Temporal pattern is a control axis separate from hormone level

The temporal pattern of a hormone drive is a control axis separate from its level. The same GnRH molecule activates when pulsatile (41 output pulses) but suppresses when continuous (0 pulses, depolarisation block). Cycling the drive (BAT) delivers a resistant clone 13.6× its own continuous-high stress, selectively stressing the adapted clone. Principle sim-verified; clinical schedule open.

Because the substrate is an oscillator on a bistable switch, the pattern of the drive is a separate lever from its level. Pulsatile GnRH keeps the gonadotrope firing (41 pulses) while the same agent held continuously blocks it (0); and cycling whipsaws a resistant clone 13.6× harder than any constant drive.

Same molecule, opposite effect

Pulsatile GnRH re-ignites the downstream oscillator on every pulse, so the axis is activated; the same agent held continuously pins the drive past the fold, so the oscillator can no longer cycle and the axis is suppressed by desensitisation. The substrate reproduces both signs from one molecule.

Delivered as brief supra-threshold pulses the gonadotrope fires 41 times; held continuously above the depolarisation-block threshold it fires 0 times. This retrodicts the pulsatile-GnRH pump (activation) and depot GnRH agonists for precocious puberty, endometriosis and prostate cancer (suppression).

Cycling defeats adaptation

Endocrine-therapy resistance is modelled as amplified drive-coupling κ (receptor over-expression), not a deeper well. A resistant clone tolerates any constant drive by re-settling, but cycling the drive across the fold faster than it can settle inflicts a large transition stress it cannot escape.

Selectivity is measured as the integrated transition stress (mean |ds/dt|) over each schedule, with no arbitrary kill threshold. Cycling delivers the resistant clone 0.412 versus 0.0304 under continuous high — a 13.6× amplification, and it stresses the resistant clone more than the sensitive one.

This retrodicts Bipolar Androgen Therapy in castration-resistant prostate cancer and oestrogen-induced apoptosis in long-term-oestrogen-deprived breast cancer. The qualitative principle is sim-verified [V]; the clinical translation (periods, doses, schedules) is open [O] and needs trials. Not clinical advice.