Hormonal Treatments and Vaginal Moisturizers for Genitourinary Syndrome of Menopause: A Systematic Review

Elisheva R Danan; Catherine Sowerby; Kristen E Ullman; Kristine Ensrud; Mary L Forte; Nicholas Zerzan; Maylen Anthony; Caleb Kalinowski; Hamdi I Abdi; Jessica K Friedman; Adrienne Landsteiner; Nancy Greer; Rahel Nardos; Cynthia Fok; Philipp Dahm; Mary Butler; Timothy J Wilt; Susan Diem

doi:10.7326/ANNALS-24-00610

. Author manuscript; available in PMC: 2025 Aug 8.

Published in final edited form as: Ann Intern Med. 2024 Sep 10;177(10):1400–1414. doi: 10.7326/ANNALS-24-00610

Hormonal Treatments and Vaginal Moisturizers for Genitourinary Syndrome of Menopause: A Systematic Review

Elisheva R Danan ^1,², Catherine Sowerby ¹, Kristen E Ullman ¹, Kristine Ensrud ^1,^2,³, Mary L Forte ⁴, Nicholas Zerzan ¹, Maylen Anthony ¹, Caleb Kalinowski ¹, Hamdi I Abdi ⁴, Jessica K Friedman ⁸, Adrienne Landsteiner ¹, Nancy Greer ¹, Rahel Nardos ⁵, Cynthia Fok ⁷, Philipp Dahm ^6,⁷, Mary Butler ⁴, Timothy J Wilt ^1,^2,⁴, Susan Diem ^1,²

PMCID: PMC12333043 NIHMSID: NIHMS2087927 PMID: 39250810

Abstract

Background:

Postmenopausal women commonly experience vulvovaginal, urinary, and sexual symptoms associated with genitourinary syndrome of menopause (GSM).

Purpose:

Evaluate effectiveness and harms of vaginal estrogen, non-estrogen hormonal therapies, and vaginal moisturizers for treating GSM symptoms.

Data Sources:

Medline^®, Embase^®, and CINAHL^® through December 11, 2023.

Study Selection:

Randomized controlled trials (RCTs) ≥8 weeks duration enrolling postmenopausal women with ≥1 GSM symptom and reporting effectiveness or harms of hormonal interventions or vaginal moisturizers.

Data Extraction:

Risk of bias and data extraction by one reviewer, verified by a second. Certainty of evidence (COE) assessed by one reviewer, verified by consensus.

Data Synthesis:

From 11,933 citations, we identified 46 RCTs evaluating vaginal estrogen (22), non-estrogen hormones (16), vaginal moisturizers (4), or multiple interventions (4). Varied populations, interventions, comparators, and outcomes precluded meta-analyses. Compared with placebo or no treatment, vaginal estrogen may improve vulvovaginal dryness, dyspareunia, “most bothersome symptom,” and treatment satisfaction. Compared with placebo, vaginal dehydroepiandrosterone (DHEA) may improve dryness, dyspareunia, and distress, bother, or interference of genitourinary symptoms; oral ospemifene may improve dryness, dyspareunia, and treatment satisfaction; vaginal moisturizers may improve dryness (all low COE). Vaginal testosterone, systemic DHEA, vaginal oxytocin, and oral raloxifene or bazedoxifene may provide no benefit (low COE) or had uncertain effects (very low COE). While studies did not report frequent serious harms, reporting was limited by short duration studies insufficiently powered to evaluate infrequent serious harms.

Limitations:

Most studies were ≤12 weeks and used heterogeneous GSM diagnostic criteria and outcome measures. Few studies enrolled women with a history of cancer.

Conclusions:

Vaginal estrogen, vaginal DHEA, oral ospemifene, and vaginal moisturizers may improve some GSM symptoms short-term. Little long-term data exists on efficacy, comparative effectiveness, tolerability, and safety of GSM treatments.

Primary Funding Sources:

AHRQ, PCORI. PROSPERO: CRD42023400684

Introduction:

The term genitourinary syndrome of menopause (GSM) was introduced a decade ago to describe the symptoms and physical changes resulting from declining estrogen and androgen concentrations in the female genitourinary tract during and after menopause.(1, 2) GSM encompasses vulvovaginal symptoms, such as dryness and irritation,(3) urinary symptoms and clinical events including urgency, frequency, dysuria, and recurrent urinary infections,(4) and sexual symptoms, such as dyspareunia and reduced libido, arousal, and orgasm.(4–6) Physical exam findings associated with GSM include labial and clitoral atrophy, friable vaginal epithelium, and introital stenosis.(1, 2) Clinical trials and prior evidence syntheses largely targeted signs of atrophy, but presence and severity of physical changes do not directly correlate with self-reported GSM symptoms.(7–9)

GSM prevalence estimates in postmenopausal women vary from 13 to 87 percent, due to variation in the symptoms and/or signs assessed, severity, assessment tools, and study populations.(10) For example, women undergoing treatment for breast or genitourinary cancers may experience earlier menopause and higher prevalence of GSM symptoms due to chemotherapy-induced premature ovarian failure and anti-estrogen endocrine therapies such as aromatase inhibitors.(11, 12) Unlike menopausal vasomotor symptoms (i.e., hot flashes and/or night sweats), GSM symptom prevalence and intensity often increases with advancing age.(13, 14)

GSM treatments aim to relieve bothersome symptoms by mimicking or restoring premenopausal vaginal secretions and tissue integrity.(15, 16) A recent consensus review identified eight core patient-reported outcomes considered most important to patients and clinicians.(17) Vaginal estrogen and vaginal moisturizers have long been the mainstay of treatment, but newer non-estrogen local and systemic hormonal therapies have emerged.

We conducted a systematic review to evaluate the effectiveness and harms of vaginal estrogen, non-estrogen hormonal therapies, and vaginal moisturizers for treating GSM symptoms, with a focus on patient-reported outcomes.

Methods:

Data Sources and Searches:

This systematic review is part of a larger evidence report,(18) (PROSPERO registration number CRD42023400684). We searched Medline^®, Embase^®, and CINAHL^® from database inception through December 11, 2023 (Supplement A). We included vocabulary and natural language terms, along with free-text words, relevant to GSM symptoms. We supplemented our searches with citation searches of relevant systematic reviews and original research. All searches were independently peer-reviewed.

Study Selection:

We included English-language publications of randomized controlled trials (RCTs) of ≥8 weeks duration, with ≥20 participants per arm, that evaluated the effectiveness or harms of US-available hormonal interventions or vaginal moisturizers for GSM in postmenopausal women with ≥1 GSM symptom (Supplemental Table 1). Treatments included vaginal estrogen (vaginal cream, tablets, inserts, or ring), vaginal or systemic dehydroepiandrosterone (DHEA), oxytocin vaginal gel, oral selective estrogen receptor modulators (SERMs), vaginal testosterone, and vaginal moisturizers. Systemic estrogen was not included because it is used primarily to treat menopausal vasomotor symptoms and has been reviewed extensively.(19)

Titles and abstracts were initially screened for exclusion by two independent reviewers. We screened abstracts with the assistance of DistillerSR’s Artificial Intelligence System (DAISY) until the DAISY-predicted score for likelihood of inclusion was less than 0.1 percent and the inclusion rate had fallen to less than 5 percent. The remaining abstracts (~2000) with an inclusion score less than 0.1 percent were not screened by a second reviewer, but a word search of the titles and abstracts was completed to ensure that any relevant articles were not missed. At full-text screening, two independent reviewers agreed on the final inclusion or exclusion decision. Articles that met eligibility criteria were assessed for risk of bias (RoB).

Data Extraction and Quality Assessment:

We evaluated RoB using the Cochrane Risk of Bias Tool 2.0 (RoB-2).(20) For all included trials, we extracted study characteristics, baseline measures, and outcomes reported; we extracted and synthesized detailed outcomes data only for studies rated low or some concerns RoB. Outcomes of interest were identified in the Core Outcomes in Menopause (COMMA) review (17): (1) dyspareunia, (2) vulvovaginal dryness, (3) vulvovaginal discomfort/irritation, (4) dysuria, (5) change in most bothersome symptom (MBS), (6) distress, bother, or interference of genitourinary symptoms, (7) satisfaction with treatment, and (8) side effects of treatment. Additional effectiveness outcomes were identified by key informants and our technical expert panel (Supplemental Table 1). For hormonal interventions, endometrial safety evaluations and outcomes were also extracted. Endometrial stimulation can be assessed by inquiring about spontaneous vaginal bleeding, or by using progesterone challenge to provoke vaginal bleeding, transvaginal ultrasound to measure endometrial lining, or endometrial biopsy to assess for endometrial hyperplasia or carcinoma. Data were extracted into DistillerSR by one reviewer and verified by a second reviewer.(21)

Data Synthesis and Analysis:

For studies with low or some concerns RoB, we synthesized evidence for each unique comparison. Heterogeneity in populations, interventions (formulations and dosing), comparisons, outcomes, and reporting, including length of follow-up, precluded meta-analysis. Therefore, we used alternative approaches to summarize the evidence including counting studies based on direction of effect and statistical significance. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to assess the overall certainty of evidence (COE) for each COMMA outcome above (additional outcomes are reported in supplementary materials without certainty of evidence assessments).(22) We derived COE based on statistical rather than clinical significance (non-contextualized approach) in part because validated measures of clinical significance were not available.

Role of the funding source:

The Agency for Healthcare Research and Quality (AHRQ) and the Patient-Centered Outcome Research Institute (PCORI) funded the complete report (18) and evaluated, provided feedback, and approved the protocol, analyses, final report, and manuscripts.

Results:

From 11,933 unique citations, 70 publications that described 46 unique RCTs met inclusion criteria (Figure 1). An overview of study characteristics for the 33 RCTs rated low or some concerns RoB is shown in Table 1; detailed characteristics by trial are in Supplemental Table 2. Characteristics of 13 studies assessed as high RoB are provided in Supplemental Table 3. Detailed RoB ratings for all trials are in Appendix Table 1.

Table 1.

