Transdermal and Oral Hormonal Replacement Therapy and the Incidence of Vein Thromboembolism Among Postmenopausal Women

8/10/2019 Transdermal and Oral Hormonal Replacement Therapy and the Incidence of Vein Thromboembolism Among Postm

1/17

Page | 0

Transdermal and Oral Hormone Replacement Therapy and The Incidence

of Vein Thromboembolism Among Postmenopausal Women

Rizky umara Anindhita

!"!#!$#%&%

'akarta %!&&

Abstract#


2/17

Page | 1

The pathophysiology of vascular disorder are briefly reviewed within the context of

the relevance and safety of hormone replacement therapy. Estimation of data from the medical

articles in relevance to the topic and the results of several investigation studies suggest that

selective hormone replacement therapy is necessary for the majority of postmenopausal

women. The key to overcome the benefits-risks profile is individualization of hormone

replacement therapy, especially regarding the selection of the route of administration of

hormone replacement therapy

The route of hormone replacement therapy administration is an important determinant

of the risk of vein thromboembolism event in postmenopausal women using hormone therapy.

ral route of administration of hormone replacement therapy are associated with a

higher risk of vein thromboembolism among postmenopausal women. This contributes an

epidemiological evidence that transdermal route of administration may be safe with respect to

vein thromboembolism risk.

!E" #$%&' (ormone replacement therapy, )ein thromboembolism, )ascular disorder

Introduction#

)enous thromboembolism is one of the vascular diseases of the extremities which is

affecting *,+ per * persons every year*. This condition often has a potential fatal

outcome, approximately +/ to */ of cases, which is worsen by the fact that individuals who

have had a first event of venous thromboembolism are at high risk for the second event *.

%ata about the incidence of venous thromboembolism among postmenopausal women

has shown an increased within the past few years. This has been correlated to administration

of hormone replacement therapy, which is taken by the postmenopausal women to overcome

the severe climacteric symptoms.


3/17

Page | 2

0rom the recent epidemiological data, it suggests that different routes of

administration of hormone replacement therapy expose different amount of risk of the

incidence of vein thromboembolism. 1 concieve that the use of oral administration are

associated with higher risk of vein thromboembolism among postmenopausal women. This

thought is based upon the experimental study that was conducted in the 2nited &tates of

3merica which concluded that the use of oral administration increases the incidence of vein

thromboembolism, whereas the transdermal administration may be safe with respect to vein

thromboembolism risk.

Hormone replacement as the treatment of menopause

Hormone replacement therapy and its use#

(ormone replacement therapy is a treatment for women who undergo menopause, a

part of the aging process which embraces the transition from the reproductive to the non-

reproductive phase of life4. The menopause age varies with race and socioeconomic

conditions, but in western Europe and the 2&3 the average age of onset is +* years 4. 1n

outline, the condition of menopause reflects the status of women5s ovarium organ which is

one of the female reproductive system, it shows that the number of ovum to be ovulated has

decreased, thus this women will experience hormonal changes.

0rom the aspect of physiology and anatomy, female5s reproductive system involves

three hormone-secreting organ, they are the hypothalamus, anterior pituitary gland, and the

ovarium. (ypothalamus produces gonadotropin-releasing hormone 6n$(, which will affect

the anterior pituitary gland to produce follicle-stimulating hormone 0&( and luteinizing

hormone 7(. These hormones will inturn affect the ovarium to produce estrogen that will be

used in the formation and development endometrium of the uterus in follicular phase and to

be secreted to the blood. These three organ that is discussed, which is also called the


4/17

Page | 3

(ig#& (eedback )echanism *ithin the HP+ a,is

hypothalamus-pituitary-gonadal axis (86

axis plays a role to each other, which means

that there is a feedback mechanism within

this axis (ig#&*4. The estrogen produced

by the ovarium will affect the amount of

gonadotropin-releasing hormone, when there

is low estrogen level in the blood, this will

induced the hypothalamus to produce higher

level of gonadotropin-releasing hormone

which inturn causing the anterior pituitary

gland to produce high level of follicle-

stimulating hormone and luteinizing

hormone. 1n the other hand, when there is

high estrogen level, this will suppressed the

production of gonadotropin-releasing hormone and also causing the level of follicle-

stimulating hormone and luteinizing hormone to become lower.

%uring the menopausal condition, there is a marked reduction in ovarian production of

estrogen4. This is correlated by the fact that the number of ovarian follicle is decreased in

time by the age. This absence of significant estrogen production results in excessive release of

follicle-stimulating hormone and luteinizing hormone. These variation in the circulating levels

of estrogen in the menopausal condition, accounts for the variation in severity of menopausal

symptoms.

The symptoms in menopause can be divided into several groups which is shown below

in Table#&4.


