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STRESS AS A FACTOR AFFECTING THE FUNCTIONING OF THE
WOMEN'S REPRODUCTIVE SYSTEM
Ashurova Nigora Gafurovna
Bukhara State Medical Institute named after Abu Ali ibn Sino, Department
of "Obstetrics and Gynecology in Family Medicine", Bukhara, Uzbekistan
Abstract: The article examines contemporary aspects of stress-related
diseases affecting the female reproductive system. It highlights that young women
today experience the highest levels of stress, leading to conditions such as ovarian
dysfunction, premenstrual tension syndrome, and benign mammary gland
dysplasia. The mechanisms underlying these pathologies are discussed.
Additionally, the article explores the effectiveness of long-term non-hormonal
therapy using a standardized extract from Vitex agnus-castus (Ze440). It also
considers the potential of a safe non-hormonal treatment for early menopausal
symptoms based on Cimicifuga racemosa extract (Ze450), which aligns with
treatment strategies for women experiencing menopausal disorders.
Keywords: stress-induced hyperprolactinemia, premenstrual tension
syndrome, menopausal disorders
Introduction :
Stress is a complex phenomenon that can have both beneficial and harmful
effects on the human div. In some cases, it serves as a powerful motivator,
inspiring personal growth, driving goal achievement, and encouraging problem-
solving. During such moments, we experience an energy boost, work with greater
efficiency, and ultimately achieve success. This type of stress, known as eustress,
is considered positive.
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However, stress often becomes a source of anxiety and negative emotions,
forcing the div into an emergency state. In such cases, it can negatively impact
health by disrupting sleep, increasing heart rate, altering breathing patterns, and
raising blood pressure. This harmful form of stress, referred to as distress, can have
serious consequences for both physical and mental well-being.
The causes of stress vary widely and depend on an individual's characteristics
and responses. Stress reactions can be triggered by both external and internal
factors.
External factors contributing to stress include everyday challenges such as
traffic congestion, long lines in stores, and conflicts at work or within the family.
Financial difficulties, such as job loss, lack of funds, or debt, also play a significant
role. Additionally, social factors like low self-confidence, fear of judgment, and
failures in social interactions can contribute to stress. Broader issues, such as
political and economic instability, wars, natural disasters, pandemics, and financial
crises, further exacerbate stress levels.
Internal factors, on the other hand, stem from an individual's personality traits
and upbringing. These include negative thought patterns, such as over-focusing on
problems, exaggerating the significance of events, or excessive worry about the
future. Low self-esteem, fear of failure, and difficulty in asserting oneself can also
contribute to stress. Perfectionism—characterized by an unrelenting pursuit of
excellence, intolerance of mistakes, and an inability to relax—can be another
internal stressor. Additionally, dissatisfaction with life, whether due to a lack of
personal goals, an unfulfilling job, or unhealthy relationships, can further amplify
stress.
The way an individual perceives and responds to stress determines whether its
effects will be positive or negative.
The Impact of Stress on the Female Reproductive System
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Research indicates that women experience higher levels of stress compared to
men. Over the past five years, 43% of women have reported increased stress levels,
in contrast to 33% of men. This trend is further supported by a 10-point stress scale
assessment, where women, on average, rate their stress level at 5.3, while men
report a lower average of 4.6.
It is important to recognize that stress is not merely an abstract concept but a
physiological response to external stimuli. It triggers a cascade of neuroendocrine
changes that affect mental, physiological, and biochemical processes in the div.
In response to stress, the div releases hormones such as cortisol, adrenaline, and
norepinephrine, which prepare it to react in threatening situations. However, when
stress becomes chronic, its impact can be detrimental, particularly to the female
reproductive system.
Chronic stress can disrupt the hypothalamic-pituitary-ovarian axis (HPO
axis)—a key regulatory system controlling the menstrual cycle. The HPO axis
functions as follows: the hypothalamus, located in the brain, produces
gonadotropin-releasing hormone (GnRH), which stimulates the pituitary gland to
release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These
hormones then act on the ovaries, regulating egg maturation and the production of
female sex hormones—estrogen and progesterone.
Chronic stress can disrupt this delicate system at multiple levels. Stress
hormones, particularly cortisol, suppress GnRH secretion in the hypothalamus,
leading to decreased production of LH and FSH. As a result, menstrual cycle
irregularities, anovulation (lack of ovulation), infertility, and other reproductive
health issues may occur.
In addition to hormonal disruption, stress also weakens the immune system,
making the div more susceptible to infections and inflammation. Prolonged stress
increases the risk of developing autoimmune disorders such as endometriosis,
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rheumatoid arthritis, and multiple sclerosis, all of which can negatively impact
reproductive health.
Menstrual Cycle Disorders in Young Women – "Metropolis Syndrome"
Menstrual cycle irregularities are classified as ovarian dysfunction (E28)
according to the International Classification of Diseases, 10th Revision (ICD-10).
