Introduction
The use of testosterone in women for hypoactive sexual desire disorder (HSDD) remains an area that generates controversy and debate despite a growing wealth of literature and increasing use in clinical practice. Perhaps one of the main reasons is that many healthcare professionals, as well as the general public, still do not perceive testosterone as an important female hormone. The other reason may be that testosterone has been associated with androgenic adverse effects rather than being seen as a safe option of the hormone therapy armamentarium. It is therefore important that good quality contemporary evidence based guidelines are being developed and made easily accessible to healthcare professionals who prescribe, or are considering in prescribing testosterone to women. In the absence of licensing for this indication in most countries, it is also important that these professionals have the expertise to skilfully counsel women following a bio-psycho-social model, empowering them to make truly evidence based informed individualised decisions, as to whether they use testosterone supplementation.
Methodology and Outcomes
It is with these goals in mind that the International Society for the Study of Women’s Sexual Health (ISSWSH) recently convened a multidisciplinary panel of 16 US and international researchers and clinicians (both ISSWSH members and non-members) to discuss the use of testosterone in women for HSDD. The methodology involved an initial review of the literature including original research, meta – analyses, review articles, clinical practice and consensus guidelines regarding the use of testosterone and DHEA in women. The outcome differed from the global position statement [1] in that this process aimed to produce a clinically useful guideline in day to day practice.
Data from recent meta-analyses were used to assess the efficacy and safety of various testosterone preparations in women [2,3]. The resulting guideline outlined a bio-psycho-social assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD including measurement, indications, formulations, prescription, dosage, monitoring, and follow-up. A further key difference between the global consensus position statement and the ISSWSH guideline was that the latter also recommended testosterone supplementation in the late reproductive stage, in addition to postmenopausal women. The process resulted in a paper which was published simultaneously in three journals with open access [4-6].
Commentary
What are the key questions that healthcare professionals are asking about testosterone supplementation in women for HSDD, and what have we learnt from this guideline and the previous consensus statement? The next section attempts to answer some of these questions and indicates areas where there is a pressing need for new research.
- Is testosterone a female hormone?
- Yes – women produce more testosterone than estrogen physiologically; the role and physiological action of testosterone is well summarised in the guideline [4-6].
- What happens to testosterone levels through the life course?
- The decline in testosterone levels appears to be age related and occurs at least partly due to the normal loss of ovarian function. It can also occur due to iatrogenic menopause and premature ovarian insufficiency. Levels start rising again over the age of 70 years.
- Should testosterone be replaced just because levels are low?
- Many women with low systemic testosterone levels do not report HSDD (distressing low libido) or other relevant symptoms, even on direct questioning, and therefore do not require testosterone.
- Why do systemic testosterone levels not always correlate directly with HSDD symptoms?
- The intracrinological metabolism of testosterone may be more important than peripheral circulating levels. This is particularly important in the central nervous system (CNS) where DHEA and other precursors are converted to testosterone intracellularly, thereby having an effect on CNS dopamine levels.
- Who should be offered testosterone for HSDD?
- Testosterone supplementation should be considered in women after a bio-psycho-social approach has investigated other causes of low sexual desire. Combined hormonal and psychosexual approaches may be beneficial in cases with mixed etiology.
- It is encouraging that the guideline [4-6] has also recommended supplementation in the late reproductive population; many women complain of HSDD in the perimenopause before menstruation has ceased.
- Should testosterone be prescribed on its own, or with menopause hormone therapy (MHT)?
- Testosterone appears to be equally beneficial in women not using concomitant estrogen containing hormone therapy. Vaginal estrogen or DHEA may be required for vulvovaginal atrophy symptoms. Oral estrogens, especially conjugated equine estrogens, can reduce the efficacy of testosterone by increasing sex hormone binding globulin (SHBG) levels. Switching a woman from oral to transdermal estrogen may benefit their HSDD symptoms without adding testosterone.
- Are there wider benefits with testosterone therapy?
