Age and hormonal function of gonads in men. How to help men suffering from Erectile Dysfunction
How abroad, and in our country the study of male reproductive health has received little attention. We know little about the nature of age-related changes of hormonal function of the endocrine system, in particular, the state of hormonal function of the sex glands. According to the Association andrologists United States, more than 30 million men of reproductive age suffer from Erectile Dysfunction, or sexual dysfunction (the old term “impotence”). Hyperplasia of prostate cancer in 17% of men formed at the age of 50-59 years, 27% – aged 60-69 years and in 35% – aged 70-79 years. One of the 11 men developed prostate cancer, taking the frequency second only to lung cancer. The frequency of prostate cancer increases with age: in 90% of men in 85 years, revealed in situ carcinoma of the prostate. And as we know now, both prostate hormone-dependent. Age osteoporosis, which is largely due to partial androgen deficiency, diagnosed in 8 million men in the United States, and femoral neck fractures associated with osteoporosis, reaches 30%.
Androgens
Steroid producing glands, which include the gonads and adrenal glands, have a common embryonic origin. As a result of the complex process of differentiation, each iron specializes in the synthesis of the predominant androgens, estrogens or corticosteroids. The nature of steroidogenesis in these genetically determined set of different enzymes. Formation of androgens from cholesterol ester occurs in the Leydig cells of the testes and is under the regulatory control of luteinizing hormone (LH), and in the developing fetus – human chorionic gonadotropin. Functionally, it is a unified system of the pituitary – testes, which in turn is regulated by hypothalamic GnRH. At the core of its self-regulation is the principle of negative and positive feedback, the first discoveries of scientist Zavadovsky. A negative feedback mechanism of testosterone decreases of FSH and LH pulse release. In this process also involved the active metabolites of testosterone, dihydrotestosterone and estradiol.
According to modern concepts, the system of regulation and there is a positive feedback mechanism, where only estradiol, but not testosterone, provides a release of LH under certain pathophysiological conditions, such as castration or hypogonadism. Testosterone provides inhibitory effect primarily at the level of the hypothalamus and to a lesser extent – on the pituitary level.
In addition to LH and other factors can modulate the hormonal response to Leydig cells. For example, growth hormone enhances the secretion of testosterone in boys with a deficit somatotropin. Some peptides may have an activating or inhibitory effect on secretion of testosterone. These include arginine vasopressin, oxytocin, activin and endorphin. The latter can synthesize testes. Education androgens are also in the reticular zone of adrenal cortex. Their synthesis partly controlled by adrenocorticotropic hormone. In the adrenal glands produce large quantities of dehydroepiandrosterone and huge – its sulphate form. They are called adrenal androgens. Most of testosterone (more than 98%) entering the general circulation of the blood, binds to a specific transport protein – testosterone-estradiolsvyazyvayuschim globulin. Its synthesis occurs in the liver. The process of binding affect estrogen. Testosterone also binds albumin. Although this system less stable, it penetrates the blood-brain barrier, whereas the complex with globulin does not penetrate into the brain. The biological effect of implementing free testosterone. Another binding protein, called androgen binding globulin contained in the fluid of the seminal ducts. It provides a high concentration within the testis of testosterone, which is required for the possibility of the process of spermatogenesis. This protein differs from the blood globulin immunologically as well as the degree of affinity to testosterone and dihydrotestosterone.
The level of plasma testosterone levels significantly decreased with age only in the case of opportunistic diseases, but the level of free testosterone in older men decreases. With age, the content in the blood DHT slightly decreased, but its formation in the tissue of the prostate gland grow. This is the main cause of prostatic adenoma. In elderly men reduces the sensitivity of androgen target tissues prescriptions for testosterone and dihydrotestosterone, disappears circadian rhythm of androgens. Production of adrenal androgens progressively decreases after 30 years. Stress, smoking, adverse environmental factors reduce androgen production.
The biological action of androgens
Androgens provide primarily the regulation of growth and function of organs and tissues of the reproductive system.
Biological effects of androgens depend on age. In the embryonic period of testosterone provides for the formation and development of seminal vesicles, testicular appendage and vas deferens. The process of growth and development of the prostate gland, penis, scrotum, outer urethra is controlled by dihydrotestosterone, which is a metabolite of testosterone.
Androgens are necessary for normal sexual function. Testosterone initiates and supports the process of spermatogenesis, libido and spontaneous erections, but does not affect erection, due to visual stimuli. In addition, adult body androgens are necessary for the maintenance of secondary sexual characteristics, hematopoiesis, muscle and bone tissue. They have a generalized anabolic effect on protein metabolism. Androgens are involved in the differentiation of the brain. In their absence, their development is on feminine type.
Insufficient production of androgens leads to the development of various forms of hypogonadism, and excess – of different types of hyperandrogenism.
