Testosterone Metabolites Research Articles

The efficacy of using platelet-rich plasma (PRP) in the treatment of androgenic alopecia: a literature review

Androgenetic alopecia (AGA) is currently the primary cause of hair loss in both men and women. It is characterized by a progressive thinning of the hair follicles due to a shortening of the anagen phase of the hair growth cycle. The pathophysiology mainly involves the accumulation of dihydrotestosterone (DHT), a metabolite of testosterone, and a chronic perifollicular inflammatory process. The objective of this study is to evaluate, through a literature review, the validity, protocols, and efficacy of the use of platelet-rich plasma (PRP) in the treatment of patients with AGA. It is a review conducted in the first half of 2024, using the PubMed and BVS databases, employing Descritores em Ciência e Saúde (alopecia, plasma rico em plaquetas, terapia) and Medical Subject Headings (alopecia, platelet-rich plasma, therapy). Inclusion criteria consisted of: a) articles published between 2022 and 2024; b) written in Portuguese or English; c) full-text articles available for free; d) research focused on PRP therapy for the treatment of androgenetic alopecia in men. Twelve articles were included in the synthesis. Overall, the articles indicated that despite the need for standardized protocols, the use of PRP as a treatment for AGA shows promising results in the current context. The therapy demonstrated improvements in hair density and patient satisfaction, suggesting its potential as a viable option for managing androgenetic alopecia. Besides being a safe option with minimal side effects, its combination with other therapies, such as minoxidil, has brought beneficial outcomes for patients with this condition. Keywords: Alopecia, Platelet-Rich Plasma, Therapy

Abstract 3572: Role of the gut microbiome in androgen production and prostate cancer treatment resistance

Abstract Metastatic prostate cancer is often treated via a combination of androgen deprivation therapy (ADT) and the androgen receptor axis-targeted therapies abiraterone acetate + prednisone (AA/P) or enzalutamide. Unfortunately, most individuals undergoing these treatments develop resistance, termed “castration resistance”, through an unknown mechanism. Previous studies demonstrate a potential link between the gut microbiota and the treatment efficacy of endocrine therapy in metastatic castration resistant prostate cancer (mCRPC). This may be due in part to gut bacterial communities with the machinery to synthesize androgens using mechanisms distinct from human cells. For example, the bacterial desAB genes (e.g., “desmolase”) that were first described in the gut commensal bacterial species Clostridium scindens convert cortisol and prednisone to the androgenic metabolites 11β-hydroxyandrost-4-ene-3,17-dione (11OHAD) and ∆1-adrenosterone (∆1-AT), respectively. We hypothesize that androgen synthesis by the gut microbiota promotes treatment resistance to AA/P in advanced prostate cancer. This study aims to determine if androgen-converting gut bacterial species as well as circulating and fecal androgen levels correlate with AA/P treatment response in individuals with mCRPC using a combination of metagenomics and metabolomics. We further aim to demonstrate the relationship between gut bacterial androgen production and prostate cancer treatment response using an in vivo mouse model. Metagenomic sequencing showed an imbalance in microbial communities and identified the presence of androgen-synthesizing bacteria such as C. scindens in fecal samples of individuals undergoing treatment with AA/P. We also demonstrate that the relative abundance of C. scindens, as well as other species reported to generate androgens, are significantly enriched during metastatic disease progression on AA/P. Furthermore, targeted quantitative PCR of the bacterial desmolase (desA) gene demonstrated that absolute levels of desmolase are significantly higher in AA/P non-responders relative to AA/P responders, and trended higher in individuals with rising prostate-specific antigen (PSA) versus stable PSA while on AA/P. Targeted LC/MS/MS analyses of fecal samples demonstrated the presence of testosterone, dihydrotestosterone, 11OHAD, ∆1-AT, and other androgen metabolites in association with rising PSA levels in the AA/P cohort. Furthermore, we demonstrate that C. scindens converts hydrocortisone and prednisone into 11OHAD and ∆1-AT, respectively, in vitro at 48- and 72h post-treatment, which recapitulates prior published studies. Finally, we have established a prostate cancer mouse model using a VCaP xenograft in which tumor growth was significantly inhibited by abiraterone acetate in comparison to treatment with ADT alone. Additional studies will use this mouse model to study the effects of androgen metabolism by gut bacteria on AA/P efficacy. Overall, this study ascertains the ability of the human gut microbiota to harbor androgen-synthesizing bacteria, which in turn can be an alternative source of androgens that could impact the efficacy of the anti-androgen therapies used to treat metastatic prostate cancer. Citation Format: Angelica I. Cruz Lebron, Pedro A. Balbuena-Almodóvar, Luke Mummert, Sarah Ernst, Mark Markowski, Michelle Rudek, Jason Ridlon, Karen S. Sfanos. Role of the gut microbiome in androgen production and prostate cancer treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3572.

