Introduction
Male Infertility Review
About 15% of married couples fail when trying to get pregnant the first time. Most doctors diagnose primary infertility in cases where pregnancy does not occur within one year of regular sexual activity without contraception. According to statistics, 80-85% of married couples conceive within 12 months of sexual activity without contraception, and situations where pregnancy has not occurred during this period of time are regarded as possible infertility, and examination is recommended for patients. The data obtained over the past 20 years shows that in approximately 30% of cases of problems with conception, only the male factor plays a role, and approximately 20% of the violations are found both in the husband and in the wife. Thus, the male factor, at least partially, plays a role in 50% of cases of infertility.
The most important problems in identifying the male factor of infertility relate to the timing of the start of the examination, the most effective examination scheme for men and the most rational forms of therapeutic and surgical treatment methods. When solving the problem of infertility, it is extremely important to consider the married couple, as a whole, to ensure the simultaneous examination and treatment of both spouses. It was shown that the longer the period of infertility, the lower the chances of a married couple to achieve a positive result. Many families begin to worry after a few months of non-occurrence of pregnancy. In such cases, it is not recommended to continue to expect pregnancy without examining the husband. The initial stages of the examination of men should be carried out whenever patients make the main complaint of infertility. Such an examination should be fast, non-invasive and inexpensive. It is curious that in almost 50% of cases of successful treatment of infertility, when only a wife was examined and treated, her husband's spermogram revealed violations that could be regarded as moderately severe.
Male reproductive physiology
Axis hypothalamus-pituitary-testes
The hypothalamus is the main integrative center of the functional reproductive system in men. Obtaining information from the central nervous system and testicles, the hypothalamus regulates the formation and secretion of gonadotropin-releasing hormone (GRG). Neurotransmitters and neuropeptides have both inhibitory and stimulating effects on the hypothalamus. Gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus in a pulsating mode, which is an essential part of stimulating the synthesis and secretion of both pituitary gonadotropins (LH and FSH). It is interesting and paradoxical that the appointment of GnRH not in a pulsed, but in a constant mode after the initial stimulation of the release of gonadotropins of the pituitary gland leads to inhibition of the release of LH and FSH. Both luteinizing (LH) and follicle-stimulating (FSH) hormone are formed in the anterior lobe of the pituitary gland and are secreted in a pulsed mode in response to pulsating GnRH production. In the testicles, LH and FSH bind to specific receptors on Leydig and Sertoli cells. Testosterone, the main product of internal secretion of the testicle, is the main inhibitor of pituitary luteinizing hormone secretion in men. In peripheral tissues, testosterone can turn into a more powerful androgen dihydrotestosterone or a powerful estrogen - estradiol. The resulting androgens and estrogens independently regulate the secretion of LH.
The production of FSH is regulated by the feedback mechanism of the inhibin formed in Sertoli cells. The deterioration of spermatogenesis is accompanied by a decrease in the formation of inhibin and, as a consequence (by a mechanism of negative feedback), an increase in the secretion of FSH. An isolated increase in FSH levels is an important marker of the state of the germ cell epithelium of the testicles.
Prolactin secretion also has a complex relationship with the pituitary gonadotropic hormones. In men with hyperprolactinemia, elevated prolactin levels have an inhibitory effect on GnRH secretion. In addition to suppressing LH secretion and testosterone production, an increase in prolactin level can have a direct effect on the state of the central nervous system. In men with hyperprolactinemia who received testosterone replacement therapy, libido and sexual function did not recover until there was a decrease in prolactin levels.
Testicles
Leydig cells
Testosterone is secreted in a pulsed mode by Leydig cells in response to pulsating secretion of LH. Testosterone is characterized by a diurnal rhythm of secretion, with peak secretion in the early morning and a decline in the afternoon or evening. In an intact testicle after exogenous administration of LH drugs, the number of receptors for LH in the testicles decreases as a result of down-regulation. High doses of GnRH and its analogues can lead to a decrease in the number of LH receptors and thus suppress LH secretion. In practice, this feature is used for the purpose of medical castration in men with prostate cancer. Estrogens inhibit the activity of a number of enzymes involved in the synthesis of testosterone, and, thus, directly affect the formation of testosterone. There is also intra-ultrashort feedback, through which exogenous testosterone will overlap the effects of LH and suppress the production of endogenous testosterone. In healthy men, only 2% of testosterone circulating in the blood is in a free or unbound state; 44% of testosterone is associated with testosterone-estradiol-binding globulin (sex-steroid-binding globulin, SHBG), and 54% is associated with albumin or other proteins. These steroid-binding proteins modulate the action of androgens. SHBG has a higher affinity for testosterone than for estradiol, and changes in SHBG levels lead to changes in hormonal levels. The level of SHBG increases under the influence of estrogens, in the treatment of thyroid hormones, cirrhosis of the liver and may decrease under the influence of androgens, growth hormone, obesity. The biological effect of androgens is manifested in target organs containing specific protein receptors for anadrogens. Testosterone from circulating blood enters the target cells, where under the influence of the enzyme 5-alpha reductase turns into a more powerful androgen dihydrotestosterone. The main effects of androgens in target tissues include:
- regulation of the secretion of gonadotropins of the hypothalamic-pituitary system;
- initiation and maintenance of spermatogenesis;
- differentiation of internal and external genital organs in the period of prenatal development;
- promoting puberty in puberty.
