all buffers, and at high tissue concentrations. Under these conditions quantitative conversion of the receptor to specific [3H]R5020-binding 4S components was achieved with 150 or 400 mM KCl. Similar conditions proved unsuitable for receptor analysis by gel filtration (Bio-Rad agarose A0.5M or A1.5M), apparently due to [3H]R5020 dissociation from the receptor in the large volume of elution buffer. However, excellent receptor recovery (97.2 +/- 6.7%) was achieved by including 10 nM unlabeled progesterone in all preparation and elution buffers. Receptors were then detected by the addition of 5 nM [3H]R5020 to the column fractions, exchange incubation for 3-6 h at 4 degrees C, and subsequent separation of bound and free steroid by the hydroxyapatite assay. This method resulted in a consistent elution pattern suggestive of receptor heterogeneity. Identity of the peak(s) as progesterone receptor components(s) was confirmed by the lack of competition by 2 microM cortisol when added either to cytosol or during the postlabeling-exchange process. Neither the qualitative nor quantitative results of the column profiles were changed substantially in the presence of 20 mM molybdate. Although the receptor structure has yet to be established, both statistical analysis of the column profiles by computer curve-fitting procedures and rechromatography of peak fractions suggested that the rat uterine progesterone receptor may be composed of multiple components. This ligand-stabilization/postlabeling-exchange procedure provides a method for further studies of progesterone receptor biochemistry in mammalian systems. Additionally, similar procedures may stabilize other labile ligand-binding proteins for biochemical analyses and/or purification.

Animals↗
PubMed1993

Rapid stimulation of rhodamine 123 efflux from multidrug-resistant KB cells by progesterone.

Rhodamine 123 is a mitochondrial dye that is retained for prolonged periods by carcinoma cells. While investigating causes of retention of this dye, we found that 10 microM progesterone caused a rapid stimulation of efflux of rhodamine 123 within 15 min from KB V20C cells, which overexpress the multidrug resistance pump. Progesterone did not stimulate efflux from KB cells that do not overexpress the pump, and verapamil blocked rhodamine 123 efflux in the presence or absence of progesterone, indicating that rhodamine 123 is removed from KB V20C cells by the multidrug resistance pump. Progesterone, however, is unlikely to stimulate rhodamine 123 efflux by simply increasing pump activity for two reasons: (1) progesterone inhibited the efflux of daunomycin from KB V20C cells, so it did not stimulate efflux of all drugs, and (2) progesterone inhibited efflux of rhodamine 123 from L1210/VMDRC cells and had little effect on Adr MCF7 cells; both overexpress the multidrug resistance pump. In the experiments with KB V20C cells, progesterone was the most active steroid tested. At 10 microM, progesterone caused a 70-fold stimulation, desoxycorticosterone, testosterone, promegestone and estradiol about 20-fold, and others had little or no effect. Progesterone may act by a non-genomic mechanism to decrease intracellular binding of rhodamine 123, making the dye accessible to the multidrug resistance pump.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1985

The effects of steroid hormones and gonadotropins on in vitro placental conversion of pregnenolone to progesterone.

Using human term placental mitochondrial preparations, optimal conversion of [3H]pregnenolone to [3H]progesterone was obtained at 30 min incubation and with a mitochondrial protein content of 2.5-3.5 mg/ml. Estradiol, estrone, progesterone and testosterone in a dose range of 0.03-8.66 mumol inhibited the in vitro conversion of [3H]pregnenolone to [3H]progesterone by placental homogenates. All four steroids inhibited the pregnenolone to progesterone conversion in a dose-dependent manner. The ID50 (dose required to inhibit conversion of pregnenolone to progesterone by 50%) was 0.04 mumol for estradiol, 0.13 mumol for testosterone, 0.3 mumol for progesterone and 1.0 mumol for estriol. Neither gonadotropin releasing hormone (50-1000 ng) nor human chorionic gonadotropin (5-500 IU) affected the placental basal conversion rate of pregnenolone to progesterone in vitro. Our findings indicate that steroid hormones such as estradiol, estrone, testosterone and progesterone can inhibit local placental progesterone biosynthesis through inhibition of the enzyme complex 5-ene-3 beta-hydroxysteroid dehydrogenase.

Chorionic Gonadotropin↗
PubMed1986

Progesterone metabolism in T47Dco human breast cancer cells--I. 5 alpha-pregnan-3 beta,6 alpha-diol-20-one is the secreted product.

