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. The results show that in terms of the more sophisticated ratios, population aging looks less daunting than when only considering age structure. In terms of policy options, lifting labor-force participation among the general population as in Sweden, and education-selective migration if accompanied by high integration, could even improve economic dependency. On the other hand, high immigration volumes combined with both low education and integration leads to increasing economic dependency. This shows the high stakes involved with integration outcomes under high migration volumes.

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. RESULTS: The serum concentrations of testosterone and dihydrotestosterone (DHT) were markedly elevated on days 2 and 4 and were still above baseline on day 15 after a dose of 500 mg testosterone enanthate. The androgenic activity in serum increased in parallel and correlated with the hormone concentrations and remained above baseline on day 15. The urinary androgenic activity increased 4-5-fold and was closely related to the unconjugated testosterone and independent of the UGT2B17 genotype. CONCLUSIONS: The AR assay may serve as a complement to the urinary testosterone/epitestosterone (T/E) doping test, because this is profoundly influenced by the UGT2B17 deletion polymorphism. It may also be useful for detection of other illicit androgens in sports, or in the society, or for monitoring and diagnostics of androgen-related disorders.

On Putting an End to the Backlash Against Electrophysical Agents.

Electrophysical agents (EPAs) are core therapeutic interventions in academic physical therapy curricula around the world. They are used concomitantly with several other therapeutic interventions such as exercise, manual therapy techniques, medications, and surgery for the management of a wide variety of soft tissue disorders. Over the past decade, the practice of EPAs has been the subject of intense scrutiny in the U.S. This has been colored by some physical therapists publicly engaging in bashing rhetoric that has yet to be officially and publicly addressed by the guiding organizations which, together, regulate the practice of physical therapy in this country. Published in world renowned public media are unsubstantiated mocking remarks against the practice of EPAs and unethical allegations against its stakeholders. This rhetoric suggests that EPA interventions are "magical" treatments and that those practitioners who include them in their plans of care may be committing fraud. Such bashing rhetoric is in striking contradiction to the APTA's Guide to Physical Therapist Practice 4.0, which lists EPAs as one of its categories of interventions, the CAPTE's program accreditation policy, and the FSBPT's national licensing exam. The purpose of this commentary is to expose the extent of this discourse and to call to action the APTA, CAPTE, and FSBPT organizations, as well as physical therapists, with the aim at putting an end to this rhetoric.

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. The 7 murine Ugt2b (Ugt2b1, 2b5, 2b34, 2b35, 2b36, 2b37 and 2b38) enzymes were cloned and stably expressed into HEK293 cells. In vitro glucuronidation assays were performed with microsomal proteins or homogenates from mice tissues (liver, kidney, intestine, adipose, testis, prostate, epididymis, bulbo, seminal vesicle, mammary glands, uterus, and ovary) and from Ugt2b-HEK293 cells. Male and female livers, as well as male kidneys, are the major sites for androgen glucuronidation in mice. The male liver is highly efficient at glucuronidation of dihydrotestosterone (DHT) and testosterone and is enriched in Ugt2b1 and 2b5 enzymes. Androsterone and 3α-Diol are conjugated in the male kidney through an Ugt2b37-dependent process. Interestingly, castration partially abolished hepatic Ugt2b1 expression and activity, while Ugt2b37 was totally repressed. DHT injection partially corrected these changes. In conclusion, these observations revealed the substrate- and tissue-specific manner in which murine Ugt2b enzymes conjugate androgens. They also evidence how androgens modulate their own glucuronide conjugation in mice.

