This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. 10.1111/cen.13906doi: lead todifferences version between this andthe ofPleasecite article Version Record. this as been and throughtypesetting, proofreadingwhich may thecopyediting, process, pagination undergoneThis article and buthas has not for review accepted fullpeer been publication E-mail: [email protected] UK London W12 0NN Floor6th Commonwealth Building, Hammersmith Campus,Du Cane Road Department Investigative of Imperial Medicine, College London Prof. Waljit S.Dhillo C London, UK. Affiliations: Franks Authors: Running Title: therap Title Articletype : Requested Review ) ) 6804 2008 Acceptedorresponding Author: Article

: - - A systematic review randomisedof controlled trials investigatingefficacy the andsafety of 7570 0752 2 , Waljit S. Dhillo Channa N. Jayasena - - 0000 0000 1 Department of Investigative Medicine, Hammersmith Hospital, Imperial College Testosterone therapy postmenopausalfor women - - 0000 0000 y for in postmenopausal women 2 D: D: Department of Surgery & Cancer, Imperial College London, London,UK 1 1 , Fatima Alkaabi M. (( DI dDc D DI dDc D ALCHH ADTROAcWDHD ScOO D ADESR RDDARNRHCRD 1 , Curtis S.Liebers

1 , ThomasHandley

1 , Stephen

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. flushes, low mood, andsymptoms vulvovaginal of . AcceptedReduc activity. typically occurs Menopause is the cessation menstruationof and reproductive function, due to reduced ovarian Introduction clinicians treating post-menopausal women. women clear. not is This articleprovide will a concise and critical summary of cholesterol.Furthermore, the long-term safetyprofile of testosterone therapypost-menopausal in include increasedbone mineral densitydecreased and serum high density lipoprotein ( menopausal women. Some studies suggest that testosterone therapyadditional has effects which pathophysiological role of testosteroneduring the menopause is less clear. Several randomised, The clinical sequelae oestrogenof deficiency during menopause are undoubted. However,the Summary Article Key words: connection with this article. Conflict of interest: Department Health. of authors and not necessarily those of the above mentioned funders, the NHS, the NIHR, the or Doctoral Fellowship. WSD funded is by anNIHR Professorship. views The expressed are those of the fundedis by AbuDhabi the Health Services company CNJ (SEHA).is funded by anNIHR Post- BBSRC supported andis by NIHR the Imperial Biomedical Research Centre FundingFMA Scheme. Acknowledgements: ed – circulating levels oestrogenof during menopause transition or perimenopausemay hot cause controlled clinical trials suggest that testosterone therapy improves sexual function in post- Testosterone, , Women, Menopause, Sexual Dysfunction, Safety, The authors have stated explicitly there that are no conflicts interestof in The The Section of Investigative Medicine fundedis by grants from MRC, the between 45-55 of years age.

2

The hallmarkThe symptoms menopausal of 1

th e literature, guideto HDL ) )

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. AND ‘placebo OR OR random OR rand OR peri-menopausal OR perimenopause OR peri- ‘postmenopausal OR post searched using following the OR terms: ‘female OR women OR ’, AND using search terms upuntil July were 2018 considered for inclusion theto study. Databases were and Meta-Analyses (PRISMA) statement during July 2018. PubMed, was conducted in accordance with Preferredthe ReportingItems SystematicReviews for Search andselection: Materials and methods: replacement for sexual dysfunctionpostmenopausal in women. objective summary evidence the of dateto investigating effectiveness the and safety testosterone of reflects uncertainty about the safety andeffectiveness therapy.of article This aims provide to an post-menopausalwomen; however, prescribing behav currentlygrowing interest in the roletestosterone of therapyforthe treatment of sexual dysfunction in It over is 60years since testosterone therapywas first reported in the are thought includeto regulation of male characteristics. However, women depend also on physiological the action of wh A suffer from symptoms urogenital of and sexual dysfunction. menopause transition and post menopause. Itestimated is that 50 receptivity andresponsiveness, and reducedfrequency sexual of thoughts and fantasies during menopausal transition and even beyond. menopause itself. Women may vaginal experience atrophy andvaginal dryness mostly the in late transition/perimenopause are hot flushes and irregular periods, whereas amenorrhoea is required for ndrogen

Accepted Article testes ,

s are natural , and

A search of the electronic databases CENTRAL, EMBASE, MEDLINE and

steroid adrenal glands -menopausal OR postmenopause OR post-menopause OR perimenopausal libido .

8 s

2,3,4 regulating

and

Some women experience also decreasedlibido,

omised OR randomized OR randomly randomly OR menopause OR climacteric’ AND ‘testosterone’

the development andmaintenance of classically io u r isr highly variable across UK, the which 10 5,6 . (SeeFigure 1.) All studies identified 7

Androgens are synthesized in – postmenopausal women. 60% of all postmenopausal women

9

There isThere ich ich This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Acceptedhormone binding globulin (SHBG) andalbumin andcorticosteroid binding globulin. Circulating androgen Testosterone is the major ovarian androgen, and dehydroepiandrosterone (DHEA) theis major adrenal The ovaries and the adrenal glands are majorthe sources of androgen synthesis in women. males andfemales. conversion to E2or DHT to express its biological effects, it too becan considered apro-hormone in conversion to testosterone DHT or expressto their androgenic effects. circulation, DHEAS, DHEA, and may beconsidered pro-, requiring (DHEA), androstenedione, testosterone, and (DHT). Though abundant thein normal cycling women are dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone circulating and T E2have picomolar similar concentrations. The major androgens thein serum of However, androgens also play abiological role Further, women.in in premenopausal women, Oestrogens are the dominant sexhormones required for female reproductive maturationactivity. and Androgens and their role sexualin function Article subjectof participants; design study the of study, references and source of funding. randomization; treatment duration; allocation; route of administration and treatment dosage; number Data identified for all studies were: date publication; of intervention administered; blinding; consensus. A total 69of studies fulfilled the criteria for inclusion this reviewto (Figuresystematic 1). completed duplicatein by two study investigators (CSL andCNJ). Discrepancies were dealt with by Data extraction: excluded because all subjects had Rheumatoid Arthritis. dyslipidaemia, impaired memory, decreased mineral density or symptoms. One study was perimenopausal or postmenopausal women included purely pharmacokinetic outcomes.For studies be to included, weresubjects required to be allocated’. Identified studies were excluded if the abstracts were not in Englishthe language, or 13 . Androgen hormonescirculate in bloodthe streambound to carrier proteins suchsex as

Study titles abstracts and were initially screened before full-text review was presenting symptoms with sexual dysfunction, of 11

12 As testosterone requires

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. androstenedionewith or and freetotal testosterone wereWahlin-Jacobsen seen. et reportedal that the Acceptedtenth percentile were directly associated with libido, low arousal, and responsiveness. Noassociations women aged older. 45 years or In women aged 18 between an endogenous level of DHEAS below the tenth percentile and low sexual responsiveness in community-based study of 1021 randomly recruited healthy aobserved women direct association between androgens and sexual function women. in Davis al SR et reported the results of a androgen concentrations and low sexual However, function. otherstudies have shown associations natural or surgically induced) have failed demonstrateto any consistent relationship between low Some concentrations of total testosterone immunoassays measure to testosterone women; in this due is to limited accuracy and sensitivitylow at production. natural menopause and the postmenopausal seems ongoingbe an to site of testosterone androstenedione declined steeply in the early reproductiveand do not years vary as aconsequence of measured via radioimmunoassay, calculated testosterone,free dehydroepiandrosterone sulfate, and A cross-sectional study of 1423 women between the ages of 18-75 suggested total testosterone Article libido, and circumcision to prevent future penile associated is injury with recovery libido of improved . sexual function, sexual thoughts behaviour and may (atleast partially) be mediated indirectly through through aromatisation oestrogento . organisational or activational effects on brain,the which either direct may be , and bone mineral content in women. andliver, skin. receptors are located in several organs of body,the including:breast, brain, ovaries, muscle, bone, fat, androgen receptors (AR), and indirectly by conversion oestrogen to via .Androgen SHBG weakly DHEA binds not but DHEAS. testosterone highlyis bound plasma to proteins, with about 66% bound SHBGto and 33% to albumin. studies measuringstudies serum androgen levels premenopausalin andmenopausal women (whether 22,23 17

It however is importanthighlight to that there are many limitations using Moreover, testosterone knownis to havemultiple anabolic effects onmuscles, body 20 Of relevance men, in penile injury following intercourse reduces when compared with mass spectrometry. 19 It also is important to recognise that effects on sexof hormones 18

Androgens are likely to influence behaviour through 14,15,16 – . 44 years, concentrations of DHEAS below the Androgens exert biological effects by activating 24 ly ,

or or indirectlymediated . 21

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. men women or form a as of Hypoactive Disorder (HSDD). Accepteddiagnostic Associations Diagnostic and Statistical Manual of Mental prevalence of sexual dysfunction is 89.0% and 82%, respectively Index (FSFI) defined by hormone testing McCoy Female Sexu Australian born women aged 45 women using A number previous of studies have The diagnosis and prevalence of sexual dysfunction menopausal in women transition. menopausewomenduring in function sexual to significantlyrelated are 11KDHT and 11KT of levels whether investigate to required are Studies (AR). receptor androgen the of agonists potent are 11β precursor, steroid adrenal the of Articlederivatives androgen are (11KDHT) 11-ketodihydrotestosterone and (11KT) 11-ketotestosterone The post-menopause. whether a reduction endogenousin androgen production contributes sexualto dysfunction during the women.In summary, accepted is androgens it that may influence sexual behaviour, but unclearit is American Endocrine Society correlating androgen specificlevels with signs or symptoms unavailable. are Consequently, the arousal, and DHEAS positively was associated with frequency anddesire. demonstrated that endogenous testosterone was associated with masturbation frequency,libido, and prospective longitudinal study 3266women of aged 42 with libido in the total cohort of women includinghealthy women 560 aged years. 19-65 Moreover, serum leveloffree testosteroneand androstenedione were statistically significantly correlated 29 criteria in in structured postmenopausal, sexually active

for sexual dysfunction. Th ality Questionnaire rose from at 42% early menopause 88%to at late menopause questionnair . 30 28

Furthermore

recommends making against diagnosisthe of androgendeficiency in - 55 , investigated

observed that the prevalence of sexual dysfunction using the es -hydroxyandrostenedione (11OHA4). Both 11KT and 11KDHT and 11KT Both (11OHA4). -hydroxyandrostenedione . A prospective observational community based ,

cross e previous edition (DSM

the prevalence of sexual dysfunction menopausal in Malaysian and womenThai sectional studies – 52 years reportedby Randolph et JF al D isorder . 31

using Female the Sexual Function s , 32

(DSM) (DSM) provides astrict set of

- The AmericanThe Psychiatric 4) classified4) reduced libido in However, t suggest that the he newer DSM study 22,25,26,27 of of

