Hypogonadism

Hypogonadism is a syndrome accompanied by insufficiency of the functions of the sex glands and a violation of the synthesis of sex hormones. Hypogonadism, as a rule, is accompanied by underdevelopment of external or internal genitalia, secondary sexual characteristics, disorders of fat and protein metabolism (obesity or cachexia, changes in the bone system, cardiovascular disorders). Diagnosis and therapy of hypogonadism is carried out by the joint work of endocrinologists, gynecologists and gynecologists-endocrinologists (in women), andrologists (in men). The basis of treatment of hypogonadism is hormone replacement therapy. If necessary, surgical correction, plastic surgery and prosthetics of the genitals are performed.

Hypogonadism in men

Classification 

Hypogonadism is divided into primary and secondary. Primary hypogonadism is caused by a violation of the function of testicular tissue due to a defect of the testicles themselves. Chromosomal abnormalities can lead to aplasia or hypoplasia of testicular tissue, which is manifested by the lack of androgen secretion or their insufficiency for the normal formation of genitals and secondary sexual characteristics.

The occurrence of secondary hypogonadism is caused by a violation of the pituitary gland structure, a decrease in its gonadotropic function or a lesion of the hypothalamic centers regulating the pituitary gland. Primary hypogonadism, which develops in early childhood, is accompanied by mental infantilism, secondary – mental disorders.

Hypogonadotropic, hypergonadotropic and normogonadotropic hypogonadism are also distinguished. Hypergonadotropic hypogonadism is manifested by primary lesion of testicular testicular tissue in combination with elevated levels of pituitary gonadotropins. Hypogonadotropic and normogonadotropic hypogonadism occur when the hypothalamic-pituitary system is affected. Hypogonadotropic hypogonadism is associated with a decrease in the secretion of gonadotropins, as a result of which the production of androgens by testicular testicular tissue decreases. Normogonadotropic hypogonadism is caused by hyperprolactinemia, manifested by normal gonadotropin levels and reduced testicular function of the testicles.

Both primary and secondary hypogonadism can be congenital and acquired. Some forms of male infertility can serve as a manifestation of hypogonadism (from 40 to 60% of all cases of male infertility). Depending on the age of development of sex hormone deficiency, there are different embryonic, pre-pubertal (from 0 to 12 years) and post-pubertal forms of hypogonadism.

Congenital primary (hypergonadotropic) hypogonadism occurs:

• with anorhism (aplasia) of the testicles;
• in violation of omission (cryptorchidism and ectopia) of the testicles;
• with true chromatin-positive Klinefelter syndrome (combines testicular hypoplasia, hyalinosis of the walls and dysgenesis of the seminal tubules, gynecomastia, often accompanied by azoospermia (absence of spermatozoa). Testosterone production is reduced by about 50%.
• with Shereshevsky—Turner syndrome (chromosomal disease with characteristic disorders of physical development: stunting and lack of sexual development, rudimentary testes);
• with sertoli-cell syndrome or del Castillo syndrome (underdevelopment of the testicles with normal or increased amounts of gonadotropins). With this syndrome, spermatozoa are not formed, patients are infertile. Physical development occurs according to the male type;
• with incomplete masculinization syndrome – false male hermaphroditism. The reason is a decrease in tissue susceptibility to androgens.

Acquired primary hypogonadism develops as a result of the impact of internal or external factors on the testicles after birth.

• with injuries, testicular tumors and early castration, it is manifested by a picture of typical eunuchism – total hypogonadism;
• with insufficiency of the germinative epithelium (false Klinefelter syndrome). It is characterized by high growth, eunuchoid physique, gynecomastia, insufficiently developed secondary sexual characteristics, small size of the genitals. By puberty, patients develop eunuchoid traits, and subsequently fertility is reduced.

Congenital secondary (hypogonadotropic) hypogonadism develops in conditions of:

• associated with damage to the hypothalamus – an isolated form with damage only to the reproductive system. It is characterized by a total deficiency of gonadotropins, while there may be a deficiency of lutropin or folitropin;
• in Kallman’s syndrome, it is characterized by gonadotropin deficiency, underdevelopment of the genitals and secondary sexual characteristics, a decrease or absence of sense of smell (hyposmia or anosmia). Eunuchoidism is noted (often in combination with cryptorchidism), various malformations: splitting of the upper lip and hard palate, shortening of the frenulum of the tongue, facial asymmetry, six–fingered, gynecomastia, cardiovascular disorders.
• with pituitary nanism (pituitary dwarfism). There is a sharp decrease in somatotropic, luteinizing, follicle-stimulating, thyroid-stimulating and adrenocorticotropic hormones, which is manifested by a violation of the function of the testicles, adrenal glands and thyroid gland. It is characterized by a lack of sexual characteristics, dwarf growth of less than 130 cm, infertility.
• with congenital pangypopituitarism (craniopharyngioma) caused by a congenital brain tumor. Growing, it squeezes the tissues of the pituitary gland, disrupting its functions. The production of gonadotropins, as well as hormones regulating the functions of the adrenal cortex and thyroid gland, decreases. Leads to a lag in the physical and sexual development of the child.
• in Maddock syndrome, an extremely rare form of hypogonadism that occurs when the gonadotropic and adrenocorticotropic functions of the pituitary gland are insufficient. It is characterized by a gradual increase in hypocorticism. After puberty, there is a lack of function of the genital glands – eunuchoidism, hypogenitalism (underdevelopment of the genitals and secondary sexual characteristics), impotence, infertility.

Acquired secondary hypogonadism develops when:

• adiposogenital dystrophy – manifested by obesity and hypogenitalism. The insufficiency of the gonadotropic function of the pituitary gland is noted. It manifests itself from the age of 10-12. Hypothalamic-pituitary pathology with pronounced clinical symptoms is not observed. Eunuchoid proportions of the skeleton are characteristic, usually sexual dysfunction and infertility. Due to dystrophic changes in the heart and vascular hypotension, shortness of breath, biliary dyskinesia, flatulence may develop.
• Lawrence–Moon–Bardet-Bidl syndrome (LMB), Prader-Willi syndrome. LMB syndrome is manifested by obesity, low intelligence, retinal pigmented dystrophy and polydactyly. Cryptorchidism, testicular hypoplasia, gynecomastia, erectile dysfunction, scant facial hair, armpits, pubic area, kidney development defects are possible. Prader–Wili syndrome, unlike LMB syndrome, has multiple anomalies (Gothic palate, epicanthus, etc.), pronounced muscle weakness against the background of a decrease in the amount of androgens and gonadotropins in the blood. Both syndromes are attributed to functional disorders of the pituitary gland and hypothalamus.
• hypothalamic syndrome due to damage to the hypothalamic-pituitary region as a result of an infectious-inflammatory, tumor process, traumatic brain injury.
• hyperprolactinemic syndrome – accompanies infertility and disorders of sexual function, and it occurs in childhood and adolescence, causes a delay in sexual development and hypogonadism.

Causes

Androgen deficiency may be caused by a decrease in the amount of hormones produced or a violation of their biosynthesis as a result of pathology of the testicles themselves or a violation of hypothalamic-pituitary regulation.

Etiological factors of primary hypogonadism are often:

• congenital underdevelopment of the genital glands that occurs with genetic defects – for example, dysgenesis (violation of the tissue structure) seminal tubules; dysgenesis or aplasia of the testicles (anarchism, monarchism). Harmful effects on the pregnant woman’s body play a negative role in the occurrence of congenital pathology. A violation of testicular prolapse can lead to a hypogonadal state.
• toxic effects (chemotherapy of malignant tumors, organic solvents, nitrofurans, pesticides, alcohol, tetracyclines, hormonal drugs in large doses, etc.)
• infectious diseases (epidemic mumps, measles orchitis, epididymitis, deferentitis, vesiculitis)
• radiation damage (in contact with X–rays, radiation therapy)
• acquired testicular injuries – trauma, torsion of the spermatic cord, varicocele, testicular inversion; testicular atrophy and hypoplasia after operations of orchipexy, herniation, surgical interventions on the organs of the scrotum.

Some cases of primary hypogonadism are idiopathic. Modern endocrinology does not have sufficient data on the etiology of idiopathic hypogonadism.

With primary hypogonadism, there is a decrease in the level of androgens in the blood, the development of a compensatory reaction of the adrenal glands to hypoandrogenization, an increase in the production of gonadotropins.

Disorders of hypothalamic-pituitary regulation (inflammatory processes, tumors, vascular disorders, pathology of embryonic development) lead to secondary hypogonadism. The development of hypogonadism can be caused by pituitary adenomas producing growth hormone (with acromegaly) or adrenocorticotropic hormone (with Cushing’s disease), prolactinoma, postoperative or post-traumatic hypothalamic-pituitary dysfunction, hemochromatosis, aging processes accompanied by an age-related decrease in blood testosterone levels.

