1. health and fitness
2. disease
3. cancer

WOMEN'S
HEALTH
I
Vagina Estrogen Use in
Menopause: Is It Safe?
MSN, FNP-BC, PhD Candidate;
Jesse Greenblum, MD, MS, FACOG; and
Donna Neff, PhD, APRN-BC
Catherine Greenblum,
enopause, defined as the
absence of menstrual periods for 1 year following the
loss of ovarian function,' is a normal transition from the reproductive stage to the non-reproductive
stage of a woman's life. Whereas
some women transition through
menopause with little difficulty,
others have symptoms that disrupt
their
lives. Discomfort
from
menopausal
symptoms,
vaginal
aryness, ana ayspareunia bas been
shown to have a significant adverse
impact on quality of life (QOL).2
The number of women who can
potentially be affected by troublesome menopausal
symptoms is
large: 35 million women in the
United States were aged ;,,55 years
in 2004/ and this number will
approach 60 million in the next
decade.' About 50% of menopausal women experience urogenital symptoms, including atrophic
vaginitis, within 3 years of menopause,',6 but <25% of affected
M
women discuss the problem with
their healthcare practitioner.
Because modern women live as
much as one third of their life in
the postmenopausal state, NPs
need to identify those requiring
treatment for" menopause-related
urogenital symptoms and improve
their QoL.
Vaginal estrogens have a low
risk profile and are safe to use in
most menopausal women with
moderate to severe symptomatic
vaginal atrophy who are unresponsive to non-hormonal treatments.
Vaginal estrogen preparations are
more effective than oral estrogen
preparations in relieving urogenital symptoms. These vaginal preparations-available
as a cream,
tablet, or ring-are equally effective in treating urogenital atrophy
and accompanying symptoms of
vaginal dryness, irritation, and dyspareunia. Of note, vaginal tablets
and rings deliver consistent low
doses of estrogen, whereas cream
preparations do not provide precise dose delivery.
Low-dose topical vaginal estrogen therapy does not require addition of progesterone therapy to
protect the uterus because circulating blood estradiol (El) levels
remain low. However, genital
bleeding, which may be an early
sign of endometrial cancer, must
be investigated in women using a
vaginal estrogen product. Evidence
of minimally elevated blood E2
levels in topical vaginal estrogen
users suggests that breast tissues
will not be affected by this treatment. Therefore, menopausal
women with hormone-dependent
breast cancer-in
consultation
with their oncologist-may consider the use of low-dose vaginal
estrogen to ease distressing urogenital symptoms.
7,8
9
Pathophysiology of
Vaginal Atrophy
The layers of the vaginal mucosa,
which is estrogen sensitive, are
composed of parabasal, intermediate, and superficial
cells.
Parabasal cells are the smallest and
least mature, with large nuclei and
a round shape. Intermediate cells
are larger and polygon-shaped,
with nuclei measuring >6 mcm.
Superficial cells are the most
mature cells, with a polygon shape
and a nucleus that measures <6
mcm.lO In menopausal women,
systemic declines in estrogen levels
correspond to decreased cellular
maturation.
The maturation index of vaginal cells is used to evaluate qualitative response of the vaginal tissue
to estrogen. The index is read from
left to right as the percentages of
parabasal cells, intermediate cells,
and superficial cells. Under the
influence of estrogen, mature
superficial cells predominate, with
few intermediate cells. In an estrogen-deprived environment, a shift
to the left occurs: Parabasal cell
numbers rise and superficial cell
numbers fall,lOleading to gradual
atrophic changes in the tissues of
the vagina, vulva, urethra, and
trigone area of the bladder.
With these atrophic changes,
urogenital tissue loses elasticity,
vaginal-blood flow decreases, and
vaginal secretions diminish, causing the vaginal epithelium to thin
and become more vulnerable to
trauma, infection, and inflammation. The normally acidic vaginal
pH is maintained by the secretion
of lactic acid by lactobacilli during
glucose metabolism. Estrogen-deficient vaginal epithelial cells produce less glycogen, resulting in a
decrease in lactobacilli and lactic
acid. As a consequence, vaginal pH
becomes more alkaline (pH range,
5.5-6.8), increasing a woman's vulnerability to vaginal and urinary
tract infections (UTIs). Vaginal
atrophy is the end result of estrogen deficiency associated with
menopause.2,5,8,10-12
Symptoms of vaginal atrophy
include vaginal dryness, itching,
irritation, dyspareunia, urinary frequency, and recurrent UTI.
