Добавил:
ivanov666
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Age endocrinology. Study aid for students of medical universities
.pdf
51
contraceptives contain synthetic analogues of estrogen and progesterone. The most
commonly used estrogen analog is ethinyl estradiol. The progestin component in oral
contraceptives is more diverse, with varying degrees of androgenic activity. A
systematic review of 22 studies evaluating the effects of contraceptives on cognition
concluded that oral contraceptives may improve verbal memory performance. It was
also concluded that the effect of contraceptives on visuospatial abilities depends on
the androgenicity of the progestin component. In particular, improvements in the
mental background were associated with the progestin component with androgenic
activity and deterioration with antiandrogenic types of drugs. The studies also
examined the effects of exogenous testosterone on cognition in a dose- and agedependent manner in the women included in the studies. As a result: in women of
reproductive age, a single dose of testosterone (at concentrations equal to the level of
testosterone in men) improves visual spatial abilities.
Thus, increases in sex hormone levels during prenatal and puberty appear to
contribute to sex differences in cognition, with the strongest evidence linking
androgens to spatial reasoning and brain lateralization abilities. There is no
convincing evidence of significant cognitive changes during the phases of the
menstrual cycle. At the same time, the available data indicate a potential positive
effect of contraceptives on speech abilities (potentially associated with the estrogen
component), on spatial thinking (depends on the androgenicity of the progestin
component). However, further research is needed to fully understand the impact of
various contraceptive drugs (and their components) on cognitive function.
6.3. CHANGES IN SEX HORMONES AND COGNITION
THROUGHOUT LIFE: POSTMENOPAUSE, AGING
The natural transition to menopause is associated with fluctuations and,
ultimately, a decrease in the synthesis of estrogen and progesterone by the ovaries, as
well as an increase in serum FSH. Menopause can also be induced surgically for
medical reasons. The impact of both menopause (natural and surgical) and aging on
cognitive function is complex, with considerable individual variability. In addition to
menopause, cognitive function is likely to be affected by affective disorders, life
experiences and psychosocial stress, as well as a genetic predisposition to cognitive
impairment.
Natural menopause is often characterized by subjective cognitive complaints,
especially in terms of memory. Studies have confirmed that natural menopause is
associated with decreased verbal memory and verbal fluency, and subjective memory
52
complaints have also been associated with objective changes in attention and working
memory that are not solely attributable to sleep or mood disturbances, but suggest an
association with changes in the HPG axis hormones.
Early surgical menopause is associated with an increased risk of cognitive
impairment and dementia later in life. The hormonal changes associated with bilateral
oophorectomy depend on the timing of the oophorectomy. Bilateral oophorectomy
before natural menopause causes a sharp drop in estrogen levels, as well as
progesterone and testosterone levels. Several large-scale studies, including the Mayo
Clinic cohort study on oophorectomy and aging; a nationwide Danish cohort study,
The Religious Orders Study and the Memory and Aging Study, report an increased
risk of cognitive impairment and dementia with age after oophorectomy. However,
women who started hormone replacement therapy after premenopausal
oophorectomy and continued it until the natural age of menopause did not have an
increased risk of developing Alzheimer's disease (AD).
Age-related declines in cognitive functions are recorded in most cognitive
areas of the brain. Sex differences in cognitive changes in healthy aging have been
explored in several studies. In a longitudinal study of healthy older adults (part of the
Baltimore Study on Aging), McCarrey and colleagues confirmed existing theories
suggesting baseline sex differences in cognition as well as demonstrating sex
differences in cognitive changes during aging. At baseline (mean age 64.1–
69.7 years), women outperformed men on tests of verbal reasoning, including verbal
memory and fluency. Men demonstrated superior spatial reasoning compared to
women at baseline and higher rates of further cognitive decline in relation to
psychomotor speed with increasing age.
