Much has been written about the effects of aging on reproductive function, especially female fertility. Much less is known about how aging may affect the contractility of the smooth muscle within the uterus, the myometrium. The myometrium is active through a woman’s entire life, not just during pregnancy. Here we will discuss briefly the contractile functions of the uterus and the changes it undergoes throughout the stages of a woman’s life from menstruation and the menopause, before evaluating the evidence for any changes in myometrial contractility and responses as women age, with a particular focus on women of advanced maternal age. We present original contractility analysis for the widest data set for human myometrium so far examined, and determine inherent spontaneous activity as well as responses to depolarisation and stimulation with oxytocin. Our data show that in the non-pregnant state there is a significant decrease in contractility for both spontaneous and depolarised-induced contractions, with age. We suggest that muscle atrophy and down regulation of Ca channels may account for this. Interestingly in pregnant myometrium we found a wide range of contractile ability between women and little evidence for decreased spontaneous activity between the ages of 25–40. Oxytocin responses appear to be more affected by aging, a finding that is consistent with previously reported clinical findings, and may partly be the result of membrane lipids such as cholesterol, increasing as women age. The marked differences between the age-related decline of force beyond age 30 in non-pregnant uterus, and the lack of difference in the pregnant state over this period, shows that the uterus retains its ability to respond to gestational hormones. The growth of the pregnant uterus and increase in content of myofibrillar proteins, may abolish any previous age-related force deficit. This finding is consistent with what is apparent for postmenopausal women in their 50s and 60s; that with the appropriate hormonal stimulation the uterus can allow an embryo to implant, and then without further intervention, carry the foetus to term. It is tempting therefore to speculate that unlike other well documented declines in female reproductive functions with age, the myometrium remains able to function into a woman’s 7th decade.

Better tocolytics are required to help prevent preterm labour. The gaseotransmitter Hydrogen sulphide (H2S) has been shown to reduce myometrial contractility and thus is of potential interest. However previous studies used NaHS, which is toxic and releases H2S as a non-physiological bolus and thus alternative H2S donors are sought. GYY4137 has been developed to slowly release H2S and hence better reflect endogenous physiological release. We have examined its effects on spontaneous and oxytocin-stimulated contractility and compared them to NaHS, in human and rat myometrium, throughout gestation. The effects on contractility in response to GYY4137 (1 nM–1 mM) and NaHS (1 mM) were examined on myometrial strips from, biopsies of women undergoing elective caesarean section or hysterectomy, and from non-pregnant, 14, 18, 22 day (term) gestation or labouring rats. In pregnant rat and human myometrium dose-dependent and significant decreases in spontaneous contractions were seen with increasing concentrations of GYY4137, which also reduced underlying Ca transients. GYY4137 and NaHS significantly reduced oxytocin-stimulated and high-K depolarised contractions as well as spontaneous activity. Their inhibitory effects increased as gestation advanced, but were abruptly reversed in labour. Glibenclamide, an inhibitor of ATP-sensitive potassium (KATP) channels, abolished the inhibitory effect of GYY4137. These data suggest (i) H2S contributes to uterine quiescence from mid-gestation until labor, (ii) that H2S affects L-type calcium channels and KATP channels reducing Ca entry and thereby myometrial contractions, (iii) add to the evidence that H2S plays a physiological role in relaxing myometrium, and thus (iv) H2S is an attractive target for therapeutic manipulation of human myometrial contractility.

No abstract

No abstract

No abstract