Sexual health
Vol. 14 No 4 | Summer 2012
Tibolone and libido: not a trivial pursuit
Dr Sylvia Rosevear

This article is 12 years old and may no longer reflect current clinical practice.

In view of tibolone’s effect on preserving or enhancing libido, it is an effective alternative for those seeking hormone replacement therapy for dysfunctional menopausal symptoms.

The use of tibolone needs to be seen in the context of the use of hormone replacement therapy (HRT) for ameliorating menopausal symptoms with consideration of their side effects and long-term consequences. Loss of libido at a time of already debilitating symptoms and changed lifestyle may be clinically very important. The use of tibolone for compensation may not be a trivial consideration.

The publication of the Women’s Health Initiative (WHI) study in 20021 resulted in prescriptions for HRT being in the doldrums for the last decade, with declarations of unacceptable risks of HRT in terms of increased hazards of serious sequelae such as stroke, breast cancer, venous thromboembolism and cardiovascular complications associated with its use. The reporting of an increased relative risk in adverse effects, while real, had the effect of alarming women as to an exaggerated risk compared to the real numbers of an increased risk of breast cancer. As a consequence, practitioners tend to focus on treating predominantly vasomotor symptoms (for the shortest duration in the transition period of the menopause) and overlook HRT’s wider prophylactic role. Vasomotor symptoms may have a cascading effect on many organ systems and they can be quantified in terms of severity (Greene score). They may be associated with considerable cognitive deficits (Maki, AMS conference 2012).

HRT may have the effect of improvement in cognitive information processing recognising that the best may be a transdermal oestrogen, for example, oestradiol. Micronised progesterone (Utrogestan®) appears to have the safest profile of the current progestogens. Alternatively, transdermal oestradiol plus the progesterone component in the form of a Mirena intrauterine system (IUS) may be ideal. These modalities of delivery are most likely to mitigate against the increase the major morbidities associated with prolonged use of HRT – thromboembolism, stroke, breast cancer and cardiovascular events.

Table 1. Contraindications for prescribing Tibolone.

Undiagnosed genital bleeding
Women over 60
Women with risk factors for stroke – eg hypertension, smoking, diabetes and atrial fibrillation.
Pregnancy and lactation
Known past or suspected breast cancer
Known or suspected oestrogen-dependent malignant tumour
Endometrial hyperplasia
Previous or current venous thromboembolism (DVT, pulmonary embolism)
Known thrombophilic disorders (eg protein C, protein S or antithrombin deficiency)
History of arterial thromboembolic disease (eg angina, myocardial infarction, stroke or TIA)
Acute liver disease or with abnormal liver function tests


Despite the well-publicised adverse long-term effects of HRT, there is evidence in a meta-analysis of randomised controlled trials that there is a decrease in both cardiovascular events and mortality in those commencing HRT under the age of 60.2 This has led to the concept of a ‘window of opportunity’ for the efficacy of HRT close to the onset of menopause. Two trials, the Early versus Late Intervention Trial with Estradiol (ELITE) and Kronos Early Estrogen Prevention Study (KEEPS), will seek to address this issue.3

Tibolone is one alternative in the armamentarium of HRT although cost may be a consideration at $45–55 per month, as it is unsubsidised both in Australia and New Zealand. It is derived from naturally occurring steroids.4 It is given in a daily oral dose of 2.5mg for the relief of hot flushes, sweats and other troublesome symptoms resulting from a surgical or natural menopause (which may be also premature) in the postmenopausal woman. After being taken orally, it is rapidly metabolised into the three compounds that characterise its therapeutic effects. The 3α hydroxyl and 3β hydroxyl metabolites have predominantly oestrogenic activity and the third, a Δ4–isomer of tibolone and the parent compound, has predominantly progestogenic and androgenic activities. The mechanism of action of oestrogens, and hence tibolone, on hot flushes is unknown, but they may act by modulating central noradrenergic activity, which plays a role in thermoregulation, narrowing the thermoneutral zone.5,6

In vitro studies demonstrate reduction in the levels of active oestrogens in breast cancer cells. It has atrophic effects or weakly proliferative effects on the endometrium. Tibolone has a unique benefit in that it does not cause an increase in breast density as conventional oestrogen containing HRT.7 Conventional HRT is problematic because of the increased breast density which results in false positive recalls with breast screening and difficulty in discerning true pathology because of the increase in breast density.

