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Introduction Teratozoospermia is one of the main causes of male infertility.
With the development of genetic technologies such as high-throughput sequencing, the research on special types of teratozoospermia, such as azoospermia and round-headed spermatozoa, has become increasingly in-depth and perfect.
However, its diagnosis and treatment need to be standardized
.
Disease overview Anacephalospermia (ASS) is a very rare and severe teratozoospermia, which refers to the presence of most sperm in the semen with headless sperm tails or tailless sperm heads, and a small number of sperm with loose head and tail connections
.
At present, there are no statistics on the incidence rate at home and abroad
.
Cytospermia is a rare and special type of teratozoospermia that causes male infertility.
Cynospermia is mainly characterized by a rounded sperm head and acrosome deletion.
The incidence of male infertility is about 0.
1%
.
According to the proportion of round-headed spermatozoa, there are two types of round-headed spermatozoa: type I is also called complete type, that is, 100% of the semen is round-headed sperm; type II is also called partial type, and the proportion of round-headed sperm in the semen exceeds 80%.
, but some normal acrosome or small acrosome sperm
.
Etiology and Genetic Research Acephalospermia is mainly caused by inherited disease-causing gene mutations
.
In the Chinese population, key gene mutations in head-to-tail junctions have been identified as causative factors for ASS, of which SUN5, PMFBP1, TSGA10, BRDT, HOOK1, CEP112, SPATC1L, and ACTRT1 are reported causative genes
.
Pathogenic variants in PICK1, SPATA16, and DPY19L2 have been shown to cause complete deletion of the acrosome and round-headed sperm in human sperm
.
Other reported human globospermia-related genes are: SPACA1, ZPBP1, SPINK2, CCDC62, C2CD6, CCIN, C7orf61, DHNA17 and GGN4
.
Diagnosis 1.
Clinical manifestations Patients with cephalospermia and round-headed spermatozoa are usually infertile and generally have no special clinical symptoms
.
2.
Morphological features of spermatozoa The initial diagnosis of spermatozoa can be performed by light microscopy (see Figures 1A and 1B)
.
30% to 100% of sperm in semen are missing head, disconnected head and tail or loose connection
.
ASS has typical ultrastructural abnormalities in HTCA (Fig.
1C–F)
.
The genetic mechanism and etiology of the defect in type I headless spermatozoa are not well understood
.
The breakpoint of type II headless sperm is between the nucleus and the proximal centriole
.
The breakpoint of type III headless sperm is between the distal centriole and the mid-sperm flagella
.
Some of the fractured heads had a bulge at the rear end and lacked the implant socket and base plate
.
Figure 1 Morphology of human headless spermatozoa by light and electron
microscopy
The most prominent feature of type Ⅰ round head spermatozoa under the light microscope is that the sperm heads are all small round heads
.
In addition to a certain proportion of round-headed spermatozoa, type II round-headed spermatozoa also have some pointed heads, irregular heads, and even sperm with normal head morphology (see Figure 2)
.
Under the electron microscope, the loose nucleoplasm and vacuolization of spermatozoa can be observed, which may be related to incomplete histone replacement and abnormal chromatin condensation; mitochondria in the neck are significantly reduced and disorderly arranged; some sperm flagellar microtubules "9 + The 2” structure is chaotic or even missing (see Figure 3)
.
Fig.
2 Gross light microscope morphology of spermFig 3 Sperm ultra-electron microscope morphology , patients with sperm parameters within the normal range also exist
.
The characteristics of sperm motility and concentration in patients with round-headed spermatozoa still need to be further confirmed by large-scale studies, especially in combination with the analysis of disease-causing genes and mutation sites
.
4.
Genetic diagnosis A number of genes have been found to lead to human azoospermia.
Among them, SUN5, PMFBP1 and TSGA10 have been reported in many papers or in different races, and they are definite causative genes
.
The genetic mechanism and etiology of type I ASS are still unclear and require further study
.
Mutations in three genes, SUN5, PMFBP1 and HOOK1, have been confirmed to be related to the occurrence of type II ASS
.
Type III ASS has been shown to be associated with TSGA10 and BRDT mutations
.
