Hypogonadism

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

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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, since hypogonadism contributes not only to the appearance of sexual disorders and a decrease in the quality of life, but also to the occurrence of osteoporosis and cardiovascular diseases.

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Causes hypogonadism

The causes of hypogonadism are polymorphic. Among congenital forms of hypogonadism, the main role is given to chromosomal and genetic anomalies, among acquired forms - to trauma and toxic effects, as well as brain tumors.

Secondary hypogonadism occurs due to decreased secretion of gonadotropic hormones and insufficient stimulation of the sex glands by them. Secondary hypogonadism can also develop with Itsenko-Cushing's disease, myxedema, adrenal cortex tumors and other endocrine diseases. Signs of hypogonadism can also appear with some non-endocrine diseases, such as liver cirrhosis. Hypogonadism can occur with a developmental defect of the male reproductive system - cryptorchidism.

Primary hypogonadism is accompanied by hypersecretion of gonadotropic hormones and is called hypergonadotropic hypogonadism. In secondary hypogonadism, there is a decrease in the secretion of gonadotropic hormones - this is hypogonadotropic hypogonadism. Determining the form of hypogonadism is important for the doctor, since the appointment of adequate treatment depends on it. Less common is normogonadotropic hypogonadism, which is characterized by low production of T with 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 the testicles, but also in the latent insufficiency of the hypothalamic-pituitary regulation.

Symptoms hypogonadism

Symptoms of hypogonadism depend not only on the degree of deficiency of sex hormones in the body, but also on the age (including the intrauterine period of life) at which the disease arose. Embryonic, prepubertal and postpubertal forms of hypogonadism are distinguished.

Embryonic forms of androgen deficiency are manifested by anorchism. Androgen deficiency that occurs in the early embryonic period (before the 20th week) leads to severe pathology - hermaphroditism.

Prepubertal, as well as embryonic, forms of hypogonadism are accompanied by the absence (or weak expression) of secondary sexual characteristics and the formation of eunuchoid syndrome. The term "eunuchoidism" was proposed by Griffith and Duckworth, it was introduced into clinical terminology in 1913 by Tandler and Gross. Patients with this syndrome, as a rule, are distinguished by tall stature, disproportionate body build (long limbs, relatively shortened torso). Skeletal muscles are poorly developed, often there is a deposition of subcutaneous fat according to the female type, true gynecomastia.

The skin is pale, secondary hair growth does not appear during puberty or is very sparse. The voice does not mutate - it remains high in tone. The genitals are underdeveloped: the penis is small, the testicles are reduced or absent, the scrotum is insufficiently pigmented, atonic, without the folds characteristic of adult men.

Main symptoms of hypogonadism

• Decreased libido.
• Erectile dysfunction.
• Decreasing the intensity of orgasm.
• Deterioration of spermogram parameters.
• Increased irritability.
• Decreased ability to concentrate.
• Decrease in cognitive function, memory impairment.
• Depression.
• Insomnia.
• Decreased muscle mass and strength
• Decreased vital energy.
• Bone pain due to osteoporosis.
• Reduction of pubic hair.
• Decreased size and density of the testicles.
• Gynecomastia.
• Increased amount of adipose tissue.
• Vasomotor disorders (sudden hyperemia of the face, neck, upper body, feeling of heat (“hot flashes”), fluctuations in blood pressure, cardialgia, dizziness, feeling of shortness of breath).
• Decreased skin tone and thickness.

Postpubertal forms of hypogonadism are characterized by the disappearance of secondary sexual characteristics in initially healthy sexually mature men: decreased facial and body hair, thinning scalp hair, testicular hypoplasia, and impaired sexual function (decreased sexual desire; decreased and weakened erections; changes in the duration of sexual intercourse, weakening and sometimes disappearance of orgasm). Some patients experience vegetative-vascular disorders and increased fatigue.

To detect deviations in the male phenotype, careful clarification of the anamnesis is necessary. Incorrect presentation of the fetus, prematurity, difficult labor should alert the doctor to the possibility of androgen deficiency in the future. It is necessary to pay attention to the constitutional features of the patient. Cryptorchidism detected in boys indicates the possibility of testicular deficiency.

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

Hypogonadism may be accompanied by gynecomastia, which also occurs in other pathological conditions not associated with pathology of the male gonads, such as liver cirrhosis. Testicular damage may be combined with dysfunction of the olfactory organs.

