Differential Effects Of Progesterone Research Articles

Differential effects of progesterone on social recognition and the avoidance of pathogen threat by female mice

Although pathogen threat affects social and sexual responses across species, relatively little is known about the underlying neuroendocrine mechanisms. Progesterone has been speculated to be involved in the mediation of pathogen disgust in women, though with mixed experimental support. Here we considered the effects of acute progesterone on the disgust-like avoidance responses of female mice to pathogen threat. Estrous female mice discriminated and avoided the urinary and associated odors of males subclinically infected with the murine nematode parasite, Heligmosomoides polygyrus. These avoidance responses were not significantly affected by pre-treatment with progesterone. Likewise, brief (1 min) exposure to the odors of infected males attenuated the subsequent responses of females to the odors of the normally preferred unfamiliar males and enhanced their preferences for familiar males. Neither progesterone nor allopregnanolone, a central neurosteroid metabolite of progesterone, had any significant effects on the avoidance of unfamiliar males elicited by pre-exposure to a parasitized male. Progesterone and allopregnanolone, did, however, significantly attenuate the typical preferences of estrous females for unfamiliar uninfected males, suggestive of effects on social recognition. These findings with mice indicate that progesterone may have minimal effects on the responses to specific parasite threat and the expression of pathogen disgust but may influence more general social recognition and preferences.

Differential effects of progesterone on the combined estradiol benzoate-sulpiride stimulation of plasma luteinizing hormone and prolactin concentrations in geldings

Differential effects of progesterone on the combined estradiol benzoate-sulpiride stimulation of plasma luteinizing hormone and prolactin concentrations in geldings

Differential effects of progesterone and medroxyprogesterone on delay eyeblink conditioning in ovariectomized rats

Ovarian hormones modulate acquisition processes involved in classical conditioning. Although progesterone has been indirectly implicated, its role in classical conditioning of the eyeblink response has not been directly investigated. We assessed the effects of daily dosing of progesterone or medroxyprogesterone (MPA), a non-metabolized synthetic progestin, upon the acquisition of a classically conditioned eyeblink response in ovariectomized (OVX) female rats. Rats were dosed 4h prior to each training session with 0.1 or 1.5mg/kg of either of these hormones or sesame oil. A delay conditioning paradigm was employed using a 500ms conditioned stimulus coterminating with a 10ms 10V unconditioned stimulus. At the low dose, progesterone and MPA rats did differ from each other, with MPA-treated rats learning slower, but neither group differed from OVX-oil or Sham-oil controls. No group differences in acquisition were observed at the higher dose. During extinction trials, high-dose MPA-treatment and OVX-oil groups extinguished quicker than the high-dose progesterone-treated group. In addition, unconditional response (UR) amplitudes were lower in all OVX groups, regardless of hormone or oil treatment, compared to the sham-oil group. Since MPA did not affect extinction, it is likely the slower extinction in the progesterone-treated rats is due to a metabolite of progesterone. Corticosterone is discussed as a likely candidate for such a role. In addition, we found chronic absence of ovarian hormones decreased UR amplitudes, although differences in UR amplitudes were not associated with changes in the acquisition process. These results are discussed with respect to differences in the hormonal effects upon acquisition versus extinction processes and how these data may explain reports of learning differences in women based on oral contraceptive usage.

Differential Effects of Progesterone on COX-2 and Mn-SOD Expressions Are Associated with Histone Acetylation Status of the Promoter Region in Human Endometrial Stromal Cells

