Azoospermia and maturation arrest: malfunction of valves in erect poster of humans leads to hypoxia in sperm production site.

Maturation arrest (MA) of spermatogenesis is diagnosed on histology as interruption of spermatogenesis before the final stage without impairment of Sertoli or Leydig cells. It is considered a condition of irreversible or absolute infertility. Varicocele, which represents impairment in the testicular venous drainage system, has been shown to be a bilateral disease. Malfunction of the valves increase the hydrostatic pressure in the testicular venous system that exceeds the pressure in the arterial system leading to hypoxia in the testicular microcirculation and in the seminiferous tubules, the sperm production site. Sperm production deteriorates, and ultimately progresses to azoospermia. Our prediction was that MA, if genetic factors are excluded, is the final stage of long standing hypoxia. This would indicate that MA is not always an independent disease entity, but may represent progressive process of deterioration of the testicular parenchyma beyond azoospermia. By histology and electron microscopy, our prediction confirmed, at least partially, that MA is associated with degenerative ischaemic changes in the seminiferous tubules. Adequate treatment of bilateral varicocele by microsurgery or super-selective sclerotherapy of the internal spermatic veins including associated network of venous bypasses, vertically oriented, may resume the flow of oxygenated blood. If irreversible damages did not occur and ischaemia is not too long standing, limited sperm production may be restored, at least partially.

Azoospermia and Sertoli-cell-only syndrome: hypoxia in the sperm production site due to impairment in venous drainage of male reproductive system.

Sertoli-cell-only (SCO) syndrome, or germ cell aplasia, is diagnosed on testicular biopsy when germ cells are seen to be absent without histological impairment of Sertoli or Leydig cells. It is considered a situation of irreversible infertility. Recent studies have shown that varicocele, a bilateral disease, causes hypoxia in the testicular microcirculation. Destruction of one-way valves in the internal spermatic veins (ISV) elevates hydrostatic pressure in the testicular venules, exceeding the pressure in the arteriolar system. The positive pressure gradient between arterial and venous system is reversed, causing hypoxia in the sperm production site. Sperm production deteriorates gradually, progressing to azoospermia. Our prediction was that, if genetic problems are excluded, SCO may be the final stage of longstanding hypoxia which deteriorates sperm production in a progressive process over time. This would indicate that SCO is not always an independent disease entity, but may represent deterioration of the testicular parenchyma beyond azoospermia. Our prediction is confirmed by histology of the seminiferous tubules demonstrating that SCO is associated with extensive degenerative ischaemic changes and destruction of the normal architecture of the sperm production site. Adequate treatment of bilateral varicocele by microsurgery or by selective sclerotherapy of the ISV resumes, at least partially, the flow of oxygenated blood to the sperm production site and restored sperm production in 4 out of 10 patients. Based on our findings the following statements can be made: (i) SCO may be related in part of the cases to persistent, longstanding testicular parenchymal hypoxia; (ii) germ cells may still exist in other areas of the testicular parenchyma; and (iii) if genetic problems are excluded, adequate correction of the hypoxia may restore very limited sperm production in some patients.

Is varicocele prevalence increasing with age?

Varicocele is a bilateral vascular disease which occurs when the one-way valves in the internal spermatic veins, the testicular venous drainage system, malfunction. Based on new findings and fluid-mechanics analysis we showed that this process results in vertical blood columns, which cause pathological hydrostatic pressure in the testicular venous microcirculatory system. Ultimately, these pressures exceed the pressure in the arteriolar system. This unique phenomenon of reversal of pressures gradient between the arteriolar and venular systems leads to persistent hypoxia in the testosterone production site, namely, the Leydig cells. The result of bilateral varicocele is decreased testosterone production. Adequate treatment of bilateral varicocele significantly elevates the testosterone production. We found that the prevalence of varicocele increases with age with a rise of about 10% for each decade of life with the incidence reaching 75% in the eight decade of life. Based on our findings the following statements can be made: (1) varicocele prevalence is increased over time. (2) The rise of the incidence is about 10% for each decade of life. (3) 75% of men in the eight decade of their life have varicocele. As varicocele decreases testosterone production and it is reversible by appropriate treatment, it raises two interesting and important issues to be studied: (i) it is possible that varicocele accelerates the process of the ageing male. (ii) It is possible to retard, at least partially, the process of ageing in men by adequate treatment of bilateral varicocele.

