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Gonadal Steroids hormones play an important role in the reproductive and non-reproductive systems. Estrogen has important rule in cardiovascular system as it has vasodilator effect and reduces or prevents platelet activation. In addition, it improves the profile of circulating lipoproteins. All of which may explain why women at premenopausal age are less likely to have heart disease than menopause women or men. E2 play a grate effect on the skeletal system as it is one of the strongest regulators of osteoblast and osteoclast function, and it is responsible for the reduction of adipose tissue and regulation of the body weight, and also has dermatological effect,hence it stimulates the proliferation of keratinocytes and prevents their apoptosis, in addition to the progesterone which increases collagen synthesis. Estrogen is necessary for the functioning and integrity of the tissues of the urinary system specially of the lower urinary tract. Sex steroid are crucial for nervous system, as progesterone is important for production of neurosteroid, and estrogen is currently used in Parkinson’s and Alzheimer’s disease because of its effects on mental health. The androgens also have a crucial biological effects on neural, muscle, bone, adipose tissue,prostate, cardiovascular, haemopoietic, and the reproductive systems. The gonadal steroid hormones play an important role in immune system and regulating the immune response against different viral or bacterial infections.
Department of the Obstetrics and Gynaecology, Medical College of Hammurabi, University of Babylon, Hilla.Babylon, Iraq
*Address all correspondence to: nissrenmalik@uobabylon.edu.iq;, maliknassrin@yahoo.com
1. Introduction
Gonadal Steroid hormones (GSH) play an important role in reproductive and non-reproductive systems. As this effect occurs early in the fetus’ life, gonads are initially present at the fifth weeks and developed on the medial surface of mesonephric ridges.
Therefore, sexual development and discrimination are depending on the type of hormones and gonads that present. GSH play an important role in determining sexual function and behavior. Structures of the central nervous system, such as the hypothalamus, midbrain, amygdala, cortex and anterior pituitary gland, contain androgens and estrogen receptors. The GSH must bind to specific receptors to produce cellular response. While binding of receptor antagonists generally lead to inactivation of these receptors [1].
This chapter explain the effect of sex hormones on the human body and the differences in their action in both genders.
Sex hormones are chemical structures derived from cholesterol, and they are a group of steroidal hormones act as chemical messengers in the body. The activity of steroid hormones is carried out by receptors on extracellular proteins belonging to the family of nuclear substances. Through genomic and non-genomic action, these receptors intervene transduction of signals in a manner of specific context [2].
2.1 Estrogen receptor
2.1.1 Genomic activity
Estrogen binds to SHBG in the blood and in the interstitial fluid, where it penetrates the cell membrane and enters the cell nucleus and binds to receptors. These 2 genes are encoded for 2 estrogen isoforms α and β.
The hormone- receptors structures forms dimer (usually ERα-ERα, ERβ- ERβ or ERα- ERβ) that bind to a specific nucleotide sequence, namely, Estrogen-response elements (EREs) in regions that control different genes regulation of transcription [3] (see Figure 1 ).
Figure 1.
Genomic action of steroid hormones (estrogen) in the cell.
Estrogen acts through several nuclear receptors. Estrogen affects the endometrium, the vagina and the breast [4]. And it interact with Calcitonin, parathyroid hormone, vitamin D and interleukin. Estrogen stimulates the division and growth of the skin cells, connective tissue and mucosal membrane [5].
2.1.2 Non genomic activities
The rapid effects of estrogen, such as the removal of Ca2+ granular cells and uterine blood-flow are mediated by non-genomic actions [3].
Non-genomic activity occur without bind to cellular receptors of estrogen. The beneficial effects of estrogen on blood vessels are an important non-genomic effect [5]. It affects not only blood vessels in the reproductive system, but also the cerebral, coronary and carotid arteries.
Production of nitrous oxide, mediates vasodilation and endothelial protection. Estrogen also stimulates the production of prostacyclin vasodilating, prevents vasoconstriction and prevents platelet aggregation. Also Acetylcholine dilates blood vessels only in the presence of estrogen [6].
2.2 Progesterone receptors
Like estrogen, progesterone act through nuclear receptors, progesterone action is by 2 isoform of progesterone receptors (PR-A and PR-B). These 2 isoforms differ in fact that PR-B has an extra (164) amino acid at N-terminal region termed the B-upstream segment,and this is absent in PR-A.And any mutations of amino acids in B-upstream segment lead to loss of PRB specific gene regulation activity. Normally in human tissues, PR-A and PR-B are as a rule present at same levels but impairment of this ratio regulation lead to tissue abnormalities like that occur in breast cancers [7].
Like estrogen progesterone receptors has genomic and non -genomic activities as shown in Figure 2 .
Figure 2.
Mode of progesterone action by genomic and non- genomic action.
2.3 Androgen receptors
Androgen is one of steroid hormone nuclear receptor family. The location of androgen receptors is on the X chromosome. And these receptors composed of 3 functional domains: the ligand binding domain, the DNA binding domain, and N-terminal transcriptional regulation domain ( Figure 3 ).
Figure 3.
Functional domains of the androgen receptor (AR): N-terminal domain, DNA binding domain (DBD), ligand binding domain. AF-1 – Transcriptional activating function 1. AF-2 – Transcriptional activating function 2. H – Hinge region. NLS –nuclear localization signal. NES – Nuclear export signal.
The DBD is the most highly protected part among the various types of the steroid hormone receptors in the nucleus,while the N-terminal domain in androgen receptor is the mostly changeable. And due to the highly protected quality of DNA binding domain among steroid hormone receptors (nuclear receptors), and having selective androgen response elements, this will result in particular activation of the androgen receptors.
The dihydrotestosterone bind to the androgen receptors with a twofold and more affinity with less dissociation of about fivefold in comparison with testosterone.
Like estrogen and progesterone there are 2 ways of ligand-dependent androgen receptors action, DNA dependent (genomic) and DNA independent (non-genomic) binding ( Figure 4 ).
Figure 4.
Mechanisms of ligand-dependent androgen receptor (AR) action.
The androgens have a crucial biological effects on, muscle, bone, adipose tissue,prostate, neural, cardiovascular, haemopoietic,immune, and the reproductive systems [8].
The biological effects of the AR mutation lead to insensitivity of receptors to androgens in men, resulting feminization of external genitalia of the male (XY female) [9].
Studies in animals with AR deficiency have shown that androgenic signaling is associated with a greater number of women with premature ovarian senility, associated with follicular atresia. Subsequent analysis of AR-free mice showed defects in lutenization of the ovarian follicle [10, 11, 12].
As a result of the development of the reproductive system, androgens (especially testosterone and 5α-dehydrotestosterone), induces and maintain secondary sexual characteristics, stimulate male reproductive activity and assist in the production of the sperms. The prostate epithelium is also sensitive for androgen, and androgen signaling is necessary to maintain cell homeostasis in the adult prostate. As the apoptosis in epithelial cells affects the prostate, can be altered by the supplementation of androgens [13].
A predictive model of AR in the prostate showed that strategic paracrine signals control the proliferation of epithelial cells [14].
The effect of AR on the prostate pro-survival, plays a vital role in the pathogenesis of the prostatic cancers. It has been shown 75 years ago that prostate cancer regeneration occurs due to androgen deprivation after castration [15].
In many ways, this is due to the transport of androgens to the prostate, which are involved in metabolism, in the formation of the cell cycle and in the control of growth factors signaling [16].
In addition, the epithelial AR signal is correlated with an ‘infection’ in the prostate, which is independent of the parasitic AR signal in the stroma. AR increases VEGF-related angiogenesis and increases prostate growth, therefore, AR is an important treatment for prostate cancer. AR signaling has been shown to cause cancers in other organs, including breast, bladder, pancreas, ovary and endometrium [17, 18].
Although estradiol and progesterone levels vary during menstruation, estrogen and progesterone levels are always higher in women than in men [1] ( Table 1 ).
Estradiol and progesterone have many effects depend on its relation to the venereal system. All steroid hormones have a great effect on the ovaries, fallopian tubes, uterus, external genitalia, hypothalamus and pituitary gland. Estrogen, progesterone and androgen, have significant effects on non-reproductive tissues [1].
3.1 Cardiovascular system
A significant lower risk of CVD has shown in premenopausal women than men and postmenopausal women. Estrogen support the vasodilation effect through relaxation of smooth muscle via increases the production of nitric oxide, which helps maintain low platelet activity, and the angiogenesis is stimulated by estrogen production.
Variation in the epidemiology, incidence and sequel of cardiovascular diseases in both sexes indicate changes in susceptibility to hereditary cardiovascular diseases that can result from several factors. In other cases, gender differences are important in expression of genes (especially X-chromosome genes), incidence of heart disease,as explained previously at the same age, cardiovascular disease is more common in men than in women [19].
