Normal levels of thyroid hormones and TSH in pregnancy [1].
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Subclinical hypothyroidism (SCH), frequently observed in pregnancy is defined as high TSH with normal T4 and T3 level. The growing fetus is entirely dependent on mother thyroid hormones in the first 12 weeks; hence, any abnormalities during this period should be detected early and preventive measures initiated as decreased thyroid hormones is known to affect the mother and the fetus adversely.
\nPresence of anti-TPO antibody is a major risk factor for progression to overt hypothyroidism. After widespread use of fortified Iodine rich food and extra supplementation of iodine in pregnancy, the knowledge and prevalence of autoimmune clinical and subclinical hypothyroidism with presence of various antibodies against thyroid tissues and metabolic factors gains more importance. Adverse obstetric and fetal outcomes particularly attributed to anti TPO antibodies makes its study even more clinically relevant. It is important to know the burden of anti-TPO antibody associated SCH cases due to their differences in management.
\nA palpable increase in size of the thyroid gland is observed in normal pregnancy which is also associated with a bruit [1]. There is an established increased renal clearance of iodide leading to increased thyroid iodide clearance with associated raised uptake of 131Iodide by the thyroid glands during pregnancy. This results in a relative iodine deficient status in the pregnant mother. There is also an increase in TBG (thyroid hormone binding globulin) for which total thyroxine exhibits a raised value but free thyroxine and free triiodothyronine (fT3) is mostly normal (\nTable 1\n).
\nParameter | \nChanges during pregnancy | \nNormal values (up to) | \n
---|---|---|
TSH | \nReaches nadir during first trimester; then plateaus | \n4.0 mIU/L | \n
T4 | \nIncreases in first trimester; then plateaus | \n150 ng/mL | \n
fT4 | \nUnchanged | \n30 pg/mL | \n
T3 | \nIncreases in first trimester; then plateaus | \n2 ng/mL | \n
fT3 | \nUnchanged | \n4 pg/mL | \n
Normal levels of thyroid hormones and TSH in pregnancy [1].
The synthesis of thyroid hormones is regulated by HPT axis, i.e., hypothalamus-pituitary-thyroid axis. The TRH released from hypothalamus acts positively on pituitary gland which releases TSH [1]. The TSH in turn stimulates the thyroid gland to synthesize and release T4 and T3. The thyroid gland gives negative feedback signal to hypothalamus and pituitary and thus excess of its synthesis is controlled and regulated. During pregnancy, in addition to the normal regulatory mechanisms, hCG also plays a significant role in regulation of thyroid hormone synthesis. hCG mostly the asialo-hCG fraction secreted from the placenta is known to have weak TSH simulating action and this plays an important role in maintaining the thyroid hormone levels, whose demand is increased in pregnancy due to fetal dependency on mother’s thyroid hormones almost exclusively up to 12 weeks of gestation and hCG acts by contributing to thyrotropic action of placenta. This also results in mild hyperthyroidism status in early pregnancy.
\nPolyclonal antibodies directed against some epitopes of thyroperoxidase molecule are present in the blood of some healthy individuals and patients having auto immune thyroid disorders [1, 2, 3]. Anti-TPO antibodies from auto immune thyroid patients act as competitive inhibitors of enzymatic activity though those from healthy subjects are not seen to block thyroperoxidase [4, 5]. These antibodies mostly belong to IgG class, more often IgG1and IgG4 subtypes [6]. Prevalence of anti-TPO antibodies are more common than other anti-thyroid antibodies and more symbolic for thyroid hormone imbalance. Excess of oxidative stress markers in blood are seen with anti-TPO antibodies indicating it to be an inducer of oxidative stress [7]. Apart from hypothyroid patients, anti-TPO antibodies are also detected in Graves’ disease patients. These antibodies possess the potential of crossing the placenta barrier to variable extent [8], though its effect on the neonate is debatable.
\nFew studies document that children born to anti TPO antibody positive pregnant women supposedly suffer from compromised motor and neuropsychological development [9]. There can be behavioral problems, attention deficit disorders in the off springs associated with raised titers of anti TPO antibody in the mothers during pregnancy [10]. Couple of literatures substantiate that children of anti TPO antibody positive mothers have lower brain to body mass ratio, decreased weight of brain and smaller head circumference compared to those of anti TPO antibody negative mothers [11, 12].
\nAs the influence and outcome on off springs of increased anti TPO antibody concentration during pregnancy is of greater significance, longer follow up studies is required to gather more data on this important clinical aspect of neuropsychological development of the children.
\nPolyclonal anti thyroglobulin (Tg) antibodies are found in the serum of healthy subjects whereas oligoclonal antibodies are seen in patients having auto immune thyroid disorders. It has been hypothesized that normal blood levels of Tg induce self-tolerance in T cells as low levels of antigens are usually responsible for development of self-tolerance. But this self-tolerance is not seen in case of B cell activity resulting in healthy individuals having very low levels of anti-Tg antibodies which is usually below detection limits. Higher levels of Tg following tissue damage, or due to conformation alteration of the Tg molecule in presence of high iodine levels, or in presence of very high TSH levels, there is alteration in the titers of the anti-Tg antibody. The anti-Tg antibodies are predominantly of IgG4 though minor proportions of IgA and IgM class are also seen. The functional consequence of anti-Tg antibodies is hitherto not known. Circulating antibodies were detected in healthy young subjects and in people >60 years of age to an extent of 10–15%. Presence of anti-Tg antibodies have been documented in auto immune thyroid disorders, Graves’ disease and in patients with non-thyroid immune disorders. These antibodies like anti TPO antibodies can cross the placenta barrier but its effects are not very substantially known [1].
\nThese antibodies bind to thyroid cell membrane at/near TSH receptor and mimics the action of TSH as “occupied” receptor. This leads to excess thyroxin synthesis by the gland which escapes feedback control mechanisms. It is demonstrated frequently in Grave’s disease-also known as long acting thyroid stimulator (LATS) antibodies.
\nExcess of synthesis of thyroid hormones is known as hyperthyroidism and deficiency leads to hypothyroidism. Both the conditions are associated with deleterious effects to various metabolic processes of the body [1].
\nThyroid hormones T4 and T3 affect almost every metabolic processes of the body. Pregnancy is considered to be a physiologically altered state of metabolism as the body tries to cater to the needs of the growing fetus. There is an increased need of thyroid hormones in pregnancy as the developing fetus is completely dependent on maternal thyroid hormones till 12 weeks of gestation. Hence, the gland becomes over stimulated and hyperactive to secrete more T4 and T3 to meet the increased demand and this is brought about through hypothalamus-pituitary-thyroid axis regulatory mechanisms. Thyroxin and TBG (thyroid binding globulins) levels rise in pregnancy along with a simultaneous decrease in TSH (thyroid stimulating hormone) level [13]. A placental deiodinase enzyme also results in more thyroid hormone synthesis in pregnancy [14, 15, 16]. hCG is known to have a TSH simulating effect and hence attributes to raise the thyroid hormone synthesis to meet the increased demand via its thyrotrophic effect [17]. Absolute fetal dependency on mother’s thyroid hormones can result in adverse obstetric and fetal outcome if the increased demand for T4 and T3 is not met adequately in the first 12 weeks of gestation [18]. There has also been documented evidences that proper placental development is also dependent on thyroid hormones and lack of it can result in improper placenta formation [19] with adverse obstetric outcomes like abruptio placentae, preeclampsia, miscarriages, preterm delivery, low birth weight (LBW), IUGR (intrauterine growth retardation) and small for gestational age babies (SGA) [20, 21, 22]. Impaired intellectual development of off springs of hyper/hypothyroid mothers has also been documented [23].
