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of vaginal lubrication, atrophy of the vaginal epithelium and dyspareunia are
associated primarily with estrogen deficiency, however, there is no relationship
between estrogen levels and sexual motivation. Androgens are directly related to the
improvement of all aspects of sexual behavior: subjective arousal, vaginal blood
flow, libido, orgasm. Existing randomized controlled trials in both surgical and
natural menopausal women with sexual health problems have shown that testosterone
supplementation (both motor therapy and in conjunction with estrogen
supplementation) helps improve sexual function.
However, some evidence on the benefits and harms of testosterone therapy is
conflicting and limited. The Society of Endocrinologists has suggested that testing
therapy be considered for three to six months in menopausal women with low sexual
desire accompanied by stress. It is important to note that the routine use of
testosterone preparations in menopausal women is not recommended due to the lack
of long-term data on the safety and efficacy of this therapy.
Today, we are faced with another problem in the aspect of testosterone
therapy — testosterone levels do not always correlate with the level of female libido
and general well-being. Perhaps this phenomenon occurs due to the difficulty in
diagnosing and correctly determining the limits of the norm of free and total
testosterone for the female population.
Estrogen and testosterone are the main components of the female libido, and it
has not yet been precisely established whose role is decisive. An interesting fact is
that in all female mammals (except humans), only estrogen plays an important role in
shaping sexual behavior. This makes humans unique among other mammals in this
matter.
Conducted studies on rodents, ungulates, carnivores showed that females
stopped mating completely after oophorectomy. But this process was reversible with
the introduction of exogenous estrogens, without the use of androgens. Particularly
indicative was the experiment on rhesus monkeys, hormonal fluctuations during the
month and the menstrual cycle of which is very close to the human. Sexual
motivation in female rhesus monkeys is significantly reduced after bilateral
adnexectomy and can be fully restored with estrogens.
In humans, however, things are different and there are a number of studies that
demonstrate that testosterone supplementation increases the effectiveness of low-dose
estrogen therapy. There are suggestions that testosterone enhances female libido
through aromatization to estrogen and through a dynamic relationship between
testosterone, estrogen and sex hormone-binding globulin.
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Since both estradiol and testosterone peak mid-cycle, theoretically one or both
of them could be responsible for the mid-cycle peak in women's sex drive. However,
estradiol exhibits a much more pronounced and shorter mid-cycle peak than
testosterone. Thus, circulating estradiol levels increase by more than 800 % within 3–
4 days in the middle of the cycle, while circulating testosterone levels increase by
about 150 % within 6–8 days.
Only one third of circulating testosterone is the result of direct ovarian and
adrenal secretion; the remaining two-thirds result from peripheral conversion of
precursors, including delta-4-androstenedione (A4) and DHEA, in non-steroidproducing tissues. Testosterone is converted to estradiol by aromatase and to
dihydrotestosterone (DHT) by 5-alpha reductase in target tissues as well as in the
periphery (mainly adipose tissue).
There are no clearly established indications for testosterone therapy for
women. However, doctors have been treating women with testosterone for decades to
alleviate some of the symptoms associated with androgen deficiency.
An indication for the use of testosterone preparations, according to experts
from the International Menopause Society and the Endocrine Society, is a diagnosis
of hypoactive sexual desire disorder (HSDD), which includes any of the following
symptoms lasting at least 6 months:
1) lack of motivation for sexual activity, either due to a decrease/absence of
spontaneous desire (sexual thoughts or fantasies), or due to a decrease/absence of
response, lack of desire and erotic cues and stimulation, or an inability to maintain
desire or interest through sexual activity;
2) loss of desire to initiate or participate in sexual activity, including behavioral
responses such as avoidance of situations that may lead to sexual activity.
In addition, these manifestations must be accompanied by “clinically
significant personal stress, which includes disappointment, grief, guilt, incompetence,
loss, sadness, or anxiety”.
Therefore, in the presence of a correct diagnosis of HSDD, after obtaining
informed consent from the patient, individualized testosterone therapy for 3–
6 months can be offered in order to achieve an average testosterone level. The
existing recommendations indicate that in the absence of a clear improvement in
well-being or with severe side effects, the use of testosterone should be discontinued
earlier than six months.
