Globozoospermia syndrome: An update

Commentary:

The article “Globozoospermia syndrome: An update” offers a clear and comprehensive review of globozoospermia, a rare cause of male infertility. Globozoospermia is characterized by round-headed sperm that lack an acrosome, a feature essential for fertilization. This review explores the origins and frequency of the condition, current diagnostic tests, and available treatment options.

Pathogenesis and Epidemiology:
The authors offer an easy-to-follow explanation of the structural abnormalities in globozoospermia, such as defects in the sperm’s cytoskeleton. They distinguish between two types of globozoospermia and discuss factors affecting its occurrence, which adds a useful perspective for understanding this condition.

Sperm Parameters and Diagnostic Approach:
The review covers sperm characteristics in men with globozoospermia, including sperm count, movement, and volume. The authors detail study findings on these parameters, which are helpful for diagnosis and treatment planning. Summary tables provide quick references for clinicians and researchers.

DNA/Chromatin Integrity and Sperm DNA Fragmentation:
This section is particularly informative on how DNA abnormalities in sperm, like poor chromatin structure and high DNA fragmentation, impact fertility. The authors stress that sperm DNA quality is crucial for successful reproduction.

Genetic Features:
The authors highlight the genetic basis of globozoospermia, noting the importance of certain genes (like DPY19L2) that contribute to the condition. They recommend genetic screening in populations with high rates of related marriages, where inherited forms of globozoospermia may be more common.

Fertilization Potential and Treatment:
The review explains that conventional ICSI techniques have limited success with globozoospermic sperm and suggests alternatives, such as calcium ionophores and recombinant PLC-zeta, to improve fertilization outcomes.

Conclusion:
The authors effectively summarize the need for new diagnostic and treatment options for globozoospermia. They emphasize how the condition impacts DNA quality and male fertility, making this review an invaluable resource for clinicians and researchers in reproductive medicine.

Take Home Message: Ashok Agarwal contributed this last item.
❖ Globozoospermia is characterized by round-headed sperm lacking an acrosome, which impacts the sperm’s ability to fertilize an egg.
❖ Genes like DPY19L2 are crucial, and genetic testing may be recommended in high risk populations, such as those with consanguineous marriages.
❖ Globozoospermic sperm often have high DNA fragmentation and poor chromatin packaging, reducing fertilization success.
❖ Conventional ICSI alone is less effective; alternative approaches like assisted oocyte activation (AOA) with calcium ionophores are often required.

In summary, globozoospermia faces three critical challenges: unclear genetic mechanisms despite links to genes like DPY19L2, limited treatment options with only moderate success in ICSI with Assisted Oocyte Activation, and inconsistent diagnostic
criteria for distinguishing between partial and total globozoospermia, complicating clinical diagnosis and management.

Q1. What are the primary morphological characteristics of globozoospermia?

Hamid Kalantari: Globozoospermia is primarily characterized by the presence of roundheaded spermatozoa with cytoskeleton defects around the acrosome, resulting in the absence of acrosomes.

Q2. How does globozoospermia differ between type I and type II in terms of sperm morphology?

Hamid Kalantari : Globozoospermia is classified into two subtypes: complete (type-I: 100% round-headed spermatozoa) and partial (type-II: >20% round-headed spermatozoa)

Q3. What is the estimated prevalence of globozoospermia among infertile men?

Hamid Kalantari: Globozoospermia is considered a rare condition with an estimated prevalence of less than 0.1% among infertile men.

Q4. What are the key differences in sperm parameters between globozoospermic men and normozoospermic controls?

Hamid Kalantari: The key differences are significant. Here are the primary distinctions:
• Sperm Concentration: Globozoospermic men often exhibit a lower sperm concentration than normozoospermic controls, although this difference may not always be statistically significant.
• Motility: Globozoospermic men exhibit a significant reduction in both total and progressive motility. Studies indicate that globozoospermic samples have notably lower sperm motility rates, with one study reporting a total motility of approximately 40%, compared to higher rates observed in normozoospermic controls.

• Morphology: Globozoospermic men typically have a very high percentage of spermatozoa with abnormal morphology, characterized primarily by round-headed sperm lacking acrosomes. In contrast, normozoospermic men exhibit a higher proportion of normally shaped sperm.
• Sperm DNA Integrity: Globozoospermic men have a higher rate of sperm with abnormal chromatin packaging and increased DNA fragmentation. For instance, the rate of CMA3- reacted spermatozoa (indicating protamine deficiency) is significantly higher in globozoospermic men (approximately 66%) compared to normozoospermic controls (around 21%).
• Apoptotic Spermatozoa: A higher percentage of apoptotic spermatozoa is observed in globozoospermic men, with studies reporting rates of around 17.6% versus 6% in normozoospermic controls. This suggests elevated sperm cell mortality and impairment in globozoospermic men.

Q5. How does the absence of an acrosome in globozoospermic spermatozoa affect fertility?

Hamid Kalantari: The absence of an acrosome in globozoospermic spermatozoa severely impairs fertility, as the acrosome is essential for fertilization. Without it, sperm cannot undergo the acrosome reaction or penetrate the zona pellucida, both of which are necessary for successful egg fertilization.