The seminiferous tubules contain germ cell epithelium at different stages of maturation, as well as their supporting Sertoli cells. The seminiferous tubules make up 85-90% of the volume of the testicles. Sertoli cells are a constant population of non-dividing microenvironment cells. They are located on the basement membrane of the seminiferous tubules and are interconnected by tight junctions. These tight joints, together with the closely interconnected muscle cells of the peritubular space, form the hemato-testicular barrier. The functional significance of the hemato-testicular barrier is to create a unique microenvironment necessary for ensuring spermatogenesis, and to maintain the immunological privilege of the testicle. This isolation is very important, since the formation of sperm occurs from puberty, which is much later than the formation of the self-recognition function of the immune system. If sperm production was not immunologically protected, the differentiating cells would be recognized by the immune system as foreign and destroyed. Sertoli cells are involved in both the nutritional support of developing spermatogenesis cells and the phagocytosis of dead cells. Spermatogonia and young spermatocytes are located in the seminiferous tubules closer to the basement membrane and, as they mature, move to the upper layers, deep into the lumen of the tubules.
Spermatogonia lie directly above the basement membrane, and in the direction of the tubular lumen, primary spermatocytes, secondary spermatocytes and spermatids are sequentially located. There are 13 different types of germ cell epithelium cells, representing different stages of sperm maturation.
Spermatogenesis
Spermatogenesis is a complex process in which primitive germ cells, or spermatogonia, divide, reproducing stem-like stem cells, or give rise to daughter cells that further differentiate into spermatocytes. Further division of spermatocytes gives rise to cell lines, eventually differentiating into spermatids and further into spermatozoa. Differentiation includes the condensation of the nucleus, the formation of the acrosome, the loss of most of the cytoplasm, the formation of the tail and the movement of the mitochondria into the middle part of the spermatozoon, which becomes the "engine room" of the cell, ensuring the work of the tail. A group of germ cell epithelium cells that simultaneously enter spermatogenesis processes is called generation. Cells of the same generation are at the same stage of development. There are six stages of the development of germ cell ephelium. The development of sperm from the first stage to the sixth is one cycle. In humans, the duration of each cycle is approximately 16 days, and the path of transformation from early spermatogonia to mature sperm takes 4.6 cycles. Thus, the duration of spermatogenesis in humans is about 74 days.
Hormonal regulation of spermatogenesis
There is a close structural and functional connection between the two separate parts of the testicle, the seminiferous tubules, and the surrounding interstitial tissue. The luteinizing hormone of the pituitary gland affects spermatogenesis, indirectly, by stimulating the production of testosterone. FSH target cells - Sertoli cells. Thus, testosterone and FSH are hormones that directly affect the epithelium of the seminiferous tubules. Androgen-binding protein formed by Sertoli cells and participating in the intracellular transport of testosterone can play the role of a testosterone reservoir inside the seminiferous tubules in addition to testosterone entering from the testicles into the epididymis canaliculi. The close relative positioning of Leydig cells and seminiferous tubules, as well as the formation by Sertoli cells of androgen-binding globulin, maintains a high concentration of testosterone in the microenvironment of differentiating spermatogenesis cells. The hormonal changes necessary to start spermatogenesis occur independently of the process of maintaining spermatogenesis. To maintain spermatogenesis, for example, when turning off the pituitary gland, only testosterone is needed. However, if the function of the germ cell epithelium is turned off as a result of the absence of testosterone, then to restart spermatogenesis, both FSH and testosterone are required.
Transport - maturation - storage of sperm
Although, the formation of spermatozoa occurs in the testicle, the processes of maturation, storage and transport of spermatozoa are provided by the epididymis (epididymis). Spermatozoa that are in the seminiferous tubules of the testicle are immobile and incapable of fertilization. Their maturation is completed outside the testicle in the duct of the appendage. The convoluted testicular tubules end in the testicular network, which in turn forms the outlying tubules (ductuli efferentes). The testicular fluid and spermatozoa flow from the testicle to the head of the epididymus through these effeminate tubules. The epididymis and epididymis epididymis has a head, body and tail, and consists of a single, highly tortuous duct, the length of which is about 5-6 meters. Although the duration of transport along the duct of the epididymis varies depending on the age and sexual activity of the man, on average this time is 4 days. It is during the period of maturation in the head and body of the epididymis that spermatozoa acquire an ever increasing mobility and ability to fertilize an egg cell.
In addition to the maturation of sperm, the epididymis acts as a "storage" or reservoir of male germ cells. It is estimated that the outer sperm reservoir contains about 440 million sperm, more than 50% of which is in the tail of the epididymis. From the tail of the epididymis, the spermatozoa enter the vas deferens, a muscle tube 30-35 cm long. Due to the peristaltic contractions of the duct wall, the contents of the vas deferens enter the vas deferens canal (ductus ejaculatorius) and then, through emission and ejaculation, into the urethra. During emission, the secret of the seminal vesicles and prostate enters the posterior urethra. The ejaculatory contractions of the ejaculatory duct and bladder neck muscles are controlled by the sympathetic nervous system.
