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1.
Metabolism ; 107: 154241, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32304754

RESUMO

BACKGROUND: Hyperandrogenism is one of the major characteristics of polycystic ovary syndrome (PCOS). Abnormal miR-125b-5p expression has been documented in multiple diseases, but whether miR-125b-5p is associated with aberrant steroidogenesis in preantral follicles remains unknown. METHODS: Steriod hormone concentrations and miR-125b-5p expression were measured in clinical serum samples from PCOS patients. Using a mouse preantral follicle culture model and a letrozole-induced PCOS mouse model, we investigated the mechanism underlying miR-125b-5p regulation of androgen and oestrogen secretion. RESULTS: The decreased miR-125b-5p expression was observed in the sera from hyperandrogenic PCOS (HA-PCOS) patients. In mouse preantral follicles, inhibiting miR-125b-5p increased the expression of androgen synthesis-related genes and stimulated the secretion of testosterone, while simultaneously downregulating oestrogen synthesis-related genes and decreasing oestradiol release. Ectopically expressed miR-125b-5p reversed the effects on steroidogenesis-related gene expression and hormone release. Mechanistic studies identified Pak3 as a direct target of miR-125b-5p. Furthermore, inhibiting miR-125b-5p facilitated the activation of ERK1/2 in mouse preantral follicles, while inhibiting Pak3 abrogated this activating effect. These results were recapitulated in letrozole-induced PCOS mouse ovaries. Of note, inhibiting PAK3 antagonised the positive effect of miR-125b-5p siRNA on the expressions of androgen synthesis-related enzymes and testosterone secretion. Luteinizing hormone (LH) inhibited miR-125b-5p expression, and stimulated Pak3 expression. CONCLUSION: High serum LH concentrations in PCOS patients repress miR-125b-5p expression, which further increases Pak3 expression, leading to activation of ERK1/2 signalling, thus stimulating the expression of androgen synthesis-related enzymes and testosterone secretion in HA-PCOS.


Assuntos
MicroRNAs/genética , Folículo Ovariano/metabolismo , Esteroides/biossíntese , Androgênios/biossíntese , Androgênios/genética , Animais , Estradiol/metabolismo , Estrogênios/biossíntese , Estrogênios/genética , Feminino , Regulação da Expressão Gênica/genética , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/metabolismo , Letrozol , Hormônio Luteinizante/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo
2.
Endocrinology ; 161(2)2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32020188

RESUMO

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism, and we previously found that androgens activate endoplasmic reticulum (ER) stress in granulosa cells from patients with PCOS. In addition, recent studies demonstrated the accumulation of advanced glycation end products (AGEs) in granulosa cells from PCOS patients, which contribute to the pathology. Therefore, we hypothesized that androgens upregulate the receptor for AGEs (RAGE) expression in granulosa cells by activating ER stress, thereby increasing the accumulation of AGEs in these cells and contributing to the pathology. In the present study, we show that testosterone increases RAGE expression and AGE accumulation in cultured human granulosa-lutein cells (GLCs), and this is reduced by pretreatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor in clinical use. Knockdown of the transcription factor C/EBP homologous protein (CHOP), an unfolded protein response factor activated by ER stress, inhibits testosterone-induced RAGE expression and AGE accumulation. The expression of RAGE and the accumulation of AGEs are upregulated in granulosa cells from PCOS patients and dehydroepiandrosterone-induced PCOS mice. Administration of the RAGE inhibitor FPS-ZM1 or TUDCA to PCOS mice reduces RAGE expression and AGE accumulation in granulosa cells, improves their estrous cycle, and reduces the number of atretic antral follicles. In summary, our findings indicate that hyperandrogenism in PCOS increases the expression of RAGE and accumulation of AGEs in the ovary by activating ER stress, and that targeting the AGE-RAGE system, either by using a RAGE inhibitor or a clinically available ER stress inhibitor, may represent a novel approach to PCOS therapy.