Overview of Study Characteristics for Included Trials Rated Low or Some Concerns RoB

Intervention vs. Comparator	# studies N=total participants (n=per study) Publication Year	Length of follow-up (# studies)	Intervention(s) studied (# studies)	Funder (# studies)	Location (# studies)	COMMA Outcomes Assessed (# studies)

Vaginal estrogen vs. Placebo	9 studies (29–37)	8 weeks (1)	Vaginal estradiol:	Industry (4)	US (2)	Dryness (7)
	N=2,292 total	12 weeks (8)	Softgel 4 mcg or 10 mcg (1)	Foundation (1)	US & Canada (2)	Dyspareunia (7)
			Tablet 10 mcg (1)	Government (1)	Brazil (2)	Discomfort/irritation (4)
			Gel 25 mcg (1)	Academia (1)	Thailand (1)	Dysuria (1)
			Cream 0.003% (1)	None (1)	India (1)	Change in MBS (4)
	(range n=40–573)		Vaginal conjugated estrogen (0.625 mg/g)	Not reported (1)	Not reported (1)	Distress/bother (1)
	2009–2020		Cream 0.5g (2); 1g (3)			Treatment satisfaction (1)
						Adverse effects (9)

Vaginal estrogen vs. No treatment	study (25)	36 weeks	Vaginal estradiol ring 2 mg	Industry	Norway	Dryness
	N=108					Dyspareunia
	1999					Discomfort/irritation
						Dysuria
						Adverse effects

Vaginal estrogen dose or delivery method comparison	3 studies (38–40)	12 weeks (2)	Vaginal estradiol ring 2 mg vs. Vaginal conjugated estrogen (0.625mg/g), 1g or 2g, or	Industry (1)	US (1)	Dryness (2)
	N=441	15 weeks (1)	Vaginal estradiol cream 50mcg vs. 100 mcg	Foundation (1)	Australia (1)	Dyspareunia (3)
	(range n=50-196)			Not reported (1)	Not reported (1)	Discomfort/irritation (2)
	1995-2023					Dysuria (1)
						Treatment satisfaction (2)
						Adverse effects (2)

Vaginal estrogen vs. Overactive	2 studies (24, 41)	12 weeks (2)	Vaginal estradiol ring 7.5 mcg/day vs. Oral oxybutynin 5 mg, or	Industry (1)	US (1)	Adverse effects (2)
Bladder pharmaceuticals	N=139 (n=59–80) 2009 – 2011		Vaginal conjugated estrogen (0.625mg/g), 1g, + oral tolterodine 2 mg, vs.Oral tolterodine 2 mg	Not reported (1)	Taiwan (1)

Vaginal DHEA vs. Placebo	4 studies (26, 42–44)	12 weeks (4)	Vaginal DHEA	Industry (3)	US & Canada (3)	Dryness (4)
	N=1,472		Ovule 3.25 mg or 6.5 mg	Government (1)	Canada (1)	Dyspareunia (4)
	(range n=216–558)		Ovule 3.25 mg or 6.5 mg or 13 mg			Discomfort/irritation (1)
	2009 – 2018		Ovule 6.5 mg			Change in MBS (2)
			Gel 3.25 mg or 6.5 mg			Distress/bother (1)
						Adverse effects (4)

Oral DHEA vs. Placebo	1 study (45) N=93 2009	52 weeks	Oral DHEA 50 mg capsule	Not reported	Australia	Distress/bother Adverse effects

Oral Ospemifene vs. Placebo	4 studies (46–50)	12 weeks (4)	Oral ospemifene 60 mg (3)	Industry (4)	US (3)	Dryness (3)
	N= 2,802	1 year (1)	Oral ospemifene 60 mg or 30 mg (1)		Europe (1)	Dyspareunia (3)
	(range n=426–919)					Discomfort/irritation (1)
	2010 – 2019					Treatment satisfaction (1)
						Adverse effects (4)

Oral Raloxifene or Bazedoxifene (+/- vaginal estrogen) vs. Placebo (+/- vaginal estrogen)	3 studies (51–53)	12 weeks (1)	Bazedoxifene 20 mg (1)	Industry (2)	US (3)	Dryness (1)
	N= 929	3 months (1)	Raloxifene 60 mg (2)	Not reported (1)		Dyspareunia (2)
	(range n=91–652)	6 months (1)				Dyuria (1)
	2003–2010					Distress/bother (1)
						Treatment satisfaction (1)
						Adverse effects (2)

Vaginal Oxytocin vs. Placebo	2 studies (54, 55)	8 weeks (1)	Vaginal oxytocin gel 1x1mL	Industry (1)	Sweden (1)	Dryness (2)
	N=257	12 weeks (1)	Vaginal oxytocin gel 2g	Academia (1)	Iran (1)	Dyspareunia (2)
	(n=96 and n=161)					Discomfort/irritation (2)
	2020					Change in MBS (1)
						Adverse effects (2)

Vaginal Testosterone vs. Placebo	2 studies (28, 33)	12 weeks (1)	Vaginal testosterone cream 300 mcg, 1g	Foundation (2)	Brazil (1)	Dryness (2)
	N=84	26 weeks (1)			Australia (1)	Dyspareunia (2)
	(n=44 and n=40)					Adverse effects (1)
	2014-2018

Vaginal Testosterone vs. Vaginal Estrogen	1 study (27)	12 weeks	Vaginal estradiol ring 7.5 mcg/day vs.	Industry	US	Adverse effects
	N=76		Vaginal testosterone cream 0.5g
	2017

Vaginal Moisturizer vs. Placebo	4 studies (23, 30, 33, 56)	12 weeks (4)	Polyacrylic acid vaginal cream	Foundation (1)	US (1)	Dryness (4)
	N=418		Lactic acid vaginal gel	Academia (1)	Slovakia (1)	Dyspareunia (3)
	(n=40–200)		Bioadhesive polycarbophil-based vaginal gel	Government (1)	South Korea (1)	Change in MBS (1)
	2011 – 2022		Hyaluronic acid vaginal gel	Industry (1)	Brazil (1)	Treatment satisfaction (2)
						Adverse effects (4)

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Abbreviations: COMMA=Core Outcomes in Menopause; DHEA=dehydroepiandrosterone; g=gram; MBS=most bothersome symptom; mcg=microgram; mg=milligram; mL=milliliter; US=United States

Trials typically enrolled women in their 50s; the exceptions were a trial of vaginal moisturizer for breast cancer survivors (mean age 45–46 years),(23) and two trials of vaginal estrogen focused on urinary outcomes (mean age ≥ 65 years).(24, 25) Among studies that reported race/ethnicity (~60%), white women were ~80% of the study population. About half of trials required moderate to severe GSM symptoms for inclusion. Required objective verification of vaginal atrophy using vaginal cytology or pH varied by intervention type: nearly all trials of vaginal DHEA, oral ospemifene, and vaginal oxytocin restricted study inclusion to those with objective verification of atrophy, compared with one-third of vaginal estrogen and one-quarter of vaginal moisturizer trials. Women with risk factors for cardiovascular disease, cancer, or venous thromboembolism (VTE) were largely excluded from study participation. Only 4 trials enrolled current or treated cancer patients. (23, 26–28)

Even multi-arm studies provided comparisons to placebo only, with no head-to-head comparative effectiveness trials. Many studies reported an improvement in symptoms from baseline in the placebo group. Findings for the most reported outcomes (vulvovaginal dryness and dyspareunia) and selected adverse effects outcomes are presented below for each intervention (studies with multiple interventions are described in each relevant section). Results for vulvovaginal dryness and dyspareunia are shown in Table 2, and for additional COMMA outcomes in Appendix Tables 2–7; detailed results for all effectiveness and harms outcomes are in Supplemental Tables 4 and 5. Table 3 provides GRADE statements for all COMMA outcomes.

Table 2.