Progesterone is a major hormone controlling normal breast development and function. In breast cancer, progesterone may be involved in tumor growth regulation, and the concentration of the intracellular receptor proteins for progesterone are used to distinguish hormone dependent from autonomous tumors. We have been studying the cytoplasmic and nuclear distribution of progesterone receptors after progesterone treatment of cultured T47Dco human breast cancer cells. Anomalous behavior of the receptors, when progesterone was compared to synthetic progestins, suggested that progesterone was being rapidly metabolized by the cells. We have now studied this metabolism in detail. When progesterone is added to medium of proliferating cells, it disappears with a half life of 2-4 h. A single metabolite (P-metabolite) is quantitatively released into the medium, but its release is delayed 10-14 h. The quantitative conversion of progesterone to P-metabolite was confirmed using two independent methods: gas chromatography with internal standards, and 14C-radioisotope measurements. We have used gas chromatography, gas chromatography/mass spectrometry, thin layer chromatography and nuclear magnetic resonance to identify the final metabolic product released into the medium as 5 alpha-pregnan-3 beta,6 alpha-diol-20-one.

Breast Neoplasms↗
PubMed1986

Biochemical characterization of the progesterone receptor in the chick bursa of Fabricius.

In a previous work we demonstrated estrogen-inducible progesterone binding sites in the bursa of Fabricius. In the present study these were characterized and compared to the progesterone receptor (PR) in the chick oviduct. When the size of the binding sites was analyzed with sucrose gradient centrifugation, 2 peaks of bound progesterone were obtained. The sedimentation coefficients of the peaks were 8-9 S and 3-4 S. In size exclusion HPLC only 1 peak was seen with a size corresponding to the 8-9 S in the sucrose gradient. The Stokes radius was 7.7 nm. When the ionic strength was elevated or CaCl2 was added, smaller steroid binding forms were detected. The sizes of these progesterone binding molecules at low and high ionic strength and in the presence of CaCl2 were equal in bursa and oviduct when analyzed with HPLC. The Stokes radii of these forms were 5.6 nm in high salt and 2.1 nm with CaCl2. The steroid binding components in the bursa cytosol eluated as 2 peaks from the DEAE column with KCl gradient. The peaks corresponded to the so-called A and B components in the chick oviduct. In the presence of molybdate, bound progesterone eluated as one peak from DEAE in both oviduct and bursa. The progesterone binding capacity was shown to be heat labile with equal half-lives in the bursa and the oviduct. Progesterone and ORG 2058 had a high affinity for the binding site and their binding was specific for progestins. It is concluded that the estrogen-inducible progesterone binding site in the bursa of Fabricius resembles the oviductal progesterone receptor in structural and binding properties.

Animals↗
PubMed1987

Effects of different schedules of progesterone treatment on mammary tumorigenesis and uterine adenomyosis in SHN virgin mice.

As a possible step to estimate the factors controlling the effects of progesterone on mammary tumorigenesis, 3 groups of SHN virgin female mice were treated as follows beginning 2.5-4 months of age: Group A received the subcutaneous implantation of silastic tube containing progesterone (low dose) during the initial 4 months followed by progesterone pellet implantation (high dose) every 2 months. Group B was implanted with progesterone pellet throughout the experiment. Group C was given the vehicle only. Whereas there was little difference among groups in mammary tumorigenesis during the initial 4 months of treatments, tumorigenesis was significantly stimulated in group B thereafter. On the contrary, group A was different little from group C even after progesterone pellet implantation. The results indicate that the effects of progesterone on mammary tumorigenesis are affected by the 'preceding' progesterone conditions and that there is a critical period for manifestation of the effects of progesterone on mammary tumorigenesis, which is before 8 months of age at most. While all mice developing mammary tumors developed uterine adenomyosis in each group, the progression was enhanced by both low and high doses of progesterone.

Animals↗
PubMed1992

The effects of metabolic stress on plasma progesterone in healthy volunteers and schizophrenic patients.

