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Effects of hormone replacement modalities on low
density lipoprotein composition and distribution in
ovariectomized cynomolgus monkeys.
Manning JM; Campos G; Edwards IJ; Wagner WD; Wagner JD; Adams
MR; Parks JS
Department of Comparative Medicine, Bowman Gray School of
Medicine of Wake Forest University, Winston-Salem, NC 27157,
USA.
Atherosclerosis (Ireland) Apr 5 1996, 121 (2)
p217-29
This study was designed to determine the effect of several
hormone replacement therapies on LDL size, density,
heterogeneity, and composition in surgically postmenopausal
cynomolgus monkeys fed an atherogenic diet. Groups (n = 5
each) of ovariectomized cynomolgus monkeys were untreated
(control), or treated with conjugated equine estrogens,
medroxyprogesterone acetate (progesterone), combined
estrogen-progesterone, or tamoxifen for 9 weeks. There were no
differences among treatment groups in total plasma, LDL, or
HDL cholesterol or triglyceride concentrations. Plasma LDL
were isolated by ultracentrifugation and size exclusion
chromatography and subfractionated by density gradient
centrifugation for subsequent chemical analysis. Estrogen
treatment was associated with significantly smaller (measured
as LDL molecular weight, 3.9 +/- 0.2 g/mu mol) and denser
plasma LDL (1.034 g/ml peak density) compared with control
(4.5 +/- 0.1 g/mu mol; 1.030 g/ml peak density) or
progesterone-treated animals (4.6 +/- 0.2; 1.029 g/ml peak
density). LDL from the estrogen group were relatively enriched
in protein and triglyceride and poor in cholesteryl ester and
apolipoprotein F (apoE) compared to the control group.
Triglyceride enrichment with estrogen treatment occurred
predominantly in the lighter, larger LDL subfractions (d =
1.015-1.025 g/ml), which were reduced in concentration (26 +/-
10 mg cholesterol/dl) compared to control (61 +/- 19mg/dl) or
progesterone treated animals (67 +/- 16 mg/dl). Combined
estrogen-progesterone or tamoxifen treatment resulted in
changes in LDL that followed the same trend as those observed
with estrogen treatment. We conclude that short-term estrogen
treatment of ovariectomized cynomolgus monkeys results in
changes in plasma LDL size, density, and composition while
having no apparent effect on overall plasma lipid
concentrations.
Cause-specific mortality in women receiving hormone
replacement therapy.
Schairer C; Adami HO; Hoover R; Persson I
Environmental Epidemiology Branch, National Cancer Institute,
Rockville, MD 20892-7374, USA.
Epidemiology (United States) Jan 1997, 8 (1)
p59-65
To assess the risks and benefits of menopausal hormone
replacement therapy, we followed a 23,346-member,
population-based cohort of Swedish women who were prescribed
menopausal estrogens for an average of 8.6 years for
mortality. Compared with the general population, the
standardized mortality ratio for all-cause mortality in this
cohort was 0.77 (95%confidence limits = 0.73, 0.81). Deaths in
each of the 12 major categories of causes of death except for
injuries occurred 12% to 86% less frequently than expected. We
examined in detail four specific causes of death according to
the type of hormone prescribed, namely weak estrogens
(primarily estriol), more potent estrogens (primarily
estradiol and conjugated estrogens) in combination with a
progestin, and more potent estrogens without a progestin.
Mortality from endometrial cancer was not related to the
prescription of weak estrogens or an estrogen-progestin
combination, but mortality was 40% higher in women prescribed
more potent estrogens without a progestin. Women prescribed
weak estrogens, more potent estrogens, and the combined
estrogen-progestin regimen were at reduced risk of death from
ischemic heart disease (standardized mortality ratios of 0.7,
0.6, and 0.4, respectively). The more potent estrogens and the
estrogen-progestin combination were associated with a marked
reduction in risk of intracerebral hemorrhage (standardize
mortality ratios of 0.4 and 0.6, respectively) and "other"
cerebrovascular disease, but not other types of stroke. The
concern that use of progestins would lead to psychic disorders
related to suicide received no support from our results.
Breast cancer results are described elsewhere. These data
provide little evidence of an adverse effect of the combined
estrogen-progestin regimen as compared with estrogens alone on
mortality. They do indicate, however, that both selection
factors and biology may contribute to the almost
across-the-board-reduction in mortality associated with
hormone replacement therapy.
Hormone replacement therapy increases trabecular
and cortical bone density in osteoporotic women.