Hypogonadism
Common manifestations of hypogonadism depend on the time of its development – before puberty or after its completion. Hypogonadism in men is characterized by decrease of production of Leydig cells and testicular testosterone reduction or absence of spermatogenesis. The latter is known to be regulated along with follicle-stimulating hormone and testosterone and, above all the testosterone circulating in the testis, where its high concentration is required to maintain spermatogenesis.
Hypogonadism may be due to violations in the complex of the hypothalamus – pituitary gland. In this case, it is defined as gipogonadotropny hypogonadism. In the primary function of the testes formed violation hypergonadotropic hypogonadism. Separation is due to the level of gonadotropins: in one case, it is high, in another – low. In any variant of the true hypogonadism requires constant replacement therapy for correction of all functions due to lack of production of testosterone. The classic version of hypothalamic disorders are idiopathic hypogonadism and gipogonadotropy Kallmana syndrome, and acquired dysfunction Pituitary: adenoma, cranio-cerebral trauma, radiation or surgical removal of the pituitary gland. The causes of primary testicular lesions can be both genetic (such as Klinefelter syndrome, congenital anorchism) and acquired lesions of the testes, such as trauma, neopuskanie testicles into the scrotum (cryptorchidism true), testicular cancer or systemic diseases such as hemochromatosis.
With regard to perceptions of age hypogonadism, they have recently undergone significant changes. Few endocrinology, andrology allow older men develop menopause or andropause, analogous to menopause in women. Today, the overwhelming majority of experts consider this state as a “progressive partial androgen deficiency syndrome” (PPADS). Lack of menopausal age in men or have weak expression and its physiological basis. Unlike women, whose age develops menopause, characterized by a sharp drop in the secretion of estrogen. High gonadotropin and lack of ovulation in aging men Leydig cells of the testes do not stop the secretion of testosterone, and they retain spermatogenesis even in old age. The age reduction in Leydig cell function due to several factors, both external and internal, but above all the influence of oxygen free radicals. They have their damage and thereby reduce the ability of individual Leydig cells to support the process of steroidogenesis at an optimal level. The functions of all systems, including spermatogenesis, steroidogenesis in the testes and the synthesis of adrenal androgens decline with age. Total blood testosterone that is associated with a specific transport protein, does not change dramatically in the elderly, as well as its metabolite 5a-dihydrotestosterone. At the same time the level of biologically active free testosterone is significantly reduced in direct proportion to age. Parallel increases in blood levels of luteinizing hormone.
It should be noted that the decline of testosterone occurs simultaneously with an increase in capacity of a specific transporter protein, which increases testosterone deficiency in the aging organism. Along with this change occurs and the daily rhythm of its secretion, which is manifested a significant decrease in the concentration of testosterone in elderly men in the morning. It should be emphasized that there are huge individual differences in the population. For example, the content of testosterone below the lower limit of normal recorded in 7% of men aged 40-60 years and 20% – in a group of men aged 60-80 years. Found that the average drop in testosterone levels in men aged 40-70 years occurs at a rate of 1% per year. It must be emphasized that the various diseases, as well as stressful situations, inhibit the production of testosterone. Men, for example, from cardiovascular disease in the elderly have lower testosterone levels than men of the same age without such pathology.
Now it is assumed that a cluster of risk factors for cardiovascular disease, also known as syndrome X or metabolic syndrome (recently proposed to name its neuroendocrine syndrome) include: insulin of resistance, high triglycerides, low high-density lipoprotein, and hypertension, and they develop mainly in men with visceral obesity. This syndrome is associated with low testosterone levels and low activity of growth hormone, which is also accompanied by low levels of insulin-like growth factor-1. Preliminary data on the positive effect of substitution therapy with testosterone in men with visceral obesity. It happens and the normalization of the above parameters of the metabolic syndrome. It should be noted that, according to recent data, especially the good clinical effect of correction of metabolic syndrome was registered with the combined treatment of growth hormone and testosterone compounds. In this case, significantly reduced weight of visceral adipose tissue, insulin sensitivity increased, total cholesterol and triglycerides in the blood drop, parallel to a decrease in diastolic pressure.
Conventional wisdom about the direct relationship between the level of testosterone in sexual potency outcome: a study shaken. It is not a pattern. In many cases, this relationship is absent, revealed the huge individual differences. Sexual potency may be high at low levels of the hormone, and vice versa. As already mentioned, together with androgens, produced by testicles, adrenal glands synthesize so-called adrenal androgens – dehydroepiandrosterone (DGA) and its sulphate form, as well as androstenedione. Their synthesis is strictly dependent on age. Dehydroepiandrosterone sulfate is produced in large quantities – up to 30-40 mg per day. Its biological significance is largely undefined. Maximum production DGA reaches to 30-35 years, and then he begins to fall at a speed of approximately 60 ng / ml per year. For 60 years its level does not exceed 30% compared with age 25-30 years and continues to decline with the aging of the organism, reaching a minimum. The age reduction of sulfate production DGA runs parallel with the deterioration of general condition. Accompanying somatic, psychosomatic illness, as well as metabolic disorders, including diabetes, greatly exacerbate the situation, hastening the fall of secretion of this hormone. In this case, its level can have a dramatic decline in young men. Therefore the DGA is now showing increased interest. He was particularly increased after it has been demonstrated to improve the overall health and quality of life for all the main parameters after oral administration of DGA group of persons over 60 years. Although in this case have been reported to improve libido and sexual potency.
