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A long-acting superactive analog of LH-RH, D-Trp6-LH-RH was given to 23 normal men by several routes of administration (iv, im, sc, continuous infusion) and in increasing doses of 1 to 50 microgram. LH and FSH responses were obtained at doses as low as 2.5 microgram. The maximal absolute LH and FSH increment in response to a 10 microgram iv bolus injection of this analog was similar to 100 microgram of LH-RH. In addition, after administration of the analog the LH and FSH level was maintained at a higher than basal level for at least 8 hours. With a 50 microgram iv bolus injection, from 30 minutes onwards the increases in LH levels were significantly greater (P less than 0.05) than those elicited by the 10 microgram dose for at least 8 hours. Maximum release of LH and RSH was observed when this same dose was given as continuous infusion for 8 hours (P less than 0.05). There seemed to be no significant differences between the im and sc routes. Following the administration of the D-Trp6-LH-RH, testosterone levels were maintained above the normal values (P less than 0.02). The high potency and prolonged duration of action of this compound suggest its potential usefulness for increasing testosterone levels and for stimulation of spermatogenesis in men.

Sertoli cells synthesize and secrete a number of cell-specific products including androgen binding protein (ABP), as well as "serum proteins" such as transferrin. The secretion of these proteins is regulated by extra-testicular hormones such as FSH and insulin; Leydig cell-produced steroids and proopiomelano-cortin-derived peptides; and the presence of peritubular myoid cells and/or factors secreted by these cells. Many of the Sertoli cell proteins are secreted in a cyclic fashion during the different stages of the spermatogenic cycle suggesting communication between Sertoli cells and developing germ cells. The availability of quantitative measurements for Sertoli cell-specific proteins such as ABP make it feasible to follow Sertoli cell function in vivo by measuring these products in serum. A bidirectional secretion of proteins by Sertoli cells is proposed to explain the presence of specific peptides in the male reproductive tract and blood.

Three male patients, diagnosed to have hypogonadotopic hypogonadism, were treated with intramuscular injections of 10 microgram of D-Trp6-luteinizing hormone-releasing hormone (D-Trp6-LH-RH) every 8 hours for more than 90 days (13 to 17 weeks). The gonadotropin and testosterone concentrations reached levels twice as great during the treatment as those measured previously and on one occasion increased 5-fold. Before treatment, the patients were clinically in grade 1 on Tanner's scale (Growth at Adolescence, Second Edition. Oxford, Blackwell Scientific Publications, 1962) but after treatment they advanced to grades 2 to 4. Testicular sizes before treatment were between 2 and 2 according to the scales of Waaler et al. (Acta Paediatr Scand [Suppl]249:1, 1974) and afterwards between 4 and 10. The penis of one of the patients grew 3 cm. The testicular biopsy after treatment showed significant increases in the number of Leydig and Sertoli cells. After treatment, spermatogonia were present in increased number, together with a much higher population of cells corresponding to additional stages of development (spermatids). We are of the opinion that therapy with D-Trp6-LH-RH may be beneficial for such patients.

Nine anovulatory patients with hypothalamic-pituitary dysfunction were treated with d-Trp6-luteinizing hormone-releasing hormone, an analog with far greater gonadotropin-releasing activity than luteinizing hormone-releasing hormone. Four of eight patients, who were formerly unsuccessfully treated with clomiphene, human chorionic gonadotropin, and human menopausal gonadotropin, ovulated after treatment with the peptide alone or with peptide preceded by clomiphene, and three became pregnant. The ninth patient, who had amenorrhea and anovulation due to excessive loss of weight caused by anorexia nervosa, also ovulated after treatment with the analog. These results demonstrate the effectiveness of this potent analog for induction of ovulation and pregnancy and point favorably toward clinical applications.

Specific RIAs for rat transferrin (rTF) and androgen-binding protein (rABP) were used to determine whether the secretion of these proteins was coordinately regulated in the Sertoli cell under a variety of conditions. Sertoli cell-enriched primary cultures were prepared from the testes of 20-day-old rats, and rTF and rABP were assayed in medium from the same culture. There was a strong effect of cell density on both rABP and rTF secretion per cell, with increased secretion per cell at high densities. Human TF (hTF), FeSO4, and desferrioxamine had little or no effect on rTF secretion. The age of the animal at the time of preparation of cells for culture had a strong effect on the pattern of rTF and rABP secretion in vitro; however, the effects of animal age, time in culture, and medium supplementation differed for the two proteins. In cultures prepared from 20-day-old animals, insulin, epidermal growth factor, and testosterone stimulated both rTF and rABP secretion, although to different extents. Retinoic acid was required for the stimulation and maintenance of rTF secretion, but had no effect on rABP secretion in the presence of insulin, hTF, and epidermal growth factor. Conversely, FSH and isoproterenol stimulated rABP, but not rTF, secretion. These data suggest that the secretion of rABP and rTF by Sertoli cells is under differential control.