The Climacteric, Menopause and HRT
The climacteric is the period of time which precedes
the final cessation of menstruation, and may last for 1-10 years. It indicates a
gradual decline in ovarian function and reproductive capacity during the late
30s and early 40s, even in women with regular menstrual function. In contrast
to puberty, which represents the development of reproductive capability, the
climacteric signifies the beginning of the end of that capability.
Both ovarian and hypothalamic ageing have been documented as causes for the onset
of the climacteric period. Few related endocrine changes can be seen during the
late thirties and early forties:
1. The earliest
changes reflect the gradual decline in the number of preantral and small antral
follicles. The level of antimullerian hormone drops first, followed after some
time by reduction in inhibin B production. This later change reduces the
inhibitory effects on the hypothalamus and pituitary gland, leading to
increased production of follicle stimulating hormone (FSH). There are no
significant changes in the levels of oestradiol, inhibin A or luteinising hormone (LH) at this early
2. Higher levels of
FSH start rising earlier during the luteal phase of the cycle, resulting in
early recruitment of follicles for the subsequent cycle, even before the start
of menstruation in the current one. Accordingly, the recruited follicle will be
more advanced during the early follicular phase of the subsequent cycle, and
will only need a short period of time to attain full maturation. This leads to
a short follicular phase and polymenorrhoea, which are early signs of
incipient ovarian failure. The level of oestrogen may be
high during the whole cycle in some cases, with the possibility of luteal phase
dysfunction. The increase in FSH level usually affects few cycles only
initially. More cycles will be slowly affected, till ultimately a high FSH
level becomes detectable in all cycles. This can still happen while the patient
has regular menstruation.
3. With further
decrease in the number of follicles, excessive FSH is produced coupled with
slower response by the remaining less sensitive ones. This results in a longer
follicular phase, inadequate ovulation, and occasionally dysfunctional
uterine bleeding. The cycles become less frequent
and anovulatory over time, before total cessation of menstruation.
Coinciding with the decline in oocytes numbers,
cytogenetic studies and in vitro fertilisation treatment cycles showed the
arrangement of the chromosomes on the myotic spindle in metaphase II
incidence of aneuploidy in the resulting embryos.
Independent of ovarian aging, changes in the negative
feedback mechanism due to hypothalamic ageing have also been suspected to occur in regularly
menstruating women in their late 30s and early 40s. This can initiate or at
least be a contributing factor to the high FSH levels documented during the
early follicular phase in these women. Certain observations have been mentioned
in support of this point
Changes in the
level of inhibin B and oestradiol do not explain changes in the
level of FSH in all women in their late thirties and early forties who have
regular menstrual cycles;
The occurrence of
hot flushes in women between the ages of 35-40 years despite having regular
cycles and normal oestradiol level;
Failure of the pituitary
gland to respond to an oestrogen challenge test with LH surge is a common observation in women during the
climacteric period (1);
Reduced LH pulse
frequency and increased pulse width during the mid follicular phase in
regularly menstruating women in their forties can be related to changes in the
negative feedback mechanism, and partly explain the age related
changes in reproductive potential (2).
Natural menopause is a term used in retrospect to
indicate the last menstruation, one year after its occurrence in women >45
years of age. In contrast to puberty, the age at menopause has not changed over
the last century and remained stable in different communities and families. In
western countries, the average age at the menopause is 51 years. Permanent
cessation of menstruation before the age of 40 or 45 years is termed premature
and early menopause respectively. Nonetheless, the term premature menopause is
not acceptable by many patients, and can be medically incorrect as will be
discussed in Chapter 10. On the other hand, surgical menopause can occur when
the ovaries are removed, at any time, before the average age of natural
Certain factors have been documented to affect the
age at which the natural menopause may occur. A woman’s age at menopause is
very much affected by the age her mother reached the menopause, reflecting the
importance of genetics in this respect. This familial trait has been supported
by twins’ studies. Smoking, lower educational attainment, being separated,
divorced or widowed, unemployment and history of heart disease have been
reported to be independently associated with earlier natural menopause. On the
other hand, parity, prior use of oral contraceptives and Japanese
race/ethnicity were associated with a later age at natural menopause (3). Similarly, a multiethnic study which involved
103,893 women in 2008 (4) showed that
race/ethnicity was a significant independent predictor of the timing of natural
menopause. All other factors including smoking, age at menarche, parity and
body mass index did not significantly alter the effect of
race/ethnicity-specific hazard ratio. This is agreeable with a previous report
which showed that all lifestyle and reproductive factors explained the
difference in age at natural menopause in less than 10% of the cases, after
studying 2182 twin pairs (5). Accordingly single
ethnic group studies are liable to miss this important effect of race/ethnic
Despite all the research conducted in this field of
reproductive endocrinology, there are no set reliable biochemical criteria to
predict the exact age at the menopause. Measuring early follicular phase FSH
levels is useless in this respect, as high levels can be detected many years
before the menopause. This test may be useful in showing a low ovarian reserve
and fertility potential, when a high level is reported. Even in this context, a
normal level in women in their late thirties does not indicate normal fertility
potential. The following general points have been found to be helpful in
predicting an early menopause:
of early menopause;
Twelve or more
months of amenorrhoea at or beyond the age of 45 years is associated with 90%
chance of no further menstruation;
History of 3-11
months of amenorrhoea at or beyond the age of 45 years is associated with 95%
chance of the menopause within 4 years.
Poor response to
controlled ovarian hyperstimulation at the first in vitro fertilisation (IVF)
treatment cycle has been associated with a higher risk of early menopause
(<46 years), in comparison to women who developed more than 3 follicles (6, 7).
Endocrine changes associated with the natural
The menopause is followed by a hypoestrogenic state
due to ovarian failure, with peripheral adipose tissue producing a major
fraction of the circulating oestrone, which is the main oestrogen in this age
group. This depends on the BMI of the individual patient. There is little
progressive decline in adrenal androgens production after the menopause,
following the maximum decline which occurs between the ages of 20 - 40 years.
This results in 70-80% reduction in dehydroepiandrosterone (DHEA) production
rate by the age of 70 years (8). This decline in
adrenal androgens production is not matched by any decline in cortisol
production as reported by Liu et al in 1990 (9).
