RU2525182C1 - Method of treating patients suffering from chronic prostatitis with partial androgen deficiency - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: androgens are introduced into the body under laboratory control of testosterone. An androgen source is dermal administration of the preparation androgel 5 g in the interval of 48-72 hours in a pulse mode for 2-3 months. After laboratory control additionally involving the serum analysis for intestinal cell-stimulating and follicle-stimulating hormones, sex hormone binding globulin, prostatic specific antigen, sperm fertility, the dermal administration of androgens is continued for another 2-4 months. If the above values fall beyond the norms, the prescribed androgens are withdrawn for 2-4 months.

EFFECT: invention provides preventing side effects of substitution androgen therapy.

1 ex

Description

The invention relates to medicine, specifically andrology, and is intended for the treatment of patients with chronic prostatitis associated with partial androgen deficiency (normal low testosterone (T) of blood serum, T indicators in the "gray zone" - 9-12 nmol / l), which is observed when chronic prostatitis associated with some forms of sexual dysfunction (erectile dysfunction, decreased libido), metabolic syndrome (obesity, type II diabetes mellitus, vascular atherosclerosis, gout, asthenic neurosis, depression her) and other similar conditions.

A known method of treating patients with chronic prostatitis associated with androgen deficiency, using the drug Androgel, described in the Instructions for medical use.

Indications for use. Replacement therapy for endogenous testosterone deficiency. Dosage and administration. The recommended dose is 5 g of gel (i.e. 50 mg of testosterone) applied once a day at about the same time, preferably in the morning. An individual daily dose can be adjusted by a doctor depending on the clinical and laboratory parameters in patients, but should not exceed 10 g of gel per day. Correction of the dosage regimen should be carried out in steps of 2.5 g of gel per day. If the concentration is low, the dose can be increased, but not more than 10 g of gel per day. In patients taking androgens for a long period, in addition to laboratory measurements of testosterone concentration, it is necessary to periodically check the following laboratory parameters: prostatic specific antigen (PSA), calcium, hemoglobin, hematocrit (to detect polycythemia) and functional liver tests.

Pharmacokinetics of the drug androgel. The degree of absorption of testosterone through the skin varies from about 9% to 14% of the applied dose (50 mg in 5 g of gel = 4.5-7 mg T). After absorption through the skin, testosterone enters the systemic circulation in relatively constant concentrations for 24 hours. The concentration of testosterone in serum increases from the first hour after the use of the drug Androgel, reaching a constant value from the second day (1 day from the start) of treatment. With the external route of administration of the drug, there are no supraphysiological peaks in the concentration of testosterone in the blood that occur during the injection method of administration. The use of 5 g of Androgel causes an average increase in plasma testosterone concentration by approximately 2.5 ng / ml (8.7 nmol / L). After discontinuation of treatment, the concentration of testosterone begins to decrease approximately 24 hours after the last dose. The concentration returns to its original level after about 72-96 hours (3-4 days) after taking the last dose.

(Solvay Pharma. Instructions for the medical use of the drug ANDROGEL (Androgel) Registration number in Russia: LS-000869).

This method is an analogue of the proposed proposal. The disadvantages of this method are as follows.

1. The condition for the application of the method is a clear laboratory androgen deficiency (below 10 nmol / l). The possibility of treating relative androgen deficiency (10-14 nmol / L) with this method does not say anything in the Instruction.

2. The method provides only daily use of the drug. Dosage adjustment is suggested with daily use of ½ (2.5 mg) or a double (10 mg) dose of the drug. The instructions do not say anything about the possibility of using the drug in a different, not daily rhythm. This is not accidental, since the known method is intended for the treatment of overt, and not relative, androgen deficiency, in which the goal is replacement and not stimulation-training androgen therapy. With replacement therapy, it is necessary to maintain a constant concentration of T, which is achieved by daily use of the drug. During stimulation-training therapy, the pulsed use of the drug is necessary, with the rhythmic alternation of increasing and decreasing the level of T in serum (“swinging” of the hormonal regulation system). In addition, daily use of the drug with relative androgen deficiency is fraught with the complications described below (and therefore not recommended), and with rhythmic administration every other day (or at intervals of 72-96 hours), these complications do not develop.