\nVarious studies have registered in their findings that placenta has strong affinity for T3 and is dependent on thyroid hormones for its growth. Triiodothyronine/T3 is plays a significant role in placental trophoblastic growth by its likely effect on growth factors like EGF (epidermal growth factor) and hormone like 17 beta estradiol [19, 24, 25]. Small for gestational age babies (SGA) and intra uterine growth retardation of fetus (IUGR) are most likely results of impaired growth of placental trophoblasts [26, 27]. Fetal thyroid hormones have been found to be decreased in IUGR babies compared to gestation matched normal fetal serum. Inflammation associated with impaired uteroplacental circulation are registered to be causative factors for development of serious disorders like eclampsia and preeclampsia in pregnancy. These situations are also documented to be associated with increased oxidative stress by various studies [28]. Hence various studies now put inflammation under major focus in development of preeclampsia and pre-term labor in pregnancy. Thyroid hormones act on DNA and regulate expression of various genes which also includes genes associated with inflammation. As inflammation is now considered to be an important causative factor for development of pre-eclampsia, thyroid hormones are also corroborated by various studies to be responsible for this [29]. Analysis of maternal and cord blood has validated this hypothesis and revealed a low T4 with raised TSH level in preeclampsia cases which has also been linked with placental inadequacy.
\nVarious studies have also found an association of gestational diabetes mellitus (GDM) with impaired thyroid status. Inverse correlation between metformin and TSH value further strengthens this association. Thus, screening of all pregnant women for thyroid function along with anti TPO antibody measurement has been advised by many studies, particularly in “at risk “cases of GDM [30, 31, 32, 33]. Both thyroid dysfunction and diabetes mellitus are known to adversely affect obstetric and fetal outcome and now gradually gathering data proves that very often both the conditions coexist in pregnancy depicting an association between them and hence early screening, intervention and timely management is advocated by various studies [34, 35, 36, 37].
\nThe need for iodine increases in pregnancy (daily requirement of iodine −150–200 μg/day, 250 μg/day in pregnancy) leading to an iodine deficient status if not adequately supplemented. Apart from iodine deficiency, the other most common factor for thyroid hormone deficiency has been attributed to anti-TPO antibodies. Hypothyroidism is registered to be more prevalent in Asian countries compared to their Western counterparts. As such thyroid disorders have wide geographical variations attributed to dietary factors, level of various goitrogens in diet and their consumption level, deficiencies of micronutrients like selenium, iron and most importantly iodine. Autoimmune thyroid diseases are also more prevalent in Asian countries and accumulating literatures suggest it to be more substantial in Indian population with greater prevalence of anti TPO antibody positivity.
\nHigh TSH level with normal T4 level is known as subclinical hypothyroidism (SCH). Subclinical hypothyroidism is one of the most common type of thyroid dysfunction that is found to be associated with pregnancy [38, 39]. The increased need of thyroid hormones to meet the extra demand by the growing fetus in the first 12 weeks of gestation is dealt by hCG due to its thyrotrophic action as discussed earlier and also via hypothalamus-pituitary-thyroid axis regulation which usually results in small painless enlargement, i.e., goiter formation in pregnant women [1]. This also results in increased need of iodine in pregnancy.
\nHence, endemic areas of iodine deficiency have shown a higher prevalence of clinical or subclinical hypothyroidism in general and in particular in pregnant women. Because of increased thyroid hormone production, increased renal iodine excretion, and fetal iodine requirements, dietary iodine requirements are higher in pregnancy than they are for non-pregnant adults. The requirement of iodine is 250 μg/day in pregnancy. Recommendation by American Thyroid Association (ATA) is women who are planning pregnancy or currently pregnant, should supplement their diet with a daily oral supplement that contains 150 μg of iodine in the form of potassium iodide [40]. This should optimally start 3 months in advance of planned pregnancy.
\nHowever, apart from iodine deficiency, the other most significant cause of hypothyroidism in recent times is presence of anti thyroperoxidase antibody, i.e., anti TPO antibody and anti Tg (anti thyroglobulin) antibody in the serum. The thyroperoxidase enzyme as described above is highly essential for oxidation of trapped iodine and its incorporation into tyrosine molecule for synthesis of thyroxin. Anti TPO antibody destroys the thyroperoxidase enzyme and hence prevents the iodination of tyrosine molecule and overall synthesis of thyroxin is hampered resulting in hypothyroidism. This autoimmune basis of hypothyroidism is now more relevant after iodine deficiency has been tackled by fortification of food products with iodine/with iodine supplementation as potassium iodide. In pregnancy, immune regulatory cytokines and cells are present in the mother’s circulatory system and accumulate in the decidua and can modify autoimmune responses influencing the symptoms of autoimmune disease [41].
\nPresence of anti-TPO antibody is a major risk factor for progression to overt hypothyroidism. Various studies reveal a prevalence of 2–17% of euthyroid pregnant women being anti-TPO antibody positive. Still data from Indian scenario is extremely limited. TPO antibodies are able to cross the placenta. At the time of delivery, cord blood anti TPO Ab levels strongly correlate with third-trimester maternal anti TPO antibody concentrations [8]. However, concrete documentation of maternal passage of either anti TPO antibodies or anti Tg antibodies affecting the fetal thyroid function is still debatable [9, 10, 11, 12].
\nIt has been documented that euthyroid pregnant women who are positive for thyroid peroxidase autoantibody (anti TPO antibody) also are at increased risk of various complications of pregnancy including miscarriage, preterm birth, pregnancy-induced hypertension (PIH), intrauterine death (IUD), and intrauterine growth retardation (IUGR) [42, 43].
\nA number of etiologies have been hypothesized as the cause of the relationship between various pregnancy related complications like miscarriage, IUGR, pre-eclampsia, pre term delivery and autoimmune thyroid antibodies. To enumerate a few: (a) prior presence of a restrained degree of hypothyroidism, (b) thyroid antibodies reflecting an immunological imbalance inclining towards auto immunity in the pregnant female, (c) direct effects of thyroid autoantibodies on the placenta or the fertilized ovum. The above hypotheses have been corroborated by the observation of higher levels of TSH within the normal range noted in various meta-analysis studies indicating a milder degree of thyroid failure in euthyroid pregnant women with thyroid auto antibodies positivity [41, 44, 45, 46].
\nPregnancy is considered to be a goitrogenic status, particularly in the Iodine deficiency scenario. Increased need of thyroid hormones, TSH simulating actions of beta HCG with super added iodine deficiency actually leads to volumetric increase in the gland and not just vascular engorgement which also has been biochemically corroborated by observations of high serum Thyroglobulin levels, more T3 secretion and small rise in basal TSH level at delivery. Studies supports that there is actual goiter formation in pregnancy which can be tackled to a measurable extent by adequate iodine supplementation [47].
\nPresence of anti TPO antibodies is mostly associated with Hashimoto’s thyroiditis, Graves’ disease, nodular goiter and thyroid carcinoma [1]. Anti TPO antibody positivity in pregnancy is mostly associated with overt or subclinical hypothyroidism during pregnancy sometimes associated with a goiter which is often painless. Post-delivery, there are incidences of postpartum thyroiditis with a milder form of Graves’ disease lacking the typical symptomatic features which after a few months, changes to hypothyroidism and development of small painless goiter [1, 48, 49].
\nIt is important to know the burden of anti-TPO antibody associated SCH cases due to their differences in management. This is even more important in case of pregnant women as presence of anti TPO antibody makes them more vulnerable to clinical hypothyroidism and hence its detection at early pregnancy helps in its better management. The management for pregnant women with subclinical hypothyroidism with anti TPO Ab positive and negative differs from each other.
\nSetting the reference limits for thyroid hormones and TSH in pregnancy is a debatable fact due to different laboratories giving different values and there is gross geographical variation too. Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease during Pregnancy and Postpartum (ATA 2011) recommends a trimester specific range of TSH in pregnancy which is lower than in normal adult, i.e., first trimester: 0.1–2.5 mIU/L, second trimester: 0.2–3.0 mIU/L, third trimester: 0.3–3.0 mIU/L [40]. However, the recent guidelines of ATA recommend “When available, population- and trimester-specific reference ranges for serum TSH during pregnancy should be defined by a provider’s institute or laboratory and should represent the typical population for whom care is provided. Reference ranges should be defined in healthy anti TPO Ab-negative pregnant women with optimal iodine intake and without thyroid illness. If internal or transferable pregnancy-specific TSH reference ranges are not available, an upper reference limit of ∼4.0 mIU/L may be used” (ATA-2017) [50]. In the absence of accredited trimester specific reference ranges for thyroid hormones and TSH levels in pregnancy in India, the current practice is to use the reference limits set by ATA as per 2017 guidelines [50].