Data - a 5 This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. werestudies restricted participantsto on their sexual function menopause. All studies excluded women with psychological or medical conditions could that i a effects of testosterone therapy during oestrogen replacement. Some have studies included women with administration. Some trials have used testosterone replacement alone, whereas others have studied the sexualof dysfunction trials have investigated the effects of testosterone therapy post in combination with oestrogen) in Greenblatt alet Effects Sexual Medicine (McCabe 2016), and summarisedis in Table1. classification system for female sexual dysfunction has been byproduced International the Society of there has been criticism the of DSMV criteria among (McCabe experts 2016). An alternative prevalencethe of sexual dysfunctionestimated using the structured questionnaire However,tools. Europe. 70 years thein US; the prevalence of HSDD was reported 12% as analysed the prevalence of symptomssexual associated with distress overin 3,500 women aged 20 physical health conditions. significant enough cause to distress theto individual, and not be attributable other to mental or sexual/erotic cues. sexual thoughts or fantasies, andreduced initiation of sexual activity absent arousal from external Disorder definedis symptomsas including classification has HSDDsplit gender-specific into diagnoses; Female Sexual interest/Arousal Acceptedge Article - associated (‘natural’) menopause, whereas others have included women with surgically induced 34 of testosterone supplementationon sexual function Therefore, the prevalence HSDDof defined using DSM-5 strict criteria muchis lower than .

in in 33 1950 conducted These These symptoms have to need persisted minimum for a duration 6months, of be (Table 2 in keeping with DSMthe The Women’s International Study Health of andSexuality ) . These trials h postmenopausal women

t he first randomi with long term partners. absent or significantly reduced interest sexual in activity, ave - utili 4 and s ed s ed . Since then, several study - 5 diagn

different dosing regimens and routes of

of of

35 ostic criteria.ostic Furthermore, most - testosterone therapy menopausal women symptoms with –

19% 19% in US the and 6%

randomi s

(alone or (alone or in ed (WISHeS)

controlled – 13% 13% in mpact – This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. significant increase in libido from baseline when compared with placebo (67% vs 48%; P=0.05) and reached total serumtestosterone levels 91ng/dLof by weekexperiencedand 24 a statistically supplementation 300,(150, 450μg) or orSubjects placebo; receiving the 300μg testosterone dose Braunstein et al. compared with placebo (1.56 episodes vs. with 0.73 episodes per 4 weeks), and improvedlibido. al. increased significantly during testosterone supplementation when compared with placebo. Buster et increase from 3.922.94 to episodes per 4-weeks the placebo in group = (p Libido0.0003). activity measured (as byfrom the SAL) 4.92 2.82to episodes per 4weeks, when comparedan with women, testosterone administration significantly increased the frequency total of satisfying sexua supplementation for at least 3months before randomisation.Simon et al. 24for weeks duration. surgically induced menopause to daily dermal patch administration of placebo or 300μg testosterone testosterone therapy.Three theof largest published studies randomised postmenopausal women with oestrogen with without or progestin therapy. Most studies haveinvestigated the effects of transdermal investigated whether testosterone improves sexual function postmenopausalin women taking Transdermal testosterone administration: Cochranereview. testosterone administration postmenopausalin women also been have summarised a in recent Sexual Activity Log; Profile Female of Sexual Function; Personal DistressThe result Scale. of self-reported instrument. used assessto sexual function among postmenopausal women, an is and anonymous patient-based Some activity?”; 30 days contains and seven items (e.g. “Are you satisfied with your present frequency sexual of modifiedthe McCoy’s sex scale Most trials measured sexual function using validated symptom scores. Some authors

Accepted42 Article

observed in 533women thattestosterone increased total satisfying sexual activity when studies

“How enjoyable sex is for you?”, and “How often doyou have an during sex?”). 39,40 45

used used the Female sexual function index (FSFI),standardis which is a 49

randomised 447

42,44, 41

45 Other Other authors

All womenAll included in these trials had received oestrogen 38

which covers sexual experience and responsiveness during the last women one to of 3 different daily doses of testosterone 42,43,44,45,46,47,48 42,43,44,45,46,47,48

Several placebo-controlled double-blind studies have have used the followingvalidated scales 44

observed that in 562 6 ed ,36,37 ,36,37

questionnaire have used was also :

l This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. conclusions are in-keeping with two recent systematic reviews of the literature. Acceptedimproves symptoms sexual dysfunction of womenin natural with or surgical menopause. These multiple randomised placebo-controlled studies suggest that testosterone therapy significantly summary, studies several suggest transdermal testosterone increasesexual activity. Collectively these following 6months of TTP administration when compared with placebo menopausalin women.In Events (SSEs; p=0.0089), p=0.0007,libido and reduced personal distress (p=0.0024) were observed SAL tomeasure satisfying sexual episodes as primarytheir Increases in endpoint. Significant Sexual randomised 272 women to transdermal testosterone patch (TTP; 300μg/day) placebo, or and used the Panay al. et surgical menopause. interesting determine to the whether effects of testosterone differed between womennatural or with a vs. 300μg placebo; testosterone, 2.1, p<0.001 vs. placebo). participants in placebothe group (episodes per 4weeks: placebo, 0.7; 150μg testosterone, 1.2, P=0.11 significantly Satisfying greater Sexual Events (SSEs) 4-weekover a when compared period with week period. surgical) and HSDD placebo to or testosterone patch at doses the 150μg 300μg or day per over a24 vs. placebo). The largest RCTperformed date to randomisedArticle 814women menopause with or (natural testosterone when compared with placebo (placebo, 0.5 testosterone, +/-0.23; 2.1+/- 0.28,p<0.0001 testosterone reported a significantly greater increase in sexual events measured using SAL during change from baseline thein number satisfying of sexual events using SAL. the Women allocated to testosterone patch (300μg/day) twice weekly 24 for weeks. were They then followed upto measure a oral oestrogen (with or without progestin). Participantsrandomised were placeboto transdermal or effects of testosterone patch 549 in women natural with menopause whowere taking astable dose of respectively,when compared with placebo in postmenopausal women. Shifren et al. testosterone supplementationreaching serum total testosterone concentrations of 44.5 and122.5ng/dL significant changeslibido in satisfying or sexual activity wereobserved during 150- similar smaller studies. frequencyin satisfying of activity sexual (79% vs 43%; p=0.049); these results concordantare with 43 48

conducted a 6-month placebo-controlled, double-blind trial (the ADORE study). They

Participants randomised to 300μgthe but group, not the 150μg group reported

46,50 However, it is important to note placebothe response was substantial. No Though not reported, it would be 18, 49

However, it is μg/d 450 or 47

studied the - μg/d - This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. double-blind study. Sexual function was significantly higher in the testosterone groupcompared when Acceptedplacebo or testosterone undecanoate 40mg combination with in oral a oestrogen in randomised Tungmunsakulchai et al. significantlytestosterone with compared placebo,to as well studies as 2006in satisfactionsex, with frequency sexual of activity, interest in sex score alland total increased Sexualitywas observed score in 2002 a study 50surgically of menopausal women effects of sex steroids sexualin function in post-menopausal women. Similar increase in McCoy lubrication. hormones onsexual function may bepartially mediated indirectly through improved vaginal placebo; oestrogen with testosterone, 147,p<0.01 vs. placebo). This implies that effects of sex (Percentage improvement McCoy in Sexuality score: placebo, 18.6; oestrogen only, 42.4,p<0.05 vs. scores increased in all treatment groups, were but highest in oestrogenthe with testosterone group placebo, oestrogen only, or oestrogen with testosterone over a12-week period. application was investigated 75menopausal in women (natural or surgical),were randomised who to non-transdermalof application of testosterone in post-menopausal women. Urogenital topical Other routes of testosterone administration Article aromatisation). this would suggest that testosterone is not simply acting supplement to bodily exposure (via women whoseserum oestradiol levelsreplete are e.g. serum E2levels- 300 600pmol/L) during HRT; specificallyinvestigate if the testosterone therapy improvespost-menopausal sexual function in improving GnRHin libido agonist-induced . . For instance in men, inhibition prevents testosterone administration from consider what to extent any effects of androgens on sexual function are attributable aromatisation to to post-menopausalin women pharmacological exert or physiological It actions. is also important to level of circulatingtestosterone. Therefore, questions remain toas whether testosterone administration important to consider that symptoms sexual of dysfunction do not have a clear relationship with low 20 Studies are needed delineateto the relative importance of vulvovaginal vs. cerebral 40 investigated the effects of twice weekly administration either of oral : Recent : clinical trials have investigated the administration 51 Finally, would it be helpful to 36 6

McCoy Sexuality and 2007. 52 ; en joyment of 37

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. womenobserved significant increases in upper lower and body strength with testosterone compared to Accepteddouble-blind randomized study by Dobs colleagues, and with 40naturally andsurgically menopausal stair-climb powerwere observed, with the greatest improvements at highestthe Furthermore,dose. improvements in several domains sexual of function, lean body mass, chest-press power, and loaded injections of placebo, 3,or 6.25, 12.5 25or mg testosterone enanthate 24for weeks. Dose-dependent oestrogen regimen during the 12-week period, and run-in were thenrandomised to receiveweekly IM underwent without or with received a standardized transdermal In double-blinded another randomised study by al., Huang et somatic symptoms between the treatment groups. regimens prevented bone loss at the spine and hip. vaginal dryness and ) were improved significantly by both treatments. both Also, treatment (2.5 mg) daily for 2years. Menopausal symptoms somatic of origin flushes,(hot either oral (1.25 mg), esterified or estrogens (1.25 mg) combined with randomised double-blind bytrial Watts et al.investigated surgically 66 menopausal women received naturallyboth andsurgically postmenopausal women increase and sexual arousal andlibido. trial. They concluded that a combined estrogen androgen therapy enhance can the quality of life for Article& testosterone 150 mg, 8.5mg, testosterone 150 mg, placebo or 1M in a controlrandomised Sherwin et al, studied 10premenopausal 43surgical menopause who received either estradiol 8.5 mg alone. estrogens esterified with achieved Treatment with the combination was well tolerated. those than greater significantly were and treatment combination with baseline fromincreased desire of frequency and desire or interest sexual measuring methyltestosterone and Scores SHBG. estrogens suppressed and testosterone bioavailable esterified of concentration the increased significantly of combination the with were Treatment Questionnaire Interest Sexual investigated. the on rated as desire or interest sexual of alone; levels in estrogens changes esterified oral or methyltestosterone / estrogens esterified combined oral either al et Lobo placebowith (FSFI scores: placebo, 28.6 ± 3.6; testosterone, 25.3 6.7,± p=0.04 vs. placebo). 53 efre a obebid admzd ra o 21 oteoasl oe receiving women postmenopausal 221 of trial randomized double-blind a performed 53-55

