Progestin Resistance & Management – Comprehensive Bullet-Point Notes

Citation & Publication Details

Authors: Mu Lv, Peiqin Chen, Mingzhu Bai, et al.
Article: “Progestin Resistance and Corresponding Management of Abnormal Endometrial Hyperplasia and Endometrial Carcinoma.”
Journal: Cancers (MDPI) 2022, Volume 14, Article 6210.
DOI: https://doi.org/10.3390/cancers14246210
Dates: Received $6\,Nov\,2022$ → Accepted $14\,Dec\,2022$ → Published $15\,Dec\,2022$ .
Open-access under CC-BY 4.0 licence.
Key affiliations: Tongji Univ., Shanghai Jiao Tong Univ., Fudan Univ., Univ. of Texas Southwestern, etc.
Equal contribution: Mu Lv & Peiqin Chen. ‡ Senior author: Wenxin Zheng.

Epidemiology & Clinical Background

Endometrial cancer (EC) incidence is rising and presents at younger ages.
Endometrial hyperplasia (EH)
- Abnormal proliferation of glands/epithelium.
- Progresses to atypical EH (AEH) or endometrioid intra-epithelial neoplasia (EIN).
EC traditional dualistic model
- Type I (≈ $80\%$ ): estrogen-dependent, better prognosis.
- Type II: non-estrogen-dependent, poorer prognosis.
Standard therapy: hysterectomy → irreversible loss of fertility; recurrence still possible.
Conservative option: high-dose progestin (MPA, MA, LNG-IUS) used for fertility preservation and palliation of advanced disease.
- Complete remission ≈ $70\%$ .
- Primary/secondary progestin resistance ≈ $30\%$ .

Therapeutic Mechanisms of Progestin

General pathway: ligand binds cytoplasmic PR → nuclear translocation → attachment to progesterone-response element (PRE) → transcription of target genes.
Three PR locations: nuclear, membrane, mitochondrial.
Additional crosstalk via estrogen receptor (ER) & androgen receptor (AR).

1 Cell-Cycle Arrest

G0/G1 block via lncRNA NEAT1 → miR-146b-5p axis.
Repression of Wnt/β-catenin (↓LEF1, $c\text{-}myc$ , $MMP9$ ).
G2/M arrest when combined with alsterpaullone.
Non-genomic PI3K/AKT activation through GPR30.

2 Anti-angiogenesis

↓VEGF production (progesterone, MPA, 17α-OH-progesterone).
↓bFGF transcription; antagonises estrogen-stimulated bFGF.
↑Thrombospondin-1 via PR.

3 Induction of Apoptosis

Up-regulates Fas/FasL/FADD → caspase-8 cascade.
↑GPR30 → ERK-1/2 inactivation.
Activates $CACNA2D3/Ca^{2+}/p38$ MAPK axis.
Triggers ER-stress (↑HERPUD1) through PR-B.

4 Cell Differentiation

Historical findings: pseudodecidual change, squamous differentiation post-progestin.
Long-term (12–24 wk) histology: metaplasia, ↓atypia, ↓gland:stroma ratio, ↓mitosis.
Mechanistic link: suppression of Bcl-2 promotes maturation.

5 Anti-inflammatory Effects

Alters lymphocyte milieu: ↑NK, ↓Tregs.
↓NF-κB via A20/ABIN-2, ↓MMP release.

6 Inhibition of EMT & Metastasis

↑T-cell infiltration, ↓TGF-β signalling, ↑E-cadherin, ↓vimentin.

7 Modulation of ER/AR Signalling

↓ER synthesis, ↑ER degradation.
Induction of $17\text{-}HSD$ -2 converts $E<em>2\rightarrow E</em>1$ .
Up-regulates AR; MPA acts as partial AR agonist.

8 Stromal–Epithelial Paracrine Regulation

Stromal PR activation releases factors that
- Inhibit PI3K/AKT in epithelial cells.
- Induce glycodelin & $17\text{-}HSD$ -2.
HAND2 in stroma suppresses FGF-mediated epithelial proliferation.

Mechanisms of Progestin Resistance

A Aberrant PR Signalling

↓PR level / PRA-PRB imbalance
- High PR = $72\%$ response vs $12\%$ if PR-negative.
- PRB dominance predicts sensitivity; ratio $PRB/(PRA{+}PRB)$ critical.
Epigenetic silencing
- CpG hyper-methylation at PRB promoter.
Post-translational events
- Phosphorylation (Ser294/Ser345 by MAPK) → altered ubiquitination & degradation.
- SUMOylation at Lys388 ↓transcription $6{-}10\times$ .
Coregulator dysregulation
- SRC-1 ↓, SRC-2/3 ↑ → impaired PR transcription.
PR-linked pathways driving resistance
- EGFR/TGFα → MAPK → ↓PR.
- PI3K/AKT/mTOR (ligand-independent PR functions).
- Suppressed apoptosis (↓Fas/FasL, ↑Bcl-2).
- Nrf2 oxidative-stress axis.
- EMT gene switch (↓E-cadherin, ↑N-cadherin, vimentin).

B Other Signalling Abnormalities

Persistent PI3K/AKT activation by MPA in resistant cells.
FAM83B, FKBP51, PTEN loss, GRP78 over-expression all feed into PI3K/AKT.

C Metabolic-Immune-Microenvironment Factors

Estrogen excess & ER isoform shift (↓ERα, ↑ERβ) in resistant cells.
Obesity: ↓SHBG, ↑ovarian/adipose estrogen; insulin resistance ↑GPER.
Chronic inflammation (M2 macrophage cytokines: TNF-α, IL-1β/6) epigenetically suppress PR.
Lipid-metabolic enzymes: ↑SREBP-1, ↑DHCR24 (cholesterol synthesis) correlate with ↓PR.
IGF-I/II suppress PR & activate AKT/p70S6K.

