Hypogonadism

Hypogonadism, or testicular failure - a pathological condition, the clinical picture of which is caused by a decrease in the level of androgens in the body, is characterized by underdevelopment of the genitals, secondary sexual characteristics and, as a rule, infertility. Hypogonadism in men is caused by a deficiency of testosterone or the resistance of target tissues to androgens.

[1], [2], [3], [4], [5], [6], [7], [8]

Epidemiology

The prevalence of hypogonadism in the male population is more than 1.2%, but many cases remain undiagnosed. This leads to the lack of timely treatment and disability of patients, as hypogonadism promotes only the appearance of sexual disorders and a decrease in the quality of life, but also the occurrence of osteoporosis and cardiovascular diseases.

[9], [10], [11], [12], [13], [14]

Causes of the hypogonadism

The causes of hypogonadism are polymorphic. Among the congenital forms of hypogonadism, the main role is played by chromosomal and genetic abnormalities, among the acquired forms - traumas and toxic effects, as well as brain tumors.

Secondary hypogonadism occurs due to a decrease in the secretion of gonadotropic hormones and inadequate stimulation of the sex glands. Secondary hypogonadism can also develop with Ithenko-Cushing's disease, myxedema, adrenal cortex tumors and other endocrine diseases. Signs of hypogonadism may appear in certain non-endocrine diseases, for example, in liver cirrhosis. Hypogonadism can occur when the development of the reproductive system in men - cryptorchidism.

Primary hypogonadism is accompanied by hypersecretion of gonadotropic hormones and is called hypergonadotropic hypogonadism. With secondary hypogonadism, there is a decrease in the secretion of gonadotropic hormones - hypogonadotropic hypogonadism. The establishment of the form of hypogonadism is important for the doctor, since the proper treatment depends on this. Less common is normogonadotropic hypogonadism, which is characterized by low T production at a normal level of gonadotropins. It is assumed that it is based on mixed disorders in the reproductive system, expressed not only in the primary lesion of testicles, but also in the hidden insufficiency of hypothalamic-pituitary regulation.

Symptoms of the hypogonadism

Symptoms of hypogonadism depend not only on the degree of deficiency in the body of sex hormones, but also on age (including the intrauterine period of life) in which the disease occurred. There are embryonic, preubertate and postpubertate forms of hypogonadism.

Embryonic forms of androgen insufficiency are manifested by anarchism. Deficiency of androgens, which occurred in the early embryonic period (before the 20th week), leads to severe pathology - hermaphroditism.

Dopupertative, as well as embryonic, forms of hypogonadism are accompanied by the absence (or weak expression) of secondary sexual characters and the formation of eunuchoid syndrome. The term "eunuchoidism" was proposed by Griffith and Duckworth, in clinical terminology he was introduced in 1913 by Tandler and Gros. Patients with this syndrome, as a rule, are of high growth, disproportionate physique (long limbs, relatively short trunk). Skeletal musculature is poorly developed, it is often observed the deposition of subcutaneous fat by the female type, true gynecomastia.

The skin is pale, secondary hair in the pubertal period does not appear or is very scarce. Mutation of the voice does not occur - it remains high in tone. Genital organs are underdeveloped: the penis is small in size, the testicles are reduced or absent, the scrotum is not pigmented enough, it is atonic, without the characteristic folding of men.

The main symptoms of hypogonadism

• Decreased libido.
• Violation of an erection.
• Reducing the brightness of orgasm.
• Deterioration of spermiogram indexes.
• Increased irritability.
• Decreased ability to concentrate.
• Decreased cognitive function, memory impairment.
• Depression.
• Insomnia.
• Decreased muscle mass and strength
• Decrease in vital energy.
• Bone pain due to osteoporosis.
• Reduction of pubic hair.
• Decrease in the size and density of the testes.
• Gynecomastia.
• Increase the amount of adipose tissue.
• Vasomotor disorders (sudden hyperemia of the face, neck, upper body, heat (tides), fluctuations in blood pressure, cardialgia, dizziness, lack of air).
• Decreased tone and thickness of the skin.

