madman
Super Moderator
Abstract
In this study, the efficiency of intracavernosal alprostadil + oral clomiphene citrate (CC) treatment in late-onset hypogonadism (LOH) accompanied by penile vasculogenic erectile dysfunction (PVED) in patients irresponsive to phosphodiesterase type 5 inhibitor treatment was evaluated. A total of 31 patients with concurrent PVED and LOH were included in the study. The patients were given intracavernosal alprostadil (10–20 μg) and oral CC (50 mg) every day for 12 weeks. Before and after treatment, a 15-question International Index of Erectile Function (IIEF-15) questionnaire, Erection Hardness Score (EHS), Sexual Encounter Profile (SEP)2 and SEP3 levels were analyzed, and follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, and prostate-specific antigen (PSA) levels were measured. In all, 41.9% of patients had a pure arterial deficiency, 19.3% had a pure venous deficiency, and 38.7% had arterial + venous (mixed) deficiency. A significant increase was detected in total testosterone, FSH, LH and PSA values after treatment when compared to values before treatment (p < .001, p < .001, p < .001 and p = .034 respectively). Significant recovery was observed in IIEF-15 subscores, EHS, and SEP2-SEP3 results. In PVED patients accompanied by LOH, intracavernosal alprostadil and oral CC combination are an efficient, low cost, safely applicable, and tolerable treatment.
1 | INTRODUCTION
Erectile dysfunction (ED) refers to difficulty in starting and maintaining an adequate erection for satisfactory sexual performance and the stability of this condition (Burnett et al., 2018). The estimated prevalence of ED in men > 40 years of age is almost 50% (Bella, Lee, Carrier, Benard, & Brock, 2015). Different therapeutic agents have been developed for ED treatment, and their effect mechanism depends on the understanding of erection physiology. In ED treatment-resistant patients, lifestyle changes as a first-line treatment option and phosphodiesterase type 5 inhibitors (PDE5 inhibitors) as a second-line treatment option are used. PDE-5 inhibitors are noninvasive, generally well-tolerated, and efficient in most males. Intracavernosal injections (ICUs), such as alprostadil and papaverine, can be used in 25%–50% of patients who are irresponsive to the treatment and who contraindicate PDE5 inhibitors (Bella et al., 2015; Hatzimouratidis et al., 2019).
The International Society of Andrology (ISA), International Society for the Study of the Aging Male, and the European Association of Urology defined late-onset hypogonadism (LOH) as a clinical and biochemical syndrome forming as the result of aging in males (Nieschlag et al., 2006). Symptoms and impaired quality of life can be observed due to multiple organs being affected in the clinical stage of this syndrome, which demonstrates itself biochemically in decreasing serum testosterone levels (Nieschlag et al., 2005). It has been shown that total testosterone biochemically decreases by an annual rate of 0.8% and bioactive testosterone decreases by an annual rate of 1.6% in males after the age of 40. The cause of the lower decrease in total testosterone compared to bioactive or free testosterone is considered to be the increase in sex hormone-binding globulin with aging. Hypogonadism prevalence was reported as ranging at 2%–30% between the ages of 40 and 59 and as 20%–45% between the ages of 60 and 69 and gradually increases with age (Huhtaniemi, 2014; Nieschlag et al., 2005; Üçer & Gümüş, 2014). Provision of a treatment to replace missing testosterone is suggested in symptomatic individuals with a total testosterone level below 346 ng/dl (12 nM) (Kim & Moon, 2011; Wang et al., 2009).
There are many studies showing that clomiphene citrate (CC) can be used as an alternative to testosterone treatment. Clomiphene citrate increases testosterone production in the testicles through hypothalamic-pituitary feedback inhibition. Clomiphene most likely does not have any negative effect on spermatogenesis. Additionally, CC application is an advantageous method in terms of treatment cost (Guay, Bansal, & Heatley, 1995; Taylor & Levine, 2010).
In ED, the combination of pharmacotherapeutic treatments may have a positive and synergic effect for improving erectile function since these agents can treat patients by targeting different points in the erection physiological pathway (Duncan et al., 2019). In this study, the efficiency of intracavernosal alprostadil and oral CC combination treatment in LOH accompanied by penile vasculogenic ED (PVED) patients irresponsive to PDE inhibitor treatment is evaluated.
2.2 | Treatment protocol
Alprostadil (Jectera®, Vem Pharmaceuticals) application was administered using a 0.5-inch and 27- to 30-gauge needle. Visible veins were avoided by injecting in the dorsolateral direction of the proximal third of the penis. Starting dose was 10 mcg in all patients. The first injection was made by the health staff, and the patient was trained for its application at home before sexual intercourse. Patients applied the drugs themselves at home after the starting dose. The alprostadil dose was increased to 20 μg in patients who could not provide sufficient erection for vaginal penetration with 10 μg. Oral CC 50 mg (Klomen®, Koçak Farma Pharmaceuticals, And Chemical Industry Inc.) was used daily for testosterone replacement. Intracavernosal alprostadil and oral CC combination treatment were used for 12 weeks.
