Hormone replacement therapy may prevent the development of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement

Beretta, Lorenzo; Caronni, Monica; Origgi, L; Ponti, Alessandro De; Santaniello, Alessandro; Scorza, Raffaella

doi:10.1080/03009740600844498

Cited by 64 publications

(50 citation statements)

References 11 publications

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“…Future studies are needed to investigate the possible correlation between plasma estrogen levels, pulmonary levels of ERb and ERa, and the severity of PH in these women. The fact that (1) postmenopausal women have an increased risk for the development of pulmonary hypertension (46), and that (2) hormone replacement therapy may prevent the development of PH in these patients further supports the beneficial role of E2 in patients with PH (47). Other investigators have also suggested that severe PH has now become overwhelmingly a disease of postmenopausal women (48).…”

Section: The Estrogen Paradox In Phmentioning

confidence: 77%

Estrogen Rescues Preexisting Severe Pulmonary Hypertension in Rats

Umar

Iorga²,

Matori³

et al. 2011

Am J Respir Crit Care Med

126

155

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Rationale: Pulmonary hypertension (PH) is characterized by progressive increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure, and death. Current treatments only temporarily reduce severity of the disease, and an ideal therapy is still lacking. Objectives: Estrogen pretreatment has been shown to attenuate development of PH. Because PH is not often diagnosed early, we examined if estrogen can rescue preexisting advanced PH. Methods: PH was induced in male rats with monocrotaline (60 mg/kg). At Day 21, rats were either treated with 17-b estradiol or estrogen (E2, 42.5 mg/kg/d), estrogen receptor-b agonist (diarylpropionitrile, 850 mg/kg/d), or estrogen receptor a-agonist (4,4',4"-[4-Propyl-(1H)-pyrazole-1,3,5-triyl] trisphenol, 850 mg/kg/d) for 10 days or left untreated to develop RV failure. Serial echocardiography, cardiac catheterization, immunohistochemistry, Western blot, and real-time polymerase chain reaction were performed. Measurements and Main Results: Estrogen therapy prevented progression of PH to RV failure and restored lung and RV structure and function. This restoration was maintained even after removal of estrogen at Day 30, resulting in 100% survival at Day 42. Estradiol treatment restored the loss of blood vessels in the lungs and RV. In the presence of angiogenesis inhibitor TNP-470 (30 mg/kg) or estrogen receptor-b antagonist (PHTPP, 850 mg/kg/d), estrogen failed to rescue PH. Estrogen receptor-b selective agonist was as effective as estrogen in rescuing PH. Conclusions: Estrogen rescues preexisting severe PH in rats by restoring lung and RV structure and function that are maintained even after removal of estrogen. Estrogen-induced rescue of PH is associated with stimulation of cardiopulmonary neoangiogenesis, suppression of inflammation, fibrosis, and RV hypertrophy. Furthermore, estrogen rescue is likely mediated through estrogen receptor-b.Keywords: pulmonary hypertension; estrogen; neoangiogenesis; estrogen receptors; inflammation Pulmonary hypertension (PH) is a chronic lung disease characterized by pulmonary vascular remodeling and progressive increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy and RV failure (RVF). End-stage RVF has long been regarded as a terminal state of pathological cardiopulmonary remodeling, including fibrosis and chamber dilation, being unresponsive to available therapies. Advanced PH is most often treated with aggressive nonpharmacological therapies, such as lung transplantation, but this approach is only feasible for a fraction of patients. In the past decade, cell and gene therapies have shown great potential for treatment of PH in animal models (1, 2) and humans (3). However, effective pharmacological therapy for treatment of patients with advanced PH would be much more practical and much more cost effective. Several agents have been identified to attenuate the development of PH when the therapy is started before the initiating stimuli (4-6). Unfortunately, up to now, there has been no id...

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Section: The Estrogen Paradox In Phmentioning

confidence: 77%

Estrogen Rescues Preexisting Severe Pulmonary Hypertension in Rats

Umar

Iorga²,

Matori³

et al. 2011

Am J Respir Crit Care Med

126

155

View full text Add to dashboard Cite

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“…These factors include the several effects of estrogens on their different receptors and opposite effects (especially on cell proliferation) exerted by several peripheral estrogen metabolites. Although the loss of reproductive hormones associated with postmenopausal status may be a risk factor for both PAH (4,42,51) and CAD (6,13,23,55), it is unclear to what extent the increase in both risks after reaching menopause represents hormonal changes vs. simply advancing age. It may in the end be that regulated, physiological estrogen production by the body is useful but that we can't recapitulate that with exogenous estrogen.…”

