Lifestyle Concerns for Metabolic Syndrome in Present-day Society with Special Reference to Poly Cystic Ovary Syndrome (PCOS) in Employed Women

Review Article

Austin J Womens Health. 2024; 10(1): 1065.

Lifestyle Concerns for Metabolic Syndrome in Present-day Society with Special Reference to Poly Cystic Ovary Syndrome (PCOS) in Employed Women

Rahal A¹*; Kumar A²

¹Division of Animal Health, ICAR-CIRG, Makhdum, Farah-281122, Mathura, India

²Division of Animal Biotechnology, College of Biotechnology, SVPUAT, Modipuram-250110, Meerut, India.

*Corresponding author: Rahal A Division of Animal Health, ICAR-CIRG, Makhdum, Farah-281122, Mathura, India. Email: rahalanu72@gmail.com

Received: November 29, 2023 Accepted: January 09, 2024 Published: January 16, 2024

Abstract

Chronic Vascular Disease (CVD), obesity, diabetes mellitus type II, insulin resistance, hyperinsulinemia, hyperandrogenism and infertility are intricately interwoven conditions and collectively form metabolic syndrome and significantly affect the psychological and physiological defensive performance of the body. In the current lifestyle scenario, metabolic syndrome is ubiquitous across the globe and mainly originate from stress induced by feeding habits, profession, social, psychological, nutritional and environmental factors. To further complicate the situation, the dimensions of the metabolic syndrome are successfully transferred to an individual’s progeny with considerable magnifications. The most important concerns are regarding infertility and infertility rate in adolescence mainly resulting from poor semen quality in male and polycystic ovary syndrome in females. Both the conditions might be the outcome of any of the metabolic disorders. Unless public awareness and astringent measures are taken to address all the dimensions of metabolic syndrome, it may continue to aggravate and pose a boundless challenge to the progress of society. Thus, it seems imperative to understand the mechanism and management strategies to minimize its impact on society. The current review is an attempt to give the insight of metabolic syndrome with special reference to Polycystic Ovary Syndrome (PCOS) in employed females as it makes a significant contribution to the worldwide pandemic of lifestyle-related persistent syndrome.

Keywords: Metabolic syndrome; Polycystic ovary syndrome (PCOS); Stress; Female

Introduction

Chronic Vascular Diseases (CVDs) contributed in about 32% of total global deaths in 2019, and 85% of that were due to heart attack and stroke with three quarters in low- and middle-income countries. In addition to this, the incidence of death due to hypertension, high blood sugar and obesity have been 10.85, 6.5 and 5.02 million in 2019 worldwide [1]. To further elaborate the global health status [2] almost 10 percent of men and 14 percent of women presently are obese and it is nearly double the rate of obesity in 1980. World Health Organization (WHO) reports that the share of overweight or obese children and adolescents has risen from 4% in 1975 to around 18% in 2016 [3] with unequal distribution around the globe, being skewed towards low- and middle-income countries, with numbers more than doubling across them, and tripling in low income countries, compared to 2010.

The global share of the population with overweight has been forecasted to incessantly increase by in total 2.3% from 2022 and estimated to reach 43.41% in 2028 [4]. Surprisingly, even under-nutrition countries like Bangladesh, Cambodia, China, India, Nepal, and Vietnam, have seen the prevalence of overweight and obesity in women increase by anywhere from 3.5 to 38.5 percent a year from the 1990s through the mid-2000 [5]. If nothing is done to reverse the epidemic, It is estimated that the number of children aged 5-19 years living with obesity worldwide will increase from 158 million in 2020 to 254 million by the year 2030 [6]. The World Obesity Atlas 2022, published by the World Obesity Federation (WOF), also predicts that one billion obese people globally [7], with an incidence rate of 20% in women and 14% in men by 2030. The shift from traditional diets to overeating on Western diets being blamed monotonously, one paradox of this alleged “nutrition transition” is that even as obesity rates rise, underweight persists, sometimes within the same household [8]. To further add to it, low- and middle-income countries often face a dual burden-the infectious diseases with malnutrition and, increasingly, the debilitating chronic diseases linked to obesity and Western lifestyles. The health significance of this dual burden can be emphasized by the fact that rates of many non-infectious health conditions, such as heart failure and stroke, were substantially higher in COVID-19 recovered people compared to their counterparts. These health issues may be considered as a reflection of globalization, urbanization and early ageing in the population as the major forces driving social, economic and cultural change.