Mantled howler monkey males assess their rivals through formant spacing of long-distance calls.

Formant frequency spacing of long-distance vocalizations is allometrically related to body size and could represent an honest signal of fighting potential. There is, however, only limited evidence that primates use formant spacing to assess the competitive potential of rivals during interactions with extragroup males, a risky context. We hypothesized that if formant spacing of long-distance calls is inversely related to the fighting potential of male mantled howler monkeys (Alouatta palliata), then males should: (1) be more likely and (2) faster to display vocal responses to calling rivals; (3) be more likely and (4) faster to approach calling rivals; and have higher fecal (5) glucocorticoid and (6) testosterone metabolite concentrations in response to rivals calling at intermediate and high formant spacing than to those with low formant spacing. We studied the behavioral responses of 11 adult males to playback experiments of long-distance calls from unknown individuals with low (i.e., emulating large individuals), intermediate, and high (i.e., small individuals) formant spacing (n = 36 experiments). We assayed fecal glucocorticoid and testosterone metabolite concentrations (n = 174). Playbacks always elicited vocal responses, but males responded quicker to intermediate than to low formant spacing playbacks. Low formant spacing calls were less likely to elicit approaches whereas high formant spacing calls resulted in quicker approaches. Males showed stronger hormonal responses to low than to both intermediate and high formant spacing calls. It is possible that males do not escalate conflicts with rivals with low formant spacing calls if these are perceived as large, and against whom winning probabilities should decrease and confrontation costs increase; but are willing to escalate conflicts with rivals of high formant spacing. Formant spacing may therefore be an important signal for rival assessment in this species.

Fabrication of silastic testosterone enanthate implants to achieve virilizing levels of serum testosterone in swine

The aim of this study was to create a continuous drug delivery system that would yield serum testosterone levels in sexually mature, female pigs consistent with serum testosterone levels of human transgender men. Testosterone enanthate was mixed with medical grade silicone at a ratio of 20 % by weight, placed in silastic tubing to cure at room temperature for 24 h, then removed from the tubing mold and stored at 4 °C until surgical implantation. Testosterone enanthate oxidizes at high temperatures which is why the implants had to be stored cold. Each implant was 9 cm long and contained 0.56 g of testosterone enanthate. A minimum of one implant (0.56 g testosterone enanthate) and a maximum of four implants (2.24 g testosterone enanthate) were placed in the cervical subcutaneous fat of each pig. After implantation, serum testosterone was assessed over 40 days. Silastic testosterone enanthate implants increase serum testosterone and maintain it in a relatively constant state in a dose-dependent manner for ∼ 21–25 days post-implantation.•Effective method for subcutaneous delivery of large quantities of testosterone or testosterone metabolites in compact implants to large animal biomedical model species.•Maintains increased circulating testosterone levels for up to 3, 4 weeks post-implantation in pigs.

Testosterone concentrations in juvenile male polar bears (Ursus maritimus)

The ex situ polar bear population in the United States is not sustainable. Current management practices include pairing mates at five to six years of age, but there is evidence that wild bears have sired cubs as early as two years old. Timing acquisition of sexual maturity in male polar bears could aid in determining when mates should be paired in ex situ populations. To address this, non-invasive fecal testosterone metabolite monitoring was evaluated as a technique for establishing age of sexual maturity in 14 male polar bears (aged 1–6.9 years) for 1–6 years. Testosterone metabolite concentrations were monitored throughout the year and evaluated by breeding season (Jan. 1 – May 21) compared to non-breeding season (May 22 – Dec. 31). Sexual maturity was defined as when testosterone metabolite concentrations were significantly greater during breeding season than non-breeding season and bi-weekly averages were elevated above baseline for a minimum of ten weeks during breeding season mimicking patterns in adult male polar bears. Testosterone metabolite concentrations ranged from 5.9 to 8342 ng/g. One bear met the defined criteria at two years of age and an additional three bears met criteria at three years old. Due to the sampling strategy and the requirements set forth by the definition of sexual maturity, there were confounding results. In two cases, bears determined to be sexually mature the year prior, were not categorized as mature the next year. Another bear demonstrated greater testosterone metabolite values during the non-breeding season than breeding season. This study demonstrated the variability in fecal testosterone metabolites in juvenile polar bears and results suggest that hormone assessment alone is not adequate for determining sexual maturity in ex situ male polar bears. However, if used in tandem with behavioral monitoring and semen collection, when possible, could aid breeding management decisions for ex situ populations.