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. The effects of norUDCA on the formation of the cholestatic lithocholic acid-glucuronide derivative and of rifampicin on hepatic norUDCA glucuronidation were also explored. In vitro glucuronidation assays were performed with microsomes from human tissues (liver and intestine) and HEK293 cells expressing human UGT enzymes and variant allozymes. UGT1A3 was identified as the major hepatic UGT enzyme catalyzing the formation of norUDCA-23G. Correlation studies using samples from a human liver bank (n = 16) indicated that the level of UGT1A3 protein is a strong determinant of in vitro norUDCA glucuronidation. Analyses of the norUDCA-conjugating activity by 11 UGT1A3 variant allozymes identified three phenotypes with high, low, and intermediate capacity. norUDCA is also identified as a competitive inhibitor for the hepatic formation of the pro-cholestatic lithocholic acid-glucuronide derivative, whereas norUDCA glucuronidation is weakly stimulated by rifampicin. This study identifies human UGT1A3 as the major enzyme for the hepatic norUDCA glucuronidation and supports that some coding polymorphisms affecting the conjugating activity of UGT1A3 in vitro may alter the pharmacokinetic properties of norUDCA in cholestasis treatment.

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. Moreover, genetic variation in androgen metabolizing UGT enzymes and the intra-prostatic levels of glucuronidated DHT metabolites were investigated. METHODS: We collected peripheral serum, serum from the local prostatic veins and prostatic tissue from 25 patients undergoing radical prostatectomy. The serum and intra-tissular level of different androgen metabolites were determined by immunological assays and gas chromatography-mass spectrometry (GCMS), respectively. RESULTS: We found a significant positive correlation between the local prostatic serum DHT levels and (a) prostate weight and (b) circulatory serum levels. There were no correlation between in intra-prostatic hormonal levels and local DHT serum levels. The DHT metabolite 3α-diol-17-glucuronide and 3α-diol-3-glucuronide were significantly associated with UGT2B17 deletion and UGT2B15 Asp85Tyr polymorphisms, respectively. CONCLUSION: These results indicate that local prostatic DHT production has an influence on systemic serum DHT levels. Moreover, our results support the evidence that the prostate is the main DHT producer and that UGTs are important in the intra-prostatic regulation of androgens.

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. RESULTS: Genetic variation in the PDE7B gene was found to be associated with the serum level of testosterone. Individuals homozygous for PDE7B rs7774640 G allele had a smaller increase (2.5-fold) in the serum testosterone levels compared with carriers of the A allele (3.9-fold, P=0.0006). In addition, genetic variation in the PDE7B gene significantly influences the testosterone/epitestosterone ratio, a biomarker of testosterone doping. Our in-vitro incubation studies confirmed that PDE7B serves as a catalyst of the hydrolysis of testosterone enanthate. The UGT2B17 deletion polymorphism did not show any significant association with serum testosterone levels or the other androgen metabolites investigated. CONCLUSION: We have shown that PDE7B is involved in the hydrolysis of testosterone enanthate and that genetic variation in the PDE7B gene is a determinant of the systemic levels of testosterone after administration of testosterone enanthate. It is reasonable to believe that the genetic variation in testosterone bioavailability may be correlated to varying effects of this androgen, whether it is used for replacement therapy or abused in doping. Thus our results may be important to consider in doping test programmes and in therapeutics with androgens and other esterified drugs.

Gonadotropin-releasing hormone agonists in the treatment of prostate cancer.

