Group items tagged

4-hydroxyestradiol and 16α-hydroxyestrone increasing proliferation and decreasing apoptosis in a manner similar to estradiol; however, these effects were achieved only at concentrations 10-fold higher than estradiol (39). In contrast, 2-hydroxyestradiol did not have substantial proliferative or antiapoptotic effects

In our study, the associations with both 2-hydroxyestrone and 16α-hydroxyestrone were nonsignificantly inverse and we did not observe a consistent trend or significant associations between the 2-hydroxyestrone:16α-hydroxyestrone ratio and breast cancer risk

Ratios of the 3 hydroxylation pathways were not significantly associated with risk although the 2:16-pathway and 4:16-pathway ratios were suggestively inversely associated

a significant inverse association with the ratio of parent estrogens to estrogen metabolites

several potentially estrogenic and genotoxic mechanisms

Estrogen metabolites also can be genotoxic

Catechol estrogens can be oxidized into quinones and induce DNA damage directly through the formation of DNA adducts, or indirectly via redox cycling and generation of reactive oxygen species

the oxidized forms of the catechol estrogens differ in their ability to damage DNA through adducts, with oxidized 2-catechols forming stable and reversible DNA adducts and oxidized 4-catechols forming unstable adducts, which lead to depurination and mutations

2- and 4-catechols have been shown to produce reactive oxygen species and induce oxidative DNA damage

act independently from the ER

16α-Hydroxyestrone also may be genotoxic

While the catechol estrogens have estrogenic and genotoxic potential, the methylated catechol estrogens, which are catechol estrogens with one hydroxyl group methylated, have been hypothesized to lower the risk of breast cancer

The suggested mechanisms are indirect, by decreasing circulating levels of catechol estrogens and thereby the opportunity for catechols to exert genotoxic or proliferative effects, or direct, by inhibiting tumor growth and inducing apoptosis

the balance between phase I (oxidation) and phase II (methylation) metabolism of estrogen may be important in hormonally related cancer development.

Despite the estrogenic and genotoxic potential of many of the estrogen metabolites, we only observed a significantly increased breast cancer risk with one estrogen metabolite, 17-epiestriol, which has particularly strong estrogenic activity and binds to both ERα and ERβ with an affinity comparable with estradiol

some steroid hormone-induced nuclear events can occur in minutes

the genomic effects of steroid hormones take longer, with changes in gene expression occurring on the timescale of hours

Classical steroid hormone signaling occurs when hormone binds nuclear receptors (NR) in the cytoplasm, setting off a chain of genomic events that results in, among other changes, dimerization and translocation to the nucleus where the ligand-bound receptor forms a complex with coregulators to modulate gene transcription through direct interactions with a hormone response element (HRE)

NRs have been found at the plasma membrane of cells, where they can propagate signal transduction often through kinase pathways

Membrane-localized ER, PR and AR have been reported to modulate the activity of MAPK/ERK, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), nitric oxide (NO), PKC, calcium flux and increase inositol triphosphate (IP3) levels to promote cell processes including autophagy, proliferation, apoptosis, survival, differentiation, and vasodilation

ERα36, a 36kDa truncated form of ERα that lacks the transcriptional activation domains of the full-length protein. Membrane-localized ERα36 can activate pathways including protein kinase C (PKC) and/or mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to promote the progression of various cancers

G protein-coupled receptor 30 (GPR30), also referred to as G protein-coupled estrogen receptor (GPER), is a membrane-localized receptor that has been observed to respond to estrogen to activate rapid signaling

hormone-responsive G protein coupled receptor is Zip9, which androgens can activate

GPRC6A is another G protein-coupled membrane receptor that is responsive to androgen

androgen-mediated non-genomic signaling through this GPCR can modulate male fertility, hormone secretion and prostate cancer progression

non-NR proteins located at the cell surface can bind to steroid hormones and respond by eliciting rapid signaling events

Estrogens have been shown to induce rapid (i.e. seconds) calcium flux via membrane-localized ER (mER)

ER-calcium dynamics lead to activation of kinase pathways such as MAPK/ERK which can result in cellular effects like migration and proliferation

