Conservative treatment of erectile dysfunction

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Currently, there are quite a large number of methods of medical treatment of erectile dysfunction (ED). The choice of the method is determined by its invasiveness. In case of insufficient effectiveness of a less invasive technique, they switch to a more invasive one. Thus, most clinicians begin treatment with the appointment of oral phosphodiesterase type 5 inhibitors (PDE-5), with insufficient effectiveness of which other oral drugs, intracavernous injections or vacuum devices are prescribed. It is also possible to conduct a combined treatment. If such methods are ineffective, it is possible to conduct surgical interventions, but the need for them is becoming less frequent.

Aphrodisiacs in the treatment of erectile dysfunction

For many centuries, various stimulants, mainly of plant origin, have been used to prolong sexual longevity, many of which belong to the category of hallucinogens, psychostimulants and narcotic drugs. Such drugs are currently combined under the name aphrodisiacs. These drugs owe their name to Aphrodite, the Greek goddess of love. Despite the fact that the effectiveness of various aphrodisiacs has not been proven and their use has no scientific justification, the market for such funds is quite large at the present time. Due to the lack of reliable information about the mechanisms of action and effectiveness of these substances does not exist, we do not consider it necessary to dwell on individual representatives of this extensive class of “drugs”.

The existing methods and methods of correction for the treatment of erectile dysfunction can be combined into four main groups: psychosexual, drug, vacuum-erector therapy, as well as surgical treatment. In recent years, the interest of researchers has also begun to attract the possibility of lifestyle correction in the treatment of erectile dysfunction.

Lifestyle correction as a treatment for erectile dysfunction

The primary task of every doctor is to improve the patient’s condition. Therefore, the primary goal in the management of patients with ED is to determine the cause of the disease and its treatment. It is known that ED can be combined with reversible factors, such as, for example, lifestyle or taking medications, which can be corrected by the use of special therapeutic techniques. For all patients, the positive effect of eliminating risk factors before or simultaneously with the start of direct treatment is recognized, even if this is not enough to completely cure ED.

However, as mentioned earlier, in some patients, the correction of unfavorable lifestyle factors, such as insufficient physical activity, smoking and obesity, allows for the restoration of erectile function, which is associated with an improvement in the impaired functional ability of the endothelium. This direction in the treatment of erectile dysfunction is currently attracting special interest of researchers.

Psychosexual therapy in the treatment of erectile dysfunction

In patients with significant psychological problems, psychosexual therapy can be used, both in the form of monotherapy and in combination with other treatment. For the first time, the method of psychosexual therapy was proposed by Masters and Johnson in the 60s . In general, psychosocial factors play a role in all forms of ED, even in cases of purely organic ED, there is almost always a secondary reactive psychological component. Psychosexual therapy in the form of direct communication with the patient alone or, if possible, with both the patient and his partner, can give positive results in the treatment of both organic and purely psychogenic ED.

Hormone therapy in the treatment of ED

The history of hormone therapy for ED began with the famous French neurologist Charles Edward Brown-Secard (1817-1894), already mentioned above. In 1889, at the age of 72, Brown-Secar gave himself an injection of extract from the testicles of dogs and guinea pigs, after which he noted an improvement in physical and mental performance, easier urination and getting rid of constipation. In the future, such famous scientists as Steinach, Lespinasse and many others were “noticed” in the creation and application of various “elixirs of youth” and anti-aging operations.

The substance responsible for numerous “anti-aging” effects was first identified in the Netherlands in 1935 and was called testosterone.

Currently, the attitude of doctors to hormone replacement therapy (HRT) in men continues to be contradictory. Popular terms such as” andropause “and” male menopause ” actually differ significantly from similar conditions in women and in many cases are clinically ambiguous.

Although there is no doubt that the concentration of androgens in the blood of men decreases with age, there is currently no accurate data on the number of men who really suffer from androgen deficiency, which is due to both the lack of clear biochemical criteria and the complexity of clinical differentiation of hypogonadism manifestations from the actual manifestations of aging. Among such signs, many authors also consider erectile disorders.