Progesterone differently regulates TNFα-induced gene expression of cyclooxygenase-2 (COX-2) and manganese superoxide dismutase (Mn-SOD) in human endometrial stromal cells (ESC). The present study investigated the mechanisms by which TNFα and progesterone affect the expressions of COX-2 and Mn-SOD in ESC. ESC were incubated with TNFα and progesterone. COX-2 and Mn-SOD mRNA expression was determined by real-time RT-PCR. Nuclear factor (NF)-κB binding to the promoter region or histone acetylation status of the NF-κB response element was analyzed by a chromatin immunoprecipitation assay. TNFα increased COX-2 and Mn-SOD mRNA levels. Progesterone (10(-6) M) suppressed TNFα-induced COX-2 mRNA expression, whereas TNFα-induced Mn-SOD expression was not inhibited by progesterone. The inhibitory effect of progesterone was abolished by knockdown of progesterone receptors by small interfering RNA. Chromatin immunoprecipitation assay revealed that TNFα increased NF-κB binding at both the COX-2 promoter and the Mn-SOD enhancer and that progesterone inhibited only the NF-κB binding at the COX-2 promoter. The histone acetylation level of the NF-κB response element of the Mn-SOD enhancer was lower than that of the COX-2 promoter. However, when histone acetylation was induced by histone deacetylase inhibitors, progesterone inhibited the TNFα-induced NF-κB binding to the Mn-SOD enhancer. TNFα increased COX-2 and Mn-SOD expression via NF-κB activation. Progesterone inhibited COX-2 expression by inhibiting the binding of NF-κB to its response element but did not inhibit TNFα-induced Mn-SOD expression. The gene-specific action of progesterone may be due to the difference in chromatin structure at the NF-κB response elements in the COX-2 promoter and Mn-SOD enhancer.

Differential effects of progesterone and genital stimulation on sequential inhibition of estrous behavior and progesterone receptor expression in the rat brain

The effect of genital stimulation, either by vaginocervical stimulation (VCS) using a calibrated vaginal probe combined with manual flank stimulation (FS), or by mounts performed by the male, on the hypothalamus and preoptic area concentration of the progesterone receptors A (PR-A) and B (PR-B) was assessed in ovariectomized (ovx) estrogen-primed rats. VCS/FS or stimulation provided by male mounts, even without intromission, significantly decreased PR-B concentration in the hypoythalamus. Down regulation of PR produced by genital stimulation was quantitatively similar to that elicited by progesterone (P) administration. Bilateral or unilateral transection of the pelvic or the pudendal nerves prevented down regulation elicited by VCS/FS. Repeated VCS/FS elicited lordosis behavior in most ovx estrogen primed rats, but the lordosis intensity was lower than that observed in response to P. P administered to ovx estrogen primed rats, induced sequential inhibition, i.e., failure to display estrous behavior in response to a second P injection (24 h after the initial P injection). VCS/FS failed to elicit sequential inhibition, since rats responded with normal estrous behavior to the second injection of P. This suggests that down regulation by VCS, by contrast with P, failed to inhibit the subpopulation of PR involved in the facilitation of estrous behavior by P.

Activated protein C resistance among postmenopausal women using transdermal estrogens

Although the route of estrogen administration is known to be an important determinant of the thrombotic risk among postmenopausal women using hormone therapy, recent data have shown that norpregnane derivatives but not micronized progesterone increase venous thromboembolism risk among transdermal estrogens users. However, the differential effects of progesterone and norpregnanes on hemostasis have not yet been investigated. We set up a cross-sectional study among healthy postmenopausal women aged 45 to 70 years. The impact of activated protein C (APC) on endogenous thrombin potential was investigated in the plasma samples of 108 women who did not use any hormone therapy (n = 40) or who were treated with transdermal estrogens combined with micronized progesterone (n = 30) or norpregnane derivatives (n = 38). After exclusion of women with factor V Leiden and/or G20210A prothrombin gene mutations, there was no significant change in APC sensitivity among women who used transdermal estrogens combined with micronized progesterone compared with nonusers. Women using transdermal estrogens combined with norpregnanes were less sensitive to APC than were nonusers (P = 0.003) or users of transdermal estrogens combined with micronized progesterone (P = 0.004). In addition, prothrombin fragment 1 + 2 concentration was higher in users of transdermal estrogens plus norpregnanes than in nonusers (P = 0.004). Other hemostatic parameters did not vary significantly across the different subgroups. Transdermal estrogens combined with norpregnanes may induce APC resistance and activate blood coagulation. These results provide a biological support to epidemiological data regarding the potential thrombogenic effects of norpregnanes. However, these findings need to be confirmed in a randomized trial.

Influence of gender and estrous cycle in the forced swim test in rats.

