Hypogonadism may be defined either as serum concentration of T (either total T, bioavailable T or free T) or as low T plus symptoms of hypogonadism
The Baltimore Longitudinal Study on Aging reported the incidence of total serum T < 325 ng/dL to be 20% for men in their 60s, 30% for men in their 70s and 50% for men over 80
The Massachusetts Aging Male Study reported that 12.3% of men aged 40 to 70 had a total serum T of < 200 ng/dL with 3 or more symptoms of hypogonadism
The Boston Area Community Health Study reported that 5.6% of men aged 30 to 70 were hypogonadal, as defined by total serum T < 300 ng/dL; or, free serum T < 5 ng/dL plus 3 or more symptoms of hypogonadism
In a health screening project among 819 men in Taiwan, the prevalence of hypogonadism (total serum T < 300 ng/dL) ranged from 16.5% for men in their 40s, 23.0% for men in their 50s, 28.9% for men in their 60s, and 37.2% for men older than 70 years of age
The prevalence of hypogonadism among men in Taiwan is higher than the prevalence reported in the Massachusetts Male Aging Study
CAG repeat sequence, within the androgen receptor (AR). Rajender et al[12] reviewed over 30 studies on the AR trinucleotide repeat and infertility
suggestion that CAG repeat length may determine androgen responsiveness, this issue is not clearly settled
reported prevalence of low T in older men range from 5.6% to 50%
Those in the hypogonadal group (n = 4269) had direct health care costs, that exceeded the eugonadal group (n = 4269) by an average of $7100 over the course of the observation window
higher economic burden and presence of co-morbidities for hypogonadism
minor to moderate improvements in lean mass and muscle strength
increased bone mineral density
modest enhancement in sexual function
reduced adiposity
lessening of depressive symptoms
Meta-analyses of clinical TRT trials as of 2010 have identified three major adverse events resulting from TRT: (1) polycythemia; (2) an increase in prostate-related events; and (3) and a slight reduction in serum high-density lipoprotein (HDL) cholesterol
polycythemia (> 3.5-fold increase in risk
TRT produced a 40% prostate enlargement in older hypogonadal male Veterans over 12 mo
no published analysis has reported measurable increases in prostate cancer risk or Gleason score in men undergoing TRT, or in hypogonadal men with a history of prostate cancer undergoing TRT
the prostate which highly expresses the type II 5α-reductase enzyme. Inhibition of this enzyme via finasteride (a type II 5α-reductase inhibitor) or dutasteride (a dual type I and II 5α-reductase inhibitor) reduces circulating DHT 50%-75% and > 90%, respectively[47], and reduces prostate mass[48] and prostate cancer risk
Normally estradiol partially regulates testosterone levels, at the hypothalamus, blunting LH and FSH release from the pituitary. As a selective estrogen receptor modulator, CC interrupts this pathway, and consequently there is a greater stimulation for the production of testosterone in Leydig cells
The majority of the gene expression changes reported here are only induced by DHT and testosterone, and not by estradiol, indicating that in adolescent males androgen receptor, not ERα, activation is critical for these responses
It is less clear whether ERβ is involved or not as DHT, via conversion to 3β-diol has a high affinity for ERβ
the testosterone-induced, AR-driven modulation of molecular indices of dopamine responsivity of the nigrostriatal pathway may involve regulation of dopamine feedback inhibition in the somatodendritic field and post-synaptic dopamine action in the terminal field.
Animal study finds that Bisphenol A exposure in utero has profound different effects in male offspring versus female offspring. In the male offspring there appears to be an up regulation of the HPA axis. The opposite appears true in the female off spring. Additionally, the receptors are effected differently as well.
