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THE GENITOURINARY SYNDROME OF MENOPAUSE TREATMENT
Santiago Palacios.+ Andrea Mejía.+ Jose Luis Neyro*
+Palacios Institute of women´s health Madrid (Spain)
*Hospital Universitario de Cruces. Bilbao. Spain
Published in https://www.ncbi.nlm.nih.gov/pubmed/26366797
Climacteric. 2015;18 Suppl 1:23-9. doi: 10.3109/13697137.2015.1079100.
ABSTRACT
Vagina, vulva, vestibule, labia majora/minora, and bladder trigone have a high
concentration of estrogen receptors; therefore they are a sensitive biological
indicator of serum levels of these hormones in women. The decrease of
estrogens produce a dysfuntion called Genitourinary syndrome of menopause
The principal therapeutic goal in the genitourinary syndrome of menopause is to
relieve symptoms. Treatment options, as well as local and systemic hormonal
treatment are changes in lifestyle and non hormonal treatments mainly based
on the use of moisturizers and lubricants. Also recently appears the
ospemifeme, the first selective hormone receptor modulator (SERM) for
dispareunia and vulvovaginal atrophy treatment and the use of vaginal laser.
This revew is made with the intention of giving recommendations on the
prevention and treatment of genitourinary syndrome of menopause.
Keywords. Genitourinary syndrome of menopause., moisturizers, systemic and
local estrogen, TSEC, ospemifene, vaginal laser
INTRODUCTION
Vagina, vulva, vestibule, labia majora/minora and bladder trigone have a high
concentration of estrogen receptors, therefore they are a very sensitive
Palacios S y Neyro JL. Climacteric, 2015 Página 1
biological indicator of serum levels of these hormones in women (1). The
estrogen loss produces a vulvovaginal dysfunction generating a decrease in
vaginal lactobacilli and a pH increase leading to the appearance of genitourinary
symptoms (2), as vaginal dryness, pruritus, dyspareunia, and urinary symptoms
(3). Approximately 50% of postmenopausal patients have urogenital atrophy
related symptoms (4).
It has been proposed a new terminology to refer to the vulvovaginal atrophy or
atrophic vaginitis and it is The Genitourinary Syndrome of Menopause. It is
considered that the two first terms that have been used so far, do not include the
variety of signs and symptoms that occur during this time, especially do not
include te ones related to urinary tract symptoms (dysuria, nocturia etc). It has
also been seen that not all people are comfortable talking about vulva and/or
vagina and the term atrophy may have a despective connotation (5).
This review is made with the intention of giving recommendations on the
prevention and treatment of genitourinary syndrome of menopause. We have
taken into account the position papers of other scientific societies, by reviewing
double-blind trials, metaanalysis and review of the Cochrane published in
Pubmed in the last 20 years.
TREATMENT
The main therapeutic goal of genitourinary syndrome of menopause is the relief
of symptoms (6). Treatment options include, in addition to local and systemic
hormonal therapy, lifestyle changes, and non hormonal treatments mainly based
on the use of moisturizers and lubricants. Recently appears the ospemifeme,
the first selective estrogen receptor modulator (SERM) for dispareunia and
vulvovaginal atrophy treatment and the use of vaginal laser.
NON HORMONE THERAPY:
-Lifestyle Modification
Always keep in mind the risk factors that accelerate estrogen deprivation, and
advise the patient to avoid them. One of them is smoking, which produce an
increase of estrogenic metabolism and it`s consumption is associated with
increased vaginal atrophy (7).
The body mass index (BMI)> 27 kg/m2 and no physical exercise involves an
increased risk of vaginal symptoms, possibly because there is less vascular
supply of genitourinary area (8).
Sexual intercourse or masturbation decrease symptoms related to vaginal
atrophy improving elasticity and lubrication and increasing vascularization due
to mechanical stimulus and therefore an improvement in symptoms as
dispareunia (9). However, it has not been established the type of sexual activity
required to prevent the symptoms of the genitourinary syndrome of menopause.
Vaginal dilators are another option for women. These can improve vaginal
function, help vaginal relaxation and can be progressively adjusted to different
sizes (10).