Summary of Outcome Reporting for Vulvovaginal Dryness and Dyspareunia

Comparison	# trials Total N	Follow-up	Measurement tool	Author, year	Intervention	Intervention Mean change	Comparator Mean change	Direction of effect^***	Summary COE
Vulvovaginal Dryness
Vaginal estrogen vs. placebo	7 trials N=2,072	12 weeks	FSFI Lubrication^*	Constantine, 2017 (32)	Estradiol tab 4 mcg Estradiol tab 10 mcg	1.8^* 2.2^*	1.6^*	↑	Low ⨁⨁◯◯ Improve
				Fernandes, 2014 (33)	CEC 1g 3x/wk	1.3^*	1.0^*	?
				Mitchell, 2018 (30)	Estradiol 10 mcg	1.4 (95% CI 1.1, 1.8)	1.2 (0.8, 1.6)	↔
			4-point severity^†	Archer, 2018 (31)	Estradiol cream	−1.4 (95% CI −3.2, 0.4)	−1.2 (−3, 0.6)	↑
				Bachmann, 2009 (36)	CEC 0.5g 21/7 ↑ CEC 0.5g 2x/wk ↔	−1.1^ −0.8^	−0.7^ −0.8^	↑↔
				Freedman, 2009 (37)	CEC 1g 2x/wk	79% improved 33% resolved	58% improved 16% resolved	↑
				Lima, 2013 (34)	CEC 0.5g daily	No data (graph improvement)		?
Vaginal estrogen vs. no treatment	1 trial N=108	36 weeks	Patient diary^‡	Eriksen, 1999 (25)	Estradiol ring 2 mg	81% symptom resolution	17% symptom resolution	↑	Low ⨁⨁◯◯ Improve
Vaginal DHEA vs. placebo	4 trials N=1472	12 weeks	FSFI Lubrication^*	Barton, 2018 (26)	DHEA 0.25% ↔ DHEA 0.5% ↑	1.3 (95% CI 1.0, 1.6) 1.6 (1.3, 1.9)	1.1 (0.7, 1.4)	↔↑	Low ⨁⨁◯◯ Improve
			FSFI Lubrication^*	Labrie, 2018 (61)	DHEA 0.5%	2.1^*	1.6^*	↑
			4-point severity^†	Archer, 2015 (43)	DHEA 0.25% DHEA 0.5%	−1.3 (95% CI −1.5, −1.1) −1.5 (−1.7, −1.3)	−1.0 (−1.3, −0.7)	↑
			MENQOL^§	Labrie, 2009 (62)	DHEA 0.25% DHEA 0.5% DHEA 1.0%	45% decrease 50% 54%	23%	↑
Oral ospemifene vs. placebo	3 trials N=1771	12 weeks	FSFI Lubrication^*	Archer, 2019 (48)	Ospemifene 60 mg	1.3 (95% CI 1.1, 1.5)	0.9 (0.7, 1.1)	↑	Low ⨁⨁◯◯ Improve
			FSFI Lubrication^*	Archer, 2019 (48)	Ospemifene 60 mg	difference of LSM 0.40 (95% CI 0.07, 0.73)
				Bachmann, 2010 (46)	Ospemifene 30 mg	−1.2^**	−0.8^**	↑
			4-point severity^†		Ospemifene 60 mg	−1.3^**
			4-point severity^†	Portman, 2014 (47)	Ospemifene 60 mg	−1.3 (95% CI −3.5, 0.9)	−1.1 (−3.1, 0.9)	↔
Vaginal moisturizer vs. placebo	4 trials N=418	12 weeks	FSFI Lubrication^*	Fernandes, 2014 (33)	Polyacrylic acid vaginal cream	1.5^*	1.0^*	?	Low ⨁⨁◯◯ Improve
			FSFI Lubrication^*	Mitchell, 2018 (30)	Polycarbophil gel	0.9 (95% CI 0.6, 1.3)	1.2 (0.8, 1.6)	↔
			VAS^{^\|\|}	Lee, 2011 (23)	Lactic acid vaginal gel	−4.0^*	−1.4^*	↑
		3 months	VRS Dryness Scale^¶	Nappi, 2022 (56)	Hyaluronic acidbased vaginal gel	71.7% improved by ≥2 points	35.3% improved by ≥2 points	↑
Vaginal testosterone vs. placebo	2 trials N=84	26 weeks	FSFI Lubrication^*	Davis, 2018 (28)	Testosterone cream 300 mg/mL	0.6 (IQR 0, 2.4)	0 (−0.15, 1.35)	↔	Very low ⨁◯◯◯ Uncertain
		26 weeks		Davis, 2018 (28)	Testosterone cream 300 mg/mL	linear regression beta coefficient 0.76 (95% CI −0.21, 1.72)		↔
		12 weeks		Fernandes, 2014 (33)	Testosterone cream 300 mcg/g	2.3^*	1.0^*	?
Oral raloxifene vs. placebo	2 trials N=274	3 months	4-point severity^†	Parsons, 2003 (52)	Raloxifene 60 mg	No data (reported graphically)		↔	Low ⨁⨁◯◯ No difference
Oral raloxifene vs. placebo	2 trials N=274	6 months	4-point severity^†	Pinkerton, 2003 (53)	Raloxifene 60 mg	No data (reported graphically)		↔	Low ⨁⨁◯◯ No difference
Vaginal oxytocin vs. placebo	2 trials N=243	8 weeks	FSFI Lubrication^*	Abedi, 2020 (63)	Oxytocin gel 400 IU	1.7^*	0.4^*	↑	Very low ⨁◯◯◯ Uncertain
Vaginal oxytocin vs. placebo	2 trials N=243	12 weeks	4-point severity^†	Fianu Jonasson, 2020 (54)	Oxytocin gel 400 IU	−1.2^**	−1.2^**	↔	Very low ⨁◯◯◯ Uncertain
Dyspareunia
Vaginal estrogen vs. placebo	7 trials N=2,072	12 weeks	FSFI Pain¹	Constantine, 2017 (32)	Estradiol tab 4 mcg ↔ Estradiol tab 10 mcg ↑	2.2^* 2.6^*	1.9^*	↔↑	Low ⨁⨁◯◯ No difference
				Fernandes, 2014 (33)	CEC 1g 3x/wk	1.7^*	1.0^*	?
				Mitchell, 2018 (30)	Estradiol 10 mcg	1.4 (95% CI 0.9, 1.8)	0.9 (0.5, 1.4)	↔
			4-point severity^†	Archer, 2018 (31)	Estradiol cream	No data (reported graphically)		↔
				Bachmann, 2009 (36)	CEC 0.5g 21/7	−1.4^**	−0.4^**	↑
					CEC 0.5g 2x/wk	−1.4^**	−0.7^**
				Freedman, 2009 (37)	CEC 1g 2x/wk	70% improved 34% resolved	40% 9%	↑
				Lima, 2013 (34)	CEC 0.5g daily	No data (graph improvement)		↔
Vaginal estrogen vs. no treatment	1 trial N=108	36 weeks	Patient diary^‡	Eriksen, 1999 (25)	Estradiol ring 2 mg	71% symptom resolution	10%	↑	Low ⨁⨁◯◯ Improve
Vaginal DHEA vs. placebo	4 trials N=1472	12 weeks	FSFI Pain¹	Barton, 2018 (26)	DHEA 0.25% ↔ DHEA 0.5% ↑	1.4 2.0	1.0	↑	Low ⨁⨁◯◯ Improve
			FSFI Pain¹	Labrie, 2018 (61)	DHEA 0.5%	2.2^*	1.6^*	↑
			4-point severity^†	Archer, 2015 (43)	DHEA 0.25% DHEA 0.5%	−1.0 −1.3	−0.9	↑
			4-point severity^†	Labrie, 2009 (62)	DHEA 0.25% DHEA 0.5% DHEA 1.0%	−1.2 −1.6 −1.4	−0.4	↑
Oral ospemifene vs. placebo	3 trials N=2,062	12 weeks	FSFI Pain¹	Archer, 2019 (48)	Ospemifene 60 mg	1.47 (95% CI 1.2, 1.7)	1.01 (0.8, 1.2)	↑	Low ⨁⨁◯◯ Improve
			FSFI Pain¹	Archer, 2019 (48)	Ospemifene 60 mg	difference of LSM 0.45 (95% CI 0.11, .080)		↑
			4-point severity^*	Bachmann, 2010 (46)	Ospemifene 30 mg ↔ Ospemifene 60 mg ↑	−1.0^ −1.2^	−0.9^**	↔↑
			4-point severity^*	Portman, 2013 (50)	Ospemifene 60 mg	−1.5 (95% CI −3.7, 0.7)	−1.2 (−3.4, 1)	↑
Vaginal moisturizer vs. placebo	3 trials N=338	12 weeks	FSFI Pain¹	Fernandes, 2014 (33)	Polyacrylic acid vaginal cream	1.7^*	1.0^*	?	Very low ⨁◯◯◯ Uncertain
			FSFI Pain¹	Mitchell, 2018 (30)	Polycarbophil gel	1.0 (95% CI 0.7, 1.4)	0.9 (0.5, 1.4)	↔
			VAS^{^\|\|}	Lee, 2011 (23)	Lactic acid vaginal gel	−2.8^*	−2.0^*	↑
Vaginal testosterone vs. placebo	2 trials N=84	26 weeks	FSFI Pain¹	Davis, 2018 (28)	Testosterone cream 300 mg/mL	Median 1.2 (IQR 0, 3.2)	0.4 (0, 1.4)	↔	Very low ⨁◯◯◯ Uncertain
		26 weeks		Davis, 2018 (28)	Testosterone cream 300 mg/mL	linear regression beta coefficient 0.76 (95% CI −0.48, 2.00)
		12 weeks		Fernandes, 2014 (33)	Testosterone cream 300 mcg/g	2.8^*	1.0^*	?
Oral raloxifene vs. placebo	2 trials N=274	12 weeks	4-point severity^†	Parsons, 2003 (52)	Raloxifene 60 mg	No data (reported graphically)		↔	Low ⨁⨁◯◯ No difference
Oral raloxifene vs. placebo	2 trials N=274	6 months	4-point severity^†	Pinkerton, 2003 (53)	Raloxifene 60 mg	No data (reported graphically)		↔	Low ⨁⨁◯◯ No difference
Vaginal oxytocin vs. placebo	2 trials N=243	8 weeks	FSFI Pain¹	Abedi, 2020 (63)	Oxytocin gel 400 IU	2.2	0.6^*	↑	Very low ⨁◯◯◯ Uncertain
Vaginal oxytocin vs. placebo	2 trials N=243	12 weeks	4-point severity^†	Fianu Jonasson, 2020 (54)	Oxytocin gel 400 IU	−0.88	−1.05^**	↔	Very low ⨁◯◯◯ Uncertain

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Abbreviations: CEC=conjugated estrogens cream; COE=certainty of evidence; DHEA=Dehydroepiandrosterone; FSFI=Female Sexual Function Index; LSM=least square mean; mcg=microgram; MENQOL=Menopause-Specific Quality of Life; mg=milligram; VAS=Visual Analogue Scale; VRS=Verbal Rating Scale

Direction of Effect Symbols: Based on statistical comparison between arms; ↑ intervention statistically significantly better than comparator; ↔ no statistically significant difference; ? no statistical comparison

Scale score interpretation:

FSFI (0=worst to 6=best);

^†

4-point severity (0=none to 3=severe);

^‡

Patient diary (none, mild, moderate, or severe);

^§

MENQOL (decreased score indicates improvement);

^||

VAS (0=best to 10=worst);

^¶

WRS Dryness Scale (0=absent to 3=severe)

Mean difference calculated by review team (trial only reported baseline and follow-up means)

^**

Trial did not provide precision statistics (e.g., SD, SEM, 95% CI)

^***

Direction of effect is based on statistical significance.

Table 3.

