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British Journal of Clinical Pharmacology Mar 2021The aim of this study was to characterize the pharmacokinetic/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17-hydroxyprogesterone and...
AIMS
The aim of this study was to characterize the pharmacokinetic/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17-hydroxyprogesterone and androstenedione in children with congenital adrenal hyperplasia (CAH).
METHODS
A nonlinear mixed-effect modelling approach was used to analyse cortisol, 17-hydroxyprogesterone and androstenedione concentrations obtained over 6 hours from children with CAH (n = 50). A circadian rhythm was evident and the model leveraged literature information on circadian rhythm in untreated children with CAH. Indirect response models were applied in which cortisol inhibited the production rate of all three compounds using an I model.
RESULTS
Cortisol was characterized by a one-compartment model with apparent clearance and volume of distribution estimated at 22.9 L/h/70 kg and 41.1 L/70 kg, respectively. The IC values of cortisol concentrations for cortisol, 17-hydroxyprogesterone and androstenedione were estimated to be 1.36, 0.45 and 0.75 μg/dL, respectively. The inhibitory effect was found to be more potent on 17OHP than D4A, and the IC values were higher in salt-wasting subjects than simple virilizers. Production rates of cortisol, 17-hydroxyprogesterone and androstenedione were higher in simple-virilizer subjects. Half-lives of cortisol, 17-hydroxyprogesterone and androstenedione were 60, 47 and 77 minutes, respectively.
CONCLUSION
Rapidly changing biomarker responses to cortisol concentrations highlight that single measurements provide volatile information about a child's disease control. Our model closely captured observed cortisol, 17-hydroxyprogesterone and androstenedione concentrations. It can be used to predict concentrations over 24 hours and allows many novel exposure metrics to be calculated, e.g., AUC, AUC-above-threshold, time-within-range, etc. Our long-range goal is to uncover dose-exposure-outcome relationships that clinicians can use in adjusting hydrocortisone dose and timing.
Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Androstenedione; Biomarkers; Child; Humans; Hydrocortisone
PubMed: 32652643
DOI: 10.1111/bcp.14470 -
Gynecological Endocrinology : the... Jun 2023To evaluate the efficacy of dietary supplementation with a combination of antioxidants (lipoic acid, -acetylcysteine, vitamin B, and -adenosyl-L-methionine) for the... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To evaluate the efficacy of dietary supplementation with a combination of antioxidants (lipoic acid, -acetylcysteine, vitamin B, and -adenosyl-L-methionine) for the modulation of metabolic, endocrine, and clinical parameters in comparison with oral contraception in non-diabetic women newly diagnosed with polycystic ovary syndrome (PCOS).
METHODS
This was a prospective, partially randomized, multicenter study in which non-diabetic women with PCOS were recruited under routine clinical practice conditions and distributed in three groups to receive the following regimen for 6 months: 1) antioxidant combination (MN group); 2) oral contraception (OC group); or 3) oral contraception and the antioxidant combination (MN + OC group). General recommendation of healthy diet and regular exercise was given to all patients. Metabolic, endocrine, clinical, and quality of life parameters were recorded at baseline and after 6 months of therapy.
RESULTS
A total of 96 women with PCOS were included in the study. After 6 months of treatment, the homeostasis model assessment-estimated insulin resistance (HOMA-IR) level was reduced only in the MN group, with a significant mean reduction of -0.92 points. Androstenedione was significantly reduced in all groups. Clinical parameters that significantly improved in all groups were hirsutism, acne, irregular menstruation, and quality of life, with no statistical differences between the groups.
CONCLUSIONS
This study showed that the antioxidant combination might be a suitable therapy for patients with PCOS when oral contraceptive is not indicated, because in all groups clinical parameters, irregular menstruation as well as androstenedione and quality of life were significantly improved with no statistical difference between groups.
