DOI: 10.1111/tog.
12539 2019;21:37–42
The Obstetrician & Gynaecologist
http://onlinetog.org
Vaginal estrogen deficiency
a,
Shirin Khanjani MD PhD MRCOG, * Nick Panay
a
Clinical Lecturer and Subspecialist Trainee in Reproductive Medicine, Institute of Reproductive and Developmental Biology, Hammersmith
Hospital, London W12 0NN, UK
b
Consultant Gynaecologist, Specialist in Reproductive Medicine, Imperial College NHS Healthcare Trust, London W12 0HS, UK
c
Consultant Gynaecologist, Specialist in Reproductive Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London SW10 9NH, UK
d
Honorary Senior Lecturer, Imperial College London, London SW10 9NH, UK
*Correspondence: Shirin Khanjani. Email: s.khanjani@imperial.ac.uk
Accepted on 2 July 2018.
Key content
 Vaginal estrogen deficiency occurs with declining serum estradiol
levels in menopause and premature ovarian insufficiency.
 The symptoms most commonly involve vulval and vaginal dryness,
pruritis, dyspareunia and discharge.
 Treatment is simple and easily accessible and can be
hormonal and nonhormonal.
 Nonhormonal treatments are particularly helpful for women who
cannot take estrogen. They include simple treatments such as local
lubricants and moisturisers, and newer modalities of
treatment, including laser.
 Vaginal estrogen is the most commonly used form of hormonal
treatment. However, selective estrogen receptor modulators,
tissue-selective estrogen complexes, androgens and
dehydroepiandrosterone have recently been introduced and are
effective and safe.
Please cite this paper as: Khanjani S, Panay N. Vaginal estrogen deficiency. The Obstetrician & Gynaecologist. 2019;21:37–42. https://doi.org/10.1111/tog.12539
Introduction
Pathophysiology
The female genital tract (vulva, vestibule, cervix and uterus) and
the bladder and urethra are rich in estrogen receptors.1 Vaginal
estrogen deficiency occurs with declining serum estradiol levels,
i.e. in menopause and premature ovarian insufficiency. The
decline in estrogen levels results in reduced blood flow to the
epithelium of the vulva, vestibule, vagina and cervix. Moreover,
the superficial to parabasal cell proportion decreases with the
loss of glycogen and lactobacilli, causing the skin in the area to
become thin and vulnerable. Vaginal pH can increase to 6–8
(from 4–5 in the premenopausal status), making the vagina
more susceptible to infection. Vaginal dryness follows as a result
of decreased secretions.2–4 Menopause can influence and alter
expression of genes involved in extracellular matrix metabolism
in the vagina.5 Additionally, changes occurring in the bacterial
population of the vagina in postmenopausal women may have a
profound effect on vulvovaginal atrophy (VVA), vaginal dryness
and sexual health.6,7 Together, these changes result in a pale
appearance, which may contain small petechiae and/or other
signs of inflammation.8
ª 2019 Royal College of Obstetricians and Gynaecologists
Reviews
b,c,d
BSc FRCOG MFSRH
Learning objectives
 To understand the pathogenesis, symptoms and diagnosis
of vulvovaginal atrophy.
 To appreciate attitudes and stances towards vulvovaginal atrophy.
 To understand management options for vaginal estrogen deficiency.
Ethical issues