Endocrine changes that accompany aging may also contribute to age-related
cognitive decline. Sex differences are also observed in neurodegenerative processes
during brain aging. In women, the production of estrogen and progesterone decreases
significantly with reproductive aging. The main forms of estrogen are estriol
(elevated during pregnancy and not well understood for effects on cognition), 17βestradiol (the most potent form of estrogen), 17α-estradiol, and estrone. After
menopause, the ratio of estadiol to estrone changes, towards an increase in estrone
compared to estradiol. Unlike estrogen, female testosterone and its precursors decline
gradually with age, starting in the third or fourth decade. Testosterone can be
converted via aromatase to estradiol, which exerts its action via estrogen receptors; or
through 5α-reductase to dihydrotestosterone, which realizes its action through
androgen receptors. In contrast to the dramatic decline in gonadal hormone levels in
53
women, men are known to experience a slight and progressive decline in testosterone
and DHEA, and an associated increase in LH, FSH, and SHBG.
6.4. SEX HORMONES AND GENDER DIFFERENCES
IN ALZHEIMER'S DISEASE
For men and women, the age-related decrease in the concentration of sex
steroid hormones is associated with an increased risk of cognitive decline. About 60–
80 % of all dementias are due to AD, and about two-thirds of those diagnosed with
them are women. Increasing life expectancy in women complicates the interpretation
of sex differences in AD prevalence estimates. With increasing life expectancy (with
no change in mean age at menopause), women now spend approximately one third of
their lives with significantly reduced levels of estradiol and progesterone (compared
to premenopause). The decrease in postmenopausal ovarian production of hormones
and the associated loss of their neuroprotective effects are associated with an
increased incidence of AD in women. There is also preliminary evidence to suggest
that a later age at menopause and/or a longer reproductive period (indicative of a
longer exposure of female sex hormones to the body) may be associated with higher
cognitive performance and slower cognitive decline.
Gonadotropin levels, especially LH, have been shown to play a role in
cognitive decline. In postmenopausal women, a decrease in estrogen levels leads to
an increase in LH production. LH receptors are expressed in cognitively relevant
areas of the brain such as the hippocampus, which is affected in AD. The level of LH
is inversely proportional to cognitive functions. High plasma LH levels were
significantly associated with memory impairment (in men without dementia), poor
cognition (according to CAMCOG: Cambridge Cognitive Survey) in older women
without dementia; and plasma levels of beta-amyloid. Consequently, there is growing
evidence that LH is involved in the development and progression of AD.
Women genetically predisposed to developing AD have a higher rate of
cognitive and functional decline after being diagnosed with AD, adjusted for sex, age,
education, and severity of dementia. Sexual dimorphism in AD has been noted in
several mouse models. For example, there were significant gender differences in the
aging trajectory, with female brains showing age-related changes earlier than male
brains. Transgenic mouse models also provided evidence suggesting increased
cognitive impairment, impaired hippocampal neurogenesis, and increased AD -type
pathologies in females compared to transgenic amyloid x presenilin 1 (APPxPS1)
precursor protein male models. Decreased sex steroid levels in female rodents after
54
oophorectomy contribute to an AD -like pathogenesis (eg, increased levels of soluble
β-amyloid protein (Aβ) in the brain).
Gender also appears to modulate the influence of genetic risk factors in the
etiology of AD. For example, an allele of the APOE gene (ε 4), the strongest known
genetic marker for late onset (ie, 65+) AD, makes women at a higher risk of
developing AD than men. A meta-analysis found a stronger association between
APOE-ε4 tau and CSF levels in women compared to men, especially among amyloid-
positive women. Changes in postmenopausal estrogen levels have been hypothesized
to underlie the sex difference in tau APOE-ε4 and CSF, possibly through direct
mechanisms such as estradiol's ability to reduce tau protein hyperphosphorylation or
indirectly through estrogen's ability to reduce beta-amyloid toxicity. Other genetic
variants have also demonstrated a sex-specific effect on the risk of AD development
and progression, such as the Met66 allele of the brain-derived neurotrophic factor
(BDNF) gene, associated with a higher risk of AD in women compared to men.
6.5. SEX HORMONES IN THE TREATMENT OF COGNITIVE IMPAIRMENT:
IS IT POSSIBLE?
While the evidence supporting an association between lower estrogen levels
and the risk of developing AD is relatively strong, the effect of hormone therapy
containing estrogens on improving cognitive function (eg, in postmenopausal
women) or reducing the risk of developing AD remains controversial. For example,
The Women's Health Initiative Memory Study (WHIMS), Women's Health Initiative
(WHI) hormone therapy studies using a modified mental health questionnaire (3MS)
concluded that premarin (estrogen plus synthetic progestin) was associated with an
increased risk of developing dementia and cognitive decline. The WHI and WHIMS
have generated significant public and scientific debate about the risks (risk of cancer,
cardiovascular disease, and dementia) associated with hormone therapy, however, the
initial interpretation of the WHIMS results has been criticized on a number of issues.