17β-estradiol (E2) has been reported to promote angiogenesis through the activation of GPER

Membrane NRs may also mediate rapid signaling through crosstalk with growth factor receptors (GFR)

A similar crosstalk occurs between the receptor tyrosine kinase insulin-related growth factor-1 receptor (IGF-IR) and ERα. Not only does IGF-IR activate ERα, but inhibition of IGF-IR downregulates estrogen-mediated ERα activity, suggesting that IGF-IR is essential for maximal ERα signaling

Further, ER activates IGF-IR pathways including MAPK

GPER is involved in the transactivation of the EGFR independent of classical ER

tight interconnection between genomic and non-genomic effects of NRs.

non-genomic pathways can also lead to genomic effects

androgen-bound AR associates with the kinase Src at the plasma membrane, activating Src which then leads to a signaling cascade through MAPK/ERK

However, Src can also increase the expression of AR target genes by the ligand-independent transactivation of AR

extranuclear steroid hormone actions can potentially reprogram nuclear NR events

estrogen modulated the expression of several genes including endothelial nitric oxide synthase (eNOS) via rapid signaling pathways

epigenetic changes can then mediate genomic events in uterine tissue and breast cancer cells

Hall and colleagues44 have reported that ER-β functions as a transdominant inhibitor of ER-α transcription and that it acts to decrease overall cellular sensitivity to estradiol

The expression of ER-β was diminished in high-grade dysplasias when compared to normal glands and lower grade lesions.

The transition from normal to low/moderate dysplastic glands in the peripheral zone was marked by the appearance of ER-β homogeneously immunostained nuclei in secretory as well as basal cells with no changes in the localization of the other receptors.

proliferative signals mediated by AR in basal cells or by ER-α and AR in stromal cells may be opposed by the purported growth-inhibitory action of ER-β25, 26, 27, 28 localized in basal cells.

The diminution of ER-β expression in high-grade dysplasias and grade 4/5 cancers may be therefore related to the alteration of DNA methylation pattern in CpG islands of the promoter, resulting in down-regulation of the receptor at the transcriptional level

based on the proposed anti-proliferative function of the receptor,25, 26, 27, 28 the presence of ER-β in secretory cells of low/moderate-grade lesions may represent a transient abortive attempt to counter growth of these cells

the attrition of receptor-positive basal cells in the high-grade dysplasias may signify a continuing loss of growth inhibitory function mediated by ER-β in these precursor lesions

Our findings in prostate therefore differ from those reported for human colon cancer in which Folley and colleagues48 demonstrated that a selective loss of ER-β protein but not receptor message expression occurs in these neoplasms

Our findings therefore differed from those of Bonkhoff and colleagues33 who found immunostaining for the receptor in high-grade dysplasias and grade 4/5 carcinomas. Using in situ hybridization these authors also reported that a high percentage of dysplasias and carcinomas in their study contained cells that expressed ER-α message

Leptin is a potent anorexigenic and catabolic hormone secreted by adipose cells that reduces food intake and increases energy expenditure

E2 not only modulates leptin receptor mRNA in the ARC and VMH, but also increases hypothalamic sensitivity to leptin, altering peripheral fat distribution

ghrelin. It acts on growth hormone secretagogue receptors (GHSR1a) located in the ARC and is a potent stimulator of food intake

It thus appears that of the two ERs, ERα plays a predominant role in the CNS regulation of lipid and carbohydrate homeostasis.

Both ERs have been identified in the ARC

Stimulation of MCH neurons increases food intake and fat accumulation while its inhibition leads to decreased food intake and reduced fat accumulation.

Both ERs have been identified in the LH

both ERs have been identified in this nucleus

The PVN is the region of the hypothalamus with the highest expression of ERβ and is reported to be weakly ERα positive

The VMH is ERα regulated

Skeletal muscle is responsible for 75% of the insulin-induced glucose uptake in the body

GLUT4 is highly expressed in muscle and represents a rate-limiting step in the insulin-induced glucose uptake

data suggest that in the physiological range, E2 is beneficial for insulin sensitivity, whereas hypo- or hyperestrogenism is related to insulin resistance

In aging female rats, E2 treatment improves glucose homeostasis mainly through its ability to increase muscle GLUT4 content on the cell membrane

It is evident that ERα and ERβ have distinct actions and that much more research is needed to clearly identify the function of each receptor in muscle.