3. With the known method (in the Instructions), laboratory monitoring of testosterone, PSA, calcium, hemoglobin, hematocrit, liver samples is recommended, but nothing is said about laboratory monitoring of luteinizing (LH) and follicle-stimulating (FSH) hormones, as well as globulin binding sex hormones (SHBG). This is also not accidental, because with obvious androgen deficiency, changes in these indicators do not prevent the continuation of androgen replacement therapy. And with the relative (partial) androgen deficiency of an aging man - PADAM-syndrome (Partial Androgen Deficience of Ageing Man) - a decrease in these laboratory parameters below normal is a reason for canceling this therapy. Nothing is said about the control of spermographic parameters, which may decrease below normal with excess testosterone and inhibition of follicle-stimulating hormone.

A known method of treating patients with chronic prostatitis (associated with partial androgen deficiency), comprising 4-5 courses of physiotherapy with an interval of 3-6 months, characterized in that before each course of physiotherapy determine the concentration of testosterone in the blood, and with its rates of 12-18 nmol / l Intramuscular administration of the drug of prolonged testosterone-Nebido 1000 mg once every 3 months is prescribed, and when the indicator exceeds 18 nmol / l, the nebido injection is skipped. Treatment is resumed (with clinical and laboratory need) 3-6 months after skipping the next injection.

(Patent for invention 2364402 of the Russian Federation dated 04.24.2008. A method for the treatment of patients with chronic prostatitis / Ysilevsky Yu.M. et al.).

This method is closest to the claimed technical solution for the techniques and the achieved result and therefore is selected as a prototype.

The disadvantage of this method is its poor handling. Being injected intramuscularly into the body, testosterone acts theoretically uniformly for 3 months, and in the event of complications, side effects and undesirable effects, the doctor cannot change the effect of the testosterone administered on the target organs. The interval between injections, therefore, is at least 3-6 months, which is not optimal for the processes of pituitary regulation of the stimulatory-training action of injected testosterone. Laboratory control of the levels of LH, FSH, SHBG and spermogram indices in this method is also not provided, since in the conditions of its use it may be belated in nature, which will require separate additional treatment measures.

That is, it is necessary to control the end time of the period of partial androgen deficiency in order to timely stop this type of therapy.

Complications, adverse events and side effects of androgen therapy on the organs of the male reproductive system in the absence of androgen deficiency are as follows.

1. Adverse effects of excess testosterone on the prostate gland. An enlargement of the prostate gland (especially in an aging man, with initial changes in benign hyperplasia). The dysuric phenomena associated with this (increased urination, deterioration on the I-PSS scale, according to uroflowmetry). A reversible increase in PSA from 2 to 4 ng / l, i.e. to the formal limit of the upper limit of the norm, which does not yet require a prostate biopsy for further diagnosis. Progression of subclinical undiagnosed prostate cancer.

2. Adverse effects of excess testosterone on sperm fertility. Deterioration of all spermographic indicators (quantitative and qualitative). Reducing the size of the testicles.

3. Complications, adverse events and side effects of androgens in the absence of androgen deficiency on other organs of the body are described in the Instructions for their use. Testosterone preparations should be prescribed with caution to patients with coronary heart disease and arterial hypertension, epilepsy and migraine, heart, liver and kidney failure, and the risk of developing sleep apnea. These factors are well known and are not considered in the framework of the proposed method.

The objective of the proposed method is the prevention of side effects and adverse effects of androgen replacement therapy due to the pulsed stimulation-training effect on the hormonal regulation of the function of the testicles by the pituitary gland.

This problem is solved by the fact that in the method of treating patients with chronic prostatitis with partial androgen deficiency, including the introduction of androgens into the body under laboratory control of the testosterone content, a distinctive feature is that the skin administration of 5 g androgel is used as a source of androgens in the range of 72-96 hours , i.e. in a pulsed mode, for 2-3 months, and after laboratory monitoring, which additionally includes determination of serum luteinizing and follicle-stimulating hormones, sex hormone-binding globulin, and prostatic specific antigen, as well as sperm fertility indicators, cutaneous administration of androgens continues for another 2 -4 months, if these indicators do not go beyond normal, or, otherwise, cancel the appointment of androgens for a period of 2-4 months.

The difference between the proposed method from the known.

1. Due to the fact that the mechanism of action of androgens is not associated with the replacement of deficiency (as in the analogue), but with the stimulation of the pituitary gland function and the training of regulation of this function, this leads to a different pulsed regimen of androgen administration in the interval 72-96 hours during which testosterone is intentionally reduced to the initial level. This factor “spurs” the mechanism of hormonal regulation of testicular function by the pituitary gland.

