Section 1 – Geoffrey

Geoffrey is 46 years old with a diagnosis of type 2 diabetes since his late thirties. He comes to seek help for erectile dysfunction (ED). Geoffrey is remarried with a younger wife and they are keen to start a family as soon as possible. He is worried about the effect of his ED on their relationship.

What are the important features of Geoffrey’s clinical history to establish?

Section 2

Allow Geoffrey to describe the problem in his own words but try to elicit whether the ED is intermittent or permanent, and whether the onset was gradual (usually the case in an organic cause of ED such as diabetes) or sudden (suggestive of a psychogenic cause). Do spontaneous erections occur (suggestive of intact neurovascular supply)? Is there a loss of libido (may suggest hypogonadism)? Tactful enquiry into Geoffrey’s relationship with his partner and any problems they may have is relevant; if possible, involve Geoffrey’s partner in discussions (NICE, 2023).

Review comorbidities, including anxiety and depression, which might affect ED (and bear in mind that ED itself could lead to anxiety and depression, loss of self-esteem and loss of sexual confidence). Go through Geoffrey’s medication list for drugs that might adversely affect erections (e.g. phenothiazines, SSRI antidepressants, beta-blockers), and check smoking and alcohol history and any recreational drug use.

What examination and investigations are relevant to Geoffrey’s ED?

Section 3

It would be appropriate to examine genitals and secondary sexual characteristics for any abnormality. Small testes, reduced body hair and gynaecomastia suggest androgen deficiency. Are there any penile abnormalities (Peyronie’s disease, hypospadias, phimosis)? Check blood pressure, BMI and peripheral pulses, looking for hypertension, obesity and peripheral vascular disease to identify factors contributing to ED.

HbA_1c and lipid profile are essential investigations, and consideration should be given to checking a fasting morning serum testosterone level: certainly if there is a suggestion of hypogonadism (Hackett et al, 2018).

 
Geoffrey’s ED has progressed over the last year, such that he rarely maintains an erection long enough for satisfactory sexual intercourse. His partner is fit and well. Geoffrey is known to have diabetic retinopathy and nephropathy. He is an ex-smoker who consumes around 20 units of alcohol per week. Physical examination is unremarkable.

Current medication:

• Metformin 1 g twice daily.
• Dapagliflozin 10 mg once daily.
• Insulin glargine 26 units once daily
• Ramipril 10 g once daily.
• Atorvastatin 20 mg once daily.

 
Morning fingerprick blood glucose readings are running between 7–11 mmol/L, with no hypoglycaemia.

Recent test results:

• Blood pressure 145/92 mmHg.
• BMI 29.2 kg/m².
• HbA_1c 61 mmol/mol.
• eGFR 71 mL/min/1.73 m².
• ACR 15 mg/mmol.
• Total cholesterol 4.7 mmol/L; non-HDL cholesterol 2.9 mmol/L.
• LFTs and TFTs normal.

 
What risk factors does Geoffrey have for developing ED?

Section 4

Intact nerve and vascular supply to the penis is necessary for satisfactory erectile function, alongside an adequate hormonal environment (Hackett et al, 2018). There is a high prevalence of ED in men with diabetes (Kouidrat et al, 2017). In Geoffrey’s case, hypertension, dyslipidaemia and hyperglycaemia are all implicated in atherosclerotic vascular disease. Hyperglycaemia and hypertension are also important risk factors for neuronal damage. Geoffrey’s raised BMI and alcohol consumption may also contribute to his ED.

What general advice and medical management could you offer Geoffrey to help manage his ED?

Section 5

Encourage Geoffrey to focus attention on lifestyle issues, targeting reversible risk factors that might adversely affect erections (NICE, 2023). Eating healthily, taking regular exercise and aiming for weight loss are all worthwhile targets (Cheng et al, 2007). A reduction in alcohol consumption may well benefit Geoffrey’s ED, although low to moderate alcohol intake (keeping to less than 14 units/week) does not appear to be harmful (Chew et al, 2009). It is of great importance that Geoffrey no longer smokes, as this is a key contributor to atherosclerotic disease; smoking cessation has been shown to reduce ED (Harte and Meston, 2012).

Good control of Geoffrey’s hyperglycaemia, hypertension and dyslipidaemia are fundamental in attenuating progression of vascular and neuronal disease that impact on ED. Specific pharmacological treatment can bring a rapid response to ED (Hackett et al, 2018). However, adjustment to lifestyle and dealing with metabolic risk factors are longer-term interventions that will bring benefits relatively slowly.

