1. Sex, quality of life at menopause and management Elizabeth Farrell Head, Menopause Unit, Monash Medical Centre, Clayton, & Director , Jean Hailes Foundation for Women’s Health, Clayton, Australia March 2007 Taipei

2. DISCLOSURES Educational and research grants
Symposium or meeting speaker
Organon
Novo-Nordisk
Schering

3. Sexual well being & function
Complex influences & changes in middle-aged women
MWMHP ( 438 Australian woman aged years)
Relate to aging, psychosocial & physical factors
Prior level of sexual function
Losing or gaining a partner
Feelings towards partner
Oestradiol level
Mood
Age
Incremental decline with menopause related to decreasing oestradiol level
(Dennerstein L, Lehert P, Burger H, Guthrie J, Am J Med 2005)
Melbourne Women’s Midlife health Project (MWMHP)
Is A longitudinal therefore prospective study of 438 Australian woman, aged years, by the 9th year had a 88% retention rate. This study looked at natural history of the menopause in Australian born women. The changes occur in relation to aging, psychosocial and physical factors.
The study found that the most important factors influencing sexual function were; Prior level of sexual function
Losing or gaining a partner, Feelings towards partner, Oestradiol level, Mood, age.

4. Menopause & Sexual function
MWMHP measured sexual function and distress
Sexual dysfunction increased from 42%-88% from the early to late menopause transition
Decreasing scores correlated with decreasing oestradiol not androgens
In the postmenopause phase
Decline in sexual arousal and interest
Frequency of sexual activites
Total score
Increase in vaginal dryness
Dyspareunia
Increase in partner’s problems in sexual performance
(Dennerstein L, Alexander JL, Kotz K Annu Rev Sex Res 2003)
The study used an annual McCoy Female Sexuality Questionnaire (MFSQ) & Female Sexual Distress Scale and showed a doubling of sexual dysfunction from early to late menopause transition. The decreasing scores correlated to decreasing oestradiol levels but not to androgen levels. There was a decline in all aspects of sexual function including arousal, interest and frequency of sexual activities. There was also an increase in the atrophic symptoms of the menopause and partner sexual dysfunction.

5. Androgen levels Cross sectional study of 1423 women aged 18-75 years
Androgens decline steeply in the early reproductive years
Do not vary because of the menopause
Postmenopausal ovary continues to produce androgens
Over 55 years after BSO lower total T and free T level
(Davison S et al JCEM 2005)
No single androgen level is predictive of low female sexual function
(Davis SR, Davison SL, Donath S, Bell R JAMA 2005)
Another study from Melbourne was a cross sectional study to document the effects of age and the effects of natural and surgical menopause on androgen levels women. The study showed a steep decline in the early reproductive years with no variation over the menopause transition. There was a decline in total and free T after Bilateral salpingo-oophorectomy compared to women with their ovaries intact.
The study further showed that a single androgen level was not a predictor of low sexual function.

6. Total testosterone Davison et al JCEM 2005
The results of the study showed this initial decline in the twenties and thirties and no change in relation to the menopause
Davison et al JCEM 2005

7. Livial (Tibolone) - STEAR (Selective Tissue estrogenic activity regulator)
Treats menopausal symptoms
Enhances mood and sexual well-being
No stimulation of breast tissue
Low incidence of breast tenderness
Neutral effects on cardiovascular system
No endometrial proliferation
Treats vaginal atrophy
NOTES
• Livial® is a tissue-selective estrogenic activity regulating (STEAR) therapy which, results in desired estrogenic effects in tissues like the brain, bone and vagina, while avoiding the undesired estrogenic effects on the endometrium and the breast.
After oral ingestion it is converted into three active metabolites: 4 isomer, 3a-hydroxy metabolite and 3b-hydroxy metabolite. These metabolites give Livial its full range of effects.
• Livial® is a well established treatment option for relief of climacteric symptoms and the prevention of osteoporosis.
• Livial® effectively controls climacteric symptoms, such as hot flushes and night sweats, urogenital symptoms including vaginal dryness and epithelial atrophy and prevents osteoporosis1. Livial’s® effect on mood and libido will be discussed in the following slides.
Reference
1. Rymer JM. The effects of tibolone. Gynecol Endocrinol 1998;12:213–20.
Prevents postmenopausal bone loss
Rymer, Gynecol Endocrinol 1998