However, there was nosignificant difference in 56

71 menopausal women whopreviously A a This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. digitally quantified absolute percent or dense mammographic area in postmenopausal women when Acceptedperformed follow-up a study suggesting that oneyear of therapyTTP hadnosignificant effect on the testosterone group when compared with no cases in placebo the group. However, the same authors The randomised controlled trial by al. et Davis concluded that this wasnot inconsistent with background rates for women the in same age-group. Three cases of invasive during 4years ofadministration; TTP however, the authors 300μg)dose, over in 900 women sur with performed open-label, an uncontrolled safety andtolerability of trial transdermal testosterone (daily therapy post- in therapy increases the risk breast of cancer. The only published long-term investigation of testosterone tissues, most notably breast tissue women,in Breast Cancer risk: adverse effects between treatment groups. study. ; however, most were mild and rarely resulted withdrawal in from the associated with testosterone therapy were skin reactions, unwantedArticle hair growth, and vaginal (hirsutism)acne. and Accordingly, clinical trials reported that mostthe common adverse effects Testosterone therapy anticipated is causeto symptoms androgen of excess such as excess Non-sexual effects of testosterone therapy dependent. whether theobserved effects of testosterone administration on sexual function are truly dose dysfunction regardless of the route of administration. Further studies are required to investigate In conclusion, compared to placebo, some suggest nosignificant difference between the treatment groups. arousal/interest, placebo. 18,44,46,50,52,57,63,64,65,66 57 Whilst the majority studies of observed testosterone significantly increased sexual

most but not all studies suggest testosteronethat improves symptoms sexual of menopausal women been has conducted by product’s the manufacturer 39,42,52,57,58

Exogenous sex steroids may the stimulate growth sex-hormoneof dependent frequency of

Fu rthermore, two published studies observed nosignificant difference in gical menopause and HSDD, for up to 4 years duration. 67,68 69,70

48 39,57,59

over 24 weeks observed 4cases of breast cancer in so itis relevant considerto whether testosterone

and frequencyand sexual of activity 47,52,59 . 63 They 39,58,60,61,62 39,58,60,61,62

when This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. o therapy onserum is lipids likely beminor, to which is relevanceof whendiscussing therapeutic women.However, available the evidence allows us speculateto that any effects of testosterone testosterone supplementation malignancy onrisks of and in postmenopausal years of TTP therapy. increase in haematocrit, or adverse changes in glycemic markers lipid or profile following 4 upto observe no change with testosterone. effectsthe of testosterone ontriglycerides; some studies observe adecrease observedothers a decrease. cholesteroltotal with someobserving nochange with testosterone compared placebo,to significant change in lipid profilewith at all testosterone. low-density lipoprotein (LDL), disarrangements such as high-densityreduced lipoprotein (HDL) Dyslipidemia oestrogen and testosteronetreatment peras normal practice. continuous or cyclic progestin therapy non-hysterectomized to women administered combined theat highest dose by endometrial atrophy. compared with 150g/d testosterone (2.7%) placeboor (2.6%). Endometrial bleeding was accompanied endometrial bleeding was reported more frequently on 300g/dthe dose testosterone (10.6%) receive patch a delivering 300μg 150or testosterone of day per placebo. or They observed that oestrogen. Davis et al. Endometrial effects: no significant increase breastin proliferative cell activity testosterone with compared placebo. to months TTP administration 99postmenopausal in women. compared with placebo Acceptedptions with patients. Article : Whilst: many studies have suggested that testosterone administration may lipid cause

Testosterone promotes endometrial atrophy when given concomitant without 63 48 71

Further, long-term are studies required investigateto the potential effects of investigated endometrial findings 814women in randomly assigned to ; ; these data areconcordant withresults study of a by Hofling et al 55,57,76,77 18,49

someindicate nochange LDL,in A pattern similar of inconsistency the in literature observedis with 79

The authorsof a 2011studyfailed to observe any significant 48

It therefore is important provideto concurrent 78,79,80 72

Furthermore, HoflingFurthermore, also al observed et

Studies seem inconsistent regarding 18,49,55,57,66,74,75,76, 74,75,77

a decrease LDL, in 55,57,76,77 77

and an increase in

whereas others 74,75,79 of

76 6 whilst

or or no 73

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. However, other studiesdata d studies have shown an increased risk cardiovascular of events in men treated with testosterone. if the risk of thromboembolic and cardiovascular disease is altered during therapy. Cardiovascular effects: required to provide more conclusive evidence. effects of increasing BMD specific at locations thein body,longer-term further but are studies postmenopausal women. In summary, earlydata suggest that testosterone may some have beneficial compared to placebo. observed markers of bone formation (IGF-1 andP1CP) were significantly higher with testosterone difference in bone biochemical markers (Ntx, Dpd or BSAP) between treatment groups,another with testosterone compared oestradiol to Inalone. addition, whilst Miller et al implantsobserved BMD increased significantly at for body, vertebraetotal L1-L4 andthe trochanter by Davis al et hipthe and lumbar spine with testosterone treatment when compared placebo.Further,to a 1995 study compared HRT to alone, whilst a study by Barrett-Connoret al 1992. effect on bone mineral density (BMD) in any tested site concordant with studya by Garnett et in al therapy, andcompared it to oestrogen alone. They concluded that testosterone had nosignifican trials, fourof which reported onbone densitometry duringcombined testosterone oestrogenand El The reported effectstestosterone of on bone of naturally postmenopausal women heterogeneous. are independent of each other, serumoestradiol concentration, and other recognised risk factors. increased risk of subsequent hip fracture and high endogenous testosterone with a decreased risk, level of testosterone. They observed higher circulating of serum levels SHBG associated is with an postmenopausal women aged 50 Bone Mineral Density

Accepted Articlera iyah et al. 82

However, Miller et al 59 18

o conducted n 34postmenopausal women with oestradiol alone, or oestradiol plus testosterone 84 : No trials have reported long-term rates fracture during testosterone therapy in

The Exogenous testosterone increases haematocrit, so it is important considerto a Women’s Health Initiative Observational Study 93,676 of systematic review and meta-analysis,which included 35 randomised 83 id

observed BMD of the hip increased significantly with testosterone

not provideany evidence of an association between testosterone and – 79 years investigated fracture hip risk in relation the to circulating 68

observed an increase BMD bothin at 83

observed no 85 Some recent 81

86,87,88 t

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. significantly increase fibrinogen levelswith testosterone compared placebo.to diastolic pressure compared placebo. to placebo treatments.Studies appear to agree that testosterone has no significant effect on systolic and contrast,a 2014 study cardiovascular disease, such Interleukin-6, as Tumour Necrosis Factor-Alpha and Homocysteine. In high-sensitivity C-Reactive Protein (hsCRP,) but had no effects on other inflammatory markers of by Kocoska-Maras et al in 2009 lipoprotein cholesterol, total cholesterol, body fat mass triglycerides. and observed a favorable effect testosteroneof therapy postmenopausal in women, such high as density cardiovascular outcomes in postmenopausal women wasconducted Spoletini by et al 2014; they resistance compared with placebo. Moreover asystematic review of testosterone therapy on peak oxygen consumption, distance walked over the 6-min walking muscle test, strength and insulin (the releasingTTP 300ug/ day) was associated with significant functional improvements assessed by double blind, randomized, placebo-controlled study in women heart with failure, testosterone therapy insulin resistance without side-effects in elderly female patients with stable chronic . In a Data suggest that the testosterone improves exercise tolerance, muscle strength, and been frequent during short-term observations (12 thromboembolic events short-termin trials. Furthermore, adverse cardio-metabolic changes have not any significant differences in event for rates anycardiovascular outcomes, disease including venous randomised control trials comparing testosterone therapy women in placebo with have observed not There nois specific evidence about the cardiovascular effect womenin treated with testosterone. The have been not established for the testosteronetreatment of low levels due to aging. have lowtestosterone levels caused by certain medical conditions. The safety and benefit of these Dr levels healthyin older men not is authorised thein EU.In StatesUnited the (U.S. theof use of these medicines in patients over 65years ageof and the ofuse testosterone boost to these ( cardiovascular events. EU

Accepted Articleug Administration (FDA) cautions that prescription testosterone are approved only men for who ) for) the treatment of male hypogonadism. is There experience limited on safetythe andefficacy 100 89,90,91

observed no significant difference hs-CRPin between levels testosterone and

Testosterone-containing medicines are licensed European in the Union 99

observed testosterone counteracts oestrogenthe induced rise in 84,100 – Testosteronehas also been observed to 24 months) women in treated with testosterone. 94,95,96,97,98 77

In summary, despite ),

In astudy addition, the U.S.the Food and 92,93 28

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Wisniewski alet on 26 naturally andsurgically postmenopausal women discovered testosterone Accepted impairedbe with testosterone, but noother memory were functions affected. significantly increased by 1.57units vs placebo. compared to placebo, but at 26weeks, the Cogstate International Shopping List Test (ISLT) score 2014 studyobserved testosterone therapy had no effect oncognition after 12 weeks of treatment studies indicating nochange verbal in fluency, or any other measures function. of cognitive no but other aspects cognitiveof function were affected. This is directin contrast manyto other significantly increased divergent thinking, (fantasies and fluency speech,) of compared placebo,to menopause.the A study by Krug et 12postmenopausal al on women observed testosterone The effects steroidof hormones on human cognition are considerable of interest, particularly during Cognitive function: absencethe of long-term large scale trials. studies agree that testosterone has no effect on BMI, nothere is consensus on effectsits on massfat in fat massin observed freemass fat increased difference in both abdominal and visceral fat volumesbetween treatment Article groups. increased with testosterone by vs 11% placebo, directin contrast with a2014 study stating no bodymass of the legs, arms trunk. and A study by et Duarte al mass significantly increased, consistent with another study other treatment groups, similar with a study by Davis al, et postmenopausal women are inconclusive when it comesbody to composition. Studiesseem agree to that testosterone has no significant effect on BMI compared placebo, to Anthropometric measurements: testosterone therapy remain unclear. many being studies conducted onthis topic, the long-term cardiovascular consequences of 74,78

with one indicating decrease a in % fat tissue with testosterone.

