From the literature it appears that the prevalence of sexual problems
Sexual dysfunction in the
in women is high, that the prevalence increases with age, and thatthe menopausal transition has a negative influence on sexuality [2- peri- and postmenopause
8]. The prevalences of sexual dysfunctions may be underestimatedin several of the surveys cited in the present paper as only sexually Status of incidence, pharmacological treatment and possible risks
active women are included in the surveys. Hypoactive sexual desire A secondary publication
is the most frequently reported sexual problem in women, rangingfrom 15-25% in the premenopausal women to 40-50% in the post- Nina Gregersen, MD1, Pernille Tine Jensen, MD, PhD2 & menopausal women. Lubrication problems are reported in 10-15% Annamaria G. Elena Giraldi, MD, PhD3 of the premenopausal women increasing to 25-30% of the postmen-opausal women. Problems with orgasm occur in approximately 20%of all age groups; however, there is a tendency towards a higher fre-quency among the youngest women. Dyspareunia is rare among 1) Department of Urology, Aalborg Hospital, Aarhus University Hospital,2) Herlev University Hospital, Department of Gynecology and Obstetrics, younger women (approximately 5%), it increases with age but fluc- 3) H:S Rigshospitalet, Sexological Clinic, Division of Sexological Research tuates greatly among the postmenopausal women. The reported Correspondence: Nina Gregersen, Blegdalsparken 7 st. tv., DK-9000 Aalborg, prevalence of dyspareunia in the latter group varies between 12%- Denmark, E-mail: ninagregersen@dadlnet.dk Conflicts of Interest: Hired and paid as a consultant by Pfizer, Annamaria Gi- Thus, there is an association between the menopausal transition, raldi has been project coordinator and chief responsible in medical trials age and an increasing prevalence of FSD. However, it remains un- conducted on the effect of a new selective estrogen receptor modulator and clear which factors related to the menopause that contribute the sildenafil on female sexual dysfunction in postmenopausal women. Subse-quent teaching of general practitioners, for which Ms. Giraldi has also been most to the observed increase. It is known from several studies that responsible was organized and paid for by Pfizer. Similarly, Pernille Jensen multiple factors influence female sexuality: The general health of the received payment as a consultant in the same medical trials.
woman, hormonal changes, the woman’s previous sexual function,partner’s erectile dysfunction, changed life- and partner status, the woman’s expectation to her sexual life during the peri- and post-menopause and her acceptance of physiological and psychological The frequency of female sexual dysfunction increases with age, and the men- During the menopausal transition there is a sudden drop in the opausal transition has a negative effect on the sexuality. Pharmacological endogen estrogen level, whereas a gradual decline in the androgen treatment options for female sexual dysfunction during the peri- and post- level starts around the age of 25 resulting in a low level around the menopause include hormone therapy or sildenafil. A limited number of ran-domized, controlled trials have been conducted and evidence suggests that menopause. It is well known that the postmenopausal low estrogen systemic hormone therapy with estrogen, estrogen/progesterone, estro- level produces vaginal atrophy, which predisposes to lubrication gen/testosterone and tibolone have a positive impact on sexual dysfunction problems. Few studies have elucidated the prognostic significance of during the peri- and postmenopause. Further, there is evidence that treat- a drop in the endogen hormone level for the occurrence of FSD in ment with local estrogen relieves vaginal dryness and dyspareunia. Recentknowledge on side effects related to hormone therapy necessitates careful the postmenopause. Dennerstein et al have in their prospective, ob- evaluation of the indication for hormone therapy and the duration of post- servational population-based study demonstrated that a drop in se- menopausal hormone therapy should be as short as possible. Long-term side rum estradiol is correlated to reduced sexual desire and sexual re- effects of testosterone have not yet been fully investigated. A positive effect of sponsivity, defined as arousability, orgasm and sexual pleasure. In sildenafil has been observed in a limited group of women; those with arousal the same study there was no correlation between serum androgen problems but with no desire problems. The results suggest an intensified fo-cus on new pharmaceutical products for the treatment of female sexual dys- levels and FSD [4, 10]. Minor studies on both pre- and postmeno- function in the postmenopause. For the time being the effect of testosterone pausal women as well as women with surgically induced menopause therapy and tibolone on female sexual dysfunction is being investigated.