Overview of GRADE Statements for Each Intervention and Outcome

Intervention vs. comparator	Vulvovaginal Dryness	Vulvovaginal Discomfort / Irritation	Dysuria	Dyspareunia	Change in MBS	Distress, Bother, or Interference of Symptoms	Treatment Satisfaction	Adverse Effects
Vaginal estrogen vs. Placebo	Low^a,b ⨁⨁◯◯ Improves	Very low^a,b,c ⨁◯◯◯ Uncertain	Low^a,c ⨁⨁◯◯ No difference	Low^a,b ⨁⨁◯◯ No difference	Low^a,c ⨁⨁◯◯ Improves	Moderate^d ⨁⨁⨁◯ No Difference	Low^a,d ⨁⨁◯◯ Higher	Low^a,c ⨁⨁◯◯ No difference
Vaginal estrogen vs. No treatment	Low^a,d ⨁⨁◯◯ Improves	Low^a,d ⨁⨁◯◯ No difference	Low^a,d ⨁⨁◯◯ No difference	Low^a,d ⨁⨁◯◯ Improves	NR	NR	NR	N/A
Vaginal estrogen ring vs. Vaginal estrogen cream	Low^a,d ⨁⨁◯◯ No difference	Very low^a,c,d ⨁◯◯◯ Uncertain	Low^a,d ⨁⨁◯◯ No difference	Low^a,d ⨁⨁◯◯ No difference	NR	NR	Moderate^a ⨁⨁⨁◯ Higher	N/A
Vaginal DHEA vs. Placebo	Low^a,e ⨁⨁◯◯ Improves	Very low^a,f ⨁◯◯◯ Uncertain	NR	Low^a,e ⨁⨁◯◯ Improves	Very low^a,b,e ⨁◯◯◯ Uncertain	Low^a,d ⨁⨁◯◯ Improves	NR	Low^a,c ⨁⨁◯◯ More
Oral DHEA vs. Placebo	NR	NR	NR	NR	NR	Very low^e,f ⨁◯◯◯ Uncertain	NR	Very low^c,f ⨁◯◯◯ Uncertain
Vaginal oxytocin vs. Placebo	Very low^a,b,d ⨁◯◯◯ Uncertain	Very low^a,f ⨁◯◯◯ Uncertain	NR	Very low^a,b,d ⨁◯◯◯ Uncertain	Moderate^d ⨁⨁⨁◯ No Difference	NR	NR	Low^c,d ⨁⨁◯◯ No difference
Oral ospemifene vs. Placebo	Low^a,b ⨁⨁◯◯ Improves	High ⨁⨁⨁⨁ No difference	NR	Low^a,b ⨁⨁◯◯ Improves	NR	NR	High ⨁⨁⨁⨁ Higher	Low^a,c ⨁⨁◯◯ No difference
Oral raloxifene and/or BZA vs. Placebo	Low^a,d ⨁⨁◯◯ No difference	Low^a,d ⨁⨁◯◯ No difference	Low^a,d ⨁⨁◯◯ No difference	Low^a,d ⨁⨁◯◯ No difference	NR	Low^a,d ⨁⨁◯◯ Improves less	Very low^a,c,f ⨁◯◯◯ Uncertain	N/A
Vaginal testosterone vs. Placebo	Very low^d,f ⨁◯◯◯ Uncertain	NR	NR	Very low^d,f ⨁◯◯◯ Uncertain	NR	NR	NR	Very low^c,f ⨁◯◯◯ Uncertain
Vaginal moisturizer vs. Placebo	Low^a,c ⨁⨁◯◯ Improves	NR	NR	Very low^a,b,c ⨁◯◯◯ Uncertain	Low^a,d ⨁⨁◯◯ No difference	NR	Very low^a,c,d ⨁◯◯◯ Uncertain	Moderate^a ⨁⨁⨁◯ No difference

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Abbreviations: AE=adverse event; BZA=bazedoxifene; CO2=carbon dioxide; DHEA=dehydroepiandrosterone; Er:YAG=Erbium-doped yttrium aluminum garnet laser; HA=hyaluronic acid; MBS=most bothersome symptom; NR=not reported; N/A=not assessed

Certainty of evidence (COE):

High certainty (⨁⨁⨁⨁): We are very confident that the true effect lies close to that of the estimate of the effect.

Moderate certainty (⨁⨁⨁◯): We are moderately confident in the effect estimate; the true effect is likely to be close to the effect estimate, but there is a possibility that it is substantially different.

Low certainty (⨁⨁◯◯): Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.

Very low certainty (⨁◯◯◯): We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Explanations for downgrading:

^a.

Downgraded one level for study limitations (one or more trials assessed as “some concerns” RoB)

^b.

Downgraded one level for inconsistency (effect varied across trials)

^c.

Downgraded one level for study limitations (one or more trials did not provide adequate statistical reporting)

^d.

Downgraded one level for imprecision (total sample size less than OIS of 400)

^e.

Downgraded one level for imprecision (SD crosses no-effect threshold)

^f.

Downgraded two levels for imprecision (total sample size much less than OIS of 400)

^g.

Downgraded one level for imprecision (no or few events)

Vaginal Estrogen:

Sixteen RCTs (24 publications) were assessed as low (30, 32, 33, 38) or some concerns (24, 25, 27, 29, 31, 34–37, 39–41) RoB; all reported adverse effects and 14 reported at least one COMMA effectiveness outcome.

Vaginal Estrogen vs. Placebo (k=9)

Nine trials (29–37) (n=40–573) reported outcomes following 8 or 12 weeks of treatment with vaginal estrogen compared with placebo. Vaginal estrogen formulations and dosing frequency varied (Table 1; Supplemental Table 2).

All seven trials that assessed vaginal dryness observed more improvement in the estrogen group than in the placebo group, though only four trials (31, 32, 36, 37) found that the difference in improvement was statistically significant (Table 2). For example, Constantine 2017 (32) reported an improvement of 2.2 points on the 7-point Female Sexual Function Index (FSFI; 0=worst to 6=best) lubrication domain for vaginal estradiol 10 mcg softgel vs. 1.6 for placebo (p=0.001). Mitchell 2018 (30) found no difference on FSFI lubrication for vaginal estradiol 10 mcg tablet compared with placebo tablet; and 2 trials (33, 34) did not provide a statistical comparison of the difference. Overall, low-certainty evidence indicates that vaginal estrogen, compared with placebo, may improve vulvovaginal dryness.

Six of seven trials that assessed dyspareunia observed more improvement in the estrogen group than in the placebo group, although only three trials (32, 36, 37) found that the difference in improvement was statistically significant. For example, Bachmann 2009 (36) reported a −1.4 point improvement on a 4-point dyspareunia severity scale (0=none to 3=severe) for conjugated estrogens cream twice weekly vs. −0.7 for placebo (p≤0.01); two trials (30, 31) found no statistically significant difference on FSFI pain domain; and two trials (33, 34) did not provide a statistical comparison of the difference. Overall, low-certainty evidence indicates that vaginal estrogen, compared with placebo, may result in little to no difference in dyspareunia.

Trials reported rare serious adverse effects (SAEs) that were not considered treatment-related (Supplemental Table 5). Six trials reported study discontinuation due to AEs, which ranged from 0.5 to 23% for estrogen participants (due to allergic vaginitis, mastalgia, or pelvic pain, for example) and 0 to 7.4% for placebo participants.(31, 32, 34, 36, 37, 57)

Vaginal Estrogen vs. No Treatment (k=1)

One small trial (25) (n=108) compared vaginal estradiol ring with no treatment for 36 weeks and reported resolution of vulvovaginal dryness and dyspareunia for 81% and 71% of symptomatic vaginal estrogen users, respectively, compared with 17% and 10% of symptomatic control participants (p=0.001 and p=0.003). Low-certainty evidence indicates that vaginal estrogen, compared with no treatment, may improve vulvovaginal dryness and dyspareunia.

Five participants in the vaginal estradiol ring group discontinued due to local discomfort, hot flushes, or more frequent UTIs. No control participants discontinued due to AEs.

Vaginal Estrogen Dose or Delivery Method Comparisons (k=3)

Two moderate-sized trials (38, 39) (n=195 and 196) compared vaginal estrogen ring with vaginal conjugated estrogens cream for 12 or 15 weeks. One trial (29) graphically displayed more frequent resolution of vulvovaginal dryness and dyspareunia for participants who used the ring compared with cream, while the other (39) stated only that “equivalence criteria were satisfied;” neither found a statistically significant difference in improvement between treatment arms. An additional small trial (33) (n=50) compared two doses of estradiol cream applied to the vulvar vestibule for 12 weeks and found no significant difference between groups for any outcome.

One of the three trials (39) reported 3 SAEs that were not considered treatment-related, as well as one breast cancer diagnosis at an unspecified point after the 12-week treatment period. In the same trial, 4% of participants in the vaginal estradiol ring group discontinued due to vaginal discomfort, headache, and dizziness, while none of the vaginal conjugated estrogens cream participants discontinued due to AEs. The other trial (29) comparing vaginal estrogen ring with cream found similar discontinuation rates in the ring group (7% due to AEs including nausea, headache, abdominal pain, backache, urinary infection, candida infection, and vaginal bleeding, and additional 1.5% discontinued because the ring fell out) and cream group (8% due to abdominal/pelvic discomfort, backache, breast discomfort, and candida infection).

Vaginal Estrogen vs. Overactive Bladder Pharmaceuticals (k=2)

Two small trials (24, 41) (n=59–80) compared vaginal estrogen alone with oral oxybutynin alone, or with tolterodine combined with vaginal estrogen for 12 weeks and reported urinary outcomes (Supplemental Table 4). Neither reported SAEs or discontinuation due to AEs; specific AEs are reported in Supplemental Table 5.

Non-Estrogen Hormonal Interventions:

Seventeen RCTs (31 publications) of non-estrogen hormonal interventions were assessed as low or some concerns RoB; 16 reported at least one COMMA effectiveness outcome.

DHEA

Vaginal DHEA vs. Placebo (k=4)

Four moderate-sized RCTs (26, 42–44) (n=216–558) compared vaginal DHEA with placebo for 12 weeks. All 4 reported that the improvement in dryness and dyspareunia in the vaginal DHEA versus placebo group was statistically significant. For example, Archer, 2015 (43) used a 4-point severity scale and reported a −1.5-point improvement for dryness and a −1.3-point improvement for dyspareunia for vaginal DHEA 6.5 mg vs. −1.0 and −0.9, respectively, for placebo (p=0.01 for both). Overall, low-certainty evidence indicates that vaginal DHEA, compared with placebo, may improve vulvovaginal dryness and dyspareunia.

Only one trial (43) reported SAEs: 3.5% in DHEA group vs none in placebo group. Three trials (26, 42, 43) reported that 1.5 to 11.4% of DHEA participants discontinued treatment due to AEs (including hot flushes, vaginal intraepithelial lesion, application site discharge, vaginal bleeding, and suicidal ideation), compared with 1.2 to 9.5% of placebo participants.

Oral DHEA vs. Placebo (k=1)

One small trial (58) (n=93) compared oral DHEA 50 mg with placebo for 52 weeks and assessed quality of life (Supplemental Table 4). The authors reported no SAEs in either group over 52 weeks and study discontinuation due to AEs in six oral DHEA participants (facial hair and acne, skin rash, facial hair, vaginal discharge, and vaginal bleeding) and three placebo participants.

