Tadalafil and Hormonal Interactions in Female Physiology

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.3-6 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.7-11 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).

Frequently Asked Questions (FAQs) about Cialis for Women

In total, 405 subjects (317 females, 88 males) were enrolled in a 16-week, double-blind, double-dummy, placebo-controlled multicenter study. Subjects were randomized into groups receiving placebo or 2.5, 10, 20, or 40 mg of tadalafil once daily. 6MWD was recorded before and after 16 weeks of treatment with tadalafil or placebo in a cohort of 340 subjects (264 females, 76 males).3 Clinical worsening was defined as death, lung or heart-lung transplantation, atrial septostomy, hospitalization due to worsening PAH, initiation of new PAH-approved therapy, or worsening World Health Organization (WHO) functional class over the 16 weeks. 6MWD and WHO functional class were measured at baseline and at weeks 4, 8, 12, and 16. When examining the effect of sex on change in 6MWD and TCW, only the tadalafil-treated patients were included (n = 323; males = 71, females = 252).

Table 4.

For the univariate analyses, the Wilcoxon rank sum test was used to assess the effect of sex on change in 6MWD. A log-rank test was used to assess the effect of sex on TCW. Females were subdivided by age as a surrogate for menopausal status: 14–44 years, premenopausal; 45–54 years, perimenopausal; and ≥55 years, postmenopausal (based on the average age of menopause, 52.4 years).25 The linear trend test with first degree of orthogonal polynomials was used to assess the effect of age on change in 6MWD among females and separately for males within the same age groups. A log-rank test was performed on TCW by age among females. Kaplan-Meier plots were constructed to investigate clinical worsening by sex and age.

Incidence not known

Multivariate linear regression and Cox proportion hazards models were constructed to assess the effect of sex on change in 6MWD and TCW, respectively, by adjusting for age, sex, race, etiology of PAH, WHO functional class, background therapy with bosentan, and baseline 6MWD. Goodness of model fit, colinearity, and numerical stability tadalafil 40mg were also evaluated. Baseline characteristics by sex and menopausal status were collected and are reported in Tables 1 and 2. Between male and female patients, there was a significant difference in baseline weight, PAH etiology, and age. The female cohort was slightly younger (mean age: 53 vs. ERAs have demonstrated a more robust change in 6MWD in female patients, while tadalafil has demonstrated a significant increase in 6MWD in male patients.12,13 The etiology of this sex difference between the treatment agents is unknown and could possibly involve differences in nitric oxide (NO) and endothelin signaling between the sexes.14,15 Multiple animal studies have demonstrated that estrogen decreases pulmonary arterial vasoconstriction by decreasing expression of endothelin 1 and increasing release of NO and prostaglandin.8,16-20 Neither of these studies addressed the effect of menopause on treatment response or evaluated time to clinical worsening (TCW) as a clinical end point. In the general population, many vasoreactive conditions, such as migraine headache and Raynaud’s phenomenon, increase after menopause.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.17,21-24 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 prevalence of PAH in this population compared with that in men and younger women.

Tadalafil is a commonly prescribed and well-tolerated PDE-5 inhibitor. Multiple studies have indicated that treatment with PDE-5 inhibitors improves outcomes in PAH, but none have reported any sex-specific or menopausal status–specific treatment effects on TCW.2,3 Our present study examines sex-specific treatment responses to tadalafil by assessing change in 6MWD and TCW using data from the pivotal randomized, placebo-controlled Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) trial.3 We also report the effects of menopausal status on treatment response to tadalafil using age as a surrogate for menopausal status. Patient selection included those enrolled in the PHIRST study.3 For the purposes of this study, deidentified information was used, and therefore a separate institutional review board was not required. For the initial PHIRST study, the local institutional review boards or independent ethics committees approved the protocol, and written consent was obtained from all patients.3 Subjects were at least 12 years of age and had symptomatic PAH (the youngest male was 19 years old; the youngest female was 14 years old). Subjects exposed to anorexigens or given a diagnosis of connective tissue disease, HIV infection, congenital pulmonary shunts, or idiopathic PAH were included in this study. The hemodynamic criteria for PAH included mean pulmonary arterial pressure of ≥25 mmHg, pulmonary arterial wedge pressure of ≤15 mmHg, and pulmomary vascular resistance of ≥3 Wood units.