have demonstrated a correlation between reduced sexual desire and Sexual dysfunction in women (Female Sexual Dysfunction, FSD) is multi-factorial and influenced by physiological, psychological, socialand emotional factors. FSD is defined in four diagnostic groups: de- PHARMACOLOGICAL TREATMENT
sire-, arousal-, orgasm- and pain problems. Recently, it has been FSD is traditionally treated with sexological counselling and/or hor- suggested that the woman herself should assess the dysfunction as mones. However, within the past years, the successful development distressful to be diagnosed as having a sexual dysfunction [1]. There of new pharmacological treatments of erectile dysfunction in men are only a limited number of well-conducted population surveys on has resulted in an increasing focus on the development of new phar- the prevalence of FSD. Further, relatively few randomized, control- macological treatment options for FSD. Pharmacological treatment led trials of pharmacological treatment of FSD have been carried options of FSD in postmenopausal women can be hormonal (estro- gen, estrogen/progesterone, estrogen/testosterone, and tibolone) ornon-hormonal (sildenafil). Several uncontrolled studies of the effect of these products on FSD in postmenopausal women have been A computer-based search in PubMed was conducted with the key conducted. However, as previously mentioned, we have decided to words: Sexual function, female sexual dysfunction, sexual dysfunction, focus on the limited number of randomized, blinded, placebo con- sexuality, postmenopausal [women], androgen deficiency syndrome, trolled trials (Table 1).
menopause, dyspareunia, vaginal atrophy, vaginal dryness, hormonereplacement therapy (HRT), estrogen, tibolone, sildenafil, Viagra, tes- SYSTEMIC ESTROGEN
tosterone and androgen. Papers through 2004-2005 were selected and Estrogen is fat-soluble and exerts its effect on intracellular receptors.
reviewed for design and content, further using their references to lo- The estrogen-receptor complex penetrates to the nucleus of the cell cate other relevant papers. It was decided to focus on randomized, where it is bound reversibly to the DNA, and then induces mRNA controlled trials with regard to the effect of pharmacological treat- synthesis, protein synthesis and mitosis activity. This leads to the ef- ment of sexual problems during the peri- and postmenopause. fects of estrogen, among these the proliferation of the vaginal mu-cous membrane. In addition, estrogen receptors are present in other D A N I S H M E D I C A L B U L L E T I N V O L . 5 3 N O . 3 / A U G U S T 2 0 0 6 Table 1. Overview of randomized, controlled studies of pharmacological treatment of sexual dysfunction in postmenopausal women.
Dennerstein L et al 1980 (16) . . RCT, DB, PC, CO Nathorst-Böös J et al 1993 (17). RCT, DB, PC Kökcü A 2000 (18) . . . . . . . . . . . RCT, SB Nathorst-Böös J et al 1997 (19). RCT, DB Wu MH et al 2001 (20) . . . . . . . RCT, SB Suckling J et al 2003 (21) . . . . . RCT, DB Sarral P et al 1998 (22) . . . . . . . RCT, DB Lobo RA et al 2003 (23). . . . . . . RCT, DB Flöter A et al 2002 (24) . . . . . . . RCT, DB, CO Shifren JL et al 2000 (25). . . . . . RCT, DB Buster JE et al 2005 (26) . . . . . . RCT, DB, PC Simon J et al 2005 (27) . . . . . . . RCT, DB, PC Laan E et al 2001 (28) . . . . . . . . RCT, DB, PC, CO Palacios S et al 1995 (29). . . . . . RCT, SB, PC Basson R et al 2002 (30) . . . . . . RCT, DB, PC Berman J et al 2003 (31) . . . . . . RCT, DB, PC Basson R and Brotto L 2003 (32) RCT, DB, PC, CO RCT = Randomized, controlled study; DB = Double blind; SB = Single blinded; PC = Placebo controlled; CO = Cross-over study; E+T = Estrogen + testosterone; E+P = Estrogen-progesterone; NA = Not Available; ↑: Increase/Improvement; ↓: Decrease; →: No change* A positive effect of tibolone was found on all measured goals, but compared to estrogen-progesterone treatment the only additional effect of tibolone was measured on sexual activity, pleasure and satisfaction.
tissues, e.g. in the central nervous system (CNS), the pituitary gland ported by studies in which the effect of estrogen has been compared to other hormone treatments [18-20].
