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Prostate Cancer and Prostatic Diseases Dec 2023Prostate cancer (PCa) typically spreads to the bone, and this distribution is attributed to the central role of the microenvironment in progression. However, metastasis...
BACKGROUND
Prostate cancer (PCa) typically spreads to the bone, and this distribution is attributed to the central role of the microenvironment in progression. However, metastasis to the adrenal glands, while not as common, does occur. The biology that accounts for adrenal metastases may be attributed to the unique local steroid metabolome and co-clinical characterization may elucidate the role steroid biosynthesis plays in PCa progression.
METHODS
Three patients with metastatic PCa who had archived tumor tissue from an adrenalectomy were retrospectively identified, and one adrenal metastasis was developed into a xenograft (MDA-PCa-250). The adrenal metastases were characterized by performing somatic DNA whole exome sequencing (WES), RNA-Seq, immunohistochemistry (IHC), and steroid metabolite quantitation. The influence of steroid metabolites on adrenal metastasis cells and tumor growth was tested in vitro and in vivo.
RESULTS
Clinically, adrenalectomy was performed during castration-resistant oligometastatic disease, and two men experienced resensitization to leuprolide. Somatic DNA WES revealed heterogeneous alterations in tumor suppressor and DNA damage repair pathway genes. Adrenal metastases had active androgen receptor (AR) signaling by IHC, and RNA-Seq supported a potential role for adrenal androgen precursor metabolism in activating the AR. Steroid quantitation suggested the adrenal androgen precursors were converted into testosterone in these metastases, and stable isotope tracing of an organoid from MDA-PCa-250 confirmed the capability of adrenal metastases to biosynthesize testosterone from adrenal precursors. In vitro testing of a cell line derived from MDA-PCa-250 showed that testosterone and cortisol stimulated tumor cell growth. In vivo experiments demonstrated that MDA-PCa-250 grew in intact mice with circulating testosterone, but not in castrated mice.
CONCLUSIONS
PCa adrenal metastases depend upon AR signaling driven by androgen precursors, androstenedione and dehydroepiandrosterone, available in the microenvironment, despite the presence of heterogeneous somatic DNA alterations. Moreover, MDA-PCa-250 provides a preclinical model that can recapitulate the unique androgen-dependence of adrenal metastases.
CLINICAL TRIAL REGISTRATION
This study does not report the clinical results of a clinical trial, but it does use samples from a completed clinical trial that is registered with clinicaltrials.gov (NCT01254864).
Topics: Male; Humans; Animals; Mice; Androgens; Prostatic Neoplasms; Receptors, Androgen; Retrospective Studies; Steroids; Testosterone; DNA; Cell Line, Tumor; Tumor Microenvironment
PubMed: 36100698
DOI: 10.1038/s41391-022-00590-x -
Frontiers in Pharmacology 2023The Internet has become an important source for easy access to doping substances, where people and athletes may acquire, outside pharmacies and without a (medical)...
The Internet has become an important source for easy access to doping substances, where people and athletes may acquire, outside pharmacies and without a (medical) prescription. These online websites do not always offer quality-assured products, and are outside the regular distribution channels of medicines. The aim of this study was to estimate the availability and accessible information on the Internet about the sale of three doping substances (oxandrolone, DHEA, androstenedione). Cross-sectional exploratory study, being an observation at a point in time of the online availability of these three doping substances (WADA S1 category: anabolic agents), purchased from Spain, Puerto Rico, Canada, United States, Ukraine and Russia. The characteristics of the websites, the countries the webs sold to, the pharmaceutical forms offered and the recommendations for its use were analyzed by using a computer tool designed . There were significant differences between countries in the number of webpages that sold the products (Chi-square test, < 0.05). Oxandrolone was available for purchase mainly when buying from Spain (27.12%) and Ukraine (26.58%), in websites dedicated to sports (77.26%). For DHEA, most of the pages offered it if the search was done from Canada (23.34%) and Russia (21.44%). Products containing androstenedione or DHEA are claimed to enhance sports performance or for sports use without providing details. Compared to the total number of websites checked, the proportion of pharmacies offering these products was low, ranging from 4.86% for DHEA to 15.79% for androstenedione. The three substances selected are easily available without control through the Internet. Only a small number of websites offering them were online pharmacies, and requested a prescription. Most of the doping substances are purchased from the country where they are requested. Product information described benefits for sports performance, but did not do the same with their side effects. It would be advisable for these products to be sold through pharmacies, to guarantee their quality and provide evidence-based information on their safe use, benefits and risks, and only with a prescription. Athletes should be encouraged to consult health professionals about those supplements suitable for their type of training and sports objectives.
PubMed: 38111382
DOI: 10.3389/fphar.2023.1305080 -
The New England Journal of Medicine Jun 2024Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to...
BACKGROUND
Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels.
