HSD11B1 / HSD11B2 — the cortisol shuttle

11β-hydroxysteroid dehydrogenase types 1 and 2 (11β-HSD1 and 11β-HSD2) are opposing enzymes that control tissue-level glucocorticoid tone independently of circulating cortisol. 11β-HSD1 (gene HSD11B1) is an NADPH-dependent reductase in the endoplasmic reticulum (ER) of metabolic tissues — liver, visceral adipose, skeletal muscle, bone, skin, and brain — that regenerates active cortisol from inert cortisone, locally amplifying glucocorticoid signaling in a tissue-specific manner. 11β-HSD2 (gene HSD11B2) is an NAD+-dependent dehydrogenase highly expressed in kidney and placenta that rapidly inactivates cortisol to cortisone, creating a mineralocorticoid-selective microenvironment and protecting the mineralocorticoid receptor (MR) from cortisol-driven illicit activation. Together they constitute the pre-receptor glucocorticoid shuttle: the same circulating cortisol concentration can produce profoundly different local tissue effects depending on which isozyme dominates. In aging, upregulation of 11β-HSD1 in visceral adipose, skeletal muscle, bone, and skin contributes to a phenotype of “local Cushing’s” — tissue-level glucocorticoid excess without systemic hypercortisolism. Loss-of-function or inhibition of 11β-HSD2 permits cortisol to illicitly activate MR, driving hypertension and vascular aging.

Page scope: This is a combined two-isozyme page covering the HSD11B1 / HSD11B2 functional pair. HSD11B1 is the primary entry (uniprot: P28845) and HSD11B2 is documented in complex-subunits: + the identity table below. Individual stub pages can be seeded when warranted; wikilinks on both should cross-reference this combined page.

Identity

Protein	Gene	UniProt	NCBI Gene	HGNC	Ensembl	Length	MW
11β-HSD1	HSD11B1	P28845	3290	HGNC:5208	ENSG00000117594	292 aa	~34 kDa
11β-HSD2	HSD11B2	P80365	3291	HGNC:5209	ENSG00000176387	405 aa	~44 kDa

Mouse orthologs: Hsd11b1 (NCBI Gene 15483); Hsd11b2 (NCBI Gene 15484). Both are one-to-one mouse orthologs with conserved enzymatic direction and tissue expression patterns.

GenAge-human: Neither HSD11B1 nor HSD11B2 has a curated GenAge entry as of 2026-06-14. gap/needs-canonical-id

Enzymatic mechanism and cofactor distinction

The two isozymes catalyze reactions in opposite directions and use different cofactors — a fact with pharmacological and functional consequences:

Property	11β-HSD1	11β-HSD2
Direction (in vivo)	Reductase (cortisone → cortisol)	Dehydrogenase (cortisol → cortisone)
Cofactor	NADPH (regenerated by hexose-6-phosphate dehydrogenase in the ER lumen)	NAD⁺
ER topology	Luminal active site, type II membrane protein	Luminal active site
Km for cortisol	~1–5 µM (lower affinity; reductive direction)	~10–100 nM (high affinity; oxidative direction)
Predominant tissues	Liver, visceral adipose, skeletal muscle, bone, brain, skin	Kidney cortex (proximal and distal tubules), placenta
Clinical relevance	”Local Cushing’s” in metabolic tissues; drug target	Apparent mineralocorticoid excess (AME); MR selectivity gating

The reductase direction of 11β-HSD1 depends on NADPH supplied by hexose-6-phosphate dehydrogenase (H6PD) within the ER lumen. This dependency means that ER luminal NADPH/NADP+ ratio is a co-determinant of net glucocorticoid reactivation — a feature with implications for metabolic disease states where ER redox is disturbed ¹.

