An Overview Of Diabetes Mellitus Biology Essay

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Diabetes mellitus is a very common cause of CRF. Diabetes mellitus may lead to different disorders in uremic patients like sexual dysfunction. In fact, diabetes mellitus is a known risk factor for sexual function disorders (Grandjean and Moran, 2007; Lewis et al., 2004; Enzlin et al., 2002; 2003). Erectile dysfunction as a sexual function disorder is very prevalent among diabetic men (Mulligan et al., 1988 ; Feldman et al., 1994a ). McKinlay (2000) demonstrated that in diabetic patients there is a noticeable association between diabetes mellitus and erectile dysfunction. Erectile dysfunction, being diagnosed as a consequence of endothelial or vascular dysfunction, is correlated with diabetes mellitus (Solomon, Man and Jackson, 2003; Grossman et al., 2004). Concerning the relationship between diabetes mellitus and sexual dysfunction, Messina et al. (2007) said that diabetes is a main factor correlated with erectile dysfunction in patients on hemodialysis. In fact, they claimed almost all diabetic patients with CRF experienced erectile dysfunction. A meta-analysis study by Navaneethan et al. (2010) concerning prevalence of sexual dysfunction in CKD patients confirmed a significant association between sexual dysfunction and diabetes mellitus. They also found a high correlation between erectile dysfunction and diabetes mellitus in twenty cross-sectional studies. Diabetes mellitus is proved to be, on its own, a risk factor of erectile dysfunction in CRF patients on hemodialysis (Rosas et al., 2001; Naya et al., 2002; Neto, de Freitas Rodrigues, Saraiva Fittipaldi and Moreira, 2002). Some certain medical conditions such as diabetes in male hemodialysis patients are highly associated with erectile dysfunction (Arslan et al., 2002; Neto, de Freitas Rodrigues, Saraiva Fittipaldi and Moreira, 2002; Miyata et al., 2004; Peng et al., 2007). Malekmakan et al. (2011), in a research on epidemiology of erectile dysfunction in hemodialysis patients, found that there is a significant association between erectile dysfunction and higher blood sugar in these patients. Another research (Mumtaz et al., 2009) represented that diabetes mellitus can be accounted for as one of the most important factors of erectile dysfunction among male hemodialysis patients. As the findings of this study indicates that erectile dysfunction is three times more common in diabetic patients than non-diabetics, and that severe erectile dysfunction showed the prevalence rate of 42.4 percent in diabetics while 18.4 percent in non-diabetic patients. Rosas et al. (2001) stated that uremic patients with diabetes mellitus had twice the chance of experiecing erectile dysfunction comparing with subjects without diabetes. Also, Cerqueira and Glina (2002) demonstrated that the prevalence rate of erectile dysfunction in uremic patients having diabetes mellitus was as high as 99 percent. Peng et al. (2007), consistent with previous studies, stressed the presence of the correlation between diabetes mellitus and erectile dysfunction in male patients undergoing hemodialysis. They showed there were problems in the domains of intercourse satisfaction, erectile function and orgasmic function in men hemodialysis patients having diabetes, while diabetes mellitus did not affect sexual desire. The findings of this research agree with previous studies, where diabetes lead to neurogenic and endothelium mediated relaxation of penile smooth muscle. This study pointed out that the desire for sexual activity is not adversely affected by diabetes in male hemodialysis patients. Regarding causal relationship between erectile dysfunction and diabetes mellitus, there is disagreement over which aspect of diabetes is directly the cause of impotence, but most frequently the vascular disease is accounted for it (Jevitch, Edson, Jarman and Herrera, 1982). Large vessel atheromatous disease is forty times more common among men with diabetes than non-diabetics. Diabetes mellitus brings about ultrastructural changes in cavernosal tissues. These changes include increased collagen deposition, reduction in smooth muscle content, thickening of basal lamina and loss of endothelial cells. Endothelial and neurogenic relaxant responses interfered by NO are impaired in diabetes mellitus (Mersdorf et al., 1991; Cartledge, Eardley and Morrison, 2001). Other aspects of diabetes mellitus like gonadal dysfunction, autonomic neuropathy, impaired neurogenic and endothelium mediated relaxation of penile smooth muscle are also implicated in diabetic patients having erectile dysfunction (Neto, de Freitas Rodrigues, Saraiva Fittipaldi and Moreira, 2002). Pertaining this issue, Leao et al. (2010) stated that diabetes mellitus is a main disease correlated with ESRD and is greatly prevalent in hemodialysis patients. They stressed that diabetes can lead to erectile dysfunction as a result of gonadal dysfunction, autonomic neuropathy, impaired neurogenic and endothelium mediated relaxation, and particularly by vascular damage. Unlike the studies that emphasized a significant correlation between diabetes mellitus and erectile dysfunction, some researches do not support the idea; as Steele et al. (1996a) believed that erectile dysfunction is not experienced so differently among diabetics and non-diabetic patients. Also a research by Nassir (2010) found no noticeable difference between diabetic and non-diabetic dialysis patients as far as erectile function is concerned. He found that 82% of diabetics and 75% of non-diabetics among patients entering dialysis experienced erectile dysfunction. Also, a research on 180 hemodialysis patients (Miyata et al., 2004) found erectile dysfunction in 86.8% of non-diabetic and 95.5% of diabetic hemodialysis patients. Furthermore, concerning the association between the severity degrees of erectile dysfunction and diabetes mellitus in hemodialysis patients, Rosas et al. (2001) pointed out that the severity of erectile dysfunction is not predictable by the subjects' history of diabetes in hemodialysis patients.