Lupeol, an androgen receptor inhibitor, enhances the chemosensitivity of prostate cancer stem cells to antiandrogen enzalutamide-based therapy

Enzalutamide is an androgen receptor (AR) antagonist commonly used in the treatment of prostate cancer (CaP). However, due to the potential toxicity and development of resistance associated with Enzalutamide-based therapy, there is a need to explore additional compounds that can enhance its therapeutic effectiveness while minimizing toxicity. Lupeol is a pharmacologically active triterpene having anticancer effects. The objective of this study was to explore Lupeol's potential in enhancing the chemosensitivity of chemoresistant CaP cells to Enzalutamide in vitro and in a mouse model. To test our hypothesis, we performed cell viability and luciferase reporter gene assay, flow cytometry, animal studies, and histopathological analysis. Finally, we analyzed the change in selective metabolites in the prostate tissue by LCMS. Results demonstrated that a combination of Lupeol and Enzalutamide could better (i) suppress the Cancer Stem Cells (CSCs) and chemoresistant cells (PTEN-CaP8 and PC3) viability and migration, (ii) increase cell cycle arrest, (iii) inhibit the transcriptional activity of AR, c-MYC, c-FLIP, and TCF (iv) inhibit tumor growth in a mouse model (v) protect Enzalutamide-induced adverse effects in prostate glands and gut tissue (vi) decrease levels of testosterone and methionine metabolites. In conclusion, Lupeol enhances the pharmacological efficacy of Enzalutamide and reduces the adverse effects. Thus, Lupeol could be a promising adjuvant for improving Enzalutamide-based treatment outcomes and warrant further research.

Maternal steroids during pregnancy and their associations with exposure to lifetime stressful life events, prenatal stress appraisal and psychological functioning

BackgroundDuring pregnancy, steroids enable physiological adaptations in response to many factors, including maternal stress or psychological functioning. While stress and psychological dysfunction can have endocrine-disrupting effects beyond cortisol disruption, associations between prenatal maternal stress or related psychological dysfunction and the broader steroid milieu remain understudied. AimTo assess associations between independent and joint maternal stress and psychological functioning measures and steroid profiles in pregnancy (22–40 gestational weeks) in the Programming of Intergenerational Stress Mechanisms (PRISM) birth cohort (n = 334). MethodsSerum metabolomics detected 42 steroids and their metabolites, which were grouped into five classes (pregnenolone, androgens, estrogens, progestin, and corticosteroids). The Perceived Stress Scale, Life Stressor Checklist-Revised, and Edinburgh Postnatal Depression Scale indexed lifetime traumatic/non-traumatic stressors, global prenatal stress appraisal, and depressive symptoms during pregnancy, respectively. Exposures were categorized as high-low using the corresponding 3rd quartiles. We assessed associations between both individual and joint stress exposures with steroid classes using linear mixed effect models and with individual steroids using linear regressions. We also examined fetal sex-specific effects. ResultsHigh prenatal perceived stress was independently associated with lower levels of androgens and estrogens in the overall sample [β (95%CI): androgens: −0.13 (−0.25;−0.01); estrogens: −0.16 (−0.31;−0.01)], particularly among women carrying males [androgens: −0.22 (−0.39;−0.05); estrogens: −0.28 (−0.50;−0.07)]. Results on estrogens were consistent when considering joint exposure to both greater lifetime stressors and higher prenatal perceived stress. We also found a single testosterone metabolite—5alpha-androstan-3alpha,17alpha-diol disulfate—negatively associated with both individual high perceived stress and joint exposure to high lifetime stressors and high perceived stress among women carrying males. ConclusionsIncreased maternal perceived stress experienced in pregnancy was independently associated with lower maternal androgen and estrogen levels during pregnancy in the overall sample, particularly among women carrying males. Results on estrogens were consistent when we considered the joint exposure of increased lifetime stressors and higher prenatal perceived stress.

