Androgeny a tuková tkáň
Účinky androgenů
- Regulation of body fat distribution
- Direct effects on adipocyte differentiation in a depot-specific manner
- Modulation of adipocyte size and fat compartment expansion
- Insulin signalling
- Lipid metabolism
- Fatty acid uptake
- Adipokine production
- Stimulatory effect on lipolysis
- Impairment of adipocyte differentiation
- Zhoršení insulin signalling
- Effects are frequently gender-specific
- testosterone regulates the expression of genes in glucose metabolism in men
- Promote insulin sensitivity
Hladiny androgenů
- Testosterone
- Major circulating androgen
- In plasma as
- Free or unbound testosterone
- Albumin-bound
- Sex hormone-binding globulin [SHBG]-bound [52]
- In lean men
- Cca 50% of testosterone is bound to albumin and other proteins
- 44% is bound to SHBG
- Proportional to the SHBG levels [52]
- 2% is unbound
- Bioavailable testosterone
- Albumin-bound fraction and free testosterone
- Positively related to
- Muscle strength
- Total body bone mineral density [52]
- Negatively related to
- fat mass in healthy elderly men [52]
- SHBG
- Production in the liver
- Increased by
- estrogen [52]
- Downregulated
- Obesity
- Insulin resistance [52]
- Testosterone
- Can act directly
- Converted to the more potent androgen 5-dihydrotestosterone (DHT)
- By 5?-reductase
- To estrogens
- By aromatase (ARO)
- ARO activity detected in adipose tissue
- Important role for this enzyme in obesity, central fat accumulation, and metabolic syndrome [52]
- estrogen receptors (ERs) + ARs
- Abundantly expressed in the adipocyte
- Suppress adipose tissue accumulation
- Improve insulin sensitivity [52]
- Short-term aromatase inhibition in healthy young and elderly men
- Decline in serum leptin [52]
Balance between generation and irreversible inactivation
Balanc mezi aktivací a deaktivací aktivních forem
- Tightly controlled by
- Isoenzymes of AKR1C
- 5 alfa-reductase
- Others
AKR1C2 and AKR1C3
- Crucial in the regulation of local androgen bioavailability within adipose tissue
- Control the balance between
- Activation of androstenedione (A) to testosterone (T)
- By the 17ß-hydroxysteroid dehydrogenase activity (17ß-HSD) of AKR1C3 [27]
- Inactivation of 5?-dihydrotestosterone (DHT) to 5?-androstane-3?,17ß-diol
- By the 3?-hydroxysteroid dehydrogenase (3?-HSD) activity of AKR1C2 [27]
- Androgen inactivation
- Predominant reaction in fat
- Particularly in the abdominal subcutaneous (SC) depot [27]
Citlivost na androgeny
- Receptory
- Regulace, mutace,...
- Postreceptorová regulace
- Signální kaskáda
Androgenní receptory (AR)
- Ligand-activated transcription factor
- AR regulates adiponectin production and serum adiponectin levels
- High in hypogonadal men
- Reduced by testosterone therapy
- Testosterone infusion also decreases adiponectin in mice
- At least partially mediated via AR [51]
- Mice with myocyte-specific AR ablation
- Have lower intra-abdominal fat
- These mice exhibit a fast-to-slow fiber conversion
- Without major change in muscle mass
- Without affecting muscle strength [51]
- AR deficiency
- Induced insulin resistance in skeletal muscle
- Decrease in the transcription factor Peroxisome proliferator-activated receptor-gamma coactivator alpha - PGC1 alpha
- PGC1 alpha
- Stimulates mitochondrial biogenesis
- Skeletal muscle oxidative fibers [51]
- Male whole-body AR-deficient mice
- Obesity without increase energy intake
- Decreased locomotor activity
- Reduced brown adipose tissue thermogenesis [51]
- Control of adipose tissue mass via central and peripheral effects in male rodents [51]
- Extension of the polymorphic polyglutamine (CAG repeat number) of the exon 1 of the AR
- Modulates androgen effects
- AR activities are attenuated according to the length of triplet residues
- Expression of AR
- Plasma androgen concentration
- Directly contributing to the prevalence of central adiposity [52]
- CAG repeat polymorphism in the AR gene
- Modulate body fat mass