These include: the point of view that estrogens can only have a neuroprotective effect
on healthy neurons, and not on those damaged by the disease in connection with this;
version of the “critical window” or “timing” hypothesis, which assumes that hormone
therapy is effective only when it is started at the beginning of postmenopause or
immediately in premenopause (WHIMS included women with an average of 15 years
in postmenopause). Cognitive benefits and/or risks also depend on the type of
hormone therapy. The hormone therapy in the WHIMS study was Premarin, which is
approximately 50 % sulfated estrone, 1 % estradiol, and synthetic progesterone. This
55
is important because 17β-estradiol has a proven positive effect on cognition, while
estrone has been associated with negative effects on cognition.
In the past decade, several observational and randomized, placebo-controlled
trials have provided evidence that hormone therapy can reduce the risk of AD and
that early administration has a protective effect, while later it has no or even side
effects. However, two clinical studies testing the hypothesis of the timing of hormone
therapy in healthy postmenopausal women failed to provide evidence that a greater
effect on cognition is associated with earlier hormone therapy. The Kronos Early
Estrogen Prevention Study (KEEPS) assessed cognitive function in a total of 662
early postmenopausal women after four years of either oral conjugated estrogens
(CEE) plus micronized progesterone or transdermal estradiol plus micronized
progesterone. The results showed that the cognitive functions of the experimental
groups receiving hormone therapy and the placebo group did not differ significantly
from each other. The ELITE study compared five years of oral micronized 17βestradiol (with vaginal micronized progesterone gel) with placebo in women stratified
as “early” menopause (within 6 years of last menstrual period) or “late” (greater than
10 years after menopause). Compared with placebo, estradiol started within 6 years
of menopause had no effect on verbal memory, executive functions, or thinking,
unlike estradiol given 10 or more years after menopause. Of note, the results of these
two large clinical trials showed that there were no adverse cognitive outcomes
associated with hormone therapy. At the same time, further studies are required to
determine the timing of the appointment of hormone therapy to reduce the risk of
developing cognitive impairment, including dementia.
With regard to the hormone regimen, the combination of CEE/synthetic
medroxyprogesterone acetate (MPA) in continuous mode has not shown a positive
effect on cognitive function (regardless of the time of appointment and duration of
administration), while estrogen alone (including studies using ultra-low doses of
transdermal estradiol and CEE), as well as estradiol valerate in combination with
diongest or norechindron, led to an improvement in cognitive functions. The type of
progestogen (progesterone versus various synthetic progestins) was found to be very
significant in terms of its effect on cognitive function. Synthetic MPA is the most
commonly used progestin in hormone therapy regimens, and current evidence
suggests that MPA, unlike progesterone, has a negative effect on markers of
neuroprotection and neurogenesis. Although there are few studies on progesterone
treatment in postmenopausal women, a small 12-week study with 200 mg of
progesterone daily showed improvements in verbal working memory. A number of
observational and clinical studies using testosterone in postmenopausal women have
56
shown that low doses of the hormone (reproducing premenopausal levels) are
associated with improved verbal learning and memory. In older men (over 65 years
of age) with impaired memory and low testosterone levels, testosterone
administration did not show any improvement in memory or other cognitive
functions. Thus, the current evidence does not justify the administration of any type
of hormone therapy to improve cognition or reduce the risk of dementia, and further
research is needed to investigate the potential benefit of estrogens, progesterone,
testosterone, and/or combinations of these to improve cognition and reduce the risk
of AD.
Selective estrogen receptor modulators (SERMs) such as raloxifene provide
estrogen therapy with mixed agonist/antagonist properties, thus avoiding a number of
the adverse risks associated with estradiol therapy. Raloxifene has an antagonistic
effect on estrogen receptors in the mammary gland and uterus, while maintaining an
agonistic effect in bone and brain tissues. Raloxifene, currently approved for use in
postmenopausal women with osteoporosis, has a dose-dependent effect on cognitive
function. Thus, a systematic review of the effect of raloxifene on cognitive function
in postmenopausal women showed that a dose of 120 mg/day can improve cognitive
function. However, further research is needed on the role of SERMs in reducing the
risk of AD and improving cognitive function.
