Principles of testosterone therapy in menopause and perimenopause (HRT)

Testosterone replacement in menopause

NICE suggest that a clinician considers testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective (1)

However, it notes: "At the time of publication (November 2015), testosterone did not have a UK marketing authorisation for this indication in women. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented (1)

Testosterone in women

• testosterone is an important female hormone
  • healthy young women produce approximately 100 - 400 mcg per day
  • represents three to four times the amount of estrogen produced by the ovaries.
  • approximately half of endogenous testosterone and precursors are derived from the ovaries e.g. androstenedione and half from the adrenal glands e.g. ehydroepiandrosterone
  • some of the effects are direct and some due to peripheral conversion to estrogen by aromatase
  • testosterone levels naturally decline throughout a woman’s lifespan
    • loss of testosterone is particularly profound after iatrogenic i.e. surgical and medical menopause and premature ovarian insufficiency when testosterone production decreases by more than 50%

Function of testosterone in women:

• contributes to libido, sexual arousal and orgasm by increasing dopamine levels in the central nervous system
• maintains normal metabolic function, muscle and bonestrength, urogenital health, mood and cognitive function

Reduced levels of testosterone in women (2):

• can lead to a number of distressing sexual symptoms such as low sexual desire, arousal and orgasm
• can also contribute to a reduction in general quality of life, tiredness, depression, headaches, cognitive problems, osteoporosis and sarcopenia.

Other effects reduced testosterone can have in the post-menopause (2):

• after the menopause, estrogen levels fall to undetectable levels
  • consequently, the small amount of remaining testosterone may predispose to androgenic symptoms, especially acne, increased facial hair growth and male pattern baldness
  • Personal genetics are key to the susceptibility to these problems

Female Testosterone Replacement – indications

• are no testosterone products for female use licensed in the UK.
• requires specialist advice and management

Commonly used testosterone replacement in menopause (3)

• Testogel® ([Besins Healthcare UK Ltd] 1% testosterone gel in 5.0 g sachets containing 50 mg testosterone): starting dose 1/10 of a sachet/day = 5 mg/day, that is, each sachet
  should last 10 days
• Tostran® ([Kyowa Kirin Ltd] 2% testosterone gel in a canister containing 60 g): starting dose 1 metered pump of 0.5–10 mg on alternate days — each canister should last 240 days
• AndroFeme® ([Lawley Pharmaceuticals] 1% testosterone cream in 50 ml tubes with screw cap) (only available privately): starting dose 0.5 ml/day = 5 mg/day, that is, each tube should last 100 days

Criteria for treatment:

• testosterone replacement in menopausal women is used if hormone replacement therapy (HRT) alone is not effective. Testosterone gel is used in addition to HRT in this setting

Review criteria:

• the BMS advise (2) that response may not be immediate, taking 8-12 weeks in some instances for the effect to become clinically significant. It is therefore advised that treatment should trialled for a minimum of 3 months and maximally for 6 months before being discontinued due to lack of efficacy. Duration of use should be individualised and evaluated at least on an annual basis, weighing up pros and cons according to benefits and risks, as per HRT advice from the British Menopause Society

Monitoring:

• BMS advise that testosterone assays can be performed to support a diagnosis of Female Androgen Deficiency Syndrome (FADS) also referred to as Hyposexual Sexual Desire Disorder (HSDD) / Female Sexual Interest and Arousal Disorder (FSIAD), however there can be practical problems with obtaining these. They recommend that the gold standard would be to measure free testosterone, however a calculation can be performed to work out the Free Androgen Index (FAI) using total testosterone and sex hormone binding globulin (SHBG) levels if free testosterone assays are not available. FAI monitoring can be useful for determining appropriateness of testosterone initiation, response to treatment and maintaining levels in normal range and thus reducing risk of hormonal side effects

Testosterone assays – interpretation of results

• not mandatory to perform testosterone level estimation prior to or for monitoring treatment - however can be useful
• a low FAI < 1.0% in women with symptoms of low sexual desire and arousal, supports the use of testosterone supplementation
• repeat estimation at the 2-3 month follow up visit can be performed to demonstrate if there has been an increase in levels, though clinical response is of paramount importance
• useful to demonstrate that values are being maintained within the female physiological range, typically < 5%, thus making androgenic side effects less likely

