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Endocrinology and Metabolism Clinics of... Mar 2021Congenital adrenal hyperplasia encompasses a group of autosomal recessive defects in cortisol biosynthesis, and 21-hydroxylase deficiency accounts for 95% of such cases.... (Review)
Review
Congenital adrenal hyperplasia encompasses a group of autosomal recessive defects in cortisol biosynthesis, and 21-hydroxylase deficiency accounts for 95% of such cases. Non-classic 21-hydroxylase deficiency is due to partial enzymatic defects, which present with normal cortisol synthesis, but excessive production of adrenal androgens, including 11-oxygenated androgens. Non-classic 21-hydroxylase deficiency is relatively common, and its phenotype resembles closely that of polycystic ovary syndrome. This review focuses primarily on non-classic 21-hydroxylase deficiency, its clinical features, diagnosis, and management.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Endocrinologists; Female; Humans; Polycystic Ovary Syndrome
PubMed: 33518183
DOI: 10.1016/j.ecl.2020.10.008 -
Nature Reviews. Endocrinology Jun 2022Treatment for congenital adrenal hyperplasia (CAH) was introduced in the 1950s following the discovery of the structure and function of adrenocortical hormones. Although... (Review)
Review
Treatment for congenital adrenal hyperplasia (CAH) was introduced in the 1950s following the discovery of the structure and function of adrenocortical hormones. Although major advances in molecular biology have delineated steroidogenic mechanisms and the genetics of CAH, management and treatment of this condition continue to present challenges. Management is complicated by a combination of comorbidities that arise from disease-related hormonal derangements and treatment-related adverse effects. The clinical outcomes of CAH can include life-threatening adrenal crises, altered growth and early puberty, and adverse effects on metabolic, cardiovascular, bone and reproductive health. Standard-of-care glucocorticoid formulations fall short of replicating the circadian rhythm of cortisol and controlling efficient adrenocorticotrophic hormone-driven adrenal androgen production. Adrenal-derived 11-oxygenated androgens have emerged as potential new biomarkers for CAH, as traditional biomarkers are subject to variability and are not adrenal-specific, contributing to management challenges. Multiple alternative treatment approaches are being developed with the aim of tailoring therapy for improved patient outcomes. This Review focuses on challenges and advances in the management and treatment of CAH due to 21-hydroxylase deficiency, the most common type of CAH. Furthermore, we examine new therapeutic developments, including treatments designed to replace cortisol in a physiological manner and adjunct agents intended to control excess androgens and thereby enable reductions in glucocorticoid doses.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Biomarkers; Glucocorticoids; Humans; Hydrocortisone
PubMed: 35411073
DOI: 10.1038/s41574-022-00655-w -
The Journal of Sexual Medicine May 2021The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal... (Review)
Review
International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.
BACKGROUND
The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD).
AIM
To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD.
METHODS
The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method.
OUTCOMES
A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up.
RESULTS
Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data.
CLINICAL IMPLICATIONS
This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring.
STRENGTHS & LIMITATIONS
This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging.
CONCLUSION
Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need. Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. J Sex Med 2021;18:849-867.
Topics: Female; Humans; Libido; Male; Sexual Behavior; Sexual Dysfunctions, Psychological; Sexual Health; Testosterone
PubMed: 33814355
DOI: 10.1016/j.jsxm.2020.10.009 -
Kidney disease associated with androgenic-anabolic steroids and vitamin supplements abuse: Be aware!Nefrologia 2020The excessive chase for beauty standards and the rise of muscle dysmorphia have ultimately led to an increase in androgenic-anabolic steroids (AAS) and intramuscular... (Review)
Review
The excessive chase for beauty standards and the rise of muscle dysmorphia have ultimately led to an increase in androgenic-anabolic steroids (AAS) and intramuscular injections of vitamins A, D and E (ADE) abuse, which is associated with several adverse effects and has become a public health issue. This review of literature discusses kidney injury associated with the use of AAS and ADE, highlighting the mechanisms of acute and chronic renal lesion, such as direct renal toxicity, glomerular hyperfiltration and hypercalcemia. Future perspectives regarding evaluation and early diagnosis of kidney injury in these patients are also discussed.
