Human Reproduction, Vol. 15, (Suppl. 1), pp.

60-73, 2000

The relative effects of progesterone and

progestins in hormone replacement therapy
G.M.C.Rosano1'3, C.Sarais2, S.Zoncu2 and G.Mercuro2
'Department of Cardiology, H.San Raffaele Roma-EUR, Via Elio Chianesi
33, 00144 Rome, and institute of Cardiology, University of Cagliari,
09124 Cagliari, Italy
3
To whom correspondence should be addressed

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

Hormone replacement therapy (HRT) was initially given to protect women
against osteoporosis and alleviate menopausal symptoms, such as hot flashes,
depression, sleep disturbances, and vaginal dryness. In view of the under-
standing of oestrogen deficiency as a major trigger for the acceleration of
cardiovascular risk after menopause, HRT may also be proposed as a
substantial beneficial cardioprotective agent. Progestins, which may be added
to oestrogen in combined HRT to reduce the risk of uterine malignancy,
have a number of potential adverse effects on the cardiovascular system
which could even attenuate the benefit of unopposed oestrogen replacement
therapy in post-menopausal women.
Key words: cardiovascular system/coronary artery disease/hormone replacement •
therapy

Introduction

Women are protected until the menopause from the development of coronary
artery disease and lag behind men in the incidence of myocardial infarction and
sudden death by 20 years (Gordon et al, 1978). The reasons for this protection
are largely unclear, but significant protection is given by ovarian hormones since
castrated women not taking oestrogen replacement therapy show an incidence of
coronary artery disease similar to that of men of similar age (Wuest et al, 1953).
Furthermore, a large body of evidence (large scale case-control and cohort
studies) has been accumulated to suggest that oestrogen replacement therapy
after either surgical or natural menopause is associated with a 50% reduction in
cardiovascular mortality and morbidity (Bush et al, 1987; Hunt et al., 1987;
Paganini-Hill et al, 1989; Stampfer and Colditz, 1991; Grodstein et al, 1997).
Consequently, post-menopausal oestrogen replacement therapy is becoming a
legitimate component of preventive health care for women and the protection
against coronary artery disease is presently considered the most significant benefit
of this therapeutic strategy.
60 Human Reproduction Volume 15 Supplement 1 2000 © European Society of Human Reproduction and Embryology
 The relative effects of progesterone and progestins in HRT

Apart from the data available from the Nurse's Health Study (Grodstein et al,
1996), the majority of case-control or cohort studies have been conducted using
unopposed oestrogen replacement therapy which, however, is now prescribed
only in women who have undergone a hysterectomy. In the remainder, progestins
are prescribed in order to protect the endometrium from the hyperplastic and
potentially carcinomatous effects of prolonged unopposed oestrogen replace-
ment therapy.
There is evidence that progesterone receptors are present at the level of vasal
endometrium and of smooth muscular fibrocytes in animal (Lin et al, 1986) and
human arterial walls (Ingegno, 1988). Hormonal vascular effects may be mediated
through these receptors as well as through a functional resetting of oestradiol
receptors (Horowitz and Horowitz, 1982; Lin et al, 1982).

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

Progestin affects arterial function, both by inducing a state of vasomotor
instability and by causing vasoconstriction of oestrogenized vessels; in this way,
progestin may influence the cardioprotective effect of oestrogens. Because of the
benefit of oestrogen replacement therapy on cardiovascular diseases, it is of
pivotal importance to know whether or not the addition of progestin could have
a negative effect on the clinical cardiovascular protection given by oestrogen.

Progestins and lipid profile

It is well known that ovarian hormones have a great effect on lipid metabolism.
Unopposed oestrogen replacement therapy beneficially affects the lipid profile in
menopausal women by lowering total serum cholesterol and low density lipopro-
tein (LDL)-cholesterol, and increasing high density lipoprotein (HDL)-choles-
terol, especially the HDL2 subfraction (Tikkanen et al, 1982; Godsland et al,
1987; Samsioe, 1990; Walsh et al, 1991; Soma et al, 1991; Srivastava et al,
1993). The effects of oestrogens upon plasma lipids are due to their reduction
in hepatic triglyceride lipase, that degrades HDL, and to their stimulation of
HDL-cholesterol production and synthesis of apolipoprotein (apo) A-I (Samsioe,
1990). Furthermore, oestrogen replacement therapy stimulates the removal of
cholesterol from the systemic circulation resulting in an increased reverse
cholesterol transport. The oestrogen-induced reduction in LDL-cholesterol seems
to be dependent upon hepatic and non-hepatic effects (Tikkanen et al, 1982;
Samsioe, 1990). Oestrogens enhance the synthesis and secretion of very low
density lipoprotein (VLDL) but also reduce the catabolism of VLDL to LDL by
enhancing the VLDL uptake by the liver. Another beneficial effect of oestrogens
upon LDL-cholesterol metabolism is the increase in the rate of LDL removal
from the plasma which seems to be dependent upon the up-regulation of LDL
receptors both in the liver and in the peripheral tissues (Walsh et al, 1991).
In contrast to oestrogens, progestins administered alone induce hepatic lipase
activity, increasing, in this way, the degradation of HDL-cholesterol; whereas,
the addition of progestin to oestrogens tends to attenuate the increase in serum
HDL-cholesterol and the decrease in LDL-cholesterol. These effects of progestins
upon lipid profile seem to depend on their biochemical structures, doses and
61
G.M.C.Rosano et al.

regimens. Progestins with pure progestogenic effect do not alter the lipid
metabolism, 19-nortestosterone derivatives reduce HDL-cholesterol while 17-oc-
hydroxyprogesterone derivatives, e.g. medroxyprogesterone acetate (MPA), the
most widely used progestin, seem to have little effect and progesterone no effect
upon plasma lipids (Tikkanen, 1986; Rijpkema et al, 1990; Grady et al, 1992;
PEPI Trial, 1995). Early studies showed that norethisterone acetate (NETA) or
levonorgestrel had a strong detrimental effect upon lipid metabolism (20-30%
reduction in HDL-cholesterol) so that they were labelled as androgenic; however,
the early results were, at least in part, the result of over-treatment. It must be
underlined that since 19-nortestosterone derivatives are not subject to a major
hepatic first-pass, their usage produces similar effects upon lipid metabolism,
irrespective of oral or non-oral route of administration.