Function: the tissue glucocorticoid shuttle

The critical conceptual point is that circulating cortisol concentration is not the only determinant of tissue glucocorticoid exposure. Two tissues with the same plasma cortisol level can have dramatically different intracellular free cortisol depending on local 11β-HSD activity:

A tissue high in 11β-HSD1 (e.g., visceral adipose, liver) reactivates the cortisone pool, amplifying effective cortisol locally.
A tissue high in 11β-HSD2 (e.g., kidney) rapidly inactivates arriving cortisol, protecting the high-affinity MR from inappropriate cortisol occupancy.

In normal physiology, this spatial partitioning ensures that: (1) stress signals are amplified in metabolic tissues where glucocorticoid effects are needed for acute mobilization of energy; and (2) aldosterone-selective tissues are not chronically over-exposed to the far more abundant cortisol.

11β-HSD1: context-dependent reductase

In mature adipocytes, 11β-HSD1 acts as a reductase (generating cortisol from cortisone), whereas in undifferentiated adipose stromal cells it transiently favors the dehydrogenase direction, facilitating differentiation ². This switch ensures that pre-adipocyte commitment to the adipocyte lineage occurs under a low-cortisol microenvironment, while the mature adipocyte — now expressing the NADPH-generating H6PD — amplifies cortisol. The switch is a model for how 11β-HSD1 direction is cell-state-dependent, not fixed.

11β-HSD2: mineralocorticoid receptor guardian

In the kidney collecting duct and distal nephron, the MR has comparable affinity for cortisol and aldosterone (~0.5–1 nM Kd each). Because circulating cortisol is 100–1000× more abundant than aldosterone, MR would be constitutively cortisol-occupied without 11β-HSD2 activity. 11β-HSD2 maintains the mineralocorticoid-selective microenvironment by converting cortisol → cortisone before it can act on MR. Loss of 11β-HSD2 activity (genetic or pharmacological) thus allows cortisol to illicitly activate MR, producing apparent mineralocorticoid excess (AME) — see Disease associations below. See nr3c2 for the full MR structural and signaling context.

Expression and aging changes

11β-HSD1 tissue expression

Highest expression: liver, adipose tissue, skeletal muscle, bone (osteoblasts, osteoclasts), brain (frontal cortex, hippocampus, cerebellum), and skin (particularly dermis). Lower expression in kidney (where 11β-HSD2 dominates) ¹.

Aging-associated upregulation of 11β-HSD1 in skin: 11β-HSD1 expression in human skin increases with age and is preferentially elevated at sun-exposed facial sites versus unexposed trunk skin. In a study of 30 healthy volunteers (age range 23–74 years), 11β-HSD1 immunoreactivity and enzyme activity were significantly higher in older subjects and positively correlated with markers of skin aging (thinning, collagen loss) ³. This age-associated upregulation is consistent with glucocorticoid-driven skin atrophy being partly a local phenomenon.

Adipose 11β-HSD1 in metabolic aging: 11β-HSD1 expression and activity in omental (visceral) adipose tissue are elevated in obese and metabolic-syndrome subjects; this local cortisol amplification promotes adipogenesis and drives portal glucocorticoid excess (the “portal theory” of visceral fat) ⁴. gap/needs-replication — the portal theory’s specific quantitative contribution to hepatic insulin resistance versus systemic cortisol effects is debated.

11β-HSD2 tissue expression

Kidney cortex (tubular epithelium), placenta, colon, salivary glands, prostate, and vascular endothelium. In the context of aging, declining kidney 11β-HSD2 activity has been proposed to contribute to age-associated hypertension and sodium retention, though this is not definitively established ¹. gap/needs-human-replication

Aging relevance

1. Local glucocorticoid amplification in visceral adiposity

The “local Cushing’s” concept describes how 11β-HSD1-mediated cortisol regeneration in visceral adipose creates a tissue-level glucocorticoid excess that drives adipogenesis, insulin resistance, dyslipidemia, and hepatic gluconeogenesis — all without systemic hypercortisolism. In adipose-selective 11β-HSD1 transgenic mice (aP2-HSD11B1), ~2–3 fold overexpression of 11β-HSD1 in adipose produced visceral obesity, hypertension, dyslipidemia, and insulin resistance despite normal circulating corticosterone — a direct experimental model of “metabolic syndrome from adipose glucocorticoid amplification” ¹. The key aging implication is that adipose 11β-HSD1 upregulation with age, combined with central adiposity accretion, constitutes a self-amplifying loop contributing to deregulated-nutrient-sensing.