- Vaginal moisturizers:
Their main use is to relieve symptoms, especially vaginal dryness. Regular use
of vaginal moisturizing provides symptomatic relief by changes in the vaginal
epithelium. On their composition there are sustances capable of accumulating
water such as hyaluronic acid, which has the property of retaining a large
amount of water (about 100 times its weight), and then releasing it slowly
optimizing water balance. This substance also facilitates cell migration during
inflammation and cellular repair process thus having a role in maintaining tissue
integrity.
Liposomes are also present in some of these preparations. There are artificially-
prepared spherical vesicles composed of a lamellar phase lipid bilayer that can
store water inside and then release it slowly, so its effect is prolonged in time.
However, the most used moisturizing products are the policarbofilics gels that
Palacios S y Neyro JL. Climacteric, 2015 Página 3
adhere to epithelial cells and maintain 60 times the retention of water in the
epitheial wall.
Moisturizers are typically used twice a week. Information available about their
efficacy, which is compared with local estrogenic preparations, has found an
improvement in the vaginal dryness and pH, similar in both products.
Moisturizers do not modify the maturation index as estrogen does (11).
-Lubricants.
In addition to regular use of moisturizing, the use of a lubricant during
intercourse may reduce the irritation caused by the friction of the tissue. They
are water soluble products with oil, glycerin or silicone base (10). Lately, these
products have been developed to avoid altering the physical properties of the
condom and to do not alter the viability and motility of the sperm due to an
identical pH and osmolarity of te semen and cervical mucus (7).
Given the wide availability of lubricants, women should try various products until
she finds the one that best suits her needs.
- Other alternative and complementary treatments
Homeopathy has not proven effective in clinical trials compared to placebo.
Properties of certain plants have been used, such as aloe vera, calendula, dong
quai, cat's claw, borage, chamomile, lavender or green tea, but there is not
enough scientific evidence to their recommendation (7).
The information on the effect of oral phytoestrogen supplements on vagina is
controversial. Some publications report that prolonged consumption of soja (12)
or isoflavone`s supplements (13) have an effect on the maturation of the vaginal
epithelium (although this does not imply an improvement of symptoms).
HORMONE THERAPY:
It is the most effective treatment and the first line indication in the treatment for
moderate to severe vasomotor symptoms and vaginal atrophy (14).
-Systemic hormonal therapy
It is indicated for the relief of the diferente menopausal symptoms mainly
vasomotor syndrome and vaginal atrophy improving quality of life. Exogenous
estrogen administration restores normal vaginal pH, increases the thickness
and it revascularizes the epithelium which increases vaginal lubrication. As a
result, systemic hormonal therapy relieves symptoms related to the
genitourinary syndrome of menopause which include dryness, irritation,
pruritus, dyspareunia and urinary urgency, and may also decrease the incidence
of lower urinary tract infections (7).
There are several publications that support the indication of systemic hormone
therapy for the treatment of the genitourinary syndrome of menopause. A meta-
analysis of 58 studies in 1998 found that among the different systemic
preparations, those that conrtain only estriol seem less effective (15). However,
there are few publications about the use of long term systemic hormonal therapy
at this level.
The Women's Health Initiative (WHI) found that 74% of patients were still feeling
symptomatic improvement after one year of systemic hormone therapy (16). The
fact that up to 26% of women using systemic hormonal therapy continue to
experience symptoms of urogenital atrophy is sufficient reason to justify not
recommend starting the systemic hormonal therapy in women with vaginal
symptoms only, and that many women initially require a combination of systemic
and local estrogen therapy especially when it is used at low doses (17).
There is now a new alternative to systemic hormone therapy with
estrogen/gestagens, there are the Tissue-selective estrogen complex (TSEC)
which combine a SERM (bazedoxifene) with conjugated equine estrogens
(CEE) and are designed not only to improve menopausal symptoms but to
prevent osteoporosis, while maintaining the benefits of estrogen therapy on
vasomotor symptoms and vulvovaginal atrophy but antagonizing stimulation
effects on endometrium and mammary gland. The two studied doses of BZA/CE
(20mg of BZA with 0,425mg of CE and 20 mg of BZA with 0,625mg of CE), have
Palacios S y Neyro JL. Climacteric, 2015 Página 5
shown to improve the percentage of superficial cells, reducing basal cells. Thus,
20mg of BZA with 0.625 mg of CE reduce in a 56% the severity of symptoms
caused by atrophic vulvovaginitis and normalizes vaginal histology and pH. This
efficacy persists until two years (18-20).
