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PubMed2007

The human fetal adrenal gland, corticotropin-releasing hormone, and parturition.

Labor initiation is a complex process that remains to be fully elucidated. An area of active research involves the study of the different mechanisms that may lead to successful signaling for parturition. This review focuses on the fetal-derived signals that lead to the initiation of labor. These signals may also play a role in preterm labor when activated prematurely. Studying these signals may prove important in the prediction, diagnosis, and possible intervention in preterm labor.

Adrenal Glands↗
PubMed2006

Feto-placental communication system with the myometrium inpregnancy and parturition: the role of hormones, neurohormones, inflammatory mediators, and locally active factors.

Pregnancy is a unique condition in which the conceptus is allowed to implant, survive, develop, and reach a considerable organ growth and maturation within the maternal body despite the fact that it is half genetically different from the mother. Moreover, it deeply influences the overall endocrine, metabolic, and immunological functions of the recipient mother. These objectives are accomplished through the establishment of several communication systems in which a large array of substances produced by the feto-placental unit reach specific maternal target organs and/or systems and modulate their function. The myometrium is a fundamental reproductive tissue involved in pregnancy maintenance as well as in labor onset and progression and is a potential target organ for such a communication system. An appropriate regulation of myometrial function is a key condition required for pregnancy to develop physiologically until full term is reached and for labor to start. Emerging experimental and clinical evidence suggests that a very complex feto-placental biomolecular communication system exists with the myometrium and is actively operative in the control of myometrial contractility in pregnancy and parturition through the production of a continuously increasing number of substances with endocrine, paracrine, and immunoregulatory actions.

Female↗
PubMed2003

Cervical dilatation related to uterine electromyographic activity and endocrinological changes during prostaglandin F(2alpha)-induced parturition in cows.

The temporal relationship between changes in cervical dilatation, uterine electromyographic (EMG) activity, and maternal plasma concentrations of estradiol 17beta (E(2)), progesterone (P(4)), and 13,14-dihydro-15-keto-prostaglandin-F(2alpha) (PGFM), was investigated in six parturient cows. Calving was induced with a single injection of a synthetic analogue of prostaglandin F(2alpha) (PG) on Day 274 of gestation. Cervical dilatation was measured continuously by measuring the transit time between two implanted ultrasound crystals while at the same time uterine EMG activity was measured through two silver electrodes sutured on the myometrial surface until the expulsive stage of calving had been reached. In blood samples collected at 4-h intervals, starting at the moment of PG injection, the mean plasma E(2) concentration gradually increased and was significantly elevated at 28 h after PG injection. At 4 h after PG treatment, the mean P(4) concentration had dropped significantly and continued to decrease until a value of around 1 ng/ml was reached, where it stayed until the onset of expulsion. Mean plasma PGFM concentrations increased steadily after PG injection, reaching significantly elevated concentrations at 20 h after treatment. In the five cows that delivered calves in anterior positions, uterine EMG activity, expressed as root mean square (RMS in microV), started to increase at a mean interval (+/- SD) of 13.1 +/- 3.7 h following PG treatment. The increase in EMG activity was significantly correlated with changes in plasma PGFM concentrations. In these cows, dilatation of the caudal cervix started after a mean (+/- SD) interval of 28.5 +/- 1.5 h following PG treatment and dilatation progressed at a mean (+/- SD) rate of 2.25 +/- 0.24 cm/h. In one cow with a calf in the posterior position, uterine EMG activity and dilatation started at 15.8 h and 31.8 h, respectively, after induction of calving. We conclude that a predictable sequence of physiological changes occurs around induction of calving, which allows specific timing of future studies on cellular and biochemical changes within the cervix during parturition.

Animals↗
PubMed2003

Down-regulation of the alpha- and beta-subunits of the calcium-activated potassium channel in human myometrium with parturition.