Abstract P384: Cytochrome P450 1B1-Testosterone Metabolite 6β-Hydroxytestosterone Promotes Ang II-induced Hypertension And Neuroinflammation Via Group IV Cytosolic Phospholipase A 2 α In Paraventricular Nucleus Of Male Mice

We reported previously that Ang (angiotensin) II-induced hypertension depends on the activation of group IV cPLA 2 α (cytosolic phospholipase A 2 α). Moreover, we showed that testosterone (T) metabolite 6β-hydroxytestosterone (6β-OHT) generated by CYP1B1 (cytochrome P450 1B1) in the paraventricular nucleus (PVN) promotes Ang II-induced hypertension and neuroinflammation in male mice. This study determined the relationship of cPLA 2 α and CYP1B1-T derived 6β-OHT in the PVN to Ang II-induced hypertension and neuroinflammation in male mice. cPLA 2 α knockdown in the PVN by transduction with adenovirus (Ad)-cPLA 2 α-short hairpin (sh)RNA (200 nL, bilaterally, 5.4X10 11 pfu/mL) but not its control Ad-scrambled (Scr)-shRNA (2.5X10 11 pfu/mL) in wild-type (WT) male mice, inhibited Ang II (700 ng/kg/min, s.c., two weeks)-induced increase in systolic blood pressure (Day 12- SBP mmHg, tail-cuff) (126±4 vs 167±4, respectively, P<0.05, n=4/group). Moreover, reconstitution of cPLA 2 α in the PVN by Ad-cPLA 2 α-DNA (5.5X10 9 pfu/mL), but not its control Ad-GFP-DNA (1.0X10 11 pfu/mL) in cPLA 2 α -/- mice restored the increase in SBP (153±6 vs 117±4, respectively, P<0.05, n=4/group). Ang II-induced increase in mean arterial blood pressure (MAP mmHg, radiotelemetry) that was minimized in WT-orchidectomized (ORX) or intact Cyp1b1 -/- mice were restored by ICV injections of 6β-OHT (1.5 μg/2 μL/alternate day), but it was attenuated by ICV (2 μL, single injection) Ad-cPLA 2 α-shRNA, but not its control Ad-Scr-shRNA (114±4 vs 150±7, and 121±2 vs 154±9, respectively, P<0.05, n=4-6/group). Ang II-induced increase in MAP was restored by 6β-OHT, but not its vehicle (2-hydroxypropyl-β-cyclodextrin in CSF, 2 μL/alternate day) in Ad-cPLA 2 α-DNA transduced ORX- cPLA 2 α -/- mice (165±6 vs 121±2, respectively, P<0.05, n=4/group). The number of TMEM119 + microglia and GFAP + astrocytes in PVN, markers of neuroinflammation, followed the changes in BP in the above groups produced by Ang II. In conclusion, T-CYP1B1 metabolite 6β-OHT promotes Ang II-induced hypertension and neuroinflammation by a mechanism dependent on cPLA 2 α in the PVN. Therefore, agents that reduce CYP1B1 or cPLA 2 α activity could be useful for treating Ang II/T-dependent hypertension and neuroinflammation in males.

Predicting Sex in White Rhinoceroses: A Statistical Model for Conservation Management.

Ensuring the effective management of every rhinoceros population is crucial for securing a future for the species, especially considering the escalating global threat of poaching and the challenges faced in captive breeding programs for this endangered species. Steroid hormones play pivotal roles in regulating diverse biological processes, making fecal hormonal determinations a valuable non-invasive tool for monitoring adrenal and gonadal endocrinologies and assessing reproductive status, particularly in endangered species. The purpose of this study was to develop a statistical model for predicting the sex of white rhinoceroses using hormonal determinations obtained from a single fecal sample. To achieve this, 562 fecal samples from 15 individuals of the Ceratotherium simum species were collected, and enzyme immunoassays were conducted to determine the concentrations of fecal cortisol, progesterone, estrone, and testosterone metabolites. The biological validation of the method provided an impressive accuracy rate of nearly 80% in predicting the sex of hypothetically unknown white rhinoceroses. Implementing this statistical model for sex identification in white rhinoceroses would yield significant benefits, including a better understanding of the structure and dynamics of wild populations. Additionally, it would enhance conservation management efforts aimed at protecting this endangered species. By utilizing this innovative approach, we can contribute to the preservation and long-term survival of white rhinoceros populations.

It is all About the Chase: Neurosteroidogenesis in Male Rats is Driven by Control of Mating Pace.

