Creative Touch Permanent Makeup and Aesthetics

The hypothalamic–pituitary–adrenal (HPA) axis – CRH → ACTH → cortisol – is the body’s principal stress response cascade, operating at two levels in skin: systemically via adrenal cortisol, and locally via a fully functional peripheral cutaneous HPA equivalent in which keratinocytes, melanocytes, sebocytes, and hair follicles produce CRH, ACTH, and cortisol autonomously. 11β-HSD1 in keratinocytes amplifies local cortisol by converting inactive circulating cortisone to active cortisol – an amplification mechanism that increases with psychological stress and correlates negatively with barrier function. UV radiation independently activates the cutaneous HPA axis in a wavelength-dependent pattern. ACTH cleavage from pro-opiomelanocortin (POMC) co-produces α-MSH and β-endorphin alongside cortisol, generating melanogenic and anti-inflammatory signals in parallel. Chronic HPA dysregulation produces glucocorticoid-driven skin structural changes – reduced epidermal thickness, fibroblast suppression, collagen loss, MMP upregulation – that are histologically identical to accelerated skin ageing.

The HPA axis evolved as a survival mechanism: acute stress activation produces a rapid cortisol surge that mobilises energy, suppresses non-essential immune activity, and prepares the organism for immediate physical demand. The response is designed to be transient – cortisol feeds back to the hypothalamus and pituitary to suppress further CRH and ACTH release, restoring baseline within hours. Chronic psychological stress dysregulates this feedback loop, maintaining elevated cortisol output that produces cumulative consequences across every tissue expressing glucocorticoid receptors – including the skin, which expresses glucocorticoid receptors on keratinocytes, fibroblasts, melanocytes, sebocytes, endothelial cells, and hair follicle cells. ^[6]

The Central HPA Cascade

Corticotropin-Releasing Hormone

Corticotropin-Releasing Hormone (CRH) is a 41- amino acid peptide produced by parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) in response to psychological stress, circadian signals, and inflammatory cytokines (IL-1β, IL-6, TNF-α – each capable of independently activating the HPA axis via hypothalamic CRH stimulation). CRH binds CRH-R1 receptors on corticotroph cells of the anterior pituitary, triggering ACTH synthesis and release. ^[8] CRH also acts on intestinal mast cells, which express CRH-R1 receptors – a mechanism confirmed in human volunteers by which psychological stress increases small intestinal permeability via mast cell degranulation, amplifying systemic LPS translocation and the downstream cutaneous inflammatory load that compounds direct cortisol-mediated skin effects. ^[10] The gut consequences of this pathway are developed in the Gut-Skin Axis entity.

CRH also acts directly on skin. Keratinocytes, melanocytes, and sebocytes express functional CRH-R1 receptors and respond to CRH with downstream glucocorticoid production – the basis of the peripheral cutaneous HPA axis described below. At sebocytes, CRH-R1 activation directly stimulates sebaceous lipid synthesis, establishing a local mechanism by which cutaneous CRH – produced in response to UV or inflammatory stress – drives sebum overproduction independently of systemic adrenal output. ^[9] This is one mechanistic reason why stress-related acne can persist even in individuals with apparently normal systemic cortisol levels – the sebaceous stimulus may be cutaneous-HPA-driven rather than systemically mediated.

Adrenocorticotropic Hormone

Adrenocorticotropic Hormone (ACTH) is a 39-amino acid peptide cleaved from the precursor protein pro-opiomelanocortin ( POMC) by the prohormone convertase PC1 in anterior pituitary corticotrophs. POMC cleavage produces not only ACTH but also β-endorphin, α-melanocyte-stimulating hormone (α-MSH), and β-MSH – melanocortins with their own skin-relevant actions including melanogenesis stimulation and anti-inflammatory effects. This means that HPA axis activation produces a coordinated set of skin signals beyond cortisol alone: α-MSH released alongside ACTH has direct melanogenic and anti-inflammatory effects at the skin, explaining in part why stress-related skin changes are not purely cortisol-mediated. ^[3]

Systemically, ACTH binds melanocortin-2 receptors (MC2R) on adrenal cortex zona fasciculata cells, stimulating cholesterol conversion to cortisol via the steroidogenesis pathway. In skin, ACTH acts on melanocortin receptors expressed on keratinocytes and melanocytes, stimulating local cortisol and corticosterone production – demonstrating functional adrenal-equivalent steroidogenesis at the cutaneous level. Adrenal androgen production (DHEA, DHEA-S) is co-stimulated by ACTH alongside cortisol, providing the mechanistic link between HPA activation and stress-related androgen-driven sebum overproduction and acne exacerbation.^[9]