The effects of testosterone and its derivatives (primarily dihydrotestosterone and estradiol) in adults are very diverse and include an effect on reproductive functions, secondary sexual characteristics, a positive effect on mood and libido, an anabolic effect on bone and muscle tissue. In addition, testosterone and its derivatives have an effect on the cardiovascular and hematopoietic systems, the distribution of adipose tissue and many other systems and organs. The effect of androgens on erectile function remains unclear. Today, it is obvious that it is very multifaceted and individual. Since ancient times, it has been known that some eunuchs remained able to achieve an erection for many years after castration. Studies have not revealed a direct relationship between the level of blood testosterone and erectile function in various men, at the same time, individual fluctuations in the level of androgens can affect the quality of an erection.

Currently, the administration of testosterone preparations for erectile dysfunction is considered indicated only in patients with clinical and laboratory signs of hypogonadism.

Among the currently existing testosterone preparations, oral preparations, preparations for intramuscular and subcutaneous administration, as well as transdermal forms are distinguished.

The complexity of the oral route of administration of androgenic drugs lies in the fact that when passing through the liver, many of their forms undergo metabolism and inactivation. The half-life of testosterone itself does not exceed 10 minutes, and therefore the secretion of testosterone by Leydig cells occurs constantly, with a peak in the morning hours. Existing androgenic oral drugs are either structurally protected from decomposition in the liver (mesterolone) or are absorbed into the lymph as part of chylomicrons (testosterone undecanoate). A common disadvantage for all oral drugs is pronounced fluctuations in their blood levels, as well as significant differences in bioavailability in different patients, and therefore their use is currently limited.

The most widely used androgen drugs in the treatment of erectile dysfunction are testosterone enanthate and testosterone cypionate, which are used in the form of intramuscular injections . These drugs have proven their clinical effectiveness for several decades. In most cases, they reach their maximum concentration in the blood plasma within 72 hours after administration . During the next 10-21 days, the testosterone level progressively decreases . The most commonly used oil solutions of testosterone enanthate and cypionate, which are administered in doses of 200 to 400 mg every 3-4 weeks . An important disadvantage of such drugs is the presence of significant fluctuations in the level of testosterone in the blood when they are used. At the same time, in the first days after administration, the testosterone level often significantly exceeds, and in the last days it is inferior to physiological values.

A relatively new drug is testosterone undecanoate for intramuscular administration. When using it, a stable level of testosterone within physiological values is achieved within three days after administration and persists for about 12 weeks. In this regard, the interval between intramuscular injections of testosterone undecanoate (10-14 weeks or 4 times a year) is almost 5 times higher than that for testosterone enanthate or cypionate. The interval between the first and second injections should be 6 weeks, between the subsequent ones-12 weeks.

Among the testosterone preparations for cutaneous use, patches and gels are distinguished. The first patches containing testosterone were proposed in the early 90s of the twentieth century and were intended for application to the skin of the scrotum. In addition to the inconveniences associated with fixation, the use of such patches is accompanied by increased levels of dihydrotestosterone in the blood, which is explained by the restoration of the injected testosterone 5a-reductase contained in the skin of the scrotum. Patches for use outside the scrotum are deprived of this disadvantage, but they often (32% of cases) cause skin irritation, and 12% of patients develop allergic dermatitis . Testosterone-containing gels are less likely to cause skin irritation and allow you to achieve adequate levels of the hormone in the blood . A form for application to the cheek mucosa is also proposed.

Currently, the development of testosterone preparations implanted subcutaneously in the form of granules and microcapsules is continuing . Characterized by a significant duration of action (up to 6 months) these drugs also have significant disadvantages, the main of which is the need for surgical interventions during installation and removal.

The main concerns when prescribing testosterone drugs are associated with the possibility of stimulating the growth of foci of prostate cancer. This point of view is based on the fact that prostate cancer is a hormone-dependent tumor, the main method of treatment for which, if radical removal is impossible, is surgical or drug castration. However, these concerns were not confirmed in the studies conducted, which did not reveal an increase in the level of prostate-specific antigen (PSA) above the standard values and an increase in the frequency of prostate cancer in men receiving testosterone replacement therapy . However, a finger rectal examination of the prostate and a study of the blood PSA level are mandatory for all men over the age of 45 before starting treatment with testosterone drugs, as well as every 3 months during the first year of treatment and annually thereafter . In addition, the presence of prostate cancer, as well as infravesical obstruction associated with benign prostatic hyperplasia, are absolute contraindications to testosterone replacement therapy.

