Around 50% of ageing, obese men presenting to the diabetes clinic have lowered testosterone levels relative to reference ranges
based on healthy young men
The absence of high-level evidence in this
area is illustrated by the Endocrine Society testosterone therapy in men with androgen deficiency clinical practice guidelines
(Bhasin et al. 2010), which are appropriate for, but not specific to men with metabolic disorders. All 32 recommendations made in these guidelines
are based on either very low or low quality evidence.
A key concept relates to making a distinction between replacement and pharmacological testosterone therapy
The presence of symptoms was more closely linked to increasing age than to testosterone levels
Findings similar to type 2 diabetes were reported for men with the metabolic syndrome, which were associated with reductions
in total testosterone of −2.2 nmol/l (95% CI −2.41 to 1.94) and in free testosterone
low testosterone is more predictive of the metabolic syndrome in lean men
Cross-sectional studies uniformly show that 30–50% of men with
type 2 diabetes have lowered circulating testosterone levels, relative to references based on healthy young men
In a recent cross-sectional study of 240 middle-aged men (mean age 54 years) with either type 2 diabetes, type 1 diabetes
or without diabetes (Ng Tang Fui et al. 2013b), increasing BMI and age were dominant drivers of low total and free testosterone respectively.
both diabetes and the metabolic syndrome are associated with a modest reduction in testosterone, in magnitude comparable
with the effect of 10 years of ageing
In a cross-sectional study of 490 men with type 2 diabetes, there was a strong independent association of low testosterone
with anaemia
In men, low testosterone is a marker of poor health, and may improve our ability to predict risk
probably the most important point made in this article
low testosterone identifies men with an adverse metabolic phenotype
Diabetic men with low testosterone are significantly more likely to be obese or insulin resistant
increased inflammation, evidenced by higher CRP levels
Bioavailable
but not free testosterone was independently predictive of mortality
It remains possible that low testosterone is a consequence of insulin resistance, or simply a biomarker,
co-existing because of in-common risk factors.
In prospective studies, reviewed in detail elsewhere (Grossmann et al. 2010) the inverse association of low testosterone with metabolic syndrome or diabetes is less consistent for free testosterone
compared with total testosterone
In a study from the Framingham cohort, SHBG but not testosterone was prospectively and independently associated with incident
metabolic syndrome
low SHBG (Ding et al. 2009) but not testosterone (Haring et al. 2013) with an increased risk of future diabetes
In cross-sectional studies of men with (Grossmann et al. 2008) and without (Bonnet et al. 2013) diabetes, SHBG but not testosterone was inversely associated with worse glycaemic control
SHBG may have biological actions
beyond serving as a carrier protein for and regulator of circulating sex steroids
In men with diabetes, free testosterone, if measured by gold standard equilibrium dialysis (Dhindsa et al. 2004), is reduced
expensive, laborious process filled with variables
Low free testosterone remains inversely associated with insulin resistance, independent of SHBG (Grossmann et al. 2008). This suggests that the low testosterone–dysglycaemia association is not solely a consequence of low SHBG.
Experimental evidence reviewed below suggests that visceral adipose tissue is an important intermediate (rather than a
confounder) in the inverse association of testosterone with insulin resistance and metabolic disorders.
testosterone promotes the commitment of
pluripotent stem cells into the myogenic lineage and inhibits their differentiation into adipocytes
testosterone regulates the metabolic functions
of mature adipocytes (Xu et al. 1991, Marin et al. 1995) and myocytes (Pitteloud et al. 2005) in ways that reduce insulin resistance.
Pre-clinical evidence (reviewed in Rao et al. (2013)) suggests that at the cellular level, testosterone may improve glucose metabolism by modulating the expression of the glucose-transported
Glut4 and the insulin receptor, as well as by regulating key enzymes involved in glycolysis.
More recently testosterone has
been shown to protect murine pancreatic β cells against glucotoxicity-induced apoptosis
Interestingly, a reciprocal feedback also appears to exist, given that not only chronic (Cameron et al. 1990, Allan 2013) but also, as shown more recently (Iranmanesh et al. 2012, Caronia et al. 2013), acute hyperglycaemia can lower testosterone levels.
