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Journal of Cachexia, Sarcopenia and... Aug 2023Androgens are anabolic steroid hormones that exert their function by binding to the androgen receptor (AR). We have previously established that AR deficiency in limb...
BACKGROUND
Androgens are anabolic steroid hormones that exert their function by binding to the androgen receptor (AR). We have previously established that AR deficiency in limb muscles impairs sarcomere myofibrillar organization and decreases muscle strength in male mice. However, despite numerous studies performed in men and rodents, the signalling pathways controlled by androgens via their receptor in skeletal muscles remain poorly understood.
METHODS
Male AR (n = 7-12) and female AR mice (n = 9), in which AR is selectively ablated in myofibres of musculoskeletal tissue, and male AR , in which AR is selectively ablated in post-mitotic skeletal muscle myofibres (n = 6), were generated. Longitudinal monitoring of body weight, blood glucose, insulin, lipids and lipoproteins was performed, alongside metabolomic analyses. Glucose metabolism was evaluated in C2C12 cells treated with 5α-dihydrotestosterone (DHT) and the anti-androgen flutamide (n = 6). Histological analyses on macroscopic and ultrastructural levels of longitudinal and transversal muscle sections were conducted. The transcriptome of gastrocnemius muscles from control and AR mice was analysed at the age of 9 weeks (P < 0.05, 2138 differentially expressed genes) and validated by RT-qPCR analysis. The AR (4691 peaks with false discovery rate [FDR] < 0.1) and H3K4me2 (47 225 peaks with FDR < 0.05) cistromes in limb muscles were determined in 11-week-old wild-type mice.
RESULTS
We show that disrupting the androgen/AR axis impairs in vivo glycolytic activity and fastens the development of type 2 diabetes in male, but not in female mice. In agreement, treatment with DHT increases glycolysis in C2C12 myotubes by 30%, whereas flutamide has an opposite effect. Fatty acids are less efficiently metabolized in skeletal muscles of AR mice and accumulate in cytoplasm, despite increased transcript levels of genes encoding key enzymes of beta-oxidation and mitochondrial content. Impaired glucose and fatty acid metabolism in AR-deficient muscle fibres is associated with 30% increased lysine and branched-chain amino acid catabolism, decreased polyamine biosynthesis and disrupted glutamate transamination. This metabolic switch generates ammonia (2-fold increase) and oxidative stress (30% increased H O levels), which impacts mitochondrial functions and causes necrosis in <1% fibres. We unravel that AR directly activates the transcription of genes involved in glycolysis, oxidative metabolism and muscle contraction.
CONCLUSIONS
Our study provides important insights into diseases caused by impaired AR function in musculoskeletal system and delivers a deeper understanding of skeletal muscle pathophysiological dynamics that is instrumental to develop effective treatment for muscle disorders.
Topics: Animals; Female; Male; Mice; Androgens; Diabetes Mellitus, Type 2; Dihydrotestosterone; Flutamide; Muscle Contraction; Muscle, Skeletal; Receptors, Androgen
PubMed: 37208984
DOI: 10.1002/jcsm.13251 -
Dermatology and Therapy Aug 2023Finasteride and dutasteride are 5-alpha reductase selective inhibitors (5ARIs). They were introduced as therapeutic agents for the treatment of benign prostatic... (Review)
Review
Finasteride and dutasteride are 5-alpha reductase selective inhibitors (5ARIs). They were introduced as therapeutic agents for the treatment of benign prostatic hyperplasia in 1992 and 2002, respectively; finasteride has also been approved for the treatment of androgenetic alopecia since early 2000. These agents inhibit the conversion of testosterone (T) to 5α-dihydrotestosterone (5α-DHT), limiting steroidogenesis and playing a crucial role in the physiological function of the neuroendocrine system. Therefore, it has been proposed that blocking androgen synthesis with the use of 5ARIs would be beneficial in the treatment of various diseases related to states of hyperandrogenism. This review describes the dermatological pathologies in which 5ARIs have been used as part of the treatment, evaluation of the efficacy, and knowledge of the safety profile. Specifically, we discuss the application of 5ARIs in androgenetic alopecia, acne, frontal fibrosing alopecia, hirsutism, and the implications of adverse events associated with its use to inform about the applications of 5ARIs in general dermatology practice.