A number of preclinical studies suggest that progesterone may play an important role in the stress response, however, the effects of stress on progesterone in humans has not been established. Also, several lines of evidence indicate that schizophrenia may be associated with abnormal neurobiological responses to stress, but the effects of stress on progesterone in schizophrenia has not been investigated. The purpose of the present study was to examine the effects of stress on plasma progesterone and cortisol in healthy subjects and to determine if schizophrenic patients have altered stress-induced plasma progesterone levels compared to normal controls. Stress was induced through administration of 2-deoxyglucose (2DG), a glucose analog that impairs glucose metabolism resulting in a clinical state comparable to hypoglycemia. There were significant increases in plasma progesterone and cortisol levels following 2DG-induced glucoprivic stress in healthy controls. There was no relationship between stress related progesterone and cortisol elevations. Schizophrenic patients, in comparison to controls, had significantly greater 2DG-induced elevations in progesterone levels but no differences in stress-related cortisol levels. There was evidence that basal progesterone and cortisol levels were elevated in the schizophrenic patients. The implications of these data are discussed.

Adaptation, Physiological↗
PubMed1984

The desensitization effect of progesterone on female rat sexual behavior is not due to interference with estrogen priming.

In order to determine if progesterone interferes with estradiol's priming action on progesterone-facilitated sexual behavior, we tested the responsiveness of progesterone-desensitized female rats to the serotonin receptor antagonist, methysergide, and the neuropeptide, luteinizing hormone-releasing hormone. Threshold doses of both compounds were established. Progesterone treatment, which caused a decrease in the lordosis rating in response to a moderate dose of progesterone did not inhibit responsiveness to threshold doses of methysergide or luteinizing hormone-releasing hormone. The results of this study support the notion that progesterone does not interfere with estradiol's priming action on progesterone-facilitated sexual receptivity. Furthermore, they suggest that progesterone's desensitization effect is specific to progesterone-facilitated lordosis.

Animals↗
PubMed1988

Effects of progesterone on open field behavior of food deprived ovariectomized female rats.

The effects of intraperitoneal progesterone administration on the open field behavior of ovariectomized female Wistar rats were studied in two experiments. Subjects were challenged with 5 different doses of progesterone (0, 10, 20, 40, 80 mg/kg body weight) during 5 successive days of open field testing (5 min a day) in the first experiment. Progesterone dose-dependently decreased rearing and object inspection, but did not affect total ambulation. In the second experiment food pellets were presented in the open field and subjects were repeatedly tested at regular intervals after progesterone administration on each of 5 consecutive testing days. Three doses of progesterone (0, 40, 80 mg/kg body weight) were administered during the final 3 days of the second experiment. Eighty mg/kg progesterone decreased rearing activity, but increased ambulation; motivation to retrieve food pellets was not affected. These effects of 80 mg/kg progesterone were observed at least as long as 2 hours after injection. Forty mg/kg progesterone did not produce such effects. These results, in conjunction with those of other experiments show that progesterone affects open field behavior in a way similar to central depressant drugs.

Animals↗
PubMed1990

Concentrations of 13, 14-dihydro-15-keto prostaglandin F2 alpha after pulsatile progesterone administration at the time of luteolysis of heifers.

Progesterone was administered in pulses to 12 dairy heifers from days 17.5 to 22.5 post-estrus in order to determine its ability to modify secretion of PGF2 alpha around the time of luteolysis. Control heifers exhibited pulses of PGFM concomitant with a sharp decline in progesterone concentrations and thus these pulses were temporally associated with luteolysis. Additional pulses of PGFM were observed in heifers receiving exogenous progesterone, but these were not statistically predictable by either dose of progesterone (50 or 100 micrograms) or time of administration (3 or 6 hour intervals). However, all heifers (4/4) treated with progesterone at 3 hour intervals had additional pulses of PGFM as compared to only one heifer (1/4) treated at 6 hour intervals. When pulses of PGFM were induced by exogenous progesterone there was a substantial lag time between the initiation of progesterone treatment and their occurrence. The limited response to progesterone administration and the lack of synchrony is not consistent with an ability of exogenous progesterone to directly stimulate secretion of PGF2 alpha at the time of luteolysis.

Animals↗
PubMed1992

Biotinylated anti-progesterone monoclonal antibodies specifically target the uterine epithelium and block implantation in the mouse.