With absolute androgen deficiency and androgen therapy with a replacement goal, it is necessary to maintain a constant concentration of testosterone in the body throughout the course of treatment. Pulse administration of androgens will not be effective in this case due to the depletion of the intrinsic mechanism of hormonal regulation of the pituitary-gonadal axis.

2. The proposed control over additional laboratory parameters - LH, FSH, serum SHBG - and spermogram indicators is directly related to the claimed mechanism of action and is aimed at preventing possible side effects and undesirable effects of androgen therapy as such.

3. A new distinctive feature follows from this, according to which “the administration of androgens is continued for another 2-4 months, if these indicators do not go beyond normal, or, otherwise, they cancel the appointment of androgens for a period of 2-4 months. The criteria “2-4 months” were obtained practically: “1 month” - too often, which is unprofitable and burdensome for the patient; “5-6 months” is rare enough not to miss possible side effects and undesirable effects.

The rationale for the proposed method is as follows.

At intervals of administration of the drug for 72-96 hours, a natural (after 24 hours) decrease in testosterone to the initial level is observed. At the same time, the production of pituitary hormones (LH and FSH) is naturally stimulated in order to maintain testosterone levels at the level of the day the drug is used. This is the essence of stimulation-training, pulsed use of the drug, “swinging” the system of pituitary regulation of the level of sex hormones. If during laboratory control there is a decrease in LH, FSH, SHBG and spermogram indicators below normal, this means that the pituitary regulation system is depleted and this type of therapy must be canceled. Practice shows that the restoration of testicular and pituitary gland function occurs within 2-4 months after discontinuation of treatment (coincides with the period of sperm maturation - 72 days). This is the period after which this type of therapy can be resumed if there are still indications for it.

The method is as follows.

They diagnose chronic prostatitis and partial androgen deficiency (T = 9-12 nmol / L) in a patient with symptoms such as metabolic syndrome (atherosclerosis, obesity, diabetes, gout, arterial hypertension, decreased libido, erectile dysfunction, depression). In a laboratory study, LH, FSH, SHBG, serum PSA and ejaculate spermography are additionally determined. All the above indicators do not go beyond the norm. Uroflowmetric indicators are within normal limits. In transrectal ultrasound (TRUS), the volume of the prostate is up to 40 ml (prostate adenoma of the 1st stage).

Along with etiopathogenetic treatment, Androgel 5 g is prescribed for skin administration once every 2-3 days (after 48-72 hours) for a period of 2-3 months (20-60 sachets). Re-determine all of the above indicators. If the indicators remain within normal limits, this therapy is continued for another 2-3 months and once again the above indicators are determined. If the indicators are reduced below normal, then this therapy is stopped for a period of 2 to 4 months (depending on the rate of increase of clinical manifestations) and then, after the next study of laboratory parameters, which are restored to normal, the next regular course of identical androgen therapy is prescribed according to the same plan .

An example of a specific implementation of the method.

Patient E., 60 l. Diagnosis: Chronic prostatitis.

Metabolic syndrome (endothelial dysfunction, systemic vascular atherosclerosis, obesity, gout, type II diabetes mellitus, arterial hypertension, sexual dysfunction). PADAM syndrome (partial androgen deficiency of an aging man). Benign prostatic hyperplasia of the 1st Art. (V = 30 ml).

Laboratory biochemical blood parameters: glucose - 7.3 mmol / L (N up to 5.8), uric acid - 532 mmol / L (N up to 450), cholesterol 6.1 mmol / L (N up to 5.2).

Laboratory hormonal blood counts.

2008.02.29. T = 9.2 nmol / L (N = 8.4-28.7); LH = 6.7 mIU / ml (N 1.5-9.3); FSH = 9.6 mIU / ml (N 1.4-18.1); SHBG = 35 nmol / L (N 10-57); PSA = 1.2 ng / ml (N 0-4). Spermogram: normozoospermia, sperm concentration 32 million / ml, motility - 55%, morphologically normal forms - 30%.

The treatment was undertaken according to the prototype method (administration of the drug Nebido 4 ml intramuscularly 1 time for 3 months).

As a result, after 3 months: T = 17.9 nmol / L; LH = 0.14 mIU / ml; FSH = 2.5 mIU / ml; SHBG = 40 nmol / L; PSA = 4.0 ng / ml.

Spermogram: oligo II-astheno-terato-zoospermia, concentration of 7 million / ml, motility 27%. Morphologically normal forms - 27%. With TRANUSH prostate V prostate = 33 ml.