From a clinical standpoint, the
pubic hair appears thinner, the
vaginal introitus narrows, and the
vaginal walls may show petechiae,
have increased friability, and lack
rugae. When the vaginal mucosa
becomes inflamed, the condition
is termed atrophic
vaginitis.
Symptoms of atrophic vaginitis
include burning, leukorrhea, and
malodorous yellow discharge. For
women who remain sexually active
in their older years, atrophic
vaginitis, decreased vaginal secretions, and dyspareunia are important concerns. Many women do
not seek relief for these symptoms,
and only a small percentage of
affected women are treated with
estrogenY NPs and their menopausal patients should know that
vaginal atrophy and atrophic
vaginitis and its associated symptoms are reversible with vaginal
estrogen therapy.
11,13
13
8
5
8
Endogenous and Exogenous
Estrogens
Endogenous estrogen is primarily
responsible for development and
maintenance of female secondary
sex characteristics and the reproductive system. E2, the main intracellular estrogen, is significantly
more potent than its metabolitesestrone and estriol. The primary
source of estrogen in a normally
menstruating woman is the ovarian follicle, which secretes 70-500
Vaginal estrogen is dispensed in
cream, tablet, and ring formulations. Vaginally administered
estrogen, which causes only a
slight increase in the blood E2
level, has fewer contra indications
and adverse systemic effects than
does oral HT. Because locallyapplied estrogen has minimal systemic absorption, this treatment
has no effect on vasomotor symptoms or bone density.8
Vaginal estrogen avoids firstpass metabolism and inactivation
by hepatic enzymes, which may
reduce adverse effects.!3,22,23
Numermore never even started it because
ous studies over the years have
of the increased risks for breast
found low-dose, locally-applied
cancer, thromboembolism, cardioestrogen highly effective in reversvascular events, stroke, and demening urogenital atrophic changes
tia that were reported in the WHI. 18
related to estrogen depletion, with
Nevertheless, many women still
no significant effect on the
require treatment for vasomotor
endometriumY4 The WHI reportand/ or urogenital symptoms assoed that oral estrogen use increased
ciated with menopause! Oral HT
the risk for stroke by 12 cases per
remains the most effective treat10,000 person-years, but it did not
ment for menopausal symptoms in affect the incidence of heart disease
general, 19,20
although not all women
or breast cancer in women who
are candidates for this therapy.
used this treatment for an average
Absolute contraindications to oral of 6.8 years.25
HT include a personal history of
Vaginal creams. Vaginal creams
breast cancer, gynecologic, or estro- have been in use longer than other
gen-dependent cancers; deep vein forms of topical estrogen. A typical
Menopause Hormone Therapy
dosing regimen for conjugated
Approved by the US Food and thrombosis; pulmonary embolism;
Drug Administration in 1942,17 arterial thromboembolic disease, estrogen cream 0.625 mg (eg,
Premarin Vaginal Cream) is a loadoral hormone therapy (HT) was including stroke or myocardial
infarction; liver dysfunction or dis- ing dose of 2-4 g/day for 2 weeks
the standard of care for menofollowed by a dose of 0.5-1 g up to
pausal women for 60 years. Since ease; and undiagnosed genital
2
the results of the Women's Health bleeding. ! These contraindications
3 times weekly, The goal is to use
Initiative (WHI) study were pub- preclude the use of oral HT for the lowest dose that provides
symptomatic relief. One drawback
lished in July 2002, millions of many symptomatic menopausal
women.