Study points to association of low Estradiol and spermatogenesis in males in infertile couples. The authors eluded to the association of low Estradiol with low Testosterone, and BMI which is the likely etiology. Low BMI will result in low aromatase activity. For men, the majority of Estradiol production occurs from Testosterone via aromatase activity. Estradiol likely exists in a "U" shaped pattern of benefit: to low hinders optimal physiologic function and contributes to inflammation and disease in men.
really interesting abstract. Bisphenol A (BPA) is a xenoestrogen. This animal study finds that BPA down regulated ER-beta in the brains of male rats. It also blocked the production of GABA(A)alpha 2 receptor. These long term effects were evident in anxiety and depression in adult mice.
Pregnancy exposure would set up an ER-alpha dominance in the male brain increasing risk of continuous ER alpha stim.
Total serum testosterone consists of free testosterone (2%–3%), testosterone bound to sex hormone binding globulin (SHBG) (45%) and testosterone bound to other proteins (mainly albumin −50%)
Testosterone binds only loosely to albumin and so this testosterone as well as free testosterone is available to tissues and is termed bioavailable testosterone
Testosterone bound to SHBG is tightly bound and is biologically inactive
Bioavailable and free testosterone are known to correlate better than total testosterone with clinical sequelae of androgenization such as bone mineral density and muscle strength
peak levels seen in the morning following sleep, which can be maintained into the seventh decade
Samples should always be taken in the morning before 11 am
The reliable measurement of serum free testosterone requires equilibrium dialysis. This is not appropriate for clinical use as it is very time consuming and therefore expensive.
With increasing age, a greater number of men have total testosterone levels just below the normal range or in the low-normal range. In these patients total testosterone can be an unreliable indicator of hypogonadal status.
It is advised that at least two serum testosterone measurements, taken before 11 am on different mornings, are necessary to confirm the diagnosis.
Patients with serum total testosterone consistently below 8 nmol/l invariably demonstrate the clinical syndrome of hypogonadism and are likely to benefit from treatment. Patients with serum total testosterone in the range 8–12 nmol/l often have symptoms attributable to hypogonadism and it may be decided to offer either a clinical trial of testosterone treatment or to make further efforts to define serum bioavailable or free testosterone and then reconsider treatment. Patients with serum total testosterone persistently above 12 nmol/l do not have hypogonadism and symptoms are likely to be due to other disease states or ageing per se so testosterone treatment is not indicated.
Total testosterone levels fall at an average of 1.6% per year whilst free and bioavailable levels fall by 2%–3% per year.
With advancing age there is also a reduction in androgen receptor concentration in some target tissues and this may contribute to the clinical syndrome of LOH
Metabolic clearance declines with age
Gonadotrophin levels rise during aging (Feldman et al 2002) and testicular secretory responses to recombinant human chorionic gonadotrophin (hCG) are reduced
There are changes in the lutenising hormone (LH) production which consist of decreased LH pulse frequency and amplitude, (Veldhuis et al 1992; Pincus et al 1997) although pituitary production of LH in response to pharmacological stimulation with exogenous GnRH analogues is preserved
the decreases in testosterone levels with aging seem to reflect changes at all levels of the hypothalamic-pituitary-testicular axis
Circulating testosterone (T) in men declines progressively by 0.4–2% per year from the third decade onward
late-onset hypogonadism (LOH) (6, 7), whereas others have used various terms including andropause, male menopause, and androgen deficiency syndrome of the aging male.
Many pesticides function as androgen receptor antagonists. Others as Xenoestrogens. Estrogen-like toxins and androgen receptor antagonists...a potent cocktail to disrupt male androgen signaling.
lower levels of SHBG and serum testosterone were found in more recently born men. Preceding generations of men produced higher testosterone levels than men born in more recent generations.
Study finds that inhibition of aromatase activity in diabetic male rats provided renal protection. There has been debate about the effects of testosterone therapy on the renal system. However, I propose that aromatase activity and conversion to estrogen is the negative effects of Testosterone. Other than over dosing men. Though this is a rat study, this study does support the theory.
SHBG decreases in response to androgens, and in the presence of hypothyroidism, and insulin resistance.
