Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility

Science, Journal Year: 2020, Volume and Issue: 370(6523)

Published: Dec. 18, 2020

A high-quality rhesus macaque genome Genome technology has improved substantially since the first full organismal genomes were generated. Applying new technology, Warren et al. refined of macaque, a model nonhuman primate. Long-read and other recent advances in sequencing applied to generate with far fewer gaps helped refine locations numbers repetitive elements. Furthermore, authors performed resequencing among populations identify genetic variability macaque. Thus, previously incomplete inaccurate set sequence information is now fully resolved, improving gene mapping for biomedical comparative studies. Science , this issue p. eabc6617

Language: Английский

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New insights into anti-Müllerian hormone role in the hypothalamic–pituitary–gonadal axis and neuroendocrine development

Cellular and Molecular Life Sciences, Journal Year: 2020, Volume and Issue: 78(1), P. 1 - 16

Published: June 20, 2020

Abstract Research into the physiological actions of anti-Müllerian hormone (AMH) has rapidly expanded from its classical role in male sexual differentiation to regulation ovarian function, routine clinical use reproductive health and potential as a biomarker diagnosis polycystic ovary syndrome (PCOS). During past 10 years, notion that AMH could act exclusively at gonadal levels undergone another paradigm shift several exciting studies reported unforeseen throughout Hypothalamic–Pituitary–Gonadal (HPG) axis. In this review, we will focus on these findings reporting novel across HPG axis discuss their impact significance better understand human disorders characterized by either developmental alterations neuroendocrine circuits regulating fertility and/or function adult life. Finally, summarize recent preclinical suggesting elevated may potentially be contributing factor central pathophysiology PCOS other diseases.

Language: Английский

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Adipocyte and steroidogenic cell cross-talk in polycystic ovary syndrome

Human Reproduction Update, Journal Year: 2021, Volume and Issue: 27(4), P. 771 - 796

Published: Jan. 28, 2021

Abstract BACKGROUND Metabolic and endocrine alterations in women with polycystic ovary syndrome (PCOS) affect adipose tissue mass distribution. PCOS is characterised by hyperandrogenism, obesity adipocyte dysfunction. Hyperandrogenism drives dysfunctional secretion of potentially harmful adipocytokines. Glucocorticoids sex-steroids modulate development function. For their part, products interact adrenal ovarian steroidogenic cells. Currently, the relationship between cells not clear, for these reasons, it important to elucidate interrelationship without PCOS. OBJECTIVE AND RATIONALE This comprehensive review aims assess current knowledge regarding adipocytes animal models humans or SEARCH METHODS We searched articles published English Portuguese PubMed. Keywords were as follows: syndrome, steroidogenesis, glands, theca cells, granulosa adipocytes, adipocytokines, obesity, enzyme activation, cytochrome P450 enzymes. expanded search into references from retrieved articles. OUTCOMES differentiation Dysfunctional play roles metabolic pathways animals Most adipokines participate regulation hypothalamic–pituitary–adrenal axes. In PCOS, hyperinsulinemia poor fertility are common; various depending on species. Women secrete unbalanced levels products, higher leptin lower adiponectin. Leptin expression positively correlates body index, waist/hip ratio total cholesterol, triglyceride, luteinising hormone, oestradiol androgens. inhibits production and, may 17-hydroxylase aromatase activities. Adiponectin negatively correlate fat mass, waist–hip ratio, glucose, insulin triglycerides, decrease androgen altering hormone receptor, acute regulatory protein, cholesterol-side-chain cleavage 17-hydroxylase. Resistin index testosterone, promotes The potential benefits treatment require more investigation. WIDER IMPLICATIONS data conflicting humans. Polycystic an excellent model investigate among manifest some pathological conditions associated hyperandrogenism products. animals, cross-talk vary according species, suggests opportunities test new medications prevent even reverse several sequelae Further studies required possible therapeutic application obese non-obese Meanwhile, when appropriate, metformin use alone, flutamide, be considered purposes.

