Dopamine in human follicular fluid is associated with cellular uptake and metabolism-dependent generation of reactive oxygen species in granulosa cells: implications for physiology and pathology

Saller, S.; Kunz, Lars; Berg, Dieter; Berg, U.; Lara, Hernán E.; Urra, J. Andreu; Hecht, S.; Pavlik, R.; Thaler, Christian J.; Mayerhofer, Artur

doi:10.1093/humrep/det422

Cited by 28 publications

(36 citation statements)

References 57 publications

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“…2). Our results confirmed findings in previous studies, which showed that dopamine induces apoptosis in PCOS-derived GCs (Saller et al 2014). However, our mRNA expression data showed a significant decrease in CASP9, which plays an important role in apoptosis.…”

Section: Discussionsupporting

confidence: 92%

“…Women with PCOS present increased MAO activity in hyperluteinized ovaries and GCs, which might be attributed to the increased number of transformed corpus luteum as a consequence of diminished luteolysis (IvaniÅeviÄ-MilovanoviÄ et al 2003, Saller et al 2014). This increased MAO-A/B activity might be associated with the increase in dopamine metabolism in GCs derived from women with PCOS previously described by our group (Gómez et al 2011).…”

Section: Discussionmentioning

confidence: 99%

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Dysregulated genes and their functional pathways in luteinized granulosa cells from PCOS patients after cabergoline treatment

Ferrero¹,

Díaz-Gimeno²,

Sebastián-León³

et al. 2018

Reproduction

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Polycystic ovarian syndrome (PCOS) is a common reproductive disorder frequently associated with a substantial risk factor for ovarian hyperstimulation syndrome (OHSS). Dopamine receptor 2 (D2) agonists, like cabergoline (Cb2), have been used to reduce the OHSS risk. However, lutein granulosa cells (LGCs) from PCOS patients treated with Cb2 still show a deregulated dopaminergic tone (decreased D2 expression and low dopamine production) and increased vascularization compared to non-PCOS LGCs. Therefore, to understand the PCOS ovarian physiology, it is important to explore the mechanisms that underlie syndrome based on the therapeutic effects of Cb2. Here, LGCs from non-PCOS and PCOS patients were cultured with hCG in the absence/presence of Cb2 ( = 12). Subsequently, a transcriptomic-paired design that compared untreated vs treated LGCs within each patient was performed. After transcriptomic analysis, functions and genes were prioritized by systems biology approaches and validated by RT-qPCR. We identified that similar functions were altered in both PCOS and non-PCOS LGCs treated with Cb2; however, PCOS-treated LGCs exhibited more significant changes than non-PCOS. Among the prioritized functions, dopaminergic synapse, vascular endothelial growth factor (VEGF) signaling, apoptosis and ovarian steroidogenesis were highlighted. Finally, network modeling showed ,, ,, ,, and as key genes implicated in these pathways in Cb2 response, which might be potential biomarkers for further studies in PCOS.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Dysregulated genes and their functional pathways in luteinized granulosa cells from PCOS patients after cabergoline treatment

Ferrero¹,

Díaz-Gimeno²,

Sebastián-León³

et al. 2018

Reproduction

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“…A potential role of the sympathetic nerve system in regulating inflammatory processes in PCOS has been proposed (Shorakae et al 2015). Studies in cultured human in vitro fertilization-derived granulosa cells showed that NE and dopamine stimulate the generation of reactive oxygen species (Saller et al 2014). In the present work, it was observed that the SON section decreases nitrite release and the mRNA expression of the inflammatory transcription factor Nfkb in PCO MФ.…”

Section: Figuresupporting

confidence: 53%

Sympathetic innervation regulates macrophage activity in rats with polycystic ovary