Plasma SHBG levels tend to increase with increasing age
The apparent metabolic clearance rate of testosterone is decreased in elderly as compared to younger men
Testosterone circulates predominantly bound to the plasma proteins SHBG and albumin, with high and low affinity respectively
Testosterone is secreted in a pulsatile fashion
Current clinical guidelines suggest at least two measurements
In adult men, there is a well-documented diurnal variation (particularly in younger subjects) in testosterone levels, which are highest in the early morning and progressively decline throughout the day to a nadir in the evening
In older men, the diurnal variation is blunted
it is standard practice for samples to be obtained between 0800 and 1100 h.
Testosterone and DHEA decline, whereas LH, FSH, and SHBG rise
DHT remains constant despite the decline of its precursor testosterone
Longitudinal studies show an average annual decline of 1–2% total testosterone levels, with decline in free testosterone more rapid because of increases in SHBG with aging
Massachusetts Male Aging Study (MMAS) data show DHEA, DHEAS, and Ae declining at 2–3% per year
DHT showed no cross-sectional age trend
Androstanediol glucuronide (AAG) declined cross-sectionally with age in the MMAS sample, at 0.6% per year
The EMAS data show that, consistent with the longitudinal findings of MMAS (Figure 1), the core hormonal pattern with increasing age is suggestive of incipient primary testicular dysfunction with maintained total testosterone and progressively blunted free testosterone associated with higher LH
This author proves the point in the review of these two studies, that TT may remain constant in aging men, however, FT drops.
obesity impairs hypothalamic/pituitary function
Androgen deprivation in men with prostate cancer has been associated with increased insulin resistance, worse glycemic control, and a significant increase in risk of incident diabetes
Low serum testosterone is associated with the development of metabolic syndrome 116, 117 and type 2 diabetes. 118 SHBG has been inversely correlated with type 2 diabetes
Improvement in insulin sensitivity with testosterone treatment has been reported in healthy 121 and diabetic 122 adult men
In studies conducted in men with central adiposity, testosterone has been shown to inhibit lipoprotein lipase activity in abdominal adipose tissue leading to decreased triglyceride uptake in central fat depots. 123
E2 and the inflammatory adipocytokines tumour necrosis factor α (TNFα) and interleukin 6 (IL6) inhibit hypothalamic production
of GNRH and subsequent release of LH and FSH from the pituitary
Leptin, an adipose-derived hormone with a well-known role
in regulation of body weight and food intake, also induces LH release under normal conditions via stimulation of hypothalamic
GNRH neurons
In human obesity, whereby adipocytes are producing elevated amounts of leptin, the hypothalamic–pituitary axis becomes
leptin resistant
there is evidence from animal studies
that leptin resistance, inflammation and oestrogens inhibit neuronal release of kisspeptin
Beyond hypothalamic action, leptin also directly inhibits the stimulatory action of gonadotrophins on the Leydig cells
of the testis to decrease testosterone production; therefore, elevated leptin levels in obesity may further diminish androgen
status
Prostate cancer patients with pre-existing T2DM show a further deterioration of insulin resistance and worsening of diabetic
control following ADT
ADT for the treatment of prostatic carcinoma in some large epidemiological studies has been shown to be associated with an
increased risk of developing MetS and T2DM
Non-diabetic men undergoing androgen ablation show increased occurrence of new-onset diabetes and demonstrate elevated
insulin levels and worsening glycaemic control
increasing insulin resistance assessed by glucose tolerence test and hypoglycemic clamp was shown to be associated
with a decrease in Leydig cell testosterone secretion in men
The response to testosterone replacement of insulin sensitivity is in part dependent on the androgen receptor (AR)
Low levels of testosterone have been associated with an atherogenic lipoprotein profile, characterised by high LDL and triglyceride
levels
a positive correlation between serum testosterone and HDL has been reported in both healthy and diabetic
men
up to 70% of the body's insulin sensitivity is accounted for by muscle
Testosterone deficiency is associated with a decrease in lean body mass
relative muscle mass is inversely associated
with insulin resistance and pre-diabetes
GLUT4 and IRS1 were up-regulated in cultured adipocytes and skeletal
muscle cells following testosterone treatment at low dose and short-time incubations
local conversion of testosterone to
DHT and activation of AR may be important for glucose uptake
inverse correlation between testosterone levels and adverse mitochondrial function
orchidectomy of male Wistar rats and associated testosterone deficiency induced increased absorption of glucose
from the intestine
(Kelley & Mandarino 2000). Frederiksen et al. (2012a) recently demonstrated that testosterone may influence components of metabolic flexibility as 6 months of transdermal testosterone
treatment in aging men with low–normal bioavailable testosterone levels increased lipid oxidation and decreased glucose oxidation
during the fasting state.
