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1.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806551

RESUMO

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model; however, additional therapies may be needed to improve IR and renal injury.


Assuntos
Coração/efeitos dos fármacos , Síndrome do Ovário Policístico/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Compostos Benzidrílicos/farmacologia , Di-Hidrotestosterona/farmacologia , Modelos Animais de Doenças , Feminino , Glucosídeos/farmacologia , Hiperandrogenismo/tratamento farmacológico , Hiperandrogenismo/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico , Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
2.
Life Sci ; 276: 119409, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33781825

RESUMO

Polycystic ovary syndrome is a common reproductive disorder in the female of reproductive age, which is characterized by hyperandrogenism, insulin resistance, cystic ovary and infertility. The level of pro-inflammatory adipokine, visfatin is elevated in PCOS conditions in human and animal. In this study, letrozole induced hyperandrogenised PCOS mice model have been used to unravel the effects of visfatin inhibition. The results showed that letrozole induced hyperandrogenisation significantly (p < 0.05) elevates ovarian visfatin concentration from 66.03 ± 1.77 to 112.08 ± 3.7 ng/ml, and visfatin expression to 2.5 fold (p < 0.05) compared to control. Visfatin inhibition in PCOS by FK866 has significantly (p < 0.05) suppressed the secretion of androgens, androstenedione (from 0.329 ± 0.07 to 0.097 ± 0.01 ng/ml) and testosterone levels (from 0.045 ± 0.003 to 0.014 ± 0.0009 ng/ml). Ovarian histology showed that visfatin inhibition suppressed cyst formation and promotes corpus luteum formation. Visfatin inhibition has suppressed apoptosis and increases the expression of BCL2 along with increase in the proliferation (GCNA expression elevated). Visfatin inhibition has increased ovarian glucose content (from 167.05 ± 8.5 to 210 ± 7 mg/dl), along with increase in ovarian GLUT8 expression. In vitro study has also supported the in vivo findings where FK866 treatment significantly (p < 0.05) suppressed testosterone (control-3.84 ± 0.44 ng/ml, 1 nM FK866-2.02 ± 0.048 ng/ml, 10 nM FK866-1.74 ± 0.20 ng/ml) and androstenedione (control-4.68 ± 0.91 ng/ml, 1 nM FK866-3.38 ± 0.27 ng/ml, 10 nM FK866-4.55 ± 0.83 ng/ml) production from PCOS ovary. In conclusion, this is first report, which showed that visfatin inhibition by FK866 in hyperandrogenised mice ameliorates pathogenesis of PCOS. Thus, it may be suggested that visfatin inhibition could have a therapeutic potential in PCOS management along with other intervention.


Assuntos
Acrilamidas/farmacologia , Citocinas/antagonistas & inibidores , Modelos Animais de Doenças , Hiperandrogenismo/tratamento farmacológico , Letrozol/toxicidade , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Piperidinas/farmacologia , Síndrome do Ovário Policístico/tratamento farmacológico , Androgênios/metabolismo , Animais , Glicemia/metabolismo , Feminino , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/metabolismo , Hiperandrogenismo/patologia , Resistência à Insulina , Camundongos , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia
3.
J Steroid Biochem Mol Biol ; 206: 105806, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33340681

