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Menopausal Hormone Therapy and Sexual Health

Key messages

• Female sexual dysfunction (FSD) is a multidimensional problem combining biological, Dr Tobie De Villiers Consultant Gynaecologist psychological and interpersonal elements of multiple etiologies Panorama MediClinic • FSD can occur at any age, but is most common around middle age as a result of both normal Department of Obstetrics and Gynaecology aging and the specific hormonal changes that occur at Stellenbosch University • Menopause-associated deprivation leads to urogenital epithelial thinning, reduced Past President, International Menopause Society lubrication during sexual arousal and dyspareunia. Decline in levels may result in decreased libido and decreased sexual activity, and fatigue • In peri- and postmenopausal women, before considering other treatments specifically aimed at sexual symptoms, associated medical conditions first need to be evaluated and treated • Other physiological, psychological, sociocultural, interpersonal and lifestyle factors may also be important and should be addressed • Interventional options for FSD include hormonal therapies such as , testosterone, combined estrogen/testosterone and • Non-pharmacological approaches should be used first, focusing on lifestyle and psychosexual therapy, moisturizers and lubricants • Symptomatic vulvovaginal atrophy (VVA) may be treated with vaginal moisturizers, lubricants, low-dose therapy • Hormonal therapy (HT) with estrogens alone or in combination with improves sexual function when used in women with menopausal symptoms or in early postmenopause • Tibolone has androgenic effects and may be first choice for women who need HT and where desire and arousal are the main problems in terms of sexual dysfunction • Local vaginal estrogen specifically aims at treating dryness and discomfort during intercourse and is 100% effective in VVA, with no systemic effects • Testosterone therapy may be helpful in carefully selected postmenopausal women with female sexual interest/arousal disorder. However, there are no laboratory tests to determine a threshold for mandatory treatment in women and there are no testosterone preparations available specifically for use in women, so using testosterone for FSD in South Africa needs to be undertaken with care.

Introduction The International Menopause Society (IMS) defines female sexual dysfunction (FSD) as a multidimensional problem combining biological, psychological and interpersonal elements of multiple etiologies.1 FSD can occur at any age, but is most common around middle age as a result of both normal aging and the specific hormonal changes that occur at menopause.2 This article was made possible by an unrestricted educational Menopause-associated estrogen deprivation leads to urogenital epithelial sponsorship from MSD, which thinning, reduced lubrication during sexual arousal and dyspareunia. had no control over content Decline in testosterone levels may result in decreased libido and decreased sexual activity, and fatigue. Around menopause there are numerous medical conditions that can be associated with sexual dysfunction, including diabetes mellitus, cardiovascular disease, hypertriglyceridemia, hypertension, neurological disease, genitourinary disease and psychiatric disorders. These

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first need to be evaluated and treated before considering other treatments specifically aimed at sexual symptoms. The consequences of menopause-related sexual dysfunction may not be reversible unless specific therapy is initiated. Hormonal deficiency in particular is not a condition that tends to decrease in severity over time. Interventional options available include hormonal therapies such as estrogens, testosterone, combined estrogen/testosterone, tibolone and (DHEA). Psychosocial treatment options may also be useful and include body awareness, individual psychotherapy, couple therapy and social interventions. Physical options include lubricants, physiotherapy and vaginal dilator training. Hormone therapy (HT) for female sexual dysfunction Five specific domains of sexual dys- because of the different drugs and doses function may be identified in women, that have been used in clinical trials, dif- with considerable overlap between them ferent tools to evaluate sexual function, (Figure 1). and the differences in the particular pop- ulations studied. Sexual desire Sexual arousal Nevertheless, a Cochrane review pub- disorders disorders lished in 2013 assessed the effect of HT on sexual function in perimenopausal and postmenopausal women.3 It con- cluded that HT treatment with estrogens alone or in combination with progesto- Orgasmic gens was associated with a small to mod- Dyspareunia disorder erate improvement in sexual function, particularly pain, when used in women Vaginismus with menopausal symptoms or in early postmenopause (within five years of Figure 1. Domains of sexual dysfunction in women amenorrhoea), but not in unselected postmenopausal women. The levels of In postmenopausal women with FSD, evidence were moderate to high. sexual desire and sexual arousal are The effects and benefits of HT most affected. Dyspareunia is most included: amenable to treatment with hormone • Less pain therapy. Vaginismus is more common in • Increased frequency of sexual activity younger women and less important after • Increased arousal menopause. • Increased enjoyment of sex It is difficult to determine the true • Increased number of orgasms effect of HT on sexual function based on • No effect on libido, desire or interest the literature published so far, partially in sex

Hormonal treatment of Vulvovaginal atrophy (VVA) The aim of HT in women with VVA is of life and sexual function as a whole. to restore urogenital physiology and Local vaginal estrogen specifically to alleviate symptoms. Non-hormonal aims at treating dryness and discomfort approaches seldom restore premenopau- during intercourse and is 100% effective sal anatomy or physiology and do not in VVA. It will also reduce episodes of provide a long-term solution. Systemic recurrent urinary tract infections (UTIs). (oral or transdermal) HT effectively It has no systemic effects. Consequently, treats VVA in most cases, but will not be progesterone is not needed to protect the effective in 10-25% of women. However, endometrium, but there will also be no it does also alleviate other menopausal effect on other associated symptoms of symptoms, such as vasomotor symptoms, menopause. which in turn may improve both quality

