Failure of BPH treatment - Dr. Francisco Fonseca

5α-reductase inhibitors and their side effects

21/08/2020

Prof. Centenary Dr. Fernando Gentil

16/01/2021

Patients progress from benign prostatic hyperplasia (HPB), even taking medication and failing treatment.

Maintaining clinical treatment for BPH may be desirable, but it is difficult in the long run. When indicated to improve symptoms that may have worsened at any given time, patients use the drugs regularly. However, we know that BPH is a chronic disease, and sometimes symptoms have been present for more than 5 years, and their clinical evolution shows periods of clinical improvement and worsening.

failure of BPH treatment

Symptoms of HPB storage and emptying

The symptoms that most negatively impact the quality of life of patients are the storage symptoms, such as urinary frequency, urgency, incontinence, waking up to urinate and incontinence on exertion. In the acute phase, if storage symptoms are predominant, patients seek medical help. The people who present the obstructive symptoms they realize that they are not well, but as they do not bother them seriously, they delay their consultations to find out why this is happening. Therefore, they know that it takes time to empty their bladder and that their urinary stream is weak, but they are resigned and think it is caused by age. However, your bladder is slowly deteriorating.

First-line treatments

Generally the clinical benefits with the introduction of α-blockers can be seen quickly, in days or even a week from the start. On the other hand, therapy with i5a-reductase inhibitors may begin to improve urination symptoms 1 to 2 months after it starts. Its effect with 90% of the maximum response, assessed by the drop in (international score for lower urinary tract symptoms) IPSS and improvement in urinary flow, can occur between 6 to 8 months from its onset. In both treatment strategies, they do not work in around 30% of cases. Understanding why this is the goal of this chapter.

However, after the acute phase, resistance to treatment begins, whether the therapy is mono or combination therapy. It is estimated that in one year, 70% of patients abandon treatment. When the combined treatment is offered in a single dose, by combining the drugs in a single remedy, it is generally better accepted. However, some patients may be taking these drugs monotherapy or combined for years. (Gui, 2019)

α-blockers do not shrink the prostate

Os α-blockers they are unable to reduce the volume of the prostate like 5a-reductase inhibitors, which better protect the lower urinary tract from possible growth of BPH, with a fall in IPSS and the voiding stream. Thus, patients using only a-blockers are more prone to clinical progression of the disease due to prostate growth, progressive residual enlargement, possibility of lower urinary tract infection, worsening of the detrusor, reduced bladder compliance (bladder elasticity and capacity bladder). Therefore, they can present in their evolution urinary retention, hematuria, gall bladder, development of trabeculation and bladder diverticulum and mandatory surgery.

Os α-blockers nonselective and selective have relief of symptoms and improvement of the voiding stream and none has been shown to be more effective than the other, but side effects are more pronounced in non-selective and first generation. Selective α-blockers have less cardiovascular and related side effects, but worsen ejaculatory effects.

Type 5 phosphodiesterase inhibitors

Os phosphodiesterase type 5 inhibitors (PDE-5) showed improvement in IPSS scores, but without affecting Q_Max or the volumes of post-voiding residual urine. However, they are a good indication for patients with early erectile dysfunction. However, as a-blockers do not suppress the evolution of BPH progression.

Os anticholinergics in the treatment of BPH and LUTS it is usually indicated when patients still have urgent symptoms despite the use of blockers. Detrusor hyperactivity and the active bladder associated with the bladder are seen in 45–50% of men with BPH when assessed with the urodynamic study.

Combined treatment

O combined treatment it is widely used for patients with LUTS and BPH, when the prostates are larger than 40 grams and with PSA ≥ 1,5 ng / mL, it can reduce the progression of the disease, avoiding urinary retention and reducing the indication for surgery. However, this treatment can have more side effects by adding them individually by the combined drugs. THE disease progression can be reduced by around 60% of cases (MTOPS and CombAT studies). However, prostates over 100 grams do not usually have the desired response and these cases are best treated by surgery.

In addition, the adenomatous structure is variable among patients, with some having greater glandular content than stromal and vice versa. This can be assessed by digital rectal examination, and the softer prostates are more fibroelastic and have greater glandular content. On the contrary, the firmer ones have greater stromal content. Possibly, the softer ones are more responsive to 5 reductase inhibitors.

Reasons for failure to treat BPH

A failure in medical therapy happens for one of three reasons:

Patient is not adherent to treatment,
Ineffectiveness of the desired action to treatment
Side effects or
Disease progression.

Several studies show that treatment maintenance is around 30% in 1 year. The reason for abandonment may be caused by the desired clinical improvement in urination, price of drugs, ineffective treatment and its side effects. In addition, many older patients can use various remedies to treat different concomitant illnesses that affect them at this stage of life.

Α-blockers and 5α-reductase inhibitors can express a density of receptors within the lower adenoma, reaching up to 30%. Thus, the therapeutic response does not happen.

Cellular ratios at the molecular level

Epigenetic changes, polymorphisms in two 5α-reductase genes and methylation of the 5α-reductase promoter may explain why some men do not express 5α-reductase. However, age and (Body mass index) High BMI are associated with methylation, which explains why obesity and age are associated with a higher probability of failure in 5ARI therapy.

Chronic inflammation may be the main cause

Another factor that is no less important for the occurrence of therapeutic failure is due to the chronic prostate inflammation (prostatitis) that can release a series of cytokines that will feed the autocrine and paracrine effect of HPB, proliferation of epithelial and stromal cells. Thus, it can increase the production of growth factor and angiogenesis. These patients usually have larger prostates and are more prone to urinary retention. Some studies show clinical improvement in the use of cyclooxygenase isoform 2 (COX-2) inhibitors, which can be an interesting potential therapeutic target for BPH, but are little used in daily life.

Follow-up of patients undergoing treatment

The inefficiency of the therapeutic proposal must be evaluated in the first, third month and one year by clinical evaluation, with imaging tests and, if possible, with flowmetry and in special cases with urodynamic study. Thus, only with clear judgment can treatment be considered to be effective. Otherwise, patients with BPH should undergo surgical clearance of the BPH. In patients with important side effects, treatment should be interrupted because it causes disastrous consequences such as falls and fractures in elderly and more fragile patients.

The importance of ultrasound

However, it is worth mentioning that some situations are mandatory unambiguous indications of unobstructive surgery, such as detrusor with thickness greater than 1 cm, prostate protrusion index in the bladder (PPI) greater than 10 mm, recurrent hematuria, recurrent urinary retention, bladder calculus, hydronephrosis secondary to HPB with or without kidney failure, recurrent urinary tract infection and presence of bladder diverticulum.

Patients with prostate protrusion index in the elevated bladder (IPP), caused by the enlargement of the middle lobe, they should not be submitted to clinical treatment, because the detrusor is already suffering continuously and can deteriorate it, sometimes in a definitive way. In the same way, it can be said that the patient with thickening of the detrusor may be the cause of failure of BPH treatment. These patients have passed the time to start clinical treatment.

However, if you would like to know more about this and other diseases of the genitourinary tract, access our content area for patients to understand and gain knowledge. There are more than 140 articles on various urological subjects available for your reading. Culture always makes a difference. You will be surprised!

Reference

Yellow ZG, Kaplan SA. BPH: Why Do Patients Fail Medical Therapy? Curr Urol Rep. 2019 Jun 6; 20 (7): 40.