The impact of vulvovaginal atrophy on the quality of life of many
women is profound but underestimated.
 Vulvovaginal atrophy is underdiagnosed and undertreated.
 Considering that more women are spending a significant
proportion of their lives in the postmenopausal period,
understanding the diagnosis and treatment of vulvovaginal
atrophy must develop in synchrony with this growing unmet need.
Keywords: hormone replacement therapy / menopause /
vaginal atrophy
Symptoms
Symptoms of vaginal estrogen deficiency most commonly
include vaginal dryness (75%), dyspareunia (40%), vulval and
vaginal pruritis and discharge. The urinary tract is also
commonly affected, leading to urinary frequency and urgency,
nocturia, dysuria and incontinence. Recurrent urinary tract
infections occur in up to 20% of postmenopausal women
because of atrophy of the urothelium in response to
estrogen deficiency.9–11
Vaginal estrogen deficiency can have a profound effect on
quality of life. The impact of VVA on the quality of life of
many women continues to be underestimated. In a recent
European survey, 54% of respondents said they discussed
their sexual health concerns only when the healthcare
professional asked, and 33% said they were too shy to
discuss them.11,12 Treatment is usually safe and effective, and,
therefore, suffering in silence is not justified.
Diagnosis
Assessment tools have been developed to facilitate the formal
diagnosis and classification of the severity of VVA. The
37
 Vaginal estrogen deficiency
Vaginal Health Index is commonly used: clinicians rate both
the appearance of the vaginal mucosa and production of
secretions on a scale of 1–5.13 In 2014, the North American
Menopause Society/International Society for the Study of
Women’s Sexual Health Consensus Panel introduced the
Genitourinary Syndrome of Menopause (GSM), an over-
arching terminology that describes various menopausal
symptoms and signs including genital, sexual and
urinary symptoms.14 The GSM assessment tool considers
three categories of elasticity, lubrication and tissue integrity;
an anatomical section that includes vulval, vaginal and
urethal anatomy; and two objective measures, vaginal pH
and vaginal maturation. These seven components each
receive a score from 0–3 based on severity of the condition.
A total score is then calculated by adding each of the scores
together to give a total out of 21. A score of 0–7 is considered
to be mild atrophy, 7–14 moderate atrophy and >14 severe
atrophy. The score system refers to the degree of atrophy
rather than the ‘syndrome’ itself. This tool has not yet been
validated and is therefore not in routine use.11 Publication of
outcomes from clinical trials will provide further insight into
improving existing and developing diagnostic tools.
Attitudes and stances
In 2015, the English Longitudinal Study of Ageing reported
that 53.7% of women between the ages of 50 and 90 years are
sexually active.15 In 2016, the results of the REVIVE (REal
Women’s VIews of Treatment Options for Menopausal Vaginal
ChangEs) survey were reported. This study was conducted in
four European countries (Italy, Germany, Spain and the UK)
and considered the perceptions, experiences and needs of
postmenopausal women with regard to sexual and vaginal
health.12 The opportunity for treatment varied among different
countries. The UK participants were significantly older, with
almost one-quarter being over 65 years of age, and had the
highest proportion of women experiencing recent vulval and
vaginal atrophy (52.8%). Most Italian and Spanish participants