SERMs

Oral Ospemifene vs. Placebo (k=4)

Four moderate-to-large trials (46, 48, 49, 59) (n=426–919) compared oral ospemifene with oral placebo for 12 to 52 weeks. Three trials (46, 48, 59) assessed vulvovaginal dryness and dyspareunia and observed more improvement in the ospemifene group than in the placebo group. The difference in improvement was statistically significant (for the 60 mg dose) in all three trials for dyspareunia, but only two trials (46, 48) for dryness. For example, Bachmann, 2010 (46) used a 4-point severity scale and reported a −1.3-point improvement of dryness and a −1.2-point improvement of dyspareunia for oral ospemifene 60 mg vs. −0.8 and −0.9, respectively, for placebo (p=0.02 for both). Overall, low-certainty evidence indicates that oral ospemifene, compared with placebo, may improve vulvovaginal dryness and dyspareunia.

Four trials (46, 48, 49, 59) reported SAEs up to 12 weeks at low rates (up to 1.9%), including a deep venous thrombosis (DVT) in one ospemifene patient (49) that was considered probably treatment related. In two trials with 52 weeks of follow-up, SAE rates were higher for ospemifene participants in one trial (60) and higher in placebo participants in the other (49). Four trials reported that 1.6 to 7.5% of ospemifene participants discontinued due to AEs such as hot flushes within 12 weeks, compared with 1.0 to 4.9% of placebo participants. At 52 weeks, two trials (49, 60) reported ospemifene discontinuation rates were 4.8–13.5%, compared with 2.0–9.7% for placebo.

Oral Raloxifene or Bazedoxifene vs. Placebo (k=3)

Two trials evaluated raloxifene versus placebo for 3 or 6 months.(52, 53) In the 6-month trial (53) (N=91), all participants also received vaginal estrogen ring. There was similar improvement in dryness for both groups and greater improvement in dyspareunia for the placebo group, but none of these comparisons was statistically significant. In the 4-arm, 3-month trial (52) (N=187), participants were also randomized to vaginal estrogen cream or vaginal moisturizer. There was greater improvement in dryness, but less improvement in dyspareunia, for the raloxifene plus moisturizer versus the placebo plus moisturizer group. There was less improvement in dryness, but greater improvement in dyspareunia, for the raloxifene plus vaginal estrogen versus the placebo plus vaginal estrogen group. However, none of the differences in vulvovaginal dryness or dyspareunia between oral raloxifene and oral placebo in women receiving vaginal estrogen or vaginal moisturizer were statistically significant (results shown graphically, data not provided). Overall, low-certainty evidence indicates that oral raloxifene, compared with placebo, may result in little to no difference in vulvovaginal dryness or dyspareunia. Treatment discontinuation due to AEs was 4% in both study arms for one trial,(53) and ranged from 2 to 13% across study arms in the other trial(52) (highest in the raloxifene plus vaginal estrogen cream group; one DVT reported in that group).

One large (N=664), 6-month, 4-arm trial (51) evaluated bazedoxifene alone, bazedoxifene in combination with 0.45 mg or 0.625 mg oral conjugated estrogens, or placebo, but did not provide comparisons of outcomes for bazedoxifene alone versus placebo groups (n=215) apart from quality of life (Supplemental Table 4). SAEs occurred in up to 3% of participants in each arm but were not considered treatment related, including one case of breast cancer in a participant who received bazedoxifene with oral estrogen. Treatment discontinuation due to AEs was 7% for both bazedoxifene and placebo groups.

Oxytocin

Vaginal Oxytocin vs. Placebo (k=2)

Two small trials (54, 55) (n=96–161) compared vaginal oxytocin with placebo for 8 or 12 weeks. One trial (55) reported a statistically significant improvement in vulvovaginal dryness and dyspareunia in the vaginal oxytocin vs. placebo group, while the other (54) found no difference between groups for dryness, and non-significantly greater improvement in dyspareunia in the placebo group. Overall, evidence was very uncertain about the effect of vaginal oxytocin, compared with placebo, on vulvovaginal dryness and dyspareunia.

One trial (54) reported one SAE in the vaginal oxytocin group that was considered unlikely to be related to treatment. Discontinuation due to AEs was higher in the vaginal oxytocin group in one study (54) and similar in the other.(55)

Testosterone

Vaginal Testosterone vs. Placebo (k=2)

Two small trials (28, 33) (n= 40, 44) evaluated vaginal testosterone compared with placebo for 12 or 26 weeks. Both trials observed more improvement in vulvovaginal dryness and dyspareunia in the vaginal testosterone group than in the placebo group; in one trial the difference in improvement between groups was not statistically signficant,(28) while the other trial did not provide a statistical comparison.(33) Evidence is very uncertain on the effects of vaginal testosterone versus placebo.

No trials assessed SAEs or discontinuation due to AEs for vaginal testosterone compared with placebo.

Vaginal moisturizers:

Four RCTs (23, 30, 33, 56) (8 publications) of vaginal moisturizers were assessed as low or some concerns RoB.

Vaginal moisturizer vs. Placebo (k=4)

Four small to moderate-sized trials (23, 30, 33, 56) (n=40–200) compared vaginal moisturizers with placebo for 12 weeks. Vaginal moisturizer formulations and dosing regimens varied.

Three of the four trials that assessed vulvovaginal dryness observed more improvement in the moisturizer group than in the placebo group, though the difference in improvement was only statistically significant in two of these trials (23, 56). For example, Lee 2011 (23) reported a −4.0-point improvement on an 11-point visual analogue scale for lactic acid gel vs. −1.4 for placebo (p=0.001). One study (30) found no difference and one (33) did not provide a statistical comparison of the difference between groups. Overall, low-certainty evidence indicates that vaginal moisturizer, compared with placebo, may improve vulvovaginal dryness.

Three trials assessed dyspareunia and all observed greater improvement in the moisturizer group than in the placebo group. Of these, one (23) trial found that the improvement in the vaginal moisturizer versus placebo group was statistically significant. Lee 2011 reported a −2.8-point improvement on an 11-point visual analogue scale for lactic acid gel vs. −2.0 for placebo (p=0.04); one trial (30) found no significant difference and one trial (33) did not provide a statistical comparison of the difference. Overall, low-certainty evidence indicates that vaginal moisturizer, compared with placebo, may result in little to no difference in dyspareunia.

Two studies (23, 56) reported no SAEs and low rates of discontinuation in all treatment groups (in one study attributed to vaginal irritation).

Endometrial surveillance and outcomes for hormonal therapies:

Vaginal estrogen:

Ten trials (n=1,093 randomized to vaginal estrogen) assessed endometrial safety of vaginal estrogen after 8 to 36 weeks using endometrial biopsy at baseline and 12 weeks,(32) transvaginal ultrasound at baseline and 8 or 12 weeks,(29, 34, 35, 39, 40, 57) progesterone challenge at 12 weeks,(38, 39) or inquiry about vaginal bleeding at 12 weeks (30, 38, 40) or 36 weeks (25) (Supplemental Table 5). Across vaginal estrogen participants in all studies, there was one case of endometrial hyperplasia in an endometrial polyp and no cases of endometrial malignancy; mean endometrial thickness increased by up to 0.5 mm (compared with up to 0.1 mm for placebo participants); vaginal bleeding was reported by n=19 estrogen participants across 4 trials (with n=400 participants assigned to vaginal estrogen) that inquired about bleeding (range n=0–13 per trial).

Non-estrogen hormonal therapies:

Eleven trials assessed endometrial safety of vaginal (43, 44) or oral DHEA,(58) ospemifene,(48, 49, 59, 60) bazedoxifene,(51) or raloxifene,(53) vaginal oxytocin,(54) and vaginal testosterone(33) using endometrial biopsy or transvaginal ultrasound after 8 to 52 weeks.

Across 4 ospemifene trials (n=1,700 randomized to ospemifene), there was one case of endometrial hyperplasia in an oral ospemifene participant (49) and no cases of endometrial malignancy; mean endometrial thickness increased by up to 1.1 mm for both ospemifene and placebo participants; 6% of ospemifene participants had an endometrial lining ≥5 mm at 12 weeks (47) or 52 weeks (49) (compared with <2% of placebo participants). Proliferative endometrial findings (including atypical and disordered types) were reported in ospemifene participants (30 total cases across 3 studies with n=1,237 participants assigned to ospemifene (48, 49, 60)), compared with 1 case of weakly proliferative endometrium among n=646 assigned to placebo.

Transvaginal ultrasound identified endometrial thickness 5.5 mm in one oral DHEA participant at week 36.(58) Studies of vaginal DHEA (42, 43), oral bazedoxifene (51) and raloxifene,(53) vaginal oxytocin,(54) and vaginal testosterone (57) found no evidence of endometrial stimulation.

Discussion:

We systematically reviewed hormonal treatments and vaginal moisturizers for GSM symptoms. Among higher quality trials, we identified four treatments with potential benefits (vaginal estrogen, vaginal DHEA, oral ospemifene, and vaginal moisturizers) and five treatments that may not offer benefit or have insufficient evidence. There were no head-to-head trials comparing any effective therapies. Two patient-reported outcomes may not improve with any intervention (vulvovaginal discomfort/irritation and dysuria). Data on harms were limited by healthy trial populations, brief follow-up, and inconsistent outcome reporting. Certainty of evidence (COE) for most comparisons was low or very low.

Although vaginal estrogen is considered the mainstay of GSM treatment, more than half of higher quality trials comparing vaginal estrogen with placebo did not find a statistically significant benefit for dyspareunia, one of the most common GSM symptoms. This finding differs from prior evidence reviews. For example, a 2019 systematic review reported that 8 of 11 trials showed dyspareunia improvement for vaginal estrogen.(64) We attribute this difference to more restrictive study inclusion criteria in our analysis. Several studies in the 2019 review evaluated vaginal estradiol 25 mcg tablets, which were withdrawn from the US market in 2010(65, 66) and excluded from our review. Other trials did not have ≥20 participants per arm, ≥8 weeks of follow-up, or ≥1 GSM symptom for study entry, or were high risk of bias.

Compared with vaginal estrogen, vaginal DHEA and oral ospemifene trials more consistently demonstrated a statistically significant benefit for vulvovaginal dryness and dyspareunia. Vaginal DHEA and ospemifene trials were larger, more commonly industry-sponsored, and more uniform than vaginal estrogen trials.

Vulvovaginal discomfort/irritation (including itching or burning) or dysuria outcomes were evaluated in few studies and no treatments demonstrated efficacy for these outcomes. Prior reviews have also found little evidence to support benefit of vaginal estrogen for these symptoms,(64) or else grouped all symptoms together.(67) Reviews of vaginal DHEA (68, 69) and ospemifene (70) did not evaluate vulvovaginal discomfort/irritation or dysuria. We conclude that patients who are primarily bothered by GSM symptoms other than dryness and dyspareunia may find little benefit from available treatments.

