Fall In Progesterone Levels Research Articles

Changes in the Placental Glucocorticoid Barrier During Rat Pregnancy: Impact on Placental Corticosterone Levels and Regulation by Progesterone1

Glucocorticoid excess in utero inhibits fetal growth and programs adverse outcomes in adult offspring. Access of maternal glucocorticoid to the glucocorticoid receptor (NR3C1) in the placenta and fetus is regulated by metabolism via the 11beta-hydroxysteroid dehydrogenase (HSD11B) enzymes, as well as multidrug resistance P-glycoprotein (ABCB1)-mediated efflux of glucocorticoids from the syncytiotrophoblast. This study determined expression of genes encoding the two HSD11B isoforms (Hsd11b1 and Hsd11b2), the two ABCB1 isoforms (Abcb1a and Abcb1b), and Nr3c1 in the junctional and labyrinth zones of rat placentas at Days 16 and 22 of normal gestation (Day 23 is term). To assess possible regulation of the Hsd11b and Abcb1 isoforms by glucocorticoids and progesterone, their placental expression was also measured at Day 22 after partial progesterone withdrawal from Day 16 (maternal ovariectomy plus full estrogen and partial progesterone replacement) or after treatment with dexamethasone acetate (1 microg/ml of drinking water from Day 13). Expression of Hsd11b1 mRNA increased in the labyrinth zone (the site of maternal-fetal exchange) from Day 16 to Day 22, whereas that of Hsd11b2 fell dramatically. Consistent with these changes, corticosterone levels increased 10-fold in the labyrinth zone over this period. Expression of both Abcb1a and Abcb1b was markedly higher in the labyrinth zone compared with the junctional zone on both days, consistent with the proposed barrier role of ABCB1 in the placenta. Nr3c1 mRNA expression was similar in the two placental zones at Day 16 but increased 3-fold in the labyrinth zone by Day 22. Partial progesterone withdrawal increased Hsd11b1 mRNA and protein expression in the labyrinth zone but decreased Nr3c1 mRNA expression. These data show that the dynamic expression patterns of the placental HSD11Bs in late gestation are associated with dramatic shifts in placental corticosterone. Moreover, the late gestational rise in labyrinthine Hsd11b1 seems to be driven by the normal prepartum fall in progesterone level.

Long-term Potentiation in the Accessory Olfactory Bulb: A Mechanism for Olfactory Learning

One context of olfactory learning that has been investigated in some detail concerns the memory, established at mating, and formed by the female mouse to the odours (pheromones) of the mating male. This olfactory memory is vital for mitigating pregnancy block that might otherwise be induced by his pheromones (Keverne and Rosser, 1986). Pheromones from an unfamiliar male, for which no memory has been formed, activate the vomeronasal system with their receptors in the vomeronasal organ, thereby initiating a neuroendocrine reflex that suppresses prolactin secretion from the pituitary (Keverne, 1983). The removal of luteotrophic support results in a fall in progesterone levels and a return to oestrus. Therefore, it has been hypothesized that the pheromonal memory functions as a gate to suppress or modulate the specific pheromonal signal (Brennan et al., 1990; Kaba and Nakanishi, 1995; Brennan and Keverne, 1997; Brennan, 2001). The pheromonal memory is acquired with one trial learning, depends upon mating and lasts for several weeks (Keverne and de la Riva, 1982; Kaba et al., 1988). The neural changes underlying memory formation occur in the accessory olfactory bulb (AOB), the first relay in the vomeronasal system, independently of the main olfactory system and the hippocampus (Brennan et al., 1990; Kaba and Nakanishi, 1995; Brennan and Keverne, 1997). Microcircuits in the AOB include the prominent reciprocal dendrodendritic synapse between mitral cells, a single class of projection neurons and granule cell interneurons. Glutamate released from mitral cell dendrites activates the dendrites of granule cells, which in turn mediate GABAergic dendrodendritic inhibition back onto mitral cell dendrites (Jia et al., 1999; Taniguchi and Kaba, 2001). This feedback inhibition at the reciprocal synapses regulates mitral cell activity (Jia et al., 1999; Taniguchi and Kaba, 2001). The formation of the pheromonal memory requires the association of the pheromonal and the mating signals in the AOB. The mating signal is conveyed by noradrenergic projections from the locus coeruleus. Artificial vaginocervical stimulation (Rosser and Keverne, 1985) or mating (Brennan et al., 1995) promotes the release of noradrenaline (NA) in the AOB. Blockade of α-adrenergic receptors in the AOB immediately after mating prevents the formation of the pheromonal memory (Kaba and Keverne, 1988), as does removal of noradrenergic innervation of the AOB prior to mating (Rosser and Keverne, 1985). Furthermore, memory formation is associated with neurochemical and morphological changes at the mitral–granule cell reciprocal synapses (Brennan et al., 1995; Matsuoka et al., 1997, 2004). Despite advances such as these, however, an important void in our knowledge of electrophysiological aspects has remained: a longlasting increase in synaptic strength, known as long-term potentiation (LTP), has been little investigated. Moreover, the cellular and synaptic mechanisms underlying noradrenergic modulation of pheromonal learning are also unknown. To address these questions, we have carried out a series of experiments in AOB slices. Induction of LTP at the mitral-to-granule cell synapse in the AOB