Remember that attention should be directed, where necessary, to managing anxiety, depression and other psychological issues and addressing relationship difficulties. The holistic nature of ED management lends itself to management in primary care.

How might you tackle Geoffrey’s raised blood pressure?

Section 6

An ideal blood pressure target for Geoffrey would be 130/80 mmHg given his diabetic nephropathy and retinopathy (NICE, 2021; 2022). If his raised blood pressure is confirmed, further antihypertensive therapy is indicated; however, the choice of agent can have important consequences for his ED. Beta-blockers and thiazide-like diuretics can adversely affect ED and are better avoided (Khan et al, 2002).

ACE inhibitors, angiotensin receptor blockers (ARBs) and calcium channel blockers are agents of choice, with alpha-blockers (e.g. doxazosin) also a reasonable option. Consideration could be given to replacing an ACE inhibitor with an ARB, as there is evidence that ARBs have a beneficial effect on ED and are the first-line choice to treat hypertension in people with ED (Hackett et al, 2018).

 
Geoffrey is commenced on amlodipine 5 mg once daily, to add to his ramipril.

How about control of dyslipidaemia and hyperglycaemia?

Section 7

Control of both dyslipidaemia and hyperglycaemia could be tightened in Geoffrey’s case. The dose of atorvastatin is increased to 40 mg once daily. Geoffrey is instructed to increase his dose of insulin glargine to 28 units once daily, with further 2-unit increases as needed every 5 days, aiming for morning capillary blood glucose readings in the range of 5–8 mmol/L.

Consideration could be given to replacing the insulin glargine with a GLP-1 receptor agonist, which should provide a similar level of glycaemic control without the risk of hypoglycaemia, facilitate weight loss and offer a degree of cardiovascular protection.

Apart from the benefit to his ED, why else is it important to deal with Geoffrey’s hypertension and dyslipidaemia?

Section 8

ED is an important cardiovascular risk factor (Vlachopoulos et al, 2013), and appears to be a particularly good predictor of cardiovascular events (myocardial infarction and stroke) in men with diabetes (Ma et al, 2008). Attention to hypertension and dyslipidaemia is important in dealing with this raised cardiovascular risk (Salonia et al, 2021).

It has been suggested that the smaller diameter of penile arteries compared to coronary arteries renders them more susceptible to atherosclerotic occlusion, and that ED occurs 3–5 years ahead of symptomatic coronary artery disease (Hackett et al, 2017; Salonia et al, 2021).

Can you think of any other medical conditions that can cause ED you should look out for?

Section 9

Testosterone deficiency arising from hypogonadism (or less commonly, hypopituitarism) is important to consider as a reversible cause of ED, remembering that this also has wider health implications. Low testosterone levels are more common in people with type 2 diabetes than the general population (Corona et al, 2009). Thyroid disease, hyperprolactinaemia and Cushing’s disease are other hormonal abnormalities associated with ED.

Lower urinary tract symptoms, most commonly related to benign prostatic hypertrophy, are associated with ED and so may be worth enquiring about (Rosen et al, 2003).

So how would you specifically manage Geoffrey’s ED?

Section 10

Geoffrey would be a good candidate for a phosphodiesterase-5 (PDE5) inhibitor (NICE, 2023). These agents facilitate the action of nitrous oxide (NO) by inhibiting the breakdown of NO-induced cyclic-GMP by the enzyme PDE5. Enhanced levels of cyclic-GMP cause relaxation of penile smooth muscle and vasodilation, allowing greater arterial blood flow into the penis and thus penile engorgement.

The four available PDE5 inhibitors are sildenafil, vardenafil, tadalafil and avanafil, and the first three are now available generically and so can be prescribed without restriction on the NHS.

Trial data suggest that PDE5 inhibitors can successfully treat ED in men with type 2 diabetes but are less effective in those with a longer duration of diabetes, poorly controlled glycaemia and diabetes complications such as vascular disease and neuropathy (Goldstein et al, 2003). It is also worth noting that PDE5 inhibitors can benefit lower urinary tract symptoms, and indeed tadalafil holds a licence for benign prostatic hyperplasia.