RESUMO

Polycystic ovary syndrome (PCOS) is a heterogeneous disease defined by the presence of at least two of the following features: hyperandrogenism, oligoanovulation (OA), and polycystic ovarian morphology (PCOM). Hyperandrogenism is considered the cornerstone of PCOS. However, the most prevalent phenotype in Chinese women with PCOS is OA + PCOM [normo-androgenic PCOS (NA-PCOS)]. It has been reported that PCOS women have higher androgen levels in follicular fluid (FF), but whether NA-PCOS women have the same intrafollicular steroid profiles as hyperandrogenic PCOS (HA-PCOS) women has not been explored. In this study, we analyzed 17 steroids in stimulated size-matched ovarian follicles (16-18 mm) from 166 controls and 141 PCOS women [87 NA-PCOS and 54 HA-PCOS women, defined by a single serum testosterone (T) immunoassay measurement] using liquid chromatography tandem mass spectrometry, and investigated their relationship with baseline characteristics. No significant differences in intrafollicular steroid levels and product/precursor ratios between NA-PCOS and HA-PCOS women were observed, though HA-PCOS women had significantly higher serum luteinizing hormone and T levels than NA-PCOS women. NA-PCOS and HA-PCOS women had significantly higher levels of androstenedione (AD), T and free androgen index, higher enzyme activity of P450c17 (AD/17OH-progesterone), 3ßHSD2 (17OH-progesterone /17OH-pregnenolone) and P450c11 (corticosterone /11-deoxycorticosterone), lower levels of pregnenolone, 17OH-pregnenolone and 11-deoxycorticosterone, and decreased enzyme activity of P450aro (estrone/AD and estradiol/T) and 5α-reductase (dihydrotestosterone/T) in FF than controls. NA-PCOS women had significantly higher intrafollicular cortisol levels and lower 11ßHSD2 (cortisone/cortisol) activity than controls. Baseline serum T levels were slightly correlated with intrafollicular estrogens (E1: r = 0.192, p = 0.019; E2: r = 0.248, p = 0.002; E3: r = 0.248, p = 0.002) and androgens (DHEAS: r = 0.276, p = 0.001; AD: r = 0.185, p = 0.032; T: r = 0.173, p = 0.044) in controls and PCOS women respectively. Serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) were correlated with intrafollicular cortisol (AMH: r = 0.380, p = 0.000; AFC: r = 0.177, p = 0.036) and corticosterone (AMH: r = 0.212, p = 0.048; AFC: r = 0.219, p = 0.009) levels in PCOS women. In conclusion, NA-PCOS and HA-PCOS women had statistically similar steroid metabolome profiles in FF, both of which showed a generally decreased steroidogenesis and hyperandrogenism compared to controls.


Assuntos
Hiperandrogenismo/sangue , Metaboloma/genética , Síndrome do Ovário Policístico/sangue , Esteroides/sangue , Adulto , Androgênios/sangue , Androstenodiona/sangue , Hormônio Antimülleriano , Estradiol/sangue , Estrogênios/sangue , Feminino , Líquido Folicular/metabolismo , Humanos , Hidrocortisona/sangue , Hiperandrogenismo/genética , Hiperandrogenismo/metabolismo , Hiperandrogenismo/patologia , Hormônio Luteinizante/sangue , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Esteroides/metabolismo , Testosterona/sangue , Adulto Jovem
5.
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
6.
Medicina (Kaunas) ; 56(3)2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32120970

RESUMO

Background and Objectives: Polycystic ovary syndrome (PCOS) is one of the most prevalent disorders among women of reproductive age. It is considered as a pro-inflammatory state with chronic low-grade inflammation, one of the key factors contributing to the pathogenesis of this disorder. Polycystic ovary is a well-established criterion for PCOS. The present investigation aimed at finding the role of hyperandrogenism, the most important feature of PCOS, in the development of this inflammatory state. To address this problem, we adopted a model system that developed polycystic ovary morphology (PCOM), which could be most effectively used in order to study the role of non-aromatizable androgen in inflammation in PCOS. Materials and Methods: Six rats were used to induce PCOM in 21-days-old female Wistar albino rats by using a pre-determined release of dihydrotestosterone (DHT), a potent non-aromatizable androgen, achieved by implanting a DHT osmotic pump, which is designed to release a daily dose of 83 µg. Results: After 90 days, the rats displayed irregular estrous cycles and multiple ovarian cysts similar to human PCOS. Elevated serum inflammatory markers such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), and the presence of a necrotic lesion in the liver, osteoclast in the femur, multinucleated giant cells and lymphocytes in the ovary based on histopathological observation of DHT-treated rats clearly indicated the onset of inflammation in the hyperandrogenic state. Our results show no significant alterations in serum hormones such as luteinizing hormone (LH), follicle stimulating hormone (FSH), insulin, and cortisol between control and hyperandrogenised rats. DHT was significantly elevated as compared to control. mRNA studies showed an increased expression level of TNF-α and IL-1ß, further, the mRNA expression of urocortin 1 (Ucn-1) was stupendously elevated in the liver of hyperandrogenised rats. Conclusions: Thus, results from this study provide: (1) a good PCOM model system in order to study the inflammatory changes in PCOS aspects, (2) alteration of inflammatory markers in PCOM rats that could be either due to its direct effect or by the regulation of various inflammatory genes and markers in the liver of hyperandrogenic state suggesting the regulatory role of DHT, and (3) alteration in stress-related protein in the liver of PCOM rats.