Postpubertate forms of hypogonadism are characterized by the disappearance of secondary sexual characteristics in initially healthy mature men: a reduction in facial and body hair, thinning of hair on the head, hypoplasia of testicles, and violation of sexual functions (decreased sexual desire, reduction and weakening of erections, change in the duration of sexual intercourse, sometimes the disappearance of orgasm). Some patients experience vegetative-vascular disorders, increased fatigue.

To identify abnormalities in the male phenotype, care must be taken when clarifying the anamnesis. Incorrect presentation of the fetus, premature birth, severe delivery should alert the doctor with regard to the possibility of developing androgen deficiency in the future. It is necessary to pay attention to the constitutional features of the subject. Discovered in boys cryptorchidism suggests the possibility of developing testicular failure.

Incorrect formation of the external genitalia most often indicates a genetic pathology and requires not only a clinical but also a genetic examination of the patient. However, some defects in the development of external genitalia can be detected in men and without symptoms of testicular failure. For example, hypospadias are possible in the absence of any symptoms of testicular failure.

Hypogonadism may be accompanied by gynecomastia, which occurs in other pathological conditions, not associated with the pathology of the male sex glands, for example, cirrhosis of the liver. The defeat of testicles can be combined with a violation of the function of the sense of smell.

[15], [16], [17]

Forms

Various classification of hypogonadism in men has been published - L. M. Skorodok et al., V. Clayton et al., E. Teter.

Primary hypogonadism (hypergonadotropic) - is due to damage to Leydig cells

• Congenital:
  • anarchism;
  • Klinefelter's syndrome;
  • XX-syndrome in men;
  • Shereshevsky-Turner syndrome in men;
  • syndrome del Castillo  (Sertoli-cell syndrome);
  • syndrome of incomplete masculinization.
• Acquired:
  • infectious-inflammatory lesion of testicles;
  • hypogonadism caused by exposure to unfavorable external factors;
  • tumors of testicles;
  • injury.

Secondary hypogonadism is caused by disorders of the hypothalamic-pituitary system, leading to a decrease in the secretion of LH hormone, stimulating testosterone production in Leydig cells

• Congenital:
  • Callman's syndrome;
  • isolated deficiency of luteinizing hormone;
  • pituitary fascism;
  • craniopharyngioma;
  • Maddock's syndrome.
• Acquired:
  • infectious-inflammatory lesion of the hypothalamic-pituitary region;
  • adiposogenital dystrophy;
  • tumors of the hypothalamic-pituitary region;
  • loss of tropic functions as a result of traumatic or surgical damage to the hypothalamic-pituitary region;
  • hyperprolactinemic syndrome.

By the duration of the disease:

• permanent hypogonadism. In most cases, hypogonadism is a lifelong chronic disease;
• transitional (symptomatic) hypogonadism. In some cases, hypogonadism is temporary in some endocrine system diseases (hypothyroidism, hyperoprolactinaemia, decompensation of diabetes mellitus, obesity), as well as violations of the liver or kidney function or under the influence of drugs (iatrogenic hypogonadism), and does not require independent treatment, as the androgen secretion is restored after treatment of the underlying disease, elimination of factors that inhibit the synthesis of testosterone.

[18], [19], [20], [21], [22], [23], [24], [25], [26]

Diagnostics of the hypogonadism

Since testosterone deficiency can be a manifestation of a number of endocrine diseases (prolactinoma, hypothyroidism, etc.), examination and treatment should be carried out by an endocrinologist.

The principal task in examining a patient with hypogonadism is to determine the possible level of damage: central (hypothalamic-pituitary) or peripheral (testicular).