78

observed no significant difference in bodyfat 101

when given testosterone vs placebo, but othersobserved nochange 28 105

One studyobserved A 2006study byZang al et on 63 57 80

indicating significant increases lean in whilst a 2005 study 74 observed visceral significantlyfat im with testosterone compared to mediate verbal memory to 106 57

A 2002 study by

84 Overall, whilst 100 observed lean body

One study 103,104,105 74,84

but 102

A

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. co HSDDfor Female or sexual dysfunction, selected study participants were screened exclude to disease future, academic-sponsored studies are needed addressto this concern. Finally, to fulfill the criteria published literature towards studies supporting the usage of testosterone postmenopausalin women; performed date to have been industry It funded. is plausible that reporter bias might have skewed the cardiovascular disease or breast cancer. It also is important to consider that manytrials the clinical of cautious approach might beappropriate for postmenopausal women with risk factors for testosterone therapyolder in men (albeit when administered at much higher doses) risks of cardiovascular disease, or breast cancer. In view ofthe controversy regarding safety the of Currently, there is limited long-term evaluating data whether testosterone replacement increases the Limitations of data: determined whether somatic symptoms vaginal or dryness are altered during testosterone therapy. studies suggest that testosterone does not affect menopausalflushes and hot it remains beto significant difference in sweating andvaginal dryness between treatment groups. psychological symptoms Testosterone with compared to placebo frequency and severit studies seem agree to testosterone therapy no has significantbeneficial effect on suppressing somaticboth and vasomotor symptoms compared Oestrogen to alone. 40naturallyto and surgically menopausal women and observed testosterone significantlyimproved A 2002study by Dobs and colleagues Physical symptoms: testosterone postmenopausalin women. testosterone therapy; it is therefore difficult drawto conclusions on predictedthe effects of summary, published studies date to have observed variety a of effects on cognition following cognitive function being (cube affected, comparison, shape memory identical or pictures). significantly increased building memory compared placebo, to score despite noother aspects of

-morbidities. It therefore, is not known whether postmenopausal women with disease comorbidities Accepted Article

y. 58,65,68,108

A further A further studyobserved nosignificant improvement somaticin or gave esterified oestrogens with or without methyltestosterone 58

while anotherobserved no 57

However, majoritythe of 68 In summary,most 109 ; asimilarly; 107

In This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. failed. therapy minority for the of post-menopausal womenfor whom management other have strategies term safety data.However with these caveats, there is sufficient evidence recommendto testosterone counseling onthe risks and benefits, particularly the limited effect of testosterone and the lack long of considering offering this treatment to postmenopausal women, is necessary it provide to full designed administerto much higher doses (to men) must therefore If be used. clinicians are licensed products thein UK for female administration of testosterone; testosterone preparations evidence regarding general recommendations for testosterone therapy women. in line with the US Endocrine Society Clinical Practice Guidelines, there currentlyis insufficient warrant further detailedinvestigations, although nomajor safety concerns have been raised In to date. effects of hyperandrogenaemia.Possible impacts on lipid metabolism, cardiovascular and cancer risk tolerated and safeadverse effects predominantly of consist localised skin reactions andcosmetic satisfactory sexual activity month.Inper short-term, the testosterone therapy generally is well hypoactive sexual desiredisorder. The effect size is with modest, approximately one additional as controlled clinical trials suggest that testosterone therapy significantly improves sexual function related sexual dysfunction, depending onthe criteria employed.Several randomised, placebo dysfunction women.in Furthermore, there is considerable variation in prevalencethe of menopause- a lack evidence of implicating deficient endogenoustestosterone thein evolution of sexual quality of Endogenous life. testosteronemay influence sexual behaviour women.in However, there is Sexual dysfunction is common a problem postmenopausal in women, may which profoundly affect reflect everyday clinical practice. would also benefit from testosterone therapy. This the extentlimits whichto published data may Conclusion

Accepted Articlesessed using validated questionnaires, post-menopausalin women sexual with dysfunction or

28 There There are also no – This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted Article References 7. 6. 5. 4. 3. 2. 1. 28. 27. 26. 25. 24. 23. 22. 21. 20. 19. 18. 17. 16. 15. 14. 13. 12. 11. 10. 9. 8.

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Endocrinol Metab.Endocrinol lowand density, high density, d on withcompared apolipoprotein esterified alone estrogens and other apolipoproteinsinCIII very low Martin et SE, LA al.Chiuve of Effect the combination methyltestosterone and of estrogens esterified replacementtestosterone therapy. A,Nathorst Floter 2006;1 glucose factors, inflammatory and visceralmetabolism fat: a randomized study. MP, LMDuarte al. InfluenceLeao et of methyltestosterone postmenopausal plasma therapy on lipids, 10.1097/01.gme.0000232033.92411.51 postmenopausalproliferation in women. M,al. Al Hofling et Hirschberg density. mammographic breast E M,al.Hofling et Lundstrom Testosterone during addition menopausal hormone therapy: on effects MetabEndocrinol mammographic densityon women in postmenopausal notreceiving estrogentherapy.systemic AL,Hirschberg SR,LK, I,Davis Lodhi von Schoultzof The B. effect transdermal testosterone Wagner Med Invest T, KunimiYasui A, K, Tani Matsui S, S, Yamamoto postmenopausal M.Irahara Androgen in women. breasthuman cancer in long M, The K. Lippman G,Huff Bolan effectsof androg profiles. lipid estrogens inconjugated surgically women. menopausal Effects on mineraldensity, bone symptoms and Barrett Inst. Cancer North libido; Cancer with Central decreased cancer TreatmentGroup survivors protocol N02C3. DL, DBetal. Barton to trial Randomized controlled Wender transdermalevaluate testosteronein female 1993;82(6):919-924. on endometrialhistologyeffects serum inwomen.lipoproteins postmenopausal and LR, A esterified Toomey Cet Hickok al. of without estrogenscomparison withmethyltestosterone: and study. placebo-controlled the combined,treatmentor for hot flashes menopausal randomized, of a in women: double-blind, esterified estrigens and methyltestosterone, Allgoodet A alone andLiu efficacyJ, al. Safety of low-dose 10.1097/GME.0000000000000195 inand esteem, mood women ovarian insufficiency.with primary GM,MartinezGuerrieri Effects et PEof al. physiologic testosteronetherapy on ofself- quality life, oestrogen.transdermal therapytestosterone patch for Casson P, L, Nachtigall Lucas V,Schofield SimonMelson C, J, and JA.tolerability Safety of of reactivity cerebralvascular arteries. supplementationhormone replacement of M,the L al.Penotti Effects therapy et on of androgen Sironi 10.1210/jcem- in behavior women.postmenopausal on sexual psychophysiology and Effects Dixen et of Myersandrogen,andal. estrogen, LS, progestin J 10.1111/j.1743-6109.2006.00406.x vs. postmenopausal ofin placebo women.testosterone dose acute Heiman A, al. and JR Genital et ofHeard-Davison measurement subjective the time an courseof effects and sexuality. et P McCloud al. SR, TestosteroneenhancesDavis estradiol's effectson postmenopausal bone density study.comparative Hormonal MG,Dow DMal. ofHart sexualtreatments et women: in unresponsiveness postmenopausal a 10.1210/jcem.87.4.8362 DOI: 2002;87(4):1509-1516 bodytherapyreplacement on in postmenopausalcomposition women. Nguyen AS, Tal.Differential Dobs et effectsoforal estrogen versus oral estrogen-androgen and physical functionperformance randomized a in trial. oophorectomy: without women with or Effects on sexual function, composition,body muscle H menopause.in profiles surgical estrogens plus and androgen bone menopausal on mineral density, andsymptoms, lipid NB, Notelovitz MC,Watts M,Timmons B, Addison oralComparison Downey estrogens of WA, LJ. Wiita 351 cross MM, Sherwin Gelfand BB, Androgen enhances Brender sexual in females:W. A motivation prospective postmenopausalin with women hypoactive sexual desire uang G,Basaria Travison S, uang Testosterone dose TG, al. et

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and esterified treatments. estrogen and Shifren Preliminary JL observationsFriebely JS, et al. on differing psychological effects of conjugated Metabolism. androgen G,Tang E al. Huang et 10.3109/09513590903056134 for markers disease. cardiovascular inflammatory Kocoska sex hormones. GM,Vitale Rosano I, diseasedifferent toSpoletini C. Cardiovascular is in women, it of men? The role 10.3109/13697137.2014.887669. systematic review. women: postmenopausal a C, Vitale I, Spoletini Pelliccia F,RosanoFossati C, GM. and cardiovascular Androgens disease in women older withand failure. chronic heart Effectsal . of et testosterone in VolterraniM G, men theinterval Schwartz , older Q-T on JB Caminiti , study.randomized, double-blind, pilot placebo-controlled Testosterone. a women et l therapyVolterrani in M withfailure: G, Iellamo F, heart chronic a Caminiti , elderlyfemale with patients in treatment failurechronic heart . Clinical . Karam leffects M G, a six and metabolic et of Volterrani R, testosteroneCaminiti , months https://www.fda.gov/Drugs/DrugSafety/ucm436259.htm heart risk of increased attack and with use. t & Administration.Food Drug U.S. medicines. testosterone Agency. Medicines European 2013;98(5):1891 highlyhealthy, functioning older with men low Barry KL, et Hildreth Moreau testosterone DW, and KL, al.progressive Effects of resistance exercise in A medications: systema G,Maseroli Rastrelli E, al.Corona Cardiovascular G,et risk withassociated testosterone therapy. J,UrbanBaillargeon R DOI: 10.1186/17412013;11:108. A review systematic men: and meta BJ, G,Cowling XuFreeman CM. Schooling therapy L, and cardiovascular among Testosterone events and stroke ininfarction, with men low levels. testosterone O'Donnell R, Baron Vigen CI, al. Association et testosterone AE, of therapy with mortality, myocardial testosterone therapy prescription Greenland S,Finkle risk RidgewayIncreased non WD, al. of GK,et in postmenopausaltherapy women. S, PA, Komesaroff Ling Sudhir Cardiovascular K. physiology androgens of 10.1080/09513590400021193 comp A,Nathorst Floter mineral density. without testosterone: and micronized on effect biochemical markers of bone metabolism and bone MJ Souza al.Miller De BE, et administration ofSublingual micronized estradiol and progester 1992;79(6):968 followingtherapydensity bone with and withestradiol estradiol testosterone implants. T,al.StuddTheGarnett J et effectsof estradiol plasma levels and Metabolism.Endocrinology with Concentrations Hormone Fracture in Risk Postmenopausal Hip Women. Globulin and SexLaCroix Lee JS, L, Associations et of Sex al. Serum AZ, Hormone-Binding Wu with in lipids relationships postmenopausal women. Effects SR,et KZ al. Davis estradiol of with and withoutWalker testosterone on body composition and 10.1097/GME.0000000000001059 randomized, placebo versus cream AO T,et Fernandes al. testosteronePedro Hormonal, metabolic, and endometrial safety of vaginal 10.1016/j.fertnstert.2005.12.039 insulin postmenopausalon sensitivity women. in Carlstrom H,KEffects Zang et withal. treatment testosteroneof alone with inor combination estrogen women. postmenopausal Nguyen S, Tal.ofBasaria Effect methyl et testosterone ad estosterone testosteroneestosterone due for toproducts low aging; requires tolabelling informchange possible of osition in oophorectomized women. - Ann Pharmacother Maras L, al.Hirschberg Testosterone et AL addition therapy estrogen to - deficient

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.