Large-conductance, calcium-dependent potassium (BKCa) channels are implicated in maintaining uterine quiescence during pregnancy. The mechanisms whereby calcium sensitivity of the BKCa channel is dramatically removed at parturition remain unknown. The aim of the present study was to investigate whether this loss of calcium sensitivity of the BKCa channel with the onset of labor is associated with changes in the protein expression of the alpha- and/or beta-subunit or arises from a physical dissociation of the alpha-subunit from the beta-subunit. The beta-subunit is a key determinant of BKCa-channel Ca2+ sensitivity. Western blot analysis, using alpha- and beta-subunit-specific antibodies, detected bands of 110-125 and 36 kDa, respectively. Protein expression levels of the alpha-subunit in term labor myometrium were significantly reduced compared with term pregnancy without labor. Furthermore, alpha-subunit levels at term pregnancy were significantly increased relative to the nonpregnant state, whereas levels at preterm gestations were unchanged. Densitometric analysis demonstrated significantly decreased beta-subunit levels in term and preterm labor samples compared with term nonlabor samples. Immunoprecipitation studies revealed the presence of both the alpha- and beta-subunits in samples taken before or after the onset of labor. We conclude that during labor, the alpha-subunit is not physically uncoupled from the beta-subunit, but a decline occurs in the level of beta-subunit protein, which may underlie the loss of calcium and voltage sensitivity of the BKCa channel with labor. Furthermore, reduced beta-subunit protein in preterm labor myometrium implies that ion channels may also contribute to pathophysiological labor.

Adult↗
PubMed2003

Differential regulation of apoptosis in the corpus luteum of pregnancy and newly formed corpus luteum after parturition in rats.

Apoptosis contributes to luteal regression in many species. In the postpartum rat, there are two different types of corpora lutea (CL) in the ovary: CL of pregnancy (CLP) and newly formed CL (NCL). To investigate the regulation of apoptosis in the two different types of CL during luteal regression, apoptosis and caspase-3 activity were examined in the CL obtained on Days 7, 15, and 21 of pregnancy and Days 0, 1, 3, 5, 7, and 9 postpartum. Furthermore, the effect of lactation on apoptosis in the CL was examined in two groups of postpartum rats: lactating rats that nurse more than 10 pups, and nonlactating rats that nurse no pups. Apoptotic cells were detected after Day 21 of pregnancy. In the CLP, remarkable increases in the number of apoptotic cells on Days 5 and 9 postpartum were observed in nonlactating rats (P < 0.01), but not in lactating rats. Changes in caspase-3 activity in the CLP were not consistent with those in number of apoptotic cells. In the NCL, an increase in apoptosis was found only on Day 5 postpartum in nonlactating rats (P < 0.01), but not in lactating rats. Changes in caspase-3 activity in the NCL were consistent with those in number of apoptotic cells. In conclusion, apoptosis is, at least in part, involved in luteal regression after parturition, and lactation appears to inhibit apoptosis. This study also suggests the presence of a caspase-3-independent mechanism for apoptosis in CLP regression in the rat.

Animals↗
PubMed2004

Effects of leptin on fetal plasma adrenocorticotropic hormone and cortisol concentrations and the timing of parturition in the sheep.

We investigated whether leptin can suppress the prepartum activation of the fetal hypothalamus-pituitary-adrenal (HPA) axis and delay the timing of parturition in the sheep. First, we investigated the effects of a 4-day intravascular infusion of recombinant ovine leptin (n = 7) or saline (n = 6) on fetal plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations, starting from 136 days gestation (i.e., at the onset of the prepartum activation of the fetal HPA axis. The effects of a continuous intrafetal infusion of leptin (n = 7) or saline (n = 5) from 144 days gestation on fetal plasma ACTH and cortisol concentrations and the timing of delivery were also determined in a separate study. There was an increase in fetal plasma ACTH (P < 0.01) and cortisol (P < 0.001) concentrations when saline was infused between 136-137 and 140-141 days gestation. Plasma ACTH and cortisol concentrations did not rise, however, when leptin was infused during this period of gestation. When leptin was infused after 144 days gestation, there was no effect of a 4- to 5-fold increase in circulating leptin on fetal ACTH concentrations. In contrast, leptin infusion from 144 days gestation suppressed (P < 0.05) fetal plasma cortisol concentrations by around 40% between 90 and 42 h before delivery. There was no difference, however, in the length of gestation between the saline- and leptin-infused groups (saline infused, 150.2 +/- 0.5 days; leptin infused, 149.8 +/- 1.0 days). In saline-infused fetuses, there was a significant negative relationship between the plasma concentrations of cortisol (y) and leptin (x) between 138 and 146 days gestation (y = 81.4 - 7.7x, r = 0.38, P < 0.005). This study provides evidence for an endocrine negative feedback loop between leptin and the HPA axis in fetal life.

