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Breast Cancer Research : BCR Oct 2022Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between...
BACKGROUND
Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.
METHODS
Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.
RESULTS
We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.
CONCLUSIONS
TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.
Topics: 17-alpha-Hydroxyprogesterone; Adult; Aldosterone; Androstenedione; Breast Neoplasms; Dehydroepiandrosterone Sulfate; Estradiol; Female; Genome-Wide Association Study; Gonadal Steroid Hormones; Humans; Hydrocortisone; Longitudinal Studies; Mendelian Randomization Analysis; Progesterone; Sex Hormone-Binding Globulin; Testosterone
PubMed: 36209141
DOI: 10.1186/s13058-022-01553-9 -
The Journal of Clinical Endocrinology... Feb 2022Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production....
CONTEXT
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production.
OBJECTIVE
This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD.
METHODS
This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.
RESULTS
Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (-66%), 17OHP (-64%), and androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios.
CONCLUSION
Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.
Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Young Adult; 17-alpha-Hydroxyprogesterone; Administration, Oral; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Androstenedione; Azabicyclo Compounds; Biomarkers; Dose-Response Relationship, Drug; Oxadiazoles; Receptors, Corticotropin-Releasing Hormone; Testosterone; Treatment Outcome
PubMed: 34653252
DOI: 10.1210/clinem/dgab749 -
The Journal of Clinical Endocrinology... Oct 2023Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital...
CONTEXT
Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin.
OBJECTIVE
To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH.
METHODS
This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.
RESULTS
8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone.
CONCLUSION
Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.
Topics: Male; Adult; Humans; Female; Adolescent; Androgens; Adrenal Hyperplasia, Congenital; Androstenedione; 17-alpha-Hydroxyprogesterone; Testosterone; Adrenocorticotropic Hormone
PubMed: 37216921
DOI: 10.1210/clinem/dgad270 -
Journal of Endocrinological... Aug 2022The aim of this study was to examine the hormonal profile in early-pubertal girls with obesity. We hypothesized that these patients might already present hormonal...
PURPOSE
The aim of this study was to examine the hormonal profile in early-pubertal girls with obesity. We hypothesized that these patients might already present hormonal alterations with POCS-like features.
METHODS
Cross-sectional study in a sample of 283 peri-pubertal girls (prepubertal and early-puberty subgroups), aged 6.1-12.0 years, diagnosed with obesity (BMI-SDS > 2.0, 97th percentile), so-called obesity group. They all underwent clinical examination and blood testing for hormonal measurements (leptin, TSH, FT4, IGF-1, IGFBP3, prolactin, insulin, FSH, LH, estradiol, ACTH, cortisol, 17-OH-P, DHE-S, androstenedione, testosterone and free testosterone). A control group was recruited: 243 healthy girls, aged 6.3-12.1 years, with normal BMI status.
RESULTS
Prepubertal girls with obesity had significantly higher values (p < 0.05) for BMI-SDS, leptin, insulin and HOMA-IR levels than control group. Early-pubertal girls with obesity also had significantly higher values (p < 0.05) for BMI-SDS, leptin, IGF-1, IGFBP3, insulin and HOMA-IR, LH, ratio LH/FSH, ACTH, DHE-S, androstenedione, testosterone and free testosterone levels than control group. In early-pubertal girls with obesity (not prepubertal girls), there was a positive correlation (p < 0.01) between leptin levels with LH, androstenedione and testosterone, and HOMA-IR with LH and testosterone levels. There was also a positive correlation (p < 0.01) between IGF-1 levels with LH, androstenedione, DHE-S and testosterone; and LH levels with testosterone.
CONCLUSION
The results obtained support our hypothesis that an abnormal hormonal profile with POCS-like features can already be detected (insulin resistance and hyperinsulinemia, increased secretion of LH and ACTH, and overproduction of ovarian and adrenal androgens) in early-pubertal girls with obesity.