Relation of nonobstructive aortic valve calcium to carotid arterial atherosclerosis.

Recently it was shown that subjects with aortic valve calcium (AVC) are at increased risk for future cardiovascular disease including stroke. We hypothesized that the increased risk of stroke may be due to an association with carotid artery atherosclerotic disease. Between 1995 and 1999 our laboratory made a diagnosis of AVC without significant stenosis in 3,949 patients. Of those, 279 patients without other cardiac structural exclusion criteria (148 men and 131 women; mean age 73 +/- 9 years, range 45 to 90) underwent carotid artery duplex ultrasound for various indications, and formed the study group. Age- and sex-matched patients without AVC (n = 277), who underwent carotid artery duplex ultrasound during the same period and for the same indications, served as the control group. Compared with the control group, the AVC group had a significantly higher prevalence of carotid stenosis (> 40% to 60%, 89% vs 78% [p < 0.001]; >60% to 80%, 43% vs 23% [p <0.001];and > 80% to 100%, 32%vs 14% [p < 0.001]). The AVC group had a similar, significantly higher prevalence of > or = 2-vessel disease and bilateral carotid stenosis (stenosis levels of > 20% to 40%, >40% to 60%, > 60% to 80%, and > 80% to 100%). In multivariate analysis, AVC, but not traditional risk factors, was the only independent predictor of severe carotid atherosclerotic disease (stenosis > 80% to 100%; p = 0.0001). Thus, there is a significant association between the presence of AVC and carotid atherosclerotic disease.

Association between mitral annulus calcification and peripheral arterial atherosclerotic disease.

The authors previously demonstrated a significant association between the presence of mitral annulus calcification (MAC) and aortic atheroma, carotid atherosclerotic disease, and coronary artery disease. The present study was designed to determine whether an association exists between MAC and peripheral arterial atherosclerotic disease. Of the 805 patients in whom the diagnosis of MAC was made by transthoracic echocardiography between 1995 and 1997, 77 patients (40 men and 37 women; mean age, 73.1 +/- 11.4 years; range, 44-90 years) underwent peripheral arterial testing for various indications, and comprised the study group. They were compared with 58 age-matched and sex-matched patients without MAC (30 men and 28 women; mean age, 73.2 +/- 11.8 years; range, 31-93 years) who underwent peripheral arterial testing during the same period for the same indications (control group). MAC was defined as a dense, localized, highly reflective area at the base of the posterior mitral leaflet detected by transthoracic echocardiography. An ankle/brachial systolic pressure index (ABI) was calculated by dividing the higher dorsalis pedis or posterior tibial Doppler-derived pressures by the higher of the 2 upper extremity systolic pressures. ABI was graded as follows: normal > or = 1, abnormal < 1, mild 0.71 to 0.99, moderate 0.41 to 0.7, and severe < or = 0.4. No differences were found between the groups in indications for referral for peripheral arterial testing and in risk factors for atherosclerosis except for hypertension, which was found to be significantly more prevalent in the study group (66% vs 41%, p = 0.004). The study group included 151 limbs, and the control group included 113 limbs. The mean ABI was significantly lower for all limbs in the MAC group (0.56 +/- 0.27 vs 0.87 +/- 0.24, p = 0.0001), abnormal ABI < 1 (94% vs 68%, p = 0.001), moderate peripheral arterial disease (44% vs 25%, p = 0.001), and a severe disease (27% vs 1%, p = 0.001). Of the 77 patients with MAC, 73 (95%) had a disease (right and/or left limbs) compared with 40 of 58 (69%) in the control group (p = 0.001). Bilateral disease (Doppler index < 1 for both right and left limbs), and severe bilateral disease (Doppler index < or = 0.4 for both right and left limb) were also found to be significantly more prevalent in the MAC group (87% vs 60%, p = 0.001; and 12% vs 0%, p = 0.007, respectively). There is a significant association between the presence of MAC and peripheral arterial disease. This information strengthens our hypothesis that MAC may be an important marker for generalized vascular atherosclerotic disease.