Appendix 1. Literature Search Strategy

Appendix 1. Literature Search Strategy

Among the Medical Subject Headings (MeSH) searched were estrogens, conjugated; conjugated equine estrogen; Premarin; estradiol; Vagifem; Estring; Estrace; estriol; estrogen replacement therapy; atrophy; vaginal diseases; atrophic vaginitis; vaginal discharge; dysuria; urinary incontinence; overactive bladder; sexual dysfunction; dyspareunia; randomized controlled trial; controlled clinical trial; comparative study; prospective study; cross-over study; meta-analysis; and systematic review. We did not attempt to identify unpublished articles or abstracts, and we did not contact study authors.The search was limited to human subjects and English language.Reference lists of selected articles and review papers were screened for additional eligible references.

Appendix 2. Non–Placebo-Controlled Studies of Vaginal Estrogen in Women WithGenitourinary Syndrome of Menopause

Study Author, Country, y / Study Quality / Intervention (n) / Comparator (n) / Follow-Up Duration
Ayton,(31)Australia, 1996 / A / Estradiol vaginal ring, once (131) / Conjugated estrogen cream⁺1 g
Daily 21d, then none 7d(63) / 12wk
Bachmann,(32) USA, 1997 / B / Estradiol vaginal ring, once (129) / Conjugated estrogen cream 2 g 3x perwk (67) / 12 wk
Nachtigall,(33) USA, 1995* / * / Estradiol vaginal ring, once (129) / Conjugated estrogen cream 2 g 3x per wk (67) / 12 wk
Barentsen,(34) The Netherlands, 1997 / A / Estradiol vaginal ring, once (83) / Estriol 0.5 mg cream
Daily 2wk, then 3x per wk (82) / 12 wk
Capobianco,(35) Italy, 2012 / A / Estriol 1 mg ovule
Daily 2 wk, then 2 ovules 1x per wkplus PFMT (103) / Estriol 1 mg ovule
Daily 2 wk, then 2 ovules 1x per wk (103) / 24 wk
Chompootaweep,(36) Thailand, 1998 / B / Conjugated estrogen cream 1 g
3x per wk for 1 wk, then 2x per wk for 1 wk, then 1x per wk for 6 wk (20) / OCP vaginally 1x per wk (20) / 8 wk
Dickerson,(37) USA, 1979 / B / Estradiol 0.01% cream 0.2 mg
Daily 2 wk (20) / Conjugated estrogen cream 2 g
Daily 2 wk (10) / 2 wk
Dugal,(38) Norway, 2000 / A / Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk (46) / Estriolvagitory 0.5 mg
Daily 2 wk, then 2x per wk (46) / 24 wk
Henriksson,(39) Sweden, 1994 / A / Estradiol vaginal ring, once (112) / Estriolpessary 0.5 mg
Daily 3 wk, then 2x per wk (53) / 12 wk
Kicovic,(40) Italy, 1980 / C / Estriol cream 1 mg
Daily 3 wk, then 2x per wk (23) / Estriol cream 0.5 mg (30) or
Estriol suppository 0.5 mg (21)
Daily 3 wk, then 2x per wk / 16 wk
Lose,(41) Denmark, 2000 / B / Estradiol vaginal ring
Every 12 wk(134) / Estriolpessary 0.5 mg
Daily 3 wk, then every other day (117) / 24 wk
Manonai,(42) Thailand, 2001 / B / Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk (27) / Conjugated estrogen cream 1 g
Daily 2 wk, then 2x per wk(63) / 12 wk
Mattson,(43) Sweden, 1983 / B / Estriol cream 0.5 mg
Daily 2 wk, then 2x per wk (15) / Estriol suppository 0.5 mg
Daily 2 wk, then 2x per wk (15) / 8 wk
Mattson,(44) Sweden, 1989 / C / Estradiol vaginal tablet 25 μg
Daily 3 wk, then 2x per wk (20) / Estradiol vaginal tablet 50 μg
Daily 3 wk, then 2x per wk (20) / 9 wk
Mettler,(45) Germany, 1991 / C / Estradiol vaginal tablet 25 μg
Daily 2 wk, then 1x per wk (17) / Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk (34) / 52 wk