There is
also evidence that testosterone regulates insulin sensitivity directly and acutely
In men with prostate cancer commencing androgen deprivation therapy, both total as well as, although not in all studies (Smith 2004), visceral fat mass increases (Hamilton et al. 2011) within 3 months
More prolonged (>12 months) androgen deprivation therapy has been associated with increased risk of diabetes in several
large observational registry studies
Testosterone has also been shown to reduce the concentration of pro-inflammatory cytokines in some, but not all studies, reviewed
recently in Kelly & Jones (2013). It is not know whether this effect is independent of testosterone-induced changes in body composition.
the observations discussed in this section suggest that it is the decrease in testosterone that causes insulin
resistance and diabetes. One important caveat remains: the strongest evidence that low testosterone is the cause rather than
consequence of insulin resistance comes from men with prostate cancer (Grossmann & Zajac 2011a) or biochemical castration, and from mice lacking the androgen receptor.
Several large prospective studies have shown that weight gain or development of type 2 diabetes is major drivers of the
age-related decline in testosterone levels
there is increasing evidence that healthy ageing by itself is generally not associated with marked reductions in
testosterone
Circulating testosterone, on an average 30%, is lower in obese compared with lean men
increased visceral fat is an important component in the association of low testosterone and insulin resistance
The vast majority of men with metabolic disorders have functional gonadal axis suppression with modest reductions in testosterone
levels
obesity is a dominant
risk factor
men with Klinefelter syndrome have an increased risk of metabolic disorders. Interestingly, greater body fat
mass is already present before puberty
Only 5% of men with type 2 diabetes have elevated LH levels
inhibition of the gonadal axis predominantly takes place in the hypothalamus,
especially with more severe obesity
Metabolic factors, such as leptin, insulin (via deficiency or resistance) and ghrelin
are believed to act at the ventromedial and arcuate nuclei of the hypothalamus to inhibit gonadotropin-releasing hormone (GNRH)
secretion from GNRH neurons situated in the preoptic area
kisspeptin has emerged as one of the
most potent secretagogues of GNRH release
hypothesis that obesity-mediated inhibition of kisspeptin signalling contributes to the suppression
of the HPT axis, infusion of a bioactive kisspeptin fragment has been recently shown to robustly increase LH pulsatility,
LH levels and circulating testosterone in hypotestosteronaemic men with type 2 diabetes
A smaller study with a similar experimental design found that acute testosterone withdrawal reduced insulin sensitivity
independent of body weight, whereas oestradiol withdrawal had no effects
suppression of the diabesity-associated HPT axis is functional, and may hence be
reversible
Obesity and dysglycaemia and associated comorbidities such as obstructive sleep apnoea (Hoyos et al. 2012b) are important contributors to the suppression of the HPT axis
weight gain and development
of diabetes accelerate the age-related decline in testosterone
Modifiable risk factors such as obesity and co-morbidities are more strongly associated with a decline in circulating testosterone
levels than age alone
55% of symptomatic androgen deficiency reverted to a normal testosterone or an asymptomatic state after 8-year follow-up,
suggesting that androgen deficiency is not a stable state
Weight loss can reactivate the hypothalamic–pituitary–testicular axis
Leptin treatment resolves hypogonadism in leptin-deficient men
The hypothalamic–pituitary–testicular axis remains responsive to treatment with aromatase inhibitors or selective oestrogen
receptor modulators in obese men
Kisspeptin treatment increases LH secretion, pulse frequency and circulating testosterone levels in hypotestosteronaemic men
with type 2 diabetes
change in BMI was associated with the change in testosterone (Corona et al. 2013a,b).
weight loss can lead to genuine reactivation
of the gonadal axis by reversal of obesity-associated hypothalamic suppression
There is pre-clinical and observational evidence that chronic hyperglycaemia can inhibit the HPT axis
in men who improved their glycaemic control over time, testosterone levels increased. By
contrast, in those men in whom glycaemic control worsened, testosterone decreased
testosterone levels should be measured after successful weight loss to identify men with an insufficient rise
in their testosterone levels. Such men may have HPT axis pathology unrelated to their obesity, which will require appropriate
evaluation and management.
Systemic illness i.e. inflammation is associated with impaired HPA function and gonadal function. This can be translated as low T. Low Testosterone is a biomarker of poor health in men.
GELDING theory (Gut Endotoxin Leading to a Decline IN Gonadal function)
trans-mucosal passage of bacterial lipopolysaccharide (LPS) from the gut lumen into the circulation is a key inflammatory trigger underlying male hypogonadism
Obesity and a high fat/high calorie diet are both reported to result in changes to gut bacteria and intestinal wall permeability, leading to the passage of bacterial endotoxin (lipopolysaccharide- LPS) from within the gut lumen into the circulation (metabolic endotoxaemia), where it initiates systemic inflammation.
Endotoxin is known to reduce testosterone production by the testis, both by direct inhibition of Leydig cell steroidogenic pathways and indirectly by reducing pituitary LH drive, thereby also leading to a decline in sperm production.