Language: Английский

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Polycystic ovary syndrome as a plausible evolutionary outcome of metabolic adaptation

Reproductive Biology and Endocrinology, Journal Year: 2022, Volume and Issue: 20(1)

Published: Jan. 10, 2022

Abstract As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and ovarian morphology. It linked with insulin resistance through preferential abdominal fat accumulation that worsened obesity. Over the past two millennia, menstrual irregularity, male-type habitus sub-infertility have been described in women confirm these clinical features PCOS were antiquity. Recent findings normal-weight hyperandrogenic show exaggerated lipid subcutaneous (SC) stem cells during development to adipocytes vitro occurs combination reduced sensitivity highly-lipolytic intra-abdominal vivo. This phenotype may be an evolutionary metabolic adaptation balance energy storage glucose availability fatty acid oxidation for optimal use reproduction. review integrates fundamental endocrine-metabolic changes healthy, similar PCOS-like traits present animal models which tissue differentiation completed fetal life as humans support concept has ancestral developmental origins.

Language: Английский

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Current concepts of polycystic ovary syndrome pathogenesis

Current Opinion in Pediatrics, Journal Year: 2020, Volume and Issue: 32(5), P. 698 - 706

Published: Sept. 3, 2020

Purpose of review This provides a model for understanding polycystic ovary syndrome (PCOS) pathophysiology and updates the evidence on which it is based. Then, highlights complimentary molecular genetic epigenetic advances in PCOS cause. Recent findings Important studies into cause built 2014 discovery novel regulatory protein variant that underlies typical steroidogenic abnormalities: DENND1A.V2 (differentially expressed normal neoplastic development, isoform 1A, 2). Over 30 DENND1A gene variants have been found, vast majority upstream coding sequence potentially regulatory. These are individually uncommon but collectively plausibly 50% PCOS. Anti-Müllerian hormone (AMH)/AMH receptor with decreased function possibly 6.7% DENNND1A was recently reported to belong signaling network upregulates luteinizing expression insulin mitogenic signaling. Prenatal androgen administration has proven be potent regulator causes transgenerational epigenomic changes mouse similarities those human daughters. Summary In addition finding how contribute pathogenesis, better mechanisms action diverse tissues can expected expand our pathogenesis.

Language: Английский

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The role of gonadotropin‐releasing hormone neurons in polycystic ovary syndrome

Journal of Neuroendocrinology, Journal Year: 2022, Volume and Issue: 34(5)

Published: Jan. 17, 2022

Abstract Given the critical central role of gonadotropin‐releasing hormone (GnRH) neurons in fertility, it is not surprising that GnRH neural network implicated pathology polycystic ovary syndrome (PCOS), most common cause anovulatory infertility. Although many symptoms PCOS relate proximately to ovarian dysfunction, reproductive neuroendocrine system ultimately drives function through its regulation anterior pituitary gonadotropin release. The typical cyclical changes frequency release are often absent women with PCOS, resulting a persistent high‐frequency drive promoting (i.e., relatively high luteinizing and low follicle‐stimulating concentrations) contribute hyperandrogenemia ovulatory dysfunction. However, specific mechanisms underpinning neuron dysfunction remain unclear. Here, we summarize several preclinical clinical studies explore causes aberrant secretion disordered pathophysiology.

