Increased dietary fat consumption is associated with colon cancer development. The exact mechanism by which fat induces colon cancer is not clear, however, increased bile acid excretion in response to high-fat diet may promote colon carcinogenesis. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, and bile acids are endogenous ligands of FXR. FXR is highly expressed in the intestine and liver where FXR is essential for maintaining bile acid homeostasis. The role of FXR in intestine cancer development is not known. The current study evaluated the effects of FXR deficiency in mice on intestinal cell proliferation and cancer development. The results showed that FXR deficiency resulted in increased colon cell proliferation, which was accompanied by an up-

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Abstract.The effect of T3 on basal and LH mediated synthesis and secretion of testosterone and oestradiol by puberal rat Leydig cells was studied in vitro. Percoll gradient purified Leydig cells (1 x 103) were cultured for 48 hours at 34 ° C in a medium containing a range of 5-400 ng/mL concentration of T3 or ovine LH after 24 hours initial culture at 37 °C. T3 increased testosterone and oestradiol secretions in a dose dependent manner which reached the saturation point with 50 ng dose. While the minimum effective dose of T3 (25 ng) potentiated the stimulatory effect of the minimum effective dose of LH (25 ng) on testosterone secretion, it suppressed the effect of the saturation dose of LH (100 ng). Fifty ng T3 quelled the stimulatory effect of either dose of LH. Both doses of T3 increased oestradiol secretion, irrespective of the dose of LH. Addition of androstenedione (500 ng/mL) to the culture medium enhanced 25 ng T3 induced testosterone and oestradiol secretions. While androstenedione potentiated the stimulatory effect of T3 (25 ng) on LH (25 ng) induced testosterone and oestradiol secretions, it reversed the inhibitory effect of 50 ng T3 on LH mediated testosterone secretion which was accompanied by a decrease in oestradiol secretion. Puromycin (35 pg/mL) suppressed the stimulatory effect of T3 on basal and LH mediated testosterone and oestradiol production. Taken together, the present results indicate a direct stimulatory effects of T3 on basal production of testosterone and oestradiol by Leydig cells and its modulatory effect on LH mediated steroidogenic activity varies depending upon the intensity of LH stimuli.

Leydig cell steroidogenic activity under basal and stimulated conditions was studied in hypothyroid rats. Hypothyroidism was induced at a prepubertal age (30 days postpartum) by surgical thyroidectomy, and L-thyroxine (T4) supplementation (6 micrograms/100 g body weight/day for 30 days) to hypothyroid rats was begun after 30 days. Hypothyroidism for 60 days reduced serum LH and FSH without affecting prolactin. Serum and intratesticular testosterone and the specific activity of Leydig cell 3 beta- and 17 beta-hydroxysteroid dehydrogenases diminished in hypothyroid rats. The stimulatory effect of LH on Leydig cell steroidogenic activity and cAMP was also adversely affected in hypothyroid rats. All these changes were reversed by T4 supplementation. The present results suggest that prepubertal hypothyroidism suppresses both basal and stimulated Leydig cell activity in adult rats.

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The gonadotropin follicle-stimulating hormone (FSH) is required for initiation and maintenance of normal gametogenesis and acts through a specific, cell-surface receptor (Fshr) present only on Sertoli and granulosa cells in the gonads. Despite extensive examination of the transcriptional mechanisms regulating Fshr, the sequences directing its expression to these cells remain unidentified. To establish the minimal region necessary for Fshr expression, we generated transgenic mice carrying a yeast artificial chromosome (YAC) that contained 413 kilobases (kb) of the rat Fshr locus (YAC60). Transgene expression, as determined by RT-PCR, was absent from immature testis and Sertoli cells, limited to germ cells of the adult testis, and never observed in the ovary. While the data is limited to only one transgenic line, it suggests that the 413kb region does not specify the normal spatiotemporal expression pattern of Fshr. Comparative genomics was used to identify potential distal regulatory elements, revealing seven regions of high evolutionary conservation (≥80% identity over 100bp or more), six of which were absent from the transgene. Functional examination of the evolutionary conserved regions (ECRs) by transient transfection revealed that all of the ECRs had modest transcriptional activity in Sertoli or myoid cells with two, ECR4 and ECR5, showing differential effects in expressing and non-expressing cells. These data reveal that distal regulatory regions (outside the 413kb in YAC60) are required for appropriate temporal and spatial Fshr expression and implicate the identified ECRs in transcriptional regulation of Fshr.

