| 41. |
- Risal, S., et al.
(författare)
-
Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders
- 2021
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- If and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring's psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F-0) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F-1) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F-3) in the androgenized lineage. In contrast, following the male germline, F-3 male offspring (mF(3)) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F-3 females in the androgenized lineage and eight genes in the obese lineage. In mF(3) male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F-1 and F-2 offspring in the female germline did not develop anxiety-like behavior, while the F-2 male offspring (mF(2)) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.
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| 42. |
- Risal, Sanjiv, et al.
(författare)
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Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome
- 2023
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Ingår i: Cell Reports Medicine. - : Cell Press. - 2666-3791. ; 4:5
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Tidskriftsartikel (refereegranskat)abstract
- The transgenerational maternal effects of polycystic ovary syndrome (PCOS) in female progeny are being revealed. As there is evidence that a male equivalent of PCOS may exists, we ask whether sons born to mothers with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a register-based cohort and a clinical case-control study, we find that PCOS-sons are more often obese and dyslipidemic. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in first-generation (F1) male offspring are passed down to F3. Sequencing of F1–F3 sperm reveals distinct differentially expressed (DE) small non-coding RNAs (sncRNAs) across generations in each lineage. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism, strengthening the translational relevance and highlighting a previously underappreciated risk of transmission of reproductive and metabolic dysfunction via the male germline.
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| 43. |
- Samad, Manisha, 1995, et al.
(författare)
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Elevated circulating adiponectin levels do not prevent anxiety-like behavior in a PCOS-like mouse model
- 2024
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Polycystic ovary syndrome (PCOS) is associated with symptoms of moderate to severe anxiety and depression. Hyperandrogenism is a key feature together with lower levels of the adipocyte hormone adiponectin. Androgen exposure leads to anxiety-like behavior in female offspring while adiponectin is reported to be anxiolytic. Here we test the hypothesis that elevated adiponectin levels protect against the development of androgen-induced anxiety-like behavior. Pregnant mice overexpressing adiponectin (APNtg) and wildtypes were injected with vehicle or dihydrotestosterone to induce prenatal androgenization (PNA) in the offspring. Metabolic profiling and behavioral tests were performed in 4-month-old female offspring. PNA offspring spent more time in the closed arms of the elevated plus maze, indicating anxiety-like behavior. Intriguingly, neither maternal nor offspring adiponectin overexpression prevented an anxiety-like behavior in PNA-exposed offspring. However, adiponectin overexpression in dams had metabolic imprinting effects, shown as lower fat mass and glucose levels in their offspring. While serum adiponectin levels were elevated in APNtg mice, cerebrospinal fluid levels were similar between genotypes. Adiponectin overexpression improved metabolic functions but did not elicit anxiolytic effects in PNA-exposed offspring. These observations might be attributed to increased circulating but unchanged cerebrospinal fluid adiponectin levels in APNtg mice. Thus, increased adiponectin levels in the brain are likely needed to stimulate anxiolytic effects.
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| 44. |
- Shao, Linus Ruijin, 1964, et al.
(författare)
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Down-Regulation of Cilia-Localized IL-6R{alpha} by 17{beta}-Estradiol in Mouse and Human Fallopian Tubes.
- 2009
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Ingår i: American journal of physiology. Cell physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 297:1, s. C140-51
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Tidskriftsartikel (refereegranskat)abstract
- The action of Interleukin-6 (IL-6) impacts female reproduction. Although IL-6 was recently shown to inhibit cilia activity in human fallopian tubes in vitro, the molecular mechanisms underlying IL-6 signaling to tubal function remain elusive. Here, we investigate the cellular localization, regulation, and possible function of two IL-6 receptors (IL-6Ralpha and gp130) in mouse and human fallopian tubes in vivo. We show that IL-6Ralpha is restricted to the cilia of epithelial cells in both mouse and human fallopian tubes. Exogenous 17beta-estradiol (E2), but not progesterone (P4), causes a time-dependent decrease in IL-6Ralpha expression which is blocked by the estrogen receptor (ER) antagonist ICI 182,780. Exposure of different ER-selective agonists, PTT or DPN, demonstrated an ER subtype-specific regulation of IL-6Ralphaalpha in mouse fallopian tubes. In contrast to IL-6Ralpha, gp130 was detected in tubal epithelial cells in mice but not in humans. In humans, gp130 was found in the muscle cells and was decreased in the periovulatory and luteal phases during the reproductive cycles, indicating a species-specific expression and regulation of gp130 in the fallopian tube. Expression of tubal IL-6Ralpha and gp130 in IL-6 knockout mice was found to be normal; however, E2 treatment increased IL-6Ralpha, but not gp130, in IL-6 knockout mice compared to wild-type mice. Furthermore, expression levels of IL-6Ralpha, but not gp130, decreased in parallel with estrogenic accelerated oocyte-cumulus complex (OCC) transport in mouse fallopian tubes. Our findings unveil a potential role for cilia-specific IL-6Ralpha in the regulation of OCC transport and suggest an estrogen-regulatory pathway of IL-6Ralpha in the fallopian tube. Key words: estrogen, IL-6R, cilia, fallopian tube.
