Hormone replacement therapy and osteoarthritis – degenerative joint disease

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

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.

Outline of this article

• The controversies surrounding hormone levels and osteoarthritis.
• We commonly ask patients to check the following hormone levels to help optimize healing.
  • Hypothyroidism and joint pain
  • The controversy surrounding chronic pain and cortisol levels
• The scientific connection between hormone levels, chronic pain, and inflammation.
  • Estrogen and degenerative disc disease.
  • Testosterone and cartilage growth.
  • The role of estrogen in joint pain. Does estrogen deficiency make “bone on bone”?
  • The role of estrogen replacement in joint pain.
  • The connection between low estrogen levels and degenerative disc disease and osteoporosis.
• Hormone replacement therapy may reduce the need for a second total joint replacement.
• There is a connection between painkillers and hormone replacement therapy that makes the pain worse.
• Hypothalamus – Negative Opioid GnRH. What does this mean? Altered Testosterone.

The controversies surrounding hormone levels and osteoarthritis

We are going to go to a June 2021 study in the journal Frontiers in Endocrinology (1) and we are going to start with the end of the research and work our way back.  Here is how the researchers concluded this paper:

“Sex steroid levels fluctuate over time and measurements are often imprecise and experiment design cannot always be perfect. (Tests and studies are inherently flawed because of many functionating factors). . .the (MRI) method can to some extent mitigate data migration. (Further, you may not be able to trust the MRI readings to accurately portray the severity or cause and effect of the patient’s osteoarthritis).”

Not only are the results controversial, but the methods of achieving those results are controversial as well. Controversial in medicine means, not definitive, or in the case of hormone replacement or supplementation, too high levels of certain hormones can make osteoarthritis worse, not enough of the same hormones can make osteoarthritis worse, varying levels of serum hormone levels in individuals can help alleviate osteoarthritis.

According to these researchers, studies have shown:

• A well-established increase in osteoarthritis during or soon after menopause is well documented.
• Estradiol is a known protective factor against osteoarthritis.
• The use of oral estrogen was found to be associated with a decreased incidence of radiographic hip osteoarthritis in elderly Caucasian women.
• A case-control study of women aged over45 years found that short-term HRT (up to 5 years) was associated with an increased risk of hip osteoarthritis, while long-term treatment had a nonsignificant protective effect.
• In premenopausal Caucasian women with mild knee osteoarthritis, a clinical diagnosis of osteoarthritis was positively correlated with serum estradiol level. These findings indicate that the effects of reproductive hormones vary according to age and concentration.

Here is a brief summation of the good and bad of hormone concentrations on joint pain.

• This study’s results revealed positive causal effects of serum concentrations of Testosterone on the risk of hip osteoarthritis.
• There was a potential positive association between Dihydrotestosterone and hip osteoarthritis as well while little evidence of the association between sex steroids levels and overall osteoarthritis was found.
• In a group of healthy middle-aged men with no symptoms of knee osteoarthritis or risk factors, the serum-free testosterone level was associated with the rate of tibial cartilage loss leading to the development of arthritis 2 years later. (Low-Testosterone).
• In a cross-sectional study, a higher concentration of serum testosterone was associated with higher cartilage volume, possibly due to greater physical activity and stress on the articular cartilage. Thus, chronic stress and damage to weight-bearing joints—especially the hip and knee—can contribute to testosterone. However, the protective effects of E2 and DHEAS on osteoarthritis.

If this is confusing to you, it is typically confusing to doctors as well. This is why understanding hormone levels can be important in joint health.

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, whereas 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. In research like that above and that below the delicate balance of hormones can be easily altered to become catabolic – that is they are breaking down your joints.

Hypothyroidism and joint pain

When someone is diagnosed with hypothyroidism they typically have more symptoms than joint pain. Hypothyroidism can be caused by many problems and is a situation where the thyroid gland is not producing sufficient amounts of thyroid hormones for the body to run on. Weight gain, fatigue, joint pain are among the many symptoms. There is also a controversy in medicine over the role of “subclinical hypothyroidism.”  Subclinical hypothyroidism is suggested in a patient when thyroid-stimulating hormone (TSH) tests come back slightly above the normal range but below the average range needed for a hypothyroid diagnosis.

A 2017 paper (24) from Bukovinian State Medical University in Ukraine studied the function of the thyroid gland in patients with osteoarthrosis, the incidence and forms of hypothyroidism, and their effects on the clinical treatment of osteoarthrosis. A complex examination involved 312 patients with osteoarthrosis aged 37-76 years.