-Local estrogen therapy
Local estrogen therapy not only relieves most of the side effects of systemic
therapy, it is probably also more effective in the treatment of genitourinary
symptoms of menopause. The low dose of local hormone therapy may also
improve sexual satisfaction, as they improve lubrication and increase blood flow
and vaginal sensitivity. Different active substances and dosage forms are
available for the local estrogen treatment (Table I).
A 2006 Cochrane review (21) identified 37 clinical trials, including 19
randomized comparisons of oestrogenic preparations administered
intravaginally in 4162 postmenopausal women for at least three months. The
comparative analysis of these trials was limited by variations in methodology,
reduced sample sizes and heterogeneity in the treatment regimens. However,
we can say that creams, pessaries, tablets and estradiol vaginal rings were
equally effective in relieving the symptoms of vaginal atrophy, and significantly
better than placebo and non hormonal gels in moderate severe symptoms.
The Cochrane 2006 (21) review, in addition to the effectiveness, analyzed 14
clinical trials on safety with these treatments. This study showed significant
adverse effects on the type of uterine bleeding, breast and perineal pain only for
conjugated equine estrogen cream on standard doses and not for other
preparations, which tolerability is excellent. However, all preparations may be
associated with fewer adverse events, like vaginal irritation or itching or
increased in vaginal discharge.
A review of topical estrogens (3) concluded that there was no evidence of
endometrial proliferation after 6-24 months of use, so that the literature provides
consistent information regarding the safety of vaginal estrogen in low dose
preparations and does not support concurrent use of systemic progestins for
endometrial protection. This evidence has been supported in recent clinical
practice guidelines of the International Menopause Society (IMS) (17) and The
North American Menopause Society (NAMS) (14).
Moreover, there is weak evidence to prove safety beyond 1 year of use for any
vaginal product. Currently, there is no reason for women with symptomatic
vaginal atrophy do not use the local low dose estrogen therapy for as long as
necessary depending on the presence of symptoms (17).
Most breast and gynecological cancers are hormone-sensitive, so that an
important issue is the safety of using local hormone therapy in oncological
patients (estrogen-dependent breast carcinoma, ovarian, endometrial and
cervical adenocarcinoma). Squamous cell cancers of cervix not respond to
hormones, but local radiotherapy may reduce the number of estrogen receptors
and reduce accordingly the response to topical hormonal therapy (17).
Following any gynecological cancer may be appropriate to discuss the relative
risk of estrogen use with an oncology team and the patient. For women with
estrogen-dependent breast cancer are preferable start with non hormonal
therapies, but when they are not effective, vaginal estrogen may be used in the
lowest effective doses and after informed consent from the patient (14).
EMERGING THERAPIES
-Ospemifene
It is the first nonhormonal oral alternative for the genitourinary syndrome of
menopause (22). It is a selective estrogen receptor modulator (SERM) that
selectively exerts agonist effects on vaginal tissue (23). Ospemifene 60 mg has
been shown to reduce the symptoms of dyspareunia and vaginal dryness
significantly compared with placebo in a Phase III randomized trial (23).
Importantly, the evaluated efficacy is maintained for more than 1 year in ≥93%
Palacios S y Neyro JL. Climacteric, 2015 Página 7
of patients who received Ospemifene. The long term safety of Ospemifene up to
1 year proves no clinically or significant adverse effects on endometrium (24).
In a study of women with dyspareunia, one daily tablet of 60 mg of ospemifene
significantly improved maturation index and vaginal pH and reduce the severity
of dyspareunia (25). Based on these Phase III data, Ospemifene has been
approved by the FDA for the treatment of moderate to severe dyspareunia.
In another study it was demonstrated the efficacy and tolerability of oral
ospemifene to treat symptoms of vulvovaginal atrophy associated with
menopause (26), in women with clear symptoms of vulvo vaginal atrophy.
Significant improvements in the proportion of parabasal and superficial cells
maturation index, and decreased vaginal pH was found. Changes begun at four
weeks and these results were maintained throughout the study. In addition, in
the population of patients with ≥85% compliance (at least 10 weeks of
treatment), the mean reduction from baseline to week 12 in the severity score of
vaginal dryness reported by women receiving placebo vs ospemifene was
statistically significant. The overall effectiveness of Ospemifene is highlighted by
the significantly greater number of patients who responded to active treatment
versus placebo.