The Peripheral Cutaneous HPA Axis

The most clinically significant – and least widely appreciated – aspect of HPA axis biology for aesthetics practice is that the skin does not merely respond to systemic cortisol. It produces its own. Human skin expresses all the functional elements of the central HPA cascade: CRH and CRH-R1, POMC and its processing enzymes PC1 and PC2, ACTH and melanocortin receptors, and the steroidogenic enzymes (P450scc, 3β-HSD, P450c11, 11β-HSD1) required to synthesise cortisol from cholesterol precursors. ^[7]

This peripheral cutaneous HPA axis operates as a local autocrine/paracrine stress response system:

• Keratinocytes produce CRH, ACTH, and cortisol, and express CRH-R1 – they can both initiate and respond to local HPA-equivalent signalling. Keratinocyte cortisol production increases during wound healing, contributing locally to the immune modulation required for orderly repair.

• Melanocytes produce ACTH-driven cortisol and respond to α-MSH (from POMC cleavage) with melanogenesis upregulation – a potential mechanism for stress-related hyperpigmentation that operates without requiring systemic adrenal activation.

• Hair follicles have a fully autonomous HPA-equivalent system: organ-cultured human scalp hair follicles produce CRH, ACTH, and cortisol, and demonstrate negative feedback regulation of CRH expression by cortisol – mirroring the central hypothalamic feedback mechanism in a single follicular unit. ^[4] This means follicular stress responses – including the cortisol-mediated inhibition of hair growth that contributes to stress-triggered telogen effluvium – can occur locally, independent of systemic cortisol levels.

• Sebocytes respond to both local CRH (via CRH-R1) and ACTH (via melanocortin receptors) with enhanced sebaceous lipid synthesis, establishing dual cutaneous HPA pathways for stress-driven sebum overproduction.

UV radiation is an additional, non-psychological activator of the cutaneous HPA axis. UVR triggers wavelength-dependent upregulation of CRH, POMC-derived peptides, ACTH, and cortisol in the epidermis – establishing a local neuroendocrine stress response to sun exposure that operates in parallel with the UV-driven inflammatory and DNA damage pathways. ^[5] Repeated daily UV stress therefore chronically activates the cutaneous HPA axis, contributing to the local glucocorticoid burden in sun-exposed skin above and beyond systemic cortisol output – a mechanism that may partly explain the accelerated structural ageing of chronically sun-exposed skin relative to sun-protected skin in the same individual.

11β-HSD1: The Peripheral Amplifier

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme converts cortisone – the inactive circulating form of cortisol – back to active cortisol within peripheral tissues including skin. Under psychological stress, 11β-HSD1 expression increases in keratinocytes, amplifying local active cortisol concentration beyond what systemic adrenal output alone delivers. ^[2] The 11β-HSD1 expression level itself correlates negatively with skin barrier function – higher enzyme expression predicts worse barrier competency – and selective SSRI treatment that reduces psychological stress reduces both 11β-HSD1 expression and TEWL, confirming the mechanistic chain from stress to 11β-HSD1 to barrier disruption. Cortisol also directly suppresses filaggrin expression in keratinocytes – the structural protein central to stratum corneum integrity, corneocyte cohesion, and transepidermal water retention – providing a barrier-impairing mechanism that operates more rapidly than the structural collagen and fibroblast changes of chronic glucocorticoid excess and that is relevant even at cortisol elevations below the threshold required to produce histological dermal changes. This enzyme therefore represents a convergence point where systemic HPA output (which determines circulating cortisone substrate) and peripheral cutaneous HPA amplification (which determines conversion rate to active cortisol) interact to determine the actual glucocorticoid burden experienced by skin cells and through which both the TEWL increase and filaggrin suppression of psychological stress ultimately operate.

HPA Axis Dysregulation and Skin Ageing

Long-term glucocorticoid excess – whether from exogenous corticosteroid therapy or chronic endogenous HPA activation – produces a specific pattern of skin structural changes that mirrors intrinsic skin ageing: decreased epidermal thickness, loss of rete ridge architecture at the dermal-epidermal junction, reduced fibroblast number and activity, and disruption of the dermal collagen network. ^[1] Glucocorticoids suppress fibroblast proliferation and collagen synthesis through glucocorticoid receptor-mediated transcriptional repression of COL1A1 and COL1A2, while simultaneously upregulating MMP expression – the same degradation-weighted ECM remodelling driven by UV and TNF-α through different upstream routes. Chronic HPA dysregulation therefore produces accelerated structural skin ageing through a mechanism that is biochemically identical to, and clinically additive with, photoageing.