Treatment of Erectile Dysfunction in a Hypogonadal Male

Abstract

Anecdotal evidence suggests that hypogonadal men who failed to respond to sildenafil citrate changed their response when supplemented with androgens. The author presents the case of a middle-aged man with hypogonadism who experienced success with sildenafil citrate with supplemental testosterone.

A 46-year-old white male presented with complaints of progressive erectile dysfunction (ED) with an onset 18 months previously. He averages a 50% to 60% erection and can achieve penetration approximately 50% of the time; he ejaculates and achieves orgasm routinely. His libido is significantly reduced—he rated his libido compared to 5 years previously as a 4 on a scale of 1 to 10. He had difficulty stating whether this was reduced prior to the onset of his ED (although his wife believes it was). He saw a local urologist who prescribed sildenafil citrate. He did not receive a satisfactory response at either 50 or 100 mg. He was later separately prescribed alprostadil and atorvastatin without significant improvement. At that time, he had undergone no investigation for his ED.

His past medical history was significant for mild hypertension and a 10 pack a year smoking history. He denied having diabetes, dyslipidemia, coronary artery, or peripheral vascular disease. He has minimal alcohol intake and ceased cigarette smoking more than a decade ago. He is an advertising executive working 10-hour days and lost his mother to breast cancer 3 years ago.

At his initial interview he was present with his 40-year-old wife, who seemed supportive and concerned about the etiology of his problems, especially his libido alterations. They have 2 children, 7 and 4 years of age. She stated that they used to have sexual relations 2 to 3 times per week and now frequency was less than once every 2 weeks. His review of systems is noncontributory; specifically, he had no urologic symptoms suggestive of lower urinary tract problems.

He completed the International Index of Erectile Function (IIEF) questionnaire. The erectile function (EF) domain score was 16 (maximum, 30) without sildenafil citrate and he estimated 19 with sildenafil citrate. His libido domain score was 4 (maximum, 10) on and off sildenafil citrate. Of the 10 questions on the Morley questionnaire he had 5 yes responses.

In discussing his use of sildenafil citrate it was clear that he had not used the medication correctly: he took doses in proximity to food and he had tried the 100-mg dose on only 1 occasion. Our conversation focused on a sildenafil citrate rechallenge and defining the etiology of his problem. He was given a prescription for 100 mg sildenafil citrate and explicit instructions pertaining to the correct method of use, and was instructed to use it on at least 4 occasions.

Blood was drawn for a lipid profile and a total testosterone level. He was also counseled regarding the role of duplex Doppler penile ultrasound (DUS) to define the potential for curability of his ED. He elected to undergo this on another day.

Two weeks later he returned for a penile ultrasound examination. His peak systolic velocities were 25 and 27 cm/s on right and left side (normal, ≥ 30 cm/s) and his end diastolic velocities were 1.5 and 1.8 cm/s (normal, ≤ 3 cm/s), respectively. On this occasion he stated that despite using sildenafil citrate correctly he had at best only a 60% response and his EF domain score was 20. His total testosterone level was 218 ng/dL (normal, 240–827 ng/dL) and his lipid profile was normal.

The DUS indicated that he had bilateral cavernosal artery insufficiency. He was counseled regarding the link between penile vascular disease and coronary artery disease and was referred to a cardiologist. He was also counseled regarding the link between testosterone levels and PDE5 inhibitor response. He was also advised to undergo a bone densitometry study.

He had a repeat total testosterone level, free testosterone level, and luteinizing hormone (LH) and prolactin levels. His total level was 209 ng/dL, his free level was 44 pg/mL (normal, 50–210 pg/mL), his LH level was 2.4 U/L (normal, 1–12 U/L) and his prolactin level was 8 ng/mL (normal, 1–15 ng/mL). He was started on 1% testosterone gel at 5g/d. Two weeks later his total and free testosterone levels were 448 ng/dL and 78 ng/dL, respectively. In a telephone interview, he and his wife noted that his libido had improved significantly. He was kept on this dose of 1% testosterone gel and was rechallenged with sildenafil citrate. After 3 100-mg doses, he and his wife admitted that the response was now satisfactory. His IIEF EF domain score was now 24 and his libido domain score was 7. Six months later he was still responsive to sildenafil citrate and continued on 5 g/d of 1% testosterone gel.

Discussion

Anecdotal evidence suggests that hypogonadal men who failed to respond to sildenafil citrate change their sildenafil citrate response when supplemented with androgens. Guay and colleagues¹ demonstrated that 75% of men (n = 44) with hypogonadism responded to sildenafil citrate whereas 85% of men with hypogonadism who had androgen supplementation responded. Shabsigh and colleagues² conducted a randomized, placebo-controlled study in 75 men with hypogonadism (defined as serum total testosterone levels ≤ 400 ng/dL) who had failed to respond to sildenafil citrate. Half of the patients received 5 g/d of transdermal testosterone gel. Subjects were evaluated for sexual function, primarily based on the IIEF, quality of life, and serum testosterone levels at baseline and weeks 4, 8, and 12. Testosterone-treated subjects had greater improvement in erectile function compared to those who received placebo, reaching statistical significance at week 4 but not at weeks 8 or 12. Similar trends were observed for improvements in orgasmic function, overall satisfaction, total IIEF score, and percentage of IIEF responders.

Sildenafil citrate is a PDE5 inhibitor that requires the presence of nitric oxide (NO) for its effect. It has been demonstrated that NO levels vary with androgen levels within the penis. Castrated rats demonstrate markedly diminished expression of nitric oxide synthase (NOS) and PDE5 activity is higher in the presence of testosterone.^3–5 The level of serum testosterone that is required for the preservation of NOS levels and PDE5 activity in the penis is undetermined. The available clinical data combined with clinical experience with hypogonadal patients suggest that men with low serum testosterone levels who fail to respond to sildenafil citrate (and potentially other PDE5 inhibitors) may be responsive to oral erectogenic medication after testosterone supplementation. All patients with ED at baseline have an early morning serum testosterone level. In men who have a low serum total testosterone and who fail a sildenafil citrate challenge, transdermal testosterone supplementation is discussed. The primary route of administration discussed is transdermal gel applied to skin, which in men with hypogonadism has been shown to elevate serum testosterone levels into the physiological range.⁶

Main Points.

• Anecdotal evidence suggests that hypogonadal men who failed to respond to sildenafil citrate changed their sildenafil citrate response when supplemented with androgens.

• Sildenafil citrate is a PDE5 inhibitor that requires the presence of nitric oxide (NO) for its effect; NO levels vary with androgen levels within the penis.

• In men who have a low serum total testosterone and who fail a sildenafil citrate challenge, transdermal testosterone supplementation has been shown to elevate serum testosterone levels into the physiological range.