Nitric oxide (NO) is a biologically active toxic molecule and messenger molecule, NO is widely present in human testes, epididymis, vas deferens and prostate, and may regulate spermatogenesis, testosterone secretion and apoptosis of spermatogonia. When the concentration of NO is physiological, it can regulate sperm function, promote sperm maturation, and enhance sperm metabolic rate and viability;
However, when the NO concentration is too high, it will promote the overexpression of inducible nitric oxide synthase (iNOS) in the body, and the overexpressed iNOS damages normal cells by inhibiting enzymes in the mitochondrial respiratory chain and DNA, thus reducing the spermatogenic function, acrosome reaction rate and sperm motility of spermatogenic cells. iNOS activity and NO concentration in seminal plasma were significantly elevated in the testes of rats with varicose veins and were correlated with vessel diameter.
1. Mechanism of testicular microcirculatory disorders
In varicocele, the absence or dysplasia of the intraventricular valves in the spermatic cord can easily cause venous blood reflux and aggravate the intraventricular pressure in the spermatic cord. The increase in intraventricular pressure in the spermatic cord can directly promote the contraction of the micro-artery and pre-capillary sphincter on the one hand; on the other hand, it can also induce sympathetic excitation in the spinal cord, prompting the contraction of the small testicular arteries and micro-artery, leading to further increase in the resistance to venous blood flow and increase in the intra-testicular blood pressure, thus This will affect the blood supply to the testes and cause metabolic disorders in the testes.
Salama et al. observed the changes of testicular microvascular blood flow in rats with varicocele by laser Doppler flowmeter and found that the testicular microvascular blood flow was significantly decreased and the degree of decrease in blood flow was proportional to the degree and duration of varicocele.
Cozzolino et al. suggested that varicocele can cause small testicular interstitial vasculopathy, which in turn causes changes in testicular microcirculation and impairs the normal material metabolism of the spermatogenic tubules, damaging the spermatogenic epithelium and thus affecting its spermatogenic function. This may be caused by the impairment of the energy of the testicular microcirculatory vascular bed in varicocele patients, which affects sperm production.
2. Renal and adrenal metabolite reflux mechanisms
Mac Cleod first proposed the hypothesis of renal and adrenal metabolite reflux in 1965. He believed that when the left spermatic vein is varicose, the blood in the left renal vein refluxes to the spermatic vein and brings the metabolites of the kidney and adrenal glands to the left testis, causing testicular toxicity and damage. Among these metabolites, 5-hydroxytryptamine (5-HT), prostaglandin F2α (PGF2α), catecholamines and steroids are thought to have a significant impact on the spermatogenic function of the testis.
Devoto et al. showed that varicocele can cause abnormal accumulation of 5-HT in the testis, and the abnormal accumulation of 5-HT can cause excessive vasoconstriction in the testis. This can lead to swelling and degeneration of interstitial cells and testicular interstitial fibrosis, which can affect testosterone synthesis and also contribute to the shedding of immature sperm before maturation.
PGF2α is a bioactive substance and a vasoconstrictor. Animal experiments have shown that high concentrations of PGF2α have an anti-spermatogenic effect, and varicocele can cause a significant increase in the concentration of PGF2α in both testes, with the varicocele side being the one that increases significantly.
The elevated PGF2α concentration in the testis of varicocele may be produced by the testis itself or by the regurgitation of PGF2α from the kidneys or adrenal glands into the testis. The high concentration of PGF2α in the testis not only has a direct killing effect on sperm, but also reduces the blood supply to the testis by constricting the testicular arteries, and stimulates the contraction of testicular varicocele-like muscle cells, leading to testicular varicocele lesions and eventually causing infertility. Ultimately, this leads to infertility.
Catecholamines, including epinephrine and norepinephrine, were found to be significantly increased in local concentrations of norepinephrine and epinephrine in patients with varicocele, suggesting that the excessive local increase of norepinephrine and epinephrine may be closely related to the pathophysiological process of infertility caused by varicocele, as norepinephrine and epinephrine attack spermatogenic cells through the production of oxygen radicals by autoxidation. This leads to excessive apoptosis of spermatogenic cells, which may be an important cause of infertility in patients with varicocele.
3. Apoptotic mechanism
An important progress in the research of the pathological mechanism of male infertility caused by varicocele is the abnormal apoptosis of spermatogenic cells, which is also an important cellular molecular mechanism of male infertility caused by varicocele. In the process of spermatogenesis, in order to ensure normal reproductive function, it is necessary to maintain the proper ratio of spermatogenic cells to supporting cells, so 25-75% of spermatogenic cells have to undergo apoptosis.
It can be seen that apoptosis of testicular spermatogenic cells plays an important regulatory role in the process of spermatogenesis, and spermatogenic dysfunction is closely related to abnormal apoptosis. by comparing testicular biopsy results of 46 patients with infertile varicocele, 18 patients with fertile varicocele and 8 patients with obstructive azoospermia with normal spermatogenesis, Hassan et al. found that testicular interstitial cells and apoptotic spermatogenic cells in the 2 groups of patients with varicocele The apoptotic index of testicular interstitial cells and spermatogonia was significantly higher in the two groups of patients with varicocele than in patients with obstructive azoospermia, and in the group with varicocele combined with infertility, the severity of spermatogenic impairment was proportional to its apoptotic index, suggesting that spermatogonia apoptosis is not only a pathological mechanism of spermatogenic impairment due to varicocele, but also related to the degree of spermatogenic impairment.