Possible adverse effects of testosterone therapy

• reported adverse effects are shown below; if thought to be linked, the dosage should be reduced or treatment stopped. These include:
  • increased body hair at site of application (occasional problem) – spread more thinly, vary site of application, reduce dosage
  • generalised Hirsutism (uncommon)
  • alopecia, male pattern hair loss (uncommon)
  • acne and greasy skin (uncommon)
  • deepening of voice (rare)
  • enlarged clitoris (rare)
• testosterone appears to be safe when used transdermally and in low doses
  • transdermal testosterone is not associated with an increase in blood pressure and has no adverse effects on lipid profile
  • no changes in renal function, liver function, or blood cell indices with transdermal testosterone in women
  • no increased risk of breast cancer in the short term and it does not appear to stimulate the endometrium
  • currently not known how safe it is to prescribe testosterone to women who have breast cancer, and this would be a decision for a secondary care menopause service, on a case-by-case basis and after discussion with an oncologist
    

When should testosterone be avoided or used with caution?

• during pregnancy or breastfeeding
• active liver disease
• history of hormone sensitive breast cancer – off label exceptions to this may be agreed in fully informed women with intractable symptoms not responding to alternatives
• competitive athletes – care must be taken to maintain levels well within the female physiological range
• women with upper normal or high baseline testosterone levels / FAI.

International Menopause Society, has produced a Global Position Statement to provide clear guidance regarding the prescribing and measurement of testosterone for female testosterone therapy, as well as advice on testosterone prescribing practices that have the potential to be ineffectual or cause harm (3)

• concluded that testosterone can be effective at improving sexual wellbeing for postmenopausal women with hypoactive sexual desire dysfunction (HSDD)
  
  
  • recognised benefits included improved sexual desire, arousal, orgasm, and pleasure, together with reduced concerns and distress about sex
    
    
  • measure testosterone levels at baseline and at 3–6 weeks after treatment initiation. Patients should be monitored for their clinical response to treatment and assessed for signs of androgen excess, with a serum total testosterone level every 6 months to screen for overuse
    
    
  • advise cessation after 6 months if there has been no response to treatment

A joint position statement by the British Menopause Society, Royal College of Obstetricians and Gynaecologists and Society for Endocrinology states with respect to testosterone therapy and the menopause (4):

• testosterone supplementation can be considered in women with low sexual desire if systemic HRT resulting in adequate levels of oestrogen with or without progestogen has not been effective
• there is lack of evidence to support testosterone supplementation for the purpose of prevention or improving cognitive function, musculoskeletal health, improving
  bone density or fracture prevention. Testosterone supplementations should therefore not be offered for these indications

Contributor/Reviewer:

• Dr Louise Newson,GP and Menopause Specialist (July 14th 2020)

Open Image in Modal

• for further information about HRT and the menopause then see the links below:
  • https://www.menopausedoctor.co.uk/
  • https://balance-app.comhttps://balance-app.com//

Notes (5):

• testosterone supplementation on its own is not recommended because of the side effects of bloating, acne, and hair growth
• switching women from oral to transdermal HRT can increase the levels of free circulating testosterone, testosterone supplementation is recommended for women who continue to experience low libido and fatigue despite adequate oestrogen replacement
• contraindications to testosterone use include:
  • active liver disease
  • hormone-sensitive breast cancer
• a review suggests total testosterone levels should always be checked prior to commencement and again 6-12 months after initialising therapy with the aim of keeping levels within the female's physiological range (5)

Reference:

• NICE (2015). Menopause: Diagnosis and management
• British Menopause Society. Testosterone replacement in menopause(February 222nd 2020)
• Scott A, Newson L. Should we be prescribing testosterone to perimenopausal and menopausal women? A guide to prescribing testosterone for women in primary care. BJGP 2020; 70: 203-204.
• Joint position statement by the British Menopause Society, Royal College of Obstetricians and Gynaecologists and Society for Endocrinology on best practice recommendations for the care of women experiencing the menopause.Post Reproductive Health 2022, Vol. 0(0) 1-2
• Chakrabarti R, Chakrabarti R. Prescribing hormone replacement therapy: key considerations for primary care physicians. Br J Gen Pract. 2023 Jun 29;73(732):330-332. doi: 10.3399/bjgp23X733473. PMID: 37385757.