The concept of “normal” levels of a hormone, including testosterone, relatively, for any age, but more so for men over 60 years. The biological action of the hormone, in this case, testosterone, is determined not only by its absolute level in the blood of the general circulation, but also the level of sensitivity of tissues and target organs and their response. Therefore, an individual may be a situation where high levels of testosterone, and biological effects due to breakage of the receptor apparatus is not shown, such as syndrome of resistance to androgens.
In principle, possible to identify a group of individuals with testosterone deficiency. In this case, repeated determinations of testosterone in his blood level should be below 4 ng / ml. At the same time will be recorded continuously elevated levels of luteinizing hormone. However, strictly speaking, we can not only on the basis of hormonal parameters relate this group of individuals classified as suffering from senile hypogonadism, as it is impossible to characterize their biological effects at the level of organs and tissues of the target each individual.
Must be remembered also that decreases with age not only the production of androgens. At the present time clearly demonstrated age-related decrease in the synthesis of growth hormone with its secretion falls by 1.4% per year, reduced the frequency of its pulse discharge. The same time decreases the secretion of hypothalamic releasing hormone, which activates the synthesis of growth hormone in the adenohypophysis. Decreases with age and level of its mediator – insulin-like growth factor – 1. The result is a decrease in muscle mass and strength, the growth of obesity, especially visceral, and increased body mass index. Administration of growth hormone to older people is accompanied by the anabolic effect, increasing bone density, improve muscle strength and decrease in adipose tissue. However, at present we know nothing about the possible side effects of such substitution.
It is now known as the reduction of melatonin secretion in older men with a violation of its circadian rhythm. This is accompanied by a deterioration in mood, memory and sleep disorders.
Diagnosis of hypogonadism
Testosterone deficiency is characterized by decreased libido, decline in sexual fantasies and morning erections, low mood, accompanied by a decrease in physical and intellectual activity, irritability and fatigue. Reduced muscle mass and strength complements the clinical picture of androgen deficiency.
One of the major symptoms of the ongoing hypogonadism in young men – a decrease in prostate volume, which can be determined accurately ultrasound. Reduced volume of ejaculate also showed a small volume of the prostate and seminal vesicles. Long been known as well. that hypogonadism, osteoporosis, and therefore forms a risk factor for fractures. Objectively, the degree of decrease in bone mass can be estimated on the densitometer, and therefore holding densitometry necessary to assess the severity of osteoporosis. As is well known. Age significantly affects the formation of osteoporosis in both men and women. At present, in countries where women are widely used postmenopausal replacement therapy could slow the development osteporozov and thereby reduce the frequency of fractures. Men have also so far not able to say depending on the degree of osteoporosis by the age of hypogonadism. However, in in vitro studies with bone tissue showed a positive effect of androgens on the proliferation of osteoblasts, which is realized, obviously. through the androgen receptor. The presence of osteoblast cells of two enzymes – aromatase and 5-a-reductase, which convert testosterone into estrogen and 5-a-dihydrotestosterone, as evidence of their possible role in maintaining the balance of bone metabolism in a male body. We describe the clinical cases of low estrogen and low birth weight were associated with older men with osteoporosis. Thus for a long time they also recorded a low level of testosterone. As mentioned, testosterone has a positive effect on erythropoiesis, so men with hypogonadism are weakly expressed anemia, which in older men need to differentiate from anemia due to other causes. To correct an adequate diagnosis of hypogonadism is absolutely necessary certain hormones. In this case, a key hormone that is known to be testosterone. If its concentration in the morning plasma levels below 12 nmol / L (<4 ng / ml), then this shows a decline of its production Leydig cells of the testes. Re-definition of testosterone is necessary. If you re-defined as low levels of hormones, thereby confirming the diagnosis of hypogonadism. In the case of severe obesity and the old men must be the definition and specific transport binding globulin sex steroids. This will help in interpreting the results of determination of testosterone. Since it is known that in obese and with age comes an increase in capacity of this transport protein that lowers the level of biologically active testosterone. An adequate differential diagnosis of primary and secondary hypogonadism should determine the level of gonadotropins – luteinizing and follicle-stimulating hormone. In the primary version of gonadotropins are elevated, and in the case of secondary hypogonadism – reduced. In the case of the latter option, you must carry out a functional test of hypothalamic-releasing hormone – lyuliberinom or its equivalent, with a view. to assess the reserves gonadotrofov adenohypophysis. If it appears that the low secretion of gonadotropins recorded their increase, it will be the basis for treating this form of hypogonadism caused by breakdown of the complex hypothalamic-pituitary, pulsed introduction lyuliberina. Usually, it is shown in the so-called idiopathic forms gipogonadotropped hypogonadism.