4.Reactive oxygen mechanism
ROS (reactive oxygen species) are highly reactive oxygen-containing groups, which are required for normal reactions such as sperm capacitation and acrosome reaction. ROS include H2O2 and unstable radicals containing unpaired electrons in peripheral orbitals such as superoxide anion, hydroxyl radical, nitrogen radical, etc.
ROS can cause lipid peroxidation in cell membranes, generating large amounts of lipid per oxide (LPO), which attacks cellular biofilms and limits the activation of adenylate cyclase, causing a decrease in cyclic adenosine monophosphate (cAMP), leading to single- and double-strand breaks in spermatogenic cells or sperm DNA, resulting in spermatogenic cell damage and causing male infertility or embryonic defects.
Oxidative stress due to varicocele can occur in the plasma, testis, epididymis and seminal plasma. Increased oxidative stress in the plasma is one of the causes of DNA damage and apoptotic disorders of spermatogenic cells due to varicocele. Patients with varicocele have excess xanthine oxidase and NO in the spermatic veins, which can lead to oxidative stress and thus affect the spermatogenic function of the testis.
Mostafa et al. showed that the level of antioxidants in the spermatic vein blood was significantly lower in patients with varicocele infertility, while the level of ROS was significantly higher. The elevated ROS may be one of the causes of male infertility due to varicocele.
5.Sexual hormone change
Each process of spermatogenic cells developing into sperm depends on the level of sex hormones, and it is controversial whether varicocele causes changes in the level of sex hormones. He Xuejun et al. pointed out that the hypothalamic-pituitary-gonadal axis disorder caused by varicocele is related to its damage to mesenchymal cells, and varicocele can cause testicular mesenchymal cell edema and mesenchymal vasculopathy. LH promotes the secretion of testosterone by testicular interstitial cells, and promotes the diffusion of testosterone into the varicocele for spermatogenesis, while FSH has the effect of enhancing the secretion of testosterone stimulated by LH.
However, Wang Yixin et al. concluded that serum FSH, LH and testosterone were within the normal range in patients with varicocele, and Zedan et al. concluded that serum levels of FSH, LH and prolactin (PRL) were significantly higher in infertile patients with varicocele compared with fertile patients with varicocele, while testosterone levels were not significantly changed, and testosterone levels in semen were significantly lower.
Chang Jiang et al. used spermatic venous blood and peripheral blood from patients with varicocele to compare with the control group respectively, and the results showed that FSH and LH values in peripheral blood from patients with varicocele increased, and testosterone values did not differ significantly from the control group; while FSH and LH values in spermatic venous blood increased, and testosterone values decreased. Therefore, the role of sex hormone changes in varicocele infertility needs to be further studied.
6.Immunological factors
Studies have found that 5%-15% of the factors causing male infertility are related to immune factors, and the mechanism of varicocele infertility is also related to autoimmunity. Spermatozoa are antigenic and under normal circumstances the body does not produce an active immune response due to the isolation of the blood-seminiferous tubule barrier in the reproductive system. In the case of varicocele, the venous pressure in the testicular tissue is increased and the accumulation of toxic substances leads to the destruction of the blood-seminiferous tubule barrier, resulting in the release of sperm into the bloodstream and the production of anti-sperm antibodies (AsAb), which interfere with normal sperm production and maturation, prevent sperm from gaining energy or penetrating the egg cell membrane, impair the ability of sperm to penetrate the cervical mucus, cause sperm agglutination and braking, and affect the fertilization and development of the egg. This can lead to infertility.
7. Epididymal damage
Epididymis is the site of sperm transport, storage and maturation. Varicocele can cause abnormal function of epididymis and affect sperm maturation, resulting in reduced male fertility. Ma Xiaoru et al. used animal experiments to show that the epididymis mainly showed a large number of vacuoles in epithelial cells, atrophy of epididymal ducts, and a significant increase in the number of intraepithelial halo and bright cells when varicoceles were present under light microscopy.
Electron microscopy mainly showed a large number of lysosomal particles and residual vesicles in the main cells, enlargement of the main cell volume, expansion of the endoplasmic reticulum, blurring of the mitochondrial cristae, vacuolation of the Golgi complex, nuclear chromatin fixation, sparse microvilli on the surface of the epithelial cells, and visible focal fracture and destruction. Thus, it is pointed out that the alteration of the epididymal structure is one of the reasons affecting the reduced fertility of patients with varicocele.
In summary, varicocele can affect the structure and function of the testes and epididymis through a variety of pathways, and various different mechanisms affect the development, maturation and fertilization ability of sperm, ultimately leading to sperm dysfunction and morphological abnormalities and affecting male fertility.