One of the contributing factors to ovarian dysfunction is sleep disturbances, which
are particularly common among residents of large cities due to excessive light
pollution and chronic stress exposure. As a result, sleep disorders are considered
part of the so-called "metropolis syndrome."
For many women, the fast-paced urban lifestyle has a dual impact. On one
hand, it offers comfort, cutting-edge technology, and opportunities for personal and
career growth. On the other hand, it brings environmental challenges, poor dietary
habits, sleep disruptions, circadian rhythm disturbances, and psychological
changes such as stress, depression, and aggression, all of which negatively affect
reproductive health. Studies show that menstrual irregularities occur 1.5 times less
frequently in rural women compared to their urban counterparts. This may be
attributed to "metropolis syndrome," where urban dwellers are more exposed to
environmental stressors, leading to circadian rhythm disruptions and reduced
melatonin production.
Melatonin is synthesized at night in a cyclical pattern regulated by the day-
night cycle. Research has shown that Vitex agnus-castus (chaste tree) fruit extract
enhances melatonin secretion in a dose-dependent manner, indicating its beneficial
effects on sleep disturbances associated with menstrual cycle irregularities.
A double-blind, placebo-controlled study involving reproductive-aged
women with premenstrual syndrome (PMS) symptoms demonstrated that taking 20
mg of standardized Vitex agnus-castus extract (Prefemin, Amaxa Ltd, UK) for
three months led to a statistically significant reduction in PMS symptoms,
including menstrual cycle normalization. In contrast, a lower dose (8 mg) had only
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minor effects comparable to placebo, while a higher dose (30 mg) did not provide
any additional significant benefits over the 20 mg dose.
Premenstrual Tension Syndrome – A Modern Women's Life Aspect
Premenstrual Tension Syndrome (classified as N94.3 in the International
Classification of Diseases, 10th Revision - ICD-10) is defined as recurring
physical, cognitive, behavioral, and mood changes occurring in the premenstrual
phase. Approximately 90% of women report experiencing some symptoms
associated with premenstrual tension syndrome, which negatively impact their
daily functioning and are commonly referred to as premenstrual syndrome (PMS)
[17].
The diagnostic criteria for premenstrual tension syndrome were established in
2000 by the American College of Obstetricians and Gynecologists (ACOG) [18].
According to these criteria, the presence of at least one physical (such as bloating,
breast tenderness/swelling, swelling of the lower limbs, headaches) or
psychological (such as irritability, mood swings, episodes of anger, depression,
emotional instability, difficulties in personal or social life) symptom that appears
five days before menstruation and resolves within four days after its onset,
occurring in at least three consecutive cycles without the use of medication,
indicates a diagnosis of premenstrual tension syndrome [18].
Benign Breast Dysplasia – A Leading Condition in Women's Reproductive
Health
In 1981, the World Health Organization (WHO) introduced the term “breast
dysplasia / fibrocystic disease”, defining it as a condition characterized by a wide
range of proliferative and regressive changes in breast tissue, with an altered ratio
of epithelial and connective tissue components . In the International Classification
of Diseases, 10th Revision (ICD-10), this condition is classified as “benign breast
dysplasia” (N60). The terms "benign breast dysplasia" and "fibrocystic disease" are
synonymous, referring to a group of breast disorders caused by an imbalance
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between epithelial and connective tissue components, leading to localized or
diffuse proliferative and regressive changes with varying clinical manifestations.
Since the breasts are part of the reproductive system, their diagnosis and
treatment are closely linked to assessing and addressing changes in reproductive
organs. Sex hormones play a crucial role in the development of breast conditions,
making hormonal imbalance a key factor in the progression of these disorders.
Identifying and treating benign breast diseases is an essential step in breast cancer
prevention, as early intervention can help manage risks and maintain breast health.
Fetal Growth in an Adverse Intrauterine Environment and Fetal
Programming
Experimental and clinical studies suggest that early-life stress can cause long-
lasting changes in gene expression due to epigenetic modifications, leading to
various metabolic and neurodevelopmental disorders. Research indicates that low
birth weight is associated with an increased risk of metabolic syndrome and
vascular diseases in adulthood, likely due to alterations in key hormonal pathways
that regulate growth and development.
Stress is characterized as a disruption of homeostasis, and it is proposed that
the fetus may respond to adverse intrauterine conditions by increasing placental
CRH levels. As a result, abnormal trophoblast invasion, inadequate remodeling of
spiral arteries, and high-resistance placental blood vessels can contribute to
placental dysfunction, representing a state of compromised homeostasis. Such
intrauterine stressors can lead to elevated placental CRH levels, increasing the risk
of obstetric complications such as preeclampsia, intrauterine growth restriction
(IUGR), and preterm birth.