Adrenocorticotropic Hormone↗
PubMed2004

Impaired nipple development and parturition in LGR7 knockout mice.

LGR7 is a G-protein coupled receptor with structural homology to the gonadotrophin and thyrotrophin receptors. Recently, LGR7 was deorphanized, and it was shown that relaxin is the ligand for LGR7. To further study the function of this receptor, mice deficient for LGR7 were generated by replacing part of the transmembrane-encoding region with a LacZ reporter cassette. Here we show that LGR7 is expressed in various tissues, including the uterus, heart, brain, and testis. Fertility studies using female LGR7-/- mice showed normal fertility and litter size. However, some females were incapable of delivering their pups, and several pups were found dead. Moreover, all offspring died within 24 to 48 h after delivery because female LGR7-/- mice were unable to feed their offspring due to impaired nipple development. In some male LGR7-/- mice, spermatogenesis was impaired, leading to azoospermia and a reduction in fertility. Interestingly, these phenomena were absent in mutant mice at older ages or in later generations. Taken together, results from LGR7 knockout mice indicate an essential role for the LGR7 receptor in nipple development during pregnancy. Moreover, a defect in parturition was observed, suggesting a role for LGR7 in the process of cervical ripening.

Animals↗
PubMedDate not supplied

HLA-G antigen and parturition: maternal serum, fetal serum and amniotic fluid levels during pregnancy.

OBJECTIVE: To determine whether soluble HLA-G1 (sHLA-G1) concentrations in maternal serum and in amniotic fluid are lower at term than in the second trimester. METHODS: In this prospective study amniotic fluid and maternal serum samples were aspirated from 21 pregnant women during genetic amniocentesis at 16-20 weeks' gestation, and from 19 women undergoing a cesarean section at term. In the latter group arterial umbilical cord blood was aspirated as well. sHLA-G1 levels were determined using ELISA assay. This assay included the anti-HLA-G monoclonal antibodies 87G and 16G1, both as capture antibodies and horseradish-peroxidase-labeled rabbit anti-human beta(2)-microglobulin antibodies, as the detection antibody. The relative concentrations of sHLA-G1 were measured from the absorbancy of the blue product at 650 nm. Student's t test was used for statistical analysis. RESULTS: sHLA-G1 levels in amniotic fluid were significantly lower at term than in the second trimester (0.160 +/- 0.05 vs. 0.272 +/- 0.150 OD units; p < 0.05). Levels of sHLA-G1 in maternal serum declined toward term, but the difference from the second trimester was not statistically significant (0.266 +/- 0.157 vs. 0.205 +/- 0.120 OD units; p = 0.193). There was a strong correlation of sHLA-G1 concentrations between cord serum and maternal serum (R(2) = 0.79; p < 0.001), but not between cord serum and amniotic fluid (R(2) = 0.00004) or amniotic fluid and maternal serum (R(2) = 0.02). CONCLUSIONS: sHLA-G1 antigen expression is higher in amniotic fluid than in maternal-fetal compartments and significantly decreases toward term. We speculate that the declining amniotic fluid sHLA-G1 levels may stimulate a maternal immunological response against the fetus and contribute to the initiation of parturition.

Amniotic Fluid↗
PubMed2004

Mechanisms underlying "functional" progesterone withdrawal at parturition.