That is, despite the increase in blood testosterone and positive clinical and subjective dynamics, inhibition of the production of gonadotropic pituitary hormones (LH and FSH) was noted, which led to a deterioration of spermogram, an increase in PSA and prostate volume. This type of treatment due to the presence of adverse events, it was decided to stop.

After 6 months, laboratory hormonal indicators are as follows.

T = 9.3 nmol / L (return to background); LH = 8.47 mIU / ml (tension in the pituitary-gonadal axis); FSH = 10.4 mIU / ml; SHBG = 35 nmol / L; PSA = 1.4 ng / ml. Spermogram: normozoospermia - 54 million / ml, motility - 51%, morphologically normal forms - 30%. With TRUS, the prostate volume = 30 ml.

Taken treatment according to the claimed method. Along with etiopathogenetic treatment, Androgel 5 g was prescribed cutaneously once every 2 days (after 48 hours) for a period of 2 months (30 sachets). After 2 months of treatment, the laboratory indicators are as follows. T = 22.3 nmol / L; LH = 1.9 mIU / ml; FSH = 3.5 mIU / ml; SHBG = 37 nmol / L; PSA = 1.7 ng / ml. Spermogram: normozoospermia - 26 million. With prostate transplantation, prostate volume = 32 ml.

That is, positive clinical, subjective and laboratory dynamics without the undesirable effects of an overdose of androgens. It is advisable to continue this therapy for another 2 months.

After 4 months from the start of treatment, the following indicators.

T = 31.0 nmol / L; LH = 0.1 mIU / ml; FSH = 9.4 mIU / ml; SHBG = 39 nmol / l; PSA = 3.9 ng / ml. OligoIII-zoospermia (unit sperm). That is, undesirable phenomena have occurred: inhibition of the production of luteinizing hormone, responsible for the production of Leydig's own testosterone; inhibition of sperm fertility; an increase in PSA (within normal limits) and prostate volume. With TRUS, the prostate volume = 34 ml. This type of treatment due to the presence of adverse events, it was decided to suspend (in accordance with the claimed method) for a period of 4 months.

4 months after the suspension of the use of Androgel, the laboratory indicators are as follows.

T = 10.8 nmol / L; LH = 4.5 mIU / ml; FSH = 2.3 mIU / ml; SHBG = 33 nmol / L; PSA = 2.0ng / ml; spermogram - normozoospermia - 92 million / ml, motility - 46% (fast progressive - 42%), viability - 90%, morphologically normal forms - 58%. Prostate volume = 29 ml. Therapy according to the claimed method, it is advisable to roll over. Along with etiopathogenetic treatment, the Androgel preparation 5 g was administered percutaneously once every 3 days (after 72 hours) for a period of 3 months (30 sachets). After 3 months treatment indicators are as follows.

Indicators of metabolic syndrome decreased. The mood is high, the libido has increased, the erectile function of the penis is normal.

T = 15.6 nmol / L; LH = 2.8 mIU / L; FSH = 8.2 mIU / L; SHBG = 33 nmol / L; PSA = 2.3 ng / ml. Spermogram - normozoospermia - 158 million / ml, motility - 41% (fast progressive - 36%), viability - 84%, morphologically normal forms - 30%. Prostate volume = 31 ml. Uroflowmetry - N. There is no nocturnal pollakiuria.

That is, thanks to the application of the claimed method of treatment, it was possible to obtain a persistent positive effect without the appearance of undesirable effects, side effects and complications.

The advantage of the proposed method compared to the known one consists in prescribing testosterone treatment to patients with partial androgen deficiency, who need not the replacement, but the stimulating and training action of androgens.

The positive effect of the claimed method is the prevention of side effects and undesirable effects of androgen replacement therapy (as such).

Claims (1)

A method for the treatment of patients with chronic prostatitis with partial androgen deficiency, including the administration of androgens under the laboratory control of the testosterone content, characterized in that the source of androgens uses a cutaneous administration of the drug androgel 5 g in the range of 48-72 hours, in a pulse mode, for 2- 3 months, and, after laboratory confirmation of normal levels in serum of testosterone, luteinizing, follicle-stimulating hormones, sex hormone-binding globulin, and prostatic Skogen specific antigen, as well as indicators of sperm fertility, cutaneous administration of androgens continued for 2-4 months, and if these indicators fall outside normal androgen cancel the appointment for a period of 2-4 months.