Bagur A; Wittich A; Ghiringhelli G; Vega E; Mautalen C
Departamento de Medicina, Hospital de Clinicas Jose de San
Martin, Facultad de Medicina, Universidad de Buenos Aires,
Argentina.
Medicina (B Aires) (Argentina) 1996, 56 (3)
p247-51
Twenty five postmenopausal Caucasian women with established
osteoporosis or severe osteopenia were treated with continuous
combined estrogen/progesterone (2 mg 17 beta estradiol and 5
mg medroxiprogesterone) and 1000 mg of calcium daily. The mean
age of the patients was 57 +/- 6 years (range 44 to 69 years),
and the average postmenopausal interval was of 10.7 +/- 4.2
years. The bone mineral density (BMD) of the lumbar spine and
proximal femur was determined using DXA densitometer at
baseline, 12 and 24 months of treatment. Serum and urine
measurements were done at baseline and 12 months. After 24
months of treatment bone mineral density increased at the
trochanter 10.2% p < 0.001, lumbar spine 9.6% p < 0.001,
Ward's triangle 8.6% p < 0.005 and femoral neck 5.7% p <
0.001 in comparison to basal levels. In the first year of
treatment serum alkaline phosphatase and urinary
hydroxiproline diminished significantly in comparison to basal
levels (p < 0.001, for both). In conclusion, this study
indicates that continuous combined estrogen progesterone
therapy decreases bone turnover and increases BMD of the
spine, femoral neck and trochanter in established
osteoporosis.
DHEA: a hormone with multiple effects.
Khorram O
Department of Obstetrics and Gynecology, University of
Wisconsin Medical School, Madison 53792, USA.
Curr Opin Obstet Gynecol (United States) Oct 1996, 8 (5)
p351-4
Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS)
represent the major androgens secreted by the adrenal gland.
Various functions including metabolic, immune, and cognitive
effects have been attributed to this steroid and are reviewed
here. Since the levels of DHEA correlate with general good
health, and aging is associated with a decline in the
secretion of this steroid, a growing interest in replacement
of DHEA in elderly people has developed. The findings from
recent studies of replacement of DHEA in elderly people are
discussed.
Mammographic changes in women on hormonal
replacement therapy.
Erel CT; Seyisoglu H; Senturk ML; Akman C; Ersavasti G;
Benian A; Uras C; Altug A; Ertungealp E
Department of Obstetrics and Gynecology, Cerrahpasa School of
Medicine, Istanbul University, Turkey.
Maturitas (Ireland) Aug 1996, 25 (1) p51-7
OBJECTIVES: In the present retrospective study, we aimed to
determine the frequency and the types of mammographic changes
of breast parenchyma in women receiving hormone replacement
therapy (HRT). We also investigated whether there was an
association between mammographic changes and some clinical and
hormonal characteristics of the women on HRT.
METHODS: One-hundred and eight women were included into the
study. Of the 108 women, 19 were climacteric, four premature
menopause, 50 spontaneous menopause and 35 surgical menopause.
Prior to the start of HRT, an initial mammography was
performed and it was repeated at 6- to 18-month intervals
according to the women's status. Estrogen alone was started
for 35 surgical menopause women and a combination of estrogen
plus progesterone for the remaining 73 women.
RESULTS: Group I consisted of 96 women with no parenchymal
changes or a decrease in parenchymal density on mammography,
whereas group II consisted of 12 women with an increase in
parenchymal density (11%) during the mean period of 24 months.
Endogenous E2 levels were significantly higher in group II
than in group I (52.4 +/- 42.3 pg/ml vs. 32.3 +/- 29.3 pg/ml,
P < 0.05). Climacterium or types of menopause did not
affect the mammographical density changes. Neither the type
nor the duration of HRT had an effect on mammographic density
increase.
CONCLUSIONS: We concluded that the endogenous E2 level
might be an important role in screening the women
mammographically. Long-term follow-up studies were concluded
to be needed in order to evaluate the effects of HRT on
mammographic changes.
Androgen replacement therapy in women: myths and
realities.
Casson PR; Carson SA
Department of Obstetrics and Gynecology, Baylor College of
Medicine, Houston, Texas, USA.
Int J Fertil Menopausal Stud (United States) Jul-Aug 1996, 41
(4) p412-22
In recent years, much attention has been directed at the
potential of androgen replacement in the menopausal woman.