8. Livial: Effects on sexual well-being
Effects of Livial on endogenous androgen status in post menopausal women
Livial
placebo 80 70 ** 60 50 40 30 20
NOTES
The objective of this trial was to compare the effects of 3 months’ tibolone treatment with the effects of placebo on sexual function (in particular, vaginal blood flow, sexual desire and arousability) and climacteric symptoms in postmenopausal women. It was a randomised, double blind, cross-over study conducted in 38 postmenopausal women who received tibolone 2,5 mg daily or placebo. Blood samples were taken for the measurement of total testosterone (TT), sex hormone binding globulin (SHBG), free androgen index (FAI; total T/SHBG), dehydroepiandrosterone sulfate (DHEAS) and A (Androstenedione)
Total testosterone was significantly lower with tibolone (1.32 vs 1.44 nmol/l, p<0.05), whereas FAI was significantly higher (6.35 vs. 2.81, p<0.0001). There were significant reductions in SHBG with tibolone (30.16 vs nmol/l, p<0.0001) whereas A (Androstenedione) was marginally lower with tibolone and there was no difference found with DHEAS.
References
1. Laan E, Lunsen HW van, Evaraerd W. The effects of tibolone on vaginal blood flow, sexual desire and arousablilty in postmenopausal women. Climacteric 2001;4:28-41. ** 10 * TT
FAI A
DHEAS
SHBG
(nmol) (nmol) (µmol) (nmol)
** P< between groups
* P< 0.05 between groups
Laan et al., Climacteric 2001

9. Livial: Effects on sexual well-being
Effects on postmenopausal endogenous androgen status: Livial vs. EPT
% change at 12 months
140
120
Livial (n = 50)
100
E2/NETA (n = 50) 80 60 * 40
NOTES
The objective of this randomized, double-blind, prospective 1-year study was to determine serum parameters reflective of androgen status in postmenopausal women (n=100) using Livial® (2.5 mg; n = 50) or continuous combined 17-estradiol (2 mg) and norethindrone acetate (E2+NETA, 1 mg; n = 50).
The main outcome measures were: total testosterone (total T), dehydroepiandrosterone sulfate (DHEAS), androstenedione (A) and sex-hormone-binding globulin (SHBG), and calculated free testosterone (free T). Changes from baseline within and between groups were assessed after 6 and 12 months.
There were significant changes in the Livial®group compared with baseline after both 6 and 12 months. Levels of free T doubled, total T decreased slightly, SHBG levels were halved, while DHEAS increased by approximately 20% and FSH decreased. In the E2+NETA group, levels of free T, total T, A and FSH all decreased, whilst SHBG increased. Pre-trial levels of DHEAS, A, and total T were significantly higher in the E2+NETA group. The changes from baseline were significantly different between the groups throughout the study due to the different extent of FSH reduction, and opposite changes of free T, SHBG and DHEAS1.
References
1. Doeren M, Ruebig A, Coelingh Bennink HJT, Holzgreve W. Differential effects on the androgen status of postmenopausal women treated with tibolone and continuous combined estradiol and norethindrone acetate replacement therapy. Fertil Steril 2001;75: 20 * *
-20
-40
-60
Total T
SHBG
T:SHBG A
DHEAS
p < between groups
Dören et al., Fertil Steril 2001