\nRecent guidelines of ATA recommends regular monitoring of thyroid status in women with overt and subclinical hypothyroidism (treated or untreated) or those at risk for hypothyroidism (e.g., patients who are euthyroid but anti TPO antibody or anti Tg antibody positive, post-hemithyroidectomy, or treated with radioactive iodine) with a serum TSH measurement approximately every 4 weeks until completion of second trimester and at least once near 30 weeks gestation [50]. Sub clinical hypothyroidism in anti TPO antibody negative and positive cases in pregnancy are differently managed with levothyroxine (LT4) as per the recommendations of ATA 2017 guidelines [50] (\nTable 2\n).
\n\n | TSH value | \nT4/T3 | \nAnti TPO | \nTherapy with LT4 | \n
---|---|---|---|---|
1 | \nWithin the pregnancy-specific reference range or <4.0 mIU/L (if specific reference range unavailable) | \nNormal | \nNegative | \nNot recommended | \n
2 | \nTSH >10.0 mU/L | \nNormal | \nNegative | \nStrong recommendation | \n
3 | \nTSH >2.5 mU/L and below the upper limit of the pregnancy-specific reference range | \nNormal | \nPositive | \nWeak recommendation | \n
4 | \nTSH greater than the upper limit of the pregnancy-specific reference range but below 10.0 mU/L | \nNormal | \nNegative | \nWeak recommendation | \n
5 | \nTSH greater than pregnancy-specific reference range or >4.0 mIU/L (if specific reference range unavailable) | \nNormal | \nPositive | \nStrong recommendation | \n
Recommendations by ATA 2017 guidelines regarding management of sub clinical hypothyroidism in pregnancy [50].
Recently, some researchers speculated that assisted conception in women positive for anti-thyroid antibodies had poor outcome of in vitro fertilization, even if they were euthyroid. Studies do document that anti thyroid antibodies positive patients had low fertilization rate, implantation rate, and pregnancy rate and high abortion rate. Regarding the question how these antibodies interfered with fertilization, embryo development as well as implantation potential still remains unanswered. The hypothesis is that the antibodies may bind to either the surface of the egg and/or embryo and interfere with fertilization and subsequent embryo development. Alternatively, the presence of the auto antibodies in the endometrial tissue may exert detrimental effect on embryo implantation leading to early pregnancy loss [51, 52, 53, 54].
\nMore and more evidences worldwide have pointed towards anti TPO antibody to be associated with clinical and subclinical hypothyroidism with adverse obstetric and fetal outcomes. As the management differs for subclinical hypothyroidism in anti TPO antibody positive and negative pregnant women hence more studies should be undertaken pertinent to different geographical areas regarding the prevalence of autoantibodies and their effect on pregnancy and on the off springs in the long term. The trimester specific reference ranges for different areas should also be specified with larger cohort of studies particularly for countries like India where there are wide geographical and ethnic variations. The area where there is severe lacking of data with respect to India is regarding the effects of autoimmune subclinical hypothyroidism on the obstetric, fetal outcomes and most importantly on the off springs in the long run. Hence, longer follow-up studies with larger cohorts is necessary to gather more evidences regarding this important endocrinal disorder in pregnancy in India.
\nRheumatoid arthritis (RA) is defined as a chronic, inflammatory joint disease that without effective and timely treatment can lead to irreversible disability by cumulative joint damage. This autoimmune disease is characterized in most cases by autoantibodies against immunoglobulin G (RF) and citrullinated proteins (ACPAs) [1, 2, 3]. The alterations in the immune response is only one face of the disease since it has been described as a heterogeneous disease [4, 5]. This is supported by the wide variation in responsiveness to different rheumatic treatments [6]. Research suggests this might be due to variations in the distribution/expression of estrogen receptors (ERs) in immune cells; ERs often bind to promoter regions in the DNA associated with transcription factors (e.g., NF-κB, SP1, AP-1, C/EBPb) that are important for immune cell function [7].
The relation of immune response and estrogens in RA began with the observation of S. Hench in 1938, where he found pregnancy ameliorated RA, this was the basis for the formulation of his hypothesis sustaining that hormone deficiency could lead to the development of RA, but at that moment, he hypothesized adrenal insufficiency as the responsible of RA pathogenesis [8]. Furthermore, administration of corticosteroids was prescribed for RA patients and the results of the therapy were considered “a miracle cure for RA,” but in the case of women, the regulation of adrenal glands seems to be only a part of the therapy. Other studies demonstrate that sexual hormones seem to have a very important role in RA pathogenesis. For example, in vitro studies demonstrated that the achieved concentrations of cortisol do not affect inflammatory cell function, as did the serum of pregnant women, which is rich in sexual hormones. Also the corticosteroid levels return to normality 3 days after delivery, which does not coincide with the pattern of rheumatoid arthritis relapse, common after the third month of delivery [9]. This antecedent opened a new field of study focused on hormones and RA. When concentrations of hormones were analyzed in synovial fluid, a correlation was found in this tissue including, dehydroepiandrosterone (DHEA) which levels are inversely correlated with disease severity and associated with autoimmunity [10, 11] and corticotrophin-releasing hormone (CRH) which levels remain constant in synovial fluids and tissues from RA patients despite the steroid treatment [12]. The dysregulated production of estrogen levels in RA is not exclusive of women; higher estradiol (E2) concentrations and decreased androgen levels have been found in women and men synovia [13]. These concentrations are correlated with those measured in serum in 66% of the patients (14 of 21 patients). The estradiol mean concentrations was 38.25–9.74 pg/ml in serum and 18.83–5.70 pg/ml in synovia; these concentrations showed a positive correlation (R = 0.79, P < 0.0003) [13, 14, 15].
Fluctuations in estrogen levels appear to remarkably impact immunologic profile. Estrogen concentration during lactation is slightly low compared to normal levels (35.9–54.4 pg/ml vs. 63.3–216 pg/ml) upon the normal higher levels (100–400 pg/ml in the late follicular stage) (Table 1); together, prolactin and estrogen levels could lead to a change in immune response [16, 17].
Phase | Sub phase | Estrogen concentration [E2] pg/ml |
---|---|---|
Ovulation | Early follicular | 30–100 pg/ml |
Late follicular | 100–400 pg/ml | |
Luteal Phase | 60–150 pg/ml | |
Pregnancy | 1 semester | 188–2497 pg/ml |
2 semester | 1278–7197 pg/ml | |
3 Semester | 6137–3460 pg/ml | |
Postpartum | Lactation | 35.9–54.4 pg/ml |
No lactation | 97.10 pg/ml | |
Weaning | 81.6 pg/ml |
Average levels of estrogens on distinct phases of the reproductive cycle.
Autoimmune diseases affect approximately 8% of the population, out of this percentage 78% are women [18, 19] and for the specific case of RA, the proportion is 3 to 1 compared to men [20, 21]. Also, RA is much more severe in women compared to men (Table 2). For example, in a multiple logistic regression analysis for all point and period remissions, male gender seemed to be a strong predictor of remission; for women, the frequency of remission at 18, 24, and 60 months was 30.4, 32.1, and 30.8%, respectively; meanwhile for men, the remission rate was 41.7, 48.0, and 52.4% [22]. Additionally, in another study from a total of 1709 RA patients, (77% female) women had a longer disease duration (P < 0.001) despite the fact that at baseline, women had a lower frequency of anti-CCP positivity (P = 0.03) and lower CRP (P < 0.001), and at 12 months, men achieved remission more frequently (18% vs. 12%, P = 0.045) compared to women [23].