Assuntos
Estresse do Retículo Endoplasmático , Produtos Finais de Glicação Avançada/metabolismo , Células da Granulosa/metabolismo , Hiperandrogenismo/metabolismo , Síndrome do Ovário Policístico/etiologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Benzamidas/uso terapêutico , Estudos de Casos e Controles , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Ácido Tauroquenodesoxicólico/uso terapêutico , Testosterona
3.
Eur J Obstet Gynecol Reprod Biol ; 243: 125-132, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31693949

RESUMO

Polycystic ovary syndrome (PCOS) risk factors overlap with breast cancer, and the hormonal profile may be implicated in breast cancer pathogenesis. This study aims to report a literature review considering epidemiological and molecular mechanisms that correlate PCOS and breast cancer, as well as the influence of PCOS treatment on the incidence of breast cancer. Epidemiological studies failed to adjust potential variables that affect the risk and have thus provided inconclusive results. Molecular effects of androgenic pathways in breast cancer have been studied and androgens seem to have an inhibitory effect on mammary epithelial proliferation. However, increased bioavailable androgens were associated with recurrence of breast cancer due to conversion to oestrogens. Sex hormone-binding globulin has a role in hormone-dependent cancers and can be considered a marker for PCOS; a gene profile has already been linked to breast cancer risk in these patients. PCOS medical treatment is a promising tool for stratifying breast cancer risk due to the metabolic influence and hormonal environment. Clinical reports are inconsistent, emphasizing the need for further studies with a prospective design. In the future, the role of pharmacological interventions in PCOS will increase knowledge and awareness of breast cancer pathogenesis and will help to refine breast cancer risk stratification.


Assuntos
Neoplasias da Mama/epidemiologia , Síndrome do Ovário Policístico/epidemiologia , Androgênios/metabolismo , Anovulação/tratamento farmacológico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/metabolismo , Clomifeno/uso terapêutico , Anticoncepcionais Orais Combinados/uso terapêutico , Anticoncepcionais Orais Hormonais/uso terapêutico , Estrogênios/metabolismo , Feminino , Fármacos para a Fertilidade Feminina/uso terapêutico , Humanos , Hiperandrogenismo/epidemiologia , Hiperandrogenismo/metabolismo , Hipoglicemiantes/uso terapêutico , Letrozol/uso terapêutico , Metformina/uso terapêutico , Indução da Ovulação , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Fatores de Risco , Globulina de Ligação a Hormônio Sexual/metabolismo
4.
Horm Metab Res ; 51(10): 639-648, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31578050

RESUMO

The aim of the study is to determine the impact of different anthropometric measurements of fat distribution on baseline sex-steroid concentrations and corticosteroidogenic enzyme activity in women with polycystic ovary syndrome compared to those with regular menstrual cycles. The current cross-sectional study included 106 normal cycling controls and 268 polycystic ovary syndrome patients. Patients with polycystic ovary syndrome, diagnosed by Rotterdam criteria, were divided in normoandrogenemic (n=91) and hyperandrogenemic (n=177). Anthropometric, biochemical, and hormone parameters were assessed and correlated with corticosteroidogenic enzyme activities in all three groups. Corticosteroidogenic enzyme activities were calculated using product-to-precursor ratios. Regarding sex-steroids individually, anthropometric parameters correlated with the concentrations of several androgens in polycystic ovary syndrome patients, most of them in patients with biochemical hyperandrogenism. The androgen precursors androstenedione, 17-hydroxyprogesterone, and dehydroepiandrosterone were less correlated with anthropometric parameters. The 17,20 lyase activity, in both Δ4 and Δ5 pathways, correlated with several anthropometric measurements in normo- and hyperandrogenemic polycystic ovary syndrome patients. The 17,20 lyase enzyme activity (Δ4 pathway) also correlated with conicity index, visceral adiposity index, and lipid accumulation product in the control group. 17-Hydroxylase activity positively correlated with waist-height ratio in both polycystic ovary syndrome groups. In contrast, 17-hydroxilase negatively correlated with the conicity index. Anthropometric markers of adiposity are associated with androgen levels and their precursors in blood. Body fat distribution correlates with the activities of some steroidogenic enzyme in both normo-and hyperandrogenemic polycystic ovary syndrome phenotypes. The molecular mechanisms involved in these associations are largely unclear and more investigations are required.


Assuntos
Androgênios/sangue , Biomarcadores/análise , Distribuição da Gordura Corporal , Hiperandrogenismo/fisiopatologia , Síndrome do Ovário Policístico/fisiopatologia , Esteroide 17-alfa-Hidroxilase/metabolismo , Adulto , Idoso , Antropometria , Estudos de Casos e Controles , Estudos Transversais , Feminino , Seguimentos , Humanos , Hiperandrogenismo/metabolismo , Pessoa de Meia-Idade , Síndrome do Ovário Policístico/metabolismo , Prognóstico
5.
PLoS One ; 14(9): e0223274, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31568518