It is less common to have bleeding with tibolone.8 It is very important to make sure the woman does not have undiagnosed vaginal bleeding on commencement of tibolone and that there are no other contraindications to its use (see Table 1).

Tibolone has a trophic effect on mood and libido, which may be its unique feature compared to other HRTs, possibly a consideration for its preferred use in the treatment of menopausal symptoms. It preserves bone mineral density, as measured with DEXA, with a reduction in bone resorption. The androgenic effects decrease high-density lipoprotein cholesterol, triglycerides and lipoprotein and may increase blood fibronolytic activity. It improves vaginal dryness and vaginal atrophy.

The individual demands of the patient are often at odds with the clinical trial data and assessment of risk is both subjective and does not take account of the impact of menopausal symptoms on an individual’s day-to-day life satisfaction. Sexual functioning and performance involves a multiplicity of organ systems that include anatomical, physiological, endocrine, psychological and social features of performance and response. Implicit in low libido are symptoms consistent with female androgen insufficiency (low libido, decreased energy and wellbeing) or hypoactive sexual desire disorder.

Tibolone as HRT in the postmenopausal woman has possible therapeutic advantages to preserve libido. This may be a consideration where the monotony and the mundane combine to produce the mediocre and finally the melancholic in relation to libido or lack of it. Tibolone with HRT and daily oral DHEA provided significant improvement in sexual function postmenopausally in a randomised controlled trial.9 However, the evidence suggests that tibolone, with respect to maintaining libido, should not be considered a panacea or placebo to reverse the reality or the concept of low libido being part of the pension plan. Neither is it the female equivalent of silendafil, which may be effective just to treat arousal.10 Silendafil for women does not increase desire. It may increase orgasm because of the physiological function to increase blood supply to the clitoris. It only works with normal testosterone levels.

Tibolone improves sexual function in postmenopausal women, but this does not imply it has an effect on female sexual dysfunction.11 Tibolone was compared with continuous combined transdermal oestradiol (E2/norethisterone acetate (NETA) (50 microg/140 microg) in naturally postmenopausal women with sexual dysfunction. Improved sexual function was assessed by the Female Sexual Function Index (FSFI). A 25 per cent satisfying sexual event rate was found with a reduction in sexuality-related personal distress in the tibolone group. The FSFI, is a detailed 19-item questionnaire, which includes sexual desire, arousal, lubrication, orgasm, satisfaction and pain.

The Cochrane review12 cautions against the long-term safety of tibolone compared to combined HRT and there is uncertainty over its risk profile. The LIBERATE study13 confirmed that tibolone can significantly increase breast cancer in high-risk women who had been surgically treated within a five-year period for breast cancer (for whom usual oestrogen and combined HRT therapies are contraindicated). This study was adequately powered to detect the risk of breast cancer recurrence. The risk was an average of 15 extra recurrences every 1000 women each year. Over 70.1 per cent of recurrence events were distant metastases ultimately leading to death. On the basis of these findings the trial was stopped at 3.1 years. Unpublished data, according to the Cochrane review from the Million Women Study (Beral 2007), suggested a higher risk of fatal stroke with tibolone versus other hormonal therapies (RR 1.58, 95 per cent CI 1.06 to 2.37). The risk of stroke compared to placebo was assessed in the LIFT study14 which was stopped after 33 months because unexpectedly there was 2.3 more events every 1000 women per year. The study participants were between 60 and 85. Its effects were to decrease the risk of fracture and breast cancer but an increased risk of stroke. Thus tibolone should not generally be used in elderly women.