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted Article 107. 106. 105. 104. 103. 102. 124. 123. 122. 121. 120. 119. 118. 117. 116. 115. 114. 113. 112. 111. 110. 109. 108.

10.1073/pnas.0812757106 behaviour.Proc Natleconomic Sci USA. 2009;106(16):6536 Acad N, Kocoska Zethraeus Steril. Fertil women. 1997;68(6):1125 B. PM, estrogenVasodilator Sarrel of notdiminished effects are by androgen in postmenopausalWilta 10.1097/gme.0b013e318148bb99 (53) the in receptors women.postmenopausal of Sahlin H, L al.Effects Zang et testosteroneon andtreatment estrogen of the of distribution sex hormone women. Sahlin H, L al.Effects Zang et testosterone treatment endometrialproliferationof on postmenopausalin women. postmenopausal Hailes H,al.Effect J combined et Burger oestradiol implants of and on testosterone of libido in 2265.2012.04374.x women. postmenopausal Mortiz H, Effects Zang Tandal. testosteroneoestrogen of et on serum therapy metabolites in Endocrinol therapy onwith quality hormone lifein post of Pino M, JE,Del Blumel VallejoAprikian Sarra Castelo D, S, S, loss of treatment of sexual inte estrogensCombined esterified and methyltestosterone esterified versus estrogens in alone the Swanson JK, ZipfelWarnock SG,Borel RW, LM, JJ,Brennan Study ESTRATEST Group. Clinical on cognitive .therapy MC,von Effect A. Moller AF, Bartfai B, of Schoultz Radestad and estrogen testosterone replacement 2016;23(7):792 or testosterone, polyaestrogen, Costa T, Fernandes withsexual desire hypoactive disorder. of associatedrelevance benefits with tran S, Shifren Kingsberg J, RodenbergKoochaki K, C, Derogatis P, EvaluationWekselman L. ofthe clinical desirehypoactive sexual disorder. sexual sexual function, activityand persona log, sexual in activity desire, sexual satisfying and personal as distress by thefemalemeasured profile of Graziottin LR, Schmitt Koochaki Bitzer S, A, DeRogatis Clinically PE, J, C. Rodenberg changes relevant trial. in womenpostmenopausal being with testosterone: treated A randomized,placebo Dav sexual desire disorder. on thetestosterone cream sexual with women motivation of hysterectomized menopausal hypoactive El on orgasm inand postmenopausal women. methyltestosterone to combined hormone therapy with estrogen Fonseca SR, Abdo VR, CH, Penteado AM,the JM, EC. Effects Junior of Bagnoli of addition Baracat MedN Engl J AD, Coviello S, TG,Basaria Travison et Gynecology. levels hormone in and hot the flushes surgical MM. Sherwin Gelfand BB, parenteral of estrogen administrationEffects of and androgen on plasma 2002;58(3):150 methyltestosterone treatment cognitive task on performance postmenopausalin women. AB, TTEvaluation Nguyen Wisniewski of al. high et Menopause. MC,et AB Molleral.testosterone Effects of Bartfai and estrogenreplacement on memory function. 10.1111/cen.12459 noton women therapy.postmenopausal oestrogen Fal.Jane Transdermal SR, et Davis testosteroneimproves verbal learning in and memory 2011;95(1):152 fluency, verbal verbal memory, in and spatial ability healthy Kocoska Investigation.Endocrinological hysterectomized G, et al. EffectsHuang of Wharton W 10.1038/sj.npp.1300200 in women.postmenopausal thinking Molle R, MAcute Krug al. of influences estrogen andon testosterone et divergent and convergent 10.1089/152460901300039548 - Hage G,Eden Manga Hage RZ.JA, double A is SR, Goldstat SR, Papalia R,Effects is al. aromataseMA, et of inhibition on sexual function well and

Menopause J Clin EndocrinoJ Metab. - Maras L, Zethraeus N et al. al. N et Zethraeus L, Maras . 2008;24(12):691

2010;17(5):983 1984;148(5):552 .

2010;363(2):109 - - - 8. doi:10.1097/GME.0000000000000613. 8. DOI: 155. DOI: 157. . women 2006;13(1):37

- av L, er A, acr L, Pinto LF, Baccaro AO, Pedro LH, Paiva - Maras al.A randomized et L trial Climacteric

with low Br Med (Clin Res Ed). J Clin (Oxf). Endocrinol 10.1159/000064491 10.1159/000064491 10.1016/j.fertnstert.2010.05.062

- - Gynecol Endocrinol 989.DOI: 695. - 557. DOI: 557. rest in surgicallyrest menopausal women 2015;38(4):455 - crylic acid on vaginal atrophy: controlled vaginal trial. on randomized acid a crylic - 122. 122.

45. 45. 2007;92(6):2169 testosterone

. J Sex MedJ Sex

2007;10(4):335 Neuropsychopharmacology.

- A testosterone 1127

J Sex MedJ 10.1097/gme.0b013e3181dc2e40 randomized al. Adverse al. withevents testosterone associated administration. 10.1016/0002 sdermal testosterone treatment insdermal treatment testosterone postmenopausal women - blind, randomized, blind, placebo

Climacteric - .

menopausal women with dysfunct sexual menopause - levels: alevels: dose 2009;6(1):175

461. DOI:

2012;77(2):288 distressl women scale in postmenopausal with . 2013;29(2):173 - . 1987;

2175. DOI:

administration cognitive function on in - 2007;4(4):1001 - Clin Endocrino (Oxf).

343. dose estrogen dose and high trial the effect of of - . 9378(84)90746

294(6577):936 2008;11(1):17 of the of of estrogen and effect testosterone on 10.1007/s40618

Menopause. .

American American postmenopausal - - response response 183. 183. 10.1210/jc. - Branco C. Effect C. androgensBranco of combined - - s s and onprogestogens energy sexual 295.DOI: eo M Efcc o vgnly applied vaginally of Efficacy AM. Neto - 2003;28(8):1538 176. -

6538. DOI: - 1008. . Menopause Journal of Obstetrics Journal of & - - - -

controlled the controlled of trial of effect

25. randomized 937 2008;15(2):233 4 testosterone

2014;81(4):621 2006

- 10.1111/j.1365 014

-

dose estrogen estrogen dose plus women - - 2171 0213 .

- 2005;12(4):374 1545. DOI:1545. -

controlled trial. trial.

. -

and and estr 3 FertilitySterility. & -

ion. 239.DOI: - Journal Journal of Horm Res. 628.DOI: - Gynecol Gynecol Menopause. ogen on - 384. -

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted Article 126. 125.

relationships with in lipids relationships postmenopausal women. Effects SR,et KZ al. Davis estradiol of with and withoutWalker testosterone on body composition and 10.1210/jc.2015 administration. testosterone during G,Pencina KM Huang al. Functional voice et t - 1669

J Clin EndocrinolJ Metab. esting detects vocal changes pitchearly in women Menopause.

2015;100(6):2254 2000;7(6):395 - 2260. DOI:2260. - 401.

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted Article medicine Sexual of Table 1. Dysfunction FemaleArousal Sexual DesireDysfunction Hypoactive Sexual dysfunctionsSexual PainfulOrgasm Hypohedonic Orgasm Syndrome) (Post PostcoitalSyndrome ArousalDisorder PersistentGenital Pa Female Genital Dysfunction Female Orgasmic inDysfunction - Orgasmic Illness Definitions of female sexual dysfunction recommended by International Society of femaleDefinitions recommended sexual dysfunction by

-

Pelvic

(ISSM)

subjective arousal is typically,is subjective arousal but Anydesire. awareness of absence ofthe sexual andinterest throbbing, pulsattingling, genital arousalunwanted (ie, intrusive, and Spontaneous, genitalcontact. without musclespelvic floor withor hypertonicityoveractivity or of or (iv)markedcontact; as aresultor ofduring, genital pelvic pa vulvovaginal anxietyor about (iii) markedgenitalcontact; fear or vulvovaginalpelvicduring or (ii) marked intercourse; vaginalduring (i) penetration following:of withthe atleast one recurrent or difficulties Persistent sensation decreasedintensity of orgasmic (ii) markedlyorgasm and/or frequencyabsence ofof, or Mark (i) ofgenitalresponse. her subjectiveadequate an assessment c maintain arousal or untilattain recurrent or inability Persistent to sexualactivity. or fantasies thoughts desirefor and absence of erotic or sexual or recurrent or deficiency Persistent ISSM orgasm. shortly pelvicor during pain after Theofoccurrence genital and/or orgasm. lowlevel withofpleasure sexual acquired decreasedLifelong or or activity. symptoms other after sexual malaise,, fatigue, and physical and/or as symptoms such Negativefeelings, experiences, forpersists hours arousal or days. orgasm feeling one the and of unrelievedis arousal by atleast invariably,not The unpleasant. ompletion of the sexualof the activity, ompletion 35 Definitions Definitions

and DSM-Vand Criteria comparison. for

ed delay ed marked in, in in anticipation in of,

ing) in ing)

activity:marked(i) marked delay in, infrequency of, almostall experiencedor occasionson all ofsexual ofof either Presence following symptoms and activityalmost sexualin all encounters. non genitalor externalsexual/erotic cues; (vi)absent/reduced inresponse to interest/arousal any internal or sexualall encoun excitement/pleasuresexualduring activity almost in (iv)absent/reduced initiate; sexual typically and partner’s attemptsto unreceptiveto ofinitiation fantasies;sexual no/reduced activity (iii) activity;a (ii) following:sexualabsent/reducedinterest (i) in as manifestedinterest/arousal, atleastbyof three the Lacksignificantly of sexual or reduced into Split below. diagnoses DSM No DSM No DSM No DSM No DSM No vaginal penetration. tightening ofmusclespelvic floor attemptedduring vaginal(iv)marked penetration; or tensing in anticipation of, during, marked (iii) fear vulvovaginalor about or attempts;vaginalor during penetration intercourse (ii) marked intercourse; orvulvovaginal pelvic pain following:of vaginalthe (i) penetration during recurrent or difficulties Persistent with intensityof orgasmic sensations. absence of or orgasm;markedly (ii) reduced - V Criteria - - - - V criteria. V diagnostic criteria. V diagnostic criteria. V diagnostic V diagnostic bsent/reduced sexual/erotic bsent/reduced thoughts or - genital sensations sexual during ters;(v)absent/reduced sexual