They found decreased DHEA/17-hydroxypregnenolone and
androsdenedione/17-hydroxyprogestgesgterone ratios which they attributed to
decreased 17, 20-desmolase enzymatic activity. Furthermore, they attributed the
decline in DHEA blood levels to reduced pulse amplitude without any changes in
its circadian (daily) or ultradian (pulse frequency) secretion patterns. On the
other hand, ovarian androgens production normally decline over the reproductive
years with the maximum decline rate being just before the menopause (10). There is 50% reduction of the daily production
rate of androstenedione mainly from the ovaries, with the adrenals being the
main source in postmenopausal women.
There is also a small decline in the level of sex hormone biding
globulin (SHBG), but not significant enough to affect the free androgen index.
DHEA forms the main circulating androgen during the postmenopausal period, and
it is readily converted to oestrogen and testosterone. This forms the
theoretical background for using it as a food supplement after the menopause to
provide a form of hormone replacement therapy, and as an anti-aging agent as
Thyroid gland dysfunction is also more frequent
during the late reproductive years, and after the menopause. Women are almost 8
times more likely to have such problems in comparison to men of the same age
group. Clinical and subclinical thyroid diseases have been reported in 2.4% and
23.2% of postmenopausal women respectively by Schindler in 2003 (1). Among those with the subclinical disease, 73.8%
were hypothyroid and 26.2% were hyperthyroid. Accordingly, this same author
recommended routine screening of thyroid function in the climacteric period to
determine subclinical thyroid diseases. This is especially so as subclinical
hypothyroidism may be associated with dislipidaemia in the form of high total
cholesterol, high low density lipoprotein (LPL) cholesterol, and low high density
lipoprotein (HDL) cholesterol. Such a deranged lipid profile can increase the
risk of cardiovascular problems in these patients. The risk is also increased
because of the reduced oestrogen / androgen ratio. Oestrogen medication can
affect the thyroid status by increasing the level of thyroxine binding globulin (TBG); hence reducing the level of free
thyroxine in circulation. This may aggravate problems in women with subclinical
hypothyroidism. Conversely, transdermal HRT has
no similar effect on TBG, as it has no first hepatic pass and should be used by patients with
hypothyroidism on HRT. On the other hand, hyperthyroidism has a detrimental
effect on bone density, and can induce osteoporosis. This effect has been documented
even in healthy postmenopausal women with persistently low normal thyroid
stimulation hormone (TSH), by Kim et al in 2006 (12).
The same authors suggested that low normal TSH levels may not be physiological
for postmenopausal women, and during treatment of hypothyroidism, and may not
be adequate for avoiding osteoporosis.
in LH dynamics
Beside the changes in FSH level alluded to before,
more subtle changes have also been documented in LH secretion. Increased LH
pulse frequency and amplitude have been documented during the luteal phase of
the cycle during the late reproductive years. Different reports documented
changes or no changes during the follicular phase. Nevertheless, the evidence
is more compelling towards decreased LH pulse frequency and amplitude during
the mid follicular phase in older women during their reproductive years (2). This was attributed on one side to ageing or
enhanced hypothalamic-pituitary negative feedback mechanism, or to increased oestradiol level at
that point of the cycle. This later point can be a reflection of the rapid
recruitment and larger follicles occasionally seen during the early part of the
cycle in women with polymenorrhoea, as alluded to before.
Eventually, elevated LH levels throughout the cycle are observed in ovulatory
women by the age of 45 years (13).
in body habitat
A noticeable observation is the change in body
composition during the late climacteric period, and after the menopause. This
is manifested in the form of central obesity which may be due to:
oestrogen / androgen ratio favours an android or central body fat
deposition, which can be reversed by oestrogen medication.
2. Decreased energy
expenditure due to
resting metabolic rate;
- Higher risk
Following the menopause oestrogen withdrawal symptoms
can be acute, intermediate or delayed. The most distressing symptoms are the
acute ones which can affect the patients’ quality of life, but the delayed ones
carry more long term medical risks.
Nearly 80% of postmenopausal women experience acute
symptoms which can be vasomotor or psychological in nature, but not all of them
seek medical advice. The two main vasomotor symptoms are hot flushes and night
sweats, but many women may present with headaches, palpitations and fainting
attacks. A wide range of psychological symptoms can be seen including depressed
mood, sleep disturbance, mood swings, lack of concentration, loss of memory,
fatigue and anxiety state. Many younger women in their late
thirties and early forties, who have regular menstrual cycles, may also have
oestrogen deficiency symptoms mainly premenstrually. It is important to exclude
other medical conditions which can give similar symptoms, especially in
patients not responsive to HRT. Such conditions include anaemia, sleep apnoea,
panic attacks and hyperventilation, thyroid dysfunction, clinical depression,
diabetic autoimmune dysfunction, carcinoid syndrome and phaeochromocytoma.
Hot flushes make the most important and distressing
acute vasomotor symptom, which can affect patients’ lives negatively in many
ways. They may be associated with night sweats which disturb the patient’s
sleeping pattern, leading to fatigue and inability to perform every day life
duties. Nearly 20% of women can be badly affected and will need medical help.
Though they are mainly related to oestrogen withdrawal, oestrogen levels have
not been found to be significantly different in women with and without hot
Furthermore, stimulation of the sympathetic nervous system can also start an
episode of hot flushes, indicating its importance in this respect. In fact
increased catecholamines production in the brain has been documented in
women during episodes of hot flushes (15).
Sociocultural factors are most likely involved as well, as the incidence of hot
flushes was reported as 82% in American women (16),
60% in Swedish women (17), with yet lower
figures in developing countries (18). More
recent publications almost duplicated this trend. The effect of ethnic origin
has also been shown by an article published by Monterrosa et al in 2009 (19). They found that
impairment of quality of life in postmenopausal women varied according to race
in different Columbian groups. Urogenital symptoms were more severe in
indigenous and black women, whereas somatic and psychological symptoms were
more severe in Hispanics.