Over the decades, the society has observed a massive transition in gender-role attitudes, work and family identity salience, and division of household labour over the generations. Although, with both husband–wife employed gives them a financial balance and various fulfilment in life by creating a great deal of satisfaction, contributing to a sense of well-being and self-worth. However, the supposed need to accomplish more and more in very limited time produces a false sense of urgency leading to negative physiological changes in the individuals and subjecting them to potentially harmful stress [9]. Moreover, some jobs are boring, unchallenging, socially isolating as well as poorly paid and without prestige/security and contribute to occupational stress leading to psychological ill health. Modern society seems to be governed by “survival of the fittest”, each trying their best to provide the best to their family and the employment, and all pleasure of living appear to completely disappear from their life, their mere existence burdened with stress and tension [10] leading them to face stress related illnesses.

Today stress is ubiquitous with a demanding work environment, a busy nuclear household with confined residential and work premises, fewer chances to interact socially and ease out, each adding to a racing heart, irritability and other psychosocial effects. Stress activates hypothalamus-pituitary-adrenal axis inducing a fear or flight response-fear not to lose and flight to surpass others in the race. During the entire process, physiological parameters undergo a change to meet the sudden outstanding demand of tissues. Apparently, it seems to be okay, the change being temporary in nature but what if they continue to become a part of the daily routine and exhaust the resources.

What is Stress- a Boon or Blight in Disguise

Stress is the Outcome of a Physiological, Psychological or Environmental Challenge or Change: A short-term stress is helpful. It increases alertness and work efficiency but long-term stress can lead to serious health troubles. Work stress is an important current problem because the rate of transitory incapacitation, frequent absenteeism and untimely retirement, among others in the workplace are alarming. The after effects of stress are manifested not only in the individual and his family, but the productivity of the work organisation as well, thereby making people resort to measures adopted either for prophylactic or therapeutic remedies to overcome health related issues with the annual monetary losses occurring due to reduced productivity linked to stress [11-12]. This holds true especially in the case of modern day females, who faces-“do it all” syndrome, especially in orthodox societies like India. At the work front also, the high achieving women tend to show perfectionism, a strong inner critic, and a desire to be approved of by others. In an attempt to excel professionally, the Indian females have placed them in a grave situation where they remain attached physically and psychologically to all their household duties along with their liabilities at professional front, often ignoring health markers until they are at absolute breaking point [13-14]. Stress is also associated to various behavioural and hormonal disorders like tom-boy behaviour [15], increased anti-Mullerian Hormone (AMH) levels in the serum during adolescence [16] and higher prevalence of disorders related to autism spectrum [17].

Childhood Stress Leads to Later Life Compromised Health and Fertility

“Early Life Stress” (ELS) is an independent risk factor for chronic disease, compromising the neuroendocrine, immune, metabolic, and cardiovascular systems [18]. Stress affects the flexibility of metabolically active tissues. Adverse childhood stress causes weight gain more rapidly in women compared with men [19]. Also stress-related eating is more prevalent among adolescent girls (43%) compared with boys (15%), presenting a strong association with obesity rates in females [20]. Obesity acts as a predisposing factor for the initiation or development of physical as well as mental disorders in females. There are published reports that associate obesity with cancers of breast, kidney, gallbladder, endometrium and oesophagus. Obesity directly affects reproductive health with a negative impact on the rate of fertility and chances of contraception. It has also been found associated with cases of miscarriage, improper labour pains leading to higher rate of caesarean and other high-risk conditions related to obstetrics along with higher rate of neonatal and maternal mortality, congenital abnormalities in new born. It is further linked with mental health as a major cause of depression and disorders like anxiety, neurodegenerative conditions and lack/ irregular sleep [21]. Further, diabetes is also considered as a major risk factor inviting stroke, heart attack and other coronary heart diseases with almost 44% greater prevalence in women [22]. Maternal separation modulates the adult life HPA axis sensitivity and behavioral and metabolic responses in a sex-dependent manner [23-24]. Feeding of omega-3-deficient diet leads to increased food intake, higher body weight gain, higher plasma leptin and insulin, more chances of impaired tolerance for glucose and increased level of PEPCK in the man liver [25]. Another study conducted on females provided a diet with high-sucrose content for the period of ten weeks showed a positive impact on insulin, leptin and visceral fat levels with significant levels of augmentation in insulin resistance.