Assuntos
Citocinas/sangue , Di-Hidrotestosterona/efeitos adversos , Hiperandrogenismo/metabolismo , Mediadores da Inflamação/sangue , Síndrome do Ovário Policístico/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Hormônio Foliculoestimulante/sangue , Hiperandrogenismo/induzido quimicamente , Insulina/sangue , Fígado/metabolismo , Hormônio Luteinizante/sangue , Síndrome do Ovário Policístico/complicações , Ratos , Ratos Wistar , Urocortinas/metabolismo
7.
J Endocrinol ; 245(2): 291-300, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32171180

RESUMO

Polycystic ovary syndrome (PCOS), one of the most common female endocrine disorder, is a prevalent cause of infertility. Hyperandrogenism is a key feature in PCOS and is correlated with increased expression of VEGF and cytokines in the ovaries. We have previously shown that pigment epithelium-derived factor (PEDF), an endogenous protein, presents potent anti-angiogenic and anti-inflammatory activities in the ovary and negates the effects of cytokines and VEGF. Additionally, PEDF plays a role in both pathophysiology and treatment of ovarian-hyperstimulation syndrome (OHSS), frequently seen in PCOS patients. We established hyperandrogenic-PCOS models, both in vivo, using mice exposed prenatally to dihydrotestosterone (DHT) and, in vitro, using human primary granulosa cells (hpGCs) and human granulosa cell line (KGN). In PCOS-induced mice, the mRNA levels of I l-6, V egf and Amh were higher than those of control; yet, treatment with rPEDF decreased these levels. Moreover, treating OHSS-induced PCOS-mice with rPEDF alleviated all OHSS symptoms. Stimulation of hpGCs with DHT resulted in downregulation of PEDF mRNA expression, concomitantly with a significant increase in IL-6 and IL-8 mRNAs expression. However, co-stimulation of DHT with rPEDF attenuated the increase in cytokines expression. The anti-inflammatory effect of PEDF was found to be mediated via PPARγ pathway. Our findings suggest that rPEDF treatment may normalize the ovarian angiogenic-inflammatory imbalance, induced by PCOS-associated hyperandrogenism. Moreover, the therapeutic potency of PEDF in preventing OHSS symptomes offers a rationale for using PEDF as novel physiological treatment for PCOS sequels.


Assuntos
Anti-Inflamatórios/metabolismo , Proteínas do Olho/metabolismo , Hiperandrogenismo/metabolismo , Fatores de Crescimento Neural/metabolismo , Síndrome do Ovário Policístico/metabolismo , Serpinas/metabolismo , Transdução de Sinais/fisiologia , Animais , Linhagem Celular , Di-Hidrotestosterona , Modelos Animais de Doenças , Feminino , Células da Granulosa/metabolismo , Humanos , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/complicações , Camundongos , Ovário/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente
8.
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
9.
Mol Med Rep ; 21(3): 1461-1470, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016479

RESUMO

The present study was designed to elucidate the underlying mechanisms of Bao Gui capsule (BGC) against hyperandrogenism, insulin resistance and leptin resistance of PCOS. Letrozole was used to induce a PCOS model in rats, which were then randomly divided into four groups (n=9): Control, Model, high­dose BGC (BGC­H) and low­dose BGC (BGC­L) group. Serum levels of follicle­stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2), insulin, leptin, and interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α (TNF­α) in the hypothalamus were determined by ELISA. Protein levels of cytochrome P450c17α and cytochrome P450 aromatase (P450arom) in ovaries were determined by immunohistochemistry and western blot analysis. Additionally, the expression of GLUT4 in uterus and muscle tissue, and NF­κB, IKKß and SOCS3 mRNA levels in the hypothalamus were evaluated. BGC significantly reduced body weight gain and decreased serum levels of LH/FSH, T, log T/E2, insulin and leptin compared with the PCOS model rats. Furthermore, BGC markedly reduced the expression of P450c17α and significantly increased the expression of P450arom in ovaries, and increased the expression of GLUT4 in uterus and muscle tissues. BGC also effectively reduced the level of IL­6 and TNF­α, and the expression of IKKß, NF­κB and SOCS3 in the hypothalamus of PCOS model rats. These results suggest that BGC may effectively improve hyperandrogenism, insulin resistance, endometrial receptivity and the low­grade chronic inflammation in the hypothalamus.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hiperandrogenismo/tratamento farmacológico , Resistência à Insulina , Fitoterapia , Preparações de Plantas/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Animais , Citocinas/sangue , Endométrio/efeitos dos fármacos , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Transportador de Glucose Tipo 4/metabolismo , Hiperandrogenismo/metabolismo , Hipotálamo/metabolismo , Insulina/sangue , Leptina/sangue , Hormônio Luteinizante/sangue , Síndrome do Ovário Policístico/metabolismo , Ratos , Testosterona/sangue , Útero/metabolismo
10.
Clin Chim Acta ; 502: 214-221, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31733195