Each hot flushing episode may last 1-5 minutes, but
can be longer. The patient feels warmth or heat in the face, shoulders and neck
area depending on the severity of the attack. This may be associated with
reddening of the skin and profuse sweating, which corresponds to the
distribution of the cervical sympathetic trunk. Such visible changes are
usually seen in approximately 50% of the patients. It is usually followed by
feeling cold and shivering. The intensity of the symptoms varies between women,
and at different times in the same woman. In general, surgical menopause is usually
associated with more severe symptoms than the natural one. Prolonged and
repeated flushing episodes may lead to telangiectasia and classical rosacea of
the face (20). Occasionally, symptoms may follow
intake of spicy food or caffeine, hot bath or shower, cigarette smoking,
alcohol consumption, and anxiety state. Women perception of the menopause and
its implications on health, family relations and sexuality depends on their
cultural background and own personality. This may have direct bearing on their
coping abilities, and how they react to oestrogen deficiency symptoms. Other
predisposing factors include family history of hot flushes, and a high body
mass index. Episodic hot flushes may last for up to 5 years in 65%, 6 – 10
years in about 25% and >11 years in 10% of affected postmenopausal
The exact causes for hot flushes are still
speculative and many factors have been implicated. In a recent review in 2009,
Andrikoula et al (21)
discussed few possible factors related to women predisposition to hot flushes.
- The mean
blood pressure was found to be higher in women who had hot flushes than in
those who did not have similar episodes. This is despite of the fact that
the blood pressure may drop during the episodes themselves.
postmenopausal women with hot flushes were found to have higher
electrodermal activity during stress.
- Lower total
plasma antioxidant activity, lower concentration of reduced sulfhydryl
groups, and higher plasma concentration of lipoperoxides have also been
found in women who had hot flushes, compared to those who were not
similarly affected (22).
All these factors are known to increase
cardiovascular disease risks in women with hot flushes. A recent report by the
Women’s Health Across the Nation Heart Study (23)
showed that women who had hot flushes had reduced brachial artery flow-mediated
dilation, and greater aortic calcification.
of body temperature
Body temperature is controlled by thermoregulatory means
of neuroendocrine and autonomic structures that keep the core body temperature within certain range of threshold values (24). The upper or ‘sweating’ threshold is involved
with release of heat, and the lower or ‘shivering’ threshold with heat
conservation and renewed production. These thresholds maintain the
thermoneutral zone (25), which is regulated by
different parts of the central nervous system (CNS), including the spinal cord,
brain stem, limbic system and the preoptic area of the hypothalamus. The
initial impulses about body core temperature are sent by sensors found in
different parts of the body, including the spinal cord, intra-abdominal veins
and the gastrointestinal tract. The final role is played by peripheral blood
vessels which dilate or constrict to lose or preserve heat respectively, in
response to impulses form the CNS. This system is modulated by serotonergic and
noradrenergic impulses. Hot flushes occur when the core body temperature
increases above the sweating threshold, which leads to peripheral
vasodilatation with increased blood flow to lose heat. On the other hand, when
the core body temperature falls below the shivering threshold, peripheral
vasoconstriction leads to heat conservation within the body. The question to
ask now is why some and not all women have hot flushes, and to different
degrees of intensity? It has been suggested that women prone to hot flushes
have a narrow thermoregulatory zone (core body temperature range), at which
neither sweating nor shivering occurs (24). This zone may be further narrowed by sympathetic
stimulation, which explains why stressful stimuli bring about hot flushes. On
the other hand, drugs that suppress the sympathetic tone widen this zone. A
similar effect is also caused by oestradiol. (26).
The differential diagnosis of vasomotor symptoms includes anxiety state, thyrotoxicosis, carcinoid syndrome and phaeochromocytoma. Accordingly, usual medical
acuity should be exercised to exclude these possibilities before assuming
oestrogen deficiency symptoms, especially in younger women. Older symptomatic
women not responding to HRT should also be investigated for these
possibilities. Twenty four hours urine 5-HIAA (5-hydroxyindolacetic acid)
should be measured in suspected cases of carcinoid syndrome. False negative
results are not uncommon, as the excretion rate is variable, and the test may
need to be repeated. On the other hand, false high urine 5-HIAA can be caused
by certain types of food including bananas, pineapples, coffee and chocolates.
Suspected cases of phaeochromocytoma should be investigated with plasma and 24 hour urine catecholamines and metanephrines. These tests have got
certain limitations. Catecholamines have got short half-life which may lead to
a false negative result if a single assay is performed during intervals between
surges of high blood pressure (27). Accordingly,
measurement of metanephrines is preferred as they act as direct tumour markers
and indicators of catecholamine release (28).
Inaccuracy of 24 hour urine collection can lead to false positive and false
negative results, if the collection time exceeded or was less than 24 hours
respectively. In a recent study Lenders et al found plasma metanephrines
measurement had 100% sensitivity for diagnosing phaeochromocytoma, compared to
89% for the urinary products (29). This
discrepancy caused by problems with urine collection was corrected by measuring
the urinary metanephrines-to-creatinine ratio, which improved the sensitivity
to 100% (28).
These symptoms usually occur within 1-3 years after
the menopause, and about 50% of women may have them by the 5th – 8th
year. They are mainly related to loss of skin and joints collagen and
urogenital atrophy; the later one being more distressing.
Prolonged lack of oestrogen can lead to atrophy of
the vaginal skin and the area of the vestibule, and may affect 60% of
postmenopausal women. This figure may be an underestimation of the real
incidence, as it is usually an under diagnosed and inadequately treated
condition (30). It
can lead to burning sensation, irritation and rawness which may affect sexual
relationship. Superficial dyspareunia can be a real problem, which can progress
to vaginismus, loss of libido and apareunia. A figure of 32% has been quoted
for women who lost sexual relations because of vaginal skin dryness and atrophy
(31). The problem can be magnified by atrophy of
the epithelium covering the urethra and trigone, as they share an embryonic
origin with the lower vagina from the urogenital sinus. This can lead to
increased frequency of micturition, and other voiding problems. Unlike hot
flushes, symptoms of vaginal atrophy tend to get worse with time and may show
for the first time 10 years after the menopause. Some statistics have been
reported by Dennerstein et al in 2000 (32) in
relation to the development of vaginal dryness. They quoted an incidence of 3%
in perimenopausal women, and 21% and 47% incidence one and three years after
the menopause respectively.
