Prof. Giovanni Alei - Attività di Ricerca
•Histological Lesions in the Testis of Infertile Men with Varicocele

Varicocele frequently causes male infertility and histological lesions at the contralateral testis. The most frequent lesions found in this study included maturation arrest in the spermatidic phase, cellular and acellular thickening of the tubular wall, and degeneration of the Leydig cells. These lesions were typical of varicocele and their simultaneous presence suggests that scrotal temperature and modified endocrine secretion of the interstitial testis play a role in the pathogenesis of this type of infertility.

INTRODUCTION
Varicocele is a varicose dilatation of the veins of the subsidiary pampiniform plexus of the spermatic vein. For anatomical reasons it is more frequent on the left side (90%) but may be present on the right; it is often bilateral, but in these cases it is always more severe on the left. It has been reported that 30-39% of cases of male infertility are due to varicocele [2, 4, 6, 91. Varicocele is present, independently of infertility, in 1- 13% of males [1, 5, 8]. Controversy still exists as to the pathogenesis and the histological lesions that should be considered typical of infertility due to varicocele. With regard to pathogenesis, various and often conflicting hypotheses have been advanced. Hyperthermia, however, is considered to be directly or, more likely, indirectly responsible for the lesions observed. The goal of the present study was to establish which histological lesions are most frequent and therefore most typical of testicular infertility due to varicocele. Recognition of these typical lesions may be of use in (a) excluding the presence of other concomitant types of pathology in inducing infertility, (b) confirming indications for surgery, and (c) advancing a prognosis based on the reversibility of the lesions observed. Furthermore, the characteristics of these histological lesions may provide some indications as to the probable pathogenesis of the infertility.

MATERIALS AND METHODS
Biopsy specimens were collected from the unaffected testis of 42 patients with varicocele. In those cases in which biopsy specimens were removed from both sides, only that from the side opposite the varicocele was considered. In those cases presenting bilateral varicocele (14% of cases) the biopsy specimen from the less severely affected side was considered. It is impossible to detect significant and typical lesions in a severely affected testis, or even an atrophic testis affected by varicocele. In the testis apparently not affected by varicocele or other disease, the lesions observed are characteristic and certainly indicative of the vascular pathogenesis involved.

TABLE 1 Histological Lesions Induced by Varicocele in the Contralateral Testis

LOCATION

PATHOLOGICAL CHANGE

PERCENT

Interstitial

Involution of Leydig cells (vacuolar degeneration, trapping, etc.)

90

tissue

Thickening vessel walls

62

 

Reduction in Leydig cell/fibroblast ratio

20

 

Massive fibrosis

7.4

 

Hyperplasia (relative) of Leydig cells

2.4

Tubular wall

Thickening of acellular layers
(PAS-positive substance 4%)
(PAS-negative substance 36%)

40

 

Combined cellular and acellular thickening (PAS negative)

40

 

Thickening or hyperplasia of cellular layers

38

Seminiferous

Severe maturational arrest (oligospermiogenesis)

72

epithelium

Severe maturational arrest (spermatocyte spermatogonial phase)

24

 

Acquired Sertoli cell only syndrome

4

The histological specimens were fixed in Bouin's solution and embedded in paraffin; the sections were then stained with HOPA according to Tonutti and with PAS-hematoxylin.

RESULTS
Lesions were found in the seminiferous epithelium, the tubular walls, and the interstitial tissue (Table 1). Lesions in the seminiferous epithelium involved maturation arrest at the various stages, associated in some cases with other lesions, e.g. , a tendency to intraluminal desquarnation of the seminal elements or a reduced number of elements (hypospermatogenesis). Oligospermiogenesis, i.e., a reduced mean number of more mature spermatids per tubular section (Fig. IA) [8], was the most frequent finding in the seminiferous epithelium (72% of cases). More severe maturational arrest in the spermatocyte and spermatogonial phases was observed in 24% of cases. In the other 4% germinal aplasia, i.e., acquired Sertoli cell only syndrome, was observed. Lesions in the tubular walls were present in almost all cases (Fig. IB). Concomitant PASnegative cellular and acellular thickening was observed in a high percentage of cases. The acellular substance was PAS positive in only two cases (4%). The lesions in the interstitial tissue were of particular interest. In most cases they involved various forms of involution of the Leydig cells: e.g., vacuolar degeneration, trapping, and other lesions of which there is little mention in the literature (Fig. 2). True hyperplasia of the Leydig cells occurred very rarely (Table 1). Compared with normal subjects, plasma and seminal fluid levels of testosterone and dihydrotestosterone in patients with varicocele are markedly reduced [10].

DISCUSSION
The lesions observed in the testis, and thus able to be considered typical of varicocele are (a) oligospermiogenesis, (b) cellular or acellular parietal tubule thickening, particularly if associated, and (c) degenerative involution of the Leydig cells with thickening of the vessel walls. Evidence of these lesions simultaneously is probably an indication that varicocele alone is responsible for infertility in the patient, and the absence of other signs enables concomitant pathology to be excluded. The absence of even one of these lesions leads to some doubt regarding the role of varicocele. In all cases in which there is an increase in temperature, a humoral mechanism is responsible for the lesions in the contralateral testis. The Leydig cells are directly involved in the manifestation of these lesions; modifications in these cells and their poor response to endocrine treatment appear to confirm this hypothesis. In the cases presenting PAS-positive thickening, autoimmune factors may be involved; however, further evidence is required to support this suggestion. In many of the cases in which the histological lesions consist of mild or severe


FIGURE 1. Lesions due to varicocele. A. Seminiferous epithelium lesions. This appears similar to normal seminiferous epithelium, but the mean count of more mature spermatids in this case was decreased with respect to the normal mean (oligospermiogenesis). HOPA (X 188). B. Tubular wall lesions. PAS-negative cellular (a) and acellular (b) thickening, PAS-positive basement membrane, and normal wall thickness (arrow) are seen. PAS-hematoxylin. x 300.



FIGURE 2. Lesions due to varicocele. A. Tubular wall. Observe thickening of the vessel walls (a) and signs of trapping of Leydig cells (b). PAS-hematoxylin. x 188. B. Interstitial testicular tissue. Vacuolar degeneration is seen in a group of Leydig cells; in the upper area note issues of the tubular sclerosis and cells undergoing fibroblastic involution.

degeneration of the Leydig cells, the maturational arrest of spermatogenesis, and thickening of the tubular wall, particularly of the acellular PAS-negative type, surgical intervention may lead to fertility.

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