Globozoospermia | |
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Other names | Round-headed sperm syndrome [1] |
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Figure 1: Diagram representing the morphology of normal sperm. Areas surrounded by an orange box represent areas changed in the sperm of an individual with globozoospermia. Orange boxes highlight the specifics of the changed areas in globozoospermia. |
Globozoospermia is a rare and severe form of monomorphic teratozoospermia. This means that the spermatozoa show the same abnormality, and over 85% of spermatozoa in sperm have this abnormality. [1] Globozoospermia is responsible for less than 0.1% of male infertility. [2] It is characterised by round-headed spermatozoa without acrosomes, an abnormal nuclear membrane and midpiece defects. [1] Affected males therefore suffer from either reduced fertility or infertility. [2] Studies suggest that globozoospermia can be either total (100% round-headed spermatozoa without acrosomes) or partial (20-60% round acrosomeless spermatozoa with normal sperm also identified in the sperm count), [3] however it is unclear whether these two forms are variations on the same syndrome, or actually different syndromes. [2]
Infertility in this condition results from the sperm heads missing their acrosome. These sperm, therefore, have a characteristic round or spherically shaped head. Given the absence of the acrosome, these sperm are unable to penetrate the oocyte and are unable to achieve fertilization through conventional means; however, these sperm are able to fertilize the egg through in vitro fertilization with intracytoplasmic sperm injection, which is the treatment of choice for these patients. [4]
Studies have suggested mutations or deletions in three genes are responsible for this condition: SPATA16, PICK1 and DPY19L2. [1] ICSI (intracytoplasmic sperm injection) has previously been used to assist reproduction in globozoospermic patients, however it has not been particularly effective in all patients, due to low fertilisation rates. [2]
There are two types of globozoospermia:
Aside from the effect on fertility globozoospermia is symptomless. People with globozoospermia have normal physical and mental development, normal clinical features and normal hormonal profile. [3]
Genes mutated in globozoospermia | Gene product and its normal function | Mutation's effect on sperm in globozoospermia |
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DPY19L2 – most frequent mutation in globozoospermia | Transmembrane protein localised on the acrosome of spermatids. It contributes to normal acrosome formation by anchoring the acrosome to the spermatozoa nucleus. | Sperm head elongation and acrosome formation fails causing a round-headed sperm to form so sperm are unable to bind the zona pellucida and fertilise the oocyte. Sperm concentration in the semen also reduces. |
PICK1 | Cytosolic protein found in the proacrosomal vesicles of round spermatids. It functions during protein trafficking. | Proacrosomal vesicles fail to merge causing a round-headed sperm to form so sperm are unable to bind the zona pellucida and fertilise the oocyte. |
SPATA16 | A protein:protein interaction domain located in proacrosomal vesicles and golgi apparatus. It plays a role in spermatogenesis and acrosome formation. | Acrosome is absent creating round-headed sperm unable to bind the zona pellucida and fertilise the oocyte. The gene was first identified in a family with three out of six brothers being homozygous for the mutation; their sperm was acrosomeless and showed round headedness. [7] |
Table 1: Gene mutations that have been identified in globozoospermia and the impact these mutations have on sperm function and successful fertilization. [3]
The presence of round headed sperm in a semen analysis sample confirms the diagnosis of globozoospermia. The lack of acrosome can be ascertained by either morphology staining or immunofluorescence. [8]
Until 1995, the only options for people with globozoospermia who wished to conceive were adoption or sperm donation. [9] With the advancement of assisted reproductive techniques (ART) it is now possible for those with globozoospermia to conceive using their own sperm. [10] The main technique used is intracytoplasmic sperm injection (ICSI) where fertilisation is achieved by a single sperm being injected into the egg. [11] Some studies have shown it is possible for a viable embryo to be created with this technique alone, [6] however others have found it necessary to also use calcium ionophore treatment for fertilisation to be successful. [10] Calcium ionophore treatment is used to artificially activate the oocyte. This treatment may be necessary as globozoospermic sperm can be less likely to activate the oocyte, an important stage in fertilisation. [10]
The treatment options currently available focus on overcoming the prognosis of infertility which is associated with globozoospermia. So far there are no treatment options to prevent or cure globozoospermia.