4 | DISCUSSION
Erectile dysfunction prevalence increases with age. While the prevalence changes between 1% and 10% globally in males under 40 years of age, it increases to 15% for males between 40 and 49, 30% for those between 50 and 59, 40% for those between 60 and 69, and 50%–100% for males between 70 and 90 years of age (Lewis et al., 2010).
ED pathology can be vasculogenic, neurogenic, anatomic, drug-related, and/or psychogenic. Vasculogenic ED among these forms is the most common among the organic causes of ED (Yafi, Jenkins, & Albersen, 2016). Vasculogenic ED starts due to vessel wall destruction and decreasing vascular elasticity caused by factors, such as high blood pressure, diabetes, dyslipidemia, and smoking. Hypoxia caused by decreased cavernosal oxygenation may normally cause a decrease in prostaglandin E1 levels, inhibiting pro-fibrotic cytokines, such as transforming growth factor β1. As shown in different rat models, these pro-fibrotic cytokines increase collagen accumulation replacing the smooth muscle and cause a decrease in penis elasticity (Moreland, 1998). As the smooth muscle/collagen ratio decreases and collagen content increases, the ability of corpus cavernosum to compress subtunical veins decreases, and Veno-occlusive dysfunction forms (Nehra et al., 1996).
Interestingly, we observed that testosterone level and post-treatment Intercourse Satisfaction Scores demonstrated a significant increase in the penile arterial ED subgroup compared to venogenic ED and mixed ED groups in this study. Penile arterial insufficiency is responsible for 55% of EDs, and in patients irresponsive to treatment with PDE5 inhibitors, severe penile arterial flow insufficiency rate was recorded at 90% (Rogers et al., 2010). Our patient group had an arteriogenic deficiency (pure arteriogenic + mixed) component at a rate of 80.6% (25/31). High treatment success may be related to this condition.
Low patient number, the inability to evaluate partner sexual function and a treatment duration limited to 3 months constitute the limitations of this study.
In PVED patients accompanied by LOH, intracavernosal alprostadil and oral CC combination is an efficient, low cost, and safely applicable and tolerable treatment.
5 | CONCLUSION
Hormonal and penile vasculogenic causes are important in patients with ED. Especially in concurrent LOH and PVED patients irresponsive to PDE5 inhibitors treatment, CC and intracavernosal alprostadil combination treatment may provide significant recovery in sexual and hormonal parameters. This combination treatment is an efficient, affordable, and tolerable treatment method. It should be considered that treatment results are slightly improved in PVED, especially in cases of dominant arterial deficiency.
In this study, the efficiency of intracavernosal alprostadil + oral clomiphene citrate (CC) treatment in late-onset hypogonadism (LOH) accompanied by penile vasculogenic erectile dysfunction (PVED) in patients irresponsive to phosphodiesterase type 5 inhibitor treatment was evaluated. A total of 31 patients with concurrent PVED and LOH were included in the study. The patients were given intracavernosal alprostadil (10–20 μg) and oral CC (50 mg) every day for 12 weeks. Before and after treatment, a 15-question International Index of Erectile Function (IIEF-15) questionnaire, Erection Hardness Score (EHS), Sexual Encounter Profile (SEP)2 and SEP3 levels were analyzed, and follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, and prostate-specific antigen (PSA) levels were measured. In all, 41.9% of patients had a pure arterial deficiency, 19.3% had a pure venous deficiency, and 38.7% had arterial + venous (mixed) deficiency. A significant increase was detected in total testosterone, FSH, LH and PSA values after treatment when compared to values before treatment (p < .001, p < .001, p < .001 and p = .034 respectively). Significant recovery was observed in IIEF-15 subscores, EHS, and SEP2-SEP3 results. In PVED patients accompanied by LOH, intracavernosal alprostadil and oral CC combination are an efficient, low cost, safely applicable, and tolerable treatment.
1 | INTRODUCTION
Erectile dysfunction (ED) refers to difficulty in starting and maintaining an adequate erection for satisfactory sexual performance and the stability of this condition (Burnett et al., 2018). The estimated prevalence of ED in men > 40 years of age is almost 50% (Bella, Lee, Carrier, Benard, & Brock, 2015). Different therapeutic agents have been developed for ED treatment, and their effect mechanism depends on the understanding of erection physiology. In ED treatment-resistant patients, lifestyle changes as a first-line treatment option and phosphodiesterase type 5 inhibitors (PDE5 inhibitors) as a second-line treatment option are used. PDE-5 inhibitors are noninvasive, generally well-tolerated, and efficient in most males. Intracavernosal injections (ICUs), such as alprostadil and papaverine, can be used in 25%–50% of patients who are irresponsive to the treatment and who contraindicate PDE5 inhibitors (Bella et al., 2015; Hatzimouratidis et al., 2019).