In 1979, the first prostate cancer patient was treated with a GnRH agonist at the Laval University Medical Center in Quebec City, Canada, thus rapidly leading to the worldwide replacement of surgical castration and high doses of estrogens. The discovery of medical castration with GnRH agonists was soon followed by fundamental changes in the endocrine therapy of prostate cancer. Most importantly, the excellent tolerance accompanying the treatment with GnRH agonists has been a key factor that permitted a series of studies demonstrating a major reduction in the death rate from prostate cancer ranging from 31 to 87% at 5 yr of follow-up in patients with localized or locally advanced prostate cancer. In fact, a one third reduction in prostate cancer deaths has been calculated in the metaanalysis of all available studies. The general acceptance of this discovery by patients and physicians is illustrated by world sales above 3.0 billion U.S. dollars in 2003. Although extremely efficient in achieving complete medical castration and well tolerated, with no other side effects than the expected hypoandrogenicity, GnRH agonists should not be administered alone. In fact, shortly after discovery of the castration effects of GnRH agonists, we observed that approximately 50% of androgens remain in the prostate after castration, thus leading to the recognition of the role of adrenal dehydroepiandrosterone as an important source of the androgens synthesized locally in the prostate and in many peripheral target tissues. We therefore developed combined androgen blockade (CAB), whereby the androgens of both testicular and adrenal origins are blocked simultaneously at start of treatment with the combination of a GnRH agonist to block the testis and a pure antiandrogen to block the action of the androgens produced locally. CAB, first used in advanced metastatic disease, has been the first treatment shown to prolong life in prostate cancer. Most interestingly, in 2002, we made the observation that CAB alone given continuously for 6.5 yr or more leads to cure of the disease in at least 90% of cases, thus suggesting that androgen blockade combining a GnRH agonist and a pure antiandrogen could well be the most efficient treatment of localized prostate cancer, and thus offering the possibility of practically eliminating death from prostate cancer.

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 method uses deuterated standards but does not involve enzymatic hydrolysis, a major improvement over previous techniques. Estrone (E(1)), E(1)-sulfate, E(2), the 3-G of E(1), E(2), 2-methoxy-E(1) (2-MeOE(1)) and 2-methoxy-E(2) (2-MeOE(2)), and the 17-G of E(2) were measured in serum of 19 premenopausal and 10 postmenopausal healthy women. Two extractions, solid-phase and liquid-liquid, were performed to isolate the estrogens. Estrogens were then quantified by mass spectrometry in the negative MRM ion mode using an API3200 spectrometer with a turbo ionspray source. The method selectively measured estrogen glucuronides with sensitivity > or = 5 pg/mL, accuracy 90-111%, and reproducibility (CV = 1.4-13.3%). The method is applicable between 5 and 1000 pg/mL. For the ovarian follicular phase, the major metabolite found was E(1)-3G, with E(2)-3G and 2-MeOE(1)-3G found in lesser amounts (54, 10.4, and 7.8 pg/mL, respectively) These concentrations are 2.6- to 3-fold greater than found for luteal-phase estrogens. The concentrations of E(2)-17G and 2-MeOE(2)-3G were usually less than the limit of quantification. In serum of postmenopausal women, E(1)-3G was the most abundant estrogen found (30.9 pg/mL). Our method profiles estrogens and estrogen-glucuronides and may represent a new tool to identify biomarkers in hormone-dependent diseases.

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. Most interestingly, the same amounts of androgens and estrogens are found in postmenopausal women (n=369) and castrated men of comparable age. The most significant therapeutic implication of these findings is the absolute need to add a pure (nonsteroidal) antiandrogen to castration in men with prostate cancer in order to block the action of the 25 to 50% DHT left in the prostate after castration. Not adding an antiandrogen to castration in men treated for prostate cancer is equivalent to not prescribing a blocker of estrogens in women suffering from breast cancer because they are postmenopausal and have low circulating estradiol.

Activators of the farnesoid X receptor negatively regulate androgen glucuronidation in human prostate cancer LNCAP cells.

Androgens are major regulators of prostate cell growth and physiology. In the human prostate, androgens are inactivated in the form of hydrophilic glucuronide conjugates. These metabolites are formed by the two human UGT2B15 [UGT (UDP-glucuronosyltransferase) 2B15] and UGT2B17 enzymes. The FXR (farnesoid X receptor) is a bile acid sensor controlling hepatic and/or intestinal cholesterol, lipid and glucose metabolism. In the present study, we report the expression of FXR in normal and cancer prostate epithelial cells, and we demonstrate that its activation by chenodeoxycholic acid or GW4064 negatively interferes with the levels of UGT2B15 and UGT2B17 mRNA and protein in prostate cancer LNCaP cells. FXR activation also causes a drastic reduction of androgen glucuronidation in these cells. These results point out activators of FXR as negative regulators of androgen-conjugating UGT expression in the prostate. Finally, the androgen metabolite androsterone, which is also an activator of FXR, dose-dependently reduces the glucuronidation of androgens catalysed by UGT2B15 and UGT2B17 in an FXR-dependent manner in LNCaP cells. In conclusion, the present study identifies for the first time the activators of FXR as important regulators of androgen metabolism in human prostate cancer cells.