Reference | Year | Features men | Features women | Main findings |
---|---|---|---|---|
BARFOT [22] | 2007 | DAS28 = 5.09 CRP 27 | DAS28 5.37 CRP 18 | Women had a much lower remission rate than men, although their disease activity before treatment seemed similar |
AIR [23] | 2014 | DAS28 = 5.6 CRP 32 ERS 34 CCP positives 80.7% | DAS28 5.6 CRP 28 ERS 33 CCP positives 74.7% | At 12 months, men achieved remission more frequently (18% vs. 12%, P = 0.045). In anti-TNF failure, remission rates were higher in men than in women |
QUEST RA n = 6400 [24] | 2009 | DAS28 = 3.8 ESR 23 HAQ = 0.8 | DAS28 4.3 ESR 30 HAQ = 1.1 | 30% of men and 17% of women in QUEST-RA were in DAS28 remission |
AIR n = 1709 [23] | 2014 | Lower frequency of anti-CCP (P = 0.03) Lower CRP (P < 0.001) | Female had longer disease duration At 12 months, men achieved remission more frequently (18% vs. 12%, P = 0.045) |
Baseline and remission characteristics of RA in men vs. women: comparison of different clinical characteristics of female RA patients compared to male RA patients and the difference in remission rates documented on various studies.
The estrogen dysregulation has been associated with disease severity and acceleration of lumbar facet joint damage in arthritis [25, 26]. Added to this, some disorders of the reproductive system seem to increase the risk to develop RA, for example, physician-diagnosed polycystic ovary syndrome (RR 2.58; 95% CI, 1.06–6.30) and endometriosis (RR 1.72; 95% CI, 0.93–3.18) [27, 28]. Suggesting an important role of sex hormones and menstrual cycle regulation as risk factors associated with autoimmune diseases.
These differences could be attributed to the fact that women respond after immunization with a more exacerbated antibody production and an increase in cell-mediated responses. Thus, female patients show higher CD4+ T-cell counts, higher levels of IgM, and T-helper 1 (Th1) cytokine production [29]. This suggests that differences in immune response could be mediated by the hormonal ratios observed during pregnancy and postpartum in women with RA.
There is an increased risk of RA worsening or new onset of disease especially after the first trimester postpartum (Table 3), where several immune and hormonal changes are detected like: elevation of monocyte-related transcripts [30], decrease in corticosteroids, estrogen, progesterone, IL-4, IL-10, and humoral immunity, and increase of TNF-α and IFN-γ [31]. These postpartum flares occur within the first 4 months in most patients with chronic RA [32, 33], even a 62% had more affected joints at postpartum; these results were similar when the analysis was restricted to tender joints only [32]. Aggravation of disease activity (in 6 of 9 patients with RA) was detected at 6 and 12 weeks postpartum as a progressive decrease in leucocyte counts and increased CPR, whose levels where normal during pregnancy [34]. In the “Pregnancy induced Amelioration of Rheumatoid Arthritis” (PARA) study, 118 patients were followed up until 26 weeks postpartum and levels of autoantibodies anti-CCP, IgM-RF, IgG-RF, and IgA-RF were measured. The median levels of autoantibodies during pregnancy were stable and declined postpartum. When hemodilution was taken into account, an increase in the levels of antibodies explains the symptom onset as well as the start of symptoms due to inflammatory processes directly related to immunoglobulin actions [8].
Reference | Period evaluated after delivery (months) | Percentage/fold increase of RA onset |
---|---|---|
Oka [35] | <6 | 9.7% 2.7% |
6–12 | ||
Del Junco et al. [36] | N.E. | 5 fold |
Nelson et al. [37] | <6 | 9.7% |
Iijima et al. [33] | 12 | 0.08% |
Silman et al. [38] | 3 | 5 fold onset |
Ostensen et al. [34] | 3–6 | 66.6% |
Percentage of healthy subjects who presented RA onset after delivery or post-partum.
These dramatic postpartum changes can explain why there is a three to fivefold increased risk of onset during the first 3 months postpartum, with the highest risk being after a first pregnancy [38], in the cohort of Iijima composed by 2547 patients, and the same results were obtained [33]. The available studies on pregnancies in women with RA suggest that outcomes are worse than in the general population [39].
Such RA onset coincides with hormonal changes in the postpartum period, and only the changes during postpartum contribute to RA. During breastfeeding prolactin [40] by itself increases the antibody production and pro-inflammatory cytokines [41] and after the first pregnancy the risk of RA increases several times [42]. An additional link between sex-hormones and increased risk of RA come from data showing that the administration of drugs for lactation suppression which mainly are high-dose estrogens, increased risk of RA development [26]. Given that several cytokines are regulated by estrogens, so a decrease in this hormone could be responsible for flare and disease onset as it contributes to the activation of the immune system necessary for the delivery [43].
Estrogen seems to orchestrate several key features of the immune response and may be a critical factor in the incidence and severity of the disease in women. Small variations in estrogen concentration can have a very wide range of effects, even some of them could be opposite even when they are provoked by the same molecule.
Since 1980, it was noted that young women with rheumatoid arthritis (RA) report an exacerbation of symptoms just before or at the time of menstruation, it could possibly be related to “premenstrual tension syndrome” and alteration in pain perception [44], but in a study where only objective measures of disease activity were measured, a significant cyclical change in finger joint size (FJS) was seen in 4 of 7 patients with RA, with all peaks occurring within 6 days of the start of menstruation [45] while on contrary, the morning stiffness was reduced during the post-ovulatory phase where estrogen and progesterone are high [46], indicating that this worsening of symptoms might be related to variations in hormone levels [47]. Based on this evidence, a relation between low levels of estrogen (at luteal phase) can correspond to enhancement of RA symptoms. Contrary to what occurs on pregnancy, where high estrogen levels seem to have a protective effect. Until now there is no follow up study available to display the effect of cyclical variations in estrogen levels and symptoms severity in RA patients.
As stated previously, the relationship of RA onset and sex hormones has been widely studied. This phenomena was described first 80 years ago [8] and was noticed that pregnant patients with RA usually go into remission [48] in a 20–40% by the third trimester and 50% had low disease activity [49]. Prospective studies have shown that only 48–66% of women with RA experience improvement in pregnancy, with 20% becoming quiescent by the third trimester and 16% in complete remission (no joints with active disease without therapy) [32, 50].
It has been hypothesized that estradiol might be the principal regulator of immune response during pregnancy, nevertheless other estrogens might be implicated in this immune regulation, as an example we can cite estriol (E3) which is mainly produced during pregnancy [51, 52], and estetrol (E4) is synthesized exclusively by the fetal liver during pregnancy being able to reach the maternal circulation through the placenta [53]; thus, these two estrogens, specifically E4 could have an important role in the immune regulation during pregnancy; nevertheless, there is scarce information about its possible function during pregnancy.
A shift from a Th1/Th17 pro-inflammatory response to a Th2/Treg response has been observed in pregnancy [54, 55]. This could explain the decrease of IL-2 during pregnancy, while soluble TNF receptor, p55 and p75, increases [56]. The role of the immune system in pregnancy is very important. It has been observed that a depletion of immune cells can cause the termination of the pregnancy. Nevertheless, it is not very clear how such changes in T helper cell function could impact the implantation process. It has been suggested that the response could be induced by trophoblastic cells that can secrete IL-6, IL-8, MCP-1, and GRO-α, early in pregnancy [43].
During the first trimester, NK cells, dendritic cells, macrophages, and regulatory T cells (Treg) infiltrate the decidua and accumulate around the trophoblastic cells [57, 58, 59]. This regulation of the immune response could be the cause beneath the clinical improvement observed in RA during pregnancy.
RA onset is common in the peri-menopausal age, which is not the case with SLE [60] and while hormone replace therapy (HRT) is proposed as therapy for women with RA, OCP and postmenopausal hormones significantly increased the risk of SLE [61]. Also, there is an inverse trend for RA incidence when women reach menopause after 51 years compared to those who reach menopause before 45 years of age. This is consistent with a decline in the production of sex hormones and suggesting that changes in immune regulation due to the availability of estrogen receptors in immune cells and circulating estrogens might also have an effect on RA onset on these late menopausal women [26].
