What is Livial (tibolone), a synthetic hormone replacement therapy medication, used for in peri- and post-menopausal women?

What is Livial (Tibolone)?

Livial (tibolone) is a synthetic hormone replacement therapy medication with weak estrogenic, progestogenic, and androgenic actions, used primarily to treat menopausal vasomotor symptoms (hot flashes and night sweats), vaginal dryness, and sexual dysfunction in postmenopausal women. 1

Mechanism of Action and Unique Properties

Tibolone is metabolized into three major active compounds that produce tissue-selective effects: 2

• 3α-hydroxytibolone and 3β-hydroxytibolone (estrogenic metabolites)
• Δ4-isomer (progestogenic and androgenic metabolite)

In breast tissue specifically, tibolone inhibits the enzyme sulfatase, which regulates estrogen formation and thereby decreases local estrogen stimulation. 1 This mechanism distinguishes it from conventional hormone therapy, as tibolone inhibits proliferation of human breast cells and stimulates apoptosis in breast cancer cell lines. 1

Standard Dosing

The standard therapeutic dose is 2.5 mg daily, administered continuously without interruptions. 3 A lower dose of 1.25 mg daily may offer similar efficacy with potentially better tolerability, though 2.5 mg is the dose most extensively studied in clinical trials. 3

Clinical Efficacy

Tibolone effectively manages multiple menopausal symptoms: 1, 3

• Reduces hot flashes and sweating episodes by approximately 75% compared to placebo (though only the 2.5 mg dose showed statistical significance) 4
• Improves vaginal dryness through local estrogenic effects 1, 5
• May enhance sexual function more effectively than standard hormone therapy, likely due to androgenic effects that increase free testosterone levels 1, 2
• Positive effects on mood and libido, with particular benefit for women experiencing persistent fatigue and blunted motivation 2
• Prevents bone loss and reduces fracture risk 5

Advantages Over Conventional Hormone Therapy

Tibolone causes significantly less vaginal bleeding compared to combined estrogen-progestin therapy (15 RCTs, n=6342; OR 0.32,95% CI 0.24 to 0.42). 4 The incidence of breast tenderness is low, and mammographic density does not increase with tibolone, in contrast to combined hormone therapy. 1

Critical Safety Concerns and Contraindications

Absolute Contraindications

Breast cancer history is a major contraindication for tibolone use. 3 The LIBERATE trial, a large prospective randomized placebo-controlled study of tibolone in breast cancer survivors, was halted early due to safety concerns showing a 1.5-fold increased risk of tumor recurrence (OR 1.50; 95% CI 1.21 to 1.85). 1, 4

Additional absolute contraindications include: 3

• Known or suspected estrogen-dependent malignant tumors
• Undiagnosed vaginal bleeding
• Untreated endometrial hyperplasia
• Previous or current venous thromboembolic disorders
• Known thrombophilic disorders
• Active or recent arterial thromboembolic disease
• Acute liver disease or history of liver disease with abnormal liver function tests
• Porphyria

Stroke Risk in Older Women

In osteoporotic women with a mean age over 60 years, tibolone was associated with more than double the risk of stroke (OR 2.18,95% CI 1.12 to 4.21) after 2.8 years of use. 4 This finding is particularly concerning and limits the use of tibolone in women beyond 10 years of menopause.

Paradoxical Breast Cancer Data

Interestingly, in a separate trial of osteoporotic women with negative mammograms (n=4506), tibolone was associated with a reduction in breast cancer compared to placebo (OR 0.32,95% CI 0.13 to 0.79), though this trial was not specifically designed to assess breast cancer outcomes and event numbers were low. 4 This paradoxical finding contrasts sharply with the increased recurrence risk in women with prior breast cancer.

Comparative Effectiveness

When compared to equipotent doses of combined hormone therapy, tibolone is less effective in relieving vasomotor symptoms (two RCTs, n=545; OR 4.16,95% CI 1.50 to 11.58), but produces significantly less vaginal bleeding. 4 The discontinuation rate for tibolone is approximately 25%, which is lower than conventional hormone replacement preparations. 5

Common Side Effects

The most frequently reported side effects include: 3, 6

• Weight gain (major reason for discontinuation in 11.28% of users) 6
• Bloating and edema 6
• Acne and hirsutism (due to androgenic effects) 3
• Mood changes 3
• Vaginal bleeding (12.69% of users, though often related to recent prior estrogen therapy) 6

The overall drop-out rate due to side effects is only 2.66%, indicating generally good tolerability. 6

Availability and Regulatory Status

Tibolone is available in Europe and Australia but is not approved in the United States. 1

Clinical Bottom Line

Tibolone represents a viable alternative to conventional hormone therapy for postmenopausal symptom management in carefully selected women under age 60 or within 10 years of menopause, particularly those experiencing sexual dysfunction or who wish to avoid vaginal bleeding. 3, 4 However, it should be avoided entirely in women with a history of breast cancer, and used with extreme caution (if at all) in women over 60 due to stroke risk. 1, 4 The tissue-selective effects make it pharmacologically distinct from standard estrogen-progestin therapy, but the long-term safety profile remains concerning enough that most guidelines recommend conventional hormone therapy as first-line treatment when appropriate. 4