Causes of male infertility Hypothalamus – Pituitary – Testis Feedback: When the concentration of testosterone in the blood is lower than normal, the hypothalamus and pituitary are stimulated to produce gonadotropins, which increase the ability to act on the interstitial cells of the testes to produce testosterone and reach normal levels. Negative feedback: when the concentration of testosterone in the blood is higher than normal, the hypothalamus and pituitary gland are stimulated to inhibit the secretion of gonadotropins, so that the secretion of testosterone in the testes is reduced and reaches the normal concentration. (I) Pre-testicular factors There are two major organs, the pituitary gland and the hypothalamus, in front of the testes, which are the endocrine centers of the body. Lesions of hypothalamus and tenderness can cause various endocrine disorders, thus leading to male infertility. 1, hypothalamus lesions lead to pituitary, testicular dysfunction and lead to male infertility common diseases are: (1) Kallman syndrome: the incidence rate of this disease 1: 10 000, clinical manifestations of puberty after the testicles are soft and small (about 3 ml), or combined with cryptorchidism, the penis is childish. There is no beard, axillary hair, pubic hair, no laryngeal nodes, and the voice is female-like. Feminization of gynecomastia, delicate skin, female alteration of pelvis and hips, or female body shape; no sperm or even no semen; complete or incomplete loss of sense of smell; cleft lip, cleft palate, congenital deafness, and delayed bone age in some patients (72.5%). Serum FHS, LH and T are low. (2) Congenital hypogonadotropic syndrome: clinical manifestations include obesity, low muscle tone, slower intellectual response, short hands, feet and stature, and hypogonadism. Serum FHS, LH and T are low. (3) Selective LH deficiency: Clinical manifestations are normal secondary sexual parts, normal testicular volume, breasts may be feminized, low volume of semen analysis, and occasional small amount of sperm in semen. Serum measurement of FSH is normal while LH and T are low. Selective FSH deficiency: This disease is rare. The secondary sexual characteristics are normal, serum LH and T are normal, but FSH levels are reduced. Semen analysis may show azoospermia or severe oligospermia. Pituitary lesions (1) pituitary hypoplasia: often due to pituitary surgery, trauma or tumor causing pituitary secretion insufficiency. Taking hypopituitarism caused by pituitary tumor as an example, clinical manifestations are inconspicuous or gradual fading of the second sex, headache, vision loss, small and soft testicles, decreased libido, erectile dysfunction and infertility. In addition to the decrease of serum FSH, LH and T values, it may also be combined with the decrease of cortisol and growth hormone at the same time, which is manifested as total hypopituitarism. (2) Hyperprolactinemia: Elevated prolactin reduces the pulsatile release of gonadotropin-releasing hormone (GnRH), leading to decreased secretion of LH and FSH, resulting in lower testosterone levels, causing male sexual dysfunction (ED) and spermatogenic dysfunction. Elevated prolactin is often caused by pituitary adenomas or microadenomas. Large adenomas may manifest as headache and loss of vision, while patients with microadenomas may not have headache and loss of vision. What they have in common is the elevation of prolactin (PRL), the decrease of FSH, LH and T, and the hypogonadism leading to ED and infertility. 3.Other endocrine diseases such as hyper or hypothyroidism can also affect the function of pituitary and hyperthermia, causing infertility; adrenal diseases such as adrenal tumors cause elevated peripheral androgens, which inhibit the secretion of LH and FSH and affect the production of spermatozoa. (ii) Testicular factorsThe testes are responsible for the secretion of androgens and the production of spermatozoa. Testicular lesions can cause loss or decline of reproductive function in men. There are two major categories of testicular lesions: congenital and acquired. 1, congenital testicular lesions (1) genetic abnormalities: in recent years, it was found that some azoospermia, oligospermia patients let the chromosome karyotype is normal, but there are subtle mutations through the genes, such as the microdeletion of AZF gene. (2) Klinefelter syndrome: a disease of gonadal hypoplasia with genetic characteristics. The karyotype is 47, XXY, and it is caused by the failure of one of the parents to separate the chromosomes during meiosis in the process of gamete formation. Clinical manifestations include small, hard testes, gynecomastia, FSH↑, LH↑, and T↓. Mother (46XX) Father (46XY)｜ ｜ 24XX 22 0 23XY 22 0 Mother (46XX) Father (46XY)｜ ｜ 23X 23X 24XY 220 (3) XYY Syndrome: It is caused by the failure of the Y chromosome to separate during the second meiosis in the process of the father’s sperm formation. The patient is tall and often has pustules and thrush. The personality has violent behavior. Semen analysis is mostly severe oligozoospermia or azoospermia, with normal or high serum FSH, LH, and T. Testicular biopsy reveals impaired sperm maturation. (4) XX man syndrome (sexual inversion syndrome): the karyotype is 46, XX, according to the study, the