Furthermore, excessive fetal cortisol levels can play a critical role in growth
restriction and contribute to fetal programming, which links prenatal stress to long-
term health outcomes. Elevated fetal cortisol may impair normal fetal growth and
increase susceptibility to diseases in later life, including cardiovascular conditions
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and insulin resistance. The hypothalamic-pituitary-adrenal (HPA) axis, which
regulates stress responses, is particularly vulnerable to programming during fetal
development.
Impact of Prenatal Stress on HPA Axis Programming and Long-Term
Health.
Experimental studies in pregnant rats have demonstrated that exposure to
various stressors, such as a low-protein diet and physical restraint, can lead to
increased corticosteroid secretion later in life. Similarly, in humans, low birth
weight—an indicator of prenatal stress—is linked to elevated plasma cortisol
levels, dysregulated HPA axis function, and heightened cortisol responses to
psychological stress. These physiological adaptations, triggered by adverse
prenatal conditions, support fetal survival by restricting growth but may increase
the risk of metabolic diseases if the postnatal environment is relatively stable.
The extent to which early environmental factors influence HPA axis
programming depends on the timing and severity of intrauterine stress. A cross-
sectional study involving 68 boys and 72 girls suggested that prenatal stressors not
only contribute to low birth weight but also have long-term effects on stress
responses, with male newborns displaying altered adrenocortical reactivity to stress
and females exhibiting changes in baseline adrenocortical activity. This suggests
that HPA axis programming may be gender-specific. Additionally, recent
epidemiological data indicate that preterm birth is associated with reduced long-
term survival and reproductive potential.
Hyperprolactinemia in Menopausal Women
Elevated prolactin levels under stress are not only common in younger women
but also in those of menopausal age. The risk of developing breast cancer increases
with age , despite the decline in estrogen levels in a woman's div. Prolactin can
act as a catalyst for breast cancer development by inducing cell proliferation and
inhibiting apoptosis.
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Additionally, prolactin stimulates metabolic processes in breast tissues and,
importantly, enhances the sensitivity of breast receptors to estradiol, leading to an
increase in estrogen receptor density. As a result, hyperprolactinemia often causes
excessive estrogenic influence on target organs, outweighing the effects of
progesterone, which may contribute to hormonal imbalances and an increased risk
of estrogen-dependent conditions.
The Role of Maternal Stress in Fetal Development
Both experimental and clinical studies have linked prenatal maternal stress—
defined as stressful experiences during pregnancy—to adverse birth outcomes such
as preterm birth and low birth weight, as well as an increased risk of long-term
diseases in offspring. Elevated maternal glucocorticoid levels and maternal
exposure to glucocorticoids have been associated with intrauterine growth
restriction (IUGR), insulin resistance, and persistent dysregulation of the
hypothalamic-pituitary-adrenal (HPA) axis in the child.
While
maternal
corticotropin-releasing
hormone
(CRH)
and
adrenocorticotropic hormone (ACTH) do not cross the placenta, maternal
glucocorticoids can, making them a primary factor in transmitting prenatal stress
to the fetus. The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in
the placenta serves as a protective barrier by converting active cortisol into its
inactive form, cortisone. However, elevated maternal glucocorticoid levels or
decreased 11β-HSD2 activity can increase fetal exposure to glucocorticoids,
potentially disrupting normal development.
Research in both animals and humans suggests that various prenatal
stressors—including maternal anxiety, relationship conflicts, and even large-scale
events like natural disasters—can elevate the risk of metabolic and
neurodevelopmental disorders in offspring. These may include insulin resistance,
type 2 diabetes, cardiovascular disease, impaired cognitive function, behavioral
disorders, autism, and schizophrenia. Additionally, maternal depression, anxiety,
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stress, and poor diet during pregnancy have been strongly linked to low birth
weight, preterm birth, and insulin resistance in children.
Conclusion:
Women’s reproductive health is a complex and delicate system, highly
responsive to various negative factors, including both acute and chronic stress. As
a common aspect of modern life, stress can negatively impact health and quality of
life, manifesting as ovarian dysfunction, premenstrual syndrome (PMS), and
benign breast dysplasia.
To mitigate the effects of stress on reproductive health, the use of Prefemin
(Amaxa Ltd, UK) is recommended. This standardized extract of Vitex agnus-castus
(Ze440) demonstrates dose-dependent effectiveness, with optimal therapeutic
benefits at a daily dose of 20 mg. Based on clinical trials, the European Medicines
Agency has classified Ze440 (Prefemin, Amaxa Ltd, UK) under the status of “well-
established medicinal use” for the comprehensive treatment of menstrual cycle
disorders. Long-term use has shown that a once-daily tablet is well-tolerated, with
minimal risk of side effects.
Menopause marks a significant transition in a woman's life, requiring an
individualized medical approach to preserve physical, emotional, and overall
quality of life. The management of early menopausal symptoms with the non-
hormonal, effective, and safe medication Cimicifuga forte (Amaxa Ltd, UK) is
recommended to alleviate vasomotor symptoms, prevent weight gain, and reduce
insulin resistance.
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