What is the relationship between free and total testosterone levels when adjusting testosterone dosing in women?

Relationship Between Free and Total Testosterone in Women and Its Impact on Dosing

When adjusting testosterone dosing in women, clinicians should target total testosterone levels in the mid-normal range for premenopausal women while monitoring free testosterone to avoid excessive levels that may limit therapeutic benefits.

Understanding Testosterone Measurements in Women

Total vs. Free Testosterone

• Total testosterone: Represents all testosterone in circulation, including:
  • Testosterone bound to sex hormone-binding globulin (SHBG) (60-70%)
  • Testosterone bound to albumin (30-40%)
  • Free (unbound) testosterone (1-2%)
• Free testosterone: Only the unbound portion that is biologically active and available to tissues

Reference Ranges for Women

• Normal ranges for a 30-year-old woman 1:
  • Total testosterone: 15-46 ng/dL (520-1595 pmol/L)
  • Free testosterone: 1.2-6.4 pg/mL (4.16-22.2 pmol/L)
  • Bioavailable testosterone: 1.12-7.62 ng/dL (38.8-264.21 pmol/L)
  • SHBG: 18-86 nmol/L

Measurement Considerations

• Morning samples are preferred due to diurnal variation 2
• Accurate measurement requires:
  • Liquid chromatography-tandem mass spectrometry for total testosterone
  • Equilibrium dialysis for free testosterone (gold standard) 3
  • Multiple fasting morning samples for reliable assessment

Dose-Response Relationship in Women

Key Difference from Men

Unlike men, women demonstrate a bell-shaped dose-response curve for testosterone therapy 4:

• Low doses: Insufficient therapeutic effect
• Mid-range doses: Optimal therapeutic benefits
• High doses: Diminishing returns or negative effects on sexual function

Clinical Implications

This unique dose-response relationship means:

1. Exceeding the optimal testosterone threshold may:

   • Fail to provide additional sexual benefits
   • Potentially decrease sexual interaction
   • Increase risk of adverse effects (aggression, virilization) 4

2. Monitoring both total AND free testosterone is essential because:

   • SHBG levels vary between women
   • Changes in SHBG affect the free testosterone fraction
   • Free testosterone better reflects bioactive hormone status 2

Practical Dosing Approach

Initial Assessment

Before initiating therapy:

• Establish baseline total and free testosterone levels
• Calculate free testosterone index (total testosterone/SHBG ratio) if free testosterone measurement unavailable 2
• Assess for symptoms of testosterone deficiency

Dosing Strategy

1. Start with low doses of testosterone formulated specifically for women
2. Target total testosterone levels in the mid-normal range for premenopausal women 5
3. Monitor free testosterone to ensure it remains within physiologic range
4. Adjust dosing based on both:
   • Clinical response (symptom improvement)
   • Laboratory values (total and free testosterone levels)

Administration Methods

• Transdermal preparations are preferred for women 5
• When using male formulations (off-label), use cautiously with appropriate female dosing 5
• Subcutaneous administration can provide stable testosterone levels between injections 6
• Avoid compounded products due to lack of safety and efficacy data 5

Monitoring Protocol

Laboratory Monitoring

• Measure total testosterone levels to maintain in physiologic premenopausal range 5
• Monitor free testosterone to ensure appropriate bioavailable levels
• Assess SHBG if changes in clinical response occur despite stable total testosterone

Clinical Monitoring

• Evaluate for signs of androgen excess:
  • Acne
  • Hirsutism
  • Voice changes
  • Clitoromegaly
• Assess therapeutic response:
  • Sexual desire and function
  • Overall well-being

Common Pitfalls to Avoid

1. Relying solely on total testosterone for dosing decisions

   • Free testosterone better reflects bioactive hormone status
   • SHBG variations significantly impact free testosterone levels

2. Excessive dosing

   • Unlike men, higher doses in women may not provide additional benefits
   • May actually decrease sexual function and increase side effects

3. Inadequate monitoring

   • Both laboratory values and clinical symptoms must be monitored
   • Regular assessment for androgen excess is essential

4. Using male reference ranges

   • Women require much lower testosterone doses than men
   • Female-specific reference ranges must be used for interpretation

By understanding the unique relationship between free and total testosterone in women and recognizing the bell-shaped dose-response curve, clinicians can optimize testosterone therapy to achieve maximum benefits while minimizing adverse effects.