G03: Sex hormones and modulators of the genital system

You are dosing into a feedback loop. Exogenous hormone suppresses endogenous secretion, so the measured concentration is the drug plus a baseline that moves in response to it [1,2]. Start from turnover (indirect response), not a direct-effect model [3,4], and add an explicit feedback term when modeling the axis itself [5] (see pharmacodynamics).

Baseline is rhythmic, so sampling time is a covariate. Testosterone follows a circadian rhythm, most pronounced in younger men [6,7]; in premenopausal women LH, FSH, estradiol and progesterone vary across the menstrual cycle [8,9]. A pre-dose sample drawn at an arbitrary hour is one point on a rhythm, not a baseline [10,11].

Response outlasts exposure. Steroids act through nuclear receptors and gene transcription [12], so endpoints such as luteinising hormone, spermatogenesis and prostate specific antigen move on the timescale of the affected system, not of plasma concentration [1,13].

Flip-flop is the norm. Depot injections, implants, transdermal systems and vaginal rings make the formulation set the input rate [14,15]. For non-removable depots absorption is slower than elimination, so the apparent terminal half-life belongs to the vehicle [16,17].

Mechanistic extrapolation. PBPK dominates here, predicting how CYP3A inducers such as efavirenz or rifampicin lower ethinylestradiol and progestin exposure, and whether dose adjustment preserves contraceptive efficacy [18,19].