Post-coital administration of a mouse monoclonal antibody (mAb) against progesterone (DB3; IgG1) prevents pregnancy in several species. Our previous studies in mice have shown that passively transferred DB3 specifically targets the uterus before the expected time of implantation, probably through progesterone-binding sites. DB3 and two other anti-progesterone mAbs, i.e. 11/34 (IgG1) and 11/64 (IgM), were biotinylated and 9 nmol of each (a dose known to reduce pregnancy rate by greater than 80% with unconjugated mAbs) was injected into BALB/c female mice 32 h post coitum (p.c.). The biotin-mAb complexes were highly effective in blocking pregnancy (83-100%) compared with control animals that had received the biotinylated MOPC21 myeloma protein P3 (IgG1). Using the streptavidin-FITC (fluorescein isothiocyanate) reporter complex or second-stage anti-biotin-FITC antibodies, biotinylated conjugates of DB3, 11/34 and 11/64 were specifically localized on the uterine luminal epithelium at 68 h p.c. (i.e. 36 h after i.p. injection). Neither P3-biotin-treated pregnant mice nor biotinylated anti-progesterone mAb-treated pseudopregnant females showed a positive reaction. In addition, the localization of biotin-conjugated anti-progesterone mAbs could be blocked by absorption of the antibodies with free progesterone or progesterone conjugates prior to injection. These results show that localization to the uterine epithelium occurs with different anti-progesterone mAbs, and that this phenomenon is probably associated with progesterone-binding sites on the luminal epithelium.

Animals↗
PubMed1987

Effects of progesterone withdrawal on uterine prostaglandin levels in the ovariectomized pregnant rat.

Prostaglandin (PG) levels increase dramatically just before parturition in the rat. Coincident with this dramatic increase in uterine PGs is a precipitous decrease in plasma progesterone and enhanced plasma estradiol levels. The purpose of the present study was to mimic the progesterone withdrawal phenomenon in the presence and absence of estradiol in ovariectomized pregnant rats and determine the effects on uterine PGF, PGE, thromboxane B2 (TxB2) and 6-keto-PGF1a (6KF) levels. Rats were ovariectomized on day 16 of pregnancy and silastic inserts containing progesterone and estradiol placed s.c. in two groups of rats (I and II) while the third group (III) received progesterone only. On day 19 of pregnancy progesterone was withdrawn from groups II and III and rats sacrificed 0, 6, 12 and 24 hours later. Uterine tissue was assayed for PGs by radioimmunoassay. Progesterone withdrawal in the absence of estradiol (III) administration significantly (p less than .05) elevated PGE, TxB2 and 6KF, but not PGF, at the 24 hour period compared to controls (I). When progesterone was withdrawn in the presence of exogenously administered estradiol (II) only PGF showed enhancement (p less than .05) over III at the 24 hour period thus indicating a specific effect of estradiol on the PGF metabolic pathway. In conclusion, these data indicate that: (1) progesterone withdrawal is a potent stimulus for uterine PG production and is probably a major contributor to the augmented uterine PGE, TxB2 and 6KF levels at term in the pregnant rat; and (2) progesterone withdrawal in the presence of exogenously administered estradiol enhances uterine PGF production thus indicating a specific effect of estradiol on PGF production.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

The antitumor potency of progesterone antagonists is due to their differentiation potential.

A new therapy for the progesterone receptor positive mammary carcinoma may be the treatment with progesterone antagonists. This new class of antihormones causes a strong inhibition of tumor growth comparable to the potency of ovariectomy in a panel of experimental mammary carcinomas. The mechanisms of the strong tumor-inhibiting action of progesterone antagonists on experimental mammary carcinomas mainly depends on a progesterone receptor mediated process leading to induction of terminal differentiation and a blockade of the cell cycle. To further characterize the antitumor mechanism of progesterone antagonists we analyzed the effects of Onapristone and ZK 112.993 on DMBA- and MNU-mammary tumors of the rat and MXT-tumors of the mouse after different therapy intervals. These hormone-dependent mammary tumors normally display intraductal growth in papillary, cribiform or solid formation, whereas after treatment periods of 2-6 weeks with progesterone antagonists they displayed dysplastic ductal and acinous formations, usually filled with secretory material. Whereas tumor size, mitotic index, and the grade of tumor malignancy decreased distinctly, the volume fraction of glandular structures in the tumors as well as the appearance of apoptosis increased 3-fold compared to the controls. In addition, the mammary glands of progesterone antagonist treated animals showed the morphological features of differentiation with the appearance of secretory activity. Interestingly, the staining pattern of some of the lectins used, especially UEA 1 binding pattern, fits to the concept of differentiation since recent studies revealed a higher degree of fucosylation only in benign lesions of human breast cancers. Therefore, these data underline the concept of a differentiation potential of progesterone antagonists on progesterone receptor positive mammary carcinomas.

Animals↗