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79 [36] days). A log-rank test did not show a consistent effect of sex on TCW for tadalafil-treated patients (P = 0.49). This difference in TCW between the sexes was found to be not statistically significant in the multivariate analysis (P = 0.41). To assess the impact of menopausal status on treatment response, female subjects were subdivided by age as a surrogate for menopausal status (Table 4). Tadalafil treatment demonstrated a consistent beneficial effect on change in 6MWD from baseline compared with placebo in these subgroups. Patients with a 6MWD of <150 or >450 m were excluded. Patients treated with intravenous epoprostenol, inhaled or intravenous iloprost, or subcutaneous or intravenous treprostinil were excluded.

• Tadalafil's role in female sexual health is promising but unconfirmed.
• It may be used alongside counseling for better outcomes.
• The medication helps enhance blood flow to the clitoris and labia.
• Not recommended as a first-line treatment for women.
• Tadalafil research involves small sample sizes so far.
• Its use in women is increasingly accepted in clinical trials.
• Women should discuss potential risks with healthcare providers.
• It is available in some countries specifically for research use.
• Further evidence needed to recommend widespread use.

Patients taking a maximum dose of bosentan (125 mg) twice daily for a minimum of 12 weeks at the time of screening continued to receive bosentan in addition to the study medicine.

• Tadalafil is a phosphodiesterase type 5 inhibitor, acting on blood vessels.
• Its potential benefits for women focus on increased genital blood flow.
• Tadalafil is not approved by FDA for female sexual disorders.
• Some clinical trials report moderate improvements in women.
• It is sometimes combined with hormonal treatments.
• Psychological factors also influence female sexual satisfaction.
• Tadalafil’s effects on orgasm intensity are under research.
• Women with pre-existing health conditions should exercise caution.
• Dose adjustments may be necessary based on individual response.

In total, 405 subjects (317 females, 88 males) were enrolled in a 16-week, double-blind, double-dummy, placebo-controlled multicenter study. Subjects were randomized into groups receiving placebo or 2.5, 10, 20, or 40 mg of tadalafil once daily. 6MWD was recorded before and after 16 weeks of treatment with tadalafil or placebo in a cohort of 340 subjects (264 females, 76 males).3 Clinical worsening was defined as death, lung or heart-lung transplantation, atrial septostomy, hospitalization due to worsening PAH, initiation of new PAH-approved therapy, or worsening World Health Organization (WHO) functional class over the 16 weeks. 6MWD and WHO functional class were measured at baseline and at weeks 4, 8, 12, and 16. When examining the effect of sex on change in 6MWD and TCW, only the tadalafil-treated patients were included (n = 323; males = 71, females = 252). For the univariate analyses, the Wilcoxon rank sum test was used to assess the effect of sex on change in 6MWD. A log-rank test was used to assess the effect of sex on TCW. Females were subdivided by age as a surrogate for menopausal status: 14–44 years, premenopausal; 45–54 years, perimenopausal; and ≥55 years, postmenopausal (based on the average age of menopause, 52.4 years).25 The linear trend test with first degree of orthogonal polynomials was used to assess the effect of age on change in 6MWD among females and separately for males within the same age groups. A log-rank test was performed on TCW by age among females. Kaplan-Meier plots were constructed to investigate clinical worsening by sex and age. Multivariate linear regression and Cox proportion hazards models were constructed to assess the effect of sex on change in 6MWD and TCW, respectively, by adjusting for age, sex, race, etiology of PAH, WHO functional class, background therapy with bosentan, and baseline 6MWD. Goodness of model fit, colinearity, and numerical stability tadalafil 40mg were also evaluated. Baseline characteristics by sex and menopausal status were collected and are reported in Tables 1 and 2.

• Tadalafil is being researched to treat female sexual desire disorder.
• It acts by increasing blood flow to genital tissues.
• Efficacy results are mixed and require further investigation.
• It is available under strict medical supervision in trials.
• Side effects in women include headaches and flushing.
• Some studies suggest benefits for postmenopausal women.
• It is not approved for general use in female sexual dysfunction.
• Women should always consult healthcare providers before trying.
• Its future depends on ongoing scientific validation.

Between male and female patients, there was a significant difference in baseline weight, PAH etiology, and age. The female cohort was slightly younger (mean age: 53 vs. 57 years).

