Infertility is a major issue in the world today, with an estimate of 48 million couples worldwide and 1 in 7 couples in the UK experiencing infertility problems (Datta et al., 2016). Infertility is defined as a failure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse (Vander Borght and Wyns, 2018). Studies suggest that 50% of infertility cases are due to a female factor, 20–30% due to a male factor, and the remaining 20–30% are a combination of both (Agarwal et al., 2015).
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One factor contributing to male infertility, is associated with problems arising from the acrosome. The acrosome is a cap like structure located on the tip of the sperm head, overlying the nucleus. The acrosome is enclosed by a membrane, divided in two parts, the Inner Acrosomal Membrane, and the Outer Acrosomal Membrane.
In mammals, the acrosome develops during the final stage of spermatogenesis, called spermiogenesis, in four distinct phases: Golgi, cap, acrosome and maturation (Muciaccia et al., 2013). In the Golgi phase, proacrosomic granules are formed from the trans-Golgi network. These granules accumulate in the medullary region of the Golgi and fuse together to form a single large acrosomic granule that establishes close contact with the nuclear envelope. During the cap phase, the spherical acrosomic granule grows and merges with additional vesicles from the Golgi apparatus. This step causes the acrosome to go from being spherical to a flatter shape that spreads over the surface of the nucleus. In the acrosome phase, the nucleus then starts to elongate, and the acrosome follows this modification, until it is covering two-thirds of the nuclear surface. Finally, during the maturation phase, the acrosome develops its species-specific shape and size (Muciaccia et al., 2013).
A rare genetic condition called Globozoospermia, is characterised by round headed cells which show defects in their morphology and function. These sperm cells have no acrosome and are therefore infertile.
In humans, the sperm must penetrate the cumulus oophorous and the zona pellucida to reach and fuse with the egg located in the ampulla of the fallopian tube. The acrosome contains essential enzymes that are required for the sperm to penetrate the zona pellucida, thus, only capacitated sperm that have completed the acrosome reaction can accomplish this (Belmonte, 2016). Capacitation and the acrosome reaction, an exocytotic process, are therefore essential for fertilization.
This review will therefore examine the literary evidence that the acrosome reaction is required for fertilization. This will be done by looking at the pathways involved in capacitation and the acrosome reaction and how these affect the sperms ability to fuse with the female egg.
Capacitation is an essential step before the sperm can undergo the acrosome reaction. This was discovered independently by Chang (1951) and Austin (1952), in the early 1950s. From their observations, using rabbit and rat samples, they observed that fresh sperm obtained directly from the epididymis were incapable of penetrating the zona pellucida immediately and the sperm required some time in the female tract before penetrating the zona pellucida and fertilizing an egg (Austin, 1951). Their observations were crucial for future developments of in vitro fertilization, which became a reality in 1978 with the birth of Louise Brown (Steptoe and Edwards, 1978). The process of capacitation is however still poorly understood.
Capacitation occurs in the female tract, after ejaculation, as the spermatozoon is travelling towards the egg. Capacitation can be achieved in vitro by incubating the sperm in an appropriate culture medium (Signorelli et al., 2013). It can be divided into two processes, the fast and early events, and the slow and late events. In the fast events, the flagella is activated which causes vigorous and asymmetric movement. This occurs as soon as the sperm leaves the epididymis. The sperm plasma membrane loses cholesterol which increases the membrane fluidity and causes changes to the intracellular ion concentration and hyperpolarization of the plasma membrane. (Signorelli et al., 2013). The slow events consist of, changes in the movement pattern known as hyperactivation and ability to carry out the acrosome reaction due to phosphorylation of tyrosine proteins. Both the fast and slow events are regulated by the activation of the cAMP/PKA pathway (Signorelli et al., 2013).
During capacitation, cholesterol is removed from the sperm plasma membrane by albumin, increasing the membrane permeability. The approximate lipid content found in mammalian sperm consists of 70% phospholipids, 25% neutral lipids (cholesterol) and 5 % glycoprotein (Mann and Lutwak-Mann, 1981), with cholesterol being the main sterol in the cellular plasma membrane with approximately 90%. The ratio of cholesterol/phospholipid in human sperm is 0.83. Davis (1981) found a correlation between the cholesterol/phospholipid ratio in sperm and the time required to complete capacitation. He observed that the higher the cholesterol/phospholipid ration, the longer incubation time was needed before the sperm achieved capacitation (Davis, 1981). This was confirmed by Ostemeier et al. (2018), who observed that the timing of capacitation differed among men but was consistent within men. Sugraroek et al. (1991) also reported higher cholesterol/phospholipid ratios in men with unexplained infertility, due to a lower phospholipid content.
