Testosterone

1 How much and where does it come from?

Testosterone is an important female hormone. Healthy young women produce approximately 100 – 400 mcg per day. This 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. dehydroepiandrosterone. 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%.

2 What is its role in women?

Testosterone contributes to libido, sexual arousal and orgasm by increasing dopamine levels in the central nervous system. Testosterone also maintains normal metabolic function, muscle and bone strength, urogenital health, mood and cognitive function.

3 What is the impact of testosterone deficiency?

This can lead to a number of distressing sexual symptoms such as low sexual desire, arousal and orgasm. Other contributory factors which should be taken into account when assessing women with these symptoms include psychosexual, physical, iatrogenic and environmental. Testosterone deficiency can also contribute to a reduction in general quality of life, tiredness, depression, headaches, cognitive problems, osteoporosis and sarcopenia.

4 What other effects can testosterone have in the post-menopause?

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.

5 Diagnosing Female Androgen Deficiency Syndrome (FADS) also referred to as Hyposexual Sexual Desire Disorder (HSDD) / Female Sexual Interest and Arousal Disorder(FSIAD)

Although for research purposes validated questionnaires are used, the diagnosis of FADS in the clinical setting should be a pragmatic one based primarily on symptoms. Testosterone levels may be supportive of the diagnosis but symptoms do not always correlate with low testosterone levels as brain intracrinology may be more important than peripheral levels.

6 Testosterone assays – measurement

The assessment and interpretation of testosterone levels is problematic, particularly as the majority of testosterone is protein bound. Free testosterone assays are the gold standard but are rarely available, particularly in the public sector. Total testosterone can be measured, but for greater accuracy sex hormone binding globulin (SHBG) levels should be taken into account using the following calculation to work out the Free Androgen Index = Total Testosterone x 100 / SHBG.

7 Testosterone assays – interpretation of results

Although it is not mandatory to perform testosterone level estimation prior to or for monitoring treatment, it 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. It is also useful to demonstrate that values are being maintained within the female physiological range, typically < 5%, thus making androgenic side effects less likely.

8 Female Testosterone Replacement – indications

There are no testosterone products for female use licensed in the UK. The previous license for female testosterone patches was for women with HSDD following surgical menopause on concomitant estrogen; similar efficacy and safety data also exist for natural menopause and for women not using concomitant HRT. The licenses for patches and implants were both withdrawn for commercial reasons;however, the safety and efficacy data for these products remain valid. By extrapolation of these data it is deemed acceptable for products licensed in men (mainly gels) to be prescribed off label in female doses. It is not uncommon in clinical practice to use medicines outwith their product licence as long as this meets the criteria proposed by the GMC and MHRA on prescribing an unlicensed medicine or using a medicine off-label (i.e. No suitably licensed products available / Be satisfied there is sufficient evidence or experience of using the medicine to demonstrate its safety and efficacy / Make a clear record of reasons for prescribing an unlicensed medicine / give patients, or those authorising treatment on their behalf, sufficient information about the proposed treatment).

NB 1: This paper refers to testosterone replacement in menopause, both natural and surgical. There are very few data for testosterone replacement in premenopausal women which remains a controversial area requiring more research.

9 What are the currently available options

The available products keep changing for commercial reasons – this section of the factsheet in particular will be updated regularly to maintain its relevance. An audit will be carried out to assess what preparations are available in different areas of the UK to make this guidance as realistic as possible.

Note 1: When treating low sexual desire /arousal it is also important that urogenital tissues are adequately estrogenised in women with vulvovaginal atrophy / genitourinary syndrome of the menopause e.g. through use of vaginal estrogen, to avoid dyspareunia.

Note 2: Although the NICE NG23 guideline recommends that systemic HRT should be prescribed before a trial of testosterone, there are trial data in women with HSDD which indicate that testosterone used without systemic estrogen, is equally effective and safe.

Note 3: Tibolone is weakly androgenic, progestogenic and estrogenic – although it is an option for women with low sexual desire it is not sufficiently androgenic nor estrogenic in many women. The progestogenic effect is not required in hysterectomised women and may cause unnecessary adverse effects.

Note 4: Compounded bioidentical testosterone preparations are not recommended by the regulatory authorities or the menopause societies.