Progesterone withdrawal causes endothelin release from cultured human uterine microvascular endothelial cells.

Current theories on the physiology of menstrual bleeding in humans offers an explanation for the shedding of the endometrium as a result of a breakdown of the extracellular matrix due to an inflammatory reaction. The link between the fall in progesterone levels and these events is not clear. Neither has an explanation been presented for the vasoconstriction in the coiled arteries occurring during menses. We have hypothesized a chain of events where the fall in progesterone levels induces an upregulation of the thrombin receptor in the small uterine arteries leading to an increased thrombin response and subsequent endothelin release. Endothelial cells from human umbilical cord (HUVECs) and from human small uterine arteries (UtMVECs) were cultured under conditions partly resembling the female hormonal cycle with progesterone withdrawal. Following progesterone increase and subsequent withdrawal, we found an increased production of thrombin receptor and an increased release of endothelin from UtMVECs compared with HUVECs. Endothelin release in response to progesterone withdrawal in UtMVECs can offer an explanation for the vasoconstriction seen in the coiled arteries during menses in humans.

Effects of progesterone, oestradiol benzoate and cloprostenol on luteal function in the heifer.

The effects of treatment with intravaginal progesterone (PRID) oestradiol benzoate and cloprostenol at various stages of the oestrous cycle were examined in 2 experiments. In Exp. 1, PRIDs were inserted for 14 days commencing on Day 3, 10 or 17 of the oestrous cycle and half the animals in each group received 5 mg oestradiol benzoate at PRID insertion. Plasma samples were collected daily from the time of PRID insertion for 16 days, then every 4 days for a further 24 days. Samples were analysed for plasma progesterone concentration. In Exp. 2, heifers were treated on Day 10 as in Exp. 1, but half of each treatment group received 750 micrograms cloprostenol at PRID insertion. In Exp. 1, treatment with PRID alone appeared to inhibit endogenous progesterone production when treatment began on Day 3, but not when treatment began on Days 10 or 17. Treatment with oestradiol benzoate at the time of PRID insertion depressed progesterone levels, from about 2-5 days after injection. When treatment began on Day 10, the fall in progesterone levels after oestradiol benzoate was preceded by a marked rise in levels. In Exp. 2, treatment with cloprostenol markedly reduced peripheral concentrations of progesterone and also removed the effect of oestradiol. We suggest that oestradiol benzoate had a luteolytic effect, depressing luteal progesterone production when given on Days 3, 10 or 17 and that when given on Day 10 there was a transitory luteotrophic effect which preceded its luteolytic action.