In some researches, the association between sexual dysfunction and diabetes mellitus is studied among female hemodialysis patients. Steele et al. (1996a) found that there was a correlation between diabetes with female sexual dysfunctions in the domains of desire, orgasm, and clitoral sensitivity. Peng et al. (2005) also emphasized such an association among female hemodialysis patients in the orgasm and desire domains as well as clitoral sensation. They pointed that there are few studies of sexual dysfunction in diabetic women, hence, further research concerning the effect of diabetes on female sexual dysfunction is required. Also, the laboratory findings of a research (Basok et al.,2009) demonstrated that the value of glucose was remarkably higher in women CRF patients with sexual dysfunction than in those with normal sexual function.

3.3 Cardiovascular Diseases

Risk factors for cardiovascular diseases include physical inactivity, diabetes mellitus, obesity, tobacco use, hyperlipidemia, and hypertension many of which are the same risks for ESRD that can cause sexual function disorders (Leao et al., 2010). Sexual dysfunction in patients with CKD has been found to be significantly correlated with adverse cardiovascular outcomes (Goldstein 2000; Seidman and Roose, 2006 ; Makhlouf, Kparker and Niederberger, 2007). Bellinghieri, Mallmace and Savica (2008) mentioned the role of testosterone hormone amount in pathogenesis of cardiovascular diseases. Lower concentration of testosterone in blood both among men with cardiovascular diseases and those with uremia raised the hypothesis of pathological association between low testosterone in uremic men and risk of cardiovascular diseases. Therefore, low testosterone can be considered a risk factor for sexual dysfunction which is shared in the pathogenesis of both cardiovascular diseases and uremia. Feldman et al. (1994a) demonstrated that erectile dysfunction as a sexual function disorder was associated with heart disease and hypertension in general population. Men with heart disease and hypertension are more likely to experience erectile dysfunction (Mulligan et al., 1988 ). Herein, Stuart and Steven (2000) pointed out the role of cardiovascular disease as the genesis of erectile dysfunction. Cardiovascular disease and erectile dysfunction share many risk factors, and their pathophysiology is mediated through endothelial dysfunction (Greenstein et al., 1997; Sullivan, Keoghane and Miller, 2001; Chiurlia et al., 2005). Erectile dysfunction is a disorder associated with hypertension and cardiovascular disease, and it is increasingly recognized as a consequence of endothelial or vascular dysfunction (Solomon, Man and Jackson, 2003; Grossman et al., 2004). Some studies (Fung, Bettencourt and Barrett-Connor, 2004; Min et al., 2006; Baumhakel and Bohm, 2007) demonstrated that cardiovascular disease and its risk factors enhance the risk of later erectile problems. Erectile difficulties can be considered an early warning sign of future cardiovascular events ( Chiurlia et al., 2005 ; Thompson et al., 2005 ). Several researches (Neto, de Freitas Rodrigues, Saraiva Fittipaldi and Moreira, 2002; Arslan et al., 2002 ; Miyata et al., 2004 ; Peng et al., 2007) supported the idea that certain medical conditions like heart disease are highly related to erectile dysfunction. Erectile dysfunction is prevalent in men having cardiovascular disease and is probably casued by shared factors that impair the vascular mechanisms and hemodynamic. Vasculogenic erectile dysfunction is prevalent in ESRD, and cardiovascular disease can be the early sign of a systemic vasculogenic state (Leao et al.,2010). McKinlay (2000) also found a correlation