• Testogel [Besins Healthcare UK] (1% testosterone gel in 5.0g sachets containing 50mg testosterone): Starting dose 1/10 of a sachet/day = 5mg/day i.e. each sachet should last 10 days.
• Tostran [Kyowa Kirin Ltd] (2% testosterone gel in a canister containing 60g ) : Starting dose 1 metered pump of 0.5g = 10mg on alternate days – each canister should last 240 days.
• AndroFeme¹ [Lawley Pharma] (1% testosterone cream in 50ml tubes with screw cap): Starting dose 0.5ml/day = 5mg /day i.e. each tube should last 100 days.
• Testosterone Implants² [Smartway Pharma] (100mg implanted pellets) Unlicensed – imported from USA

1. AndroFeme is not currently available in the NHS and is being imported from Western Australia by special license from the MHRA. Designed for female usage.

2. Testosterone implants are currently unlicensed in the UK and can only be used privately or through agreement of the local formulary committee with appropriate monitoring of hormone levels and adverse effects. Designed for female usage.

10 How should testosterone gel/cream be used?

The testosterone gel/cream should be to applied to clean dry skin (lower abdomen/upper thighs) and allowed to dry before dressing. Skin contact with partners or children should be avoided until dry and hands should be washed immediately after application. The area of application should not be washed for 2-3 hours after application.

11 Response to testosterone therapy and duration of use

The loss of sexual desire is complex and may have hormonal, medical, psychosexual and psychosocial aetiologies. In clinical trials of women with HSDD, approximately 2/3 of women responded positively to testosterone therapy (compared to 1/3 using placebo). The trials demonstrated 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 all menopause societies.

12 What are the possible adverse effects of testosterone therapy

Response to testosterone with regards to efficacy and adverse effects, is highly variable. This is most likely due to varying absorption, metabolism and sensitivity to testosterone. Not uncommonly, adverse effects occur because healthcare professionals and their patients are confused about the appropriate preparation and dose which should be used in women, due to the lack of specific female preparations and information sheets. Clinical trials have demonstrated that as long as appropriate female physiological doses are prescribed adverse androgenic effects are not problematic and virilising problems do not occur.

Reported adverse effects are shown below; if thought to be linked, the dosage should be reduced or treatment stopped.

• 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)

Randomised controlled trials and meta analyses have not shown an increased risk of cardiovascular disease or breast cancer although longer term trials would be desirable.

13 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.

Do I need a blood test?

Blood tests are not able to diagnose whether or not you need testosterone but are used as a safety check to ensure you are not getting too much on top of your own natural levels. Blood tests before starting, might be suggested and repeated after 3-6 months on treatment.

Is it available on the NHS?

NICE Guidance on menopause states that testosterone can be considered for those that need it (NG23).

Testosterone can be prescribed on the NHS if the prescriber is familiar with it and is willing to prescribe it ‘off licence’. Some prefer not to take this decision and refer to a specialist for advice before prescribing. Other GPs will have prescribing restrictions which mean they are not able to offer it.