The hypofunction of the male sex glands is diagnosed, in addition to the data of anamnesis, by biotopological research, on the basis of examination of the radiography of the skull and hands with wrist joints, determination of the sex chromatin and karyotype, morphological and chemical analysis of the ejaculate, and if necessary, testicular biopsy. The most informative direct determination in the plasma level of gonadotropins (LH and FSH), testosterone (T) and, according to indications, prolactin (PRL).

Less informative are urinary excretion rates of 17-ketosteroids (17-CS). Determination of hormone levels in plasma allows you to establish a diagnosis of primary or secondary hypogonadism. High content of gonadotropins in it points to primary (hypergonadotropic) hypogonadism, low - to secondary (hypogonadotropic) hypogonadism. There may be forms of hypogonadism with isolated deficiency of LH and FSH. It is important to determine the level of prolactin in the plasma, which allows attributing some forms of hypogonadism to the group of hyperprolactinemic hypogonadism.

The study of ejaculate characterizes the state of reproductive function of testicles. Normal ejaculate testifies to a sufficient level of sex hormones in the patient's body. This is the simplest and most accessible method, allowing indirectly to judge the hormonal status of the reproductive system in men. A testicular biopsy reveals the state of spermatogenesis and has great diagnostic value when obturation of the vas deferens.

The method of ultrasound scanning of the pelvic organs, which allows to judge the location of testicles with cryptorchidism, and also about their magnitude, is increasingly used.

The examination should include the following diagnostic methods

• hormonal examination;
• definition of karyotype;
• MRI of the brain.

The hormonal examination is aimed at assessing the functional state of the hypothalamus-pituitary-testicle system, on the basis of which it is possible to differentiate hypogonadotropic hypogonadism from primary testicular pathology. Hormonal examination includes determining the levels of the following hormones in the blood:

• LH and FSH;
• testosterone;
• SHGS;
• estradiol,
• prolactin;
• TTG

The simplest and most accessible indirect method for diagnosing hypogonadism is to determine the so-called bone age using the X-ray method. Androgens affect the structure of bone tissue and cause sexual differentiation of the skeleton. During puberty, the process of ossification of metaepiphyseal zones is completed under the direct influence of androgens. Deficiency of androgens, available in hypogonadism, leads to inhibition of the processes of ossification of the cartilage and osteoporosis. Therefore, almost all such patients have changes in the osteoarticular system. Since the maturation of the skeleton depends on the saturation of the body with sex hormones, the bone age directly reflects the degree of sexual maturity of the organism.

There are several X-ray methods for determining bone age, which take into account the degree of maturity of the skeleton, the degree of its differentiation and synostosis. The most indicative of these processes in the bones of the wrist and hand. Bone age allows you to accurately determine the onset of puberty.

Thus, the increase in testicles in the volume (the first sign of puberty) corresponds to the bone age of 13.5-14 years, and pubertal growth occurs at the bone age of 14 years. After puberty activation of the gonad function, a synaptic syncope of the epiphysis with metaphysis in the first metacarpal bone occurs. Complete puberty radiographically characterized by the disappearance of transverse striation in the long tubular bones of the forearm in place of the closed epiphyseal lines. This makes it possible to immediately distinguish the prepubertal biological age from pubertal, since the appearance of sesamoid ossicles in the first metacarpophalangeal joint (bone age corresponds to 13.5 years) in the absence of synostosis in the first metacarpophalangeal articulation indicates the preservation of the infantile state. The presence of synostosis in the first metacarpophalangeal articulation testifies to the active inclusion of the function of the sex glands. It should take into account the state of other endocrine glands, also affecting the differentiation of the skeleton (adrenal glands, thyroid gland, etc.).

Bone age of the patient is determined by comparing the results of the study of chest X-rays (detection of phases and stages of osteogenesis) with the appropriate standards. In determining the bone age, other signs of osteogenesis disorders (asymmetry of ossification, perversion of the order of osteogenesis, etc.) should be taken into account, and attention should be paid to its extreme variants (the earliest and latest period of ossification and development of synostosis), which may be due to different and , in particular, hereditary factors.