between hypertension and erectile dysfunction in general population. Leao et al. (2010) expressed that many factors including heart disease, hypertension and atherosclerosis can help develop erectile dysfunction in patients under hemodialysis. Erectile dysfunction and cardiovascular disease are closely associated pathological processes, and their relationship is well documented (Russell, Khandheria and Nehra, 2004). Bellinghieri and Santoro (2006) stated that many of the erectile dysfunction risk factors are supposed to be the same as those for cardiac disease. Erectile dysfunction is considered a symptom of vascular endothelial injury. Thus, impotence or other symptom related to erectile dysfunction can be expected to appear toegther with cardiovascular disease, and the presence of erectile dysfunction is accompanied with the existence of cardiovascular disease. Concerning this issue, Rodger et al. (1984) showed that 11 percent of dialysis men suffering erectile function disorder are involved in arteriogenic impotence. Using an interesting interpretation, Leao et al. (2010) stated that symptoms of erectile dysfunction can be imagined as "the tip of the iceberg" of endothelial multisystemic injury. Jackson and Padley (2008) emphasized that erectile dysfunction may be present even no cardiac symptoms is observed 3-5 years before any coronary event. Jackson (2009) stated that the common relationship between erectile dysfunction and cardiovascular disease has convinced some researchers to explore if the onset of erectile problems can be considered a predictor of the existence of cardiovascular disease, and also to find a correlation between of erectile dysfunction severity and the number of coronary arteries being extensively atherosclerotic. Inci et al. (2008) confirmed an association between coronary artery calcium scores (CACS) and hemodialysis patients' erectile dysfunction. They found that in patients with severe erectile dysfunction, coronary artery calcium scores were noticeably higher. The research also indicated a moderate negative association between coronary artery calcium scores (CACS) and the IIEF-5 (a short form of the IIEF-15 questionnaire for only assessment of erectile function) and then concluded that the severity degree of erectile dysfunction increases as coronary artery calcium scores (CACS) rises. A study (Giuliano, Leriche, Jaudinot and de Gendre, 2004) showed that according to the IIEF-5 performed on 3906 men of normal population having only hypertension, overall prevalence rate of erectile dysfunction was 67 percent. Also, an article (Neto, de Freitas Rodrigues, Saraiva Fittipaldi and Moreira, 2002) represented that erectile dysfunction is observed with a higher prevalence among uremic patients having also hypertension problem. This article stated that in uremic patients with erectile dysfunction, hypertension is the most common medical condition with 81.4% prevalence. Hypertension was related to erectile dysfunction in male suffering CKD (Navaneethan et al., 2010). However, some researches did not find any important potential effect of hypertension on erectile dysfunction (Steele et al., 1996a; Rosas et al., 2001; Naya et al., 2002; Cerqueira and Glina, 2002; Nassir, 2010). Findings in a research (Gomez, de la Cueva, Wauters and Lemarchand-Beraud, 1980) represented that although prevalence of erectile dysfunction seems to be higher among patients with hypertension, the increase is not statistically remarkable. A research by Furthermore, Messina, et al. (2007) also supported this conclusion. Hypertension as a variable for assessment of atherosclerosis was not considered a risk factor for sexual dysfunction in female (Basok et al., 2009).