80% of E2 production in men, that will cause low T in men, comes from SQ adiposity. This leads to increase in visceral adiposity.
Only 5% of men with type 2 diabetes have elevated LH levels (Dhindsa et al. 2004, 2011). This is consistent with recent findings that the inhibition of the gonadal axis predominantly takes place in the hypothalamus,
especially with more severe obesity
Metabolic factors, such as leptin, insulin (via deficiency or resistance) and ghrelin
are believed to act at the ventromedial and arcuate nuclei of the hypothalamus to inhibit gonadotropin-releasing hormone (GNRH)
secretion
kisspeptin has emerged as one of the
most potent secretagogues of GNRH release
Consistent with the hypothesis that obesity-mediated inhibition of kisspeptin signalling contributes to the suppression
of the HPT axis, infusion of a bioactive kisspeptin fragment has been recently shown to robustly increase LH pulsatility,
LH levels and circulating testosterone in hypotestosteronaemic men with type 2 diabetes
Figure 4
Interestingly, a recent 16-week
study of experimentally induced hypogonadism in healthy men with graded testosterone add-back either with or without concomitant
aromatase inhibitor treatment has in fact suggested that low oestradiol (but not low testosterone) may be responsible for
the hypogonadism-associated increase in total body and intra-abdominal fat mass
This does not fit with the research on receptors, specifically estrogen receptors. These studies that the authors are referencing are looking at "circulating" levels, not tissue levels.
A smaller study with a similar experimental design found that acute testosterone withdrawal reduced insulin sensitivity
independent of body weight, whereas oestradiol withdrawal had no effects
Obesity and dysglycaemia and associated comorbidities such as obstructive sleep apnoea (Hoyos et al. 2012b) are important contributors to the suppression of the HPT axis
This is supported by observational studies showing that weight gain and development
of diabetes accelerate the age-related decline in testosterone
Weight loss can reactivate the hypothalamic–pituitary–testicular axis
The hypothalamic–pituitary–testicular axis remains responsive to treatment with aromatase inhibitors or selective oestrogen
receptor modulators in obese men
Kisspeptin treatment increases LH secretion, pulse frequency and circulating testosterone levels in hypotestosteronaemic men
with type 2 diabetes
Several observational and randomised studies reviewed in Grossmann (2011) have shown that weight loss, whether by diet or surgery, leads to substantial increases in testosterone, especially in morbidly
obese men
This suggests that weight loss can lead to genuine reactivation
of the gonadal axis by reversal of obesity-associated hypothalamic suppression
There is pre-clinical and observational evidence that chronic hyperglycaemia can inhibit the HPT axis
in those men in whom glycaemic control worsened, testosterone decreased
successful weight loss combined with optimisation of glycaemic control may be sufficient to normalise circulating
testosterone levels in the majority of such men
weight loss, optimisation of diabetic
control and assiduous care of comorbidities should remain the first-line approach.
This obviously goes against marketing-based medicine
In part, the discrepant results may be due to the fact men in the Vigen cohort (Vigen et al. 2013) had a higher burden of comorbidities. Given that one (Basaria et al. 2010), but not all (Srinivas-Shankar et al. 2010), RCTs in men with a similarly high burden of comorbidities reported an increase in cardiovascular events in men randomised
to testosterone treatment (see section on Testosterone therapy: potential risks below) (Basaria et al. 2010), testosterone should be used with caution in frail men with multiple comorbidities
The retrospective, non-randomised and
non-blinded design of these studies (Shores et al. 2012, Muraleedharan et al. 2013, Vigen et al. 2013) leaves open the possibility for residual confounding and multiple other sources of bias. These have been elegantly summarised
by Wu (2012).
Effects of testosterone therapy on body composition were metabolically favourable with modest decreases in fat mass and
increases in lean body mass
This suggests that testosterone has limited effects on glucose metabolism in relatively healthy men with
only mildly reduced testosterone.
it is conceivable that
testosterone treatment may have more significant effects on glucose metabolism in uncontrolled diabetes, akin to what has
generally been shown for conventional anti-diabetic medications.
the evidence from controlled studies show that testosterone therapy consistently reduces fat mass and increases
lean body mass, but inconsistently decreases insulin resistance.