• Clinical hypothyroidism was found in 4.44% and subclinical hypothyroidism in 13.78% of patients.
• Hypothyroidism contributed to the deterioration of the course and outcome of the treatment of osteoarthritis.
• Manifestations of hypothyroidism were observed in patients with osteoarthritis with its significant systemic manifestations, high comorbidity rate, in individuals aged over 50, especially 60 years, mainly in women (83,72%).
• In patients with osteoarthritis aged over 50 years with a high comorbidity rate, it is advisable to conduct an ultrasound examination of the thyroid gland, to measure the levels of TSH, free thyroxine in order to diagnose hypothyroidism early and to treat it timely as one of the ways to improve the overall outcomes of the treatment of osteoarthritis patients.

A February 2022 study in The Journal of Arthroplasty (25) analyzed the potential influence of subclinical hypothyroidism on improvement in patient-reported outcome measures following primary total knee replacement. What the researchers found was “Subclinical hypothyroid patients have a slower functional recovery than (normal thyroid) patients, and trended toward lower improvements in patient-reported scores. Depression was the most important negative factor.”

The controversy surrounding chronic pain and cortisol levels

A May 2020 study in the journal Osteoarthritis Cartilage (26) studied the direct impact of cortisol levels on chronic pain. Cortisol does influence pain and inflammation in the body. How much of that influence impacts osteoarthritis is unknown. The researchers of this study noted several previously published studies that identified an association between cortisol levels and the presence of chronic pain in conditions such as rheumatoid arthritis, low back pain, or whiplash. Research however was lacking in the association of cortisol and pain in people with osteoarthritis. This study tried to make that association. After examining the previously published material, the researchers found diagnosis difficulties between cortisol and pain, dependent on how and when cortisol is measured. Evidence from three studies may suggest increased cortisol levels in patients with pain but the conclusions have a high risk of bias.

This, however, is usually not the impact of cortisol that doctors look for. It is the impact of stress on healing. The stress hormone in your body that controls when you wake up and when you go to sleep is called cortisol. Blood cortisol levels are supposed to be high in the morning and low in the evening. The high levels in the morning help you wake up and the low levels in the evening help you feel tired in preparation for sleep. With chronic pain, high cortisol levels put the body in alert mode, and insomnia results. The increased cortisol production eventually wears the body down, resulting in increased fatigue. This explains why many chronic pain patients have difficulty sleeping and complain of non-restful sleep.

A highly cited study in the journal Physical Therapy (27) notes: “Although stressful events may be an inevitable part of life, a prolonged or exaggerated response to pain or non–pain-related stressors may intensify sympathetic and neuroendocrine activity, exhaust cortisol, and perpetuate widespread pain and inflammation. Elevated cortisol levels following acute stress may facilitate the consolidation of fear-based emotional memories and condition a sensitized physiologic stress response.”

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

Chronic inflammation is clearly an indication of a joint in distress. The inflammation is trying, in most cases is vainly to fix something.

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 led 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 extracellular 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.
  • An October 2021 study (6) made a connection between estrogen deficiency and bite force in TMJ osteoarthritis.

Estrogen and degenerative disc disease

In a March 2018 study published in the International Journal of Clinical and Experimental Pathology, (7) investigators looked at the reports that estrogen depletion is associated with disc degeneration and specifically looked at the effect and mechanism of estrogen on disc degeneration of the cartilage endplate. In their animal study, the researchers reported that decreased estrogen levels may accelerate degeneration of the cartilage endplate by increasing calcification and that calcification develops from chronic inflammation. Estrogen may offer protective benefits against this inflammation and developing degenerative disc disease.

Due to the decrease of estrogen and estrogen receptor (ER) in postmenopausal women, they have a higher risk of intervertebral disc degeneration than men. Estrogen receptors have many functions. Among them in simplest terms, estrogen through these receptors binds itself to certain proteins to initiate tissue growth or repair. In a February 2021 study published in the European Review for Medical and Pharmacological Sciences (8), researchers found that the two estrogen receptors ERα and ERb interact with the protein CCN5 (Cellular Communication Network Factor 5) to initiate protection of the spinal discs and their innards.