of vaginal estrogen cream is its
women and their practitioners
Vaginal
HT-Menopausal
inconsistent dosing. The dose
have been reassessing their decisions about oral HT use. Prior to women whose primary aim is to depends on the amount of cream
the publication of the WHI find- treat urogenital symptoms, as inserted by the user, who may have
ings, approximately 6 million US opposed to vasomotor symptoms, . difficulty administering identical
women were using oral HT, but by are advised to use vaginal estrogen amounts each time. Many women
therapy.8 Vaginally administered
May 2003, only 2.7 million
also find the cream messy and
women were using oral HT. estrogen creams have been pre- inconvenient.13,23 Vaginal cream
Therefore, millions of women
scribed for >50 years to treat must be inserted at least 12 hours
stopped using oral HT and many symptomatic urogenital atrophy.7 prior to intercourse; studies have
mcg of E2 daily, depending on the
phase of the menstrual cycle.
Blood E2 levels modulate pituitary
secretion of the gonadotropinsluteinizing hormone (LH) and follicle-stimulating hormone (FSH)through a negative feedback 100p.14
In premenopausal
women,
blood E2 levels fluctuate with the
menstrual cycle, ranging from 9 to
196 pg/mL. In menopausal
women, ovarian production of
estrogen declines, and blood E2
levels range from 0 to 30 pg/mL.15
Most endogenous
estrogen in
menopausal women is converted
from androstenedione (secreted by
the adrenal cortex) into the weaker
hormone estrone. LH and FSH levels rise as decreased levels of E2
become inadequate to suppress
their secretion. Exogenous estrogens, given in high enough doses,
can restart the negative feedback
loop, suppressing LH and FSH to
premenopausal levels. Exogenous
estrogens are well absorbed through
the gastrointestinal tract, mucous
membranes, and skin, and directly
affect squamous endothelial tissues
of the genitourinary tract.14,16
-shown decreased estrogen absorption in women and elevated E2 levels in their partners if they engage
in intercourse sooner than 12
hours after application. 26
Conjugated estrogen cream, relative to a tablet or a ring, has been
found to raise circulating E2 levels;'3,2?however, at low maintenance doses, E2 levels remain in
the menopausal
range (0-30
pg/mL). The cream also has slightly more side effects than the tablet
or the ring. ,2? No randomized,
controlled
data are available
regarding the use of a vaginal
cream containing E2 (eg, Estrace
Vaginal Cream), as opposed to
conjugated estrogen.8
Vaginal tablet. Vagifem, the
only low-dose estrogen-containing
vaginal tablet on the market, contains 25 mcg of 17 beta-estradiol in
a hydrophilic cellulose-derived
matrix.28This product is indicated
for the treatment of atrophic
vaginitis associated with the estrogen deficiency of menopause. The
tablet is inserted vaginally using an
applicator. The tablet matrix
hydrates and adheres to the vaginal
wall, where E2 is gradually released
and absorbed into the vaginal
epithelium as the tablet dissolves.
Vagifem, at a maintenance dosage
of one tablet twice weekly, has
minimal
systemic absorption
(Table 1).2830Laboratory reference
values for ovulating and postmenopausal women appear in
Table 2.'5,22,31,32
Vaginal rings. The vaginal ring
marketed in the United States
(Estring) delivers 7.5 mcg of E2
consistently over 24 hours. The
ring is worn continuously for 3
months. Blood E2 levels are not
raised significantly by the ring, and
blood levels of E2, FSH, and LH
remain in the menopausal range
(Table 3).28,33Vaginal delivery of
•
EFFECTS OF THE VAGINAL TABLEpo
.
B
•
78.4 ±21.5
60.1 ±18.2
Week 12
67.4 ±17.8
51.0 ±12.2
Week S2
62.9 ±1O.6
44.8 ±7.5
Study results (N = 24) are based on twice-weekly maintenance therapy with Vagifem.
E2, estradiol; FSH, Follicle-stimulating hormone; LH, luteinizing hormone.