RESUMO

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women that is comprised of two out of the following three features: hyperandrogenism, oligo- or amenorrhea, or polycystic ovaries. In addition to infertility, many women with PCOS have metabolic dysregulation that increases the risk of developing type 2 diabetes, hypertension, and non-alcoholic fatty liver disease. Changes in the gut microbiome are associated with PCOS and gut microbes may be involved in the pathology of this disorder. Since PCOS often manifests in the early reproductive years, puberty is considered to be a critical time period for the development of PCOS. Exposure to sex steroid hormones during development results in permanent, organizational effects, while activational effects are transient and require the continued presence of the hormone. Androgens exert organizational effects during prenatal or early post-natal development, but it is unclear whether androgen excess results in organizational or activational effects during puberty. We recently developed a letrozole-induced PCOS mouse model that recapitulates both reproductive and metabolic phenotypes of PCOS. In this study, we investigated whether letrozole treatment of pubertal female mice exerts organizational or activational effects on host physiology and the gut microbiome. Two months after letrozole removal, we observed recovery of reproductive and metabolic parameters, as well as diversity and composition of the gut microbiome, indicating that letrozole treatment of female mice during puberty resulted in predominantly activational effects. These results suggest that if exposure to excess androgens during puberty leads to the development of PCOS, reduction of androgen levels during this time may improve reproductive and metabolic phenotypes in women with PCOS. These results also imply that continuous letrozole exposure is required to model PCOS in pubertal female mice since letrozole exerts activational rather than organizational effects during puberty.


Assuntos
Inibidores da Aromatase/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hiperandrogenismo/tratamento farmacológico , Letrozol/farmacologia , Síndrome do Ovário Policístico/tratamento farmacológico , Reprodução/fisiologia , Adulto , Fatores Etários , Androgênios/biossíntese , Animais , Técnicas de Tipagem Bacteriana , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Preparações de Ação Retardada/administração & dosagem , Modelos Animais de Doenças , Ciclo Estral/efeitos dos fármacos , Feminino , Humanos , Hiperandrogenismo/genética , Hiperandrogenismo/metabolismo , Hiperandrogenismo/patologia , Insulina/sangue , Hormônio Luteinizante/sangue , Camundongos , Camundongos Endogâmicos C57BL , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Maturidade Sexual/fisiologia , Testosterona/sangue
6.
Front Horm Res ; 53: 177-186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31499491

RESUMO

Hyperandrogenism with or without polycystic ovary syndrome can be sustained by an extreme form of insulin resistance (IR), and is thus a secondary form of hyperandrogenism, which may be due to a defect in insulin signal transduction or in the adipose tissue. Severe IR due to adipose tissue dysfunction is the most frequent form, which may be the result of a deficiency in the adipose tissue, that is, the lipodystrophies, or to the unrestrained accumulation of adipose tissue. These forms are in some cases produced by a single-gene defect. The diagnosis remains predominantly clinical by examining patients in their underwear and looking out for clinical hallmarks, supported by biochemical biomarkers. Gene screening is necessary to corroborate the diagnosis of some forms. Clinicians who deal with hyperandrogenic disorders should be alerted to the forms that are secondary to severe IR, as they are not as uncommon as often imagined and frequently respond to tailored therapies.


Assuntos
Tecido Adiposo/metabolismo , Androgênios/metabolismo , Hiperandrogenismo/diagnóstico , Resistência à Insulina , Doenças Metabólicas/diagnóstico , Humanos , Hiperandrogenismo/metabolismo , Doenças Metabólicas/metabolismo
7.
Front Horm Res ; 53: 100-107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31499493

RESUMO

About 1% of ovarian tumors that comprise testicular cell types can cause hyperandrogenism followed by characteristic virilization. Androgenic group of tumors originated mainly from sex-cord stromal ovarian tumors are including steroid cell tumors, Leydig tumors, granulosa cell tumors, Sertoli cell tumors, Sertoli-Leydig cell tumors, gonadoblastomas, and some other rare forms as ovarian metastases from neuroendocrine tumors. Germline or somatic mutations in some genes like DICER1, STK11, and FOXL2 are associated with the development of some sex cord-stromal ovarian tumors. Basal serum testosterone concentrations above 7 nmol/L could indicate an androgen-secreting tumor. Other ovarian and adrenal androgens should be determined and functional endocrine testing including low-dose dexamethasone suppression test, gonadotrophin-releasing hormone (GnRH) agonist test, imaging methods, and selective venous sampling should be performed. Surgery is the first-line treatment for most of the tumors. Women who are not good surgical candidates could benefit from use of GnRH agonist to control hyperandrogenism. In some cases, chemotherapy and/or radiation therapy is required while some tumors respond on antiangiogenic agents used alone or in combination with chemotherapy. Metabolic implications and long-term outcomes of ovarian androgen-secreting tumors are unknown and require more detailed follow-up in multicentric and longitudinal clinical studies.