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

Effect of progestins on coronary atherosclerosis and vascular reactivity

The vasodilator and anti-atherogenic effects of oestrogens on normal and

diseased arteries are well known. Oestrogens reduce the progression of coronary
atherosclerosis in both animals and humans; in addition, when administered
either acutely (20 min) or chronically (3 years), they can reverse the acetylcholine-
induced vasoconstriction in animals and humans (Pick et al, 1952; Stamler et al,
1953; Williams et al, 1990; Adams et al, 1997; Geary et al, 1998). Although
the mechanisms involved in this protective effect on coronary reactivity have
not been clearly established, it may be supposed that oestrogens act by increasing
the production of nitrous oxide and preserving it from the oxidative degradation.
(Niki and Nkano, 1990).
Adams et al. (1997) evaluated the effect of oestrogen replacement therapy
with and without progestins in ovariectomized monkeys fed with an atherogenetic
diet. Oestradiol-17(3 was found to reduce by 50% the degree of coronary
atherosclerosis; the adjunct of progesterone did not antagonize the anti-atherogenic
effect of oestradiol-17|3. In another study, the same group evaluated in the same •
animal model the effect of the most widely prescribed compounds for hormone
replacement therapy (HRT) in the USA, i.e. conjugated equine oestrogens (CEE)
and MPA. CEE reduced by 70% the degree of coronary atherosclerosis while the
adjunct of MPA resulted in a non-significant decrease of coronary atherosclerosis
(Adams et al, 1990, 1997).
Taken together, these data suggest that while there is no significant difference
in the anti-atherogenic effect of oestrogens, the adjunct of progesterone or
progestins to oestrogen replacement therapy produce a different impact on the
progression of coronary artery disease. Therefore, natural progesterone seems to
be the drug of choice for treating patients at risk of cardiovascular disease.
Regarding the vascular activity of progestins, the effect of progesterone on
rabbit coronary arteries in vitro were evaluated and demonstrated an endothelium-
independent relaxation induced by progesterone (Jiang et al, 1992). In addition,
Miller and Vanhoutte, (1991) assessed arterial relaxation in coronary artery strips
62
 The relative effects of progesterone and progestins in HRT

Table I. Effect of sequential oestrogen-progestin treatment upon uterine artery pulsatility index
in menopausal women

Author Treatment scheme Pulsatility index change

compared with oestrogens
alone

Marsh et al. (1994) 17(3-oestradiol + CEE or NETA vl-ioestrogen phase

Hillard et al. (1992)
de Ziegler et al. (1994)
Bonilla-Musoles et al. (1995)
de Ziegler et al. (1991)
iNETA
17(3-oestradiol + NETA sLioestrogen phase
iNETA
17(3-oestradiol + nomegestrol sloestrogen and combination
phase
17(3-oestradiol + MPA •Icombination phase
17(3-oestradiol + vaginal •iioestrogen and
progesterone combination phase

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

CEE = conjugated equine oestrogens; MPA = medroxyprogesterone acetate; NETA =
norethisterone acetate.

from ovariectomized dogs treated with oestrogen, progesterone or oestrogen plus

progesterone. The relaxation response was similar in the coronary arteries of
animals receiving oestrogen and in those receiving progesterone. On the contrary,
it was minimally reduced in the group receiving the combined therapy. Therefore,
it seems that there is little or no detrimental effect of progesterone on the
cardiovascular protective effect of oestrogens. Pure progesterone, however, is
not commonly used in HRT and the progestogens used have vascular and
metabolic effects which are different from those of progesterone.
Synthetic progestins seem to antagonize the beneficial effect of oestrogens
upon blood flow and vasodilation in normal (non-atherosclerotic) experimental
animals. Williams et al. (1994) evaluated the separate and combined effects of
CEE and MPA on coronary reactivity of atherosclerotic monkeys. Oestrogen
increased coronary dilator responses and blood flow reserve while co-administra-
tion of MPA (Clarkson, 1994) resulted in a 50% reduction in the dilator response.
This effect does not seem to be attributable only to MPA but to synthetic
progestins in general. On the other hand, different progestins and therapeutic
regimens have different effects upon vascular reactivity. Progestins given in a
cyclical regimen are likely to produce unfavourable vascular effects. Conversely,
continuous combined regimens appear to reduce the potential detrimental effects
of progestins (Penotti et al, 1993; Yim et al, 1998).
Few data are currently available on the vascular effect of oestrogen-progestin
therapy in menopausal females apart that from the study of uterine arteries,
which may respond to hormone stimulation differently from other arteries. Some
investigators have evaluated the effect of oestrogen-progestin therapy upon the
pulsatility index, which is a measure of arterial stiffness (Penotti et al, 1993).
A decrease in pulsatility index is indicative of a better arterial compliance. As
shown in Table I, some progestins (e.g. NETA), reduced the beneficial effect of
oestrogens upon pulsatility index, while progesterone had no detrimental effect
upon the beneficial decrease of pulsatility index induced by transdermal oestradiol-

63
G.M.C.Rosano et ah

E-NETA

Figure 1. Effect of the adjunct of different progestins to oestrogens upon brachial artery flow-mediated
dilatation (percentage change compared with baseline study). CEE = conjugated equine oestrogens; MPA
medroxyprogesterone acetate; E-NETA = 17(3-oestradiol + norethisterone acetate.