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Forms

Various classifications of hypogonadism in men have been published - L. M. Skorodok et al., B. Clayton et al., E. Teter.

Primary hypogonadism (hypergonadotropic) - caused by damage to Leydig cells

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

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

• Congenital:
  • Kallman syndrome;
  • isolated luteinizing hormone deficiency;
  • pituitary dwarfism;
  • craniopharyngioma;
  • Maddock syndrome.
• Acquired:
  • infectious and 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 duration of the disease:

• permanent hypogonadism. In most cases, hypogonadism is a lifelong chronic disease;
• transient (symptomatic) hypogonadism. In some cases, with a number of endocrine diseases (hypothyroidism, hyperprolactinemia, decompensation of diabetes mellitus, obesity), as well as liver or kidney dysfunction or under the influence of drugs (iatrogenic hypogonadism), hypogonadism is temporary, does not require independent treatment, since the secretion of androgens is restored after treatment of the underlying disease and elimination of factors that suppress testosterone synthesis.

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

Hypofunction of male gonads is diagnosed, in addition to anamnesis data, biotopological examination, based on X-ray examination of the skull and hands with wrist joints, determination of sex chromatin and karyotype, morphological and chemical analysis of ejaculate, and, if necessary, testicular biopsy. The most informative is direct determination of the plasma level of gonadotropins (LH and FSH), testosterone (T) and, if indicated, prolactin (PRL).

Less informative are the indicators of urinary excretion of 17-ketosteroids (17-KS). Determination of plasma hormone levels allows to establish the diagnosis of primary or secondary hypogonadism. High content of gonadotropins in it indicates primary (hypergonadotropic) hypogonadism, low - secondary (hypogonadotropic) hypogonadism. There may be forms of hypogonadism with isolated deficiency of LH and FSH. Determination of plasma prolactin level is of great importance, which allows to classify some forms of hypogonadism into the group of hyperprolactinemic hypogonadism.

Ejaculate examination characterizes the state of the reproductive function of the testicles. Normal ejaculate indicates a sufficient level of sex hormones in the patient's body. This is the simplest and most accessible method that allows indirectly judging the hormonal status of the reproductive system in men. Testicular biopsy reveals the state of spermatogenesis and has great diagnostic value in case of obstruction of the vas deferens.

The method of ultrasound scanning of the pelvic organs is becoming increasingly widespread, allowing one to judge the location of the testicles in cryptorchidism, as well as their size.

The examination should include the following diagnostic methods

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

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

• LH and FSH;
• testosterone;
• GSPG;
• estradiol,
• prolactin;
• TSH

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

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. These processes are most indicative in the bones of the wrist and hand. Bone age allows for a fairly accurate determination of the onset of puberty.

Thus, the increase in testicle volume (the first sign of puberty) corresponds to a bone age of 13.5-14 years, and the pubertal growth spurt occurs at a bone age of 14 years. After pubertal activation of the gonadal function, synostosis of the epiphysis with the metaphysis in the first metacarpal bone occurs. Complete sexual maturity is radiologically characterized by the disappearance of transverse striations in the long tubular bones of the forearm at the site of the closed epiphyseal lines. This allows one to immediately distinguish prepubertal biological age from pubertal age, since the appearance of sesamoid bones 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 an infantile state. The presence of synostoses in the first metacarpophalangeal articulation indicates the active inclusion of the function of the sex glands. In this case, it is necessary to take into account the state of other endocrine glands that also affect skeletal differentiation (adrenal glands, thyroid gland, etc.).

The patient's bone age is determined by comparing the results of the study of X-ray images of the hands (identification of phases and stages of osteogenesis) with the corresponding standards. When determining the bone age, it is necessary to take into account other signs of osteogenesis disorders (asymmetry of ossification, distortion of the order of osteogenesis, etc.) and pay attention to its extreme variants (the earliest and latest time of appearance of ossification points and development of synostoses), which can be caused by various and, in particular, hereditary factors.

It is important to remember that there are differences in bone age among residents of different latitudes. It is well known that puberty among residents of southern latitudes occurs earlier than among their peers in the North. At the same time, in a number of ethnographic regions of the world, almost identical data on the maturation of the bone skeleton can be found. This is due to a number of features, primarily climatic factors. When using the presented table of bone age, attention should be paid to the extreme variants of the earliest and latest ossification periods, taking into account the patient's place of residence.

