La Edad Crítica de la Mujer
MATURITAS
Mayo, 1996.- Suplemento
R Punnonen, R Tuimala: Preface. Maturitas 23: Suppl.
(MAY 1996) :S1
Artículos
P Tuohimaa, M Blauer, S Pasanen, S Passinen, A Pekki, R Punnonen,
H Syvala, J Valkila, M Wallen, J Valiaho, YH Zhuang, T Ylikomi. Mechanisms
of action of sex steroid hormones: Basic concepts and clinical correlations
. Maturitas 23: Suppl. (MAY 1996) :S3-S12
- The review deals with the clinically important aspects of the basic
mechanisms of sex steroid hormones. Steroids can act through two basic
mechanisms: genomic and non-genomic. The classical genomic action is mediated
by specific intracellular receptors, whereas the primary target for the
non-genomic one is the cell membrane. Many clinical symptoms seem to be
mediated through the non-genomic route. Furthermore, membrane effects of
steroid and other factors can interfere with the intranuclear receptor
system inducing or repressing steroid- and receptor-specific genomic effects.
These signalling pathways may lead to unexpected hormonal or anti-hormonal
effects in patients treated with certain drugs. Steroid receptors (SRs)
are members of a large family of nuclear transcription factors that regulate
gene expression by binding to their cognate steroid ligands, to the specific
enhancer sequences of DNA (steroid response elements) and to the basic
transcription machinery. SRs are phosphoproteins, which are further phosphorylated
after ligand binding. The role of phophorylation in receptor transaction
is complex and may not be uniform to all SRs. However, phosphorylation/dephosphorylation
is believed to be a key event regulating the transcriptional activity of
steroid receptors. SR activities can be affected by the amount of SR in
the cell nuclei, which is modified by the rate of transcription and translation
of the SR gene as well as by proteolysis of the SR protein. There is an
auto- and heteroregulation of receptor levels. Some of the SRs appear to
bind specific protease inhibitors and exhibit protease activity. The physiological
significance of this weak proteolytic activity is not clear. Some SRs are
expressed as two or more isoforms, which may have different effects on
transcription. Receptor isoforms are different translation or transcription
products of a single gene. Isoform A of the progesterone receptor is a
truncated form of PR isoform B originating from the same gene, but it is
able to suppress not only the gene enhancing activity of PR-B but also
that of other steroid receptors. From the clinical point of view, it is
important to note that the final hormonal effect in a target tissue is
dependent on the cross talk between different nuclear steroid receptors
and on expression of receptor isoforms.
E Hirvonen: Progestins. Maturitas 23: Suppl. (MAY
1996): S13-S18
- 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.
KK Vihko: Gonadotropins and ovarian gonadotropin receptors during
the perimenopausal transition period . Maturitas 23: Suppl.
(MAY 1996): S19-S22
- As an early sign of perimenopause, the menstrual cycles become irregular.
Associated with this irregularity, serum gonadotropin levels increase.
There are studies correlating these changes to ovarian follicular morphology
and number, but no reports are available, to our knowledge, correlating
the increases in gonadotropin levels to respective cellular receptors.
In fact, the regulation of gonadotropin receptors is poorly understood
in the human. The action of gonadotropins on gonadal function is mediated
through specific binding of the hormones to receptors located on the surface
of target cells followed by activation of intracellular second messenger
systems. In the ovary, the target cells for FSH are granulosa cells of
ovarian follicles, while the action of LH is mediated through binding of
the ligand to theca, granulosa and luteal cells. The cell-surface receptors
for gonadotropins are located respectively on these cell types. The molecular
nature of FSH receptors and LH receptors has been characterized in many
species, and their structure is well-known both on the protein and nucleic
acid level. Despite the vast amount of studies in rodents, there is limited
information available on the regulation of gonadotropin receptors in the
human. In a recent study, serum LH and FSH levels were correlated to respective
receptor levels in ovarian tissue in order to better understand gonadotropin
action and the physiology of the menopause in the human. High serum gonadotropin
levels in perimenopause suggested the existence of low ovarian gonadotropin
receptor levels. In most patients who are still experiencing cyclic menstrual
bleeding no FSH receptors were detected possibly due to severe disturbances
in follicular FSH receptor synthesis prior to ovarian follicle exhaustion.