Topics: Acute Kidney Injury; Anabolic Agents; Androgens; Humans; Hypercalcemia; Kidney; Kidney Diseases; Testosterone Congeners; Vitamin A; Vitamin D; Vitamin E; Vitamins
PubMed: 31585781
DOI: 10.1016/j.nefro.2019.06.003 -
American Journal of Physiology.... Jul 2020Mitochondrial injury in granulosa cells is associated with the pathogenesis of polycystic ovary syndrome (PCOS). However, the protective effects of melatonin against...
Mitochondrial injury in granulosa cells is associated with the pathogenesis of polycystic ovary syndrome (PCOS). However, the protective effects of melatonin against mitochondrial injury in the granulosa cells of PCOS remain unclear. In this study, decreased mitochondrial membrane potential and mtDNA content, increased number of autophagosomes were found in the granulosa cells of PCOS patients and the dihydrotestosterone (DHT)-treated KGN cells, with decreased protein level of the autophagy substrate p62 and increased levels of the cellular autophagy markers Beclin 1 and LC3B-II, while the protein levels of PTEN-induced kinase-1 (PINK1) and Parkin were increased and the level of sirtuin 1 (SIRT1) was decreased. DHT-induced PCOS-like mice also showed enhanced mitophagy and decreased mRNA expression. Melatonin treatment significantly increased the protein level of SIRT1 and decreased the levels of PINK1/Parkin, whereas it ameliorated the mitochondrial dysfunction and PCOS phenotype in vitro and in vivo. However, when the KGN cells were treated with siRNA to knock down SIRT1 expression, melatonin treatment failed to repress the excessive mitophagy. In conclusion, melatonin protects against mitochondrial injury in granulosa cells of PCOS by enhancing SIRT1 expression to inhibit excessive PINK1/Parkin-mediated mitophagy.
Topics: Adult; Animals; Antioxidants; Autophagosomes; Autophagy; Beclin-1; Case-Control Studies; Cell Line; DNA, Mitochondrial; Dihydrotestosterone; Female; Granulosa Cells; Humans; Melatonin; Membrane Potential, Mitochondrial; Mice; Microtubule-Associated Proteins; Mitophagy; Polycystic Ovary Syndrome; Protein Kinases; Sirtuin 1; Ubiquitin-Protein Ligases
PubMed: 32343612
DOI: 10.1152/ajpendo.00006.2020 -
International Journal of Molecular... Oct 2022Androgens are an important and diverse group of steroid hormone molecular species. They play varied functional roles, such as the control of metabolic energy fate and... (Review)
Review
Androgens are an important and diverse group of steroid hormone molecular species. They play varied functional roles, such as the control of metabolic energy fate and partition, the maintenance of skeletal and body protein and integrity and the development of brain capabilities and behavioral setup (including those factors defining maleness). In addition, androgens are the precursors of estrogens, with which they share an extensive control of the reproductive mechanisms (in both sexes). In this review, the types of androgens, their functions and signaling are tabulated and described, including some less-known functions. The close interrelationship between corticosteroids and androgens is also analyzed, centered in the adrenal cortex, together with the main feedback control systems of the hypothalamic-hypophysis-gonads axis, and its modulation by the metabolic environment, sex, age and health. Testosterone (T) is singled out because of its high synthesis rate and turnover, but also because age-related hypogonadism is a key signal for the biologically planned early obsolescence of men, and the delayed onset of a faster rate of functional losses in women after menopause. The close collaboration of T with estradiol (E2) active in the maintenance of body metabolic systems is also presented Their parallel insufficiency has been directly related to the ravages of senescence and the metabolic syndrome constellation of disorders. The clinical use of T to correct hypoandrogenism helps maintain the functionality of core metabolism, limiting excess fat deposition, sarcopenia and cognoscitive frailty (part of these effects are due to the E2 generated from T). The effectiveness of using lipophilic T esters for T replacement treatments is analyzed in depth, and the main problems derived from their application are discussed.
