<<

. 16
( 51 .)



>>

Progesterone responsive gene
PRA antagonises transcriptional activity of PRB
Figure 2.5 Mechanisms leading to production of estrogens and progesterone throughout human
pregnancy


2002). There are two isoforms of the progesterone receptor that are splice variants
of the single progesterone receptor gene. Progesterone receptor B (PRB) is the usual
longer variant which mediates most actions of progesterone, while progesterone
receptor A (PRA) is a shortened variant which lacks a key activating domain and
acts as a dominant negative or repressor of the PRB activity. Mesiano showed that
labor is associated with an increase in myometrial expression of PRA. As the ratio of
PRA to PRB increases so more contraction associated genes, such as the estrogen
receptor (ER), oxytocin receptor and the prostaglandin synthesizing enzyme COX2
are expressed (Figure 2.6). Thus increased expression of PRA drives the balance
towards contraction and reduces the progestational block to contraction. Recent
data from Mesiano using a human myometrial cell line suggest that stimulation of
PRA expression relative to PRB is via the protein kinase C pathway raising the pos-
sibility that prostaglandins or oxytocin may drive this process physiologically.
Using the same myometrial tissue, investigators have also begun to use genomic
approaches to identify genes which change with the onset of parturition.
83 The regulation of human parturition


Estrogens Progesterone




ER PRB PRA
Co




on
ntr




ati
act




la x
ion



Re
CAPs

Myometrial cell



Contraction
Figure 2.6 A model for the interactions between PRA and PRB leading to functional progesterone
withdrawal and the onset of parturition in the human myometrium at term


Table 2.1 Genes identi¬ed by SSH to be upregulated in labor

Gene GenBank accession no.

Known genes
Oxytocin receptor X64878
MMP9 NM004994
Fibronectin U60068
IL-8 M28130
Genes not previously linked with labor
MnSOD S77127
B23 M23613
IFN 1-8d X57351
EF1 J04617
Cyclophilin Y00052
-actin X13839

Four novel genes were also identi¬ed with no matching sequences
in databases. EF: elongation factor; IFN: interferon; IL: intraleukin
MnSOD: manganese superoxide dismutase; SSH: suppression
subtractive hybridization.


Chan et al. using a subtraction hybridization approach identi¬ed a number of
genes which were upregulated at the time of labor (Chan et al., 2002). Interestingly
many of these genes are known to be involved in in¬‚ammatory activation path-
ways such as intraleukin-8 (IL-8) (see Table 2.1). A school of thought has for many
84 R. Smith et al.


years suggested that in¬‚ammation is a major component of the pathway to partu-
rition and that it represents the loss of the immune tolerance shown by the mother
for the fetal tissues. In¬‚ammation appears to play a major role in the onset of par-
turition in the murine model (Bethin et al., 2003). However recent cloning studies
in the horse have revealed that normal parturition occurs in this species even when
the foal is genetically identical to the mare (Galli et al., 2003). Clearly a breakdown
of immune tolerance is not the mechanism of parturition in this species. This does
not exclude a role for in¬‚ammatory agents in the process of human delivery.
Whether in¬‚ammation initiates parturition or follows as a consequence of the
process remains a hot topic. Progesterone is known to have anti-in¬‚ammatory
properties and perhaps the pathways may be linked by withdrawal of the anti-
in¬‚ammatory effects of progesterone as PRA is expressed. Alternatively perhaps
in¬‚ammatory pathways lead to the rising concentrations of PRA.
Certainly in vitro prostaglandins are capable of stimulating PRA expression and
prostaglandins are an element of in¬‚ammation. Prostaglandin production is
known to play a key role in parturition in many mammals such as the prostaglandin
mediated luteolysis which occurs in goats and even in humans prostaglandins are
potent stimulators of parturition which are used clinically. Interestingly, adminis-
tration of progesterone to women at high-risk of preterm delivery, either intra-
muscularly or intravaginally (Meis et al., 2003; Pomianowski, 2003), appears to
increase the response to tocolytics, whether this occurs via an effect on the oxytocin
receptor (Zingg et al., 1998) or by the antiin¬‚ammatory action of progesterone, or
some other mechanism remains unclear. Nevertheless these data may represent an
important clue to the nature of human parturition.
Current data support the view that the timing of birth in many women is deter-
mined by events at the beginning of pregnancy. Placental CRH production is
linked either directly or indirectly to this process and strong statistical relation-
ships exist between maternal plasma concentrations and the timing of birth. At the
end of pregnancy labor is associated with a functional progesterone withdrawal
leading to the expression of many contraction associated proteins. Many in¬‚am-
matory genes are activated at the time of labor but it is not yet clear whether the
expression of these genes is a consequence of labor or an initiator of the functional
progesterone withdrawal. The inevitability of delivery in the human suggests the
presence of more than one pathway leading to labor: a failsafe system. Studies to
date in humans indicate evidence for in¬‚ammatory pathways, oxytocin activated
pathways, progesterone withdrawal and a maturational process linked to placental
CRH production. Work from Steve Lye™s laboratory also suggests that physical fac-
tors in the form of stretch may play a role perhaps explaining the earlier onset of
labor observed in multigravidas and in the presence of a large fetus (Lye et al.,
2001). Although the full picture remains to be assembled the parts are beginning to
85 The regulation of human parturition