11-Ketotetranor PGF metabolites, a suitable indicator for measuring prostaglandin release during the normal oestrous cycle and early pregnancy in the goat

Peripheral plasma levels of 15-ketodihydro-PGF 2α, 11-ketotetranor PGF metabolites and progesterone were measured during normal oestrous cycle and early pregnancy in six goats. The does were synchronized before the start of the study by means of 10 mg of PGF 2α. Blood samples were collected twice daily until day 12 of the oestrous cycle and subsequently every 3 h until the onset of oestrus, at which time the does were mated. The blood sampling protocol was repeated until day 28 of pregnancy. High pulsatile peaks of 15-ketodihydro-PGF 2α and 11-ketotetranor PGF metabolites were observed during the last days of the oestrous cycle, indicating PGF 2α releases. This coincided with a fall in progesterone levels. During early pregnancy no such peaks of prostaglandin metabolites were recorded and high levels of progesterone were maintained. In the goat, analysis of the 11-ketotetranor PGF metabolites seems to be a better indicator of PGF 2α release than the analysis of 15-ketodihydro-PGF 2α. The former metabolites are more long-lived in the circulation and are thus easier to detect.

Effect of exogenous progestogens on plasma concentrations of the oxytocin-associated neurophysin and 13,14-dihydro-15-keto-prostaglandin F in intact and ovariectomized ewes over the time of expected luteal regression.

Plasma concentrations of the prostaglandin F metabolite 13,14-dihydro-15-keto-prostaglandin F (PGFM), the oxytocin-associated neurophysin (OT-N) and progesterone were monitored by radioimmunoassay (RIA) in five ewes sampled from the jugular vein at hourly intervals between 0700-1900 h from Days 12-16 of the estrous cycle. These hormones were also determined in plasma samples collected at similar times from five intact and five ovariectomized ewes given twice daily injections of medroxyprogesterone acetate (MPA) over Days 10 to 20 after the last observed estrus. In both the control and intact MPA-treated ewes, coincident surges of OT-N and PGFM were observed in jugular plasma during the time of luteal regression. No significant differences were noted in the number and amplitude of OT-N and number of PGFM peaks between the control and intact MPA-treated animals, although in the latter the amplitude of the PGFM peaks was significantly reduced (P less than 0.01). No marked surges in the plasma concentrations of PGFM or OT-N were observed in the ovariectomized ewes given exogenous MPA. This latter finding is consistent with previous proposals, suggesting that the ovaries are a major source of oxytocin in the ewe. In addition, the observation that exogenous progestogens in the intact ewes did not influence the number and peak height of the OT-N surges, indicates that a fall in progesterone levels during the normal cycle is not obligatory for oxytocin release although it may facilitate the release of uterine PGF2 alpha.

Concentrations of oestradiol-17β and progesterone in the plasma of dairy heifers before and after cloprostenol-induced and natural luteolysis and during early pregnancy

Plasma oestradiol-17β and progesterone levels were measured in seven nulliparous, dairy heifers (British Friesian breed) that were administered cloprostenol (a synthetic analogue of prostaglandin F 2α) between days 8 and 14 of the oestrous cycle and inseminated (AI) 72 and 96 h later, and in seven heifers inseminated (AI) at natural oestrus. In both treated and untreated heifers, the beginning of the progesterone fall and the oestradiol-17β rise associated with luteolysis appeared to be synchronous but, whereas the rate of fall in progesterone level was greater for the treated heifers, that of the oestradiol-17β rise did not differ between treated and untreated heifers. Mean pre-ovulatory peaks of oestradiol-17β were 8 pg/ml and 10 pg/ml for treated and untreated heifers respectively. A post-ovulatory peak of oestradiol-17β in plasma 5–6 days after the pre-ovulatory peak occurred in all heifers whether or not conception had taken place. It is suggested that 7 days after the initiation of oestradiol-17β secretion by the pre-ovulatory follicle, another follicle begins to mature and secrete oestradiol-17β and that the progress of the latter towards full maturation and potential ovulation is stopped by rising progesterone levels from the corpus luteum; as a result in normal, non-pregnant cattle an interval of about 21 days elapses before another ovulation (of another follicle) takes place. In the event of premature luteolysis (in the present study induced between the 8th and 14th day) there is no evidence that the timing of this luteolysis influences the time taken for a follicle to enter the final stages of pre-ovulatory maturation, when increasing amounts of oestradiol-17β are secreted. Thus the interval between ovulations may not be less than 7 days but, depending on corpus luteum survival, may vary between 7 and 21 days. In one heifer after natural luteolysis a normal plasma oestradiol-17β peak followed but this was not associated with ovulation and corpus luteum formation. The second oestradiol-17β peak 6 days after the first, however, evidently assumed the ovulatory role; presumably the secreting follicle concerned, not being subject to inhibition by progesterone rising to luteal levels, matured fully and ovulated. Thus the second, normally post-ovulatory, oestradiol-17β peak in cattle can, in the event of failure of ovulation at the normal time, itself assume the ovulatory function, the oestrous cycle length then being about 28 days.