10. Livial: Effects on mood and sexual well-being
The effect of Livial on endorphins
Mean b-endorphin (fmol/ml)
Livial (n = 16)
placebo (n = 14) 16 16 ** * 12 12 * 8 8
NOTES
The menopause is associated with a reduction in endorphin levels and this is thought to contribute to mood disorders. The mood-elevating effect of Livial® may be due to its ability to increase plasma endorphin levels.
• As shown in the slide, it has been demonstrated that, after the menopause, levels of b-endorphin decrease significantly compared to premenopausal women. This decrease in b-endorphin can be reversed by treatment with Livial®. An increase in b-endorphin levels has been observed in the pituitary of ovariectomized rats after treatment with Livial®. Furthermore, a similar effect was seen in a study involving 30 postmenopausal women who were treated with Livial® (2.5 mg/day) over a period of six months. Levels of b-endorphin were found to return to premenopausal levels after approximately eight weeks of treatment, in contrast to levels in those women receiving placebo, which were unchanged1.
References
1. Genazzani AR, Petraglia F, Facchinetti F, et al. Effects of Org OD 14 on pituitary and peripheral b-endorphin in castrated rats and post-menopausal women. Maturitas 1987;Suppl 1:35–48. 4 4
Pre Post Before 1 2 6
menopausal treatment Months’ treatment
*p < 0.05; **p < between groups
Genazzani et al., Maturitas 1987

11. Livial: Effects on sexual well-being
The effects of Livial on vaginal blood flow, sexual desire and arousability
Vaginal Pulse Amplitude (mV)
Vaginal Pulse Amplitude (mV)
changes vs. baseline
n = 37 5 3
Premenopausal * 4
Postmenopausal
+ Livial 2 3
Postmenopausal
+ Placebo * 2 1
NOTES
The aim of this randomized, double-blind, cross-over study was to compare the effects of 3 months of treatment with Livial® or placebo on sexual function (in particular, vaginal blood flow, and sexual desire and arousability) and climacteric symptoms in postmenopausal women (n=38).
Vaginal blood flow during erotic stimulation by fantasy and film was measured using a vaginal photoplethysmograph and subjects completed sexual function questionnaires and daily diaries.
Livial® significantly increased baseline vaginal pulse amplitude (VPA) levels compared with placebo. There were significant treatment differences in VPA in favor of Livial® during fantasy periods, but not during erotic film stimulation. This may point to two possible pathways of female sexual response.1
References
1. Laan E, Lunsen HW van, Evaraerd W. The effects of tibolone on vaginal blood flow, sexual desire and arousablilty in postmenopausal women. Climacteric 2001;4:28-41. 1
Baseline
Erotic Fantasy
* p < 0.05 between Livial and placebo for postmenopausal women
Laan et al., Climacteric 2001

12. Livial: Effects on mood and sexual well-being
Effect on libido: Livial vs. placebo
Change in scale 2
Livial (n = 14)
Placebo (n = 14) 1
NOTES
• Livial® has shown to improve libido. A one-year, placebo-controlled study involving 28 postmenopausal women used a questionnaire about sexual desire to evaluate the effect of Livial® (2.5 mg/day) on libido1. The questionnaire, which was completed after three, six and twelve months of treatment, evaluated 10 specific aspects of sexual desire which were rated on a scale of –3 (much decreased) to +3 (much improved). These specific aspects related to the degree of sexual attraction, sexual interest, initiation of sexual activity, sexual fantasies, coital activity, intensity of orgasmic response, and coital difficulty.
• Livial® significantly improved sexual desire after three months and this improvement was maintained until the end of treatment, whereas placebo failed to elicit a positive effect1.
• The beneficial effects of Livial® on libido are thought to be due to the alleviation of flushes, sweating and vaginal dryness, but also to its androgenic characteristics.
Reference
1. Palacios S, Menendez C, Jurado AR, Castano R, Vargas JC. Changes in sex behaviour after menopause: effects of tibolone. Maturitas 1995;22:155–61.
libido
pain
Sexual
attraction
initiation
fantasies
excitement
activity
orgasm
responsiveness
partner initiation -1
Aspects of sexual desire
+3 = much improved; 0 = no change; –3 much decreased
Livial significantly different for all values at 12 months (p <0.01)
Palacios et al., Maturitas 1995

