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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 -
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 -
Biochemical and Biophysical Research... Nov 2019Raised brain levels of testosterone (Tes), as well as single nucleotide polymorphisms of P-glycoprotein (P-gp) that cause impaired transport function, are associated...
Raised brain levels of testosterone (Tes), as well as single nucleotide polymorphisms of P-glycoprotein (P-gp) that cause impaired transport function, are associated with increased risk of suicide. Here, we examined whether Tes and its precursors and metabolites are substrates of P-gp, using several in vitro methods. In ATPase assay, increased ATP consumption was observed as the concentrations of Tes, dihydroepiandrosterone (Dhea), androstenedione (Ado), and dihydrotestosterone (Dht), but not androstenediol (Adol), were increased, suggesting that these four androgens are transported by P-gp. Furthermore, Tes and Ado, though not Dhea or Dht, increased the intracellular accumulation of Rhodamine 123 (Rho123), a typical substrate of P-gp, in a P-gp-overexpressing cell line, suggesting that they inhibit Rho123 efflux and thus are substrates or inhibitors of P-gp. A membrane permeability study using P-gp-overexpressing cells in Transwell inserts indicated that the permeability coefficients of both Ado and Tes in the basal-to-apical direction (excretion) are significantly higher than those in the apical-to-basal direction. Moreover, transport of both Ado and Tes was significantly suppressed by verapamil, a typical P-gp inhibitor. These results indicate that Tes and Ado are endogenous substrates of P-gp. These findings provide a physiological basis for understanding previously reported associations of P-gp dysfunction and raised brain levels of Tes with suicidal behavior, and may open up new possibilities for treating patients at risk of suicide.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adenosine Triphosphatases; Androstenedione; Animals; Brain; Cell Culture Techniques; Cell Line; Cell Membrane; Cell Membrane Permeability; Dose-Response Relationship, Drug; Humans; Protein Binding; Rhodamine 123; Risk; Suicide; Swine; Testosterone; Verapamil
PubMed: 31585733
DOI: 10.1016/j.bbrc.2019.09.067 -
Reproductive Biology and Endocrinology... Jun 2022According to current definitions of Polycystic Ovary Syndrome (PCOS), hyperandrogenism is considered as a key element in the pathogenesis of this common endocrinopathy....
BACKGROUND
According 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).
METHODS
A 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.
RESULTS
In 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.
CONCLUSIONS
PCOS 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.
Topics: Adipokines; Androgens; Androstenedione; Apelin; Cohort Studies; Desoxycorticosterone; Female; Follicular Fluid; Humans; Hyperandrogenism; Polycystic Ovary Syndrome; Pregnenolone; Resistin; Retrospective Studies; Testosterone
PubMed: 35701786
DOI: 10.1186/s12958-022-00959-6 -
International Journal of Molecular... May 2021Breast cancer is the most common malignancy in women with high mortality. Sensitive and specific methods for the detection, characterization and quantification of... (Review)
Review
Breast cancer is the most common malignancy in women with high mortality. Sensitive and specific methods for the detection, characterization and quantification of endogenous steroids in body fluids or tissues are needed for the diagnosis, treatment and prognosis of breast cancer and many other diseases. At present, non-invasive diagnostic methods are gaining more and more prominence, which enable a relatively fast and painless way of detecting many diseases. Metabolomics is a promising analytical method, the principle of which is the study and analysis of metabolites in biological material. It represents a comprehensive non-invasive diagnosis, which has a high potential for use in the diagnosis and prognosis of cancers, including breast cancer. This short review focuses on the targeted metabolomics of steroid hormones, which play an important role in the development and classification of breast cancer. The most commonly used diagnostic tool is the chromatographic method with mass spectrometry detection, which can simultaneously determine several steroid hormones and metabolites in one sample. This analytical procedure has a high potential in effective diagnosis of steroidogenesis disorders. Due to the association between steroidogenesis and breast cancer progression, steroid profiling is an important tool, as well as in monitoring disease progression, improving prognosis, and minimizing recurrence.
Topics: Androstenedione; Biomarkers, Tumor; Breast Neoplasms; Dehydroepiandrosterone; Dihydrotestosterone; Estradiol; Estrone; Female; Gas Chromatography-Mass Spectrometry; Humans; Immunoassay; Metabolic Networks and Pathways; Metabolomics; Recurrence; Tandem Mass Spectrometry
PubMed: 34070921
DOI: 10.3390/ijms22115878 -
Environmental Health : a Global Access... Sep 2023Knowledge of whether prenatal exposure to ambient air pollution disrupts steroidogenesis is currently lacking. We investigated the association between prenatal ambient...