Milk progesterone profiles and the double injection of cloprostenol in post partum beef cows.

The time to resumption of ovarian cycles was determined in 27 post partum beef suckler cows by twice weekly milk progesterone analysis and was 24.5 +/ 1.6 (SEM) days. Treatment of 87 cows with a double injection of 500 micrograms cloprostenol at an interval of 11 days resulted in 55 cows (63.2 per cent) responding by a fall in progesterone levels and ovulation. Thirty-eight of these cows (43.7 per cent of total) subsequently conceived to a timed double insemination. Eight (9.2 per cent) had high progesterone levels at the second injection had failed to respond; three (3.4 per cent) had a prolonged period of low progesterone levels after the first injection which were still low when the second was given. A further 21 cows (24.1 per cent) had low progesterone levels at the time of the second injection but could not be categorised further with certainty because of lack of previous samples. These cows were treated at a significantly earlier stage post partum than the rest and in fact were treated earlier than the recommended day 42. However, four of the 21 cows conceived to the timed insemination resulting in a total conception rate of 48.3 per cent.

Differences in Hormonal Patterns During the First Postabortion Menstrual Cycle after Two Techniques of Termination of Pregnancy

Fifteen patients underwent first-trimester abortion by one of two techniques. In group P, seven patients received prostaglandin vaginal suppositories during the 12 hours prior to vacuum aspiration, whereas eight patients in group V were aborted by aspiration alone. During the first postabortion menstrual cycle, daily peripheral blood levels of several hormones, including follicle-stimulating hormone (FSH), luteinizing hormone, human chorionic gonadotropin, estradiol, and progesterone, were determined. Patients in group P demonstrated a more rapid fall in progesterone levels following pregnancy termination (P less than 0.01). They also experienced a more physiologic first postabortion cycle as evidenced by a larger preovulatory estradiol peak (P less than 0.05) and a more normal luteal phase as judged by both the duration and elevation of progesterone levels. Certain endocrine changes common to both groups but different from those of normally menstruating women were also observed. These consisted of short-term spurts of progesterone secretion in many patients (10 of 15) prior to ovulation and exaggerated levels of FSH during the early follicular phase.

Testosterone and progesterone in peripheral plasma during the oestrous cycle of the mare

Measurements every day or every other day showed that testosterone levels ranging from 15 to 70 pg/ml were higher at oestrus in 4 of the 6 mares studied. In these 4 mares, another testosterone peak occurred 11--13 days before the next oestrus either before (3 mares) or after the fall in progesterone levels.

SERIAL MEASUREMENT OF ARTERIAL PLASMA PROGESTERONE LEVELS THROUGHOUT GESTATION AND PARTURITION IN INDIVIDUAL RATS

Daily blood samples were taken from 6, chronically cannulated, fully conscious rats to measure plasma progesterone levels throughout gestation. Progesterone levels in individual rats fluctuated by up to 28 ng/ml per day, but tended to be consistently higher or lower than the group mean. The accuracy of predicting progesterone levels in individual rats from previous values was examined. Progesterone levels on day 7 of gestation were negatively correlated with foetal weights near term. There was little indication that high progesterone levels at any stage of gestation lead to increased foetal or placental weights. Progesterone levels on day 17 were positively correlated with the number of corpura lutea but there was little relationship between progesterone and either the number or total mass of the placentas. Serial blood samples taken from a second group of 6 rats at 2 hourly intervals showed that the time between the major fall in progesterone levels to below 12 ng/ml and the onset of parturition was relatively constant (varying by only 8 h) despite a 29 h range in the total length of gestation.