Masculine sexual behaviors are dependent on androstane-derived steroids; however, the modulatory effects of mating, and of mating control, on androstane neurosteroidogenesis remain largely unknown. Herein, we investigated the effects of mating control, prior sexual experience, and age on brain region specific neurosteroidogenic responses in male rats. Effects of acute sexual experience were tested in naïve male rats that either remained sexually- naïve, were exposed to a standard mating chamber, or were either given control of the mating pace in a standard mating chamber (male control) or mated wherein the female stimulus rat controlled the mating pace in a paced-mating chamber (female control). Aged (10-12 months) sexually responsive male rats were similarly euthanized from the homecage or engaged in male controlled or female controlled mating. All rats were euthanized immediately following exposure conditions for radioimmunoassay of steroids in midbrain, hypothalamus, hippocampus and cortex. Consummatory sexual behavior in male vs. female-controlled mating paradigms was altered by age and prior sexual experience. Male-controlled mating increased androstane neurosteroid metabolism, such that complementary increases in the testosterone (T) metabolite 5α-androstane-3α-17β- diol (3α-diol) in the midbrain and hypothalamus of male rats corresponded to decreases in the prohormone, T. 3α-diol were increased in the hippocampus in response to the context alone, and to a lesser degree in response to mating. Mating diminished neurosteroidogenesis in the cortex. Neurosteroidogenesis was overall reduced in aged male rats compared to naïve controls, however, these effects were more prominent in sexually non-responsive aged male rats. Extending previous findings, these results indicate differential production of androstane neurosteroids in a mating exposure, age and brain region dependent manner.

Persistent high exposure to exogenous phthalates and endogenous sex hormones associated with early pubertal onset among children: A 3.5-year longitudinal cohort study in China

BackgroundEarly onset of puberty could have significant impacts on childhood health, but the extent to which it was affected by phthalate esters (PAEs) and sex hormone disruption was not understood. The aim of this study is to investigate the associations between exposure to PAEs and sex hormone disruption and early onset of puberty in children. MethodsA longitudinal cohort study was conducted in China from May 2017 to Oct 2020, involving 740 children during consecutive visits. The onset of puberty was evaluated using Tanner definition, and early puberty was defined as an onset age less than the first 25 %, with cut-offs of 10.33 and 8.97 years for boys and girls, respectively. Serum testosterone (TT), estradiol (E2) and urinary PAE metabolites were measured during three visits. Generalized linear models were used to explore the associations between PAE and sex hormones with the age of puberty onset, while log-binomial regressions were applied to assess the associations of persistent exposure to PAEs and sex hormones with early pubertal onset. ResultsApproximately 86.0 % of boys and 90.2 % of girls completed puberty onset from pre-puberty, and more than 95 % of participants had PAE concentrations higher than the limit of detection. Boys showed higher exposure to PAE pollutants and higher TT levels. Persistent exposure to PAEs was positively associated with early pubertal onset in girls (ARR = 1.97, 95 %CI = 1.12, 3.46). Moreover, persistent exposure to PAEs and E2 had synergistic associations with early pubertal onset in both boys (ARR = 4.77, 95 %CI = 1.06, 21.54) and girls (ARR = 7.07, 95 %CI = 1.51, 33.10). However, PAEs and TT had antagonistic associations only in boys (ARR = 0.44, 95 %CI = 0.07, 2.58). ConclusionLong-term exposure to PAEs might increase the risk of early pubertal onset, and it appears to work in synergy with E2, while in antagonism with TT in boys’ early pubertal onset. Reducing PAEs exposure might promote pubertal health.

Non-invasive assessment of fecal glucocorticoid and androgen metabolites in the pygmy hippopotamus (Choeropsis liberiensis)

The pygmy hippopotamus (Choeropsis liberiensis) is an endangered species endemic to the Upper Guinea Forest ecosystem in West Africa. We have limited information concerning the species’ reproduction and well-being under managed care. We therefore developed non-invasive methods for characterizing gonadal androgen and adrenal hormone profiles in pygmy hippos using fecal samples collected from 12 males and 12 females housed in North American zoological institutions. We aimed to: 1) identify and validate enzyme immunoassays (EIAs) for measuring metabolites of corticosteroids and testosterone in feces; and 2) test whether gonadal activity is correlated with previous breeding history, season or type of housing. For glucocorticoids, several EIAs for measuring metabolites were investigated. A group-specific EIA exhibiting cross-reactivity with 11,17-dioxoandrostane (DOA) metabolites of cortisol most clearly reflected adrenocortical activity in response to pharmocological challenge with adrenocorticotropic hormone (ACTH) in both males and females. However, day-to-day concentrations of this metabolite in the feces of pygmy hippos that did not undergo ACTH challenge were near the detection limits of the assay, making this EIA impractical for assessing glucocorticoid activity in this species. Another group-specific EIA, exhibiting cross-reactivity with 5α-pregnane-3β,11β,21-triol-20-one, produced biologically relevant data and evidence of an appropriate response to pharmacological challenge with exogenous ACTH. The testosterone metabolite assay C196 (Arbor Assays, Ann Arbor, Michigan, USA) also produced biologically coherent data: adult males exhibited the highest mean androgen metabolite concentrations (477 ng/g), followed by adult females (259 ng/g) and juvenile males (160 ng/g). Proven breeding males had higher, but not significantly different, mean concentrations (472 ng/g) to unproven males (352 ng/g; P = 0.400). Similarly, adult males housed outdoors year-round in subtropical climates exhibited higher, but not statistically different mean concentrations (554 ng/g) to males in temperate climates that were housed indoors at least part of the year (412 ng/g; P = 0.208). There were, however, significant differences in mean concentrations among seasons for adult males, with higher values in spring (546 ng/g) and summer (542 ng/g) than in autumn (426 ng/g) and winter (388 ng/g, P = 0.003). In conclusion, we identified EIAs for the measurement of fecal metabolites of androgens and glucocorticoids that can be used for further studies to monitor gonadal activity in male pygmy hippos and adrenocortical activity in both sexes. We also identified a seasonal trend in male gonadal activity in this species under managed care in North America. Finally, our findings highlight an important consideration when using non-invasive methods for evaluating fecal cortisol metabolites: ACTH used for pharmacological validation of an EIA does not necessarily equate to biological relevance.