Progesterone is a major factor maintaining uterine quiescence throughout pregnancy. In most species, peripheral progesterone levels decline before initiation of labor, and treatments that inhibit progesterone synthesis or action cause termination of pregnancy and/or premature deliveries. These findings suggest that progesterone withdrawal is required for activation of myometrial contractions. However, in humans, circulating progesterone levels remain elevated until birth, which leads to the notion that a "functional" progesterone withdrawal occurs before parturition. The apparent loss of progesterone sensitivity at term could be a consequence of several different mechanisms including: (1) the catabolism of progesterone in the uterus into inactive compounds; (2) alterations in progesterone receptor (PR) isoform ratios; (3) changes in cofactor protein levels affecting PR transactivation; and (4) inflammation-induced trans-repression of PR by nuclear factor kappaB. All of these mechanisms are potentially capable of decreasing uterine progesterone responsiveness at term, thus enabling the expression of pathways that originally were blocked by progesterone in early pregnancy. However, the specific uterine genes whose transcription is directly controlled by PR, and thus affected by "functional" progesterone withdrawal, remain to be identified.

Female↗
PubMed2003

Neuroendocrine responses to stress in mice: hyporesponsiveness in pregnancy and parturition.

Hypothalamo-pituitary-adrenal axis secretory responses to stress were compared in female virgin, late pregnant, parturient, and lactating mice. The basal plasma ACTH concentration was not different in pregnancy or lactation compared with virgins, but corticosterone concentration and corticosteroid-binding globulin capacity were greatly elevated in late pregnancy. Secretory responses to novel environment were attenuated in pregnant, but not lactating, mice compared with virgin females, whereas ACTH responses to forced swimming were attenuated in both groups. The expression of immediate early gene (nur77) mRNA increased in paraventricular nucleus neurons after stress exposure in virgin and lactating, but not pregnant, mice. During parturition, the basal ACTH concentration was similar to virgin and pregnant controls and did not increase with stress. Oxytocin secretion in response to either novel environment or forced swimming was unchanged in any reproductive group, whereas vasopressin secretion was decreased by both stressors, but only in virgins. Pretreatment with oxytocin receptor antagonist centrally had no effect on ACTH responses to stress in either virgin or pregnant mice. Pretreatment with an opioid receptor antagonist increased ACTH responses to stress in virgin mice, indicating opioid inhibition, but had no effect in pregnancy. Thus, in mice hypothalamo-pituitary-adrenal hyporesponsiveness in late pregnancy is a consequence of reduced responsiveness of paraventricular neurons, but inhibition by opioids or intracerebral oxytocin does not appear to be involved.

Adrenocorticotropic Hormone↗
PubMed2003

Variation in the expression of orexin and orexin receptors in the rat hypothalamus during the estrous cycle, pregnancy, parturition, and lactation.

The widespread distribution of mRNA encoding orexin- 1 (OX1R) and -2 receptors (OX2R) in the central nervous system suggests that orexin may be involved in multiple functional pathways. Central administration of orexin stimulates feeding and also affects ovarian steroid-dependent luteinizing hormone secretion, suggesting involvement of orexin in the regulation of reproductive function. To investigate a possible role for orexin in reproductive function, we examined variations in prepro-OX, OX1R, and OX2R mRNA levels in the female rat hypothalamus during the estrous cycle, pregnancy, parturition, and lactation using competitive reverse transcription-polymerase chain reaction. During the estrous cycle, only OX1R mRNA expression during late proestrus was significantly higher than that at metestrus. The prepro-OX and OX1R mRNA levels on d 1 of lactation were significantly higher than that during late pregnancy and lactation. Immunohistochemistry revealed the presence of orexin-A immunoreactive cells and the OX1R subtype in the lateral hypothalamic area as well as the magnocellular neurons of the paraventricular (PVN) and supraoptic (SON) nuclei, respectively, in pregnant and lactating rats. These results suggest a role for orexin in reproduction that may be involved in regulating physiological function in early lactation through important binding sites in hypothalamic PVN and SON.

Animals↗
PubMed2002

Simple method for assaying serum oxytocin and changes of serum oxytocin level during parturition in cynomolgus monkeys.

