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Hypogonadism and where hormone replacement therapy begins.

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Hypogonadism is known to occur in approximately 5 adult men out of 1000 (in most European countries). Despite fairly clear clinical manifestations of testosterone deficiency in adult men, which include decreased libido, erectile dysfunction, oligospermia or azoospermia, decreased bone density, regression of secondary sexual characteristics, loss of muscle mass and muscle strength, and impaired mood, they are not always recognized by clinicians or attributed to other diseases. However, with the accumulation of information about the importance of the role of androgens in the development, function and health of the male body, testosterone deficiency is receiving more and more attention as hypogonadism in adult men is related to health issues, economic viability and quality of life. Men of advanced age have climacteric disorders in the foreground, diagnosis and treatment of which represent obvious difficulties, taking into account age polymorrhagic character. Scientific researches of great importance in clinical practice give more and more evidence of benefit of testosterone replacement therapy usage in adult men.

Physiological effects of androgens
Endogenous androgens include testosterone and its more active metabolite, dihyde-rotestosterone. They have different functions in different periods of life. During embryonic development, androgens play a key role in the differentiation of the male genital organs-prostate, seminal vesicles, penis and scrotum. Testosterone is necessary to stimulate sexual behavior and functions, initiate sperm production, and develop male secondary sexual characteristics: specific body hairiness (on the face, pubis, chest and armpits), throat growth and vocal cord thickening. Androgens also cause a growth spurt in adolescence and possible growth arrest due to the closure of epiphyseal growth plates.

At maturity, androgens are essential for the maintenance of reproductive function and secondary male sexual characteristics. In addition, testosterone affects muscle mass and strength, fatty tissue distribution, bone mass, erythropoiesis, spermatogenesis, and libido and potency. Moreover, androgens may have a nonspecific effect on the general metabolism, mood and well-being.

Thus, androgens not only play the most important role in adolescent growth and development, but also are involved in maintaining the health of a man in his adulthood and determine the course of menopause. Hormones in this group have a significant physiological impact on many organs and tissues, including reproductive organs tissues, sexual function and behavior, the hematopoietic system, muscles, bones, skin and hair.
 Despite the fact that the biological effect of androgens varies depending on the period of life, the regulation of hormone production by testicles and mechanisms of hormonal action at different stages, from early embryonic development to old age, are the same.
 Testosterone, the predominant androgen in male blood plasma, is produced predominantly (95%) by the testes from cholesterol, and in much smaller quantities by the adrenal cortex. In turn, the precursor of testosterone, cholesterol, may be produced de novo in Leydig cells or derived from plasma lipoproteins. Only a small amount of testosterone is stored in the testicles. Therefore, a complete turnover of testosterone in blood occurs approximately 200 times per day, and the daily amount of testosterone released into the blood plasma is approximately 6 mg.

 Testosterone is transported in plasma by the sex-steroid-binding globulin or in bound form with albumin or other proteins; only small part of it remains in free form in dynamic equilibrium with bound fractions. Circulating testosterone in plasma is largely converted to dihydrotestosterone in the target tissues (including skin, liver, and prostate) by the enzyme 5a-reductase. Testosterone is also metabolized to estradiol through the aromatase enzyme complex in the testicles, brain and adipose tissues. In many tissues, testosterone activity depends on its reduction to dihydrotestosterone, which is also bound by cytosolic androgen receptors. At this point, the steroid-receptor complex translocates into the nucleus, where it activates transcription and changes at the cellular level related to the action of androgens. Testosterone production is controlled by hypothalamic-pituitary hormones.

Impulsive releases from hypothalamus of LH releasing hormone (LHRH) which is also called gonadotropin-releasing hormone (GHRH) stimulate hypophysis to release luteinizing (LH) and follicle stimulating (FSH) hormones. As for the main effects of these gonadotropins in the male body, the luteinizing hormone stimulates testosterone production by Leydig cells and promotes testicular development, while the follicle stimulating hormone together with testosterone regulates spermatogenesis and sperm maturation. In addition, the latter increases the activity of luteinizing hormone and testosterone synthesis.
 The release of luteinizing and follicle stimulating hormones is regulated by testosterone through negative feedback. In addition, follicle stimulating hormone release is selectively inhibited by inhibin, a polypeptide produced by Sertoli cells located in the testicles, and stimulated by activin.