Rioux,(46) Canada, 2000 / B / Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk (80) / Conjugated estrogen cream 2 g
Daily 21d, then none 7d(79) / 24 wk
Trevoux,(47) France, 1982 / C / Estriol cream 0.5 mg
Daily 3 wk, then 2x per wk (54) / Estriol suppository 0.5 mg
Daily 3 wk, then 2x per wk (28) / 8 wk
Weisberg,(48) Australia, 2005 / A / Estradiol vaginal ring
Every 12 wk(126) / Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk(59) / 48 wk
Antoniou,(49) Greece, 1997 / B / Estradiol vaginal ring every 12 wkand 100mg vaginal progesterone suppository 7 d per mo (28) / Transdermal estradiol 50 μg per d andlevonorgestrel-releasing intrauterine device (28) / 52 wk
Botsis,(50) Greece, 1997 / B / Conjugated estrogen cream 1 g
Frequency unspecified (36) / Tibolone 2.5 mg orally
Daily (36) / 6 mo
Gupta,(51) USA, 2008 / A / Estradiol vaginal ring, once (12) / Transdermal estradiol 14 μg per d (12) / 12 wk
Holmgren,(52) Sweden, 1989 / C / Estradiol vaginal ring, once (11) / Vaginal estradiol ring
20-30 μg per d (11) / 12 wk
Long,(53, 54) China, 2006 / B / Conjugated estrogenoral tablet0.625mg per day (27) / Conjugated estrogen cream 1 g
Daily (30) / 12 wk
Biglia,(55) Italy, 2010 / C / Estriol cream 0.25mg 2x per wk (10) orestradiol vaginal tablet 12.5 μg2x per wk (8) / Non-hormonal moisturizer (Replens®) 2.5 g
2x per wk (8) / 12 wk
Ekin,(56) Turkey, 2011 / C / Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk (21) / Hyaluronic acid 5 mg tablet
Daily (21) / 8 wk
Nachtigall,(57) USA, 1994 / C / Conjugated estrogencream 2 g
Daily (15) / Non-hormonal moisturizer (Replens®)
3x per wk (15) / 12 wk
Parsons,(58) USA, 2003 and Kessel,(59) USA, 2003† / B / Conjugated estrogencream 1 g
Daily 2 wk, then 2x per wk(46) / Non-hormonal moisturizer (Replens®)
Daily 2 wk, then 2x per wk(47) / 12 wk
Raghunandan,(60) India, 2010# / B / Conjugated estrogen cream 1 g
Daily 2 wk, then 2x per wk(25) / Nonhormonal KY lubricant gel
Daily 2 wk, then 2x per wk(25) / 12 wk
Pinkerton,(61) USA, 2003 / A / Estradiol vaginal ring every 12 wkand daily oral placebo (45) / Estradiol vaginal ring every 12 wkand daily oral raloxifene 60 mg (46) / 6 mo
Raz,(62) Israel, 2003 / A / Estriolpessary 0.5 mg
2x per wkand daily oral placebo (86) / Vaginal pessary placebo
2x per wkand daily oral nitrofurantoinmacrocrystal 100 mg (85) / 9 mo

wk, week; PFMT, Pelvic Floor Muscle Therapy; OCP, oral contraceptive pill containing 250 μglevonorgestrel plus 30 μgethinyl estradiol.

⁺ Conjugated estrogen cream (Premarin) concentration in all studies involved: 0.625 mg per 1 g cream.

*, Supplemental companion paper to Bachmann 1997.(32)

†, Study also contains randomization to oral Raloxifene or placebo; only the oral placebo patients receiving conjugated estrogen or non-hormonal moisturizer creams were considered for this review.

#, Study also contains a third comparison group receiving both conjugated estrogen cream and 0.5 gm 2% testosterone (1 mg) cream; only the conjugated estrogen cream versus non-hormonal lubricant gel comparison was considered for this review.

Rahn DD, Carberry C, Sanses TV, Mamik MM, Ward RM, Meriwether KV, et al. Vaginal estrogen for genitourinary syndrome of menopause: a systematic review. ObstetGynecol 2014;124.

The authors provided this information as a supplement to their article.