With secondary hypogonadism, there is a low level of gonadotropins, leading to a decrease in the secretion of androgens by the testicles.

One of the forms of male hypogonadism is a decrease in sperm production at normal testosterone levels, as well as extremely rare cases of a decrease in testosterone levels without a decrease in sperm production.

Symptoms

Clinical manifestations of hypogonadism are due to the age of onset of the disease and the degree of androgen deficiency. Violation of androgen production in the prenatal period can lead to the development of bisexual external genitalia.

If testicular lesion occurred in boys in the pre-pubertal period, sexual development is delayed, typical eunuchoidism is formed: disproportionately high growth associated with delayed ossification of epiphyseal (growth) zones, undeveloped chest and shoulder girdle, long limbs, underdeveloped skeletal muscles. There may be the development of female-type obesity, true gynecomastia, hypogenitalism, which manifests itself in the small size of the penis, lack of pigmentation and folding of the scrotum, testicular hypoplasia, underdevelopment of the prostate gland, lack of facial and pubic hair, underdevelopment of the larynx, high voice.

In cases of secondary hypogonadism, obesity often occurs, symptoms of hypofunction of the adrenal cortex, thyroid gland, manifestations of panhypopituitarism, lack of sexual desire and potency are possible.

If a decrease in testicular function develops after puberty, then the symptoms of hypogonadism are less pronounced. There is a decrease in the size of the testicles, slight facial and body hair, female-type fat deposits, loss of elasticity and thinning of the skin, infertility, decreased sexual function, vegetative-vascular disorders.

Testicular reduction is observed in almost all cases of male hypogonadism (the exception is if the disease started recently). A decrease in testicular size is usually closely related to a decrease in sperm production. With the loss of the sperm-producing function of the testicles, infertility develops with the cessation of testosterone production, libido decreases, regression of secondary sexual characteristics occurs, erectile dysfunction, generalized symptoms are noted (decreased muscle strength, fatigue, general weakness).

Diagnostics

It is based on patient complaints, anamnesis data, a study of the general status using anthropometry, examination and palpation of the genitals, assessment of clinical symptoms of hypogonadism, the degree of puberty.

According to the X-ray examination, the bone age is estimated. To determine the mineral saturation of bones, densitometry is performed. Radiography of the Turkish saddle determines its size and the presence of a tumor. The assessment of bone age allows for the timing of ossification of the wrist joint and hand to accurately determine the onset of puberty. The onset of puberty is associated with the formation of the sesamoid bone in the I metacarpophalangeal joint (approximately 13.5 — 14 years). The appearance of anatomical synostoses indicates full puberty. This feature makes it possible to distinguish pre-puberty from puberty. When assessing bone age, it is necessary to take into account the possibility of earlier (for patients from southern regions) and later (for patients from northern regions) ossification, as well as the fact that osteogenesis disorder may be caused by other factors. With pre-pubertal hypogonadism, there is a lag of several years of the “bone” age from the passport.

Laboratory examination of semen analysis (spermogram) in hypogonadism is characterized by azo- or oligospermia; sometimes it is not possible to get an ejaculate. The level of sex and gonadotropins is measured: serum testosterone (total and free), luteinizing, follicle-stimulating hormone and gonadoliberin, as well as anti-Muller serum hormone, prolactin, estradiol. The testosterone content in the blood is reduced.

With primary hypogonadism, the level of gonadotropins in the blood is increased, with secondary – it is lowered, sometimes their content is within the normal range. Determination of the serum estradiol level is necessary for clinically pronounced feminization and secondary hypogonadism, in the case of estrogen-producing testicular or adrenal tumors. The level of 17-CS (ketosteroids) in the urine with hypogonadism may be normal or decreased. If Klinefelter syndrome is suspected, a chromosomal analysis is indicated. Testicular biopsy rarely provides information for diagnosis, as well as assessment of prognosis or treatment.

Treatment

Hypogonadism therapy is carried out strictly individually, and is aimed at eliminating the cause of the disease. The purpose of the treatment is to prevent the lag of sexual development, in the future – malignancy of testicular tissue of the testicles and infertility. Treatment of hypogonadism should be carried out under the supervision of a urologist and an endocrinologist.

Treatment of hypogonadism depends on its clinical form, the severity of disorders in the hypothalamic-pituitary and reproductive systems, concomitant pathologies, the time of onset of the disease and the age of diagnosis. Therapy of hypogonadism begins with the treatment of the underlying disease. Treatment of adult patients consists in the correction of androgen deficiency and sexual dysfunction. Infertility caused by congenital and pre-pubertal hypogonadism is incurable, especially in the case of aspermia.