B Vonschoultz, G Soderqvist, M Cline, E Vonschoultz, L Skoog:
Hormonal regulation of the normal breast . Maturitas 23:
Suppl. (MAY 1996): S23-S25
- The breast is a target organ for reproductive hormones but basic knowledge
on hormonal effects is very poor, Available data indicate that the breast
is regulated in a specific manner which is distinct from the endometrium
and other target organs. It seems clear that the breast undergoes cyclic
changes during the menstrual cycle and that in vivo there is a direct stimulatory
action of progestogens on the breast. In surgically postmenopausal female
macaques continuous combined estrogen/progestogen therapy was found to
induce greater proliferation than estrogen alone.
R Erkkola: Female menopause, hormone replacement therapy, and
cognitive processes. Maturitas 23: Suppl. (MAY 1996): S27-S30
- Objectives: To give definitions
of and to describe the research techniques for cognitive functions. Further,
to describe the effect of female aging and hormone replacement therapy
on cognitive functions. Methods: Literature
search of pertinent publications and description of initial steps of own
research projects. Conclusions: Effect
of aging and hormone replacement therapy on cognitive functions has been
researched very insufficiently, and with conflicting conclusions. The best
available information suggests that hormone replacement therapy might bring
about considerable benefit in this regard, and be of advantage even in
trying to prevent senile dementia.
B Delignieres : Hormone replacement therapy: Clinical benefits
and side-effects . Maturitas 23: Suppl. (MAY 1996) : S31-S36
- 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 mid-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.
I Persson: Cancer risk in women receiving estrogen-progestin
replacement therapy . Maturitas 23: Suppl. (MAY 1996): S37-S45
- Objectives and methods: The epidemiological
literature was reviewed in order to evaluate the relationship between hormone
replacement therapy and risk of cancer in the breast and reproductive organs.
Results: For breast cancer, there is no evidence of an overall
increase in the risk. According to several studies, but not all, the duration
of intake seems to affect the risk. Many years of intake of both estradiol
compounds and conjugated estrogens can be assumed to increase the risk
of breast cancer 1.5-2-fold. The addition of progestins does not seem to
alter (reduce) the duration-risk relationship. The magnitude of risk increase
is likely to be small and may be explained partly by methodological problems,
or by differences in study populations. The prognosis in patients with
HRT-related breast cancer seems to be more favourable than for non-exposed
breast cancer patients. Because of the importance of the issue, and inconsistencies
in results, further research is urgent. Especially, there is an urgent
need to define sub-groups of women who would be susceptible to an adverse
influence of HRT. Regarding endometrial cancer, a duration-dependent strong
risk relationship with long-term intake of estrogens only is established.
The level of risk increase is about 10-fold after 10 or more years of intake,
a risk relationship that seems to decrease after discontinuation of treatment.
Added progestins for at least 10 days per cycle can reduce or eliminate
the risk increase. Tumors occurring after estrogen replacement have favourable
biological characteristics. Future research will be needed to define the
long-term safety of various progestin regimens. Ovarian cancer risk does
not seem to be affected by HRT, Available data are inconsistent and contradictory.
Due to the pronounced protective effect of oral contraceptives, further
research is needed to measure effects of estrogen-progestin combined regimens.
Cervical cancer risk has not been shown to be affected by HRT. Conclusions.
It is concluded that hormone replacement therapy, with estrogens alone
or estrogens combined with progestins, may have important effects on the
risk of cancer, particularly in the breast and endometrium. Therefore,
when making a risk-benefit assessment of long-term HRT, possible risk relationships
should be considered.
S Ylaherttuala, J Luoma, H Kallionpaa, M Laukkanen, P Lehtolainen,
H Viita. Pathogenesis of atherosclerosis . Maturitas 23:
Suppl. (MAY 1996): S47-S49
- Atherosclerosis is a disease which affects large and medium-sized arteries.