A novel and simple assay system using a 96-well ELISA plate was established for measuring serum oxytocin in cynomolgus monkeys. This method omits the centrifuge for B/F separation because the second anti-rabbit IgG antibody-coated ELISA plate can easily separate the first anti-oxytocin rabbit antibody-bound radiolabeled oxytocin. Since this method has the advantage of omitting B/F separation, it becomes possible to measure a large number of samples with simple steps. In addition, accurate and reproducible results could be obtained by this method. The optimal reaction condition made it possible to measure more than 8 pg/ml of serum oxytocin. The changes of serum oxytocin level in relation to the first delivery was determined in a total of 11 female monkeys who were divided into two groups, infant-accepting mothers (4 monkeys) and infant-rejecting ones (7 monkeys). The serum oxytocin levels of pre-delivery (one to 4 days before delivery) and post-delivery (within 12 hr after delivery) in infant-accepting mothers were 33.6 +/- 4.57 and 43.5 +/- 16.4 pg/ml, respectively. Those in infant-rejecting mothers were 39.0 +/- 9.6 and 31.4 +/- 7.0 pg/ml. Two-way ANOVA (accepting/rejecting x pre/post) revealed a significant interaction of two factors (F (1, 9) = 5.39, p < 0.05). This result implies the possibility of a different pattern of oxytocin secretion between infant-accepting and infant-rejecting mothers during parturition.

Animals↗
PubMed2006

Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition.

Peroxisome proliferator-activated receptors (PPARalpha, PPARbeta/delta and PPARgamma) are a family of nuclear receptors that are activated by binding of natural ligands, such as polyunsaturated fatty acids or by synthetic ligands. Synthetic molecules of the glitazone family, which bind to PPARgamma, are currently used to treat type II diabetes and also to attenuate the secondary clinical symptoms frequently associated with insulin resistance, including polycystic ovary syndrome (PCOS). PPARs are expressed in different compartments of the reproductive system (hypothalamus, pituitary, ovary, uterus and testis). Conservative functions of PPARs in mammalian species could be suggested through several in vivo and in vitro studies, especially in the ovary and during placental development. Several groups have described a strong expression of PPARgamma in ovarian granulosa cells, and glitazones modulate granulosa cell proliferation and steroidogenesis in vitro. All these recent data raise new questions about the biologic actions of PPARs in reproduction and their use in therapeutic treatments of fertility troubles such as PCOS or endometriosis. In this review, we first describe the roles of PPARs in different compartments of the reproductive axis (from male and female gametogenesis to parturition), with a focus on PPARgamma. Secondly, we discuss the possible molecular mechanisms underlying the effect of glitazones on PCOS. Like other 'insulin sensitizer' molecules, such as metformin, glitazones may in fact act directly on ovarian cells. Finally, we discuss the eventual actions of PPARs as mediators of environmental toxic substances for reproductive function.

Corpus Luteum↗
PubMed2007

Oxytocin and parturition: a role for increased myometrial calcium and calcium sensitization?

Preterm birth is associated with the majority of all death and chronic disability related to pregnancy, birth and the neonatal period. The costs to families and to the health care system are enormous. Current approaches to prevent or arrest preterm labour have been unsuccessful. This failure is largely based on our poor understanding of the regulation of the timing and maintenance of parturition. Oxytocin (OT) is the most potent known uterine stimulant. It is produced in the hypothalamus and secreted into the maternal bloodstream. However, OT also is produced within the uterine decidua in late gestation and the concentrations increase around the time of labour onset. The receptor for OT (OTR) is a G-protein coupled receptor linked through G alpha(q/11) to phospholipase C (PLC). Activation of PLC causes increased inositol trisphosphate (IP3) and diacyl glycerol (DAG). IP3 activates specific receptors in the sarcoplasmic reticulum to release Ca2+ into the cytosol. This may induce further influx of Ca2+ from the extracellular space and the increased Ca2+, after binding to calmodulin, activates myosin light chain kinase to phosphorylate myosin light chains (MLC) and cause contraction of the myocyte. DAG activates protein kinase C (PKC), several isoforms of which have been implicated in uterine contraction, but the substrates for this enzyme in the uterine myocyte are essentially unknown. Oxytocin may also cause "Ca2+-sensitization," a process whereby there is a greater contractile force generated from a given increase in cytosolic Ca2+, although the contribution of this process to myometrial contraction remains an area of debate. This phenomenon occurs mainly due to inhibition of myosin light chain phosphatase (MLCP), the enzyme that reverses the phosphorylation of MLC. There are several important potential mediators of this MLCP-inhibitory pathway in the myometrium, including the small monomeric G-protein RhoA, its downstream kinase Rho-associated kinase (ROK). and the 17-kDa PKC-potentiated inhibitor of protein phosphatase 1c (CPI-17). The roles in the myometrium of other recently identified MLCP interacting molecules also requires further investigation. These Ca2+-sensitization pathways could be important in the mechanisms underlying pre-term or term labour. An increased understanding of the complexities of the multitude of regulatory mechanisms for uterine contractility may lead to new pharmacologic agents for the prevention or reversal of uterine contractions. This, in turn, is necessary to facilitate the development of novel and effective strategies to reduce the incidence of preterm birth.