Sexual dysfunction in mid-life women has also been
positively correlated to depressive symptoms and poor general health. It is
remarkable that women who showed higher total testosterone and free
testosterone index, but not oestrogen, had better sexual drive and relationship
(33). This may justify the use of testosterone
supplements to improve this aspect of patients’ lives. Intrinsa (Procter and
Gamble) transdermal patches can be used every 3-4 days, and provide 300 µg
testosterone every day. Patients should be warned against androgenic side
effects which can be permanent. Other adverse effects include migraine headaches, insomnia, weight gain and breast
Changes in collagen fibres can affect tendons tensile
strength, leading to painful joints on movement. This is usually a neglected
problem, and occasionally a diagnosis of arthritis is made. Certain women are
liable to lose their skin moisture and elasticity more than others, which
results in wrinkles and premature ageing. This can have devastating
psychological effects. Skin ageing is usually affected by many factors being
genetic, environmental or hormonal. Natural or intrinsic ageing is usually characterised by smooth pale finely
wrinkled skin, and dryness. On the other hand, photo-ageing which follows excessive exposure to the sun is
characterised by severe deep wrinkles, as well as pigmentation changes, such as
solar lentigo and mottled pigmentation (34). A woman in her 50s may look much older than her
siblings, especially those on HRT which is known to preserve skin moisture, as
well as collagen and elastic tissues integrity. Nevertheless, the last author (34) questioned the use of HRT for the sole indication
to prevent or reverse skin ageing. This view may well change with time,
especially as topical conjugated oestrogen cream medication resulted in
significant improvement of fine facial wrinkles in postmenopausal women (35). Beside the cosmetic issues, decrease in skin
collagen and thickness have been found to correspond to reduction in bone
mineral density (36). Accordingly, it can be
used as an early indication for investigating bone density, to pre-empt future
Long term effects of oestrogen deficiency
The two main problems in this group are osteoporosis and coronary heart disease (CHD). The mostly
affected bones are the femur neck and vertebral column. Long term
hypo-oestrogenism can be complicated with femoral neck and vertebral crush
fractures, as well as wrist and Colles fractures. It is estimated that 1 in 7
postmenopausal women sustain a fractured neck of femur. Furthermore, 40-50%
will sustain such a fracture before the age of 75 years. The serious point
about these statistics is that about 3 of 5 postmenopausal women will not lead
an independent life after a fractured hip, and there is 20% mortality within
one year. This is on top of the large expenses necessary to care for these
women. With advancing years after the menopause, osteoporosis gets worse but
more so in the following groups of patients:
history of osteoporosis;
- Low peak
bone mass by the age of 20 years;
- Early age at
production of oestrone by adipose tissue in underweight patients;
used of corticosteroids;
The relationship between osteoporosis and hypo-oestrogenism can be related to
excessive parathyroid hormone activity, and reduced calcitonin secretion with
increased osteoclastic activity. Oestrogen counteracts parathyroid hormone and
1, 25 dihydro vitamin D bone resorbing action. It also stimulates calcitonin
secretion. On the other hand, oestrogen receptors are found in bone.
Accordingly, it can act directly by increasing proliferation of osteoblasts
through production of IGF-1 and TGF-β, and inhibits osteoclasts differentiation
from their bone marrow precursors.
The other important effect of long term oestrogen
deficiency is on cardiovascular disease (CVD), which accounts for 1 in 4 deaths
in women after the age of 50 years.
There are more deaths from breast cancer in women under the age of 50
years than from strokes and ischaemic heart disease combined. This pattern is
reversed after the menopause. Furthermore, the life time risk of death from
heart attacks, stroke and hip fractures is greater than the risk of death from
breast cancer. The risk of CVD increases with time, irrespective of the age
when the menopause occurred. However, endothelial-dependent vasodilatation
usually deteriorates after the menopause and attains similar levels to older
men by the 6th decade of life (37). This
follows a significant decline in the oestrogen protective effect on vascular
endothelial function, which is a critical factor in causing CVD. Oestrogen
modulates endothelial function by enhancing nitrous oxide (NO) release and by promoting
vasodilatation (38). The postmenopausal state is
also associated with higher levels of inflammation markers including
interleukin-6 (IL-6) and tumour necrosis factor-a (TNF-a), as well as
reduced antioxidants which indicate increased oxidative stress (39). Many other factors
increase the risk of CVD including obesity, high blood pressure, diabetes
mellitus, smoking, raised triglycerides and LDL cholesterol and reduced HDL
It is clear that quality of life can be affected in
different ways at different stages of the climacteric and postmenopausal
periods. This is a distressing situation, as more women now live well beyond
their 70th birthday. Such a long life is associated with increased
risk of postmenopausal medical problems. Central obesity and its detrimental
effects on CVD have already been alluded to. On the other hand, there is a
tendency for blood pressure to increase with age in women. By the age of 69
years, almost 80% of women have hypertension (40). Even a high normal blood pressure of 140/90 is
associated with increased risk of CVD, and small reductions in blood pressure result
in major reduction in CVD risk. In mathematical terms, it has been suggested
that reduction of 10 mm Hg in systolic pressure during the menopausal
transition results in 25% reduction in cardiovascular events. It is evident
that many factors can be addressed to reduce the risk of CVD through changes in
life style, loss of weight, regular exercise, strict control of diabetes and
high blood pressure.
It is unfortunate that a lot of confusion has clouded
the management of the menopause with HRT, because of much publicised increased
risk of breast cancer, and coronary heart disease. This
is partly due to the initial conclusions drawn from the Women Health Initiative
Study (41), and other
similar publications. Unfortunately, the medical profession fell into the traps
set by the Media, and magnified the negative points in these reports, in spite
of the known flaws with those studies. Many young women, even those with
premature ovarian failure have been deprived of HRT, and are leading miserable
lives. Alternative remedies of unquantified benefits found the right void in
the market to fill, and understandably their unproven alleged safety has been
magnified by the selling vendors.
Many well balanced articles have been published to
put things into their real perspective in relation to HRT use. In 2008 an
expert group (42) published important key
practice points, in relation to HRT use. They suggested that the risks involved
with HRT should be conveyed in absolute numbers rather than percentages.
Furthermore, they recommended HRT for young postmenopausal women to maintain
quality of life, and for primary prevention of cardiovascular risks. They even
recommended testosterone supplementation for women with hypoactive sexual
desire disorder (HSDD) and unexplained tiredness. Regarding breast cancer risk,
they suggested that young postmenopausal women who are about to start HRT for
the first time should be counselled that breast cancer risk does not increase
for the first 7 years. They also stated that unopposed oestrogen replacement
therapy for hysterectomised women does not increase breast cancer risk, and may
even lead to a small reduction in the risk. On the other hand, they stated that
phytoestrogens and herbs are less effective than classical HRT, and their
quality control is questionable. It is important here to reiterate the
beneficial antioxidant and anti-inflammatory effects of oestrogen alluded to
before. Furthermore, adequate exposure to oestrogen during the menopause
transition is believed to reduce or even prevent vascular endothelial
dysfunction by the expression of functioning oestrogen receptors a (ERa) which are
mediators of nitrous oxide release (39).
