Effects of cyclosporine on the hypothalamic-pituitary-gonadal axis in the male rat: mechanism of action.
In the intact adult male rat, cyclosporine (CsA) induces a significant decrease in serum testosterone (T), serum LH, and intratesticular T. To elucidate the mechanism of action of this CsA-induced hypogonadotropic hypogonadism, castrated male rats were treated with oral CsA (30 mg/kg.day) or vehicle alone, and serum LH was measured after 1, 2, and 4 weeks of treatment. Surprisingly, serum LH was higher in these CsA-treated castrated rats at 1, 2, and 4 weeks than in castrated controls. To provide insight into the cause of this increase in serum LH, a T implant (8 mm) was inserted (at week 5 of treatment) in both CsA-treated and control castrated animals, and serum LH was measured 1 week after insertion of the T implant. Serum LH levels decreased to control values after insertion of the T implant. Subsequently, two other groups of rats received 8-mm T implant at the time of castration and were then treated up to 4 weeks with either CsA or vehicle alone. Serum LH showed a significant decrease in these CsA- plus T-treated animals compared to the vehicle- plus T-treated animals. A GnRH stimulation test performed after 2 weeks of CsA/vehicle treatment showed a significant increase in serum LH in all the rats 30 min after GnRH administration (1, 10, 30, and 100 ng/100 g BW, ip), indicating a normal pituitary response. The increase in LH after exogenous GnRH treatment was more significant in CsA-treated intact rats than in the controls. There was no difference in creatinine clearance between intact and castrate T-treated rats regardless of whether they received CsA. These studies indicate that the hypogonadotropic hypogonadism induced by CsA in intact male rats is mediated through the hypothalamic-pituitary axis, primarily at its hypothalamus end, does not seem to be due to the nephrotoxicity of CsA, and is modulated by T and/or its metabolites.
Sikka
S C
SC
Department of Surgery, University of California-Los Angeles School of Medicine, Torrance 90509.
Bhasin
S
S
Coy
D C
DC
Koyle
M A
MA
Swerdloff
R S
RS
Rajfer
J
J
D000818:Animals; D003404:Creatinine / Q000097:blood / Q000652:urine; D003524:Cyclosporins / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008657:Metabolic Clearance Rate; D009919:Orchiectomy; D010902:Pituitary Gland / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D013737:Testis / Q000187:drug effects / Q000502:physiology*; D013739:Testosterone / Q000097:blood / Q000378:metabolism / Q000494:pharmacology
D003524:Cyclosporins; D013739:Testosterone; D007986:Luteinizing Hormone; D003404:Creatinine