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| 45. |
- Shrestha, Man Mohan, et al.
(författare)
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Adiponectin Deficiency Alters Placenta Function but Does Not Affect Fetal Growth in Mice
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067 .- 1661-6596. ; 23:9
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Tidskriftsartikel (refereegranskat)abstract
- Adiponectin administration to pregnant mice decreases nutrient transport and fetal growth. An adiponectin deficiency, on the other hand, as seen in obese women during pregnancy, alters fetal growth; however, the mechanism is unclear. To determine the role of adiponectin on placenta function and fetal growth, we used adiponectin knockout, adiponectin heterozygote that displays reduced adiponectin levels, and wild-type mice on a control diet or high fat/high sucrose (HF/HS) diet. Triglycerides (TGs) in the serum, liver, and placenta were measured using colorimetric assays. Gene expression was measured using quantitative RT-PCR. Adiponectin levels did not affect fetal weight, but it reduced adiponectin levels, increased fetal serum and placenta TG content. Wildtype dams on a HF/HS diet protected the fetuses from fatty acid overload as judged by increased liver TGs in dams and normal serum and liver TG levels in fetuses, while low adiponectin was associated with increased fetal liver TGs. Low maternal adiponectin increased the expression of genes involved in fatty acid transport; Lpl and Cd36 in the placenta. Adiponectin deficiency does not affect fetal growth but induces placental dysfunction and increases fetal TG load, which is enhanced with obesity. This could lead to imprinting effects on the fetus and the development of metabolic dysfunction in the offspring.
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| 46. |
- Stener-Victorin, Elisabet, et al.
(författare)
-
Acupuncture
- 2018
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Ingår i: Infertility in Women with Polycystic Ovary Syndrome. - Cham : Springer. - 9783319455341 - 9783319455334 ; , s. 227-245
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Bokkapitel (refereegranskat)abstract
- Acupuncture involving insertion of thin sterile needles into the skin, muscles, and fibrous/fat tissues is a part of traditional Chinese medicine (TCM). Western medical acupuncture described in this chapter is an adaptation of Chinese acupuncture using current knowledge of anatomy, physiology, pathology, and evidence-based medicine, instead of using concepts such as meridians, yin/yang, and circulation of qi. This chapter describes the use of acupuncture in the treatment of women with polycystic ovary syndrome (PCOS) from a western medical approach including potential mechanism of action, experimental data as well as clinical data.
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| 47. |
- Stener-Victorin, E., et al.
(författare)
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Animal Models to Understand the Etiology and Pathophysiology of Polycystic Ovary Syndrome
- 2020
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Ingår i: Endocrine Reviews. - : The Endocrine Society. - 0163-769X .- 1945-7189. ; 41:4
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Tidskriftsartikel (refereegranskat)abstract
- More than 1 out of 10 women worldwide are diagnosed with polycystic ovary syndrome (PCOS), the leading cause of female reproductive and metabolic dysfunction. Despite its high prevalence, PCOS and its accompanying morbidities are likely underdiagnosed, averaging > 2 years and 3 physicians before women are diagnosed. Although it has been intensively researched, the underlying cause(s) of PCOS have yet to be defined. In order to understand PCOS pathophysiology, its developmental origins, and how to predict and prevent PCOS onset, there is an urgent need for safe and effective markers and treatments. In this review, we detail which animal models are more suitable for contributing to our understanding of the etiology and pathophysiology of PCOS. We summarize and highlight advantages and limitations of hormonal or genetic manipulation of animal models, as well as of naturally occurring PCOS-like females.