During ejaculation, the bladder neck muscles contract and the external sphincter relaxes, and the sperm moves along the urethra due to rhythmic contractions of the perineal and bulbourethral muscles. It has been established that the first portion of the ejaculate contains a small volume of fluid from the vas deferens, but contains a large number of spermatozoa. The main volume of seminal fluid is formed in the seminal vesicles and in a smaller amount in the prostate. Seminal vesicles provide sperm nutrient substrate - fructose, as well as prostaglandins and coagulating substances. The generally accepted function of seminal plasma is to create a buffer in the acidic environment of the vagina. The clot formed by the sperm after ejaculation is diluted for 20-30 minutes under the influence of proteolytic enzymes of the prostate. The secret of the prostate also adds zinc ions, phospholipids, spermine, phosphatase to seminal fluid. The first portion of the ejaculate is characterized by the maximum content of spermatozoa and prostate gland secretion, while the second portion is represented primarily by the secretion of seminal vesicles and contains fewer spermatozoa.
Fertilization
Fertilization usually occurs in the fallopian tubes in the post-ovulation period. During the periovulatory period (in the middle of the menstrual cycle), changes in the cervical mucus occur - its quantity increases, it becomes more extensible and watery - creating favorable conditions for sperm penetration into the uterus and protecting sperm from the high content of the vagina. To carry out fertilization within the female reproductive tract, spermatozoa undergo physiological changes known as capacitation. When interacting with the egg cell, a new type of movement, called hyperactive motility, occurs in the sperm cell. At the same time, the spermatozoon undergoes morphological changes, called the acrosome reaction (acrosome reaction), which consists in releasing lytic enzymes and exposing the structures of the spermatozoon. As a result of these changes, the sperm cell is able to reach the egg cell, pass through several layers of its shell, and enter the ooplasm.
Clinical examination
History of the disease
The basis for examining a patient with infertility is a thorough history taking and physical examination. It is necessary to find out if the patient has suffered from such specific children's diseases as cryptorchidism, postpubertal orchitis caused by mumps, trauma or testicular torsion. Premature puberty may indicate adrenogenital syndrome, while delayed puberty may indicate Kleinfelter syndrome or idiopathic hypogonadism. It is necessary to clarify whether there was no influence of diethylstilbistrol in the period of intrauterine development, since this is accompanied by an increase in the frequency of epididymal cysts and cryptorchidism. A detailed assessment should be conducted of the possible influence of occupational risk factors, negative environmental factors, excessive overheating or exposure of the organism. Thus, chemotherapy of oncological diseases has a dose-dependent and potentially damaging effect on the germ cell epithelium of the testicles. It is necessary to clarify whether drugs that potentially affect the reproductive cycle in men have been used: anabolic steroids, cimetidine, spironolactone. Sulfasalazine and nitrofurantoin may affect sperm motility. Drugs and excessive use of alcohol are associated with a decrease in the number of sperm and hormonal disorders. Sometimes the risk of reproductive impairment can increase the previous therapeutic and surgical diseases and their treatment. Deterioration in sperm quality is observed in men with undescended one of the testicles. Previous surgical treatment, surgery on the bladder neck, or removal of the retroperitoneal lymph nodes in testicular cancer can cause retrograde ejaculation or lack of emission. Also, diabetic neuropathy can lead to retrograde ejaculation, and in some cases of impotence. In the surgical treatment of a hernia of the inguinal region, damage can occur to both the vas deferens and the blood vessels of the testes. In patients with bladder fibrosis, as a rule, there is no vas deferens, seminal vesicles, epididymis. Any increase in temperature or a general disease can lead to a deterioration of spermatogenesis. In this case, violations in the ejaculate are detected within 3 months after the event, since the process of spermatogenesis from the beginning to the formation of mature spermatozoa takes about 74 days. In addition, a different period of time is necessary for the transport of sperm through the tubules. Sometimes, even events that occurred in the previous 3-6 months are important. Attention should be paid to the sexual habits of a person, such as the regularity of sex, the frequency of ejaculation, the use of special lubricants, as well as the patient's perception of the features of the ovulatory cycle. It surely turns out that the patient was examined and was previously treated for infertility; features of reproductive function in past marriages. Recurrent infections of the respiratory tract and infertility in men may be associated with ciliary dyskinesia syndrome, in which the number of spermatozoa remains normal, but the spermatozoa are immobile due to ultrastructural defects. Cartagene's syndrome - a common variant of ciliary dyskinesia syndrome is characterized by chronic bronchiectasis, sinusitis, situs inversus and impaired sperm motility. In Young's syndrome, also associated with lung diseases, the ultrastructure of the cilia is not disturbed, but the outflow of sperm from the epididymis is difficult due to the thickening of the sperm. The examination for these patients is characterized by azoospermia. Loss of sexual desire, accompanied by headaches, visual impairment and galactorrhea may indicate a pituitary tumor. Other diseases leading to infertility include thyroid disease, epilepsy, and liver disease. Interestingly, epilepsy itself is not the cause of infertility, but its usual treatment with dilantin (phenytoin) affects reproductive function. Receiving dilantin leads to a decrease in the secretion of FSH. Chronic systemic diseases such as kidney disease or sickle cell anemia are accompanied by disorders of the reproductive hormonal background.
