Sexual dysfunction: Is it all about hormones?

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1 Sexual dysfunction: Is it all about hormones? Angelica Lindén Hirschberg, MD, PhD, Professor Department of Women s and Children s Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

2 Female sexuality

3 Mechanisms Sexually excitatory processes Dopaminergic pathways Noradrenergic pathways Sexually inhibitory processes Opioid Endocannabinoid Serotonin systems

4 Female sexual dysfunction Hypoactive sexual desire disorder (HSDD) decreased libido causing distress Arousal disorder decreased lubrication to sexual stimuli Orgasm disorder Dyspareunia, vaginismus

5 Prevalence and epidemiology Prevalence of at least one manifestation of sexual dysfunction in women is 40 to 50% irrespective of age! Hyposexual desire disorder (HSDD) is reported in 9% of women aged 18-40, 12% in women aged and 7% in women over 65 (Shifren et al 2008) Low sexual desire increases with age, whereas distress about low sexual desire decreases with age (West et al 2008) The highest rate of HSDD was observed in young surgically menopausal women (20%) (West et al 2008)

6 Causes of female sexual dysfunction Partner and life situation General health, abuse problems and psychiatric disorders, e.g. depression Medications - antidepressants, hormonal contraception Genital diseases chronic fungal infection, lichen sclerosus Pain without somatic cause, vaginismus Estrogen deficiency decreased lubrication, vaginal dryness, sexual pain Lack of testosterone decreased libido

Estrogen Estrogen has no direct effect on sexual desire but is important for the body's sexual response Estrogen stimulates proliferation of the vaginal epithelium, promotes

7 Estrogen Estrogen has no direct effect on sexual desire but is important for the body's sexual response Estrogen stimulates proliferation of the vaginal epithelium, promotes lubrication and blood perfusion and protects against pathogens. Estrogen deficiency is clearly associated with vaginal dryness, pruritus and itching, burning, as well as dyspareunia.

8 Estrogen levels during life

9 Testosterone Testosterone stimulates libido and orgasm Central effect in hypothalamus and limbic systems Directly via androgen receptors or indirectly via conversion to estrogen by aromatase

10 adrenal Androgen production in women ovarium A-4 DHEA DHEAS T (0,5-1,5 nmol/l) A-4 T (0,5-1,0 nmol/l) E2 T DHT estrogenreceptor androgenreceptor target cell

11 Circulating testosterone in women women SHBG albumin T 73% T 25% free T 1-2%

12 Androgen levels in women at different ages Davison et al 2005

13 Androgen levels related to menopaus Davison et al 2005

14 Hormone levels after oophorectomy Estrogen levels decrease drastically to the postmenopausal level after oophorectomy Testosterone levels decrease 50% or more after oophorectomy (Hughes et al 1991)

15 Androgen levels in women with sexual dysfunction Women 35 to 70 years with sexual dysfunction in blue and controls in red. Basson et al, Menopause 2010

16 Oral contraceptives What is known about combined OCs and sexuality? Sexual dissatisfaction has been reported to be among the best predictors of OC discontinuation (Sanders et al 2001; Burrows et al 2012) Meta-analysis has shown increased, decreased and no change in sexual desire (Pastor et al 2013) Most studies were non-randomized and uncontrolled!

J Clin Endocrinol Metab 2016;101: 4046-4053 Randomized 340 Combined OC

17 J Clin Endocrinol Metab 2016;101: Randomized 340 Combined OC treatment (150 µg levonorgestrel and 30 µg ethinylestradiol) OC treatment drop out Placebo 171 Evaluation by the Profile of Female Sexual Function (PFSF) before and after three months of treatment 3 drop out Completed 164 Completed 168

18 Sexual function A: Profile of Female Sexual Function (average of the 7 domains) p = Placebo OC Treatment B: Profile of Female Sexual Function: Domains p = p = p = Desire Arousal Orgasm Pleasure Concern Responsiveness Self-image Placebo OC Treatment

19 Sexual activity and distress B: Sexual Activity Log p = Placebo OC Treatment A: Personal Distress Scale p = Placebo OC Treatment

20 Changes in testosterone levels A: Total Testosterone Placebo Baseline Follow-up OC Treatment There were no correlations between changes in testosterone levels and changes in sexual function! B: Free Testosterone Placebo Baseline Follow-up OC Treatment

21 Conclusion Our placebo-controlled randomized study supports a negative impact of a levonorgestrel-containing oral contraceptive on sexual desire, arousal and pleasure in young women The results should be recognized and considered during contraceptive counselling It is important to evaluate alternative OC combinations in placebo-controlled studies

22 Treatment of female sexual dysfunction Sex therapy, psychotherapy Local estrogen treatment for vulvovaginal atrophy Systemic hormone therapy for sexual function Testosterone treatment for decreased libido Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) Flibanserin a centrally acting 5-HT1A receptor agonist and a 5-HT2A antagonist producing a decrease in serotonin activity and an increase in dopamin and NA activity

23 Hormone therapy for sexual function in menopausal women Nastri et al Cochrane review 2013: HT treatment with estrogen alone or in combination with progestogens is associated with a small to moderate improvement in sexual function specifically in women with menopausal symptoms The current evidence does not suggest an important effect of tibolone, raloxifene and bazedoxifene, alone or combined with estrogens on sexual function

25 Testosterone treatment The testosterone patch was approved by the European Medicines Agency but it was later withdrawn by the manufacturer Well-tolerated increased hair growth the most common side-effect No increased risk so far of breast cancer, adverse effects on the endometrium, lipids or cardiovascular and thromboembolic events Today there is no testosterone therapy approved for treatment of women Testosterone preparations for men could be used

26 2014 Endocrine Society Guidelines on androgen therapy They recommend against to make a diagnosis of androgen deficiency syndrome because there is a lack of a well-defined syndrome They recommend against the routine use of DHEA/DHEAS due to limited data on effectiveness and safety including in women with adrenal insufficiency They support short-term use (3- to 6-month trial) of testosterone in postmenopausal women with HSDD Women should be monitored for signs of androgen excess

27 Flibanserin Recently approved in the USA for treatment of HSDD i premenopausal women. Not yet approved for postmenopausal women. 100 mg daily dose resulted in a significant increase in satisfying sexual events Flibanserin is contraindicated with alcohol due to hypotension and syncopy

28 Summary Hypoactive sexual desire disorder is rather common in women of all ages. Hormonal factors like estrogen and testosterone could be involved and particularly in young surgically menopausal women Treatment of vulvovaginal atrophy should be offered Short term trial of testosterone treatment could be offered in women with HSDD Flibanserin?

29 Thank you for your attention!

Therapy and Sexual Health

Menopausal hormone therapy and sexual health Earn 3 CPD Points online Menopausal Hormone Therapy and Sexual Health Key messages Dr Tobie De Villiers Consultant Gynaecologist Panorama MediClinic Department