Higher Androgen Concentrations Research Articles

FRI382 High Androgen And Progesterone Metabolite Concentrations In Naturally Matured Follicles Are Concurrent With High Serum Anti-Müllerian Hormone Concentrations

Abstract Disclosure: T. Du Toit: None. M. Von Wolff: None. A.C. Swart: None. M. Groessl: None. C.E. Flueck: None. Infertility in women is routinely evaluated with the assessment of circulating steroid levels. Profiling steroid levels in follicular fluid (FF) would provide a focused evaluation of the ovarian endocrine milieu and is therefore better suited to identify key hormones potentially involved in dysfunctional follicular growth. The anti-Müllerian hormone (AMH) level in serum is a well-established clinical marker to estimate the ovarian reserve in assisted reproductive technology, while the AMH level in FF serves as a new prognostic marker for oocyte developmental potential. However, AMH-linked changes in the follicular steroid milieu have not been fully explored. We conducted an AMH-dependent analysis of the FF endocrine milieu. Hormones were quantified using LC-MS (n=42) and ELISA (n=4) in FF of 83 women undergoing natural cycle in vitro fertilisation. Patients were age-matched and classified into 4 statistically different (p<0.0001) groups according to serum AMH levels: group A (<1.1 pmol/L, n=20); group B (1 - 7.14 pmol/L, n=21); group C (7.14 - 35.5 pmol/L, n=21); and group D (>35.5 pmol/L, n=21). Group D was designated as our polycystic ovary syndrome (PCOS)-like group, as high serum AMH is a marker for PCOS. We characterised androgen and progesterone metabolic pathways in FF. Androstenedione (A4) and testosterone (T) levels differed significantly between the groups (p<0.01) and were highest in group D at 60 nmol/L and 4.7 nmol/L, respectively. The levels of 11-ketoandrostenedione (11KA4) and 11β-hydroxyandrosterone (adrenal-origin) also differed between the groups (p<0.05), with higher 11KA4 levels (±2.7-fold) quantified in group D. In parallel with serum AMH, FF AMH differed between the groups (p<0.0001), together with luteinizing hormone/FSH, A4/dehydroepiandrosterone, estradiol(E2)/T and E2/A4 ratios. In comparison to groups A, B and C combined, the PCOS-like group D showed significantly increased downstream progesterone metabolite levels –11α-hydroxyprogesterone [OHP4], 17α,20α-diOHP4, 16α-OHP4 and 5α-pregnanolone, with lower FSH levels. Our results show that the follicular milieu is significantly different when high AMH levels are measured compared to when AMH levels are low, marked by: (i) higher progesterone metabolite levels in follicles and (ii) higher A4 and T levels, concomitant with unchanged E2 levels suggesting that androgens were not fully converted to estrogens in these follicles. Our study furthermore corroborates other studies reporting an intrafollicular hyperandrogenic state in women with increased circulatory AMH levels. In summary, our study not only provides data based on a broad steroid profile that the follicular androgen endocrine milieu is affected in women with high serum AMH levels, but it also provides a model for the premature progesterone increase in PCOS women which leads to a reduction in the embryo implantation rate. Presentation: Friday, June 16, 2023

The Effect on Inflammation of Adherence to the Mediterranean Diet in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS), which is common in women of reproductive age worldwide, is a syndrome that reduces the lifelong quality of life and poses a significant risk for various diseases. PCOS is a combination of symptoms of hyperandrogenism, oligo-anovulation, and polycystic ovarian morphology (PCOM). In PCOS, which is characterized by chronic low-grade inflammation, some inflammatory cytokines are increased. This review aimed to explain possible mechanisms of inflammation in PCOS and the effects of Mediterranean diet components on reducing this inflammation. Although the exact mechanisms of inflammation in PCOS are not yet fully known, it is stated that it is mediated by obesity, insulin resistance, and high androgen concentration. This inflammatory state negatively impacts the risk of future health problems and the quality of life of PCOS. Therefore, strategies to reduce inflammation are thought to be important. Dietary adjustments have important effects in reducing this inflammation and preventing disease. At this point, the Mediterranean diet, which has been proven to have a protective effect against many diseases, draws attention. Among the components of the Mediterranean diet, especially omega-3, antioxidants and dietary fiber may contribute to the reduction of inflammation through different mechanisms. PCOS is characterized by chronic low-grade inflammation, which increases women's risk of health problems, both now and in the future. Reducing inflammation is therefore extremely important, and it can be achieved with adherence to the Mediterranean diet. Inflammation pathways and the effect of the components of the Mediterranean diet in PCOS. AGE, advanced glycation end products; NF-κB, nuclear factor kappa-B. Obesity, insulin resistance, and hyperandrogenism may cause inflammation in PCOS through different mechanisms. Antioxidants, omega-3, and dietary fiber, which are the main components of the Mediterranean diet, may be effective in reducing this inflammation in PCOS. (Created with BioRender.com).