33

criteria.

or as resultor of

one

(ormore) This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted 2014 Fernandes T, 2007 DePaula FJF, 2006 Nathorst 2010 RaghunandanC, Author and date Questionnaire). Epidemiological Studies scale); Q-Les-Q Life of (Quality Enjoyment andSatisfaction (Homeostatic Model Assessment); HAM-D (Hamilton Rating for Depression); CES-D (Centre for (Low Density Lipoprotein); IL (Interleukin); hsCRP (high sensitivity C-Reactive Protein); HOMA AUC Under (Area Curve); FNA Needle (Fine Aspirate); HDL (HighArticle Density Lipoprotein); LDL Density); BMI (); MCA (Middle Cerebral Artery); ICA (InternalCarotid Artery); Mass); FM (Total Body Fat Mass); P(); FFM (Free Fat Mass); BMD (Bone Mineral Sexual Self-Rating Scale): SIQ Interest (Sexual Questionnaire); PI (Pulsatility Index); FFM (Free-Fat (Apoprotein); BISF-W Index (Brief Sexual of Functioning for Women); SRS (Sabbatsberg Revised Receptor); AR (Androgen Receptor); PR (Progesterone Receptor); LPA (Lipoprotein A); APO VPA (Vaginal Pulse Amplitude); TFS (Tape/Film FAI Scale); Index); Androgen (Free ER (Oestrogen Changes Sexual of Functioning Questionnaire (CSFQ); E2(Oestradiol); NA ( Acetate); IGFBG-1 (Insulin-Like Factor Growth Binding Globulin-1); TNF-A (Tumour Necrosis Factor-A); (Wechsler Intelligence Scale-Revised); VCAM-1 (Vascular Cell Adhesion Molecule-1); EPTTest); (Oestrogen-Progestin Therapy); RBMT (Rivermead Behavioural Memory WAIS- Test); Muscular); PGWB (Psychological General Well-Being Index); ISLT (International Shopping List acetate); (transdermalTTP testosterone patch); EE (esterified oestrogens); E(oestrogen); IM (Intra- (dehydroepiandrostenedione); CEE (conjugated equine oestrogens); MP (medroxyprogesterone questionnaire). Drugs: EP (estrogen-); (testosterone);T MT (methyltestosterone); DHEA Episodes); PFSF (Profile of Female Sexual Function); CSFQ-F-C (Changes in sexual functioning (Psychological General Well-Being SAL Scale); (Sexual activity Log); SSEs (Satisfying Sexual (Sabbatsberg Sexual Self- Index Sexual of Functioning Women); for McCoy (McCoy Female Sexuality Questionnaire); SSSS bone mineral density breast or symptoms. FSFI Sexual (Female Function Index); BISF-W (Brief women presenting with symptoms sexual dysfunction, of dyslipidaemia, impaired memory, decreased women. Table 2: 39 37 36 6

-

Boos J, J, Boos

For studies beto included, subjects were required be to perimenopausal or postmenopausal Summary of systematic review of testosterone therapy and peri- post-menopasualin

80 85 53 75 subjects of Number

rating Scale); WHQ (Women’s Health Quest

3 months 3 gel placebo + 10mg+ EP gel EP testosterone aged Postmenopausal 50 RCT,crossover study weeks 12 +T E (KY Jelly) E; (1mg); Placebo study 3 Twiceweeklyarms: Postmenopausal RCT Study Design (300μg); Polyacrylicacid Dermaltestosterone oestrogen; arms: 4 aged Postmenopausal 40 RCT inmonths total 4 + MT 4)EP MT(2m); + placebo 2.5mg(2m) (4m);then EP study ++ 4 EP arms:MTPlacebo; EP aged Postmenopausal 49 RCT.

(2m) then (2m)then placebo (2m)

- - - 70 63 65

–

Topical.

placebo lubricant group. placebo orgasmwith compared the arousal improvementsandin treatment showedNo groups FSFI: (p<0.05)2.5±0.4 and baseline to placebo. significantincrease compared showeda statistically 2.5mg EP+MT groups, McCoy’s: placebo. for (p<0.001) testosteronevs. “significantly improved McCoyQuestionnaire: p<0.0 18.6% Placebo: +T: E 147% 42% E: McCoyimprovement: Findings 1

ionnaire); PGWB

stated None stated None Yes stated None Funding Industry

R

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. AcceptedDavis2006 SR, 2005 Braunstein GD, Simon2005 J, Article 2010PanayN, 2005 BusterJE, 2015 R, Tun gmunsakuchai gmunsakuchai 45

40

44 43 46

42

61 447 562 272 533 70

(PHARMACEUTICAL) trial controlled Randomized,double 24 150μg;TTP 300μg;TTP TTP 450μg twice Placebo; weekly transdermal arms. 4 24 women Surgicallymenopausal aged RCT weeks 24 (300μg); +E+ TTP E Placebo. 26 women Surgicallymenopausal aged RCT months 6 +TTP E (300μg); Placebo agedMenopausal 40 RCT weeks. 24 (300μg);Twice weekly ++TTP E E P women Surgicallymenopausal RCT weeks 8 Twiceweeklydoses +T E (40mg) + E Placebo aged Postmenopausal 40 RCT weekstimes week3 for12 a (placebo). (moisturiser);lubricant Oil 24 patch Placebo TTP(300µg/day); 20 women Surgicallymenopausal aged - - - - weeks 70 received 70 70 70 received 70 weeks

- - 70 blind, placebo blind,

- 60

-

(p=0.0089). T:0.53 1.69; P: baseline SAL:SSE/4wk increase from (p=0.001) 0.73 increase Placebo: Testosterone:increase of 1.56 SSE SAL: = 0.04) (p 25.3 ± 6.7 Placebo ± T3.6 28.6 FSFI: Adversemostly mildevents placebo. withPGWB T (P=0.04) vs and (P=0.003) increasein lesseningof sexual concerns sexualself responsiveness(P=0.005), sexual (P=0.03), (P=0.02),o arousal Significantsexualincrease in withT (P=0.003) vs placebo in Significant reduction PDS forT (P=0.06) vs placebo frequencyweeksat24 of SSE weeklyincrease 43% in (P=0.02) withplacebo T to compared Significant increase in PFSF differentfrom placebo. 150 p=0.049). place satisfyingsexual activityvs. and frequency p=0.05), of (67% vs placebo 48%; 300μg increases TTP vs. libido PFSF: = 0.0003) (p 0.98 P: T:2.10 baseline SAL:fromSSE/4wk increase

- μg/d andμg/d 450

bo (79% vs 43%; bo

- image (P=0.04), image(P=0.04),

- μg/d not

rgasm

Yes Yes stated. None Yes Yes Yes

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted , Sherwin 1985 Lobo Floter2002 A, Article2000 ShifrenJL, Davis2008 SR, 2006 ShifrenJL,

2003 53

52 54 48

47 50

53 221 50 75 814 549

0.625 mg 0.625 =of esterifiedestrogens (n women40 aged Naturallymenopausalsurgically or Double weeks 24 E(2mg/day)+Placebo E(2mg/day)+T(40mg/day); Oral: 45 women Surgicallymenopausal aged pla Randomized,double times weeksweek 2 for4 a 2TTP(total 300µg/day) placebo+1TTP(150µg/day); 1 placebo patch; 2 31 women Surgicallymenopausal aged RCT weeks. 24 300μg TTP arms: TTP3 150μg; DailyPlacebo; 40 women Surgicallymenopausal aged RCT weeks. 24 Twiceweekly. + Testosterone E±P (300μg) + E±P Placebo agedMenopausal 40 RCT 1M mg mgtestosterone 150 or estradiol 8.5 or mg 8.5 Estradiol mg testosterone 150 _ menopauseSurgical43 premenopausal10 RCT Questionnaire Sexual Interestdesireasthe on rated level changeofin sexual or interest months 4 = (n methyltestosterone 107) 1.25 ofmg esterifiedestrogens and of combinationor the 111) of0.625 mg - - - cebo 60 received 60 received 56 received 70

- - blind randomized blind trial controlledtrial.

-

65 received 65

- -

70 blind, crossover,blind,

or placebo placebo or

compared with placebo withcomparedplacebo activitypleasure and scorefor frequency of sexual significantly2TTP increased with 2TTP. placebo, with and1TTP in 1 2 women 3 with adverse effects Not significant (p=0.11) episodes,150μg 1.2 TTP (p<0.001) 0.7 Placebo 300μg 2.1 TTP baseline SAL:fromSSE/4wk increase (p<0.0001). ± 0.5 Placebo 0.23 ± T0.28 2.1 frombaseline. averageSAL: SSEs increase fromdifference baseline. significant but vsno placebo, total in severity.increase Significant or moderate (59%) (37%) Increasesexual arousal in Increaselibido in methyltestosterone esterifiedestrogenand receivingcombination of the women functioningin significantlysexua improved for the explanation hormonal aplausible suppression ofSHBG provide testosterone and unbound Increasedlevels circulating of side weightno withT, Allgain. but mild reported bodyswelling moderate. womenmild to 5 1 with placebo,asand defined 3 Acnewomen in with Tseen liver enzymes. or full change in No count blood score. total activity,interes withfrequency of sexual enjoymentof satisfaction sex, scoreincreased with T: totalMcCoy Questionnaire (P=0.03)

- effects reversible.

hirsutismscore for T

t in sex in and t

- orgasm

l Yes Yes Yes Not stated Not stated None Yes

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted2002 Dobs AS, ArticleHuangG,2014 Watts,1995 55

57 56

40 71 66

4 months 4 EE(1.25mg)+MT(2.5mg) EE(1.25mg); Tablet: aged41 Naturallymenopausalsurgically and RCTdouble weeks. 24 IMinjection. Via E+T25mg E+T12.5mg E+T6.25mg E+T3mg E+Placebo arms. 5 21 women Surgicallymenopausal aged RCT mg) (2.5 methyltestosterone daily esterified oral received Surgically weeks 96 Randomized,double months 8 For years For 2 - 60 received 60

esterified

-

76

estrogens

menopausal

-

blind

estrogens

(1.25 mg) (1.25 and - blind Trial blind

women

(1.25 mg), or (1.25

placebo (p<0.05). placebo when compared group to T the significant 25mg in Changes BISF treatments improved significantly both by vaginaldr flushes, somatic(hot origin symptomsMenopausal of EE+MTgroup. decreasedsignificantly in HDLtriglycerides and significantly.Cholesterol, decreasedLDL cholesterol increasedsignificantly and group, EE HDL In cholesterol P<0.01) error standard mean (n=24; baseline score +/ densitywith compared mineralspinal increase bone in associatedwith significant hip; EE+MTcombined and loss bone prevented atspine treatmentBoth regimens somaticsymptoms, sexual Significantimprovement in and (P=0.014) (P=0.031) 16 weeks withMT at10 sex significantlyfor in interest and increased SIQ SRS with(P=0.041) MT and pleasure/orgasm (P=0.05) frequency/psychosexual incre BISF only.with EE Significantdecrease LDL in LDL. changein withtriglycerideMT,no but HDL and cholesterol, Significantdecrease total in only bodystrength with MT Significantlowerincrease in to 130kg 107 (P<0.0024) increasedsignifica and23kg(P<0.036) leg press significantlyfrom 20kgto body Upper pressincreased (P=0.077) significant not for fat tissue withtissue MT but (P=0.002) Significantdecrease %fat in with EE+MT trunk (P=0.007) bodymass arms of legs, and Significantlean increase in asedfor - - W: Wsignificantly

onlystatistically ynessinsomnia) and

3.4+/

ntly from ntly

- 1.2%,

-

Yes stated None Yes

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted2001 PenottiM, 1990 Myers LS, Article2007 Heard Davis 1995 SR 1983MGT, Dow 60