- Serum concentrations of leptin and insulin in men
- Direct effect upon adipocyte sensitivity to androgens
- Phenotypic effects on body fat mass could be explained by in case of a long AR CAG repeat
- estrogen action more than androgen action
- Increased estrogen/androgen ratio
- Hypothalamic—pituitary—gonadal axis reduced testosterone feedback
- Increased LH stimulation, increased androgen production
- Subsequent higher conversion to estrogens [52]
Selective androgen receptor modulators (SARMs)
- Novel class of AR ligands
- Act like testosterone with tissue-selectivity in men
- Ideal SARM
- Anabolic activity on muscle and bone
- Without androgenic action in the prostate [51]
- Extension of androgen therapy to geriatric functional decline in men
- Not suitable in T2D is
- Prostate and cardiovascular risks [51]
Androgeny v různých tkáních
Svalovina mužů a testosteron
- Suppressing effect of testosterone on white adipose tissue (WAT) mass in males
- Indirectly mediated via AR signaling in skeletal muscle
- Stimulates the commitment of pluripotent mesenchymal stem cells into myogenic lineage
- At the same time suppressing the adipogenic lineage
- Non-canonical Wnt signaling
- Induces the expression of IGF1
- Nuclear accumulation of beta-catenin, a myogenic and anti-adipogenic stem cell factor [51]
- Male adipocyte-specific androgen receptor KO (ARKO) in mice
- no increase in fat mass
- Direct AR action in adipose tissue is not necessary for the control of fat mass
- Increased production of leptin by adipose tissue without leptin resistance [51]
- Decrease in PGC1 alfa expression in skeletal muscle
- In T2D subjects
- Associated with insulin resistance [51]
Játra mužů a testosteron
- Low testosterone levels
- Associated with hepatic steatosis in men [51]
- Male hepatocyte-specific ARKO (HARKO) mice
- Hepatic steatosis when fed a high-fat diet
- Females did not
- Decreased hepatic peroxisome proliferator-activated receptor (PPAR?) expression
- Decreased fatty acid oxidation
- Increased hepatic sterol regulatory element binding protein 1c
- Increased de novo lipid synthesis [51]
- Hepatic insulin resistance
- Adiposity
- Hyperinsulinemia
- Hepatic steatosis
- Decreased mRNA transcript profiles for fatty acid ß-oxidation
- Increased genes for lipid storage [51]
- Mice deficient in 5 alfa -reductase type 1 (5 alfa R1-/-) (converts testosterone to the active androgen DHT)
- Hepatic steatosis
- Decreased hepatic expression of genes involved in insulin signaling when fed a Western diet
- Adiposity
- Hyperinsulinemia
- Hepatic steatosis
- Decreased mRNA transcript profiles for fatty acid ß-oxidation
- Increased genes for lipid storage [51]
- Non-selective 5 alfa-reductase inhibitor finasteride in obese male Zucker rats
- Induced hyperinsulinemia
- Hepatic steatosis [51]
- AR actions in liver
- Important to prevent hepatic steatosis [51]
Mozek a nadrogeny
- AR more abundantly expressed in the brain of male than in females
- AR also functions in the male hypothalamus
- Favor central leptin action [51]
- AR-deficient male mice
- Leptin fails
- Promote STAT3 nuclear localization in arcuate nucleus (ARC) neurons
- Does not suppress food intake
- Does not reduce body weight [51]
- Neuronal specific ARKO (NARKO) mice
- Develop obesity
- Insulin resistance
- Glucose intolerance
- Show hypothalamic insulin resistance
- Activation of hypothalamic NF?B that increases inflammation [51]
Beta-cells in males a androgeny
- testosterone protects early apoptotic damage induced by streptozotocin in male rat pancreas through AR
- testosterone stimulates islet insulin mRNA and content in culture and in vivo
- testosterone accelerates the hyperglycemic decompensation in an AR-dependent manner
- ß-cell specific AR knockout mouse (ßARKO-/y) Male
- Decreased glucose-stimulated insulin secretion (GSIS)
- Glucose intolerance
- ß-cell failure to compensate diet-induced insulin resistance [51]
- In cultured human islets treated with flutamide, an AR antagonist