Therefore, it has been suggested that variation in sex steroid hormones have the key role on cardiovascular pathophysiology. Androgens and estrogens are mainly male and female sex hormones respectively, they are found in different levels and with different biological effects in the body in men and women.
Unlike androgens, which are dangerous due to the risk of heart disease and atherosclerosis, estrogens have a protective effect. In fact, a decrease in plasma Estrogen and elevated androgen is associated with an increase in cardiovascular disease in men and women during their menopause time (average age of menopause is between 51 and 52 years). This indicates an enhancing risk of getting cardiovascular disease in postmenopausal women and also in women who have developing hyperandrogenism [20, 21].
3.1.1 Characteristics of the action of sex hormones on the cardiovascular system, development of atherosclerosis and coagulation
Due to their metabolic and vasoactive properties, sex hormones directly or indirectly affect cardiac function through genomic and non-genomic mechanisms [22, 23, 24].
This effect is mainly depend on the receptors, such as estrogen/testosterone are found in different cardiac cells in humans and animals.
The contractions of the vascular walls was same in male rats (in normal and castrated), but it more evident in female with removed ovaries, indicating specific differences in vascular tone with estrogen in both sexes [25, 26].
3.1.1.1 Oestrogenic effects
Estrogen affects vascular function through genomic and non-genomic mechanisms [27, 28, 29].
In fact, administration of estrogen in vivo leads to vascular dilatation that occurs 5 to 20 minutes after ingestion and is not associated with any change in gene expression. The responses shown to be sex-related. In this regard, intracoronary, administration of estradiol increases coronary blood flow in women, but has not been demonstrated in male with coronary diseases [30].
Acute vasodilation effect of estrogen is endorsed by endothelial related and unrelated mechanism. The properties related to estrogen retention and transport of secondary ions (antagonist action of this hormone on ca2+), while the endothelial related mechanism are highly dependent on the types of endothelial cells associated with the active estrogen receptor (EPs) by the activity of endothelial nitric oxide.
In addition, effect of 17β-estradiol on endothelial, NO synthesis and releases has been suggested to be happen through ER alpha activation [31, 32], while ER-β shows stronger role in the non-genomic effects of estrogen include changes in blood vessels. The expression of extracellular genes and proteins is initiated by two different nuclear ER (α and β) [27, 28, 29].
Both ERα and ER β have significant physiological effects on blood vessels. Animal studies have shown that ERα protects against vascular damage and atherosclerosis [33, 34].
ER- also controlled genes are involved in the regulation of blood volume and blood pressure [35, 36].
Since the expression of sex hormone receptors may vary with sex, and type of gonad, so the sex-related changes in vascular response may be related to specific receptor density in vascular tissue, why do women have more ER than in men [37] in addition, although this activity is low in postmenopausal women, ER intensity decreases dramatically in women with cardiovascular and cerebrovascular disease.
These data may indicate a decrease in the protective effect of estrogen in women who have deprive from it for a long time. In fact, estrogen’s effects on endothelial function depend on duration from starting menopause rather than chronological age of the menopause [38, 39].
In general, estrogen dilates the systemic arteries [24, 27], improves the coronary artery and peripheral endothelial function, prevents coronary artery spasm and reduces endothelial secretion in women with coronary heart disease [27, 28, 40, 41, 42].
Estrogen also affects blood vessels in men. Previous studies have shown that defective mutations in estrogen synthesis or receptor expression are associated with vascular endothelial dysfunction and atherosclerosis [43, 44].
Male estrogen levels are depend on androgen production. Almost 80% of plasma 17-estradiol in men formed from testosterone aromatization and androstendione into estrogen. In addition, estradiol is produced directly in male blood vessels, where it stimulates ERs of endothelial smooth muscle cells. It has been noted that aromatase deficiency and endothelial dysfunction in men with atherosclerosis, low dose of estrogen improves endothelial function [45, 46].
Furthermore, endothelial dysfunction occurs in normal men who receive aromatase inhibitors [23, 47, 48].
Sex hormones can affect the level of vasomotor tones, altering different responses to vascular factors, such as norepinephrine, angiotensin II (AII) or aldosterone. In fact, norepinephrine less likely to cause constriction of blood vessels in women, than men.
Endogenous estrogen helps in control of blood pressure in premenopausal women due to its vasodilation effect. High blood pressure in women occurs after about ten years and is higher in older women than in men at the same age [49, 50, 51].
Human and animal studies have shown that atherosclerosis affected by gender. Many animal models with atherosclerosis cause early and more severe symptoms, regardless of male or female fat and hypertension.
Estrogen and androgen motivate metabolic, hemodynamic and humeral effect which affect in turn the CV profile. In addition, these hormones can directly affect the development of atheromas through various blood stimuli. In women, the loss of estrogen (menopause or after surgery) is associated with hardening of the arteries. When estrogen/hormone therapy is started immediately after menopause, the severity of atherosclerosis decreases [52, 53].
HRT starts in younger women (50–59 years) lead to a low rate of cardiovascular event and lower mortality within 10 years after menopause [54, 55].
For this reason, there is sometimes a balance between the positive and negative effects of exogenous estrogen on blood vessels. The use of hormone replacement therapy prevents hardening of the arteries. Before the appearance of atherosclerosis, only when hormones are started before the advancing atherosclerosis over time after menopause. The current concept is that there is a ‘window of opportunity’ in the peri-menopausal or early postmenopausal years through which the taking of hormonal replacement therapy might reduce the diseases and fatality from cardiovascular diseases by preventing the formation of atheroma [20, 24, 56, 57].
The significant effects of estrogen can only be achieved with oral medicines that are caused by first liver passages of hormones, that stimulate enzyme activity in the organs. In some patients, antithrombin III decreases, factor VII and X are dose dependent increase [58].
3.1.1.2 Mediated Effects of testosterone
The function of the endothelium derived NO in testosterone induced vasodilation is unclear in many studies. Inhibitors of NO synthesis and endothelium-denuded tissue are used in some studies and have suggested a partial contribution, while other studies did not link the role of NO to vasodilation induced by testosterone [59, 60, 61]. Testosterone-induced, an endothelium independent relaxation,not related to gender, and not mediated by hormonal receptor but appear to include the opening of K + channels and L-type calcium channel block [62, 63].
There is a difference in the amount of estrogen in the expression of androgen receptors in the blood stream, which indicates the density of different types of receptors in men, proposing sex linked response to androgen [23, 24, 59, 64].
Although the effects of testosterone in men are not fully understood, the effects of androgens in women are less clear, but appear to be related to estrogen levels. In woman changing her sex rule to male (transsexual) who receive long-lasting testosterone, same plasma concentration is obtained. The diameter of brachial arteries is larger with impaired nitrate induced vasodilation, Nonetheless, the shape and pattern are similar to that in female at the same age. In postmenopausal women treated with estrogen, blood testosterone is about five times increase in concentration than normal levels with improved vasodilation [65, 66]. Testosterone has an estrogen-like effect in women [67] and, in place of estrogen levels, the estradiol/testosterone ratio plays an important role in the androgenic effects of women with atherosclerosis.
Negative correlations have been found between levels of free testosterone and coronary heart disease in men undergoing coronary angiography [68, 69]. In addition, low androgen levels have been reported in men who have larger intima media thickness.
Potential androgenic effects in women are assessed based on observations from women with serious medical conditions, such as PCOS. Women with PCOS suffer from heart disease and atherosclerosis due to high testosterone levels, and elevated risk of having myocardial infarction (MI), a risk factor was used on (33) females have PCOS, and (132) with same age normal females. The risk factor sample was determined from independent risk factors for MI in a prospective population study of (1462) females done in Göteborg, Sweden, the factors were age, diagnosed hypertension, and diabetes mellitus, increased waist/hip circumference ratio (central obesity), serum level of triglyceride. A frequently elevated risk (relative risk of 7.4) of having MI was seen for females with poly cystic ovary syndrome in compression to the normal females with same age [70].
3.2 Lipid metabolism and sex hormones
Sex hormones can directly or indirectly affecting the lipid profile, lipoprotein, HDL, LDL, and triglycerides, the last two are important in development of CVD. This is mainly due to the impaired production of estrogen [71, 72]. Estrogen stimulates lower triglyceride levels, synthesis of HDL and apoliporotein A-I in the liver. It also improve reversion of transport of cholesterol. As a result, these hormones reduce total cholesterol levels and LDLc levels too, levels of triglycerides and it increases the levels of HDL. Testosterone can affect fat metabolism due to its specific androgenic effects and the role as aromatization substrate to Estradiol (E2).