ERα (NR3A1) and ERβ (NR3A2) that are encoded by ESR-1 and ESR-2 genes expressed on human chromosomes 6 and 14, respectively [62]. It is estimated that both receptors regulate 40% of the genes in cell line U2OS [63], but despite both are estrogen receptors (ERs), ERα and ERβ microarray analysis had demonstrated that they regulate different genes [7, 64, 65]. The activation of one or other of these ERs has specific effects in distinct, non-overlapping or even antagonist effects determined by factors like distribution, expression, dimerization, splice variant ER isoforms, signaling pathways triggered, physiological stage, and interaction with specific co-activators/−repressors [62]. One example of the distribution of these receptors is given in T lymphocytes, CD4+ cells which have higher ERα levels, B cells have higher ERβ expression than ERα and CD8+ cells have lower expression of both receptors [66], murine splenic DCs express ERα but has negligible ERβ expression and bone marrow-derived and peritoneal macrophages also express ERα and few if any ERβ [67, 68], so given the expression, lower or higher concentrations of estrogens will be needed to activate the receptors with the lowest expression [69].
In general terms, the effect of ERα on the immune system is more prominent than ERβ due to regulating multiple NF-kB pathway members to control cytokine responses. This, given that ERs are ligand-dependent transcription factors that mediate long-range chromatin interactions and form complexes at gene regulatory elements, thus promoting epigenetic changes and transcription [70]. Also, its promotion of strong antigen-specific Th1 cell responses was demonstrated in ERα-deficient mice where E2 effects on Th1 responses were not observed [71], apart from but this receptor is not only delimited to the cells at periphery, its expression seems to have effects in the thymus and spleen since deletion of ERα led to hypoplasia of both organs and contribute to the increased frequency of immature CD4 + CD8+ thymocytes and decreased CD4 + CD8− cells [72].
As mentioned previously, estrogen receptors (ER) are expressed in the immune cells; TaqMan RT-PCR analyses indicate that in CD4 + T-helper cells express higher concentrations of ERα, B cells ERβ, and CD8+ T cells; monocytes express both ERs at lower concentrations [66]; this proportion is important because despite both receptors are present in all PBMCs, the functions elicited by their activation vary depending on the proportion of each receptor on such cells. A wider description of such differential effects is made for several cell types:
T cells: CD4+ T responds to E2 administration at low physiological levels (of 60–100 pg/ml in castrated female mice) increasing antigen specific responses, production of IFNγ and IL2 as well as inducing FoxP3 positive Treg cell differentiation [71, 73, 74, 75]. During the reproductive cycle CD4+, T cells increase on preovulatory (late follicular) [76], decrease in the luteal phase (60–150 pg/ml) compared to the early follicular phase (30–100 pg/mL) [77] and increased in the first trimester of pregnancy (8.9%, vs. 4.4% of controls) and 6–8 weeks following delivery [78]. Regarding CD8+ T cells, there is not much evidence, in models of collagen-II induce RA, CD8+, lymphocytes were significantly diminished in the spleen of the estradiol-treated animals and were suppressed in the thymus [79].
Fibroblast-like synoviocytes: on FLS (Figure 1), estrogens induce an increase of MMP invasion of cartilage when these cells were transfected with ERα, thus estrogen levels can influence joint erosion degradation of extracellular matrix [80]. Regarding this antecedent, an increase in hormonal levels at synovia could influence cytokine levels but it is not clear if the effects of estrogen upon certain cytokines like TNF-α, IL-10, and IL-6 are unidirectional or could be an initial trigger of aromatase activity. For example, TNF-α, IL-1, and IL-6 stimulate fibroblast aromatase activity in a dose-dependent manner; the aromatase enzyme complex is involved in the peripheral conversion of androgens (testosterone and androstenedione) to estrogens (estrone and estradiol, respectively) [81].
E2 cell receptors in different cell populations: different effects of estrogen concentrations upon estrogen receptors ER-α and ER-β present on each cell. Left: receptors and cells were they are present. Horizontal red arrow: gradient of estrogen concentrations. Blue arrows: decrease of an effect by estrogen concentration. Red arrows: increase of an effect by estrogen concentrations. This is an original image made explicitly for this publication and not subject to copyright.
B cells: concentrations of E2 ranging 75 pg/ml or above activate ERs, leading to an upregulation of CD22, SHP-1, BCL-2, and V-CAM-1. This can alter the survival of immature B cells that would normally be deleted [82]. Also a decrease in transitional B cells and increased marginal zone B cells [83] has been observed. In the presence of estrogen, BAFF increased its expression by 5-fold, but this characteristic was more pronounced in cells isolated from women than in those from man [84]. An overexpression of BAFF in transgenic mice leads to manifestations of autoimmune disease [85], and similar BAFF increase has been reported in the serum of patients with RA, [86] even at early stages of RA and correlates with the titers of IgM rheumatoid factor and anti-cyclic citrullinated peptide autoantibody (R = 0.76 and R = 0.49) [87]. It has been hypothesized that high levels of estrogens during pregnancy could prevent B cell apoptosis and therefore enhance survival of autoreactive cells [88]. Implications of estrogen signaling on auto reactive B cell expansion and autoantibodies production have not been evaluated in the clinical setting.
Another field with scarce exploration and understudied outcome of the estrogen therapy on RA is the modification and decrease of autoantibodies by estrogen action. This novel mechanism is not clearly elucidated and a lot of investigation in this topic is needed, but the little existing evidence demonstrate that estrogens can influence antibodies production and activity by modification of glycosylation of antibodies like galactosylation of human IgG in healthy individuals [89]. The changes in immunogenesis of antibodies by estrogens was demonstrated in an experiment were the induction of anti-C11 autoantibodies was measured, lower anti-C11 levels were observed in the estrogen treated group as compared with their controls [90]. The same behavior was observed by Nielsen et al. [91] and further investigations demonstrated than on CIA models sustained levels of 0.36 mg of estradiol (comparable to estrus phase) had similar quantities of IgG anti-CII antibodies than controls but have not developed RA, this was due to the different Ig subclasses. Estradiol-treated mice produced more IgG1, and mice from the placebo group produced significantly higher levels of IgG3 [92]. Other changes that estrogens induce in autoantibodies are an increase in sialylation, which has been observed during pregnancy and within 3 months post-delivery (when RA risk is presumably higher) [93]. Antibodies sialylation affects inflammation; in the case of RA, the transition from preclinical asymptomatic autoimmunity to clinical phases is associated with a change in the sialylation of antibodies [94, 95, 96]. Changes in sialylation by estrogens have been explored already in RA patients. E2 treatment increases sialylation on postmenopausal RA women [97], so taken together if E2 induces anti-inflammatory IgG by inducing St6Gal1 expression in antibody-producing cells [98].
Estrogen concentration: it seems to exist a cut-off point in the concentration of estrogens that determine different effects, because sensitivity of receptors even at sub physiological concentrations of estrogens. For example, in a model of collagen-induced arthritis (CIA) in female mice, after type II collagen (CII) immunization those treated with the ER antagonist ICI 182,780 (which binds to both ERα and ERβ but not to the surface receptor) doses that insufficient to block estrus cycle, were sufficient for block the E3-mediated suppression of CIA [99, 100]. On the range of higher concentrations, estradiol (E2) can inhibit the production of pro-inflammatory cytokines, like TNF-
Estrogen chemical modifications: as mentioned before, a correlation exists between estrogen concentration in synovial fluid and serum estrogens (R = 0.79, P < 0.0003), and concentration of free estrogens (E2) is higher in RA as compared to controls [13, 14, 15]. Therefore, measured estrogen concentration in synovia could reflect a general overview of estrogen body concentrations. There is a significantly higher level of androstenedione (a precursor of estrone and estradiol) in synovial fluid of RA patients as estrone (E1), suggesting that these higher levels are the result of an elevated activity of aromatase [14]. Available steroid pre-hormones are rapidly converted to estrogens, which seems to have pro-inflammatory activity in the synovial tissue. When analyzed more in detail, it was found that increased estrogen concentrations in RA synovial fluid (in women as in men) were 16α-hydroxyestrone and 4-hydroxyestradiol (hydroxylated forms), while the estrone levels were detected increased on RA patients, the 2-hydroxyestrone showed no differences comparing RA vs. healthy controls [14], and depending on its modifications, estrogens can trigger very different effect in the body. For example, the hydroxylated forms of estradiol, 16OH-E2 and 2OH-E2 enhance the proliferation of THP-1 (Figure 2) monocytes at high concentrations (10−9 M). Meanwhile, the hydroxylated estrones 4OH-E1 and 2OH-E1 enhance cell proliferation at low concentration (10−10 M), [107], which are inhibited by antiestrogen drugs [108], except for 2OH-E1, which still induced proliferative effect (10−10 M) [107]. In some cases, estrogens produce the same affect but have different target cells in a dose dependent manner because of the proportion of expression of ERs; E2 and endocrine disrupting chemicals (EDCs) affect cell mutagenesis through ERα. At 10–8 M is observed an inhibition on the mitogenesis of B cells and at 10–6 M in T cells. For the EDCs (diethylstilbestrol, bisphenol-A, p-nonylphenol, and di-2-ethylhexylphthalate), the concentrations needed for this effect were higher, from 10 to 6 to 10–5 M [69].