Chronic stress is also considered as a major risk factor associated with anxiety and depression. Change in behaviour due to mood disturbances is also associated with fatigue and physical inactivity, which in turn contribute to increased CVD risk [26]. Moreover, any depression or CVD may result in the activation of neurobiological pathways that are common in both diseases, such as the hypothalamic pituitary adrenal (HPA) axis, the autonomic nervous system, and the inflammatory response [27-28], encompassing a bidirectional relationship between depression and CVD [29]. Significant neuronal hyperactivation occurs in both sexes across multiple brain regions in response to repeated mild stress. Dramatically high induction (Fos as marker) occurs in amygdala and the piriform cortex along with tolerant frontal cortex following repeated exposure in females while modest sensitization in the frontal cortex with minimal affected other brain areas is observed in males. These differences in synaptic adaptations and patterns of brain activation are likely to contribute to observed sex differences in stress-induced behaviours.

The hypothalamic-pituitary-gonadal HPG hormonal cascadebegins with the release of gonadotropin-releasing hormone (GnRH), stimulating the synthesis and the pulsatile release of the gonadotropins, Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH), which in turn arouse the production of gametes and the release of sex steroids, including estrogen, progesterone, and testosterone. Both the HPA and the HPG axes well coregulate one another both centrally and peripherally, by complex positive and negative feedback loops, alongwith other neuroendocrine signals. Chronic stress downregulates the hypothalamic GnRH pulse generator, leading to hypothalamic amenorrhea [30], and can be accompanied by reproductive dysregulations associated with other targets along the HPG axis.

Infertility affects a remarkable one in four couples in developing countries. Stress is a common and commonly underappreciated cause of reproductive dysfunction. Stress influences reproductive function at all levels. Stress can interfere with reproductive function at all levels of the reproductive axis [31]. It can suppress libido, reward, and mating behavior at the level of the brain, particularly the ventral tegmental area. It interferes with the hypothalamic GnRH pulse generator and LH and FSH release from the anterior pituitary. It suppresses oocyte maturation, ovulation at the level of the gonads, as well as increasing the likelihood of ovarian cysts and affecting both ovarian and testicular steroidogenesis. Stress is also detrimental to pregnancy outcomes postconception, reducing the likelihood of successful blastocyst implantation. Infertility itself is stressful, and gets overloaded with its aftereffects like social pressures, testing, diagnosis, treatments, failures, unfulfilled desires and even economic costs with which it is associated.

Manoeuvring stress no matter whether it is accompanied with self-assured victory or aggressive survival fight, may negatively impact male fertility, by increasing adrenergic activation, leading to additional vasoconstriction in the testes [32], resulting in a lower testosterone level and decreased spermatogenesis. Acute stress may impair testicular function, with higher levels of cortisol causing apoptosis of both germ cells and Leydig cells [33]. The Leydig cell is the primary target of glucocorticoid regulation in the testes with direct inhibition of transcription of genes encoding testosterone biosynthetic enzymes such as cytochrome P450-dependent cholesterol side chain cleavage enzyme, and cytochrome P450-dependent 17a-hydroxylase/C17–C20lyase [34], causing a decline in testosterone production. The reduced Luteinizing Hormone (LH) and testosterone pulsing reduces both spermatogenesis and sperm quality [35] in a linear negative association [36]. Thus, overall a negative association of fecundability with stress score in men with low semen quality [37] represents a public health concern.

