My talk today deals with metabolic syndrome and sexual dysfunction.
Although many different clinical criteria for the definition of metabolic syndrome exist…
… all of them give great importance to glycometabolic control.
So, first of all, we focused our analysis in this paper - published in European Urology in 2004 - on patients with diabetes mellitus.
Diabetes mellitus and erectile dysfunction are quite often associated. And in particular Rollo hypothesized this kind of association for the first time in the late 18 th century.
Many other authors have investigated the relationship between erectile dysfunction in patients with diabetes mellitus around the world.
It has also been demonstrated that there is a direct correlation between erectile dysfunction in patients with diabetes mellitus and the duration of the disease, the glycometabolic control and the presence of co-morbid chronic complications, such as you can see, 70% if we have autonomic neuropathy, or diabetic foot.
In this paper we studied the clinical characteristics of diabetes mellitus induced erectile dysfunction in a consecutive series of 1,027 patients seeking medical care for the first time at our andrologic clinic.
For this proposal we used SIEDY structured interview. This is a structured interview, previously published and validated by our group, which consists of three scales, which identify and quantify the three different pathogenic components simultaneously present in ED patient s. In particular: scale one deals with the organic component; scale two with the relational component, and scale three with the intrapsychic component.
Applying ROC curve analysis, we found that a score higher than 3.5 on SIEDY scale one is predictive of organic disturbances underlying ED, i.e. pathological penile Doppler ultrasound, with a sensitivity and specificity of about 70 percent.
Considering subjective erectile parameters we found that patients with diabetes mellitus have more severe subjective erectile parameters; in fact they reported higher scores in SIEDY question s regarding erection not sufficient for penetration or lack of morning / nocturnal erection s.
Furthermore, we found that patients with diabetes mellitus reported a higher prevalence of gradual onset of the disorder.
We previously demonstrated that these two conditions, gradual onset of disorder, and the reduction in the reported nocturnal erection s should be considered organic symptoms, rather than psychogenic symptoms of ED. So, diabetes mellitus induced erectile dysfunction is associated with a higher organic component of ED.
In fact, looking at objective erectile parameters, and in particular penile ultrasound , after adjustment for confounding factors, we found that patients with diabetes mellitus reported lower basal and dynamic peak systolic velocity at penile doppler ultrasound.
Furthermore, we found an inverse relation between both basal and dynamic peak systolic velocity …
… and glycometabolic control as assessed by glycosylated hemoglobin .
Looking at nocturnal penile tumescence test we found that patient with diabetes reported a high prevalence of pathological nocturnal penile tumescence test .
So, diabetes mellitus induced erectile dysfunction is also associated with more severe subjective erectile parameters.
Diabetes mellitus induced erectile dysfunction is characterized by a higher organic component of ED, and worse subjective and objective erectile parameters.
Looking carefully at our data we found an interesting thing. Patients with diabetes mellitus reported later referral to andrologists, so they reported a higher prevalence of the duration of ED for more than two years.
This finding from De Berardis, Italy shows that among type II diabetes mellitus patients 63% of them reported by their physician had never investigated their sexual problem s.
This result is very important considering this other result. Looking at the prevalence of hypoactive sexual desire using SIEDY structure d interview we found that patients with diabetes mellitus reported lower prevalence of hypoactive sexual desire.
Diabetes mellitus induced erectile dysfunction patients when interviewed want to resolve the problem.
This agrees with other findings from Fedele et al., Padova, Italy showing that patients with diabetes mellitus are interested in resolving this problem despite age.
So diabetes mellitus induced erectile dysfunction is characterized by a higher organic component of ED, worse subjective and objective erectile parameters, later referral, and lower prevalence of hypoactive sexual desire. We must think about ED in patients with diabetes mellitus.
What about hormonal parameters?
We found in this paper that the prevalence of hypogonadism increased as function of patient’s age, both in patients with and without diabetes mellitus. This prevalence was higher in patients with diabetes mellitus raising a statistical difference in the sixth decade.