Topics: Female; Humans; Androstenedione; Antioxidants; Insulin Resistance; Menstruation Disturbances; Polycystic Ovary Syndrome; Prospective Studies; Quality of Life; Contraceptives, Oral; Dietary Supplements
PubMed: 37356455
DOI: 10.1080/09513590.2023.2227277 -
Frontiers in Endocrinology 2022The long-standing knowledge that Sertoli cells determine fetal testosterone production levels is not widespread, despite being first reported over a decade ago in... (Review)
Review
The long-standing knowledge that Sertoli cells determine fetal testosterone production levels is not widespread, despite being first reported over a decade ago in studies of mice. Hence any ongoing use of testosterone as a marker of Leydig cell function in fetal testes is inappropriate. By interrogating new scRNAseq data from human fetal testes, we demonstrate this situation is also likely to be true in humans. This has implications for understanding how disruptions to either or both Leydig and Sertoli cells during the masculinization programming window may contribute to the increasing incidence of hypospadias, cryptorchidism, testicular germ cell tumours and adult infertility. We recently discovered that activin A levels directly govern androgen production in mouse Sertoli cells, because the enzymes that drive the conversion of the precursor androgen androstenedione to generate testosterone are produced exclusively in Sertoli cells in response to activin A. This minireview addresses the implications of this growing understanding of how exposures affect fetal masculinization for future research on reproductive health, including during programming windows that may ultimately be relevant for organ development in males and females.
Topics: Activins; Androgens; Animals; Humans; Male; Mice; Sertoli Cells; Testis; Testosterone
PubMed: 35685219
DOI: 10.3389/fendo.2022.898876 -
Pediatric Research Jun 2022Premature adrenarche is a condition of childhood adrenal androgen excess (AAE) in the absence of gonadotropin-dependent puberty, and has been linked to insulin...
BACKGROUND
Premature adrenarche is a condition of childhood adrenal androgen excess (AAE) in the absence of gonadotropin-dependent puberty, and has been linked to insulin resistance and progression to metabolic syndrome. Microbial dysbiosis is associated with progression of inflammatory states and chronic diseases. Here, we aimed to examine the salivary microbiomes of children with AAE and assess the relationship with adrenal androgens and metabolic parameters.
METHODS
In a prospective cross-sectional study of children with AAE and healthy controls, adrenal and metabolic parameters were characterized and salivary microbiome was profiled using V3-V4 16S rDNA gene amplicon sequencing.
RESULTS
There was increased α-diversity in AAE (5 M, 15 F) compared to controls (3 M, 8 F), with positive correlation of 11OHA4, 11KA4, testosterone, androstenedione, DHEA, and DHEAS. Subanalyses showed increased α-diversity in both overweight/obese AAE and normal weight AAE compared to normal weight controls. Genus Peptostreptococcus, Veillonella, and Streptococcus salivarius were increased in normal weight AAE. Genus Prevotella, Abiotrophia, and Neisseria were increased in overweight/obese AAE.
CONCLUSION
These pilot data demonstrate differences in salivary microbiome profiles of children with and without AAE. Further studies are needed to assess the causal relationships between adrenal androgens, metabolic dysfunction, and salivary microbiome composition.
IMPACT
This study is the first to report the salivary microbiome of prepubertal children with adrenal androgen excess (AAE). α-Diversity is increased in the salivary microbiome of children with AAE independent of weight status, and in this study cohort several serum androgens are positively associated with α-diversity. Several taxa that have been associated with periodontal disease and inflammation are found to be significantly increased in AAE.
Topics: Androgens; Child; Cross-Sectional Studies; Dehydroepiandrosterone; Humans; Microbiota; Obesity; Overweight; Prospective Studies
PubMed: 34341500
DOI: 10.1038/s41390-021-01661-w -
Endocrinology, Diabetes & Metabolism Jul 2021A recent Mendelian randomization study has suggested a causal role for sex hormone-binding globulin (SHBG), total testosterone and free testosterone in the pathogenesis...
The relationships of sex hormone-binding globulin, total testosterone, androstenedione and free testosterone with metabolic and reproductive features of polycystic ovary syndrome.
OBJECTIVE
A recent Mendelian randomization study has suggested a causal role for sex hormone-binding globulin (SHBG), total testosterone and free testosterone in the pathogenesis of polycystic ovary syndrome (PCOS). The aim of this study was to assess the relationships of SHBG, androstenedione, total and free testosterone with the individual metabolic and reproductive features of PCOS.