 
Geoffrey is prescribed sildenafil 50 mg and advised to use this one hour before intended sexual intercourse. It is explained that sexual stimulation is required for the treatment to be effective.

What side effects of PDE5 inhibitors should you warn Geoffrey about?

Section 11

Headache, flushing, dizziness, nasal congestion and dyspepsia are relatively common side effects of PDE5 inhibitors, so warn Geoffrey about these. Priapism is rare but if an erection persists (>4 hours) then medical help needs to be sought. PDE5 inhibitors should be used cautiously in people who are predisposed to priapism, including those with sickle cell anaemia, myeloma or leukaemia (NICE, 2023).

What are the contraindications and cautions when using PDE5 inhibitors?

Section 12

PDE5 inhibitors are contraindicated if the individual is taking any form of nitrates (glyceryl trinitrate [GTN] spray, isosorbide mononitrate, isosorbide dinitrate) and also nicorandil, as these are NO donors and combination of these therapies can induce profound vasodilation (and thus hypotension).

Care should be taken if an alpha-blocker such as doxazosin is being taken, as the PDE5 inhibitor may aggravate the problem of postural hypotension (start with lower doses of PDE5 inhibitor; for example, sildenafil 25 mg once daily).

Dose reduction is advisable in those with significant renal or hepatic impairment (avoid in severe hepatic impairment) and should also be considered initially in those over 65 years of age.

Further contraindications include a recent myocardial infarction or cerebrovascular accident, severe/unstable heart disease, angina precipitated by sexual intercourse and hypotension (blood pressure <90/60 mmHg). PDE5 inhibitors should be avoided in severe hepatic impairment.

A further reason to avoid PDE5 inhibitors would be in those who have lost vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION) – a condition linked to PDE5 inhibitors; if sudden visual disturbance occurs following use, treatment should be suspended and medical review sought. Where there is an anatomical abnormality of the penis (e.g. Peyronie’s disease) it may not be feasible to use a PDE5 inhibitor.

 
After one month, Geoffrey is tolerating sildenafil well. He reports improvement in quality of erections but consistency remains elusive.

What strategies might you now use to improve matters for Geoffrey?

Section 13

Firstly, ensure that Geoffrey is taking the sildenafil an hour ahead of use and bear in mind that absorption can be delayed by a large meal. Is Geoffrey managing to reduce his alcohol consumption? It can take repeated attempts before ascertaining that response to PDE5 inhibitor treatment is inadequate.

The next step would be to consider a higher dose of sildenafil. To decide whether a PDE5 inhibitor is effective or not, it is recommended that eight attempts at maximum dose with appropriate sexual stimulation should be tried. If response remains unsatisfactory, consider switching to an alternative PDE5 inhibitor (Hackett et al, 2018).

 
An important reason for lack of response to a PDE5 inhibitor is a low testosterone level (Corona et al, 2014). Accordingly, a morning testosterone blood test is arranged for Geoffrey.

How do we interpret a testosterone level and act on this?

Section 14

A testosterone level <8 nmol/L indicates deficiency, and a reasonable chance of responding to testosterone replacement therapy, whilst 8–12 nmol/L indicates borderline deficiency, which may benefit from a trial of treatment (Hackett et al, 2016). A low total testosterone can be more accurately explored by measuring sex hormone-binding globulin (SHBG) and albumin levels and calculating free testosterone. Around 60% of testosterone is strongly bound to SHBG (not bioavailable); the remaining 40% is either loosely bound to albumin or unbound testosterone, and this comprises the bioavailable free testosterone.

If testosterone level is low, the test should be repeated along with luteinising hormone (for hypopituitarism) and prolactin (for hyperprolactinaemia) levels (Dean et al, 2015).

Remember that those men taking testosterone replacement should have regular checks of FBC (for polycythaemia), PSA and LFTs.

 
A morning testosterone level comes back at 13.4 nmol/L (i.e. within normal range). With this reassurance, Geoffrey is prescribed sildenafil 100 mg as needed. This succeeds in improving his ED, although he does find that the need to plan ahead and loss of spontaneity are detrimental to his relationship with his partner.

Are you able to offer Geoffrey a solution to this problem?

Section 15

There are small differences in side effects and relative contraindications between the available PDE5 inhibitors, but probably the most clinically significant feature is the long half-life of tadalafil (approximately 17 hours), which enables it to provide 24 hour permanent support for ED.