13
LABORATORY REFERENCE VALUES FOR OVULATING
AND MENOPAUSAL WOMEN15,22,31,32
E2 (pg/ml)
FSH (mU/mL)
LH(mU/mL)
Follicular phase of
menstrual cycle
30-150
2,5-10.2
1.9-12.5
Luteal phase of menstrual cycle
100-210
1.5-9.1
0.5-16.9
0-30
30-150
30·150
Phase
Menopause (untreated)
Hormone levels vary widely during the menstrual cycle, and reference values vary widely from laboratory to
laboratory.
E2, estradiol; FSH, follicle-stimulating hormone; LH, luteinizing hormone.
estrogen by a ring has not been
found to affect the endometrium
and has been well tolerated.
Some older women may lack the
dexterity needed to position the
ring. In addition, the ring may be
dislodged with intercourse, douching, or bowel movements.
Femring, an estradiol acetatecontaining vaginal ring, is available
in two dose strengths: 0.05 and 0.1
mg/ day. This product, like Estring,
is inserted vaginally and left in
place for 3 months. Although vaginal atrophy is an indication for
use, Femring delivers a systemic
dose of estrogen, and its indications, contraindications, and side
effects are the same as those for
oral estrogens. 8
'4,28
Progestogens and Vaginal
Estrogen Use
Progestogens
include
progesterone, the hormone secreted by
the ovary and placenta, and progestins, synthetic steroids that
mimic the actions of endogenous
progesterone. Progestins were first
isolated in 1933, and progesterone
itself was synthesized in the
1940s.
Progestins are derived mainly
from testosterone or progesterone,
and differ strikingly from one
another. Progestins range from
medroxyprogesterone acetate (eg,
Provera,Cycrin,
Amen) with a
weak androgenic effect to fourthgeneration agents such as dienogest
and drospirenone (derived from
34
cancer risk by 8 cases per 10,000
women after 5.2 years of use. The
WHI also showed that women who
used oral conjugated equine estrogens alone for an average of 6.8
53 ±15.1
26.9 ±6.8
years had no greater risk of breast
cancer and, compared with the
56.6 ±15.4
26.3 ±5.6
placebo group, had 7 fewer cases of
Study results are based on use of the vaginal ring, which delivers 7.5 mcg of estradiol consistently per 24 hours.
breast cancer per 10,000 women.
E2, estrodial; FSH, follicle-stimulating hormone; lH, luteinizing hormone.
Menopausal
women
with
breast cancer, like most other
menopausal women, rarely discuss
spironolactone) with no androuse a progestogen to oppose the vaginal symptoms and dyspareunia with their clinician. Urogenital
genic effect. Progestins prevent
estrogen in these women. 13.
symptoms due to estrogen depleoverproliferation of endometrial
tion reduce QoL and add distress
tissue, which can occur in the Vaginal Estrogen Use in
to a population already stressed by
presence of unopposed estrogen.
Women with Breast Cancer
physical changes. Given the
In women with an intact uterus, Approximately 270,000 menoincreased survival rates of women
use of oral estrogens requires
pausal women were diagnosed
with breast cancer, previously
addition of a progestogen to prewith breast cancer in the United
ignored QoL concerns are now
vent overstimulation
of the
States in 2007.37 Among these being addressed. Women diagendometrium, which can result in
women, 50%-75% report urogeni- nosed with breast cancer who fail a
endometrial
hyperplasia
and
tal atrophy and decreased QoL.
trial of non-hormonal treatment
endometrial cancer.
First-line treatment for vaginal dry- may consider a carefully moniBy contrast, in low-dose vaginal
ness in this patient population is tored course of low-dose vaginal
estrogen users, circulating E2 levels
non-pharmacologic; vaginal lubri- estrogen to treat urogenital atros
remain in the menopausal range.
cants (eg, K-YJelly) and moisturizphy. Well-documented evidence of
Although long-term data are lackers
(eg, Replens). Lubricants may minimally elevated blood E2 levels
ing, available studies do not
make intercourse less painful, but associated with topical estrogen
demonstrate endometrial proliferthey
do not affect the maturation
treatment appears to suggest that
ation or increased endometrial
index
of vaginal tissue or lower breast tissues will not be affected.37
cancer rates with unopposed vagivaginal pH. Vaginal moisturizers
A recent prospective study of
nal estrogen use. ?36 Endometrial
such as Replens reduce urogenital
>18,000
women showed no
proliferation does not normally
occur unless serum E2 levels rise symptoms by increasing mean cell increase in breast cancer rates for
41
well above the menopausal range volume, positively affecting the women using vaginal estrogens.
maturation
of
vaginal
epithelium.