Whether hormone therapy using estrogen/estrogen combined with progesterone actually does alleviate FSD has been debated for LOCAL ESTROGEN
many years and remains controversial. Clinical experience and the Estrogen can be administered vaginally as creams, pessaries, tablets results of several studies have shown that urogenital discomforts or estradiol releasing ring. The local administration results in a con- arising in relation to the menopausal transition can be alleviated siderable local effect but a minimal systemic effect.
with estrogen. Postmenopausal women treated with estrogen report A Cochrane review from 2003 of local estrogen treatment of vagi- less vaginal irritation, vaginal dryness and pain during intercourse.
nal atrophy analyzed 16 studies of 2129 surgically induced or natu- However, only a limited number of studies have investigated this in a rally postmenopausal women. Evidence pointed towards that local randomized design. A study from 1980 on 36 women with surgically estrogen treatment has a positive effect on vaginal dryness and dys- induced menopause demonstrated that estrogen-only treatment, pareunia regardless of application form. However, the tablets dem- compared with placebo or levonorgestrel, significantly improved the onstrated significantly better effect compared to either creams or the women’s sexual desire, lubrication, orgasm frequency and overall vaginal ring/pessary. None of the treatments altered the sexual de- sexual pleasure [16]. Nathorst-Böös et al demonstrated in a large study from 1993 of 239 naturally postmenopausal women that es-trogen-only treatment significantly increased the frequency of sex- SYSTEMIC ESTROGEN AND ANDROGEN
ual activity and sexual fantasies, improved the level of sexual pleas- Like estrogen, testosterone is a steroid which crosses the cell mem- ure and vaginal lubrication, and decreased dyspareunia compared to brane and is bound to intracellular receptors after being trans- placebo [17]. Hence, only a limited number of randomized trials formed into dihydrotestosterone. Subsequently, the receptor-hor- have investigated the effect of estrogen treatment on the sexual func- mone complex penetrates the nucleus of the cell resulting in protein tion in comparison to placebo. However, both studies show a posi- synthesis. Like estrogen receptors, testosterone receptors are present tive effect. The positive effect of estrogen on FSD is further sup- both in peripheral tissues and in the CNS. D A N I S H M E D I C A L B U L L E T I N V O L . 5 3 N O . 3 / A U G U S T 2 0 0 6 Results from several studies suggest that testosterone may have a was only superior regarding sexual satisfaction and pleasure [19].
positive effect on FSD in the postmenopause. There are currently no Two minor randomized studies have demonstrated that tibolone registered hormone products with a combination of estrogen and compared to estrogen-progesterone treatment incurs better results testosterone or testosterone-only, for the treatment of menopausal on sexual desire and dyspareunia [18, 20].