Shervin B.B., Gelfand M.M. Back in 1985, they conducted one of the most
comprehensive studies to date on the effectiveness of estrogen and testosterone
therapy to improve sexual functioning in postmenopausal women. The authors
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administered estrogen-only, testosterone-only, estrogen plus testosterone, or placebo
treatment to 53 menopausal surgical women immediately following oophorectomy.
The authors found that women's self-reported levels of sexual desire did not differ
between the testosterone-only and estrogen plus testosterone treatment groups, and
that both treatments increased sexual desire more than estrogen-only or placebo
treatment. There was also no clinically significant difference in the assessment of
levels of sexual desire between the estrogen-only treatment groups and the placebo
group.
In another study, Fleter et al administered estradiol valerate alone or in
combination with testosterone propionate to 50 surgically menopausal women. The
results of the study showed that sexual desire increased in both cases compared to
baseline, but combination therapy was more effective in this regard. The researchers
hypothesized that testosterone may increase the effectiveness of low-dose estrogen
therapy in postmenopausal women.
In a double-blind, randomized, controlled trial published in the New English
Journal of Medicine in 2008, testosterone was used in postmenopausal women in the
absence of concomitant estrogen therapy. Professor Davies et al used testosterone
preparations at two different dosages (150 and 300 mcg/day) as a transdermal patch
in 814 postmenopausal women who were not using estrogen therapy. The
effectiveness of therapy was evaluated for 24 weeks, and safety for 52 weeks.
Participants were examined, hormonal studies, instrumental studies were performed
at 6, 12, 24, 36 and 52 weeks. After the first year of treatment, women were offered
to continue therapy for another year. Treatment efficacy measurements were based on
weekly sexual activity journal report data, a distress scale, and a female sexual
function profile.
A total of 589 participants (or 72 %) completed the 52-week course of
treatment or had a 52-week follow-up visit after previously discontinued treatment.
The authors reported that the 300 mcg/day testosterone transdermal patch
significantly increased sexual desire at both 8, 12 and 24 weeks of treatment
compared with placebo. Also of interest is the authors' statement that the transdermal
patch at 150 mcg/day did not increase physiological circulating testosterone levels
(>50 ng/dL) and did not increase sexual desire at 12 weeks from the start of
treatment, but there was an increase in sexual desire at 24 weeks from the start of
therapy. compared to placebo. Therapy efficacy did not differ significantly between
women in natural menopause and women in surgical menopause. Of the 464 women
who completed treatment within 52 weeks, 179 agreed to continue randomized
treatment for another year; 132 people completed 104 weeks of prescribed therapy.
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There were no clinically significant changes in vital signs, weight, biochemical or
hematological parameters up to 104 weeks. Serum androgen levels during the
extension period did not differ significantly from levels at 1 year. In one woman who
received 300 micrograms of testosterone for 104 weeks, 3 months after
discontinuation of therapy, infiltrating ductal breast cancer was detected by
mammography (mammogram at 52 weeks was normal). The increased hair growth
observed during the study was not significantly associated with elevated serum
testosterone levels. This phenomenon may be due to the individual sensitivity of
receptors to the action of testosterone. Despite an increase in hair growth, women
who received 300 mcg of testosterone per day did not stop therapy more often than
women from other groups. The frequency of other androgenic adverse events (acne,
deepening of the voice, alopecia) were similar in all three groups and were rated as
mild. There was also no conclusive evidence of accumulation of free or total
testosterone concentrations during the 52-week study period or during study
extension. The concentrations of sex hormone-binding globulin, free and total
estradiol and estrone did not show a clear correlation over time. Free testosterone
concentrations at week 52 in the 300 mcg/day group were slightly higher than the
reference range for premenopausal women up to 49 years of age, but approximately
in line with the mean for women aged 18 to 24 years. To date, this study remains the
only one in which postmenopausal women were administered physiological
testosterone in the absence of concomitant estrogen therapy.