However concerns remain that, in
(>70 pmol/L).36 Accordingly, current recommendations from The Replens has no reported cytologic women with breast cancer, doreffects on the maturation index.37 mant micrometastases
may be
North
American
Menopause
Society (NAMS) do not recom- Replens may also reduce the pH of stimulated to grow: Further studmend progestogen use in women 'vaginal secretions, resulting in ies are in progress; results are
using vaginal estrogen to treat vagi- fewer episodes of atrophic vaginitis eagerly anticipated by practitioners
and UTI; however, study results on and patients alike.37
nal atrophy. However, women
3s 4o
using estrogen cream must be care- these effects are conflicting. '
Many women with a breast can- Recommendations
fully monitored. The possibility of
inconsistent dosing and the ability cer diagnosis are discouraged from In 2004, the American College of
of estrogen cream to raise blood E2 using hormonal therapies of any Obstetricians and Gynecologists
levels at higher doses mean that kind. Evidence to support this (ACOG) assembled an expert panel
prescribers should consider moni- advice is conflicting as well. Results that issued guidelines regarding HT
toring the endometrium
with of the WHI showed that use of oral use.19ACOG emphasized that each
biopsy or ultrasonography or to estrogen/progestin increased breast menopausal woman, in consulta-
•
EFFECTS OF THE VAGINAL RING28,33
35
2S
22
37
35
2
2
8
tion with her practitioner, should used twice weekly, but women
consider the use of ill in terms of its should be re-evaluated after 6
risks, benefits, and altematives. In months to 1 year.6 Women with
addition, the panel recommended hormone-dependent cancers may
that ill use be re-evaluatedperiodi- consider use of low-dose, locallycally and at least annually, that the applied estrogen for distressing
lowest dose for the least amount of urogenital symptoms. With vagitime should be used, and that alter- nally-applied estrogen in low
native therapies should be reconsid- doses, circulating estrogen levels
remain in the menopausal range.
ered. NAMS' recommendations
echo ACOG's guidelines,43 as do Evidence of minimally elevated
those of the National Associationof blood E2 levels associated with
Nurse Practitioners in Women's topical estrogen treatment suggests
Health (NPWH).44
that breast tissues will not be
Vaginal estrogens have a low affected. The vaginal estrogen
risk profile and are safe to use in tablet and the ring deliver consismost women with moderate to tent low dosing, but extra caution
severe symptomatic vaginal atro- must be taken with estrogen cream
phy who are unresponsive to non- preparations because dose delivery
hormonal treatments.
Topical is not precise. 37•
vaginal preparations have been
found superior to oral estrogen Catherine Greenblum is a nurse pracpreparations in terms of relieving titioner in private practice and a PhD
urogenital symptoms.2 A review of candidate at the University of Fl011da,
the literature shows that vaginal Jesse Greenblum is an obstetriestrogen cream, tablet, and ring cian/gynecologist in private practice,
formulations are equally effective and Donna Neff is an assistant profesin treating urogenital atrophy and sor of nursing at the University of
accompanying symptoms of vagi- Florida, all in Gainesville. The
nal dryness, irritation, and dys- authors state that they do not have a
pareunia, and are used as long as financial interest in or other relationsymptoms remain. At low doses, ship with any commercial product
vaginal estrogens do not require named in this article.
concurrent progesterone therapy to
protect the uterus because circulat- Acknowledgment
ing blood E2 levels remain in the This manuscript was reviewed by
menopausal range. However, any Jesse Greenblum, MD, FACOG, a
undiagnosed genital bleeding in board certified obstetrician/gynethese women should be investigat- cologist, for content. Tables 1, 2,
ed because it may be an early sign and 3 have not been published
of endometrial cancer. Of note, previously.