Topics: Adrenocorticotropic Hormone; Androgens; Androstenedione; Cross-Sectional Studies; Female; Follicle Stimulating Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Obesity; Puberty; Puberty, Precocious; Testosterone
PubMed: 35412268
DOI: 10.1007/s40618-022-01797-4 -
Annales D'endocrinologie Aug 2023Congenital adrenal hyperplasia (CAH) is a genetic disease caused by an enzyme deficiency interrupting adrenal steroidogenesis. It most frequently involves... (Review)
Review
Congenital adrenal hyperplasia (CAH) is a genetic disease caused by an enzyme deficiency interrupting adrenal steroidogenesis. It most frequently involves 21-hydroxylase, which induces adrenal insufficiency with hyperandrogenism. Restoring hormonal balance is difficult with glucocorticoids, which are the gold-standard treatment. Strict normalization of conventional biomarkers (17-hydroxyprogesterone and delta-4 androstenedione) is often obtained at the cost of iatrogenic hypercortisolism. Optimizing the management of these patients first involves using more specific biomarkers of adrenal steroidogenesis in difficult situations, and secondly using therapeutics targeting the induced hypothalamic-pituitary-adrenal axis disorder. 11-oxygenated androgens are candidates for biochemical monitoring of Congenital adrenal hyperplasia (CAH), in particular 11-ketotestosterone. Numerous new therapeutic agents are currently being explored, the prime goal being to reduce glucocorticoid exposure, as no strategy can fully replace it at present. They can be divided into 3 categories. The first includes "more physiological" hydrocortisone administration (modified-release hydrocortisone and continuous subcutaneous infusion of hydrocortisone hemisuccinate); the second includes corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) receptor antagonists and anti-ACTH antibodies; and the third includes steroidogenesis inhibitors. Finally, experiments on gene and cell therapies suggest the possibility of lasting remission or even cure in the future.
Topics: Humans; Adult; Adrenal Hyperplasia, Congenital; Hydrocortisone; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Glucocorticoids; Biomarkers
PubMed: 36842612
DOI: 10.1016/j.ando.2023.01.008 -
Methods in Molecular Biology (Clifton,... 2023The phytosterol-biotransforming strains can be selected from Mycobacterium sp. using a high concentration of β-sitosterol. The selection is made by culturing the...
The phytosterol-biotransforming strains can be selected from Mycobacterium sp. using a high concentration of β-sitosterol. The selection is made by culturing the strains in a medium enriched with 14 g/L of β-sitosterol as the unique source of carbon. During 2 months, the bacterial cultures are transferred successively. The extraction of the biotransformation products is made with methanol and ethyl acetate. The qualitative and quantitative analyses are made by means of thin-layer chromatography, gas-liquid chromatography (GLC), and GLC-mass spectrometry. Under these conditions, it is observed that after seven transfers, the strains Mycobacterium sp. MB-3683 and Mycobacterium fortuitum B-11045 increase their biotransformation capacity from 20% to 64% and from 34% to 55%, respectively. The products in the highest proportion identified for each trial are androstenedione and androstadienedione. The results suggest that the high substrate concentration could be a selective mechanism to obtain strains more efficient in the biotransformation of β-sitosterol into steroidal bases.
Topics: Phytosterols; Gas Chromatography-Mass Spectrometry; Androstenedione; Carbon; Chromatography, Thin Layer
PubMed: 37642837
DOI: 10.1007/978-1-0716-3385-4_3 -
Pediatric Annals Jun 2023In the quest for winning the game, some athletes take various chemicals (ie, drugs, herbs, or supplements) in attempts to develop greater strength, endurance, or other...
In the quest for winning the game, some athletes take various chemicals (ie, drugs, herbs, or supplements) in attempts to develop greater strength, endurance, or other elements that bring a competitive advantage. There are more than 30,000 chemicals sold throughout the world with unrestrained and unproven claims; however, some athletes consume them with hopes of increasing their athletic abilities, often without knowledge of the potential adverse effects and with limited evidence of efficacy. Complicating this picture is that research on ergogenic chemicals is typically conducted with elite adult male athletes and not with athletes who are in high school. A few of these ergogenic aids include creatine, anabolic androgenic steroids, selective androgen receptor modulators, clenbuterol, androstenedione, dehydroepiandrosterone, human growth hormone, ephedrine, gamma hydroxybutyrate, caffeine, stimulants (amphetamines or methylphenidate), and blood doping. In this article, we describe the purpose of ergogenic aids as well as the potential side effects. .
Topics: Humans; Male; Child; Central Nervous System Stimulants; Doping in Sports; Sports; Amphetamines; Athletes
PubMed: 37280002
DOI: 10.3928/19382359-20230411-02 -
Frontiers in Endocrinology 2022Although the role of steroid hormones in lipid levels has been partly discussed in the context of separate sexes, the causal relationship between steroid hormones and...
BACKGROUND
Although the role of steroid hormones in lipid levels has been partly discussed in the context of separate sexes, the causal relationship between steroid hormones and lipid metabolism according to sex has not been elucidated because of the limitations of observational studies. We assessed the relationship between steroid hormones and lipid metabolism in separate sexes using a two-sample Mendelian randomization (MR) study.
METHODS
Instrumental variables for dehydroepiandrosterone sulfate (DHEAS), progesterone, estradiol, and androstenedione were selected. MR analysis was performed using inverse-variance weighted, MR-Egger, weighted median, and MR pleiotropy residual sum and outlier tests. Cochran's Q test, the MR-Egger intercept test, and leave-one-out analysis were used for sensitivity analyses.
