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Review
. 2014 Feb;171(3):567-79.
doi: 10.1111/bph.12281.

Pulmonary arterial hypertension: basis of sex differences in incidence and treatment response

K M Mair  1 , A K Z Johansen, A F Wright, E Wallace, M R MacLean
Affiliations
Review

Pulmonary arterial hypertension: basis of sex differences in incidence and treatment response

K M Mair et al. Br J Pharmacol. 2014 Feb.

Abstract

Pulmonary arterial hypertension (PAH) is a complex disease characterized by elevated pulmonary arterial pressure, pulmonary vascular remodelling and occlusive pulmonary vascular lesions, leading to right heart failure. Evidence from recent epidemiological studies suggests the influence of gender on the development of PAH with an approximate female to male ratio of 4:1, depending on the underlying disease pathology. Overall, the therapeutic strategy for PAH remains suboptimal with poor survival rates observed in both genders. Endogenous sex hormones, in particular 17β oestradiol and its metabolites, have been implicated in the development of the disease; however, the influence of sex hormones on the underlying pathobiology remains controversial. Further understanding of the influence of sex hormones on the normal and diseased pulmonary circulation will be critical to our understanding the pathology of PAH and future therapeutic strategies. In this review, we will discuss the influence of sex hormones on the development of PAH and address recent controversies.

Keywords: oestrogen; pulmonary arterial hypertension; serotonin; sex hormones; testosterone; vascular remodelling.

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Figures

Figure 1
Figure 1
Oestrogen metabolism in PAH. The circulating C19 precursors, testosterone and androstenedione are converted by CYP19A1 to 17β oestradiol and oestrone respectively. These metabolites then undergo hydroxylation at the C2, C4 or C16 positions by activity of CYP enzymes, including CYP1B1. While hydroxylation at C2 produces anti-proliferative metabolites, C16 hydroxylation induces proliferative metabolites. The CYPs are therefore key determinants of metabolite formation and can perturb the pathway towards an anti- or pro-proliferative state. Hydroxylated oestrogens can be further metabolized to the methoxyestrogens, which may also influence PASMC proliferation.
Figure 2
Figure 2
Schematic representation of androgen and oestradiol metabolism. Sex hormones are derived from cholesterol and converge on the circulating precursor DHEA and its sulphated form (DHEA-S). Both males and females possess the enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) that enables the conversion androgens to testosterone. The enzyme 5α-reductase then converts testosterone into the more potent metabolite DHT, which is subsequently deactivated by HSD enzymes. Testosterone can also be metabolized by the cytochrome P450 enzyme CYP19A1 to oestradiol which is further metabolized by HSD enzymes to oestrone and oestriol.
Figure 3
Figure 3
A schematic representation highlighting the potential therapeutic targets within sex hormone pathways in pulmonary arterial smooth muscle cells. *Metabolites of oestrogens and DHEA may also be useful in the treatment of PAH.
See this image and copyright information in PMC

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