Estrogen modifications and concentrations: image showing the differences between the effects depending of the estrogen modifications. Activity of different estrogen modifications upon proliferation of THP-1 cells and concentrations needed for achieve the effect. Green lines: increase in proliferation. Red lines: decrease in proliferation. This is an original image made explicitly for this publication and not subject to copyright.
Given the previously displayed effects of estrogens on the immune system and in RA, it is natural to suppose that a hormone therapy could have certain effects upon the disease but, the studies exploring this possibility are scarce. Three major considerations have been identified as roadblock for such research to be conducted: (1) cut-off point in estrogen levels determining the effects of this molecule on the immune system, (2) the various effects of the same molecule at different concentrations lead to different effects depending ERα or ERβ receptor, and (3) effects dependent of the chemical modification (hydroxylation) of estrogens.
The hypothesis that hormonal therapy could ameliorate RA arises from the evidence of reported improvement in multiple pregnancies and contraceptive use [109], but this evidence became more solid when the estrogen at physiological levels administration in models of type II collagen-induced arthritis model (CIA) ameliorated arthritis and suppressed T-cell-dependent autoimmune reactions [52, 90]. In this experiment, female mice were implanted with E2 release devices, which induced a chronic estrous phase, the high doses of E2 caused a 35-day delay of the onset of RA disease but without affecting frequency and severity; this delay was reduced to 10 days with lower E2 concentrations of 25 days with physiological E3 proved to be as efficient as the high dose E2 causing a 25 day delay [90]. E3 seems to have more pronounced effects than E2; this estrogen E3 is mainly produced in pregnancy [51, 52]. In EAE models, it seems that the estrogen-mediated protection is dependent upon ERα. For example in EAE homozygous ERαKO treated with estriol, no protective effect was registered, while WT mice presented a significant decrease in disease severity and significant reductions in pro inflammatory cytokines TNF, IFNγ, IL-2, and an increase in levels of the Th2 cytokine IL-5 [110]. The effect of estrogens at interact with ERα receptor is not only limited to the immune response; in murine ovariectomized mice with estrogen treatment by pellet implantation, a dramatic increase in bone mass was observed. This was mediated by ERα-mediated apoptosis of osteoclasts through activating FasL/Fas signaling [111]. This could be an indicator that similar protective effects of estrogens may be present in immune cells due to the expression of ERα in CD4 + T lymphocytes.
Estrogens have been demonstrated to have anti-inflammatory activity. In CIA models, estrogen supplementation reduced paw inflammation efficiently and decreased paw volume by 48% (P < 0·01) [91], but we need to be aware that the activity of several estrogens (E1, E2, E3, and E4) is different and it depends not only on the hormone itself but also by the specific disease or even the specific clinical profile of the patient that is taking them. 2-methoxyestradiol on CIA model (20 days after the injection of type II collagen) produce a significant decrease in the arthritis index compared with that in the control mice (P < 0.05) despite it was not as efficient as estradiol [112]. Despite this is the most tested estrogen among studies for its effect in RA, Estradiol E2, in clinical applications, shows several side effects such as: hypertension, increased coagulation, and cancer incidence but a feature that both share is that they are protective in experimental autoimmune encephalomyelitis (EAE) and CIA [113].
The clinical data available is scarce and most of the available trials only evaluate the protective effect of OCP (oral contraceptive pill) and hormone replacement therapy (HRP) for RA. In a study of association between postmenopausal hormone therapy (PMH) use and the risk of rheumatoid arthritis (RA) in a subset of the Epidemiological Investigation of RA (EIRA) study, the users of PMH had a decreased risk of ACPA-positive RA compared with never users, mainly with a combined therapy (estrogen plus progestagens), they propose that PMH use might reduce the risk of ACPA-positive RA in post-menopausal women over 50 years of age, but not of ACPA-negative RA [114].
Regarding the role of OCP use in RA, there is a theory which explains that recent decrease in incidence of RA in women in the past 50 years may be in part due to increased use of the OCP, even when may be confounded by OC use being related to pregnancy avoidance and high social class [115]. During a 14 month period, 23,000 women who were using oral contraceptives were recruited, and a similar number of those who had never used OCP as controls and evaluated every 6 month intervals. Patients were classified as “current user,” “former user,” and “never user.” The cases were categorized according to the woman’s contraceptive status at the time of RA diagnosis (event). The trend for former users was χ2 = 5.7, (p < 0.02) and for the never users χ2 = l5.0, (p < 0.01) but the current users χ2 = 0–85, (p > 005) and for those who were aged 40–44 years at diagnosis had a significantly lower risk of rheumatoid arthritis than similarly aged never users (relative risk 0.29). At the end of the follow-up, women who were using the pill at the time of diagnosis had a statistically non-significant 20% reduction in their risk of rheumatoid arthritis but early in the study current users had a significant 50% risk reduction [116]. The same cohort was classified in groups of “takers” and “never takers” and was analyzed too for the incidence of RA. The standardized rate for takers was 49% of the control rate (p < 0.01) and resulted interesting an observed tendency for an increased incidence of RA forward 35 years; this tendency was conserved only in the group of “never takers” and suppressed in the takers [117].
wIn the Swedish EIRA study (population-based case-control) including 2641 cases and 4251 controls participants were questioned about OCP (oral contraceptive pill) full term need to be mentioned consumption, and potential confounders in order to calculate the ORs adjusted for age, residential area, smoking, and alcohol consumption. Compared with never users, the OCP users had a decreased risk of ACPA-positive RA (OR = 0.84) (95% CI 0.74–0.96) compared to the never users. Also the consumption for more than 7 years decreased the risk of both ACPA-positive (p = 0.0037) and ACPA-negative RA (p = 0.0356) compared to never users of OCP [118].
Most of the studies agree that the current or ever use of the OCP has a protective effect against RA, probably more delaying the onset rather than a preventing RA. But until now there is not a final conclusion because even the meta-analysis results are contradictory. In the meta-analysis of six case-control and three longitudinal studies, the overall pooled odds ratio of the studies was 0.73 for the adjusted results (95% CI 0.61–0.85) with the conclusion that OCP consumption prevents the progression to severe disease by modifying the disease process [119]. On the contrary in a meta-analysis performed by Qi et al. in 2014, the authors identified 1116 publications in PubMed and EMBASE databases. The meta-analysis of 12 case-control and 5 cohort studies were analyzed. Potential publication bias was evaluated using Begg’s funnel plots and quantified by the Egger’s test, as a sensitivity analysis was performed to investigate the influence of potential confounding factors like age, smoking, parity/pregnancy, body mass index, and social class on risk of develop RA. Here, no statistically significant association was observed between oral contraceptives and RA risk (RR = 0.88, 95% CI = 0.75–1.03) concluding that OCP consumption was not significantly associated with RA risk [120].