Topics: Androgens; Biology; Esters; Estradiol; Estrogens; Female; Humans; Male; Steroids; Testosterone
PubMed: 36233256
DOI: 10.3390/ijms231911952 -
Journal of the Endocrine Society Mar 2022In endocrine and reproductive endocrine literature, adult female acne is considered as a possible clinical expression of hyperandrogenism, with most polycystic ovary...
In endocrine and reproductive endocrine literature, adult female acne is considered as a possible clinical expression of hyperandrogenism, with most polycystic ovary syndrome (PCOS) guidelines considering acne as a condition of androgen excess. Adult female acne, however, in the dermatological literature is considered as an inflammatory skin disease and new guidelines on adult female acne have been produced by dermatological societies, with little perspective from any endocrine or reproductive endocrine points of view. An expert task force was appointed by the AE-PCOS society to determine the current state of knowledge and provide evidence-based recommendations that could be valid for all specialists taking care of female adult acne. The following are the recommendations (level of evidence A or B): (1) diagnosis of female adult acne is mainly clinical, but a grading tool is needed for optimizing the treatment; (2) measurement of serum androgen values (total testosterone, free testosterone, and dehydroepiandrosterone sulfate) by high-quality assays is recommended in all women with adult acne; (3) in women with adult acne and proven hyperandrogenism, oral combined estroprogestins should be added to the topical or systemic treatment of acne, independently of severity of acne; (4) all second- and third-generation estroprogestins may be used, independently of the estrogen dose and progestin component; (5) spironolactone may be added to estroprogestins in women with moderate or severe hyperandrogenic adult acne, not responding to usual treatments; (6) estroprogestins may be used in nonhyperandrogenic patients with adult acne as second-line therapy.
PubMed: 35155970
DOI: 10.1210/jendso/bvac003 -
Advanced Science (Weinheim,... Jun 2023Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells....
Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa-infiltrated immune cells and the impact of androgen deprivation therapy (ADT), the first-line treatment for advanced PCa, on the PCa immune microenvironment remains limited. On the other hand, immune checkpoint blockade has revolutionized the treatment of certain cancer types, but fails to achieve any benefit in advanced PCa, due to an immune suppressive environment. In this study, it is reported that AR signaling pathway is evidently activated in tumor-associated macrophages (TAMs) of PCa both in mice and humans. AR acts as a transcriptional repressor for IL1B in TAMs. ADT releases the restraint of AR on IL1B and therefore leads to an excessive expression and secretion of IL-1β in TAMs. IL-1β induces myeloid-derived suppressor cells (MDSCs) accumulation that inhibits the activation of cytotoxic T cells, leading to the immune suppressive microenvironment. Critically, anti-IL-1β antibody coupled with ADT and the immune checkpoint inhibitor anti-PD-1 antibody exerts a stronger anticancer effect on PCa following castration. Together, IL-1β is an important androgen-responsive immunotherapeutic target for advanced PCa.
Topics: Animals; Humans; Male; Mice; Androgen Antagonists; Androgens; Immunotherapy; Macrophages; Prostatic Neoplasms; Tumor Microenvironment
PubMed: 37092583
DOI: 10.1002/advs.202206889 -
Journal of Biomedical Science Mar 2022Androgenetic alopecia (AGA) is a genetic disorder caused by dihydrotestosterone (DHT), accompanied by the senescence of androgen-sensitive dermal papilla cells (DPCs)...