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

1.1

CEE-MPA E-NETA

Figure 2. Effect of oestrogen-progestin treatments upon brachial artery resistances (percentage change
compared to baseline study).

17|3. These data underline the concept that synthetic progestins may reduce
the beneficial activity of oestrogens upon vascular reactivity, whereas natural
progesterone seems to preserve it. However, the effect of synthetic progestins-
depends not only on the type of progestin, but also on the dose and scheme of
administration.
Rosano et al. have recently evaluated the effect of two different regimens of
HRT upon forearm vascular resistance in 12 menopausal women (mean age 55
± 2 years) referred to a menopause clinic for evaluation of their HRT (Rosano
et ai, 1998). Patients entered a double-blind single cross-over study evaluating
the effect of continuous combined HRT with either CEE (0.625 mg) plus MPA
(2.5 mg) or oestradiol-17(3 (2 mg) plus NETA (1 mg), randomly administered.
Forearm vascular reactivity and blood pressure were measured at baseline and
at the end of each treatment cycle by means of high-resolution, two-dimensional
ultrasound images obtained by an ultrasound machine with a 7.5 MHz linear
array transducer. Compared with baseline values, CEE plus MPA caused a
marginal reduction of blood pressure while the association of oestradiol-17|3 plus
norethisterone acetate increased blood pressure values. A significant difference
in systolic blood pressure was noted between the two treatment phases (126 ±
12 compared with 138 it 8 mm Hg, P < 0.01). Compared with baseline values,
CEE plus MPA increased brachial artery flow-mediated dilatation by 12%, while
oestradiol-17(3 plus NETA reduced this parameter by nearly 20% (P < 0.01,
Figure 1). These changes were mainly attributable to the effect of the two
hormone regimens upon forearm vascular resistance. Indeed, brachial artery

64
 The relative effects of progesterone and progestins in HRT

E-NETA

Figure 3. Effect of oestrogen-progestin treatment upon brachial artery blood flow (percentage change to
baseline).

resistance was reduced by 15% by CEE plus MPA, while oestradiol-17(3 plus
NETA caused a 16% increase of the same (P < 0.01, Figure 2). Both oestrogen-

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

progestin treatments induced an increase in brachial blood flow, but this increase
was more pronounced following CEE plus MPA (Figure 3). Hence, the MPA
behaved as a spastic element in women, confirming the result of previous clinical
studies, carried out in menopausal women (Girauld et al, 1996) and in
experimental studies on the vascular spasticity at the coronary territory in
monkeys (Williams et al, 1994; Minshall et al, 1998).
In view of the different effects upon blood pressure and vascular reactivity
produced by different oestrogen-progestin treatments, careful selection of the
dose and type of progestin to be used during HRT seems to be crucial in order
to preserve and possibly enhance the beneficial vascular effects of oestrogens.
The decrease in aortic compliance after menopause together with the increase
in systemic vascular resistance due to ageing may contribute to the development
of atherosclerosis, while increasing afterload and myocardial oxygen consumption.
Oestrogen receptors have been seen in aortic tissue suggesting that the aorta
might be a target organ for oestrogen actions. The calcium antagonistic effect of
oestrogen may increase vessel distensibility and compliance of aorta as suggested
by the changes occurring during pregnancy. The question arises as to whether
oestrogen replacement therapy could increase aortic compliance therefore exerting
a potential beneficial effect upon the cardiovascular system and whether the
adjunct of progestins could reverse this effect. Giraud et al. (1996) evaluated the
effect of oestrogen replacement therapy alone or in a continuous combined
regimen (CEE plus MPA) upon aortic size and compliance in 26 menopausal
women. Patients were randomized to receive either CEE (0.625 mg) alone or in
combination with MPA (2.5 mg) for 3 months. The cross-sectional area of the
aorta was measured by magnetic resonance imaging before and after replacement
therapy. Aortic size (ascending aorta cross-sectional area) increased from 439 ±
7 to 466 ± 7 mm2 in patients receiving CEE alone while it remained
unchanged in patients receiving continuous combined HRT. No difference in
aortic compliance was detected by comparing the two treatments. This study
suggests that unopposed oestrogen replacement therapy increases aortic cross-
sectional area and that progestins may attenuate the oestrogen-induced increase
in arterial distensibility during combined HRT.