RESULTS
The results showed that the three steroid hormones affected lipid metabolism and exhibited sex differences. In males, DHEAS was negatively correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B ( = 0.007; = 0.006; = 0.041, respectively), and progesterone was negatively correlated with TC and LDL-C ( = 0.019; = 0.038, respectively). In females, DHEAS was negatively correlated with TC ( = 0.026) and androstenedione was negatively correlated with triglycerides and apolipoprotein A ( = 0.022; = 0.009, respectively). No statistically significant association was observed between the estradiol levels and lipid metabolism in male or female participants.
CONCLUSIONS
Our findings identified sex-specific causal networks between steroid hormones and lipid metabolism. Steroid hormones, including DHEAS, progesterone, and androstenedione, exhibited beneficial effects on lipid metabolism in both sexes; however, the specific lipid profiles affected by steroid hormones differed between the sexes.
Topics: Humans; Male; Female; Lipid Metabolism; Sex Characteristics; Cholesterol, LDL; Progesterone; Mendelian Randomization Analysis; Androstenedione; Cholesterol, HDL; Steroids; Estradiol; Apolipoproteins
PubMed: 36726474
DOI: 10.3389/fendo.2022.1119154 -
Clinical Chemistry Dec 2023Androgens are synthesized from cholesterol through sequential conversions by enzymes in the adrenal glands and gonads. Serum levels of androgens change during the... (Review)
Review
BACKGROUND
Androgens are synthesized from cholesterol through sequential conversions by enzymes in the adrenal glands and gonads. Serum levels of androgens change during the different phases of life and regulate important developmental and maturational processes. Androgen excess or deficiency can therefore present at various ages in various ways.
CONTENT
The diagnostic approach for atypical genitalia, premature pubarche, delayed pubertal onset or progression, and hirsutism or virilization, including measurement of androgens (testosterone, androstenedione, 17-OHprogesterone, dehydroepiandrosterone, and dihydrotestosterone) is discussed in the current review. Androgens can be measured in serum, saliva, urine, or dried blood spots. Techniques to measure androgens, including immunoassays and LC-MS, have their own advantages and pitfalls. In addition, pre- and postanalytical issues are important when measuring androgens.
SUMMARY
During clinical interpretation of androgen measurements, it is important to take preanalytical circumstances, such as time of blood withdrawal, into account. As immunoassays have major drawbacks, especially in samples from women and neonates, concentrations measured using these assays should be interpreted with care. Reference intervals can only be used in relation to the measurement technique and the standardization of the assay. In the near future, new androgens will probably be added to the current repertoire to further improve the diagnosis and follow-up of androgen excess or deficiency.
Topics: Infant, Newborn; Female; Humans; Androgens; Testosterone; Androstenedione; Virilism; Hirsutism; Dehydroepiandrosterone
PubMed: 37794651
DOI: 10.1093/clinchem/hvad146 -
Steroids Mar 2022Although DHEA sulfate (DS) is the most abundant steroid in the circulation, breast fluid contains an approximately 80-fold greater concentration than serum. Transport of... (Review)
Review
Although DHEA sulfate (DS) is the most abundant steroid in the circulation, breast fluid contains an approximately 80-fold greater concentration than serum. Transport of DS into cells requires organic anion transporting polypeptides (OATPs), which are specific for cell type, cell location, and substrate, but may have a broader specificity for housekeeping functions. Specific classes, which may be modified by soluble factors including neutral steroids, have been identified in the breast. After transport, DS may be cleaved to DHEA by ubiquitous sulfatases, which may be modified by the cell milieu, or DHEA may enter by diffusion. Synthesis from cholesterol does not occur because CYP17B12 and cytochrome b5 are lacking in breast tissues. Case-control studies reveal a positive association of serum DS with risk of breast cancer. The association is even greater with DHEA, particularly in postmenopausal women with HR + invasive tumors. Metabolites of DHEA, androstenedione and testosterone, are associated with breast cancer but DHEA is likely to have an independent role as well. Mechanisms by which DHEA may promote breast cancer relate to its effect in increasing circulating IGF-I, by inhibiting the suppressive effect of glucocorticoids, and by promoting retention of pre-adipocytes with aromatase activity. In addition, DHEA may interact with the G-protein coupled receptor GPER for stimulation of miR-21 and subsequent activation of the MAPK pathway. DHEA also has antitumor properties that relate to stimulation of immunity, suppression of inflammation, and elevation of adipose tissue adiponectin synthesis. The net effect may depend on the which factors predominate.
Topics: Androstenedione; Breast Neoplasms; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Humans; Testosterone
PubMed: 35122788
DOI: 10.1016/j.steroids.2022.108970