mentioning

confidence: 99%

The estrogen paradox in pulmonary arterial hypertension

Sakao

Tanabe

2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Idiopathic pulmonary arterial hypertension (PAH) is a disabling condition characterized by PA vasoconstriction and remodeling as well as in situ thrombosis and eventual right heart failure. Idiopathic PAH occurs more frequently in females than in males. The female:male ratio is 1.64 ∼ 3.88:1. Although endogenous sex hormones including estrogen have been suggested to account for the observed gender differences in PAH, a precise pathobiology for the gender differences remains uncertain. Recent studies demonstrated that estrogen exerts beneficial effects on the pulmonary vasculature. However, it seems to contradict the female predominance that is observed in idiopathic PAH. Moreover, Sweeney and Voelkel (Sweeney L and Voelkel NF. Eur J Med Res 14: 433–442, 2009) showed that early and long-term estrogen exposure might be correlated with an increased risk of the development of PAH. Here we ask the question: Is estrogen a friend or a foe? According to accumulating evidence, we postulate that the different effects of estrogens on different target cells could account for this paradox, i.e., estrogens may exert beneficial effects only on the increased muscularization of vessel walls, but not on phenotypically altered endothelial cells. The effects of estrogens on the pulmonary vasculature are potent and complex, yet not fully understood. A better mechanistic understanding may allow for future therapeutic interventions in patients with PAH.

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“…17 This postmenopausal increase is also demonstrated in PAH and is postulated to be due to estrogen withdrawal, as it has been demonstrated in animal models that lower estrogen and progesterone states produce increased pulmonary vasoconstriction. 17,[21][22][23][24] Despite the known effects of estrogen on the pulmonary vasculature, it remains unclear how menopause affects response to treatment of PAH in general, including with phosphodiesterase type 5 (PDE-5) inhibitors. A treatment agent with a postmenopausal-specific treatment benefit would be extremely valuable given the high prev-alence of PAH in this population compared with that in men and younger women.…”

mentioning

confidence: 99%

Sex and Menopause Differences in Response to Tadalafil: 6‐Minute Walk Distance and Time to Clinical Worsening

et al. 2015

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Pulmonary arterial hypertension (PAH) is a female-predominant disease, but there are little data on treatment response by sex and menopausal status. In this retrospective analysis of the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) randomized clinical trial, we assessed treatment response between the sexes by examining change in 6-minute walk distance (6MWD) and time to clinical worsening (TCW). We examined the effect of menopausal status on the same treatment measures. 6MWD was recorded before and after 16 weeks of treatment with tadalafil or placebo in the PHIRST study cohort of 340 subjects (264 females, 76 males). A univariate analysis was used to assess the effect of sex on change in 6MWD and TCW. Multivariate linear regression and Cox proportional hazards models were built for 6MWD and TCW, respectively. Women were subdivided by age as a surrogate for menopausal status. The linear trend test and the log-rank test were performed on change in 6MWD and TCW by age. For tadalafil-treated patients, a significant difference in change in 6MWD by sex (mean: 48.6 m for males vs. 34.7 m for females; P = 0.01) was found, but it was not significant in multivariate analysis (P = 0.08). There was a trend toward a female age-dependent effect in change in 6MWD; the premenopausal group showed the greatest improvement. A significant sex-or age-dependent effect on TCW was not present. In conclusion, this retrospective analysis of the PHIRST trial suggests that men and premenopausal women may experience greater functional improvement when treated with tadalafil than older women, but there was no consistent sex or menopausal effect on TCW.Keywords: pulmonary arterial hypertension, sex differences, tadalafil, 6-minute walk distance, menopause. Pulmonary arterial hypertension (PAH) is a group of disorders that are characterized by elevated pulmonary arterial resistance, leading to eventual right heart failure. 1,2 PAH is a female-predominate disease; according to the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) Registry, group 1 PAH is four times more likely in female patients than in male patients. [3][4][5][6] While the exact cause of the observed female predominance is unknown, it may potentially relate to a disruption in the protective effect of estrogen on the pulmonary vasculature and myocardium. [7][8][9][10][11] A recent study examining patient factors as a predictor of treatment response with tadalafil found male sex to be predictive of improved change in 6-minute walk distance (6MWD). 12 Despite this, there is a paucity of literature investigating the effect of menopause on response to PAH treatment. Providing more tailored therapy to patients may allow for more cost-conscious, targeted, and safer treatment for patients with PAH.Two prior sex-specific treatment response studies found opposing results for response to tadalafil and endothelin receptor antagonists (ERAs). ERAs have demonstrated a more robust change in 6MWD in female patients, while tadalafil has d...

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Hormone replacement therapy may prevent the development of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement

Abstract: HRT administration may be effective in SSc post-menopausal women, preventing the development of iPHT.

Cited by 64 publications

References 11 publications

Estrogen Rescues Preexisting Severe Pulmonary Hypertension in Rats

Estrogen Rescues Preexisting Severe Pulmonary Hypertension in Rats

The estrogen paradox in pulmonary arterial hypertension

Sex and Menopause Differences in Response to Tadalafil: 6‐Minute Walk Distance and Time to Clinical Worsening

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