Androgen and prolactin manipulation do not induce changes in immunocompetence measures in a fish with male parental care.

Prolactin and 11-ketotestosterone (11-KT) are important reproductive hormones in fishes, which may also influence immunocompetence. The immunocompetence handicap hypothesisstates that higher androgen concentrations that support secondary sex traits are traded off against a decrease in immune system function. To test the relationships between these hormones and immunocompetence, we experimentally manipulated 11-ketotestosterone and prolactin in the freshwater fish, bluegill (Lepomis macrochirus) during parental care using implants that contained either 11-KT, prolactin, or an inert control. We vaccinated individuals to stimulate the acquired immune response, then measured immunocompetence as the number of granulocytes, lymphocytes and monocytes, and the expression of interleukin 8 in each sample. We did not observe any significant differences in the immune measures among the hormone treatments. Our results indicate that in bluegill, there is no trade-off between androgens or prolactin and immunocompetence.

High androgen concentrations in follicular fluid of polycystic ovary syndrome women

BackgroundAccording to current definitions of Polycystic Ovary Syndrome (PCOS), hyperandrogenism is considered as a key element in the pathogenesis of this common endocrinopathy. However, until now, studies about ovarian androgen profile in women are very rare. Our aim was then to characterise the expression profile of the androgens in follicular fluid of 30 PCOS patients, and compare it to those of 47 Control women and 29 women with only polycystic ovary morphology on ultrasounds (ECHO group).MethodsA retrospective, single-centre cohort study was performed. The intrafollicular concentrations of the key androgens were assessed and correlated with the intrafollicular levels of some adipokines of interest. Androgens were quantified by mass spectrophotometry combined with ultra-high-performance liquid chromatography, while adipokine concentrations were measured by ELISA assays.ResultsIn PCOS patients, the intrafollicular concentrations of the androgens synthesised by ovarian theca cells, i.e., 17OH-pregnenolone, dehydroepiandrosterone, Δ4-androstenedione and testosterone, were significantly higher than those of the androgens of adrenal origin, and positively correlated with the main PCOS clinical and biological features, as well as with the adipokines mostly expressed in the follicular fluid of PCOS patients, i.e. resistin, omentin, chemerin and apelin. Conversely, Control women showed the highest levels of 17OH-progesterone, deoxycorticosterone and 11-deoxycortisol. Confirming these results, apelin levels were negatively associated with pregnenolone and deoxycorticosterone concentrations, while visfatin levels, which were higher in the Control group, negatively correlated with the Δ4-androstenedione and testosterone ones.ConclusionsPCOS is characterised by a selective increase in the intrafollicular levels of the androgens synthesised by theca cells, strengthening the hypothesis that ovarian hyperandrogenism plays a central role in its pathogenesis. Further, the significant correlation between the intrafollicular concentrations of the androgens and most of the adipokines of interest, including apelin, chemerin, resistin and omentin, confirms the existence of a close relationship between these two hormonal systems, which appear deeply involved in ovarian physiology and PCOS physiopathology.

AMH Regulation by Steroids in the Mammalian Testis: Underlying Mechanisms and Clinical Implications.