In addition to the above-mentioned causative genes for azoospermia, researchers found mutations in CEP112, SPATC1L, and ACTRT1 genes in azoospermia patients, and more research is needed to support the relationship between these genes and ASS
.
The genetic patterns of human round-head spermatozoa discovered so far are all autosomal recessive diseases
.
DPY19L2 is located at 12q14.
2 and is currently considered to be the main causative gene of human round-headed spermatozoa, with a deletion or mutation rate of 19%-77.
8%
.
For the genetic diagnosis of patients with round-headed spermatozoa, it is recommended to first screen for DPY19L2 gene deletion or/and point mutation
.
If no DPY19L2 pathogenic variant is found, gene panel or whole exome sequencing is recommended
.
Pharmacological therapy for the treatment of patients with cephalospermia is unclear
.
Sperm from patients with complete round-headed spermatozoa lack functional acrosomes, making them unable to reproduce naturally
.
It is currently considered that intracytoplasmic sperm injection (ICSI) is the only possible way to produce offspring
.
Assisted reproductive ASS patients are often unable to give birth naturally.
ICSI is the main method for obtaining biological offspring for these patients.
It can be injected into the egg cytoplasm by injecting sperm with abnormal head-to-tail connection or tailless head and decapitated tail
.
Studies have shown that patients with azoospermia who undergo ICSI can achieve good pregnancy outcomes
.
However, specific to patients with different genetic mutations, their ICSI outcomes may vary
.
There are some sperm with small acrosomes or/and normal acrosomes in the semen of some patients with round-headed spermatozoa, but the fertilization rate of in vitro fertilization (IVF) or ICSI is still lower than that of other infertile populations, and the fertilization rate of ICSI is higher than IVF
.
In recent years, the application of ICSI combined with egg activation (AOA) technology has significantly improved the fertilization rate of round-headed sperm, but some patients are still completely infertile
.
The relationship between different pathogenic genes and ISCI outcomes.
Type II ASS caused by SUN5, PMFBP1 and HOOK1 genes has better ICSI outcomes than other subtypes, with pregnancies and live births
.
For type III ASS caused by mutations in TSGA10 and BRDT genes, embryonic developmental arrest is often caused by the defect of the paternal centriole, resulting in clinical pregnancy failure
.
The study reported that patients with mutations in the SPATC1L gene did not produce transferable embryos after four ICSI attempts, suggesting that SPATC1L deficiency may affect early embryonic development
.
In contrast, the spouses of patients with ACTRT1 mutations have achieved clinical pregnancies only through artificial insemination
.
For type I ASS, ICSI outcomes are poor due to lack of distal centrioles, but these results require further observational studies
.
Homozygous deletion or point mutation of the DPY19L2 gene is the main cause of balospermia.
Therefore, most of the cases of successful birth of balospermia patients through ICSI reported at home and abroad are carriers of this gene mutation
.
Some foreign scholars have also compared the ICSI outcomes of globospermia caused by the deletion or mutation of the DPY19L2 gene and those without the gene mutation, and found that there is no significant difference in the assisted reproductive outcomes of the two types of globospermia
.
Only 1 case of successful fertility has been reported in patients with round-headed spermatozoa caused by SPATA16 gene mutation
.
Rare reports of assisted reproductive outcomes in balospermia due to mutations in other genes have been reported
.
Genetic counseling is very important for genetic diagnosis and genetic counseling of patients with balospermia and anozoospermia
.
If the patient detects a related gene mutation, it is recommended that his/her spouse also undergo related gene testing
.
If the spouse is also found to carry the related mutation in the same gene, it is recommended that the spouse undergo preimplantation genetic testing (PGT) to avoid the recurrence of anozoospermia or balospermia offspring
.
References: 1.
Andrology Branch of Chinese Medical Association.
Expert consensus on diagnosis and treatment of azoospermia.
Chinese Journal of Andrology, 2021, 27(12): 1140－1144.
2.
Andrology Branch of Chinese Medical Association.
Expert consensus on diagnosis and treatment of ovospermia .
Chinese Journal of Andrology, 2021, 27(11): 1035－1038.
