Should Add-Back Therapy Be Started with the First GnRH Agonist Injection?
No, add-back therapy does not need to be started simultaneously with the first leuprolide injection, but delaying initiation beyond the first few weeks increases vasomotor symptoms and bone loss without providing additional therapeutic benefit. 1
Optimal Timing for Add-Back Therapy Initiation
ACOG Guideline Recommendations
When relief of pain from GnRH agonist treatment supports continued therapy, add-back therapy should be added to reduce or eliminate GnRH-induced bone mineral loss without reducing efficacy of pain relief. 1 The guideline does not mandate concurrent initiation with the first injection, acknowledging practical barriers including:
- Expense and insurance coverage issues 1
- Difficulty coordinating administration timing (preferred timing is 10-14 days prior to cyclophosphamide in the fertility preservation context) 1
- Urgent need for therapy may preclude coordinated first-dose administration 1
Evidence Supporting Early vs. Delayed Initiation
Recent evidence demonstrates that deferring add-back therapy initiation increases both vasomotor symptoms and bone mineral density loss. 2 A prospective randomized trial showed that patients receiving leuprolide acetate alone experienced marked vasomotor and vaginal symptoms, while those receiving concurrent norethindrone from the start had these symptoms minimized. 3
Bone loss occurs rapidly—approximately 1% per month after onset of hypoestrogenism—making early add-back initiation critical for skeletal protection. 4
Clinical Algorithm for Add-Back Therapy Timing
First Injection Scenario
- If logistically feasible: Start add-back therapy (norethindrone acetate 5 mg daily) concurrently with or within 2 weeks of the first leuprolide injection 5, 3
- If barriers exist: Initiate leuprolide alone, but add norethindrone within the first month to minimize cumulative bone loss and vasomotor symptoms 2
Subsequent Management
- After initial symptom resolution (typically 2-3 months for endometriosis), continue both leuprolide and add-back therapy together 5
- For severe premenstrual syndrome, add-back can be initiated after 1 month of GnRH agonist monotherapy 5
Add-Back Regimen Specifications
The evidence-based add-back regimen consists of norethindrone acetate, starting at 5 mg daily and potentially increasing to 10 mg daily. 3 Alternative regimens include:
- 1 mg oral micronized estradiol daily plus 0.35 mg norethindrone daily for 2 days alternating with 2 days without norethindrone 5
- Low-dose estrogen with progestin combinations 4
Norethindrone-based add-back therapy specifically improves adherence and persistence with leuprolide treatment compared to no add-back (mean persistence 5.83 vs. 4.25 months, P<0.0001). 6
Key Clinical Pitfalls to Avoid
Delaying Add-Back Too Long
Do not wait for hypoestrogenic symptoms to develop before initiating add-back therapy. 2 By the time vasomotor symptoms are clinically apparent, measurable bone loss has already occurred. 3
Assuming Add-Back Reduces Efficacy
Add-back therapy does not interfere with the therapeutic efficacy of GnRH agonists in treating endometriosis pain or reducing endometriotic implants. 3 Combination therapy achieves equivalent suppression of gonadotropins and estrogen levels while preventing side effects. 3
Overlooking Adolescent Populations
Adolescents with endometriosis requiring GnRH agonist therapy should receive add-back therapy with careful monitoring of bone mineral density. 2 This population is particularly vulnerable to bone loss during critical bone accrual years.
Monitoring Requirements
- Bone mineral density assessment by dual-energy x-ray absorptiometry at 6- to 12-month intervals during long-term therapy 5
- Lipid profile monitoring, as norethindrone add-back causes reversible decreases in HDL-cholesterol and increases in LDL:HDL ratio 3
- Amenorrhea should be maintained after the first 3 months of combined therapy 5
Duration of Combined Therapy
Long-term GnRH agonist therapy (mean 31-38 months) with add-back is safe and effective, maintaining stable bone mineral density throughout treatment. 5 Patients using norethindrone add-back had lower rates of endometriosis-related surgery at 12 months compared to those without add-back (12.6% vs. 16.9%, P=0.021). 6