symptoms. Despite this, estrogen/testosterone combinations havebeen used off-label for some years (e.g. in the United Kingdom, the SILDENAFIL
Sildenafil is a phosphodiesterase 5 inhibitor (PDE5-inhibitor), Currently, there is an on-going discussion about the existence of which relaxes smooth muscle cells through the nitric oxide/cyclic an androgen deficiency syndrome, particularly in women with men- guanosine monophosphate (cGMP) system. Sildenafil increases the opause induced by surgery, radiotherapy, or chemotherapy. Clinical vaginal blood flow leading to increased lubrication. At this back- observations suggest that the initial positive effect of estrogen treat- ground sildenafil can theoretically be expected to increase sexual ment on FSD decreases with time. Based on these observations sev- pleasure and satisfaction in women with lubrication problems. eral studies have been conducted, to investigate the effect of estrogen A randomized study of 204 naturally postmenopausal women, and testosterone in different administration forms on FSD. who were experiencing sexual problems and not receiving any hor- In 1998 Sarrel conducted a study of 20 surgically induced or natu- mone supplements, demonstrated that sildenafil treatment com- rally postmenopausal women. Despite estrogen/estrogen-progester- pared to placebo did not result in improved sexual function regard- one treatment, all women still had menopausal symptoms, lubrica- ing lubrication, genital sensitivity, sexual pleasure or satisfaction tion problems, dyspareunia and reduced sexual desire. Following a with sexual life [30]. The lack of effect of sildenafil in this particular two week wash-out placebo period, the effect of estrogen-only treat- study can be attributed to the fact that the test group was very heter- ment versus estrogen + testosterone treatment was investigated.
ogeneous: All included women were complaining of arousal prob- Compared to the group receiving the estrogen-only treatment, the lems, but this was only the primary problem in approximately 50% group receiving the combination of testosterone and estrogen treat- of the women. Subsequent studies with sildenafil were conducted on ment reported a significant improvement in sexual desire. However, women primarily experiencing arousal and orgasm problems. Ber- there was no effect on lubrication and dyspareunia suggesting that man et al observed the effect of sildenafil on FSD in 192 surgically these are primarily influenced by estrogen [22]. In a recent, double- induced or naturally postmenopausal women. The women were re- blind randomized study of 218 surgically or naturally induced post- ceiving HRT in the form of estrogen/estrogen-progesterone. Moreo- menopausal women with hypoactive sexual desire, it was found that ver, women with low levels of plasma testosterone, received testo- estrogen and methyltestosterone treatment significantly increased sterone treatment. The study showed that in women with arousal both the level and frequency of the women’s sexual desire compared problems but no concomitant desire problems sildenafil improved to the estrogen-only treatment. These findings suggest a positive ef- genital sensitivity, lubrication, subjective arousal, orgasm and satis- fect of the androgen component of the combination treatment [23].
faction with intercourse, whereas there was no effect on those A randomized cross-over study of 44 surgically induced menopausal women who also experienced desire problems. The same study women showed that treatment with estrogen-testosterone signifi- showed no effect on desire and dyspareunia [31]. Basson & Brotto cantly improved sexual desire and pleasure compared to estrogen investigated 34 naturally postmenopausal women receiving estro- treatment only [24]. Finally, a randomized cross-over study of 65 gen-progesterone treatment for diagnosed arousal and orgasm surgically induced menopausal women, continually receiving estro- problems. The study demonstrated that sildenafil did not improve gen treatment, demonstrated that transdermal testosterone treat- orgasm and subjective sexual arousal, even though it was objectively ment significantly improved sexual activity and pleasure/orgasm measured that sildenafil increased the blood flow to the vagina dur- while sexual desire and arousability were not significantly improved [25]. Two large studies of 562 and 533 surgically induced menopau- In conclusion, the above studies only demonstrate a positive effect sal women with hypoactive sexual desire disorder have recently been of sildenafil in a selected group of women, i.e. those with arousal reported. They showed that women receiving testosterone (300 problems and no concurrent desire problems. The manufacturers of µg/day) as a transdermal patch together with concomitant oral es- the product have decided to no longer test sildenafil for treatment of trogen experienced a statistically significant increase in the fre- sexual problems in women. It therefore remains uncertain whether quency of total satisfying sexual activity, as well as a statistically sig- there would be any beneficial effects in women experiencing sexual nificant increase in sexual desire when compared to estrogen-only problems due to diseases like depression, diabetes or adverse events therapy. Significant improvements were also seen in arousal, or- gasm, pleasure, responsiveness, concerns, self-image and distresslevels for women using the female testosterone patch. Overall, ad- RISKS RELATED TO PHARMACOLOGICAL TREATMENT