Physical examination
During the examination, special attention should be paid to identifying signs of hypogonadism. As a rule, when viewed, this is detected as an underdevelopment of secondary sexual characteristics, a eunuchoid body build (the reach of the body is two tops more than the height, the ratio of the upper part of the body (from the highest point to the pubis) to the lower part of the body (from the pubis to the floor) is less than 1; not enough male pattern hair growth (axillary, pubic, on the face and body, combined with insufficient hair growth on the temples)). You also need to pay attention to the infantilism of the genitals: the small size of the penis, testicles and prostate, an underdeveloped scrotum. Some patients have markedly underdeveloped muscle development and body mass.
An important stage of the survey - a thorough examination of the testicles. Normally, the size of the testicles is on average 4.5 cm long and 2.5 cm wide with an average volume of about 20 cu. cm. To determine the size of the testicles, you can use an orchidometer or a ruler. When the vas deferens are damaged before the period of puberty, the testicles are small and compact, while when injured in adulthood, the size of the testicles is reduced, but the texture remains soft.
A characteristic feature of feminization is gynecomastia. In men with congenital hypogonadism, such defects as anosmia, impaired color vision, cerebellar ataxia, cleft lip, cleft palate often occur. Hepatomegaly may be associated with impaired hormone metabolism. Examination of the neck helps eliminate thyroid enlargement, vascular noise, or tuberosity associated with thyroid disease. Neurological examination necessarily includes the definition of visual fields and reflexes.
Abnormalities of the epididymis may be the result of an infection and a possible violation of the patency of the appendages. Examination can reveal a reduction in prostate size in men with androgen deficiency or prostate pain during an infectious process. Must be identified any violations in the structure of the penis: hypospadias, curvature, phimosis. The contents of the scrotum must be carefully palpated in patients both vertically and horizontally. In many cases, when a simple examination of the varicocele can not be seen, but when examined in the standing position, lmbo when conducting a Valsalva sample, the varicocele becomes noticeable. Varicocele often causes a decrease in the size of the left testicle, so finding the difference in the size of the right and left testicle should be the reason for a more careful search. It is necessary to palpate both vas deferens, since approximately 2% of men who have been treated with the problem of infertility show a congenital absence of ducts or seminal vesicles.
Progesticular causes of infertility
- Pathology of the hypothalamus region
- Isolated gonadotropin deficiency (Kalman syndrome)
- Isolated luteinizing hormone deficiency ("fertile eunuch")
- Isolated FSH deficiency
- Congenital hypogonadotropic syndrome
- Pathology of the pituitary gland
- Pituitary failure (tumors, infiltrative processes, operations, irradiation)
- Hyperprolactinemia
- Hemochromatosis
- Effect of exogenous hormones (excess estrogen and androgens, excess glucocorticoids, hyper and hypothyroidism)
Pathology of the hypothalamic region
Kalman syndrome, manifested by isolated deficiency of gonadotropins (LH and FSH), occurs in the form of sporadic mutations, and in the family form. And, although the incidence of the disease is low (1 case per 10,000 men), this is the second cause of hypogonadism after Kleinfelter syndrome. In Kalman syndrome, anosmia, congenital deafness, cleft lip, cleft palate, craniofacial asymmetry, renal dysfunction, color blindness are often observed. Hypothalamic GnRH is absent. When the pituitary is stimulated by exogenous GnRH, LH and FSH are released. In addition to gonadotropin deficiency (LH and FSH), the function of the anterior pituitary gland is not impaired. Inheritance is autosomal recessive, or autosomal dominant with incomplete penetrance. Differential diagnosis is carried out with delayed sexual development. A distinctive feature of Kalman syndrome is the size of the testicles less than 2 cm in diameter and a characteristic family history in terms of anosmia.
Fertile eunuch "Fertile eunuch" is a pathology associated with isolated LH deficiency of the pituitary gland. Patients are characterized by eunuchous body build with varying degrees of virilization and gynecomastia; large size of the testes and a decrease in the number of sperm in the semen. The content of FSH in the blood plasma is normal, while the level of LH and testosterone is reduced. The cause of the disease is partial deficiency of gonadotropins, in which adequate stimulation of LH testosterone synthesis is maintained and spermatogenesis is triggered, but testosterone level is insufficient for the formation of secondary male sexual characteristics.
Isolated FSH deficiency is rare. Typically, the normal development of secondary male sexual characteristics, normal testicular size and basal levels of LH and testosterone. Sperm contains from 0 to several sperm. Plasma FSH is low and does not respond to GnRH stimulation.
Congenital hypogonadotropic syndrome is characterized by secondary hypogonadism and multiple somatic disorders. Prader-Willi syndrome is manifested by hypogonadism, muscular hypotension in newborns, obesity. Lawrence-Moon-Barde-Bidle syndrome is inherited in an autosomal recessive manner and is characterized by oligophrenia, retinitis pigmentosa, polydactyly, and hypogonadism. Both syndromes are associated with impaired hypothalamic GnRH production.