METHODS
In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained.
RESULTS
A total of 103 participants underwent randomization, of whom 69 were assigned to the crinecerfont group and 34 to the placebo group; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol per liter). At week 4, the androstenedione level was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol per liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol per liter]) (least-squares mean difference, -268 ng per deciliter [-9.3 nmol per liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol per liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol per liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (least-squares mean difference, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events.
CONCLUSIONS
In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.).
PubMed: 38828945
DOI: 10.1056/NEJMoa2404655 -
The Journal of Clinical Endocrinology... Apr 2024Women with hypopituitarism remain at increased risk of morbidity and mortality. Insufficient replacement of sex steroids has been suggested as a contributing factor, but...
CONTEXT
Women with hypopituitarism remain at increased risk of morbidity and mortality. Insufficient replacement of sex steroids has been suggested as a contributing factor, but sex steroid levels in women with hypopituitarism have not been comprehensively mapped.
OBJECTIVE
To quantify sex steroids in women with hypopituitarism by a high-sensitivity assay.
METHODS
Using a combination of clinical and biochemical criteria, women with hypopituitarism (n = 104) who started growth hormone replacement 1995-2014 at a single center were categorized as eugonadal or having hypogonadotropic hypogonadism (HH). A population-based cohort of women (n = 288) served as controls. Eugonadal women and controls were categorized as pre-/postmenopausal and HH women as younger/older (≤ or >52 years). Dehydroepiandrosterone (DHEA), androstenedione, testosterone, dihydrotestosterone, progesterone, 17αOH-progesterone, estradiol and estrone were analyzed by a validated liquid chromatography-tandem mass spectrometry assay.
RESULTS
Among both premenopausal/younger and postmenopausal/older women, women with HH had lower levels of sex steroid precursors (DHEA, androstenedione) and androgens (testosterone and dihydrotestosterone) than controls. Progesterone, 17αOH-progesterone, estrone and estradiol showed similar patterns. Women with HH and adrenocorticotropic hormone (ACTH) deficiency had markedly lower concentrations of all sex hormones than those without ACTH deficiency.
CONCLUSION
This study demonstrates for the first time a broad and severe sex steroid deficiency in both younger and older women with HH, particularly in those with combined gonadotropin and ACTH deficiency. The health impact of low sex steroid levels in women with hypopituitarism requires further study and women with combined gonadotropin and ACTH deficiency should be a prioritized group for intervention studies with sex hormone replacement.
PubMed: 38570732
DOI: 10.1210/clinem/dgae197 -
Endocrine Sep 2023Polycystic ovarian syndrome (PCOS) is a common heterogeneous condition with probably multifactorial genesis. Animal studies have proven the essential role of the...
PURPOSE
Polycystic ovarian syndrome (PCOS) is a common heterogeneous condition with probably multifactorial genesis. Animal studies have proven the essential role of the sympathetic nervous system in the syndrome development, while human studies are still contradictory. The present study aims to investigate the possible influence of plasma-free metanephrine (MN), and normetanephrine (NMN), nerve growth factor (NGF), and renalase (RNL) on the hormonal and metabolic parameters in women with PCOS and healthy controls.
METHODS
Fifty patients with PCOS and 30 healthy women participated in the study. The plasma-free MN and NMN, NGF, RNL, anti-Mullerian hormone (AMH), gonadotropin, androgen levels, and metabolic parameters were investigated.
RESULTS
Plasma-free NMN and NGF concentrations were increased in PCOS individuals, while RNL levels were decreased compared to healthy volunteers. Increased plasma-free NMN (OR = 1.0213 [95%CI 1.0064-1.0364], p = 0.005) and NGF (OR = 1.0078 [95%CI 1.0001-1.0155], p = 0.046) but not MN or RNL levels were associated with a higher risk of PCOS after adjustment for age. Plasma-free NMN levels were positively associated with the LH (r = +0.253; p = 0.039). androstenedione (r = +0.265; p = 0.029), 17-OH progesterone (r = +0.285; p = 0.024), NGF (r = +0.320; p = 0.008), and AMH (r = +0.417; p < 0.001) concentrations of the investigated women. RNL levels were inversely related to the BMI (r = -0.245; p = 0.029), HOMA-IR (r = -0.250; p = 0.030), free testosterone (r = -0.303; p = 0.006) levels. systolic (r = -0.294; p = 0.008) and diastolic (r = -0.342; p = 0.002) blood pressure.
CONCLUSIONS
Increased sympathetic noradrenergic activity and NGF synthesis might be related to the increased AMH and delta-4 androgen levels in a subgroup of PCOS patients. RNL levels might influence the metabolic status of PCOS patients. Further studies are needed to explore the significance of adrenal medullar and autonomic dysfunction for developing different PCOS phenotypes and their subsequent cardiovascular complications.
