Male Infertility: 4 Hidden Causes and the Genetic Link

Semen Analysis and Male Fertility Parameters

Semen analysis serves as a crucial indicator of male fertility as well as male infertility. Abnormalities in its parameters can often signal underlying genetic causes (table 1). Genetic defects such as Y chromosome microdeletions, Klinefelter syndrome, or mutations affecting spermatogenesis can lead to conditions like azoospermia, oligospermia, or poor sperm motility and morphology. Understanding the genetic basis behind abnormal semen profiles not only aids in accurate diagnosis but also guides personalized fertility treatment and genetic counseling.

Table 1: Summary Table: Semen Analysis and Male Fertility Parameters
Parameter	Normal Reference Range	Abnormal Values / Condition	Clinical Significance
Semen Volume	1.5 – 6.0 mL	<1.5 mL (Hypospermia), >6.0 mL (Hyperspermia)	Indicates seminal vesicle and ejaculatory duct function
Sperm Concentration	≥15 million/mL	<15 million/mL (Oligospermia), 0 (Azoospermia)	Reflects spermatogenic activity
Total Sperm Count	≥39 million/ejaculate	<39 million (Subfertile), near 0 (Severe male factor)	Total reproductive potential per ejaculate
Progressive Motility	≥32%	<32% (Asthenozoospermia)	Sperm’s ability to reach and penetrate the egg
Total Motility (Progressive + Non-progressive)	≥40%	<40%	General motility including non-linear movement
Vitality (Live Sperm)	≥58%	<58% (Necrozoospermia)	Indicates percentage of living sperm cells
Morphology (Strict Kruger Criteria)	≥4% normal forms	<4% (Teratozoospermia)	Reflects structural integrity required for fertilization
pH Level	7.2 – 8.0	<7.2 (Acidic), >8.0 (Alkaline)	Reflects prostatic and seminal vesicle function
Leukocyte Count	<1 million/mL	>1 million/mL (Leukocytospermia)	Indicates infection or inflammation
Fructose Level	Positive	Negative or low (Suggests ejaculatory duct obstruction)	Energy source for sperm; reflects seminal vesicle function
Liquefaction Time	≤60 minutes	>60 min (Delayed liquefaction)	Influences sperm motility and function
Viscosity	Low to moderate	High viscosity (Impaired motility)	Can hinder sperm movement and insemination
Antisperm Antibodies	Absent or <50% MAR/IBT	>50% bound sperm (Immunologic infertility)	Immune-mediated sperm dysfunction
Reactive Oxygen Species (ROS)	Low to moderate	High ROS (Oxidative stress)	Damages sperm DNA and membranes
DNA Fragmentation Index (DFI)	<15%	>30% (High DNA damage; associated with infertility)	Associated with failed fertilization, miscarriage, IVF failure

What are 4 causes of male infertility?

Infertility is a medical condition where a couple is unable to achieve pregnancy after 12 months of regular, unprotected intercourse (or 6 months if the woman is over 35). It can affect men, women, or both, and may result from genetic, hormonal, anatomical, or lifestyle factors. It affects around one in every six couples, and in nearly half of these cases, the issue lies with the male partner. While lifestyle, infections, and environmental factors are common contributors, genetic causes of male infertility are increasingly recognized as significant. In this post, we’ll explore what are 4 causes of male infertility—with a special focus on how genetic abnormalities can silently disrupt male reproductive health. Let’s discuss these causes one by one;

Low Sperm Count (Oligospermia) and Genetic Triggers

A low sperm count—or oligospermia—is one of the most common causes of male infertility. But beyond environmental and hormonal triggers, genetic mutations and chromosomal anomalies can severely reduce sperm production (table 2).

Genetic Associations:

1. Y chromosome microdeletions (especially in AZF regions) can disrupt sperm production genes.
2. Klinefelter syndrome (47,XXY) leads to smaller testes, low testosterone, and little to no sperm production.
3. CFTR gene mutations, commonly associated with cystic fibrosis, may also block the vas deferens, reducing sperm count.

Why It Matters:

Even when lifestyle and hormonal factors are under control, an undiagnosed genetic abnormality can still prevent conception.

What Helps:

• Genetic testing (karyotyping, Y-chromosome analysis)
• Testicular sperm extraction (TESE)
• ICSI (Intracytoplasmic Sperm Injection) for assisted reproduction

Fact: About 10–15% of severe oligospermia cases are linked to genetic defects, often undetected without proper screening.

Table 2: Low Sperm Count (Oligospermia) associated Genes/Loci
Gene / Locus	Chromosomal Location	Normal Role	Effect of Mutation
DAZ (AZFc)	Yq11	RNA regulation during spermatogenesis	Deletion → Oligospermia/Azoospermia
USP9Y (AZFa)	Yq11	Promotes spermatogenesis	Mutation → Sertoli-cell-only syndrome
RBMY (AZFb)	Yq11	Involved in meiosis regulation	Mutation → Arrest of spermatogenesis
CFTR	7q31.2	Vas deferens development	Mutation → CBAVD, low sperm count
TEX11	Xq13.1	Meiotic progression	Mutation → Meiotic arrest, azoospermia
Klinefelter Syndrome	47,XXY (karyotype)	Normal testicular function	Extra X → Small testes, low testosterone, severe oligospermia

Poor Sperm Motility (Asthenozoospermia) – Genetics at Play

In many infertile men, the sperm count is normal—but sperm are unable to swim effectively. This is called asthenozoospermia. While lifestyle factors like heat and smoking matter, genetic mutations in motility-related proteins also play a role (Table 3).