- Davison A, Davison 59 61 62

58

40 40 10 34 40

Postmenopausal RCT weeks 10 Placebo E(0.625mg)+MT(5mg); E(0.625mg)+MP(5mg); E(0.625mg); Capsules: mean Postmenopausal age58 RCT visits 2 single dose Placebo MT(5mg)single dose; aged Postmenopausal 50 placebo Randomized,double yearsEvery formonths 2 3 E2(50mg)+T(50mg)implant E2(50mg)impant; Postmenopausal RCTsingle E2(50mg)+T(100mg)implant E2(50mg)implant; aged Postmenopausal 49 RCT 8 months 8 TransdermalHRT TansdermalT(40mg/day); HRT+Oral

-

controlledtrial

- blind

- blind, crossover,blind,

- - 62 54

subjectivesexual arousal, significant No difference in dose. single post (P=0.03) 4.5hours between placebo T and SignificantdifferenceVPA in alone compared (P<0.05) to E2 relevancy and (P<0.035) (P<0.01),pleasureorgasm sexuality: activity (P<0.03), E2+Tgreater in increase withE2 alone.T to compared (P<0.05)BMD trochanteric vertebralL1 body fortotal (P<0.008), SignificantBMD increase in frequencyof orgasm. generaland sexual satisfaction frequency ofinterest, sexual as wellVasomotor) as (Psychology,Somatic and symptoms menopausal for betweengroups treatment significant No difference hirsutism patients experienced 2 mild symptomswithMT vasomo functioningand libido and satisfaction. libido difference No in observed ICA.not but to(P<0.01) 0.822 from 0.780 with T (P<0.05) increased in ofgroups PI MCA atT2 Si hirsutism cases major loss, 2 1 hair comparedothergroups. to frompleasure masturbation frequency,orgasm and highest E+MT group anxiety. euphoria, or between forenergy, groups significant No difference (r=0.62) physicalsexual and sexual(r=0.60) arousal differencemental scores and betweencorrelations VPA Significantpositive(P<0.001) treatmentgroups. sexualbetween arousal mentalphysicalscores ofand gnificantdifference between

- L4 (P<0.001) and L4(P<0.001)

arousal scales arousal

tor tor

stated None Yes stated None stated None stated None

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted1999 Barrett Barton200 DL, Hickok1993 LR, ArticleJames2011 L, 2014 Guerrieri GM, 64 68

- Connor E, 65 7

67 66

311 150 26 1288 128

4 weeks 4 Placebo Tcream(10.4mg); survivors female Postmenopausal cancer crossovertrial Randomized,placebo months 6 EE(0.625mg)+placebo EE(0.625mg)+MT(1.25mg)+placebo; Tablet: aged Postmenopausal 40 RCTdouble weeks 12 Placebo MT(0.6mg/day); EE(0.3mg/day)+MT(0.6mg/day); EE(0.3mg/day)+MT(0.3mg/day); EE(0.15mg/day)+MT(0.3mg/day); EE(0.15mg/day)+MT(0.15mg/day); EE(0.45mg/day); EE(0.3mg/day); EE(0.15mg/day); Tablet: Menopausal RCT(PHARMACEUTICAL) months 12 T(150μg/day) +10mg/day Oestradiol + MP) Transdermal EPT(100μg/day) +10mg/day Oestradiol + Placebo; MP) Transdermal EPT(100μg/day Insufficiency18 aged with Postmenopausal Primary Ovarian RCT CEE(1.25mg); CEE(0.625mg); Oral: 21 women Surgicallymenopausal aged RCT,double - 65 received 65

- - blind blind

- - 42 controlled,

-

60

as severe.judged and breast bleeding pain not bleeding. Vaginal Vagin HirsutismTract and Infection, Respiratoryincrease, Upper weight Genital Pruritus, included: Acne, placebo greater2% than incidence Adversewitheffects atleast severity. flash frequency forhot and beneficial No witheffectsT between groups. significantno differenceand infrequentseveral women, but by Androgenic effectsreported rash. irritation skin or women 2 given T reported D ScaleCES Scores, Les significant No differenceQ in flushes,sweatsvaginal and symptoms menopausal (hot significant No difference in groups withcomparednon (P=0.009)and (P=0.014) hip morewithMT atlumbar spine increasedsignificantlyBMD change in No libido qualityof life. oedema,overall or headache, mo growth,as wellas negative abnormalloss hair or hair abnormal voicedeepening, between forAcne, groups significant No difference (P<0.001) compared to group placebo significantlyT increased in bioavailable Mean T Vitality StatesProfile on of Mood or totalmood CSFQ, disturbance desiresubscales,combined significant No difference in withMT. hair reports of facial5 acne and 2 alone. EE not A2 A1 seen withand MT, but Apolipoptroteins HDL3and HDL, HDL2, cholesterol, in Significant reduction groups. Endometrialcells between significant No difference in between treatment groups.

scores betweengroups. od swings, od peripheral - Q, Rosenberg Self Rosenberg Q,

subscale

- - D orHAM

MT - Esteem al

- - Yes Yes sta None stated None stated None ted

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. AcceptedChiuve2004 SE, Floter2004 A, 2006 DuarteMPC, Hofling2007 M, Article Hofling2007 M, Davis2009 SR, 74

75 71

73 72 76

79 50 37 99 99 279

12 months 12 gel(1mg/day)+Placebo E2 tablet gel(1mg/day)+MT E2 tablet(1.25mg); aged Postmenopausal 42 RCT weeks 48 FNAof breast cells E(2mg/day)+Placebo E(2mg/day)+T(40mg/day); Oral: agedMenopausal 45 placebo Randomized,double months 6 Placebo E2(2mg)daily+NA(1mg) daily+ TTP(300µg/day); E2(2mg)daily+NA(1mg) daily+ aged Postmenopausal 45 trial controlled Randomized,double weeks. 52 300μg TTParms: 3 150μg;TTP Placebo; agedMenopausal 40 RCT Dailyyears for 2 EE(1.25mg)+MT(2.5mg) EE(0.625mg)+MT(1.25mg) received women Surgicallymenopausal RCTdouble weeks 24 E(2mg/day)+Placebo E(2mg/day)+T(40mg/day); Oral: 45 women Surgicallymenopausal aged placebo Randomized,double - 60 received 60

- -

controlledtrial. controlledtrial

- blind

- - - - -

blind, placebo blind, 70 blind, crossover,blind, 65 crossover,blind,

- -

65 62

-

%densemammographic area. mammographic density or breast symptoms, significant No difference in (p=0.942) significantly werenot different 300μg 0.21±0.17 TTP 150μg 0.06±0.19 TTP 0.05±0.16 from for: placebo baseline PercentageDensity change groups. LDLtreatmentbetween significant No difference in alone.with comparedEE triglycerideswithT (P<0.05) cholesteroland total Significantdecrease HDL, in groups. hirsutismbetween treatment significant No difference in groups. dryness)trea between (13%), apoCII (14%),apoCIII (13%), apoCI HDL(24%), cholesterol total cholesterol(10%), (11%), plasmatriglycerides total MTsignificantly decreased with T placebo (P<0.001) reduction in HDL11% vs or LDL total but cholesterol, significant No difference in HOMA. insulin glucose, or changeno placebo, but in with Tincreased 11% vs visceral but groups, fat BMI change betweenin No triglycerides. total LDLcholesterol, in or chno MTbut vs placebo, decrease HDL 17% in with group. proliferativeactivity T in significant No increase in proliferation. andstromal epithelial cell as (P<0.001) wellmonths as valueto 6.2%of at6 1.1% from cellmedianproliferation totalincrease fivefold in breast groupmore Placebo than

tment

ange

Yes Yes Yes Yes stated None stated None

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted2000BE, Miller Garnett1992 T, Davis2000 SR, 2018 Fernandes T, ArticleZangH,2006 Basaria2002 S, 79

78

80 77 83 82

57 50 34 60 63 40

RCT yearsEvery formonths 2 3 E2(50mg)+T(50mg) E2(50mg); Implant: Postmenopausal RC times weeksweekly 3 12 or Glycerinplacebo lubricant E(0.625mg); T(300µg); Topicalcream: aged Postmenopausal 40 RCT months 3 T(40mg/2days)+E(2mg/day) E(2mg/day); T(40mg/2days); Oral: 44 Postmenopausal RCT weeks 16 EE(1.25mg)+MT(2.5mg) EE(1.25mg); Tablet: aged21+ Naturallymenopausalsurgically and RCTdouble weeks 10 EE(1.25mg) MT(2.5mg)+EE(1.25mg); Tablet: microionized E2(0.5mg)+microionizedmicroionized E2(0.5mg);microionized Ifhysterectomized: tablet: Sublingual women postmenopausal Naturallysurgically and RCT,double yearEvery formonths 1 6 E2(75mg)+T(100mg)implant E2(75mg)implant; Postmenopausal T,single

-

-

blind -

blind blind

- 64

-

70

treatment groups. treatmentgroups. body and mass between sensitivity, Insulin profile lipid differencesin No reported hirsutismwith MT womenmil 2 developed LDL change in No levels with(P=0.001) MT and (P<0.001) triglyceride (P=0.009), HDLcholesterol Significantdecrease total in (P=0.03) withE Significantdecrease LDL in (P=0.006) levelsMT fibrinogen group in Significantincrease in in MT reduced group(P=0.04) Plasmaviscosity significantly HDL and (17%) in VLDL (62%), significantly reduced APOCIII apoB significant No effect of MT on (P=0.06) and apoE(13%) (14%) lumbar spine but significantlybut lumbarspine difference No B in comparedHRT to alone. with T significantly (P<0.01) ofincreasedBMD hip BSAP) byDpd or year. 1 markersbiochemical (Ntx, in treatmentgroups bone difference No between groups. sitesbetween treatment densitybone atany measured significant No difference in groups. profile lipid between treatment meanmassbodyweight,fat or significant No difference in treatmentgroups. endometrialthicknessbetween significant No difference in groups. function) betweentreatment triglyceridesliver and HDL, LDL, cholesterol, serumlevelsmetabolic (total significant No difference in