DESIGN
Cross-sectional data in PCOS patients (n=96) prospectively collected in a secondary/tertiary clinic for menstrual cycle disorders.
METHODS
Multivariable regression analyses were conducted to study the associations between SHBG, androstenedione, total and free testosterone with metabolic (BMI, waist circumference, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and homeostatic model assessment for insulin resistance [HOMA2-IR]) and reproductive features (menstrual cycle length, antral follicle count, anti-Müllerian hormone, luteinizing hormone, follicle-stimulating hormone and Ferriman-Gallwey score) of PCOS.
RESULTS
Serum SHBG and free testosterone, but not total testosterone or androstenedione, were significantly associated with BMI, waist circumference, serum triglycerides, HDL cholesterol, LDL cholesterol and HOMA2-IR. The strength of the associations with serum lipids was reduced after adjustment for BMI, but not for HOMA2-IR. Total testosterone was significantly associated with antral follicle count. SHBG, total testosterone and androstenedione were significantly associated with serum AMH. Only the strength of the association for SHBG was reduced after adjustment for BMI.
CONCLUSIONS
Serum SHBG is associated with primarily metabolic features, whereas total testosterone and androstenedione are associated with reproductive features of PCOS. These results suggest a differential underlying pathophysiology for the metabolic and reproductive features of PCOS.
Topics: Androstenedione; Cross-Sectional Studies; Female; Humans; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Testosterone
PubMed: 34277990
DOI: 10.1002/edm2.267 -
Revista Brasileira de Ginecologia E... Dec 2020The present study aimed to investigate the physical performance of handgrip strength (HGS) in women with polycystic ovary syndrome (PCOS).
OBJECTIVE
The present study aimed to investigate the physical performance of handgrip strength (HGS) in women with polycystic ovary syndrome (PCOS).
METHODS
A case-control study that included 70 women with PCOS and 93 age-matched healthy women aged between 18 and 47 years with body mass index (BMI) between 18 Kg/m-39.9 Kg/m. The serum levels of total testosterone, androstenedione, insulin, estradiol, thyroid-stimulating hormone (TSH), prolactin, sex hormone-binding globulin (SHBG), and 17-hydroxyprogesterone (17-OHP) were measured. The free androgen index (FAI) and the homeostatic model assessment of insulin resistance (HOMA-IR) were calculated. The body composition regions of interest (ROIs) were assessed by dual-energy X-ray absorptiometry (DXA), and the handgrip strength (HGS) was evaluated for both the dominant and the non-dominant hands with a manual Sammons Preston (Bolingbrook, IL, US) bulb dynamometer.
RESULTS
Women with PCOS had high serum levels of total testosterone ( 0.01), androstenedione ( = 0.03), and insulin ( 0.01), as well as high FAI ( 0.01) and HOMA-IR ( = 0.01) scores. Compared with the non-PCOS group, the PCOS group had greater total lean mass in the dominant hand ( < 0.03) and greater HGS in both the dominant and the non-dominant hands ( 0.01). The HGS was correlated with lean mass ( 0.01).
CONCLUSION
Women with PCOS have greater HGS. This may be associated with age and BMI, and it may be related to lean mass. In addition, the dominance effect on muscle mass may influence the physical performance regarding HGS in women with PCOS.
Topics: Absorptiometry, Photon; Adolescent; Adult; Body Composition; Case-Control Studies; Female; Hand Strength; Humans; Middle Aged; Polycystic Ovary Syndrome; Young Adult
PubMed: 33348398
DOI: 10.1055/s-0040-1718953 -
The Journal of Sexual Medicine Aug 2021Women treated for rectal cancer are at risk of sexual dysfunction and impaired ovarian androgen production.
BACKGROUND
Women treated for rectal cancer are at risk of sexual dysfunction and impaired ovarian androgen production.
AIM
To investigate a possible association between serum levels of endogenous androgens and sexual function in women with rectal cancer.
METHODS
Women diagnosed with stage I-III rectal cancer were consecutively included and prospectively followed with the Female Sexual Function Index (FSFI) questionnaire from baseline to 2 years postoperatively and blood samples for hormone analyses, baseline to 1 year. Androgens were measured with liquid chromatography-mass spectrometry and electrochemiluminescence. The associations between the 4 measured androgens (testosterone, free testosterone, androstenedione, and dehydroepiandrosterone sulphate) and sexual function were assessed with generalized least squares random effects regression analysis in sexually active women.