Interestingly, testosterone therapy does not consistently improve glucose metabolism despite a reduction in fat mass and an
increase in lean mass
the majority of RCTs (recently reviewed in Ng Tang Fui et al. (2013a)) showed that testosterone therapy does not reduce visceral fat
yet low T is associated with an increase in visceral adiposity--confusing!
testosterone therapy decreases SHBG
testosterone is inversely associated with total cholesterol, LDL cholesterol and triglyceride (Tg) levels, but positively
associated with HDL cholesterol levels, even if adjusted for confounders
Although observational studies show a consistent association of low testosterone with adverse lipid profiles, whether testosterone
therapy exerts beneficial effects on lipid profiles is less clear
Whereas testosterone-induced decreases in total cholesterol,
LDL cholesterol and Lpa are expected to reduce cardiovascular risk, testosterone also decreases the levels of the cardio-protective
HDL cholesterol. Therefore, the net effect of testosterone therapy on cardiovascular risk remains uncertain.
data have not shown evidence that testosterone causes prostate cancer, or that
it makes subclinical prostate cancer grow
compared with otherwise healthy young men with organic androgen deficiency, there may be increased risks in older,
obese men because of comorbidities and of decreased testosterone clearance
recent evidence that fat accumulation may be oestradiol-, rather than testosterone-dependent
Interferon therapy in men with hepatitis C was found to decrease total Testosterone and Free Androgen index at the level of the gonads; this was independent of the HPA in this study.
Normal leptin levels are critical to puberty; but in obese men, increased leptin is associated with gonadal decrease in Testosterone. It appears to occur through a decrease in 17-OH progesterone to Testosterone: suggesting an inhibitory activity in the conversion of 17-OH progesterone to Testosterone in obese men.
Leptin shown to inhibit steroid hormone synthesis in the gonads via inhibition of 17beta-HSD. This is in addition to other reports of inhibition of 17,20 lyase, adrenal cortisol inhibition, inhibition of CRF, and inhibition of LH/FSH.
Animal study from '09 found that COX2 inhibitor blunted LPS decrease in testes weight, decrease in testicular interstitial fluid, and serum Testosterone. The point here is that LPS, in this animal model, decreased gonadal weight and Testosterone production and the anti inflammatory, COX2, blunted that effect.
Only abstract available here; 11-ketotestosterone found not to be susceptible to aromatase activity as is testosterone. This was a breast cell culture study. It was found to actually inhibit cell proliferation in opposition to aromatized testosterone.
lower 25(OH)D level was significantly associated with lower total T, E2, SHBG, LH and FSH levels after adjusting for age, residence area, economic status and current smoker
association between 25(OH)D status and hypogonadism in Chinese men and confirms that this relationship is present in a large population
P metabolites produced within breast tissues might be independently active hormones functioning as cancer-promoting
or -inhibiting regulatory agents
these P metabolites function as independent pro-or anti-cancer autocrine/paracrine
hormones that regulate cell proliferation, adhesion, apoptosis and cytoskeletal, and other cell status molecules via novel
receptors located in the cell membrane and intrinsically linked to cell signaling pathways
only a fraction of all breast cancer patients
respond to this estrogen-based therapy and the response is only temporary
P serves as the precursor for the major steroid hormones (androgens, estrogens,
corticosteroids) produced by the gonadal and adrenal cortical tissues.
5α-pregnane, 5β-pregnane, and 4-pregnene metabolites of P
These P-metabolizing enzymes included 5α-reductase, 5β-reductase, 3α-hydroxysteroid oxido-reductase (3α-HSO), 3β-HSO, 20α-HSO,
20β-HSO, 6α(β)-, 11β-, 17-, and 21-hydroxylase, and C17–20-lyase
Reduction
of P to 5α-pregnanes is catalyzed by 5α-reductase and the direct 5α-reduced metabolite of P is 5α-pregnane-3,20-dione (5αP).
The 5α-reductase reaction is irreversible
The two 4-pregnenes resulting from direct P conversion are 4-pregnen-3α-ol-20-one (3αHP) and 4-pregnen-20α-ol-3-one (20αHP),
catalyzed by the actions of 3α-HSO and 20α-HSO respectively
the P-metabolizing
enzyme activities identified in human breast tissues and cell lines were: 5α-reductase, 3α-HSO, 3β-HSO, 20α-HSO, and 6α-hydroxylase
In normal breast tissue, conversion to 4-pregnenes greatly exceeded the conversion to 5α-pregnanes,
whereas in tumorous tissue, conversion to 5α-pregnanes greatly exceeded that to 4-pregnenes
The results indicated that
P 5α-reductase activity is significantly higher, whereas P 3α-HSO and 20α-HSO activities are significantly lower in tumor
than in normal tissues
he results showed that production of 5α-pregnanes was higher and that of 4-pregnenes was lower in tumorigenic (e.g. MCF-7)
than in nontumorigenic (e.g. MCF-10A) cells (Fig. 3c⇑), while differences in ER/P status did not appear to play a role
The 5α-pregnane-to-4-pregnene ratios were 7- to 20-fold higher in the tumorigenic than in the nontumorigenic cell lines
altered direction in P metabolism, and hence in metabolite ratios, was due
to significantly elevated 5α-reductase and depressed 3α- and 20α-HSO activities in breast tumor tissues and tumorigenic cells.