In vitro experiments in mice, by Visconti et al. (1999) have showed that capacitation is associated with removal of cholesterol from the plasma membrane. Albumin is the most widely used cholesterol acceptor in in vitro experiments and has also been shown to be in high abundance in the oviduct (Ehrenwald, Foote and Parks, 1990). Although this was shown in bovine sperm.
Due to the loss of cholesterol from the plasma membrane, a Ca2+ influx occurs through stimulation of HCO3– and membrane channels, activating secondary messenger systems, including soluble Adenylyl cyclase, thus producing cAMP (Fig. 1). The transmembrane movement of HCO3– has been associated with an increase in intracellular pH which can be observed during capacitation. Regulation of intracellular pH is fundamental for every cellular process. During their transit through the female reproductive tract, sperm comes in contact with an alkaline pH, higher HCO3- concentration, and albumin. All these factors contribute to the cytoplasmic alkalinisation that occurs during mouse sperm capacitation (Zeng et al., 1996; Nishigaki et al., 2014). This is highly associated with hyperactivated motility, as the alkalinisation of the cytoplasm is necessary for the activation of CatSper and the activity of CatSper is fundamental for the hyperactivation of human sperm (Molina et al., 2018). It has been described that Ca2+ can directly bind to membrane phospholipids and to numerous enzymes, modifying the membrane properties and enzymatic activity (Molina et al., 2018).
Progesterone and oestrogen are inducers of capacitation. It has also been shown that O2–, H2O2 and NO promote human sperm capacitation, suggesting the oxidative nature of the process (Jin and Yang, 2017).
Hyperactivation is critical for fertilization as it facilitates the sperm release from the oviductal reservoir and the penetration through the cumulus oophorous and the zona pellucida (Molina et al., 2018). Tyrosine phosphorylation is essential for the acrosome reaction as it causes structural changes to the sperm head, which allow the sperm to bind to the zona pellucida and induce the acrosome reaction.
Capacitation is therefore an essential step for the spermatozoon to undergo before the acrosome reaction and fertilization can occur.
Figure 1: Schematic diagram of the capacitation pathway. Cholesterol efflux causes the sperm plasma membrane to be more permeable and fluid, causing an influx of Ca2+ and HCO3– ions. This activates adenyl cyclase which produced cAMP. cAMP can thereby activate PKA, which causes tyrosine phosphorylation and hyperactive motility. Figure modified
Initially, the importance of the acrosome reaction in mammalian fertilization was unclear, but the was recognized as a prerequisite for fertilization in 1958 by Austin and Bishop. (Austin and Bishop 1958). The longer the sperm bound to the surface of the egg zonae pellucidae, the more acrosome-reacted spermatozoa were found. Following this report, zona component ZP3 was identified as a sperm receptor (Bleil and Wassarman 1980; Vazquez et al. 1989)
Inducers of the Acrosome Reaction
The three main inducers of the acrosome reaction are, zona pellucida glycoproteins, progesterone and the calcium ionophore.
The zona pellucida (ZP) is a membrane that encircles the mammalian oocyte. It is composed of glycoproteins which are organized into long crosslinked fibrils that constitute the extracellular coat.
In mice, the ZP consists of three glycoproteins (ZP1, ZP2 and ZP3), while the human ZP consists of four glycoproteins, ZP1, ZP2, ZP3 and ZP4 (Wassarman, 2008). ZP3 has been found to be the receptor and inducer of the acrosome reaction (Møller et al., 1990). A study by Chiu et al. (2008) showed that native human ZP3 and ZP4 are inducers of the acrosome reaction. They also showed that the potency of native ZP was higher than that of recombinant protein. 25 pmol/ml of native human ZP3 and ZP4 was also shown to be sufficient to induce acrosome reaction in ∼24%–31% of capacitated human spermatozoa after 15 min of treatment (Chiu et al., 2008). This study is good as it allows for less use of ZP glycoproteins, as some other studies used recombinant ZP3 at levels that far exceed the estimated amount of human ZP3 present in a single human oocyte.
While ZP3 and ZP4 have been shown to induce the acrosome reaction, ZP2 acts as a secondary binding site and ZP1 may also be able to induce the acrosome reaction.Deletion of ZP glycoproteins can also cause infertility in women. Female mice that form a zona pellucida lacking ZP2 are sterile (Avella et al., 2014)
The zona pellucida is generally considered to be the primary physiological initiator of the AR in mammalian sperm.
The steroid hormone progesterone, which is secreted at micromolar levels by the oocyte and steroidogenic cumulus cells that surround it, can also initiate the acrosome reaction in vitro.
Due to the difficulty in obtaining human ZP, progesterone is the only well-characterized physiological agonist of AR in human sperm.
Both progesterone and the calcium ionophore A23187 rely on the synthesis of cAMP by sAC to elicit exocytosis in human sperm
Pathways involved in the Acrosome Reaction
Once the acrosome reaction has been induced, it activates a pathway that leads to the release of the acrosomal enzymes.