Elevated plasma testosterone levels are believed to influence the profile of lipoproteins, and cardiovascular disease is more common in both sexes. Male data show that plasma testosterone levels correlate positively with HDL-c serum levels and negatively related to triglycerides, LDL, total cholesterol, fibrinogen and PAI-1 [59, 73, 74, 75].
Several studies show that the overall effect on fat metabolism is part of the unexplained effects on excess weight and insulin resistance but clinical studies have shown that testosterone treatment do not affect HDL cholesterol in older men. The positive effects of these properties have the necessary effect [76]. The effect of testosterone therapy on female lipid profile (mainly by lowering HDL cholesterol) depends on the level of estrogen and therefore estradiol/testosterone ratio. However, HDL-c deficiency is androgenic. The reduction in HDL-c should not be assumed as a direct pro-atherogenic risk factor because it can exhibit a reduction in sub fraction of HDL3 and therefore is not associated with a significant reduction in cholesterol transport [77].
3.3 Obesity
Gender differences in body fat distribution are related to sex hormones. Although androgens have been linked to the formation of abdominal fat,. Android’s fat distribution is associated with androgen deficiency [78]. The distribution and amount of female fat is related to ovarian function. During menstruation, women gain weight, fat is distributed is gynoid, with peripheral obesity, while in menopause is in the middle (abdomen) [79, 80, 81].
In both genders, high abdominal circumference or waist/hip ratio are markers of android’s fat distribution which are associated independently with insulin resistance, serum triglycerides, low-density lipoprotein cholesterol, hypertension and increase in sympathetic drive, in addition to participating in the negative metabolic changes mentioned above, also affect hormonal metabolism due to the lack of sex hormones [82, 83].
Male testosterone supplements are designed to reduce belly fat, stimulate lipolysis and thus reduce fat accumulation. Testosterone also has beneficial effects on metabolic parameters, such as glucose and lipid metabolism, therefore, hormone replacement therapy causes weight gain in women and prevents the spread of menopausal pattern body fat. The exact mechanism of this effect is not generally known [84, 85, 86, 87].
3.4 The effect of sex hormones on bone regeneration and resorption
Deficiency of the hormone estrogen (E2) causes osteoporosis in postmenopausal women and helps to promote osteoporosis in older men. As E2 deficiency result in enhancement in the number of osteoclast cells (OC), and at the same time there is reduction in apoptosis of these cells and also increases their activity [88, 89, 90]. Sincethe formation of osteoblasts, including functional estrogen receptors (see Figure 5 ).
Figure 5.
Biological effect of estrogen on the bone.
In 1988, the understanding of the molecular basis for estrogen activity has been rapid, but fragmented and incomplete. The importance of metabolism is centered on the specific role of cytokines: IL-1, IL6, TNF-A, granulocytes, macrophage stimulating factor (M-CSF) and prostaglandin E2 (PGE2) these substances Increase in OC volume and their activity in bone marrow [91].
An elegant study by Cenci et al [92], reported that production of TNF-α by T-cells increase bone resorption in overiectomized (OVX) mice.
The authors raised the hypothesis that in overiectomized animals bone loss can be inhibited by giving either E2, TNF-a binding protein, or by inhibiting the antibodies that is specific to the TNFa.
T cell deficient OVX mice increase TNF-a production in T cells, which can increase the number of T cells instead of TNF. In this case, the tumor necrosis factor-α is not controlled by bone marrow monocytes. It increases the production of RANKL depending OC, augmenting M-CSF. TNF-a has a direct effect on OC precursors.
Estradiol B (E2) alters the bone protective effects of men and women, reducing the estrogen signal, especially in bone cells. ER A is needed to convert bone cells into bone marrow. However, the formation of osteocytes that require estrogen is difficult [93].
3.5 Sex hormones role in skin
Estrogen and progesterone, makes the skin healthy and soft and maintains the natural thickness of dermis and epidermis. Estrogen motivate, multiplies and prevent apoptotic keratinocytes. When estrogen increase collagen synthesis in the skin, progesterone inhibits matrix metalloproteases and together with estrogen decrease breaking down of collagen. Estrogen increases the production and accumulation of glycosaminoglucan in the dermis. Estrogen also promotes healing of wounds.
Several studies have shown that estrogen has an important protective function and is beneficial for skin physiology [94, 95, 96].
They have been shown to accelerate the healing of skin lesions [97]. Most women recover from inflammatory skin conditions, such as psoriasis, during pregnancy, also estrogen, shows some protective effect to photo aging of skin [98, 99, 100, 101, 102, 103, 104, 105].
3.6 Effect of sex hormones on the uro-genital tract
The urogenital tract of females developed initially from the primitive urogenital sinuses at the 4th week of intrauterine life. The estrogen receptor is located in both systems, and their levels fluctuating in the circulation.
During the menstruation, the symptoms are vary, and mainly developed in pregnancy or after menopause, when there is genital atrophy, lower urinary tract and vaginal symptoms are frequently reported. Nonetheless, aging may affect these changes. Which result in difficulty to prove the causation [106].
3.6.1 Pathophysiology
Estrogen receptors are steadily presented in the squamous epithelia of vagina and urethra in addition to the bladder-trigone in areas with metaplasia [107, 108].
However, they are not found in the epithelium of the transitional dome of the bladder, which clearly reflects the germinating roots of this tissue. The pelvic floor is also under effect of estrogens [109, 110]. In woman lower urinary tract, Estrogen raise the activity of cell cycle [111], and there is increment in the number of superficial and intermediate cells, the changes are similar to vaginal changes in postmenopausal women [112, 113, 114].
During menstruating, changes in cytology of urinary tract are almost identical with that in vaginal cytology [115]. Changes also occur in sediment after estrogen therapy [116]. Frequent changes in urinary symptoms during menstruation can be detected by the urethral pressure profilometry (UPP) [117].
The functional, anatomical, and physiological length of the urethra increases with mid menstruation and earlier luteal phase, indicating changes in serum concentration of estrogen. Changes also occur during pregnancy [118, 119], which sanctifies a relative increase in urinary out-put and gravid uterus pressure.
A recent article by the University of London School of Medicine suggested possibility of influencing hormones on bladder that mediated by progesterone [120]. Progesterone receptors are expressed in the lower urinary tract and may be associated with estrogenic status in women. Androgen receptors are found in the bladder and urinary tract of women, but their function is currently unknown [108, 121].
3.6.1.1 Estrogen and urinary incontinence
In women, during menopause are usually complaining of frequent symptoms in the urinary system. The most common are frequent micturition, bed wetting, stress and urge incontinence, they may also experience urinary tract infection and vaginal symptoms, such as itching or dryness. The specific diagnosis of the underlying pathology is based on a comprehensive clinical study and the study of urodynamic. There are many causes for urinary incontinence; these include bladder dysfunction, instability with constipation, excessive urination, fistula (between vagina and the bladder, or between vagina and ureter or with urethra) or due to diverticulum or immobility.
The causes of transient enuresis in the elderly include urinary tract infections, estrogen deficiency, restricted mobility, medications, and depression. The two most common symptoms are stress and\ or urge incontinence.
Urinary tract and pelvic tissues are sensitive to estrogen, as it play an important role in the storage mechanism. For a woman to be on the continent, the pressure of the urethra must be greater than that of the bladder. The urethra consists of four functional layers sensitive to estrogen that are involved in maintaining positive pressure, by its effect on epithelium, blood vessels, muscles and connective tissues [122].
Extracellular changes in the urinary epithelial layer have been reported in response to estrogen. There is some evidence that estrogen affects the blood vessels in the system, and can treat urinary incontinence in women by hypersensitivity to the alpha-adrenergic receptors of the ureteral smooth muscles, stimulation of collagen production around the urinary tract, increased sensitivity of the bladder, increased pressure in the urethra [123, 124].
3.6.1.2 Estrogen to prevent and treatment of enuresis
Although less research is done, the role of estrogen in the treatment of enuresis is controversial. Some have shown reliable results, but this may be due to different estrogens, different doses, and instructions over the duration. This disease is more difficult to treat. There are now two methods of meta-analysis to clarify the situation. It was the first report by the Hormones and Urogenital Therapy (HUT) Committee.
The use of estrogen has been discussed to treat all causes of enuresis in postmenopausal women [125].
Of the 166 articles in English published between 1969 and 1992, only six were considered, but this was not the case. The results showed that real stress is a major psychological development for all patients with urinary incontinence. However, the analysis of the target parameters showed no change in urine volume. The maximum pressure to close the urethra increases, but only one test significantly affects the result. In the second meta-analysis [126], potentially controlled cases and 14 indirect studies related to estrogen therapy were considered. They also found that estrogen therapy does not relieve stress, but it can help with sudden and recurring symptoms. This method can be useful for women with low stress or who need surgery. Estrogen to prevent rapid urination, and has been used to treat menopause for many years, but several controlled studies have shown its benefits. A combination of estradiol (2 mg) and 1 mg estriol (Imagine Daily) reduced urinary retention in 7 of 11 women, compared with 1 in 10 in the placebo group [127, 128].