13. Livial: Effects on mood and sexual well-being
Effect on sexuality: Livial vs. control
Sexual enjoyment
Libido
Mean scores
Mean scores
Baseline
1 year
2 years 4 4 3 * 3 *
NOTES
• As part of a larger study, Rymer and colleagues1 investigated the effects of Livial® on vaginal symptoms in postmenopausal women. A total of 46 women received Livial® for two years and 45 women not using any form of HT served as controls. All women were asked to complete a questionnaire, rating sexual enjoyment on a scale of 1 (no enjoyment) to 4 (lots of enjoyment) and libido on a scale of 1 (no interest) to 4 (lots of interest).
• There was significant improvement in libido (p < 0.05) and sexual enjoyment (p < 0.001) in the women receiving Livial®, whereas there was no change in the control group.
• Libido and sexual enjoyment improves with Livial® therapy.
Reference
1. Rymer J, Chapman MG, Fogelman I, Wilson POG. A study of the effect of tibolone on the vagina in postmenopausal women. Maturitas 1994;18:127–33. 2 2 ** ** 1 1
Livial Controls
Livial Controls
Livial group (n = 46); control group (n = 45) *p < 0.05; **p < 0.001
Rymer et al., Maturitas 1994

14. Livial: Effects on mood and sexual well-being
Effects on sexuality of postmenopausal women: Livial vs. estrogen plus androgen
Frequency of orgasm
Score 6 *
Initial values * 5
Final values 4 3 2
NOTES
The objective of this study was to evaluate whether the addition of a weak androgen to ET may improve postmenopausal bone loss and sexual activity without adverse effects on lipid pattern and to compare these effects with those observed with Livial®. One-hundred-and-twenty surgically postmenopausal women were enrolled, of whom 96 completed 1-year follow-up. Four groups of patients randomly allocated to receive either 4 mg estradiol valerate mg enanthate of dihydroandrosterone intramuscularly monthly (group A; n = 23), tibolone (Livial®) 2.5 mg/day (group T; n = 23), transdermal 17-estradiol 50 g/day (group E; n = 26) or no treatment (group C; n=24). Bone mass (dual X-ray absorptiometry), serum total cholesterol, HDL, LDL, triglycerides, apolipoproteins A1 and B and sexual activity were evaluated before starting therapy and at the end of follow-up.
All active treatment groups showed an increase in bone mineral density. Sexuality improved significantly with therapy; however, Livial® and androgens increased scores to a greater extent than ET. Compared with subjects who received ET alone, those given androgens or Livial® had greater increases in frequency of orgasms and sexual responsiveness. No differences were observed regarding general sexual satisfaction, sexual interest and frequency of orgasm1.
References
1. Castelo-Branco C, Vicente JJ, Figueras F, et al., Maturitas 2000;34:161-8. 1
E 2+ A
(n = 23)
Livial
(n=23) E2
(n=26)
Control
(n = 24)
* p < 0.05 compared with E2 and Control
Castelo-Branco et al., Maturitas 2000

15. Livial: Effects on mood and sexual well-being
Effects on the sexuality of postmenopausal women: Livial vs. estrogen plus androgen
Sexual responsiveness
Score 10
Initial values * * 8
Final values 6 4
NOTES
This slide refers to the same trial explained in the previous slide.
References
Castelo-Branco C, Vicente JJ, Figueras F, et al., Maturitas 2000; 34:161-8. 2
E2 + A
(n = 23)
Livial
(n=23) E2
(n=26)
Control
(n = 24)
* p < 0.05 compared with E2 and Control
Castelo-Branco et al., Maturitas 2000