D Cancer Stem Cells (CSCs)

Ishikawa-CSCs unresponsive to MPA; express higher AKR1C1, Nrf2, GloI, Bcl-2, survivin.
Embryonic-sac cytokine ALPP can re-differentiate CSCs & restore sensitivity.

Molecular Biomarkers of Resistance

Cell-Proliferation Markers

PI3K/AKT/mTOR activation; PTEN loss.
GRP78; MSX1 transcription factor.

Oxidative-Stress Markers

Nrf2 ↑; downstream AKR1C1, LASS2, survivin over-expressed.

Metabolic Markers

GloI, EGFR, SIRT1/FoxO1/SREBP-1 axis, DHCR24, IGF-IR.

Apoptosis Markers

Fas/FasL down-modulation; persistent Bcl-2; PDCD4 suppression via AKT.

Nucleic-Acid Regulation

miR-96/182/141/129-5p/375 target PR; anti-miR-96 ↑PR.
lncRNA HOTAIR binds LSD1 → PRB promoter silencing.
DACH1 loss → PR↓, EMT↑.
ARID1A mutation → PI3K activation, PRB loss.
HAND2 methylation predicts poor response.

Molecular Subtypes (TCGA)

Copy-number-low (Type I): PTEN mut, high PR → better progestin response.
Copy-number-high (Type II): p53 mut, PR loss.
Mismatch-repair deficiency/MSI & Lynch syndrome → > $90\%$ resistance.

Approaches to Overcome Resistance

1 Hysteroscopic Resection + Progestin

Combines complete lesion removal + histology verification.
Complete response ≈ $90\%$ ; live birth ≈ $33\%$ .
Hysteroscopy + LNG-IUS ↓recurrence vs oral progestin alone.

2 Hormonal Adjuncts

Tamoxifen (ER modulator) cyclic with progestin → $\approx33\%$ response in advanced EC.
Mifepristone (PR antagonist/agonist) synergises with MPA; induces apoptosis.
GnRH-agonist + progestin for progestin-insensitive AEH; GnRH-a + letrozole cuts systemic estrogen.
Aromatase inhibitors with progestin useful in obese pre-menopausal cases.
Androgens/AR targeting ↑PR, suppress proliferation.
4th-generation progestins (dienogest, NOMAC) active in MPA-resistant lines.

3 Cocktail Drug Regimens

Metformin ↓Nrf2–survivin, ↓GloI, restores PR; complete response $97\%$ with MPA; mitigates weight gain/glucose.
Antipsychotics
- Chlorpromazine ↑PRB, ↓IGF-IR, suppresses PI3K/AKT.
- Thioridazine ↓EGFR, inhibits PI3K/AKT/mTOR when paired with MPA.
PI3K/AKT/mTOR inhibitors
- mTOR (temsirolimus, everolimus, ridaforolimus) increase PR mRNA, useful in recurrent EC.
- PI3K inhibitor LY294002 ↑PRB & apoptosis.
- AKT inhibitor MK-2206 ↑PRB, shrinks xenografts.
Epigenetic modulators
- HDACi (LBH589): restore PR, G1 arrest.
- DNMTi (5-aza-dC) demethylate PR promoter.
- EZH2 inhibitors reduce H3K27me3, halt proliferation.

4 Embryonic Microenvironment Cytokines

IVF-derived embryonic-sac fluid (ALPP) forces CSC differentiation → resensitises to progestin.

5 Stem-Cell Therapies

Menstrual blood-derived iPSC-derived stromal fibroblasts may replace defective EMSFs.
hUCMSC-derived exosomes (miR-302a) suppress EC progression.

Clinical Trials Snapshot (2015-2022)

Drug-combination arms: cridanimod + progestin; metformin + MPA; GnRHa/letrozole protocols; PD-1 inhibitor + progesterone.
LNG-IUS-based trials: Mirena ± metformin/GnRH-a; comparisons vs oral MA/MPA.
Radiotherapy + oral progestagen (NSMP-ORANGE, $n=1611$ , phase III).
Chemotherapy ± ridaforolimus vs progestin.
Surgery combos: bariatric surgery + IUD; hysteroscopic resection + progestin.

Research Gaps & Future Directions

Vault RNAs and exosome-mediated transfer in drug metabolism & resistance remain unexplored.
Multi-omic profiling required to map resistance networks & personalise “cocktail” strategies.
Stratified therapy based on TCGA subtype, MMR/MSI, PR isoform ratio, and metabolic status (BMI, insulin).

Select Abbreviations

AEH = Atypical Endometrial Hyperplasia; AR = Androgen Receptor; CSC = Cancer Stem Cell; DNMTi = DNA Methyl-Transferase Inhibitor; EMT = Epithelial-Mesenchymal Transition; ER = Estrogen Receptor; FGF = Fibroblast Growth Factor; HDACi = Histone Deacetylase Inhibitor; LNG-IUS = Levonorgestrel Intrauterine System; MF = Mifepristone; MMR = Mismatch Repair; MPA = Medroxyprogesterone Acetate; MSI = Microsatellite Instability; Nrf2 = Nuclear Factor E2-related 2; PI3K = Phosphoinositide-3-Kinase; PR = Progesterone Receptor; PTEN = Phosphatase & Tensin Homolog; SRC = Steroid Receptor Co-activator.