Vol.1, No.2, 20- 24 (2011)
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJPM/
Open Journal of Preventive Medicine
Symptomatic changes in p ostmen opause with differen t
methods of hormonal therapy
Marcelino Hernández-Valencia*, Nydia Cordova, Antonio Vargas, Lourdes Basurto,
Renata Saucedo, Carlos Vargas, Miriam Ruiz, Leticia Manuel-Apolinar, Arturo Zárate
Endocrine Research Unit, Specialties Hospital, National Medical Center, Instituto Mexicano del Seguro Social, México City, Mexico;
*Corresponding author: mhernandezval encia@prodigy.net.mx
Received 20 April 2011; revised 30 May 2011; accepted 20 July 2011.
Objective: the diversity of opinions on the ad-
verse effects of medications used to treat post-
menopausal symptoms has prompted the use of
various routes and mechanisms of action that
need to be explored because bioavailability of
the medications can vary. In order to select the
appropriate route of administration for hormo-
nal therapy (HT), it is necessary to determine
baseline therapeutic efficacy. Design: we de-
signed a prospective, randomized study con-
sisting of four groups of postmenopausal wo-
men: group 1 received oral conjugated estro-
gens, group 2 received a synthethic steroid,
group 3 received estradiol nasally in spray form,
and group 4 used transdermal estradiol in the
form of patches. Criteri a used to evaluat e effec-
tiveness was the Greene scale, which evaluate
six components. These criteria were applied to
each patient before hormonal intervention and
then each month for 6 months. Luteinizing
hormone (LH), follicle stimulating horone (FSH)
and estradiol concentration were determined by
chemiluminescence. Student’s t-test was used
for intra-group comparisons before and after
treatment. Results: There was a significant de-
crease in the vasomotor and sexual component
(p < 0.05) with the use of four HT types. For de-
pression, a difference was observed with syn-
thetic steroids and oral estrogens. Upon ana-
lyzing the somatic component there was a de-
crease in s ymptoms w it h nasal an d transd ermal
routes. Psychological changes were observed
with the use of oral synthethic steroids and
transdermal patches. Anxiety component dem-
onstrated differences with nasal spray and oral
estrogens, although all HT forms in this com-
ponent showed a pattern of irregular changes.
Conclusions: changes in the response could be
due each route of administration and medica-
tion used. Absorption variability may exist,
which has repercussions in the control of
symptoms and should be taken into considera-
tion when selecting the appropriate route of
administration for patients beginning HT.
Keywords: Hormonal Therapy; Transdermal
Estradiol; Tibolone; Oral Estrogen; Nasal Estradiol;
Postmenopause is the stage of life when a profound
decrease occurs in the circulating concentration of es-
trogens, inducing the appearance of characteristic psy-
chosomatic symptoms [1,2]. Absence of this hor mone is
the reason for estrogens receptors not exercising intra-
cellular messages in different tissues sensitive to estro-
gens, producing a functional derangement clinically
translated by menopause symptoms that compromise
quality of life [3,4].
Due to a variety of opinions on the adverse effects of
medications used to treat menopause [5,6], diverse routes
and mechanisms of action have been used, which need to
be explored as to their responses. Differences in bioavai-
lability of medications can vary when passing through
the intestine and liver [7,8]. The actual tendency is to
find the baseline therapeutic efficacy when choosing the
appropriate route of hormonal therapy (HT) administra-
tion to provide relief for the predominant symptoms that
each patient presents at the first medical visit, since both
doctors and women are seeking the optimal way to use
HT [9,10].