3.6.1.3 Estrogen for urinary tract infections
Changes in urine production in women after childbirth increase the risk of developing UTI in women, especially during intercourse. The pH of the vagina increases and the number of lactobacilli decreases, that is colonization induces Gram-negative bacteria that play a pathogenic role in urine. In response to these changes, estrogen can be used for treatment or prophylaxis, which can occur in adult women with recurrent steroid intake [129].
3.7 Effects of testosterone on erythropoietin (EPO) and on muscle
High levels of testosterone, important for hemoglobin and hematocrit and stimulate EPO and reduction of cellular exhaustion. Testosterone increases iron absorption by red blood cells, stimulates EPO and restores EPO-bound hemoglobin [130].
As a large amount of DNA accumulates in adult muscles after birth and is made up of dependent cells, satellite cells, which are an important area for controlling muscle growth, and protein regulation in muscle fibers. Testosterone is a blood transporter that binds directly to muscles and therefore increases protein [131].
3.8 Sex hormones and brain
Estrogen is involved in many processes throughout life. Minds of men and women. For example, neurological developmental and synaptic changes resulting in sexual behavioral differentiation [132, 133].
Progesterone is important for synthesis of neurosteroid, and estrogen regulates rapid and prolonged neuroplastic processes in the central nervous system, including synaptic-cyclical changes [134, 135].
Estrogen affects many neurological functions and behaviors, such as mood, cognitive function, blood pressure regulation, motor coordination, pain and sensitivity to opioids. Many of these characteristics have small gender differences that lead to uncertainties about hormones and genetic factors, including the mitochondrial genome [136].
Brain aging is often associated with many diseases of the nervous system resulting from disorders in the workplace. Recent evidence suggests that estrogen replacement therapy may reduce the risk of degenerative diseases such as Alzheimer’s disease and cognitive decline in women [137, 138, 139].
Estrogen is the broadest group of drugs used to prevent Alzheimer’s disease (AD). These steroids are powerful neurotransmitters in vitro and in vivo and have been shown to have similar effects in preventing attention deficit disorder. This includes suppression of the amyloid expression of the pro-amyloid protein (A), Epidemiological evidence supports the use of estrogen to lower the stress at the beginning of menopause and treatment of Alzheimer’s disease [140].
Epidemiological studies have shown that women are 1.5 to 2 times Lower than men to develop Parkinson’s disease (PD), indicating a protective effect of estrogen. Experimental data show that estradiol has a protective effect on neurons and dopaminergic proteins. Studies have shown that higher levels of estrogen are associated with fewer symptoms of Parkinson’s disease and an increased risk of Parkinson’s disease in postmenopausal women. These data indicate that estrogen may have a protective effect on dopaminergic neurons [141].
3.8.1 Neuromprotective effect of estrogen
Obviously, estrogen has other functions, such as stimulating nerve cells and protecting them from stimuli caused by other diseases, such as seizures, stroke and Alzheimer’s [142, 143].
The exact role of cellular nuclear ERs detected on inhibitory effect between neurons is unclear, but one key is the function of E2 to enhance neuropeptide Y (NPY) expressing and releasing, because NPY has antiexcitatory actions [144, 145].
The second fact that E2 is neuroprotective its function is translocate ER-β to mitochondria, in addition its ability to sequestrate mitochondrial Ca2+ ion, including Bcl-2 translocation [146].
Studies on estrogen’s ability to prevent stroke and fight Alzheimer’s and Parkinson’s disease have shown that the brain can produce estrogen and possibly cholesterol [147, 148]. Like E2, androgens have a protective effect on nerve cells, the pyramidal neurons are an important type of CA1 AR nucleus. In men, nuclear ARAS may play an important role in the development of spinal synapses, not in NMDA, but in cholinergic activity [149, 150, 151].
3.8.2 The behavioral effects of sex hormones
Genital steroids affect children’s brains, especially the hypothalamus, and cause gender differences. The differences in behavior between men and women are related to the sexual ability of the three families of steroid hormones (estrogen, androgen and progesterone) in the nervous system. The classic family of receptors is associated with elements that act as transcription factors after the breakdown of layers, nuclear translation and hormonal effects of DNA [152]. Gender differences in the brain are usually anatomical, neurochemical or molecular.
The neurochemical change in sex occurs at the level of neurotransmitters, enzymes or local hormones. Molecular changes in sex, gene expression and epigenetic changes in phase signaling occur with any gender difference in the hypothalamus regulated by the regulatory effects of estradiol.
Estrogen has long been known to have a psychoactive effect. Therefore, it is believed that the inappropriate metabolism of estradiol may play a role in the development of mental illness. Differences in brain area, size, cell number or radiation intensity (for example, differences in cell size, neural complexity or morphology, dendritic cell length and number of contacts) [153].
3.9 The effect of sex hormones on the immune system
The role of estrogen in the negotiations between the internal system and the immune system was described about 15 years ago [154, 155].
Estrogen effects: macrophages, CD8 + lymphocytes and ERF3 B lymphocyte rings are also expressed in lymphoid tissue and can be membranes linked to the receptor. Estrogen and anti-estrogen binding sites (AEBS) are also found in lymphocytes [156, 157].
Regarding cytokines: TNF levels in endotoxin coatings increase significantly with estrogen, while levels of IL-6 (due to ethylene 17 in the blood) decrease [158, 159]. Active ER stimulates nuclear transcription factors and maintains NF-IL6, NF-ICB and C/EBPf3 [160, 161].
Physiological levels of estradiol in cultured human cells significantly increase the activity of the IL-1 receptor antagonist (mRNA) but it suppressed by higher estradiol concentrations [162]. Estradiol 17F3 produces IL-5 mRNA in vitro [163]. Estradiol and glucocorticoids activate secretory substances that prevent leukemia, sagging and overuse in humans [164].
And in uterus the uterine epithelial cells stimulate antigen secretion and preserve uterine E2 cells [165].
In adults, the activity of natural killer cells increases after in vitro treatment with 17G3-estradiol [166]. Estradiol increases the sensitivity of natural human prostate killer cells in classic ER [167, 168]. Cytotoxic activity of estrogen-dependent CD4 + cells [169].
The chemotactic activity of human polymorphonuclear leukocytes is greatly reduced due to the physiological concentration of estradiol (10-IOM) [170].
In short, antiestrogens act on specific estrogen receptors and lymphocytes when they affect the nervous and endocrine systems and on target cells, or tissues in the transplant system.
As the nervous system and the immune system produce a regulatory response, immune changes cause changes in the nerves and vice versa. This is a phrase was made possible by for example, the thymus is an organ that produces the steroid hormone. In addition, the immune system can convert steroid precursors into active hormones [171].
Steroid hormones are the ones that most control the immune system, as they can control signaling at the level of nuclear transcription factors [172]. However, it is not clear whether estrogen is necessary for the normal functioning of the immune system or if its effect on primary levels of estrogen in the regulation of the vaccine varies. We are not aware of the potential differences between the different steroids and estrogen receptors in the immune system. Estrogen regulates immune function differently in men and women [170, 171, 172, 173, 174, 175, 176].
Estrogen is important for building the body’s immune system against viral infections. Stabilization of the cytokine storm has been shown to control and mediate immunological changes against the influenza virus and pneumonia. Due to the effects of estrogen, SARS-CoV-2 is lower in women than in men. Some believe that SARS-CoV-2 cause stress in the endoplasmic reticulum (ER), which inturn aggreviate the infection.
This problem can controlled by estrogen as it cause degradation of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 in-fluxing Ca + 2 ions and helps activate UPR (unfolded protein responce). Data from 392 patients were analyzed and found that 26% of females and 74% of men were affected by SARS-CoV-2. It indicated that women are less affected due to the possible effect of E2 hormone in females [177].
Sex steroids roles have not limited to their reproductive function, but their roles are also shown to be extend to a lot off effects on other body systems including cardiovascular, neural, musculoskeletal, adipose tissue, dermatological, immune, and haemopoietic systems, The sex hormones include the androgens, estrogens, and progestogens, their effects are exert by either slow (genomic process) via nuclear receptors, or by rapid non-genomic process through membrane related receptors and signal cascades.