E2 prevents accumulation of visceral fat, increases central sensitivity to leptin, increases the expression of insulin receptors in adipocytes, and decreases the lipogenic activity of lipoprotein lipase in adipose tissue

In rats, ovariectomy increases body weight, intra-abdominal fat, fasting glucose and insulin levels, and insulin resistance followed by decreased phosphorylation of AMPK and its substrate acetyl-CoA carboxylase in adipose tissue

decreased adiponectin, PPARγ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2) and increased resistin

Men with aromatase deficiency have truncal obesity, elevated blood lipids, and severe insulin resistance

Although not all studies are in agreement, polymorphisms of ERα in humans have been associated with risk factors for CVDs

Human subcutaneous and visceral adipose tissues express both ERα and ERβ, whereas only ERα mRNA has been identified in brown adipose tissue

suggesting that ERα is the main regulator of GLUT4 expression in adipose tissue

An association between testosterone and WBC count was not observed

These findings are consistent with the hypothesis that in men higher androgen concentration is anti-inflammatory, and higher estrogen concentration is pro-inflammatory.

the probability of elevated CRP concentrations (≥ 3 mg/L) decreased with higher total and calculated free testosterone concentrations, while the probability increased with higher total and calculated free estradiol concentrations

there is ample evidence supporting the immunosuppressive effect of androgens

The incidence of autoimmune diseases is higher in androgen-deficient men

Studies have shown that the induction of hypogonadism in older men is followed by a significant increase in IL-6 concentrations (Khosla et al. 2002), a potent stimulator of inflammation, and that activation of the androgen receptor exerts a direct anti-inflammatory effect

It has been suggested that the mechanisms for the immunosuppressive effect of androgens could be either a direct effect on the expression of inflammatory genes (Bellido et al. 1995; Asirvatham et al. 2006), or an indirect effect through inhibition of nuclear factor-kB activation

Estradiol is the major biologically active estrogen, and about 80% is formed in adult men from the aromatization of testosterone primarily in the adipose tissue

estrogen can stimulate the transcription factor C/EBP-β, which is involved in CRP transcription

Most prior cross-sectional studies have observed inverse associations between androgen concentrations and inflammatory biomarkers

A recent study in Chinese men showed that lower concentrations of total and calculated free testosterone were associated with higher CRP concentration

Data from the Boston Area Community Health Survey also reported inverse associations between testosterone and CRP concentrations

Total testosterone was inversely associated with WBC count (Tang et al. 2007; Schneider et al. 2009; Brand et al. 2012), but calculated free testosterone was not associated with WBC

The first trial found a decrease in CRP, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNFα) but no changes in IL-6 and IL-10 concentrations between the active treatment and placebo arms

the majority of studies in the literature have not observed statistically significant associations between estradiol and inflammatory biomarkers in men, although several of them observed point estimates in the positive direction

total testosterone and estradiol compete for binding to SHBG, and seem to have opposite effects on the concentration of inflammatory biomarkers

A small randomized controlled trial of estrogen replacement therapy in prostate cancer patients showed an increase in CRP in the active treatment group versus the comparator group

Obese men are known to have lower androgen concentrations compared to their normal-weight counterparts

The strongest suggestion of an interaction was the inverse association between androstanediol glucuronide and CRP concentrations in obese participants, while the association was positive in the non-obese

A recent Chinese cross-sectional study observed stronger inverse associations between total testosterone and CRP concentrations in individuals with a BMI of 27.5 kg/m2 or greater

our results suggest that total and calculated free testosterone are modestly inversely associated with CRP concentrations, and that total and calculated free estradiol are modestly positively associated with CRP and WBC