Testosterone (T) replacement, in various forms, is widely
used. However, evidence is lacking for a profound T deficiency
state with natural menopause. Data confirming efficacy are
also scant, and side effects have been demonstrated with
prolonged therapy. The adrenal androgens,
dehydroepiandrosterone (DHEA) and dehydroepiandrosterone
sulfate (DHEA-S), also in contradistinction to T, decline
substantially with age. Preliminary studies involving
replacement of physiologic levels of DHEA have demonstrated
some potential benefits: enhancement of the immune system and
enhancement of the growth hormone axis. However, long-term
trials have not been performed to date, so this modality of
androgen replacement remains in the realm of clinical
investigation. Ovarian and adrenal androgen replacement in
menopausal women, while theoretically appealing, remains
imperfect to date and should be used judiciously, if at
all.
Sequential addition of low dose of medrogestone or
medroxyprogesterone acetate to transdermal estradiol: a pilot
study on their influence on the endometrium.
Pansini F; De Paoli D; Albertazzi P; Bonaccorsi G; Campobasso
C; Zanotti L; Pisati R; Giulini NA
Menopause and Osteoporosis Center, University of Ferrara,
Italy.
pan@dns.unife.it
Eur J Obstet Gynecol Reprod Biol (Ireland) Sep 1996, 68 (1-2)
p137-41
We evaluated bleeding pattern and endometrium following the
administration of two of the most common types of progestogens
used in hormone replacement therapy, medroxyprogesterone
acetate (MPA) and medrogestone acetate. Twenty eight patients
in spontaneous menopause were randomly allocated to two
groups. Group 1 (n = 14) received 5 mg/day of of MPA and group
2 (n = 14) received 5 mg/day of medrogestone: both the
progestogens were sequentially added for the last 12 days of a
21-day period of transdermal estradiol administration (50
micrograms per day). A 7-day treatment-free period completed
the cycle. The study treatments were administered for 6
cycles. The endomtria were checked for their thickness by
transvaginal ultrasound before starting treatment and at 6th
treatment cycle (days 6-10 of the estrogen-only phase and
during the period between days 8 and 12 of the progestogen
addition). Endometrial biopsies were performed before starting
treatment only in the patients with a positive progesterone
challenge test and in all the patients at the end of the study
during the addition of the progestogen. The bleeding pattern
was closely monitored. MPA is accompanied by a thick
endometrium with full secretory transformation in all cases.
On the contrary, the same dose of medrogestone induced a
consistent decrease of estrogen primed endometrium with only 4
cases of full secretory transformation. Four
medrogestone-treated patients dropped out due to unscheduled
bleeding. A low dose of medrogestone added to transdermal
estradiol induced incomplete transformation of endometrium and
oligo-amenorrhea more frequently than MPA, but it increased
the chances of irregular bleeding. MPA fully transformed the
endometrium: periods were thus heavier but regular. None of
the patients in either group had endometrial hyperplasia.
Hormone replacement therapy: clinical benefits and
side-effects.
de Lignieres B
Service d'Endocrinologie et Medecine de la Reproduction,
Hospital Necker, Paris, France.
Maturitas (Ireland) May 1996, 23 Suppl pS31-6
Beside well-established clinical benefits, the current
doses of oestrogens may induce clinical side-effects leading
to non-compliance and loss of efficacy. During a normal
menstrual cycle the incidence of any cyclic discomfort is
consistently reported to be lowest during the mild-follicular
phase when plasma E2 remains between 60 and 150 pg/ml. The
incidence of pregnancy-like symptoms such as bloating, breast
tenderness and mood swings tends to increase in mid-luteal
phase when E2 increases upto 150 pg/ml. On the other hand
incidence of asthenia, sleep disturbances, depressive mood,
headaches and migraines increase during perimenstrual days
when E2 drops to 40 pg/ml or below. Accordingly experimental
and human studies in castrated animals and postmenopausal
women suggest that plasma E2 around 100 pg/ml is optimal for
treatment of hot flushes, prevention of bone loss and
cardiovascular protection. Due to large interindividual
variation in estrogen clearance rate, it is unlikely that any
standardized unique dose of oral or non-oral formulations will
reproduce the optimal levels in all postmenopausal users.
Efforts for individual titration are mandatory to improve
compliance and actual efficacy on a long term. Because older
postmenopausal women tend to have a better clinical tolerance
to low E2 levels, objective markers of efficacy should also be
identified when the aim of HRT is the prevention of
osteoporosis or vascular diseases. In addition clinical and
metabolic side-effects related to added progestins can be
substantially reduced by the use of lower dose inducing
amenorrhea and by progesterone instead of synthetic
steroids.
Progestins.
Hirvonen E
Department of Obstetrics and Gynecology, Helsinki University
Central Hospital, Finland.