The benefit of transdermal testosterone system (TTS)
in a low daily dose of 300 µg has been confirmed by many clinical trials
without any significant virilizing effects even after 2 years of use. However, its
effect on metabolism, the breasts or endometrium is not elucidated yet as
discussed by Rymer et al in 2010 (4£). Appropriate
patient’s selection is also important, to reduce the unwanted complications. It
is indicated mainly for women with hypoactive sexual desire disorder as part of
a total management plan, as the condition itself is multifactorial. It may be
related to psychiatric conditions or temporary psychological issues, medical
conditions and the use of pharmacological agents. Reduced sexual desire
disorder is more common in women who had surgical menopause compared to
premenopausal women and those who had natural menopause (44). Oral testosterone formulations should be avoided,
as they undergo first-pass hepatic metabolism. Prolonged use may lead to
hepatic dysfuncion, hepatomas and hepatocelluar carcinoma. Oral medication has
also been shown to reduce high density lipoproteins (HDL), and increases
triglycerides blood levels in oestrogen treated women. It is good practice to
perform liver function tests and a fasting lipid profile before starting
testosterone mediction, and at regular intervals while on medication. It has
also been stated that testosterone medication could not be recommended without
concomitant oestrogen therapy (45).
to HRT use
HRT is contraindicated in the following conditions,
and other methods should be considered instead:
Active liver disease;
Undiagnosed genital bleeding;
Current, past or suspected breast cancer;
Oestrogen dependent malignancy e.g. endometrial carcinoma;
Active or recent venous or arterial thromboembolic
Porphyria cutanea tarda.
In these circumstances another non-hormonal
medication should be used:
which is an a adrenergic
agonist, was the only alternative available in the past. It is no longer a
second line medication, because of its many side effects which include
hypotension, fatigue, drowsiness, insomnia, constipation and dry mouth.
serotonin reuptake inhibitors (SSRI) have proved useful, in combination
with noradrenaline reuptake inhibitors (SNRI). Venlafaxine proved useful
in relieving vasomotor symptoms and low mood without having a sedative
effect, but is not useful in relation to bone density preservation. It can
be started in a dose of 37.5 mg every day. With inadequate response the
dose can be stepped up to 75 mg daily. This may reduce side effects and
improves compliance. The dose should also be tapered before stopping the
has also been shown to improve vasomotor symptoms. This was a
coincidental observation in postmenopausal women who had chemotherapy for
breast cancer. This observation has since been followed prospectively in
controlled studies. Guttoso et al in 2003 found no difference between
gabapentin and conjugated equine oestrogens in the management of hot
flushes (46). A similar conclusion has been
reached by Aguirre et al in 2010 who found gabapentin in a daily dose of
600 mg to be as effective as low dose transdermal oestradiol (25 µg/day)
in controlling moderate to severe hot flushes (47)
depressants can be used when clinical depression is diagnosed.
- Phytoestrogens, on the
other hand, can improve menopausal symptoms, but their safety in patients
with contraindications to classical HRT has not been studied.
The use of DHEA as a form of nutritional HRT
supplement has been alluded to before. It has been used in daily doses of 25 mg
and 50 mg by Genazzani et al (6) and Stomati et
al (48), respectively. They reported increased
blood levels of oestrogens, DHEA, androstenedione, testosterone,
allopregnenolone, and b-endorphins in postmenopausal
women. Beside the beneficial effects of the steroidal hormones,
allopregnenolone and b-endorphins have anxiolytic effect
and promote relaxation and feeling of wellbeing. Using the lower dose of 25
mg/day resulted in significant improvement in vasomotor symptoms and
psychological disturbances during the early and late postmenopausal years
respectively (6). Furthermore, there were no
detrimental endometrial changes even after 12 months of medication, as shown by
thin endometrial echoes during repeated ultrasound scan examinations. The exact
effective and safe daily dose of DHEA is not yet established. A case report
published by Sahelian and Borken in 1998
reported cardiac arrhythmia as a side effect of DHEA when used in a daily dose
of 25 mg (49). Another important drawback of
this medication is that monitoring blood or saliva DHEA levels do not reflect
its biological effects at tissue level. Even a more important fact is that a Cochrane review
published in 2006 found little evidence from controlled studies to support a
beneficial effect of DHEA supplementation on cognitive function of non-demented
middle-aged or elderly people (50). However, it
did not find consistent evidence of any adverse effects. Currently doses of
5-50 mg tablets are marketed through various venues including the Internet,
with no medical control.
It has been recommended that HRT should be used in
the smallest effective dose for the shortest period of time. Setting a short
time limit has been criticised as false, and treatment should be continued as
long as it is needed by the patient. Nevertheless, regular reassessment of the
indication and the dose should be done on an annual basis, at least. The
minimum effective daily starting doses for oral oestradiol have been reported
as 0.5-1.0 mg, and 0.3-0.45 mg for conjugated equine oestrogen. The equivalent
doses for transdermal oestradiol patches and oestradiol gel are 25.0-37.5 µg,
and 0.5-1.0 mg respectively. Assessment of response should be done after 2 – 3
months. About 20% of patients may not have an adequate response, and the dose
will need to be increased. The route of administration should be carefully
selected. Patients with high triglycerides blood levels and migraine headaches should avoid oral HRT, and should have
transdermal medication instead.
It is noticeable that the recommendations put forward
by many official bodies regarding the use of HRT after the publication of the
WHI study (41) have not been changed, despite
the critical reviews and the published evidence against many of these
recommendations. This is especially so for the inappropriate conclusions
regarding cardiovascular disease and breast cancer, as the results had been
generated from older postmenopausal women above the age of 60 years. In a very
critical editorial, Pines et al (4) criticised the planning and the initial conclusions
drawn from the WHI study (41), which
lead to dramatic decline in the number of women using HRT. Unfortunately, the
extrapolation of results from older women and their generalisation to
symptomatic younger patients who have just gone through the menopause has lead
to a sharp decline in the number of women using HRT. Many other reviews
criticised the study on similar grounds. The same authors (51) came to the
conclusion that women should be reassured regarding oestrogen therapy as safe
when initiated near the menopause, and under the age of 60 years. There is also
a potential to improve quality of life in symptomatic women, and reduce their
risk of future heart disease and premature death. Furthermore, they recommended
that symptomatic perimenopausal women with no inherent breast cancer risk
factors can safely use HRT for 7 years.
