Table 1.

Impact of sex hormones on cartilage degeneration

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 5 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]

ACL anterior cruciate ligament, ALP alkaline phosphatase, DHEA dehydroepiandrosterone, DHT dihydrotestosterone, DMSO dimethylsulfoxide, E2 17-ß estradiol, ER estrogen receptor, ERT estrogen replacement therapy, H₂O₂ hydrogen peroxide, iNOS inducible nitric oxide synthase, LDH lactate dehydrogenase, LSS liquid scintillation spectroscopy, MMP13 matrix metalloproteinase 13, MRI magnetic resonance imaging, OA osteoarthritis, ORX orchiectomy, OVX ovariectomy, PG progesterone, qPCR quantitative real-time polymerase chain reaction, RT-PCR reverse transcription polymerase chain reaction; TBARS thiobarbituric acid reactive substances, TIMP1 tissue inhibitor of matrix metalloproteinase 1, TRPV transient receptor potential vanilloid, T testosterone, TKR total knee replacement, TNFα tumor necrosis factor α, WOMAC Western Ontario and McMaster Universities Osteoarthritis Index