What concerns and evaluation should be considered for severe myalgia and muscle weakness in a transgender woman receiving testosterone and progesterone?

Severe Myalgia and Muscle Weakness in Transgender Women on Hormone Therapy

In a transgender woman presenting with severe myalgia and muscle weakness, immediately discontinue hormone therapy and evaluate for rhabdomyolysis by measuring creatine kinase (CK), serum creatinine, and urinalysis for myoglobinuria, while also screening for statin use, hypothyroidism, vitamin D deficiency, and other secondary causes of myopathy. 1

Immediate Diagnostic Evaluation

Critical Laboratory Assessment

• Measure serum creatine kinase (CK) urgently to differentiate benign myalgia from serious myopathy 2
• CK >10× upper limit of normal with renal impairment defines rhabdomyolysis and requires immediate hospitalization with aggressive IV hydration 2
• Obtain comprehensive metabolic panel to assess renal function (creatinine, BUN) and electrolytes 1, 2
• Perform urinalysis for myoglobinuria (dark or cola-colored urine indicates possible rhabdomyolysis) 1, 2

Secondary Causes to Evaluate

• Screen for concurrent statin therapy, as statin-induced myopathy is the most common medication-related cause of myalgia and may be potentiated by hormone therapy 1, 2
• Check thyroid function (TSH, free T4) to exclude hypothyroidism 1
• Measure 25-hydroxyvitamin D levels to identify vitamin D deficiency 1
• Assess for rheumatologic disorders such as polymyalgia rheumatica 1
• Evaluate hepatic and renal function as dysfunction increases risk for muscle symptoms 1

Hormone Therapy-Specific Considerations

Estrogen and Antiandrogen Effects in Transgender Women

While transgender women typically experience decreased muscle mass (3-5% reduction in lean body mass) and decreased muscle cross-sectional area (4% reduction in quadriceps CSA) after 12 months of gender-affirming hormone therapy, they generally maintain strength levels rather than developing weakness 1, 3, 4. The development of severe weakness is therefore atypical and warrants investigation for alternative causes 1.

Progesterone Concerns

• Progesterone use in transgender women lacks strong evidence for benefit and may increase risks of thromboembolism, stroke, and breast cancer 1
• Some patients discontinue progesterone due to poor mood effects, which could contribute to subjective muscle complaints 1
• Current guidelines do not strongly support routine progesterone use in transgender women 5

Testosterone Misadministration Risk

Verify that the patient is not inadvertently receiving testosterone rather than estrogen therapy, as this would be inappropriate for a transgender woman. If testosterone is being administered:

• Localized rhabdomyolysis has been reported with intramuscular testosterone injections, particularly in the deltoid muscle 6
• This represents a critical medication error requiring immediate correction 6

Management Algorithm

If CK is Normal (<1× ULN) and No Objective Weakness

• Continue hormone therapy with close monitoring 2
• Reassess for alternative causes: dehydration from spironolactone-induced diuresis, electrolyte disturbances, viral illness, or increased physical activity 2
• Review all concomitant medications and adjust statin dosing if applicable 1, 2
• Schedule weekly symptom assessments during the first month 2

If CK is Mildly Elevated (1-10× ULN) with Mild-Moderate Symptoms

• Discontinue hormone therapy temporarily until symptoms resolve 1
• Evaluate for secondary causes as outlined above 1
• If symptoms resolve and no contraindication exists, rechallenge with the same or lower dose of hormone therapy to establish causality 1
• If causal relationship confirmed, switch to alternative formulation (e.g., transdermal estradiol if using oral) 5

If CK is Severely Elevated (>10× ULN) or Objective Weakness Present

• Stop all hormone therapy immediately 1, 2
• Initiate aggressive IV hydration to prevent acute kidney injury 2
• Monitor renal function closely with serial creatinine measurements 1, 2
• Consider muscle biopsy if CK remains elevated or weakness persists despite drug cessation 2
• Do not rechallenge with hormone therapy until rhabdomyolysis fully resolves and alternative cause identified 2

Common Pitfalls to Avoid

Misattribution of Normal Hormone Effects

• Expected muscle changes in transgender women include decreased muscle volume and cross-sectional area, but NOT weakness 1, 3, 4
• Strength is generally well-preserved even after 36 months of hormone therapy 3
• Hemoglobin decreases to cisgender female levels after 4 months of therapy, which is expected and not pathologic 7, 3

Overlooking Drug Interactions

• Spironolactone (commonly used antiandrogen) can cause electrolyte disturbances (hypokalemia, hypomagnesemia) that may provoke muscle symptoms 2
• Concurrent statin use dramatically increases myopathy risk and requires dose adjustment or discontinuation 1, 2

Delayed Recognition of Rhabdomyolysis

• Progressive weakness, dark urine, and severe pain limiting daily activities are red flags requiring immediate evaluation 2
• Fever accompanying muscle symptoms suggests infectious or inflammatory myositis 2

Alternative Hormone Formulations if Rechallenge Needed

• Transdermal 17β-estradiol (50-100 μg/24 hours) is preferred over oral formulations due to lower thrombotic risk and avoidance of first-pass hepatic metabolism 5
• Maintain spironolactone 100-300 mg daily as antiandrogen unless contraindicated 5
• Target testosterone <50 ng/dL and estradiol 100-200 pg/mL with monitoring every 3-6 months 5