Hormone replacement therapy and degenerative joint disease

Danielle R. Steilen-Matias, MMS, PA-C, Caring Medical Florida
Ross Hauser, MD, Caring Medical Florida

Hormone replacement therapy and degenerative joint disease

Research and clinical observations tell us that hormones help drive the immune system and help repair damaged joints. A patient who experiences thinning hair, loss of sex drive, decreased muscle tone, dry skin, menstrual cramping, irregular menses, chronic fatigue, decreased body temperature and a feeling of coldness will likely have a hormone deficiency until proven otherwise. While there is new research connecting hormone deficiency with degenerative joint pain and osteoarthritis, other research studies question just how much hormone deficiency can be blamed for joint pain, if at all. It is a controversial subject. For instance, having high estradiol levels can decrease the ability of the body to make fibroblasts, the cells needed to make connective tissue. This is a consideration for women who are on birth control, as it can hamper healing ability. Low hormone levels can also alter your ability to heal, let alone make you feel sluggish and unhealthy.

We commonly ask patients to check the following hormone levels to help optimize healing

We commonly ask patients to check the following hormone levels to optimize health, healing, and aging: thyroid, TSH, DHEA, pregnenolone, estrogen, progesterone, testosterone, melatonin, and cortisol at least to start. For the person in chronic pain, it is very likely that at least one of these levels will be suboptimal. Always keep in mind that certain hormones are anabolic, meaning they grow connective tissue, where others are catabolic and promote its breakdown. When deficient, supplementing with hormones will generally enhance healing. More important is hormonal balancing, making sure that the hormonal milieu is anabolic and not catabolic.

The science connection between hormone levels, chronic pain, and inflammation

Hormones can help reduce the NEED for hip and knee replacement in overweight or obese men

  • Doctors at Monash University in Australia writing in the medical journal Osteoarthritis Cartilage (1) examined the Relationship between circulating sex steroid hormone concentrations and incidence of total knee and hip arthroplasty due to osteoarthritis in men. They found that higher concentrations of androstenedione (testosterone) were associated with a decreased risk of total knee and hip replacement for osteoarthritis in overweight and obese men. They concluded their study by suggesting that circulating sex steroids (testosterone) may play a role in preventing the development of osteoarthritis in men.

Hormones as an anti-inflammatory:

  • In animal study research at the University of Gothenburg published in the journal Arthritis Research & Therapy,(2) doctors looking at the Jekyll/Hyde aspects of estrogen on joint destruction (estrogens are both anabolic – builders – and catabolic – destroyers) found that the positive values of estrogen relieved both synovitis and joint destruction.
  • Research lead by doctors at Australia’s University of Tasmania and Monash University and published in the journal Osteoarthritis and Cartilage (3) found that women with low serum levels of endogenous estradiol, progesterone and testosterone are associated with increased knee swelling-synovitis and possibly other osteoarthritis-related structural changes.

Hormones rebuild cartilage:

  • At Wake Forrest University, (4) doctors found estrogen replacement therapy increases the production of IGFBP-2 (Insulin-like growth factor-binding protein 2 – simply as it names implies a growth factor for repair) and the synthesis of Proteoglycan (a joint lubricant) by chondrocytes (cartilage building cells found in the extracelluar matrix). The study concludes that estrogen can have a direct positive effect on adult articular cartilage.
  • Can estrogen supplementation help TMJ pain by rebuilding cartilage? Researchers at the Columbia University College of Dental Medicine in New York published their findings in the journal Scientific Reports (5) that estrogen may play in helping postmenopausal women who suffer from TMJ. Here is what they wrote:
    • Temporomandibular joint degenerative disease is a chronic form of TMJ disorder that specifically afflicts people over the age of 40 and targets women at a higher rate than men.
    • The prevalence of Temporomandibular joint degenerative disease in this population suggests that estrogen loss plays a role in the disease pathogenesis.
    • In animal research on rats, the research team showed estrogen/estradiol can promote regeneration and inhibit degeneration of the mandibular condylar fibrocartilage of the TMJ.