With the development of genetic technologies such as high-throughput sequencing, the research on special types of teratozoospermia, such as azoospermia and round-headed spermatozoa, has become increasingly in-depth and perfect.
However, its diagnosis and treatment need to be standardized
.
Disease overview Anacephalospermia (ASS) is a very rare and severe teratozoospermia, which refers to the presence of most sperm in the semen with headless sperm tails or tailless sperm heads, and a small number of sperm with loose head and tail connections
.
At present, there are no statistics on the incidence rate at home and abroad
.
Cytospermia is a rare and special type of teratozoospermia that causes male infertility.
Cynospermia is mainly characterized by a rounded sperm head and acrosome deletion.
The incidence of male infertility is about 0.
1%
.
According to the proportion of round-headed spermatozoa, there are two types of round-headed spermatozoa: type I is also called complete type, that is, 100% of the semen is round-headed sperm; type II is also called partial type, and the proportion of round-headed sperm in the semen exceeds 80%.
, but some normal acrosome or small acrosome sperm
.
Etiology and Genetic Research Acephalospermia is mainly caused by inherited disease-causing gene mutations
.
In the Chinese population, key gene mutations in head-to-tail junctions have been identified as causative factors for ASS, of which SUN5, PMFBP1, TSGA10, BRDT, HOOK1, CEP112, SPATC1L, and ACTRT1 are reported causative genes
.
Pathogenic variants in PICK1, SPATA16, and DPY19L2 have been shown to cause complete deletion of the acrosome and round-headed sperm in human sperm
.
Other reported human globospermia-related genes are: SPACA1, ZPBP1, SPINK2, CCDC62, C2CD6, CCIN, C7orf61, DHNA17 and GGN4
.
Diagnosis 1.
Clinical manifestations Patients with cephalospermia and round-headed spermatozoa are usually infertile and generally have no special clinical symptoms
.
2.
Morphological features of spermatozoa The initial diagnosis of spermatozoa can be performed by light microscopy (see Figures 1A and 1B)
.
30% to 100% of sperm in semen are missing head, disconnected head and tail or loose connection
.
ASS has typical ultrastructural abnormalities in HTCA (Fig.
1C–F)
.
The genetic mechanism and etiology of the defect in type I headless spermatozoa are not well understood
.
The breakpoint of type II headless sperm is between the nucleus and the proximal centriole
.
The breakpoint of type III headless sperm is between the distal centriole and the mid-sperm flagella
.
Some of the fractured heads had a bulge at the rear end and lacked the implant socket and base plate
.
Figure 1 Morphology of human headless spermatozoa by light and electron
microscopy
The most prominent feature of type Ⅰ round head spermatozoa under the light microscope is that the sperm heads are all small round heads
.
In addition to a certain proportion of round-headed spermatozoa, type II round-headed spermatozoa also have some pointed heads, irregular heads, and even sperm with normal head morphology (see Figure 2)
.
Under the electron microscope, the loose nucleoplasm and vacuolization of spermatozoa can be observed, which may be related to incomplete histone replacement and abnormal chromatin condensation; mitochondria in the neck are significantly reduced and disorderly arranged; some sperm flagellar microtubules "9 + The 2” structure is chaotic or even missing (see Figure 3)
.
Fig.
2 Gross light microscope morphology of spermFig 3 Sperm ultra-electron microscope morphology , patients with sperm parameters within the normal range also exist
.
The characteristics of sperm motility and concentration in patients with round-headed spermatozoa still need to be further confirmed by large-scale studies, especially in combination with the analysis of disease-causing genes and mutation sites
.
4.
Genetic diagnosis A number of genes have been found to lead to human azoospermia.
Among them, SUN5, PMFBP1 and TSGA10 have been reported in many papers or in different races, and they are definite causative genes
.
The genetic mechanism and etiology of type I ASS are still unclear and require further study
.
Mutations in three genes, SUN5, PMFBP1 and HOOK1, have been confirmed to be related to the occurrence of type II ASS
.
Type III ASS has been shown to be associated with TSGA10 and BRDT mutations
.