PubMed: 37432644
DOI: 10.1007/s13555-023-00974-4 -
Journal of Ovarian Research Jul 2023Excessive production of androgen drives oxidative stress (OS) and inflammasome activation in ovarian granulosa cells (GCs). Therefore, the induced follicular...
BACKGROUND
Excessive production of androgen drives oxidative stress (OS) and inflammasome activation in ovarian granulosa cells (GCs). Therefore, the induced follicular developmental disorder is the major cause of infertility in women with polycystic ovary syndrome (PCOS). Exercise-induced upregulation of irisin is capable of regulating metabolism by reducing OS and inflammation. Exercise has been shown to alleviate a range of PCOS symptoms, including maintaining a normal menstrual cycle, in several clinical trials.
METHODS
Female Sprague-Dawley (SD) rats and primary ovarian cells were treated with two different androgens, dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT), to simulate a hyperandrogenic environment, followed by eight weeks of exercise training and irisin intervention. The levels of reactive oxygen species (ROS), tissue inflammation and fibrosis were examined using hematoxylin and eosin (H&E) staining, western blot, quantitative real-time PCR (qRT-PCR), dichlorofluorescein diacetate (DCF-DA) probe detection, immunofluorescence staining, immunohistochemistry, and Sirius red staining.
RESULTS
Exercise for eight weeks improved polycystic ovarian morphology and decreased the levels of inflammation, OS, and fibrosis in PCOS rats. Hyperandrogen increased ROS production in ovarian cells by inducing endoplasmic reticulum stress (ERS) and activating the inositol-requiring enzyme 1α (IRE1α)-thioredoxin-interacting protein (TXNIP)/ROS-NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathway, further enhancing the levels of inflammation. Irisin suppressed the expression of IRE1α and its downstream targets, thus improving the ovarian dysfunction of PCOS rats induced by hyperandrogen.
CONCLUSION
Exercise can alleviate various phenotypes of PCOS rats induced by DHEA, and its therapeutic effect may be mediated by secreting beneficial myokines. IRE1α may be an important target of irisin for reducing OS and inflammation, thereby improving ovarian fibrosis.
Topics: Humans; Rats; Female; Animals; Polycystic Ovary Syndrome; Reactive Oxygen Species; NLR Family, Pyrin Domain-Containing 3 Protein; Endoribonucleases; Fibronectins; Rats, Sprague-Dawley; Protein Serine-Threonine Kinases; Inflammation; Fibrosis; Dehydroepiandrosterone; Carrier Proteins; Cell Cycle Proteins
PubMed: 37525261
DOI: 10.1186/s13048-023-01242-x -
Journal of Experimental Zoology. Part... Apr 2024Reptiles display considerable diversity in reproductive behavior, making them great models to study the neuroendocrine control of reproductive behavior. Many reptile... (Review)
Review
Reptiles display considerable diversity in reproductive behavior, making them great models to study the neuroendocrine control of reproductive behavior. Many reptile species are seasonally breeding, such that they become reproductively active during their breeding season and regress to a nonreproductive state during their nonbreeding season, with this transition often prompted by environmental cues. In this review, we will focus on summarizing the neural and neuroendocrine mechanisms controlling reproductive behavior. Three major areas of the brain are involved in reproductive behavior: the preoptic area (POA), amygdala, and ventromedial hypothalamus (VMH). The POA and VMH are sexually dimorphic areas, regulating behaviors in males and females respectively, and all three areas display seasonal plasticity. Lesions to these areas disrupt the onset and maintenance of reproductive behaviors, but the exact roles of these regions vary between sexes and species. Different hormones influence these regions to elicit seasonal transitions. Circulating testosterone (T) and estradiol (E2) peak during the breeding season and their influence on reproduction is well-documented across vertebrates. The conversion of T into E2 and 5α-dihydrotestosterone can also affect behavior. Melatonin and corticosterone have generally inhibitory effects on reproductive behavior, while serotonin and other neurohormones seem to stimulate it. In general, there is relatively little information on the neuroendocrine control of reproduction in reptiles compared to other vertebrate groups. This review highlights areas that should be considered for future areas of research.