OUTCOMES
The primary outcome measure was the mean change observed in the FSFI total score when the serum androgen levels changed with one unit. Secondary outcomes were the corresponding mean changes in the FSFI domain scores: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain/discomfort.
RESULTS
In the 99 participants, the median FSFI total score decreased from 21.9 (range 2.0 - 36.0) to 16.4 (3.5 - 34.5) and 11.5 (2.0 to 34.8) at 1 and 2-years follow-up. After adjustment for age, partner, psychological well-being, preoperative (chemo)radiotherapy, and surgery, total testosterone and androstenedione were significantly associated with FSFI total score (β-coefficients 3.45 (95% CI 0.92 - 5.97) and 1.39 (0.46 - 2.33) respectively). Testosterone was significantly associated with the FSFI-domains lubrication and orgasm, free testosterone with lubrication, androstenedione with all domains except desire and satisfaction, and dehydroepiandrosterone sulphate with none of the domains.
STRENGTHS AND LIMITATIONS
This is the first study investigating whether androgen levels are of importance for the impaired sexual function seen in women following rectal cancer treatment. The prospective design allows for repeated measures and the use of the FSFI for comparisons across studies. No laboratory data were collected at the 2-year follow-up, and the missing data could have further clarified the studied associations.
CONCLUSION AND CLINICAL IMPLICATION
Testosterone and androstenedione were associated with sexual function in female rectal cancer patients. The results are of interest for future intervention studies and contribute to the understanding of sexual problems, which is an essential component of the rehabilitation process in pelvic cancer survivors. Svanström Röjvall A, Buchli C, Flöter Rådestad A, et al. Impact of Androgens on Sexual Function in Women With Rectal Cancer - A Prospective Cohort Study. J Sex Med 2021;18:1374-1382.
Topics: Androgens; Female; Humans; Libido; Orgasm; Prospective Studies; Rectal Neoplasms; Surveys and Questionnaires
PubMed: 34284953
DOI: 10.1016/j.jsxm.2021.05.018 -
Journal of Veterinary Internal Medicine Jan 2021Information on steroids derived from the adrenal glands, gonads, or fetoplacental unit is minimal in newborn foals.
BACKGROUND
Information on steroids derived from the adrenal glands, gonads, or fetoplacental unit is minimal in newborn foals.
OBJECTIVE
To measure androgen concentrations in serum and determine their association with disease severity and outcome in hospitalized foals.
ANIMALS
Hospitalized (n = 145) and healthy (n = 80) foals.
METHODS
Prospective, multicenter, cross-sectional study. Foals of ≤3 days of age from 3 hospitals and horse farms were classified as healthy and hospitalized (septic, sick nonseptic, neonatal maladjustment syndrome [NMS]) based on physical exam, medical history, and laboratory findings. Serum androgen and plasma ACTH concentrations were measured with immunoassays. Data were analyzed by nonparametric methods and univariate analysis.
RESULTS
Serum dehydroepiandrosterone (DHEA), androstenedione, testosterone, and dihydrotestosterone (DHT) concentrations were higher upon admission in hospitalized foals (P < .05), were associated with nonsurvival, decreased to 4.9-10.8%, 5.7-31%, and 30.8-62.8% admission values in healthy, SNS, and septic foals, respectively (P < .05), but remained unchanged or increased in nonsurviving foals. ACTH:androgen ratios were higher in septic and NMS foals (P < .05). Foals with decreased androgen clearance were more likely to die (odds ratio > 3; P < .05).
CONCLUSIONS AND CLINICAL IMPORTANCE
Similar to glucocorticoids, mineralocorticoids, and progestagens, increased serum concentrations of androgens are associated with disease severity and adverse outcome in hospitalized newborn foals. In healthy foals, androgens decrease over time, however, remain elevated longer in septic and nonsurviving foals. Androgens could play a role in or reflect a response to disorders such as sepsis or NMS in newborn foals.