Ossification time of the hand and distal forearm in males (years)

Ossification points and synostoses	Deadlines
	The earliest	The latest	Average
Distal epiphysis of the ulna	6	10	7-7,1/2
Styloid process of the ulna	7	12	9,1/2-10
Pisiform bone	10	13	11-12
Sesamoid bones in the first metacarpophalangeal joint	11	15	13,1/2-14
Synostoses:
In the first metacarpal bone	14	17	15,1/2-16
In the II-V metacarpal bones	14	19	1b,1/2-17
In the terminal phalanges	14	18	16-1b,1/2
In the main »	14	19	1b,1/2-17
In the middle »	14	19	1b,1/2-17
Distal epiphysis of the ulna	16	19	17-18
Distal epiphysis of the radius	16	20	18-19

Before puberty, routine hormonal testing, including determination of LH, FSH and testosterone levels, is not informative, since the level of these hormones in the blood is quite low, and therefore stimulation tests should be performed to functionally assess the state of the hypothalamic-pituitary-testicular system.

Karyotype determination. Routine chromosome analysis should be performed in all patients with primary congenital hypogonadism to exclude Klinefelter syndrome and other possible chromosomal abnormalities.

MRI of the brain is performed on all patients with secondary hypogonadism to assess the anatomical state of the hypothalamic structures and the anterior pituitary gland.

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Differential diagnosis

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

Treatment hypogonadism

The diagnosis of hypogonadism is not sufficient to prescribe pathogenetic therapy. It is necessary to determine in each specific case the nature and extent of the damage to the sex glands: whether the testicular insufficiency is associated with their direct damage or is caused by a decrease in the gonadotropic activity of the hypothalamic-pituitary system. Hypogonadism caused by pathology of the sex glands themselves is called primary, and that resulting from reduced secretion of gonadotropins is called secondary.

If hypogonadism is a manifestation of another endocrine pathology, it is necessary to treat the underlying disease (prolactinoma, hypothyroidism, thyrotoxicosis, Itsenko-Cushing disease, etc.). Such patients do not need additional administration of androgenic drugs.

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

Today, there are a large number of androgen replacement therapy drugs on the pharmaceutical market. In many countries, the most popular are still injection forms of testosterone ester, which include:

• propionate and phenylpropionate.
• caproate (decanoate) and isocaproate;
• anantat;
• cypionate;
• undecanoate;
• buciclat,
• testosterone ester mixture;
• testosterone microspheres.

Testosterone propionate has a short half-life T1/2, it must be administered every 2-3 days, so it is not usually used as a monodrug. Esters such 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 contain a mixture of esters of testosterone capronate, isocaproate, propionate and phenylpropionate. Testosterone propionate begins to act quickly, but by the end of the first day its effect practically ceases, phenylpropionate and isocaproate begin to act in about a day, the effect lasts up to two weeks, and the longest-acting ester is capronate, its effect can last up to 3-4 weeks.

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

Treatment of primary hypogonadism

A mixture of testosterone esters is used:

Testosterone propionate / phenylpropionate / capronate / isocaproate / intramuscularly / 30 / 60 / 100 / 60 mg (1.0) 1 time per day for life.

The testosterone level in the blood is monitored after 3 weeks and after the injection. If the testosterone level in the blood is insufficient, the injection frequency is increased to 1 ml once every 2 weeks.

Treatment of secondary hypogonadism

Therapy in patients with normal testicular size

If fertility restoration is not required:

Testosterone propionate / phenylpropionate / capronate / isocaproate intramuscularly 30 / 60 / 100 / 60 mg (1.0) once every 3 weeks for life.

When selecting the dose of the drug, the level of testosterone in the blood is monitored 3 weeks after the last injection. If the testosterone content is below normal levels, the frequency of injections is increased to 1 ml once every 2 weeks.

If fertility restoration is necessary, therapy begins with the administration of hCG. Its dose is selected strictly individually under the control of the testosterone level in the blood, which should always be within normal limits (13-33 nmol/l) during the therapy. To stimulate spermatogenesis, menopausal gonadotropin (menotropins) is added no earlier than 3 months after the administration of hCG.

Human chorionic gonadotropin intramuscularly 1000-3000 U once every 5 days, 2 years.