Pathology of the pituitary gland
Pituitary insufficiency can be a consequence of tumors, hemorrhages, have an iatrogenic nature due to surgical interventions or irradiation during infiltrative processes. If dysfunction of the pituitary gland occurs before puberty, then the main clinical manifestations are growth retardation associated with a lack of adrenal and thyroid function. Hypogonadism, which occurs in adult males, usually develops as a result of a pituitary tumor. Complaints of impotence, decreased libido, infertility may occur several years before the onset of symptoms of tumor growth (headaches, visual impairment, reduced thyroid function, or adrenal glands). If the man has already reached normal puberty, then if the disease is not associated with adrenal insufficiency, a long period of time is required for the secondary sexual signs to disappear. Ultimately, the testicles will become soft and reduced in size. The diagnosis is established on the basis of a low level of testosterone in the blood in combination with reduced or gonadotropin concentrations at the lower limit of the norm. Depending on the severity of the decrease in the function of the pituitary gland in the blood plasma, the levels of corticosteroids, thyroxin-binding globulin and growth hormone will be reduced.
Hyperprolactinemia can cause both reproductive and sexual disorders. Prolactin-secreting pituitary tumors, from microadenomas (less than 10 mm) to macroadenomas, can lead to a decrease in libido, impotence, galactorrhea, gynecomastia and cessation of spermatogenesis. Patients with macroadenomas usually primarily complain of visual field disturbances and headaches. In this situation, examination is necessary, including computed tomography or MRI scan of the pituitary gland, laboratory determination of the hormones of the anterior pituitary, thyroid, adrenal glands. In these patients, there is a decreased level of blood testosterone with a decrease or a tendency towards the lower limit of the LH and FSH standards, which reflects the inadequate response of the pituitary to the decrease in testosterone production.
About 80% of men with hemochromatosis have impaired testicular function. In these patients, hypogonadism may develop secondarily against the background of iron deposits in the liver or may be primary, as a result of iron deposits in the testicular tissue. Iron deposits in hemochromatosis are also found in the pituitary gland, making the pituitary gland the main source of disorders.
With regard to the role of exogenous hormones, the tumors of the adrenal glands, Sertoli cells, interstitial cells of the testes can form estrogens. Cirrhosis of the liver is accompanied by an increase in endogenous estrogens. First of all, estrogens lead to suppression of the secretion of gonadotropins by the pituitary gland and as a result of the development of secondary testicular failure. Androgens can also inhibit pituitary secretion of gonadotropins and contribute to the development of secondary testicular failure. The use of anabolic steroids by some athletes can lead to temporary infertility. An increase in the formation of endogenous androgens may occur due to androgen-producing adrenal tumors, testicular tumors, but congenital adrenal hyperplasia is the most common cause. When CAH is increased androgen formation by the adrenal cortex, which leads to premature puberty and abnormally large penis size. Since the secretion of gonadotropins is suppressed, the testicles do not mature and have small sizes. In the absence of premature puberty, diagnosis is extremely difficult, since it is difficult to distinguish excessive virilization from a normal sexually mature man. It is necessary to conduct a thorough laboratory examination. In diagnostically identified cases of CAH, infertility treatment is performed using corticosteroids. Doctors often use corticosteroids in cases of idiopathic infertility. However, if during the examination the cause of violations is not established, such therapy should not be applied.
Sometimes excessive use of glucocorticoids in the treatment of ulcerative colitis, asthma, rheumatoid arthritis leads to a decrease in spermatogenesis. A possible cause of secondary testicular dysfunction is the suppression of LH secretion by elevated plasma cortisol levels. Correction of excess glucocorticoids is accompanied by an improvement in spermatogenesis.
Violation of spermatogenesis is possible due to dysfunction of the thyroid gland. Hyper-and hypothyroidism can affect spermatogenesis. Hyperthyroidism affects both the pituitary gland and the testes, altering the secretion of releasing hormones and activating the conversion of androgens to estrogens in peripheral tissues.
Testicular causes of infertility
- Chromosomal abnormalities (Kleinfelter syndrome, XX syndrome (sexual reversion syndrome), XYY syndrome)
- Noonan syndrome (male version of Turner syndrome)
- Myotonic dystrophy
- Bilateral anorchia (testicular absence syndrome)
- The presence of only Sertoli cells (aplasia of germ cell epithelium)
- Influence of gonadotoxins (drugs, radiation)
- Orhit
- Injury
- Systemic diseases (renal failure, liver disease, sickle cell anemia)
- Violations of the synthesis or effect of androgens
- Cryptorchidism
- Varicocele
A number of anomalies in the structure of somatic chromosomes are associated with male infertility. In a survey of 1,263 married couples with the problem of infertility, in 6.2% chromosomal abnormalities were found in men. In the subgroup with a reduced sperm count of less than 10 million / ml, the percentage of chromosomal abnormalities in males increased to 11%; and in men with azoospermia, the frequency of chromosomal abnormalities was 21%. However, only in isolated cases the interrelation of infertility with specific chromosomal disorders, such as D-D translocation, ring chromosomes, reciprocal translocations and a number of other aberrations, was confirmed. However, to exclude anomalies of somatic and sex chromosomes in males with severe oligospermia or azoospermia, a cytogenetic examination should be carried out.