Anti-Müllerian hormone (AMH) is a distinctive biomarker of the immature Sertoli cell. AMH expression, triggered by specific transcription factors upon fetal Sertoli cells differentiation independently of gonadotropins or sex steroids, drives Müllerian duct regression in the male, preventing the development of the uterus and Fallopian tubes. AMH continues to be highly expressed by Sertoli until the onset of puberty, when it is downregulated to low adult levels. FSH increases testicular AMH output by promoting immature Sertoli cell proliferation and individual cell expression. AMH secretion also showcases a differential regulation exerted by intratesticular levels of androgens and estrogens. In the fetus and the newborn, Sertoli cells do not express the androgen receptor, and the high androgen concentrations do not affect AMH expression. Conversely, estrogens can stimulate AMH production because estrogen receptors are present in Sertoli cells and aromatase is stimulated by FSH. During childhood, sex steroids levels are very low and do not play a physiological role on AMH production. However, hyperestrogenic states upregulate AMH expression. During puberty, testosterone inhibition of AMH expression overrides stimulation by estrogens and FSH. The direct effects of sex steroids on AMH transcription are mediated by androgen receptor and estrogen receptor α action on AMH promoter sequences. A modest estrogen action is also mediated by the membrane G-coupled estrogen receptor GPER. The understanding of these complex regulatory mechanisms helps in the interpretation of serum AMH levels found in physiological or pathological conditions, which underscores the importance of serum AMH as a biomarker of intratesticular steroid concentrations.

The Androgen Hormone-Induced Increase in Androgen Receptor Protein Expression Is Caused by the Autoinduction of the Androgen Receptor Translational Activity

The androgen receptor (AR) plays a central role in prostate, muscle, bone and adipose tissue. Moreover, dysregulated AR activity is a driving force in prostate cancer (PCa) initiation and progression. Consequently, antagonizing AR signalling cascades via antiandrogenic therapy is a crucial treatment option in PCa management. Besides, very high androgen levels also inhibit PCa cells’ growth, so this effect could also be applied in PCa therapy. However, on the molecular and cellular level, these mechanisms have hardly been investigated so far. Therefore, the present study describes the effects of varying androgen concentrations on the viability of PCa cells as well as localization, transactivation, and protein stability of the AR. For this purpose, cell viability was determined via WST1 assay. Alterations in AR transactivity were detected by qPCR analysis of AR target genes. A fluorescent AR fusion protein was used to analyse AR localization microscopically. Changes in AR protein expression were detected by Western blot. Our results showed that high androgen concentrations reduce the cell viability in LNCaP and C4-2 cell lines. In addition, androgens have been reported to increase AR transactivity, AR localization, and AR protein expression levels. However, high androgen levels did not reduce these parameters. Furthermore, this study revealed an androgen-induced increase in AR protein synthesis. In conclusion, inhibitory effects on cell viability by high androgen levels are due to AR downstream signalling or non-genomic AR activity. Moreover, hormonal activation of the AR leads to a self-induced stabilization of the receptor, resulting in increased AR activity. Therefore, in clinical use, a therapeutic reduction in androgen levels represents a clinical target and would lead to a decrease in AR activity and, thus, AR-driven PCa progression.

Influence of testosterone on purine metabolism and gout

Many different factors are involved in the regulation of purine metabolism. An important role is played by the level of sex hormones: high concentrations of androgens lead to a higher, and estrogen – to a lower level of uric acid. However, according to the results of numerous studies, it has been shown that the effect of sex hormones is not limited only to the uric acid concentration. Sex hormones affect inflammatory processes in the body by modulating the production of pro-inflammatory cytokines and regulating the corresponding signaling pathways. Androgen deficiency can lead to obesity and metabolic disorders, which can contribute to the development and course of gout. This review examines the effect of testosterone, as well as the effect of changes in its concentration on the dynamics of purine metabolism and gout.

Polycystic ovary syndrome in pediatric obesity and diabetes.