This study was undertaken to compare the effects of
different HT forms and routes of administration used to
improve each of the symptomatic components in post-
M. Hernández-Valencia et al. / Open Journal of Preventive Medicine 1 (2011) 20-24
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJPM/
This was a prospective, longitudinal and descriptive
study that included 160 healthy postmenopausal women
who were recruited from Department of Health Promo-
tion. Subjects were evaluated for admission into the
study in the Endocrine Research Unit of the Specialties
Hospital, National Medical Center, Instituto Mexicano
del Seguro Social. According to patient selection, four
study groups were formed. Each group was comprised of
40 patients randomly assigned. Group 1 received oral
conjugated estrogens (Premarin 0.625 mg). Group 2 re-
ceived a synthetic steroid (Tibolone 2.5 mg). Group 3
received estradiol nasally in the form of a spray in each
nostril (Armistor 300 µg). Group 4 used transdermal
estradiol in the form of patches that were changed every
4 days (Estraderm 1.5 mg). All groups received a daily
dose at night and patches were also changed during the
night, administered for a period of 6 months.
Included patients were postmenopasual, confirmed
hormonally by estradiol concentrations < 10 pg/mL and
FSH > 40 mIU/mL. Uterine ultrasound demonstrated
normal endometrium, and cervical cytology and mam-
mography were without changes. As a study criterion,
subjects had no history of associated treatments to cor-
rect psychoaffective symptomatology characteristic of
postmenopause. Exclusion criteria were nasal diseases,
allergies, history of abnormal bleeding and thrombo-
In none of the patients was a progestin associated with
HT due to the short length of the study where our pri-
mary objective was to observe affective changes on
postmenopausal symptoms.
All patients gave infor med consent upon ad mission to
the study, and the study was approved by the Ethics
Committee from our hospital.
2.1. Clinical Evaluation
A complete clinical evaluation was performed before
beginning treatment and then monthly until 6 months of
follow-up, where at each medical visit the response on
the climacteric symptomatology was also evaluated, as
well as occurrence of undesirable effects, and blood
samples were obtained for hormonal determinations.
The Greene scale [11] was the criteria used for evalua-
tion of symptoms and included six components: vaso-
motor, sexual, depression, somatic, psychological and
anxiety. This scale was applied to each patient before
hormonal intervention and monthly during follow-up.
This scale indicates a weighted global score that quanti-
fies the incidence and intensity of postmenopausal
2.2. Hormonal Determinations
Serum from each subject was kept in aliquots (1 - 3
mL), and hormonal determinations were tested using
commercial kits in accordance with established protocols.
Concentrations of luteinizing hormone (LH), follicle
stimulanting hormone (FSH) and estradiol were deter-
mined by chemiluminescence (Immulite, Diagnostic
Products Corpor ation, Los Angeles, CA) with a sensitiv-
ity of 0.1 mIU/mL for FSH, 0.1 mIU/mL for LH and 7.0
pg/mL for estradiol. All determinations had a coefficient
of variation intra- and inter-assay of 6.7% and 3.7%,
2.3. Statistical An alysis
Description of the results was performed using disper-
sion measures and shown as mean ± standard deviation
(M SD). Comparison between groups was determined
by two-way analysis of variance (ANOVA), with a rele-
vant post hoc test. Differences were considered statisti-
cally significant if p < 0.05.
Clinical characteristics showed no statistically sig-
nificant differences among the study groups (Table 1).
All patients included in this study completed 6 months
of treatment, and in no cases were there intense adverse
symptoms war ranting HT suspensio n.
Hormonal determinations demonstrated good phar-
macological response because the baseline concentra-
tions of gonadotrophins confirmed a significant statisti-
cal decrease (p < 0.05), taking into consideration all pa-
tients included in the study with LH 32.6 4.2 to 12.2
3.1 mIU/mL a nd FSH 81.6 9.4 to 26.4 6.3 mIU/mL,
as well as an increase in e stradio l of 10.8 2.4 to 94.7
8.6 pg/mL after 3 months and at the end of HT.
Greene scale score showed changes in symptomatol-
ogy from the first month of HT in the four groups, but
without significant differences. Statistical differences in
the study were observed at 3 months for some of the
scale components, but 6 months of HT for each scale
component was considered for analysis.