Androgens and oestrogens impact biology of the blood vessels, predominantly in a sex specific way. And this effect is a cardioprotective, while oestrogens having benefit effect in both males and females, but the effect of androgens different in the two genders. As the effect of testosterone in females rely on the estrogen levels and thereby on estradiol to testosterone ratio. Estrogens and androgens exert potent influences on the post-natal building of muscles and bones and important for their sexual dimorphism, these 2 hormones also vital for the homeostasis of both tissue in addition to the skin, adipose tissues, and regulation of body weight through adulthood, as well as integrity and function of female genitourinary system (specially the estrogen).
The nervous system is a target for effect of sex hormones. Estrogens, progestins, and androgens, all effect the function and physiology of the brain,these steroids are powerful neurotransmitters in vitro and in vivo and have been shown to have similar effects in preventing attention deficit disorder. Experimental data show that estradiol has a protective effect on neurons and dopaminergic proteins. Sex hormones also play a vital role as modulators of the immune system, as the sex steroids and immunity are closely connected, and their mutual regulation is involved in the maintenance of immune balance.
The sex steroid are considers balance of the functions and protection of the body systems, and can use for prevention and treatment of many systemic disorders, and the possibility of applying of their effects on the incidence of many organic and infectious diseases.
References
1.Bruce A. White, PhD. Introduction to the endocrine system, Endocrine and Reproductive Physiology, fourth edition, 2013,1,1-25e2.
2.Shannon Whirledge, John A. Cidlowski. Steroid Hormone Action, Yen & Jaffe’s Reproductive Endocrinology, 2019, eighth edition, chapter 5,115-131.
3.George P. Chrousos, MD. The Gonadal Hormones & Inhibitors; Basic and clinical pharmacology, ed. 13,2015;40: 1024-64.
4.Hohlweg W (1943) Ober das Sexualzentrum. Zbl Gynak 67:1357-1387.
5.C. Lauritzen. M. Oettel and E. Schillinger History of Estrogen Research, Physiology and Mechanisms of Action of Estrogens and Antiestrogens, Experimental Pharmacology, 1999, Volume 135\I, 1, 1-14.
6.Sarrel PM (1990) Ovarian hormones and the circulation. Maturitas 12:122:287-292.
7.Britta M. Jacobsen and Kathryn B. Horwitz. Progesterone Receptors, their Isoforms and Progesterone Regulated Transcription.Mol Cell Endocrinol. 2012 June 24; 357(1-2): 18-29.
8.Rachel A Davey and Mathis Grossmann. Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev 2016;37(1).
10.Shiina H, Matsumoto T, Sato T, et al: Premature ovarian failure in androgen receptor-deficient mice. Proc Natl Acad Sci USA, 2006.103(1):224-229.
11.Hu YC, Wang PH, Yeh S, et al: Subfertility and defective folliculogenesis in female mice lacking androgen receptor. Proc Natl Acad Sci USA, 2004. 101(31):11209-11214.
12.Panda B, Rao L, Tosh D, et al: Germline study of AR gene of Indianwomen with ovarian failure. Gynecol Endocrinol, 2011, 27(8):572-578.
13.Sugimura Y, Cunha GR, Donjacour AA: Morphological and histological study of castration-induced degeneration and androgen-induced regeneration in the mouse prostate. Biol Reprod1986. 34(5):973-983
14.Lai KP, Yamashita S, Vitkus S, et al: Suppressed prostate epithelial development with impaired branching morphogenesis in mice lacking stromal fibromuscular androgen receptor. Mol Endocrinol 26(1):52-66
15.Huggins C, Hodges CV: Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol 2002.168(1):9-12
16.Zhou Y, Bolton EC, Jones JO: Androgens and androgen receptor signaling in prostate tumorigenesis. J Mol Endocrinol 2015, 54(1):R15–R29.
17.Eisermann K, Fraizer G: The androgen receptor and VEGF: mechanisms of androgen-regulated angiogenesis in prostate cancer. Cancers (Basel) 2017,9(4):E32.
18.Schweizer MT, Yu EY: AR-Signaling in human malignancies: prostate cancer and beyond. Cancers (Basel), 2017, 9(1):E7.
19.Kannel W.B., Hjortland M.C., McNamara P.M. et al. Menopause and risk of cardiovascular disease: the Framingham study. Ann. Intern. Med. 1976; 85 :447-452
20.Edward Morris. The menopause and postreproductive health, Gynaecology by ten teachers, 2017, 20th edition, cha. 8; 171-94.
21.Wild S., Pierpoint T., McKeigue P., Jacobs H.S. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin. Endocrinol. (Oxf). 2000; 52 :595-600.
22.Orshal J.M., Khalil R.A. Gender, sex hormones, and vascular tone. Am. J. Physiol. Regul. Integr. Comp. Physiol. 4. 2004; 286: R233– R249.
23.Mendelsohn M.E., Rosano G.M. Hormonal regulation of normal vascular tone in males. Circ. Res. 2003; 93: 1142-1145.
24.Mendelsohn M.E., Karas R.H. Molecular and cellular basis of cardiovascular gender differences. Science 2005; 308: 1583-1587.
25.Crews J.K., Khalil R.A. Gender-specific inhibition of Ca2+ entry mechanisms of arterial vasoconstriction by sex hormones. Clin. Exp. Pharmacol. Physiol. 1999; 26 :707-715.
26.Kanashiro C.A., Khalil R.A. Gender-related distinctions in protein kinase C activity in rat vascular smooth muscle. Am. J. Physiol. Cell Physiol. 2001; 280 :C34– C45.
27.Mendelsohn M.E., Karas R.H. The protective effects of estrogen on the cardiovascular system. N. Engl. J. Med. 1999;340 :1801-1811.
28.Mendelsohn M.E. Protective effects of estrogen on the cardiovascular system. Am. J. Cardiol. 2002; 89:12E– 18E.
29.Mendelsohn M.E. Genomic and nongenomic effects of estrogen in the vasculature. Am. J. Cardiol. 2002; 90: 3F– 6F
30.Collins P., Rosano G.M., Sarrel P.M. et al. 17 Beta-estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation 1995; 92 :24-30.
31.Chambliss K.L., Yuhanna I.S., Anderson R.G., Mendelsohn M.E., Shaul P.W. ER b has non-genomic action in caveolae. Mol. Endocrinol. 2002; 16: 938-946.
32.Chen Z., Yuhanna I.S., Galcheva-Gargova Z., Karas R.H., Mendelsohn M.E., Shaul P.W. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J. Clin. Invest. 1999; 103 :401-406.
33.Pare G., Krust A., Karas R.H. et al. Estrogen receptor-α mediates the protective effects of estrogen against vascular injury. Circ. Res. 2002; 90 :1087-1092.
34.Hodgin J.B., Krege J.H., Reddick R.L. et al. Estrogen receptor alpha is a major mediator of 17beta-estradiol’s atheroprotective effects on lesion size in Apoe−/− mice. J. Clin. Invest. (2001) 107 333-340.
35.Zhu Y., Bian Z., Lu P. et al. Abnormal vascular function and hypertension in mice deficient in estrogen receptor β. Science 2002; 295: 505-508.
36.Hodges Y.K., Tung L., Yan X.D., Graham J.D., Horwitz K.B., Horwitz L.D. Estrogen receptors alpha and beta: prevalence of estrogen receptor beta mRNA in human vascular smooth muscle and transcriptional effects. Circulation 2000;101 :1792-1798.
37.Nakamura Y., Suzuki T., Sasano H. Estrogen actions and in situ synthesis in smooth muscle cells and their correlation with atherosclerosis. J. Steroid Biochem. Mol. Biol. 2005; 93: 263-268.
38.Post W.S., Goldschmidt-Clermont P.J., Wilhide C.C. et al. Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system. Cardiovasc. Res. 1999; 43: 985-991.
39.Vitale C., Mercuro G., Cerquetani E. et al. Time since menopause influences the acute and chronic effect of estrogens on endothelial function. Arterioscler. Thromb. Vasc. Biol. 2008;28 :348-352.
40.Volterrani M., Rosano G., Coats A., Beale C., Collins P. Estrogen acutely increases peripheral blood flow in postmenopausal women. Am. J. Med. 1995;99 :119-122.
41.Rosano G.M., Gebara O., Sheiban I. et al. Acute administration of 17beta-estradiol reduces endothelin-1 release during pacing-induced ischemia. Int. J. Cardiol. 2006 ;116: 34-39.
42.Adamopoulos S., Rosano G.M., Ponikowski P. et al. Impaired baroreflex sensitivity and sympathovagal balance in syndrome X. Am. J. Cardiol. 1998; 82: 862-868
43.Sudhir K., Chou T.M., Messina L.M. et al. Endothelial dysfunction in a man with disruptive mutation in oestrogen-receptor gene. Lancet 1997; 349: 1146-1147.
44.Sudhir K., Chou T.M., Chatterjee K. et al. Premature coronary artery disease associated with a disruptive mutation in the estrogen receptor gene in a man. Circulation 1997; 96 :3774-3777.