The glucocorticoids, Kisspeptin, ghrelin (hunger hormone released by gut) and GABA (inhibitory neurotransmitter) show an intricate interplay in reproductive functioning. Ghrelin, plausibly also acts via the activation of CRH neurons in these areas and indirectly through trees-regulatory areas in the medial and central nuclei to suppress LH pulsatility alongwith GnRH pulse frequency. Kisspeptin conveys information regarding systemic levels of sex steroids to GnRH neurons, and thus regulates both tonic and pulsatile GnRH release, playing a critical role in the onset of puberty [38-40]. The effects of glucocorticoids at the pituitary are possibly divergent for LH and FSH, being inhibitory and stimulatory, respectively in vitro [41].

In male gonads, 11b-hydroxysteroid dehydrogenase type 1 enzyme catalyses the oxidative inactivation of glucocorticoids and restricts their access to their receptors on Leydig cells. However, in case of excessive glucocorticoids as in severe or prolonged stress, it gets saturated and rapid repression of testosterone production may be observed. Ghrelin has also been shown to modulate testicular function both directly at the testicular level and through its systemic administration, suppressing Sertoli and Leydig cell proliferation [42]. Glucocorticoid receptors are also expressed in different cell types [43], during follicular maturation, ovulation, and pregnancy [44] within the ovary. In ovary, diminished 11b-hydroxysteroid dehydrogenase mediates cortisol-induced inhibition of ovarian steroidogenesis [45]. Ghrelin also suppresses ovarian steroidogenesis alongwith other steroid pathway enzymes, such as 3β-hydroxysteroid dehydrogenase, 17b-hydroxysteroid dehydrogenase, and cytochrome P450 aromatase [46]. Various studies revealed species specific impact of glucocorticoids on oocyte maturation and ovulatory cycle. Glucocorticoids suppress meiotic maturation in gilt oocytes [47]. In contrast, in mouse oocytes, only supraphysiological levels of glucocorticoids inhibit follicle differentiation and oocyte maturation [48]. In ewes, inconsistent effects of cortisol and dexamethasone on oocyte maturation have been demonstrated, with no effect of these glucocorticoids on the capacity of the oocytes to undergo fertilization [49].

GABAA and GABAB receptors in the mPOA are differentially involved in mediating the effects of stress on LH pulsatility, and antagonism of both receptors has been shown to block the CRH-induced inhibition of LH release in rats [50-51]. At the level of the median eminence GABA can act on the GnRH nerve terminals, leading to disruption of estrous cyclicity in rats) while blockade of GABAA receptor increases GnRH release and accelerates the onset of puberty [52-53].

Female Infertility Issues

Female infertility mainly occurs as ovulation disorders and tubal damage (~50%), while 10% to 30% of cases remain unexplained [54]. Polycystic ovarian syndrome is the most predominant heterogeneous endocrine disorder affecting 6-22% of all women globally [55]. Polycystic ovary syndrome is a complex multisystem condition with metabolic, endocrine, psychological, fertility and pregnancy-related implications at all stages of life [56-57]. According to the Rotterdam criteria, PCOS may be clinically observed as “classic PCOS” (excessive androgen secretion and irregular menstrual periods with or without ovarian cysts), “ovulatory PCOS” (augmented androgen secretion and multiple cysts), or “nonandrogenic PCOS” (irregular menstruation and multiple cysts) [58]. The underline indications for PCOS include ovarian cysts, anovulation, and endocrine variation (precisely hyperandrogenism) occurring mainly in the adolescence stage creating disturbances in hormonal balance and menstrual regularity. Anovulation (CA) is deeply rooted with an incidence of 2.2- 26% in Western countries, 2- 7.5% in China, 6.3% in Sri Lanka [59] and 9.13- 36% in India [60-61]. According to the World Health Organization (WHO), over 116 million women (3.4%) are affected by PCOS worldwide with higher prevalence (9.13%) in Indians compared to their Caucasian counterparts [62-63]. This multifactorial condition initially comorbids with obesity, type II diabetes, infertility, endometrial dysplasia, cardiovascular disorders, and/or psychotic disorders [64].