Polycystic ovary syndrome is characterized by anovulation (amenorrhea, oligomenorrhea, irregular menstrual cycles) combined with symptoms of androgen excess (hirsutism, acne, alopecia). The clear definition and diagnosis in adolescents could be challenging considering that most of symptoms occur as part of the expected physiological hormonal imbalance of puberty. Therefore, different diagnostic criteria have been elaborated. Polycystic ovary syndrome could be associated to obesity, diabetes mellitus, and metabolic syndrome. In adolescents with polycystic ovary syndrome, adiposity is associated with higher androgen concentrations and greater menstrual irregularity. Polycystic ovary syndrome in youth is considered a risk factor for type 2 diabetes mellitus in adulthood. On the other hand, increased prevalence of polycystic ovary syndrome has been shown in type 1 diabetes mellitus. The treatment of polycystic ovary syndrome in adolescents is controversial considering that adequate trials are lacking. First-line treatment comprises lifestyle modification (preferably multicomponent including diet, exercise and behavioral strategies) that should be recommended overall in the patients with polycystic ovary syndrome and overweight, central obesity and insulin resistance. Beyond non-pharmacological therapy, pharmacological agents include combined hormonal contraceptives, metformin and anti-androgens, used separately or in combination. The aim of therapy is to bring back ovulation, to normalize menses, to reduce hirsutism and acne, to reduce weight. Other important goal is the treatment of hyperlipidemia and of hyperglycemia. This narrative review aimed to review the most pertinent literature about polycystic ovary syndrome in adolescents with obesity or diabetes. We overviewed the diagnostic criteria, the pathophysiology and the possible treatment approaches.

Growth and adrenarche: findings from the CATS observational study

BackgroundThere is increasing evidence that patterns of pubertal maturation are associated with different patterns of health risk. This study aimed to explore the associations between anthropometric measures and salivary androgen...

Prenatal manipulation of yolk androgen levels affects egg size but not egg colour in a songbird

Maternal allocation of androgens to the egg yolk allows mothers to adaptively manipulate offspring phenotype. Increases of egg androgen levels have often been shown to induce sex-specific effects. Some previous studies suggest that females specifically may suffer a fitness reduction after early exposure to high androgen levels. In this study, we explored whether female birds that developed exposed to high yolk androgen concentrations would reduce their maternal investment later in life. We explored two different aspects of female reproduction in spotless starlings (Sturnus unicolor): egg coloration (a post mating sexual signal in this species) and egg size. We manipulated androgen yolk levels in a large sample of clutches of this species. We monitored the reproduction of the females that hatched from these eggs, measuring the size and colour of the eggs they laid throughout their life (from 1 to 7 years of age). We found no overall difference in egg colour in relation to treatment, clutch number or age. However, females exposed to high egg androgen levels showed a steeper decrease in egg size along the laying order than controls. This pattern likely results in a more unbalanced distribution of resources within the clutch, possibly favouring brood size reductions in experimental females. In addition, control and experimental females differed in how egg volume changed with age. These results show that some egg characteristics may be affected by the female’s exposure to yolk androgens during her own embryonic development. Our research calls for further long-term research on the influence of prenatal androgens on the fitness mechanisms regulating reproductive investment and its potential signalling role in a perspective of sexual selection. In birds, mothers prepare the offspring to the environment they will encounter at hatching by depositing a mixture of compounds into the eggs. Androgens specifically exert a variety of effects during embryo development and chick growth, but some of these may be negative in adult life. In particular, early androgen may be detrimental for females in the long term, decreasing maternal investment and fitness. Using the spotless starling as study species, we tested whether an experimental increase in yolk androgens negatively affects breeding investment, measured by egg colour (a sexual signal) and egg size. We found no effects of the treatment on egg colour. However, females exposed to high androgen levels during their development reduced egg size along the laying order more strongly than controls. This may affect nestling survival, and indicates that prenatal yolk androgens may influence some egg characteristics with known relevance for offspring viability.

Intergenerational Influences between Maternal Polycystic Ovary Syndrome and Offspring: An Updated Overview

Polycystic ovary syndrome (PCOS) is the most common heterogeneous endocrine disorder. Affecting 5%-10%1 of reproductive-aged women, PCOS is characterized by hyperandrogenemia, anovulation, and insulin resistance (IR), with long-term effects throughout the different stages of a woman's life. During gestation, women with PCOS have greater androgen concentrations.2 Intrauterine exposure to high androgen concentrations may cause fetal reprogramming or placental changes through epigenetic regulation or other mechanisms, thus causing changes in multiple systems in the offspring and ultimately affecting growth and development.

High serum Androgen and Insulin concentrations increase the tendency of Endometrial Carcinoma.