LDL (35%)

MD at MD

d

stated None stated None Yes stated None Yes stated None

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. AcceptedHuangG,2016 2003R, Krug 2001 FriebelyJS, HuangG,2014 Article2009 Kocoska Floter2005 A, 101 99

- Maras L, 102 84 103 100

71 12 34 71 50 50

EE(0.625mg); Oral: agedMenopausal <66 RCTdouble Onceweeksweekly for24 T(25mg) T(12.5mg); T(6.25mg); T(3mg); Placebo; injection: IM 21 women Surgicallymenopausal aged RCT,double weeks 48 E(2mg/day)+Placebo E(2mg/day)+T(40mg/day); Oral: 45 women Surgicallymenopausal aged placebo Randomized,double weeks 24 E2(2mg/day)+Placebo E2(2mg/day)+T(40mg/day); Oral: 45 women Surgicallymenopausal aged RCT,crossover year 1 T(1.25mg)p4(100mg)+microionized microionized D2(0.5mg)+microionized P4(100mg); microionized IfUteri: intact T(1.25mg) RCT,double days 3 Placebo TTP(6mg/day); aged Postmenopausal 47 RCT weeks 8 EE(0.625mg)+MT(1.25mg) - - - 60 received 60 received 60 received 60

crossover

-

controlledtrial

- - - blind crossover blind blind blind E2(0.5mg)+microionized

-

blind, crossover,blind,

- 65

TNF Cardiovascular disease(IL inflammatorymarkers of hsCRP, rise induced TE in counteracts group. significantlyhighe (IGF formation Markers ofbone groups. Enzymestreatment between Liver or pressure blood bodyfat, diastolic systolic and difference No total BMI, in withT treatment. significantlyincreased only Totalmassbodylean comparedHRT to alone. with Thigher (P=0.026) measures of cognition (spatial measures ofcognition significant No difference in function. otheraspects ofor cognitive subjective change in No mood comparedplacebo (P<0.07) to fluency and of speech) (fantasies divergentthinking Tsignificantly increased alone. EE MTand performancetestingbetween difference No cognitive in group visceralfatvolumes between abdominal pressure, or diastolicblood systolicor significant No difference in groups. hs adiponectin concentration, or fasting insulin glucose, significant No difference in - CRP levels CRP between - - AHomocysteine) and 1 and P1CP) were and P1CP) 1 s.

but effectsno but other on

r in T in r

-

6, 6,

Yes Yes Yes Yes stated None stated None

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. 2008 AcceptedPenteado SRL, 1984 BB, Sherwin 2002 WisniewskiAB, 2010 Moller MC, ArticleDavis2014 SR, 2011 Kocoska 104 110 108 107 106

- Maras L, 105

60 49 26 50 92 200

Oral: aged 46postmenopausal Naturallysurgically and RCT,double weeks 48 E(2mg/day)+Placebo E(2mg/day)+T(40mg/day); Tablet: 45 women Surgicallymenopausal aged placebo Randomized,double weeksDaily for 26 Placebo Tgel (300μg/day); aged Postmenopausal 55 trial controlled Randomized,double weeks 4 Placebo E2(2mg/day); T(40mg/day); Oral: aged Postmenopausal 5 RCT,double Onceweeksweekly for24 T(25mg) T(12.5mg); T(6.25mg); T(3mg); Placebo; injection: IM 41 women Surgicallymenopausal aged aged Postmenopausal 42 RCT months 3 T(150mg)+E(10mg) T(150mg); injection: IM women Surgicallymenopausal RCT,double Dailymonths for 4 EE(1.25mg)+MT(2.50mg) EE(1.25mg); - - 60 received 60 received 62

-

controlledtrial

- - -

blind blind,crossover blind

- -

blind, placebo blind, blind, crossover,blind,

- 65 - - - 77 65 60

- Difference 1.57units (P=0.03)Difference1.57units Placebo weekswith T to compared significantly increased at26 Cogstate ISLTscores groups. atweekbetween treatment 12 significant No difference seen (P>0.05) treatmentgroups abilityspatial between verbalmemoryfluency, significant No difference in groups between attention) treatment memory,functionor executive ability,verbal fluen ofproblems’):all energy(‘completelevel relief difference Perceived sexual in alone. withE flushes whencompared hot effect No suppression of on identical pictures memory shape comparison, or cube of cognitive function: difference aspectsNo other in (P<0.05) memoryT vs score on placebo Significantly building higher memoryaffected. offunction otheraspectsno impaired and delayedverbal memory not weeks, impairedat24 but Immediatememoryverbal thinning. perceived woman 1 given T had between treatments. difference No PGWB in

temporal hair hair temporal

cy, verbal

or or

Yes stated None Yes stated None Yes Yes

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. 2005 WarnockJK, 2013 Moller MC, 2016 Fernandes T, 2007 Kingsberg S, 2009 DeRogatisLR, Davis2006 SR, El -

Accepted ArticleHageG,2007 112 111 110 114 113

&

112 111

102 50 80 132 60 36

+T E +(40mg) E tablet; Placebo. aged45 menopausalSurgically women induced RCTcross weekstimes week3 for12 a Glycerin Lubricant Gel(placebo) (3g) (0.625mg); Cream Vaginal Oestrogens Conjugated (330μg);Proprionate Cream Vaginal Testosterone Cream Vaginal Acid;Polyacrylic(3g) aged Postmenopausal 40 RCT months 6 TTP Placebo; received women Surgicallymenopausal RCTs in enrolled 2 (n=1094). women Samplewhowere of132 weeks. 16 (2.5mg);E +T gelE (400μL) + women Surgicallymenopausal RCT months 3 +10mg E T E+ placebo cream ; age54 women Surgicallymenopausal mean RCTcrossover study months. 12 daily testosterone oestrogen oestrogen 8 weeks. 8 + MT EE (2.5mg) daily. tablet + EE Placebo arms. 2 32 women Surgicallymenopausal aged RCT. weeks. 24 - 61 received 61

- 60 received60

- -

progesterone + progesterone 2.0mg oral -

progesterone+ placebo; overstudy. +T gel (400μL) + Placebo.

(300μg/day)

- 70

51% vs. 39% 51% Distress vs. SSA, 30%; 44% Desirevs. 34%; 50% T vsin placebo significantly(P<0.001) higher rate Responder betweengroups. difference No SSSS in (p=0.000). vs. T: +8.8 Placebo BISF (p=0.028) placebo 11.1% testosterone group34.5% not seen. not differencestreatments between CSFQ function or PGWBscores. betweencorrelations cognitive statistical significantNo Placebo. (P<0.05)comparedE and with Lactobacilliwith in T Significantincrease of Placebo. compared(P<0.005) with treatedwith andT E (P<0.05) significantlywhen increased healthscore Vaginal Placebo. (P<0.005) (P<0.05)treatedwith andE T significantlywhen increased ≤5 Womenwith Vaginal PH - W - F -

C: SignificantC:

comparedwith

was

Yes stated None Yes Yes Yes stated None

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. AcceptedHuangG,2015 2009 Zethraeus N, Sarrel1997 PM, ZangH,2008 ArticleZangH,2007 BurgerH,1987 ZangH,2012 Blumel2008 JE, 119

117 116 114 120 115

118 113

71 200 20 31 63 20 60 47

EE(1.25mg/day)+MT(2.5mg/day) EE(1.25mg/day); Oral: Postmenopausal trial controlled Randomized,double months 3 T(40mg/2days)+E(2mg/day) E(2mg/day); T(40mg/2days); Oral: aged Postmenopausal 44 RCT months 3 T(40mg/2days)+E(2mg/day) E(2mg/day); T(40mg/2days); Oral: aged Postmenopausal 44 RCT weeks 6 E2(40mg)+T(50mg)implant E2(40mg) implant; womenreceived surgically and Natural postmenopausal RCTsingle months 3 T(40mg/2day)+E2(2mg/day) E2(2mg/day); T(40mg/2days); Oral: aged Postmenopausal 44 RCT months 3 + MT EP aged Postmenopausal 45 RCT Surgically menopausal women Surgicallymenopausal age trial controlled Double weeks 4 Placebo T(40mg/day); E(2mg/day); Oral: 50 Postmenopausal trial controlled Randomized,double weeks 8

-

blind randomized blind placebo

(1.25mg); EP + (1.25mg);Placebo EP - blind

-

65 - - blind, placebo blind, placebo blind,

- - - - 64 64 64 64

- d - - lower withE+Tlower vs alone. E expression) significantly 67 Endometrial(Ki proliferation withT (P<0.01) Significantlibidoincrease in with E2 alone. not extentbutwith T+E2 (P<0.05) and lesser with T (P<0.01) decreaseddisposal by 20% Insulin sexuallydysfunctional 68.7% Tlongerno group: change (no in placebo) (p<0.001). 26.5±5.3 baseline to T 17.3±6.2 group FSFI: groups compared togroups Placebo in and pitch 12.5 25mgT Significantdecrease voice in “Ah” Sustained Test: (P>0.05) treatmentgroups fairness)reciprocal between altruism attitudes, and (risk economic behaviour significant No difference in treatments. blood occlusion between AUCfingertip post of flow vaginal blood rate and No placebo. to endometriumT aftercompared glands in of stronger of AR ER Expression and significantdifference in

- induced glucose induced

-

-

B

- Yes Yes Yes stated None Yes Yes stated None stated None

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted Article Davis 2000 SR 126

33

Every 3 months for 2 yearsEvery formonths 2 3 E2(50mg+T(50mg)implant E2(50mg)implant; women Postmenopausal RCTsingle time week1 weeks a for 24 25mg) or T injection (3, Enanthate IM 6.25,12.5 injection Placebo; IM 41

- 62 received 62

- blind

with E2 alone. withE2 respectively) (P<0.01, P<0.05 circumferenceabdominal Significantdecreaseand hip in withnot E2 alone.but declined(P<0.05) withratio T, whereas (P<0.01) FM:FFM increased FFM significantly (P<0.05) Placebo 25mgwith T compared at decrease voice pitch in Test: Sentence Significant serumfreeT concentration. (P< 0.05) relatedto increase 0.05) in

Yes

This article is protected by copyright. All rights reserved. This article isprotected rights by All copyright. reserved. Accepted Article