were receiving VVA treatment, compared with just 28% of
postmenopausal UK women. The most common menopausal
symptom was vaginal/vulval dryness, with almost 80% of
participants reporting this in all countries except the
UK (48%). The percentage of participants with a partner was
lower in the UK (71%), as was the monthly rate of sexual
activity (49%). In the UK, the proportion of participants who
had seen a healthcare professional for gynaecological reasons in
the last year was lower than in other countries
(27% versus ≥50%), as was the proportion who had discussed
their VVA symptoms with a healthcare professional
(45% versus  67%). UK postmenopausal women therefore
waited longer before seeking help.
In 2017, the Women’s EMPOWER survey concluded
that – despite efforts – VVA continues to be under-
recognised and undertreated. Furthermore, it showed that
38
minimal progress has been made with regard to increasing
women’s awareness, knowledge or understanding of VVA.16,17
Treatment
Vaginal lubricants and moisturisers
Vaginal lubricants and moisturisers are used to reduce vaginal
dryness and pain during intercourse in women with mild to
moderate VVA. Lubricants and moisturisers work in different
ways and are particularly helpful for women who are not
medically suitable to take estrogen.18 Lubricants do not have
long-lasting effects and mainly provide short-term relief
during intercourse. A variety of vaginal lubricants are
commercially available and can be water-based, plant oil-
based, mineral oil-based or silicone-based products. Vaginal
moisturisers imitate natural secretions by rehydrating the
mucosal layer and adhering to the vaginal lining. The effect of
moisturisers is longer lasting compared with lubricants, if used
regularly. Therefore, moisturisers are not only used by women
with VVA who have painful intercourse, but also by
symptomatic women who are not sexually active. Most
vaginal moisturisers contain water, polymers and a variety of
other excipients to provide viscosity, pH buffering and
preservation. It is generally perceived that oil-based and
silicone-based lubricants are thicker in composition and longer
lasting compared with water-based lubricants. It is important
that lubricants and moisturisers match vaginal pH and
osmolality as closely as possible to maximise effectiveness
and avoid side effects such as irritation and infections.19 It
should be noted that oil-based preparations can break down
latex condoms, and therefore these products could interfere
with protection against sexually transmitted infections
and unplanned pregnancies.
Phytoestrogens
There are limited data showing that phytoestrogens can be
beneficial in alleviating symptoms of VVA. Intravaginal
application, as opposed to oral usage, has shown some
positive effects on the vaginal epithelium.20 In a randomised
placebo-controlled study, the efficacy of an isoflavone vaginal
gel for the treatment of VVA was compared with conjugated
equine estrogen and placebo.21 Women treated with
isoflavone gel and women treated with estrogen showed
similar improvements in vaginal dryness and dyspareunia.
This was significantly different to the placebo group and,
reassuringly, no changes in estradiol levels or endometrial
thickness were seen in any of the patient groups. However,
products containing phytoestrogens should be used with
caution in women who have contraindications to estrogen.20
Vaginal laser treatment
Vaginal erbium and CO2 lasers have been used to treat VVA.
The procedure is performed using a vaginal speculum and a
ª 2019 Royal College of Obstetricians and Gynaecologists