Calcitrol (1alpha,25-dihydroxyvitamin D3) inhibits androgen glucuronidation in prostate cancer cells.

Calcitriol (1alpha,25-dihydroxyvitamin D(3)), the active metabolite of vitamin D, has recently emerged as a promising therapeutic agent in the treatment of prostate cancer, the second most common cause of cancer death in American males. In the present study, we have analyzed the effects of calcitriol treatment on the expression and activity of the UDP-glucuronosyltransferase (UGT) 2B15 and 2B17 in prostate cancer LNCaP and 22Rv1 cells. These two enzymes share a crucial role in the inactivation of androgens in the human prostate. We report that calcitriol treatment results in lower glucuronide conjugation of the active androgen dihydrotestosterone and its reduced metabolites androstane-3alpha-diol and androsterone in LNCaP cells. The same treatment also drastically decreased the mRNA and protein levels of UGT2B15 and UGT2B17 in LNCaP and 22Rv1 cells. Using casodex, an androgen receptor (AR) antagonist, and AR-specific small interfering RNA probes, we show that calcitriol requires a functional AR to inhibit the expression of the UGT2B17 gene in LNCaP cells. By contrast, transient transfection and site-directed mutagenesis experiments revealed that calcitriol down-regulates UGT2B15 promoter activity through a responsive region between positions -171 and -113 bp. In conclusion, the present study identifies the vitamin D receptor activator calcitriol as a negative regulator of the UGT2B15- and UGT2B17-dependent inactivation of androgens in prostate cancer LNCaP cells. Androgens promote prostate cancer cell proliferation; thus, the reduction of their inactivation could have a limiting effect of the calcitriol antiproliferative properties in prostate cancer cells.

Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone.

Serum androgens as well as their precursors and metabolites decrease from the age of 30-40 yr in women, thus suggesting that a more physiological hormone replacement therapy at menopause should contain an androgenic compound. It is important to consider, however, that most of the androgens in women, especially after menopause, are synthesized in peripheral intracrine tissues from the inactive precursors dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) of adrenal origin. Much progress in this new area of endocrine physiology called intracrinology has followed the cloning and characterization of most of the enzymes responsible for the transformation of DHEA and DHEA-S into androgens and estrogens in peripheral target tissues, where the locally produced sex steroids are exerting their action in the same cells in which their synthesis takes place without significant diffusion into the circulation, thus seriously limiting the interpretation of serum levels of active sex steroids. The sex steroids made in peripheral tissues are then inactivated locally into more water-soluble compounds that diffuse into the general circulation where they can be measured. In a series of animal models, androgens and DHEA have been found to inhibit breast cancer development and growth and to stimulate bone formation. In clinical studies, DHEA has been found to increase bone mineral density and to stimulate vaginal maturation without affecting the endometrium, while improving well-being and libido with no significant side effects. The advantage of DHEA over other androgenic compounds is that DHEA, at physiological doses, is converted into androgens and/or estrogens only in the specific intracrine target tissues that possess the appropriate physiological enzymatic machinery, thus limiting the action of the sex steroids to those tissues possessing the tissue-specific profile of expression of the genes responsible for their formation, while leaving the other tissues unaffected and thus minimizing the potential side effects observed with androgens or estrogens administered systemically.

Inactivation of androgens by UDP-glucuronosyltransferases in the human prostate.