The present work aimed at studying the influence of the estrous cycle in the forced swim test, an animal model of depression. For this, 44 male and female Wistar rats were divided into five groups according to the hormonal state in the first day of the study: metaestrus (N = 12), diestrus (N = 8), proestrus (N = 7), estrous (N = 6) and males (N = 11). They were housed in groups of five, with water and food ad libitum under a 12/12 h light/dark cycle. Females were screened daily for the estrous cycle. The animals were subjected to two swimming sessions in a glass cylinder with water up to 15 cm at 28±2o C. The data of the first five minutes of a 15-min first session were compared to those of a 5-min second session 24 h later. The results indicate that the latency to the first immobility was substantially reduced in the second session and was longer for females in diestrus and proestrus in the first session. The results also indicate that females in diestrus and proestrus exhibited less immobility than males in the first session; females in diestrus also exhibited less immobility than females in metaestrus. Females in metaestrus and diestrus, as well as males, did not present the decrease in total immobility times in the second session. The present results are analyzed in terms of differential effects of progesterone and estrogen on a learning component and an affective component.

Differential effects of progesterone and 17β-estradiol on the Ca 2+ entry induced by thapsigargin and endothelin-1 in in situ endothelial cells

The effects of progesterone and 17β-estradiol on Ca 2+ signaling in in situ endothelial cells were investigated using front-surface fluorometry of fura-2-loaded strips of porcine aortic valve. Progesterone inhibited the thapsigargin-induced sustained [Ca 2+] i elevation (IC 50=33.9 μM, n=4), while 17β-estradiol added a transient [Ca 2+] i elevation. Progesterone and 17β-estradiol had no significant effect on the thapsigargin-induced [Ca 2+] i elevations in the absence of extracellular Ca 2+. A Mn 2+-induced decline of fluorescent intensity at 360 nm excitation was accelerated by thapsigargin. This acceleration was completely reversed by progesterone, but not by 17β-estradiol. Progesterone inhibited, and 17β-estradiol enhanced the endothelin-1 (ET-1)-induced [Ca 2+] i elevation, while both had no effect on the ET-1-induced Ca 2+ release observed in the absence of extracellular Ca 2+ or in the pertussis toxin-treated strips. Progesterone and 17β-estradiol thus had different effects on Ca 2+ signaling, especially on Ca 2+ influx, in endothelial cells.

Region-specific modulation of limbic seizure susceptibility by ovarian steroids

Gonadal steroid hormones can markedly affect seizure susceptibility. Ovariohysterectomized female rats given ovarian steroid hormone supplements were used to evaluate the effects of ovarian steroids on epileptiform activity in hippocampal slices in vitro and on flurothyl-induced seizures in vivo. Seizure susceptibility was compared in the entorhinal cortex (EC) and CA1 regions of the hippocampus perfused with Mg 2+-free medium, which leads to epileptiform discharges caused by a relief of voltage-dependent NMDA receptor block. After in vivo treatment with 500 μg of progesterone for 2 h prior to slice preparation, the latency to onset of low Mg 2+-induced epileptiform activity of slices was significantly prolonged compared to slices from controls. In contrast, progesterone replacement accelerated the development of epileptiform activity in the CA1 region. Neither estrogen alone (2×2 μg of estradiol benzoate, 48 and 24 h prior to the experiment), nor a combined treatment with estrogen plus progesterone, significantly affected seizure susceptibility in either CA1 or the EC. There were no consistent effects of estrogen or progesterone, alone or in combination, on flurothyl-induced seizures in vivo. The data suggest that in vitro, progesterone alters seizure susceptibility in a site- and seizure model-specific fashion. The differential effects of progesterone may be due to differential expression of progesterone receptor isoforms or metabolites in specific brain areas suggesting that selective modulation of NMDA receptor-dependent epileptiform activity may play a role in hormonal effects on epileptogenesis.