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Androgens and the menopause are produced by the adrenal associated with significant increases in cortex and the ovaries. Although the desire, arousal, orgasm, pleasure, reduced declining levels of estrogen are specifi- concerns, responsiveness and self-image. cally related to menopause, it is impor- The rate of androgenic adverse events, tant to remember that circulating blood primarily unwanted hair growth, was levels of total and free testosterone, higher in the group receiving 300 μg of DHEA, DHEA sulphate (DHEAS) and testosterone per day than in the placebo decline with age, com- group (30.0% vs. 23.1%), but the overall mencing a lot earlier than the late repro- incidence of adverse events was similar in ductive years, and are not a consequence the testosterone and placebo groups. of menopause per se. There is no acute change in androgens across the natural Guidelines for therapy 4 menopause. in menopause Surgical menopause is associated with a significant reduction in testosterone, The North American Menopause Society and lower androgen levels have also been (NAMS) recommends the following with reported in women with primary ovarian regard to androgen therapy:2 insufficiency/premature ovarian failure 1. A trial of testosterone therapy may be (POI). considered in carefully selected post- For female patients in South Africa, menopausal women with female sex- it is not possible to make a laboratory ual interest/arousal disorder and no diagnosis of low testosterone levels. The other aetiology for their sexual prob- assays in laboratories have been designed lems. Women must be informed of for male subjects, whereas they are insuf- potential adverse effects and unknown ficient to detect the low levels present in long-term risks. women. Furthermore testosterone levels 2. Women using testosterone should be below which a woman can be described as monitored for adverse effects, includ- being androgen-deficient and mandatory ing facial hair, acne, voice changes, levels below which testosterone should be clitoromegaly, and adverse changes supplemented have not yet been defined. in or liver function tests. Blood Several randomised clinical trials have testosterone levels should be checked demonstrated efficacy of testosterone intermittently to ensure that levels in doses appropriate for women for the remain in the normal range for repro- treatment of low sexual desire/arousal ductive-aged women. disorder. Positive results have been shown 3. Formulations of testosterone among naturally and surgically-induced approved for the treatment of men menopausal women and those using or increase the risk of excessive dosing not using HT. Exogenous testosterone when prescribed for women. improved commonly reported sexual prob- 4. There is currently no role for the use lems, such as diminished sexual desire and of DHEA in the treatment of female arousal, pleasure, and overall satisfaction. sexual disorders. The APHRODITE study was a double- blind, placebo-controlled, 52-week trial in The long-term effect of testosterone on which 814 women with hypoactive sexual the cardiovascular system and breast desire disorder were randomly assigned remain a concern. There is as yet no evi- to receive a patch delivering 150 or 300 dence for (or against) long-term safety μg of testosterone per day or placebo.5 At and women must be informed of these 24 weeks, the increase in the 4-week fre- potential side effects. quency of satisfying sexual episodes was During testosterone supplementation, significantly greater in the group receiv- laboratory tests can be used to ensure ing 300 μg of testosterone per day than that testosterone levels remain in the in the placebo group (an increase of 2.1 normal range for reproductive women episodes vs. 0.7, P < 0.001) but not in and that testosterone is not being over- the group receiving 150 μg per day (1.2 dosed. Before beginning therapy, free episodes, P = 0.11). As compared with androgen levels and binding placebo, both doses of testosterone were globulin (SHBG) should be measured.

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Testosterone supplementation should not It has comparable efficacy to estrogen in be administered if SHBG is high or low. alleviating vasomotor symptoms, and has In South Africa there are no testos- an anabolic effect on . Conversely, it terone preparations approved by the is neutral on the endometrium and does Medicines Control Council (MCC) for not cause breast tenderness. women. Furthermore, the testosterone The potential benefits of tibolone on transdermal patch that has been shown sexual function have been demonstrated to be beneficial in women has been with- in a trial in which it was compared with drawn from the market internationally. transdermal estrogen/ ace- The dose of testosterone appropriate tate (NETA) (50 μg/140 μg) in naturally for female patients is approximately one postmenopausal women with sexual dys- tenth that for males and using available function.6 Four hundred women with a testosterone preparations intended for mean age of 56 years were included. Both men results in unpredictable testosterone treatments resulted in improved overall levels and a considerable risk of overdose. sexual function, as determined by scores In addition to androgenisation, the effect on the Female Sexual Function Index on arousal is lost at high doses and the (FSFI), an increase in the frequency of prescriber must also consider the poten- sexual events, and reduction in sexuality- tial risk of medicolegal problems. related personal distress. However, in the Compounded products are without per protocol analysis at week 24, FSFI justification and are not recommended. scores were statistically significantly These preparations are not subject to higher in the tibolone group, which the regulatory control and their contents are authors attributed to the combined estro- uncertain. genic and androgenic effects of tibolone Over-the-counter products claiming to in comparison with estrogen/NETA. The supplement DHEA are unlikely to con- greatest benefits were in terms of arousal tain an active form and are likewise to be and desire, leading to better scores for the avoided. orgasm domain and total score (Figure 2). In South Africa, tibolone is the first Tibolone choice for women who need HT and where desire and arousal are the main Tibolone is a unique chemical compound problems in terms of sexual dysfunction. that is metabolized to estrogenic, pro- With tibolone, it is not necessary to fol- gestogenic and androgenic metabolites. low up for hyperandrogenisation.