when the dose of vaginal estrogen
cream results in systemic absorp- References
tion, usually associated with vagi- 1. National Cancer Institute. Menopausal
nal doses of conjugated estrogen Hormone Use: Questions and Answers. 2009.
at: http://www.cancer.gov/cancenopics/
>0.5 mg/day, therapy should Available
factsheet/Risk{menopausal-hormones
include use of a progestogen to 2. Long C, Liu C. Hsu S, et al. A randomized comavoid endometrial stimulation.27
parative study of the effeas of oral and topical estro19
19
B
B
•
B
6
Conclusion
gen therapy on the vaginal vascularization and
sexual function in hysterectomized postmenopausal
women. Menopause. 2006;13(5):737-743.
Vaginal estrogens may safely be
3. US Department of Labor, Women's Bureau.
Older Women Workers, Ages 55 and Over.
Available at: http:// www.dol.gov/wb/factsheets/
qf-olderworkers5 5.htm
4. McGinley A. Health beliefs and women's use
of hormone replacement therapy. Holist NufS Pract.
2004;18(1):18-25.
5. Bachmann G, Lobo R, Gut R, et al. Efficacy of
low-dose estradiol vaginal tablets in the treatment
of atrophic vaginitis. Obstet Gynecol. 2008;
1ll(1):67-76.
6. Robb-Nicholson C. By the way, doctor. After
stopping Prempro last year, I developed really
uncomfortable vaginal dryness. My doctor has recommended the vaginal estrogen ring. Is it safe?
Harv Womens Health Watch. 2003 Feb;IO(6):8.
7. Shulman L, Portman D, Lee W, et al. A retrospective managed care claims data analysis of medication adherence to vaginal estrogen therapy:
implications for clinical practice. J Womens Health.
2008;17( 4):569-578.
8. The North American Menopause Society. Role
of local vaginal estrogen for treatment of vaginal
atrophy in postmenopausal women: 2007 position
statement of The North American Menopause
SoGety. Menopause. 2007;14(3 pt 1):355-371.
9. Poindexter AN, Wysocki S. WHI in perspective-focus on quality oflife. The Forum: A Worlling
Group for Women's Healthcare. 2004;1(2):8-10.
10. McEndree B. Clinical application of the vaginal
maturation index. Nurse Pract. 1999;24(9):48-57.
11. Santen R, Pinkerton /, Conaway M, et al.
Treatment of urogenital atrophy with low-dose
estradiol: preliminary results. Menopause. 2002;
9(3):179-187.
12. UU J. Use of conjugated estrogens after the
Women's Health Initiative. Female Patient. 2004;
29(1 ):8-13.
13. Crandall C. Vaginal estrogen preparations: a
review of safety and efficacy for vaginal atrophy. J
Womens Health. 2002;11(10):857-877.
14. Estring Prescribing Information. New York,
NY: Pfizer. August 2008. Available at: http://
www.pflZer.com/files/produas/uspi_ estring. pdf
15. Estrogens. Quest Diagnostics. May 2008.
Available at: http://www.questdiagnostics.com/
kbase/topic/medtest/hw6200 / descrip. htm
16. Kelley C. Estrogen and its effect on vaginal
atrophy in post-menopausal women. Urol NUTS.
2007;27(1):40-45.
17. US Food and Drug Administration. FDA
Statement on Generic Premarin. May 5, 1997.
Available at: http://www.fda.gov/bbs/topics/
NEWS/NEW00565.html
18. Goldstein SR. Clinical management after hormone therapy discontinuation. Menopause Manage.
2004; 13(suppl 1):45-47.
19. American College of Obstetricians and
Gynecologists. ACOG Issues State-of-the-art
Guide to Hormone Therapy. September 30, 2004.
Available at: http://www.acog.orgffrom_home/
pub lications/press_releases/nr09- 30-04-2.cftn
20. Woodward J. Hormone therapy in menopause.
Clin Rev. 2005;15(4):46-51.
21. Premarin
Prescribing
Information.
Phila-