Gender, sex hormones and pulmonary hypertension

Most subtypes of pulmonary arterial hypertension (PAH) are characterized by a greater susceptibility to disease among females, although females with PAH appear to live longer after diagnosis. While this “estrogen paradoxȍ of enhanced female survival despite increased female susceptibility remains a mystery, recent progress has begun to shed light upon the interplay of sex hormones, the pathogenesis of pulmonary hypertension, and the right ventricular response to stress. For example, emerging data in humans and experimental models suggest that estrogens or differential sex hormone metabolism may modify disease risk among susceptible subjects, and that estrogens may interact with additional local factors such as serotonin to enhance the potentially damaging chronic effects of estrogens on the pulmonary vasculature. Regardless, it remains unclear why not all estrogenic compounds behave equally, nor why estrogens appear to be protective in certain settings but detrimental in others. The contribution of androgens and other compounds, such as dehydroepiandrosterone, to pathogenesis and possibly treatment must be considered as well. In this review, we will discuss the recent understandings on how estrogens, estrogen metabolism, dehydroepiandrosterone, and additional susceptibility factors may all contribute to the pathogenesis or potentially to the treatment of pulmonary hypertension, by evaluating current human, cell-based, and experimental model data

The role of sex in the pathophysiology of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by increased pulmonary vascular resistance and pulmonary artery remodelling as result of increased vascular tone and vascular cell proliferation, respectively. Eventually, this leads to right heart failure. Heritable PAH is caused by a mutation in the bone morphogenetic protein receptor-II (BMPR-II). Female susceptibility to PAH has been known for some time, and most recent figures show a female-to-male ratio of 4:1. Variations in the female sex hormone estrogen and estrogen metabolism modify FPAH risk, and penetrance of the disease in BMPR-II mutation carriers is increased in females. Several lines of evidence point towards estrogen being pathogenic in the pulmonary circulation, and thus increasing the risk of females developing PAH. Recent studies have also suggested that estrogen metabolism may be crucial in the development and progression of PAH with studies indicating that downstream metabolites such as 16α-hydroxyestrone are upregulated in several forms of experimental pulmonary hypertension (PH) and can cause pulmonary artery smooth muscle cell proliferation and subsequent vascular remodelling. Conversely, other estrogen metabolites such as 2-methoxyestradiol have been shown to be protective in the context of PAH. Estrogen may also upregulate the signalling pathways of other key mediators of PAH such as serotonin

Personal Drug Selection: Problem-Based Learning in Pharmacology: Experience from a Medical School in Nepal

BACKGROUND: At the Manipal College of Medical Sciences, Pokhara, Nepal, Pharmacology is taught during the first four semesters of the undergraduate medical course. Personal or P-drug selection is an important exercise. The present study was carried out to obtain student opinion about the P-drug learning sessions, the assessment examinations, and on the small group dynamics. METHOD: The practical sessions on P-drug selection are carried out in small groups. Student feedback about the session was obtained using focus group discussions. The focus groups were selected to represent both genders and the three main nationalities, Nepalese, Indians, and Sri Lankans. There were four Nepalese, five Indians, and three Sri Lankans. Within each nationality and gender category the students were randomly selected. The respondents were explained the objectives of the study and were invited to participate. Written informed consent was obtained. The discussion lasted around two hours and was conducted in the afternoon in two groups of six students each. The first author (PRS) acted as a facilitator. The responses were recorded and analyzed qualitatively. RESULTS: The overall student opinion was positive. Around 25% (3 respondents) of respondents were confused about whether P-drugs were for a disease or a patient. Group consensus was commonly used to give numerical values for the different criteria. The large number of brands created problems in calculating cost. The students wanted more time for the exercise in the examination. Formative assessment during the learning sessions may be considered. The group members usually got along well. Absenteeism was a problem and not all members put in their full effort. The physical working environment should be improved. CONCLUSIONS: Based on what the students say, the sessions on P-drugs should be continued and strengthened. Modifications in the sessions are required. Sessions during the clinical years and internship training can be considered

Inducible Transgenic Rat Model for Diabetes Mellitus Based on shRNA-Mediated Gene Knockdown

The rat is an important animal model in biomedical research, but gene targeting technology is not established for this species. Therefore, we aimed to produce transgenic knockdown rats using shRNA technology and pronuclear microinjection. To this purpose, we employed a tetracycline-inducible shRNA expression system targeting the insulin receptor (IR). Doxycycline (DOX) treatment of the resulting transgenic rats led to a dose-dependent and reversible increase in blood glucose caused by ubiquitous inhibition of IR expression and signalling. We could neither detect an interferon response nor disturbances in microRNA processing after DOX treatment excluding toxic effects of shRNA expression. Low dose DOX treatment induced a chronic state of diabetes mellitus. In conclusion, we have developed a technology which allows the specific, inducible, and reversible suppression of any gene of interest in the rat. Our first transgenic rat line generated with this method represents an inducible model for diabetes mellitus