Maturitas (Ireland) May 1996, 23 Suppl pS13-8
The history of progesterone and hormone replacement therapy
goes back to 1934 when Butenandt obtained crystalline
progesterone and Kaufmann started to treat ovariectomized
women with both estrogens and progesterone (Table 1). Today
synthetic perorally active 19-nortestosterone and
17-alpha-hydroxyprogesterone derivatives are used in addition
to contraception and hormone replacement therapy in a variety
of gynecological disorders. In hormone replacement therapy
progestin is added only to prevent development of hyperplasia
of the endometrium and its consequences. However, because
progestins may cause both subjective and metabolic adverse
effects minimum effective antiproliferative doses are
recommended. The duration of the progestin phase cannot be
shortened to less than 10 days whereas the frequency of
administration apparently can be reduced without increased
risk of hyperplasia. Development of new modes of
administration may further help in reduction of the doses.
Evidence for primary and secondary prevention of
coronary artery disease in women taking oestrogen replacement
therapy.
Bush TL
JHU Womens Research Core, Lutherville, MD, USA.
Eur Heart J (England) Aug 1996, 17 Suppl D p9-14
The increasing use of oestrogen replacement therapy in
women has focussed attention on the cardioprotective
properties it has demonstrated. Historically, it has been
shown that women enjoy a certain protection from heart
disease, a phenomenon, however, which has not been studied
extensively. Women at every age have less coronary artery
disease (CAD) than men, even when various risk factors are
accounted for, although the presence of diabetes carries equal
mortality for both sexes. However, women who do develop CAD
have a greater risk of mortality than men with CAD. Other
gender differences include a later age of onset of CAD for
women, and a difference in the type of atherosclerotic lesions
developed. Most striking is the fact that, in women,
high-density lipoprotein (HDL) seems to be a more potent
predictor of major cardiovascular events than low-density
lipoprotein (LDL), or total cholesterol. The Postmenopausal
Oestrogen and Progesterone Interventions (PEPI) Trial looked
at changes in HDL, fibrinogen, blood pressure and serum
insulin resulting from oestrogen use. Four regimens were
compared against placebo in 875 women. The results showed that
HDL was increased significantly, LDL decreased significantly,
fibrinogen levels decreased significantly, and blood pressure
and serum insulin levels were essentially unaffected by
oestrogen and oestrogen/progestin interactions. The Heart and
Oestrogen/Progestin Replacement (HERS) Study, currently
underway, is a secondary prevention trial testing the
protective effect of hormone therapy in women with documented
CAD. This trial may definitively answer the question of
whether hormones protect against CAD. After HERS, it may be
unethical to continue conducting placebo-controlled trials in
a therapy that has such documented cardioprotective
benefit.
Practical aspects of preventing and managing
athersclerotic disease in post-menopausal women.
Sullivan JM
Department of Medicine, University of Tennessee, Memphis
38163, USA.
Eur Heart J (England) Aug 1996, 17 Suppl D p32-7
Factors that exacerbate the risk of atherosclerotic plaque
formation include cigarette smoking, hypertension,
hypercholesterolaemia, sedentary lifestyle, and oestrogen
deficiency. The potentially important role of oestrogen
deficiency in this process is evidenced by the significant
increase in cardiovascular risk observed in women after
menopause, and in the marked reduction in cardiovascular
events observed in women who take hormone replacement therapy.
Oestrogen replacement therapy, through an effect on the blood
vessel wall and on serum lipids, also appears to stabilize
existing atherosclerotic plaques. The combination of oestrogen
and progesterone reduces risk of endometrial cancer while
possibly delivering the same benefits as oestrogen alone.
Other measures, such as antithrombotic therapy, exercise, and
smoking cessation, also contribute to reduced risk of
cardiovascular disease in older women.
Hormone replacement therapy is associated with
improved arterial physiology in healthy post-menopausal
women.
McCrohon JA; Adams MR; McCredie RJ; Robinson J; Pike A; Abbey
M; Keech AC; Celermajer DS
Department of Cardiology, Royal Prince Alfred Hospital,
Camperdown, Sydney, Australia.
Clin Endocrinol (Oxf) (England) Oct 1996, 45 (4)
p435-41
OBJECTIVE: Oestrogen replacement therapy is associated with
a marked reduction in coronary event rates in post-menopausal
women. As older age is associated with progressive arterial
endothelial damage, a key event in atherosclerosis, we
assessed whether hormone replacement therapy (HRT) with
oestrogen alone, or oestrogen and progesterone combined, is
associated with improved endothelial function in healthy women
after the menopause.
DESIGN: Using high resolution external vascular ultrasound,
brachial artery diameter was measured at rest and in response
to reactive hyperaemia, with increased flow causing
endothelium-dependent dilatation (flow-mediated
dilatation).