Topics: Female; Male; Animals; Reptiles; Brain; Reproduction; Testosterone; Sexual Behavior, Animal
PubMed: 38247297
DOI: 10.1002/jez.2783 -
Clinical Chemistry Dec 2023Androgens are synthesized from cholesterol through sequential conversions by enzymes in the adrenal glands and gonads. Serum levels of androgens change during the... (Review)
Review
BACKGROUND
Androgens are synthesized from cholesterol through sequential conversions by enzymes in the adrenal glands and gonads. Serum levels of androgens change during the different phases of life and regulate important developmental and maturational processes. Androgen excess or deficiency can therefore present at various ages in various ways.
CONTENT
The diagnostic approach for atypical genitalia, premature pubarche, delayed pubertal onset or progression, and hirsutism or virilization, including measurement of androgens (testosterone, androstenedione, 17-OHprogesterone, dehydroepiandrosterone, and dihydrotestosterone) is discussed in the current review. Androgens can be measured in serum, saliva, urine, or dried blood spots. Techniques to measure androgens, including immunoassays and LC-MS, have their own advantages and pitfalls. In addition, pre- and postanalytical issues are important when measuring androgens.
SUMMARY
During clinical interpretation of androgen measurements, it is important to take preanalytical circumstances, such as time of blood withdrawal, into account. As immunoassays have major drawbacks, especially in samples from women and neonates, concentrations measured using these assays should be interpreted with care. Reference intervals can only be used in relation to the measurement technique and the standardization of the assay. In the near future, new androgens will probably be added to the current repertoire to further improve the diagnosis and follow-up of androgen excess or deficiency.
Topics: Infant, Newborn; Female; Humans; Androgens; Testosterone; Androstenedione; Virilism; Hirsutism; Dehydroepiandrosterone
PubMed: 37794651
DOI: 10.1093/clinchem/hvad146 -
International Journal of Impotence... Sep 2023Finasteride and dutasteride, synthetic 5α-reductase inhibitors (5ARIs) are recommended in many guidelines for the treatment of benign prostatic hyperplasia/lower... (Review)
Review
Finasteride and dutasteride, synthetic 5α-reductase inhibitors (5ARIs) are recommended in many guidelines for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms and alopecia despite a variety of side effects like sexual, neurological, psychiatric, endocrinological, metabolic and ophthalmological dysfunctions and the increased incidence of high grade prostate cancer. The sexual side effects are common during the use of the drug but in a small subgroup of patients, they can persist after stopping the drug. This so-called post-finasteride syndrome has serious implications for the quality of life without a clear etiology or therapy. Three types of 5α-reductases are present in many organs in- and outside the brain where they can be blocked by the two 5ARIs. There is increasing evidence that 5ARIs not only inhibit the conversion of testosterone to 5α-dihydrotestosterone (DHT) in the prostate and the scalp but also in many other tissues. The lipophilic 5ARIs can pass the blood-brain barrier and might block many other neurosteroids in the brain with changes in the neurochemistry and impaired neurogenesis. Further research and therapeutic innovations are urgently needed that might cure or relieve these side effects. More awareness is needed for physicians to outweigh these health risks against the benefits of 5ARIs.
PubMed: 37697052
DOI: 10.1038/s41443-023-00759-5 -
Irish Journal of Medical Science Dec 2023Dihydrotestosterone is a more potent androgen derived from testosterone and androstenediones, but its measurement has not been routinely recommended in women with...