Accordingly considering all the age groups the prevalence of hypogonadism was higher in patients with diabetes mellitus.
Looking at the PSA levels, which is considered a marker of androgenization, we found that PSA levels were lower in patients with diabetes mellitus, raising the statistical significance in the sixth decade; so, the same decade in which we found a statistical difference in the prevalence of hypogonadism
So diabetes mellitus induced erectile dysfunction is characterized also by more hypogonadism. We must think about hypogonadism in patients with diabetes mellitus induced erectile dysfunction.
But what are the pathogenetic reasons?
First of all we found an inverse relation between testosterone and body mass index …
At linear regression analysis considering body mass index, diabetes mellitus and age as putative predictors of hypogonadism we found that body mass index, but not age and diabetes mellitus was significantly correlated with hypogonadism.
Diabetes mellitus patients are more often hypogonadal because they are more often obese.
Looking carefully at our data we found that among patients with diabetes mellitus, those with type II diabetes mellitus reported lower testosterone levels when compared to type I diabetes mellitus patients.
So, introducing in our model of linear regression analysis also type II diabetes mellitus we found that both body mass index and type II diabetes mellitus were significantly associated with hypogonadism. In particular type II diabetes mellitus patients are more often hypogonadal because they are more often obese.
Among the pathogenetic reasons we have to consider increased fat mass and type II diabetes mellitus.
Beside other classical chronic complications of diabetes, such as neuropathy, nephropathy, retinopathy and vascular disease s we have to consider hypogonadism. What kind of hypogonadism is this? Is this an overt hypogonadism, or not?
To answer these questions in this paper just published in International Journal of Impotence Research…
… we studied clinical characteristics of diabetes mellitus type II associated hypogonadism in a consecutive series of 1246 patients.
Among type II diabetes mellitus, first of all, we did not find any difference between patients with or without hypogonadism considering age. While patients with hypogonadism reported lower free-testosterone levels, a biochemical sign of an overt hypogonadism, lower testis volume, a clinical sign of an overt hypogonadism, even after adjustment for confounding factors such as body mass index, and higher prevalence of hypogonadism related symptoms, such as higher prevalence of hypoactive sexual desire, and lower intercourse frequency as assessed by SIEDY structured interview …
… have a higher prevalence of depressive symptoms as assed MHQ psychiatric test.
Diabetes mellitus induced erectile dysfunction is an overt hypogonadism because it is characterized by a higher prevalence of hypogonadism related symptoms, such as less sexual desire, less intercourse frequency and more depression.
What about metabolic syndrome?
It has recently been demonstrated that not only the individual components of metabolic syndrome, but also metabolic syndrome itself is associated with erectile dysfunction.
Using ATP-III criteria i.e. the presence of three or more of the following factors: central obesity, waist circumference higher than 102 cm, hypertrigylceridaemia: triglycerides higher than 150 mg/dL, HDL cholesterol lower than 40 mg/dL, hypertension: systolic blood pressure higher than 130, dyastolic blood pressure higher than 85 or medication for hypertension and finally, fasting plasma glucose higher than 110 mg/dL or previously diagnosed type II diabetes mellitus.
We found among a consecutive series of 803 patients a total prevalence of metabolic syndrome of about 30 percent.
We studied, thereafter, the clinical characteristic s of metabolic syndrome associated sexual dysfunction within patients reporting sexual dysfunction.
First of all, we found that the number of factors for metabolic syndrome increased as function of patient’s age. So, all the following data have been adjusted for age.
First of all we did not find any difference between patients with or without metabolic syndrome considering the prevalence of hypoactive sexual desire, premature ejaculation or delayed ejaculation.
While patients reporting a higher number of factors for metabolic syndrome, reported higher SIEDY scale one score, which is an index of organic disturbances underlying ED.
So, metabolic syndrome associated sexual dysfunction is associated with a higher organic component of ED.