5/17

Page | 4

Table#&4# -ymptoms and -igns of The .limacteric /menopause0

Vascular disturbances (ot flushes which consist of flushes and

perspiration. This is associated with increased

in skin temperature and also associated in

some way with high level of gonadotropin-

releasing hormone..hanges in target organ response 9essation of menstruation.

)aginal walls lose their rugosity and become

smooth and atrophic.

9ervix diminishes in size and decreased

production of cervical mucus.

2terus shrink in size.

Endometrium becomes atrophic.

1pidermal appendages &kin becomes thinned and wrinkled.

7oss of scalp, pubic, and axillary hair.

2one changes 7oss of trabecular bone which causes

osteoporosis. This is associated with

increased bone resorption.

.ardio3ascular complication 1ncrease in coronary heart disease.

1ncrease of serum cholesterol level.

Psychological and emotional symptoms &evere emotional disorder, such as depression

and anxiety.

Other symptoms and signs 3norexia, excessive fatigue, nausea,

vomiting, and bowel disorders.

#omen who are experiencing those symptoms and signs and cannot stand the severity

of them, are advised to take estrogen therapy as a hormone replacement therapy to overcome

those symptoms and signs. :y taking the external source of estrogen, it will increase the level

of estrogen in the blood and so will cause a feedback to hypothalamus which will decrease the

production of gonadotropin-releasing hormone and so follicle-stimulating hormone and

luteinizing hormone produced by anterior pituitary gland. This hormonal therapy mechanism

will correct the hormonal changes that occur in menopausal women. 3s by its name, hormone

replacement therapy is to take in hormone form external source to replace the endogenous

hormone of the body.

Transdermal route of administration#


6/17

Page | 5

&ystemic estrogen can be administered trandermally and it is usually used by women

who cannot tolerate or take oral forms because of nausea and other health issues ;. There are

many kind of estrogen that can be administered transdermally, as listed below in Table#%;.

Table#%;# Patch 4o* dose

/mg0

-tandard

dose /mg0

)edium

dose /mg0

Higher

dose /mg0

Highest

dose /mg0

Alora .+ .4+ *.4+ 4.+

Ortho61st /estrone0 .>4+ *.4+

Premarin /con5ugated e9uine estrogen0 .; .>4+ .? *.4+ 4.+

0rom the article titled 3ge-3djusted 7ong-Term Estrogen Therapy' 9ardiovascular

(ealth and %isease, it is stated, under sub-chapter of clinical trials on hemostasis and venous


7/17

Page | 6

thrombosis, that hormone replacement therapy which is administered orally will undergo first-

pass metabolism in the liver and this process has an effect on the production of procoagulant

factors that are synthesized in the liver. Therefore avoidance of the entero-hepatic first-pass

effect is associated with a more limited change in the hemostatic profile.

@ost of the changes in the hemostatic profiles result from oral estrogen usage, such as

conjugated e=uine estrogen 9EE, estradiol E4, or esterified estrogen EE. These changes

include an increase in the levels of tissue activator fibrinolysis inhibitor antigen, protein 9, %-

dimer, and factors )11, 1A, A indicators of increased coagulation, and a decrease in the level

of protein &, antithrombin anticoagulation, and tissue plasminogen activators fibrinolysis

B. 3ll of this changes will create a condition called hypercoagulability state which favours the

formation of venous thrombus.

The degree to which estrogen as hormone replacement therapy increases the risk of

venous thrombosis will vary primarily with the dose of estrogen and the route of estrogen

therapy and this explains why there is a higher incidence of venous thrombosis in oral route of

administration of estrogen therapy compared to transdermal route.

Vein thromboembolism#

+eneral in3estigation of 3ein thromboembolism and its pathophysiology


8/17

Page | 7

(ig#% 2lood .oagulation .ascade

)ein thromboembolism belongs to the group of vascular disease of the extremities which is

characterized by the presence of

thrombus and inflammatory

response in the vessel wall+. This

vein disorder is subdivided into

two form' deep venous thrombosis

and superficial venous thrombosisC

the difference between these two

form of venous thrombosis is that

the location of the vein, one is in

near the skin surface superficial

and the other lays deep down the

tissue deep. 3ccording to

)irchow5*D+> there are three

factors which contribute to the

formation of venous thrombosis'

disruption of the blood flow

stasis, vascular damage, and hypercoagulability. The damage of the vascular component will

trigger the activation of coagulation cascade by releasing tissue factor which activates the

extrinsic pathway and prekallikrein which activates the intrinsic pathway. :oth of these

pathways will lead to the formation of fibrin clot which later on will trap the blood corpuscle

and form a thrombus (ig#%0**. This thrombus will keeps on developing, as long as the

coagulation cascade is activated, and it will cause obstruction in the lumen of the blood vessel

and thus disturbing the flow of the blood. Thrombus that is formed can be anchored on the

wall of the blood vessel, as described before, or it can be detached from the wall of the blood


9/17

Page | 8

(ig# " Imbalance Hemostatic 4eading to Hypercoagulability

vessel and will flow with the blood, this is called thromboembolus and the obstruction of a

blood vessel by an embolus is called embolism. This embolus can pass through the

bloodstream to the heart and may get lodge in an artery and may cause blood flow obstruction

which if it is not treated it may lead to organ damage and even death >.