Topics: Humans; Female; Polycystic Ovary Syndrome; Metanephrine; Androgens; Nerve Growth Factor; Anti-Mullerian Hormone
PubMed: 37248367
DOI: 10.1007/s12020-023-03404-9 -
Huan Jing Ke Xue= Huanjing Kexue Aug 2023Sewage treatment plants (STPs) are one of the crucial barriers for the environmental emission of steroid hormones. Insights into the occurrence and fate of different...
Sewage treatment plants (STPs) are one of the crucial barriers for the environmental emission of steroid hormones. Insights into the occurrence and fate of different categories of steroid hormones in STPs could provide theoretical support for improving steroid removal by STPs. The present study investigated 22 steroid hormones in each treatment process of two STPs located in Wuxi via eight monthly sampling campaigns and compared the efficacy of Anaerobic-Anoxic-Aerobic (A/O) and reversed A/O treatments. The results showed that the total steroid concentrations in the influent and effluent were 27.7-256.8 ng·L and 5.7-211.0 ng·L, respectively, and 36.3-123.6 ng·g in the excess sludge. Androsterone, androstenedione, estrone, estriol, and progesterone were the main species detected in the STPs. The concentrations of most steroids increased with the rise of rainfall and temperature, whereas the removal rates were not significantly different between winter and summer. Secondary and tertiary treatment processes showed better performance in steroid removal compared with that in the primary treatment; however, reversed A/O did not show advantages over traditional A/O. The organic-normalized partition coefficients (lg ) of steroids ranged between 2 and 4.5. The values of lg in STP A were slightly greater than those in STP B, indicating that the partition behavior of steroids may influence their treatment efficacies.
Topics: Sewage; Progesterone; Estrone; Seasons; Temperature
PubMed: 37694631
DOI: 10.13227/j.hjkx.202208003 -
Journal of Inorganic Biochemistry Oct 2023Cholesterol, a significant constituent of the endoplasmic reticulum membrane, exerts a substantial effect on the membrane's biophysical and mechanical properties....
Cholesterol, a significant constituent of the endoplasmic reticulum membrane, exerts a substantial effect on the membrane's biophysical and mechanical properties. Cholesterol, however, is often neglected in model systems used to study membrane-bound proteins. For example, the influence of cholesterol on the enzymatic functions of type 2 cytochromes P450, which require a phospholipid bilayer and the redox partner P450-oxidoreductase (POR) for activity, are rarely investigated. Human aromatase (P450 19A1) catalyzes three sequential oxygenations of 19‑carbon steroids to estrogens and is widely expressed across various tissues, which are characterized by varying cholesterol compositions. Our study examined the impact of cholesterol on the functionality of the P450 19A1 complex with POR. Nanodiscs containing P450 19A1 with 20% cholesterol/80% phospholipid had similar rates and affinity of androstenedione binding as phospholipid-only P450 19A1 nanodiscs, and rates of product formation were indistinguishable among these conditions. In contrast, the rate of the first electron transfer from POR to P450 19A1 was 3-fold faster in cholesterol-containing nanodiscs than in phospholipid-only nanodiscs. These results suggest that cholesterol influences some aspects of POR interaction with P450 19A1 and might serve as an additional regulatory mechanism in this catalytic system.
Topics: Humans; Aromatase; Phospholipids; Oxidation-Reduction; Steroids; Cholesterol
PubMed: 37544101
DOI: 10.1016/j.jinorgbio.2023.112340 -
The World Journal of Men's Health Apr 2024The study aimed to comprehensively analyze testosterone and precursor concentrations in the testicular interstitial fluid (TIF) of men with azoospermia, exploring their...
PURPOSE
The study aimed to comprehensively analyze testosterone and precursor concentrations in the testicular interstitial fluid (TIF) of men with azoospermia, exploring their significance in the testicular microenvironment and their correlation with testicular sperm retrieval outcomes.
MATERIALS AND METHODS
We analyzed 37 TIF samples, including 5 from men with obstructive azoospermia (OA) and 32 from men with non-obstructive azoospermia (NOA). Liquid chromatography with tandem mass spectrometry quantified testosterone and precursor levels. Comparative assessments of the outcomes of testicular sperm retrieval were performed between the OA and NOA groups as well as among men with NOA.
RESULTS
Men with NOA who had not undergone hormone treatment exhibited significantly higher intratesticular concentrations of testosterone (median 1,528.1 207.5 ng/mL), androstenedione (median 10.6 1.9 ng/mL), and 17-OH progesterone (median 13.0 1.8 ng/mL) than men diagnosed with OA. Notably, in the subgroup of patients with NOA subjected to medical treatment, men with successful sperm retrieval had significantly reduced levels of androstenedione (median androstenedione 5.7 18.5 ng/mL, p=0.004). Upon a more detailed analysis of these men who underwent hormone manipulation treatment, the testosterone/androstenedione ratio (indicative of HSD17B3 enzyme activity) was markedly increased in men with successful sperm retrieval (median: 365.8 165.0, p=0.008) compared with individuals with NOA who had unsuccessful sperm recovery. Furthermore, within the subset of men with NOA who did not undergo medical treatment before microdissection testicular sperm extraction but achieved successful sperm retrieval, the ratio of 17-OH progesterone/progesterone (indicative of CYP17A1 activity) was substantially higher.