Estrogen and degenerative disc disease


In a March 2018 study published in the International journal of clinical and experimental pathology, (6) investigators looked at the reports that  estrogen depletion is associated with disc degeneration and specifically to look at the effect and mechanism of estrogen on disc degeneration of the cartilage endplate. In their animal study, the researchers reported  that decreased estrogen level may accelerate degeneration of the cartilage endplate by increasing calcification and that the calcification develops from chronic inflammation. Estrogen may offer protective benefits against this inflammation and developing degenerative disc disease.

Similarly, testosterone has been shown to have a direct effect on cartilage growth. Testosterone, for example, is an anabolic hormone (i.e. synthesized into living tissue). Anabolic hormones, which are responsible for protein synthesis, enhance the production of muscle and cartilage growth. Many people believe that testosterone is only a male hormone, but it actually plays a pivotal role in the female body chemistry as well. If one has a low testosterone level, then they will likely experience more difficulty healing.

Testosterone is made by men in the testicles, and females the ovaries. There is also a small production that is created in the adrenal glands. Although the adrenal gland is able to produce a small amount of testosterone, many patients of both genders suffer from depleted adrenals as a result of stress. This stress can arise from pain, lack of sleep, and a myriad of personal issues. So sometimes treating adrenal fatigue to optimize hormone production is called for.

  • A Swedish study published in the Journal of Bone and Mineral Research (7) recently focused on the effects of testosterone on chondrocytes (regrowing cartilage). The research concluded that testosterone promotes the differentiation of chondrocytes (producing cartilage cells) and increases collagen production.
  • An Australian study published in the Annals of the Rheumatic Diseases (8), examined whether testosterone supplementation could help prevent total knee replacement. They looked at various factors that can affect knee cartilage volume.  They found that, “serum testosterone level at baseline and urinary NTx, a marker of bone turnover were inversely related to cartilage loss.”

The role of estrogen in joint pain. Does estrogen deficiency make “bone one bone”?

A team of researchers at the China’s Institute of Medical Information recently presented two studies on the impact of estrogen deficiency on cartilage breakdown in the first study published in the journal Ultrasound in Medicine and Biology, (9) the researchers discovered: “that post-menopausal estrogen reduction induces morphologic and acoustic alterations (simply the breakdown of cartilage) in the articular cartilage of the hip and knee joints in ovariectomized rats. In the second study, these researchers also found out that the “bone on bone,” situation could be treated before it continued to degenerate into more advanced arthritis because cartilage broke down first, then the bone. This research was published in the journal BioMed Research International. (10)

Above we touched on the aspects of estrogen that may aid in joint relief, it works as an anti-inflammatory, it works in helping to rebuild cartilage. The problem with estrogen is that it does not appear consistent as a joint pain remedy.

The role of estrogen replacement in joint pain

A November 2018 study in the journal Menopause (11) examined the role of estrogen replacement in helping relieve joint pain in post-menopausal women. Estrogen replacement is somewhat controversial when it comes to managing joint pain. Some research suggests that estrogen replacement is beneficial in relieving joint pain symptoms, other research suggests a non-beneficial effect. It is this controversy that the researchers wanted to explore.

These are the learning point findings of this study:

  • A total of 10,739 postmenopausal women who have had a hysterectomy were randomized to receive daily oral conjugated equine estrogens (0.625 mg/d) or a matching placebo.
  • The frequency and severity of joint pain and joint swelling were assessed by questionnaire in all participants at the entry of participation in the study and at one year. A smaller group of patients continued to be monitored at three years and six years.


  • At the start of the study participation, joint pain and joint swelling were closely comparable in the estrogen group and the placebo groups (about 77% with joint pain and 40% with joint swelling).
  • After 1 year, joint pain frequency was significantly lower in the estrogen-alone group compared with the placebo group, as was joint pain severity, and the difference in pain between randomization groups persisted through year 3.
  • However, joint swelling frequency was higher in the estrogen-alone group. Adherence-adjusted analyses strengthen estrogen’s association with reduced joint pain but attenuate estrogen’s association with increased joint swelling.

So what is happening here?