Typical features of atherosclerosis are accumulation of intra- and extracellular
lipids, foam cell formation, proliferation of smooth muscle cells and accumulation
of connective tissue. Plasma lipids and lipoproteins play an important
role in the formation of atherosclerotic lesions, Recent evidence suggests
that oxidation of low-density lipoprotein (LDL) may play an important role
in the pathogenesis of atherosclerosis. Incidence of cardiovascular diseases
increases significantly after menopause. Part of the increase is due to
atherogenic changes in plasma lipoproteins, i.e. increase in LDL and decrease
in high density lipoprotein (HDL). Clinical endpoints of cardiovascular
diseases are usually caused by atherosclerosis and thrombosis, both of
which can be influenced after menopause by sex steroids. Hormone replacement
therapy has anti-atherogenic effects on plasma lipoprotein fractions. Recent
evidence also suggests that estrogens may have several protective effects
on the vascular wall, including direct inhibition of LDL degradation, oxidation
and smooth muscle cell proliferation.
MJ Tikkanen: Estrogens, progestins and lipid metabolism. Maturitas
23: Suppl. (MAY 1996) : S51-S55
- Objectives: To review some aspects
in the recent literature related to the effects of postmenopausal estrogen
and progestin use on major plasma lipoprotein risk factors for coronary
heart disease (CHD). Methods: Collection
of relevant information from medical journals, and by the use of Medline
and Current Contents. Results: The
beneficial effects of estrogen (LDL cholesterol reduction and HDL cholesterol
elevation) are well established. The effects on HDL are modified to different
degrees by progestins, depending on the androgenic properties of the latter:
the 'sex steroid sensitive' HDL2 subfraction is decreased by nortestosterone
derived progestins with androgenic activity. Recently developed methodology
employing stable isotopes has helped to clarify underlying mechanisms.
Progestins alone, as well as estrogen- progestin combinations have been
shown to reduce the plasma levels of Lp(a), another lipoprotein risk factor
for CHD. According to one study, estrogen administered alone had a similar
effect. Conclusions: The effects of
hormone replacement therapies on lipid metabolism have been partly established
and investigations on the underlying mechanisms are being published. This
information will be useful for developing new replacement regimens with
more protection against CHD and less adverse effects.
P Oian, B Osterud: Monocyte-platelet function and protection
against cardiovascular disease. Maturitas 23: Suppl. (MAY
1996): S57-S60
- Observational studies reveal a cardioprotective effect of hormone replacement
therapy. The precise mechanisms whereby this treatment influences disease
risk are not fully understood. Much attention has been paid to changes
in lipid and lipoprotein metabolism, but this explains only part of the
protective effect. In this short review, the roles of monocyte and platelet
function in atherogenesis and thrombus formation are discussed. It is shown
that hormone replacement therapy favourably down-regulates monocyte and
platelet reactivity, which may be important in explaining the beneficial
effect on the risk of cardiovascular disease. I
R Punnonen, H Jokela, P Dastidar, R Aine, P Laippala: Estrogen-progestin
replacement therapy and atherosclerosis . Maturitas 23: Suppl.
(MAY 1996) : S61-S64
HK Vaananen, PL Harkonen: Estrogen and bone metabolism . Maturitas
23: Suppl. (MAY 1996) :S65-S69
- Estrogen plays an important role in the growth and maturation of bone
as well as in the regulation of bone turnover in adult bone. During bone
growth estrogen is needed for proper closure of epiphyseal growth plates
both in females and in males. Also in young skeleton estrogen deficiency
leads to increased osteoclast formation and enhanced bone resorption. In
menopause estrogen deficiency induces cancellous as well as cortical bone
loss. Highly increased bone resorption in cancellous bone leads to general
bone loss and destruction of local architecture because of penetrative
resorption and microfractures. In cortical bone the first response of estrogen
withdrawal is enhanced endocortical resorption. Later, also intracortical
porosity increases. These lead to decreased bone mass, disturbed architecture
and reduced bone strength. At cellular level in bone estrogen inhibits
differentiation of osteoclasts thus decreasing their number and reducing
the amount of active remodeling units, This effect is probably mediated
through some cytokines, IL-1 and IL-6 being strongest candidates, Estrogen
regulates the expression of IL-6 in bone marrow cells by a so far unknown
mechanism. It is still uncertain if the effects of estrogen on osteoblasts
is direct or is due to coupling phenomenon between bone formation to resorption.
I
C Christiansen : Hormone replacement therapy and osteoporosis
. Maturitas 23: Suppl. (MAY 1996) : S71-S76
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