Purpose: The objective of the study was to evaluate the important role played by androgen and insulin in the development of endometrial carcinoma (EC), and their combined effect on EC risk.Methods: We enrolled 510 type I EC patients and 510 age-, time-, and nationality-matched subjects into this study. Metabolic and hormonal parameters of enrolled subjects were examined. Univariate and multivariate logistic regression analyses for EC and control subjects were performed. Type I EC risk was evaluated with respect to testosterone, androstenedione, and insulin levels based on odds ratios (ORs) using stratified data.Results: EC risk was positively associated with C-peptide, estrone, androgen (including testosterone and androstenedione) and insulin levels, BMI, WHR, family history of cancer, nulliparity, irregular menstruation, diabetes, and hypertension. In multivariate logistic regression models, high C-peptide and testosterone levels, diabetes, and hypertension were independent risk factors after adjustment for BMI, WHR, family history of cancer, high serum insulin, and estrone levels. Increased serum total testosterone and insulin levels were positively correlated with EC risk in total, premenopausal, and postmenopausal women. Androstenedione was correlated with EC in total and postmenopausal, but not in premenopausal subjects. Compared with higher testosterone and insulin, odds ratios (ORs) for higher testosterone with lower insulin and lower testosterone with higher insulin were decreased in total, premenopausal, and postmenopausal women. Similarly, compared to both higher FAI and insulin, ORs for higher FAI with lower insulin and lower FAI with higher insulin were decreased in all three groups. Coordinately, ORs for higher androstenedione with lower insulin and lower androstenedione with higher insulin were decreased in total and postmenopausal, but not premenopausal subjects.Conclusions: These findings suggested that androgen and insulin were risk factors of type I EC, and relatively high levels of both testosterone and insulin synergistically affected EC risk.

Assisted Reproduction in Congenital Adrenal Hyperplasia.

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive disorders characterized by defects of adrenal steroidogenesis due to mutations in one of the following enzymes: 21-hydroxylase (21OH), 11β-hydroxylase (11βOH), 17α-hydroxylase (17OH; also known as 17, 20-lyase), 3β hydroxysteroid dehydrogenase type 2 (3βHSD2), steroidogenic acute regulatory protein (StAR), P450 cholesterol side-chain cleavage (P450scc), and P450 oxidoreductase (POR). More than 95% of congenital adrenal hyperplasia cases are due to mutations in CYP21A2, the gene encoding the adrenal steroid 21-hydroxylase enzyme (P450c21). This work focuses on this type of CAH given that it is the most frequent one. This disease is characterized by impaired cortisol and aldosterone production as well as androgen excess. A variant of the CAH is the non-classic type of CAH (NCCAH), usually asymptomatic before the 5th year of age, diagnosed during puberty especially in patients visiting a fertility clinic. NCCAH is characterized mainly by anovulatory cycles and/or high androgen concentrations. Both types of CAH are associated with infertility. Given that the incidence of NCCAH is greater than that of CAH, patients suffering from NCCAH are more often diagnosed for the first time in a fertility clinic. Thus, screening for NCCAH should always be considered. The causes of infertility in CAH patients are multi-factorial including virilization of external genitalia, altered psychosocial development, and hormonal disorders. The main challenges encountered in assisted reproduction are the androgen excess-associated anovulatory cycles as well as the increased circulating progesterone concentrations during the follicular phase which impact endometrial receptivity, tubal motility, and cervical thickness. Administration of sufficient substitution dose of glucocorticoids usually resolves these problems and leads not only to successful assisted reproduction treatment but also to spontaneous pregnancy. Patients with CAH should be followed by a multidisciplinary team including gynecologist, endocrinologist, and pediatrician.