Assuntos
Androgênios/metabolismo , Hiperandrogenismo/metabolismo , Neoplasias Ovarianas/metabolismo , Feminino , Humanos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/terapia
8.
Front Horm Res ; 53: 1-17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31499494

RESUMO

In utero androgen excess reliably induces polycystic ovary syndrome (PCOS)-like reproductive and metabolic traits in female monkeys, sheep, rats, and mice. In humans, however, substantial technical and ethical constraints on fetal sampling have curtailed safe, pathogenic exploration during gestation. Evidence consistent with in utero origins for PCOS in humans has thus been slow to amass, but the balance now leans toward developmental fetal origins. Given that PCOS is familial and highly heritable, difficulties encountered in discerning genetic contributions to PCOS pathogenesis are puzzling and, to date, accounts for <10% of PCOS presentations. Unaccounted heritability notwithstanding, molecular commonality in pathogenic mechanisms is emerging, suggested by co-occurrence at the same gene loci of (1) PCOS genetic variants (PCOS women), (2) epigenetic alterations in DNA methylation (PCOS women), and (3) bioinformatics, gene networks-identified, epigenetic alterations in DNA methylation (female rhesus monkeys exposed to testosterone (T) in utero). In addition, naturally occurring hyperandrogenism in female monkeys singles out individuals with PCOS-like reproductive and metabolic traits accompanied by somatic biomarkers of in utero T exposure. Such phenotypic and molecular convergence between highly related species suggests not only dual genetic and epigenetic contributions to a developmental origin of PCOS but also common molecular pathogenesis extending beyond humans.


Assuntos
Androgênios/metabolismo , Hiperandrogenismo , Síndrome do Ovário Policístico , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Humanos , Hiperandrogenismo/etiologia , Hiperandrogenismo/genética , Hiperandrogenismo/metabolismo , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo
9.
Front Horm Res ; 53: 108-119, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31499500

RESUMO

Unwanted sexual hair growth has a considerable negative impact on a woman's self-esteem and quality of life. Excessive growth of terminal hair in women in a man-like pattern is defined as hirsutism and affects up to 1 in 7 women. Androgens secreted by the ovary and adrenal are the main regulator of physiological and pathological alterations of skin hair. Hirsutism is the result of the interaction between circulating serum androgens and hair follicles. Hirsutism is the most commonly used clinical diagnostic criterion of hyperandrogenism and majority of hirsutism cases are due to androgen excess. Over 80% of women with hirsutism will have polycystic ovary syndrome, about 10% will have idiopathic hirsutism, and the remaining will have rare disorders including non-classical congenital adrenal hyperplasia, hyperandrogenism with insulin resistance and acanthosis nigricans, and androgen-secreting neoplasms. Cushing's syndrome, acromegaly, thyroid dysfunction and hyperprolactinemia might be associated with hirsutism as well as the use of androgens, anabolic steroids and valproate. This paper provides an overview of the principal endocrinological aspects of hirsutism including the role of androgens in excessive hair growth and associated androgen excess disorders. Clinical evaluation and management of hirsutism are also discussed.


Assuntos
Androgênios/metabolismo , Hirsutismo/metabolismo , Hiperandrogenismo/metabolismo , Feminino , Humanos
10.
Front Horm Res ; 53: 77-91, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31499501

RESUMO

Although polycystic ovary syndrome (PCOS) is the most common androgen excess disorder, screening for Cushing's Syndrome (CS) should be considered in women with PCOS phenotype, particularly if they are also affected by other disturbances that increase their pretest probability (e.g., osteoporosis/bone fractures). Approximately 70-80% of women with CS present menstrual abnormalities, and PCOS findings are found in 46% of these patients. Diagnostic efforts should strengthen if the clinical picture is severe or of rapid onset in order to ensure the earliest and most appropriate treatment. If the diagnosis of CS is challenging, its differentiation from PCOS is not outdone: isolated PCOS may be associated to hypothalamic-pituitary-adrenal axis disruption, leading to false-positive results in screening tests. Because of this overlap, the diagnosis of CS is initially missed or delayed. Diagnostic utility of serum androgen assessment is controversial, but the widespread use of high-performance liquid chromatography and gas chromatography-mass spectrometry for urinary steroid profiling is showing promising results. According to the role of adrenocorticotropic hormone (ACTH) in adrenal androgen secretion, it is not surprising that the levels of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and androstenedione (A4) are generally elevated or in the upper normal range in patients with ACTH-dependent CS. Conversely, adrenal androgens are generally low in patients with cortisol-secreting adrenocortical adenoma. However, androgen-secreting adrenal tumors (adenoma and carcinoma) can be also associated with severe hyperandrogenism. Regression of hypercortisolism after treatment causes disappearance of hyperandrogenism. However, signs of androgen excess may be detectable in well-controlled CS as a result of ACTH compensatory response to certain adrenal steroidogenesis inhibitors.


Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Androgênios/metabolismo , Síndrome de Cushing/metabolismo , Hiperandrogenismo/metabolismo , Síndrome do Ovário Policístico/metabolismo , Comorbidade , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/epidemiologia , Feminino , Humanos , Hiperandrogenismo/diagnóstico , Hiperandrogenismo/epidemiologia , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/epidemiologia
11.
Front Horm Res ; 53: 50-64, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31499502

RESUMO

Sex steroids, except for their primary reproductive role, exert key effects on metabolic target tissues. Androgen receptors have been detected in various tissues, participating in both central and peripheral regulation of metabolism and insulin action. The physiological role of androgens in regulating multiple aspects of female insulin signaling and energy metabolism becomes evident early in utero, thus programming how insulin-targeted tissues will behave in later life. Across lifespan, distinct effects of androgens in all insulin-targeted tissues are controlled by their circulating serum levels, within a narrow window, outside of which disturbances in metabolism are observed. Thus, androgen excess in women, as documented in those with polycystic ovary syndrome, can adversely affect insulin sensitivity, promoting visceral adiposity, adipose tissue dysfunction, and, ultimately, insulin resistance.


Assuntos
Adiposidade , Androgênios/metabolismo , Hiperandrogenismo/metabolismo , Resistência à Insulina , Insulina/metabolismo , Síndrome do Ovário Policístico/metabolismo , Androgênios/sangue , Feminino , Humanos , Hiperandrogenismo/sangue , Insulina/sangue , Síndrome do Ovário Policístico/sangue
12.
Front Horm Res ; 53: 92-99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31499503

RESUMO

Androgen-secreting tumors are a rare cause of hyperandrogenism of adrenal origin. Although these tumors are identified in less than 2% of patients, the prevalence of adrenocortical carcinomas is relevant (2/3 of the cases). Those tumors are associated with simultaneous elevation of several androgens, mainly androstenedione, DHEAS, and testosterone, in more than half of the patients, as measured either by immunoassay or mass spectrometry. Despite the recent advances on the pathogenesis of adrenocortical tumors, to date no driver molecular event have been identified in those tumors. This chapter provides a comprehensive review of all studies published in the last 20 years on androgen-secreting tumors, with focus on epidemiology, clinical presentation, and hormonal profile.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Androgênios/metabolismo , Hiperandrogenismo/metabolismo , Neoplasias do Córtex Suprarrenal/epidemiologia , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/fisiopatologia , Humanos
13.
Front Horm Res ; 53: 162-176, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31499504

RESUMO

Most research efforts addressing the pathophysiology of polycystic ovary syndrome (PCOS) applied targeted approaches focusing on specific genes and/or proteins that were selected on the basis of previous knowledge about their putative roles in metabolic and signalling pathways. On the contrary, the use of nontargeted approaches is not constricted by previous knowledge on the issue and offers the potential advantage of revealing novel associations with unexpected molecules that might lead to new mechanistic explanations for the etiology and the pathophysiology of PCOS. To date, several "omics" approaches have been applied to create a holistic picture complementing the information generated by genetic studies. Proteomics and metabolomics have the potential advantage over genomics of integrating genetic and epigenetic influences, thereby facilitating interpretation of the molecular mechanisms and pathways involved in the pathogenesis of PCOS. This chapter summarizes recent advances provided by proteomic and metabolomic studies addressing PCOS and aims to offer a critical yet balanced review of the studies published to date.