Key Genetic Insights:

1. Mutations in DNAH1, DNAH5, and CFAP43/44 genes disrupt the flagella (tail structure), impairing movement.
2. Primary ciliary dyskinesia (PCD)—a genetic condition—can cause sperm flagellar defects and chronic respiratory issues.

Result:

Even if sperm reach the ejaculate, they may not be able to swim toward or penetrate the egg—limiting chances of conception.

Treatment Strategy:

• Antioxidants and lifestyle changes
• ICSI, bypassing the need for sperm motility
• Genetic counseling if PCD or similar conditions are suspected

Note: Around 20% of male infertility cases with poor motility have an underlying genetic component.

Table 3: Poor Sperm Motility (Asthenozoospermia)
Gene / Locus	Chromosomal Location	Normal Role	Effect of Mutation
DNAH1	3p21.1	Motor protein in sperm flagella	Mutation → Immotile sperm, poor motility
DNAH5	5p15.2	Dynein arm assembly in cilia	Mutation → Primary Ciliary Dyskinesia
CFAP43 / 44	10q24.1 / 1p34.2	Structure of flagella	Mutation → Flagellar disorganization, impaired motility

Abnormal Sperm Morphology – When DNA Designs Go Wrong

Sperm morphology refers to their shape and structure. A typical sperm has an oval head, midpiece, and tail. But genetic defects during spermatogenesis can lead to headless, tailless, or multiple-headed sperm—unable to fertilize the egg (Table 4).

Genetic Link:

1. Mutations in AURKC, DPY19L2, and SUN5 genes cause conditions like globozoospermia (round-headed sperm).
2. Teratozoospermia (abnormal morphology) may also stem from errors in chromatin remodeling—often genetically inherited.

Fertility Implication:

Malformed sperm are less capable of swimming, penetrating the egg, or initiating fertilization.

Solutions:

1. Morphology-based IVF selection techniques
2. ICSI to directly inject even abnormally shaped but viable sperm
3. Genetic screening before ART to prevent transmission

Did You Know? Some men have over 95% abnormally shaped sperm, yet still father children with the help of assisted techniques.

Table 4: Abnormal Sperm Morphology (Teratozoospermia)
Gene / Locus	Chromosomal Location	Normal Role	Effect of Mutation
AURKC	19q13.43	Controls chromosomal segregation	Mutation → Globozoospermia (round-headed sperm)
DPY19L2	12q14.2	Anchors acrosome to nucleus	Mutation → Globozoospermia
SUN5	20q11.22	Links nucleus to flagellum	Mutation → Headless sperm (acephalic sperm)

Hormonal Imbalance and Inherited Disorders

Hormonal balance is vital for sperm production, libido, and overall male reproductive health. While many hormonal imbalances arise from lifestyle or disease, genetic conditions often underlie serious endocrine failures (Table 5).

Genetic Causes:

1. Kallmann syndrome: Inherited defect causing GnRH deficiency and low testosterone.
2. Androgen insensitivity syndrome: The body doesn’t respond to testosterone despite normal or high levels.
3. Congenital adrenal hyperplasia (CAH): An inherited enzyme deficiency disrupting hormone production.

Clinical Symptoms:

1. Delayed puberty
2. Erectile dysfunction
3. Low sex drive
4. Small testes or undescended testicles

Available Treatments:

1. Hormonal therapy (FSH, hCG, testosterone)
2. ART where hormone correction isn’t possible
3. Genetic counseling for family planning

Insight: About 30–50% of men with non-obstructive azoospermia have genetic or chromosomal issues affecting hormone function and sperm production.

Table 5: Hormonal Imbalance & Inherited Endocrine Disorders
Gene / Locus	Chromosomal Location	Normal Role	Effect of Mutation
KAL1 (ANOS1)	Xp22.3	Migration of GnRH neurons	Mutation → Kallmann Syndrome, low GnRH & testosterone
AR (Androgen Receptor)	Xq12	Mediates testosterone action	Mutation → Androgen Insensitivity Syndrome
CYP21A2	6p21.3	Enzyme for adrenal steroid production	Mutation → Congenital Adrenal Hyperplasia
NR5A1 (SF1)	9q33	Testis development and steroidogenesis	Mutation → Testicular dysgenesis

Can Genetic Male Infertility Be Treated?

Yes. Thanks to modern reproductive medicine, men with genetically linked infertility now have options:

1. Testicular sperm extraction followed by ICSI
2. Preimplantation genetic testing (PGT) to ensure healthy embryos
3. Hormonal supplementation in genetically linked hypogonadism

Important: Genetic testing is recommended for men with:

1. Azoospermia (no sperm)
2. Severe oligospermia (<5 million/ml)
3. Family history of infertility or syndromes

Final Words: Don’t Overlook Genetics in Male Infertility

Understanding what are 4 causes of male infertility becomes even more powerful when paired with the knowledge of genetic contributions. Whether it’s a Y chromosome deletion, CFTR mutation, or a rare inherited syndrome, genetics can influence every stage of sperm development.

Early diagnosis and genetic screening not only guide treatment but also help couples make informed reproductive choices.

FAQ – Genetics and Male Infertility