The metabolic syndrome in andrology

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This short commentary is a report based on the joint Postgraduate Course run by the European Academy of Andrology and the Hellenic Society of Andrology and entitled the “Metabolic Syndrome in Andrology”. The Course was held in Athens, Greece, on 19 September 2008. The Course participation exceeded expectations, with an audience of over 200 Andrology professionals from several European countries. Due to the great interest raised by the lively discussions after each lecture, and requests from several members of Andrology and Men's Health Societies to publish a concise review of the major take home messages, members of the Organizing Committee have helped to produce the current report.

The metabolic syndrome (MetS) is a major morbidity factor in modern Western societies, accounting for the majority of deaths among the adult population. It is not a disease of specific etiology, but rather the manifestation of long-term neglect of proper diet and lifestyle conditions, resulting in metabolic deregulation, hence the proposed alternative nomenclature “dysmetabolic syndrome”. Although several definitions have been used over the course of several years (see Table 1 for details), the MetS remains, without a doubt, a major public health concern, involving in its proper diagnosis and management several medical specialties, and disciplines, such as Endocrinology, Cardiology, Psychiatry, and even Bariatric Surgery [1]. Although there is no general agreement as to the pathophysiological hierarchy of events leading to the clinical conditions associated with the MetS, the process definitely involves adipokines, inflammatory mediators, and multiple endocrine disorders, the most predominant of which remains insulin resistance [2]. The MetS is associated with various parameters of the daily lifestyle, including dietary practices, level of physical activity/exercise, involvement in stressful activities, drug use and abuse, tobacco and alcohol consumption, to name some significant contributors to its increased incidence. In any case, the MetS is a clear case of a genetic–environmental contribution of roughly equal proportions: each side can explain part, but not all, of the findings detected in every affected individual.

Table 1. Running definitions of the metabolic syndrome according to major scientific consensus statements

	WHO	EGIR	NCEP	IDF
Glucose	DM, IGT, IFG, insulin resistance (mandatory element)	Insulin resistance (mandatory) Fasting plasma glucose ≥ 6.1 mmol/l	Fasting plasma glucose ≥ 6.1 mmol/l (110 mg/dl)	Fasting plasma glucose ≥ 100 mg/dl or known DM type II
Obesity	WHR>0.9 (M) >0.85 (F)	Waist circumference	waist circumference	waist circumference ≥ 94cm (M) and ≥ 80cm (F)
	BMI>30	≥ 94cm (M), ≥ 80cm (F)	≥ 102cm (M), ≥ 88cm (F)
Lipids	TG ≥1.695 mmol/l	TG ≥ 2.0 mmol/l and/or HDL-C < 1.0 mmol/l or already treated	TG ≥ 1.695 mmol/l (150 mg/dl)	TG level ≥ 150 mg/dl or already treated
	HDL-C ≤ 0.9 mmol/l (M), ≤ 1.0 mmol/l (F)		HDL-C < 40 mg/dl (M), < 50 mg/dl (F)	HDL-C < 40 mg/dl (M), < 50 mg/dl (F) or already treated
Blood pressure	≥ 140/90 mmHg	≥ 140/90 mmHg or already treated	≥ 130/85 mmHg	≥ 130/85 mmHg or already treated
Other criteria	Microalbuminuria mandatory+2 optional	Mandatory+2 optional	Any 3

WHO, World Health Organization; IDF, International Diabetes Federation; NCEP, National Cholesterol Education Programme; EGIR, European Group for the Study of Insulin Resistance; DM, diabetes mellitus; IGT, impaired glucose tolerance; IFG, impaired fasting glucose; WHR, waist to hip ratio; BMI, body mass index; TG, triglycerides; HDL-C, high density lipoprotein cholesterol; (M), male; (F), female.

The initial concept for the MetS, as proposed by Reaven, considered insulin resistance as being the compulsory entity [3]. Nowadays, research focuses on other molecular processes that link the different components of the MetS, as well as the MetS with other endocrine functions, such as bone regeneration and reproductive health [4], [5].