 Male hypogonadism is a deficiency or absence of endogenous testosterone. Such terms as "testosterone insufficiency" and "hypoandrogenism" can be used in different classifications of hypogonadism and serve for more precise description of clinical manifestations resulting from insufficient stimulation of androgen-dependent functions.

The incidence of testosterone deficiency is unknown. Because there are many forms of it, and clinical manifestations are sometimes poorly pronounced, hypogonadism is considered to be a difficult disease to diagnose. Of the approximately 4-5 million men who have hypogonadism in the United States, only 5% receive regular testosterone replacement therapy. In clinical practice, the symptoms of male hypogonadism are often masked by other complaints of the patient and not recognized by the doctor. Therefore, estimation of the frequency of testosterone deficiency is based on identifying men with hypogonadism who have risk factors.

 Klinefelter syndrome, the most common hereditary form of primary hypogonadism, is found in 1-2.5 out of 1000 newborn boys. Klinefelter syndrome occurs in 35-50% of men with hypogonadism who require androgen replacement therapy. In the general population, hypogonadism is found in about 5 out of 1,000 men. However, recent data suggest that these estimates represent only a fraction of the actual cases of male hypogonadism. It is not always the case that abnormalities associated with age-related changes in androgen production are registered.

 Decreased testosterone levels were found in 20-50% of men with femur fractures, indicating that the frequency of acquired forms of hypogonadism is significantly higher than the frequency of congenital forms. Hypogonadism is the most common cause of secondary osteoporosis in men, which, in turn, is the most common cause of morbidity, mortality and disability due to increased risk of fractures.

 Infertility as a symptom or form of hypogonadism in the general population is present in 5-10% of men, which indicates a rather high frequency of hypogonadism. In addition, erectile dysfunction of varying degrees is observed in more than half of men over 40 years of age in the United States, and endocrine disorders, mainly hypogonadism, are found in 5-35% of cases in selected populations.

A large study (n = 890) was conducted to determine the proportion of adult men with decreased plasma levels of total (or free) testosterone. The study showed a progressive increase in the frequency of low total testosterone and free testosterone index (IST = T/CCG) determination with age as compared to the levels in the general population of men aged 20-40 years. The incidence of hypogonadism determined by low total testosterone levels was 12,19, 28, and 49% in men aged 50-59, 60-69, 70-79, and 80-89 years. The free testosterone index was decreased in 9, 34, 68, and 91% of men in the given age groups, respectively.

 Male hypogonadism is associated with insufficient testosterone secretion. Testosterone deficiency occurs in many diseases, including those associated with testicular pathology (primary testicular insufficiency) and with decreased stimulation of testicular function by gonadotropin (hypogonadotropic hypogonadism).

 Primary testicular insufficiency (primary hypogonadism) may result from genetic or developmental abnormalities (Klinefelter syndrome) or from acquired diseases (e.g. viral orchitis). Hypogonadotropic hypogonadism (secondary hypogonadism) is associated with disorders of the hypothalamic-pituitary-ovarian axis, which are hereditary (Kallman syndrome) or acquired (pituitary adenoma) nature. In addition, various congenital, chromosomal, and acquired syndromes, their combinations, or other conditions, the nature of which is still unknown, can lead to testosterone deficiency.
Most forms of hypogonadism diagnosed in adults are acquired and most often develop due to obesity, severe systemic diseases and taking some medications. A relatively large number of men develop hypogonadism as a result of other acute and chronic diseases, including acquired immunodeficiency syndrome (AIDS), sickle cell anemia, cirrhosis of the liver and renal failure.

 Testosterone levels in men may be decreased by certain medications, including ketoconazole, glucocorticoids, spironolactone, estrogens, progestagens, hGH analogues, cimetidine, phenytoin, carbamazepine, and flutemide. In addition, plasma testosterone levels may be decreased in men who consume large amounts of alcohol, marijuana, heroin, and methadone.

