Menstruation is characterised by synchronous shedding and restoration of tissue integrity. An in vivo model of menstruation is required to investigate mechanisms responsible for regulation of menstrual physiology and to investigate common pathologies such as heavy menstrual bleeding (HMB). We hypothesised that our mouse model of simulated menstruation would recapitulate the spatial and temporal changes in the inflammatory microenvironment of human menses. Three regulatory events were investigated: cell death (apoptosis), neutrophil influx and cytokine/chemokine expression. Well-characterised endometrial tissues from women were compared with uteri from a mouse model (tissue recovered 0, 4, 8, 24 and 48 h after removal of a progesterone-secreting pellet). Immunohistochemistry for cleaved caspase-3 (CC3) revealed significantly increased staining in human endometrium from late secretory and menstrual phases. In mice, CC3 was significantly increased at 8 and 24 h post-progesterone-withdrawal. Elastase+ human neutrophils were maximal during menstruation; Ly6G+ mouse neutrophils were maximal at 24 h. Human endometrial and mouse uterine cytokine/chemokine mRNA concentrations were significantly increased during menstrual phase and 24 h post-progesterone-withdrawal respectively. Data from dated human samples revealed time-dependent changes in endometrial apoptosis preceding neutrophil influx and cytokine/chemokine induction during active menstruation. These dynamic changes were recapitulated in the mouse model of menstruation, validating its use in menstrual research.
The mineralocorticoid effects of liquorice are mediated by the inhibitory effects of one of its active components glycyrrhetinic acid on 11β-hydroxysteroid dehydrogenase type 2. However, liquorice is reputed to have many medicinal properties and also contains a number of other potentially biologically active compounds. Here we have investigated the wider effects of oral liquorice on steroidogenesis focussing particularly on possible inhibitory effects of glycyrrhetinic acid on adrenal sulfotransferase activity. Salivary steroids were profiled by ELISA in groups of normal male and female volunteers after consuming either liquorice-containing or non-liquorice-containing confectionary for one week. Cortisol and cortisone levels reflected expected inhibition of 11β-hydroxysteroid dehydrogenase type 2 by glycyrrhetinic acid. Salivary aldosterone was decreased but deoxycorticosterone, dehydroepiandrosterone and testosterone were increased. To assess whether glycyrrhetinic acid directly affected steroidogenesis, free and conjugated steroids were measured in incubates of adrenocortical H295 cells, firstly, in the presence or absence of forskolin and secondly, with radiolabeled deoxycorticosterone or dehydroepiandrosterone. Glycyrrhetinic acid inhibited cortisone and enhanced cortisol synthesis consistent with 11β-hydroxysteroid dehydrogenase type 2 inhibition. Basal and forskolin-stimulated syntheses of deoxycorticosterone and dehydroepiandrosterone conjugates were also inhibited in a dose-dependent manner; glycyrrhetinic acid inhibited the conjugation of deoxycorticosterone and dehydroepiandrosterone with IC50 values of 7 μM. Inhibition of deoxycorticosterone and dehydroepiandrosterone conjugation was apparent within 4 h of starting glycyrrhetinic acid treatment and was not associated with changes in the expression of SULT 2A1 mRNA. SULT2A1 encodes the enzyme sulfotransferase 2A1 which is responsible for the sulfonation of deoxycorticosterone and dehydroepiandrosterone as well as pregnenolone and 17-hydroxypregnenolone in human adrenal glands. We suggest that the glycyrrhetinic acid constituent of liquorice increases circulating and thereby, salivary levels of unconjugated deoxycorticosterone and dehydroepiandrosterone by inhibiting their conjugation at source within the adrenal cortex. This effect may contribute to the mineralocorticoid actions of glycyrrhetinic acid and gives substance to claims that liquorice also has androgenic properties.
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