hand piece laser beam delivery system. It is hypothesised that
the vaginal laser stimulates cellular proliferation and viability
of the vaginal epithelium. A small study suggested a significant
improvement in symptoms, including vaginal dryness and
dyspareunia.22 This was followed by a recent pilot study, which
showed that erbium laser is an effective treatment for VVA in
breast cancer survivors.23 Several prospective observational
trials with both CO2 and erbium lasers have yielded
encouraging findings; however, the results of randomised
controlled trials with a sham laser control are still awaited.24,25
Local and systemic hormone replacement therapy
Treatment is indicated in menopausal women and women
with premature ovarian insufficiency who are symptomatic
of VVA. Systemic hormone replacement therapy (HRT) can
alleviate vaginal symptoms. The rise in serum estradiol levels
stimulates revascularisation and regeneration of the collagen
of vaginal and lower urinary tract epithelium. However, the
British Menopause Society recommends that when the
symptoms are predominantly vaginal or urogenital, topical
treatment should be used. Systemic HRT is best used in the
presence of vasomotor symptoms or osteoporosis. Addition
of vaginal estrogen to systematic HRT may be required,
particularly if lower doses of HRT have been used. Several
vaginal estrogen preparations are available, including
estradiol and estriol creams, tablets and rings. Controlling
the dosage is easiest with tablet or ring preparations.
Currently, it is advised that the lowest possible dose that
provides effective relief of symptoms should be used as
maintenance therapy. Numerous clinical trials have shown
that monitoring endometrial thickness and/or progesterone
treatment in asymptomatic, low-risk women receiving low-
dose vaginal estrogen is not indicated.26,27
A recent Cochrane review of 30 randomised controlled
trials, representing 6235 postmenopausal women, compared
intravaginal estrogenic preparations to one another or with
placebo. The review concluded that there was no difference in
efficacy between the various intravaginal estrogenic
preparations when compared to each other.28 The estradiol
ring was found to be most acceptable to the participants after
comparing comfort of products, ease of use and
overall product satisfaction.29
Vaginal estrogen therapy improves sexual function in
postmenopausal women with VVA. The REJOICE trial
concluded that vaginal estradiol soft gel capsules were safe
and effective for the treatment of moderate to severe
dyspareunia in women suffering from vaginal atrophy.30
Clinical trials do not support a role for systemic estrogen
therapy for the treatment of female sexual dysfunction.
Vaginal atrophy is common in women who receive
treatment for breast and most gynaecological cancers.
Detailed counselling of the patient, as well as liaison with
the oncology team, is essential before considering estrogen
ª 2019 Royal College of Obstetricians and Gynaecologists
Khanjani et al.
therapy in women with a history of breast or gynaecological
cancers. Nonhormonal options are usually the first line of
treatment in this population. Data regarding the safety of
vaginal estrogen therapy in breast cancer survivors are
limited. A case–control study of 271 women with breast
cancer on tamoxifen or aromatase inhibitors concluded that
there is no increased risk of recurrence in women on vaginal
estrogen therapy, with a mean follow-up of 3.5 years.31 In a
retrospective cohort study, 60 women with early-stage breast
cancer were treated with an estradiol tablet or estriol cream
for a median of 1 year. There was no increase in the risk of
recurrence at a median of 5.5-years follow-up.32 A more
recent study showed that in postmenopausal women with
early-stage breast cancer receiving aromatase inhibitors,
treatment with a vaginal ring or vaginal testosterone over
12 weeks met the primary safety points.33 In 2014, a meta-
analysis concluded that there is no increased risk of
recurrence in women who are taking HRT following
treatment of endometrial cancer.34 Following ovarian
cancer, although some concerns have been expressed about
systemic treatment, there are no data to suggest an increased
risk of recurrence with either systemic or local estrogen therapy.35
Treatment with selective estrogen receptor
modulators and tissue-selective estrogen complexes
Selective estrogen receptor modulators (SERMs) act as
estrogen agonists/antagonists. Although raloxifene and
tamoxifen are well-known SERMs, they are not effective in
the treatment of VVA. Ospemifene and lasofoxifene, which
were originally used to treat postmenopausal osteoporosis,
have positive effects on vaginal epithelium and can therefore
reduce the symptoms of VVA.36–38 The Postmenopausal
Evaluation and Risk Reduction with Lasofoxifene (PEARL)
study concluded that lasofoxifene significantly reduced
symptoms of moderate to severe VVA over the course of
12 weeks. Additional studies have supported these findings
and have also shown reduced dyspareunia in postmenopausal
women treated with lasofoxifene.39,40
Tissue-selective estrogen complexes (TSECs) combine
conjugated estrogens with an SERM. This combination
treats VVA, alleviates hot flushes and prevents bone loss,
while also protecting the breast and endometrium.41,42 The
first TSEC to be studied was conjugated estrogens with
bazedoxifene (CE/BZA). The Selective Estrogens Menopause
and Response to Therapy 1 (SMART-1) study found that
CE/BZA improved vaginal atrophy with reduced incidence of
dyspareunia at 2 years compared with placebo. CE/BZA
treatment was associated with less than a 1% rate of
endometrial hyperplasia over 2 years.43
Androgens and dehydroepiandrosterone
Androgens play an essential role in female sexual function.44
Studies have shown that androgen receptors (ARs) are
39
 Vaginal estrogen deficiency

