Globally, painful musculoskeletal conditions, such as low back pain and neck pain, are collectively the sixth-ranked cause of years lived with disability.1 Many of these conditions tend to be more common among adult women of more advanced age.
In a review published in Lancet Rheumatology in April 2023, researchers examined the association between changes in sex hormones with musculoskeletal pain and painful osteoarthritis (OA). The researchers furthered examined how sex hormones may mediate the resulting effects of these diseases on the body.1 A comprehensive search of PubMed was conducted to find cohort, interventional, or observational studies related to pain and hormones.1
Menopause and Pain
Several epidemiological studies on the effects of menopause and perimenopause have revealed their association with joint pain and OA.1 A study including more than 40,000 women found that OA was more common among women who had undergone natural or surgical menopause at least 1 year prior, compared with those who had a menstrual period within the past year (31% vs 24%).1 However, musculoskeletal pain is common among women with menopause, making it difficult to determine whether pain is transient or a sign of early OA or chronic pain syndrome triggered by another condition.1
Epidemiological studies report mixed results regarding the effects of menopause hormone therapy, or hormone replacement therapy (HRT), on painful musculoskeletal symptoms.1
One randomized controlled trial (RCT) indicated treatment with combined raloxifene and alfacalcidol was more effective at reducing knee pain symptoms compared with alfacalcidol alone.1 Similarly, another RCT reported testosterone improved pain scores for men with chronic pain syndrome and late onset hypogonadism, while a second indicated testosterone improved hyperalgesia in men with opioid-induced androgen deficiency. Together, results of these trials suggest sex hormone replacement may help address pain in patients with hormone deficiencies and musculoskeletal pain.1
The researchers further identified another study that indicated women were at greater risk of developing OA following surgically induced or spontaneous menopause.1 Among the study population, one-fourth of the 503 women with early-stage breast cancer who initiated aromatase inhibitor therapy discontinued treatment due to musculoskeletal symptoms.1
Similarly, patients who participated in the Women’s Health Initiative that discontinued HRT reported double the prevalence of joint pain or stiffness (26.4% vs 14.4%) and double the rate of general aches and pains (22.0% vs 11.5%), compared with those who discontinued placebo, respectively.1
The review authors stated, “Considering all of the evidence together, it is possible that the relative change in hormone concentrations, and the pace of these changes, are more important than absolute concentrations, and that stabilisation of hormone concentrations (or gradual change where possible) is likely to be critical for protection from musculoskeletal pain1.”
“Notably, there is currently no clear guidance on the tapering of HRT when stopping for non-safety reasons. Following this premise, the oral contraceptive pill or agonists of gonadotrophin-releasing hormone, which abolish hormonal fluctuations, have both been used therapeutically to improve pain in patients with conditions such as inflammatory bowel syndrome, endometriosis, and chronic pelvic pain,1” authors noted.
Sex hormones may influence pain and OA via pain sensing and perception, direct effects on connective tissue, or indirect effects on inflammatory and immune pathways.1 Their impact may depend on hormone concentrations and sex. As estrogen and testosterone loss contribute to muscle atrophy, the impact of these deficiencies may increase musculoskeletal symptoms and structural vulnerability of tissue, thus promoting OA.1
Significance of Research
The review authors advised clinicians to ask female patients about their menstruation and menopausal symptoms. Likewise, andropause and andropause symptoms should be assessed among male patients.1 Exogenous hormone therapies should only be prescribed under existing licenses, as musculoskeletal symptoms could be involved in uncontrolled menopause symptoms.1
According to the review authors, very few RCTs have examined the impact of HRT among women with painful musculoskeletal conditions, leaving a large gap in the data.1 Surprisingly, a literature search of PubMed produced only a single relevant study on the topic, which indicated estrogen may have a protective effect among patients undergoing hip arthroplasty.2
To address this gap, the review authors themselves conducted a feasibility RCT on the use of HRT among women in the postmenopausal period with painful hand OA, to determine whether patients would be willing and qualified to participate in such a trial.1 The study met feasibility criteria and progression to a full trial was deemed both possible and necessary. The review authors believe there is a need to understand whether sex-specific treatments are possible for patients with rheumatic diseases.2
The Aim of the Review
Review author Fiona Watt, PhD, FRCP, a Reader in Rheumatology and Honorary Consultant Rheumatologist at Imperial College, London, shared her thoughts on the significance of the feasibility RCT, noting that for the first time, it’s possible to conduct research that would consider this area of medicine therapeutically.
“It was interesting that even in a low number of post-menopausal women who were selected based on their hand symptoms rather than for ‘HRT indication’ of menopause related symptoms, measures of menopause related symptoms and quality of life improved in the active arm more than placebo in this study,” Dr Watt noted.
She expressed she was surprised that musculoskeletal manifestations are such a common symptom of menopause. Nearly half of women across international populations experience these symptoms during menopause, and it’s the dominant symptom for 1 in 5 women.
“And yet this is barely ever mentioned or discussed,” Dr Watt noted. “Somehow our extensive knowledge of the effects of estrogen and testosterone loss on osteoporosis distract us from the other connective tissues that sense and respond to sex hormones in the same way.”
Dr Watt wonders whether painful musculoskeletal symptoms related to diseases such as OA tend to be worse in the presence of other menopause symptoms. She suspects there’s more menopause-related musculoskeletal pain in rheumatology than she and other physicians may be aware of or are diagnosing.
“Thinking holistically and making the connection when it is there is important, asking female patients about menopause symptoms and male patients about andropause symptoms when they present with musculoskeletal painful conditions in that age range, and vice versa,” she noted.
Caution with Hormone Therapy
Dr Watt advises physicians to be cautious when stopping estrogen-containing HRT suddenly, if it’s not being discontinued for urgent safety reasons. Ample evidence demonstrating the adverse effects of sudden estrogen deficiency on the musculoskeletal system is present in research.
“Estrogen deficiency can obviously be for iatrogenic reasons,” she explained. “Making patients aware of this, for example if they have painful OA and are on HRT would seem to be a reasonable step. It’s not that they can’t stop, but that they should stop slowly and gradually and, in my opinion, there should be better guidance on this. Adverse effects of estrogen loss in this scenario probably aren’t specific to [musculoskeletal] health.”
Disclosures: Dr Watt declared affiliations with Pfizer for an unrelated program in osteoarthritis in 2020-2021.
- Gulati M, Dursun E, Vincent K, et al. The influence of sex hormones on musculoskeletal pain and osteoarthritis. Lancet Rheumatol. 2023;5(4):225-238. doi:10.1016/S2665-9913(23)00060-7
- Williams JAE, Chester-Jones M, Lowe CM, et al. Hormone replacement therapy (conjugated oestrogens plus bazedoxifene) for post-menopausal women with symptomatic hand osteoarthritis: primary report from the HOPE-e randomised, placebo-controlled, feasibility study. Lancet Rheumatol. Published online September 21, 2022. doi:10.1016/S2665-9913(22)00218-1