What are the risks of testosterone and progesterone (progestin) therapy in females with uterine fibroids?

Risks of Testosterone and Progesterone Therapy in Females with Uterine Fibroids

Progesterone therapy is contraindicated in women with uterine fibroids as it can promote fibroid growth and worsen symptoms, while testosterone therapy lacks evidence for safety in this population and may potentially stimulate fibroid growth through aromatization to estrogen.

Progesterone Therapy Risks

Mechanism and Evidence

• Progesterone and progesterone receptors are now recognized as key drivers of fibroid growth, contrary to earlier beliefs that focused solely on estrogen 1
• Fibroids express elevated levels of both progesterone receptor types (PR-A and PR-B) compared to surrounding myometrium 1
• Biochemical, histological, and clinical evidence confirms that progesterone plays a critical role in fibroid pathogenesis 2

Specific Risks of Progestin Therapy

• Progestins can stimulate fibroid cellular proliferation and growth 1, 2
• Using progestogens to manage fibroids is "like constantly adding fuel to the fire," rendering this treatment ineffective 2
• May worsen rather than improve fibroid-related symptoms including:
  • Heavy menstrual bleeding
  • Bulk symptoms
  • Pelvic pain

Clinical Implications

• The American College of Obstetricians and Gynecologists recognizes that fibroids are fueled by hormonal factors 3
• Progestins are considered first-line medical management for reducing bleeding symptoms but not for treating the fibroids themselves 1
• There is a lack of evidence supporting progestin efficacy for fibroid treatment 2

Testosterone Therapy Risks

Potential Mechanisms

• No direct evidence exists regarding testosterone therapy in women with fibroids
• Testosterone can be aromatized to estrogen in peripheral tissues
• Since fibroids are estrogen-dependent tumors (affecting up to 80% of women by age 50) 3, any therapy that increases estrogen levels may potentially stimulate fibroid growth

Clinical Considerations

• Increased suspicion for malignancy is warranted in postmenopausal women with fibroid growth or persistent bleeding 3
• Testosterone therapy could potentially mask symptoms of fibroid growth by reducing menstrual bleeding while not addressing the underlying pathology

Alternative Hormonal Approaches

Selective Progesterone Receptor Modulators (SPRMs)

• SPRMs compete at the fibroid progesterone receptor binding site in a tissue-specific manner 1
• These agents reduce both bleeding and bulk symptoms with amenorrhea rates of 70-83% 3
• Ulipristal acetate has shown fibroid volume reductions of 30% after a single course and up to 70% after 4 courses 1
• SPRMs can cause unique histological changes to the endometrium (PAEC) that are benign and reversible 1, 4
• Reports of hepatotoxicity with ulipristal acetate have been a barrier to its approval in the United States 1

GnRH Agonists/Antagonists

• For symptomatic fibroids, GnRH agonists or antagonists can reduce fibroid size by 40-50% 3
• Both are effective at significantly reducing tumor volume and are commonly used for short courses to decrease fibroid size in preparation for surgery 1
• Associated with hypoestrogenic effects including headaches, hot flushes, hypertension, and loss of bone mineral density 1

Clinical Recommendations

• Avoid progesterone/progestin therapy in women with uterine fibroids when possible
• Consider SPRMs as a more effective hormonal treatment option for fibroids when available
• For women requiring short-term symptom management before definitive treatment, GnRH agonists/antagonists may be more appropriate than progestins
• Monitor closely for fibroid growth in any woman with fibroids receiving hormone therapy
• Exercise caution with testosterone therapy in women with fibroids due to potential aromatization to estrogen

Common Pitfalls

• Assuming all hormonal therapies reduce fibroid symptoms equally
• Using progestins to treat fibroids based on outdated understanding of fibroid pathophysiology
• Failing to recognize that hormone therapy may mask symptoms while fibroids continue to grow
• Not considering the potential for malignant transformation in rapidly growing fibroids, especially in postmenopausal women