Six patients with advanced prostatic cancer were treated with a potent GnRH agonist analog (buserelin, Hoechst; 600 micrograms, intranasally, three times a day) for 6 months. The first 2-6 days of treatment were associated with a 50% elevation (P less than 0.01) in serum testosterone (T) and a simultaneous elevation of 20% (P less than 0.01) in serum prostate-specific acid phosphatase (PAP). Serum T fell to the castrate range (less than 1 nmol/liter) in all patients in 2-3 weeks, and PAP decreased concomitantly in five of the six patients. Serum LH progressively decreased by about 80% during the treatment, whereas a secondary rise of FSH levels occurred after the first month of treatment. The patients were orchiectomized after 6 months of treatment. No differences were found between the pre- and postsurgical levels of serum T or in comparison with those of six patients orchiectomized as the first therapeutic measure. Testicular endogenous T concentrations, LH and FSH receptors, and in vitro T production were measured in three testis samples and compared with those values in testis tissue obtained from five control patients. The endogenous levels and in vitro production of T were depressed by over 95% in testes from agonist-treated patients. The small residual T production responded to hCG stimulation as in control patients. Interestingly, no change was found in testicular LH receptor content, but FSH receptors decreased by 80%. The elevation in serum PAP at the beginning of the agonist treatment and the small residual testicular T production after 6 months may not be clinically important. However, they indicate the necessity of comparative long term studies between orchiectomy and GnRH agonists in the treatment of patients with prostatic cancer.
Postnatal secretion of gonadotrophin by male rats was inhibited by a potent gonadotrophin-releasing hormone (GnRH) antagonist analogue (N-Ac-4-Cl-D-Phe1,4-Cl-D-Phe2,D-Trp3,D-Phe6,des-Gly10-GnRH-D-al anylamide; Org 30039; 2 mg/kg s.c. twice daily) on days 1-5, 6-10, 11-15 or 16-20 of life. The onset of puberty was determined by monitoring the separation of the preputium from the glans penis, i.e. balano-preputial separation (BPS). Rats treated on days 1-5 matured normally, whereas all treatments between days 6 and 20 delayed BPS (P less than 0.01). In adult rats (between 110 and 160 days of age), testis weights were reduced by 21-35% (P less than 0.01) in groups treated between days 1 and 15, although weights of the accessory sex glands were normal. Testicular FSH receptors were decreased by 31-47% (P less than 0.01) in all treatment groups, whereas the LH receptor content was decreased only in rats treated between days 1 and 5 (18%; P less than 0.05) and prolactin receptor content decreased only in rats treated up to day 10 (31-33%; P less than 0.01). Concentrations of serum testosterone, LH and FSH, and pituitary contents of LH and FSH were unaffected by neonatal treatment with Org 30039. Animals treated with Org 30039 had reduced fertility which was most pronounced (88%; P less than 0.01) in rats treated between days 1 and 5. However, motile sperm were detectable in the cauda epididymis of the infertile rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Endogenous testosterone (T), LH and FSH receptors, and in vitro production of cyclic adenosine-3':5'-monophosphate (cAMP), T and some of its steroid precursors were measured in testicular tissue obtained at orchiectomy from seven prostatic cancer patients treated for 6 months with a potent gonadotropin-releasing hormone (GnRH) agonist analog (buserelin, Hoechst, 600 micrograms 3 times a day intranasally). In addition, histologic and morphometric studies were carried out on the testicular tissue. Testicular tissue from age-matched prostatic cancer patients (n = 14), whose first therapy was orchiectomy, served as controls. The peptide treatment decreased intratesticular T by 95% (P less than 0.01) and FSH receptors by 57% (P less than 0.01), but had no effect on LH receptors. The in vitro production of T decreased by 94% (P less than 0.01), but that of cAMP was unaffected. Besides T, the in vitro production of testicular 17-hydroxyprogesterone (17-OHP-4), androstenedione and 5 alpha-dihydrotestosterone (5 alpha-DHT) dropped by 71 to 90% (P less than 0.01 to 0.05) during buserelin treatment, but those of pregnenolone, progesterone and dehydroepiandrosterone (DHEA) were not affected. Histologic studies revealed considerable variation in the seminiferous epithelium of the control group, but spermatogenesis was highly suppressed in nearly all of the buserelin-treated group. The number of Sertoli cells was unaffected, but tubular diameters were reduced (P less than 0.05) by buserelin treatment. Leydig cells appeared dedifferentiated in this group, although their number per testis was not altered. These data indicate that gonadotropin suppression by GnRH agonist most likely affects testicular steroidogenesis by inhibiting 3 beta-hydroxysteroid dehydrogenase and a step(s) prior to pregnenolone formation. The treatment does not impair testicular LH binding or cAMP production, but clearly suppresses FSH receptors. Spermatogenesis in general is suppressed but with considerable variation.
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