Mechanism-based model of the effect of co-administration of exogenous testosterone and progestogens on the hypothalamic-pituitary-gonodal axis in men
Strougo, A(1), Elassaiss-Schaap, J(2), de Greef, HJMM(2), Drenth, H(1)
(1) LAP&P Consultants BV, (2) PK-PD / M&S, Clinical Pharmacology & Kinetics, Organon
Objectives: Combined administration of testosterone (T) and progestogens has been investigated for the development of a male contraceptive method. Co-administration leads to suppression of the hypothalamic-pituitary-gonodal (HPG) axis, and consequently to reversible arrestment of spermatogenesis1,2. The aim of the current project is to develop a mechanism-based model of the homeostatic feedback mechanisms in the HPG axis to describe and quantify the suppressing effects on luteinizing hormone (LH), follicle stimulating hormone (FSH), and T following co-administration of T and one of the progestogens desogestrel (DSG) or etonogestrel (ENG).
Methods: The model was developed using data obtained from 288 healthy, male subjects in five different clinical trials 1,2,3,4, where progestogen (DSG or ENG) was orally or subcutaneous administered alone or in combination with intramuscular administration of T enanthate (TE) or T decanoate (TD). The modelling was performed using NONMEM V in three stages with increasing complexity. Firstly, the status of the HPG axis prior to treatment was described. This was followed by the description of the effect of DSG administration, and subsequently after co-administration of DSG/ENG and T.
Results: The homeostatic feedback relationships between T, LH, and FSH were implemented in the model with linked turn-over models. In this model framework, LH was assumed to stimulate the zero-order production rate constant (Kin) of T, and in turn, T was assumed to inhibit the Kin of LH and FSH. The inhibitive effect of DSG/ENG on LH and FSH formation appeared to be maximal in the current data set. Since the PK of both TE and TD could not be adequately characterised, it was described by an infusion thereby assuming constant T concentrations during treatment. This assumption resulted in overestimation of the T concentrations before steady state was achieved.
Conclusions: The model adequately described the time courses of LH and FSH and to lesser extent of T. Since arrestment of spermatogenesis is caused by suppression of LH and FSH, the next step is to link this mechanism-based model to the contraceptive effect, i.e. sperm-count. This mechanism-based modelling approach enables quantification of treatment effects on suppression of the HPG axis, by combining data of three hormones. Consequently, the developed model can be used in various stages of the development of male contraceptives.
References:
[1] Wu, F.C., R. Balasubramanian, T.M. Mulders and H.J. Coelingh-Bennink, Oral progestogen combined with testosterone as a potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism, J Clin Endocrinol Metab, 84: 112-22., 1999;
[2] Anawalt, B.D., K.L. Herbst, A.M. Matsumoto, T.M. Mulders, H.J. Coelingh-Bennink and W.J. Bremner, Desogestrel plus testosterone effectively suppresses spermatogenesis but also causes modest weight gain and high-density lipoprotein suppression, Fertil Steril, 74: 707-14., 2000
[3] Brady B.M., Amory J.K., Perheentupa A., Zitzmann M., Hay C., Apter D., Anderson R.A., Bremner W.J., Huhtaniemi I., Nieschlag E., Wu F.C.W., Kersemaekers W.M.: A multi-centre study investigating subcutaneous Etonogestrel implants with injectable Testosterone Decanoate as a potential long-acting male contraceptive. Human Reproduction 2006; 21: 285-294.
[4] Cathy J. Hay, Brian M. Brady, Michael Zitzmann, Kaan Osmanagaoglu, Pasi Pollanen, Dan Apter, Frederick C.W. Wu, Richard A. Anderson, Eberhard Nieschlag, Paul Devroey, Ilpo Huhtaniemi, Wendy M. Kersemaekers: A multicenter phase IIb study of a novel combination of intramuscular androgen (Testosterone Decanoate) and oral progestogen (Etonogestrel) for male hormonal contraception. The Journal of Clinical Endocrinolgy & Metabolism 2005; 90: 2042-2049.