Replacement therapy for hypogonadism
Several drugs are available for derivatives of testosterone replacement therapy.
In most countries in the case of hypogonadism most acceptable and most common are drugs for testosterone paranteral introduction. For this purpose, now usually used testosterone enanthate. In the United States also used testosterone cypionate. As esters of testosterone, they have similar pharmacodynamics. The maximum concentration of testosterone is registered on the 3rd day of administration of the generic drugs, far exceeding the upper range of physiological concentrations. And this is one of the negative properties of drugs. In the optimal variant of testosterone levels should not go beyond its physiological fluctuations. Usually 2 weeks after administration of testosterone etantata, the content of testosterone falls to gipogonadal level. Mode injection of the drug should be individualized, depending on the nature of pharmacokinetics. In some cases it can be administered every 3 weeks.
A promising drug is testosterone butsiklat, which provides a level of testosterone within its normal vibrations for 12 weeks after a single intramuscular injection at a dose of 1000 mg. The drug has no hepatotoxic effect.
Second testosterone ester is testosterone andekanoat for injection. It is in their pharmacokinetic parameters is between testosterone enanthate and testosterone butsiklatom. In the near future are expected results of its extensive clinical trials from Online pharmacy without prescription.
Currently, as an alternative appeared patch (film) containing crystalline testosterone in the number of 10 or 15 mg. Daily use of skin so the film maintains a normal level of testosterone in the blood of the patient. Even with him for 10 years not noted significant side effects. Proper use of a regular patch delivers testosterone levels in men gipogonadalnyh within its normal modes. The principal advantage of this form is the possibility of its application by the patient. Application of plaster may be cut off immediately, as opposed to drugs for testosterone injections. And this is important in identifying a particular patient’s disease of the prostate, particularly prostate cancer. Place fixing patch on the skin of back, thigh or scrotal skin is selected individually, considered the possibility of allergic skin reactions. Crystalline testosterone for subcutaneous implantation has not received wide application. although providing the desired hormonal effect for 6 months. First of all, it involves the necessity of a small surgical intervention, as well as the complexity of its removal in the case, for example, identifying the patient’s prostate cancer. Androgen replacement therapy for prostate cancer is contraindicated.
Most recently produced interesting and encouraging results about the possibility of substitution therapy in the developing hypogonadism in aging men using androstenedione, a body which is easily converted into potent androgen – testosterone. Androstenedione, as we know, is the immediate precursor in the synthesis of testosterone in the testes. Especially good pharmacokinetics of testosterone provided by intranasal administration of androstenedione.
Monitoring during testosterone therapy in men include:
Clinical parameters:
physical activity, intellectual activity and memory, mood, sexual function (libido, the number of erections, sexual activity).
Somatic parameters:
weight. its proportions, body mass index. muscle mass and strength.
Laboratory parameters:
levels of gonadotropins (LH, FSH). testosterone, 5a – dihydrotestosterone and estradiol, as well as erythropoiesis (hemoglobin, hematocrit).
Prostate:
eyyakulyata volume, prostate size, its structure, using palpation and transrectal sonography, prostate specific antigen in serum, urine flow rate during urination.
Bone tissue:
densitometric determination of bone density, it is better to take the lumbar vertebrae.
Assessment of sexual function, its activity and mood are conducted through a unified, standardized questionnaire.
Antiandrogens
Natural progesterone is an antagonist of androgens, some of its derivatives are even more pronounced effect. Antiandrogens, competing for liaison with the androgen receptor, counteracts the effects of testosterone and dihydrotestosterone in target-tissues. The most active anti-androgens is tsiproteronatsetat. It is used to treat hirsutism, some maskulinised syndromes. as well as for treatment of adenoma and prostate cancer. The weaker antiandrogen is spironolactone and nature of non-steroidal drug flutamide. Recently synthesized and became widespread in the clinic antiandrogens, a specific blocker of 5a-reductase, finasteride, or Propecia. The drug, being derived steroid androstane series, selectively blocks 5a-reductase activity and thereby reduces the formation of dihydrotestosterone from testosterone. He practically does not bind androgen receptor. Successfully applied for the treatment of prostatic hyperplasia. Treatment requires daily use of Propecia in a dose of 5 mg, for 6-8 months significantly reduced prostate size. Using the drug is particularly important in the case of severe contraindications for surgical removal of the prostate.
