Symptomatic changes in postmenopause with different methods of hormonal therapy

doi:10.4236/ojpm.2011.12004

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Vol.1, No.2, 20- 24 (2011)

doi:10.4236/ojpm.2011.12004

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.

AB S TRAC T

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

1. INTRODUCTION

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-

menopause.

M. Hernández-Valencia et al. / Open Journal of Preventive Medicine 1 (2011) 20-24

2. MATERIALS AND METHODS

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-

phlebitis.

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

symptoms.

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%,

respectively.

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.

3. RESULTS

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

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

1(B)).

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)).

4. DISCUSSION

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 formulasnasally, orally or transder-

mallyfor the treatment of postmenopausal symptoms.

M. Hernández-Valencia et al. / Open Journal of Preventive Medicine 1 (2011) 20-24

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-

toms.

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



-estra-

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

insufficiency.

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

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.

5. ACKNOWLEDGEMENTS

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

(SNI).

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