45.Carani C., Qin K., Simoni M. et al. Effect of testosterone and of estradiol in a man with aromatase deficiency. N. Engl. J. Med. 1997 ;337: 91-95.
46.Smith E.P., Boyd J., Frank G.R. et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N. Engl. J. Med. 1994 ;331: 1056-1061.
47.Lew R., Komesaroff P., Williams M., Dawood T., Sudhir K. Endogenous estrogens influence endothelial function in young men. Circ. Res. 2003; 93: 1127-1133.
48.Kneale B.J., Chowienczyk P.J., Brett S.E., Coltart D.J., Ritter J.M. Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature. J. Am. Coll. Cardiol. 2000 ;36 :1233-1238.
49.Giralt D, Domingues-Montanari S, Mendioroz M, Ortega L, Maisterra O, Perea-Gainza M, Delgado P, Rosell A, Montaner J. The gender gap in stroke: A meta-analysis. Acta Neurol Scand. 2012;125:83-90.
50.Regitz-Zagrosek V, Oertelt-Prigione S, Prescott E, Franconi F, Gerdts E, Foryst-Ludwig A, Maas AH, Kautzky-Willer A, Knappe-Wegner D, Kintscher U, Ladwig KH, Schenck-Gustafsson K, Stangl V. Gender in cardiovascular diseases: Impact on clinical manifestations, management, and outcomes. Eur Heart J. 2016;37:24-34.
51.Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: Current outcomes and control in the community. JAMA. 2005;294:466-472
52.Lakoski S.G., Brosnihan B., Herrington D.M. Hormone therapy, C-reactive protein, and progression of atherosclerosis: data from the Estrogen Replacement on Progression of Coronary Artery Atherosclerosis (ERA) trial. Am. Heart J. 2005; 150 :907-911.
53.Hodis H.N., Mack W.J., Azen S.P. et al. Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research Group Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. N. Engl. J. Med. 2003; 349 :535-545.
54.Manson J.E., Allison M.A., Rossouw J.E. et al. Estrogen therapy and coronary-artery calcification. N. Engl. J. Med. 2007;356 :2591-2602.
55.Mendelsohn M.E., Karas R. HRT and the young at heart. N. Engl. J. Med. 2007; 21: 2639-2641
56.Arnal J.F., Scarabin P.Y., Tremollieres F., Laurell H., Gourdy P. Estrogens in vascular biology and disease: where do we stand today? Curr. Opin. Lipidol. 2007;18 :554-560.
58.Adam, W (1943) Ostrogene erzeugen Hypertrombinamie. Zbl Gynak 67:551-554
59.Wu F.C., Von Eckardstein A. Androgens and coronary artery disease. Endocr. Rev. 2003 ;24 :183-217.
60.Yildiz O., Seyrek M. Vasodilating mechanisms of testosterone. Exp. Clin. Endocrinol. Diabetes 2007;115: 1-6.
61.Von Eckardstein A., Wub F.C.W. Testosterone and atherosclerosis. Growth Horm. IGF Res. 2003; 13: S72– S84.
62.English K.M.J.R., Jones T.H., Morice A.H., Channer K.S. Testosterone acts as a coronary vasodilator by a calcium antagonistic action. J. Endocrinol. Invest. 2002; 25:455-458.
63.Jones R.D., Hugh Jones T., Channer K.S. The influence of testosterone upon vascular reactivity. Eur. J. Endocrinol. 2004; 151: 29-37.
64.McCrohon J.A., Death A.K., Nakhla S. et al. Androgen receptor expression is greater in macrophages from male than from female donors. A sex difference with implications for atherogenesis. Circulation 2000; 101: 224-226
65.McCredie R.J., McCrohon J.A., Turner L., Griffiths K.A., Handelsman D.J., Celermajer D.S. Vascular reactivity is impaired in genetic females taking high dose androgens. J. Am. Coll. Cardiol. 1998; 32:1331-1335.
66.Worboys S., Kotsopoulos D., Teede H., McGrath B., Davis S.R. Evidence that parenteral testosterone therapy may improve endothelium-dependent and -independent vasodilation in postmenopausal women already receiving estrogen. J. Clin. Endocrinol. Metab. 2001; 86:158-161.
67.Alexandersen P., Haarbo J., Byrjalsen I., Lawaetz H., Christiansen C. Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits. Circ. Res. 1999; 84:813-819.
68.Rosano G.M.C., Leonardo F., Pagnotta P. et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation (1999) :1666-1670.
69.Phillips G.B., Pinkernell B.H., Jing T.Y. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler. Thromb. 1994 ;14 :701-706.
70.Dahlgren E., Janson P.O., Johansson S., Lapidus L., Oden A.Polycystic ovary syndrome and risk for myocardial infarction.Evaluated from a risk factor model based on a prospective population study of women. Acta Obstet. Gynecol. Scand.(1992) Dec;71(8):599-604.
71.Tikkanen M.J., Vihma V., Jauhiainen M. et al. Lipoprotein-associated estrogens. Cardiovasc. Res. 2002;56:184-188.
72.Chikani G., Zhu W., Smart E.J. et al. Lipids: potential regulators of nitric oxide generation. Am. J. Physiol. Endocrinol. Metab. 2004; 287:E386– E389.
73.Hergenc G., Schulte H., Assmann G., Von Eckardstein A. Associations of obesity markers, insulin, and sex hormones with HDL-cholesterol levels in Turkish and German individuals. Atherosclerosis 1999; 145 :147-156.
74.Tchernof A., Labrie F., Belanger A., Despres J.P. Obesity and metabolic complications: contribution of dehydroepiandrosterone and other steroid hormones. J. Endocrinol. (Suppl.) 1996; 150 :S155– S164.
75.Tsai E.C., Boyko E.J., Leonetti D.L., Fujimoto W.Y. Low serum testosterone level as a predictor of increased visceral fat in Japanese-American men. Int. J. Obes. Relat. Metab. Disord. 2000 ;24: 485-491.
76.Isidori A.M., Giannetta E., Greco E.A. et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin. Endocrinol. (Oxf). 2005; 63 :280-293.
77.Tan K.C., Shiu S.W., Pang R.W., Kung A.W. Effects of testosterone replacement on HDL subfractions and apolipoprotein A-I containing lipoproteins. Clin. Endocrinol. (Oxf) 1998; 48 :187-194.
78.Khaw K.T., Barrett-Connor E. Lower endogenous androgens predict central adiposity in men. Ann. Epidemiol. 1992; 2: 675-682.
79.Poehlman E.T., Toth M.J., Gardner A.W. Changes in energy balance and body composition at menopause: a controlled longitudinal study [retraction in: Sox HC. Ann. Intern. Med. 2003; 139: 702]. Ann. Intern. Med. 1995; 123: 673-675.
80.Carr M.C. The emergence of the metabolic syndrome with menopause. J. Clin. Endocrinol. Metab. 2003 ;88 :2404-2411.
81.Tchernof A., Poehlman E.T., Despres J.P. Body fat distribution, the menopause transition, and hormone replacement therapy. Diabetes Metab. 2000; 26 :12-20.
82.Simon D., Charles M.A., Naohul K., Orssaud G. Association between plasma testosterone and cardiovascular risk factors in healthy adult men. The Telecom Study. J. Clin. Endocrinol. Metab. 1997; 82 :682-685.
83.Barrett-Connor E. Lower endogenous androgen levels dyslipidaemia in men with NIDDM. Ann. Intern. Med. 1992 ;117 :807-811.
84.Kapoor D., Malkin C.J., Channer K.S., Jones T.H. Androgens, insulin resistance and vascular disease in men. Clin. Endocrinol. (Oxf) ,2005 ;63: 239-250.
85.Anderson G.L., Limacher M., Assaf A.R. et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291 :1701-1712.
86.Katznelson L., Finkelstein J.S., Schoenfeld D.A. et al. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J. Clin. Endocrinol. Metab. 1996; 81 :4358-4365.
87.Ferrannini E., Natali A., Capaldo B. et al. Insulin resistance, hyperinsulinemia, and blood pressure: role of age and obesity. European Group for the Study of Insulin Resistance (EGIR). Hypertension 1997; 30: 1144-1149.
88.B. Lawrence Riggs.The mechanisms of estrogen regulation of bone resorption.The Journal of Clinical Investigation, November 2000, Volume 106, Number 10:1203-4.
89.Riggs, B.L., Khosla, S., and Melton, L.J., III. 1998.A unitary model for involutional osteoporosis estrogen deficiency causes both type I and type IIosteoporosis in postmenopausal women and contributes to bone loss in aging men. J. BoneMiner. Res. 13:763-773.