Differential Effects of Progesterone and Its Analogues on the Contractility of the Murine Jejunumin Vitro

Epidemiological studies have demonstrated a higher prevalence of gastrointestinal motility disturbances in women compared with men. This may partly be due to the effects of sex hormones on smooth muscle cells. To further characterize the mechanisms by which sex hormones affect intestinal smooth muscle, we studied the effects of several structurally related progestins on intestinal contractility. Segments of the murine intestine oriented along the longitudinal axis were connected to force displacement transducers. We recorded the isometric tension generated by the murine jejunum spontaneously and after cholinergic stimulation. The baseline tension, amplitude of spontaneous contractions, and increase in tension after cholinergic stimulation were measured in the presence and absence of various steroid hormones. Progesterone dose dependently decreased the contractile activity of the murine jejunum. This effect occurred within less than 1 min and could not be inhibited by a specific blocker of the progesterone receptor, suggesting a nongenomic pathway. Experiments with several progestins demonstrated a stereoselectivity of this steroid hormone effect. This was most pronounced for dihydroprogesterone: the 5α form did not affect intestinal contractility, while the stereoisomer 5β-dihydroprogesterone significantly inhibited smooth muscle tension. We conclude that progesterone significantly inhibits the contractility of the murine jejunumin vitro.The differential effects of various structural analogues argue against a nonspecific effect of the steroid hormones on the lipid bilayer with secondary functional alterations of membrane proteins. Rather, they suggest a specific interaction between the steroid hormone and a still unidentified protein that differs in its function and pharmacological profile from the known progesterone receptor.

Differential effects of progesterone on secretion of gonadotropic hormones in the rhesus monkey.

To obtain new information on the site of the inhibiting actions of progesterone (P) during the follicular phase of the cycle, we administered P continuously to 13 rhesus macaques (Macaca mulatta) from days 5 through 12 of the menstrual cycle. This treatment produced luteal-phase levels (approximately 6 ng/ml of serum) within 4 h. (FSH) concentrations dropped significantly from pretreatment amounts (P less than 0.01). During this time, both immunoreactive luteinizing hormone (LH) (n = 8 animals) and bioactive LH (n = 5) remained stable. The 17 beta-estradiol (E2) concentrations dropped significantly below base line 24 h after treatment (P less than 0.05). The decline in E2 occurred after the decline in FSH. Inhibition of FSH continued for 40 h, after which both FSH and LH rose steadily in a way that resembled a preovulatory surge on days 8 or 9 of the menstrual cycle, and then returned to base line by day 10. When gonadotropins were at their zenith, the ovary did not respond by secreting E2. None of the effects mentioned above were found in control animals treated with blank implants. These data demonstrate that P administered during the follicular phase inhibits FSH but not LH secretion. This initial inhibition probably occurs at a hypothalamic-pituitary site, but after 40 h direct inhibitory effects on the ovary cannot be ruled out. P stimulates the release of gonadotropin in female monkeys despite reduced production of E2 by the ovary.

Differential effects of progesterone on lactation and nursing behavior in late pregnant and postparturient rats

In the past, studies on the effects of progesterone injections before or after birth concentrated only on lactation or nursing behavior. The present study is a report of the effects of progesterone on both events, in the same strain of rat, across a number of groups, administered either during pregnancy or after birth. In the first part of the experiment, 2 mg doses of progesterone subcutaneously were injected into nulliparous Sprague-Dawley rats from Days 18–23 of gestation. The injections delayed the onset of birth, caused a high mortality among young, and produced young that failed to thrive. In spite of this, nursing behavior appeared normal. There were no significant differences in the latency or duration of crouching behavior between the progesterone and oil-injected control groups. Thus the difficulties appeared to be with lactation. Because mammary glands contained milk, problems with secretory activation in the glands were ruled out. Even though the pups suckled teats, they got no milk, suggesting dysfunctions in milk release. To determine whether progesterone might alter maternal behavior once it was established after birth, 2-mg doses of progesterone were injected during the first postpartal week. They were found to depress litter weights and increase the latency to crouch over pups. During the second postpartal week, the injections reduced the latency to crouch, causing females to act vigorously toward pups at a time when maternal behavior typically starts to decline. Thus, depending upon the stage of the reproductive cycle in which progesterone is introduced, it can either inhibit or enhance nursing behavior. Moreover, the action of progesterone during late gestation appears to be only on milk release.

"Differential effects of progesterone on the maternal behavior of primiparous and multiparous rats": Erratum.

"Differential effects of progesterone on the maternal behavior of primiparous and multiparous rats": Erratum.

Differential effects of progesterone on the maternal behavior of primiparous and multiparous rats.

Differential effects of progesterone on the maternal behavior of primiparous and multiparous rats.