Dimension	Status
Pathway conserved in humans?	Yes — HSD11B1/HSD11B2 are conserved; human adipose and mouse adipose enzyme show the same direction-switch
Phenotype (metabolic syndrome) conserved?	Yes — human omental adipose 11β-HSD1 elevated in T2DM and visceral obesity
Replicated in humans?	Partial — associative human data strong; pharmacological intervention trials largely negative (see Pharmacology)

2. Skin atrophy and wound healing

Glucocorticoids are established causes of skin thinning, impaired collagen synthesis, and delayed wound healing. The local 11β-HSD1-driven cortisol excess in aging skin provides a mechanism for the characteristic glucocorticoid-like skin changes of old age — thin, fragile dermis with reduced collagen — without systemic Cushing’s features. Pharmacological inhibition of 11β-HSD1 with AZD4017 in a pilot randomized controlled trial (n=38, type 2 diabetic adults) improved wound healing rate and skin integrity markers compared to placebo ⁵. This is one of the few positive human pharmacological signals for the 11β-HSD1 inhibitor class. gap/needs-replication — small-n pilot only; wound-healing endpoint is a surrogate.

3. Sarcopenia: glucocorticoid-driven muscle catabolism

Glucocorticoids promote skeletal muscle atrophy via upregulation of MuRF1 and MAFbx ubiquitin ligases, suppression of mTOR/protein synthesis, and inhibition of IGF-1/insulin signaling. Local 11β-HSD1 expression in skeletal muscle raises the question of whether muscle-autonomous cortisol amplification contributes to sarcopenia independently of circulating glucocorticoids. In a clinical observational study (n=not specified in available abstract), HSD11B1 gene expression in skeletal muscle biopsies was significantly elevated in sarcopenic versus non-sarcopenic older adults ⁶. An AZD4017 trial in obese women with idiopathic intracranial hypertension (IIH; n=31 randomized) found total lean muscle mass increased +1.2% (p<0.001) as a secondary endpoint over 12 weeks ⁷, though this was not in a sarcopenia-specific population, and the all-female obese IIH cohort (BMI 39.2 kg/m²) limits direct extrapolation to sarcopenia in community-dwelling older adults. gap/needs-replication — no dedicated sarcopenia RCT for 11β-HSD1 inhibitors exists; muscle expression data is observational. See sarcopenia for full quantitative sarcopenia criteria.

Dimension	Status
Pathway conserved?	Yes — glucocorticoid-driven muscle atrophy via MuRF1/MAFbx is conserved
Phenotype in humans?	Partial — associative (muscle HSD11B1 elevated in sarcopenia) not causal
Replicated in humans?	No — no dedicated sarcopenia intervention trial

4. Bone loss (glucocorticoid-induced osteoporosis)

11β-HSD1 is expressed in osteoblasts and osteoclasts. Glucocorticoids suppress osteoblast proliferation and survival while promoting osteoclastogenesis via GR-mediated Wnt/Runx2 pathway suppression and RANKL/OPG ratio shift. A dual-center phase II AZD4017 RCT in postmenopausal women with osteopenia (n=55 randomized: 27 AZD4017, 28 placebo) ran for 90 days. The primary endpoint — change in serum osteocalcin (a bone formation marker) — was NOT met: osteocalcin was similar between groups at 90 days (active 22.3 [SD 8.6] ng/mL vs placebo 21.7 [SD 9.2] ng/mL; treatment effect 0.95, 95% CI −2.69 to 4.60) ⁸. The bone resorption marker β-CTX was also similar at 90 days (active 0.4 [SD 0.2] ng/mL vs placebo 0.4 [SD 0.2] ng/mL; treatment effect 0.04, 95% CI −0.04 to 0.12), with no significant reduction. The authors concluded that relative impairment of bone mineral density in postmenopausal women is not mediated by local intracellular production of cortisol under normal physiological cortisol concentrations. AZD4017 did successfully inhibit 11β-HSD1 in vivo (urinary [THF+alloTHF]/THE ratio fell to 0.1 [SD 0.1] vs 0.6 [SD 0.3] in placebo, p<0.001), confirming pharmacodynamic engagement. See osteoporosis for quantitative bone density and fracture data. gap/needs-replication — the hypothesis that local 11β-HSD1 drives physiological bone loss in postmenopausal women was not supported by this 90-day RCT; pharmacological glucocorticoid-induced osteoporosis (as in Othonos 2023, where prednisolone-treated men showed bone marker protection) may respond differently from the physiological-aging context tested in Abbas 2022.