The evidence does not demonstrate efficacy of oral DHEA, raloxifene, bazedoxifene, vaginal oxytocin, or vaginal testosterone for any GSM symptom. These findings are consistent with prior recommendations;(16, 71) none of these treatments are FDA-approved for treatment of GSM.

Serious treatment-related adverse effects were uncommon in these short trials with pre-screened, healthy participants. Notable trial SAEs included one case of breast cancer each in study participants who received vaginal estrogen (39) or bazedoxifene plus oral estrogen (51), and one DVT in a participant who received ospemifene (49). Less serious, infrequent adverse effects varied by treatment. For example, vaginal estrogen was associated with vaginal bleeding, discharge, and breast tenderness; vaginal DHEA was associated with increased facial hair, voice changes, and headaches; oral ospemifene was associated with hot flushes and vaginal candidiasis. Only four trials specifically recruited individuals with current or previously treated cancer, leaving patients and clinicians with little evidence to guide treatment decisions.(23, 26–28)

All hormonal interventions included assessments of endometrial outcomes. There was evidence for proliferative endometrium with one case of hyperplasia each among ospemifene (n=1,700 assigned to ospemifene) and vaginal estrogen users (n=1,093 assigned to vaginal estrogen) with up to one year of follow-up. Most trials excluded patients with any endometrial abnormalities at baseline, though endometrial biopsy is not routinely performed prior to treatment initiation. A prior vaginal estrogen safety review found rates of endometrial cancer and hyperplasia similar to baseline population rates.(72) A systematic review of ospemifene safety concluded that the increase in endometrial thickness seen with ospemifene was statistically significant but not clinically relevant, but recommended “a correct endometrial evaluation” prior to prescription.(70) However, this recommendation does not provide specific guidance for clinicians, nor are we aware of any other professional guidelines related to endometrial evaluation prior to ospemifene use.

Our review was subject to limitations. Our ability to synthesize findings through meta-analysis was limited by heterogeneity of measurement and reporting of outcomes. The broad definition of GSM applied to this review increased the scope of applicable studies and may be consistent with how GSM is defined by clinicians in practice. However, it likely also increased heterogeneity of studies and limited strength of evidence for synthesis of findings. We derived GRADE COE based on statistical measures of significance rather than assessing effect size magnitude or clinical importance. A potential limitation of this approach is that underpowered studies are counted as not showing benefit. An alternative approach based on direction of effect only would overcome this limitation, but could potentially overstate benefits based on small numerical differences in outcome measures.(73)

Given limited populations and short study durations, effectiveness and safety findings may not generalize to more racially/ethnically diverse populations, those with milder symptoms, older patients, or extended treatment. Long-term follow-up for efficacy, tolerability, and endometrial safety represents a critical gap to guide treatment longer than one year. Additional limitations in the literature base include variability in dosing, formulations, and routes of delivery for study interventions; variable and incomplete descriptions of comparators or controls; and inconsistent and incomplete statistical analyses and reporting. Future research should also directly address the treatment of GSM among women with a history of breast cancer, those receiving breast or urogenital cancer treatment, and women at high risk for cancer. We further recommend comparative effectiveness trials for existing interventions and standardizing adverse effect reporting including AEs, SAEs, and reasons for study drop out.

In conclusion, vaginal estrogen, vaginal DHEA, oral ospemifene, and vaginal moisturizers, may all improve at least some GSM symptoms, though effects versus placebo appear to be modest in magnitude. We did not find evidence of efficacy of vaginal testosterone, vaginal oxytocin, raloxifene, or bazedoxifene for any GSM symptom. Frequent serious adverse effects were not reported, but studies were short-term, and many had small sample sizes. Future studies would be strengthened by standard definitions of symptoms and uniform diagnostic criteria for GSM, a common set of validated outcome measures and reporting standards, and attention to clinically relevant patient populations and intervention comparisons.

Supplementary Material

supplemental materials

NIHMS2087927-supplement-supplemental_materials.docx^{(547.7KB, docx)}

Acknowledgements:

We thank Amy Claussen, MLIS, for assistance developing our search strategy.

Primary Funding Source and Protocol:

This project was funded by the Patient-Centered Outcomes Research Institute (PCORI) and the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services (HHS) under Contract No. 75Q80120D00008, Task order No. 75Q80122F32006. AHRQ and PCORI Representatives provided comments on draft versions of the full evidence report. AHRQ and PCORI did not directly participate in the literature search, determination of study eligibility criteria, data analysis or interpretation, or preparation, review, or approval of the manuscript for publication. A preregistered protocol for this review can be found on the PROSPERO international prospective register of systematic reviews (http://www.crd.york.ac.uk/PROSPERO/; registration number CRD42023400684).

Appendix A. Risk of Bias Assessments

Appendix Table 1.

Risk of Bias Assessments of Randomized Controlled Trials with RoB-2

Trial Name or Author Year	Bias from randomization process	Bias from deviation from intended interventions (Assignment)	Bias from deviation from intended interventions (Adherence)	Bias from missing outcome data	Bias in measurement of outcome	Bias in selection of reported result	Overall risk of bias (Low, Some concerns, High)
Abedi, 2020 (63)	Low	Some concerns	Low	Low	Low	Low	Some concerns
Antoniou, 1997 (74)	Some concerns	Some concerns	High	Low	Low	Low	High
Archer, 2019 (48)	Low	Low	Low	Low	Low	Low	Low
Archer, 2018 (31)	Some concerns	Low	Low	Some concerns	Low	Low	Some concerns
Archer, 2015 (43)	Low	Low	Low	Low	Low	Low	Low
Ayton, 1996 (38)	Low	Low	Low	Low	Low	Low	Low
Bachmann, 2010 (46)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Bachmann, 2010 (75)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Bachmann, 2009 (36)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Bachmann, 2008 (76)	Low	Low	Low	High	Low	Low	High
Bachmann, 1997 (77)	High	Some concerns	Low	Low	Low	Some concerns	High
Barton, 2018 (26)	Low	Some concerns	Low	Low	Low	Low	Some concerns
Chompootaweep, 1998 (78)	Some concerns	High	Low	Some concerns	Low	Some concerns	High
Constantine, 2017 (79)	Low	Some concerns	Low	Low	Low	Low	Some concerns
Constantine, 2017 (32)	Low	Low	Low	Low	Low	Low	Low
Constantine, 2015 (59)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Constantine, 2019 (80)	Low	Low	Low	Low	Low	Low	Low
Davis, 2018 (28)	Low	Low	Low	Low	Low	Low	Low
De Seta, 2021 (81)	Low	Low	Some concerns	Low	High	Low	High
Derzko, 2020 (82)	Low	Low	Low	High	Low	Some concerns	High
Diem, 2018 (83)	Low	Low	Low	Low	Low	Low	Low
Dow, 1983 (84)	Low	High	High	High	Low	Some concerns	High
Eriksen, 1999 (25)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Fernandes, 2014 (33)	Low	Low	Low	Low	Low	Low	Low
Fernandes, 2018 (57)	Low	Low	Some concerns	Low	Low	Low	Some concerns
Fianu Jonasson, 2020 (54)	Low	Low	Low	Low	Low	Low	Low
Freedman, 2009 (37)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Gibson, 2020 (85)	Low	Low	Low	Low	Low	Low	Low
Goetsch, 2023 (40)	Low	Some concerns	Low	Low	Low	Some concerns	Some concerns
Goldstein, 2019 (86)	Low	Low	Low	Low	Low	Low	Low
Goldstein, 2014 (49)	Low	Low	Low	Low	Low	Low	Low
Jiang, 2016 (87)	Low	Some concerns	Low	High	Low	Low	High
Jokar, 2016 (88)	High	Some concerns	Some concerns	Low	Low	Some concerns	High
Kagan, 2010 (51)	Low	Low	Low	Low	Low	Low	Low
Kalogirou, 1996 (89)	Some concerns	High	Low	Low	Low	Some concerns	High
Kessel, 2003 (90)	Low	Some concerns	Some concerns	Some concerns	Low	Low	Some concerns
Kim, 2017 (91)	Low	Low	Some concerns	High	Low	Low	High
Kingsberg, 2016 (92)	Low	Low	Low	Some concerns	Low	Some concerns	Some concerns
Kroll, 2018 (93)	Some concerns	Low	Low	High	Low	Low	High
Labrie, 2011 (94)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Labrie, 2018 (42)	Low	Low	Low	Low	Low	Low	Low
Labrie, 2009 (44)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Labrie, 2009 (62)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Labrie, 2010 (95)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Labrie, 2014 (96)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Labrie, 2015 (61)	Low	Low	Low	Low	Low	Low	Low
Lee, 2011 (23)	Some concerns	Some concerns	Some concerns	Some concerns	Low	Some concerns	Some concerns
Melisko, 2017 (27)	Low	Low	Low	Low	Low	Low	Low
Mitchell, 2019 (97)	Low	Low	Low	Low	Low	Some concerns	Some concerns
Mitchell, 2018 (30)	Low	Low	Low	Low	Low	Low	Low
Nachtigall, 1995 (39)	Some concerns	Low	Some concerns	Low	Low	Low	Some concerns
Nappi, 2022 (56)	Some concerns	Low	Some concerns	Low	Low	Low	Some concerns
Nelken, 2011 (41)	Low	Some concerns	Low	Low	Low	Some concerns	Some concerns
Page, 2022 (98)	Low	Low	Low	Low	Low	Low	Low
Palacios, 2022 (99)	Some concerns	Some concerns	High	Low	Low	Low	High
Panjari, 2009 (58)	Low	Low	Low	Low	Low	Low	Low
Panjari, 2009 (45)	Low	Low	Low	Low	Low	Low	Low
Parsons, 2003 (52)	Low	Some concerns	Low	Some concerns	Low	Low	Some concerns
Pinkerton, 2003 (53)	Low	Low	Low	Low	Low	Low	Low
Portman, 2013 (50)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Portman, 2014 (47)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Raghunandan,2010 (35)	Some concerns	Low	Some concerns	Low	Low	Some concerns	Some concerns
Seyyedi, 2016 (100)	Low	Some concerns	Low	High	Low	Low	High
Seyyedi, 2016 (101)	Some concerns	Some concerns	Low	High	Low	Low	High
Simon, 2019 (102)	Low	Low	Low	Low	Low	Some concerns	Some concerns
Simon, 2013 (60)	Some concerns	Low	Low	Low	Low	Low	Some concerns
Simon, 2008 (103)	Low	Low	Low	High	Low	Low	High
Tanmahasamut, 2020 (29)	Low	Some concerns	Low	Low	Some concerns	Low	Some concerns
Tseng, 2009 (24)	Some concerns	Some concerns	Low	Low	Low	Some concerns	Some concerns
Zohrabi, 2020 (55)	Low	Some concerns	Low	Low	Low	Low	Some concerns

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Appendix B. Evidence Tables

Appendix Table 2.