In a further seven published studies (estrogen versus estrogen+testosterone),
the authors used testosterone as a transdermal patch and placebo in postmenopausal
women who were using estrogen therapy but were dissatisfied with it. Six of these
seven studies found that adding 300 micrograms of testosterone as a transdermal
patch to an appropriate estrogen regimen significantly increased women's sexual
desire compared to placebo. Although the authors note that this dosage results in
supraphysiological levels of circulating testosterone in the blood (greater than
50 ng/dL). It is also worth noting that the addition of testosterone at a dose of
150 mcg/day, which is accompanied by a physiological concentration of testosterone
in the blood (less than 50 ng/dl), did not lead to a significant increase in libido
compared with the control group.
Perhaps this is the fact that at the moment there are no exact diagnostic criteria
and methods for determining testosterone in women. Of course, the limitation of
diagnostic methods is due to the fact that the level of testosterone in women is much
lower than in men. It is also known that even in men, the determination of
testosterone levels by one of the most common methods (radioimmunoassay) has a
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high error. In the lower reference ranges of testosterone levels, this error is the
highest.
Also, the level of testosterone in plasma may not correctly reflect its level
inside the cells of target organs due to the possibility of its binding to globulin that
binds sex hormones.
Problems in determining the exact level of testosterone in women and the lack
of understanding of the boundaries of reference values in routine medical practice
does not allow us to accurately identify the relationship between the clinical
manifestations of sexual dysfunction in women and testosterone concentration.
However, according to world experts, the solution to this problem is to measure
the level of testosterone (and other steroid hormones) in both men and women with a
high-precision chromatography-mass spectrometry method and introduce this method
into the clinical practice of every doctor.
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8. CALCIUM-PHOSPHORUS METABOLISM
Vitamin D, its metabolites, and parathyroid hormone (PTH) are essential
components of the endocrine system that control calcium and phosphorus
homeostasis in the body. Serum vitamin D concentrations are well known to decrease
with age, which can lead to reduced intestinal absorption of calcium and the
development of secondary hyperparathyroidism. Serum PTH appears to increase with
age, independent of 25-hydroxyvitamin D, ionized calcium, phosphorus, and kidney
function. Primary hyperparathyroidism, the disease most common in postmenopausal
women, is a well-known cause of low bone mineral density and fractures. Secondary
hyperparathyroidism can also increase the risk of fractures and decrease kidney
function. Previous research has shown that older men and women, even without overt
kidney disease, have an increased risk of fractures with elevated serum phosphate
levels, even when they are within the normal range and are independent of bone
mineral density. Whether this increased fracture risk is directly related to serum
phosphate concentration or to underlying changes in levels of PTH, 1,25hydroxyvitamin D, phosphate-regulating factors such as osteocyte-secreted FGF23,
α-Klotho, remains unknown. FGF23 and α-Klotho inhibit phosphorus reabsorption
and hydroxylation of 25-hydroxyvitamin D by the kidneys. Defects in the expression
of the α-Klotho or FGF23 genes cause phosphorus retention and premature aging
syndrome in mice.
Sex steroids also play an important role in calcium and phosphorus
homeostasis. Postmenopausal women have higher serum phosphorus and calcium
concentrations than age-matched men, suggesting sexual dimorphism in calciumphosphorus metabolism and a potential association with sex hormone concentrations
in this age range. Estrogens have been shown to induce hypophosphatemia, decreased
renal calcium excretion, and increased intestinal calcium absorption.
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9. POSTMENOPAUSAL OSTEOPOROSIS:
FROM LOW ESTROGEN LEVELS TO DISEASE ONSET
To maintain structural integrity, the skeleton must be constantly updated and
repair microdamages that constantly appear in both types of bone tissue: trabecular
and cortical. The cycle of bone tissue remodeling occurs due to the balanced activity
of its constituent cells: osteoblasts (creators), osteoclasts (destroyers) and osteocytes,
which are the main trigger of all bone metabolism.
Despite the proven role of estrogens in bone metabolism, the mechanisms of
their participation are not fully known. Estrogens are able to block bone resorption
through two mechanisms: both by direct interaction with osteocytes and osteoclasts,
and by regulating the formation and activity of T cells and osteoblasts. As described
in a number of reviews, estrogens exert their influence on bone tissue through a
biological axis consisting of the nuclear factor kB receptor activator (RANK), its
natural ligand (RANKL), and the decoy receptor for RANKL, osteoprotegerin
(OPG). Of note, the RANK/RANKL/OPG axis also appears to play a key role in
mediating the putative connection between the immune system and bone.