Table 1. A summary of different treatment options for vaginal estrogen deficiency

Intervention Route Advantages Cautions

Moisturisers and Vaginal - Can alleviate symptoms of mild to moderate VVA - Lubricants only provide short-term relief during
lubricants - Can alleviate dyspareunia caused by VVA intercourse
- Can be used in women who have contraindications - Not effective in cases of severe VVA
to estrogen - Need to be pH and osmolality balanced otherwise
irritation/discharge can occur

Vaginal estrogen Vaginal - Improves symptoms without the need for - Should be used with caution in women who have
progesterone opposing treatment contraindications to estrogen
- Reverses physiological changes of menopause - Benefits only last for as long as treatment is
- Minimal systemic absorption continued

Systemic HRT Transdermal/ - Can alleviate symptoms of VVA as well as vasomotor - Is best used in the presence of vasomotor
oral symptoms and osteoporosis symptoms or osteoporosis
- Not recommended in women who have
contraindications to estrogen

Phytoestrogens Vaginal and - Some vaginal (not oral) preparations have shown - Should be used with caution in women who have
oral similar effects as vaginal estrogen contraindications to estrogen

Laser treatment Vaginal - Preliminary prospective observational data are - More long-term/sham laser randomised data
showing benefit needed to prove efficacy
- Can be used in women who have contraindications
to estrogen

Selective ER modulator Oral - Ospemifene and lasofoxifene are the most effective - More studies are needed to assess safety for the
- Are effective in treatment of VVA as well as endometrium with lasofoxifene
osteoporosis (ospemifene license is for dyspareunia)
- Can be used in women who have contraindications
to estrogen

Tissue-selective Oral - Can alleviate symptoms of vulvovaginal atrophy, hot - Relatively new treatment, longer term data
estrogen complex flushes and bone loss regarding safety would be desirable
treatment - Has potential protective effects for breast and - No product range – only one dose, which may not
endometrium be sufficiently estrogenic for some women

Androgens and DHEA Oral and - Vaginal administration appears safe and effective in - Relatively new treatment, more safety data
vaginal treatment of VVA (licence is for dyspareunia) regarding systemic effect would be desirable
- Can improve libido
- Minimal systemic absorption

Key: VVA = vulvovaginal atrophy; HRT = hormone replacement therapy; ER = estrogen receptor; DHEA=dehydroepiandrosterone

expressed in the vagina. The expression levels of ARs decrease
with age, suggesting a role for androgens in treating VVA.45 A
pilot study of women with breast cancer, who were on
aromatase inhibitors and suffering from vaginal atrophy,
showed promising results. The authors concluded that a
4-week course of vaginal testosterone improved signs and
symptoms of vaginal atrophy without an increase in systemic
estradiol levels.46 Since then, multiple studies have compared
the use of vaginal testosterone to other treatments and found
it to be safe and effective.47
Dehydroepiandrosterone (DHEA) is a precursor steroid in
the biosynthesis of sex steroids. Like estrogen and ARs, levels
of DHEA decrease with age.48 Recent trials have suggested
that oral and vaginal preparations of DHEA can improve
symptoms of VVA.49 A recent study compared the effect of
intravaginal DHEA (prasterone), conjugated equine
estrogens and estradiol on moderate to severe dyspareunia
and/or vaginal dryness. The authors concluded that 6.5 mg
prasterone used daily appears to be as efficacious as 0.3 mg
conjugated equine estrogens or 10 lg estradiol for the
treatment of VVA.50 Reassuringly, intravaginal DHEA does
not seem to increase the levels of sex steroids beyond those
normally found in menopause.51 Prasterone is now licensed
in the USA for the treatment of moderate to severe dyspareunia.
Table 1 summarises the various treatment options for
vaginal estrogen deficiency.
Conclusion
Vaginal estrogen deficiency occurs with declining serum
estradiol levels and can have extreme effects on womens’
quality of life and sexual health. It can result in VVA, pelvic
floor disorders and sexual dysfunction. Many treatment
modalities are now available; treatment should be tailored to

40 ª 2019 Royal College of Obstetricians and Gynaecologists


individual women. Recent efforts notwithstanding, VVA
continues to be suboptimally managed. With women living
longer and spending nearly half of their lives in a
postmenopausal state, education and management of VVA
must be improved.
Disclosure of interests
SK has no conflicts of interest. NP has lectured and acted in
an advisory capacity for a number of pharmaceutical
companies.
Contribution to authorship
NP instigated and edited the article. SK researched and wrote
the article. Both authors read and approved the final version
of the manuscript.
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ª 2019 Royal College of Obstetricians and Gynaecologists