PURPOSE
Dihydrotestosterone is a more potent androgen derived from testosterone and androstenediones, but its measurement has not been routinely recommended in women with hirsutism, and there is limited information in this regard with equivocal findings. This study aimed to evaluate serum dihydrotestosterone level in patients with hirsutism compared to women without hirsutism.
METHODS
In this case-control study (during 2021-2022), serum levels of total testosterone, free testosterone, and dihydrotestosterone were evaluated in 101 women with hirsutism and 101 healthy women. Hormonal levels were measured with chemiluminescent immunoassay method. Age and hormonal levels in each group, body mass index, menstrual status, complaint of decreased scalp hair density, and ovarian ultrasound findings in hirsutism group were collected and analyzed.
RESULTS
There was significant difference in free testosterone and dihydrotestosterone levels (P < 0.001) and no significant difference in total testosterone level between two groups (P = 0.628). Dihydrotestosterone level was significantly higher in women with hirsutism with menses irregularity, complaint of decreased scalp hair density, and presence of polycystic ovary on ultrasound (P < 0.05).
CONCLUSIONS
Measuring dihydrotestosterone level is not considered in routine evaluation of hirsutism, but we think that this significant difference shows that elevated level of dihydrotestosterone hormone in women with hirsutism is an important factor.
Topics: Female; Humans; Hirsutism; Testosterone; Dihydrotestosterone; Case-Control Studies; Androgens
PubMed: 37043171
DOI: 10.1007/s11845-023-03366-x -
Scientific Reports Oct 2023Penile size is closely concerned and short penis contributes serious sexual dysfunction and tremendous psychological problems to couples. Androgen is essential for...
Penile size is closely concerned and short penis contributes serious sexual dysfunction and tremendous psychological problems to couples. Androgen is essential for penile development and testosterone replacement is recommended to patients with micropenis. We previously proved that inhibiting activity of lysyl oxidase (Anti-lysyl oxidase, Anti-LOX) combined with vacuum erectile device (VED) lengthened penis by remodeling tunica albuginea. We thus explored whether HCG supplement could accelerate tunica albuginea remodeling (induced by Anti-LOX + VED) to promote penile growth. Forty-two SD male rats (4 weeks old) were purchased and divided into 7 groups: control, Anti-LOX, HCG, VED (with a negative aspirated pressure of - 300 mmHg), Anti-LOX + VED, HCG + VED, and Anti-LOX + HCG + VED. After an intervention for 4 weeks, all rats' penile length, exposed penile length, and erectile function were measured. Serum samples were collected to detect hormone levels and penile corpus cavernosum were harvested for histo-pathological analysis. All intervention groups showed significantly longer penis than controlled rats. Anti-LOX sharply increased penile length and exposed length by 15% and 9% respectively, this lengthening effect was more obvious in Anti-LOX + VED group (26% and 19%, respectively). Although HCG promoted penile length by 8%, this effect was slight for exposed length (3%). Moreover, Anti-LOX + HCG + VED dramatically increased penile length and exposed length by 22% and 18%, respectively, which was similar with that in Anti-LOX + VED (26% and 19%, respectively). HCG dramatically stimulated testosterone and dihydrotestosterone secretions than control group, whether with or without Anti-LOX and VED; while it induced more AR expression than other groups. Finally, all procedures did not improve or deteriorate normal erectile function. Although we verified that Anti-LOX + VED lengthened penis by inducing tunica albuginea remodeling, however, HCG supplement did not synergize with Anti-LOX + VED to accelerate albuginea remodeling to facilitate penile growth.
Topics: Humans; Male; Rats; Animals; Erectile Dysfunction; Penis; Penile Erection; Testosterone
PubMed: 37783699
DOI: 10.1038/s41598-023-38888-y -
The American Journal of Pathology Dec 2023Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still...
Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still unclear. It is also unclear whether hyperandrogenism and insulin resistance, the two common manifestations of polycystic ovary syndrome, affect uterine SpA remodeling. We verified previous work in which exposure to 5-dihydrotestosterone (DHT) and insulin (INS) in rats during pregnancy resulted in hyperandrogenism, insulin intolerance, and higher fetal mortality. Exposure to DHT and INS dysregulated the expression of angiogenesis-related genes in the uterus and placenta and also decreased expression of endothelial nitric oxide synthase and matrix metallopeptidases 2 and 9, increased fibrotic collagen deposits in the uterus, and reduced expression of marker genes for SpA-associated trophoblast giant cells. These changes were related to a greater proportion of unremodeled uterine SpAs and a smaller proportion of highly remodeled arteries in DHT + INS-exposed rats. Placentas from DHT + INS-exposed rats exhibited decreased basal and labyrinth zone regions, reduced maternal blood spaces, diminished labyrinth vascularity, and an imbalance in the abundance of vascular and smooth muscle proteins. Furthermore, placentas from DHT + INS-exposed rats showed expression of placental insufficiency markers and a significant increase in cell senescence-associated protein levels. Altogether, this work demonstrates that increased pregnancy complications in polycystic ovary syndrome may be mediated by problems with uterine SpA remodeling, placental functionality, and placental senescence.
Topics: Humans; Rats; Pregnancy; Female; Animals; Placenta; Polycystic Ovary Syndrome; Hyperandrogenism; Uterus; Arteries; Dihydrotestosterone; Insulin; Uterine Artery
PubMed: 37689383
DOI: 10.1016/j.ajpath.2023.08.008 -
Stem Cell Research & Therapy Aug 2023Androgenetic alopecia (AGA) is one of the most common hair loss diseases worldwide. However, current treatments including medicine, surgery, and stem cells are limited...
BACKGROUND
Androgenetic alopecia (AGA) is one of the most common hair loss diseases worldwide. However, current treatments including medicine, surgery, and stem cells are limited for various reasons. Cell-free fat extract (CEFFE), contains various cell factors, may have potential abilities in treating AGA. This study aims to evaluate the safety, effectiveness and the underlying mechanism of CEFFE in treating AGA.
METHODS
Sex hormone evaluation, immunogenicity assay and genotoxicity assay were conducted for CEFFE. In vivo study, male C57BL/6 mice were injected subcutaneously with dihydrotestosterone (DHT) and were treated with different concentration of CEFFE for 18 days (five groups and n = 12 in each group: Control, Model, CEFFE, CEFFE, CEFFE). Anagen entry rate and hair coverage percentage were analyzed through continuously taken gross photographs. The angiogenesis and proliferation of hair follicle cells were evaluated by hematoxylin-eosin, anti-CD31, and anti-Ki67 staining. In vitro study, dermal papilla cells (DPCs) were incubated with different concentrations of CEFFE, DHT, or CEFFE + DHT, followed by CCK-8 assay and flow cytometry to evaluate cell proliferation cycle and apoptosis. The intracellular DHT level were assessed by enzyme-linked immunosorbent assay. The expression of 5α-reductase type II, 3α-hydroxysteroid dehydrogenase and androgen receptor were assessed through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or/and western blot.
RESULTS
In CEFFE-treated mice, an increase in the anagen entry rate and hair coverage percentage was observed. The number of CD31-positive capillaries and Ki67-positive cells were increased, suggesting that CEFFE promoted the proliferation of DPCs, modulated the cell cycle arrest, inhibited apoptosis caused by DHT, reduced the intracellular concentration of DHT in DPCs, and downregulated the expression of AR.
CONCLUSIONS
CEFFE is a novel and effective treatment option for AGA through producing an increased hair follicle density and hair growth rate. The proposed mechanisms are through the DHT/AR pathway regulation and regional angiogenesis ability.
Topics: Male; Mice; Animals; Mice, Inbred C57BL; Alopecia; Adipose Tissue; Apoptosis; Biological Assay; Cell Extracts
PubMed: 37612726
DOI: 10.1186/s13287-023-03398-1