PATIENTS: We investigated 135 healthy women; 40 were
pre-menopausal (mean +/- SD age/26 +/- 6 years, group 1), 40
were post- menopausal and had never taken HRT (aged 58 +/- 3
years; group 2) and 55 were age-matched post-menopausal women
who had taken HRT for > or = 2 years, from within 2 years
of the menopause (aged 57 +/- 4 years; group 3). In group 3,
40 women were on combined oestrogen and progesterone and 15 on
oestrogen-only HRT.
RESULTS: In group 2, flow-mediated dilatation was
significantly reduced compared with group 1 (4.4 +/- 3.4 vs
9.6 +/- 3.6%, P< 0.001), consistent with a decline in
arterial endothelial function after the menopause. In group 3,
however, flow-mediated dilatation was significantly better
than group 2 (6.2 +/- 3.3 vs 4.4 +/- 3.4%, P = 0.01),
suggesting a protective effect of HRT. Flow-mediated
dilatation was similar in women taking oestrogen alone and in
those on combined HRT (5.5 +/- 2.8 vs 6.5 +/- 3.4%, P =
0.40).
CONCLUSIONS: Long-term HRT is associated with improved
arterial endothelial function in healthy post-menopausal
women. This benefit was observed in both the combined hormone
replacement and unopposed oestrogen therapy groups. This may
explain some of the apparent cardioprotective effect of HRT
after the menopause.
An examination of the effect of combined cyclical
hormone replacement therapy on lipoprotein(a) and other
lipoproteins.
Haines CJ; Chung TK; Masarei JR; Tomlinson B; Lau JT
Department of Obstetrics and Gynaecology, Chinese University
of Hong Kong, New Territories.
Atherosclerosis (Ireland) Jan 26 1996, 119 (2)
p215-22
Lipoprotein(a) (Lp(a)) is an independent marker of
cardiovascular disease which is relatively unresponsive to
treatment with most of the commonly prescribed lipid lowering
drugs. Concentrations of Lp(a) increase after the menopause,
and the primary aim of this study was to determine whether
combined hormone replacement therapy was effective in lowering
levels of Lp(a) in postmenopausal women. An open longitudinal
study was conducted among 42 women who had undergone a
spontaneous menopause and were attending the outpatient clinic
of the Prince of Wales Hospital, Hong Kong. All subjects were
treated with 2 mg oral estradiol daily and 5 mg
medroxyprogesterone acetate for 12 days each calendar month.
Fasting blood samples for lipoprotein measurement were taken
before the commencement of treatment and at 6 and 12 months.
Lp(a) levels showed a skewed distribution with a median value
before treatment of 9.45 mg/dl (range 1.47-95.62 mg/dl). After
6 months, there was a reduction to 7.70 mg/dl (1.12-72.59
mg/dl) (P < 0.01), and after 12 months the median
concentration was 7.14 mg/dl (0.63-69.23 mg/dl) (P < 0.001
0-12 months). There were also significant reductions in the
concentrations of apo B from 116.13 to 111.62 mg/dl and LDL-C
from 3.02 to 2.74 mmol/l (P < 0.05), plus a lowering of TC
of borderline significance. Apo A-I increased from 162.56 to
173.35 mg/dl (P < 0.01), but there were no significant
changes in HDL-C or the HDL-C subfractions. TC, LDL-C, apo B
and TG concentrations were higher and HDL-C and HDL2-C
concentrations were lower when blood was sampled during
combined treatment with estrogen and progesterone than when
estrogen was being taken alone. Levels of Lp(a) were also
lower during the estrogen only phase of treatment, but none of
these differences were statistically significant. This study
demonstrates that combined cyclical hormone replacement
therapy is effective in reducing concentrations of Lp(a). The
trend towards a more atherogenic lipid profile during the
combined phase of treatment suggests that attention should be
given to the timing of blood sampling in future studies of
this nature.
Effects of estrogens and progestogens on the
renin-aldosterone system and blood pressure.
Oelkers WK
Department of Medicine, Klinikum Benjamin Franklin
(Steglitz), Freie Universitat Berlin, Germany.