In the human prostate, dihydrotestosterone (DHT) -- the natural androgen having the highest affinity for the androgen receptor -- is not released directly into the systemic circulation from peripheral target tissues but it is rather converted in situ into two metabolites which have a low affinity for the androgen receptor: androsterone (ADT) and androstane-3alpha,17beta-diol (3alpha-DIOL). Several clinical observations indicate that these two androgen metabolites are further inactivated in the prostate by glucuronidation. In the human, the family of UDP-glucuronosyltransferase (UGT) enzymes comprises 18 members in three subfamilies: UGT1A, UGT2A and UGT2B. Identification of the substrates for each member has revealed that three UGT2B enzymes are mainly responsible for DHT, ADT and 3alpha-DIOL glucuronidation: UGT2B7, UGT2B15 and UGT2B17. Tissue distribution and cellular localization of UGT2B transcripts and proteins clearly indicate that only UGT2B15 and UGT2B17 are expressed in the prostate. Using the human prostate carcinoma LNCaP cell line, it was shown that UGT2B expression and activity are negatively regulated by several factors, including androgens. On the other hand, inhibition of UGT2B115/17 expression by small interfering RNA (siRNA) resulted in an induced response to DHT of androgen-receptor target genes such as PSA, KLK4, NKX3.1, TMPRSS2, SLC16A6 and VEGF. It is suggested that the conjugating activity of UGT enzymes in androgen target tissues is a mechanism for modulating the action of steroids and/or protecting the tissues from deleterious high concentrations of androgens.

Androgen biosynthetic pathways in the human prostate.

It is well recognized that there are two androgens, namely testosterone (T) and dihydrotestosterone (DHT); T plays an important role in the testis and muscle, and DHT is crucial for the development, function and pathology of the prostate. It is generally thought that DHT is produced from the 5alpha-reduction of circulating T before being inactivated by 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) that converts DHT into 5alpha-androstane-3alpha,17beta-diol (3alpha-diol). However, the presence of various steroidogenic enzymes in the prostate as well as the availability at high levels of various steroid precursors such as dehydroepiandrosterone sulphate (DHEAS), dehydroepiandrosterone (DHEA) and 4-androstenedione (4-dione) strongly suggest the existence of additional pathways involved in the biosynthesis and metabolism of DHT. Because steroidogenesis could be different in different species, data from the literature obtained from various human, dog, rat and mouse prostate tissues, as well as primary cells and prostatic cancer cell lines, provide a somewhat confusing picture. In the present chapter, we review the data in order to provide a clearer picture of the pathways involved in DHT biosynthesis and metabolism in the human prostate.

Inactivation by UDP-glucuronosyltransferase enzymes: the end of androgen signaling.

Conjugation by UDP-Glucuronosyltransferase (UGT) is the major pathway of androgen metabolism and elimination in the human. High concentrations of glucuronide conjugates of androsterone (ADT) and androstane-3alpha,17beta-diol (3alpha-diol) are present in circulation and several studies over the last 30 years have concluded that the serum levels of these metabolites might reflect the androgen metabolism in several tissues, including the liver and androgen target tissues. Three UGT2B enzymes are responsible for the conjugation of DHT and its metabolites ADT and 3alpha-diol: UGT2B7, B15 and B17. UGT2B7 is expressed in the liver and skin whereas UGT2B15 and B17 were found in the liver, prostate and skin. Very specific antibodies against each UGT2B enzyme have been obtained and used for immunohistochemical studies in the human prostate. It was shown that UGT2B17 is expressed in basal cells whereas UGT2B15 is only localized in luminal cells, where it inactivates DHT. By using LNCaP cells, we have also demonstrated that the expression and activity of UGT2B15 and B17 are modulated by several endogenous prostate factors including androgen. Finally, to study the physiological role of UGT2B enzymes, transgenic mice bearing the human UGT2B15 gene were recently obtained. A decrease in reproductive tissue weight from transgenic animals compared to those from control animals was observed. In conclusion, the conjugation by UGT2B7, B15 and B17, which represents a non-reversible step in androgen metabolism, is an important means by which androgens are regulated locally. It is also postulated that UGT enzymes protect the tissue from deleteriously high concentrations of active androgen.