SUN-039 Characterization of Human Adrenal Steroidogenesis during Fetal Development

Context: The endocrine function of human fetal adrenals (HFA) is activated already during first trimester, but changes in adrenal steroidogenesis during fetal life are not well characterized. Objective: This study aimed to investigate HFA steroidogenesis by analyzing adrenal glands from 1st and 2nd trimester. Design and Setting: Male and female HFA samples from gestational week (GW) 8-19 were examined, including a total of 101 samples from 83 fetuses. Main Outcome Measure(s): Expression level of steroidogenic genes and protein expression/localization were determined by quantitative PCR and immunohistochemistry, respectively, and intra-adrenal steroid levels were quantified by LC-MS/MS. Results: Transcriptional levels of StAR, CYP11A1, CYP17A1, CYP21A2, CYP11B1/2 and SULT2A1 was significantly higher in 2nd trimester compared with 1st trimester (P<0.05), while expression levels of 3β-HSD2 and ARK1C3 were unaltered between GW 8-19. All investigated steroidogenic proteins were expressed in a distinct pattern throughout GW 8-19 with most enzymes expressed primarily in the fetal zone, except 3β-HSD1/2 which was mainly expressed in the definitive zone. The abundant steroidogenic enzyme expression was reflected in overall high intra-adrenal tissue concentrations of mineralocorticoids, glucocorticoids, and androgens; cortisol was the most abundant (1,071-2,723 ng/g tissue, in average) and testosterone levels the lowest (2-14 ng/g tissue, in average). Conclusions: The expression profiles of HFA steroidogenic enzymes are distinct from 1st to 2nd trimester, with no major differences between male and female samples. The intra-adrenal steroid hormone concentrations confirms that cortisol is produced throughout 1st and 2nd trimester, suggesting continued regulation of the HPA axis during this entire period.

Characterization of Human Adrenal Steroidogenesis During Fetal Development.

ContextThe endocrine function of human fetal adrenals (HFAs) is activated already during first trimester, but adrenal steroidogenesis during fetal life is not well characterized.ObjectiveThis study aimed to investigate HFA steroidogenesis by analyzing adrenal glands from first and second trimesters.Design and SettingMale and female HFA from gestational weeks (GWs) 8 to 19 were examined, including a total of 101 samples from 83 fetuses.Main Outcome Measure(s)Expression level of steroidogenic genes and protein expression/localization were determined by quantitative PCR and immunohistochemistry, respectively, and intra-adrenal steroid levels were quantified by LC-MS/MS.ResultsTranscriptional levels of StAR, CYP11A1, CYP17A1, CYP21A2, CYP11B1/2, and SULT2A1 were significantly higher in second trimester compared to first trimester (P < 0.05), whereas expression levels of 3β-HSD2 and ARK1C3 were unaltered between GWs 8 and 19. All investigated steroidogenic proteins were expressed in a distinct pattern throughout the investigated period, with most enzymes expressed primarily in the fetal zone, except 3β-HSD1/2, which was expressed mainly in the definitive zone. Abundant steroidogenic enzyme expression was reflected in overall high intra-adrenal tissue concentrations of mineralocorticoids, glucocorticoids, and androgens; cortisol was the most abundant (1071 to 2723 ng/g tissue), and testosterone levels were the lowest (2 to 14 ng/g tissue).ConclusionsThe expression profiles of HFA steroidogenic enzymes are distinct from first to second trimester, with no major differences between male and female samples. Intra-adrenal steroid hormone concentrations confirm that cortisol is produced throughout first and second trimesters, suggesting continued regulation of the hypothalamus-pituitary-adrenal axis during this entire period.

Prostaglandin E2 triggers cytochrome P450 17α hydroxylase overexpression via signal transducer and activator of transcription 3 phosphorylation and promotes invasion in endometrial cancer.

Prostaglandin E2 (PGE2) is the most common prostaglandin in the human body, meaning that its malfunction impacts on the development of numerous diseases. Prostaglandin E synthase 2 (PTGES2) is involved in the synthesis of PGE2. In the present study, immunohistochemistry of PTGES2 was performed in 152 patients with endometrial cancer and in 66 patients with normal endometria. The results indicate a notable association among increased expression of PTGES2 and age (P=0.0092) and the depth of myometrial invasion (P<0.0001). Reverse transcription-quantitative polymerase chain reaction and western blot analysis demonstrated that cytochrome P450 17α hydroxylase (CYP17), an enzyme for androgen synthesis, is overexpressed following PGE2 stimulation via signal transducer and activator of transcription 3 (STAT3) phosphorylation. ELISA also detected increased androgen (testosterone) secretion. Further invasion of endometrial cancer cells was induced at high androgen levels and when CYP17 was overexpressed. Furthermore, the present study observed that CYP17 is overexpressed via STAT3 phosphorylation in endometrial cancer cells, which grow at a high concentration of PGE2, resulting in increased androgen secretion. Concentrations of estrogen and progesterone were not elevated, while the concentration of androgens was. Overall, a high concentration of androgens caused increased invasion of endometrial cancer cells. A high concentration of androgens, which is initiated by a high expression of PTGES2 and a high concentration of PGE2, is an important promoter of myometrial invasion in endometrial cancer.