3.4 Dyslipidemia

Disturbance of lipid metabolism which produces hypertriglyceridemia and causes reduction in levels of high-density lipoprotein, has been observed in patients experiencing CRF (Gomez, de la Cueva, Wauters and Lemarchand-Beraud, 1980). Dyslipidemia has been studied as a metabolic cause of sexual dysfunction in CKD patients. Hyperlipidemia can be a risk factor for causing ESRD and is also accompanied by sexual dysfunction as a comorbid condition in CKD patients (Leao et al., 2010). Dyslipidemia in the genesis of erectile dysfunction in various groups of patients has received enough attention in the scientific literature (Gomez, de la Cueva, Wauters and Lemarchand-Beraud, 1980). Mulligan et al. (1988) and Feldman et al. (1994a) confirmed that erectile dysfunction is more prevalent among men with hyperlipidemia. In this regard, some studies (Araujo et al., 2000; Derby et al., 2000; Feldman et al., 2000; Gazzaruso et al., 2008) proved that erectile dysfunction has a correlation with hypercholestrolemia as a kind of dyslipidemia. The matter of the association of sexual dysfunction and dyslipidemia has been surveyed in some studies. For example, Peng et al. (2005), in a research on sexual dysfunction, demonstrated that in women undergoing hemodialysis sexual dysfunction is highly associated with dyslipidemia. Their findings showed that there was a strong correlation between hypertriglyceridemia and sexual dysfunction in different domains including; quality of sexual desire, clitoral sensation, lubrication, sexual intercourse, and orgasm. In addition, hypertriglyceridemia was correlated with lower total FSFI (a tool for sexual function evaluation in women) scores in their research. They considered hypertriglyceridemia as an independent factor of dysfunction in each sexual function domain among female hemodialysis patients. As some studies (Goldstein and Berman, 1998; Tarcan et al., 1999; Shoji et al., 2001) showed, advanced atherosclerosis is found in uremic patients with increased serum triglyceride, hence, this implicates vascular failure which is the major cause of sexual dysfunction in patients with hypertriglyceridemia. Thus, these studies claimed that the vasculogenic factor of sexual dysfunction is required to receive more attention. In this regard, Goldstein and Berman (1998) introduced "clitoral and vaginal vascular insufficiency syndrome" as a medical condition in women and stated that this problem is directly related to decreased blood flow in genital system secondary to atherosclerosis of iliohypogastric/ pudendal arterial bed. Reduced pelvic blood flow results in vaginal wall and clitoral smooth muscle fibrosis, which may disturb normal dilatation and relaxation responses to sexual stimulation and lead to vaginal dryness and dyspareunia. Despite some studies trying to show an association between lipid biochemical alterations with the presence of sexual disorders such as erectile dysfunction, no significant data are found to support such hypothesis (Gomez, de la Cueva, Wauters and Lemarchand-Beraud, 1980). Basok et al. (2009) also did not find a significant correlation between female sexual dysfunction and cholesterol level as a parameter for assessment of atherosclerosis.

3.5 Serum Creatinine level

A few studies (Soykan et al., 2005; Peng et al., 2007) have mentioned that pre-dialysis creatinine levels have a significant correlation with sexual dysfunction. While Malekmakan et al. (2011) confirmed that higher pre-dialysis serum creatinine was significantly associated with erectile dysfunction, Messina et al. (2007) found an inverse result about this correlation. They demonstrated that pre-dialysis serum creatinine was noticeably lower in CRF patients with erectile dysfunction. Basok et al. (2009) proved that serum creatinine level is the main biochemical variable which has a significant assciation with female sexual dysfunction. Fujisawa et al. (2000) even found that the serum level of creatinine can highly affect the quality of life (sexual activity forms a part of life quality). Nevertheless, Raiz, Davies and Ferguson (2003) in a research on renal transplanted patients showed that creatinine level has no association with sexual function.

3.6 Hemodialysis process

Some studies demonstrated on the relationship between hemodialysis therapy and sexual function disorders. For instance, Leao et al. (2010) considered hemodialysis as one of many factors that lead to sexual dysfunction in CRF patients. A research (Zamd, Gharbi, Ramdani and Zaid, 2005) showed that 94.2% of CRF patients had sexual activity before undergoing hemodialysis (48.8% had 2-3 sexual intercourses per week), after dialysis, the persistence of sexual activity was reported among 69.8% of the patients, while the frequency reduced in 81.4% of them.