Figueroa

Mendoza

Cardozo

et al. 2018

Journal of Endocrinology

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Polycystic ovarian syndrome (PCOS) is a low-grade inflammatory disease characterized by hyperandrogenism and ovarian hyperinnervation. The aim of this work is to investigate whether bilateral superior ovarian nerve (SON) section in adult rats with estradiol valerate-induced PCOS (PCO rats) affects macrophage spleen cells (MФ) and modifies the steroidogenic ability of their secretions. Culture media of MФ from PCO rats and PCO rats with SON section (PCO-SON rats) were used to stimulate intact ovaries. Compared with macrophages PCO, macrophages from PCO-SON rats released less tumor necrosis factor-α and nitric oxide, expressed lower and mRNA and showed reduced TUNEL staining. Also, in PCO rats, the SON section decreased kisspeptin and nerve growth factor mRNA expressions, without changes in receptor mRNA levels. Macrophage secretions from PCO-SON rats decreased androstenedione and stimulated progesterone release in PCO ovaries, compared to macrophage secretions from PCO rats. No changes were observed in ovarian estradiol response. These findings emphasize the importance of the SON in spleen MΦ, since its manipulation leads to secondary modifications of immunological and neural mediators, which might influence ovarian steroidogenesis. In PCO ovaries, the reduction of androstenedione and the improvement of progesterone release induced by PCO-SON MΦ secretion, might be beneficial considering the hormonal anomalies characteristic of PCOS. We present functional evidence that modulation of the immune-endocrine function by peripheral sympathetic nervous system might have implications for understanding the pathophysiology of PCOS.

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“…This is comparable to the situation in the human ovary [3]. The reason and mechanisms for accumulation in the FF remain unknown, but may be related to the expression of NE- and DA-transporters and storage-capacities of GCs with respect to catecholamines [3,4,41] and to the ability of oocytes to metabolize DA to NE [42]. These results establish that a ligand (NE in FF) and its receptor (ADRB-2 in GCs) co-exist in the large antral monkey follicle.…”

Section: Discussionmentioning

confidence: 63%

Expression of the beta-2 adrenergic receptor (ADRB-2) in human and monkey ovarian follicles: a marker of growing follicles?

Merz

Saller

Kunz³

et al. 2015

J Ovarian Res

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BackgroundADRB-2 was implicated in rodent ovarian functions, including initial follicular growth. In contrast, ADRB-2 expression and function in nonhuman primate and human ovary were not fully known but innervation and significant levels of norepinephrine (NE), which is a ligand at the ADRB-2, were reported in the ovary.MethodsWe studied expression of ADRB-2 in human and rhesus monkey ovary (RT-PCR, immunohistochemistry; laser micro dissection) and measured levels of norepinephrine (NE; ELISA) in monkey follicular fluid (FF). 3D cultures of monkey follicles (4 animals) were exposed to NE or the ADRB-2 agonist isoproterenol (ISO), and follicular development (size) was monitored. Upon termination expression of ADRB-2, FSH receptor and aromatase genes were examined.ResultsImmunohistochemistry and RT-PCR of either human follicular granulosa cells (GCs) obtained by laser micro dissection or isolated monkey follicles revealed ADRB-2 in GCs of primordial, primary, secondary and tertiary follicles. Staining of GCs in primordial and primary follicles was intense. In large preantral and antral follicles the staining was heterogeneous, with positive and negative GCs present but GCs lining the antrum of large follicles were generally strongly immunopositive. Theca, interstitial, and ovarian surface epithelial cells were also positive. NE was detected in FF of preovulatory antral monkey follicles (0.37 + 0.05 ng/ml; n = 7; ELISA) but not in serum. We examined preantral follicles ranging from 152 to 366 μm in diameter in a 3D culture in media supplemented with follicle stimulating hormone (FSH). Under these conditions, neither NE, nor ISO, influenced growth rate in a period lasting up to one month. Upon termination of the cultures, all surviving follicles expressed aromatase and FSH receptors, but only about half of them also co-expressed ADRB-2. The ADRB-2 expression was not correlated with the treatment but was positively correlated with the follicular size at the beginning and at the end of the culture period. Hence, expression of ADRB-2 was found in the largest and fastest-in vitro growing follicles.ConclusionsThe results imply ADRB-2-mediated actions in the development of primate follicles. Drugs interfering with ADRB-2 are used to treat medical conditions and may have unexplored effects in the human ovary.

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Dopamine in human follicular fluid is associated with cellular uptake and metabolism-dependent generation of reactive oxygen species in granulosa cells: implications for physiology and pathology

Abstract: This work was supported by a grant from DFG MA1080/17-3 and in part MA1080/19-1. There are no competing interests.

Cited by 28 publications

References 57 publications

Dysregulated genes and their functional pathways in luteinized granulosa cells from PCOS patients after cabergoline treatment

Dysregulated genes and their functional pathways in luteinized granulosa cells from PCOS patients after cabergoline treatment

Sympathetic innervation regulates macrophage activity in rats with polycystic ovary

Expression of the beta-2 adrenergic receptor (ADRB-2) in human and monkey ovarian follicles: a marker of growing follicles?

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