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

3αHP inhibited whereas 5αP-stimulated proliferation

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

Note that 5α-reductase reaction is not reversible

androgens (like other steroid hormones) promote or repress the expression of genes specifying an array of cellular proteins

some evidence suggests a high number of CAG repeats may be associated with cognitive aging

diurnal variation in testosterone levels

salivary testosterone correlated negatively with participant age and positively with CAG length variation in the AR gene

CAG repeat number varied inversely with reactivity of the ventral amygdala to facial expressions of negative affect

higher salivary testosterone was likewise associated with a greater number of AR CAG repeats

relative androgen insensitivity in ARs with a larger number of CAG repeats

Because circulating testosterone is regulated via negative feedback through the hypothalamic-pituitary-gonadal axis, diminished androgen sensitivity at higher CAG repeat lengths may reduce feedback suppression of luteinizing hormone (LH). LH would then be maintained at higher levels, in turn promoting higher testosterone production

Testosterone up-regulates AVP expression in the amygdala

Oxytocin exerts an inhibitory influence on AVP expression in the central amygdala, and the synthesis of oxytocin is mediated by estrogen and estrogen receptors

Researchers tried to examine whether serum total or free testosterone would be a better/more reliable choice when studying the effect of testosterone. The results were mixed. Some reported significant associations of both serum total and free testosterone level with clinical parameters25, whereas others reported that only serum free testosterone26 or only serum total testosterone6 showed significant associations.

−0.124 nmol/L/year in serum total testosterone

In experimental studies, androgen receptor knockout mice developed significant insulin resistance rapidly

In mouse models, testosterone promoted differentiation of pluripotent stem cells to the myogenic lineage

testosterone decreased insulin resistance by enhancing catecholamine induced lipolysis in vitro, and reducing lipoprotein lipase activity and triglyceride uptake in human abdominal tissue in vivo

by promoting lipolysis and myogenesis, testosterone might lead to improved insulin resistance

testosterone regulated skeletal muscle genes involved in glucose metabolism that led to decreased systemic insulin resistance

In the liver, hepatic androgen receptor signaling inhibited development of insulin resistance in mice

independent and inverse association of testosterone with hepatic steatosis shown in a cross-sectional study carried out in humans

In short, androgen improves insulin resistance by changing body composition and reducing body fat.

Although a low serum testosterone level could contribute to the development of obesity and type 2 diabetes through changes in body composition, obesity might also alter the metabolism of testosterone

In obese men, the peripheral conversion from testosterone to estrogen could attenuate the amplitude of luteinizing hormone pulses and centrally inhibit testosterone production

leptin, an adipokine, has been shown to be inversely correlated with serum testosterone level in men

Leydig cells expressed leptin receptors and leptin has been shown to inhibit testosterone secretion, suggesting a role of obesity and leptin in the pathogenesis of low testosterone

Baltimore Longitudinal Study of Aging (BLSA) cohort made up of 3,565 middle-class, mostly Caucasian men from the USA, the incidence of low serum total testosterone increased from approximately 20% of men aged over 60 years, 30% over 70 years, to 50% over 80 years-of-age

30–44% sex hormone binding globulin (SHBG)-bound testosterone and 54–68% albumin-bound testosterone

As the binding of testosterone to albumin is non-specific and therefore not tight, the sum of free and albumin-bound testosterone is named bioavailable testosterone, which reflects the hormone available at the cellular level

Serum total testosterone is composed of 0.5–3.0% of free testosterone unbound to plasma proteins

alterations in SHBG concentration might affect total serum testosterone level without altering free or bioavailable testosterone

listed in Table​T

A significant, independent and longitudinal effect of age on testosterone has been observed with an average change of −0.124 nmol/L/year in serum total testosterone28. The same trend has been shown in Europe and Australia

Asian men residing in HK and Japan, but not those living in the USA, had 20% higher serum total testosterone than in Caucasians living in the USA, as shown in a large multinational observational prospective cohort of the Osteoporotic Fractures in Men Study

subjects with chronic diseases consistently had a 10–15% lower level compared with age-matched healthy subjects

In Caucasians, the mean serum total testosterone level for men in large epidemiological studies has been reported to range from 15.1 to 16.6 nmol/L

Asians, higher values, ranging from 18.1 to 19.1 nmol/L, were seen in Korea and Japan