It appeared, therefore, that changes in P-metabolizing enzyme activities might be related to the shift toward mammary cell
tumorigenicity and neoplasia
In vivo, changes in enzyme activity can result from changes in levels of the enzyme due to changes in expression of the mRNA coding
for the enzyme, or from changes in the milieu in which the enzyme operates (such as temperature and pH, and concentrations
of cofactors, substrates, products, competitors, ions, phospholipids, and other molecules)
Overall, the enzyme activity and expression studies strongly suggest that 5α-reductase stimulation and 3α- and 20α-HSO suppression
are associated with the transition from normalcy to cancer of the breast
The level of expression of 5α-reductase is up-regulated by estradiol and P in the uterus (Minjarez et al. 2001) and by 5α-dihydrotestosterone (DHT) in the prostate
Stimulation in cell numbers was also observed when cells were treated with other 5α-pregnanes, such as 5α-pregnan-3α-ol-20-one,
5α-pregnan-20α-ol-3-one, and 5α-pregnane-3α,20α-diol, whereas other 4-pregnenes such as 20α-HP and 4-pregnene-3α,20α-diol
resulted in suppression of cell proliferation
Stimulation of cell proliferation with 5αP and inhibition with 3αHP were also observed in all other breast cell lines examined,
whether ER/P-negative (MCF-10A, MDA-MB-231) or ER/P-positive (T47D, ZR-75-1) and whether requiring estrogen for tumorigenicity
(MCF-7, T47D) or not (MDA-MB-231), or whether they are nontumorigenic (
αHP resulted in significant increases in apoptosis and decreases in mitosis, leading to significant decreases in total
cell numbers. In contrast, treatment with 5αP resulted in decreases in apoptosis and increases in mitosis.
The opposing actions of 5αP and 3αHP on both cell anchorage and proliferation strengthen the hypothesis that the direction
of P metabolism in vivo toward higher 5α-pregnane and lower 4-pregnene concentrations could promote breast neoplasia and lead to malignancy.
he effects on proliferation and adhesion were not due to P, but
due to the 5α-reduced metabolites
The studies showed that binding of 5αP or 3αHP occurs in the plasma membrane fractions, but not in the nuclear or cytosolic
compartments
separate high-specificity, high-affinity, low- capacity receptors for 5αP and
3αHP that are distinct from each other and from the well-studied nuclear/cytosolic P, estrogen, and androgen and corticosteroid
receptors
The studies thus provided the first demonstration of the existence of specific P metabolite receptors
the receptor results suggest that
the putative tumorigenic actions of 5αP may be significantly augmented by the estradiol-induced increases in 5αP binding and
decreases in 3αHP binding.
Estradiol and 5αP resulted in significant dose-dependent increases, whereas 3αHP and 20αHP each resulted in dose-dependent
decreases in total ER
In combination, estradiol + 5αP or 3αHP
+ 20αHP resulted in additive increases or decreases respectively in ER numbers.
The data suggest that the action of 5αP on breast cancer cells
involves modulation of the MAPK signaling pathway
current evidence does not appear to support the notion that increased 5α-reductase activity/
expression might significantly alter androgen influences on breast tumor growth.
both testosterone and DHT inhibit cell growth more or less to the same extent
Fantastic read on the effects of progesterone metabolism on tumor and cancer growth. Tumorigenesis is not just about the hormone, hormone balance, but about the metabolism of hormones. This is why premarin is so carcinogenic: it is primarily metabolized by the 4-OH estrone pathway.
hormones are the link between the brain and sex for men? Yes, but a little more complex than that: interaction between the immune system (inflammation) and the endocrine system (hormones).
Small study of 13 men found that weight loss following bariatric surgery resulted in improved HPA function in 10/13. Three men had resistant HPA dysfunction. Free Testosterone was followed.
Fascinating difference in the sexes. High estradiol is found to be associated with depression in men and high Testosterone is found to be associated with depression in women. The exact mechanism or strength of association is unstated.
Interesting: study finds no association between tryptophan and serotonin levels and depression. The study found no difference between 44 "depressed" perimenopausal women and 19 "without depression". Serotonin therapy of depression?? However, poor sleep and hot flashes did.