3.7 Urea , related indices

Regarding association between sexual dysfunction and high level of urea as a result of inadequate dialysis, a research (Milde, Hart and Fearing, 1996) showed the effect of insufficient dialysis on patient's sexual desire. Also, Mumtaz et al. (2009) stated that urea is usually a criterion in quantification of the dialysis, as very high urea indicates inadequate dialysis. They studied erectile function among hemodialysis patients dividing these patients into two groups on the basis of urea amount, i.e., 200mg/dl. In their research, patients with more than 200mg/dl urea had very low IIEF (a tool for assessment of erectile function) score which is in direct correlation with erectile dysfunction. Their findings were statistically significant; patients with erectile dysfunction had high urea, i.e.,175±56.8 mg/dl compared with those without erectile dysfunction, i.e.,152±33.43 mg/dl. They elaborated on the pathophysiology of erectile dysfunction genesis and concluded that elevated urea level contribute to reduced synthesis of NO and super saturation of the O2 free radicals, and then, these O2 free radicals result in increased consumption of NO, that is a relaxing factor for penile smooth muscles. They recommended further studies for the assessment of this association and believed that researches should be done to find the effect of adequacy of dialysis on overall sexual function including erectile dysfunction. In relation with this matter, a research by Malekmakan et al. (2011) also showed that sufficient hemodialysis may help to prevent erectile dysfunction. Kt/V, an index related to dialysis adequacy, is calculated from values of pre- and post- dialysis BUN and the patient's weight (Daurgidas, 1993). A study in Brazil by Messina et al. (2007) reported that hemodialysis patients suffering erectile dysfunction had a significantly lower Kt/V. Also, a research in Iran (Malekmakan et al., 2011) emphasized that severe erectile dysfunction was more probable among the hemodialysis patients who did not have adequate dialysis. As the research indicated erectile dysfunction was more common in hemodialysis patients with a Kt/V less than 1.2 in comparison with those who had Kt/V index ≥ 1.2. Nevertheless, some studies reported that there was no significant association between prevalence of erectile dysfunction and Kt/V index in hemodialysis patients (Krishnan, Izatt, Bargman and Oreopoulos, 2003 ; Peng et al., 2007). Even a research in Brazil claimed that hemodialysis patients with adequate dialysis were more likely to present erectile dysfunction. The research argued that compounds that are important for adequate erection may be removed from the serum by hemodialysis, or a high Kt/V may be a marker of receiving more hemodialysis due to higher severity of the disease (Neto, de Freitas Rodrigues, Saraiva Fittipaldi and Moreira, 2002). Some other studies (Rosas et al., 2001; Rosas et al., 2003) also confirmed that there is no significant association between prevalence of erectile dysfunction and Kt/V index. To clarify the discrepancy concerning the correlation between Kt/V and erectile dysfunction in CRF patients on dialysis therapy, further studies seem to be required. Although, the idea of a significant association between erectile dysfunction as a type of sexual function disorder and the status of dialysis adequacy is supported by some studies, duration of dialysis seems not to have any relationship with sexual dysfunction. For instance, a prospective study (Paolo, Capotonodo, Gaggiotti and Rossi, 1990) demonstrated that intesification of sexual dysfunction happened during the first three months of dialysis treatment, and the symptoms stabilized after this adaptation period. In this study, patients who had been on dialysis for more than three months showed no difference in complaint of erectile dysfunction. Also, findings by Steele et al. (1996a) showed no relationship between dialysis duration and the start of erectile dysfunction. In a research on CRF patients under hemodialysis, Mumtaz et al. (2009) supporting this finding, reported that there is no statistically significant relationship between duration of hemodialysis and beginning of erectile difficulties. Also, some other studies (Neto, de Freitas Rodrigues, Saraiva Fittipaldi and Moreira, 2002; Cerqueira and Glina, 2002) confirmed that duration of dialysis cannot be considered a significant factor in occurrence of erectile dysfunction. Regarding the probable relationship between sexual dysfunction and duration of dialysis, Leao et al. (2010) emphasized that unexpectedly, the duration of dialytic therapy had no relation with severity of sexual function disorder.