“The current findings suggest that estrogen-alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain.” The research also points out that the estrogen can make joint swelling worse?

In the medical journal Post Reproductive Health,(12) Dr. Fiona Watt of the University of Oxford wrote that:

“Musculoskeletal pain, arthralgia (pain without inflammation)  and arthritis are all more common in women, and their frequency increases with age and in some appears to be associated with the onset of menopause. . . Although the association appears strong, a causal link between estrogen deficiency and musculoskeletal pain or different types of arthritis is lacking; there have been few studies specifically within this group of symptomatic patients, and there is much still to understand about musculoskeletal pain and arthritis at the time of the menopause, and about how we might prevent or treat this.”

In other words, as other research has pointed out, there appears to be a link between estrogen deficiency and joint pain post-menopause, but how much influence does estrogen replacement have in reducing joint pain as more than a “pain killer,” is not known. The problems of joint pain appear to be more than an estrogen deficiency.

The connection between low estrogen levels and degenerative disc disease and osteoporosis

A May 2019 study appearing in the medical journal Spine (13) suggests a connection between estrogen deficiency and back pain. The research comes from some of China’s leading medical hospitals and universities. In an animal study on rats, researchers found that estrogen deficiency exacerbated intervertebral disc degeneration induced by spinal instability, while estrogen supplementation alleviated the progression of disc degeneration related to osteoporosis.

The researchers suggested in cases of spinal instability, estrogen deficiency made it worse. Hormone replacement therapy helped slow down the progression of degenerative disc disease when osteoporosis was involved.

Hormone replacement therapy may reduce the need for a second total joint replacement

In 2015, doctors at Oxford University wrote in the journal Annals of the Rheumatic Diseases (14) that Osteolysis (bone loss and weakening around the joint implant) and subsequent prosthesis loosening is the most common cause for revision following total knee replacement or total hip replacement. Hormone replacement therapy (HRT) could reduce osteolysis. To test this idea the researchers looked at 2700 women who had Hormone Replacement Therapy after their joint replacement and  8100 women who did not. What did they find? HRT use is associated with an almost 40% reduction in revision rates after a total knee replacement or total hip replacement.

There is a connection between painkillers and hormone replacement therapy that makes pain worse

  • Doctors at Virginia Commonwealth University writing in the medical journal Opioid Endocrinopathy (15) suggested that:
    • Opioids appear to affect multiple endocrine pathways leading to abnormal levels of different hormones such as testosterone, cortisol, and prolactin.
    • Opioids appear to affect each of the pituitary hormone pathways in addition to altering bone metabolism.
    • The most commonly reported and substantial effect was hypogonadism (low testosterone) in both sexes; however, suppression of the adrenal axis may be more common than initially thought. (The hypothalamic–pituitary–adrenal axis is the interactions among three endocrine glands: the hypothalamus, the pituitary gland and the adrenal glands).
    • The doctors concluded that more research is needed to determine which opioids are more likely to cause endocrine dysfunction and which patients need to be screened and treated. Also unknown is the length of time to the development of hormonal changes after starting opioid therapy and if ending opioid therapy can normalize hormone levels.
  • Doctors of the Research Program in Men’s Health: Aging and Metabolism, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School,  Boston University School of Public Health,  and the University of Pittsburgh School of Medicine found that men with androgen deficiency (low testosterone) brought on by overuse of painkillers and other pain medications, showed improvements in pain, sexual desire, body composition, and aspects of quality of life when put on a testosterone replacement program.(16)

Is joint pain all about hormones?

For many people, hormone supplementation can help their joint pain. But what is the realistic expectation that hormones can be the treatment you need? Hormones may act in an anti-inflammatory capacity, hormones may act to help the process that rebuilds cartilage. For many people we see, if we suspect hormonal imbalance, we send them to a specialist who can help balance their hormone levels. This puts the patient in a better situation to heal.