verse events were similar in the testosterone and placebo groups. Al- Recently, adverse events to HRT have been evaluated in several large though the overall incidence of androgenic adverse events was low, studies [33-37]. They found that HRT increased the risk of ischemic the incidence was slightly higher in the testosterone group [26, 27]. heart disease, breast cancer, stroke and pulmonary embolism. Theduration of the treatment as well as socio-economic status and the TIBOLONE
presence of diabetes were significant prognostic factors regarding Tibolone is a synthetic steroid with estrogenic- and gestagenic ef- these complications. Treatment with tibolone seems to be associated fects as well as a weak androgenic effect. The effect of tibolone on with a lower risk of developing breast cancer compared to HRT with FSD has also been tested. Two minor, randomized placebo control- estrogen and progesterone but a higher risk than treatment with es- led trials have demonstrated a positive effect of tibolone regarding trogen-only [33]. However, recently a multicenter study investigat- sexual desire, lubrication and orgasm, whereas only one of the stud- ing the use of tibolone for treatment of osteoporosis in elderly ies has demonstrated a positive effect on dyspareunia [28, 29]. To in- women have been terminated as there were indications of a higher vestigate whether the androgenic effect of tibolone makes it superior risk of stroke in the tibolone group compared to placebo [38]. These to estrogen/estrogen-progesterone treatment regarding FSD, Nath- studies have prompted a revised official recommendation from the orst-Böös & Hammar conducted a randomized controlled study in Danish Medicines Agency advising that short-term hormone ther- 315 naturally postmenopausal women. An improvement was ob- apy in relation to substantial discomforts experienced during and served in the tibolone arm regarding all measured endpoints: Sexual after the menopausal transition is still well-founded. Clinical rec- desire, lubrication, orgasm, pain and overall sexual satisfaction.
ommendations from the Danish Society of Obstetrics and Gynae- However, comparing tibolone to estrogen-progesterone, tibolone cology state that hormone supplements can be applied to release D A N I S H M E D I C A L B U L L E T I N V O L . 5 3 N O . 3 / A U G U S T 2 0 0 6 FSD after the menopause [39]. The need for hormone treatment 8. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: must be carefully assessed on an individual basis, taking into ac- prevalence and predictors. JAMA 1999; 281:537-44.
count possible risks relating to the individual woman. The lowest 9. Avis NE, Stellato R, Crawford S et al. Is there an association between menopause status and sexual functioning? Menopause 2000; 7:297-309.
possible dose should be used and the treatment duration should be 10. Dennerstein L, Randolph J, Taffe J et al. Hormones, mood, sexuality, and the menopausal transition. Fertil Steril 2002; 77 Suppl 4:S42-8.
Adverse events related to local estrogen treatment are rare, but no 11. Dennerstein L, Lehert P. Modeling mid-aged women’s sexual function- studies have evaluated long-term effects beyond six months. One ing: a prospective, population-based study. J Sex Marital Ther 2004;30:173-83.
study has demonstrated that the use of estrogen cream was corre- 12. Davis S. Testosterone deficiency in women. J Reprod Med 2001; 46(3 lated with a significant increase in vaginal bleedings, breast tension and perianal pain compared to vaginal estradiol tablets [21].
13. Guay A, Jacobson J, Munarriz R et al. Serum androgen levels in healthy Treatment with testosterone is based on the principle that serum premenopausal women with and without sexual dysfunction: Part B: Re- levels of testosterone should be kept within upper normal range; duced serum androgen levels in healthy premenopausal women withcomplaints of sexual dysfunction. Int J Impot Res 2004; 16:121-9.
thereby unwanted adverse events are believed to be minimized. Po- 14. Guay AT, Jacobson J. Decreased free testosterone and dehydroepiandros- tential adverse events are acne, weight gain, hirsutism, voice changes terone-sulfate (DHEA-S) levels in women with decreased libido. J Sex and serum lipid changes. Few adverse events have been reported in Marital Ther 2002; 28 Suppl 1:129-42.
those controlled studies published on testosterone treatment, given 15. Floter A, Nathorst-Boos J, Carlstrom K et al. Androgen Status and Sexual Life in Perimenopausal Women. J North Am Menopause Soc 1997; 4:95- that the serum testosterone has been kept within the normal physio- logical level [26, 27, 41]. However, future studies are to evaluate pos- 16. Dennerstein L, Burrows GD, Wood C et al. Hormones and sexuality: ef- fect of estrogen and progestogen. Obstet Gynecol 1980; 56:316-22.