Assuntos
Hiperandrogenismo/diagnóstico , Metabolômica , Síndrome do Ovário Policístico/diagnóstico , Proteômica , Feminino , Humanos , Hiperandrogenismo/metabolismo , Síndrome do Ovário Policístico/metabolismo
14.
Front Horm Res ; 53: 135-161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31499509

RESUMO

Menopause is the period of a woman's life that is characterized by the permanent cessation of menses associated to hormonal changes, of which the most important is the decrease of estrogen levels. Following menopause, the concentrations of circulating androgens decrease. However, increased concentrations of luteinizing hormone induce androgens secretion from the ovaries and presumably from the adrenal glands. Peripheral conversion of androgens results to the circulating hormonal androgen profile. Some pathological conditions are associated with greater concentrations of androgens after menopause than in controls, with polycystic ovary syndrome (PCOS) being the commonest. These conditions can be distinguished in non-tumorous (adrenal or ovarian) or functional and tumorous (adrenal or ovarian benign or malignant) masses. Apart from PCOS, other non-tumorous (adrenal or ovarian) causes of hyperandrogenism in post-menopausal women are obesity, non-classic congenital adrenal hyperplasia (NCCAH), endocrinopathies, such as Cushing disease or acromegaly; ovarian hyperthecosis, drug use or abuse. Tumorous (adrenal or ovarian) causes include adrenal cortical cancers, adrenal benign adenomas and even incidentalomas, or ovarian tumors such as the sex-cord stromal ovarian tumors and metastases in the ovary. The diagnosis of hyperandrogenism is made through medical history, clinical examination, and laboratory tests. Total testosterone concentration of 150 ng/dL can be used at first to distinguish a malignant from a benign cause of hyperandrogenism. Dehydroepiandrosterone sulfate concentration may support adrenal source of androgens. Imaging techniques are used to localize the source of androgens: computed tomography and magnetic resonance imaging (MRI) for the adrenals and transvaginal ultrasound or MRI for the ovaries. Finally, treatment (etiologic and symptomatic) and long-term effects of hyperandrogenism are developed in this chapter.


Assuntos
Glândulas Suprarrenais/metabolismo , Androgênios/metabolismo , Hiperandrogenismo/metabolismo , Menopausa/metabolismo , Ovário/metabolismo , Síndrome do Ovário Policístico/metabolismo , Glândulas Suprarrenais/diagnóstico por imagem , Feminino , Humanos , Hiperandrogenismo/diagnóstico por imagem , Ovário/diagnóstico por imagem , Síndrome do Ovário Policístico/diagnóstico por imagem
15.
FEBS Open Bio ; 9(10): 1817-1825, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31433577

RESUMO

Polycystic ovary syndrome (PCOS) is a major cause of anovulatory sterility in women, and most PCOS patients exhibit hyperandrogenism (HA). Liver kinase b1 (LKB1) is a tumor suppressor that has recently been reported to be involved in PCOS. However, the mechanism by which LKB1 affects HA has not previously been elucidated. We report here that ovarian LKB1 levels are significantly decreased in a female mouse model of HA. Moreover, we report that LKB1 expression is inhibited by elevated androgens via activation of androgen receptors. In addition, LKB1 treatment was observed to suppress androgen synthesis in theca cells and promote estrogen production in granulosa cells by regulating steroidogenic enzyme expression. As expected, LKB1 knockdown inhibited estrogen levels and enhanced androgen levels, and LKB1-transgenic mice were protected against HA. The effect of LKB1 appears to be mediated via IGF-1 signaling. In summary, we describe here a key role for LKB1 in controlling sex hormone levels.


Assuntos
Androgênios/biossíntese , Modelos Animais de Doenças , Hiperandrogenismo/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais
16.
Life Sci ; 232: 116681, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31344428

RESUMO

AIM: This study aimed to determine whether glucocorticoid receptor (GR) signaling, mitochondrial function, and local inflammation in the ovary and uterus are intrinsically different in rats with hyperandrogenism and insulin resistance compared to controls. MAIN METHODS: Female Sprague Dawley rats were exposed to daily injections of human chorionic gonadotropin and/or insulin. KEY FINDINGS: In both the ovary and the uterus, decreased expression of the two GR isoforms was concurrent with increased expression of Fkbp51 but not Fkbp52 mRNA in hCG + insulin-treated rats. However, these rats exhibited contrasting regulation of Hsd11b1 and Hsd11b2 mRNAs in the two tissues. Further, the expression of several oxidative phosphorylation-related proteins decreased in the ovary and uterus following hCG and insulin stimulation, in contrast to increased expression of many genes involved in mitochondrial function and homeostasis. Additionally, hCG + insulin-treated rats showed increased expression of ovarian and uterine NFκB signaling proteins and Tnfaip3 mRNA. The mRNA expression of Il1b, Il6, and Mmp2 was decreased in both tissues, while the mRNA expression of Tnfa, Ccl2, Ccl5, and Mmp3 was increased in the uterus. Ovaries and uteri from animals co-treated with hCG and insulin showed increased collagen deposition compared to controls. SIGNIFICANCE: Our observations suggest that hyperandrogenism and insulin resistance disrupt ovarian and uterine GR activation and trigger compensatory or adaptive effects for mitochondrial homeostasis, allowing tissue-level maintenance of mitochondrial function in order to limit ovarian and uterine dysfunction. Our study also suggests that hyperandrogenism and insulin resistance activate NFκB signaling resulting in aberrant regulation of inflammation-related gene expression.