16. Livial: Effects on mood and sexual well-being
Effect on sexuality: Livial vs. EPT
McCoy sex scale
Livial
E2/NETA 4 3
n = 437 * 2 *
NOTES
• Livial® has shown to improve libido to a greater extent than a standard estrogen regimen.
• A double-blind, multicenter trial compared the effects of Livial® (2.5 mg/day) with 17b-estradiol (2 mg/day) + norethisterone acetate (1 mg/day) (E2/NETA; Kliogest®) in 437 postmenopausal women who received treatment for 48 weeks. Libido was assessed using the McCoy sex scale1.
• After 48 weeks, scores for all 10 factors from the McCoy sex scale were significantly improved in the Livial® group, whereas only ‘frequency’, ‘enjoyment’, ‘arousal’, ‘dryness’, ‘pain’, ‘problems’ and the overall score were significantly improved in the E2/NETA group.
• Comparing the two treatments at 48 weeks, Livial® was associated with significantly greater improvements in sexual frequency, enjoyment and satisfaction than E2/NETA.
• The additional benefits of Livial® on libido over conventional HT may be attributable to its tissue-selective androgenic effects.
Reference
1. Nathorst-Böös J, Hammar M. Effect on sexual life – a comparison between tibolone and a continuous estradiol–norethisterone acetate regimen. Maturitas 1997;26:15–20. 1 *
Frequency Enjoyment Satisfaction Total score
*E2/NETA, 17b-estradiol (2 mg/day)/norethisterone acetate (1 mg/day) p < 0.05 between groups
Nathorst-Böös and Hammar, Maturitas 1997

17. Livial: Effects on mood and sexual well-being
Effects on sexual function %
Baseline
After 4 months 10 20 30 40 50 60 * * *
n.s. * *
NOTES
The aim of this study was to assess the effect of tibolone on sexual life. Postmenopausal first-time users of hormone therapy (HT) were included in this open, multicenter study. Patients were treated with tibolone 2.5 mg daily for at least 4 months. Both at baseline and after 4 months of treatment, patients were asked to complete two different questionnaires rating their subjective assessment of their sexual problems or desires. One hundred and eighty-four women were enrolled and receive tibolone. Overall, a significant increase in women’s satisfaction with their sexual lives and a significant improvement in different aspects of libido were found. Tibolone improved several aspects of sexual life in these postmenopausal women. These effects may be due to both an increase in genital blood flow and the tissue-selective estrogenic/androgenic activity. Likewise, analysis of the VAS-based questionnaire showed that each of the items related to various dimensions of libido had improved significantly compared with baseline.
References
1. Egarter C, Topcuoglu AM, Vogl S, Sator M. Hormone replacement therapy with tibolone: effects of sexual functioning in postmenopausal women. Acta Obstet Gynecol Scand 2002; 81:
n.s.
Ability to have orgasm
Coital pain
Vaginal relaxation
Vaginal dryness
Strong sexual desire
Contentment with sex life
Little sexual desire
* P< 0.05 between groups
Results from Sexual Functioning Inventory
Egarter C. et al, Acta Obstet Scan 2002

18. Livial: Effects on mood and sexual well-being
Effects on sexual function %
Baseline
After 4 months
110 * 55
NOTES
The aim of this study was to assess the effect of tibolone on sexual life. Postmenopausal first-time users of hormone therapy (HT) were included in this open, multicenter study. Patients were treated with tibolone 2.5 mg daily for at least 4 months. Both at baseline and after 4 months of treatment, patients were asked to complete two different questionnaires rating their subjective assessment of their sexual problems or desires. One hundred and eighty-four women were enrolled and received tibolone. Overall, a significant increase in women’s satisfaction with their sexual lives and a significant improvement in different aspects of libido were found. Tibolone improved several aspects of sexual life in postmenopausal women. These effects may be due to both an increase in genital blood flow and the tissue-selective estrogenic/androgenic activity. Likewise, analysis of the VAS-based questionnaire showed that each of the items related to various dimensions of libido had improved significantly compared with baseline.
References
1. Egarter C, Topcuoglu AM, Vogl S, Sator M. Hormone replacement therapy with tibolone: effects on sexual functioning in postmenopausal women. Acta Obstet Gynecol Scand 2002; 81:
Sexual attraction
Sexual desire
Frequency
taking initiative
Partner initiative
Sexual fantasies
Sexual excitement
Change in behaviour
Coital activity
Intensity & frequency
of orgasm
Coital pain
* P< 0.05 between groups
Results of the questionnaire about sexual desire (VAS)
Egarter C. et al, Acta Obstet Scan 2002