50 40 30 20 C FB in % 10 0 arousal desire lubrication orgasm pain satisfaction total score

E2/NETA Tibolone Figure 2. Mean change from baseline in percent for the separate domain scores of the Female Sexual Function Index (FSFI) by treatment group at week 24 (intent-to-treat group, N = 372). P < 0.001 from baseline for all separate domains for both treatments. CFB = change from baseline. From J Sex Med 2008; 5(3): 646-656.6 New developments Ospemifene The recommended dose is 60 mg/day. It has an estrogen-like effect in the Ospemifene is a selective estrogen recep- (increases superficial cells, decreases tor modulator (SERM) that has been parabasal cells and lowers vaginal pH). It approved in the USA for the treatment results in a small, but statistically signifi- of VVA in postmenopausal women. cant reduction in dyspareunia. The most

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common adverse effect of ospemifene dysfunction, which impacts greatly on a is an increase in vasomotor symptoms, patient’s quality of life. Thankfully, the which has been reported to occur in 10% development of effective treatments has of treated women.7 led to greater recognition of, and solu- tions for, this problem. Combination conjugated equine In women with FSD, non-pharmaco- estrogen/ logical approaches should be used first, focusing on lifestyle and psychosexual Also in the USA, a combination of the therapy, moisturizers and lubricants. If SERM bazedoxifene (BZA) with conju- required, proven effective hormonal ther- gated estrogen (CE) is approved for the apeutic options are available. treatment of vasomotor symptoms and prevention of osteoporosis in women References with a uterus. Bazedoxifene provides 1. Al-Azzawi F, Bitzer J, Brandenburg U, et al. Therapeutic endometrial protection, so a options for postmenopausal female sexual dysfunction. 2 is not needed. Climacteric 2010; 13(2): 103.120. In the SMART 3 study, 664 healthy 2. Shifren JL, Gass MLS, for the NAMS Recommendations postmenopausal women aged 40-65 for Clinical care of Midlife Women Working Group. The North American Menopause Society Recommendations years were randomized to BZA 20 mg/ for Clinical Care of Midlife Women. Menopause 2014. CE 0.625 mg, BZA 20 mg/CE 0.45 mg, 21(10). DOI: 10.1097/gme.0000000000000319. BZA 20 mg, or placebo once daily for 3. Nastri CO, Lara LA, Ferriani RA, et al. Hormone therapy for sexual function in perimenopausal and 8 12 weeks. Changes in vaginal matura- postmenopausal women. Cochrane Database of tion, vaginal pH, and severity of the Systematic Reviews 2013, Issue 6. Art. No.: CD009672. most bothersome symptom of VVA from DOI:10.1002/14651858.CD009672.pub2. 4. Jane FM and Davis SR. A practitioner’s Toolkit for baseline were assessed at screening and at Managing the Menopause. Climacteric 2014; 17: 1-16. weeks 4 and 12. Compared with placebo, 5. Davis SR, Moreau M, Kroll R, et al. Testosterone for low BZA 20 mg/CE 0.625 or CE 0.45 mg sig- libido in menopausal women not taking estrogen. N Engl J Med 2008; 359(19): 2005-2017. nificantly increased superficial cells and 6. Nijland EA, Weijmar Schultz WC, Nathorst-Boös J, et al. decreased parabasal cells. Vaginal pH and Tibolone and transdermal E2/NETA for the treatment most bothersome symptom significantly of female sexual dysfunction in naturally menopausal women: results of a randomized active-controlled trial. J improved with BZA 20 mg/CE 0.625 mg Sex Med 2008; 5(3): 646-656. compared with placebo. Improvements in 7. Portman DJ, Bachmann GA, Simon JA; Ospemifene vaginal dryness were also observed with Study Group. Ospemifene, a novel selective modulator for treating dyspareunia associated both BZA/CE doses. The incidence of with postmenopausal vulvar and vaginal atrophy. treatment-related adverse events was sim- Menopause 2013; 20: 623-630. ilar across treatment groups. 8. Kagan R, Williams RS, Pan K, et al. A randomized, placebo- and active-controlled trial of bazedoxifene/ In conclusion, menopause and its for treatment of moderate transition represents a significant risk to severe vulvar/vaginal atrophy in postmenopausal factor for the development of sexual women. Menopause 2010; 17(2): 281.289.

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