Pharmacokinetics of human follicle-stimulating hormone in gonadotropin-deficient men

Gonadotropin treatment of hypogonadotropic infertile men usually requires regular im administration of human urinary FSH (uFSH); however, testicular function is rarely normalized despite years of treatment. As the pharmacokinetics of standard FSH doses (75 IU, two or three times weekly) in gonadotropin-deficient men are poorly characterized, we studied 10 gonadotropin-deficient men by measuring plasma FSH levels with an ultrasensitive fluoroimmunoassay (Delfia, Pharmacia) in single dose and multidose studies. The single dose studies involved blood samples taken 15 min before and 0, 1, 2, 4, 6, 8, 10, 12, 15, 18, 21, 24, 48, 72, and 96 h after the injection of 75 IU uFSH in 1 mL diluent, either sc under the abdominal wall skin or im into the deltoid muscle, in a random sequence, cross-over design (n = 7 men) and after the injection of 150 IU, sc, with additional blood sampling at 120 and 168 h (n = 7 men). The multidose studies used a fixed ascending dose sequence, with blood sampled at 24-h intervals posttreatment after at least 1 month of regular administration of either 75 or 150 IU uFSH, sc, at injection intervals of 72, 48, and 24 h (n = 6 men). From the single dose studies, pharmacokinetic variables were estimated from a one-compartment open model fitted by a weighted polyexponential curve fit of plasma FSH over time. The bioavailability of uFSH via the sc route was high (mean area under the curve, 90% for 75 IU and 143% for 150 IU vs. 75 IU, im). Peak plasma FSH levels were later (21.1 vs. 7.1 h; P < 0.001) and lower (2.0 vs. 2.7 IU/L; P < 0.001) after sc compared with im administration of 75 IU due to a slower absorption half-time (6.1 h vs. 1.4 h; P < 0.001), whereas mean residence times and clearance half-times were similar. The pharmacokinetic features of the 150- and 75-IU doses sc were essentially identical, apart from expected dose-dependent increases in peak plasma FSH level (2.8 vs. 2.0 IU/L; P < 0.001) and area under the curve (206 vs. 129 IU.h/L; P < 0.05). Multidose simulations based on the single dose pharmacokinetic models predicted that during chronic sc administration of standard FSH doses, plasma FSH levels would be in the lower half of the eugonadal range and fluctuate less than with im administration. The multidose study confirmed empirically these predictions. These studies form a pharmacological basis for a more flexible, cost-effective, and convenient self-administered sc regimen.(ABSTRACT TRUNCATED AT 400 WORDS)