Considering subjective erectile parameters we found that also patients with metabolic syndrome had more severe subjective erectile parameters. In fact, they reported higher score in SIEDY questions regarding lack of erections during intercourse and lack of morning/nocturnal erections.
Considering objective erectile parameters, in particular penile ultrasound we found an inverse correlation between both basal and dynamic peak systolic velocity and the number of factors for metabolic syndrome.
At logistic regression analysis we found that among ATP-III factors elevated blood pressure, elevated fasting glucose and elevated triglycerides were the best predictors of pathological dynamic peak systolic velocity at penile Doppler ultrasound.
Very interesting considering relational factors we found that the prevalence of metabolic syndrome increased as function of relationship span peaking after ten years. So, it could be speculated that patients with less long duration of the relationship could have a greater awareness of their body shape and this could determine better weight control.
Considering intrapsychic parameters we found that patients with metabolic syndrome, and in particular patients reporting four or five factors reported also higher somatization symptoms.
Metabolic syndrome associated sexual dysfunction is characterized by a higher organic component of ED, worse subjective and objective erectile parameters, more intrapsychic somatization and longer couple relationship.
What about hormonal parameters?
The prevalence of hypogonadism, as expected, increased in patients without metabolic syndrome as function of the final cut off used, raising about one quarter of cases using 12 nmol/l as the defining cut off.
The prevalence was much higher considering patients with metabolic syndrome, raising about 50% of patients using 12 nmol/l as the defining cut off.
Sexual dysfunction is often associated with hypogonadism with or without metabolic syndrome, and metabolic syndrome is often associated with hypogonadism, about two times higher.
Metabolic syndrome associated sexual dysfunction is characterized also by more hypogonadism.
We must think about hypogonadism in patients with metabolic syndrome associated sexual dysfunction.
What are characteristics of metabolic syndrome associated hypogonadism within patients reporting metabolic syndrome associated sexual dysfunction?
As previously reported by Muller we found an inverse relationship between testosterone levels and the number of factors for metabolic syndrome. Accordingly, the relative risk for hypogonadism, restricting our analysis to a severe form of hypogonadism: total testosterone lower than 8 nmol, increased as function of the number of factors for metabolic syndrome, and in particular when four or five factors were present, the relative risk was ten times higher.
At logistic regression analysis we found that among ATP-III factors, elevated fasting glucose and elevated waist circumference were the best predictors of hypogonadism.
Among the pathogenetic reasons we have to consider also metabolic syndrome itself.
What are the pathogenetic characteristics of this association? It is well known that an increase of visceral adiposity determines an increase of insulin circulating level s and insulin resistance leading to a reduction of sex hormone binding globulin levels, and so leading to a reduction o f total-testosterone levels. But this is not hypogonadism; this is just a feature of the reduction of sex hormone binding globulin levels. On the other hand, an increase of visceral adiposity determines an increase of aromatase activity, which could contribute to a reduction of total-testosterone leading to an increase of estrogen circulating level s. Estrogens could act at the pituitary level in males leading to negative fee-back on LH and so leading to a reduction of both total testosterone and free testosterone determining the development of hypogonadism. On the other hand, it has also been demonstrated that in obese patients there is a reduction of LH amplitude pulses. So, other factors from visceral fat could act at the pituitary level leading to a reduction of LH. On the other hand, it has also been demonstrated that other factors could act at testis level, such as leptin for example, leading to the reduction of testosterone production from Leydig cells. So, in this pathogenetic model we have to consider two different components: central component and peripheral component, and probably these two components co-exist. What happens when hypogonadism is developing? In hypogonadism there is an increase of lipoprotein lipase activity, in fact, testosterone inhibits lipoprotein lipase activity and so this determines an increase of visceral adiposity, in fact lipoprotein lipase is the most important enzyme involved in adipose tissue in the free fatty acid uptake . So this closes the hypogonadal obesity cycle described for the first time by Cohen in 1999.