Kleinfelter syndrome is a genetic disorder associated with the presence of an extra X chromosome in men. In this case, two types of karyotype predominate: 47XXY (the classic form of the syndrome), or 46 XY / 47XXY (mosaicism). The prevalence of the disease among men is approximately 1: 500. These patients are characterized by dense, small testicles, delayed sexual development, azoospermia, gynecomastia. Due to the fact that the characteristic signs of hypogonadism are not obvious before puberty, the diagnosis is usually made late. A decrease in the size of the testicles usually occurs due to sclerosis and hyalinization of the seminiferous tubules. Typical testicular size less than 2 cm in length and a volume of less than 12 cm3. Characterized by increased levels of LH and FSH. Testosterone levels range from normal to reduced and decrease with age. The level of estradiol in the blood is usually elevated. Higher levels of estrogen compared with testosterone lead to feminization in the form of gynecomastia. Approximately 10% of these patients have chromosomal mosaicism. In these cases, the characteristic signs of Kleinfelter syndrome are less pronounced and men can be fertile if there is a clone of cells in the testicles containing a normal set of chromosomes. Mild dementia, restrictive lung disease occurs in these patients more frequently than in the population. Infertility in these patients is reversible and later most require substitution therapy with androgens in order to achieve optimal virilization and normal sexual function.
XX - violation or syndrome of sexual reversion - a variant of Kleinfelter syndrome. Clinical symptoms are similar, except for growth below average and hypospadias; cases of mental disability are less common. Patients have a karyotype of 46XX. Such a paradox is explained by the expression on the cells of the HY Y antigen and presumably by the presence of Y-chromosome structures in the genome.
The frequency of XYY syndrome is approximately equal to the frequency of Kleinfelter syndrome. Phenotypic manifestations of XYY syndrome are similar to Kleinfelter syndrome, but are more variable. Sperm counts in these men range from normal to azoospermia. Patients are characterized by excessive growth and acne; antisocial behavior is observed in a large percentage of cases. The level of LH and testosterone in most patients is normal, and the level of FSH depends on the degree of damage to germ cells. Method of treatment of infertility does not exist.
Noonan syndrome is a male variant of Shereshevsky-Turner syndrome (CHO), and patients have similar manifestations: short stature, pterygoid folds on the neck, low-lying ears, cubitus valgus, visual impairment, and cardiovascular malformations. In most men with Noonan syndrome, there is cryptorchidism, decreased spermatogenesis and infertility. With a decrease in testicular function, LH and FSH levels in the blood are increased. Cytogenetic examination reveals violations of sex chromosomes such as XO / XY mosaicism. There is no treatment for infertility in these patients.
In patients with myotonic dystrophy, there is a violation of muscle relaxation after the initial contraction. Major clinical manifestations also include lens opacities, frontal baldness, and testicular atrophy. The disease is inherited in an autosomal dominant manner and its manifestations are variable. Although, in 80% of cases, testicular atrophy will occur. The period of puberty, as a rule, proceeds without features, and damage to the testes develops later in adulthood. At the same time, the function of Leydig cells remains normal and gynecomastia is not observed.
Bilateral anorchia or testicular absence syndrome occurs very rarely, approximately 1: 20,000 men. In these patients, at birth, the testes are not defined even later, due to the lack of androgen synthesis in the testes, sexual immaturity develops. The karyotype of the patients is normal; LH and FSH levels are elevated, and testosterone levels are very low. In the prenatal period of development, the testicles can be lost as a functioning organ due to injury, twisting, vascular damage or infection. However, in order for male-type differentiation to take place, functioning testicular tissue must be present for at least the first trimester of the prenatal period. In response to stimulation of hCG, testosterone levels do not increase. For patients charaterno eunuchoid body. Gynecomastia is not typical. In the course of treatment, only correction of testosterone deficiency is possible. There is no treatment for infertility in these patients.
The syndrome of the presence of only Sertoli cells or aplasia of the germ cell epithelium may arise due to various reasons: congenital absence of the germ cell epithelium, genetic defects, androgen resistance. A biopsy of the testicles reveals a complete absence of the primordial epithelium, and in the course of a clinical examination, azoospermia is combined with normal virilization; the consistency of the testicles is normal, but their size is somewhat reduced; gynecomastia is absent. Testosterone and LH levels are normal, but FSH levels are usually elevated. Sometimes in patients with other testicular diseases (epidemic parotiditis, cryptorchidism, damage due to radiation and toxic effects), the seminiferous tubules can also contain only Sertoli cells, but in these patients the size of the testicles will be reduced, and the histological examination of the material will be heterogeneous. Sclerosis and hyalinosis are more often observed as characteristic signs in these patients. Infertility treatment is not effective.
Gonadotoxins such as drugs and radiation can have a damaging effect on the germ cell epithelium, since germ cell epithelium is a rapidly dividing tissue, and the process of cell division is most sensitive to damaging effects. Cancer chemotherapy has a dose-dependent effect on the germ cell epithelium. In the period preceding puberty, the primordial epithelium of the testes is more resistant to the toxic effects of drugs than in adulthood. Alkylating drugs used in chemotherapy, such as chiromantin, cyclophosphamide, have a toxic damaging effect on the testicles. A number of patients before the start of chemotherapy may conduct cryopreservation of sperm. Tsiproteron, ketoconazole, spironolactone, alcohol contribute to the violation of testosterone synthesis. Cimetidine, a testosterone antagonist, blocks the peripheral action of testosterone in target tissues. Frequent side effects - gynecomastia and a decrease in the number of sperm. Narcotic drugs such as marijuana, heroin, methadone lead to lower plasma testosterone levels without a concomitant increase in LH levels. This indicates both central impaired and testicular disorders. A weakened testicular function was found under the influence of some pesticides, for example, dibromochloropropane. The cells of the germ cell epithelium are particularly sensitive to radiation, while the Leydig cells are relatively resistant. Irradiation at a dose of less than 600 rad leads to reversible damage to testicular cells. At higher levels of exposure, persistent disturbances are more likely to occur. Restoration of spermatogenesis can take 2-3 years even in men exposed to low doses of radiation. Elevated levels of FSH reflect the weakening of spermatogenesis. When you restore the function of the testicle, FSH levels return to normal.