While tibolone may be the preferred HRT for decreased desire in the postmenopausal period, AndroFeme® (cream containing one per cent w/v (10mg/ml) Testosterone B.P. (17β Hydroxyandrost-4-en-3-one) is the treatment of choice for low libido as an isolated symptom in the menopause. It should only be used where testosterone levels are measured and low levels identified.15 Measurement of testosterone includes total T, free T, or sex hormone binding globulin (SHBG) and FAI. Androgen values should be in the lowest quartile of normal ranges for reproductive age women (free T<5.0 pmol/L or FAI).2 There is no safety data on long-term use of AndroFeme®. It is administered as 0.5ml of cream (5mg of testosterone) as a starting dose applied once daily to the inner aspect of the upper arm or outer thigh. The dose is absorbed within 30–60 seconds. The dose is varied according to the severity of the symptoms and the clinical response. A follow-up blood test should be done within three weeks of initiating treatment. Levels should be maintained at the upper limit of normal therapeutic range for females.

When considering therapeutics in the postmenopausal woman, the question of low libido is a challenging one based on available evidence. Tibolone is an option for treating low libido in postmenopausal women, requiring HRT for symptomatic control. It has a low side-effect profile but published longer term health risks need to be evaluated for the individual and it should be avoided in those over 60 years of age.


  1. Writing group of the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trail. JAMA 2002; 288:321-33.
  2. Langer, RD, Manson, JE, Allison MA. Have we come full circle – or moved forward? The Women’s Health Initiative 10 years on. Climacteric 2012; 14: (3): 206-13.
  3. Purbrick B, Stranks K, Sum C, MacLennan AH. Future long-term trials of postmenopausal hormone replacement therapy – that is possible and what is the optimal protocol and regimen? Climacteric 2012; 15:288-293.
  4. LivialR Product Information. PI re.: A120612 v2.
  5. Freedman RR. Physiology of Hot Flashes. Am Journal Hum Biol 2001;13:453-464.
  6. Berendsen HHG, Weekers AHJ, Kloosterboer HJ. Effect of tibolone and raloxifene on the tail temperature of oestrogen-deficient rats. European J Pharm 2001;419: 47-54.
  7. Eilertsen AL, Karssemeijer N, Skaane P, Qvigstad E, Sandset PM. Differential impact of conventional and low-dose oral hormone therapy,tibolone and raloxifene on mammographic breast density, assessed by an automated quantitative method. BJOG 2008; 115: 773-9.
  8. Archer DR, Hendrix S, Gallagher JC, Rymer J, Skouby S, Ferenczy A etal. Endometrial effects of tibolone. J Clin Endocrinol Metab. 2007; 92(3): 911-8.
  9. Genazzani Ar, Stomati M, Valentino V, Pluchino N, Poti E. Casarosa al. Effect of 1-year, low-dose DHEA therapy on climacteric symptomsand female sexuality. Climacteric 2011; 14:661-8.
  10. Schoen C, Bachmann G. Sildenafil citrate for female sexual arousal disorder: a future possibility? Nat Rev Urol. 2009; 6(4):216-22.
  11. Nijland EA, Weijmar Schultz, WC, Nathorst-Boos J, Helmond FA, Van Lunsen RH et al. LISA study investigators. Tibolone and transdermal E2/NETA for the treatment of female sexual dysfunction in naturally menopausal women: results of a randomised active-controlled trial. JSex Med 2008 5(3) 646-56.
  12. Formoso G, Perrone E, Maltoni S et al. Short and long term effects of tibolone in postmenopausal women (Review) The Cochrane Collaboration. The Cochrane Library 2012 Issue 2. John Wiley & Sons Ltd.
  13. Kennemans P, Bundred NJ, Foidart JM et al. LIBERATE Study Group.Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomized, non-inferiority trial. Lancet Oncol 2009;10 (2): 135-46.
  14. Cummings SR, Ettinger B, Delmas PD et al. for the LIFT Trial Investigators. The effects of tibolone in older postmenopausal women.N Engl J Med 2008; 359: 697-707.
  15. El-Hage G, Eden JA, Zoa Manga R. A double-blind, randomized placebo-controlled trial of the effect of testosterone cream on thesexual motivation of menopausal hysterectomized women with hypoactive sexual desire disorder. Climacteric 2007;10:335-343.

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