The acrosome, in response to exocytotic inducers first swells to contact the cell membrane, second become attached to it and fuses with it, and third sheds completely along with the portion of plasma membrane that surrounds it. This is all connected to calcium signalling. Typically, AR triggers evoke a transient influx of calcium into the cytosol through plasma membrane channels; this event initiates complex signalling cascades that lead to intracellular calcium mobilization. In a study by Lucchesi et al. (2016), the role of cAMP in the acrosome reaction pathway was investigated. This was done using a cAMP sponge introduced into live human sperm, to investigate the effects of blocking the cAMP pathway. This showed that acrosome reaction triggers require sperm to induce swelling of the acrosome and to activate pathways that mobilise calcium. They also observed that progesterone requires cAMP to achieve the acrosome reaction.
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Epac proteins consist of a carboxyl-terminal catalytic region and an amino-terminal regulatory region, which harbours one cAMP-binding domain in Epac1 and two in Epac2. In the absence of cAMP the Epac’s enzymatic activity is inhibited by hindering the access of its substrates to the catalytic site. Upon binding of cAMP, a subtle conformational change allows the regulatory region to move away, lifting the autoinhibition. Epac’s catalytic portion bears a GEF activity specific for Rap1 and Rap2. The small GTPase Rap1 is necessary to achieve acrosomal exocytosis. Importantly, Rap1 exchanges GDP for GTP in response to calcium and 8-pCPT-2′-O-Me-cAMP. One of the advances reported here is that progesterone, perhaps the most widely used AR inducer, increases the population of cells with active Rap1 in the acrosomal region. Equally important is the finding that progesterone requires cAMP but not PKA to activate Rap.
Until not too long ago, it was thought that the effects of cAMP in regulated exocytosis were mediated by PKA through phosphorylation of relevant substrates. More recently, we learned that cAMP modulates exocytosis via PKA-dependent and/or PKA-independent mechanisms. The latter are mediated by guanine nucleotide exchange factors (GEFs) activated by cAMP. Furthermore, calcium-induced AR in SLO-permeabilized human sperm is mediated by cAMP/Epac and independent of PKA.
In many models, cAMP/PKA and/or cAMP/Epac facilitate the opening of calcium release channels located in intracellular stores. Metabolites such as inositol 1,4,5-trisphosphate (IP3), cyclic ADP-ribose and NAADP enhance the ability of cytosolic calcium to activate various calcium release channels located on intracellular organelles. Pharmacological blocking of these pathways impairs glucose-induced insulin secretion, indicating that intracellular calcium is required for exocytosis. What could be the link between cAMP/Epac and intracellular calcium mobilization in secretory cells? An interesting candidate is PLCε, the only effector recruited/activated by GTP-bound Rap that has been implicated in Epac-mediated secretory responses.
Sperm – Egg Fusion
The final step before fertilization, is the fusion of the sperm and egg membranes.
A monoclonal antibody to IZUMO1 was shown to inhibit sperm–egg fusion
The disruption of gene Izumo1 did not affect the zona pellucida penetration ability of spermatozoa at all, but fusing ability with the eggs was completely impaired (Inoue et al. 2005). As a result, it was found that IZUMO1 is localized on the acrosomal cap area of both outer and inner acrosomal membrane, and at the moment of acrosome reaction, IZUMO1 migrates out from outer (but not inner) acrosomal membrane to plasma membrane. https://link.springer.com/chapter/10.1007%2F978-3-319-30567-7_1
Izumo1(−/−) knockout male mice were infertile and spermatozoa lacking IZUMO1 protein accumulated in the perivitelline space of the oocyte (Inoue et al. 2015). Hence, IZUMO1 is essential for sperm–egg fusion but not for AR or for sperm penetration through the zona pellucida (ZP).
The lack of an acrosome in men and mice, causes infertility. Oberheide et al. (2017) showed that in mice, the absence of the Na+/H+ exchanger NHE8 has shown to cause infertility in mice, by disrupting the formation of the acrosome.
As mentioned previously, the formation of a functional acrosome is essential for oocyte fertilization. Spermatozoa lacking this acrosome are unable to reach the oocyte because they cannot make their way through the ZP. The failure to produce an acrosome containing sperm is called Globozoospermia and was first described in 1971 by Schirren et al. The lack of an acrosome coincides with abnormal sperm morphology. Most pronounced is the characteristic morphology of round‐headed cells, the result of no acrosome.
This review shoed that before sperm can fertilize the egg, it must first undergo capacitation. Once the sperm has capacitated it can then acrosome react and first then is the sperm able to fertilize the egg. Therefore, if one step in either the capacitation pathway or the acrosome reaction pathway is blocked, fertilization will not occur.
Patients will Globozoospermia were also shown to be infertile, as the sperm does not have an acrosome and can therefore not be capacitated, or acrosome react.
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