The main etiology and endocrine aspects of PCOS are the increased level of androgen, which is also known as “Hyperandrogenemia (HA)” and secondly the “Insulin Resistance (IR [65]. Androgen hike can impede the pulsatile release of LH:FSH, leading to follicular arrest and dysplasia [66]. There is dysregulation of the hypothalamic-pituitary-ovary axis leading to surplus gonadotropin, and in turn surplus production of LH over FSH. While LH facilitates androgen production in theca cells, FSH transforms androgens to estrogens in granulosa cells, which in turn promote follicile growth. Ultimately, the excess androgen promotes development of primordial follicles and rise in antral follicles at early GnRH stage [67].

Insulin resistance and compensatory hyperinsulinaemia are proposed as significant aetiological factors and are present in 75% and 95% of lean and overweight women with PCOS respectively [68-69].

Vicious Cycle of PCOS over Generations

The uterine environment of PCOS inflicted on pregnant women is most probably hyperandrogenic with higher 3β-HSD-1 activity and lower P450 aromatase activity in placenta tissue, which further facilitate androgengenesis [70]. Defective P450 aromatase gene and sex hormone-binding globulin gene, though infrequent, have been detected in female foetuses of such women, and have been linked to PCOS at puberty [71], perhaps altered placental steroidogenesis plays a key role in vicious cycle of PCOS pathogenesis.

Augmented androgen levels alter the placental function or metabolic profile of the females including development of hyperinsulinemia, pre-eclampsia and diminished nutrient transfer followed by progressive IR and an increased prevalence of metabolic syndrome when exposed to normal nourishment [72] and PCOS in the future. Again owing to hyperinsulinemia, augmented ovarian steroidogenesis leads to hyperandrogenemia in adulthood of female foetuses with Intrauterine Growth Restriction (IUGR), finally culminating into clinical expression of PCOS.

Evidence shows that the uterine environment can ‘programme’ reproductive efficiency prenatally. Detection of polycystic ovaries before the onset of puberty also signifies the origin of the syndrome during ‘programming’ of ovarian morphology and function at foetal maturity—perhaps during ovarian development and oogenesis under the influence of hyperandrogenemia of maternal uterus [73]. In fact maternal plasma testosterone at 18 weeks of gestation significantly correlates with early follicular-phase circulating AMH levels in female adolescent offspring [16]. The variable hormone levels during the gestation play a critical role at a specific time window during the time of system and organ differentiation. The animal model based studies related such abnormalities with pathogenesis of PolyCystic Ovarian Syndrome [16]. A study conducted on sheep developed phenotypically virilised female progeny after prenatal androgen exposure [74] while later exposure creates PCOS phenotypes with irregular ovulation and lower fertility rates [75].

The higher aromatase activity of placenta with higher plasma binding proteins protects human foetus from maternal hyperandrogenemia. Usually P450 aromatase produced by placenta metabolize androgens in to oestrogens. Thus, even in coexistence of androgen-secreting tumours, it is very unusual to see virilization of a female foetus [76]. The prenatally androgenized rats show higher expression of oestrogen and androgen receptors in placenta [77], suggesting higher placental sensitivity to sex steroids. Co-occurence of 21-hydroxylase deficient adrenal hyperplasia and prenatal androgenemia also show symptoms similar to PCOS (LH hypersecretion and reproductive dysfunction) even after postnatal therapies [71,78].

PCOS is directly associated with hereditary and environmental determinants [79]. The hereditary factors are mainly due to an hyperandrogenemia associated with premature fetal development, early puberty and adulthood, and ancestry of PCOS among close relatives [79-80]. Premature in utero development of the female facilitates more rapid onset of puberty with an increased risk of developing PCOS [81]. Occurrence of hyperinsulinemia in children of PCOS affected women prior to onset of puberty is also indicative of genetic susceptibility [81]. The environmental factors include endocrine disruptors, physical sluggishness, obesity, and the coupled insulin resistance which has a high prevalence in the urban Indian lifestyle [82].