Research into globozoospermia is aimed at improving understanding of its cause and developing treatment options. [3]
The observation has been made many times that globozoospermia arises in siblings which points towards an underlying genetic cause. [3] Recent progress has been made into determining what genes could be implicated in this pathology, with the previously mentioned genes being found to play a role. [1] There are more genes which have been shown to be mutated in globozoospermia in mice, but these are yet to be connected to the human disease process. Examples of these include Gopc, [12] Hrb and Csnka2. [13] [14] There are thousands of genes which guide the process of spermatogenesis, and knowing how they’re involved in globozoospermia is an important current area of research. [1]
The development of intracytoplasmic sperm injection made conception a possibility for patients with a variety of male infertility conditions, including globozoospermia. [15] However, fertility rates with this approach are still low, and research is ongoing into how this can be improved. [3]
It has been found that treating globozoospermia with ICSI along with oocyte activation by calcium ionophore (an ion carrier used to increase intracellular calcium [16] is more likely to result in conception than ICSI alone. [17] Another promising treatment area also looks at causing oocyte activation in conjunction with ICSI, this time using spermatic binding-proteins, phospholipase C zeta (PLCζ) and postacrosomal sheath WW domain binding protein (PAWP). [18]
A spermatozoon is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote.
Fertilisation or fertilization, also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a zygote and initiate its development into a new individual organism or offspring. While processes such as insemination or pollination, which happen before the fusion of gametes, are also sometimes informally referred to as fertilisation, these are technically separate processes. The cycle of fertilisation and development of new individuals is called sexual reproduction. During double fertilisation in angiosperms, the haploid male gamete combines with two haploid polar nuclei to form a triploid primary endosperm nucleus by the process of vegetative fertilisation.
Intracytoplasmic sperm injection is an in vitro fertilization (IVF) procedure in which a single sperm cell is injected directly into the cytoplasm of an egg. This technique is used in order to prepare the gametes for the obtention of embryos that may be transferred to a maternal uterus. With this method, the acrosome reaction is skipped.
The acrosome is an organelle that develops over the anterior (front) half of the head in the spermatozoa of humans, and many other animals. It is a cap-like structure derived from the Golgi apparatus. In placental mammals, the acrosome contains degradative enzymes. These enzymes break down the outer membrane of the ovum, called the zona pellucida, allowing the haploid nucleus in the sperm cell to join with the haploid nucleus in the ovum. This shedding of the acrosome, or acrosome reaction, can be stimulated in vitro by substances a sperm cell may encounter naturally such as progesterone or follicular fluid, as well as the more commonly used calcium ionophore A23187. This can be done to serve as a positive control when assessing the acrosome reaction of a sperm sample by flow cytometry or fluorescence microscopy. This is usually done after staining with a fluoresceinated lectin such as FITC-PNA, FITC-PSA, FITC-ConA, or fluoresceinated antibody such as FITC-CD46.
For fertilization to happen between a sperm and egg cell, a sperm must first fuse with the plasma membrane and then penetrate the female egg cell to fertilize it. While the fusion of the sperm cell with the egg cell's plasma membrane is relatively straightforward, penetrating the egg's protective layers, such as the zona pellucida, presents a significant challenge. Therefore, sperm cells go through a process known as the acrosome reaction, which is the reaction that occurs in the acrosome of the sperm as it approaches the egg.
Hyperactivation is a type of sperm motility. Hyperactivated sperm motility is characterised by a high amplitude, asymmetrical beating pattern of the sperm tail (flagellum). This type of motility may aid in sperm penetration of the zona pellucida, which encloses the ovum.