The only sticky point concerns an increased risk of
thromboembolism with age and obesity in postmenopausal women using oral HRT.
Younger overweight patients are at risk as well. To put things into
perspective, the number of additional cases of venous thromboembolism over a
5-year period was 2-6 per thousand women aged 50-59 years, as reported by the
WHI study itself (41). This
increase was seen only during the first 2 years of oral medication, in women
with a body mass index above 25 kg/m2. Accordingly, women with such
body habitat who develop vasomotor symptoms should have thorough counselling, and other
non hormonal medications can be used instead. Nonetheless, the quality of life
should always be considered in the equation when counselling these patients.
Transdermal HRT can be used in cases with severe symptoms not responsive to
other medications. Production of vitamin K-dependent coagulation factors by the liver is directly correlated to the
dose of oral oestrogen used. Furthermore, oral medication can induce activated
protein C resistance in some patients. Both effects were not seen
in patients using transdermal oestrogen HRT. Moreover, oral oestrogens reduce
the level of anti-thrombin III which inhibits activated coagulation factors (52). A recent review of the available biochemical and
clinical data by Birge in 2008 (532) suggested
that women on low dose transdermal oestrogen medication are not at increased
risk of cardiovascular disease, stroke, venous thrombotic disease, or even
breast cancer. In fact Canonico et al in 2007 showed a decrease in venous
thromboembolism in patients using transdermal menopausal hormone replacement
therapy (54). However there was no decrease in
acute CHD attacks in women with angiographically demonstrable ischaemic heart
The risk of endometrial cancer is a real one in women
using unopposed oestrogen replacement therapy (ERT). Accordingly, the endometrium should
always be protected with 12-13 days of a progestogen medication. Alternatively,
the mirena system is a good alternative for this purpose, with
the high local concentration of levonorgestrel. This is especially useful, as
continuous ERT can be given without a break, especially for patients who
developed bad vasomotor symptoms during the HRT free one week episode. It is
important to mention here that a case control study published in 2010 showed increased
risk of breast cancer, whether the mirena system was used alone or together with
ERT (56). This is a significant finding which could
sway many gynaecologists and patients from recommending and using the mirena system
respectively. However, more studies are needed to confirm this finding. Doctors
may start looking again to alternative progestogens to use. It has been mentioned
that progestogens derived from natural progesterone and dydrogesterone have
lower risk for promoting breast cancer than synthetic progestogens derived from
C21 progesterone and 19-nortestosterone (57), used
during combined therapy.
Younger symptomatic women, especially those with
premature ovarian failure, usually need a higher dose of oestrogen compared to
patients who went through the natural menopause. For non smoker healthy
patients in this group, an oral contraceptive pill will be a reasonable option
to provide the necessary oestrogen replacement, and to maintain regular
withdrawal bleeding. Older women can have dedicated HRT combined medication,
either orally or in a transdermal form. The later form is more physiological as
it does not have the first hepatic pass, in contrast to the oral route.
Women on continuous combined HRT are more at risk of having breakthrough
bleeding, which may cause alarm especially in older postmenopausal women.
Accordingly, they should have endometrial assessment if they continue to have
irregular bleeding for the first 6 months of treatment, or if they develop
abnormal uterine bleeding for the first time after long uneventful use of HRT (58).
The ideal drug to deal with postmenopausal medical
problems should have the following characteristics, as discussed in the
- It causes no
detrimental haematological or biochemical changes;
- It controls
all the acute and intermediate symptoms effectively;
- It does not
lose efficacy through tachyphylaxis after prolonged use;
- It has good
safety margin when used for long periods of time;
- It does not
cause abnormal uterine bleeding;
- It reduces
risks of cardiovascular diseases;
- It does not
increase the risk of uterine cancer;
- It does not
increase breast cancer rate;
- It prevents
osteoporosis and reduces bone fracture risks.
Obviously, none of the available drugs has all these
attributes, and we should make the best out of what is available to us
currently. Most important is the fact that hypo-oestrogenic women should not be
denied medical help and left to suffer because of our current misinformation
regarding the magnitude of the potential risks involved. Patients should be
involved in decision making, because quality of life is a personal choice. This
is especially so, as the medical evidence against using HRT is far from compelling.
oestrogen receptor modulators
Selective oestrogen receptor modulators (SERM) are non steroidal compounds which have
an oestrogenic effect on one or more target tissues, with anti oestrogenic
effect on others. The first generation SERM tamoxifen is widely used for the
treatment of breast cancer. Other second generation drugs have been produced
for the treatment of osteoporosis, especially in patients over the
age of 60 years. However, they have similar thromboembolic risks like
Bisphosphonates are used for the treatment of osteoporosis. They reduce bone turnover and
accordingly reduce spontaneous bone fractures and bone pain (58). However, reports of osteonecrosis of the jaws
have been published. The risk factors for such complication included old age,
prolonged use of the drugs, dental disease, dental extraction, prolonged use of
steroids and diabetic state. Accordingly, it has been advised by Goss (60) that before
commencing treatment with a bisphosphonate, a patient should be dentally fit
and should have regular dental checks while on treatment.
It is evident that many alternatives to HRT are
available for the treatment of osteoporosis in postmenopausal women. They have different
effects on the vertebrae and femur. Alendronate, ibandronate, intranasal
calcitonin, parathyroid hormones, raloxifene, risedronate, strontium ranelate
and zoledronate reduce the risk of vertebral fractures. At the same time
alendronate, risedronate, strontium ranelate and zoledronate reduce the risk of
hip fractures as well (61). Accordingly, there
is a wide choice for selecting the more suitable treatment, without the need to
prescribe HRT for women over the age of 60 years, and those with higher risks
of breast cancer or cardiac disease. Other important measures to reduce the
risk of fractures include intake of calcium and vitamin D, as well as
appropriate weight bearing exercise. It is also important that patients with
osteoporosis should be careful with their life style, because of their
increased liability to sustain fractures on trivial trauma.