In 15-20% of adult males, mumps can lead to the development of orchitis, usually unilateral. Bilateral orchitis occurs in approximately 10% of cases. During 1 to 6 months, or for several years after the disease, testicular atrophy may develop. Normal sperm counts are restored in less than 1/3 of men.
The peculiarity of the anatomical location of the testes puts them in the position of easily injured organs with the subsequent development of atrophy. Iatrogenic damage is possible if blood flow to the testicles is disturbed, or damage to the vas deferens during operations on the inguinal region.
Systemic diseases such as renal failure are accompanied in men by a decrease in libido, impotence, impaired spermatogenesis, and gynecomastia. LH and FSH levels are increased, and testosterone levels are lowered. The reason for the development of hypogonadism in uremia is multifactorial. Every fourth patient with uremia shows an increase in prolactin levels. An additional contribution may be an excess of estrogens. Taking antihypertensive drugs, uremic neuropathy may also play a role in the development of impotence and hypogonadism. After successful kidney transplantation, the course of uremic hypogonadism improves. A large percentage of men with cirrhosis experience testicular atrophy, impotence and gynecomastia. The level of testosterone is reduced, and the level of estradiol is increased due to a simultaneous decrease in the synthesis of androgens in the liver and an increase in peripheral conversion to estrogens. With a relatively low serum testosterone level, a moderate increase in LH and FSH is observed. Alcohol consumption also results in a decrease in blood testosterone levels, due to the suppression of testosterone synthesis in the testicles. Most men with sickle cell anemia show signs of hypogonadism. Although, LH and FSH levels can be different, testosterone levels are lowered. Hypogonadism in sickle cell anemia probably develops secondary to testicular and hypothalamic-pituitary disorders.
Rare hereditary disorders of enzymes involved in the synthesis of testosterone, accompanied by inadequate virilization, which is found at birth in the form of hermaphroditism. Separate forms of androgenic resistance lead to insufficient masculinization, infertility and the development of male sexual characteristics of the female type. The diagnosis is made on the basis of the detection of abnormal receptors for androgens in the culture of genital skin fibroblasts. Interestingly, testosterone and LH levels are elevated. Diagnosis of these disorders is expensive, and there is no effective treatment for infertility.
Cryptorchidism occurs in 0.8% of adult males. Morphological changes in undescended testes begin to develop after 2 years of age. Despite prophylactic orchidopexy, patients suffering from unilateral cryptorchidism have a reduced fertility potential. Observations show that in patients with cryptorchidism, there is dysgenesis of not only uninitiated, but also of the normal testicle. Especially severely sperm quality is impaired in men with bilateral undescended testicles. Although basal levels of LH, FSH and testosterone may be normal, the response of LH and FSH to GnRH stimulation is elevated, which may reflect impaired testicular function.
Varicocele scrotal - one of the most frequent finds in men who have addressed the problem of infertility. The cause of varicocele is a violation of the outflow of blood due to inferiority or lack of valves of the spermatic veins. Such a defect in the valvular apparatus in combination with a long vertical course of the internal spermatic vein on the left leads to more frequent formation of a left-sided varicocele (90%). The internal seed vein on the right has a more oblique course, and therefore the varicocele on the right is usually not defined. The occurrence of a unilateral, right-sided varicocele may be due to venous thrombosis, a tumor, or situs inversus. Studies using modern diagnostic methods show the occurrence of bilateral varicocele in more than 40% of cases. Among adult men, the prevalence of varicocele is about 21%, and in the group of men suffering from infertility, this figure rises to 40%. Approximately 50% of men with varicocele show a deterioration in sperm quality, although, also, in many men sperm fertility is preserved. The following mechanisms of impaired spermatogenesis in men with varicocele are suggested:
- fever in the testicles due to venous blood stasis
- retrograde intake of toxic metabolites from the adrenal glands and kidneys
- blood stasis with the development of hypoxia germ cell epithelium; and
- changes in the functioning of the hypothalamic-pituitary-testicular axis
- Recent results from experimental studies confirm the link between increased blood flow, increased temperature in the testicles and impaired spermatogenesis.
Unfortunately, 25-40% of men with infertility are diagnosed with idiopathic male infertility when the cause cannot be established. As our knowledge of the physiology of the male reproductive system improves, the group of patients with unexplained infertility will gradually decrease.
Post-testicular causes of infertility
- Violations of sperm transport
- Congenital disorders
- Acquired violations
- Functional impairment
- Impaired motility or sperm function
- Congenital disorders of the sperm tail
- Disruption of sperm maturation
- Immunological disorders
- Infections
- Sexual dysfunction
- Violations of sperm transport
Congenital anomalies of sperm transport occur quite rarely and are due to the absence or atresia of the tubular system of the male reproductive tract. In men with bladder fibrosis, the incidence of congenital hypoplasia or absence of the main part of the epididymis, vas deferens, and seminal vesicles is increased. Lack of seminal vesicles is always accompanied by azoospermia, impaired coagulation of sperm during ejaculation and the absence of fructose in the semen. In Young's syndrome associated with pulmonary pathology, the ultrastructure of the cilia is normal, but the outflow of sperm from the epididymis is difficult due to the thickening of the sperm, which leads to azoospermia.