Knowledge of whether prenatal exposure to ambient air pollution disrupts steroidogenesis is currently lacking. We investigated the association between prenatal ambient air pollution and highly accurate measurements of cord blood steroid hormones from the androgenic pathway.This study included 397 newborns born between the years 2010 and 2015 from the ENVIRONAGE cohort in Belgium of whom six cord blood steroid levels were measured: 17α-hydroxypregnenolone, 17α-hydroxyprogesterone, dehydroepiandrosterone, pregnenolone, androstenedione, and testosterone. Maternal ambient exposure to PM (particles with aerodynamic diameter ≤ 2.5 μm), NO and black carbon (BC) were estimated daily during the entire pregnancy using a high-resolution spatiotemporal model. The associations between the cord blood steroids and the air pollutants were tested and estimated by first fitting linear regression models and followed by fitting weekly prenatal exposures to distributed lag models (DLM). These analyses accounted for possible confounders, coexposures, and an interaction effect between sex and the exposure. We examined mixture effects and critical exposure windows of PM, NO and BC on cord blood steroids via the Bayesian kernel machine regression distributed lag model (BKMR-DLM).An interquartile range (IQR) increment of 7.96 µg/m in PM exposure during pregnancy trimester 3 was associated with an increase of 23.01% (99% confidence interval: 3.26-46.54%) in cord blood levels of 17α-hydroxypregnenolone, and an IQR increment of 0.58 µg/m³ in BC exposure during trimester 1 was associated with a decrease of 11.00% (99% CI: -19.86 to -0.012%) in cord blood levels of androstenedione. For these two models, the DLM statistics identified sensitive gestational time windows for cord blood steroids and ambient air pollution exposures, in particular for 17α-hydroxypregnenolone and PM exposure during trimester 3 (weeks 28-36) and for androsterone and BC exposure during early pregnancy (weeks 2-13) as well as during mid-pregnancy (weeks 18-26). We identified interaction effects between pollutants, which has been suggested especially for NO.Our results suggest that prenatal exposure to ambient air pollutants during pregnancy interferes with steroid levels in cord blood. Further studies should investigate potential early-life action mechanisms and possible later-in-life adverse effects of hormonal disturbances due to air pollution exposure.
Topics: Infant, Newborn; Female; Pregnancy; Humans; 17-alpha-Hydroxypregnenolone; Androstenedione; Bayes Theorem; Birth Cohort; Fetal Blood; Nitrogen Dioxide; Prenatal Exposure Delayed Effects; Air Pollution; Steroids; Air Pollutants; Particulate Matter
PubMed: 37674219
DOI: 10.1186/s12940-023-01010-w -
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 -
Archives of Women's Mental Health Oct 2022The aim of this study was to determine whether serum androgen levels have an effect on mindfulness and metacognition in adolescents with polycystic ovary syndrome...
The aim of this study was to determine whether serum androgen levels have an effect on mindfulness and metacognition in adolescents with polycystic ovary syndrome (PCOS). Adolescents diagnosed with PCOS were asked to answer a questionnaire that included socio-demographic information and two scales: the Mindful Attention Awareness Scale (MAAS) and the Metacognition Scale Child and Adolescent form (MCQ-C). The patients were divided into two groups, the hyperandrogenism group and the non-hyperandrogenism group, according to serum androgen levels. The scores of MAAS and MCQ-C were compared between the groups. The study sample consisted of 70 adolescents. Of these, 44 had hyperandrogenism according to a blood test. No statistically significant difference was found in MAAS scores between the hyperandrogenism and the non-hyperandrogenism groups (p = 0.79). However, the level of mindfulness was found to be lower in participants with a higher modified Ferriman-Gallwey score (mFGS) (r = 0.26, p = 0.02). Mindfulness levels were also lower for obese patients with PCOS compared to non-obese patients with PCOS (p = 0.02). Cognitive monitoring (MCQ-C-CM), one of the MCQ-C sub-scales, was significantly higher in the non-hyperandrogenism group (p = 0.03), and similarly, a positive correlation was detected between higher androgen levels and the positive meta-worry (MCQ-C-PM) sub-scale of the MCQ-C (for total testosterone; r = 0.348, p = 0.03, and for androstenedione; r = 0.35, p = 0.03). High serum androgen levels in PCOS had no effect on mindfulness, but as the modified Ferriman Gallwey score increased, mindfulness levels decreased. For the sub-scales of MCQ-C,MCQ-C-CM, and MCQ-C-PM, the scores increased as androgen levels increased. In line with the results of the present study, evaluating mindfulness in PCOS patients with increased hair growth and metacognition in PCOS patients with serum hyperandrogenism may contribute well-being in adulthood by reducing the psychological burden caused by the disease.
Topics: Adolescent; Androgens; Androstenedione; Female; Humans; Hyperandrogenism; Metacognition; Mindfulness; Obesity; Polycystic Ovary Syndrome; Testosterone
PubMed: 36074275
DOI: 10.1007/s00737-022-01264-2