1n condition where the flow of the blood is slowed or stopped stasis, the tissue of the

blood becomes inade=uately perfused with oxygen and nutrients. Therefore this condition will

cause the damaged of blood vessels which will trigger the activation of coagulation cascade

and will form thrombus, later on.

(ypercoagulability can be defined as a group of inherited or ac=uired conditions

associated with a predisposition to venous thrombosis


10/17

Page | 9

>#0 Pregnancy#

?#0 1strogen use ; as replacement therapy or contraception#

7#0 Hypercoagulability ; resistance to acti3ated protein .< deficiency antithrombin III#

$#0 Venulitis ; thromboangitis obliterans< 2ehcet@s disease#

#0 Pre3ious deep 3ein thrombosis#

Pathophysiology of hormone replacement therapy6inducing63ein

thromboembolism#

(emostasis of our blood clotting is controlled by two mechanism' coagulation

cascadeC that has an intrinsic and extrinsic pathway, a number of inactive zymogens factors

which are converted to proteases activated factors that eventually result in the conversion of

prothrombin into thrombin that will catalyzes fibrinogen into fibrin and leads to the formation

of insoluble blood clotC and anticoagulant systemC which involves antithrombin, protein 9,

and cofactor protein &. 3 balance in this system will make our blood hemostasis normal,

whereas if there is any imbalance, it will lead to either excessive blood clot formation

hypercoagulability state or lack of blood clot formation bleeding problems.

3s we have discussed before, there

are three factors that caused venous

thrombosis, according to )irchow5*D+>,

they are' disruption of the blood flow

stasis, vascular damage, and

hypercoagulability state (ig#:+. 1n the

case of hormone replacement therapy

associated with venous thrombosis, the factor that plays role of its development is factor

number three, that is hypercoagulability state. There has been some studies that investigate

that the use hormone replacement therapy induces the state of hypercoagulability which result

in the development of venous thrombosis. ne of the side effects of using the hormone

replacement therapy is that the person5s hemostatic profile is altered. There is a shift towards

(ig#:# Vircho*@s Triad


11/17

Page | 10

the production of inactive zymogens factors which are converted to proteases activated

factors and there is a reduced synthesis of antithrombin which is essential factor in

modulating the coagulation cascadeD. Therefore from this imbalance hemostatic condition,

coagulation cascades is activated, through both intrinsic and extrinsic pathway and meet the

common pathway where conversion of prothrombin into thrombin catalyzes the formation of

fibrin.

The incidence of hormone replacement therapy6inducing63ein thromboembolism#

The incidence of vein thromboembolism induced by the use of hormone replacement

therapy has been increasing from the past few years. &ome articles and even studies have been

investigating not just towards this incidence, but also how the different route of administration

affecting vein thromboembolism differ.

Taken from the article of &cience %aily @ay 4>, 4D, it is stated that hormone

replacement therapy given in skin patches, the trandermal route of administration, may cause

fewer blood clots compared to when it is given orally, further more for women who take the

oral route of administration more than double their risk of developing a blood clot?.

&till from the same article, it is also mentioned that there have been researchers who

conduct data review from eight observational studies and nine randomised controlled trials.

0rom this data review, they found that women taking the oral form of hormone replacement

therapy were two and three times more likely to develop a blood clot, and that the risk was

higher during the first year of treatment?.

The @edscape @edical ournal about hormone replacement therapy and venous

thromboembolism in postmenopausal women, had conducted a research on the topic

discussed. This research studied about the recurrency of vein thromboembolism on

postmenopausal women who were on a treatment of hormone replacement therapy and had


12/17

Page | 11

had an episode of vein thromboembolism, and compared the result when oral or trandermal

administration were used*. The result shows that transdermal estrogen use after a first vein

thromboembolism event did not expose women to an excess risk of recurrence. 1n contrast,

oral estrogens increased significantly the risk of recurrent vein thromboembolism *.

)anagement#

)enous thromboembolism is one of the major causes of morbidity and mortality, this is

due to one of its complication that is pulmonary embolism which can be fatal. To prevent and

treat this disorder, certain therapy is needed, they are called antithrombotic drug therapy. The

antithrombotic drug is classified into three catagories, depending on how the drugs work, they

are' antiplatelet drugs, anticoagulants, and fibrinolytic agents.

