Finasteride interferes with prostaglandin-induced CatSper signalling in human sperm

in Reproduction
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  • 1 Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
  • 2 Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
  • 3 International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Correspondence should be addressed to A Rehfeld; Email: rehfeld@sund.ku.dk
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Ca2+ signalling controls human sperm functions necessary for successful fertilization. Multiple endocrine-disrupting chemicals have been found to activate the CatSper Ca2+ channel and thereby interfering with Ca2+ signalling in human sperm. Finasteride is prescribed to men in the fertile age to treat hair loss and its use has been associated with impaired male fertility. Due to the structural relatedness of finasteride to the endogenous CatSper ligand progesterone, this study aimed to investigate whether finasteride affects human sperm in a progestogen-like manner. The effect of finasteride on Ca2+ signalling via CatSper in human sperm was investigated in cell suspensions by single-cell imaging. Additionally, effects on sperm penetration into viscous medium and acrosome reaction were assessed. Finasteride alone caused a minor transient rise in the intracellular, free Ca2+ concentration ([Ca2+]i) at physiologically relevant concentrations. Ca2+ signals induced by PGE1 were inhibited by finasteride displaying mixed type of inhibition consistent with multiple binding sites. Finasteride did not interfere with progesterone-induced Ca2+ signalling and no effect on acrosome reaction or sperm viability was found. Finasteride significantly decreased PGE1-induced penetration into viscous medium but in concentrations above what is measured in blood and seminal fluids during regular finasteride administration. In conclusion, the use of finasteride may affect Ca2+ signalling in human sperm through an interaction with the PGE1-binding site, but to which extend it alters the chances of a successful fertilization needs further investigation. It remains to be investigated whether finasteride administration may give rise to side effects by interfering with prostaglandin signalling elsewhere in the human body.

Supplementary Materials

    • Supplementary figure 1: Chemical structure of progesterone (left), finasteride (center), and dutasteride (right).
    • Supplementary figure 2: Changes in [Ca2+]i induced in the head and midpiece from the three different experiments used in figure VII b+c. a) Changes in [Ca2+]i induced in the head and midpiece in 7 individual sperm cells from donor 1 exposed to 5 µM finasteride at t=51.31 s and subsequently 4 µM PGE1 at t=235.54 s. b) Changes in [Ca2+]i induced in the head and midpiece in 8 individual sperm cells from donor 2 exposed to 5 µM finasteride at t=37.13 s and subsequently 4 µM PGE1 at t=185.56 s. c) Changes in [Ca2+]i induced in the head and midpiece in 9 individual sperm cells from donor 3 exposed to 5 µM finasteride at t=49.79 s and subsequently 4 µM PGE1 at t=267.19 s.
    • Supplementary figure 3: Example of raw cytometry data and quadrant gates from an acrosome reaction experiment on the image-cytometer.
    • Supplementary figure 4: Increment in cell density at 2 cm into a viscous medium (mean ± SEM, n=3) after 1 h exposure to the positive control (5 µM progesterone), 30 µM finasteride, progesterone (5 µM) added to samples preincubated with finasteride (30 µM) for 5 minutes and negative control (0.2% DMSO). The statistical analysis used on this data is a multiple linear regression with two independent variables performed in R-studio on the raw non-normalized data. * indicates treatments significantly different from the negative control with * depicting an adjusted p-value below 0.05. ns indicates that preincubation with finasteride did not have a significant inhibitory effect on the progesterone induced response compared to cells treated with progesterone only.
    • Supplementary figure 5: Ca2+-signals induced by addition of increasing concentrations of finasteride and dutasteride along with a buffer control.
    • Supplementary video 1: The video illustrates the increase in [Ca2+]i in the head and to lesser extent in the midpiece of 16 individual sperm cells after addition of first 5 µM finasteride and subsequently 4 µM PGE1. The speed of the movie is 12 times real time.

 

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