The relationship between the MetS and Andrology has attracted the attention of clinicians and researchers for some time, since it has been shown that gonadal dysfunction (decreased libido, erectile dysfunction, hypogonadism, and low testosterone levels) is an accompanying manifestation of the MetS. In fact, a considerable proportion of patients are referred to clinicians with reproductive failure (usually erectile dysfunction in males and loss of libido in females) as the presenting condition, without having associated this problem with components of the MetS, even when some of them (e.g. overt diabetes, central obesity) are evident [5], [6]. The exact pathophysiological association between erectile dysfunction and the MetS is extremely complicated, but may involve several contributing factors, such as:

Recent original research data seems to suggest that autonomic neuropathy is directly associated with erectile dysfunction, and may, in fact, predispose to generalized cardiovascular autonomic neuropathy [11]. As far as sex steroids are concerned, maintenance of adequate sex steroid levels in adult life have also been suggested to protect elderly males from the early onset of the MetS constituent entities [12]. There is evidence of a messaging system involving leptin, ghrelin, and resistin, that links obesity, insulin resistance, and distant organ dysfunction, including the gonads. The extend to which these unfavorable events may be reversed by the administration of androgen replacement therapy remains an issue of controversy, since no consensus on the optimal use of androgens has yet been reached [13], [14], [15].

The discovery of novel interaction routes among the endocrine, reproductive, and immune systems prove the central role of inflammatory cells and mediators in some cases of idiopathic male infertility. Free fatty acids and oxidized low density lipoprotein (LDL) molecules appear to act as irritants, resulting in the development of an acute phase-like systemic inflammatory reaction. Although this is neither long in duration nor of such extent as in sepsis or systemic inflammatory response syndrome (SIRS), it acts as a stress factor that inhibits normal cellular repair and induces chronic architectural damage. It is obvious that such an interaction could carry implications for the optimum treatment of the MetS and male infertility in the future [16].

Molecular endocrinology has allowed the improvement of our understanding of hormonal action in both health and disease scenarios. The recent discovery of additional modes of sex steroid function, other than the traditional androgen and estrogen receptors, has opened up a field of research that may significantly enhance our perspective on the correlation between development, metabolism, and reproduction [8], [10].

Emphasis should also be given to symptoms and signs that may alert the physician to request a complete profile for the parameters that, together, constitute the spectrum of the MetS. In the case of reproductive health and andrology, in particular, doctors are encouraged to pay particular attention to the elderly population with late-onset hypogonadism, as this is often accompanied not only by decreased sex steroid concentrations, but also by a distorted lipid profile and the gradual establishment of insulin resistance [12]. As may easily be comprehended, the need for a holistic approach to the MetS patient is more than evident, since the various components interact and a major symptom (e.g. hypertension) may be a direct consequence of hormonal/paracrine dysfunction triggered by the other factors of the syndrome (e.g. obesity, insulin resistance). Recently, the endocannabinoid system has received much attention, being supported by the development of drugs targeting this system as a possible additional/supplementary cure for the treatment of morbid obesity. There is evidence that the system plays a role in the regulation of other MetS complications, as well as in the decrease of libido and specific reproductive complications, including erectile dysfunction [11], [17].

Finally, great progress has been achieved in therapy for the MetS. Similarly, attempts to substitute androgens in elderly men experiencing low plasma testosterone counts have provided conflicting results as to their actual contribution to the improvement of the patient's metabolic status [2], [12], [18]. Naturally, sex hormone manipulations cannot, and should not, be viewed as independent therapeutic interventions, but rather as alternative/complementary treatment options, in patients whose whole hormonal profile has been examined and in whom no other significant distortions have been noticed. Contrary to this principle, in cases of detection of an additional endocrine disorder, its treatment necessarily becomes the therapeutic priority of the attending physician, since it may be a major contributor to the MetS and any co-existent fertility/reproductive problems that have been reported. In particular, this is true for patients with increased growth hormone production, who are very commonly experiencing insulin resistance, and hypothyroidism, which combines a particular proneness for poor lipid management with low libido and adrenal cortex defects, since a certain level of cross reaction between the various steroid hormones is justified, resulting in a clinical outcome that simultaneously influences sexual function and metabolic homeostasis.

In chronic, complicated situations such as the above, the need for a holistic approach to the MetS patient is imperative, and no specialty should miss the chance to evaluate the cost–benefit ratio for every individual case [19], [20], [21].

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Summary 

All of the topics mentioned above were discussed in the recent joint Postgraduate Course of the European Academy of Andrology and the Hellenic Society of Andrology. Although a written report cannot substitute for the living experience of a postgradute course, it may serve as a useful reference and revision tool for future use.

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