Acquired disruption of sperm transport is usually associated with bacterial infections leading to the development of acute or chronic inflammation in the epididymis, followed by the formation of scar tissue and obstruction. In addition to vasectomy, accidental ligation of the vas deferens is possible with surgical treatment of inguinal hernia, orchidopexy, and even during varicocelectomy.
Functional obstruction of sperm transport occurs as a result of a violation of innervation in the injury of sympathetic nerves during surgical removal of retroperitoneal lymph nodes or during operations on the pelvic organs. Violation of innervation can cause insufficient contraction of the vas deferens followed by insufficient emission, as well as impaired contraction of the bladder neck during ejaculation and, as a result, retrograde ejaculation. Damage to the spinal cord can lead to paraplegic and tetraplegia with subsequent erectile dysfunction and impaired emission and ejaculation. Many drugs, such as tranquilizers, antidepressants, antihypertensive drugs, can disrupt the work of the sympathetic nervous system.
Impaired motility and sperm function
The impairment of sperm motility and function develops secondarily due to birth defects of the sperm tail, impaired sperm maturation, and immunological disorders. Ciliary dyskinesia syndrome is a group of diseases characterized by immobility or deterioration of sperm motility, for example, Cartagener syndrome. In these diseases, the results of testicular biopsy are normal, the number of spermatozoa in the semen is normal, but the motility of the spermatozoa is either significantly reduced, or the spermatozoa are immobile. Ultrastructural defects leading to inferiority of both cilia and spermatozoa can be seen only with electron microscopy. Defects underlying ciliary dyskinesia syndrome include the absence of dynein pens, short or missing radial connections without a central cover, and the absence of central microtubules. Impaired sperm motility may also be associated with carboxymethylase protein deficiency in the sperm tail.
A normal number, but reduced sperm motility may occur after a vasectomy due to epididymis dysfunction. Chronic increase in intratubular pressure that occurs after a vasectomy can have a negative effect on the epididymis - spermatozoa cannot pass through normal stages of maturation and acquire mobility. Violation of the gamma-testicular barrier as a result of infection, trauma, or surgery is accompanied by sensitization of the body with spermatozoa antigens. Antisperm antibodies play a role in the development of infertility in 3-7% of infertile men. Immune disorders are usually not the absolute cause of infertility in a patient, but may contribute to a decrease in sperm fertility.
Infections. High concentrations of gram-negative bacteria, such as E. coli, in sperm can lead to a decrease in sperm motility. Urogenital infections, such as chlamydia, ureaplasmosis, mycoplasmosis, rarely cause infertility. Studies conducted in both animals and humans did not provide convincing data in favor of the need for cultural bacteriological studies or empirical antimicrobial therapy in asymptomatic infertile men.
Sexual dysfunction was noted in 20% of infertile men. Decreased sexual desire, erectile dysfunction, premature ejaculation are potentially correctable causes of reproductive failure. A decrease in libido and erectile dysfunction may be due to the low level of testosterone associated with organic pathology.
Diagnostic tests
Spermogram
Despite the fact that the sperm analysis is not a test for fertility, a carefully conducted study allows us to evaluate the functional state of hormonal regulation, spermatogenesis and patency of the reproductive tract. The only true indicator of fertility is the onset of pregnancy, and this phenomenon is associated with the state of the married couple as a whole. It must be borne in mind that the limits of normal semen readings are difficult to determine in fertile men during their reproductive period. Clinical studies of patients with infertility allowed us to establish "the boundaries of the norm", below which the chances of pregnancy are reduced. These boundaries are not absolute, since in some fertile men, semen parameters may be below the established limits of the norm. Conversely, men who have been treated with the problem of infertility with standard examination methods may have normal spermogram values, since a standard examination does not allow one to evaluate the functional abilities of spermatozoa. When conducting spermograms, it is strongly recommended to use the Laboratory Guide for Human Sperm Analysis and Sperm Interaction with the Cervix of the World Health Organization (WHO). Most specialists examine at least three sperm samples, whose values ??differ from each other within 20%, before making a conclusion about the state of sperm. For analysis, it is best to use a sperm sample obtained by masturbation after 2-3 days of abstinence from sex. The sample must be examined within 1-2 hours of receipt. Also for analysis it is possible, but less desirable, to use sperm samples obtained by the method of coitus interruptus or from a silicone condom that does not contain spermicides. Therefore, it is best if sperm samples are obtained directly at the site of the study. In addition to errors in conducting research in the laboratory, in different samples of sperm obtained from the same man, indicators such as density, mobility, and morphology of sperm can vary. In many ways, the duration of the abstinence period influences such a spread of indicators. With each additional day of abstinence (up to 1 week), the seed volume increases by 0.4 ml, the concentration of spermatozoa is 10-15 million, and the total number of spermatozoa is 50-90 million. The motility and morphology of spermatozoa does not change during 5-7 days of abstinence, but with a longer period, there is a decrease in sperm motility. Interpretation of semen results should take into account differences between different samples.