Dimension	Status
Pathway conserved?	Yes — 11β-HSD1 expressed in human osteoblasts; activity increases with age
Phenotype in humans?	Contested — local cortisol excess implicated in GC-induced osteoporosis; not shown for physiological aging osteopenia
Replicated in humans?	No — 90-day AZD4017 RCT (Abbas 2022) found no effect on bone turnover markers under physiological conditions; GC-context (Othonos 2023) preserved bone formation markers

5. Cognitive aging: hippocampal glucocorticoid burden

The hippocampus expresses 11β-HSD1 and is particularly vulnerable to glucocorticoid excess (see hpa-axis § Glucocorticoid cascade hypothesis). Local cortisol amplification in hippocampal neurons may contribute to the age-related impairment of long-term potentiation and spatial memory. In a double-blind randomized crossover trial, a single dose of the non-selective 11β-HSD1 inhibitor carbenoxolone (100 mg three times daily for 4 weeks) improved verbal memory in healthy elderly men (n=10) and in men with type 2 diabetes (n=12) compared to placebo ⁹. This seminal PNAS study established proof-of-concept for pre-receptor cortisol amplification as a cognitive-aging target, though the non-selectivity of carbenoxolone (it also inhibits 11β-HSD2 and has bile-acid effects) complicates interpretation. A 2024 review (Seckl, J Intern Med) notes that more selective inhibitors have not yet replicated this cognitive signal in larger trials ¹⁰. gap/needs-replication — carbenoxolone data are small-n; selective 11β-HSD1 inhibitors have not yielded positive cognitive endpoints in Phase 2 AD trials.

6. Vascular aging and hypertension: HSD11B2 loss-of-function

HSD11B2 loss-of-function mutations cause apparent mineralocorticoid excess (AME), an autosomal recessive disorder characterized by severe hypertension in childhood, hypokalemia, and suppressed renin/aldosterone (cortisol illicitly activating MR). This is a monogenic proof of concept that loss of MR protection by 11β-HSD2 drives severe vascular pathology. In a non-disease context, partial functional impairment of 11β-HSD2 (from dietary glycyrrhetinic acid — the active component of licorice; from carbenoxolone; or from lesser-studied genetic variants) also elevates blood pressure via the same mechanism. Age-related changes in kidney 11β-HSD2 activity may contribute to age-associated sodium retention and hypertension, though this is incompletely characterized in humans ¹. gap/needs-human-replication — no prospective cohort data quantifying kidney 11β-HSD2 decline with aging in humans.

Disease associations

HSD11B1:

Cortisone reductase deficiency 2 (CORTRD2; MIM #614662) — autosomal dominant; HSD11B1 loss-of-function causes hyperandrogenism (hirsutism, amenorrhea) due to compensatory ACTH-driven adrenal androgen excess. Connects HSD11B1 to adrenal steroidogenesis regulation beyond cortisol.
Metabolic syndrome / T2DM — not a monogenic association but elevated adipose HSD11B1 activity is a consistent feature.