All these data have made the Ospemifene has been approved by the European
Medicines Agency (EMA) for the treatment of moderate to severe symptomatic
vulvar and vaginal atrophy in postmenopausal women who are not candidates
for local vaginal oestrogen therapy.
Ospemifene 60 mg offers a well tolerated oral therapeutic alternative to vaginal
oestrogens for postmenopausal women with genitourinary syndrome of
menopause.
-Laser
Recently started the laser used as a noninvasive treatment option for patients
with vaginal atrophy which by stimulating the production of collagen, vaginal
tissue is improved making it more firm and elastic.
A study in Tokyo included 30 women between 33 and 56 years (mean 41.7)
with sensation of vaginal atrophy and laxity. They were given laser therapy. All
women completed the study without any adverse effects. It was presented at 2
months of the procedure a significant improvement in the strength of the pelvic
floor (76.6%) and satisfaction with sexual intercourse (70.0%). On histology
improved elasticity of the tissues was also evident. Therefore conclude that it is
a safe and effective treatment tolerable and painlessly (27).
In a 12-week pilot study (28) analyzed the symptoms before and after 3
applications of fractional CO2 laser, finding a clear and significant improvement
in symptoms. The same group (29) showed improvement in sexual function in
women with vaginal atrophy after use of the CO2 microablative laser. Other
groups have found similar results (30, 31).
So now found a new tool for treating certain symptoms of genitourinary
syndrome of menopause, as is the use of vaginal laser, having demonstrated
safety and efficacy of vulvar, vaginal, urinary symptoms and improvement in
sexual function.
-Local Androgen Treatment
Although the vagina has previously not been considered an androgen-
dependent organ, innovative animal studies suggest that androgens may have a
direct effect on vaginal structure and function, independent of estradiol (32). In
recent years, the role of testosterone in female sexual function has been
explored, with exogenous testosterone administration improving desire, libido
and arousal (33). Androgen receptors (ARs) and aromatase have been
identified with immunohistochemistry in vaginal epithelium, suggesting both
direct and indirect effects of testosterone on vaginal tissue (33).
In 2003 Baldassarre et al. demonstrated that expression of AR messenger RNA
was found to be significantly higher in premenopausal women than
postmenopausal women. Furthermore, testosterone administration was shown
to increase AR protein expression in both the vaginal mucosa and stroma (40).
Palacios S y Neyro JL. Climacteric, 2015 Página 9
A Phase I/II pilot study examined the impact of vaginal testosterone alone on
vaginal atrophy in women with breast cancer on long-term aromatase inhibitor
therapy, where estrogen is contraindicated. Twenty-one postmenopausal
women with breast cancer on aromatase inhibitors suffering from vaginal
atrophy were treated with vaginal testosterone cream (300 or 150 mcg) daily for
28 days. Vaginal atrophy symptoms, including dryness and dyspareunia,
improved significantly and this improvement continued to persist after cessation
of treatment. In the 300 mcg vaginal testosterone group, vaginal pH decreased
from 5.5 to 5.0 and showed a statistically significant 20% increase of vaginal
maturation index (35).
-Dehydroepiandrosterone
DHEA, a sex steroid precursor, has shown to have positive effects on sexual
function. However, like estrogen, levels of DHEA decline with age. Despite the
fact that a recent randomized controlled trial did not show a benefit of oral
DHEA therapy for women, advantages of intravaginal DHEA on sexual function
are still emerging (36). In postmenopausal women, vaginal DHEA has been
shown to improve vaginal maturation index scores and to decrease vaginal pH
in seven days (37).
In a prospective, double-blind, placebo-controlled Phase III clinical trial, 126
postmenopausal women with moderate to severe vaginal atrophy were
randomized to 0.0%, 0.25% (3.25 mg), 0.5% (6.5 mg) or 1.0% (13 mg)
intravaginal DHEA for a 12-week study period in order to evaluate effects on
sexual dysfunction. Intravaginal DHEA applied daily led to improvements in
sexual desire/interest, arousal, orgasm and pain with sexual activity (38). In a
follow-up study, 114 postmenopausal women with dyspareunia as the most
bothersome symptom of vaginal atrophy underwent 12 weeks of treatment of
varied doses of intravaginal DHEA. Researchers found that both vaginal
maturation index and score of pain severity during sexual activity improved
while DHEA levels remained within normal postmenopausal ranges. These
results revealed that beneficial local effects may be achieved without significant
systemic absorption (39).