RESUMO

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease characterized by clinical or laboratorial hyperandrogenism, oligo-anovulation and metabolic abnormalities, including insulin resistance, excessive weight or obesity, type II diabetes, dyslipidemia and an increased risk of cardiovascular disease. The most significant clinical manifestation of PCOS is hyperandrogenism. Excess androgen profoundly affects granulosa cell function and follicular development via complex mechanisms that lead to obesity and insulin resistance. Most PCOS patients with hyperandrogenism have steroid secretion defects that result in abnormal folliculogenesis and failed dominant follicle selection. Hyperandrogenism induces obesity, hairy, acne, and androgenetic alopecia. These symptoms can bring great psychological stress to women. Drugs such as combined oral contraceptive pills, metformin, pioglitazone and low-dose spironolactone help improve pregnancy rates by decreasing androgen levels in vivo. Notably, PCOS is heterogeneous, and hyperandrogenism is not the only pathogenic factor. Obesity and insulin resistance aggravate the symptoms of hyperandrogenism, forming a vicious cycle that promotes PCOS development. Although numerous studies have been conducted, the definitive pathogenic mechanisms of PCOS remain uncertain. This review summarizes and discusses previous and recent findings regarding the relationship between hyperandrogenism, insulin resistance, obesity and PCOS.


Assuntos
Hiperandrogenismo/metabolismo , Resistência à Insulina , Obesidade/metabolismo , Síndrome do Ovário Policístico/metabolismo , Androgênios/biossíntese , Feminino , Humanos , Hiperandrogenismo/diagnóstico , Hiperandrogenismo/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Obesidade/diagnóstico , Obesidade/tratamento farmacológico , Pioglitazona/uso terapêutico , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/tratamento farmacológico , Espironolactona/uso terapêutico
11.
Sci Rep ; 9(1): 19232, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848372

RESUMO

Polycystic ovary syndrome (PCOS) is a major reproductive disorder that is responsible for 80% of anovulatory infertility and that is associated with hyperandrogenemia, increased risk of obesity, and white adipose tissue (WAT) dysfunction. We have previously demonstrated that the combination of chronic testosterone (T) treatment and an obesogenic Western-style diet (WSD) exerts synergistic functional effects on WAT, leading to increased lipid accumulation in visceral adipocytes by an unknown mechanism. In this study, we examined the whole-genome transcriptional response in visceral WAT to T and WSD, alone and in combination. We observed a synergistic effect of T and WSD on gene expression, resulting in upregulation of lipid storage genes concomitant with adipocyte hypertrophy. Because DNA methylation is known to be associated with body fat distribution and the etiology of PCOS, we conducted whole-genome DNA methylation analysis of visceral WAT. While only a fraction of differentially expressed genes also exhibited differential DNA methylation, in silico analysis showed that differentially methylated regions were enriched in transcription factor binding motifs, suggesting a potential gene regulatory role for these regions. In summary, this study demonstrates that hyperandrogenemia alone does not induce global transcriptional and epigenetic response in young female macaques unless combined with an obesogenic diet.


Assuntos
Metilação de DNA , Dieta Ocidental/efeitos adversos , Hiperandrogenismo/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Transcrição Genética , Animais , Feminino , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/patologia , Gordura Intra-Abdominal/patologia , Macaca mulatta , Obesidade/induzido quimicamente , Obesidade/patologia , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Testosterona/efeitos adversos , Testosterona/farmacologia
12.
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
13.
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
14.
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
15.
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
16.
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
17.
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
18.
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
19.
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
20.
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
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