HSD11B2:

Apparent mineralocorticoid excess (AME; MIM #218030) — autosomal recessive; biallelic loss-of-function mutations; childhood-onset severe hypertension with hypokalemia, suppressed renin/aldosterone. Monogenic model of 11β-HSD2 relevance to cardiovascular disease.
Pre-eclampsia — reduced placental 11β-HSD2 expression, allowing excess maternal cortisol to reach fetal circulation; placental 11β-HSD2 is a developmental programming mechanism.

Pharmacology

11β-HSD1 inhibitors (the active drug-development space)

The “local Cushing’s” concept motivated substantial pharmaceutical investment in 11β-HSD1 inhibitors throughout 2005–2020. A 2020 systematic review (Gregory et al.) of 29 clinical studies found: one Phase 2 trial met its HbA1c primary endpoint in T2DM; trials in obesity, metabolic syndrome, and Alzheimer’s disease failed primary endpoints; the class has not progressed to Phase 3 or approval for any metabolic or cognitive indication ¹¹. However, positive signals in secondary endpoints (bone turnover, lean mass, wound healing) have revived interest in narrower tissue-targeted applications:

Agent	Selectivity	Status	Key result
Carbenoxolone	Non-selective (11β-HSD1 + 11β-HSD2)	Research probe; withdrawn	Cognitive benefit in small crossover RCT ⁹; hypertension risk limits clinical use
AZD4017	Selective 11β-HSD1	Phase 2; not approved	Wound healing ↑ ⁵; bone resorption marker (β-CTX) no significant change in physiological osteopenia ⁸; lean mass ↑ +1.2% (p<0.001) in obese females with IIH ⁷; prednisolone adverse-effect mitigation (bone turnover, BP, lipids) in healthy men ¹²; primary metabolic and bone endpoints not met
ABT-384	Selective 11β-HSD1	Phase 2 (Alzheimer’s); discontinued	Failed cognitive primary endpoint in AD; no publication of full trial data confirmed here gap/unsourced
INCB13739	Selective 11β-HSD1	Phase 2 (T2DM); discontinued	Improved HbA1c in the one positive Phase 2 signal per Gregory 2020 systematic review ¹¹; specific HbA1c reduction of −0.65% is from body of systematic review (full text not retrieved) gap/unsourced

Druggability tier 2 rationale (aging-context): Multiple clinical-grade 11β-HSD1 inhibitors exist (high-quality probes / Phase 2 agents). However, all have failed or been discontinued for their primary metabolic and cognitive aging indications. No 11β-HSD1 inhibitor is FDA-approved for any indication. The “local Cushing’s” target concept remains valid, but the gap between target validation (murine models, tissue-level pharmacodynamics) and clinical efficacy endpoints is wide. Renewed interest in tissue-specific endpoints (skin, bone, muscle) means this is not a dead target, but tier 1 would require proof of efficacy in a clinical aging endpoint — which does not exist. The HPA-axis page assigns the broader HPA pathway the same tier 2, consistent with this assessment.

11β-HSD1 inhibition and androgen side-effects: Because 11β-HSD1 also participates in peripheral 11-oxygenated androgen activation (converting 11-oxo-androstenedione to 11-ketotestosterone), its inhibition can drive upstream accumulation of 11-oxygenated androgen precursors. A 2024 mechanistic study documented this off-target effect ¹³ and raises a potential safety concern for prolonged 11β-HSD1 inhibitor use, particularly in women. This is not a terminal blocker but represents an undercharacterized pharmacological consequence that Phase 3 programs would need to monitor.

11β-HSD2 inhibition (licorice effect):

Dietary glycyrrhetinic acid (the active metabolite of glycyrrhizin in licorice) is a potent inhibitor of 11β-HSD2. Chronic licorice consumption elevates blood pressure via cortisol-driven MR activation (the same mechanism as AME), producing a pharmacologically-induced apparent mineralocorticoid excess. This is not a therapeutic strategy — it is a recognized hazard. Carbenoxolone (a glycyrrhetinic acid derivative formerly used for peptic ulcer) has the same liability.

