Table 1 Impact of sex hormones on cartilage degeneration
From: Sex-dependent variation in cartilage adaptation: from degeneration to regeneration
Hormones | Study design | Treatment | Analysis | Results | Implications | References |
|---|---|---|---|---|---|---|
T/DHT | In vivo; male murine model | ORX versus non-ORX | Histologic analysis of knee cartilage explants | ORX males had lower OA scores and significantly reduced OA severity | Male hormones may accentuate OA severity in this model | [111] |
In vitro; murine chondrocytes from costochondral cartilage | Cultured with media containing 10–11 M T or DHT | ALP analysis for differentiation and LSS analysis for proliferation | Male growth zone chondrocytes showed dose-dependent increases in thymidine incorporation and increased ALP activity; male or female resting zone chondrocytes showed no changes in thymidine incorporation; male resting zone chondrocytes or female chondrocytes from any regions showed no changes in ALP activity | Only male cells have a physiologic response to T and DHT treatment | [230] | |
T | In vivo; arthritic rat model | ORX followed by DHT treatment | Clinical OA evaluation, lysosomal activity, TBARS level (indicative of membrane damage) | Castrated rats exhibited elevated lysosomal activity and higher TBARS; DHT treatment after castration lowered TBARS level; castrated rats mounted a severe immune response that was reduced upon DHT application | T and DHT exhibit anti-inflammatory effects at the joint in both males and females | [94] |
In vivo; human patients with severe knee OA | Unilateral TKR | Serum T levels, knee radiograph, and WOMAC pain/function analysis 6–8 weeks after surgery | On the operative knee, higher T levels were associated with less pain in both sexes; in the non-operative knee, higher T was associated with less disability in women | T is negatively correlated with joint disability in women | [196] | |
E2 | In vivo; female murine model | OVX versus non-OVX | Histologic analysis of knee cartilage explants | Lesions seen in OVX mice were significantly more severe than those seen in control females, but less severe than those seen in control male mice | E2 loss is associated with cartilage loss/OA; suggests E2 may be chondroprotective | [111] |
In vitro; human female articular chondrocytes from OA patients | E2 exposure during proliferation-stock solutions of 10–1 M E2 in absolute ethanol diluted stepwise. Controls in 0.1% ethanol | qPCR, Western blotting, immunofluorescence | E2 suppressed MMP13 expression in female human articular chondrocytes | E2 may be chondroprotective | [76] | |
In vitro; bovine model articular chondrocytes of unspecified sex | Grown in media dosed with E2 (concentrations of 0 M, 10–11 M, 10–10 M, 10–9 M, 10–8 M, 10–7 M, 10–6 M, 10–5 M, and 10–4 M), then treated with H2O2 on day 7 for radical generation | Toxicity assay, morphology, and DNA quantification via fluorometer | Chondrocytes incubated with E2 showed better morphology than control after radical treatment; E2 chondrocytes released LDH at 7% while control released it at 61% | E2 is protective against free radical damage in chondrocytes | [231] | |
In vivo; female rabbit knee articular cartilage | Total RNA extraction of pregnant versus control rabbits | RT-PCR | Significant decrease seen in mRNA levels for type II collagen, biglycan, collagenase, TIMP1, TNFα, iNOS in pregnant rabbits | Pregnancy, which is associated with steady rises in estrogen, is associated with depression of mRNA expression in cartilage | [232] | |
In vivo; human female articular cartilage observational study | ERT current users, former users, and non-users | Examinations, anteroposterior weight-bearing radiographs | Females who never used ERT had worse OA than females who used ERT | ERT could have a protective effect on cartilage | [194] | |
In vivo; human female articular cartilage | ERT greater than or equal to 5Â years | T1 weighted fat suppressed MRI of knees | Higher tibial cartilage volume found in ERT users than non-users | ERT may prevent loss of knee articular cartilage | [193] | |
In vivo; murine model | Mice with ERα inactivation versus wild-type; OVX followed by treatment with E2 or placebo, then induced with antigen-induced arthritis | Histology, flow cytometry, T-cell proliferation assay | In wild-type mice (that have estrogen receptors), E2 treatment decreased synovitis and joint destruction; E2 did not affect ERα knockout mice | E2 works through ERα to protect against cartilage damage | [188] | |
PG | In vivo; murine knee chondrocytes | TRPV knockout mice versus wild-type controls | Quantification of chondrocytic calcium signaling with fluorescence imaging | TRPV knockout males demonstrated the most severe cartilage erosion; no significant difference found between TRPV knockout females and wild-type females at any timepoint | PG exposure may decrease TRPV4 expression | [233] |
In vitro; human tracheal epithelial cells | Media supplemented with PG | RT-PCR, Western blot, luciferase assay, calcium measurements via fluorescence imaging | PG-treated cells exhibited downregulation of TRPV4 channels | PG mediates the downregulation of TRPV4 | [178] | |
DHEA | In vivo; rabbit model with unilateral ACL transection | DHEA injection into knee joint at dose of 100 µM DHEA dissolved in DMSO | Histological evaluation, RT-PCR | Significant decrease in severity of lesions was seen after DHEA injection and MMP3 expression was downregulated in DHEA group | DHEA may be protective against the development of OA in both sexes | [33] |
T, E2, PG | In vivo; human knee cartilage | Vitamin D treatment | Sex hormone assay | High T levels correlated with lower pain levels in females, high E2 levels correlated with lower grade bone marrow lesions in females, high E and progesterone levels correlated with lower effusion–synovitis volume, high progesterone correlated with higher cartilage volume | Low levels of T, E2, and progesterone are associated with worsening OA in females, but not males | [234] |