Testing the Challenge Hypothesis in Stumptail Macaque Males: The Role of Testosterone and Glucocorticoid Metabolites in Aggressive and Mating Behavior.

The "challenge hypothesis" predicts higher male-male aggressive behavior along with increases in testosterone levels during times of reproductive challenges and social instability. In addition, in some primate species, higher glucocorticoid levels can be observed as well, but this is usually modulated by dominance rank. We studied rank-related aggressive behavior, mating activity, and fecal testosterone and glucocorticoid metabolites (fTm and fGCm) in male stumptail macaques (Macaca arctoides) in order to test some predictions of the "challenge hypothesis". Over a 20-month period, we collected data on aggressive behavior and copulation, as well as fecal samples (n = 700) to quantify fTm and fGCm in seven adult stumptail males living in captivity. During periods of mating activity, male-to-male aggression increased in higher- and middle-ranking males. Neither fTm nor fGCm levels predicted male-to-male aggression. fGCm levels (but not fTm) were positively associated with male-to-female aggression; however, this association was pronounced during periods of mating activity. fGCm levels differed according to social rank, with middle-ranking males having the highest levels. Both hormones were higher during periods of mating activity, but only in higher- and middle-ranking males. Taken together, our findings partially support the challenge hypothesis in a non-seasonal primate and shed some light on the unique social and mating system of the stumptail macaque.

Sweet Taste Receptor T1R3 Expressed in Leydig Cells Is Closely Related to Homeostasis of the Steroid Hormone Metabolism Profile

Taste receptor type 1 subunit 3 (T1R3) is initially expressed in mammal tongue for recognition and response of sweet/umami tastants and is critical to nutrient absorption, even endocrine. In this study, down-regulation of related steroidogenic enzymes such as StAR, 3β-HSD, CYP17A1, and 17β-HSD with the decrease of T1R3 expression was found in Leydig cells treated by a T1R3 inhibitor (lactisole). The abundances of progesterone, 17a-hydroxyprogesterone, androstenedione, testosterone, and deoxycorticosterone were down-regulated by 2.3, 3.5, 1.4, 1.6, and 2.2 times, respectively, after T1R3 inhibition. In addition, opposite results were found in saccharin sodium treatment. T1R3 activation contributed to intracellular cyclic adenosine monophosphate (cAMP) accumulation (14.41 ± 0.58 vs 20.21 ± 0.65) and increased testosterone (20.31 ± 3.49 vs 50.01 ± 7.44) and steroidogenic metabolite levels. Coadministration of human chorionic gonadotropin and saccharin sodium resulted in elevating the testosterone and cAMP levels and enhancing the expression levels of steroidogenic-related factors. Similarly, intratesticular injection of lactisole and saccharin sodium further confirmed that T1R3 inhibition/activation affected the expression of related steroidogenic enzymes and the testosterone levels in mice. The above findings suggest that T1R3 plays a role in testicular steroidogenesis.