Sex steroids and risk of differentiated thyroid carcinoma: Results from the EPIC study

Introduction The incidence of thyroid carcinomas has been rapidly increasing over the last 20–30 years in many Westernized countries. Large part of the increase is due to diagnostic improvements, however other changes may be involved. The only well-established risk factors for differentiated thyroid carcinomas (TC) (the most common forms of TC) are history of benign thyroid disease, notably goiter and benign nodules, and exposure to ionizing radiations (especially during childhood). However, recent studies have shown consistent evidence that body mass, including height and weight, are also positively associated with differentiated TC risk. However, mechanisms that may explain this association are currently not known but can include sex hormones. We therefore investigated the role of sex steroids and sex hormones binding globulin (SHBG) in the etiology of differentiated thyroid cancer in a case-control study nested within the large European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods Within EPIC, during follow-up, we identified 329 primary incident cases of differentiated thyroid carcinoma (133 in pre-menopausal women, 118 in postmenopausal women, and 78 in men) among subjects who participated in the study and gave a blood sample at blood collection. To these cases, 710 controls, who did not develop any cancers, apart from non-melanoma skin cancer, at the time of the diagnosis of the case, were matched on study recruitment center, sex, age, date, time, fasting status at blood collection, duration of follow-up, and, in women, menopausal status and phase of the menstrual cycle. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone (T), androstenedione (D4), dehydroepiandrosterone (DHEA), estradiol, estrone and progesterone (in pre-menopausal women only) were performed by a highly sensitive high-resolution liquid chromatography/mass spectrometry (LC-HSMS/MS) method. SHBG concentrations were measured by a validated immunoassay. Odds ratios (ORs) of TC by levels of each biomarker were estimated using conditional logistic regression models adjusted for potential confounders (including height, waist circumference, physical activity, smoking status, alcohol consumption, education level, and for women, age at first full term pregnancy, number of full term pregnancies, and exogenous hormone use). Results In pre-menopausal women, controls had a lower BMI, a shorter waist circumference, and a higher alcohol intake than the cases (24.2 vs. 25.7 kg/m2 for BMI, 76.5 vs. 80.0 cm for waist, 3.2 vs. 1.8 g/day for alcohol intake, respectively). Preliminary conditional logistic regression analyses suggest positive associations of borderline statistical significance of differentiated thyroid cancer with the concentrations of T, D4 and DHEA in pre-menopausal women (ORT3vsT1: 1.83 (95% CI: 0.99–3.39) for T; 1.99 (95% CI: 1.02–3.87) for D4; 1.84 (95% CI: 0.95–3.56) for DHEA). No associations could be observed in postmenopausal women nor in men. No associations were found with estrogens or progesterone. Conclusions This study is the first prospective study conducted on sex steroids and differentiated TC risk and will provide insights on mechanisms relating overweight and obesity to TC risk. Our preliminary results suggest a possible positive association of differentiated TC risk with high androgen concentration in pre-menopausal women but no relationship with estrogens or progesterone.

Non-invasive assessment of glucocorticoid and androgen metabolite levels in cooperatively breeding Damaraland mole-rats (Fukomys damarensis)