Chinese middle-aged men reported a similar mean serum testosterone level of 17.1 nmol/L in 179 men who had a family history of type 2 diabetes and 17.8 nmol/L in 128 men who had no family history of type 2 diabetes

The reduction of total testosterone was 0.4% per year in both groups

HK involving a cohort of 1,489 community-dwelling men with a mean age of 72 years, a mean serum total testosterone of 19.0 nmol/L was reported

pro-inflammatory factors, such as tumor necrosis factor-α in the testes, could locally inhibit testosterone biosynthesis in Leydig cells47, and testosterone treatment in men was shown to reduce the level of tumor necrosis factor-α

In Asians, a genetic deletion polymorphism of uridine diphosphate-glucuronosyltransferase UGT2B17 was associated with reduced androgen glucuronidation. This resulted in higher level of active androgen in Asians as compared to Caucasians, as Caucasians' androgen would be glucuronidated into inactive forms faster.

Compared with Caucasians, the frequency of this deletion polymorphism of UGT2B17 was 22-fold higher in Asian subjects

Other researchers have suggested that environmental, but not genetic, factors influenced serum total testosterone

The basal and ligand-induced activity of the AR is inversely associated with the length of the CAG repeat chain

In the European Male Aging Study, increased estrogen/androgen ratio in association with longer AR CAG repeat was observed

a smaller number of AR CAG repeat had been shown to be associated with benign prostate hypertrophy and faster prostate growth during testosterone treatment

In India, men with CAG ≤19 had increased risk of prostate cancer

the odds of having a short CAG repeat (≤17) were substantially higher in patients with lymph node-positive prostate cancer than in those with lymph node-negative disease or in the general population

assessing the polymorphism at the AR level could be a potential tool towards individualized assessment and treatment of hypogonadism.

In elderly men, there was reduced testicular response to gonadotropins with suppressed and altered pulsatility of the hypothalamic pulse generator

a significant, independent and longitudinal effect of age on serum total testosterone level had been observed

A significant graded inverse association between serum testosterone level and insulin levels independent of age has also been reported in Caucasian men

Low testosterone is commonly associated with a high prevalence of MES

most studies showed that changes in serum testosterone level led to changes in body composition, insulin resistance and the presence of MES, the reverse might also be possible

MES predicted a 2.6-fold increased risk of development of low serum testosterone level independent of age, smoking and other potential confounders

Other prospective studies have shown that development of MES accelerated the age-related decline in serum testosterone level

In men with type 2 diabetes, changes in serum testosterone level over time correlated inversely with changes in insulin resistance

weight loss by either diet control or bariatric surgery led to a substantial increase in total testosterone, especially in morbidly obese men, and the rise in serum testosterone level was proportional to the amount of weight lost

To date, published clinical trials are small, of short duration and often used pharmacological, not physiological, doses of testosterone

In the population-based Osteoporotic Fractures in Men Study cohort from Sweden, men in the highest quartile of serum testosterone level had the lowest risk of cardiovascular events compared with men in the other three quartiles (hazard ratio [HR] 0.70

low serum total testosterone was associated with a significant fourfold higher risk of cardiovascular events when comparing men from the lowest testosterone tertile with those in the highest tertile

Shores et al. were the first to report that low serum testosterone level, including both serum total and free testosterone, was associated with increased mortality

low serum total testosterone predicted increased risk of cardiovascular mortality with a HR of 1.38

low serum total testosterone increased all-cause (HR 1.35, 95% CI 1.13–1.62, P < 0.001) and cardiovascular mortality (HR 1.25

European Association for the Study of Diabetes 2013 suggested there was an inverse relationship between serum testosterone level and acute myocardial infarction

Diabetic men in the highest quartile of serum total testosterone had a significantly reduced risk of acute MI when compared with those in the lower quartiles

serum total testosterone level in the middle two quartiles at baseline predicted reduced incidence of death compared with having the highest and lowest levels

On the whole, prospective epidemiological data do not support the hypothesis that the 2-hydroxyestrogen pathway is protective, and the 16α-hydroxyestrogen pathway harmful, in hormone-dependent cancers

Both 2- and 4-hydroxyestrogens are catecholestrogens, and it has been suggested that catecholestrogens increase risk of oestrogen-mediated cancers through direct genotoxic effects, rather than through stimulation of cell proliferation via binding to oestrogen receptors

the evidence is stronger for 4-hydroxyestrogens than for 2-hydroxyestrogens

a significant increase in risk of breast cancer with levels of 2-OHE1 has also been reported previously, although it was limited to hormone receptor-negative tumours

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

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.