DHT Induces Arterial Stiffening in Female Wild Type Mice

Testosterone is the predominant sex hormone in men and is increased in women with polycystic ovarian syndrome (PCOS). PCOS patients also experience an increased risk for cardiovascular diseases including hypertension and arterial stiffness. Our previous work showed significant downregulation of the G protein‐coupled estrogen receptor (GPER) as well as the nuclear estrogen receptor ERα in cultured vascular smooth muscle cells in response to the testosterone metabolite dihydrotestosterone (DHT), which cannot be aromatized to estrogen. Therefore, we hypothesized that DHT may induce arterial stiffness in female mice via downregulation of vascular estrogen receptors. Two groups of female wildtype mice were treated with DHT via silastic capsule for 4 weeks; one group received a dose designed to mimic DHT levels in men while the other group received twice this dose. While post‐treatment systolic blood pressure was not different between the control, single dose, and double dose groups (111 ± 10, 106 ± 3, 110 ± 7, n=8 per group; P=0.22), intracarotid vascular stiffness measured via pulse wave velocity showed a more than two‐fold increase in single dose (4.3 ± 0.8 m/s) and double dose (4.8 ± 1.0 m/s) DHT treated mice when compared with non‐treated controls (1.9 ± 0.3 m/s; P<0.0001). These findings suggest that high testosterone levels in females may promote arterial stiffening and cardiovascular damage independent of changes in blood pressure. Future studies will include histological analysis of aortic sections using Masson’s trichrome to assess changes in the extracellular matrix as well as droplet digital polymerase chain reaction to assess changes in estrogen receptor expression. In conclusion, these findings of arterial stiffening in response to increased DHT levels in females are important for not only PCOS patients but also women using testosterone for fitness, gender transitioning, or reduced libido.

Association of urinary organophosphate esters level with sex steroid hormones levels in adult males: A nationwide study, NHANES 2013-2014.

Exposure to environmental pollution via different mechanisms is associated with multiple endocrine dysfunctions. Organophosphate esters (OPEs) are endocrine-disrupting chemicals that affect sex steroid hormones. We aimed to study the effect of OPEs and their metabolites, such as diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), bis(2-chloroethyl) phosphate (BCEP), and dibutyl phosphate (DBUP), on sex steroid hormones in males. This cross-sectional analytical study analyzed data from the 2013-2014 National Health and Nutrition Examination Survey among 763 male participants aged ≥20 years. The relationships between the metabolites of OPEs and total testosterone, estradiol, sex hormone-binding globulin, and the ratio of total testosterone to estradiol (a parameter derived from total testosterone and estradiol) were evaluated using multivariate linear regression models that were adjusted for potential confounders. A total of 763 participants, with a mean age of 44.59 (±15.59) years, were enrolled. Of these, 65.7% participants had non-Hispanic white ancestry, 9.83% had non-Hispanic black ancestry, and 15.97% had Hispanic ancestry. Participants with higher urinary level of DPHP had a lower level of total testosterone and estradiol. Moreover, higher urinary levels of BDCPP were associated with higher estradiol. According to our study, which is based on a representative population of US adults, exposure to OPEs was significantly associated with altered sex hormone levels (total testosterone and estradiol). Further studies focused on the underlying mechanisms regarding the association between each metabolite and sex steroid hormones are required.

Relationship between reproductive hormones and migration distance in a polygynous songbird, the Red-winged Blackbird (Agelaius phoeniceus)

Many bird species migrate to southern overwintering locations to avoid harsh conditions at their breeding grounds, but at the cost of an energetically demanding migration that may delay their spring reproductive development. Previous work on the relationship between migration distance and reproductive readiness has primarily focused on early season baseline testosterone in both males and females. However, for females, testosterone alone may not be the appropriate measurement of reproductive development. Estradiol, a metabolite of testosterone that is essential for breeding behaviors and reproduction, should also be measured. Furthermore, baseline testosterone varies throughout the day and may change due to social interactions that occurred prior to sampling. Injection of gonadotropin-releasing hormone (GnRH) elicits an individual’s maximum potential testosterone production, minimizing daily and social variation. We explored relationships between migration distance and reproductive status after arrival to the breeding ground in Red-winged Blackbirds (Agelaius phoeniceus). We predicted that individuals that travel a shorter distance will have higher levels of reproductive hormones upon arrival given they are able to invest less in migration and more in reproduction. This is important because individuals that breed earlier often have higher reproductive success. In females, we measured baseline estradiol and testosterone. In males, we assessed baseline and GnRH-induced testosterone. Hormone values were related to migration distance, estimated by stable isotope analysis of claw samples collected before breeding began in eastern North Dakota. We found that males with shorter inferred migration distances have higher baseline testosterone upon arrival. However, inferred migration distance was not correlated with GnRH-induced testosterone. Female inferred migration distance was not correlated with baseline testosterone, but it was correlated with baseline estradiol. Females with higher testosterone had lower estradiol, suggesting that testosterone in females is not a reliable indicator of estradiol levels, thus readiness to breed. Our observations suggest that baseline hormone levels were related to migration distance, but baseline testosterone alone may not provide a complete assessment of a male or female’s preparedness to breed following spring migration.