Assuntos
Hiperandrogenismo/metabolismo , Inflamação/metabolismo , Resistência à Insulina , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Ovário/metabolismo , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais , Útero/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Síndrome do Ovário Policístico/metabolismo , Ratos , Ratos Sprague-Dawley
17.
Gynecol Endocrinol ; 35(8): 669-672, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31056990

RESUMO

Hyperandrogenism is one of the most common causes for anovulation in women and increases the risk for metabolic disorder in PCOS patients. Autophagy plays an important role in dysfunction of endocrine and anovulation. However, the relationship between hyperandrogenism and autophagy in human granulosa cells of PCOS patients remains unclear. By collecting granulosa cells from PCOS patients and non-PCOS patients, we found that the abundance of autophagy-related genes ATG5, ATG7, BECN1 mRNA and the ratio of autophagy marker protein light chain 3B II/I (LC3 II/I) were significantly increased whereas the abundance of the autophagy substrate SQSTM1/p62 was decreased in ovarian granulosa cells from PCOS patients. Furthermore, we demonstrated that BECN1 mRNA abundance in human granulosa cells positively correlated with the basal level of serum total testosterone and androgen up-regulated the abundance of BECN1 mRNA and the ratio of LC3II/LC3I in a dose-dependent manner in cultured granulosa cells. These observations indicated that androgen-induced activation of autophagy may play an important role in the development of PCOS and to explore the autophagy mechanisms involved in PCOS yield new insight into the pathophysiology and therapy of the disorder.


Assuntos
Androgênios/fisiologia , Autofagia/fisiologia , Células da Granulosa/fisiologia , Síndrome do Ovário Policístico/patologia , Adulto , Androgênios/metabolismo , Androgênios/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Estudos de Casos e Controles , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Células da Granulosa/patologia , Humanos , Hiperandrogenismo/complicações , Hiperandrogenismo/metabolismo , Hiperandrogenismo/patologia , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Cultura Primária de Células , Adulto Jovem
18.
Biomed Res Int ; 2019: 2513067, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080813

RESUMO

Introduction: Many patients who were diagnosed as polycystic ovary syndrome- (PCOS-) related acne were not capable of sustaining or beginning oral contraceptive pills (OCPs) due to pill scaring, contraindications of OCP use, migraine, or smoking. In this situation, oral isotretinoin treatment may become an important option for PCOS-related acne. The aim of the study was to determine the effects of isotretinoin treatment on PCOS patients who were complicated with severe cystic acne. Materials and Methods: This study consisted of 40 female patients diagnosed as PCOS complicated with severe cystic acne. These patients were not eligible candidates for OCP use due to migraine, thrombophilia, heavy smoking, or pill scare. To establish baseline values of hormone levels, on days 2-5 of the menstrual cycle, venous blood samples were obtained. Moreover Modified Ferriman-Gallwey (mFG) score, acne score (AS), follicle count, and bilateral ovarian volumes were evaluated both before and after isotretinoin treatment. Results: Isotretinoin treatment significantly decreased Ferriman-Gallwey score, free testosterone, insulin level, hemoglobin level, acne score, and ovarian volume. Increased triglyceride and cholesterol levels were detected after treatment. Conclusion: Isotretinoin treatment may have beneficial effects on free testosterone, insulin, acne score, and Ferriman-Gallwey score. Solely isotretinoin administration may supply adequate healing in PCOS patients' symptoms complicated with severe cystic acne who is not eligible candidates for OCP use. This trial is registered with Clinicaltrials.gov NCT02855138.