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

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

The risk of developing PC seems to be related to the diet

In the human prostate, ERβ is expressed in the basal epithelial cells and AR in the luminal epithelium.

For many years, DHT was considered to be the main hormone guiding prostate development and function. However, the idea was challenged when in 2001 Mahendroo et al. showed that mice in which both forms of 5α-reductase had been inactivated, have a normal functional prostate [50]. The question was then raised as to what is the real function of DHT in the prostate. In 1989 we hypothesized that DHT is a precursor of an oestrogen, 5α-androstane-3β,17β-diol (3β-Adiol) and that physiological levels of an oestrogen could be produced in the total absence of aromatase [51]. We later demonstrated that 3β-Adiol is abundant in the prostate and is a good natural ligand for ERβ

The overall effect of oestrogens in the immune system is determined by a balance between ERα and ERβ signalling

The hypothesis of our group is that ERβ plays an important role in regulating the differentiation of pluripotent haematopoietic progenitor cells whereas ERα induces proliferation

In tissues and cell lines of mammary epithelium for example, it has been noticed that E2 in the presence of ERα elicits proliferation, but in the presence of ERβ it inhibits proliferation

ERα and ERβ have distinctive tissue distributions and to the great surprise of endocrinologists [7] many tissues previously thought to be ‘oestrogen-insensitive tissues’ were found to be ERβ positive and oestrogen sensitive. The most notable of the ERα-negative ERβ-abundant tissues were the epithelium of the rodent ventral prostate [8], the granulosa cells of the ovaries [9] and the parenchyma of the lungs

insulin is an important inhibitor of the synthesis of SHBG

no correlation between leptin and SHBG levels

SHBG reduction in obesity is a minor determinant of lowered androgen levels

SHBG can explain only up to 3% of the correlation

testicular T de novo production is impaired in obese men and that leptin seems to be the best hormonal predictor of this blunted response to LH stimulation

The low basal 17-OH-P levels found in massively obese men are consistent with a global impairment of Leydig cell steroidogenic function in this group of subjects.

These findings indicate that obese men have a FM-related defect in the enzymatic conversion of 17-OH-P to T, which is revealed by hCG stimulation.

Other studies have investigated the adrenal function in male obesity and have shown that basal cortisol and 17-OH-progesterone levels tend to decrease with the increase in the degree of obesity

High E2 can inhibit the expression and activity of the 17,20-lyase and may be responsible for this steroidogenic lesion

However, stimulated E2 levels were not higher in the obese than in controls, excluding the fact that the lower androgen response was due to an increased aromatization of T to E2 and that estrogens have a major role in the observed defect of 17,20-lyase activity in obese men.

the percentage increase in the 17-OH-progesterone to T molar ratio paralleled the increase in leptin levels of obese men

Multiple regression analysis indicated that the best hormonal predictor of the obesity-related reduction in T and FT basal levels and androgen changes after hCG stimulation was serum leptin concentration

insulin has no negative influences on androgen production in obese men

insulin is known to have stimulatory actions on T production that have been demonstrated in obese and normal weight men (57) and in Leydig cells in culture

the negative correlation between insulin and basal T can be partly explained by the inhibitory action of insulin on SHBG production

hypogonadal men have higher circulating leptin levels compared with hypogonadal patients under effective androgen substitution therapy

The impaired androgen response to LH stimulus was due to a defect in the enzymatic conversion of 17-OH-progesterone to T, which was disclosed by a leptin-related increase in 17-OH-progesterone to T ratio

Estrogens, which are inhibitory modulators of LH pulsatility and bioactivity