65
G.M.C.Rosano et al.

Effect of oestrogen-progestin associations upon haemostasis

Changes in the haemostatic balance play an important role in the pathophysiology
of cardiovascular disease. After the menopause, the haemostatic balance shifts
towards a state of hypercoagulability, since fibrinogen plasma, factor VII (FVII)
and plasminogen activator inhibitor type 1 (PAI-1) concentrations increase. It is
well known that post-menopausal women face an increased risk of cardiovascular
events and stroke in comparison with pre-menopausal subjects. As to the increase
of the deep vein thrombosis after menopause, this could be a true effect or a
misleading one, due to the fact that post-menopausal women are older than pre-
menopausal ones (Anderson et al., 1991).
HRT reduces cardiovascular events, whereas it may increase the incidence of
deep vein thrombosis (Devor et al., 1992), since cardiovascular events and deep

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

vein thrombosis are due to different ways of activation of the coagulation cascade.
The arterial clot is white, consisting mainly of platelets and fibrin and adhering
to a site of endothelial damage which is a prerequisite of arterial thrombogenesis.
Venous clots are red, consisting of all types of blood cells within a fibrin gel
and without appreciable adhesion to the underlying endothelial surface. Thus the
most striking difference between the thrombotic diseases in venous and arterial
vessel is the absence of endothelial damage in venous disease and the presence
of an 'acute phase reaction' within the arterial wall in arterial thrombosis
(Sporrong et al, 1990; Gebara et al, 1995; Koh et al, 1997). The increased
incidence of venous thrombosis with HRT is not attributable only to changes in
the coagulation profile, but also to variations in venous tone and blood flow
velocity which per se increase the risk of thrombosis. Recent evidence suggests,
that oestrogen replacement therapy after the menopause may lead to a decrease
of fibrinogen plasma concentrations which is attenuated, but not eliminated, by
the adjunct of progestins, apart from their different chemical classes. The effect
of oestrogen replacement therapy on FVII is still a controversial issue: some
investigators detected an increase of FVII (Boschetti et al, 1991; Kroon et al,
1994; Habiba et al, 1996; Andersen et al, 1999), but others detected a decrease •
(Scarabin et al, 1993, 1997; Lindoff et al, 1996). The hormonal effect on FVII
may depend upon dose and method of administration. A marked decrease of
PAI-1 has been found. This effect is attenuated by 19-norprogestins, but not by
MPA (Koh etal, 1997).
The decrease in fibrinogen with all routes of administration and preparations
is small and may not translate itself into a significant decrease in risk while the
large decrease in PAI-1 activity with oral oestrogen therapy (Gebara et al, 1995)
is likely to be of clinical relevance especially in women with atheromatous
arterial disease. The magnitude of the changes in haemostatic balance varies
according to different oestrogen and progestin preparation with transdermal
oestrogens. These are much less effective than oral oestrogens in causing
beneficial changes.
In conclusion, the effects of HRT upon markers of arterial risk are compatible
with a reduction of cardiovascular events; these effects are present mainly with
66
 The relative effects of progesterone and progestins in HRT

oral therapy and are not attenuated by MPA acetate or cyproterone acetate
although they are significantly reduced by 19-norprogestins.

Effect of progestins upon chest pain and myocardial ischaemia

In recent years, it has become evident that oestrogens do have anti-ischaemic

and anti-anginal properties. Rosano et al. (1993, 1996) have demonstrated that
oestradiol-17|3 improves exercise-induced myocardial ischaemia in menopausal
patients with coronary artery disease and reduces chest pain in female patients
with angina and normal coronary arteriograms. The question arises as to whether
the adjunct of progestins could influence these beneficial effects of oestrogens.

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

It has been shown that the adjunct of NETA reverses the anti-anginal properties
of oestradiol-17(3 in female patients with X syndrome and may even worsen
symptoms in these patients (Rosano et al, 1996). Recently, Rosano et al. (1997)
have reported preliminary data of a randomized double-blind cross-over study
which evaluated the effect of adjunctive therapy with cyclical progesterone
(45 mg/daily) or MPA (10 mg/daily) to oestradiol-17(3 upon exercise-induced
myocardial ischaemia in 18 post-menopausal women with coronary artery disease.
During the study two patients were withdrawn during the MPA phase because
of the development of unstable angina. In comparison to baseline, oestradiol-
17^ alone increased the time to 1 mm ST depression (ischaemic threshold) (325
± 158 versus 257 ± 143 s, P < 0.01). In five patients in whom the exercise
test was negative after oestradiol-17[3 plus progesterone, the test become positive
during oestradiol-17(3 plus MPA (P < 0.01). Compared with oestradiol-17(3
alone, oestradiol-17p plus MPA failed to increase both time to 1 mm ST
depression and exercise time. By contrast, no difference was found between
oestradiol-17(3 alone or in combination with natural progesterone in either time
to 1 mm ST depression or exercise time. This study demonstrates that in
menopausal patients with coronary artery disease, the adjunct of cyclical natural
progesterone to oestrogen replacement therapy enhances the beneficial effects of
oestrogen therapy upon exercise-induced myocardial ischaemia; instead, the
adjunct of cyclical MPA does not have such a beneficial effect and may even
precipitate acute coronary syndromes.
The effect of natural progesterone and MPA upon myocardial ischaemia may
be related to the different effect of the two hormones upon coronary blood flow
and peripheral vascular resistances. Progesterone, probably by an endothelium-
independent mechanism, may facilitate the vasorelaxing effects of oestrogens,
while MPA may partly reverse these effects. The rapid presentation of these
changes lead us to suppose that these hormonal effects are not genome-mediated
and that, on the contrary, progestins use alternative pathways, such as rapid
changes of the intracellular calcium content and the activation of protein kinase
C, as it has been recently claimed in the literature (Minshall et al, 1998).

67
G.M.C.Rosano et al.

Epidemiological studies on oestrogen and progestin efficacy in primary

and secondary cardiovascular prevention

Oestrogen replacement therapy after the menopause can provide protection

against heart disease and possibly stroke. The most substantial benefits, a 50%
reduction in cardiovascular mortality and morbidity, are conferred on current
oestrogen users (Bush and Miller, 1986; Bush et al, 1987; Grodstein and
Stompfer, 1995). Because of the large cardioprotective effect of oestrogen
replacement therapy it is important for a progestin therapy not to reduce this
cardioprotection.
Few epidemiological studies have investigated the effect of addition of a
progestogen to oestrogen therapy upon cardiovascular mortality and morbidity.