Cialis in Women: Effectiveness & Dosage

57 years). For female patients, there was a significant difference between menopausal status groups in baseline 6MWD, with postmenopausal females having the lowest baseline 6MWD. In addition, there was a significant difference in PAH pathogenesis across the sex and menopausal states. The majority of each group reported having idiopathic PAH; however, atrial septal defect was predominant in premenopausal females, and cardiovascular disease was predominant in postmenopausal females. Except where otherwise noted, data are no.

Ethical Approval

6MWD: 6-minute walk distance; PAH: pulmonary arterial hypertension; VSD: ventricular septal defect; PDA: patent ductus arteriosus; WHO: World Health Organization. For tadalafil-treated patients, males were found to have a significantly greater improvement in 6MWD compared with females (mean [SD]: 48.6 [55] m for males vs. 34.7 [54] m for females; P = 0.01; Table 3). This difference was not statistically significant in the multivariate analysis (P = 0.08) after adjusting for covariates: age, sex, race, etiology of PAH, WHO functional class, background therapy with bosentan, and baseline 6MWD. A backward model selection was performed with 0.05 as the significance level for staying in the model to assess any covariate correlation.

Table 3.

This model selection resulted in elimination of the variables background therapy with bosentan (P = 0.8854), race (P = 0.1935), and sex (P = 0.0647). P = 0.01 for the difference between male and female change in 6MWD. P = 0.49 for the difference between male and female change in TCW. Overall, tadalafil treatment demonstrated a beneficial effect on TCW for patients who experienced clinical worsening compared with placebo in both male and female patients (Table 3). Female patients randomized to receive tadalafil were found to have a shorter mean (SD) TCW compared with male patients randomized to receive tadalafil (61 [29] vs. For female patients, there was a significant difference between menopausal status groups in baseline 6MWD, with postmenopausal females having the lowest baseline 6MWD. In addition, there was a significant difference in PAH pathogenesis across the sex and menopausal states.

The majority of each group reported having idiopathic PAH; however, atrial septal defect was predominant in premenopausal females, and cardiovascular disease was predominant in postmenopausal females. Except where otherwise noted, data are no. 6MWD: 6-minute walk distance; PAH: pulmonary arterial hypertension; VSD: ventricular septal defect; PDA: patent ductus arteriosus; WHO: World Health Organization. For tadalafil-treated patients, males were found to have a significantly greater improvement in 6MWD compared with females (mean [SD]: 48.6 [55] m for males vs.

34.7 [54] m for females; P = 0.01; Table 3). This difference was not statistically significant in the multivariate analysis (P = 0.08) after adjusting for covariates: age, sex, race, etiology of PAH, WHO functional class, background therapy with bosentan, and baseline 6MWD. A backward model selection was performed with 0.05 as the significance level for staying in the model to assess any covariate correlation. This model selection resulted in elimination of the variables background therapy with bosentan (P = 0.8854), race (P = 0.1935), and sex (P = 0.0647).

Brand Name

For tadalafil-treated patients, there was a trend among female subjects for an age-dependent effect on mean change in 6MWD: the premenopausal group showed the greatest improvement (mean [SD]: 45.7 [55] m), followed by the perimenopausal (mean [SD]: 41.1 [50] m) and the postmenopausal (mean [SD]: 24.5 [54] m) group. The linear trend of the effect of age on 6MWD in females was found to be statistically significant (P = 0.02). This age-related trend was not present in male subjects subdivided into the same age groups: the younger (mean [SD]: 73.2 [48] m) and older (mean [SD]: 42.8 [56] m) men showed greater improvement than middle-aged men (mean [SD]: 34.4 [52] m). Tadalafil was found to have a beneficial effect on TCW for patients who experienced clinical worsening in all female age groups compared with placebo. P = 0.01 for the difference between male and female change in 6MWD. P = 0.49 for the difference between male and female change in TCW.