Dominant females of cooperative breeding species often use aggression to suppress reproduction of subordinate females, resulting in subordinates experiencing stress-related increases in glucocorticoid levels, which may cause reproductive down-regulation. This would suggest a general pattern with higher glucocorticoid levels in subordinate compared to dominant individuals; however, the opposite was found in a number of cooperatively breeding species. Furthermore, breeding females of the cooperatively breeding Damaraland mole-rats (Fukomys damarensis) exhibit very high androgen concentrations during the wet season, presumably to support their breeding monopoly. Hormone analysis in Damaraland mole-rats have typically been measured using plasma and urine, but faecal analysis offers additional advantages especially for field studies on this species. The present study examines the suitability of Damaraland mole-rat faecal samples for determining glucocorticoid metabolite (fGCM) and androgen metabolite (fAM) concentrations using enzyme immunoassays. Using these assays, we further evaluated the effects of breeding status on fGCM and fAM concentrations in wild-caught and captive Damaraland mole-rats. Wild-caught breeding and non-breeding males and females exhibited no differences in fAM concentrations. Immunoreactive fGCM concentrations were only high in male breeders and comparatively low in non-breeders and breeding females. Concentrations of fAMs and fGCMs were similar in captive males and females, but fAM concentrations were elevated in captive compared to wild-caught individuals, which may be related to a higher reproductive activity due to removal from the breeding female. The relatively uniform fAM and fGCM concentrations found in wild-caught mole-rats may be explained by a stable colony structure during the dry season during which this study was conducted. Limited dispersal opportunities result in lower aggression and stress levels within a colony and as a result lower fAM and fGCM concentrations.

Enlarged adipocytes in subcutaneous adipose tissue associated to hyperandrogenism and visceral adipose tissue volume in women with polycystic ovary syndrome

ContextPolycystic ovary syndrome (PCOS) is an androgen excess disorder associated with obesity and adipose tissue disturbances. Our aim was to evaluate gene expression of adipocytokines and adipocyte characteristics in abdominal subcutaneous adipose tissue (SAT) of PCOS women. DesignTwelve PCOS (PCOSw) and 12 control (Cw) premenopausal women (BMI 20–35 kg/m2) were included, with measurements of whole-body composition assessed by dual-energy X-ray absorptiometry, and abdominal subcutaneous and visceral adipose tissue (VAT) volume, by magnetic resonance imaging. An oral glucose tolerance test was performed with measurements of glucose and insulin, and sex steroids, lipid profile and serum adipocytokines were determined in the fasting sample. Adipocytokine gene expression, mean adipocyte area and macrophage infiltration were evaluated in SAT biopsies. ResultsBoth groups were comparable in age and BMI. Trunk fat mass amount (p = .043), serum and SAT leptin/adiponectin ratio (p = .034 and p = .028, respectively) and adipocyte area (p = .015) were higher in PCOSw compared to Cw. Interestingly, trunk fat mass was positively correlated with adipocyte area in PCOSw (r = 0.821, p = .023), while the inverse correlation was found in Cw (r = −0.786, p = .021). Only in PCOSw, adipocyte area was positively correlated with serum testosterone (r = 0.857, p = .014) and visceral adipose tissue volume (r = 0.857, p = .014). ConclusionsOur results indicate that PCOS women present adipose tissue dysfunction in the subcutaneous compartment, characterized by an alteration in adipocyte size and leptin/adiponectin expression and secretion, probably associated with higher androgen concentrations.

Steroid hormones and persistent organic pollutants in plasma from North-eastern Atlantic pilot whales

Persistent organic pollutants (POPs) are known to have endocrine disruptive effects, interfering with endogenous steroid hormones. The present study examined nine steroid hormones and their relationships with the concentrations of selected POPs in pilot whales (Globicephala melas) from the Faroe Islands, NE Atlantic. The different steroids were detected in 15 to all of the 26 individuals. High concentrations of progesterone (83.3–211.7pmol/g) and pregnenolone (PRE; 4.68–5.69pmol/g) were found in three adult females indicating that they were pregnant or ovulating. High androgen concentrations in two of the males reflected that one was adult and that one (possibly) had reached puberty. In males a significant positive and strong correlation between body length and testosterone (TS) levels was identified. Furthermore, positive and significant correlations were found between 4-OH-CB107/4’-OH-CB108 and 17β-estradiol in males. In adult females significant positive correlations were identified between PRE and CB149 and t-nonachlor, between estrone and CB138, -149, -187 and p,p’-DDE, between androstenedione and CB187, and between TS and CB-99 and -153. Although relationships between the POPs and the steroid hormones reported herein are not evidence of cause-effect relationships, the positive correlations between steroids and POPs, particularly in females, suggest that POPs may have some endocrine disrupting effects on the steroid homeostasis in this species.