No abstract

Abstract. Male Wistar rats were treated between 23 to 38 days of age with flutamide. Hypothalamic LRH content, pituitary gonadotrophin concentrations and plasma LH, FSH, Prl and testosterone levels were measured by radioimmunoassay. The testis, epididymis and accessory organs were weighed and the histology of the testis, and the estimation of gonadotrophin receptors were performed in the same animals. The results were compared with data obtained in control animals of the same age. Flutamide treatment induced a direct inhibition of the genital tract. On the hypothalamo-pituitary axis, flutamide acted as a pure antiandrogen able to inhibit the negative feedback of testosterone, producing an increase in pituitary LH synthesis, as well as release of LH, FSH and Prl. The high level of plasma LH stimulated hyperplasia and hypertrophy of interstitial cells of the testis. Consequently testosterone synthesis was stimulated, although the number of LH receptor sites per Leydig cell was unchanged. Sertoli cells divisions were stimulated by the high level of gonadotrophins, but Sertoli cell function and the number of FSH receptors sites per Sertoli cell were slightly decreased. The increase in the number of type A spermatogonia and early stages of meiosis of primary spermatocytes could be related to the increase in plasma levels of FSH, whereas the drastic decrease in the late stages of spermatogenesis could result from the direct inhibition of testosterone by flutamide in the seminiferous tubules.

The retinal innervation, cytoarchitectural, and immunohistochemical organization of the suprachiasmatic nucleus (SCN) was studied in the domestic sheep. The SCN is a large elongated nucleus extending rostrocaudally for roughly 3 mm in the hypothalamus. The morphology is unusual in that the rostral part of the nucleus extends out of the main mass of the hypothalamus onto the dorsal aspect of the optic chiasm. Following intraocular injection of wheat-germ agglutinin-horseradish peroxidase or tritiated amino acids, anterograde label is distributed throughout the SCN. Retinal innervation of the SCN is bilaterally symmetric or predominantly ipsilateral. Quantitative image analysis demonstrates that, although the amount of autoradiographic label is greatest in the ventral and central parts of the nucleus, density varies progressively between different regions. In addition to the SCN, retinal fibers are also seen in the medial preoptic area, the anterior and lateral hypothalamic area, the dorsomedial hypothalamus, the retrochiasmatic area, and the basal telencephalon. Whereas the SCN can be identified using several techniques, complete delineation of the nucleus requires combined tract tracing, cytoarchitectural, and histochemical criteria. Compared with the surrounding hypothalamic regions, the SCN contains smaller, more densely packed neurons, and is largely devoid of myelinated fibers. Cell soma sizes are smaller in the ventral SCN than in the dorsal or lateral parts, but an obvious regional transition is lacking. Using Nissl, myelin, acetylcholinesterase, and cytochrome oxidase staining, the SCN can be clearly distinguished in the rostral and medial regions, but is less differentiated toward the caudal pole. Immunohistochemical demonstration of several neuropeptides shows that the neurochemical organization of the sheep SCN is heterogeneous, but that it lacks a distinct compartmental organization. Populations of different neuropeptide-containing cells are found throughout the nucleus, although perikarya positive for vasoactive intestinal polypeptide and fibers labeled for methionine-enkephalin are predominant ventrally; neurophysin-immunoreactive cells are more prominent in the dorsal region and toward the caudal pole. The results suggest that the intrinsic organization of the sheep SCN is characterized by gradual regional transitions between different zones.

Adult male Wistar rats were treated with flutamide from 90 to 105 days of age. In a first experiment, testis and accessory sex organs were weighed. In the same animals, hypothalamic LRH content, pituitary gonadotrophin concentrations, plasma LH, FSH, prolactin and testosterone levels, and testicular gonadotrophin receptors were evaluated. In a second experiment, fertility was tested at the end of the treatment, and histology of the testis was performed. All the results were compared to those obtained in control animals of the same age. Accessory glands of genital tract were significantly lower in flutamide-treated animals (P < 0.01). Hypothalamic LRH, pituitary and plasma FSH, and prolactin concentrations were unchanged, while pituitary and plasma LH level and especially plasma testosterone concentration were increased (P < 0.001).Flutamide therefore exerted a strong inhibition on testosterone-dependent organs, and blocked the negative feedback of testosterone on the hypothalamo-pituitary axis, increasing the LH levels. Testis weight, intertubular tissue volume, total number and total volume of Leydig cells/testis, as well as total length and diameter of seminiferous tubules were unchanged in flutamide treated rats. However number of LH receptors/Leydig cell, nuclear area of Sertoli cells, number of FSH receptors/Sertoli cell, number of leptotene spermatocytes and of round spermatids per cross section, and yield of spermatogonial divisions were decreased after treatment. Flutamide treatment also decreased fertility by 48% (P < 0.05). This lowered fertility is likely the result of impaired spermatogenesis and/or a dysfunction of accessory sex organs.Flutamide (4'-nitro-3'-trifIuoro-methylisobutyranilide, Sch 13521), is a potent, non-steroidal antiandrogen with neither progestational nor oestrogenic effects Neumann et al. 1977). As shown previously (Viguier-Martinezetal. 1983), flutamide induces important changes in growing male rats on the hypothalamo-pituitary axis as well as on testicular physiology. The present work was designed to study the effects of flutamide treatment on the hypothalamo-pituitary testicular axis in the adult and to compare to those already obtained in the prepubertal rat. This experiment performed in adult rats could moreover allow to test the incidence of flutamide on the fertility, at the end of a short-term treatment. Such a model could be used to investigate the possible differences in the feedback control of LH and FSH, as well as to estimate the direct or indirect actions of a pure anti-androgen on the testicular physiology of the adult rat.Materials and Methods a. Animah Two groups of 15 male Wistar rats each received a daily sc injection from 90 to 105 days of age. In the control group, rats received solvent (0.2 ml arachis oil/benzyl alcohol 9:1 v/v); in the flutamide group, rats received 10 mg/kg/day of flutamide (Schering Corp. Bloomfield,