Assuntos
Acne Vulgar/tratamento farmacológico , Isotretinoína/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Acne Vulgar/metabolismo , Adolescente , Adulto , Anticoncepcionais Orais Combinados/uso terapêutico , Feminino , Humanos , Hiperandrogenismo/tratamento farmacológico , Hiperandrogenismo/metabolismo , Insulina/metabolismo , Ciclo Menstrual/efeitos dos fármacos , Ciclo Menstrual/metabolismo , Síndrome do Ovário Policístico/metabolismo , Estudos Prospectivos , Testosterona/metabolismo , Adulto Jovem
19.
Endocrinology ; 160(6): 1377-1393, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30951142

RESUMO

Ovarian theca androgen production is regulated by the pituitary LH and intrafollicular factors. Enhanced androgen biosynthesis by theca cells contributes to polycystic ovary syndrome (PCOS) in women, but the ovarian consequences of elevated androgens are not completely understood. Our study documents the molecular events that are altered in the theca and stromal cells of mice exposed to high androgen levels, using the nonaromatizable androgen DHT. Changes in ovarian morphology and function were observed not only in follicles, but also in the stromal compartment. Genome-wide microarray analyses revealed marked changes in the ovarian transcriptome of DHT-treated females within 1 week. Particularly striking was the increased expression of vascular cell adhesion molecule 1 (Vcam1) specifically in the NR2F2/COUPTF-II lineage theca cells, not granulosa cells, of growing follicles and throughout the stroma of the androgen-treated mice. This response was mediated by androgen receptors (ARs) present in theca and stromal cells. Human theca-derived cultures expressed both ARs and NR2F2 that were nuclear. VCAM1 mRNA and protein were higher in PCOS-derived theca cells compared with control theca and reduced markedly by the AR antagonist flutamide. In the DHT-treated mice, VCAM1 was transiently induced by equine chorionic gonadotropin, when androgen and estrogen biosynthesis peak in preovulatory follicles, and was potently suppressed by a superovulatory dose of human chorionic gonadotropin. High levels of VCAM1 in the theca and interstitial cells of DHT-treated mice and in adult Leydig cells indicate that there may be novel functions for VCAM1 in reproductive tissues, including the gonads.


Assuntos
Di-Hidrotestosterona , Hiperandrogenismo/metabolismo , Folículo Ovariano/metabolismo , Ovário/metabolismo , Células Estromais/metabolismo , Células Tecais/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Fator II de Transcrição COUP/metabolismo , Feminino , Hiperandrogenismo/induzido quimicamente , Camundongos , Receptores Androgênicos/metabolismo
20.
Endocrinology ; 160(5): 1193-1204, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30924862

RESUMO

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting ∼10% to 15% of reproductive-aged women worldwide. Diagnosis requires two of the following: hyperandrogenism, oligo-ovulation or anovulation, and polycystic ovaries. In addition to reproductive dysfunction, many women with PCOS display metabolic abnormalities associated with hyperandrogenism. Recent studies have reported that the gut microbiome is altered in women with PCOS and rodent models of the disorder. However, it is unknown whether the gut microbiome plays a causal role in the development and pathology of PCOS. Given its potential role, we hypothesized that exposure to a healthy gut microbiome would protect against development of PCOS. A cohousing study was performed using a letrozole-induced PCOS mouse model that recapitulates many reproductive and metabolic characteristics of PCOS. Because mice are coprophagic, cohousing results in repeated, noninvasive inoculation of gut microbes in cohoused mice via the fecal-oral route. In contrast to letrozole-treated mice housed together, letrozole mice cohoused with placebo mice showed significant improvement in both reproductive and metabolic PCOS phenotypes. Using 16S rRNA gene sequencing, we also observed that the overall composition of the gut microbiome and the relative abundance of Coprobacillus and Lactobacillus differed in letrozole-treated mice cohoused with placebo mice compared with letrozole mice housed together. These results suggest that dysbiosis of the gut microbiome may play a causal role in PCOS and that modulation of the gut microbiome may be a potential treatment option for PCOS.


Assuntos
Modelos Animais de Doenças , Microbioma Gastrointestinal/fisiologia , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Reprodução/fisiologia , Animais , Anovulação/metabolismo , Anovulação/fisiopatologia , Inibidores da Aromatase/farmacologia , Disbiose/fisiopatologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Abrigo para Animais , Humanos , Hiperandrogenismo/metabolismo , Hiperandrogenismo/fisiopatologia , Letrozol/farmacologia , Camundongos Endogâmicos C57BL , Síndrome do Ovário Policístico/diagnóstico , Reprodução/efeitos dos fármacos
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