The International Society of Andrology (ISA), International Society for the Study of the Aging Male, and the European Association of Urology defined late-onset hypogonadism (LOH) as a clinical and biochemical syndrome forming as the result of aging in males (Nieschlag et al., 2006). Symptoms and impaired quality of life can be observed due to multiple organs being affected in the clinical stage of this syndrome, which demonstrates itself biochemically in decreasing serum testosterone levels (Nieschlag et al., 2005). It has been shown that total testosterone biochemically decreases by an annual rate of 0.8% and bioactive testosterone decreases by an annual rate of 1.6% in males after the age of 40. The cause of the lower decrease in total testosterone compared to bioactive or free testosterone is considered to be the increase in sex hormone-binding globulin with aging. Hypogonadism prevalence was reported as ranging at 2%–30% between the ages of 40 and 59 and as 20%–45% between the ages of 60 and 69 and gradually increases with age (Huhtaniemi, 2014; Nieschlag et al., 2005; Üçer & Gümüş, 2014). Provision of a treatment to replace missing testosterone is suggested in symptomatic individuals with a total testosterone level below 346 ng/dl (12 nM) (Kim & Moon, 2011; Wang et al., 2009).
There are many studies showing that clomiphene citrate (CC) can be used as an alternative to testosterone treatment. Clomiphene citrate increases testosterone production in the testicles through hypothalamic-pituitary feedback inhibition. Clomiphene most likely does not have any negative effect on spermatogenesis. Additionally, CC application is an advantageous method in terms of treatment cost (Guay, Bansal, & Heatley, 1995; Taylor & Levine, 2010).
In ED, the combination of pharmacotherapeutic treatments may have a positive and synergic effect for improving erectile function since these agents can treat patients by targeting different points in the erection physiological pathway (Duncan et al., 2019). In this study, the efficiency of intracavernosal alprostadil and oral CC combination treatment in LOH accompanied by penile vasculogenic ED (PVED) patients irresponsive to PDE inhibitor treatment is evaluated.
2.2 | Treatment protocol
Alprostadil (Jectera®, Vem Pharmaceuticals) application was administered using a 0.5-inch and 27- to 30-gauge needle. Visible veins were avoided by injecting in the dorsolateral direction of the proximal third of the penis. Starting dose was 10 mcg in all patients. The first injection was made by the health staff, and the patient was trained for its application at home before sexual intercourse. Patients applied the drugs themselves at home after the starting dose. The alprostadil dose was increased to 20 μg in patients who could not provide sufficient erection for vaginal penetration with 10 μg. Oral CC 50 mg (Klomen®, Koçak Farma Pharmaceuticals, And Chemical Industry Inc.) was used daily for testosterone replacement. Intracavernosal alprostadil and oral CC combination treatment were used for 12 weeks.
4 | DISCUSSION
Erectile dysfunction prevalence increases with age. While the prevalence changes between 1% and 10% globally in males under 40 years of age, it increases to 15% for males between 40 and 49, 30% for those between 50 and 59, 40% for those between 60 and 69, and 50%–100% for males between 70 and 90 years of age (Lewis et al., 2010).
ED pathology can be vasculogenic, neurogenic, anatomic, drug-related, and/or psychogenic. Vasculogenic ED among these forms is the most common among the organic causes of ED (Yafi, Jenkins, & Albersen, 2016). Vasculogenic ED starts due to vessel wall destruction and decreasing vascular elasticity caused by factors, such as high blood pressure, diabetes, dyslipidemia, and smoking. Hypoxia caused by decreased cavernosal oxygenation may normally cause a decrease in prostaglandin E1 levels, inhibiting pro-fibrotic cytokines, such as transforming growth factor β1. As shown in different rat models, these pro-fibrotic cytokines increase collagen accumulation replacing the smooth muscle and cause a decrease in penis elasticity (Moreland, 1998). As the smooth muscle/collagen ratio decreases and collagen content increases, the ability of corpus cavernosum to compress subtunical veins decreases, and Veno-occlusive dysfunction forms (Nehra et al., 1996).
Interestingly, we observed that testosterone level and post-treatment Intercourse Satisfaction Scores demonstrated a significant increase in the penile arterial ED subgroup compared to venogenic ED and mixed ED groups in this study. Penile arterial insufficiency is responsible for 55% of EDs, and in patients irresponsive to treatment with PDE5 inhibitors, severe penile arterial flow insufficiency rate was recorded at 90% (Rogers et al., 2010). Our patient group had an arteriogenic deficiency (pure arteriogenic + mixed) component at a rate of 80.6% (25/31). High treatment success may be related to this condition.
Low patient number, the inability to evaluate partner sexual function and a treatment duration limited to 3 months constitute the limitations of this study.
In PVED patients accompanied by LOH, intracavernosal alprostadil and oral CC combination is an efficient, low cost, and safely applicable and tolerable treatment.
5 | CONCLUSION
Hormonal and penile vasculogenic causes are important in patients with ED. Especially in concurrent LOH and PVED patients irresponsive to PDE5 inhibitors treatment, CC and intracavernosal alprostadil combination treatment may provide significant recovery in sexual and hormonal parameters. This combination treatment is an efficient, affordable, and tolerable treatment method. It should be considered that treatment results are slightly improved in PVED, especially in cases of dominant arterial deficiency.