1 Hussain SM, Cicuttini FM, Giles GG, Graves SE, Wang Y. Relationship between circulating sex steroid hormone concentrations and incidence of total knee and hip arthroplasty due to osteoarthritis in men. Osteoarthritis and Cartilage. 2016 Aug 31;24(8):1408-12. [Google Scholar]
2 Engdahl C, Börjesson AE, Forsman HF, Andersson A, Stubelius A, Krust A, Chambon P, Islander U, Ohlsson C, Carlsten H, Lagerquist MK. The role of total and cartilage-specific estrogen receptor alpha expression for the ameliorating effect of estrogen treatment on arthritis. Arthritis Res Ther. 2014 Jul 15;16(4):R150. doi: 10.1186/ar4612. [Google Scholar]
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5 Robinson JL, Soria P, Xu M, Vrana M, Luchetti J, Lu HH, Chen J, Wadhwa S. Estrogen Promotes Mandibular Condylar Fibrocartilage Chondrogenesis and Inhibits Degeneration via Estrogen Receptor Alpha in Female Mice. Scientific reports. 2018 Jun 4;8(1):8527. [Google Scholar]
6 Sheng B, Zhou J, Liu X, Yuan Y, Zhang Y, Liu H, Peng S, Liu B, Chang L. Protective effect of estrogen against calcification in the cartilage endplate. International Journal of Clinical and Experimental Pathology. 2018;11(3):1660. [Google Scholar]
7 Lorentzon M, Swanson C, Andersson N, Mellstrom D, Ohlsson C. Free Testosterone is a Positive, Whereas free Estradiol Is a Negative, Predictor of Cortical Bone Size in Young Swedish Men: The GOOD Study. Journal of Bone and Mineral Research 2005; 20(8) : 1334-1339.[Google Scholar]
8 Hanna F, Ebeling PR, Wang Y, O’Sullivan R, Davis S, Wluka AE, Cicuttini FM. Factors influencing longitudinal change in knee cartilage volume measured from magnetic resonance imaging in healthy men. Ann Rheum Dis. 2005 Jul;64(7):1038-42. Epub 2005 Jan 7. [Google Scholar]
9 Wang Q, Liu Z, Wang Y, Pan Q, Feng Q, Huang Q, Chen W. Quantitative ultrasound assessment of cartilage degeneration in ovariectomized rats with low estrogen levels. Ultrasound in medicine & biology. 2016 Jan 1;42(1):290-8. [Google Scholar]
10 Wang Y, Liu Z, Wang Q, Feng Q, Chen W. Early Detection of Tibial Cartilage Degradation and Cancellous Bone Loss in an Ovariectomized Rat Model. BioMed research international. 2017;2017. [Google Scholar]
11 Chlebowski RT, Cirillo DJ, Eaton CB, Stefanick ML, Pettinger M, Carbone LD, Johnson KC, Simon MS, Woods NF, Wactawski-Wende J. Estrogen alone and joint symptoms in the Women’s Health Initiative randomized trial. Menopause. 2018 Nov;25(11):1313-1320.[Google Scholar]
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13 Liu Q, Wang X, Hua Y, Kong G, Wu X, Huang Z, Huang Z, Liu J, Yang Z, Zhu Q. Estrogen Deficiency Exacerbates Intervertebral Disc Degeneration Induced by Spinal Instability in Rats. Spine. 2019 May 1;44(9):E510-9. [Google Scholar]
14 Prieto-Alhambra D, Javaid MK, Judge A, Maskell J, Cooper C, Arden NK. Hormone replacement therapy and mid-term implant survival following knee or hip arthroplasty for osteoarthritis: a population-based cohort study. Annals of the rheumatic diseases. 2015 Mar 1;74(3):557-63. [Google Scholar]
 Demarest S, Gill R, Adler R. Opioid endocrinopathy. Endocrine Practice. 2014 Dec 22;21(2):190-8. [Google Scholar]
16 Basaria S, Travison TG, Alford D, Knapp PE, Teeter K, Cahalan C, Eder R, Lakshman K, Bachman E, Mensing G, Martel MO, Le D, Stroh H, Bhasin S, Wasan AD, Edwards RR. Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial. Pain. 2015 Feb;156(2):280-8.[Google Scholar]



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