LH also has long-term trophic effects on Leydig cells, requiring both transcription and increased translation of proteins. Chronic stimulation by LH is required for maintenance of Leydig cell steroidogenic enzyme levels and to support the steroidogenic organelle aparatus, including mitochondrial membrane potential and SER volume.
Inhibition of LH action can be achieved by hypophysectomy (91-93), suppression of gonadotropins through steroid administration (94-96), and neutralization of LH or LH-releasing hormone (GnRH) by specific antibodies (97). LH blockade eliminates the chronic effects of this hormone, causing Leydig cell atrophy and loss of cellular volume, SER, steroidogenic enzyme activities (particularly P-45017a and P-450scc), LH receptor numbers, and the ability to secrete testosterone in response to LH (91,95). In LH-deprived rats, Leydig cell structure and function are restored by LH replacement
(93,94,96). Similarly, daily injections of LH to the hypogonadal mouse markedly increase steroidogenic enzyme activities (98).
In addition to LH, FSH and local cell-cell interactions participate in the regulation to Leydig cells. FSH regulatory control of Leydig cells is based on the correlation between serum FSH levels and the steroidogenic response of Leydig cells to LH during sexual maturation in humans. Because FSH-R are present only in the Sertoli cells, FSH acts on Leydig cells indirectly through Sertoli cell-secreted factors (99,100). Huhtaniemi and colleagues (see Chapter 6), in a study of FSHP And FSH-R knockout mice, recently demonstrated FSH signaling involvement in Leydig cell development. LH alone is sufficient for normal postnatal development of Leydig cells only if FSH-R are present. In the absence of LH, FSH stimulates Leydig cell steroidogenesis (101). Sertoli cells may also modulate Leydig cell numbers via paracrine interactions (14,102,103). Several factors produced by Sertoli cells, including insulin-like growth factor (IGF) 1, epidermal growth factor (EGF)-a, transforming growth factor (TGF)-a, and TGF-P, inhibin, and activin, influence Leydig cells. TGF-P is believed to be a strong inhibitor of Leydig cell steroidogenesis, whereas IGF-1 is a stimulator. EGF-a and TGF-a stimulate steroidogenesis during adulthood but may inhibit differentiation of immature Leydig cells. Germ cells, through their interactions with Sertoli cells, are believed to affect Leydig cells indirectly (81).
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