3.8 Anemia

Some studies demonstrate the role of anemia for the genesis of sexual dysfunction in CRF patients. Palmer (1999) stressed that the treatment of anemia as a comorbid condition may cause significant positive change in sexual function in patients with CKD. Etcheverry and Tignol (1989) showed that anemia can participate in the etiology of erectile disorders in men with CRF. This idea is supported by other studies (Gomez, de la Cueva, Wauters and Lemarchand-Beraud, 1980; Sam and Patel, 2006) emphasizing that anemia is associated with erectile dysfunction in patients with CRF. Also, several researches (Campese, 1990; Prisant et al., 1994; Lawrence et al., 1997; Saenz de Tejada et al., 2005; Lew and Piraino, 2005; Bellinghieri, Savica and Santoro, 2006; Anantharaman and Schmidt, 2007; Peng et al., 2007; El et al., 2008; Abu Ali et al., 2008) claimed that anemia as a comorbid illness can contribute to sexual dysfunction in patients suffering CKD. It has been reported that low hemoglobin levels is highly associated with erectile dysfunction. It is argued that anemia could take part in the etiology of erectile disorders in hemodialysis patients by worsening the overall conditions in these patients (Messina et al., 2007; Neto, de Freitas Rodrigues, Saraiva Fittipaldi and Moreira, 2002). Nevertheless, Malekmakan et al. (2011), performing a research in Iran, claimed that hemoglobin level is not correlated with erectile dysfunction in hemodialysis patients.

3.9 Hormonal alterations

Alterations in sex hormones can bring about sexual dysfunction in CKD, in a way that, low amount of testosterone in men (due to disease or aging) is highly associated with reduced libido, while in women, alterations in estrogen or testosterone levels can lead to different sexual function disorders (Martin, 2010). In male patients with CRF, total and free testosterone levels are generally reduced, although concentration of sex hormone-binding globulin and the binding capacity are normal (Levitan et al., 1984). Lower free testosterone levels and impaired leydig cell sensitivity to human chorionic gonadotropin are discovered first with only moderate decrease in the glomerular filtration rate (GFR) and prior to basal levels of testosterone diminish (De Vries, Gooren and Oe, 1984; Lew-Starowicz and Gellert, 2009). Gonadal failure is a significant result of CRF, and in men with CKD, low testosterone levels and hypogonadism are normal (Leao et al., 2010). Loss of spontanous or fantasy-related erectile function and declined libido are obviously related to hypogonadism (Seidman and Walsh, 1999). Stuart and Steven (2000) mentioned that testosterone level reduction can contribute to sexual dysfunction. Leao et al. (2010) expressed that decrease in levels of testosterone can contribute to erectile dysfunction, oligospermia and declined libido.They confirmed that CRF results in testicular damage and impaired spermatogenesis which can cause infertility. Also, Martin (2010) stated that low testosterone levels can bring about low sexual desire and also orgasmic problem in men with CRF. Nevertheless, as Leao et al. (2010) wrote, some researches did not find any relationship between levels of serum testosterone and erectile dysfunction among CRF patients.

There are other changes in sex hormones in CKD. For example, in advanced renal failure, total plasma estrogen concentration is often enhanced, and in men with uremia, estradiol levels are usually in the normal range, suggesting a deficiency in gonadotropin function or resistance in uremia because increased luteinizing hormone (LH) levels should increase the testicular secretion of estradiol (Leao et al., 2010). In men, increased levels of LH are detected early in renal insufficiency which progressively rise with worsening renal function. Excess LH secretion can be a result of the reduced release of testosterone from leydig cells. Testosterone normally resluts in feedback inhibition of LH release, however, as a result of reduced renal clearance, metabolic clearance rate of LH is declined. The abnormal LH response to GnRH is not corrected by dialytic therapy and proceeds as before (Palmer, 1999). In men with CRF follicle-stimulating hormone (FSH) is increased, on the other hand, the ratio of LH/FSH is typically increased too (Leao et al., 2010).

The other hormonal change detected in CKD is the case of prolactin. Cerqueira and Glina (2002) demonstrated that hyperprolactinemia is an alteration which can be found in 25-55 percent of patients with CRF. Increaesed plasma prolactin level is, also, typically found in dialysed men (Gomez, de la Cueva, Wauters and Lemarchand-Beraud, 1980). Leao et al. (2010) clarified that hyperprolactinemia may be associated with secondary hyperparathyroidism which is a common disorder in CRF, and is related to loss of libido, infertility, and low circulating testosterone levels.