In the case of primary congenital and acquired hypogonadism (with preserved reserves of endocrinocytes in the testicles), stimulating therapy is used: in boys – with non-hormonal drugs, and in adult patients – with hormonal agents (small doses of gonadotropins, androgens). In the absence of the reserve ability of the testicles, the replacement intake of androgens (testosterone) is shown constantly, throughout life. With secondary hypogonadism in both children and adults, it is necessary to use stimulating hormone therapy with gonadotropins (if necessary, combining them with sex hormones). It is also shown to conduct general strengthening therapy, physical therapy.

Surgical treatment of hypogoandism consists in testicular transplantation, testicular reduction in the case of cryptorchidism, with penile underdevelopment – phalloplasty. For cosmetic purposes, a synthetic testicle is implanted (in the absence of an undescended testicle in the abdominal cavity). The operations are performed using microsurgical techniques with the control of the immunological and hormonal status of the patient and the transplanted organ. In the process of systematic treatment of hypogonadism, androgen deficiency decreases: the development of secondary sexual characteristics resumes, potency is partially restored, the severity of concomitant manifestations decreases (osteoporosis, “bone age” lag, etc.).

Hypogonadism in women

Female hypogonadism is characterized by underdevelopment and hypofunction of the genital glands – ovaries. Primary hypogonadism is caused either by congenital underdevelopment of the ovaries, or by damage to them during the newborn period. There is a deficiency of female sex hormones in the body, which causes an increase in the production of gonadotropins that stimulate the ovaries in the pituitary gland. In the blood serum, there is a high level of follicle-stimulating and luteinizing hormones (hypergonadotropic hypogonadism) and a low concentration of estrogens.

Estrogen deficiency causes underdevelopment and atrophic changes in the female genital organs, mammary glands, primary amenorrhea. If a violation in the ovaries occurred in the pre-puberty period, then there are no secondary sexual characteristics.

The causes of primary hypergonadotropic hypogonadism are congenital genetic disorder (Shereshevsky-Turner syndrome), congenital ovarian hypoplasia, infectious processes (syphilis, tuberculosis, mumps), ionizing radiation (radiation, X-ray), surgical removal of the ovaries, autoimmune ovarian lesion (autoimmune oophoritis), testicular feminization syndrome (a congenital condition in which the external the type of person corresponds to a woman with a male genotype), polycystic ovary syndrome.

Secondary female hypogonadism (hypogonadotropic) occurs with hypothalamic-pituitary pathology, characterized by a deficiency or complete cessation of the synthesis and secretion of gonadotropins regulating the function of the ovaries. It develops as a result of inflammatory processes in the brain (encephalitis, meningitis, arachnoiditis), the damaging effect of brain tumors and is accompanied by a decrease in the stimulating effect of gonadotropins on ovarian function.

Symptoms

One of the main symptoms of hypogonadism in the childbearing period is a violation of the menstrual cycle and amenorrhea. The lack of female sex hormones leads to underdevelopment of sexual characteristics: genitals, mammary glands, violation of the deposition of adipose tissue according to the female type, scant hair loss. If the disease is congenital, or it occurred in early childhood, then there are no secondary sexual characteristics. A narrow pelvis and flat buttocks are characteristic. If hypogonadism has developed in the puberty period, the sexual characteristics that have already developed remain, but menstruation stops, the tissues of the female genitals undergo atrophy.

Diagnostics

With hypogonadism, there is a noticeable decrease in the content of estrogens in the blood, an increase in the level of gonadotropins (follicle-stimulating and luteinizing hormones). Ultrasound examination reveals a uterus reduced in size (uterine hypoplasia), reduced ovaries. Radiography detects osteoporosis or delayed skeletal formation.

Treatment

With primary hypogonadism in women, drug replacement therapy with female sex hormones (ethinyl estradiol) is prescribed. In the event of a menstrual-like reaction, combined oral contraceptives containing two types of hormones – estrogens and progestogens are prescribed. Women over 40 are prescribed estradiol + ciproterone, estradiol + norethisterone. Hormone replacement therapy is contraindicated in malignant tumors of the mammary glands and genitals, cardiovascular diseases, kidney diseases, liver, thrombophlebitis, etc.

The prognosis for life with hypogonadism is favorable. Prevention of hypogonadism consists in health education of the population, observation of pregnant women and protection of their health.