Language: Английский

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Prenatal Testosterone Exposure Alters GABAergic Synaptic Inputs to GnRH and KNDy Neurons in a Sheep Model of Polycystic Ovarian Syndrome

Endocrinology, Journal Year: 2019, Volume and Issue: 160(11), P. 2529 - 2542

Published: Aug. 15, 2019

Prenatal testosterone (T)-treated female sheep display reproductive deficits similar to women with polycystic ovarian syndrome (PCOS), including an increase in LH pulse frequency due actions of the central GnRH generator. In this study, we used multiple-label immunocytochemistry investigate possibility changes γ-aminobutyric acid (GABA) neurotransmitter system at two key components generator prenatal T-treated sheep: kisspeptin/neurokinin B/dynorphin (KNDy) neurons arcuate nucleus, and preoptic area (POA) mediobasal hypothalamus (MBH). We observed a significant decrease increase, respectively, number GABAergic synapses onto POA MBH ewes; additionally, there was inputs KNDy neurons. To determine GABA on neurons, examined colocalization chloride transporters NKCC1 KCC2, which indicate stimulatory or inhibitory activation by GABA, respectively. Most both colocalized cotransporter whereas none contained KCC2 cotransporter. either 28% population alone. Therefore, suggest that, as mouse, is well subset Increased numbers animals may contribute alterations steroid feedback control increased GnRH/LH seen animal model PCOS.

Language: Английский

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Androgen Action in Adipose Tissue and the Brain are Key Mediators in the Development of PCOS Traits in a Mouse Model

Endocrinology, Journal Year: 2020, Volume and Issue: 161(7)

Published: April 17, 2020

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by endocrine, reproductive, and metabolic abnormalities. Despite PCOS being the most common endocrinopathy affecting women of reproductive age, etiology poorly understood, so there no cure symptomatic treatment suboptimal. Hyperandrogenism consistent feature observed in patients, recently aberrant neuroendocrine signaling adipose tissue function have been proposed as playing role development PCOS. To investigate brain key sites for androgen receptor (AR)-mediated PCOS, we combined white brown brain-specific AR knockout (AdBARKO) mouse model with dihydrotestosterone (DHT)-induced As expected, wildtype (WT) control females, DHT exposure induced traits cycle irregularity, ovulatory dysfunction, reduced follicle health, whereas AdBARKO did not produce features The characteristics increased adiposity, adipocyte hypertrophy, hepatic steatosis WT females were evident DHT-treated which displayed normal weight hypertrophy or liver steatosis. Dihydrotestosterone fasting glucose levels both females. These findings demonstrate that are loci androgen-mediated actions involved developmental origins data support targeting AR-driven pathways future novel therapeutic strategies

Language: Английский

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Abnormal GnRH pulsatility in polycystic ovary syndrome: Recent insights

Current Opinion in Endocrine and Metabolic Research, Journal Year: 2020, Volume and Issue: 12, P. 78 - 84

Published: April 23, 2020

Language: Английский

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The Search for the Causes of Common Hyperandrogenism, 1965 to Circa 2015

Endocrine Reviews, Journal Year: 2024, Volume and Issue: 45(4), P. 553 - 592

Published: March 8, 2024

Abstract From 1965 to 2015, immense strides were made into understanding the mechanisms underlying common androgen excess disorders, premature adrenarche and polycystic ovary syndrome (PCOS). The author reviews critical discoveries of this era from his perspective investigating these commencing with early unique pattern plasma androgens in elevation an index free testosterone concentration most hirsute women. molecular genetic basis, though not developmental biologic for is now known 11-oxytestosterones shown be major bioactive adrenal androgens. evolution lines research pathogenesis PCOS historically traced: milestones are cited areas neuroendocrinology, insulin resistance, hyperinsulinism, type 2 diabetes mellitus, folliculogenesis, secretion, obesity, phenotyping, prenatal androgenization, epigenetics, complex genetics. Large-scale genome-wide association studies led 2014 discovery unsuspected steroidogenic regulator DENND1A (differentially expressed normal neoplastic development). splice variant DENND1A.V2 constitutively overexpressed theca cells long-term culture accounts their PCOS-like phenotype. genetics complex, however: intronic copy number related phenotype severity, recent data indicate that rare variants a regulatory network other genes PCOS. Obesity exacerbates manifestations via resistance proinflammatory cytokine excess; adipose tissue also forms testosterone. Polycystic ovaries 40 percent apparently women lie on functional spectrum. Much remains learned.

Language: Английский

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