Animals↗
PubMedDate not supplied

[Pulsoximetric sensor for diagnosis of intrauterine foetus state during parturition].

Detrimental changes in the degree of blood hemoglobin saturation with oxygen are important evidence of hypoxic states and can be regarded as objective indication to surgical delivery. A new method of fetal pulsoximetry was developed. This method is based on the use of a non-disposable atraumatic pulsoximetric sensor of reflectory type for diagnosis of intrauterine foetus state during parturition. The clinical trial of the system was carried out in 44 women in childbirth and revealed clear differentiation between hypoxic states.

Adolescent↗
PubMedDate not supplied

[The influence of water immersion on the course of first stage of parturition in primiparous women].

THE AIM: To find whether, and if so to which degree, water immersion may influence the duration of the first stage of labour and to what extent progression of delivery depends on the timing of immersion. MATERIAL AND METHODS: The analysis was conducted for 205 deliveries including 100 in the control group. The following parameters were measured: 1. degree in gaping of the external opening of the uterine cervix during immersion in water; 2. time elapsed between the end of immersion and full gaping of the uterine cervix, 3. course of uterine contraction activity during and after the immersion in water. RESULTS: It was observed that the immersion in water applied to primiparae at any stage of labour, beginning from the 2-cm gaping of the external opening of the uterine cervix, decreased significantly the duration of parturition in comparison to those delivered in a traditional way. In no case the water immersion caused disturbances in the contraction activity of the uterus, instead, it raised both the amplitude and frequency of uterine contractions in a degree proportional to the uterine cervix gaping. CONCLUSIONS: In the authors' opinion the optimal timing for the application of water immersion in the primiparae is determined by a 3-cm gaping of the uterine cervix. An earlier bath at the 2-cm uterine cervix gaping also accelerated the labour but required either repeating of the immersion or a correction of weakened uterine contraction activity by oxytocin.

Adult↗
PubMed1977

Endocrine regulation of fetal development and its relation to parturition in the rhesus monkey.

Rhesus monkey fetuses were surgically prosencephalectomized (Type 2) or functionally hypophysectomized (Type 1) at 75 days gestation, then returned to the uterus until elective Caesarean section on day 145--150 (term 167 days). Deprivation of fetal hypothalamic releasing factors in Type 2 and fetal pituitary tropic hormones in Type 1 significantly delayed the ontogeny and functional development of fetal endocrine tissues. Bone ossification and growth were significantly retarded in Type 1 only, not in Type 2. In Type 1 the body and all organs except the endocrine glands were about half normal weight. The adrenals, thyroids, ovaries and testes were histologically abnormal and about one-tenth normal weight. Non-endocrine organs were histologically similar to 110-130-day fetuses. Thyroxine (T4) concentrations were significantly depressed in Type 1 fetal and maternal plasma at Caesarean section but normal in Type 2. Cortisol concentrations were normal in Type 1 fetal and maternal plasma. Types 1 and 2 plasma oestradiol concentrations were significantly lower in mothers but normal in fetuses. Type 1 placentas produced significantly less progesterone in vitro than normal. Fetal endocrine autonomy is indicated (thyrotropin-releasing factor excepted). Many of the hypothalamic and anterior pituitary hormones do not pass in effective amounts from mother to fetus. Fetal endocrine autonomy is a prerequisite for the control of both development and parturition.

Adrenal Glands↗