Further information

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.3-6 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.7-11 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 demonstrated a significant increase in 6MWD in male patients.12,13 The etiology of this sex difference between the treatment agents is unknown and could possibly involve differences in nitric oxide (NO) and endothelin signaling between the sexes.14,15 Multiple animal studies have demonstrated that estrogen decreases pulmonary arterial vasoconstriction by decreasing expression of endothelin 1 and increasing release of NO and prostaglandin.8,16-20 Neither of these studies addressed the effect of menopause on treatment response or evaluated time to clinical worsening (TCW) as a clinical end point. In the general population, many vasoreactive conditions, such as migraine headache and Raynaud’s phenomenon, increase after menopause.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.17,21-24 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.

Consent for Publication

A treatment agent with a postmenopausal-specific treatment benefit would be extremely valuable given the high prevalence of PAH in this population compared with that in men and younger women. Tadalafil is a commonly prescribed and well-tolerated PDE-5 inhibitor. Multiple studies have indicated that treatment with PDE-5 inhibitors improves outcomes in PAH, but none have reported any sex-specific or menopausal status–specific treatment effects on TCW.2,3 Our present study examines sex-specific treatment responses to tadalafil by assessing change in 6MWD and TCW using data from the pivotal randomized, placebo-controlled Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) trial.3 We also report the effects of menopausal status on treatment response to tadalafil using age as a surrogate for menopausal status. Patient selection included those enrolled in the PHIRST study.3 For the purposes of this study, deidentified information was used, and therefore a separate institutional review board was not required. For the initial PHIRST study, the local institutional review boards or independent ethics committees approved the protocol, and written consent was obtained from all patients.3 Subjects were at least 12 years of age and had symptomatic PAH (the youngest male was 19 years old; the youngest female was 14 years old).

What is Cialis (tadalafil)? How does tadalafil work?

Subjects exposed to anorexigens or given a diagnosis of connective tissue disease, HIV infection, congenital pulmonary shunts, or idiopathic PAH were included in this study. The hemodynamic criteria for PAH included mean pulmonary arterial pressure of ≥25 mmHg, pulmonary arterial wedge pressure of ≤15 mmHg, and pulmomary vascular resistance of ≥3 Wood units. Patients with a 6MWD of <150 or >450 m were excluded. Patients treated with intravenous epoprostenol, inhaled or intravenous iloprost, or subcutaneous or intravenous treprostinil were excluded. Patients taking a maximum dose of bosentan (125 mg) twice daily for a minimum of 12 weeks at the time of screening continued to receive bosentan in addition to the study medicine. Overall, tadalafil treatment demonstrated a beneficial effect on TCW for patients who experienced clinical worsening compared with placebo in both male and female patients (Table 3). Female patients randomized to receive tadalafil were found to have a shorter mean (SD) TCW compared with male patients randomized to receive tadalafil (61 [29] vs. 79 [36] days). A log-rank test did not show a consistent effect of sex on TCW for tadalafil-treated patients (P = 0.49). This difference in TCW between the sexes was found to be not statistically significant in the multivariate analysis (P = 0.41).

• Tadalafil's mechanism targets blood vessels to promote dilation.
• It may help women with blood flow-related sexual problems.
• The drug's research status means limited official approvals.
• Female studies explore impacts on sexual satisfaction and arousal.
• Its off-label use is increasing with ongoing research.
• Tadalafil could improve genital flushing and sensitivity.
• Women with cardiac risk factors should avoid tadalafil.
• Clinical trials are testing daily versus as-needed dosing.
• User reports vary, and more evidence is necessary.

To assess the impact of menopausal status on treatment response, female subjects were subdivided by age as a surrogate for menopausal status (Table 4). Tadalafil treatment demonstrated a consistent beneficial effect on change in 6MWD from baseline compared with placebo in these subgroups. For tadalafil-treated patients, there was a trend among female subjects for an age-dependent effect on mean change in 6MWD: the premenopausal group showed the greatest improvement (mean [SD]: 45.7 [55] m), followed by the perimenopausal (mean [SD]: 41.1 [50] m) and the postmenopausal (mean [SD]: 24.5 [54] m) group. The linear trend of the effect of age on 6MWD in females was found to be statistically significant (P = 0.02).

This age-related trend was not present in male subjects subdivided into the same age groups: the younger (mean [SD]: 73.2 [48] m) and older (mean [SD]: 42.8 [56] m) men showed greater improvement than middle-aged men (mean [SD]: 34.4 [52] m). Tadalafil was found to have a beneficial effect on TCW for patients who experienced clinical worsening in all female age groups compared with placebo.