We have previously demonstrated that neonatal and transient neonatal hypothyroidism modulates Leydig, Sertoli, and germ cell numbers, sex steroids and androgen binding protein concentration. The present study was undertaken to study the effect of neonatal onset hypothyroidism on Leydig and peritubular myoid cell numbers, plasma and testicular interstitial fluid (TIF) sex steroid concentration at different age groups of Wistar rats. Hypothyroidism was induced by giving 0.05% methimazole (MMI) to lactating mothers or directly to the male pups from day 1 postpartum through days 10, 15, 30, 40 and 60 postpartum. To confirm hypothyroidism, plasma thyroid hormones and TSH were assayed. Plasma and TIF testosterone, progesterone, dihydrotestosterone (DHT) and estradiol were assayed by radioimmunoassay. Leydig cell number in hypothyroid rats were less than the age-matched controls. The diameter of Leydig cells in hypothyroid rats was smaller than the controls but 10 days old hypothyroids alone had larger than control rats. A significant decrease of peritubular myoid cell number was observed in 30, 40 and 60 days hypothyroid rats and increased in 10 and 15 days hypothyroidism. Hypothyroid rats had elevated level of plasma LH and decreased GH (except day 10 postpartum). Plasma PRL level was increased in 10 and 15 days hypothyroid rats and an opposite effect was observed in 40 and 60 days hypothyroidism. Plasma testosterone, DHT and estradiol were decreased in all hypothyroid rats. However, plasma progesterone level in hypothyroid rats was significantly higher at days 10, 30, and 40 postpartum and an opposite effect was seen in 15 and 60 days experimental groups. TIF testosterone and progesterone titre showed a consistent decrease in hypothyroid rats irrespective of the duration. In hypothyroid rats, TIF DHT levels decreased significantly in days 10, 40 and 60 postpartum. However, it increased in days 15 and 30 postpartum. Except at day 10 postpartum, the level of TIF estradiol in hypothyroid rats was significantly less than their age matched controls. Our data clearly indicate that neonatal onset hypothyroidism adversely affect Leydig cell proliferation along with impaired steroidogenesis.

The effect of neonatal hypothyroidism on spermatogenesis was studied in Wistar rats of different age groups. Hypothyroidism was induced in newborn male rats from day one postpartum up to day 60 postpartum by daily administration of 0.05% methimazole (MMI) to the nursing mothers or directly through drinking water. The animals were killed at days 10, 15, 30, 40, and 60 postpartum, blood plasma was collected, and testes, epididymides, prostates, and seminal vesicles were separated and weighed. Testes were fixed in formalin for histological studies. Plasma testosterone (T), estradiol (E2), and sex hormone binding globulin (SHBG) were measured by radioimmunoassay. Hypothyroidism significantly reduced seminiferous tubule and lumen diameter. Control rats showed active spermatogenesis whereas in hypothyroid rats, the proliferation and differentiation of germ cells were arrested and their number was decreased. Plasma T, E2, and SHBG levels were significantly decreased at all ages for hypothyroid rats. The absolute weight of testes was decreased irrespective of age (except day 10 postpartum), however ventral, dorsolateral prostate, and epididymis weights were decreased at 30, 40, and 60 days postpartum. Coagulating gland weight was decreased in all age groups of hypothyroid rats. Hypothyroid rats of day 40 and 60 postpartum showed a decrease in absolute seminal vesicle weight. Relative testicular weights of hypothyroid rats decreased by postpartum day 15, 30, 40, and 60 whereas the opposite effect was observed by postpartum day 10. Relative organ weights were increased in epididymides (day 15 and 30 postpartum), seminal vesicles (day 30 and 40 postpartum), and dorsolateral prostates (day 15, 30, and 40 postpartum) and decreased in 10 and 60 day old hypothyroid rat. Ventral prostate relative weight was decreased in 40 and 60 day old rats. Th coagulating gland weight was decreased in 10, 15, and 60 days postpartum and an opposite effect was observed in 30 and 40 days hypothyroid rats. The present study clearly indicates that hypothyroidism adversely affects spermatogenesis; it also indicates that thyroid hormones are essential for normal spermatogenesis. Their effect may either be direct or indirect.