- Stejné výsledky [51]
- Metabolic dysfunction in multiple tissues including the central nervous system, liver, skeletal muscle, adipose and ß-cells:
- Androgen deficiency in males
- Nedostatečná stimulace AR [51]
- Androgen excess in females
- Nadměrná stimulace AR [51]
Androgen excess
In women
- Hyperandrogenism promotes insulin resistance in women
- Predisposes to T2D in women
- “diabetes in bearded women” by Achard and Thiers in 1921 [51]
- no effect on body weight in female mice
- Low concentration of Sex-Hormone Binding Globulin (SHBG)
- Increases free testosterone
- Strong independent risk factor for the development of T2D [51]
- Postmenopausal women with impaired glucose tolerance
- Have higher androgen activity than women with normal glucose tolerance [51]
- Androgen activity correlates with
- The degree of glucose intolerance [51]
- Higher levels of free testosterone and lower levels of SHBG
- Repeatedly associated with
- Glucose intolerance
- Insulin resistance in women [51]
- High free testosterone levels are associated with
- Higher risk of T2D in women [51]
- Estradiol levels
- Were also elevated among postmenopausal women with diabetes
- estrogen excess could also have played a role in T2D risk [51]
- Postmenopausal women, higher plasma levels of estradiol and testosterone
- Were strongly and prospectively related to increased risk of developing T2D [51]
- Metabolic response of androgen-exposed women during hyperglycemic and euglycemic-hyperinsulinemic clamps
- High testosterone levels produce insulin resistance
- By decreasing insulin-stimulated whole body glucose uptake in healthy pre- and post-menopausal women
- Hepatic insulin resistance remained unchanged
- Role for skeletal muscle in insulin resistance
- Fiber type switch na pomalá vlákna
- Confirmed in studies of female rodents [51]
- Insulin sensitivity improves
- When hyperandrogenism is reversed with anti-androgen therapy
- In association with weight loss [51]
- Androgen excess alone may be instrumental in insulin resistance
- Treatment with AR antagonists
- Suppression of ovarian androgen production with GnRH analogues in hyperandrogenic women
- Does not always improve insulin resistance
- Excess androgens in women may not be the cause, just an aggravating factor [51]
- Increases visceral adiposity in females [51]
- Women with chronic androgen excess
- Plasma testosterone is positively correlated with
- Waist circumference
- Index of visceral obesity [51]
- Androgen excess might has masculinized the function of female adipose tissue [51]
- Female mice exposed to the non-aromatizable androgen receptor agonist DHT
- DHT prevents leptin from activating brown adipose tissue (BAT) thermogenesis
- Reduced energy expenditure
- Visceral obesity [51]
- Decreased hypothalamic proopiomelanocortin (pomc) expression
- Decreased POMC neuronal innervations into dorsomedial hypothalamus (DMH)
- Visceral adiposity in hyperandrogenic females could have a central origin [51]
- Androgen-induced visceral fat distribution and accumulation
- Alteration of the melanocortin system between the ARC and DMH. [51]
- Hyperandrogenism predisposes to ß-cell dysfunction in females
- Various degrees of pancreatic ß-cell dysfunction [51]
- Functional hyperandrogenism
- Significantly higher basal insulin secretory rates
- Attenuated post-prandial insulin secretory responses [51]
- Women with hyperandrogenism
- ß-cell hyperfunction
- May predispose to secondary ß-cell failure [51]
- Female mice
- testosterone accelerates hyperglycemic decompensation in experimental models of insulin-dependent diabetes [51]
- Excess testosterone
- Induces systemic oxidative stress in female mice
- Excess AR activation in ß-cells (and/or other tissues)
- Predispose to the ß-cell dysfunction
- Could be a direct islet effect [51]
- testosterone infusion in healthy women
- Does not produce ß-cell dysfunction [51]
- Excess testosterone
- Predispose ß-cell failure through the cumulative action of various ß-cell stresses [51]