90.Manolagas, S.C. 2000. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr. Rev. 21:115-137.
91.Pacifici, R. 1996. Estrogen, cytokines, and pathogenesisof postmenopausal osteoporosis. J. Bone Miner. Res. 11:1043-1051
92.Cenci, S., et al. 2000. Estrogen deficiency induces bone loss by enhancing T cell production of TNFa. J. Clin. Invest. 106:1229-1237
93.Mikihito Hayashi, Tomoki Nakashima, Noriko Yoshimura, Kazuo Okamoto, Sakae Tanaka, Hiroshi Takayanagi, Autoregulation of Osteocyte Sema3A Orchestrates Estrogen Action and Counteracts Bone Aging, Cell Metabolism 2019; 29: 627-637
94.Susan Stevenson, Julie Thornton, Effect of estrogens on skin aging and the potential role of SERMs.Clinical Interventions in Aging 2007:2(3): 283-297
95.Thornton MJ. 2002. The biological actions of estrogens on skin. Exp Dermatol 11: 487-502.
96.Thornton MJ. 2005. Oestrogen functions in skin and skin appendages. Expert Opin Ther Targets, 9: 617-29.
97.Ashcroft GS, Ashworth JJ. 2003. Potential role of estrogens in wound healing Am. J. Clin. Dermatol, 4: 737-43.
98.Dunna SF, Finlay AY. 1989. Psoriasis: improvement during and worsening after pregnancy. Br J Dermatol, 120: 584.
99.Boyd AS, Morris LF, Phillips CM, et al. 1996. Psoriasis and pregnancy hormone and immune system interaction. Int J Dermatol, 35: 169-72.
100.Raychaudhuri SP, Navare T, Gross J, et al. 2003. Clinical course of psoriasis during pregnancy. Int J Dermatol, 42: 518-20.
101.Weinstock MA. 1994. Epidemiologic investigation of nonmelanoma skin cancer mortality: the Rhode Island Follow-Back Study. J Invest Dermatol, 102: 6S–9S.
102.Tsukahara K, Moriwaki S, Ohuchi A, et al. 2001. Ovariectomy accelerates photoaging of rat skin. Photochem Photobiol, 73: 525-31.
103.Tsukahara K, Nakagawa H, Moriwaki S, et al. 2004. Ovariectomy is sufficient to accelerate spontaneous skin ageing and to stimulate ultraviolet irradiation-induced photoageing of murine skin. Br J Dermatol, 151: 984-94.
104.Urano R, Sakabe K, Seiki K, et al. 1995. Female sex hormone stimulates cultured human keratinocyte proliferation and its RNA- and proteinsyntheticactivities. J Dermatol Sci, 9: 176-84.
105.Miller JG, Mac Neil S. 1997. Gender and cutaneous melanoma. Br J Dermatol 136: 657-65.
106.Dae Kyung Kim, MD and Michael B Chancellor, MD. Is Estrogen for Urinary Incontinence Good or Bad, Rev Urol. 2006 Spring; 8(2): 91-92.
107.Iosif CS, Batra S, Ek A, Astedt B (1981) Estrogen receptors in the human female lower urinary tract. Am J Obstet Gyneco I141: 817-820.
108.Blakeman PJ, Hilton P, Bulmer IN (1996a) Mapping estrogen and progesterone receptors throughout the female lower urinary tract. Neurourol Urodyn 15: 324-325.
109.Ingelman-Sundberg A, Rosen J, Gustafsson SA, Carlstrom K (1981) Cytosol estrogen receptors in urogenital tissues in stress incontinent women. Acta Obstet Gynecol Scand 60: 585-586
110.Smith P, Heimer G, Lindskog M, Ulmsten U (1993) Oestradiol releasing vaginal ring for treatment of postmenopausal urogenital atrophy. Maturitas 16:145-154.
111.Blakeman PJ, Hilton P, Bulmer IN (1996b) Estrogen status and cell cycle activity in the female lower urinary tract. Neurourol Urodyn 15: 325-326.
112.Samsioe G, Jansson I, Meelstron D, Svanborg A (1985) Occurrence, nature and treatmentof urinary incontinence in a 70year old female population. Maturitas 7: 335-342.
113.Smith PJB (1976) The effect of estrogens on bladder function in the female. In Management of the menopause and post menopausal years. MTP, Lancaster, pp 291-298.
114.Semmens JP, Tsai CC, Semmens EC, Loadholt HB (1985) Effects of estrogen therapy on vaginal physiology during menopause. Obstet Gyneco I66:15-18.
115.McCallin PF, Taylor ES, Whitehead RW (1950) A study of the changes in the urinary sediment during the menstrual cycle. Am J Obstet Gyneco I60: 64-74
116.Soloman C, Panagotopoulos P, Oppenheim A (1958) The use of urinary sediment as an aid in endocrinological disorders in the female. Am J Obstet Gynecol 76: 56-60
117.Van Geelen 1M, Doesburg WH, Thomas CMG, Martin CB Jr (1981) Urodynamic studies in the normal menstrual cycle: the relationship between hormonal changes during the menstrual cycle and the urethral pressure profile. Am J Obstet Gynecol 141: 384-392
118.Cutner A, Carey A, Cardozo LD (1992) Lower urinary tract symptoms in early pregnancy J Obstet Gynaecol 12: 75-78
119.Stanton SL, Kerr-Wilson R, Harris VG (1980) The incidence of urological symptoms in normal pregnancy. Br J Obstet Gynaecol 87: 897-900.
120.Cutner A, Burton G, Cardozo LD et al. (1991) Does progesterone cause an irritable bladder? Int Urogynecol J Pelvic Floor Dysfunct 98: 1181-1183.
121.Blakeman PJ, Hilton P, Bulmer IN (1997) Androgen receptors in the female lower urinary tract. Int Urogynecol J Pelvic Floor Dysfunct 8: S54.
122.Abrams P, Blaivas JG, Stanton SL et al. (1990) The standardisation of terminology of lower urinary tract function. Br J Obstet Gynaecol 97:1-16.
123.Gangar KF, Vyas S, Whitehead M, Crook D, Meire H, Campbell S (1991) Plasticity index in the internal carotid artery in relation to transdermal oestradiol and time since menopause. Lancet 338: 839-842.
124.Jackson S, Vyas S (1998) A double-blind, placebo controlled study of postmenopausal estrogen replacement therapy and carotid artery pulsatility index. Br J Obstet Gynaecol 105:408-412
125.Fantl JA, Cardozo LD, McClish DK (1994) Estrogen therapy in the management of urinary incontinence in postmenopausal women: a meta-analysis. First report of the Hormones and Urogenital Therapy Committee. Obstet Gyneco I83: 12-18
126.Sultana CJ, Walters MD (1995) Estrogen and urinary incontinence in women. Maturitas 20:129-138
127.Walter S, Wolf H, Barlebo H et al. (1978) Urinary incontinence in postmenopausal women treated with estrogens. Urol Int 33: 135-143
128.Samsioe G, Jansson I, Meelstron D, Svanborg A (1985) Occurrence, nature and treatment of urinary incontinence in a 70year old female population. Maturitas 7: 335
129.Raz R, Stamm WE (1993) A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 329: 753-756.
130.Eric Bachman, Thomas G. Travison, Shehzad Basaria, Maithili N. Davda, Wen Guo, Michelle Li, John Connor Westfall, Harold Bae, Victor Gordeuk, Shalender Bhasin. Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point. The Journals of Gerontology: Series A, Volume 69, Issue 6, June 2014, Pages 725-735
131.Ronald E. Allen, Kenneth C. Masak, Pamela K. McAllister, Robert A. Merkel Effect of Growth Hormone, Testosterone and Serum Concentration on Actin Synthesis in Cultured Satellite Cells. Journal of Animal Science, Volume 56, Issue 4, April 1983, Pages 833-837
132.MacLusky NJ, Clark AS, Naftolin F, Goldman-Rakic PC (1987) Estrogen formation in the mammalian brain: possible role of aromatase in sexual differentiation of hippocampus and neocortex. Steroids 50:459-474
133.McEwen BS, Liederberg I, Chaptal C, Krey LC (1977) Aromatization: important for sexual differentiation of the neonatal rat brain. Horm Behav 9:249-263
134.Baulieu E, Schumacher M (2000). “Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination”. Steroids. 65 (10-11): 605-12.
135.Woolley CS, McEwen BS (1993) Roles of estrogen and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J Comp Neuro I336: 293-306
136.Jordan Marrocco, PhD and Bruce S. McEwen, PhD, Sex in the brain: hormones and sex differences, Dialogues Clin Neurosci. 2016 Dec; 18(4): 373-383
137.Paganini-Hill A, Henderson VW (1994) Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidem 140: 256-261.