Summary of Outcome Reporting for Vulvovaginal Discomfort/irritation

Comparison	# trials Total N	Follow-up	Measurement tool	Author, year	Intervention	Intervention Mean change	Comparator Mean change	Direction of effect^***	Summary COE
Vaginal estrogen vs. placebo	4 trials N=1,777	12 weeks	4-point severity^†	Archer, 2018 (31)	Estradiol cream	No data (reported graphically)		↔	Very low ⨁◯◯◯ Uncertain
				Bachmann, 2009 (36)	CEC 0.5g 21/7 CEC 0.5g 2x/wk	−0.2 −0.3^**	−0.5^ −0.2^	↓ ↔
				Constantine, 2017 (32)	Estradiol tab 4 mcg Estradiol tab 10 mcg	−0.8 −0.8^*	−0.6^*	↔ ↑
				Freedman, 2009 (37)	CEC 1g 2x/wk	88.3% improved	71.7%	↑
Vaginal estrogen vs. no treatment	1 trial N=108	36 weeks	Patient diary^‡	Eriksen, 1999 (25)	Estradiol ring 2 mg	80% symptom resolution	53%	↔	Low ⨁⨁◯◯ No difference
Vaginal DHEA vs. placebo	1 trial N=16	12 weeks	4-point severity^†	Labrie, 2009 (62)	DHEA 0.25% DHEA 0.5% DHEA 1.0%	No data (authors stated a statistically significant difference was observed only for 0.5% DHEA vs. placebo)		↔ ↑ ↔	Very low ⨁◯◯◯ Uncertain
Oral ospemifene vs. placebo	1 trial N=627	12 weeks	4-point severity^†	Archer, 2019 (48)	Ospemifene 60 mg	−1.4 (95% CI −3.4, 0.6)	−1.4 (−3.4, 0.6)	↔	High ⨁⨁⨁⨁ No difference
Oral ospemifene vs. placebo	1 trial N=627	12 weeks	4-point severity^†	Archer, 2019 (48)	Ospemifene 60 mg	OR 1.03 (95% CI 0.65, 1.64)		↔	High ⨁⨁⨁⨁ No difference
Oral raloxifene vs. placebo	2 trials N=274	12 weeks	4-point severity^†	Parsons, 2003 (52)	Raloxifene 60 mg	No data (reported graphically)		↔	Low ⨁⨁◯◯ No difference
Oral raloxifene vs. placebo	2 trials N=274	6 months	4-point severity^†	Pinkerton, 2003 (53)	Raloxifene 60 mg	No data (reported graphically)		↔	Low ⨁⨁◯◯ No difference
Vaginal oxytocin vs. placebo	1 trial N=86	8 weeks	Study-specific checklist^§	Abedi, 2020 (63)	Oxytocin gel 400 IU	−5.8^*	−1.6^*	↑	Very low ⨁◯◯◯ Uncertain

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Abbreviations: CEC=conjugated estrogens cream; CI=confidence interval; COE=certainty of evidence; DHEA=Dehydroepiandrosterone; IU=international unit; mcg=microgram; mg=milligram; OR=odds ratio; SD=standard deviation; wk=week

Scale score interpretation:

^†

4-point severity (0=none to 3=severe);

^‡

Patient diary (none, mild, moderate, or severe);

^§

Study-specific checklist (lower=better)

Mean difference calculated by review team (trial only reported baseline and follow-up means)

^**

Trial did not provide precision statistics (e.g., SD, SEM, 95% CI)

^***

Direction of effect is based on statistical significance.

Appendix Table 3.

Summary of Outcome Reporting for Dysuria

Comparison	# trials Total N	Follow-up	Measurement tool	Author, year	Intervention	Intervention Mean change	Comparator Mean change	Direction of effect^***	Summary COE
Vaginal estrogen vs. placebo	1 trial N=488	12 weeks	4-point severity^†	Archer, 2018 (31)	Estradiol cream	No data (reported graphically)		↔	Low ⨁⨁◯◯ No difference
Vaginal estrogen vs. no treatment	1 trial N=108	36 weeks	Patient diary^‡	Eriksen, 1999 (25)	Estradiol ring 2 mg	50% symptom resolution	44% symptom resolution	↔	Low ⨁⨁◯◯ No difference
Oral raloxifene vs. placebo	2 trials N=187	3 months	4-point severity^†	Parsons, 2003 (52)	Raloxifene 60 mg	No data (reported graphically)		↔	Low ⨁⨁◯◯ No difference
Oral raloxifene vs. placebo	2 trials N=187	6 months	4-point severity^†	Pinkerton, 2003 (53)	Raloxifene 60 mg	No data (reported graphically)		↔	Low ⨁⨁◯◯ No difference

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Abbreviations: COE=certainty of evidence; mg=milligram

Scale score interpretation:

^†

4-point severity (0=none to 3=severe);

^‡

Patient diary (none, mild, moderate, or severe)

^***

Direction of effect is based on statistical significance.

Appendix Table 4.

Summary of Outcome Reporting for Change in MBS

Comparison	# trials Total N	Follow-up	Measurement tool	Author, year	Intervention	Intervention Mean change	Comparator Mean change	Direction of effect^***	Summary COE
Vaginal estrogen vs. placebo	4 trials N=1,003	12 weeks	4-point severity^†	Bachmann, 2009 (36)	CEC 0.5g 21/7 CEC 0.5g 2x/wk	−1.3^ −1.4^	−0.08^ −0.7^	↑	Low ⨁⨁◯◯ Improve
				Freedman, 2009 (37)	CEC 1g 2x/wk	−1.7^*	−1.1^*	↑
				Mitchell, 2018 (30)	Estradiol 10 mcg	−1.4 (95% CI −1.6, −1.2)	−1.3 (−1.5, −1.1)	↔
				Tanmahasamut, 2020 (29)	CEC 0.5g daily	−2.0 (95% CI −2.9, −1.1)	−1.6 (−2.4, −0.8)	?
Vaginal DHEA vs. placebo	2 trials N=659	12 weeks	4-point severity^†	Barton, 2018 (26)	DHEA 0.25% DHEA 0.5%	−1.6 (95% CI −1.8, −1.4) −1.8 (−2.0, −1.5)	−1.5 (−1.7, −1.3)	↔ ↑	Very low ⨁◯◯◯ Uncertain
Vaginal DHEA vs. placebo	2 trials N=659	12 weeks	4-point severity^†	Labrie, 2009 (62)	DHEA 0.25% DHEA 0.5% DHEA 1.0%	−1.2 (95% CI −1.4, −1.0) −1.5 (−1.7, −1.3) −1.3 (−1.5, −1.1)	−0.6 (−0.8, −0.4)	↑	Very low ⨁◯◯◯ Uncertain
Vaginal moisturizer vs. placebo	1 trial N=200	12 weeks	4-point severity^†	Mitchell, 2018 (30)	Polycarbophil gel	−1.2 (95% CI −1.4, −1.0)	−1.3 (−1.5, −1.1)	↔	Low ⨁⨁◯◯ No difference
Vaginal oxytocin vs. placebo	1 trial N=157	12 weeks	4-point severity^†	Fianu Jonasson, 2020 (54)	Oxytocin gel 400 IU	−1.2^**	−1.3^**	↔	Moderate ⨁⨁⨁◯ No difference

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Abbreviations: CEC=conjugated estrogens cream; CI=confidence interval; COE=certainty of evidence; DHEA=Dehydroepiandrosterone; g=gram; IU=international unit; mcg=microgram; mg=milligram; SD=standard deviation; SEM=standard error of mean; wk=week

Scale score interpretation:

^†

4-point severity (0=none to 3=severe)

Mean difference calculated by review team (trial only reported baseline and follow-up means)

^**

Trial did not provide precision statistics (e.g., SD, SEM, 95% CI)

^***

Direction of effect is based on statistical significance.

Appendix Table 5.

Summary of Outcome Reporting for Distress, Bother, or Interference of Genitourinary Symptoms

Comparison	# trials Total N	Follow-up	Measurement tool	Author, year	Intervention	Intervention Mean change	Comparator Mean change	Direction of effect^***	Summary COE
Vaginal estrogen vs. placebo	1 trial N=195	12 weeks	MENQOL^†	Mitchell, 2018 (30)	Estradiol 10 mcg	−1.0 (95% CI −1.2, −0.8)	−0.7 (−0.9, −0.6)	↔	Moderate ⨁⨁⨁◯ No difference
Vaginal DHEA vs. placebo	1 trial N=216	12 weeks	MENQOL^†	Labrie, 2009 (62)	DHEA 0.25% DHEA 0.5% DHEA 1.0%	−0.83 (95% CI −1.1, −0.6) −0.48 (−0.7, −0.3) −0.64 (−0.8, −0.4)	−0.28 (−0.5, 0)	↑ ↔ ↑	Low ⨁⨁◯◯ Improve
Oral DHEA vs. placebo	1 trial N=93	26 weeks	MENQOL^†	Panjari, 2009 (45)	DHEA 50 mg	−0.3 (95% CI −2.9, 2.3)	−0.1 (−2.5, 2.3)	↔	Very low ⨁◯◯◯ Uncertain
Oral DHEA vs. placebo	1 trial N=93	26 weeks	MENQOL^†	Panjari, 2009 (45)	DHEA 50 mg	MD −0.4 (95% CI −0.9, 0.1)		↔	Very low ⨁◯◯◯ Uncertain
Oral bazedoxifene vs. placebo	1 trial N=215	12 weeks	MENQOL^†	Kagan, 2010 (51)	Bazedoxifene 20 mg	−0.37^**	−0.67^**	↓	Low ⨁⨁◯◯ No difference

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Abbreviations: CI=confidence interval; COE=certainty of evidence; DHEA=Dehydroepiandrosterone; mcg=microgram; MD=mean difference; MENQOL=Menopause-Specific Quality of Life; mg=milligram; SD=standard deviation; SEM=standard error of mean

Scale score interpretation:

^†

MENQOL (decreased score indicates improvement)

^**

Trial did not provide precision statistics (e.g., SD, SEM, 95% CI)

^***

Direction of effect is based on statistical significance.

