A novel functional estrogen receptor on human sperm membrane interferes with progesterone effects

https://doi.org/10.1016/S0303-7207(99)00220-8Get rights and content

Abstract

We have identified an estrogen receptor of approximately 29 kDa apparent molecular weight in human sperm membranes by ligand and Western blot analysis, respectively, using peroxidase-conjugated E2 and an antibody directed against the ligand binding region of the genomic receptor (αH222). Such receptor is functional since 17βE2 induces a rapid and sustained increase of intracellular calcium concentrations ([Ca2+]i) which is completely eliminated by preincubation with αH222. 17βE2 effects on calcium are clearly mediated by a membrane receptor, as they are reproduced by the membrane-impermeable conjugate of the hormone BSA-E2. Dose-response curve for this effect is biphasic with EC50s in the nanomolar and micromolar range. In addition to calcium increase, 17βE2 stimulates tyrosine phosphorylation of several sperm proteins including the 29-kDa protein band. Preincubation of human sperm with 17βE2 inhibits calcium and acrosome reaction increases in response to progesterone. We conclude that estrogens may play a role in the modulation of non-genomic action of progesterone (P) in human sperm during the process of fertilization.

Introduction

Increasing evidence indicates that specific cell membrane receptors are involved in rapid effects of steroids (Wehling, 1997). As far as estrogens concerns, non-genomic effects of 17βE2 have been demonstrated on intracellular calcium concentrations ([Ca2+]i), cyclic adenosine monophosphate levels (cAMP), mitogen activated protein kinase activity, phospholipase C and A2, protein kinase C in different tissues and cell lines (Nemere and Farach-Carson, 1998). Estrogens are present at micromolar concentrations in follicular fluid (Frederick et al., 1991), a location that suggests a possible role of these molecules in the regulation of male and female gamete function. However, while several studies have demonstrated rapid effects of 17βE2 in human oocytes and documented its role in oocyte activation and development (for review see Revelli et al., 1998), little is known about the estrogen effects in spermatozoa (Revelli et al., 1998). The influence exerted by the lack of estrogen receptors on sperm function in estrogen receptor knock-out (ERKO) mice have been recently investigated (Couse and Korach, 1999), showing reduced motility and absence of fertilizing potential for α-estrogen receptor and no substantial modifications of male fertility for β-estrogen receptor.

Section snippets

Presence of membrane estrogen receptor in human sperm

The presence of specific binding sites for 17βE2 on human sperm surface has been suggested by several studies (Hernandez-Perez et al., 1979) although the nature of these receptors has not been investigated in these studies. We have recently identified and characterized a receptor for estrogen on human sperm membrane (Luconi et al., 1999) using functional and biochemical approaches similar to those applied by our group to characterize the non-genomic receptor for P on human sperm surface (Luconi

Effects of intracellular calcium concentrations ([Ca2+]i)

Addition of 17βE2 to fura-loaded spermatozoa induced a rapid and sustained rise in [Ca2+]i in a dose-dependent manner. Fig. 2 shows the typical calcium waves observed in response to 17βE2 (panel A) in comparison with the typical wave obtained in response to progesterone (P, panel B), a well known stimulator of calcium increase and acrosome reaction of human spermatozoa (Baldi et al., 1999). The shapes of calcium waves were quite different, indeed, while P induces a first rapid peak followed by

Conclusions

In conclusion, the estrogen receptor detected in human sperm surface is apparently involved in the activation of two different signal transduction pathways, namely an increase of [Ca2+]i and of tyrosine phosphorylation of proteins confirming the findings in other cell types for non-genomic/rapid actions of estrogens (Revelli et al., 1998). The effects of the estrogen result in inhibition of P-stimulated calcium influx and AR. Since both these steroids are present in the follicular fluid (

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