MR antagonism (spironolactone, eplerenone, finerenone) is the clinical intervention for conditions where cortisol inappropriately activates MR; these drugs act at the receptor level (downstream of 11β-HSD2) rather than at the enzyme. See nr3c2 for the MR pharmacology context.

Mendelian randomization evidence

mr-causal-evidence: partial — GWAS variants in the HSD11B1 locus have been identified in body composition, metabolic, and blood pressure GWAS studies, providing genetic instruments in principle. However, dedicated Mendelian randomization studies using HSD11B1 or HSD11B2 genetic instruments to test causal effects on aging outcomes (cognitive decline, sarcopenia, bone density, mortality) have not been published as of 2026 gap/needs-replication. The AME monogenic disease (HSD11B2 loss-of-function) provides strong biological validation but is not an MR study.

Extrapolation: model organism vs. human

Claim	Model evidence	Human translation
Adipose 11β-HSD1 overexpression → metabolic syndrome	aP2-HSD11B1 mouse: visceral obesity, hypertension, T2DM ¹	Human: omental 11β-HSD1 elevated in obesity/T2DM (observational); pharmacological inhibition did not robustly improve metabolic endpoints
Muscle 11β-HSD1 → atrophy	Rodent glucocorticoid-induced atrophy models	Human: HSD11B1 mRNA elevated in sarcopenic patients ⁶; no pharmacological muscle-specific trial
Hippocampal 11β-HSD1 → memory impairment	Aged rat models respond to 11β-HSD1 inhibition	Human: carbenoxolone improved verbal memory in small RCT ⁹; large AD trials negative
11β-HSD2 loss → hypertension	AME patients (human monogenic disease — strongest causal anchor)	Direct — causal via Mendelian experiment of nature

Pathway membership and cross-references

hpa-axis — HSD11B1 and HSD11B2 are key nodes of pre-receptor glucocorticoid metabolism within the HPA axis circuit; they set tissue-level cortisol availability independently of adrenal output
nr3c1 — glucocorticoid receptor (GR): the primary cortisol sensor in metabolic tissues; 11β-HSD1 amplifies local GR activation
nr3c2 — mineralocorticoid receptor (MR): 11β-HSD2 is the gatekeeper preventing cortisol-driven MR overstimulation in kidney and colon
crh — upstream of HPA; CRH drives ACTH/cortisol production; 11β-HSD1 amplifies cortisol downstream of this axis
chronic-inflammation — local glucocorticoid excess via 11β-HSD1 modulates tissue inflammatory tone (complex: acute GR → anti-inflammatory; chronic → immunosuppression + metabolic syndrome)
deregulated-nutrient-sensing — adipose 11β-HSD1-driven insulin resistance contributes to nutrient-sensing pathway dysregulation
sarcopenia — 11β-HSD1-driven muscle glucocorticoid excess as a component of age-related muscle loss
osteoporosis — 11β-HSD1 in osteoblasts as a mediator of bone loss
glucocorticoid-cascade-hypothesis — the broader contested causal hypothesis about cortisol driving cognitive and tissue aging; 11β-HSD1 is the tissue-amplification arm of that hypothesis