 Although the earlier data were questionable, it is now proven that in men there is a slow and prolonged (1-2% per year) decrease in total testosterone levels and its bioavailability, starting at approximately 30 years of age. Age-related changes in the male reproductive system develop more slowly and are less pronounced than the decline in ovarian function during menopause in women. The first changes occur at testicular level and include reduction in the number of Leydig cells, decrease in metabolic activity enzymes and decreased testermosterone synthesis in response to gonadotropin stimulation. Other possible causes of decreased total testosterone levels and its bioavailability in older men include chronic diseases, medications, changes in circulating sex-steroid-binding globulin, epidemiological factors (e.g. smoking and alcohol consumption), and age-related changes in the hypothalamus and pituitary gland.

The main causes of male hypogonadism
Primary hypogonadism
- Klinefelter syndrome (47, XXY and its variants)
- Cryptorchidism
- Orchitis
- Trauma or radiation damage to the testicles
- Cancer chemotherapy
- Nutritional deficiencies Myotonic muscular dystrophy
Secondary hypogonadism
- Cullman syndrome (hereditary deficiency of gonadotropin-releasing hormone)
- Tumors of the pituitary gland
- Tumors of the Turkish saddle
- Hemochromatosis
- Pathology of hypothalamus or pituitary gland
- Hypothyroidism
- Prader-Willi syndrome Severe obesity

Primary or secondary
- Older age
- Severe systemic diseases
- Occupational hazards
- Liver cirrhosis
- Sickle cell anemia
- Medication use
- Uremia
Clinical picture 
Physical examination of men with adult hypogonadism usually does not show any changes, sometimes moderate gynecomastia, decreased facial and body hair, palpation of testicles is soft and small in size may be found. Thus, the clinical manifestation of hypogonadism depends on the age at which it occurs, as well as on its cause, severity and duration of testosterone deficiency.
 Age-related testosterone deficiency may be associated with certain physiological changes, including decreased muscle mass and strength, increased fat tissue, decreased bone mass and increased incidence of osteoporosis and fractures even with minor trauma, decreased libido and increased frequency of erectile dysfunction, and impaired health.
 Testosterone deficiency in prepubertal or early pubertal period is clinically manifested by the absence of secondary sexual characteristics, youthful voice, eunuchoid body type, gynecomastia.
 In adults, testosterone deficiency results in decreased armpit and pubic hair, slower beard growth and less frequent shaving, decreased muscle mass, reduced testicular and prostate size, gynecomastia, osteoporosis, and decreased hematocrit. Decreased libido, erectile dysfunction, infertility, weakness, depression, loss of motivation, irritability, vasomotor disorders are also characteristic.
 A laboratory sign of hypogonadism is a consistently low concentration of testosterone, usually in combination with elevated (primary hypogonadism) or reduced (secondary hypogonadism) levels of luteinizing and follicle stimulating hormones. Normal testosterone levels in adult male plasma are 300-1100 ng/dL.

Testosterone replacement therapy
 Testosterone replacement therapy may be recommended for men who develop conditions associated with deficiency or absence of endogenous testosterone. The main goal of testosterone replacement therapy is to achieve plasma testosterone concentrations that are as close as possible to physiological values in men with normal gonadal function. As this therapy, physiological doses of testosterone should be used, and testosterone, dihydrotestosterone levels should be maintained within normal values. In addition, the drugs should be safe and the dosage form should be convenient for the patient. Exogenous testosterone administered to men with hypogonadism for replacement therapy has been shown to restore body weight and reduce fat tissue. Other positive effects of testosterone replacement therapy are increased libido and improved sexual function as well as mood and well-being.

 Hypogonadism without treatment is a risk factor for osteoporosis in men, and testosterone replacement therapy leads to increased bone density, which is important in old age. In children, the introduction of exogenous androgens causes accelerated growth, but can lead to disproportionate bone maturation. Taking androgens in boys before puberty for a long time can lead to closure of the epiphyseal growth zones and cessation of growth.
It has been shown that androgens stimulate erythrocyte production by increasing erythropoietin formation.
 When androgens are administered exogenously, the secretion of endogenous testosterone can be suppressed by a negative feedback mechanism by reducing the production of luteinizing hormone.

