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
The levels of LH in the ibuprofen group had increased by 23% after 14 d of administration
This increase was even more pronounced at 44 d, at 33%
We found an 18% decrease (P = 0.056) in the ibuprofen group compared with the placebo group after 14 d (Fig. 1A) and a 23% decrease (P = 0.02) after 44 d (Fig. 1C). Taken together, these in vivo data suggest that ibuprofen induced a state of compensated hypogonadism during the trial,
which occurred as early as 14 d and was maintained until the end of the trial at 44 d
We first investigated testosterone production after 24 and 48 h of ibuprofen
exposure to assess its effects on Leydig cell steroidogenesis. Inhibition of testosterone levels was significant and dose-dependent
(β = −0.405, P = 0.01 at 24 h and β = −0.664, P < 0.0001 at 48 h) (Fig. 2A) and was augmented over time
The AMH data show that the hypogonadism affected not only Leydig cells but also Sertoli cells and also occurred as early
as 14 d of administration
Sertoli cell activity showed that AMH levels decreased significantly with ibuprofen
administration, by 9% (P = 0.02) after 14 d (Fig. 1B) and by 7% (P = 0.05) after 44 d compared with the placebo group
Examination of the effect of ibuprofen exposure on both the ∆4 and ∆5 steroid pathways (Fig. 2B) showed that it generally inhibited all steroids from pregnenolone down to testosterone and 17β-estradiol; the production
of each steroid measured decreased at doses of 10−5–10−4 M. Under control conditions, production of androstenediol and dehydroepiandrosterone (DHEA) was below the limit of detection
except in one experiment with DHEA
Measuring the mRNA expression of genes involved in steroidogenesis in vitro showed that ibuprofen had a profound inhibitory
effect on the expression of these genes (Fig. 3 B–D), consistent with that seen above in our ex vivo organ model. Taken together, these data examining effects on the endocrine
cells confirm that ibuprofen-induced changes in the transcriptional machinery were the likely reason for the inhibition of
steroidogenesis.
Suppression of gene expression concerned the initial conversion of cholesterol to the final testosterone synthesis. Hence,
expression of genes involved in cholesterol transport to the Leydig cell mitochondria was impaired
A previous study reported
androsterone levels decreased by 63% among men receiving 400 mg of ibuprofen every 6 h for 4 wk
We next examined the gene expression involved in testicular steroidogenesis ex vivo and found that levels of expression of
every gene that we studied except CYP19A1 decreased after exposure for 48 h compared with controls
the changes in gene expression indicate that the transcriptional machinery behind the endocrine action
of Leydig cells was most likely impaired by ibuprofen exposure.
Together, these data show that ibuprofen also directly impairs Sertoli cell function ex vivo by inhibiting transcription
ibuprofen use in men led to (i) elevation of LH; (ii) a decreased testosterone/LH ratio and, to a lesser degree, a decreased inhibin B/FSH ratio; and (iii) a reduction in the levels of the Sertoli cell hormone AMH
The decrease in the free testosterone/LH ratio resulted primarily
from the increased LH levels, revealing that testicular responsiveness to gonadotropins likely declined during the ibuprofen
exposure. Our data from the ex vivo experiments support this notion, indicating that the observed elevation in LH resulted
from ibuprofen’s direct antiandrogenic action
AMH levels were consistently suppressed by ibuprofen both in vivo and ex vivo, indicating that this hormone is uncoupled from
gonadotropins in adult men. The ibuprofen suppression of AMH further demonstrated that the analgesic targeted not only the
Leydig cells but also the Sertoli cells, a feature encountered not only in the human adult testis but also in the fetal testis
a chemical compound, through its effects on the signaling
compounds, can result in changes in the testis at gene level, resulting in perturbations at higher physiological levels in
the adult human
The analgesics acetaminophen/paracetamol and ibuprofen have previously been shown to inhibit the postexercise
response in muscles by repressing transcription
Previous ex vivo studies on adult testis have indeed pointed to an antiandrogenicity, only on Leydig cells, of phthalates
(41), aspirin, indomethacin (42), and bisphenol A (BPA) and its analogs
ibuprofen’s effects were not restricted to Leydig and Sertoli cells, as data showed that the expression of genes
in peritubular cells was also affected
short-term
exposure
In the clinical setting, compromised Leydig cell function resulting in increased insensitivity to LH is defined as compensated
hypogonadism (4), an entity associated with all-cause mortality
compensated hypogonadic men present with an increased likelihood of reproductive, cognitive, and physical symptoms
an inverse relationship was recently reported between endurance exercise training and male sexual libido
AMH concentrations are lower in seminal plasma from patients with azoospermia than
from men with normal sperm levels
inhibin B is a key clinical marker of reproductive health (32). The function of AMH, also secreted by Sertoli cells, and its regulation through FSH remain unclear in men
the striking dual effect of ibuprofen observed here on both Leydig and Sertoli cells makes this NSAID the chemical
compound, of all the chemical classes considered, with the broadest endocrine-disturbing properties identified so far in men.
after administration of 600 mg of ibuprofen to healthy
volunteers