Abstract
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.
Highlights
ADRB-2 was implicated in rodent ovarian functions, including initial follicular growth
The catecholamines norepinephrine (NE) and dopamine were found in high concentrations in human ovarian homogenates and in follicular fluid (FF) of preovulatory follicles
Expression of ADRB-2 by intact monkey preantral and small antral follicle was confirmed by RT-PCR followed by sequencing (Figure 1G)
Summary
ADRB-2 was implicated in rodent ovarian functions, including initial follicular growth. The catecholamines norepinephrine (NE) and dopamine were found in high concentrations in human ovarian homogenates and in follicular fluid (FF) of preovulatory follicles. The source of these neurotransmitters is likely the documented innervation of the human ovary by the sympathetic nervous system or intra-ovarian neurons [1,2,3,4,5,6,7]. ADRB-2 may have physiological roles in stimulating growth/ differentiation of cells This appears to apply to tumor cells, but to our knowledge it is not known, whether ovarian tumors have been studied [15,16,17,18]
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