19. Effect of tibolone and ccCE/MPA on Sexual Function
Change on the modified McCoy Scale items at 3 months * * * * * *† *† *† *† *† *† *† * *
Interest
Fantasies
Arousal
Satisfaction
Frequency
of orgasm
Frequency
of vaginal
dryness
Frequency
of painful
intercourse
* P<0.05 vs. baseline
† P<0.05 tibolone vs. ccCE/MPA
Wu et al. Climacteric 2001;4:

20. Effect of tibolone and ccCE/MPA on Sexual Function Sexual drive, interest and/or performance
Change on the Qualiy of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) *
* P = tibolone vs. ccCE/MPA
Huber et al. Br J Obstet Gynaecol 2002;109:

21. TOTAL study – effect on total score of the McCoy’s Sexuality Questionnaire
MFSQ total sum score *
To assess the treatment effect on sexual functioning the McCoy Female Sexuality Questionnaire, Short Form of 9-items was used. This scale has been used in numerous trials to assess sexuality by describing the sexual functioning in (post) menopausal women. The MSFQ-SF has 9 items that form 4 subscales for sexual problems: sexual interest, vaginal lubrication, orgasm and satisfaction with the partner . The answers to the items are given on a 7 point scale, with high values corresponding to best outcome.
For both treatment groups, the lowest mean total sum score was observed at baseline and the highest mean total sum score at visit 3. A higher score means an improvement in sexual functioning.
For the total score at visit 3, a statistically significant difference was observed between the 2 treatment groups. The tibolone group showed a significantly larger improvement at visit 3 and endpoint as compared with the E2/NETA group.
*p<0.05 between treatment groups

22. TOTAL Study – Sexual Interest** *
In literature the lost of interest and the lost of desire is the main complaint experienced by women in the menopause.
At visit 3 and endpoint, statistically significant differences were observed between the 2 treatment groups with respect to the change from baseline in the dimension score “sexual interest”. The tibolone group showed a significantly larger increase at visit 3 and endpoint as compared with the E2/NETA group. Scores at Y axis are mean actual scores
Also note that the tibolone group has better baseline values concerning sexual interest, so there is less room for improvement
*p<0.05 between treatment groups, **p=0.003 between treatment groups

23. Livial: Effects on mood and sexual well-being
Conclusions
Livial improves mood and libido in postmenopausal women
Livial improves sexual well-being by increasing sexual desire, frequency of arousability, sexual fantasies and vaginal lubrication
Livial produces significant improvement in sexual enjoyment compared to EPT with regard to intercourse frequency and satisfaction

24. Hormone therapy Treat menopausal symptoms Hot flushes Night sweats
Vaginal dryness
Dyspareunia
Use of oestrogens may improve sexual function and in some studies further with addition of androgens
(Davis SR et al Maturitas 1995)
Horm one replacement

25. Management of Sexual Dysfunction
History and examination to exclude physical factors
Vaginal dryness, atrophic vagina, introital narrowing
Psychosocial factors
Life stress, relationship issues, previous sexual difficulties
Medications
Illness either in women or partner
Investigation when appropriate

26. Management of Sexual Dysfunction
Hormone therapy
E +/- P initially or Livial
If no improvement when testosterone low add T (off label use)
If no improvement in sexual function
Search for other causes
Counselling
Couple therapy