CRH
Placenta Myometrium

Modulated by CRH
Modulated by PRA
receptor isoforms
placental 11 -HSDs Cortisol
Represses PRB
Fetal and maternal Progesterone withdrawal
pituitary
ER


CAPs
(e.g. OTr, CX43, COX-2)

Fetal Myometrial
membranes contractility

Prostaglandins Labor


Cervical softening Birth

Figure 2.7 Proposed model for control of human parturition. HSD: hydroxysteroid dehydrogenase;
CAPs: contraction associated proteins; PRA: progesterone receptor A; PRB: progesterone
receptor B; ER: estrogen receptor



take shape (Figure 2.7). Greater understanding of this fundamental aspect of
human biology may place our treatment of women in preterm labor on a more
rational basis and perhaps reduce the frequency of cerebral palsy and other devas-
tating consequences of preterm birth.



R E F E R E N C ES


Bethin, K. E., Nagai, Y. et al. (2003). Microarray analysis of uterine gene expression in mouse and
human pregnancy. Mol. Endocrinol., 17(8), 1454“69.
Bloom¬eld, F. H., Oliver, M. H. et al. (2003). A periconceptional nutritional origin for noninfec-
tious preterm birth. Science, 300(5619), 606.
Bowman, M. E., Lopata, A. et al. (2001). Corticotropin-releasing hormone-binding protein in
primates. Am. J. Primatol., 53(3), 123“30.
Campbell, E. A., Linton, E. A. et al. (1987). Plasma corticotropin-releasing hormone concentra-
tions during pregnancy and parturition. J. Clin. Endocrinol. Metab., 64(5), 1054“9.
Chan, E. C., Fraser, S. et al. (2002). Human myometrial genes are differentially expressed
in labor: a suppression subtractive hybridization study. J. Clin. Endocrinol. Metab., 87(6),
2435“41.
86 R. Smith et al.


Cheng, Y. H., Nicholson, R. C. et al. (2000). Glucocorticoid stimulation of corticotropin-
releasing hormone gene expression requires a cyclic adenosine 3 ,5 -monophosphate regula-
tory element in human primary placental cytotrophoblast cells. J. Clin. Endocrinol. Metab.,
85(5), 1937“45.
Clifton, V. L., Read, M. A. et al. (1995). Corticotropin-releasing hormone-induced vasodilatation
in the human fetal“placental circulation: involvement of the nitric oxide-cyclic guanosine
3 ,5 -monophosphate-mediated pathway. J. Clin. Endocrinol. Metab., 80(10), 2888“93.
Ellis, M. J., Livesey, J. H. et al. (2002). Plasma corticotropin-releasing hormone and unconju-
gated estriol in human pregnancy: gestational patterns and ability to predict preterm delivery.
Am. J. Obstet. Gynecol., 186(1), 94“9.
Emanuel, R. L., Robinson, B. G. et al. (1994). Corticotrophin releasing hormone levels in human
plasma and amniotic ¬‚uid during gestation. Clin. Endocrinol. (Oxf.), 40(2), 257“62.
Europe-Finner, G. N., Phaneuf, S. et al. (1993). Identi¬cation and expression of G-proteins in
human myometrium: up-regulation of G alpha s in pregnancy. Endocrinology, 132(6), 2484“90.
Galli, C., Lagutina, I. et al. (2003). Pregnancy: a cloned horse born to its dam twin. Nature,
424(6949), 635.
Giles, W. B., McLean, M. et al. (1996). Abnormal umbilical artery Doppler waveforms and cord
blood corticotropin-releasing hormone. Obstet. Gynecol., 87(1), 107“11.
Goland, R. S., Wardlaw, S. L. et al. (1986). High levels of corticotropin-releasing hormone
immunoactivity in maternal and fetal plasma during pregnancy. J. Clin. Endocrinol. Metab.,
63(5), 1199“203.
Goland, R. S., Wardlaw, S. L. et al. (1992). Plasma corticotropin-releasing factor concentrations
in the baboon during pregnancy. Endocrinology, 131(4), 1782“6.
Goldenberg, R. L. (2002). The management of preterm labor. Obstet. Gynecol., 100(5 Pt 1),
1020“37.
Grammatopoulos, D., Dai, Y. et al. (1998). Human corticotropin-releasing hormone receptor:
differences in subtype expression between pregnant and nonpregnant myometria. J. Clin.
Endocrinol. Metab., 83(7), 2539“44.
Haig, D. (1993). Genetic con¬‚icts in human pregnancy. Q. Rev. Biol., 68(4), 495“532.
Inder, W. J., Prickett, T. C. et al. (2001). The utility of plasma CRH as a predictor of preterm
delivery. J. Clin. Endocrinol. Metab., 86(12), 5706“10.
King, B. R., Smith, R. et al. (2002). Novel glucocorticoid and cAMP interactions on the CRH
gene promoter. Mol. Cell. Endocrinol., 194(1“2), 19“28.
Liggins, G. C. (1973a). Fetal in¬‚uences on myometrial contractility. Clin. Obstet. Gynecol., 16(3),
148“65.
Liggins, G. C. (1973b). The physiological role of prostaglandins in parturition. J. Reprod. Fertil.
Suppl., 18, 143“50.
Liggins, G. C. (1994). Mechanisms of the onset of labour: the New Zealand perspective. Aust.
NewZealand J. Obstet. Gynaecol., 34(3), 338“42.
Lye, S. J., Mitchell, J. et al. (2001). Role of mechanical signals in the onset of term and preterm
labor. Front. Horm. Res., 27, 165“78.
McGrath, S., McLean, M. et al. (2002). Maternal plasma corticotropin-releasing hormone trajec-
tories vary depending on the cause of preterm delivery. Am. J. Obstet. Gynecol., 186(2), 257“60.
87 The regulation of human parturition