Table 1. Clinical characteristics of the four study groups.
Variable Nasal Synthetic Conjugated Transdermalp
Age 49.3 ± 4.247.9 ± 2.7 49.6 ± 3.6 48.1 ± 2.2NS
BMI 24.6 ± 2.825.4 ± 1.4 25.1 ± 1.6 24.9 ± 2.1NS
Age at m eno-
pause 49.3 ± 2.546.8 ± 0.5 48.7 ± 6.2 47.6 ± 1.2NS
Months of
menopause 14.2 ± 1.214.1 ± 1.1 14.8 ± 2.6 16.2 ± 1.3NS
Tot al Gr een e
score 22.1 ± 3.424.1 ± 2.3 23.4 ± 2.5 23.8 ± 3.2NS
BMI, body mass index; NS, not significant.
M. Hernández-Valencia et al. / Open Journal of Preventive Medicine 1 (2011) 20-24
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Vasomotor component demonstrated a significant de-
crease (p < 0.05) with the use of the four types of HT,
maintaining the pattern of decrease in this symptom ob-
served at 3 months (Figure 1(A)). There was a decrease
in the sexual component with the same use of HT, al-
though with an irregular pattern of decrease (Figure
For the depressive component, a difference was ob-
served with the use of oral synthetic steroids and conju-
gated oral estrogens, with a pattern of constant decrease
of symptoms even with medications where there was no
significant difference (Figure 2(A)). On analyzing the
somatic component, a decrease in symptoms was ob-
served with the use of the nasal spray and transdermal
patches, where a constant and profound decrease was
found as opposed to the other forms of therapy where
irregular changes existed (Figure 2(B)).
Figure 1. Two components of the Greene scale are observed
where the vasomotor component (Figure 1(A)) demonstrates a
statistically significant decrease (p < 0.05) with the use of all
types of hormonal therapy. The sexual component (Figure
1(B)) demonstrates same statistic al differences in al l therapies,
in addition to an irregular score distribution.
Figure 2. Significant changes in depression (Figure 2(A)) are
shown with the use of synthetic steroids and conjugated estro-
gens. Somatic component (Figure 2(B)) demonstrated statisti-
cal difference with nasal spray and transdermal patches. In all
types of therapy, a pattern of irregular ch anges was observed.
Significant changes in the psychological component
were observed with the use of synthetic oral steroids and
with transdermal patches. With the other types of HT
there was a non-significant decrease (Figure 3(A)). The
anxiety component showed a significant difference with
the use of the nasal spray and with oral conjugated es-
trogens, although all forms of HT in this component
showed an irregular pattern of changes (Figure 3(B)).
The present study in which the Greene scale score
was used allowed us to evaluate the therapeutic com-
mercial presentations of HT with the use of different
pharmacological formulasnasally, orally or transder-
mallyfor the treatment of postmenopausal symptoms.
M. Hernández-Valencia et al. / Open Journal of Preventive Medicine 1 (2011) 20-24
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJPM/
Figure 3. Psychological (Figure 3(A)) and anxiety (Figure
3(B)) components demonstrate changes with a tendency to
decrease symptoms, but only with differences in some thera-
peuti c forms as ob served in the bar for each group.
We observed that the evaluated components show dif-
ferent responses in the control of postmenopausal symp-
We observed that the vasomotor and sexual compo-
nent had a good response with all types of treatments
used in this study. However, evaluation of the sexual
component did not demonstrate improvement with regu-
lar pattern with the use of synthetic steroids. Depressive
and somatic components had an irregular response with
all the different therapeutic modalities. Because the pro-
file of symptoms decrease was inconsistent, psychologi-
cal and anxiety components also had a satisfactory re-
sponse with only some of the therapeutic modalities. The
difference was significant for up to 6 months of therapy.
This demonstrates an equivalent efficacy on using a
daily intranasal application of 300 µg/day of 17
diol, 0.625 mg orally, 1.5 mg transdermally and 2.5 mg
synthetic steroids to improve perimenopausal symptoms.