- Androgen excess-induced T2D
- Was not observed in female ßARKO-/- mice
- At least partially mediated via excess AR activation in ß-cells [51]
Polycystic ovarian syndrome (PCOS) associated with
- Insulin resistance
- Glucose intolerance
- Subsequent T2D
- Most common endocrine disorder in reproductive age women [51]
- Inadequate acute insulin release to the degree of insulin resistance
- Exaggerated early insulin response to glucose
- Not accounted for by insulin resistance
- Closely associated with hyperandrogenicity [51]
- Robust relationship between ß-cell function and free testosterone
- Excess testosterone in women leads to insulin hypersecretion [51]
- Accompanied by systemic oxidative stress [51]
- High circulating androgens [52]
- Originate from ovaries and adrenals
- Frequently suffer from the metabolic syndrome including obesity
- Simple obesity - androgen synthesis within adipose tissue
- Expression of 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD) isozymes
- Effcient conversion of androstenedione to testosterone in both subcutaneous and omental fat
- Whole fat
- 17beta-HSD5 and 4
- Preadipocytes of subcutaneous and omental origin
- 17beta-HSD5 and 4
- Increase in 17-beta-HSD5 expression upon differentiation of stromal preadipocytes to mature adipocytes [52]
- Subcutaneus fat
- Higher expression of 17beta-HSD5 než v omentu
- Aktivita increased with differentiation
- Androgen inactivation
- testosterone to androstenedione
- In omental cultures [52]
Androgen excess
In men
- High serum testosterone is associated with insulin sensitivity [51]
Protective mutations in men
- Low number of CAG repeats
- Independently associated with protective metabolic parameters
- Low body fat mass and plasma insulin [51]
- Intact AR transcription
- Favors metabolic homeostasis [51]
- Overexpression of AR selectively in muscle cells of transgenic male rats
- Increases their lean mass
- Hypertrophy of type IIb muscle fibers
- Associated with increased oxidative metabolism and metabolic rate
- Reduced adipocyte size and adipose tissue mass [51]
- Testosterone action in skeletal muscle promotes insulin sensitivity in males [51]
Androgen deficiency
In men
- Contributes to the development of metabolic syndrome and type 2 diabetes (T2D)
- Men will spend a significant proportion of their live in a state of testosterone deficiency
- Increases type 2 diabetes (T2D) risk [51]
- Leads to hypogonadism
- Total testosterone levels were always lower in diabetic men than in non-diabetic controls
- Higher testosterone levels were associated with a lower risk of incident diabetes
- Diabetic men still have lower testosterone levels even after adjustment for BMI
- Impaired fasting glucose and glucose intolerance
- Independently of obesity and metabolic syndrome in men
- Inverse correlation between total serum testosterone and the amount of visceral adipose tissue
- True in all situations of androgen deficiency:
- Hypogonadism in older men
- Inherited testosterone deficiency
- Klinefelter's syndrome [51]
- Androgen deprivation during treatment for prostate carcinoma
- Associated with low PGC1 alfa expression levels in muscle
- Promotes insulin resistance in skeletal muscle
- Decrease in PGC1 alfa-mediated oxidative and insulin sensitive muscle fibers
- Castration of male rats
- Followed by a marked insulin resistance in skeletal muscle under euglycemic, hyperinsulinemic clamp conditions
- Treatment with physiological doses of testosterone
- Completely abolishes these perturbations in insulin sensitivity [51]
- Could contribute to the accumulation of excess fat, establishing a vicious cycle [52]
- Hypogonadism induce
- Induces expansion of fat mass
- Subsequent dysregulation
- Insulin sensitivity
- Blood pressure
- Vascular reactivity
- Immunity
- Insulin resistance
- Reduced production of SHBG
- Reduction in testosterone
- Expansion of adipose mass
- Increase in aromatase (ARO) activity