CONCLUSIONS
The study suggests distinct testosterone biosynthesis pathways in men with compromised spermatogenesis and those with normal spermatogenesis. Among NOA men with successful retrieval after hormone optimization therapy, there was decreased androstenedione and increased HSD17B3 enzyme activity. These findings have diagnostic and therapeutic implications for the future.
PubMed: 38772536
DOI: 10.5534/wjmh.230265 -
Clinical Chemistry and Laboratory... Jun 2024Steroid hormone levels of patients may be monitored via dried blood spot (DBS) sampling at home. Stability of steroid hormones in DBS samples, however, needs to be...
OBJECTIVES
Steroid hormone levels of patients may be monitored via dried blood spot (DBS) sampling at home. Stability of steroid hormones in DBS samples, however, needs to be established.
METHODS
DBS samples from healthy volunteers were collected and stored at various temperatures. Steroid hormone concentrations in DBS were measured directly, at day 2, day 7 and day 14 following storage at 37 °C and after 7 days, 14 days, 3 months and 6 months following storage at -20 °C, 4 °C and room temperature (RT). Cortisol, cortisone, corticosterone, testosterone, androstenedione, and 17-hydroxyprogesterone (17-OHP) were assessed using LC-MS/MS.
RESULTS
All steroids were stable (±15 %) up to 14 days when stored at 37 °C, except for cortisone (only stable until 2 days). All steroids were stable up to 6 months when stored at -20 °C, 4 °C and RT. However, there were some exceptions, for androstenedione at RT (only stable until 7 days), for 17-OHP when stored at -20 °C (only stable until 3 months), for cortisone at RT and 4 °C (only stable until 14 days), and cortisol at RT (only stable until 3 months).
CONCLUSIONS
Overall, we demonstrated stability of steroid hormone concentrations in DBS under various conditions which may be encountered during shipping to the diagnostic laboratory and during long-term storage before analysis.
PubMed: 38874994
DOI: 10.1515/cclm-2024-0142 -
The Journal of Clinical Endocrinology... Jun 2024Androstenedione (A4) and testosterone (T) are produced by both the adrenal glands and the gonads. The adrenal enzyme 11β-hydroxylase (CYP11B1) executes the final step...
CONTEXT
Androstenedione (A4) and testosterone (T) are produced by both the adrenal glands and the gonads. The adrenal enzyme 11β-hydroxylase (CYP11B1) executes the final step in cortisol synthesis; CYP11B1 also uses A4 and T as substrates, generating 11-hydroxyandrostenedione and 11-hydroxytestosterone, respectively. It has been suggested that CYP11B1 is expressed in the gonads, yet the circulating levels of all 11-oxygenated androgens (11-oxyandrogens) are similar in males and females of reproductive ages, despite enormous differences in T.
OBJECTIVE
To assess the gonadal contribution to the circulating pool of 11-oxyandrogens.
METHODS
We used liquid chromatography-tandem mass spectrometry to measure 13 steroids, including traditional and 11-oxyandrogens in: (I) paired gonadal and peripheral vein blood samples obtained during gonadal venograms from 11 patients (7 women), median age 37 (range 31-51 years); and (II) 17 women, median age 57 (range 41-81 years) before and after bilateral salpingo-oophorectomy (BSO). We also compared CYP11B1, 17α-hydroxylase/17,20-lyase (CYP17A1), and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) mRNA expression in adrenal, ovarian, and testicular tissue.
RESULTS
A4, T, estradiol, estrone, progesterone, 17α- and 16α-hydroxyprogesterone were all higher in gonadal veins vs. periphery (p < 0.05 for all), while four 11-oxyandrogens were similar between matched gonadal and peripheral vein samples. Equally, in women who underwent BSO, A4 (median [interquartile range]: 59.7 [47.7-67.6] ng/dL vs. 32.7 [27.4-47.8] ng/dL, p < 0.001) and T (24.1 [16.4-32.3] vs.15.5 [13.7-19.0] ng/dL, p < 0.001) declined, while 11-oxyandrogens remained stable. Gonadal tissue displayed negligible CYP11B1 mRNA.
CONCLUSION
Despite producing substantial amounts of A4 and T, human gonads are not relevant sources of 11-oxyandrogens.
PubMed: 38885296
DOI: 10.1210/clinem/dgae420