1 of 3 Testosterone gel or sachets for the treatment of low sex drive in the menopause This leaflet will answer some of your questions about the use of testosterone gel or sachets for the treatment of low sex drive in the menopause. If you have any questions or concerns, please speak to a doctor, nurse or pharmacist caring for you. What is testosterone? Testosterone is one of the sex hormones that women produce. Many people think of it as the “male” hormone, but women need to have testosterone too. In fact, women produce three times as much testosterone than oestrogen before the menopause. Levels of testosterone in your body gradually reduce as you become older and reduce very abruptly in those women who have had an oophorectomy (an operation to have their ovaries removed). Testosterone is also produced by the adrenal glands. It may have a direct action of being used by the body to increase sex drive, or some of it can be converted into oestrogen, which again may help with symptoms. When a woman’s level of testosterone decreases, she may find that she desires sex less often, and when she does have sex, it is not as pleasurable as it used to be, even though she still desires her partner. There is some evidence that having lower testosterone levels can also affect your mood and increase your risk of being depressed. When you are in the menopause, if you are on hormone replacement therapy (HRT), especially after your ovaries have been removed, you may still have the symptoms of lack of testosterone. These can be low libido, lack of energy, increased tiredness, difficulty concentrating or headaches. A diagnosis can be made on personal history alone. A blood test is generally not required, but may be useful to confirm a diagnosis. Medicine – taking an unlicensed medicine The use of Tostran® and Testogel® for the treatment of low sex drive is unlicensed, which means that the manufacturer of the medicine has not specified it can be used in this way. However, there is evidence that it works to treat this particular condition. The leaflet, Unlicensed medicines – a guide for patients, has more information about unlicensed medicines. If you would like a copy, please ask your doctor, nurse or pharmacist. Alternatively you can call the Pharmacy Medicines Helpline (details are at the end of this leaflet). 2 of 3 What symptoms can testosterone help with? The National Institute for Health and Care Excellence (NICE) suggests that if women are suffering from menopausal symptoms such as decreased libido, then testosterone may be helpful and can be tried. This is why the medication is being tried for you now. Testosterone will normally be combined with standard hormone replacement therapy (HRT) as it works best when there is oestrogen as well. How is testosterone given? Testosterone is usually given as a gel to rub into the skin, and there are a couple of different products that might be used. Please note that none of the products are specifically marketed for testosterone replacement in women. They are designed as hormonal replacement therapy in men. Because of this, the instructions for use in the menopause will be different to information contained in the manufacturers’ leaflet – it is very important that you follow our instructions and not the manufacturer’s leaflet. Tostran® 2% is a gel in a pump dispenser, and one measured pump (which contains 10 milligrams of testosterone) is usually used three times a week. Testogel® is a testosterone products that come as a gel in a sachet. One sachet is usually used over the course of one week (given as a daily dose of a small portion of the pack). The medicine can take several months to work and it is not effective for every woman. Younger women who have had an early menopause often notice benefits from using testosterone. If you have had your ovaries removed in an operation, then it is very likely that your levels of testosterone will become low very quickly. This is because your ovaries produce the majority of testosterone in your body. The gel should be applied to clean and dry skin and allowed to dry before you get dressed. You should not have contact with any other person while it is drying (approximately 10-minutes), and you should wash your hands after it has been applied. The area that it is on should not be washed for three hours after application to allow it to be absorbed. Is blood test monitoring required? Blood testing for testosterone is not essential but can be useful. The test is not very sensitive in women. The relief of symptoms and lack of side effects is a more helpful assessment. If you find that testosterone is beneficial then you would normally continue to use this while you are taking the standard HRT What should I do if I forget to take the medicine? If you miss a dose, take it as soon as you remember. If it is close to the time your next dose is due (within a day) do not take the missed dose and continue with your normal schedule. It is important not to take two dosages of the gel to make up for missing one. What are the side effects from using testosterone? There are usually no noticeable side effects of testosterone as it is given to restore testosterone to levels before the menopause. However, some side effects are dose dependent and include:  hirsutism, increased facial or body hair (common)  alopecia, male patter hair loss (less common)  acne and greasy skin (less common)  deepening of voice (rare)  enlarged clitoris (rare) 3 of 3 While we have a lot of information about long-term side effects of oestrogen and progesterone replacement therapy in the menopause, there is less information as to any long term effects of testosterone replacement therapy. There is a theoretical concern of possible increased cancer risk, and heart disease, following testosterone use, but there is currently no information to say if there is an actual risk or not. The doctor or nurse looking after you can always discuss your specific risks and benefits from using this if you have any further questions. Very occasionally, women notice some increased hair growth or skin changes in the area in which they have rubbed the gel. This may be avoided by changing the area of skin on which you rub the gel. Other reported side effects include acne and, if taken in large doses, voice changes. How do I get a repeat prescription? Initially your doctor or nurse at the Menopause Clinic will provide your prescription, but when the medication doses and your symptoms are stable, your GP will be able to take over the prescription, and you can get further supplies from your local chemist. Pharmacy Medicines Helpline If you have any questions or concerns about your medicines, please speak to the staff caring for you or call our helpline. t: 020 7188 8748, Monday to Friday, 9am-5pm Your comments and concerns For advice, support or to raise a concern, contact our Patient Advice and Liaison Service (PALS). To make a complaint, contact the complaints department. t: 020 7188 8801 (PALS) e: This email address is being protected from spambots. You need JavaScript enabled to view it. t: 020 7188 3514 (complaints) e: This email address is being protected from spambots. You need JavaScript enabled to view it. Language and accessible support services If you need an interpreter or information about your care in a different language or format, please get in touch. t: 020 7188 8815 e: This email address is being protected from spambots. You need JavaScript enabled to view it. NHS 111 Offers medical help and advice from fully trained advisers supported by experienced nurses and paramedics. Available over the phone 24 hours a day. t: 111 Contact us If you have any questions or concerns about testosterone, please contact the nurse consultant, t: 020 7188 3023, Wednesday, 2-4pm or e: This email address is being protected from spambots. You need JavaScript enabled to view it.. For more information leaflets on conditions, procedures, treatments and services offered at our hospitals, please visit w: www.guysandstthomas.nhs.uk/leaflets Leaflet number: 4675/VER1 Date published: January 2019 Review date: January 2022 © 2019 Guy’s and St Thomas’ NHS Foundation Trust A list of sources is available on request Our values: Put patients first | Take pride in what we do | Respect others | Strive to be the best | Act with integrity