138.Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG (1994) Estrogen replacement therapy in older women: comparisons between Alzheimer’s disease cases and nondemented control subjects. Arch Neurol 51: 896-900;
139.Tang M-X, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, Andrews H, Mayeux R (1996) Effect of estrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348: 429-432
140.James W. Simpkins, Evelyn Perez, and Meharvan Singh. The Potential for Estrogens in Preventing Alzheimer’s Disease and Vascular Dementia, Ther Adv Neurol Disord. 2009 Jan; 2(1): 31-49
141.Yang Hyun Lee, Jungho Cha, Seok Jong Chung, Han Soo Yoo, Young H. Sohn, Byoung Seok Ye and Phil Hyu Lee. Beneficial effect of estrogen on nigrostriatal dopaminergic neurons in drug-naïve postmenopausal Parkinson’s disease Scientific Reports volume 9, Article number: 10531 (2019)
142.Henderson VW, Paganini-Hill A. 1994. Oestrogens and Alzheimer’s disease. Annu Prog Repord Med 2: 1-21.
143.McCullough LD, Blizzard K, Simpson ER, Oz OK, Hurn PD. 2003. Aromatase cytochrome P 450 and extragonadal estrogen play a role in ischemic neuroprotection. J Neurosci 23: 8701-8705
144.Nakamura NH, Rosell DR, Akama KT, McEwen BS. 2004. Estrogen and ovariectomy regulate mRNA and protein of glutamic acid decarboxylases and cation-chloride cotransporters in the adult rat hippocampus. Neuroendocrinology 80: 308-323
145.Ledoux VA, Smejkalova T, May RM, Cooke BM, Woolley CS. 2009. Estradiol facilitates the release of neuropeptide Y to suppress hippocampus-dependent seizures. J Neurosci 29: 1457-1468
146.Nilsen J, Brinton RD. 2004. Mitochondria as therapeutic targets of estrogen action in the central nervous system. Curr Drug Targets CNS Neurol Disord 3: 297-313.
147.Hojo Y, Hattori T-a, Enami T, Furukawa A, Suzuki K, et al. 2003. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P 450 aromatase localized in neurons. Proc Natl Acad Sci U S A 101: 865-870
148.Hajszan T, Milner TA, Leranth C. 2007. Sex steroids and the dentate gyrus. Prog Brain Res 163: 399-415
149.Pike CJ, Nguyen T-VV, Ramsden M, Yao M, Murphy MP, Rosario ER. 2008. Androgen cell signaling pathways involved in neuroprotective actions. Horm Behav 53: 693-705.
150.Romeo RD, McCarthy JB, Wang A, Milner TA, McEwen BS. 2005a. Sex differences in hippocampal estradiol-induced N-methyl-D-aspartic acid binding and ultrastructural localization of estrogen receptor-alpha. Neuroendocrinology 81: 391-399
151.Romeo RD, Staub D,Jasnow AM, Karatsoreos IN, Thornton JE, McEwen BS. 2005b. Dihydrotestosterone increases hippocampal N-methyl-D-aspartate binding but does not affect choline acetyltransferase cell number in the forebrain or choline transporter levels in the CA1 region of adult male rats. Endocrinology 146: 2091-2097
152.King WJ, Greene GL. Monoclonal antibodies localize oestrogen receptor in the nuclei of target cells. Nature. 1984; 307: 745-747.
153.McCarthy MM, Auger AP, Bale TL, De Vries GJ, Dunn GA, Forger NG, Murray EK, Nugent BM, Schwarz JM, Wilson ME. The epigenetics of sex differences in the brain. J Neurosci. 2009; 29: 12815-12823.
154.Grossman CJ (1984) Regulation of the immune system by sex steroids. Endocr Rev 5:435-455
155.Grossman CJ (1985) Interactions between the gonadal steroids and the immune system. Science 227:257-261
156.Baral E, Nagy E, Berczi I (1996) The effect of tamoxifen on the immune response. In Kellen JA (ed) Tamoxifen. Beyond the anti estrogen. Birkhiiuser, Boston, MA, USA, P 137
157.Mosselman S, Polman J, Dijkema R (1996) ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett 392: 49-53
158.Zuckerman SH, Bryan-Poole N, Evans GF, Short L, Glasebrook AL (1995) In vivo modulation of murine tumor necrosis factor and interleukin-6 during endotoxemia by estrogen agonists and antagonists. Immunology 86:18-24
159.Zuckerman SH, Ahmari SE, Bryan-Poole N, Evans GF, Short L, Glasebrook AL (1996) Estriol: a potent regulator of TNF and IL-6 expression in murine model of endotoxemia. Inflammation 20: 581-597
160.Stein B, Young MX (1995) Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-TCB and C/EBP, B. Mol Cell Bioi 15:4971-4979
161.Ghosh SK, Zhang DH, Ray A (1997) Repression of interleukin-6 gene expression by 17 f3-estradiol: inhibition of the DNA-binding activity of the transcription factors NF-IL6 and NF-Jd3 by the estrogen receptor. FEBS Lett 409: 78-85
162.Lee BY, Huynh T, Prichard LE, McGuire J, Polan ML (1995) Gonadal steroids modulate Interleukin-l receptor antagonist mRNA expression in cultured human monocytes Biochem Biophys Res Commun 209:279-285
163.Wang Y, Campbell HD, Young IG (1993) Sex hormones and dexamethasone modulate Interleukin-5 gene expression in T lymphocytes. J Steroid Biochem Mol Bioi 44: 203
164.Bamberger AM, Erdmann I, Bamberger CM, Jenatschke SS, Schulte HM (1997) Transcriptional regulation of the human ‘leukemia inhibitory factor’ gene: modulation by glucocorticoids and estradiol. Mol Cell Endocrino I127: 71-79
165.Wira CR, Rossoll RM (1995) Antigen presenting cells in the female reproductive tract influence of the estrus cycle and antigen presentation by uterine epithelial and stromal cells. Endocrinology 136: 4526-4534
166.Sorachi K, Kumagai S, Sugita M, Yodoi J, Imura H (1993) Enhancing effect of 17f3 estradiol on human NK cell activity. Immunol Lett 36: 31-36
167.Screpanti I, Felli MP, Toniato E, Meco D, Martinotti S, Frati L, Santoni A, Gulio A (1991) Enhancement of natural killer-cell susceptibility of human breast cancercells by estradiol and v-Ha-ras oncogene. Int J Cancer 47: 445-449
168.Albertini MR, Gibson DFC, Robinson SP, Howard SP, Tans KJ, Lindstrom MJ Robinson RR, Tormey DC, Jordan YC, Sondel PM (1992) Influence of estradiol and tamoxifen on susceptibility of human breast cancer cell lines to lysis by lymphokine activated killer cells. J Immunother 11: 30-39
169.Muller D, Chen M, Vikingsson A, Hildeman D, Pederson K (1995) Estrogen influences CD4+ T-Iymphocyte activity in vitro in J3z-microglobulin-deficient mice. Immunology 86:162-167
170.Ito I, Hayashi T, Yamada K, Kuzuya M, Naito M, Iguchi A (1995) Physiological concentrations of estradiol inhibits polymorphonuclear leucocyte chemotaxis via a receptor mediated mechanism. Life Sci 56: 2247-2253
171.Berczi I, Nagy E (1997) Hormones as immune modulating agents. In: Krezina TF (ed) Immune modulating agents. Marcel Dekker, Inc. New York, NY, USA, p 75
172.Berczi I (1986) Gonadotropins and sex hormones. In: Berczi I (ed) Pituitary function and immunity. CRC Press, Boca Raton, FL, USA, P 185.
173.Berczi I, Baragar FD, Chalmers 1M, Keystone EC, Nagy E, Warrington RJ (1993) Hormonesin self tolerance and autoimmunity: a role in the pathogenesis of rheumatoid arthritis? Autoimmunity 16: 45-56
174.Cutolo M, Sulli A, Barone A, Seriolo B, Accardo S (1993) Macrophages, synovial tissue and rheumatoid arthritis. Clin Exp Rheumatoll 1: 331-339
175.Lahita RG (1996) The basis of gender effects in the connective tissue diseases. An Med Interne Paris 147:241-247
176.Wilder RL (1996) Adrenal and gonadal steroid hormone deficiency in the pathogenesis of rheumatoid arthritis. J Rheumatol Supp I44: 10-12
177.Sana Shabbir, Assad Hafeez, and Muhammad Jawad Khan Estrogen shields women from COVID-19 complications by reducing ER stress, Med Hypotheses. 2020 Oct; 143: 110148.
Written By
Nassrin Malik Aubead
Submitted: November 30th, 2020Reviewed: December 26th, 2020Published: February 10th, 2021
Open access peer-reviewed chapter