Topics: Androgens; Animals; Animals, Newborn; Cross-Sectional Studies; Horse Diseases; Horses; Prospective Studies; Sepsis
PubMed: 33277956
DOI: 10.1111/jvim.15974 -
Advances in Clinical and Experimental... Mar 20213β-HSD deficiency is a rare type of congenital adrenal hyperplasia (CAH), which is caused by HSD3B2 gene mutations.
BACKGROUND
3β-HSD deficiency is a rare type of congenital adrenal hyperplasia (CAH), which is caused by HSD3B2 gene mutations.
OBJECTIVES
In order to improve the understanding and diagnosis of the disease, we analyzed and summarized the clinical characteristics, genetic variants and treatment for 3 children with 3β-HSD deficiency in this study.
MATERIAL AND METHODS
A summary of the clinical data, hormone levels (17-hydroxyprogesterone, adrenocorticotropic hormone, cortisol, testosterone, dehydroepiandrosterone, androstenedione, renin, and aldosterone), therapeutic drugs, and gene sequencing results from 3 3β-HSD deficiency patients was created.
RESULTS
The 3 patients developed external genital abnormalities and adrenal insufficiency in infancy. Steroid hormone levels were consistent with 3β-hydroxysteroid dehydrogenase deficiency. Gene sequencing for the 3 patients detected complex heterozygous mutations in the HSD3B2 gene, which confirmed the diagnosis of 3β-HSD deficiency type II. Among the mutation types, c.154_162delinsTCCTGTT and c.674T>A have not been reported in the literature. The 3 children were treated with glucocorticoid and mineralocorticoid replacement, which controlled the adrenal insufficiency satisfactorily. In 2 male patients, external genital dysplasia manifested as hypospadias and small penis. After long-acting testosterone intramuscular injection to increase the penis size, the hypospadias were repaired. Mild masculinization in the female patient resulted in skin pigmentation and clitoral hypertrophy; however, no surgical intervention was required.
CONCLUSIONS
The main clinical manifestations of 3β-HSD deficiency were adrenal insufficiency and sex hormone synthesis dysfunction. There was a strong phenotype correlation between the observed clinical manifestations in conjunction with steroid hormone levels and HSD3B2 mutations. The novel mutations c.154_162delinsTCCTGTT and c.674T>A were classified as pathogenic variants. Adrenal cortical function control was satisfactory after hormone replacement therapy, and hypospadias and small penis were attenuated using testosterone replacement therapy during mini-puberty for optimal surgical outcome.
Topics: Adrenal Hyperplasia, Congenital; Child; Female; Heterozygote; Humans; Hydrocortisone; Male; Mineralocorticoids
PubMed: 33757164
DOI: 10.17219/acem/131220 -
ELife Dec 2023Children undergoing cancer treatments are at risk for impaired fertility. Cryopreserved prepubertal testicular biopsies could theoretically be later matured to produce...
Children undergoing cancer treatments are at risk for impaired fertility. Cryopreserved prepubertal testicular biopsies could theoretically be later matured to produce spermatozoa for assisted reproductive technology. A complete spermatogenesis has been obtained from mouse prepubertal testicular tissue, although with low efficiency. Steroid hormones are essential for the progression of spermatogenesis, the aim of this study was to investigate steroidogenesis and steroid signaling in organotypic cultures. Histological, RT-qPCR, western blot analyses, and steroid hormone measurements were performed on cultured mouse prepubertal testicular tissues and age-matched controls. Despite a conserved density of Leydig cells after 30 days of culture (D30), transcript levels of adult Leydig cells and steroidogenic markers were decreased. Increased amounts of progesterone and estradiol and reduced androstenedione levels were observed at D30, together with decreased transcript levels of steroid metabolizing genes and steroid target genes. hCG was insufficient to facilitate Leydig cell differentiation, restore steroidogenesis, and improve sperm yield. In conclusion, this study reports the failure of adult Leydig cell development and altered steroid production and signaling in tissue cultures. The organotypic culture system will need to be further improved before it can be translated into clinics for childhood cancer survivors.
Topics: Child; Adult; Humans; Male; Animals; Mice; Androgens; Semen; Testis; Progesterone; Estrogens; Signal Transduction
PubMed: 38095307
DOI: 10.7554/eLife.85562