Appendix Table 6.

Summary of Outcome Reporting for Treatment Satisfaction

Comparison	# trials Total N	Follow-up	Measurement tool	Author, year	Intervention	Intervention Reported result	Comparator Reported result	Direction of effect^***	Summary COE
Vaginal estrogen vs. placebo	1 trial N=195	12 weeks	11-point Likert^†	Mitchell, 2018 (30)	Estradiol 10 mcg	Mean (95% CI): 8.6 (3.4, 13.8)	8.1 (2.1, 14.1)	↑	Low ⨁⨁◯◯ Higher
Oral ospemifene vs. placebo	1 trial N=419	12 weeks	5-point Likert^‡	Archer, 2019 (48)	Ospemifene 60 mg	% “very/moderately satisfied”: 69.7%	53.5%	↑	High ⨁⨁⨁⨁ Higher
Vaginal moisturizer vs. placebo	2 trials N=280	12 weeks	11-point Likert^†	Mitchell, 2018 (30)	Polycarbophil gel	Mean (95% CI): 7.7 (1.3, 14.1)	8.1 (2.1, 14.1)	↔	Very low ⨁◯◯◯ Uncertain
Vaginal moisturizer vs. placebo	2 trials N=280	3 months	4-point Likert scale^§	Nappi, 2022 (56)	Hyaluronic acid-based vaginal gel	“Overall, patients highly satisfied with treatment” (data not available)		?	Very low ⨁◯◯◯ Uncertain
Oral bazedoxifene vs. placebo	1 trial N=215	12 weeks	MS-TSQ^\|\|	Kagan, 2010 (51)	Bazedoxifene 20 mg	% reporting overall satisfaction: 40.4%	47.4%	?	Very low ⨁◯◯◯ Uncertain
Oral raloxifene vs. placebo	1 trial N=187	3 months	7-point Likert^¶	Parsons, 2003 (52)	Raloxifene 60 mg	“Median overall satisfaction values increased by 1.00 from baseline across treatment groups, indicating improvement”		↔	Very low ⨁◯◯◯ Uncertain

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Abbreviations: COE=certainty of evidence; mcg=microgram; MS-TSQ=Menopause Symptoms-Treatment Satisfaction Questionnaire; mg=milligram; SD=standard deviation

Scale score interpretation:

^†

11-point Likert (0=not satisfied to 10=completely satisfied);

^‡

5-point Likert (0=worst to 4=best);

^§

4-point scale (0=dissatisfied or very dissatisfied to 3=greatly satisfied);

^||

MS-TSQ (0=worst to 4=best);

^¶

7-point Likert (1=worst to 7=best)

^***

Direction of effect is based on statistical significance.

Appendix Table 7.

Summary of Outcome Reporting for Adverse Events

Comparison	# trials Total N	Follow-up	Author, year	Intervention	Reported result	Intervention n (%)	Comparator n (%)	Summary COE
Vaginal estrogen vs. placebo	5 trials N=2,070	12 weeks	Archer, 2018 (31)	Estradiol cream	Any AE	134 (46.9)	130 (45.3)	Low ⨁⨁◯◯ No difference
			Bachmann, 2009 (36)	CEC 0.5g 21/7 CEC 0.5g 2x/wk		21/7: 95 (66.4) 2x/wk: 100 (71.4)	21/7: 46 (63.9) 2x/wk: 47 (69.1)
			Constantine, 2017 (32)	Estradiol tab 4 mcg Estradiol tab 10 mcg		4 mcg: 97 (50.8) 10 mcg: 94 (49.2)	111 (57.8)
			Freedman, 2009 (37)	CEC 1g 2x/wk		83 (55.3)	72 (46.5)
			Mitchell, 2018 (30)	Estradiol 10 mcg		Any MedDRA-classified AE: 50 (49) Any study questionnaire AE: 26 (26)	Any MedDRA-classified AE: 46 (46) Any study questionnaire AE: 24 (24)
Vaginal DHEA vs. placebo	3 trials N=1,256	12 weeks	Archer, 2015 (43)	DHEA 0.25% DHEA 0.5%	Any AE	3.25 mg: 48 (55.8) 6.5 mg: 46 (52.9)	35 (43.8)	Low ⨁⨁◯◯ More AEs
			Barton, 2018 (26)	DHEA 0.25% DHEA 0.5%		There were no statistically significant differences between groups in any grade toxicity. (Data NR by authors)
			Labrie, 2018 (61)	DHEA 0.5%		179 (47.9)	77 (42.8)
Oral DHEA vs. placebo	1 trial N=93	26 weeks	Panjari, 2009 (45)	DHEA 50 mg	Any AE	31 AEs (5 androgenic AEs, 26 other AEs)	24 AEs (0 androgenic AEs, 24 other AEs)	Very low ⨁◯◯◯ Uncertain
Oral ospemifene vs. placebo	3 trials N=2,372	12 weeks	Archer, 2019 (48)	Ospemifene 60 mg	SAEs	5 (1.6)	3 (1.0)	Low ⨁⨁◯◯ No difference
			Bachmann, 2010 (46)	Ospemifene 30 mg Ospemifene 60 mg		30 mg: 5 (1.8) 60 mg: 0 (0)	4 (1.5)
			Portman, 2014 (47)	Ospemifene 60 mg		2 (1.3)	3 (1.9)
Vaginal moisturizer vs. placebo	4 trials N=418	12 weeks	Fernandes, 2014 (33)	Polyacrylic acid vaginal cream	Any AE	“No adverse events reported in either arm."		Moderate ⨁⨁⨁◯ No difference
			Lee, 2011 (23)	Lactic acid vaginal gel		19 (38.8)	16 (32.7)
			Mitchell, 2018 (30)	Polycarbophil gel		Any MedDRA-classified AE: 53 (53) Any study questionnaire AE: 22 (22)	Any MedDRA-classified AE: 46 (46) Any study questionnaire AE: 24 (24)
		3 months	Nappi, 2022 (56)	Hyaluronic acid-based vaginal gel		“5 AEs were reported in 4 patients, one of moderate intensity and the others considered mild."	None
Vaginal testosterone vs. placebo	1 trial N=38	26 weeks	Fernandes, 2014 (33)	Testosterone cream 300 mcg/g	Any AE	“did not show androgenic side effects such as acne, increased hair growth, and clitoral hypertrophy.”	No AEs reported	Very low ⨁◯◯◯ Uncertain
Vaginal oxytocin vs. placebo	1 trial N=161	12 weeks	Fianu Jonasson, 2020 (54)	Oxytocin gel 400 IU	SAEs	n=1	n=0	Low ⨁⨁◯◯ No difference

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Abbreviations: AE=adverse effect; CEC=conjugated estrogens cream; COE=certainty of evidence; DHEA=Dehydroepiandrosterone; g=gram; IU=international unit; mcg=microgram; mg=milligram; SAE=serious adverse event

Footnotes

Disclaimer: This is the result of work supported with resources and use of facilities of the Minneapolis VA Health Care System. The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily reflect the position or policy of the U.S. Department of Veterans Affairs (VA), AHRQ or PCORI. Therefore, no statement in this report should be construed as an official position of or imply endorsement by the VA, AHRQ, or PCORI. AHRQ retains a license to display, reproduce, and distribute the data and the report from which this manuscript was derived under the terms of the agency’s contract with the author.

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PERMALINK

Hormonal Treatments and Vaginal Moisturizers for Genitourinary Syndrome of Menopause: A Systematic Review

Elisheva R Danan, MD, MPH

Catherine Sowerby, BA

Kristen E Ullman, MPH

Kristine Ensrud, MD

Mary L Forte, PhD, DC

Nicholas Zerzan, MPH

Maylen Anthony, MPH

Caleb Kalinowski, M.S.

Hamdi I Abdi, M.P.H.

Jessica K Friedman, PhD

Adrienne Landsteiner, PhD, MPH

Nancy Greer, PhD

Rahel Nardos, M.D., M.S.

Cynthia Fok, M.D., M.P.H.

Philipp Dahm, M.D., M.H.Sc.

Mary Butler, PhD

Timothy J Wilt, MD, MPH

Susan Diem, MD, MPH

Abstract

Background:

Purpose:

Data Sources:

Study Selection:

Data Extraction:

Data Synthesis:

Limitations:

Conclusions:

Primary Funding Sources:

Introduction:

Methods:

Data Sources and Searches:

Study Selection:

Data Extraction and Quality Assessment:

Data Synthesis and Analysis:

Role of the funding source:

Results:

Figure 1. Literature Flow Diagram.

Table 1.

Table 2.

Table 3.

Vaginal Estrogen:

Vaginal Estrogen vs. Placebo (k=9)

Vaginal Estrogen vs. No Treatment (k=1)

Vaginal Estrogen Dose or Delivery Method Comparisons (k=3)

Vaginal Estrogen vs. Overactive Bladder Pharmaceuticals (k=2)

Non-Estrogen Hormonal Interventions:

DHEA

Vaginal DHEA vs. Placebo (k=4)

Oral DHEA vs. Placebo (k=1)

SERMs

Oral Ospemifene vs. Placebo (k=4)

Oral Raloxifene or Bazedoxifene vs. Placebo (k=3)

Oxytocin

Vaginal Oxytocin vs. Placebo (k=2)

Testosterone

Vaginal Testosterone vs. Placebo (k=2)

Vaginal moisturizers:

Vaginal moisturizer vs. Placebo (k=4)

Endometrial surveillance and outcomes for hormonal therapies:

Vaginal estrogen:

Non-estrogen hormonal therapies:

Discussion:

Supplementary Material

Acknowledgements:

Primary Funding Source and Protocol:

Appendix A. Risk of Bias Assessments

Appendix Table 1.

Appendix B. Evidence Tables

Appendix Table 2.

Appendix Table 3.

Appendix Table 4.

Appendix Table 5.

Appendix Table 6.

Appendix Table 7.

Footnotes

References:

Associated Data

Supplementary Materials