McLean, M., Bisits, A. et al. (1995). A placental clock controlling the length of human pregnancy.
Nat. Med., 1(5), 460“3.
Meis, P. J., Klebanoff, M. et al. (2003). Prevention of recurrent preterm delivery by 17 alpha-
hydroxyprogesterone caproate. New England J. Med., 348(24), 2379“85.
Mesiano, S., Chan, E. C. et al. (2002). Progesterone withdrawal and estrogen activation in human
parturition are coordinated by progesterone receptor A expression in the myometrium.
J. Clin. Endocrinol. Metab., 87(6), 2924“30.
Ni, X., Chan, E. C. et al. (1997). Nitric oxide inhibits corticotropin-releasing hormone exocytosis
but not synthesis by cultured human trophoblasts. J. Clin. Endocrinol. Metab., 82(12), 4171“5.
Ni, X., Nicholson, R. C. et al. (2002). Estrogen represses whereas the estrogen-antagonist ICI
182780 stimulates placental CRH gene expression. J. Clin. Endocrinol. Metab., 87(8), 3774“8.
Patel, F. A., Funder, J. W. et al. (2003). Mechanism of cortisol/progesterone antagonism in the
regulation of 15-hydroxyprostaglandin dehydrogenase activity and messenger ribonucleic
acid levels in human chorion and placental trophoblast cells at term. J. Clin. Endocrinol.
Metab., 88(6), 2922“33.
Petraglia, F., Sutton, S. et al. (1989). Neurotransmitters and peptides modulate the release of
immunoreactive corticotropin-releasing factor from cultured human placental cells. Am. J.
Obstet. Gynecol., 160(1), 247“51.
Pieber, D., Allport, V. C. et al. (2001). Interactions between progesterone receptor isoforms in
myometrial cells in human labour. Mol. Hum. Reprod., 7(9), 875“9.
Pomianowski, K. (2003). Natural progesterone prevents preterm birth in high-risk pregnancies.
J. Fam. Pract., 52(7), 522“3.
Prickett, T., Ellis, J. et al. (2000). The Utility of Plasma CRH as a Predictor of Premature Labour and
Delivery. Sydney, Australia: ICE.
Robinson, B. G., Emanuel, R. L. et al. (1988). Glucocorticoid stimulates expression of corticotropin-
releasing hormone gene in human placenta. Proc. Natl. Acad. Sci. USA, 85(14), 5244“8.
Robinson, B. G., D™Angio, Jr., L. A. et al. (1989). Preprocorticotropin releasing hormone: cDNA
sequence and in vitro processing. Mol. Cell. Endocrinol., 61(2), 175“80.
Smith, R., Chan, E. C. et al. (1993). Corticotropin-releasing hormone in baboon pregnancy.
J. Clin. Endocrinol. Metab., 76(4), 1063“8.
Smith, R., Mesiano, S. et al. (1998). Corticotropin-releasing hormone directly and preferentially
stimulates dehydroepiandrosterone sulfate secretion by human fetal adrenal cortical cells.
J. Clin. Endocrinol. Metab., 83(8), 2916“20.

<<

. 16
( 51 .)



>>