A special note will be made at this point about the
management of patients with urogenital atrophy. It has already been stated that
the condition is under diagnosed, despite its immense negative effects on the
patients’ health and sexuality. This is especially so in patients who had
breast cancer, as the use of HRT is considered inappropriate or not a preferred
option by the patient, because of safety issues. It may not be appreciated that
almost 45% of patients on systemic HRT still suffer from urogenital symptoms (62). In both
groups of patients vaginal oestrogen medication can be used to reverse the
atrophic skin changes and relieve the associated symptoms. It is also effective
in increasing the number of periurethral blood vessels in postmenopausal women
(63). This may explain the significant
improvement in urinary stress incontinence felt by patients while on similar
treatment, shown by a metaanalysis conducted by Cody et al in 2009 (64). Paradoxically, the same authors reported that
systemic conjugated equine oestrogen replacement therapy made incontinence
worse in some patients. This was in disagreement with a randomised prospective
study conducted by Long et al in 2006 (65). They
found improved blood flow around the bladder neck and mid-urethra, and almost
equal relief of symptoms of overactive bladder and stress incontinence
following oral and transvaginal oestrogen replacement therapy, despite lower
serum oestradiol levels following vaginal medication.
There is no evidence that transvaginal oestrogen
replacement therapy increases the recurrence rate of breast cancer, as shown by
a small study (66). Larger controlled randomized
trials are necessary to confirm its absolute safety. Long term follow up
studies showed no need to recommend the use of progestogens with this
medication, as no evidence of endometrial proliferation could be shown even
after 6-24 months of treatment (27). A
distinction should be made between oestriol and conjugated equine oestrogen
cream on one hand, and oestradiol tablets and low dose oestrogen rings on the
other, as the first two can cause small increase in serum oestradiol (67). A metaanalysis published by Suckling et al in
2006 (68) reported significant uterine bleeding,
breast pain and perineal pain following conjugate equine oestrogen use when
compared to vaginal tablets in one study. It also reported significant
endometrial stimulation by one study following the use of the same cream when
compared to the vaginal ring. Accordingly, one should use oestradiol tablets
(vagifem 25 µg, Novo Nordisk) or low-dose oestrogen rings (estring, Pfizer) for
long term HRT, to guard against these side effects. Oestrogen vaginal tablets
and cream are licensed for continuous use for 3-6 months in the United Kingdom,
whereas low-dose vaginal ring is licensed for two years. One study showed that
most women preferred using the ring over other vaginal medications because it
was convenient and under their own personal control (69).
The ring should be changed every 3 months. In a more recent literature review,
Santos and Clissold (70) recommended the use of
vaginal promestriene which is a synthetic analogue of oestradiol by patients
who present with severe vulvo-vaginal symptoms and history of breast cancer. This
view can be explained by previous findings by Wolff et al in 1982 (71) who documented a good local anti-atrophic effect
following vaginal promestriene with no oestrogen-like systemic effects.
Endometriosis, fibroids and HRT
Two other special groups of patients need to be
addressed as well; those with history of endometriosis and those with uterine fibroids. The first
group is usually made of younger women who had radical surgery to remove the
endometriosis, including bilateral oophorectomy. Older women with history of
endometriosis who were treated medically or by conservative surgery before the
menopause may also need HRT. A small undefined risk of recurrence or malignant
transformation of endometriosis had been suggested, but the general consensus
is that the benefits of using HRT far outweigh the risks, as suggested by
Soliman and Hillard (72). This is especially so
for patients who had surgery at a young age. It is generally advisable to use
combined HRT with both oestrogen and progestogen, as unopposed oestrogen
imposes a higher risk for recurrence. Nonetheless, there are no clinical trials
to address the role of progestogens in this respect, as stated by the same
The effect of HRT on fibroids is similarly not well
quantified, and the risk of increase in fibroids size has been used as a factor
to deny women HRT, especially those who were symptomatic before the menopause.
An increase (73) and
no change in the size of the fibroids (74) have been reported after using oral HRT, in doses
of 0.625 conjugated equine oestrogens, with 5.0 mg or 2.5 mg
medroxyprogesterone acetate (MPA) respectively. The first authors
documented the change in size only during the first 2 years of medication (73). On the other hand, a randomized study showed
significant increase in fibroids size after using transdermal 50 µg of ethinyl oestradiol and 5 mg MPA for one year.
Tibolone (xxxx) which has oestrogenic, progestogenic and androgenic effects did
not cause an increase in fibroids size in the same study (75). This fact has been confirmed by other studies (76, 77), which makes it
a good option for postmenopausal women with fibroids who need HRT. Even with
increased fibroids size, there are no related symptoms usually. Nonetheless,
intracavitary fibroids can behave differently, and can cause abnormal uterine
bleeding (78), but this was not a universal
observation for all patients with similar lesions. Following a hysteroscopic
study, Perrone et al (79) described intrauterine
lesions in 37% and 26% of the patients who did or did not have abnormal uterine
bleeding respectively while on HRT. Other benefits attributable to tibolone are
that it reduced blood pressure, TNF-a and glycaemia
levels in healthy postmenopausal women without any bad effect on other
inflammatory factors. It did, however, reduce HDL-cholesterol levels (80). These factors should be considered when
breast conditions and HRT
Women with histologically diagnosed atypia have 4-5
fold increased risk of developing breast cancer (81).
The Women’s Health Initiative Study showed increased diagnosis of benign breast
conditions associated with combined and unopposed HRT use (82). However, neither HRT method was shown to impose a
higher risk of cancer in patients with benign breast conditions than the
observed general population risk (83, 84). Current evidence shows that HRT, both combined or
unopposed, does not affect the prophylactic effect of bilateral oophorectomy
until the age of 50 years in premenopausal women with BRCA1 and BRCA2 mutations (85). There is
no data for postmenopausal women to make affirmative conclusions. More
information will be available after the publication of the Epidemiological
Familial Breast Cancer, Cancer Research UK report.
examinations and mammography
Women should have a full general examination before
starting HRT, including weight and blood pressure. The role of repeated breast
examinations is controversial, as it did not reduce breast cancer mortality in
different studies. It can also result in a high number of false positive
results, which may lead to unnecessary investigations and anxiety (86). Similarly, routine baseline mammography is not
indicated before starting HRT, as recommended by the Royal College of
Radiologists (87, 88).