Q6. What role does sperm DNA fragmentation play in globozoospermia?

Hamid Kalantari: Studies have shown that globozoospermic spermatozoa (GS) often exhibit elevated levels of DFI, attributed to defects in chromatin packaging and protamine deficiency. Such high levels of DFI in GS can affect fertilization and embryo development.

While ICSI can bypass some barriers to fertilization, fragmented DNA in sperm can still negatively impact fertilization rates and subsequent embryo development. Although fertilization may occur, the quality of the resulting embryos can be compromised, leading to lower implantation rates and an increased risk of miscarriage.

Hamid Kalantari, MSc: Short Biography

Q1. How do environmental factors potentially contribute to the development of partial Globozoospermia?
Karan Vadher: Environmental factors such as exposure to endocrine-disrupting chemicals (e.g., phthalates and BPA), heavy metals (lead, cadmium, mercury), and particulate matter can disrupt hormonal balance, particularly testosterone, and cause oxidative stress, damaging sperm DNA and proteins. These disruptions impair sperm maturation, leading to morphological defects like partial Globozoospermia. Other contributors include radiation, lifestyle factors, and occupational exposure, which affect spermatogenesis and sperm quality. Mechanisms include hormonal disruption, cellular damage, interference with acrosome formation, and epigenetic modifications.

Q2. What are the current treatment strategies for patients with Globozoospermia undergoing assisted reproduction?
Karan Vadher: For patients with Globozoospermia undergoing assisted reproduction, the primary treatment strategies include ICSI and Intracytoplasmic Morphologically Selected Sperm Injection or IMSI. The IMSI offers higher magnification for better sperm selection.
Assisted Oocyte Activation (AOA) using calcium ionophores is often employed to enhance fertilization rates. Sperm selection techniques like Magnetic Activated Cell Sorting (MACS) and microfluidics can improve sperm quality before ICSI. In more severe cases, testicular sperm extraction methods, such as TESA, TESE, and Micro TESE, are the methods of choice.

Q3. What is the impact of Globozoospermia on conventional intracytoplasmic sperm injection (ICSI) outcomes?
Karan Vadher: Globozoospermia significantly impacts conventional ICSI outcomes, primarily resulting in low fertilization rates due to acrosome deficiency. Even with techniques like IMSI and AOA, poor or no embryo development is common, with high
embryo fragmentation and often no blastocyst formation. Additionally, Globozoospermia is associated with lower pregnancy and live birth rates, along with an increased risk of miscarriage.

Q4. How does sperm motility in globozoospermic patients compare to that in patients with other forms of male infertility?
Karan Vadher: In globozoospermic patients, sperm motility is often compromised compared to other forms of male infertility. The abnormal round-headed shape, absence of an acrosome, and disrupted cytoskeletal structure impair the sperm’s ability to swim effectively. While Globozoospermia primarily affects morphology, it also reduces progressive motility, which is crucial for successful fertilization.

Q5. What are the key findings from recent studies on semen parameters in Globozoospermia men?
Karan Vadher: Recent studies on Globozoospermia reveal that men with this condition display severe morphological abnormalities, with less than 1% normal sperm forms in complete cases and around 1% in partial cases. Sperm motility is often compromised due to the absence of the acrosome. Findings on semen volume and concentration vary across studies, showing mixed results. Additionally, globozoospermic patients have high sperm DNA fragmentation, which is linked to poor fertilization, impaired embryo development, and higher miscarriage rates.

Karan Vadher, MSc: Short Biography

Q1. How does the presence of cytoplasmic droplets (CDs) around the nucleus impact sperm motility in globozoospermia?
Jane Ezeukwu: The presence of cytoplasmic droplets around the nucleus in globozoospermia significantly impacts sperm motility and is believed to contribute to impaired sperm motility. These cytoplasmic droplets may lead to sperm dysfunction due to abnormal positioning and retention within the cell, reducing its ability to move effectively.

Q2. What is the significance of coiled tails in globozoospermic spermatozoa?
Jane Ezeukwu: Coiled tails represent a morphological abnormality that affects sperm function. It is a structural defect and an important characteristic of globozoospermic spermatozoa. The sperm's ability to move is greatly reduced when the tail is coiled, and that impedes the sperm from swimming toward the egg for fertilization. This plays a significant role in the overall reduced fertility observed in men with globozoospermia.

Q3. How do WHO standards from different years affect the interpretation of semen parameters in globozoospermic patients?
Jane Ezeukwu: In globozoospermic patients, WHO standards and criteria for evaluating semen parameters have changed over time, and this has impacted the interpretation of these parameters. The WHO standards for sperm morphology have become more stringent over time. In the 1999 edition, criteria for normal sperm morphology were less strict, which allows for a broader definition of what constituted "normal." In contrast, the 2010 WHO edition introduced more stringent criteria, leading to a higher proportion of sperm being classified as abnormal. For patients with globozoospermia, these criteria result in a more severe diagnosis.
The 2010 WHO manual lowered reference limits for semen parameters like sperm concentration, motility, and morphology. As a result, semen samples previously considered to be normal under older standards might be classified differently under the updated criteria.