Another endocrine disorder that male patients under dialysis therapy may experience is gynecomastia. Gynecomastia seems to be common within the first months of dialysis and then starts to regress as dialysis continues (Leao et al., 2010). Approximately 30 percent of male on maintenance hemodialysis encounter gynecomastia, and yet its pathogenesis in this context is unclear (Palmer, 1999).

Several researchers have studied the relationship between sexual function disorders and alterations of sex hormones among females involved in ESRD. Palmer (1999) represented that CRF may be followed by disturbances of reproductive hormones, which may disturb hypothalamic-pituitary function and lead to female sexual dysfunction. According to a research (Gomez, de la Cueva, Wauters and Lemarchand-Beraud, 1980), endocrine features of female uremic hypogonadism include increased serum concentrations of gonadotropins (LH, FSH) and prolactin and reduction of circulating estradiol. Martin (2010) expressed that dysfunctional pituitary-gonadal axis in women suffering CKD (resulting in anovulation and amenorrhea in many) have a part in low sexual desire. Orgasmic, being a common disorder in women with CKD, is connected to the anovulatory state. Dyspareunia, which is associated with estrogen deficiency (Vulvovaginal atrophy), is found in 25 percent of women on hemodialysis. In this regard, a research (Lim, Henriquez, Sievertsen and Frohman, 1980) suggested that anovulatory cycles are the rule in uremic women. As Leao et al. ( 2010 ) represented, at the time of ovulation lack of progestational effects and failure in elevating basal body temperature would be expected. Futhermore, estradiol concentration and the preovulatory peak in LH are frequently absent. The failure of LH to rise partly suggests a disturbance in the positive estradiol feedback pathway. In addition, Cayan et al. (2004) and Oksuz and Malhan (2006) showed that in the presence of menopause status, female sexual dysfunction had a significantly higher prevalence. Leao et al. (2010) emphasized that elevated circulating prolactin levels would be commonly expected among women with CRF. In the same way, in men with CRF, the hypersecretion of prolactin in this setting seems to be autonomous. Increased prolactin levels can disturb hypothalamic-pituitary function and lead to sexual dysfunction and galactorrhea. But a reseach by Basok et al. (2009) did not show any significant association between female sexual dysfunction and the levels of FSH, LH, testosterone, prolactin, and estradiol. Some researches show that some changes in menstruation and fertility status are expected in women with CKD. Anantharaman and Schmidt (2007) found that, in women with ESRD, the frequency of menstruation is variable between 8 to 10 percent. Palmer (1999) stated that it is common for women suffering CKD to complain of declined libido, decreased ability to reach orgasm and also amenorrhea and anovulation during predialysis stage. Estradiol levels may lower in amenorrheic patients and it can secondarily result in vaginal atrophy and dryness and consequently discomfort during intercourse will be expected. Concerning fertility status in women with CRF, a research by Okundaye, Abrinco and Hou (1998) and another by Holley and Reddy (2003) demonstrated that pregnancy is not expected and even successful conception is rare in women on dialysis. Also, Ginsburg and Owen (1993) and Anantharaman and Schmidt (2007) stated that women with ESRD have extremely low rates of fertility, though it is difficult to quantify. In this regard, Basok et al. (2009) mentioned that the majority of uremic women had anovulation, hence infertility, yet most of patients unaware of their infertility felt afraid of pregnancy, and thus, this condition could reduce their sexual desire. They expressed that the abnormalities in ovulation can usually be reversed among uremic women patients, and successful pregnancy is expected with a well-functioning kidney transplant. Therefore, it seems that successful renal transplantation is the most effective means for women with CRF to restore to normal sexual desire. In addition to the alterations in sex hormones levels, neuroendocrine disturbances such as changes in levels of serotonin, dopamine, and melanocortins are very common in sexual dysfunction which is caused by neuroendocrine disorders ( Martin, 2010 ).