57
7. AGE-RELATED SEXUAL DYSFUNCTION.
THE ROLE OF TESTOSTERONE PREPARATIONS
IN ITS CORRECTION
Sexual dysfunction is a fairly common problem among women of all ages, but
this problem becomes especially relevant during premenopause and menopause (both
natural and surgical). Sexual dysfunction negatively affects the quality of life and
psycho-emotional state. Moreover, the severity of this process can be quite severe, up
to debilitating. Thus, according to the results of the International Women's Health and
Sexuality Survey, it was found that 9–26 % of women in menopause (both natural
and surgical) suffer from a persistent, anxiety-provoking and quality-of-life-reducing
lack of sexual desire.
This problem is multifactorial and often interdisciplinary, which is why it
should be solved taking into account psycho-emotional (depression, anxiety,
relationships in a couple, dissatisfaction with one's own figure, etc.), biological (age,
presence of concomitant pathology) and religious characteristics that prevent
sexuality. But still one of the most important factors affecting the sexual health of
women are sex hormones.
Of course, sex hormones do not independently cause sexual desire, but the
female libido is clearly subject to hormonal regulation.
Evaluation of sexual dysfunction is best done on the basis of a biopsychosocial
model, which should include life history, sexual history, and physical examination.
To make a diagnosis and identify the causes of sexual dysfunction, there is often no
need for laboratory diagnostics. It is also necessary to understand whether a woman's
problem with desire and arousal is a pathology or a normal change in sexual response
in response to an external stimulus, for example.
The concept of sexual dysfunction combines several components — a disorder
of sexual desire and arousal, an orgasmic disorder, dyspareunia or a disorder of
penetration.
Sex drive disorder
For the diagnosis of sexual desire disorder, the American Psychiatric
Association uses the DSM — 5 biopsychosocial model criteria:
1. Absence or pronounced decrease in sexual interest, characterized by at least
three of the following signs:
- complete absence or pronounced decrease in erotic fantasies;
58
- complete absence or marked decrease in sexual activity;
- complete absence or pronounced decrease in arousal and/or pleasure during
sexual activity in the vast majority of sexual contacts (in 75–100);
- immunity to the partner's attempts to start sexual contact and/or lack of desire
and motivation to start sexual activity;
- complete absence or pronounced decrease in sensitivity (genital and/or non-
genital) during sexual intimacy in the vast majority of sexual contacts (in 75–100 %);
- complete absence or pronounced decrease in sexual arousal and interest in
response to any internal or external erotic signals (oral, visual, written, etc.)
2. The above symptoms must persist for at least six months
3. The above symptoms must cause the person severe discomfort and be a
clinically significant disorder
4. The above symptoms cannot be explained by other non-sexual mental
disorders, a consequence of a severe relationship disorder (partner violence), a
consequence of other significant stressors and/or medications, a consequence of
severe comorbidities.
Orgasmic disorder
The concept of female orgasm disorder includes rare orgasms, lack of orgasms,
pronounced delay in orgasm, reduced orgasm intensity for at least six months in 75–
100 % of sexual contacts. It is necessary to establish the fact of the presence or
absence of an orgasm, as some women may not pay attention to this, considering this
the norm. It is also necessary to understand whether the orgasmic disorder causes
discomfort and complaints in this woman. More than half of women who do not
achieve a regular orgasm do not report stress and discomfort about this. If distress
exists, then it is worth assessing it according to the biopsychosocial model described
above, with the addition of a few clarifying questions.
1. Does this difficulty occur during self-stimulation, or during sexual activity
with a partner, or both?
2. Does this difficulty occur with different sexual contacts (vaginal, oral,
manual) and with different sexual partners?