Serum hormone levels in women undergoing abortion with intra-amniotic, extra-amniotic or intra-muscular administration of 15(S)15-methyl-prostaglandin F 2α

The serum levels of estradiol-17β, progesterone and HPL have been estimated by specific radioimmunoassay in thirty women undergoing abortion with 15-methyl-PGF 2α given by intra-amniotic, extra-amniotic or intra-muscular route. A significant decline in the levels of these hormones was observed in 27 cases in which the pregnancy was terminated. However, in the remaining three cases, 15-methyl-PGF 2α was found to be unsuccesful, and no significant change in the hormone levels was evident. The decline in these hormones was more marked by intra-muscular route, than that observed by the other routes. The pattern of estradiol-17β decline was more consistent when compared with progesterone and HPL. The levels of progesterone and HPL, in a few cases, rather showed an increase in the initial hours of 15-methyl-PGF 2α administration before the decline began and this pattern was more prominent on extra-amniotic administration. In general, the decline in the hormone levels was slower in cases which took longer time for abortion than cases with shorter induction-abortion time (IAT). The decline in estradiol-17β levels was about 65 percent at six hour of intra-muscular administration of 15-methyl-PGF 2α, whereas the corresponding fall with intra-amniotic and extra-amniotic routes was 29 and 22 percent, respectively. However, the net drop in its levels during IAT was not significantly different (range 70 to 80 percent) by the three routes. About 38 percent fall in progesterone levels was observed at six hour of intra-muscular administration whereas, by intra-amniotic the fall was 19 percent. The net decline in progesterone levels, during IAT, was in the range of 46 to 60 percent by the three routes. Similarly, intra-muscular 15-methyl-PGF 2α evoked a sharper decline in HPL levels as compared with other routes. The total decline during IAT was 58 to 66 percent. The results, thus indicated that the abortion with 15-methyl-PGF 2α was associated with a fall in the serum hormone levels, which could be resultant effect of alterations in the hormone production by the foeto-placental unit. This along with the uterine contractions may play a significant role in the abortifacient action of 15-methyl-PGF 2α.

On the Role of Prostaglandins in Parturition in the Rat11

Treatment of both intact and hypophysectomized pregnant rats on days 19 and 20 of pregnancy with PGF2alpha results in a rapid fall in plasma progesterone concentrations by day 20 followed by premature delivery on day 21. Administration of depoprovera did not prevent the PGF2alpha-induced fall in progesterone levels but premature littering was adverted. Indomethacin, an inhibitor of prostaglandin biosynthesis, postponed the onset of parturition by 20 h when administered in late pregnancy but rats treated with both indomethacin and PGF2alpha delivered at the normal time. Treatment of both intact and hypophysectomized animals with indomethacin delayed the fall in plasma progesterone concentrations which normally occurs between days 21 and 22 of pregnancy. Concomitant PGF2alpha treatment of rats receiving indomethacin caused plasma progesterone levels to fall in a pattern similar to controls. These findings indicate that endogenous PGF2alpha induces a fall in blood progesterone concentrations which is followed by increased myometrial activity.

Inhibition of myometrial activity in the pregnant rabbit: evidence for a "new" factor.