Osteoclast progenitors differentiate under the action of macrophage colonystimulating factor and RANKL. The latter cytokine, expressed in osteoblast
membranes, promotes differentiation of osteoclast precursors to mature osteoclast for
bone resorption through interaction with RANK. The osteoclastogenic effect can be
prevented by OPG, which is produced by osteoblasts and stromal cells and competes
with RANKL for RANK binding. In addition, estrogens can desensitize the osteoclast
precursor to RANKL by binding to nuclear factor-κβ (NF-κβ), which prevents
RANKL production and promotes OPG release [9]. Finally, estrogens interfere with
osteoclast RANK signaling, thereby inhibiting their differentiation. Thus,
hypoestrogenemia affects the “healthy” balance between RANKL and OPG, which
leads to an increase in the lifespan of osteoclasts and an increase in bone resorption.
T and B lymphocytes play an important role in the complex web of biological
interactions that underlie the influence of estrogens on bone homeostasis. In
particular, T cells are considered to be the main regulators of both the life cycle and
the metabolism of osteoclasts/osteoblasts. These immune cells are able to induce
bone loss by producing several bone-resorbing cytokines, including RANKL,
interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α). In addition, a decrease
in estrogen levels has a direct effect on cytokine synthesis in T cells, as shown in
experiments on ovariectomized (OvX) rodents and in clinical studies.
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Pro-inflammatory cytokines are not the only factors that have been shown to
lead to bone loss caused by estrogen deficiency. Preclinical and epidemiological data
indicate that excessive accumulation of oxidants, in particular ROS, may contribute
to the imbalance between resorption and bone formation that underlies the
development of postmenopausal osteoporosis.
9.1 REACTIVE OXYGEN SPECIES (ROS) AND ANTIOXIDANTS:
AGING AND AGE-ASSOCIATED DISEASES
ROS, the most common biological oxidizers, are capable of knocking electrons
out of all biomolecules, including DNA, proteins, carbohydrates, and lipids. Such
changes in biomolecules are potentially toxic to cells, since the damage caused easily
spreads to neighboring cells if there is no adequate antioxidant counteraction. A
striking example of the contagious cytotoxicity of ROS is lipid peroxidation of cell
membranes. The release of a single electron from polyunsaturated fatty acids
included in phospholipids starts a chain reaction that diffuses throughout the lipid
biolayer and, ultimately, leads to an irreversible structural and functional change in
plasma membranes.
ROS are constantly produced by different cellular structures: mitochondria
during the obligatory process of oxidative phosphorylation and, to a lesser extent, by
the cytosol, membrane, peroxisome, and endoplasmic reticulum, and therefore their
effect on cell health is not always toxic. Accordingly, it is now established that ROSoxidation causes biological damage only when a critical threshold is exceeded. A
number of endogenous factors (inflammation and dysmetabolic syndrome),
environmental factors (pollution, smoking) can accelerate the production of ROS,
thereby increasing the risk of developing diseases. In addition, the severity of the
consequences depends not only on the quantity, but also on the quality of the
oxidizing agents involved in the process. In fact, the ROS family includes various
members ranging from highly unstable/reactive free radicals (molecules lacking one
or more electrons) to weakly reactive non-radical molecules such as hydrogen
peroxide (H2O2). The production of the latter compound depends on the enzyme
superoxide dismutase (SOD), which catalyzes the dismutation of the peroxide radical
(O2), which in turn is produced by various enzymes located in the mitochondria,
cytosol, or membrane. In a hypothetical classification based on antioxidant activity,
SOD and other enzymes capable of neutralizing H2O2 such as catalase (CAT) and
glutathione peroxidase (Gpx) take first place. These three enzymes have been
designated as the first line of defense due to their unique ability to directly clear ROS
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in vivo. There are other endogenous enzymatic and non-enzymatic antioxidants such
as glutathione (a natural substrate of Gpx, thioredoxin, coenzyme Q and uric acid
(UA, the most abundant antioxidant in plasma). The core of the antioxidant defense
system is a complex network of enzymes, signaling molecules and transcription
factors, which arise as a result of the evolutionary adaptation of cells to life in an
environment rich in oxygen.
