Androgen Glucuronidation in Mice: When, Where, and How.

Glucuronidation, catalyzed by UDP-glucuronosyltransferase UGT2B enzymes, is a major inactivating and elimination pathway for androgen hormones in humans. Whether Ugt2b enzymes from mice are also reactive with these hormones have never been investigated. The present study aimed at evaluating the capability of murine tissues and Ugt2b enzymes to glucuronidated androgens.

Population aging, migration, and productivity in Europe.

This paper provides a systematic, multidimensional demographic analysis of the degree to which negative economic consequences of population aging can be mitigated by changes in migration and labor-force participation. Using a microsimulation population projection model accounting for 13 individual characteristics including education and immigration-related variables, we built scenarios of future changes in labor-force participation, migration volumes, and their educational composition and speed of integration for the 28 European Union (EU) member states. We study the consequences in terms of the conventional age-dependency ratio, the labor-force dependency ratio, and the productivity-weighted labor-force dependency ratio using education as a proxy of productivity, which accounts for the fact that not all individuals are equality productive in society.

Concentration range of serum sex steroids in normal postmenopausal women and those with diagnosis of vulvovaginal atrophy.

Objective: The aim of the study was to determine the range of serum sex-related steroids in normal postmenopausal women and in women of the same age with a diagnosis of vulvovaginal atrophy (VVA).

Methods: Validated mass spectrometry-based assays coupled to gas or liquid chromatography were used over a 10-year period for steroid measurements. Serum samples were obtained in up to 1,512 women aged 55 to 65 years.

Androgens in women are essentially made from DHEA in each peripheral tissue according to intracrinology.

The objective is to review how the cell-specific amounts of intracellular androgens are all made in women from circulating dehydroepiandrosterone (DHEA) in each peripheral tissue, independently from the rest of the body. Following 500 million years of evolution, approximately three dozen cell-specific intracrine enzymes have been engineered in human peripheral tissues whereby the inactive sex steroid precursor DHEA mainly of adrenal origin is transformed into the appropriate minute intracellular amounts of androgens. These intracellular androgens are inactivated in the same cells, with no biologically significant release of active androgens in the circulation.

Science of intracrinology in postmenopausal women.

Objective: To illustrate the marked differences between classical endocrinology that distributes hormones to all tissues of the body through the bloodstream and the science of intracrinology, whereby each cell of each peripheral tissue makes a small and appropriate amount of estrogens and androgens from the inactive precursor dehydroepiandrosterone (DHEA), DHEA being mainly of adrenal origin. Because only the inactivated sex steroids are released in the blood, influence in the other tissues is avoided.

Methods: Molecular biology has been used for the identification/characterization of the steroid-forming and steroid-inactivating enzymes, whereas steroids have been measured by mass spectrometry-based assays validated according to the US Food and Drug Administration guidelines.

Multiple roles for UDP-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes in androgen metabolism and prostate cancer evolution.

In the prostate, approximately 50% of androgens are from adrenal steroids, mainly dehydroepiandrosterone (DHEA), its sulfate and androstenedione. These compounds are converted first into testosterone, and then into the active hormone dihydrotestosterone (DHT). After having activated the androgen receptor (AR), DHT is reduced into androstane-3α-DIOL (3α-DIOL) and androsterone (ADT), which are subsequently converted into 2 inactive and easily excretable metabolites: 3α-DIOL-17glucuronide (3α-DIOL-17G) and ADT-3glucuronide (ADT-3G).

Using microsimulation to reassess aging trends in Canada.

Population aging is the population issue of the XXI century and many indices are used to measure its level and pace. In Science (2010), Sanderson and Scherbov suggested improvements to the measure of elderly dependency ratio. They identified several limitations to the use of chronological age as the main variable and proposed a new index, the Adult Disability Dependency Ratio, defined as the number of adults at least 20 years old with disabilities divided by the number of similarly aged adults without disabilities.

Testosterone challenge and androgen receptor activity in relation to UGT2B17 genotypes.

Background: We investigated the androgen receptor (AR) bioluminescense response in serum and urine before and after testosterone challenge in different genotypes of the UGT2B17 enzyme, which catalyses testosterone glucuronidation.

Material And Methods: The androgen receptor activity was determined using a yeast-based bioluminescence assay. The androgens were analysed using LC-MS/MS, and the individuals were genotyped for UGT2B17 deletion polymorphism using real-time polymerase chain reaction.

Differential expression of the androgen-conjugating UGT2B15 and UGT2B17 enzymes in prostate tumor cells during cancer progression.

Context: Androgens play major roles in prostate cancer initiation and development. In prostate cells, the human uridine diphosphate-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes inactivate androgens.

Objective: We investigated in vivo how UGT2B15 and UGT2B17 expressions are affected during prostate cancer development.

Serum sex steroids measured in middle-aged European and African-Caribbean men by gas chromatography-mass spectrometry.