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

Nachtigall et al. (1979) reported a 68% reduction in the risk of myocardial
infarction in women given oestrogen and cyclic progestin in comparison with
women receiving placebos. Falkeborn et al. (1992) found that women prescribed
an oestrogen-progestin combination had a 50% reduction in the risk of myocardial
infarction, when compared with women in the general population, while the risk
reduction in women receiving oestrogen alone was 26%. Similarly, Psaty et al.
(1994) reported a reduction in the risk of myocardial infarction in women
receiving oestrogen alone (relative risk 0.69) or oestrogen-progestin combination
(relative risk 0.68) as compared with non-users. Based on these results, it seems
conceivable to say that the risk of major coronary events is substantially reduced
by combined HRT and that progestins do not decrease the cardioprotective effect
of oestrogens.

Post-menopausal oestrogen/progestin interventions (PEPI) trial

The PEPI trial aimed to examine (control versus placebo) the differences between
CEE and three different oestrogen-progestin combinations using CEE plus MPA
or CEE plus natural progesterone on four risk factors for coronary artery
disease: (i) HDL-cholesterol; (ii) systolic blood pressure; (iii) 2 h serum insulin
concentrations; and (iv) fibrinogen concentrations (PEPI Trial, 1995). All the
HRT regimens used proved to be more efficient than placebos in increasing mean
HDL-cholesterol with a maximal efficacy of oestrogen alone (+5.6 mg/dl). The
remaining therapeutic schemes were progressively less efficacious, as follows:
CEE plus progesterone (+4.1 mg/dl), CEE plus cyclic MPA ( + 1.6 mg/dl), and
CEE plus continuous MPA (+1.2 mg/dl). On the other hand, all regimens showed
similar decreases in LDL-C concentration (average -15.9 mg/dl) and an increase
in mean triglyceride concentrations (average +12.7 mg/dl).
The PEPI study apparently did not show any effect of HRT upon blood pressure
in menopausal women. However, the study was conducted in normotensive women
in whom it would have been difficult to detect any blood pressure lowering effect.
Finally, no regimen modified the mean changes in 2 h insulin concentrations,
the primary outcome measure for carbohydrate metabolism, while fibrinogen
68
 The relative effects of progesterone and progestins in HRT

concentrations were significantly lower after all HRT, in comparison with

placebos, with no differences being found between the treated groups.

Nurses' Health Study

A recent 16 year follow-up report of 59 337 women included in the Nurses'

Health Study suggested that those currently taking oestrogen in combination with
progestins (more commonly MPA) had a significant reduction in their risk of
heart disease (Grodstein et al, 1996). During follow up, the authors documented
a total of 54 non-fatal myocardial infarctions, 186 cardiac deaths and 572
strokes (285 ischaemic, 155 haemorrhagic, 132 non-specified) and 553 coronary
revascularization surgical procedures. The authors found that women who took

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

oestrogen with progestin had a 61% reduction in the risk of a major coronary
event as compared with the risk among women who had never used HRT
(multivariate adjusted RR 0.39; 95% confidence interval 0.19 to 0.78) and a 40%
reduction as compared to those women who took oestrogen replacement therapy
(RR 0.60; 95% confidence interval 0.43-0.83). Despite this protective effect
upon cardiac events, oestrogen therapy alone or in combination with progestins
did not show any protective effect against stroke.

Heart and oestrogen/progestin replacement study

It must be pointed out that the above studies were conducted on healthy women
and that, consequently, the effect of the adjunct of a progestin to oestrogens in
patients at risk for cardiovascular disease may be different because of the effect
of progestins upon lipid profile and vascular functions. The results of the recently
published heart and oestrogen/progestin replacement study have added some
critical data on the effect of HRT for secondary prevention in women with
coronary artery disease (Hulley et al, 1998).
The heart and oestrogen/progestin replacement study did not show any
protective effect of CEE and MPA (2.5 mg in a continuous combined regimen)
on cardiovascular end points in elderly women with coronary artery disease and
suggested a possible increase in the occurrence of acute coronary events during
the first year of hormone therapy. However, the study is affected by several
important methodological and statistical problems which make its interpretation
difficult and its conclusions useless for clinical practice.
The first problem with the study is the relatively old age of the study population
(67.5 years). Women at this age are rarely considered for initiation of HRT. The
major concern with the study is that, although conducted in a relatively large
patient population, it does not have enough statistical power to detect significant
differences between patients allocated to HRT or placebo. Indeed the sample
size of the study was calculated on the basis of a yearly event rate of 5% in the
placebo group, while the observed event rate in this group was 3.3%. With such
69
G.M.C.Rosano et al.

an event rate the sample size should have been at least twice of the reported
study. Another important problem is the relatively short duration of the study.
The 'per protocol' estimated duration of the trial should have been 4.75 years,
while the study was interrupted without a clear explanation at 4.1 years, when
there was a significant trend towards a reduction in cardiac events in the hormone
treated group. If the study had continued to its planned duration it would have
probably shown a significant reduction in the occurrence of coronary events in
the hormone-treated patients.
Another important issue which makes the results of the study difficult to
interpret is the high use of statins administered for hypercholesterolaemia in the
placebo group (22%). The use of statins significantly reduces cardiovascular
mortality and morbidity in patients with coronary artery disease, as shown by

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

the Scandinavian simvastatin survival study, in which female cardiovascular
mortality was seen to decrease by >35% (Miettinen, 1997). Therefore patients
allocated to the placebo group were treated with drugs able to influence the
results of the study. Finally, heart and oestrogen/progestin replacement study did
not evaluate unopposed oestrogen replacement therapy, other combined
oestrogen-progestin association or women without coronary artery disease.
Based on the above considerations, the heart and oestrogen/progestin replace-
ment study should not be regarded as a negative, but rather as an inconclusive
investigation and its findings should not be extrapolated to other hormone
regimens or to healthier, younger individuals. No women should be interrupting
their oestrogen replacement therapy or HRT regimens because of the heart and
oestrogen/progestin replacement study.