It should be remembered that there are differences in bone age among residents of different geographical latitudes. It is well known that puberty among the inhabitants of southern latitudes occurs earlier than their peers in the North. However, in some ethnographic regions of the world, almost identical data on the maturation of the skeleton of bone can be found. It is caused by a number of features and, first of all, by climatic factors. Using the presented table of bone age, it is necessary to pay attention to extreme variants of the earliest and latest terms of ossification taking into account the patient's residence.

Duration of ossification of the hand and distal forearm in males (years)

Ossification points and synostosis	Timing
	The earliest	Latest	Medium
Distal epiphysis of the ulna	6th	10	7-7,1 / 2
The styloid process of the ulna	7th	12	9.1 / 2-10
Pisiform bone	10	13	11-12
Sesamoid bones in I metacarpophalangeal joint	Eleven	15	13.1 / 2-14
Synostoses:
In I metacarpal bone	14	17th	15.1 / 2-16
In II-V metacarpal bones	14	19	1b, 1 / 2-17
In the terminal phalanges	14	18	16-1b, 1/2
In the core "	14	19	1b, 1 / 2-17
In the middle »	14	19	1b, 1 / 2-17
Of the distal epiphysis of the ulna	16	19	17-18
Of the distal epiphysis of the radius	16	20	18-19

Before the onset of puberty, routine hormonal examination, including the determination of levels of LH, FSH and testosterone, is not informative, since the level of these hormones in the blood is low enough, in connection with which for the functional assessment of the state of the hypothalamic-pituitary-testicle system, stimulation tests should be performed.

Definition of karyotype. A standard chromosomal assay should be performed for all patients with primary congenital hypogonadism to exclude Klinefelter's syndrome and other possible chromosomal abnormalities.

MRI of the brain is performed for all patents with secondary hypogonadism for assessing the anatomical state of the hypothalamic structures, and the anterior pituitary gland.

[27], [28], [29], [30], [31], [32]

Differential diagnosis

Permanent hypogonadism must be differentiated with the so-called symptomatic hypogonadism, which can occur with hypothyroidism, thyrotoxicosis, hyperprolactinaemia, Ithenko-Cushing's disease and iatrogenic hypogonadism (due to toxic effects of environmental factors or medication).

Treatment of the hypogonadism

The diagnosis of "hypogonadism" is not sufficient for the purpose of pathogenetic therapy. It is necessary in each case to find out the nature and extent of the lesion of the sexual glands: whether the testicles are deficient in their direct damage or whether it is caused by a decrease in the gonadotropic activity of the hypothalamic-pituitary system. Hypogonadism, caused by the pathology of the sex glands themselves, is called primary, and resulting from a decreased secretion of gonadotropins - secondary.

If hypogonadism is a manifestation of another endocrine pathology, it is necessary to treat the underlying disease (prolactinoma, hypothyroidism, thyrotoxicosis, Ithenko-Cushing's disease, etc.). In the additional appointment of androgenic drugs such patients do not need.

If hypogonadism is an independent disease or symptom of the disease (panhypopituitarism, etc.), patients need constant replacement therapy with androgen drugs (primary, secondary hypogonadism) or with gonadotropin drugs (secondary hypogonadism), i.e. Prescribing drugs is life-long. The goal of pharmacotherapy of hypogonadism is complete normalization of the solo state: the disappearance of clinical symptoms of the disease and the restoration of secondary sexual characteristics. The dose of the drug is selected individually under the control of the testosterone level in the blood, which should always be within the normal range (13-33 nmol / l) against the background of the therapy.