HRT (hormone replacement therapy) has been studied in regard to RA new-onset. On a study in a prospective cohort of 31,336 Iowa women (from 55 to 69 years) followed up during 11 years, 158 incident cases of RA were registered. Of the factors that showed an inverse association with RA, the authors identified pregnancy (P trend =0.01) and age at menopause (P trend =0.03), whereas polycystic ovary syndrome (relative risk [RR], 2.58; 95% confidence interval [CI], 1.06–6.30), endometriosis (RR, 1.72; 95% CI, 0.93–3.18), and hormone replacement therapy (RR, 1.47; 95% CI, 1.04–2.06) were positively associated with RA. If HRT is administered before RA is associated with a higher risk of developing the disease, studies suggest that when HRT is administered during RA, they have a favorable effect. In 88 postmenopausal women with RA who received HRT, vitamin D3, and calcium supplementation or vitamin D3 and calcium supplementation alone for 2 years, HRT use had a significant effect upon active RA, ameliorating effects on inflammation (ESR p = 0.025) DAS28 (p = 0.036) and was associated with slower progression of radiological joint destruction (p = 0.026) [121]. The continuous hormonal therapy given to suppress menstruation for regulation of menstrual bleeding, pelvic pain, and dysmenorrhea seems to have demonstrated improvement in RA [122].
Recently, novel hormone analogs have been developed. ERB-041 is a selective ERβ agonist and has showed interesting effects in several inflammatory rodent models, including endometriosis, rheumatoid arthritis, inflammatory bowel, and sepsis [123, 124] where a strong effect on reduction of inflammation was observed. This selective effect was the antecedent for the development of other ERβ agonists like MF101 [125] that could be useful to modulate the inflammation and cytokine production in RA. No clinical trial data on these molecules have been published so far.
Given the higher prevalence of RA cases that occur in women, is natural to suspect that such differences are due to sexual hormones, specifically estrogens, which have been explored as part of pathophysiology, development, and progression of RA disease. Antecedents point to estrogens as strong modulators of immune response and function associated to RA. The role that sex hormones play in the development, cell activation, and alterations in immune function in autoimmune diseases is still a matter of intense research. The administration of estrogens may have a protective effect on RA development or in the onset of disease, delaying it. Also, experimental evidence suggests that estrogens demonstrated anti-inflammatory activity in animal models of RA. Such effects are mediated by modifications in antibody production and in post-translational modification of antibodies like sialylation (addition of syalic acid), involved on increased risk of RA in conditions with low estrogen levels such as menopause. Estrogens administration to RA patients could be a strategy to improve the quality of life through hormone replacement therapy (HRT). This, in resource limited settings were biological therapy cannot be afforded and in patients that are refractory to standard MTX therapy or that have failed to respond to such therapies.
Maria Fernanda Romo García thanks CONACyT (Consejo Nacional de Ciencia y Tecnologia); National Council of Science and Technology for scholarship 297364/CVU 560269.
No conflict of interest is declared.
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She performed (inter)national tasks as vice-president of the Concilium Anaesthesia and related committees. \nShe performed research in several fields, with over 100 publications in (inter)national journals and numerous papers on scientific conferences. \nShe received several awards and is a member of Honour of the Dutch Society of Anaesthesia.",institutionString:null,institution:{name:"Albert Schweitzer Hospital",country:{name:"Gabon"}}},{id:"83089",title:"Prof.",name:"Aaron",middleName:null,surname:"Ojule",slug:"aaron-ojule",fullName:"Aaron Ojule",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Port Harcourt",country:{name:"Nigeria"}}},{id:"295748",title:"Mr.",name:"Abayomi",middleName:null,surname:"Modupe",slug:"abayomi-modupe",fullName:"Abayomi Modupe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:null,institutionString:null,institution:{name:"Landmark University",country:{name:"Nigeria"}}},{id:"94191",title:"Prof.",name:"Abbas",middleName:null,surname:"Moustafa",slug:"abbas-moustafa",fullName:"Abbas Moustafa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94191/images/96_n.jpg",biography:"Prof. Moustafa got his doctoral degree in earthquake engineering and structural safety from Indian Institute of Science in 2002. He is currently an associate professor at Department of Civil Engineering, Minia University, Egypt and the chairman of Department of Civil Engineering, High Institute of Engineering and Technology, Giza, Egypt. He is also a consultant engineer and head of structural group at Hamza Associates, Giza, Egypt. Dr. Moustafa was a senior research associate at Vanderbilt University and a JSPS fellow at Kyoto and Nagasaki Universities. He has more than 40 research papers published in international journals and conferences. He acts as an editorial board member and a reviewer for several regional and international journals. His research interest includes earthquake engineering, seismic design, nonlinear dynamics, random vibration, structural reliability, structural health monitoring and uncertainty modeling.",institutionString:null,institution:{name:"Minia University",country:{name:"Egypt"}}},{id:"84562",title:"Dr.",name:"Abbyssinia",middleName:null,surname:"Mushunje",slug:"abbyssinia-mushunje",fullName:"Abbyssinia Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Fort Hare",country:{name:"South Africa"}}},{id:"202206",title:"Associate Prof.",name:"Abd Elmoniem",middleName:"Ahmed",surname:"Elzain",slug:"abd-elmoniem-elzain",fullName:"Abd Elmoniem Elzain",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Kassala University",country:{name:"Sudan"}}},{id:"98127",title:"Dr.",name:"Abdallah",middleName:null,surname:"Handoura",slug:"abdallah-handoura",fullName:"Abdallah Handoura",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Supérieure des Télécommunications",country:{name:"Morocco"}}},{id:"91404",title:"Prof.",name:"Abdecharif",middleName:null,surname:"Boumaza",slug:"abdecharif-boumaza",fullName:"Abdecharif Boumaza",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Abbès Laghrour University of Khenchela",country:{name:"Algeria"}}},{id:"105795",title:"Prof.",name:"Abdel Ghani",middleName:null,surname:"Aissaoui",slug:"abdel-ghani-aissaoui",fullName:"Abdel Ghani Aissaoui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/105795/images/system/105795.jpeg",biography:"Abdel Ghani AISSAOUI is a Full Professor of electrical engineering at University of Bechar (ALGERIA). He was born in 1969 in Naama, Algeria. He received his BS degree in 1993, the MS degree in 1997, the PhD degree in 2007 from the Electrical Engineering Institute of Djilali Liabes University of Sidi Bel Abbes (ALGERIA). He is an active member of IRECOM (Interaction Réseaux Electriques - COnvertisseurs Machines) Laboratory and IEEE senior member. He is an editor member for many international journals (IJET, RSE, MER, IJECE, etc.), he serves as a reviewer in international journals (IJAC, ECPS, COMPEL, etc.). He serves as member in technical committee (TPC) and reviewer in international conferences (CHUSER 2011, SHUSER 2012, PECON 2012, SAI 2013, SCSE2013, SDM2014, SEB2014, PEMC2014, PEAM2014, SEB (2014, 2015), ICRERA (2015, 2016, 2017, 2018,-2019), etc.). His current research interest includes power electronics, control of electrical machines, artificial intelligence and Renewable energies.",institutionString:"University of Béchar",institution:{name:"University of Béchar",country:{name:"Algeria"}}},{id:"99749",title:"Dr.",name:"Abdel Hafid",middleName:null,surname:"Essadki",slug:"abdel-hafid-essadki",fullName:"Abdel Hafid Essadki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Nationale Supérieure de Technologie",country:{name:"Algeria"}}},{id:"101208",title:"Prof.",name:"Abdel Karim",middleName:"Mohamad",surname:"El Hemaly",slug:"abdel-karim-el-hemaly",fullName:"Abdel Karim El Hemaly",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/101208/images/733_n.jpg",biography:"OBGYN.net Editorial Advisor Urogynecology.\nAbdel Karim M. A. El-Hemaly, MRCOG, FRCS � Egypt.\n \nAbdel Karim M. A. El-Hemaly\nProfessor OB/GYN & Urogynecology\nFaculty of medicine, Al-Azhar University \nPersonal Information: \nMarried with two children\nWife: Professor Laila A. Moussa MD.