Steroids (United States) Apr 1996, 61 (4)
p166-71
Endogenous 17 beta-estradiol (E2) and low parenteral doses
of exogenous E2 are vasodilators. High dose estrogens,
especially ethinylestradiol (EE) and mestranol, stimulate the
synthesis of hepatic proteins including coagulation factors,
sex hormone binding globulin, and angiotensinogen (Aogen). In
the steady state, high plasma levels of Aogen produce only a
very small increase of angiotensin II (AII) and plasma renin
activity, because AII inhibits the secretion of renin and
lowers plasma renin concentration. However, the increase in
AII is sufficient for a slight reduction in renal blood flow
and a slight increase in exchangeable sodium and blood
pressure; in susceptible women, blood pressure may rise
considerably. Effects of estrogens on the brain may also be
involved in blood pressure changes. Endogenous progesterone is
a mineralocorticoid receptor antagonist. Endogenous or
exogenous progesterone leads to sodium loss and a compensatory
increase in renin secretion, plasma renin activity, AII, and
plasma aldosterone, e.g. in the second half of the menstrual
cycle. Synthetic progestogens are commonly devoid of the
mineralocorticoid receptor antagonistic effect of
progesterone, and some are weak estrogen receptor agonists.
Combined use of EE and synthetic progestogens may therefore
enhance estrogen effects on body sodium and blood pressure. A
new progestogen (Drospirenone) with an antimineralocorticoid
effect like that of progesterone is described that slightly
lowers body weight and blood pressure in a contraceptive
formulation together with EE. An almost ideal oral
contraceptive would be progestogen like Drospirenone together
with a low dose natural estrogen that does not stimulate Aogen
synthesis. Since most oral formulations for postmenopausal
estrogen replacement also stimulate hepatic protein synthesis
(including Aogen) to some extent, the transdermal route of E2
application for contraceptive purposes should also be
investigated, since it has reduced potential for undesirable
side effects.
Effects of progestogens on haemostasis.
Kuhl H
Department of Obstetrics and Gynecology, J.W. Goethe
University Frankfurt, Germany.
Maturitas (Ireland) May 1996, 24 (1-2) p1-19
Epidemiological data suggested an involvement of the
progestogen component in the pathomechanism of venous and
arterial diseases during intake of oral contraceptives. The
influence of progestogens on haemostasis parameters depend on
type and dose of the progestogen, the presence of an estrogen,
the route of application, and the duration of use. Treatment
of women with progestogen-only preparations caused only minor
effects on coagulation and fibrinolysis. Similarly, during
hormone replacement therapy with natural estrogens, the
additional application of progestogens induced no unfavourable
changes on haemostasis. In contrast, the use of ovulation
inhibitors resulted in an acceleration of coagulation and
fibrinolysis. This is primarily induced by the marked action
of ethinylestradiol on hepatic and vascular function.
Progestogens with androgenic properties may counteract the
estrogen-induced changes in the hepatic synthesis of platelet
aggregation and readiness for coagulation. Estrogen and
progesterone receptors are localized in endothelial and smooth
muscle cells of the vessel wall, but there are differences in
the response of veins and arteries to sex steroids. Estrogens
and progestogens may influence collagen and elastin synthesis,
and the release of vasoactive compounds and of factors
controlling fibrinolysis from endothelium. In veins,
progestogens may increase distensibility and capacitance
resulting in a decreased blood flow. In predisposed women,
this may lead to venous stasis and thrombosis. In arteries,
progestogens may act as vasoconstrictors, and may enhance
vasospasms at sites of injured endothelium which finally may
lead to ischemic diseases.
Effects of hormone therapy on bone mineral density:
results from the postmenopausal estrogen/progestin
interventions (PEPI) trial. The Writing Group for the
PEPI
JAMA (United States) Nov 6 1996, 276 (17) p1389-96
Contract/Grant No.: U01-HL40154, HL, NHLBI; U01-HL40185, HL,
NHLBI; U01-HL40195, HL, NHLBI
Comment in JAMA 1996 Nov 6;276(17):1430-2
OBJECTIVE: To assess the effects of hormone therapy on bone
mineral density (BMD) in the spine and hip of postmenopausal
women.
DESIGN: A 3-year, multicenter, randomized, double-blinded,
placebo-controlled clinical trial.
PARTICIPANTS: A total of 875 healthy women aged 45 to 64
years recruited at 7 clinical centers.
INTERVENTIONS: Treatments were (1) placebo; (2) conjugated
equine estrogens (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus
medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4)
CEE, 0.625 mg/d plus MPA, 2.5 mg/d daily; or (5) CEE, 0.625
mg/d plus micronized progesterone (MP), 200 mg/d for 12
d/mo.