+

(after 3 months from the start of therapy)

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

The evaluation of the treatment effectiveness in relation to spermatogenesis is carried out no earlier than 6 months after the start of combined therapy with gonadotropins. If this therapy is ineffective after 2 years, they switch to therapy with androgen drugs, and the problem of infertility is solved with the help of IVF.

Therapy in patients with testicular shrinkage

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

Human chorionic gonadotropin 1000-3000 IU once every 5 days, long-term

The dose of human chorionic gonadotropin is selected strictly individually under the control of the blood testosterone level, which should always be within the normal range (13-33 nmol/l) during the therapy. The testosterone level is assessed at the end of the first month of treatment on the 3-4th day after the last injection of human chorionic gonadotropin. If the testosterone content is below normal (13-33 nmol/l), the dose of the drug is increased to 2000 IU, the assessment of the therapy effectiveness is repeated after 1 month. If the dose is ineffective: 2000 IU, it must be increased to 3000 IU. Increasing the dose above 3000 IU is inappropriate.

If monotherapy with hCG is ineffective, combination therapy may be used.

Human chorionic gonadotropin intramuscularly 1000-3000 IU once every 5 days, long-term

Testosterone propionate / phenylpropionate / capronate / isocaproate intramuscularly 30 / 60 / 100 / 60 (1.0) once every 4 weeks, lifelong

The adequacy of the selected dose is assessed 4 weeks after the injection of the testosterone ester mixture, 3-4 days after the next injection of hCG.

Evaluation of treatment effectiveness

Evaluation of the effectiveness of treatment, regardless of the normalization of clinical symptoms, should be carried out under the control of hormonal parameters. The level of testosterone in the blood should be within the normal range (13-33 nmol/l). In secondary hypogonadism, determining the level of testosterone is sufficient. In primary hypogonadism, it is also advisable to determine the level of LH, which, with an adequately selected dose, should also be within the normal range (2.5-10 IU/l)

The adequacy of the selected dose is assessed at the end of the first month of treatment: on the 3rd-4th day after the last injection of hCG or 3 weeks after the injection of a mixture of testosterone esters. If the indicators are normal, it is advisable to conduct a repeat check after 6 months. Subsequently, laboratory testing is performed once every 6-12 months.

Evaluation of spermatogenesis (it can be restored in secondary hypogonadism) should be carried out no earlier than 2 years after the start of combined gonadotropin therapy.

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Complications and side effects of treatment

Side effects of androgen use develop when using inadequately high doses. Androgen overdose leads to the appearance of:

• acne vulgaris;
• hematocrit level.

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Errors and unjustified appointments

The most common errors are related to the incorrect selection of the dosage of the drug.

Insufficient androgen or hCG dosage leads to:

• development and progression of osteoporosis;
• sexual dysfunction, which is manifested by decreased libido, insufficient erection, and small volume of ejaculate;
• muscle weakness;
• depression;
• decreased performance

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

• testosterone undecanoate (for oral administration) - given the low effectiveness of the drug, it is indicated only for age-related androgen deficiency;
• human chorionic gonadotropin - its use in primary hypoganadism is unjustified;
• mesterolone - take into account the lack of a full spectrum of androgen action, it is not indicated for continuous therapy;
• Fluoxymesterone, methyltestosterone cause liver damage - from increased levels of enzymes in the blood and cholestasis to the development of peliosis (cysts filled with blood) and neoplasms, negatively affect lipid metabolism. Their use in many countries and Western Europe has been discontinued altogether.

In rare cases, there are errors associated with the unjustified prescription of androgenic drugs for symptomatic hypogonadism, which occurs against the background of hypothyroidism, thyrotoxicosis, hyperprolactinemia, Itsenko-Cushing's disease. Also quite often there is an unjustified prescription of androgenic drugs in athletes to increase muscle mass and physical activity. In cases of systematic hypogonadism, it is necessary to treat the underlying disease, which leads to independent restoration of testosterone secretion. Additional prescription of androgenic drugs is not required.

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Forecast

Adequate replacement therapy usually leads to improved well-being and reduced symptoms. Hair growth on the trunk and limbs begins within 6-8 months from the start of treatment. Penis growth in previously 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 start of treatment. Ejaculation, which was absent at the start of treatment, is restored after 2-3 months. Normalization of bone density is noted no earlier than 6-8 months from the start of therapy.

With timely initiation of treatment for secondary hypogonadism, spermatogenesis may be restored in some cases. In patients with primary hypogonadism, spermatogenesis cannot be restored.

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