Q4. What are the implications of acrosome vesicle fusion defects in the pathogenesis of globozoospermia?
Jane Ezeukwu: As spermatogenesis proceeds, Golgi-derived vesicles merge to form the acrosome, an essential structure for the sperm. In globozoospermia, the acrosome fails to form due to improper fusion of Golgi-derived vesicles during spermatogenesis, this leads to the absence of a functional acrosome, which is essential for sperm to penetrate the egg. As
a result, sperm cannot undergo the acrosome reaction, causing severe impairment of fertilization capabilities as well as infertility. These defects worsen the functional impairment of globozoospermic sperm.

Q5. How does the round-headed morphology of spermatozoa in globozoospermia affect fertilization potential?
Jane Ezeukwu: The inability of the round‐headed spermatozoa to bind or penetrate the zona pellucida severely limits their ability to fertilize the egg, this is due to the lack of an acrosome which is crucial for penetrating the zona pellucida of the egg. It also impairs sperm motility and function which contributes to the reduced fertilization potential of globozoospermic spermatozoa.

Jane Ezeukwu, MSc: Short Biography

Q1. What are the main findings of electron microscopy studies on globozoospermic spermatozoa?

Dr. Marjan Sabbaghian: The key findings from these studies include

a) having round, acrosomeless heads due to the absence or malformation of the acrosome;

b) misshapen and irregular nucleus;

c) various flagellar defects, such as coiling of the flagellum around the head or midpiece; d) cytoplasmic droplets around the head and/or midpiece;

e)microtubules and fibrous sheath abnormalities.

Q2. How do the findings from transmission electron microscopy (TEM) studies contribute to the understanding of globozoospermia?

Dr. Marjan Sabbaghian: By using TEM studies, scientists can get a detailed look at the structural issues in sperm cells that cause globozoospermia. These studies reveal key problems like the missing acrosome, various shape defects, and irregularities in the cell’s cytoplasm. Understanding these abnormalities is essential for grasping how this condition affects male fertility.

Q3. What role do genetic factors play in the development of globozoospermia?

Dr. Marjan Sabbaghian: Globozoospermia is a syndrome with an autosomal recessive pattern of inheritance (both of the alleles must have mutations). Genetic factors play a major role in the development of globozoospermia.

The main genes involved are:

(1) DPY19L2 - Mutations in this gene are found in about 70% of globozoospermia cases. The DPY19L2 protein is involved in acrosome development and sperm head elongation;

(2) SPATA16 - Encodes a testis-specific protein localized to the Golgi apparatus and proacrosomal vesicles, playing a role in acrosomal enzyme sorting and modification.

(3) PICK1 - Involved in protein trafficking, including the acrosome. PICK1-deficient mice are infertile due to globozoospermia;

(4) ZPBP1 - Encodes an acrosomal protein. Heterozygous mutations have been found in some patients with abnormal sperm head morphology.

Q4. How do the structural defects in globozoospermic spermatozoa impact the success of ART procedures?

Dr. Marjan Sabbaghian: Globozoospermic sperm cells usually show significant structural issues, such as missing acrosomes and problems with the cytoskeleton around the nucleus.
The structural defects seen in globozoospermic spermatozoa present significant challenges for ART procedures, primarily due to their inability to fertilize oocytes naturally and their association with genetic abnormalities. However, advancements in ART techniques tailored for these patients show potential for improving reproductive outcomes.

Q5. What are the potential molecular mechanisms underlying the absence of acrosomes in globozoospermic spermatozoa?

Dr. Marjan Sabbaghian: The absence of acrosomes in globozoospermic spermatozoa is a complex phenomenon linked to various molecular mechanisms, primarily involving genetic mutations and defects in cellular processes during spermatogenesis. Here are the key mechanisms identified in the literature: Mutations in Specific Genes including SPATA16,GOPC, and VPS54. These genes are involved in vesicle transport from the Golgi apparatus, which is essential for acrosome biogenesis.

Q6. How do the classification of globozoospermia into type I and type II influence clinical management?

Dr. Marjan Sabbaghian: In summary, the classification of globozoospermia into Type I and Type II significantly influences clinical management strategies, particularly regarding the choice of assisted reproductive technologies and the need for genetic evaluations (e.g., the mutation in DPY19L2 gene). Understanding these distinctions help clinicians tailor treatment plans that optimize the chances of conception and address the specific needs of each patient.

Q7. What are the challenges in diagnosing globozoospermia using standard semen analysis?


Dr. Marjan Sabbaghian: Diagnosing globozoospermia through standard semen analysis is challenging due to the nature of the method and the specific characteristics of the condition.
These challenges include the inherently subjective characteristics of morphological evaluations, overlap with other conditions that make it difficult to pinpoint globozoospermia as the primary issue, inconsistencies in laboratory methodologies, and the rarity of the syndrome, which may lead to under-recognition in clinical settings. Consequently, a cautious approach is necessary, often requiring supplementary testing to confirm the diagnosis and guide effective treatment options.

Marjan Sabbaghian, MSc, PhD: Short Biography