BACKGROUND
Androgenetic alopecia (AGA) is a genetic disorder caused by dihydrotestosterone (DHT), accompanied by the senescence of androgen-sensitive dermal papilla cells (DPCs) located in the base of hair follicles. DHT causes DPC senescence in AGA through mitochondrial dysfunction. However, the mechanism of this pathogenesis remains unknown. In this study, we investigated the protective role of cyanidins on DHT-induced mitochondrial dysfunction and DPC senescence and the regulatory mechanism involved.
METHODS
DPCs were used to investigate the effect of DHT on mitochondrial dysfunction with MitoSOX and Rhod-2 staining. Senescence-associated β-galactosidase activity assay was performed to examine the involvement of membrane AR-mediated signaling in DHT-induced DPC senescence. AGA mice model was used to study the cyanidins on DHT-induced hair growth deceleration.
RESULTS
Cyanidin 3-O-arabinoside (C3A) effectively decreased DHT-induced mtROS accumulation in DPCs, and C3A reversed the DHT-induced DPC senescence. Excessive mitochondrial calcium accumulation was blocked by C3A. C3A inhibited p38-mediated voltage-dependent anion channel 1 (VDAC1) expression that contributes to mitochondria-associated ER membrane (MAM) formation and transfer of calcium via VDAC1-IP3R1 interactions. DHT-induced MAM formation resulted in increase of DPC senescence. In AGA mice models, C3A restored DHT-induced hair growth deceleration, which activated hair follicle stem cell proliferation.
CONCLUSIONS
C3A is a promising natural compound for AGA treatments against DHT-induced DPC senescence through reduction of MAM formation and mitochondrial dysfunction.
Topics: Animals; Anthocyanins; Cellular Senescence; Dihydrotestosterone; Hair Follicle; Mice; Mitochondria
PubMed: 35255899
DOI: 10.1186/s12929-022-00800-7 -
Climacteric : the Journal of the... Apr 2022Postmenopausal hyperandrogenism is a state of relative or absolute androgen excess originating from the adrenal glands and/or ovaries clinically manifested by the...
Postmenopausal hyperandrogenism is a state of relative or absolute androgen excess originating from the adrenal glands and/or ovaries clinically manifested by the presence of terminal hair in androgen-dependent areas of the body, and other manifestations of hyperandrogenism such as acne and alopecia or the development of virilization. In such circumstances, physicians must exclude the possibility of rare but serious androgen-producing tumors of the adrenal glands or ovaries. Worsening of undiagnosed hyperandrogenic disorders such as polycystic ovary syndrome, congenital adrenal hyperplasia, ovarian hyperthecosis, Cushing syndrome and iatrogenic hyperandrogenism should be considered for differential diagnosis. Elevated serum testosterone not only causes virilizing effects, but also will lead to hypercholesterolemia, insulin resistance, hypertension and cardiac disease. An ovarian androgen-secreting tumor, which is diagnosed in 1-3 of 1000 patients presenting with hirsutism, comprises less than 0.5% of all ovarian tumors. Adrenal tumors, including non-malignant adenomas and malignant carcinomas, are less common than ovarian tumors but cause postmenopausal virilization. Measurement of serum testosterone, sex hormone-binding globulin, dehydroepiandrosterone sulfate, androstenedione and inhibin B is necessary in postmenopausal women with the complaints and signs of hyperandrogenism. Some tests to discard Cushing syndrome should also be done. After an etiological source of androgen hypersecretion has been suspected, we recommend performing magnetic resonance imaging of the adrenal glands or ovaries. Medical management with gonadotropin-releasing hormone agonist/analogues or antagonists has been reported for women who are either unfit for surgery or in whom the source of elevated testosterone is unidentified.
Topics: Androgens; Cushing Syndrome; Female; Humans; Hyperandrogenism; Male; Ovarian Neoplasms; Polycystic Ovary Syndrome; Postmenopause; Testosterone; Virilism
PubMed: 33988479
DOI: 10.1080/13697137.2021.1915273