- Peripheral conversion of testosterone to estradiol
- Increased estrogen levels induce a reduction of LH pulse
- Reduction in androgen production [69]
- Excess of circulating leptin
- Disrupts testicular steroidogenesis
- Suppression of androgen production
Falling testosterone levels in men
- Contributor to poor life quality
- V.s. effects of ageing on the hypothalamic-pituitary-gonadal (HPG) axis
- Increasing prevalence of obesity and chronic illness
- Only small minority of ageing men do testosterone levels fall below the normal range
- Studies failing to show consistent benefit suplementace
- Clinical syndrome
- Sub-physiological testosterone concentrations
- Disruption of the HPG axis [52]
Klinefelter's syndrome (KS)
- Manifests before or during puberty
- Chromosomal aberration (mostly 47,XXY) affecting ~0.2% of male newborns [52]
- Markedly low testosterone levels
- Elevated gonadotrophin levels (primary hypogonadism)
- Small testes
- Decreased libido, erectile dysfunction
- Poor beard growth
- Infertility (with azoospermia) [52]
- Tall stature
- Sparse pubic hair
- Gynaecomastia
- Decreased muscle mass [52]
- Decreased muscle strength
- Low bone mineral density (BMD)
- Anaemia
- Decreased physical function [52]
- Increased risk of
- Diabetes
- Obesity [52]
- Bone fracture
- Increased mortality [52]
Hypogonadism after puberty - hypothalamic-pituitary disease
- E.g. tumour, infiltration, trauma, radiation [52]
- Low testosterone levels
- Low gonadotrophin levels (secondary hypogonadism)
- Tend to develop the same features as men with KS with the exceptions of: [52]
- Small testis [52]
- Poor beard growth
- Abnormal height
- Can occur also due to disruption at more than one level of the HPG axis [52]
- Opioids in the hypothalamus, pituitary and testis inhibit secretion of:
- Gonadotropin-releasing hormone (GnRH) [52]
- Luteinizing hormone [52]
- testosterone [52]
Testosterone levels fall with ageing
- European Male Ageing Study (EMAS)
- 2,736 men aged >40 for
- Average of 4.4 years
- 0.1 nmol/l (0.04%) per year reduction in total testosterone
- 3.83 pmol/l (0.77%) per year reduction in free (not protein bound) testosterone concentrations
- Fall below the normal range in a minority of ageing men [52]
- Boston Area Community Health Survey (BACH)
- 16 and 26% of men aged 70–79 have a total testosterone concentration that is <10.5 nmol/l
- 11 and 22% of men aged <50 [52]
- Not all studies have observed lower testosterone levels in older men
- Healthy men describe no difference in testosterone concentrations between older and younger [52]
- Multiple mechanisms
- Testicular and hypothalamic function decline with age
- Leydig cell number is ~44% lower in men aged 50–76 than in men aged 20–48
- Secretory capacity of the testes is substantially lower in older men
- Declining testicular function appears to be the main cause [52]
- Hypothalamic GnRH secretion is lower in older men
- But not pituitary LH reserve [52]
- Obesity contributes to the decline in testosterone
- Total and visceral fat mass increase with ageing peaking normally at 65 years
- Obese men (BMI > 30 kg/m2) x (BMI 20–25 kg/m2)
- Lower total
- Lower free testosterone
- Decline more quickly
- LH concentrations are not elevated
- Suggesting a hypothalamic-pituitary defect
- Elevated cytokine concentrations
- Insulin resistance [52]
- Chronic illness
- Role in the fall in testosterone levels
- Lower testosterone levels than healthy men
- LH concentrations are not elevated
- Cardiovascular disease (CVD) and type 2 diabetes (T2DM)
- Increased concentrations of pro-inflammatory cytokines [52]
- Statin use [52]
- vitamin D deficiency [52]
- Adult onset male hypogonadism [52]
- Non-specific [52]
- Overlap with many symptoms that develop with normal ageing
- Loss of libido increased
- Erectile dysfunction increased
- Total testosterone <11 nmol/l
- Free testosterone <220 pmol/l
- ~3% of men aged 60–69 [52]
- ~0.1% of men aged 40–49 [52]