A23187 is a mobile ion-carrier that forms stable complexes with divalent cations. A23187 is also known as Calcimycin, Calcium Ionophore, Antibiotic A23187 and Calcium Ionophore A23187. It is produced at fermentation of Streptomyceschartreusensis.
Azoospermia factor (AZF) is one of several proteins or their genes, which are coded from the AZF region on the human male Y chromosome. Deletions in this region are associated with inability to produce sperm. Subregions within the AZF region are AZFa, AZFb and AZFc. AZF microdeletions are one of the major causes of male infertility for azoospermia and severe oligozoospermia males. AZF is the term used by the HUGO Gene Nomenclature Committee.
The cation channels of sperm also known as Catsper channels or CatSper, are ion channels that are related to the two-pore channels and distantly related to TRP channels. The four members of this family form voltage-gated Ca2+ channels that seem to be specific to sperm. As sperm encounter the more alkaline environment of the female reproductive tract, CatSper channels become activated by the altered ion concentration. These channels are required for proper fertilization. The study of these channels has been slow because they do not traffic to the cell membrane in many heterologous systems.
In vitro maturation (IVM) is the technique of letting the contents of ovarian follicles and the oocytes inside mature in vitro. It can be offered to women with infertility problems, combined with In Vitro Fertilization (IVF), offering women pregnancy without ovarian stimulation.
The Genetics & IVF Institute (GIVF) is an international provider of infertility and genetics services and products, and also engages in biomedical research in these fields. The Institute was founded in 1984 by Dr. Joseph D. Schulman and associates. GIVF headquarters are in Fairfax, VA, US, and its facilities include locations in Pennsylvania, Minnesota, California, and Texas in the United States, as well as in China, Mexico, and several other countries.
Teratospermia or teratozoospermia is a condition characterized by the presence of sperm with abnormal morphology that affects fertility in males.
Oocyteactivation is a series of processes that occur in the oocyte during fertilization.
Jacques Cohen is a Dutch embryologist based in New York, U.S. He is currently a Director at Reprogenetics LLC, Laboratory Director at ART Institute of Washington at Walter Reed National Military Medical Center, and Scientific Director of R & D at IVF-online.
The history of in vitro fertilisation (IVF) goes back more than half a century. In 1959 the first birth in a nonhuman mammal resulting from IVF occurred, and in 1978 the world's first baby conceived by IVF was born. As medicine advanced, IVF was transformed from natural research to a stimulated clinical treatment. There have been many refinements in the IVF process, and today millions of births have occurred with the help of IVF all over the world.
Antisperm antibodies (ASA) are antibodies produced against sperm antigens.
The intracytoplasmic morphologically selected sperm injection (IMSI) is a laboratory technique used for In vitro fertilisation treatments. High-quality sperms are injected into the egg for fertilization, it is an advanced version of ICSI.
Spermatogenesis-associated protein 16 is a mammalian protein encoded by the SPATA16 gene. SPATA16, also known as NYD-SP12, is a developmental protein that aids in differentiation of germ cells for spermatogenesis and participates in acrosome formation for appropriate sperm-egg fusion. SPATA16 is located on chromosome 3 at position 26.31 and is a member of the tetratricopeptide repeat-like superfamily, which facilitate interactions and assemblies between proteins and protein complexes.
Sarah Martins da SilvaFRCOG is a British gynaecologist and researcher specialising in male infertility. Martins da Silva is a Clinical Reader in reproductive medicine at the University of Dundee. She also works as an honorary consultant gynaecologist at Ninewells Hospital in Dundee, specialising in fertility problems and assisted conception. She was named one of the BBC's "100 Women of 2019" for her contribution to fertility science.
Dmitri Dozortsev is a Russian-American physician scientist, inventor and researcher. Dozortsev's contributions in research and publications are mostly in the areas of human reproductive medicine and biology. In particular, he is best known for his studies of in vitro fertilisation and embryo transfer. Dozortsev currently serves as President of the American College of Embryology and as Director of Omni-Med laboratories.
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