Background: Differences in circulating steroid hormone levels have been hypothesized to explain ethnic differences in steroid-related diseases. The aim of this study was to determine the serum levels of a wide panel of steroid hormones, both androgens and estrogens, in healthy middle-aged African-Caribbean and European men.

Design And Methods: Serum steroid hormone levels were determined in men participating in a systematic public health study funded by the French National Health Insurance system.

Correlation between circulatory, local prostatic, and intra-prostatic androgen levels.

Background: Testosterone is converted to the more potent androgen dihydrotestosterone (DHT) in the prostate. DHT and androgen metabolites are inactivated by uridine diphospho (UDP)-glucuronosyl transferase (UGT) enzymes. Here we have studied the influence of the prostate gland on the systemic levels of DHT.

Bioavailability of testosterone enanthate dependent on genetic variation in the phosphodiesterase 7B but not on the uridine 5'-diphospho-glucuronosyltransferase (UGT2B17) gene.

Objective: To study the disposition of serum testosterone and seven of its metabolites before and after 2 days of an intramuscular dose (500 mg) of testosterone enanthate in relation to the phosphodiesterase (PDE7B) and the uridine 5'-diphospho-glucuronosyltransferase (UGT2B17) genotypes.

Methods: Patients were genotyped for UGT2B17 deletion polymorphism and single nucleotide polymorphisms in the PDE7B gene. The involvement of PDE7B in hydrolysis of enanthate was assessed in human liver homogenates.

Profiling of endogenous estrogens, their precursors, and metabolites in endometrial cancer patients: association with risk and relationship to clinical characteristics.

Background: Endometrial cancer (EC) predominantly occurs after menopause and is strongly related to steroid hormones, particularly estrogens. However, the relationship between these hormones and clinical characteristics remains unaddressed.

Experimental Design: We analyzed the circulating levels of 18 steroids including adrenal precursors, androgens, estrogens, and their glucuronide metabolites, using specific and validated methods based on tandem mass spectrometry.

Plasma estrone sulfate assay in men: Comparison of radioimmunoassay, mass spectrometry coupled to gas chromatography (GC-MS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Background: Estrogens are involved in the natural history of the prostate cancer and estrone sulfate, the quantitatively main circulating plasma estrogen in men, has been associated with an aggressive form of this cancer. A convenient and accurate plasma assay of this steroid has become important.

Methods: We simultaneously assayed estrone sulfate in the plasma of one hundred men aged 30-50 years, according to LC-MS/MS, GC-MS after solvolysis of E(1)S, radioimmunoassay after a chromatographic purification step, and a direct RIA commercial kit.

Circulating estrogens in endometrial cancer cases and their relationship with tissular expression of key estrogen biosynthesis and metabolic pathways.

Background: Endometrial cancer is the most common gynecological malignancy. Estrogen exposure is strongly associated with endometrial cancer. Whereas this cancer occurs predominantly in postmenopausal women lacking estrogen production by ovaries, the conversion of adrenal androgen-estrogen precursors to estradiol (E(2)), estrone (E(1)), and its sulfate (E(1)-S) has been well documented in peripheral tissues.

Profiling endogenous serum estrogen and estrogen-glucuronides by liquid chromatography-tandem mass spectrometry.

Estrogens, namely, 17beta-estradiol (E(2)), are conjugated to glucuronides (G), and this metabolic conversion is part of their tissular-concentration control-mechanism. This inactivation process has been observed, in addition to the liver, in several estrogen-dependent tissues and the resulting polar metabolites are detected in circulation. We developed and validated a highly sensitive and specific mass spectrometry-based method to directly measure estrogen-G serum levels.

The human UGT1A3 enzyme conjugates norursodeoxycholic acid into a C23-ester glucuronide in the liver.

Norursodeoxycholic acid (norUDCA) exhibits efficient anti-cholestatic properties in an animal model of sclerosing cholangitis. norUDCA is eliminated as a C(23)-ester glucuronide (norUDCA-23G) in humans. The present study aimed at identifying the human UDP-glucuronosyltransferase (UGT) enzyme(s) involved in hepatic norUDCA glucuronidation and at evaluating the consequences of single nucleotide polymorphisms in the coding region of UGT genes on norUDCA-23G formation.

Comparable amounts of sex steroids are made outside the gonads in men and women: strong lesson for hormone therapy of prostate and breast cancer.

The objective of this study was comparison of circulating androgens and their metabolites as well as estrogens measured for the first time by a validated mass spectrometry technology in 60-80-year-old men and women of comparable age. Castration in men (n=34) reduces the total androgen pool by only about 60% as indicated by the decrease in the serum levels of the glucuronide metabolites of androgens compared to intact men (n=1302). Such data are in agreement with the 50 to 75% decrease in intraprostatic dihydrotestosterone (DHT) concentration after castration.