In vivo Administration of Testosterone Propionate in Cattle Analyzed by High Performance Liquid Chromatography-Tandem Mass Spectrometry: An Enzymatic Hydrolysis Study and Drug Abuse Issues

This study involved an animal experiment in which testosterone propionate was intramuscularly injected into four steers, and the ensuing urine samples were analyzed using high-performance liquid chromatography-tandem mass spectrometry. The enzymatic hydrolysis conditions were analyzed using analysis of variance (ANOVA) and response surface methodology employing a 33 Box-Behnken design. A survey study was performed in which 48 urine samples were collected from eight untreated steers to estimate the endogenous levels of testosterone metabolites, and it was found that 17β-testosterone was not detected in the majority of the samples, whereas 17α-testosterone was present in 43 of the 48. Drug abuse was identified within 11 days of 17β-testosterone administration. The ratio between both isomers was also assessed; however, a cut-off limit based on an untreated population could not be estimated due to the absence of the beta isomer. Therefore, there may be a correlation between the exogenous use of testosterone in castrate animals and high levels of 17β-testosterone, although confirmation through further investigation would be required.

Correlates of hormonal modulation in mantled howler monkey males, Alouatta palliata.

The study of hormone modulation may offer important insight into the responses of individuals to environmental challenges. Here we studied C-peptide, thyroid hormone (T3), glucocorticoid (GC), and testosterone (T) metabolites of mantled howler males to assess: 1) correlations among hormones; 2) individual and temporal variation in hormone concentrations; and 3) the influence of ecological, climatic, behavioral, social, and reproductive factors on hormone variation. We studied 10 adult males at La Flor de Catemaco (Mexico) from January 2012 to December 2016. We collected information on food availability; ambient temperature; time budgets; male involvement in mating, agonistic interactions, and interactions with extragroup males. We analyzed C-peptide concentrations in urine samples and T3, GC, and T in fecal samples. C-peptide was negatively correlated with other hormones, whereas T3, GC, and T were positively related. Hormonal variation was unrelated to individual or yearly differences. Food availability was positively related to C-peptide and T3, and negatively related to GC. Involvement in mating was positively related to T3 and T, whereas the rate agonistic interactions was positively related to GC and T. The rate of interactions with extragroup males was positively related to T. When males mated, the increase in C-peptide and the decrease in GC with increasing food availability were less notable. Hormonal variation in mantled howler monkey males is generally stable, but it is influenced by several factors. Our results offer a broad picture of the hormonal modulation of mantled howler monkey males in response to diverse challenges.

Clinical Value of Serum Levels of 11-Oxygenated Metabolites of Testosterone in Women With Polycystic Ovary Syndrome.

Recent data suggested that 11-oxygenated androgens may be the preponderant circulating androgens in women with PCOS. However, the pathophysiological significance of these hormones remains unclear. The aim of this study was to evaluate the relationships between serum 11-OH testosterone (11-OHT) and 11-keto testosterone (11-KetoT) and clinical and biochemical hyperandrogenism, as well as the metabolic parameters, in women with PCOS. The main classic and 11-oxygenated androgens were measured by LC-MS/MS and direct equilibrium dialysis in 123 women with PCOS, diagnosed according to the Rotterdam criteria, and 38 healthy controls. Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp. Serum 11-oxygenated androgens were higher in women with PCOS than in controls. Elevated levels of 11-OHT and 11-KetoT were found in 28.5% and 30.1% of PCOS women, respectively, whereas free testosterone (FT) was increased in 61.0% of them. Serum 11-oxygenated androgens showed a limited performance in recognizing women with classically defined hyperandrogenism. Unlike FT, 11-oxygenated androgens did not show significant relationships with anthropometric and metabolic parameters, except for a direct association with insulin sensitivity. In multivariable analysis, 11-OHT and 11-KetoT, directly, and FT, inversely, remained significant independent predictors of insulin sensitivity. Serum levels of 11-oxygenated androgens are higher in women with PCOS than in controls. However, these hormones show a poor performance in recognizing women with hyperandrogenism, as currently defined. The relationships of these androgens with insulin sensitivity strongly differ from that of FT, suggesting a different role of classic and 11-oxygenated androgens in the pathophysiology of PCOS.