To date, there is a large number of androgenic drugs on the pharmaceutical market for substitution treatment. Until now, injection molds of testosterone are most popular in many countries, including:

• propionate and phenylpropionate.
• capronate (decanoate) and isocapro- nate;
• ananthate;
• cypionate;
• undecanoate;
• bicyclate,
• a mixture of testosterone esters;
• testosterone microspheres.

Testosterone propionate has a short half-life of T1 / 2, it must be injected every 2-3 days, so as a monopreparation it is usually not used. Such ethers, as cypionate and enanthate, have an average duration of action, they are usually used every 7-14 days.

In our country, the most common combination drugs for intramuscular injection, containing a mixture of testosterone esters of capro- nate, isocapro- nate, propionate and phenylpropionate. Testosterone propionate starts to act quickly, but by the end of the first day its effect practically ceases, phenylpropionate and isocapro- nate begin to function about a day later, the action lasts up to two weeks, and the longest acting ether is capro- nate, its action can last up to 3-4 weeks .

Recently, testosterone esters have been synthesized, such as bucyclate and undecanoate, which last for up to three months. Approximately the same time of action and a special form of the drug - microencapsulated, from which gradually after injection, testosterone is released. However, all injection forms have a number of drawbacks - the need for colas, and most importantly, fluctuations in the concentration of testosterone in the blood from supra to subphysiological, which is felt by a number of patients. Recently, a new form of testosterone undecanoate for intramuscular injection has been synthesized, which has a duration of up to 12 weeks and does not have a peak concentration rise. However, this form is not registered in Ukraine.

Treatment of primary hypogonadism

A mixture of testosterone esters is used:

Testosterone propionate / phenylpropionate / capro- nate / isocapro- nate / intramuscularly / 30/60/100/60 mg (1.0) 1 time per day for life.

Control of testosterone levels in the blood is performed after 3 weeks and after injection. With insufficient testosterone content in the blood, the injection frequency is increased to 1 ml once every 2 weeks.

Treatment of secondary hypogonadism

Therapy in patients with normal testicle size

If fertility recovery is not required:

Testosterone propionate / phenylpropionate / capro- nate / isocapro- nate intramuscularly 30/60/100/60 mg (1.0) once every 3 weeks for life.

When choosing a dose of the drug, control of testosterone levels in the blood is performed 3 weeks after the last injection. If the testosterone content is lower than normal, the injection frequency is increased to 1 ml once every 2 weeks

If it is necessary to restore fertility therapy begins with the introduction of HC. His dose is selected strictly individually, under the control of testosterone levels in the blood, which should always be within the limits of normal indices (13-33 nmol / l). To stimulate spermatogenesis, not earlier than 3 months after the administration of HG, menopausal gonadotropin (menotropin) is added.

Gonadotropin chorionic intramuscular 1000-3000 units 1 time in 5 days, 2 years.

+

(3 months after the start of therapy)

Menotropins intramuscularly 75-150 IU 3 times a week, 2 years

Evaluation of the effectiveness of treatment for spermatogenesis is carried out not earlier than 6 months after the start of combined therapy with gonadotropins. If this therapy is ineffective after 2 years, they switch to androgen therapy, and the problem of infertile marriage is solved by IVF.

Therapy in patients with a decrease in the size of the testicles

Regardless of the expediency of restoring spermatogenesis to increase the size of the testicles, therapy begins with the use of gonadotropins:

Gonadotropin chorionic 1000-3000 ED 1 time in 5 days, long

The dose of chorionic gonadotropin is chosen strictly individually under the control of testosterone level in the blood, which should always be within the limits of normal indices (13-33 nmol / l). The testosterone level is estimated at the end of the first month of treatment on the 3-4th day after the last injection of the chorionic gonadotropin. If the content of testosterone is below the normal values (13-33 nmol / l), the dose of the drug is increased to 2000 units, the evaluation of the effectiveness of the therapy is repeated after 1 month. If the dose is ineffective: in 2000 units it must be increased to 3000 units. An increase in the dose above 3000 ED is impractical.

