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RM Sharpe, C McKinnell, C Kivlin, and JS Fisher

Disorders of testicular function may have their origins in fetal or early life as a result of abnormal development or proliferation of Sertoli cells. Failure of Sertoli cells to mature, with consequent inability to express functions capable of supporting spermatogenesis, is a prime example. In a similar way, failure of Sertoli cells to proliferate normally at the appropriate period in life will result in reduced production of spermatozoa in adulthood. This review focuses on the control of proliferation of Sertoli cells and functional maturation, and is motivated by concerns about 'testicular dysgenesis syndrome' in humans, a collection of common disorders (testicular germ-cell cancer, cryptorchidism, hypospadias and low sperm counts) which are hypothesized to have a common origin in fetal life and to reflect abnormal function of Sertoli (and Leydig) cells. The timing of proliferation of Sertoli cells in different species is reviewed, and the factors that govern the conversion of an immature, proliferating Sertoli cell to a mature, non-proliferating cell are discussed. Protein markers of maturity and immaturity of Sertoli cells in various species are reviewed and their usefulness in studies of human testicular pathology are discussed. These markers include anti-Mullerian hormone, aromatase, cytokeratin-18, GATA-1, laminin alpha5, M2A antigen, p27(kip1), sulphated glycoprotein 2, androgen receptor and Wilms' tumour gene. A scheme is presented for characterization of Sertoli-cell only tubules in the adult testis according to whether or not there is inherent failure of maturation of Sertoli cells or in which the Sertoli cells have matured but there is absence, or acquired loss, of germ cells. Functional 'de-differentiation' of Sertoli cells is considered. It is concluded that there is considerable evidence to indicate that disorders of maturation of Sertoli cells may be a common underlying cause of human male reproductive disorders that manifest at various life stages. This recognition emphasizes the important role that animal models must play to enable identification of the mechanisms via which failure of proliferation and maturation of Sertoli cells can arise, as this failure probably occurs in fetal life.

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R. M. Sharpe, J. B. Kerr, C. McKinnell, and M. Millar

This study assessed whether changes in production of seminiferous tubule fluid underlie the previously described androgen-dependent changes in protein secretion by seminiferous tubules at stages VI–VIII of the spermatogenic cycle. Testosterone withdrawal was induced in adult rats by administration of ethane dimethane sulfonate (EDS) and temporal changes in lumen area, the volume of seminiferous tubule fluid and testicular interstitial fluid were assessed and compared with the changes in secretion of [35S]methionine-labelled proteins in vitro by isolated seminiferous tubules at stages VI–VIII. Testicular interstitial fluid was reduced by about 50% by day 4 and later after EDS treatment when compared with controls. In contrast, the volume of seminiferous tubule fluid was unaffected at days 3 and 4 but was reduced by about 50% at days 6 and 8 after EDS treatment. In perfusion-fixed control testes, the lumen area of seminiferous tubules at stages VII–VIII was significantly greater than at stages I–VI and IX–XIV. This difference was also evident at 4 days after EDS treatment, but was abolished at 6 and 8 days after treatment. The volume of testicular interstitial fluid was reduced significantly at 3 and 4 days after EDS treatment, but was further reduced (about 50%) at 6 and 8 days. Administration of 25 mg testosterone esters every 3 days to EDS-treated rats prevented all of the changes described above. As the decrease in protein secretion by seminiferous tubules at stages VI–VIII following androgen withdrawal precedes the changes in lumen area and volume of seminiferous tubule fluid, it is concluded that there is differential control of these two androgen-dependent processes. The present data add to the evidence showing that testosterone plays a central role in regulating the production and movement of fluids (and therefore of nutrients) to and within the testis.

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C McKinnell, PT Saunders, HM Fraser, CJ Kelnar, C Kivlin, KD Morris, and RM Sharpe

The aims of this study were: (i) to investigate the cellular immunoexpression of androgen receptor and oestrogen receptor beta in the testes of the common marmoset (Callithrix jacchus) during neonatal life compared with their expression at later ages; (ii) to establish whether neonatal marmoset Sertoli cells are targets for androgens or oestrogens or both; and (iii) to investigate the relationship between neonatal plasma testosterone concentrations and androgen receptor immunoexpression by abolishing the neonatal testosterone surge with a potent GnRH antagonist. Androgen receptor and oestrogen receptor beta immunoexpression were evaluated in neonatal animals aged 1-4 days, 4 weeks and 6 weeks, and compared with immunoexpression in animals aged 18-22 weeks (early infancy), 35 weeks (late infancy), 58-62 weeks (late pubertal) and > 100 weeks (adult). Immunoexpression of androgen receptor in the reproductive tract was also evaluated at each age. Sertoli cell immunoexpression of androgen receptor was weak or absent in neonatal animals, but increased substantially in infant animals, reaching adult levels by the end of infancy. In contrast, immunoexpression of androgen receptor during the neonatal period was strong in testicular interstitial cells and very strong in epithelial cell nuclei throughout the reproductive tract, and did not change greatly with age in these cells or tissues. Similarly, immunoexpression of oestrogen receptor beta was prominent in many Sertoli cells and in the germ cells of neonatal animals, and was relatively constant throughout life. Weak immunoexpression of androgen receptor in neonatal Sertoli cells was associated with high plasma testosterone concentrations (2.7-5.5 ng ml(-1)), whereas strong Sertoli cell immunoexpression was associated with baseline (approximately 0.12 ng ml(-1)) testosterone concentrations in infant animals and with > 10 ng ml(-1) in late pubertal and adult animals. Immunoexpression of androgen receptor and oestrogen receptor beta was also evaluated in co-twin males aged 4 and 35 weeks, after treatment from birth to 4 weeks or from week 25 to week 35, respectively, with either vehicle or with GnRH antagonist at a dose known to suppress the neonatal testosterone surge completely. Only GnRH antagonist treatment during weeks 25-35 reduced androgen receptor immunoexpression, whereas immunoexpression of oestrogen receptor beta was unaffected by treatment during either period. On the basis of these findings it is suggested that: (i) neonatal marmoset Sertoli cells may be targets primarily for oestrogens rather than androgens; (ii) androgen receptor expression in the testes of neonatal and infant marmosets is not regulated in a straightforward way by testosterone; and (iii) high neonatal concentrations of plasma testosterone are not absolutely necessary for expression of androgen receptor in marmoset testes at this time.