The situation is rather different in patients with personal history of benign
breast disease with atypia, or first degree family history of premenopausal
breast cancer (86). Patients between the ages of
50-65 years should be encouraged to have regular 3-yearly mammograms. Both
combined and unopposed oestrogen HRT reduce the diagnostic sensitivity and
specificity of mammography (89, 90). Reduced sensitivity could lead to increased
interval cancer rates, delays in diagnosis, and worsens prognosis. On the other
hand, reduced specificity may lead to increased positive false diagnostic
implants and tachyphylaxis
A final note is due at this point about oestradiol
implants which were very popular in the past in doses of 25, 50 and 100 mg.
They were mainly used after surgical removal of the ovaries to deliver
oestradiol in a controlled manner over prolonged periods of time, hence reduce
the need for frequent medication. They were also used for general management of
postmenopausal symptoms, at a time when other non-oral medications were not
available. However, they are not as popular now and many young doctors may not
even have seen any being inserted. Unfortunately, a few women using oestradiol
implants develop tachyphylaxis, which indicates recurrence of postmenopausal
symptoms despite high plasma oestradiol levels. This was related to the rate of
fall in oestradiol blood level, rather than the absolute level itself (91). Such phenomenon was seen more often in patients
who had history of psychopathology or surgical menopause (92), and had more frequent implant insertions.
Prevention of tachyphylaxis should be an important objective, even before
initiating this type of medication, as treatment is difficult once the problem
is already established. Templeman et al in 1998 found no relationship between
the recurrence of symptoms and oestradiol blood level (93).
They also found that repeating implants adminstration without taking notice of
oestradiol blood level resulted in continuous increase in its basal level. This
should be expected as implants usually continue releasing oestradiol for much
longer periods of time than the 6 monthly gaps usually used between
medications. This was shown by a case report published by Wardle and Fox in
1989 (94). Oestradiol levels were 1211 pmol/l,
673 pmol/l and 169 pmol/l one year, 18 months and 3 years after the last
implant insertion respectively. Counselling patients regarding the lack of
agreement between symptoms score and oestradiol blood levels, and the medical
risks related to high oestradiol blood levels was shown to reduce the
possibility of developing tachyphylaxis (93).
Patients should understand that the main biochemical objective of HRT is to
restore premenopausal oestradiol blood levels with exogenous medication, and no
extra oestradiol will be administered when blood levels >400 pmol/l. Such levels
were maintained by 50 mg oestradiol implant insertions every 9.7 – 11.7 months
as reported by Buchler et al in 1995 (95). They
concluded that there was no need for more frequent prescriptions of oestradiol
implants, and suggested annual adminstration instead.
There are no controlled studies regarding treatment
of established cases of oestradiol tachyphylaxis. Further implant insertions
should be avoided, as long as oestradiol blood level is high. The importance of
thorough patients’ counselling regarding the medical risks of super
physiological oestradiol blood levels has been alluded to before. Symptoms may
be controlled by prescription of small doses of transdermal oestradiol,
testosterone implants, or combined noradrenaline / serotonin reuptake inhibitors
(Venlafaxine). The later treatment modality may be combined with a smaller
implant (25 mg instead of 50 mg) in difficult cases, and progressively
prolonging the period between implant insertions. Patients with psychiatric
manifestations who are more prone to develop tachyphylaxis should receive
Women live longer nowadays after the menopause, and
expect better quality of life than their mothers and grandmothers. Accordingly,
good control of the acute vasomotor symptoms, and reduction of the long term
problems related to osteoporosis and CVD became a pressing medical necessity.
This will also reduce the national budget necessary to cater for women who have
already developed such problems. The current available options of different
medications, both hormonal and non hormonal are wide enough to suit different
needs. Proper selection and regular follow up on one hand, and adequate
education of the patients on the other, are necessary. Family history and other
risk factors of breast cancer, thrombophilia, and dyslipidaemia should be taken
It is important to differentiate between women below
and above the age of 60 years, when dealing with HRT. The effect of age in relation to breast
cancer risk is well known. Furthermore, HRT is considered a promoter of
pre-existing malignancy rather that an initiator of malignant transformation (96, 97), and promotes oestrogen receptor positive tumour
(98). It is also associated with low grade
invasive cancer at diagnosis. The review article published by Hodis and Mack in
2009 (99) explicitly addressed the risk of
coronary heart disease (CHD) in relation to HRT. The main difference between
the outcome of randomised controlled studies and the observational ones, mainly
the WHI, was the age of the patients studied. The first group dealt with
younger women, whereas the later ones dealt with older ones in relation to the
menopause. Both HRT and SERMs reduced the risk of CHD in women <60 years,
and in those who started treatment within 10 years of the menopause. Similarly,
the current data
showed no increased risk of stroke with HRT in younger (50–59 years)
normotensive postmenopausal women, particularly when lower doses were
prescribed soon after menopause (100). A major
support for the use of HRT in young women during the menopause transition, or
soon after the menopause came from the writing group on behalf of the Workshop
Consensus Group of the International Menopause
Society in 2009 (40).
These recommendations agree with the scientific finding that oestrogens have
beneficial and protective effects on the vascular endothelium. Such effect is
even evident during the normal menstrual cycle in premenopausal women because
of the variations in circulating oestrogen levels. Endothelial-dependent vascular
dilation is greater during the later part of the follicular phase compared to
the earlier part of the cycle (101). Beside its
vasodilatation effect, oestrogen also has direct antioxidant and anti-inflammatory
effects, both in vivo and in vitro (39).
At this point it is important to re-emphasise the need to convey risks
in absolute numbers rather than percentages (42) to avoid
needless alarm. This is well illustrated by the data related to breast cancer
risk. The calculated risk by the age of 50-70 years for women who never used
HRT is 45 cases per 1000 women. Using HRT for 5, 10 and 15 years is expected to
result in 2, 6 and 12 extra breast cancers per 1000 women respectively, by the
age of 70 years (102). Expressing these figures
as percentages of the basal risk of 45 cases per 1000 will give alarming
increased risks of 4.4%, 14.2% and 26.6% respectively.
high time for the regulatory authorities to change their recommendations which
were made after the publication of the WHI, to match the new evidence and
critical appraisal of that study and other similar ones. This view has been
voiced before by many experts in the field (103, 104). HRT is safe and beneficial, when used
by the right patient, and under the right supervision. Furthermore, women
should be treated as individuals, and their views should be taken into consideration when they request HRT.
The risk-benefit ratio should be assessed and discussed with them, before
prescribing any type of medication.
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