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| 48. |
- Stener-Victorin, Elisabet, 1964, et al.
(författare)
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Changes in HbA(1c) and circulating and adipose tissue androgen levels in overweight-obese women with polycystic ovary syndrome in response to electroacupuncture
- 2016
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Ingår i: Obesity Science & Practice. - : Wiley. - 2055-2238. ; 2:4, s. 426-435
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Tidskriftsartikel (refereegranskat)abstract
- Aim Insulin sensitivity is similar to 40% lower in women with polycystic ovary syndrome (PCOS) than in controls. We tested the hypothesis that 5 weeks of electroacupuncture treatment improves glucose regulation and androgen levels in overweight/obese women with PCOS. Seventeen women with PCOS, aged 18 to 38years, with a body mass index (BMI) >= 25 kg/m(2) and diagnosed with PCOS were included in this experimental and feasibility study and subjected to five weeks of electroacupuncture treatments three times/week. The primary outcome was changes in whole-body glucose homeostasis measured by euglycemic hyperinsulinemic clamp before and after the intervention. Secondary outcome were changes in HbA(1c), circulating catecholamines, adipocyte size and adipose tissue expression of sex steroids and nerve growth factor (NGF). No significant change in glucose homeostasis was observed, but HbA(1c) decreased by 9.5% (p=0.004), circulating testosterone decreased by 22% (p=0.0007) and dihydrotestosterone decreased by 12% (p=0.007). The two vagal activity markers of plasma serotonin levels and the dopamine metabolite homovanillic acid decreased by 21% (p=0.027) and 20% (p=0.011), respectively. Adipose tissue concentrations of testosterone decreased by 18% (p=0.049), and androstenedione decreased by 13% (p=0.035), and mature NGF/proNGF ratio, a marker of sympathetic activity, increased (p=0.04). These changes occurred without changes in anthropometrics. Five weeks of electroacupuncture treatment improves HbA(1c) and circulating and adipose tissue androgens in women with PCOS. This effect is mediated, at least in part, via modulation of vagal activity and adipose tissue sympathetic activity. Based on these findings, we have recently initiated a randomized controlled study (NTC02647827).
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| 49. |
- Stener-Victorin, Elisabet, et al.
(författare)
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Origins and Impact of Psychological Traits in Polycystic Ovary Syndrome
- 2019
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Ingår i: Medical sciences. - : MDPI. - 2076-3271. ; 7:8
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Forskningsöversikt (refereegranskat)abstract
- Women with polycystic ovary syndrome (PCOS) exhibit compromised psychiatric health. Independent of obesity, women with PCOS are more susceptible to have anxiety and depression diagnoses and other neuropsychiatric disorders. During pregnancy women with PCOS display high circulating androgen levels that may cause prenatal androgen exposure affecting the growing fetus and increasing the risk of mood disorders in offspring. Increasing evidence supports a non-genetic, maternal contribution to the development of PCOS and anxiety disorders in the next generation. Prenatal androgenized rodent models reflecting the anxiety-like phenotype of PCOS in the offspring, found evidence for the altered placenta and androgen receptor function in the amygdala, together with changes in the expression of genes associated with emotional regulation and steroid receptors in the amygdala and hippocampus. These findings defined a previously unknown mechanism that may be critical in understanding how maternal androgen excess can increase the risk of developing anxiety disorders in daughters and partly in sons of PCOS mothers. Maternal obesity is another common feature of PCOS causing an unfavorable intrauterine environment which may contribute to psychiatric problems in the offspring. Whether environmental factors such as prenatal androgen exposure and obesity increase the offspring’s susceptibility to develop psychiatric ill-health will be discussed.
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| 50. |
- Stener-Victorin, Elisabet, et al.
(författare)
-
Proteomic analysis shows decreased Type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS
- 2024
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Ingår i: eLife. - : eLife Sciences Publications Ltd. - 2050-084X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders in women. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead tochanges in protein levels and biological function. Methods: To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation. Results: Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue. Conclusions: Our results suggest that hyperandrogenic women with PCOS have higher levels of extramyocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.
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