Tadalafil is licensed to be taken daily at a low dose (2.5–5.0 mg once daily) to facilitate erections in those anticipating sexual activity at least twice a week. This option would suit Geoffrey and his partner well in their desire for spontaneous sexual activity and, of course, their wish to achieve a pregnancy.

Geoffrey is prescribed tadalafil 5 mg od. 3 years later Geoffrey and his partner have 2 young children.

Section 16 – John

John is 70 years old, with type 2 diabetes and ischaemic heart disease. He is using tadalafil for ED on a daily basis. His medication list includes metformin, linagliptin, aspirin, atenolol, amlodipine, ramipril, doxazosin and atorvastatin.

One evening, John is feeling “out-of-sorts” and decides to use his GTN spray, having not used this for over a year. He suffers a brief loss of consciousness, the paramedics are called and hypotension and tachycardia are noted, after which John makes an uneventful recovery.

How would you interpret John’s loss of consciousness and what actions would you take to prevent a recurrence?

Section 17

It seems likely that the GTN spray induced a profound vasodilation in the presence of tadalafil. The use of the alpha-blocker doxazosin as an antihypertensive is in particular likely to have aggravated postural hypotension. The use of nitrates alongside a PDE5 inhibitor is contraindicated, and reduced doses of PDE5 inhibitor/doxazosin should have been considered.

It is worth investigating whether John really needs the GTN spray. It may be possible to discontinue this agent, and this would allow John to continue using tadalafil. What is John’s resting blood pressure – could the doxazosin dose be reduced, discontinued or substituted by another antihypertensive?

However, if availability of the GTN spray is considered essential, an alternative approach to ED management other than using PDE5 inhibitors may be necessary.

Section 18 – Trevor

Trevor is 65 years old and has had type 2 diabetes for 4 years. Before his diagnosis of diabetes, Trevor was diagnosed with prostatic carcinoma (organ-confined) and underwent laparoscopic (nerve-sparing) prostatectomy. However, since this operation, he has suffered ED, which has proved unresponsive to sildenafil, vardenafil and tadalafil at maximum doses despite adequate levels of testosterone. He sees you, together with his wife, seeking further help for his ED, explaining that their sex life is still important to them.

Trevor is taking metformin for his diabetes, irbesartan for hypertension and atorvastatin for dyslipidaemia. He also uses intermittent self-catheterisation to overcome the effects of a urethral stricture.

How can Trevor be helped in these circumstances?

Section 19

Having verified that Trevor has been unresponsive to a variety of PDE5 inhibitors, used correctly at appropriate dose, the next option would be to consider prostaglandin therapy. Alprostadil (prostaglandin E1) can be applied locally to try and improve erectile function.

Alprostadil (Caverject, Viridal) administered by intracavernosal injection has good efficacy (around 75%) and does not require an intact nerve supply to the penis (Porst, 1996). Erection is achieved around 10 minutes following injection and persists for 30–40 minutes (Hackett et al, 2018).

It is essential that proper training, counselling and support accompany initiation of this treatment. Patients should be aware of the risk of priapism and the need to seek medical help for detumescence in the case of prolonged erections (>4 hours) in order to avoid chronic penile damage. Initial advice is to exercise (by walking up and down stairs) to deviate blood supply to the muscles, but if this does not succeed then aspiration of blood from the corpus cavernosa with a 19-gauge butterfly needle can be attempted and, beyond this, pharmacological treatments in the setting of a hospital emergency department (Hackett et al, 2018).

Intraurethral alprostadil (medicated urethral system for erection [MUSE]) would appear a less suitable option for Trevor, not only because it is less efficacious (30–60% success rate) but also because it would, in Trevor’s case, be relatively contraindicated because of his urethral stricture. Alprostadil cream (Vitaros) is now available for topical use via an applicator.

 
Trevor was referred to the Specialist Urology Nurse, with a view to commencing alprostadil injections. Following dose titration and continued education, Trevor was able to achieve good reproducibility of erectile function, and both he and his wife were very satisfied with the outcome.

What other treatments for ED are you aware of?

Section 20

Treatment options beyond PDE5 inhibitors and alprostadil include intracavernosal injection of phentolamine/aviptadil (Invicorp), vacuum erection devices, low-intensity extracorporeal shockwave therapy and, ultimately, penile prosthesis (Hackett et al, 2018, Salonia et al, 2021).