- Symptoms of hypogonadism do not correspond to low testosterone concentrations [52]
Men on androgen depletion therapy for prostate cancer
- At high risk to develop T2D
- Marked hyperglycemia and decreased pancreatic ß-cell function [51]
- Men undergoing androgen deprivation therapy for nonmetastatic prostate cancer
- Significant increase of BMI and fat mass
- Increased incidence of diabetes and cardiovascular disease [52]
Inhibitory aromatázy u mužů
- Aromatization of testosterone into 17ß-estradiol (E2)
- Critical to energy homeostasis in males
- testosterone functions as a prohormone in men
- To provide E2 for tissue metabolism [51]
- Orchidectomized male rodents
- Treated with either testosterone or E2
- Remain lean [51]
- Treated with the pure androgen DHT –that cannot be converted to E2
- Develop obesity [51]
- Restoration of adiposity was due to testosterone conversion into E2 acting on ERs
- This is also true in men for whom testosterone replacement suppresses adiposity
- Blocked in the presence of an aromatase inhibitor [51]
Mutations that increase visceral obesity in males
- Aromatase
- ER genes
- CAG repeat polymorphisms in the AR gene
- Decreases AR-mediated gene transcription
- Genetic androgen resistance [51]
- Male mice with global deletion of the AR
- Develop late onset visceral obesity
- With leptin resistance
- Insulin resistance
- Increased lipogenesis in adipose tissue and liver [51]
Dopamine agonist therapy
- First-line therapy for men with hyperprolactinaemia
- Increase testosterone levels
Low testosterone level and desire of fertility
- Gonadotrophin therapy
- Pulsatile gonadotrophin-releasing hormone
- If LH levels are not elevated
Testosterone replacement therapy in men
- Associated with a significant reduction in
- Fasting plasma glucose
- HBA1c
- fat mass
- Triglyceride in men
- Androgens prevents visceral fat accumulation and improves insulin sensitivity [51]
- testosterone in elderly patients with coronary heart failure improving
- Functional capacity
- Heart rate
- Muscle strength
- Glucose metabolism [69]
Testosterone teraphy
- Intramuscular
- Every 3–12 weeks
- Buccal
- Transdermal
- Daily administration
- Oral testosterone and 17-alpha-alkylated androgen preparations
- Not recommended
- Liver toxicity
- Variable clinical response
- 17 randomised clinical trials (RCTs)- 656 men (mean age 57.5 years)
- testosterone therapy in men with a total testosterone concentration <12 nmol/l:
- Moderately improved:
- Sexual symptoms
- Sexual function
- Had no such effect in eugonadal men
- Positive effect of testosterone therapy in hypogonadal men with depression
- Increase in physical function in men
- Aged 75 or greater
- With two or more Fried frailty criteria
- 10 mg/day improved muscle strength
- Supra-physiological dose
- Greater incidence of cardiovascular-related events
- Improves lumbar Bone Mass Density by 8%
- Suppression of hepcidin
- Increases haemoglobin levels
- Cca 1 g/dl
- Haematocrit by ~3%
- >3-fold risk of erythrocytosis [52]
- Increases prostate-specific antigen levels
- Tends to increase the risk of prostate biopsy [52]
- no increased risk of prostate cancer
- Continuing caution is required
- Androgens may have a long latency in promoting the growth of pre-existing prostate cancer
- Observational studies and a meta-analysis
- Associations between testosterone therapy and a 30–54% increased risk of cardiovascular-related events
- FDA: all these studies had significant limitations
- Currently there is insufficient evidence for an association
- Make clear that a low testosterone level due to ageing is not an indication for testosterone therapy
- Cardiovascular safety monitoring of testosterone therapy in older men is required [52]
Contraindications to testosterone therapy
- Erythrocytosis (haematocrit >52%)
- Prostate cancer
- Breast cancer
- Untreated obstructive sleep apnoea
- Uncontrolled heart failure
- Severe lower urinary tract symptoms
- International Prostate Symptom Score >19
- Desire for fertility