Conclusions

The data available at present on the cardiovascular effect of progestins suggests

that the adjunct of these hormones to oestrogen replacement therapy may have *
different effects upon the cardiovascular system and that these effects depend on
type, dosage and route of administration of progestins. Some progestin therapies
may antagonize the favourable cardiovascular effect of oestrogens. Furthermore,
the therapeutic scheme of administration (continuous or sequential) may influence
the cardiovascular effects of the hormones and it is therefore possible that similar
hormones have different effects according to their schemes of administration.
While in menopausal women without risk factors for coronary events any
progestin can be safely administered, in menopausal patients at risk for coronary
artery disease, natural progesterone seems to be the progestational agent of
choice as it avoids the unwanted detrimental effect of synthetic progestins.
Further randomized studies are warranted to evaluate the effect of oestrogen
replacement therapy and HRT upon cardiovascular events in menopausal women.
Until completion of these studies HRT should be seen by cardiologists with no
early enthusiasm but also with no fear.
70
 The relative effects of progesterone and progestins in HRT

References
Adams, M.R., Kaplan, J.R. and Manuck, S.B. (1990) Inhibition of coronary artery atherosclerosis
by 17-beta estradiol in ovariectomized monkeys: lack of an effect of added progesterone.
Atherosclerosis, 10, 1051-1057.
Adams, M.R., Register,T.C, Wagner, J.D. et al. (1997) Effects of estrogens and progestins on the
pathogenesis of atherosclerosis in nonhuman primates. In Forte, T.M. (ed.), Hormonal, Metabolic
and Cellular Influences on Cardiovascular Disease in Women. Futura Publishing Company Inc,
New York, USA, pp. 39-53.
Andersen, L.F., Gram, J., Skouby, S.O. and Jespersen, J. (1999) Effects of hormone replacement
therapy on hemostatic cardiovascular risk factors. Am. J. Obstet. GynecoL, 180, 283-289.
Anderson, F.A. Jr., Wheeler, H.B., Goldberg, R.J. et al. (1991) A population-based perspective of
the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism.
The Worcester DVT Study. Arch. Intern. Med., 151, 933-938.

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

Bonilla-Musoles, E, Marti, M.C., Ballester, M.J. et al. (1995) Normal uterine arterial blood flow
in postmenopausal women assessed by transvaginal color Doppler sonography: the effect of
hormone replacement therapy. J. Ultrasound Med., 14, 497-501.
Boschetti, C , Cortellaro, M., Nencioni, T. et al. (1991) Short- and long-term effects of hormone
replacement therapy (transdermal estradiol vs oral conjugated equine estrogens, combined with
•medroxyprogesterone acetate) on blood coagulation factors in postmenopausal women. Thromb.
Res., 62, 1-8.
Bush, T.L. and Miller, V.T. (1986) Effects of pharmacologic agents used during menopause: impact
on lipids and lipoproteins. In Mishell, D. Jr (eds), Menopause: Physiology and Pharmacology.
Year Book Medical, Chicago, USA. pp. 187-208.
Bush, T.L., Barret-Connor, E. and Cowan, L.D. (1987) Cardiovascular mortality and
noncontraceptive use of estrogen in women: results from Lipid Research Clinics Program Follow
up Study. Circulation, 75, 1102-1109.
Clarkson, T.B. (1994) Progesterone and cardiovascular disease. J. Reprod. Med., 44, 180-184.
De Ziegler, D., Bessis, R. and Frydman, R. (1991) Vascular resistance of uterine arteries:
physiological effects of estradiol and progesterone. Fertil. Steril., 55, 775-779.
De Ziegler, D., Zartarian, M., Micheletti, M.C. et al. (1994) The cyclic administration of
nomegestrol acetate does not alter the vasodilating effects of estradiol on the uterine artery.
Contracept. Fertil. Sex., 22, 767-770.
Devor, M., Barrett-Connor, E., Renvall, M. et al. (1992) Estrogen replacement therapy and the
risk of venous thrombosis. Am. J. Med., 92, 275-282.
Falkeborn, M., Persson, I., Adami, H.O. et al. (1992) The risk of acute myocardial infarction after
estrogen and estrogen-progestogen replacement. Br. J. Obstet. GynecoL, 99, 821-828.
Geary, R.L., Adams, M.R., Benjamin, M.E. et al. (1998) Conjugated equine estrogens inhibit
progression of atherosclerosis but have no effect on intimal hyperplasia or arterial remodeling
induced balloon catheter injury in monkeys. J. Am. Coll. Cardioi, 31, 1158-1164.
Gebara, O.C.E., Mittlemann, M.A., Sutherland, P. et al. (1995) Association between increased
estrogen status and increased fibrinolytic potential in the Framingham Offspring Study.
Circulation, 91, 1952-1958.
Giraud, G.D., Morton, M.J., Wilson, R.A. et al. (1996) Effect of estrogen and progestin on aortic
size and compliance in postmenopausal women. Am. J. Obstet. GynecoL, 174, 1708-1718.
Godsland, I.F., Wynn, V, Crook, D. et al. (1987) Sex, plasma lipoproteins and atherosclerosis:
Prevailing assumptions and outstanding questions. Am. Heart J., 114, 1467-1503.
Gordon, T., Kannel, W.B., Hjortland, M.C. et al. (1978) Menopause and coronary heart disease:
the Framingham Study. Ann. Intern. Med., 89, 157-161.
Grady, D., Rubin, S.M., Petitti, D.B. et al. (1992) Hormone therapy to prevent disease and prolong
life in postmenopausal women. Ann. Intern. Med., 117, 1016-1037.
Grodstein, F. and Stampfer, M.J. (1995) The epidemiology of coronary heart disease and estrogen
replacement therapy in postmenopausal women. Prog. Cardiovasc. Dis., 38, 199-210.
Grodstein, E, Stampfer, M.J., Manson, J.E. et al. (1996) Postmenopausal estrogen and progestin
use and the risk of cardiovascular disease. N. Engl. J. Med., 335, 453^-61.
71
G.M.C.Rosano et al.