In addition to the above-mentioned causative genes for azoospermia, researchers found mutations in CEP112, SPATC1L, and ACTRT1 genes in azoospermia patients, and more research is needed to support the relationship between these genes and ASS
.
The genetic patterns of human round-head spermatozoa discovered so far are all autosomal recessive diseases
.
DPY19L2 is located at 12q14.
2 and is currently considered to be the main causative gene of human round-headed spermatozoa, with a deletion or mutation rate of 19%-77.
8%
.
For the genetic diagnosis of patients with round-headed spermatozoa, it is recommended to first screen for DPY19L2 gene deletion or/and point mutation
.
If no DPY19L2 pathogenic variant is found, gene panel or whole exome sequencing is recommended
.
Pharmacological therapy for the treatment of patients with cephalospermia is unclear
.
Sperm from patients with complete round-headed spermatozoa lack functional acrosomes, making them unable to reproduce naturally
.
It is currently considered that intracytoplasmic sperm injection (ICSI) is the only possible way to produce offspring
.
Assisted reproductive ASS patients are often unable to give birth naturally.
ICSI is the main method for obtaining biological offspring for these patients.
It can be injected into the egg cytoplasm by injecting sperm with abnormal head-to-tail connection or tailless head and decapitated tail
.
Studies have shown that patients with azoospermia who undergo ICSI can achieve good pregnancy outcomes
.
However, specific to patients with different genetic mutations, their ICSI outcomes may vary
.
There are some sperm with small acrosomes or/and normal acrosomes in the semen of some patients with round-headed spermatozoa, but the fertilization rate of in vitro fertilization (IVF) or ICSI is still lower than that of other infertile populations, and the fertilization rate of ICSI is higher than IVF
.
In recent years, the application of ICSI combined with egg activation (AOA) technology has significantly improved the fertilization rate of round-headed sperm, but some patients are still completely infertile
.
The relationship between different pathogenic genes and ISCI outcomes.
Type II ASS caused by SUN5, PMFBP1 and HOOK1 genes has better ICSI outcomes than other subtypes, with pregnancies and live births
.
For type III ASS caused by mutations in TSGA10 and BRDT genes, embryonic developmental arrest is often caused by the defect of the paternal centriole, resulting in clinical pregnancy failure
.
The study reported that patients with mutations in the SPATC1L gene did not produce transferable embryos after four ICSI attempts, suggesting that SPATC1L deficiency may affect early embryonic development
.
In contrast, the spouses of patients with ACTRT1 mutations have achieved clinical pregnancies only through artificial insemination
.
For type I ASS, ICSI outcomes are poor due to lack of distal centrioles, but these results require further observational studies
.
Homozygous deletion or point mutation of the DPY19L2 gene is the main cause of balospermia.
Therefore, most of the cases of successful birth of balospermia patients through ICSI reported at home and abroad are carriers of this gene mutation
.
Some foreign scholars have also compared the ICSI outcomes of globospermia caused by the deletion or mutation of the DPY19L2 gene and those without the gene mutation, and found that there is no significant difference in the assisted reproductive outcomes of the two types of globospermia
.
Only 1 case of successful fertility has been reported in patients with round-headed spermatozoa caused by SPATA16 gene mutation
.
Rare reports of assisted reproductive outcomes in balospermia due to mutations in other genes have been reported
.
Genetic counseling is very important for genetic diagnosis and genetic counseling of patients with balospermia and anozoospermia
.
If the patient detects a related gene mutation, it is recommended that his/her spouse also undergo related gene testing
.
If the spouse is also found to carry the related mutation in the same gene, it is recommended that the spouse undergo preimplantation genetic testing (PGT) to avoid the recurrence of anozoospermia or balospermia offspring
.
References: 1.
Andrology Branch of Chinese Medical Association.
Expert consensus on diagnosis and treatment of azoospermia.
Chinese Journal of Andrology, 2021, 27(12): 1140－1144.
2.
Andrology Branch of Chinese Medical Association.
Expert consensus on diagnosis and treatment of ovospermia .
Chinese Journal of Andrology, 2021, 27(11): 1035－1038.