When non-pregnant rabbits were linked to 20- or 29-day pregnant rabbits by a cross-circulation technique, the frequency of intra-uterine pressure cycles in the former fell from pre-treatment values of around 8 cycles/b mm to 0.4 cycles/b mm at the end of cross-circulation (P <0.001). Maximum amplitude fell less abruptly from 29 mm Hg to 19 mm Hg (P <0.05). Following the cross-circulation which lasted 1 h, activity recovered so that in approximately 2 h maximum amplitude had returned to pretreatment levels and frequency to 50% of pretreatment levels. Similar experiments using progesterone-treated non-pregnant animals in the place of the pregnant does had no effect on the uterine activity of their partners during 1 h of cross-circulation despite the fact that the blood progesterone level of the treated animals was 93 ng/mI. Intravenous injections of large doses of progesterone were also ineffective within a similar time period. Since the latency of the progesterone effect on the myometrium is 8-12 h, the existence of a second myometrial inhibitory substance which acts in conjunction with progesterone in maintaining pregnancy is postulated. It is well established that in the pregnant rabbit ovarian output and hence peripheral plasma levels of progesterone decline after mid-term reaching low titers at parturition (Mikhail, Noah and Allen, 1961; Hilliard, Spies and Sawyer, 1968; Kendall and Liggins, 1972; Challis, Devies, and Ryan, 1973). It is generally accepted that this fall in progesterone level permits the gradual evolution of myometrial sensitivity to oxytocin during the last few days of pregnancy (Knaus, 1926; Csapo, 1955; Schofield, 1957; Fuchs, 1964). However, there are reasons to believe that a waning progesterone influence on the myometrium cannot adequately account for all the changes occurring in the uterine muscle preparatory to parturition. Fuchs (1964) and Porter and Schofield (1966) reported

Progesterone Concentration in the Peripheral Plasma of Pregnant Goats after Ovariectomy and Replacement Therapy

Summary Three goats were ovariectomiscd at the end of the fourth month of gestation, and serial jugular venous plasma samples assayed for progesterone concentration, hi each case, within 5 min. of ovariectomy, there was an abrupt fall in progesterone level with abortion of live foetuses approximately 20 hr. later. Pregnancy was maintained in another 4 ovariectomiscd goats by daily intramuscular injections of progesterone and peripheral plasma progesterone levels were less than those measured in normal pregnancies.

Progesterone levels in the systemic plasma of pregnant, cycling and ovariectomized cows.

Summary. The levels of progesterone in the systemic plasma of eight normal and two ovariectomized cows were estimated by gas chromatography. During the last month of pregnancy, levels varied mostly in the 2·5 to 7·5 ng/ml range (0·5 to 3·0 ng/ml at calving). For six of the eight cows, there was a significant fall in level during this period; pooling of the data for all eight showed a highly significant fall. Levels near the time of ovulation, whether or not this was associated with behavioural oestrus, were below 2 ng/ml ; they rose and fell during ovulation cycles as corpora lutea grew and regressed. Mean peak level for twenty-two cycles was 9·0 ng/ml and occurred on average 13 days after ovulation. The time of most rapid fall in progesterone level was, on average, 4 days before ovulation. Mean levels during the first 14 days after oestrus in normal cycles were not different from those during the first 14 days after insemination in early pregnancies; they then declined in the cycles but not during the early pregnancies. Mean progesterone levels in the plasma of ovariectomized cows up to 200 days after the operation were below 2 ng/ml; levels showed a slow but significant rise during this period.

Effect of ergocornine on ovarian synthesis of progesterone and 20 alpha-hydroxy-pregn-4-en-3-one in the pseudopregnant rat.

ABSTRACT The ovarian content of progesterone (P) and 20α-hydroxy-pregn-4-en-3-one (20αOHP) was measured in rats given a subcutaneous injection of 1 mg ergocornine methanesulphate (ECO) on day L4 of pseudopregnancy and in untreated pseudopregnant controls. The progesterone content in the ovaries of the treated rats declined, after a latency of 12 h, to 44% of the control level at 24 h, and to 30% at 30 to 72 h after the ECO injection. This fall in progesterone level coincided with a sharp rise in 20αOHP content of the ovaries and consequent inversion of the P/20αOHP ratio, from 1.9–3.8 in the controls to 0.24–0.45 in the ECO-treated rats. The total P + 20αOHP content of the ovaries remained similar in treated and control rats, except for a significant fall 48 h after ECO injection. The changes in ovarian steroid content after ECO administration mimic those observed during spontaneous prooestrus and oestrus and account for the interruption of the progestational state brought about by the drug. The results negate the postulate that ECO exerts its pregnancy-interrupting action in the rat by direct inhibition of ovarian 3β-hydroxysteroid dehydrogenase and are consistent with the view that this action of the drug is mediated by suppression of prolactin secretion by the pituitary gland; such a suppression may be secondary to an excitatory effect on the hypothalamus.