If the monotherapy of CG is ineffective, then combined therapy may be used.

Gonadotropin chorionic intramuscular 1000-3000 units once every 5 days, prolonged

Testosterone propionate / phenylpropionate / capro- nate / isocapro- nate intramuscularly 30/60/100/60 (1,0) every 4 weeks, for life

Assessment of the adequacy of the selected dose is carried out 4 weeks after the injection of a mixture of testosterone esters, 3-4 days after the next injection of HG.

Evaluation of treatment effectiveness

Evaluation of treatment effectiveness, independent of the normalization of clinical symptoms, should be led by a system under the control of hormonal parameters. The level of testosterone in the blood should be within the normal range (13-33 nmol / l). With secondary hypogonadism, the testosterone level is sufficient. With primary hypogonadism, it is also advisable to determine the level of LH, which should also be within normal limits (2.5-10 IU / L)

The adequacy of the selected dose is assessed at the end of the first month of treatment: on the 3-4th day after the last injection of HC or 3 weeks after the injection of a mixture of testosterone esters. Under normal conditions, it is advisable to repeat the control for 6 months. In the future, a laboratory examination is carried out once every 6-12 months.

Evaluation of spermatogenesis (it can recover with secondary hypogonadism) should be performed no earlier than 2 years from the start of the combined gonadotropins.

[33], [34], [35], [36], [37], [38], [39], [40], [41]

Complications and side effects of treatment

Side effects of the use of androgens develop when using inadequately high doses. Overdose of androgens leads to the appearance of:

• acne vulgaris;
• level of hematocrit.

[42], [43], [44], [45], [46], [47], [48], [49], [50]

Errors and unreasonable appointments

The most common mistakes associated with improper selection of a dose of a drug

Insufficient dose of androgens or hC leads to:

• development and progression of osteoporosis;
• violation of sexual function, which is manifested by a decrease in libido, insufficient erection, as well as a small amount of ejaculate;
• muscle weakness;
• depression;
• decrease in efficiency

Often there are mistakes caused by the wrong choice of the drug for the replacement therapy of hypogonadism:

• testosterone undecanoate (for oral administration) - given the low effectiveness of the drug, is only indicated for age-related androgen deficiency;
• chorionic gonadotropin - with primary hypogonadism, the application is unreasonable;
• meridional - take into account the lack of a full spectrum of androgen action is not indicated for constant therapy;
• fluoxymesterone, methyltestosterone cause liver damage - from increasing levels of enzymes in the blood and cholestasis before the development of peliosis (cysts filled with blood) and neoplasms, adversely affect lipid metabolism. Their use in many countries and Western Europe is generally stopped.

In rare cases, there are errors associated with the unreasonable use of androgenic drugs with symptomatic hypogonadism, which occurs against a background of hypothyroidism, thyrotoxicosis, hyperprolactinaemia, and Itenko-Cushing's disease. Also, there is often enough unreasonable prescription of androgenic drugs in athletes to increase muscle mass and physical activity. In cases of systematic hypogonadism, treatment of the underlying disease, which leads to independent recovery of testosterone secretion, is necessary. Additional androgenic drugs are not required.

[51], [52], [53], [54], [55]

Forecast

Adequate replacement therapy, as a rule, leads to an improvement in well-being and a reduction in symptoms. The beginning of hair growth on the trunk, limbs occurs within 6-8 months from the beginning of treatment. The growth of the penis in untreated patients is observed at any age during the first 6-10 months of treatment. Sexual function is restored within 1-2 months from the beginning of treatment. The ejaculation that was absent at the beginning of treatment is restored in 2-3 months. Normalization of bone tissue density is observed no earlier than 6-8 months after initiation of therapy

With the timely start of treatment for secondary hypogonadism, in some cases, restoration of spermatogenesis is possible. In patients with primary hypogonadism, recovery of spermatogenesis is impossible.

[56], [57]