Grodstein, F., Samfer, M.J., Colditz, G.A. et al. (1997) Postmenopausal hormone replacement
therapy and mortality. N. Engl. J. Med., 336, 1769-1775.
Habiba, M , Andrea, A., Phipps, B. and Al-Azzawi, F. (1996) Thrombophilia and lipid profile in
post-menopausal women using a new transdermal oestradiol patch. Eur. J. Obstet. Gynecol.
Reprod. Biol, 66, 165-168.
Hillard, T.C., Bourne, T.H., Whitehead, M.I. et al. (1992) Differential effects of transdermal
estradiol and sequential progestogens on impedance to flow within the uterine arteries of
postmenopausal women. Fertil. Steril, 58, 959-963.
Horowitz, K.B. and Horowitz, L.D. (1982) Canine vascular tissues are targets for androgens,
estrogens, progestins and glucocorticoids. J. Clin. Invest., 69,750-758.
Hulley, S., Grady, D., Bush, T. et al. (1998) Randomized trial of estrogen plus progestin for
secondary prevention of coronary heart disease in postmenopausal women. /. Am. Med. Assoc,
280, 605-613.
Hunt, K., Vessey, M., Me Pherson, K. et al. (1987) Long-term surveillance mortality and cancer
incidence in women receiving hormone replacement therapy. Br. J. Obstet. Gynaecol, 94,

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

620-635.
Ingegno, M.D., Money, S.R., Thelmo, W. et al. (1988) Progesterone receptors in human heart and
great vessels. Lab. Invest., 59, 353-356.
Jiang, C, Sarrel, P.M. and Lindsay, D.C. (1992) Progesterone induces endothelium-indipendent
relaxation of rabbit coronary artery in vitro. Eur. J. Pharmacol, 211, 163-167.
Koh, K.K., Mincemoyer, R., Bui, M.N. et al. (1997) Effects of hormone-replacement therapy on
fibrinolysis in postmenopausal women. N. Engl. J. Med., 336, 683-690.
Kroon, U.B., Silfverstolpe, G. and Tengborn, L. (1994) The effects of transdermal estradiol and
oral conjugated estrogens on haemostasis variables. Thromb. Haemost., 71, 420^423.
Lin, A.L., McGill, H.C. and Shain, S.A. (1982) Hormone receptors of the baboon cardiovascular
system. Circ. Res., 50, 610-616.
Lin, A.L., Gonzales, R. Jr., Carey, K.D. and Shain, S.A. (1986) Estradiol-17(3 affects estrogen
receptor distribution and elevates progesterone receptor content in the baboon aorta.
Arteriosclerosis, 6, 495-504.
Lindoff, C , Peterson, F., Lecander, I. et al. (1996) Transdermal estrogen replacement therapy:
beneficial effects on hemostatic risk factors for cardiovascular disease. Maturitas, 24, 43-50.
Marsh, M.S., Bourne, T.H., Whitehead, M.I. et al. (1994) The temporal effect of progestogen on
uterine artery pulsatility index in postmenopausal women receiving sequential hormone
replacement therapy. Fertil. Steril, 62, 771-77'4.
Miettinen, T.A., Pyorala, K., Olsson, A.G et al. (1997) Cholesterol-lowering therapy in women
and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian
Simvastatin Survrval Study (4S). Circulation, 96, 4211-4218.
Miller, V.M. and Vanhoutte, P.M. (1991) Progesterone and modulation of endothelium-dependent"
responses in canine coronary arteries. Am. J. Physiol, 261, R1022-R1027.
Minshall, R.D., Stanczyk, F.Z., Miyagawa, K. et al. (1998) Ovarian steroid protection against
coronary artery hyperreactivity in rhesus monkeys. J. Clin. Endocrinol Metab., 83, 649-659.
Nachtigall, L.E., Nachtigall, R.H., Nachtigal, R.D. et al. (1979) Estrogen replacement therapy II:
a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems.
Obstet. Gynecol, 54, 74-79.
Niki, E. and Nakano, M. (1990) Estrogens as antioxidants. Methods Enzymol, 186, 330-333.
Paganini-Hill, A., Ross, R. and Henderson, B.E. (1989) Postmenopausal oestrogen treatment and
stroke: a prospective study. Br. Med. J., 297, 519-522.
Penotti, M., Nencioni, T., Gabrielli, L. et al. (1993) Blood flow variations in internal carotid and
middle cerebral arteries induced by postmenopausal hormone replacement therapy. Am. J. Obstet.
Gynecol, 169, 1226-1232.
PEPI Trial, Writing Group (1995) Effects of estrogen or estrogen/progestin regimens on heart
disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin
Interventions (PEPI) trial. J. Am. Med. Assoc, 273, 199-208.
Pick, R., Stamler, J. and Rodbard, S. (1952) The inhibition of coronary atherosclerosis by estrogen
in cholesterol-fed chicks. Circulation, 6, 276-280.
72
 The relative effects of progesterone and progestins in HRT