3.10 Pharmacological therapy

Medication is a responsible factor for sexual dysfunction. Leao et al. (2010) argued that uremic patients are typically multi-medicated, and a review of these patients medications will reveal that some drugs such as diuretics, antidepressants, antihypertensives, and H2 antagonists can contribute to sexual dysfunction. According to a research (Espinoza, Gracida, Cancino and Ibarra, 2006) there is a relationship between erectile dysfunction and the medications prescribed to treat comorbid conditions with CKD, especially antihypertensive drugs like β-blockers and diuretics . Leao et al. (2010) expressed that pharmacological therapy is one of the factors which contribute to erectile dysfunction in hemodialysis patients. They mentioned antihypertensive medications and β-blockers as factors implicated in erectile dysfunction. They, also, explained that the relationship between hypertension and erectile function is often complicated by the impact of antihypertensive medications. Many medications are reported to cause sexual dysfunction, especially antihypertensive drugs, anti-ulcer drugs, mood stabilizers, anxiolytics, antidepressants and antipsychotics (Feldman et al., 1994a; Gitlin, 1994). Stuart and Steven (2000) stated that medication is considered a significant determinant for sexual dysfunction and also emphasized that antidepressants may have some sexual side effects. They pointed out that antidepressants may lead to sexual adverse effects in the drive phase (e.g. decreased libido, though this is difficult to distinguish from declined sexual satisfaction related to pervasive anhedonia), the arousal phase (e.g. erectile dysfunction, although this association is complicated by relationship to preexisting organic factors and to major depression), and the release phase (e.g. delayed orgasm or anorgasm). Gitlin (1994) explained that as far as different classes of antidepressants are concerned, sexual dysfunction is detected mostly with serotonin reuptake inhibitors, to some extent less frequently with monoamine oxidase inhibitors, and even less than that with tricyclic antidepressants. Also, it is proved that in some men taking tricyclic antidepressants painful ejaculation occurs (Balon et al., 1993), and with serotonergic medications, such as selective serotonin reuptake inhibitors, orgasmic delay seems to be very common, followed by declined libido and then arousal problems (Ashton, Hamer and Rosen, 1997). In addition, it should be noted that sexual dysfunction symptoms can also be a result of psychotropic drugs with anticholinergic activity (Van der Kolk, Shader and Greenblatt, 1978). Bromocryptine, a drug taken in the treatment process of ESRD, can decrease prolactin secretion in men suffering advanced renal disease, and has an inconsistent effect on sexual function and libido (Leao et al., 2010). It should be mentioned that some medications that are prescribed in treatment of comorbidities with CRF, have no negative effects on sexual functions. For instance, there is an inverse relationship between angiotensin converting enzyme inhibitors and erectile dysfunction (Rosas, Wasserstein, Kobrin and Feldman, 2001; Rosas et al., 2003). Leao et al. (2010) supported this idea, mentioned that these drugs are usually used in CRF and argued that they have sometimes had positive effects on erectile function. Finally, with attention to disagreement on the impacts of medications on sexual difficulties, Leao et al. (2010) recommended that further studies are required to prove an association between medications in CRF and sexual dysfunction.

3.11 Miscellaneous

Several researches had surveyed some probable causal variables for creating of sexual function disorders such as prostate diseases, hepatitis, and BMI among uremic patients. The probable correlation between those variables and sexual dysfunction are discussed briefly as following:

3.11.1 Prostate Diseases

It is shown that there is a correlation between prostate diseases in men and erectile dysfunction. A research by Rosas et al. (2001) argued that a history of prostatic disorder can be a statistically important predictor of erectile dysfunction. As the research shows, the prostate diseases including prostatic cancer, benign prostatic hypertrophy or prostatic surgery is 15.3% prevalent in uremic patients with erectile dysfunction.

3.11.2 Hepatitis

Hepatitis C infection is detected in some ESRD patients undergoing dialysis therapy. Hepatitis can have effects on sexual function in dialysis patients, as Mumtaz et al. (2009) showed hepatitis C infection impacts sexual function both in male and female. They demonstrated that in male hemodialysis patients, hepatitis C result in declined libido, erectile dysfunction and decreased sexual satisfaction. Of course, Steele et al. (1996a) had previously found that erectile dysfunction was present in 39% HCV patients with CRF under peritoneal dialysis on the basis of IIEF (a questionnaire for evaluation of erection function in men) score.

3.11.3 BMI

Some researchers have studied the association of body weight and/or body mass index (BMI) with sexual function disorders such as erectile dysfunction. Malekmakan et al. (2011), for example, found an important association between lower pre-dialysis weight and body mass index (BMI) and erectile dysfunction; however, this correlation has not been confirmed in some other studies.