\nSons: Mohamad A. M. El-Hemaly Jr. MD. Died March 25-2007\nMostafa A. M. El-Hemaly, Computer Scientist working at Microsoft Seatle, USA. \nQualifications: \n1.\tM.B.-Bch Cairo Univ. June 1963. \n2.\tDiploma Ob./Gyn. Cairo Univ. April 1966. \n3.\tDiploma Surgery Cairo Univ. Oct. 1966. \n4.\tMRCOG London Feb. 1975. \n5.\tF.R.C.S. Glasgow June 1976. \n6.\tPopulation Study Johns Hopkins 1981. \n7.\tGyn. Oncology Johns Hopkins 1983. \n8.\tAdvanced Laparoscopic Surgery, with Prof. Paulson, Alexandria, Virginia USA 1993. \nSocieties & Associations: \n1.\t Member of the Royal College of Ob./Gyn. London. \n2.\tFellow of the Royal College of Surgeons Glasgow UK. \n3.\tMember of the advisory board on urogyn. FIGO. \n4.\tMember of the New York Academy of Sciences. \n5.\tMember of the American Association for the Advancement of Science. \n6.\tFeatured in �Who is Who in the World� from the 16th edition to the 20th edition. \n7.\tFeatured in �Who is Who in Science and Engineering� in the 7th edition. \n8.\tMember of the Egyptian Fertility & Sterility Society. \n9.\tMember of the Egyptian Society of Ob./Gyn. \n10.\tMember of the Egyptian Society of Urogyn. \n\nScientific Publications & Communications:\n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Asim Kurjak, Ahmad G. Serour, Laila A. S. Mousa, Amr M. Zaied, Khalid Z. El Sheikha. \nImaging the Internal Urethral Sphincter and the Vagina in Normal Women and Women Suffering from Stress Urinary Incontinence and Vaginal Prolapse. Gynaecologia Et Perinatologia, Vol18, No 4; 169-286 October-December 2009.\n2- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nFecal Incontinence, A Novel Concept: The Role of the internal Anal sphincter (IAS) in defecation and fecal incontinence. Gynaecologia Et Perinatologia, Vol19, No 2; 79-85 April -June 2010.\n3- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nSurgical Treatment of Stress Urinary Incontinence, Fecal Incontinence and Vaginal Prolapse By A Novel Operation \n"Urethro-Ano-Vaginoplasty"\n Gynaecologia Et Perinatologia, Vol19, No 3; 129-188 July-September 2010.\n4- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n5- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n6- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n7-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n8-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n9-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n10-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n11-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n12- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n13-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n14- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n15-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n\n16-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n17- Abdel Karim M. El Hemaly. Nocturnal Enureses: An Update on the pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecology/?page=/ENHLIDH/PUBD/FEATURES/\nPresentations/ Nocturnal_Enuresis/nocturnal_enuresis\n\n18-Maternal Mortality in Egypt, a cry for help and attention. The Second International Conference of the African Society of Organization & Gestosis, 1998, 3rd Annual International Conference of Ob/Gyn Department � Sohag Faculty of Medicine University. Feb. 11-13. Luxor, Egypt. \n19-Postmenopausal Osteprosis. The 2nd annual conference of Health Insurance Organization on Family Planning and its role in primary health care. Zagaziz, Egypt, February 26-27, 1997, Center of Complementary Services for Maternity and childhood care. \n20-Laparoscopic Assisted vaginal hysterectomy. 10th International Annual Congress Modern Trends in Reproductive Techniques 23-24 March 1995. Alexandria, Egypt. \n21-Immunological Studies in Pre-eclamptic Toxaemia. Proceedings of 10th Annual Ain Shams Medical Congress. Cairo, Egypt, March 6-10, 1987. \n22-Socio-demographic factorse affecting acceptability of the long-acting contraceptive injections in a rural Egyptian community. Journal of Biosocial Science 29:305, 1987. \n23-Plasma fibronectin levels hypertension during pregnancy. The Journal of the Egypt. Soc. of Ob./Gyn. 13:1, 17-21, Jan. 1987. \n24-Effect of smoking on pregnancy. Journal of Egypt. Soc. of Ob./Gyn. 12:3, 111-121, Sept 1986. \n25-Socio-demographic aspects of nausea and vomiting in early pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 35-42, Sept. 1986. \n26-Effect of intrapartum oxygen inhalation on maternofetal blood gases and pH. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 57-64, Sept. 1986. \n27-The effect of severe pre-eclampsia on serum transaminases. The Egypt. J. Med. Sci. 7(2): 479-485, 1986. \n28-A study of placental immunoreceptors in pre-eclampsia. The Egypt. J. Med. Sci. 7(2): 211-216, 1986. \n29-Serum human placental lactogen (hpl) in normal, toxaemic and diabetic pregnant women, during pregnancy and its relation to the outcome of pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:2, 11-23, May 1986. \n30-Pregnancy specific B1 Glycoprotein and free estriol in the serum of normal, toxaemic and diabetic pregnant women during pregnancy and after delivery. Journal of the Egypt. Soc. of Ob./Gyn. 12:1, 63-70, Jan. 1986. Also was accepted and presented at Xith World Congress of Gynecology and Obstetrics, Berlin (West), September 15-20, 1985. \n31-Pregnancy and labor in women over the age of forty years. Accepted and presented at Al-Azhar International Medical Conference, Cairo 28-31 Dec. 1985. \n32-Effect of Copper T intra-uterine device on cervico-vaginal flora. Int. J. Gynaecol. Obstet. 23:2, 153-156, April 1985. \n33-Factors affecting the occurrence of post-Caesarean section febrile morbidity. Population Sciences, 6, 139-149, 1985. \n34-Pre-eclamptic toxaemia and its relation to H.L.A. system. Population Sciences, 6, 131-139, 1985. \n35-The menstrual pattern and occurrence of pregnancy one year after discontinuation of Depo-medroxy progesterone acetate as a postpartum contraceptive. Population Sciences, 6, 105-111, 1985. \n36-The menstrual pattern and side effects of Depo-medroxy progesterone acetate as postpartum contraceptive. Population Sciences, 6, 97-105, 1985. \n37-Actinomyces in the vaginas of women with and without intrauterine contraceptive devices. Population Sciences, 6, 77-85, 1985. \n38-Comparative efficacy of ibuprofen and etamsylate in the treatment of I.U.D. menorrhagia. Population Sciences, 6, 63-77, 1985. \n39-Changes in cervical mucus copper and zinc in women using I.U.D.�s. Population Sciences, 6, 35-41, 1985. \n40-Histochemical study of the endometrium of infertile women. Egypt. J. Histol. 8(1) 63-66, 1985. \n41-Genital flora in pre- and post-menopausal women. Egypt. J. Med. Sci. 4(2), 165-172, 1983. \n42-Evaluation of the vaginal rugae and thickness in 8 different groups. Journal of the Egypt. Soc. of Ob./Gyn. 9:2, 101-114, May 1983. \n43-The effect of menopausal status and conjugated oestrogen therapy on serum cholesterol, triglycerides and electrophoretic lipoprotein patterns. Al-Azhar Medical Journal, 12:2, 113-119, April 1983. \n44-Laparoscopic ventrosuspension: A New Technique. Int. J. Gynaecol. Obstet., 20, 129-31, 1982. \n45-The laparoscope: A useful diagnostic tool in general surgery. Al-Azhar Medical Journal, 11:4, 397-401, Oct. 1982. \n46-The value of the laparoscope in the diagnosis of polycystic ovary. Al-Azhar Medical Journal, 11:2, 153-159, April 1982. \n47-An anaesthetic approach to the management of eclampsia. Ain Shams Medical Journal, accepted for publication 1981. \n48-Laparoscopy on patients with previous lower abdominal surgery. Fertility management edited by E. Osman and M. Wahba 1981. \n49-Heart diseases with pregnancy. Population Sciences, 11, 121-130, 1981. \n50-A study of the biosocial factors affecting perinatal mortality in an Egyptian maternity hospital. Population Sciences, 6, 71-90, 1981. \n51-Pregnancy Wastage. Journal of the Egypt. Soc. of Ob./Gyn. 11:3, 57-67, Sept. 1980. \n52-Analysis of maternal deaths in Egyptian maternity hospitals. Population Sciences, 1, 59-65, 1979. \nArticles published on OBGYN.net: \n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n2- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n3- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n4-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n5-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n6-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n7-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n8-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n9- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n10-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n11- Abdel Karim M. El Hemaly*, Ibrahim M. 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