Y chromosome is translocated to the X chromosome, and there is a testicular determinant gene (SRY gene) on the translocated chromosome, but the AZR gene is translocated. Clinical manifestations are male, FSH, LH, E2↑, T↓, small and hard testes, feminized breasts, short penis, and no sperm. (Karyotype is 46, XY/46, XX, 46, XY true hermaphroditism). (5) Noonan syndrome: karyotype XO, also XO/XY chimerism. Clinical manifestations include short stature, wide eye spacing, low-set ears, elbow ectropion, ptosis and cardiovascular abnormalities, testicular atrophy, and spermatogenic dysfunction to infertility. (6) Other chromosomal abnormalities: the most common of them is autosomal translocation, which is manifested as oligospermia in some patients, and some patients make their wives produce repeated miscarriages. (7) Androgen receptor abnormality: the abnormality of androgen receptor is manifested as abnormal function or reduced number. Receptor abnormalities can lead to androgen antagonism. LH and T values in the serum are elevated while FSH is normal, and the clinical manifestation is only oligospermia or azoospermia. (8) Support cell syndrome (spermatogenic cell dysplasia): the etiology of this disease is unknown and may be multifactorial, including congenital embryonic cell deficiency, genetic defects, or androgen antagonism. Clinical manifestations include normal male secondary sexual characteristics, normal testicular size and texture, no feminization of the breasts, and no sperm in the semen. Blood tests showed elevated FSH with normal LH and T levels. Testicular biopsy shows only supportive cells and spermatogenic cells are rare. (9) Cryptorchidism: also known as testicular descent insufficiency, its incidence is relatively high, with an incidence of 3%~4% in full-term male infants, 1%~1.6% at one year of age, and 0.8% in adult men. Cryptorchidism occurs unilaterally in 2/3 of cases, and bilateral cryptorchidism in 1/3 of cases. 2 years of age after the testis has not descended, the spermatogenic function of the testis will be significantly affected, and the higher the position of the cryptorchidism is, the greater the effect is, and with unilateral cryptorchidism, the function of the testis of the opposite side will also be significantly affected. The clinical manifestation is oligospermia or azoospermia, and the serum FSH, LH and T values may be in the normal range. (10) Varicocele: The incidence of varicocele is 10-15% in adult men and about 30% in infertile men. The incidence of varicocele is about 30% in infertile men. Varicocele does not affect fertility 100% of the time, but only 40% of the time. About 90% of varicocele occurs on the left side. Bilateral varicocele was previously thought to be rare, but with the introduction of color Doppler, it has been found that about 40% of cases of varicocele are bilateral. The clinical manifestations are oligospermia or azoospermia. After surgical treatment about 40% of patients, spermatogenic function will be improved. (11) Sperm ultrastructural abnormalities: under electron microscopy, some infertile men are found to have tiny abnormalities in sperm structure, such as axial filament defects that prevent sperm from moving. Axonal filament defects are often combined with respiratory cilia defects, so the two together called cilia immobilization syndrome. In addition, there are spermatozoa hypoplasia. 2, acquired testicular lesions. Human survival in the natural environment is inevitably subject to a variety of unexpected injuries. (1) Testiculitis: when the testes are infected with microorganisms such as viruses, bacteria, and syphilis spirochetes, testicular inflammation occurs, destroying the seminiferous tubules, damaging the spermatogenic epithelium, and affecting the function of mesenchymal stromal cells, resulting in spermatogenesis disorders and affecting fertility. One of the most common is the combination of viral orchitis after mumps, which often causes testicular atrophy. (2) Testicular injury: when the testicle is hit, bruised or twisted by external force, it will cause damage to the testicular tissues, and in some cases, it will cause testicular atrophy, which will result in spermlessness; when the testicular blood vessels are mistakenly injured by the surgery, it will also cause testicular atrophy and affect the function of spermatogenesis in a serious case. (3) Physical injury: among various physical factors, the influence of environmental temperature on spermatogenic function of testis is a hot spot in the current research, which shows that the increase of environmental temperature of testis will cause the increase of apoptosis of spermatogenic cells, with spermatogonia and spermatocytes as the main ones. There are also reports suggesting that steam baths, tight pants and high-temperature workers with high scrotal ambient temperatures can also affect spermatogenic function and cause infertility. In addition spermatogenic cells are very sensitive to ionizing radiation. Such as X-ray, γ-ray and “electronic fog” on men’s reproductive function has a multifaceted impact, can inhibit testicular mesenchymal stromal cells to produce androgens, so that spermatogenic cells chromosomal mutations. Others, such as noise, vibration and microwave spermatogenesis