Abstract Dominant paradigms in endocrinology and oncology conceptualize sex steroids primarily as tissue-specific mitogenic signals. Here, a systemic framework is proposed in which sex hormones (estrogens, androgens, progesterone) function as higher-order regulators of somatic integrity by maintaining coordinated transcriptional, epigenetic, and genome-stability programs across tissues. The model posits that chronic attenuation of physiological sex steroid signaling—whether due to endocrine aging or sustained neuroendocrine suppression—does not merely reflect reproductive decline but induces a progressive destabilization of regulatory architecture. This destabilization manifests as (i) weakened transcriptional support for differentiation and repair, (ii) cumulative epigenetic permissiveness at loci governing plasticity and stress-response programs, and (iii) reduced genomic maintenance capacity.Collectively, these changes define a systemic biological condition termed the permissive state: a measurable multi-omic configuration in which evolutionarily conserved cell-autonomous survival programs become increasingly accessible to activation. Under such conditions, cellular phenotypes characteristic of malignant transformation—plasticity, metabolic autonomy, stress tolerance, and proliferation—become progressively more likely to emerge and to confer selective advantage.This framework integrates concepts from evolutionary biology (antagonistic pleiotropy, disposable soma theory), endocrinology, epigenetics, and systems biology into a coherent causal architecture linking endocrine decline to age-dependent cancer susceptibility. Importantly, the model generates falsifiable predictions, including the existence of a measurable permissive-state signature preceding malignancy, the temporal dependence of hormone replacement effects on baseline regulatory integrity, and experimentally testable causal relationships in animal and cellular systems. The framework reframes carcinogenesis not solely as a consequence of mutational accumulation, but as an emergent property of systemic regulatory destabilization, with implications for cancer prevention strategies aimed at preserving organismal regulatory integrity.
Zakir Causevic (Mon,) studied this question.