It should, however, be mentioned that each method has a
different kinesis: the intranasal route has a pulse activity
each day of application and the oral route has a sustained
activity during the entire day of administration [12,13].
Changes in the response to each route of administration
and medication used may be due to the fact that estro-
gens demonstrate their metabolic effects at the intracel-
lular level because they interact with specific receptors
in the cells of the effector organs to form dimerization
that stimulates DNA synthesis. Therefore, estradiol is
primarily metabolized in the liver where its principal
metabolites are estriol and estrone, which are less active
although also metabolized in the liver [14]. For its part,
transdermal therapy delivers estrogen unaltered directly
into the bloodstream, bypassing the liver, whereas ti-
bolone is metabolized in three ways and according to the
tissue acts as estrogen, androgen and progestagenic ac-
tivity [15]. It should be kept in mind that absorption
variability may exist among women and the different
routes used; therefore, variability may also exist in the
control of symptoms, which should be taken into con-
sideration when selecting the appropriate route of ad-
ministration in patients who will begin HT.
Scoring variation on the Greene scale has demon-
strated great efficacy to quantify the incidence and in-
tensity of perimenopausal symptoms, which have been
widely validated. In no case was endometrial swelling
observed. This was closely observed because estradiol
was used as monotherapy for a 6-month period to exclu-
sively evaluate HT response with differences in routes of
administration. The Women’s Health Initiative (WHI)
study demonstrated that a relative risk exists with the use
of estrogens associated with progestin [16]. There were
also no cases of adverse effects such as mastodynia and
transvaginal spotting. There were no clinical changes
observed related to peripheral venous problems, which
could suggest a state of hypercoagulation during the
period of observation. One of the criteria for study in-
clusion was no vascular history or peripheral venous
All routes of administration demonstrated beneficial
clinical effects for the control of postmenopausal symp-
toms. In order to achieve this, it is important to mention
that patients with gynecological and schizoaffective dis-
orders should significantly participate in the accom-
plishment of prophylactic indications and HT. Also, HT
should be adapted according to the requirements of each
patient and should be approached on the basis of per-
sonal history and expectations of HT. However, long-
term use of estrogen may have potential risks, vaginally
delivered estrogen therapies (cream, tablet or ring) are
also very effective for treating vaginal dryness after
menopause. But the TH have both protective benefits
M. Hernández-Valencia et al. / Open Journal of Preventive Medicine 1 (2011) 20-24
Copyright © 2011 SciRes. http://www.scirp.org/journal/OJPM/
and potential risks like breast cancer, stroke or heart at-
tack or heart attack and blood clot development, since
older women, obese/diabetic women have much higher
levels of a marker associated with inflammation, protein
kinase C (PKC). Estrogen can either exacerbate or in-
hibit inflammatory processes depending upon whether
PKC or protein kinase A (PKA) is constitutively active
within cells. This fact probably explains the seemingly
conflicting results of estrogen-only therapy between
younger and older women; old age is associated with
higher levels of inflammation markers like PKC. Fur-
thermore, since estrogen also produces a biphasic re-
sponse, younger, normal-weight women are best advised
to take only physiological doses of the natural hor mone.
Openly accessible at
We can conclude from these results that HT should be
initiated for relief of symptoms through suitable selec-
tion of the route of administration and drug that has the
greatest effect on the predominant symptoms of each
pati ent , for whic h me d ica l eva l uati o n wa s soug ht.
The authors thank the personnel of the Endocrine Research Unit of
the Specialties Hospital, National Medical Center of the Instituto
Mexicano del Seguro Social for medical care and follow-up. Addition-
ally, we thank Sharon Morey for editorial assistance in this manuscript.
The study was financed in part by the Fondo para la Investigaciión
en Salud (FIS) of the IMSS and by the National Council Investigators
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