also has a hindering effect. (4) Chemical factors: Many chemical substances have obvious effects on men’s reproductive function: environmental endocrine disruptors include pesticides, herbicides, insecticidal phosphorus, environmental estrogen and benzene. These chemical poisons are common in the natural environment, therefore, in the past half century, the number and quality of men’s spermatozoa have declined significantly, which has caused a great deal of concern around the world; in addition, anticancer drugs will increase the apoptosis of spermatogenesis; certain metal elements such as aluminum, manganese, chromium, cobalt, cadmium, etc. on the spermatozoa have a toxic effect; long-term smoking, alcohol abuse on spermatozoa also have an impact. (5) Systemic diseases: such as chronic renal failure, cirrhosis, etc. will affect the function of hypothalamus-pituitary-gonadal axis, so that the level of testosterone decreases, affecting the sexual function and spermatogenesis, leading to male infertility. (c) Post-testicular factors. Post-testicular factors include sperm transportation disorders, sexual dysfunction, reproductive tract infections and autoimmune factors. 1, sperm transportation disorder. If spermatogenesis is normal, but cannot enter the female reproductive tract normally, it is impossible to make the female fertile, so sperm transportation disorder is an important factor in male infertility. Sperm transportation disorders include two major causes: obstruction of the vas deferens tract and sexual dysfunction. (1) Congenital absence of vas deferens and seminal vesicle glands: Congenital hypoplasia or absence of vas deferens accounts for 11%~50% of congenital obstruction of the reproductive tract, and it can be unilateral or bilateral. It is usually combined with absence of seminal vesicle glands and partial absence of epididymis. Clinical manifestations include normal secondary sexual characteristics, normal testicular size, poorly palpable vas deferens, and occasional absence of seminal vesicle glands on ultrasound. Serum FSH, LH, and T values are in the normal range, semen analysis has no spermatozoa, and epididymal puncture or testicular biopsy has spermatozoa of normal morphology. (2) Acquired vasovaginal obstruction: it is more common in clinic and accounts for about 60%~70% of obstructive azoospermia. Most of them are gonococcal urethritis urethritis is not completely cured, the germs invade the vas deferens and epididymis, causing chronic inflammatory changes, forming fibrous scars and obstruction. Others such as mycoplasma and chlamydia infections involve the vas deferens and epididymis. Acute bacterial epididymitis that is not cured evolves into chronic epididymitis, leading to vas deferens obstruction, and hard inflammatory nodules in the head and tail of the epididymis are often palpable on physical examination. Normal spermatozoa can be seen in epididymal puncture or testicular biopsy. 2.Sexual dysfunction. Sexual dysfunction includes low libido, penile erectile dysfunction, penetration disorders, and ejaculation disorders (including non-ejaculation, retrograde ejaculation). Sexual dysfunction affects sexual intercourse and ejaculation, so that sperm cannot be normally imported into the female reproductive tract, resulting in infertility. This kind of disease also belongs to the sperm transportation disorder. 3.Reproductive tract infections. Including non-specific bacterial infections, gonococcal infections, mycoplasma and chlamydia infections, toxoplasmosis infections, tuberculosis infections caused by chronic prostatitis and seminal vesiculitis, resulting in abnormal plasma composition, changes in the internal environment of spermatozoa and affecting spermatozoa vitality, semen liquefaction abnormalities, and spermatozoa fertilization ability is reduced. The increase of white blood cells in semen and the increase of oxidized free radicals have a serious impact on the vitality, viability and fertilization of sperm. 4, autoimmune factors. There are blood-testis barriers and immunosuppressive substances in the human reproductive system, which do not produce autoimmune reactions or anti-sperm antibodies under normal conditions. If the reproductive system is traumatized or infected, the antigens in the seminal plasma and on the membrane of the spermatozoa will enter the body and produce anti-sperm antibodies. This antibody has a braking and killing effect on the sperm and affects the egg, the fertilized egg, and the embryo. Therefore, about 20% of patients with clinical immune infertility. Endocrine examination 1, FSH, LH, T-normal, to exclude endocrine diseases, if no sperm, suggests that the vas deferens obstruction. 2.FSH.LH.T-decrease, suggesting central (hypothalamus, pituitary) disease, suggesting CT or nuclear magnetic resonance. 3, FSH, LH elevated, low T – suggests primary hypogonadism. 4, FSH high, LH, T normal – if oligospermia, azoospermia, suggesting spermatogenic epithelial damage. 5, FSH, LH, T low, PRL high – high prolactinemia, lesions in the pituitary gland. 6, FSH low, LH, T normal – suggesting selective FSH deficiency. 7, LH low, FSH, T normal – suggestive of selective LH deficiency. 8, FSH, LH, T low, E2 high – estrogen-secreting testicular or adrenal tumor.