All men before the start of treatment, as well as every 3 months during the first year of therapy and annually thereafter, it is necessary to conduct studies of the level of hematocrit . This is due to the fact that testosterone stimulates erythropoiesis and in some patients a significant increase in the number of red blood cells can be accompanied by a dangerous increase in blood viscosity.

When specific therapy is required in the treatment of erectile dysfunction, a comprehensive approach is necessary. The patient and his partner, if possible, should be informed about the invasiveness, cost and reversibility of treatment.

The ideal remedy for the treatment of erectile dysfunction should meet the following characteristics: high and fast effectiveness, non-invasiveness, absence of toxic and side effects, timely and, if possible, prolonged action.

To date, there are three main directions in the pharmacotherapy of ED: treatment with intracavernous injections, oral drugs and drugs of different groups.

PDE5 inhibitors

Before proceeding to the presentation of data on representatives of the most important class of medications for the treatment of ED, PDE-5 inhibitors, we consider it necessary to describe in more detail the biochemical aspects of erectile function and its disorders. The currently known cardiovascular effects of PDE5 inhibitors will be considered separately.

Biochemical aspects of erection and mechanisms of action of PDE5 inhibitors in the treatment of erectile dysfunction.

The role of cyclic guanosine monophosphate (cGMP) in the regulation of the functional activity of smooth muscle cells of various organs has been studied in sufficient detail. The single mechanism of action of cGMP for all organs is the activation of cGMP-dependent protein kinases. In the tissue of the cavernous bodies, NO, released from the nerve endings or endothelial cells of blood vessels, initiates this biochemical cascade: NO diffuses into the smooth muscle cells of the vessels and combines with the enzyme guanylate cyclase (HC), as a result of which the activity of this enzyme significantly increases . This leads to an increase in the production of cGMP, which, in turn, activates a protein kinase that phosphorylates several different proteins, which leads to a decrease in the intracellular concentration of Ca2+ ions as a result of the release of ions from the cell and their accumulation in the sarcoplasmic reticulum. The result of the described process is the relaxation of the smooth muscle cells of the vessels of the penis, leading to an increase in arterial inflow, followed by activation of the venocclusive mechanism.

treatment of erectile dysfunction

The concentration of cGMP in all cells is determined by the ratio between the level of its production HZ and the rate of its decay, which occurs as a result of the action of enzymes of the phosphodiesterase group. A violation of the balance between these two processes leads to a decrease in the intracellular concentration of cGMP, which is most often found in the tissue of cavernous bodies with a violation of the release of NO by endothelial cells (endothelial dysfunction). In this regard, the effect on the activity of PDE5 type, which is the dominant form of this enzyme in the cavernous tissue, can be considered a logically justified method of correcting such disorders , which, as already discussed above, manifest themselves in the form of ED.

It should be noted that under conditions of PDE inhibition, even a slight increase in the activity of HC can lead to a sharp increase in the intracellular concentration of cGMP and, accordingly, a decrease in the tone of smooth muscle cells. This circumstance is the reason that the use of nitrates is a strict contraindication for the appointment of PDE-5 type inhibitors due to the possibility of developing severe hypotension.

Three drugs from this group currently available on the market, sildenafil, tadalafil and vardenafil, are competitive and reversible inhibitors of cGMP hydrolysis by the catalytic center of the PDE type 5 molecule. Sildenafil and vardenafil have a purine ring in their molecular structure, similar to cGMP. The presence of additional elements in the molecules of these drugs ensures their higher affinity for PDE-5 compared to cGMP and high selectivity to this particular form of the enzyme.

PDE-5 is a complex protein having two main functional regions of approximately the same size. There are a catalytic region (K-region) and a regulatory region (P-region). The catalytic area is the site of exposure to sildenafil, vardenafil and tadalafil. The P-region of PDE-5 regulates the degree of activation of the enzyme.

The K-region contains one catalytic center, to which cGMP binds, as a result of which it is hydrolyzed to inactive 5 – GMF, which is quickly separated from the PDE-5 molecule. Since sildenafil, vardenafil and tadalafil are structurally similar to cGMP, they block the catalytic center and prevent cGMP from binding to it. The molecules of these drugs form additional bonds with the PDE-5 molecule, which provides them with several thousand times higher affinity for the PDE-5 catalytic region compared to cGMP. Another important advantage of these drugs is that they are not subjected to hydrolytic action. As a result, the breakdown of cGMP is disrupted and its accumulation in smooth muscle cells is noted.

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