Limitations and gaps

#gap/needs-human-replication — Causal role of 11β-HSD1-driven cortisol amplification in age-related sarcopenia in community-dwelling older adults (as opposed to pharmacological corticosteroid-induced sarcopenia) is not established. Muscle HSD11B1 expression data are observational ⁶.
#gap/needs-human-replication — Kidney 11β-HSD2 decline with healthy aging as a contributor to age-associated hypertension has not been quantified in prospective human studies.
#gap/needs-replication — The cognitive benefit of 11β-HSD1 inhibition shown in the carbenoxolone RCT ⁹ has not been replicated with a selective inhibitor in a sufficiently powered trial. The AD trials with AZD4017 and ABT-384 failed or were discontinued without clear mechanistic resolution.
#gap/unsourced — ABT-384 Phase 2 full trial data and outcome details were not confirmed from published sources during this seeding; the compound is documented as discontinued in reviews but individual primary results require verification.
#gap/contradictory-evidence — 11β-HSD1 inhibition provides strong preclinical evidence of metabolic benefit, but clinical translation to primary metabolic endpoints has been largely negative. The discordance may reflect species differences, insufficient target engagement, endpoint insensitivity, or dose limitation due to 11-oxygenated androgen accumulation ¹³.
#gap/contradictory-evidence — AZD4017 reduced bone formation marker decline in prednisolone-treated healthy men ¹² but had no effect on bone turnover markers in postmenopausal women with osteopenia under normal physiological cortisol ⁸. This suggests the bone-protective effect of 11β-HSD1 inhibition may be specific to the exogenous glucocorticoid context, not physiological bone aging.
#gap/needs-canonical-id — GenAge-human entries for HSD11B1 and HSD11B2 not found; confirm on next lint pass.