Characterization of common UGT1A8, UGT1A9, and UGT2B7 variants with different capacities to inactivate mutagenic 4-hydroxylated metabolites of estradiol and estrone.

The oxidative metabolism of estrone (E1) and estradiol (E2) to form carcinogenic 4-hydroxy-catecholestrogens (4-OHCE) is associated with uterine and breast carcinogenesis. In this study, we conducted functional analyses of genetic variants in the UDP-glucuronosyltransferase UGT1A8, UGT1A9, and UGT2B7 enzymes primarily involved in the inactivation of 4-OHCEs. Compared with UGT2B7*2 (H268Y), UGT2B7*1 exhibited a 2-fold lower efficiency (intrinsic clearance) at conjugating 4-hydroxyestrone and 4-hydroxyestradiol at positions 3 and 4 caused by altered capacities (Vmax) and affinities (Km). The -79 G>A promoter variation, characterizing the UGT2B7*2g haplotype, leads to a 50% reduction of transcription (P < 0.001) in human endometrial carcinoma-1B cells. Furthermore, a >12-fold decreased intrinsic clearance of the *1 proteins was induced by selected amino acid substitutions in UGT1A8 (*3 C277Y) and UGT1A9 (*3 M33T). Frequencies of the low-activity alleles in Caucasians were 45% for UGT2B7*1, 5% for the -79A promoter variant, 1.2% for UGT1A8*3, and 2.2% for UGT1A9*3. Supporting a protective role in two organs sensitive to 4-OHCE-induced damages, the expression of UGT enzymes was shown by immunohistochemistry in normal breast and endometrial tissues and confirmed by Western blotting in a subset of samples. Altogether, findings suggest that specific polymorphisms in UGT genes may modulate the exposure to carcinogenic metabolites of E2 and potentially lead to an altered risk of breast and endometrial cancers in women carrying the variant alleles.

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. RESULTS: Serum estrone sulfate (E1S) and androsterone glucuronide (ADT-G), the main metabolites of estrogens and androgens, respectively, were 16.9% (P = 0.005) and 16.1% (P = 0.001) higher in women not diagnosed with moderate/severe VVA than those diagnosed with VVA. Serum estrone (E1) was 14.5% (P < 0.0001) higher in women with no diagnosis of VVA, whereas the other steroids did not show meaningful differences. The limited biological significance of serum estradiol (E2) and testosterone is supported by the lack of statistical significance in the serum concentrations of these two steroids between the two groups. Most importantly, for the women without a diagnosis of VVA, the normal upper limit (95 centile) of serum E2 was 9.15 pg/mL (n = 364) and 10.7 pg/mL (n = 67) for a weighted average of 9.99 pg E2/mL. A limit of 10 pg E2/mL has recently been found by two other laboratories. When comparing 50- to 59-year-old and 70- to 79-year-old women, serum E2, E1S, ADT-G, and DHEA were, respectively, 24.4%, 22.6%, 27.0%, and 85.9% higher in the younger group. CONCLUSIONS: Somewhat higher values, namely, 16.9% and 16.1%, are observed in the serum concentrations of the estrogen (E1S) and androgen (ADT-G) metabolites in normal compared with women with a diagnosis of VVA. Such data indicating a lower estrogenic and androgenic global exposure in women diagnosed with VVA offers an opportunity for the local intravaginal administration of DHEA to replace the deficiency in endogenous DHEA.

Sex steroid levels and cortical bone size in young men are associated with a uridine diphosphate glucuronosyltransferase 2B7 polymorphism (H268Y).

