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Approximately 0.3% of testosterone is converted into estradiol by aromatase (CYP19A1)

the recommendation for injectable testosterone esters is to check the serum concentration midway between injections

it is recommended for serum testosterone to be evaluated 3 to 12 hours after application of the transdermal patch

testosterone concentrations should be checked 2–3 months after initiation of therapy and after adjusting the dose

a study from 1989 utilizing testosterone transdermally containing 5, 10, or 15 mg of testosterone showed that peak concentrations of testosterone were achieved 3 to 8 hours after scrotal application in hypogonadal men

It is used for many medications and has the advantage of high bioavailability, absence of hepatic first pass metabolism, increased therapeutic efficacy, and steadiness of plasma concentrations of the drug

evaluate serum testosterone at the end of the dosing interval for testosterone pellets

increased amount of fat leads to increased extragonadal aromatase activity, resulting in increased concentrations of estradiol. High circulating concentrations of estradiol down regulate the HPG axis and decrease the amount of circulating testosterone

Up to 80% of plasma estradiol originates from aromatization of testosterone and less than 20% of estradiol in the circulation is secreted by the testes

A PSA concentration, digital rectal examination, and hematocrit should be performed at baseline and at 3 months, 6 months, then yearly after TRT is initiated.

measure serum testosterone any time after the patient has been on treatment with gel for at least 1 week

If the hematocrit rises above 54%, treatment should be discontinued

elderly men having higher estradiol serum concentrations than postmenopausal women

Other factors that have been considered include: maternally derived antibodies, maternal infection, heavy metal exposure, folic acid supplementation, epigenetics, measles, mumps, rubella vaccination, and even electromagnetic radiation.

female gender may predict greater tic severity in adulthood

male gender is a major risk factor for TS (with a male:female prevalence ratio estimated at ~4:1)

the typical age of onset coincides with adrenarche (6–7 years old); symptoms increase in severity until the beginning of puberty (12 years old) and then undergo a spontaneous amelioration, which becomes apparent with the end of puberty (at 18–19 years of age)

TS is diagnosed later in females than males

ample evidence supports the involvement of DAergic dysfunctions in TS

a number of clinical observations showed that tics in TS patients could be exacerbated by anabolic androgens

steroidogenic enzymes and androgen receptors may serve as putative therapeutic targets for this disorder

Unlike males, tic severity is typically increased after puberty in females

26% of females were found to experience exacerbation of tics in the estrogenic phase of the menstrual cycle, and this phenomenon was found to be correlated with increased tic severity at menarche

biochemical hallmark of adrenarche is the acquisition of 17,20 lyase activity by cytochrome P450 C17 (CYP17A1)

increased synthesis of dehydroepiandrosterone (DHEA) and androstenedione, which leads to the growth of axillary and pubic hair as well as enhancement in the oiliness of the skin

leading to enhancement of interleukin-12 secretion and natural killer cell function

Helixor VA preparations

A multivariable GEE model indicated that the odds for patients experiencing an AE following mAb therapy were nearly 5 times higher compared with that for mAb plus VA

VA preparations (Iscador Ltd) did not inhibit chemotherapy-induced cytostasis or cytotoxicity and showed an additive inhibitory effect at higher concentrations of VA.

previous in vitro investigations have shown that VA preparations have either no or minor effects on a range of CYPs, suggesting that VA-drug interactions based on drug metabolism are unlikely

mAb do not undergo hepatic metabolism but undergo proteolytic catabolism throughout the body

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

ibuprofen displayed broad transcription-repression abilities involving steroidogenesis, peptide hormones, and prostaglandin synthesis

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

14 d or at the last day of administration at 44 d