Footnotes

doi:10.1152/physrev.00020.2012 · Chapman K, Holmes M, Seckl J · Physiological Reviews 2013 · review · n=N/A · authoritative comprehensive review of 11β-HSD1 and 11β-HSD2 biology, tissue distribution, cofactor dependence, transgenic mouse models, and drug-development landscape; 293 citations as of 2023; gold-standard mechanistic reference for this page ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶
doi:10.1210/jcem.87.3.8301 · Bujalska IJ et al. · J Clin Endocrinol Metab 2002 · in-vitro (human omental adipose stromal cells) · n=N/A · 11β-HSD1 switches from dehydrogenase (cortisol→cortisone) in undifferentiated cells to reductase (cortisone→cortisol) in mature adipocytes; cell-state-dependent enzyme directionality; promotes adipogenesis in the mature-adipocyte context; model: human adipose stromal cells ↩
doi:10.1038/jid.2010.257 · Tiganescu A, Walker EA, Hardy RS et al. · J Invest Dermatol 2011 · observational (human biopsy study) · n=30 · 11β-HSD1 expression and activity increase with age in human skin and are higher at sun-exposed (facial) vs unexposed (trunk) sites; correlate with skin-aging markers; model: human dermal tissue ↩
doi:10.1111/j.1463-1326.2012.01582.x · Pereira CD, Azevedo I, Monteiro R, Martins MJ · Diabetes Obes Metab 2012 · review · n=N/A · 11β-HSD1 in pathophysiology of obesity, metabolic syndrome, and T2DM; portal theory of visceral fat reviewed; mouse transgenic model (aP2-HSD11B1) and human observational data synthesized ↩
doi:10.1530/EJE-21-1197 · Ajjan RA, Tiganescu A (last) et al. · Eur J Endocrinol 2022 · rct (pilot) · n=38 (T2DM adults) · AZD4017 vs placebo; wound healing rate and skin integrity markers improved; selective 11β-HSD1 inhibition; model: type 2 diabetic adults; small-n pilot ↩ ↩²
doi:10.1007/s40520-023-02574-w · Schluessel S et al. · Aging Clin Exp Res 2023 · observational · n=not specified in abstract · HSD11B1 gene expression in skeletal muscle biopsies elevated in sarcopenic vs non-sarcopenic older adults; first direct human muscle-gene expression data linking 11β-HSD1 to sarcopenia; model: human muscle biopsy ↩ ↩² ↩³
doi:10.1210/clinem/dgaa766 · Hardy RS, Botfield H, Markey K et al. · J Clin Endocrinol Metab 2021 · rct · n=31 randomized (17 AZD4017, 14 placebo) · obese women (BMI 39.2 ± 12.6 kg/m²) with idiopathic intracranial hypertension (IIH); 12-week treatment; primary endpoint: lumbar puncture opening pressure (intracranial pressure); lean muscle mass increased +1.2% (p<0.001) total with AZD4017 vs no change in placebo (secondary endpoint); proximal +1.1% p<0.05, distal +1.0% p<0.05; total cholesterol −7.9% (p<0.01); HDL +8.2% (p<0.05); lean-mass finding is a secondary endpoint in a non-sarcopenia, all-female, obese IIH cohort; population: obese women 18–55 years · model: obese women with IIH (PMC7765633) ↩ ↩²
doi:10.1210/clinem/dgac100 · Abbas A, Schini M, Ainsworth G et al. (last: Stewart PM) · J Clin Endocrinol Metab 2022 · rct (dual-center, double-blind, placebo-controlled) · n=55 randomized (27 AZD4017, 28 placebo); analyzed n=22 AZD4017, n=24 placebo at primary endpoint · postmenopausal women with osteopenia; 90-day treatment; primary endpoint (osteocalcin) NOT met (treatment effect 0.95, 95% CI −2.69 to 4.60); β-CTX (secondary) also NOT significantly changed (treatment effect 0.04, 95% CI −0.04 to 0.12); AZD4017 confirmed on-target (urinary [THF+alloTHF]/THE reduced from 0.6 to 0.1 vs placebo 0.6); authors conclude local 11β-HSD1-driven cortisol does not regulate bone turnover under normal physiological conditions · model: postmenopausal women with osteopenia ↩ ↩² ↩³
doi:10.1073/pnas.0306996101 · Sandeep TC, Yau JL, MacLullich AM et al. · PNAS 2004 · rct (crossover) · n=10 (healthy elderly men) + n=12 (T2DM men) · 4-week carbenoxolone 100 mg three times daily vs placebo; verbal memory improved on carbenoxolone in both groups; non-selective 11β-HSD1/2 inhibitor; proof-of-concept for pre-receptor cortisol in cognitive aging; model: older adult men ↩ ↩² ↩³ ↩⁴
doi:10.1111/joim.13741 · Seckl J · J Intern Med 2024 · review · n=N/A · comprehensive update on 11β-HSD biology in the brain; notes that selective 11β-HSD1 inhibitors have not yet replicated carbenoxolone cognitive signals in powered trials; Alzheimer’s program failures discussed; ongoing interest in skin, bone, and muscle applications ↩
doi:10.1016/j.metabol.2020.154246 · Gregory S, Hill D, Grey B, Ketelbey W et al. · Metabolism 2020 · systematic-review · 29 studies (1,925 papers screened, 29 included in narrative synthesis) · 11β-HSD1 inhibitor use in human disease; one Phase 2 trial met HbA1c endpoint in T2DM; MetS, obesity, and AD trials failed primary endpoints; concludes translation remains challenging (abstract-confirmed; full text not retrieved — green OA download failed) ↩ ↩²
doi:10.1038/s41467-023-36541-w · Othonos N, Pofi R et al. (last: Tomlinson JW) · Nature Communications 2023 · rct (double-blind placebo-controlled) · n=32 randomized (16 AZD4017, 16 placebo), 15/arm completed per-protocol · healthy men; AZD4017 400 mg BD + prednisolone 20 mg once-daily for 7 days; primary endpoint (change in glucose disposal [Gd] by hyperinsulinaemic euglycaemic clamp) NOT met (p=0.17 between groups); secondary: hepatic insulin sensitivity worsened in placebo but not AZD4017 (M/I value low-insulin p=0.001); circulating triacylglycerol rise prevented in AZD4017 arm; nighttime diastolic BP rose in placebo (+4.6 mmHg, p=0.03) but not AZD4017; bone formation markers (osteocalcin, P1NP) protected; prednisolone anti-inflammatory action (OX40 assay) largely preserved; model: healthy adult men (mean age 38 years) ↩ ↩²
doi:10.1096/fj.202302131R · Schiffer L, Storbeck KH (last) et al. · FASEB J 2024 · in-vitro mechanistic + human study · n=not fully specified · 11β-HSD1 inhibition drives accumulation of 11-oxygenated androgen precursors; potential off-target androgenic effect of the drug class; relevant to safety monitoring for prolonged use especially in women ↩ ↩²

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