In 2015 Labrie et al. (40) looked at the time course of moderate to severe
symptoms including dyspareunia, vaginal dryness, and irritation/itching in 521
women who received prasterone daily for 52 weeks. They looked at the
symptoms in women who had 5% or less superficial cells and a vaginal pH
above 5.
Similar results were observed on vaginal dryness and irritation/itching. Highly
significant beneficial effects (p<0.0001 vs baseline for all) were observed at
gynecological examination on vaginal secretions, color, epithelial integrity and
epithelial surface thickness (40).
EXPERT OPINION
The genitourinary syndrome of menopause, caused by estrogen deficiency is
responsible for the appearance of symptoms affecting quality of life, such as
vaginal dryness and/or dyspareunia or urinary symptoms and affects at least
40% of postmenopausal women.
The treatment will aim to restore the urogenital epithelium and relieve
symptoms. For symptoms such as vaginal dryness, dyspareunia or other
symptoms associated with this syndrome, the first line of treatment are
moisturizers (Evidence IA) and vaginal lubricants (Evidence IIB) (Table II and
Figure 1). If they do not provide adequate improvementof symptoms or they
continue to be moderate to severe symptoms, estrogens are used. Estrogens
are the most effective treatments. In cases of vaginal atrophy, the choice is local
estrogen therapy (Evidence IA). In cases coexist with vasomotor symptoms
affecting quality of life, the choice is systemic hormonal therapy (Evidence IA) or
the combination of BZE/CE (Evidence IA) (Figure 1). The local estrogenic or
systemic treatments can be combined with moisturizers and lubricants.
Recently they have also appeared new therapeutic alternatives such as
ospemifene (Evidence IA). It is a selective estrogen receptor modulator (SERM)
Palacios S y Neyro JL. Climacteric, 2015 Página 11
that selectively exerts agonist effects on the vaginal tissue. It is the first non
hormonal oral alternative for the genitourinary syndrome of menopause. Vaginal
laser is emerging as another possible option for noninvasive treatment of
genitourinary syndrome of menopause. (Table II and Figure 1).
Furthermore, although currently still experimental, treatment with androgens in
addition to estrogen may be greatly beneficial in relieving vulvovaginal atrophy
associated with sexual dysfunction.
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Table I Estrogens for topical use: Maintenance dose
Compound Presentation Dose
Estriol Ovules
Vaginal cream
Vaginal gel
Initiation dose:
0.5mcg/day for 2 weeks
Maintenance dose:
50mcg/g daily for 3
weeks, then every 72
hours.
Estriol
Ovules
Vaginal cream
Vaginal gel
0.5mcg twice a week
0.5mcg twice a week
50mcg twice a week
Promestriene Vaginal cream 10mcg twice a week
17 b-estradiol
Vaginal tablets
Vaginal ring
10mcg twice a week
6.5-9.5mcg/day
Conjugated equine Vaginal cream 0.312mcg twice a week
estrogens
Table II. Level of Evidence of treatments for genitourinary syndome of
menopause
TREATMENTS Level of Evidence
Lifestyle
Sexual activity
Obesity
Exercise
Smoking
II-2B
III-C
III-C
II-3B
Vaginal moisturizers
2-3 times / week
Improvement of
symptoms
I-A
Vaginal lubricants For sexual activity II-2B
Other treatments
Homeopathy
Phytotherapy
Phytoestrogens
III-D
III-D
II-3D
Systemic and local
hormonal therapy
Improvement of
symptoms
I-A
Palacios S y Neyro JL. Climacteric, 2015 Página 19
and trophism I-A
Vaginal laser
Improvement of
symptoms
and trophism
I-A
Figure 1. Approach to tHe patient with genitourinary syndrome of menopause
“I have symptoms of vaginal dryness, dyspareunia and/
or urinary symptoms”
¿How much are you affected?
Not or mild
Moderate to
severe
No treatment or moisturizers/
lubricant
Estrogens treatment:
-Local: for only genitourinary
symptoms
-Systemic: if they are also
vasomotor symptoms Contraindication or don`t
want estrogens
Evaluate treatment with
moisturizers, SERM
(ospemifene) and / or laser
Persistence of symptoms
Palacios S y Neyro JL. Climacteric, 2015 Página 21
Yes
No
Maintenance treatment or treatment on demand