The example of antiplatelet

drugs are' aspirin, clopidogrel,

ticlopidine, abciximab, and

tirofiban. These drugs affect the

process of platelet aggregation on

different stages. 3spirin produces

its antithrombotic effect by

irreversibly acelating and inhibiting

platelet cyclooxygenase 9A-*,

an enzyme which play role in the

synthesis of thromboxane 34, which

is needed in platelet recruitment and

activation. 9lopidogrel and ticlopidine also work the same as aspirin but they work onto

different enzyme, which is adenosine diphosphatase 3%8ase. 3bciximab and tirofiban

(ig#> -ite of Action of Antiplatelet

Brugs


13/17

Page | 12

(ig#? )echanism of Action of Heparin and 4o*6)olecular6

Weight Heparin

belongs to a class of 6811bF111a receptor antagonist. This class works to prevent the activated

platelet to bind to adhesive molecules, such as fibrinogen and von #illebrand factor and

therefore inhibit the process of platelet aggregation (ig#>*. 3spirin is usually administered

at doses of


14/17

Page | 13

intial bolus of + units or D unitsFkg, followed by an infusion of *D unitsFkg per hour. The

dose of low-molecular-weight heparin used is given *+-4 unitsFkg once daily. #arfarin, as

an oral anticoagulant, works by blocking vitamin ! epoxide reductase which means that

vitamin ! epoxide cannot be reduced and therefore inhibiting the role of vitamin !-dependent

factors, such as factor 11, )11, 1A, and

A, in the coagulation cascade (ig#7

*. The dosing used for warfarin is

usually started at a dose of +-* mg,

which is then titrated to correlate the

normal value of prothrombin time.

0ibrinolytic drugs that are used

to treat vein thromboembolism degrade the thrombi that has formed on the wall of the blood

vessel. They are administered systemically or can also be administered via catheters directly

into the substance of the thrombus. &treptokinase acts on the fibrinolytic system by acting on

plasminogen, make a conformational

change and thus exposing its active

site which is able to degrade fibrin to

fibrin degradation products (ig#$ and

*. #hen given systemically, this

drug is given as an 1) infusion of *.+ million

units over ;-> minutes.

(ig#$ The (ibrinolytic -ystem

(ig# )echanism of Action of -treptokinase

(ig#7 )echanism of Action of Warfarin


15/17

Page | 14

.onclusion#

1n conclusion from what 1 get in my data review from several text books, articles, and

medical journals, the results provide a contribution to an epidemiological evidence that

transdermal hormone replacement therapy may be safe with respect to vein thromboembolism

risk in general. This review can give an important consideration and input for women at high

vein thromboembolism risk who re=uire hormone replacement therapy for severe

postmenopausal symptoms. $educing vein thromboembolism risk by using transdermal

hormone replacement therapy could improve the benefits-risks profile of hormone therapy

among postmenopausal women.

References#

*. )alerie , 6enevieve 8:, ac=ueline 9, (elene (@, @arianne 9, "ves &8. (ormone

Therapy and $ecurrence of )enous Thromboembolism 3mong 8ostmenopausal #omen. The

Gorth 3merican @enopause &ociety 4**C *D+' BDD-B?;.

4. &ymonds E@, &ymonds 1@. Essential bstetrics and 6ynaecology. 7ondon' 9hurchill

7ivingstoneC 4B. p. 4++-4+?.

;. Elder 3, @essinger :, Thacker (7. &pecial 1ssues in #omen5s (ealth' (ormonal (ealth

1ssue of Early and 7ate 8ostmenopausal #omen. 1n' 7andefeld 9&, 8almer $@, ohnson @3,

ohnston 9:, 7yons #7, editors. 9urrent 6eriatric %iagnosis and Treatment. Gew "ork'

@c6raw (illC 4B. p. ;+?-;>>.

B. 3nonymous. 3ge-3djusted 7ong-Term Estrogen Therapy' 9ardiovascular and %isease.

4>. 3vailable from' http'FFwww.medscape.comFviewarticleF+4;D+*HB accessed @ay ;,

4**.
http://www.medscape.com/viewarticle/523851_4http://www.medscape.com/viewarticle/523851_4


16/17

Page | 15

+. 9reager @3, 7oscalzo . )ascular %isease of the Extremities. 1n' 0auci 3&, !asper %7,

7ongo %7, :raunwald E, (auser &7, ameson 7, 7oscalzo , editors. (arrison5s 8rinciples

of 1nternal @edicine. Gew "ork' @c6raw (illC 4D. p. *+


17/17

Page | 16

Documents

Transdermal and Oral Hormonal Replacement Therapy and the Incidence of Vein Thromboembolism Among Postmenopausal Women