 Large doses of androgens can also suppress spermatogenesis by inhibiting follicle-stimulating hormone secretion.
 Androgens cause retention of nitrogen, sodium, potassium, phosphorus and decrease urinary excretion of calcium. Androgens are known to stimulate protein synthesis and inhibit protein catabolism. However, nitrogen balance improves only with a sufficient intake of calories and protein. There is currently insufficient data on the effectiveness of androgens to accelerate fracture healing or recovery from surgery.

Medication forms
 Natural testosterone, when administered orally, sublingually or intramuscularly, is quickly absorbed and destroyed, and it is difficult to maintain its physiological level. Therefore, effective androgen therapy requires either a dosage form, which ensures constant testosterone release, or the use of its synthetic analogues. Before AndroGel (1% testosterone gel) came on the market, oral androgen derivatives, intramuscular injection of long-acting testosterone ester, and transdermal testosterone patch were used for androgen replacement therapy in the United States.

Oral dosage forms
Some 17-alkyl derivatives of testosterone (e.g., methyltestosterone, fluoxymesterone, oxandrolone) are used for oral or sublingual administration. Although they are metabolized in the liver slower than natural testosterone, they need to be taken several times a day, their androgenic properties are low or variable, and the plasma concentration of alkyl derivatives cannot be determined by any method. In addition, alkylated androgens can be hepatotoxic and, due to their metabolic properties, can increase low-density lipoprotein levels and dramatically decrease high-density lipoprotein levels.

Intramuscular injection
 Intramuscular injections of testosterone depot esters (testosterone enanthate and testosterone cypionate) in oil suspension are widely used for replacement therapy. The esterification of testosterone increases its solubility and slows down its release into the bloodstream. Injections may be administered once every 2-3 weeks in the usual adult dosage of 150-200 mg. These drugs raise plasma testosterone levels to the upper limit of normal or slightly higher in the first few days after injection, which decreases to the lower limit of normal or slightly lower at the end of the injection interval. Fluctuations in testosterone levels over a wide range can lead to fluctuations in libido and mood and predispose to the appearance of acne, polycythemia, and gynecomastia. Injection of testosterone esters should usually be done in the clinic and may be accompanied by pain at the injection site, bleeding, bruising, or allergic reactions to the solvent (sesame or cottonseed oil).

Transdermal patch
The transdermal patch allows a slow release of testosterone into the bloodstream, without the need for testosterone derivatives. These systems, available in patch form, provide physiological levels of testosterone in the plasma, mimicking the circadian rhythm observed in healthy men.

 There are no fluctuations typical of injectable forms. However, many men consider transdermal testosterone delivery systems unacceptable from a cosmetic point of view; patches can cause skin irritation, and also peel off. Using a patch that is glued to the scrotum results in some increase in dihydrotestosterone levels, probably due to high levels of the 5a-reductase enzyme in the scrotal skin, resulting in increased testosterone metabolism. In addition, due to the size of the patch and the need for weekly preparation (e.g. shaving) of the scrotal skin, this form is uncomfortable or unacceptable for some men. If the patch is fixed on another part of the body, it avoids a number of technical problems, but often causes local skin reactions. According to clinical studies, about 50% of men using the testosterone patch experience mild to moderate erythema and 12% experience a burning sensation at the application site. Treatment interruption due to these reactions or generalized dermatitis with transdermal systems has been shown to occur in 10% of patients in clinical studies and in 30-50% in practice.

Transdermal gel is applied once a day to the skin (usually in the shoulder, upper arm or abdomen area). The gel therapy is non-invasive, painless, and can be applied at home. Local reactions when using the gel are minimal.
Another advantage of the gel is that it is unnoticeable to others. Testosterone in gel form is absorbed from the skin surface and enters the bloodstream, with a constant plasma concentration observed within 24 hours. Reduced testosterone levels return to normal within three days of treatment.
The gel should not be applied to the genital area. Avoid contact of the skin with the skin of another person to exclude transfer of the drug to him. After applying the gel, it is recommended that you wash your hands with soap and water. Patients are also advised to cover the gel area with clothing to reduce the chance of transmission. Patients' partners have a slightly higher risk of exposure to the gel and should be monitored for symptoms of virilization.
Thus, timely diagnosis of testosterone deficiency, individual selection of an effective drug for replacement therapy, further monitoring of the patient will ensure his good health and decent quality of life regardless of age.

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