3. Has the person experienced this before?
Problems with orgasm may be acquired or present since the onset of sexual
activity. Lifelong anorgasmia may indicate that the woman is unfamiliar with selfstimulation, that she lacks adequate sex education, or that sexual communication with
her partner is inadequate. Delayed or reduced intensity of orgasm may indicate
59
insufficient blood flow to the genital area due to, for example, age-related decline in
sex hormone levels. In this case, this complaint will not be a manifestation of an
orgasmic disorder. Also, if the patient reports difficulty achieving orgasm during
sexual activity with a partner, but not during self-stimulation, then this may be a sign
of inadequate sexual stimulation.
The concept of female orgasmic disorder includes: a significant delay in
orgasm, irregular orgasms and/or absence, less intense orgasm for six months in 75–
100 % of sexual contacts. After identifying the problem, it is worth clarifying
whether these problems bring discomfort to the woman. After all, about half of
women who do not achieve orgasm during sexual activity do not consider this a
problem. If stress exists, then it is worth trying to find out what these complaints are
connected with. Is this a change in previous orgasmic functioning? Does this
difficulty occur during self-stimulation, joint sexual activity, or both? Does this
difficulty occur with different sexual activities (eg, oral, manual, vaginal penetration)
and with different sexual partners?
Difficulties with orgasm can be lifelong (present from the onset of sexual
activity) or acquired (starting from a period of no dysfunction). Lifelong anorgasmia
may indicate that the patient is not familiar with self- stimulation or lacks adequate
sex education. Delayed or less intense orgasms may be due to decreased blood flow
to the genitals and dulling of genital sensations that come naturally with age. The
physician must determine whether orgasmic difficulties occur only with certain types
of stimulation, situations, or partners. If a patient reports difficulty during sexual
activity with a partner but not during self-stimulation, this may be the result of
inadequate sexual stimulation. Biological factors requiring investigation and
treatment include medical conditions and the use of drugs that affect sexual
functioning.
Dyspareunia and penetration disorder
Dyspareunia, vaginismus and penetration disorder can be combined into one
group of disorders associated with pain during sexual intimacy and characterized by a
feeling of fear, anxiety, pronounced spasm of the muscles of the pelvis, abdomen and
perineum, which persists or recurs periodically for six months. This complaint may
be lifelong or acquired (eg, after a long period of non-sexual activity). The clinician
should determine whether the pain occurs with initial vaginal penetration, deeper
penetration, or both.
60
Correction of female sexual dysfunction should be carried out taking into
account those factors that could lead to it or support it. Often, specialists from various
fields should deal with this problem: a gynecologist, an endocrinologist, a
psychotherapist, a masseur, a physiotherapist.
Testosterone and women's sexual health. Historical aspect
Experience with testosterone in both men and women began with its discovery
in 1935. For women, testosterone was prescribed to correct the menstrual cycle and to
suppress the growth of oncological processes in the mammary gland. And even then,
all participants in the experiments noted a persistent increase in libido and sexual
desire. And it was then that the side effects of testosterone were first described:
virilization, coarsening of the voice, enlargement of the clitoris, growth of unwanted
facial hair. It is worth noting that these symptoms were noted against the background
of supraphysiological doses (75–350 mg/week).
Despite the fact that so far no androgenic drug has been registered for the
treatment of sexual dysfunction, a lot of experience has been accumulated around the
world in the use of these drugs in women.
The role of sex hormones in women's sexual health
In this review article, I would like to consider the role of hormonal therapy,
namely, testosterone preparations in the correction of sexual dysfunction in women in
world practice. Sex hormones play an important role in the regulation of sexual desire
in both men and women. The gradual decrease in ovarian function and, accordingly,
the level of sex hormones in premenopause and menopause leads to the extinction of
sexual desire in most women. But this problem can affect women at any age with a
decrease in ovarian reserve or surgical menopause.
A Cochrane review found that estrogen replacement therapy in combination
with progesterone in menopausal women was associated with a modest improvement
in sexual function, especially pain. Estrogen treatment has been effective in
correcting genitourinary syndrome and associated dyspareunia during menopause. It
is worth considering that the route of administration of estrogens can affect sexual
function. So oral estrogen preparations can increase the level of sex hormone binding
globulin, which will reduce the amount of free active testosterone, which, in turn, will
negatively affect sexual function. Transdermal estrogen preparations do not have
such a suppressive effect on female sexuality. Of course, a decrease in the formation
Соседние файлы в предмете [НЕСОРТИРОВАННОЕ]