MAIN OUTCOME MEASURES: Bone mineral density at baseline, 12
months, and 36 months. RESULTS: Participants assigned to the
placebo group lost an average of 1.8% of spine BMD and 1.7% of
hip BMD by the 36-month visit, while those assigned to active
regimens gained BMD at both sites, ranging from 3.5% to 5.0%
mean total increases in spinal BMD and a mean total increase
of 1.7% of BMD in the hip. Changes in BMD for women assigned
to active regimens were significantly greater than those
assigned to placebo. Women assigned to CEE plus continuous MPA
had significantly greater increases in spinal BMD (increase of
5%) than those assigned to the other 3 active regimens
(average increase, 3.8%). Findings were similar among those
adhering to assigned therapy, although, among adherent
participants, there were no significant differences in BMD
changes among the 4 active treatment groups. Older women,
women with low initial BMD, and those with no previous hormone
use gained significantly more bone than younger women, women
with higher initial BMD, and those who had used hormones
previously.
CONCLUSIONS: Postmenopausal women assigned to placebo
demonstrated decreased BMD at the spine and hip, whereas women
assigned to estrogen therapy increased BMD during a 36-month
period. These findings demonstrate that estrogen replacement
therapy increases BMD at clinically important sites.
Transdermal estrogen replacement therapy in normal
perimenopausal women: effects on pituitary-ovarian
function.
De Leo V; Lanzetta D; D'Antona D; De Palma P
Department of Obstetrics and Gynecology, University of Siena,
Italy.
Gynecol Endocrinol (England) Feb 1996, 10 (1)
p49-53
The effects of 6 months of hormone replacement therapy by
transdermal estradiol patches (0.05 mg/day for 21 days) and
oral progestogens (10mg/day for 10 days) on
hypothalamic-pituitary-ovarian function was evaluated in 32
perimenopausal women, aged 42-47 years, with irregular
anovulatory cycles and menopausal symptoms. Hormone levels
evaluated on the 8th and 24th day of the cycle preceding
therapy showed follicle-stimulating hormone (FSH) levels above
15 mIU/ml, estradiol less than 45 pg/ml and progesterone less
than 800 pg/ml. During therapy, there was an improvement in
menopausal symptoms, a decrease in luteinizing hormone (LH)
and FSH levels, an increase in estradiol levels and the
transdermal patches were well tolerated. At the end of
therapy, 19 women continued to have regular ovulatory cycles
with progesterone levels similar to those in luteal phase. FSH
and LH concentrations were significantly lower than before
therapy. This study shows that hormone replacement therapy not
only improves menopausal symptoms but may also restore the
hypothalamic-pituitary-ovarian function.
The effects of androgens and other sex hormones on
serum lipoproteins
Reiner Z
Klinika za unutarnje bolesti KBC Rebro, Zagreb.
Lijec Vjesn (Croatia) Mar 1996, 118 Suppl 1
p33-7
This review summarizes recent data on the effects of
endogenous and exogenous androgens, estrogens and progesterone
on serum lipoproteins levels and composition in humans. Sex
steroid hormones modulate serum lipoprotein metabolic
mechanisms and influence atherosclerosis and coronary heart
disease. In general, androgens lower HDL and raise LDL levels
and Lp(a) thus promoting the atherogenic process. As it is
true with estrogens, the lipoprotein effects of androgens are
more pronounced with oral than with parenteral administration.
Millions of women use oral contraception and postmenopausal
women use more and more some form of hormone replacement
therapy. The HDL-raising effect of estrogen replacement seems
to be mediated by an increase in apoprotein AI production and
not by a decrease in the clearance rate. Estrogens lower LDL
levels by accelerating the rate of LDL catabolism which is due
to an increase in the number of hepatic LDL receptors. They
also improve endothelium-dependent vasodilatation which might
be mediated by an antioxidant action of estrogens. These facts
could explain well known cardioprotective effects of
estrogens. Androgen progestins, especially older such as
norgestrel, lower HDL and raise LDL thus diminishing or
eliminating the benefits of estrogens on cardiovascular system
while newer progestins have a lesser effect on circulating
lipoproteins. (55 Refs.)
Hormonal and environmental factors affecting cell
proliferation and neoplasia in the mammary gland.
Snedeker SM; Diaugustine RP
Hormone and Cancer Workgroup, National Institute of
Environmental Health Sciences, Research Triangle Park, NC
27709, USA.