Our data seem to suggest a peripheral component. In fact , among patients reporting metabolic syndrome, we found that those with hypogonadism reported a higher LH circulating levels.
Metabolic syndrome is often associated with sexual dysfunction, and also low testosterone is often associated with sexual dysfunction. On the other hand sexual dysfunction could determine the development of metabolic syndrome. We found that patients with higher relationship span have a higher prevalence of metabolic syndrome. And also sexual dysfunction has been associated with lower testosterone. But what kind of hypogonadism is the metabolic syndrome associated hypogonadism?
To answer this question we studied the clinical characteristic of metabolic syndrome associated hypogonadism within patients with metabolic syndrome associated sexual dysfunction.
Among patients with metabolic syndrome we did not find any difference considering age between patients with or without hypogonadism.
While patients with hypogonadism reported lower free and bioavailable testosterone leve ls, a biochemical sign of an overt hypogonadism, lower testis volume, a clinical sign of an overt hypogonadism, even after adjustment for confounding factors such as body mass index and waist …
… higher prevalence of hypogonadism related symptoms, such as higher prevalence of hypoactive sexual desire, and low intercourse frequency as assessed by SIEDY structur ed interview.
We describe the clinical characteristic s of metabolic syndrome associated sexual dysfunction within patients reporting sexual dysfunction and the clinical characteristic s of metabolic syndrome associated hypogonadism within patients with metabolic syndrome associated sexual dysfunction.
The main characteristics of metabolic syndrome associated sexual dysfunction are higher organic component of ED, worse erections, more somatization and longer relationships.
While the main characteristics of metabolic syndrome associated hypogonadism are essentially hypogonadal symptoms.
Hypogonadism in diabetes mellitus induced erectile dysfunction and metabolic syndrome associated sexual dysfunction is a new complication easy to resolve with testosterone.
Finally, let me thank all the people who collaborated with me in this work, and particular thanks to professor Maggi.
Audience Question: Which role plays leptin, and grealin and adiponectin in the relationship between metabolic syndrome and erectile dysfunction?
Dr. Corona: It is difficult to know what are the pathogenetic mechanisms underlying hypogonadism associated with metabolic syndrome. It has been demonstrated that some adipose hormones, such as leptin, as reported yesterday by professor Fabbri, could determine a reduction of testosterone production from Leydig cell s. In fact they demonstrated the presence of the receptor for leptin at testis level. But, also other authors reported a prevalence of hypogonadotropic hypogonadism in patients with diabetes mellitus. I think that these two components are present. Depending on the characteristics of the population finding the prevalence of central component or the prevalence of peripheral component.
Audience Question: You haven’t really touched on the subject of prevention. It has been 15 years ago that a headmaster was sent to me. He had already been medically bordered because of mental and physical dysfunction. He did not respond to Metformin and oral sulfonylurea and diet. I had to put him on insulin. And then in 1989, 1990, I first thought to put in testosterone implant. His testosterone was low and he came back three months later and he said he realized he had been brain dead before that. He had been able to wean off his insulin and his sugar was now well controlled. Should we wait till the male hits 105 cm or the female 95; should we already be looking at the waist when it is passing 85 cm in men, 75 in women, and considering metformin and looking at their sex hormones to prevent them dying or being prematurely incapacitated?
Dr. Corona: I totally agree with you. I think that we need some longitudinal studies using metformin or Thiazolidinedione drugs to show the effect on testosterone. I totally agree with you about the importance of prevention of the weight control for metabolic syndrome and for hypogonadism in metabolic syndrome.
Audience Question: The problem with the glitazones is that they do not reduce, if anything they increase, body fat, and the new reports about visual impairment with glitazones, never mind PDIs.
Dr. Corona: Yes, but they are all insulin coadjutants so the problem is as reported by Pitteloud in the JCM that there is direct correlation between low testosterone and insulin resistance.
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