The adverse event profile of sildenafil is similar in women and 17. Nathorst-Boos J, Wiklund I, Mattsson LA et al. Is sexual life influenced men: Headache, facial flushing, dizziness, rhinitis, upper dyspep- by transdermal estrogen therapy? A double blind placebo controlledstudy in postmenopausal women. Acta Obstet Gynecol Scand 1993; sia and visual disturbances. The adverse events are described as mild and transient in the present cited studies [30-32].
18. Kokcu A, Cetinkaya MB, Yanik F et al. The comparison of effects of tibo- lone and conjugated estrogen-medroxyprogesterone acetate therapy on CONCLUSION
sexual performance in postmenopausal women. Maturitas 2000; 36:75-80.
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21. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in The treatment of FSD in postmenopausal women should be based postmenopausal women. Cochrane Database Syst Rev 2003;:CD001500.
on an individual assessment where the points of reference are the 22. Sarrel P, Dobay B, Wiita B. Estrogen and estrogen-androgen replacement woman’s subjective discomforts, risk factors and potential underly- in postmenopausal women dissatisfied with estrogen-only therapy. Sex-ual behavior and neuroendocrine responses. J Reprod Med 1998; 43:847- ing causes of the problem. If pharmacological treatment of FSD is deemed indicated, several randomized studies have demonstrated a 23. Lobo RA, Rosen RC, Yang HM et al. Comparative effects of oral esteri- positive effect of systemic hormone therapy with estrogen/estrogen- fied estrogens with and without methyltestosterone on endocrine pro- progesterone, combined estrogen and androgen as well as with tibo- files and dimensions of sexual function in postmenopausal women with lone. Moreover, local estrogen therapy has demonstrated a positive hypoactive sexual desire. Fertil Steril 2003; 79:1341-52.
24. Floter A, Nathorst-Boos J, Carlstrom K et al. Addition of testosterone to effect on vaginal dryness and dyspareunia. One study has demon- estrogen replacement therapy in oophorectomized women: effects on strated a significant effect of sildenafil on lubrication problems in sexuality and well-being. Climacteric 2002; 5:357-65.
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The known side effects of hormone therapy and the compara- 26. Buster JE, Kingsberg SA, Aguirre O et al. Testosterone patch for low sex- tively sparse effect of sildenafil necessitate an intensified focus on ual desire in surgically menopausal women: a randomized trial. Obstet new areas in the field of pharmacological treatment options of FSD.
Internationally, most research is being conducted with testosterone 27. Simon J, Braunstein G, Nachtigall L et al. Testosterone patch increases but the risk of potential side effects demands long-term follow-up.
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29. Palacios S, Menendez C, Jurado AR et al. Changes in sex behaviour after menopause: effects of tibolone. Maturitas 1995; 22:155-61.
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31. Berman JR, Berman LA, Toler SM et al. Safety and efficacy of sildenafil 2. Bachmann GA, Leiblum SR. The impact of hormones on menopausal citrate for the treatment of female sexual arousal disorder: a double- sexuality: a literature review. Menopause 2004; 11:120-30.
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38. www.dkma.dk. Discontinuation of a clinical trial of Livial® (tibolone).
39. Andersen LF FAGELONLPAPAPE. Guidelines concerning peri- and postmenopausal hormon therapy (in Danish) http://www.dsog.dk/files/Guidelines_HT_23_01_05.pdf. 2005. 40. Laegemiddelstyrelsen. Alvorlige bivirkninger fører til ændrede ret- ningslinier for brugen af hormonbehandling i EU (in Danish).
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D A N I S H M E D I C A L B U L L E T I N V O L . 5 3 N O . 3 / A U G U S T 2 0 0 6

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