Prog Clin Biol Res (United States) 1996, 394
p211-53
Although estrogens have been identified as key endocrine
hormones in the control of early mitogenesis and development
in the mammary gland, local control of cell proliferation
during ductal morphogenesis may be regulated by polypeptides
such as TGF-alpha or TGF-beta. Many breast tumors are estrogen
dependent, and some breast tumor cell lines are known to
produce TGF-alpha, suggesting that the mitogenic pathways
controlling early normal mammary growth and the growth of some
breast tumors may be similar. While progesterone does not
appear to be important in the early program of ductal growth,
progesterone and estrogen are necessary for the cyclic
proliferation of mammary ductal cells that occurs during the
menstrual cycle, and for lobuloalveolar growth during
pregnancy. Since increased cell division enhances the chances
for the formation of a malignant phenotype in the breast,
exogenous hormones containing estrogen alone or estrogen and
progesterone may increase breast cancer risk. While DES is no
longer prescribed to prevent abortions, it demonstrates that
high doses of an estrogen during a period of mammary
proliferation can affect breast cancer risk. Whether the
addition of progestogens to estrogen replacement therapy
enhances breast cancer risk in postmenopausal women remains an
unanswered question because of the lack of large,
well-controlled prospective studies. There currently is no
evidence to indicate that the progestogen-containing subdermal
contraceptive Norplant increases breast cancer risk. However,
it has not been determined if the elevation of serum estrogens
reported in some Norplant users affects breast cancer risk.
There is little evidence that combined OCAs enhance breast
cancer risk in most women. More research is needed to
substantiate the findings that OCA use in young women,
especially before a first full-term pregnancy, may enhance
breast cancer risk. Animal studies indicate that there are
critical periods of susceptibility to chemical carcinogens,
since the number and malignancy of tumors are increased when
carcinogens are administered to young virgin animals during
the proliferative period of ductal morphogenesis. Since the
breast appears to be most susceptible to the carcinogenic
effects of ionizing radiation during the first decade of life,
exposure to other carcinogenic agents during the period of
early breast development may be important in determining
breast cancer risk. Therefore, more studies are needed to
confirm the observation that heavy drinkers and heavy smokers
are at higher risk for developing breast cancer when they
start smoking or drinking at an early age. The observation
that serum and urinary estrogen levels increase with alcohol
consumption may provide a basis for the higher risk of
developing breast cancer in heavy drinkers. While the
restriction of methyxanthine intake may alleviate the symptoms
associated with fibrocystic breast disease in some women,
there is not enough evidence to suggest that a reduction in
caffeine intake will reduce breast cancer risk. Evidence for
an association between electromagnetic radiation and breast
cancer is limited. Electromagnetic radiation may only pose a
risk in certain occupations with exposure to very high levels
for extended periods of time. It is not known whether exposure
to PCBs transplacentally or though the lipid fraction of human
milk can affect breast cancer rates in female offspring. The
higher risk of breast cancer in women with elevated DDE levels
in their blood underscores the importance of determining the
extent to which environmental contaminants affect breast
cancer risk.
The menopause and hormone replacement therapy:
lipids, lipoproteins, coagulation and fibrinolytic
factors.
Tikkanen MJ
Department of Medicine, Helsinki University Central Hospital,
Finland.
Maturitas (Ireland) Mar 1996, 23 (2) p209-16
OBJECTIVES: To review the recent literature concerning the
effects of the menopause and hormone replacement therapy (HRT)
on the plasma lipoprotein and hemostatic system, as well as on
the interaction between these two coronary heart disease (CHD)
risk factor systems.
METHODS. Collection of information from relevant scientific
journals, and by the use of Medline and Current Contents.
RESULTS: The mainly beneficial effects of unopposed oral
estrogen replacement on the plasma lipoprotein pattern are
preserved to different degrees after addition of progestin to
the regimen. Nortestostorone-derived progestins tend to lower
HDL cholesterol levels more than progesterone derivatives. The
slight triglyceride-elevating effect on conjugated equine
estrogens was in a large study not significantly counteracted
by progesterone derivatives but can, according to other
studies, be reversed by nortestosterone-derived progestins. A
limited number of studies on transdermal administration of
estradiol has suggested that the effects on plasma
lipoproteins are smaller than during oral administration.
There is no convincing evidence that currently used HRT
regimens would significantly increase the risk of thrombosis.
Nevertheless, the finding in some studies that plasma
triglyceride elevations could in theory be associated with
impaired fibrinolysis and enhanced coagulation merit further
attention as some HRT regimens tend to increase plasma
triglyceride levels. From a theoretical point of view,
transdermal estrogen delivery would be preferable in women at
risk for thrombosis, as they have less pronounced effects on
liver functions, including production of hemostatic factors
and very-low-density lipoprotein triglycerides.
CONCLUSIONS: While the numerous existing HRT regimens
provide many alternative and useful possibilities, further
studies are needed concerning (a) novel progestins with
minimal HDL cholesterol lowering effects, (b) transdermal and
other non-oral routes for HRT, 8 possible antioxidative
properties of estrogen and (d) metabolic links between the
lipoprotein and hemostatic risk factor systems.
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