Dietary antioxidants such as vitamins E (α-tocopherol) and C, β-carotene and
lycopene are currently known. Although all these molecules under in vi tr o
demonstrate antioxidant capacity, only α-tocopherol is truly effective in vivo. This
property is associated with its relatively high concentration in the body, especially in
the membranes of cells with high levels of ROS. Preclinical studies indicate the
antioxidant effect of dietary polyphenols. Some members of this family, in particular
curcumin (turmeric) and resveratrol (grape), have the specific ability to stimulate a
general xenobiotic response in target cells. In fact, they activate several protective
molecules such as SOD and CAT.
The central paradigm in redox balance is that ROS/RNS only become
pathological when they suppress the pool of innate (endogenous) and acquired
(dietary) antioxidants. Disruption of this redox homeostasis is a prelude to OxS, a
condition that seriously affects cell integrity and function, leading to a number of
diseases.
9.2. ESTROGEN DEFICIENCY AND OXIDATIVE STRESS
OxS is considered a common pathogenic factor in the “postmenopausal
syndrome”, which includes a number of disorders (vasomotor complaints, cognitive
impairment and urogenital dystrophy) and diseases such as PO. Postmenopausal
estrogen decline is thought to be the “spark” that triggers OxS.
Experiments in ovariectomized (OVX) animals have provided the most
compelling evidence to support the potential antioxidant activity of 17 beta-estradiol
(E2), the body's predominant estrogen type. A huge number of studies show that
bilateral oophorectomy causes a redox imbalance, characterized by an increase in the
level of lipid peroxidation markers and a decrease in the activity of antioxidant
enzymes [13]. Notably, estrogen administration suppresses OxS in OvX rats,
suggesting an antioxidant role for these hormones.
However, the concept of estrogen as an antioxidant is not unanimously
accepted, mainly due to conflicting results from clinical trials. Postmenopausal
women showed higher serum levels of markers of lipid peroxidation and lower levels
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of small molecular weight or enzymatic antioxidants compared with women of
reproductive age. In contrast, other authors have failed to prove the occurrence of
OxS in postmenopausal women and questioned the hypothesis of an inverse
correlation between E2 levels and peripheral markers of oxidative damage.
However, there is increasing evidence in the literature regarding the
antioxidant potential of estrogens. However, at present, the mechanisms by which
these hormones provide tissue protection against OxS and the relationship between
OxS and osteoporosis are still unclear. The most common hypotheses are given
below.
Hypothesis 1: Estrogens directly inhibit oxidative processes
The idea of the antioxidant properties of estrogens first arose with Sack M.N.
et al. (1998). And the authors found that intra-arterial infusion of E2 in
postmenopausal women caused a decrease in peroxide damage to low-density
lipoprotein (LDL) and these positive effects disappeared after cessation of therapy.
However, physiological levels of E2, even in women of reproductive age, are much
lower than the threshold at which estrogens have a direct antioxidant effect in vitro.
In this regard, the initial hypothesis of Sack M. N. was called into question.
Hypothesis 2: Estrogens increase the expression of antioxidant enzymes
Viña J. et al. (2013) were the first to demonstrate definitively that estrogens
modulate molecular signaling pathways involved in cellular redox homeostasis.
Together with other researchers, they demonstrated that E2 stimulates the expression
of SOD and Gpx. The interaction between E2 and mitochondrial receptors sharply
reduces the rate of ROS formation and simultaneously increases the integrity of the
membranes of these organelles. Accordingly, estrogen deficiency in OvX animals has
repeatedly demonstrated a low activity of protective enzymes and an increase in
oxidation processes.
Hypothesis 3: Estrogens prevent redox imbalance
by suppressing sources of peroxidation
E2 can prevent redox imbalance indirectly by modulating and harmonizing the
regional distribution of adipose tissue in the female body. The level of oxidative
damage is closely related to the amount, type and location of adipose tissue.
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