Health Hazards of PCOS

In India, metabolic syndrome is quite prevalent (nearly 50 percent) in geriatrics, reaching an alarming 63.1% among urban members [83]. Metabolic syndrome clusters typically include abdominal obesity, insulin resistance, hypertension, and dyslipidemia, the presence of which confers higher risk of cardiovascular disease and diabetes mellitus. While all the metabolic syndromes favour the disruption of hypothalamic-pituitary-ovary axis, hyperinsulinemia particularly, goes hand-in hand with hyperandrogenemia along with insulin resistance for the progress of PCOS, thus, establishing a vicious cycle through which they stimulate each other. Various published reports associated PCOS with two fold higher rate of metabolic syndrome [84], 2.5 to 4.5 fold higher chances of impaired glucose tolerance and Type 2 diabetes [85], higher level of blood pressure and dyslipidaemia in almost 70% of PCOS cases [86-87]. The pathophysiology of PCOS is greatly exacerbated by obesity and diabetes. In obese people, PCOS facilitates the progress of IR and hyperinsulinemia [88-89]. Women with PCOS have a higher threat of Gestational Diabetes (GDM) [90] and mental and feeding disorders like anxiety, depression and bipolar disorders [91-92]. Both PCOS and GDM are predisposing factors for IR, weight gain [93], pregnancy-related hypertension, pre-eclampsia, and infant hypoglycemia. According to the International Diabetes Federation PCOS is a major and non-modifiable predisposing factor for Type 2 diabetes. Understanding of pathogenesis of PCOS revealed IR as a common component in between PCOS and T2D. The expression of T2D-related genes also play critical role in PCOS [94]. It results in the development of IGT in almost 20% of PCOS affected women [64]. The process of development of PCOS is also found associated with obesity [95] and pancreatic β-cell dysfunction [96].

Stress in Postmenopause Female

Indian women have a higher body fat percentage for a given BMI when compared with their western counterparts. Obesity accelerates CVD after menopause [97] owing to its association with autonomic dysregulation, with striking sympathetic hyperactivity and downregulated parasympathetic tone. The Registrar General of India has also projected CVD as the most important cause of death in women [98]. During menopause parasympathetic tone protection is lost leading to higher sympathetic control. Moreover, menopause is commonly associated with obesity, and metabolic syndromes owing to a decline in the levels of estrogens. Although obesity further helps in conversion of peripheral androgens to estrogens including Estradiol (E2) [99], unfortunately, these estrogens lack cardiovascular protectivity. Even after a myocardial infarction episode, women find it harder to pin down stress and discomfort and often experience lower quality of life compared with men.

Blood pressure regulation also shows gender variation, possibly due to influences of female sex hormones on the cardiovascular function [100] leading to higher prevalence of orthostatic intolerance in young women at premenopausal stage and higher levels of MSNA and increased blood pressure in older women at postmenopausal stage.

Urban/Rural Lifestyle Changes

Till date, urban development has been quite lucrative with better prospects of education, job opportunities, infrastructure, medical facilities contributing in the betterment of living standards. What we fail to recognise is the other side of the coin, which is an essential concurrence. Urban society lacks open spaces, is polluted, and has an inflated cost of living with hectic and stressful lives that makes its people susceptible to problems of obesity, infertility and depression. People living in urban areas tend to live in a hierarchical organisational setup and tend to build defence mechanisms trying hard not to reveal their real self. They live programmed lives constantly with no fixed eating schedule and lack of exercise which makes them impatient, and emotionally distressed to further add to the burden. The recent report of Centre for Urban Design and Mental Health (UD/MH), reported significantly higher rates of mental health related disorders in cities in comparison to rural areas with nearly 40% higher risk of depression, over 20% more of anxiety, and double the risk of schizophrenia, in addition to loneliness, isolation and stress [101]. The differences in health impact of urban vs rural lifestyle can clearly be appreciated from the covid era where urban society faced a greater morbidity with more fatal outcomes as compared to rural masses which had comparatively meagre awareness and medical aids.

Lifestyle is intricately interwoven with Generalised Chronic Stress, Obesity, Menopause, PCOS and Hormonal Imbalance (Figure 1)

Citation: Rahal A. Kumar A. Lifestyle Concerns for Metabolic Syndrome in Present-day Society with Special Reference to Poly Cystic Ovary Syndrome (PCOS) in Employed Women. Austin J Womens Health. 2024; 10(1): 1065.