CONTEXT: Sex steroids are involved in the regulation of pubertal cortical bone expansion in males. In vitro studies have indicated that the enzyme uridine diphosphate glucuronosyltransferase (UGT) 2B7 has the capacity to glucuronidate sex steroids and their metabolites. OBJECTIVE: Our objective was to determine the impact of the H(268)Y polymorphism in the UGT2B7 gene on interindividual variation of serum levels of sex steroids and cortical bone dimensions. PARTICIPANTS: The population-based cohort Gothenburg Osteoporosis and Obesity Determinants study consists of 1068 young adult Swedish men (age 18.9 yr). MAIN OUTCOME MEASURES: Serum levels of sex steroids and the three major glucuronidated androgen metabolites, androstane-3alpha,17beta-diol-17glucuronide, androstane-3alpha,17beta-diol-3glucuronide, and androsterone-glucuronide, were analyzed. Cortical and trabecular volumetric bone mineral density and cortical bone size were measured by peripheral quantitative computer tomography. RESULTS: Serum levels of testosterone (YY 9% over HH; P < 0.01), dihydrotestosterone (YY 10% over HH; P < 0.01), and estradiol (YY 8% over HH; P < 0.01) were associated with the UGT2B7 H(268)Y polymorphism. The polymorphism was associated with androstane-3alpha,17beta-diol-17glucuronide and androstane-3alpha,17beta-diol-3glucuronide (P < 0.01), but not with androsterone-glucuronide serum levels. In addition, the UGT2B7 H(268)Y polymorphism was an independent predictor of cortical bone size, reflected by periosteal circumference and cortical moment of inertia (P < 0.01), in both the weight-bearing tibia and nonweight-bearing radius. CONCLUSIONS: The UGT2B7 H(268)Y polymorphism is independently associated with cortical bone size and serum sex steroid levels in young adult men. Subjects homozygous for the Y allele had higher serum testosterone and larger cortical bone size than subjects homozygous for the H allele. However, the underlying mechanism behind these associations is unknown and has to be studied further.

The uridine diphosphate glucuronosyltransferase 2B15 D85Y and 2B17 deletion polymorphisms predict the glucuronidation pattern of androgens and fat mass in men.

CONTEXT: Previous in vitro studies have demonstrated that the UDP glucuronosyltransferase (UGT)2B15 and UGT2B17 glucuronidate androgens and their metabolites. OBJECTIVE: Our objective was to determine in vivo whether the UGT2B15 D85Y and the UGT2B17 deletion polymorphisms predict androgen glucuronidation and body composition. PARTICIPANTS: Two population-based cohorts including young adult (n = 1068; age = 18.9 yr) and elderly (n = 1001; age = 75.3 yr) men were included in the study. MAIN OUTCOME MEASURES: Serum and urine levels of testosterone (T) and dihydrotestosterone (DHT) were measured by gas chromatography-mass spectrometry, and serum levels of the major glucuronidated androgen metabolites androstane-3alpha,17beta-diol(androstanediol)-3-glucuronide, androstanediol-17-glucuronide, and androsterone-glucuronide were measured by liquid chromatography-tandem mass spectrometry. Body composition was measured by dual-energy x-ray absorptiometry. RESULTS: Both the UGT2B15 D85Y and the UGT2B17 deletion polymorphisms were associated with serum levels of androstanediol-17-glucuronide (P < 0.001) but not with levels of androstanediol-3-glucuronide or androsterone-glucuronide in both cohorts. Glucuronidation of T and DHT was associated with the UGT2B17 deletion but not with the UGT2B15 D85Y polymorphism, suggested by strong associations between the deletion polymorphism and urine levels of these two hormones. Both polymorphisms were associated with several different measures of fat mass (P < 0.01). The UGT2B17 deletion polymorphism was associated with insulin sensitivity (P < 0.05) as indicated by the homeostasis model assessment index. CONCLUSIONS: The UGT2B15 D85Y and the UGT2B17 deletion polymorphisms are both predictors of the glucuronidation pattern of androgens/androgen metabolites. Our findings indicate that UGT2B17 is involved in 17-glucuronidation of mainly T but also of DHT and androstanediol and that UGT2B15 is involved in the 17-glucuronidation of androstanediol. Furthermore, these two polymorphisms are predictors of fat mass in men.