In men

A May 2020 study in the journal Bone and Joint Research (9) found that men with low levels of estradiol were more likely to have a low bone mineral density of the lumbar spine. According to the researchers: “In this nationally representative study of the USA, men with lower total estradiol were more likely to have osteopenia, which was particularly evident among younger men, men with less-than-daily dairy consumption, and current or former smokers.”

Testosterone and cartilage growth

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 in 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 (10) recently focused on the effects of testosterone on chondrocytes (re-growing 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 (11), 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.”

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

• Doctors at Monash University in Australia wrote in the medical journal Osteoarthritis Cartilage (12) 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.

We will talk more about testosterone below.

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

A team of researchers 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, (13) 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. (14)

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 inconsistent data about menopausal hormone replacement therapy was alluded to in a December 2018 study in the journal Menopause. (15) Here the researchers wrote: “The incidence of osteoarthritis increases after menopause, and may be related to hormonal changes in women. Estrogen deficiency is known to affect the development of osteoarthritis, and menopausal hormone therapy is suggested to be related to the development of osteoarthritis. However, the relationship between knee osteoarthritis and menopausal hormone therapy remains controversial.” In this study, the medical histories of 4,766 postmenopausal women were collected from women who had been taking hormone replacement therapy for more than one year. What the researchers found among this group was was evidence that “the prevalence of knee osteoarthritis was lower in participants with menopausal hormone therapy than in those without menopausal hormone therapy.” Those getting hormone therapy had less knee osteoarthritis.

The role of estrogen replacement in joint pain

A November 2018 study in the journal Menopause (16) examined the role of estrogen replacement in helping relieve joint pain in post-menopausal women. Again we discuss the controversy in the benefits of estrogen replacement when it comes to managing joint pain. As already discussed, some research suggests that estrogen replacement is beneficial in relieving joint pain symptoms, other research suggests a non-beneficial effect.

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.

FINDINGS:

• 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, the 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 estrogen can make joint swelling worse?

In the medical journal Post Reproductive Health,(17) 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 (18) 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 (19) 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 the pain worse

Doctors at the San Francisco VA Health Care System and the University of California, San Francisco examined middle-aged women veterans for possible painkillers/opioid over-prescription and the problems that these prescriptions may cause. One concern was the seemly lack of understanding of the role of hormone replacement and opioid combinations.

In their study published in the Journal of General Internal Medicine (20) (October 2019), these doctors wrote:

“Among midlife women Veterans with chronic pain, those with evidence of menopausal symptoms had increased odds of long-term opioids, high-dose long-term opioids, and long-term opioids co-prescribed with Central Nervous System depressants, independent of known demographic and clinical risk factors.” In other words, opioids are prescribed without clearly knowing the impact of these post-menopausal service veterans.

Comment: In middle-aged women, there can be types of prescriptions at play including those to help alleviate hormonal problems. It is not clear whether the combination of hormones and painkillers is causing more problems than they are helping.

• Doctors at Virginia Commonwealth University writing in the medical journal Opioid Endocrinopathy (21) 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. (22)

What are we seeing in this image?

Opioid endocrinopathy products have many negative effects on the endocrine system along with just having chronic pain causes anabolic hormones to decline such as growth hormone DHEA and testosterone which have negative effects on bone and soft-tissue ligament density sometimes patients need natural hormone replacement in addition to other treatments to reduce the chronic pain. Below the image is a further summary.

Hypothalamus – Negative Opioid GnRH. What does this mean? Altered Testosterone.

A paper published in the British Journal of Pain (23) explains this negative opioid effect this way: ” The effects of opioids on the endocrine system are becoming increasingly apparent, although more research is required to further elucidate (understand) the mechanisms by which these happen. It affects both sexes, but the clinical signs are more obvious in males. Direct action of opioids on the hypothalamus (the region of the brain which does among other things, regulate hormone levels) reduces the release of GnRH (Gonadotropin-releasing hormone), and thereby adversely affects luteinizing hormone levels, and subsequently testosterone synthesis and secretion. Symptoms include infertility, decreased sexual function, loss of muscle mass and anxiety and/or depression”

The breakdown of the chemical chain can be explained further, but it is very likely that the above-described symptoms of this opioid effect of infertility, decreased sexual function, loss of muscle mass, and anxiety and/or depression is enough to help you understand the impact of this effect.

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.

Questions about our treatments?

If you have questions about your knee pain and how we may be able to help you, please contact us and get help and information from our Caring Medical staff.

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References

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This article was updated March 12, 2022

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