Decreased lipid oxidation coupled with diet-induced chronic FA elevation is linked to increased accumulation of myocellular
lipid, in particular diacylglycerol and/or ceramide in myocytes
In
the Chang human adult liver cell line, insulin receptor mRNA expression was significantly increased following exposure to
testosterone
Testosterone deprivation via castration of male rats led to decreased expression of Glut4 in liver tissue, as well as adipose and muscle
oestrogen was found to increase the expression of insulin receptors in insulin-resistant HepG2 human liver cell
line
FFA decrease hepatic
insulin binding and extraction, increase hepatic gluconeogenesis and increase hepatic insulin resistance.
Only one, albeit large-scale,
population-based cross-sectional study reports an association between low serum testosterone concentrations and hepatic steatosis
in men (Völzke et al. 2010)
This suggests that testosterone may confer some of its beneficial effects on hepatic lipid metabolism via conversion to
E2 and subsequent activation of ERα.
hypogonadal men exhibiting a reduced lean body mass and an increased fat mass, abdominal or central obesity
visceral adipose tissue was inversely correlated with
bioavailable testosterone
there was no change in visceral fat mass in aged men with low testosterone levels
following 6 months of transdermal TRT, yet subcutaneous fat mass was significantly reduced in both the thigh and the abdominal
areas when analysed by MRI (Frederiksen et al. 2012b)
ADT of prostate cancer patients increased both visceral and subcutaneous abdominal fat in a 12-month prospective
observational study (Hamilton et al. 2011)
Catecholamines are the major lipolysis regulating hormones in man and
regulate adipocyte lipolysis through activation of adenylate cyclase to produce cAMP
deficiency of androgen action decreases lipolysis and is primarily
responsible for the induction of obesity (Yanase et al. 2008)
may be some regional differences in the action of testosterone on
subcutaneous and visceral adipose function
proinflammatory adipocytokines IL1, IL6 and TNFα are increased in obesity with a downstream effect that stimulates
liver production of CRP
observational evidence suggests that
IL1β, IL6, TNFα and CRP are inversely associated with serum testosterone levels in patients
TRT has been reported to significantly reduce these proinflammatory mediators
This suggests a role for AR in the metabolic actions of testosterone on fat accumulation and adipose tissue inflammatory
response
testosterone treatment may have beneficial effects on preventing the pathogenesis of obesity by inhibiting adipogenesis,
decreasing triglyceride uptake and storage, increasing lipolysis, influencing lipoprotein content and function and may directly
reduce fat mass and increase muscle mass
Early interventional
studies suggest that TRT in hypogonadal men with T2DM and/or MetS has beneficial effects on lipids, adiposity and parameters
of insulin sensitivity and glucose control
Evidence that whole-body insulin sensitivity is reduced in testosterone deficiency and increases with testosterone replacement
supports a key role of this hormone in glucose and lipid metabolism
Impaired insulin sensitivity in these three tissues is
characterised by defects in insulin-stimulated glucose transport activity, in particular into skeletal muscle, impaired insulin-mediated
inhibition of hepatic glucose production and stimulation of glycogen synthesis in liver, and a reduced ability of insulin
to inhibit lipolysis in adipose tissue