Psaty, B.M., Heckberr, S.R., Atkins, D. et al. (1994) The risk of myocardial infarction associated
with the combined use of estrogens and progestins in postmenopausal women. Arch. Int. Med.,
154, 1333-1339.
Rijpkema, A.H.M., Van Den Sanden, A.A. and Ruijs, A.H.C. (1990) Effects of postmenopausal
oestrogen-progestogen replacement therapy on serum lipids and lipoproteins: a review. Maturitas,
12, 259-285.
Rosano, G.M.C., Sarrel, P.M., Poole-Wilson, PA. et al. (1993) Beneficial effect of oestrogen on
exercise-induced myocardial ischemia in women with coronary artery disease. Lancet, 342,
1133-1136.
Rosano, G.M.C., Peters, N.S., Lefroy, D. et al. (1996) 17-(3 estradiol therapy lessens angina in
postmenopausal women with syndrome X. J. Am. Coll. Cardiol, 28, 1500-1505.
Rosano, G.M.C., Chierchia, S.L., Morgagni, G.L. et al. (1997) Effect of the association of different
progestogens to estradiol 17(3 therapy upon effort-induced myocardial ischemia in female patients
with coronary artery disease. J. Am. Coll. Cardiol., 2 (Suppl. A), 344A.
Rosano, G.M.C., Leonardo, F., Cerquetani, E. et al. (1998) Comparative effects of continuos

Downloaded from http://humrep.oxfordjournals.org/ by guest on February 11, 2014

combined hormone replacement therapy regimens on brachial artery blood flow. [Abstr.] J. Am.
Coll. Cardiol, 2 (Suppl. A), 459A.
Samsioe, G. (1990) Effects of estrogen in various lipid constituents. Consultant, 30, 58-62.
Scarabin, P.Y., Plu-Bureau, G., Bara, L. et al. (1993) Haemostatic variables and menopausal status:
influence of hormone replacement therapy. Thromb. Haemost., 70, 584-587.
Scarabin, P.Y., Alhenc-Gelas, M , Plu-Bureau, G. et al. (1997) Effects of oral and transdermal
estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women.
A randomized controlled trial. Arterioscler. Thromb. Vase. BioL, 17, 3071-3078.
Soma, M., Fumagalli, R., Paoletti, R. et al. (1991) Plasma Lp(a) concentration after estrogen and
progestogen in postmenopausal women. Lancet, 337, 612-615.
Sporrong, T., Mattsson, L.A. Samsioe, G. et al. (1990) Hemostatic changes during continuous
estradiol-progestogen treatment of postmenopausal women. Br. J. Obstet. Gynecol., 91, 939-944.
Sfivastava, R.A.K., Baumann, D. and Schonfeld, G. (1993) In vivo regulation of LDL receptors
by estrogen differs at the post-transcriptional level in rat and mouse. Eur. J. Biochem., 216,527-538
Stamler, J., Pick, R. and Katz, L.N. (1953) Prevention of coronary atherosclerosis by estrogen-
androgen administration in the choleterol-fed chick. Circ. Res., 1, 94-98.
Stampfer, M.J. and Colditz, G.A. (1991) Estrogen replacement therapy and coronary heart disease:
a quantitative assessment of the epidemiologic evidence. Preventive Med., 20, 47-63.
Tikkanen, M., Nikkala, E.A., Kuusi, T. et al. (1982) High density lipoprotein-2 and hepatic lipase:
reciprocal changes produced by estrogen and norgestrel. J. Clin. Endocrinol. Metab., 54,
1113-1117.
Tikkanen, M.J. (1986) Postmenopausal hormone replacement therapy:effects of progestogens on
serum lipids and lipoproteins. A review. Maturitas, 8, 7-17.
Walsh, B.W., Schiff, I., Rosner, B. et al. (1991) Effects of postmenopausal estrogen replacement
on the concentrations and metabolism of plasma lipoproteins. N. Engl. J. Med., 325, 1196-1204.
Williams, J.K., Adams, M.R. and Klopfestein, H.S. (1990) Estrogen modulates responses of
atherosclerotic coronary arteries. Circulation, 81, 1680-1687.
Williams, J.K., Honore, E.K., Washburn, S.A. and Clarkson, T.B. (1994) Effects of hormone
replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys.
/. Am. Coll. Cardiol., 24, 1757-1761.
Wuest, J.H., Dry, T.J. and Edwards, J.E. (1953) The degree of coronary atherosclerosis in bilateral
oophorectomized women. Circulation, 1, 801-808.
Yim, S.F., Lau, T.K, Sahota, D.S. et al. (1998) Prospective randomized study of the effect of add-
bank hormone replacement therapy on vascular function during treatment with gonadotropin-
releasing hormone agonists. Circulation, 98, 1631-1635.

73