- In clinical practice women may report improvement of energy, mood or cognitive functioning as well as HSDD when given testosterone. However, data from randomised trials and meta analyses thus far do not support these effects. The guideline [4-6] confirms that trials have not been large enough nor long enough to determine the effects of testosterone on cognitive health, mood and musculoskeletal health. Well-designed studies are required, with memory, depression, sarcopenia and bone density/fracture as primary outcome measures, to provide much needed data.
- Are there side effects and risks?
- Adverse effects of testosterone in women are uncommon if levels are maintained within the female physiological range. The commonest are excess hair growth and acne, which are usually reversible with dosage reduction. More data are required for the long term effects on cardiovascular and breast outcomes, but short term data are reassuring.
- Why is testosterone not licensed for women (apart from in Australia)?
- The guideline [4-6] indicates the concern that regulators have due to the lack of long term safety data, despite some products such as patches and implants having previously been licensed. The recent licensing of 1% testosterone cream in Australia may encourage other regulators to follow suit given the unmet clinical need. Equally important has been the reluctance of the pharmaceutical industry to finance further clinical studies to achieve licensing of female androgenic products, but there is renewed interest from some companies.
- How long should testosterone be continued?
- The guideline [4-6] recommends consideration of a “drug holiday” after 6-12 months; this could be problematic in women where it takes 3-6 months to fully evaluate efficacy of treatment. The guideline acknowledges that long term treatment may be required. In line with MHT recommendations, there should at least be annual evaluation of ongoing use, carefully weighing benefits and risks.
- Monitoring?
- Total testosterone and SHBG levels should be checked pre-treatment to establish a baseline for future monitoring and to ensure that they are not in the upper range before treatment is commenced. Levels are rechecked shortly after commencing treatment and then on a regular basis to ensure they remain within the female physiological range, at least a couple of times per year.
- Audit and research?
- In order to achieve global licensing of testosterone use in women, more long term data are not only desirable, but are essential. In the absence of long term prospective randomised controlled trials, the best way to gather these data will be through registries and post marketing surveillance, which is likely to be a pre-condition of licensing by most regulators.
- Treatment options
- The guideline [4-6] advises against the use of compounded varieties of testosterone. In most countries, licensed male testosterone preparations can be titrated to female doses (1/10th). However, where these are not available, compounded varieties may need to be used. If so, compounding pharmacies should meet industry standards for purity of Active Pharmaceutical Ingredients and Good Manufacturing Practice. In some countries e.g. Italy, DHEA use is more common than testosterone; it is therefore imperative that quality research is conducted with DHEA in HSDD.
Special populations
More testosterone data are required in key populations such as:
- Women with premature ovarian insufficiency, both spontaneous and iatrogenic.
- Women with hypothalamic amenorrhoea.
- Premenopausal women on combined hormonal contraception.
- Women on SSRIs and other psychoactive medications.
- Women with a history of hormone sensitive malignancy e.g. breast or endometrial cancer.
Nick Panay
Professor of Practice, Imperial College London, UK
President Elect, International Menopause Society
References
- Davis SR, Baber R, Panay N, et al. Global Consensus Position Statement on the Use of Testosterone Therapy for Women. J Clin Endocrinol Metab. 2019; 104(10):4660-4666.
https://pubmed.ncbi.nlm.nih.gov/31498871/ - Achilli C, Pundir J, Ramanathan P, Sabatini L, Hamoda H, Panay N. Efficacy and safety of transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder: a systematic review and meta-analysis. Fertil Steril. 2017;107:475–82.e415.
https://pubmed.ncbi.nlm.nih.gov/27916205/ - Islam RM, Bell RJ, Green S, Page MJ, Davis SR. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. Lancet Diabetes Endocrinol 2019;7(10):754–766.
https://pubmed.ncbi.nlm.nih.gov/31353194/ - Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women’s Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. Climacteric. 2021 Dec;24(6):533-550.
https://pubmed.ncbi.nlm.nih.gov/33792440/ - Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women’s Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. J Sex Med. 2021 May;18(5):849-867.
https://pubmed.ncbi.nlm.nih.gov/33814355/ - Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women’s Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. J Womens Health (Larchmt). 2021 Apr;30(4):474-491.
https://pubmed.ncbi.nlm.nih.gov/33797277/
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