Azoospermia is the

medical condition A disease is a particular abnormal condition that negatively affects the structure or function (biology), function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medica ...

of a man whose

semen Semen, also known as seminal fluid, is an organic bodily fluid created to contain spermatozoa. It is secreted by the gonads (sexual glands) and other sexual organs of male or hermaphroditic animals and can fertilize the female ovum. Semen i ...

contains no

sperm Sperm is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail known as a flagellum, whi ...

. It is associated with

male infertility Male infertility refers to a sexually mature male's inability to impregnate a fertile female. In humans it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, ...

, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population and may be seen in up to 20% of male infertility situations in Canada. In a non-pathological context, azoospermia is also the intended result of a successful

vasectomy Vasectomy, or vasoligation, is an elective surgical procedure for male sterilization or permanent contraception. During the procedure, the male vasa deferentia are cut and tied or sealed so as to prevent sperm from entering into the urethra and ...

Classification

Azoospermia can be classified into three major types as listed. Many conditions listed may also cause various degrees of

oligospermia Terms oligospermia, oligozoospermia, and low sperm count refer to semen with a low concentration of sperm and is a common finding in male infertility. Often semen with a decreased sperm concentration may also show significant abnormalities in sperm ...

rather than azoospermia. Pretesticular and testicular azoospermia are known as non-obstructive azoospermia, whereas post-testicular azoospermia is considered obstructive.

Pretesticular

Pretesticular azoospermia is characterized by inadequate stimulation of otherwise normal testicles and genital tract. Typically,

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, an ...

(FSH) levels are low (hypogonadotropic) commensurate with inadequate stimulation of the testes to produce sperm. Examples include

hypopituitarism Hypopituitarism is the decreased (''hypo'') secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is know ...

(for various causes),

hyperprolactinemia Hyperprolactinaemia is the presence of abnormally high levels of prolactin in the blood. Normal levels average to about 13 ng/mL in women, and 5 ng/mL in men, with an upper normal limit of serum prolactin levels being 15-25 ng/mL ...

, and exogenous FSH suppression by

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...

Chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

may suppress spermatogenesis. Pretesticular azoospermia is seen in about 2% of azoospermia. Pretesticular azoospermia is a kind of non-obstructive azoospermia.

Testicular

Testicular azoospermia means the testes are abnormal, atrophic, or absent, and sperm production severely disturbed to absent. FSH levels tend to be elevated (hypergonadotropic) as the feedback loop is interrupted (lack of feedback inhibition on FSH). The condition is seen in 49–93% of men with azoospermia. Testicular failure includes absence of failure production and low production and maturation arrest during the process of

spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...

. Causes for testicular failure include congenital issues such as in certain genetic conditions (e.g.

Klinefelter syndrome Klinefelter syndrome (KS), also known as 47,XXY, is an aneuploid genetic condition where a male has an additional copy of the X chromosome. The primary features are infertility and small, poorly functioning testicles. Usually, symptoms are su ...

), some cases of

cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...

Sertoli cell-only syndrome Sertoli cell-only syndrome (a.k.a. Del Castillo syndrome and germ cell aplasia ) is a disorder characterized by male sterility without sexual abnormality. It describes a condition of the testes in which only Sertoli cells line is present in seminif ...

as well as acquired conditions by infection (

orchitis Orchitis is inflammation of the testes. It can also involve swelling, pains and frequent infection, particularly of the epididymis, as in epididymitis. The term is from the Ancient Greek ὄρχις meaning "testicle"; same root as ''orchid''. Si ...

), surgery (trauma, cancer), radiation, or other causes.

Mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...

s releasing inflammatory mediators appear to directly suppress

sperm motility Sperm motility describes the ability of sperm to move properly through the female reproductive tract (internal fertilization) or through water (external fertilization) to reach the egg. Sperm motility can also be thought of as the ''quality'', whi ...

in a potentially reversible manner, and may be a common pathophysiological mechanism for many causes leading to inflammation. Testicular azoospermia is a kind of non-obstructive azoospermia. Generally, men with unexplained hypergonadotropic azoospermia need to undergo a chromosomal evaluation.

Post-testicular

In post-testicular azoospermia, sperm are produced but not ejaculated, a condition that affects 7–51% of azoospermic men. The main cause is a physical obstruction (obstructive azoospermia) of the post-testicular genital tracts. The most common reason is a

done to induce contraceptive sterility. Other obstructions can be congenital (for example,

agenesis In medicine, agenesis () refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue. Many forms of agenesis are referred to by individual names, depending on the organ affected: * A ...

of the

vas deferens The vas deferens or ductus deferens is part of the male reproductive system of many vertebrates. The ducts transport sperm from the epididymis to the ejaculatory ducts in anticipation of ejaculation. The vas deferens is a partially coiled tube ...

as seen in certain cases of

cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...

) or acquired, such as

ejaculatory duct obstruction Ejaculatory duct obstruction (EDO) is a pathological condition which is characterized by the obstruction of one or both ejaculatory ducts. Thus, the efflux of (most constituents of) semen is not possible. It can be congenital or acquired. It is a ...

for instance by infection. Ejaculatory disorders include

retrograde ejaculation Retrograde ejaculation occurs when semen which would be ejaculated via the urethra is redirected to the urinary bladder. Normally, the sphincter of the bladder contracts before ejaculation, sealing the bladder which besides inhibiting the releas ...

and

anejaculation Anejaculation is the pathological inability to ejaculate despite an erection in males, with (''orgasmic'') or without (''anorgasmic'') orgasm. Causes It can depend on one or more of several causes, including: * Sexual inhibition * Pharmacologic ...

; in these conditions sperm are produced but not expelled.

Unknown

Idiopathic azoospermia is where there is no known cause of the condition. It may be a result of multiple

risk factor In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection. Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often use ...

s, such as age and weight. For example, a review in 2013 came to the result that oligospermia and azoospermia are significantly associated with being

overweight Being overweight or fat is having more body fat than is optimally healthy. Being overweight is especially common where food supplies are plentiful and lifestyles are sedentary. , excess weight reached epidemic proportions globally, with mo ...

(

odds ratio An odds ratio (OR) is a statistic that quantifies the strength of the association between two events, A and B. The odds ratio is defined as the ratio of the odds of A in the presence of B and the odds of A in the absence of B, or equivalently (due ...

1.1),

obese Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...

(odds ratio 1.3) and morbidly obese (odds ratio 2.0), but the cause of this is unknown.
The review found no significant relation between oligospermia and being

underweight An underweight person is a person whose body weight is considered too low to be healthy. A person who is underweight is malnourished. Assessment The body mass index, a ratio of a person's weight to their height, has traditionally been used t ...

Genetics

Genetic factors can cause pretesticular, testicular, and post-testicular azoospermia (or

) and include the following situations: The frequency of chromosomal abnormalities is inversely proportional to the semen count, thus males with azoospermia are at risk to have a 10–15% (other sources citing 15–20% incidencePadubidri; Daftary (2011).'' Shaw's Textbook of Gynaecology, 15e. ''p. 205. ) abnormalities on karyotyping versus about <1 % in the fertile male population. Pretesticular azoospermia may be caused by congential

Kallmann syndrome Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. To distinguish it from other forms of hypog ...

, Prader-Willi syndrome and other genetic conditions that lead to

GnRH Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released f ...

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chorioni ...

deficiency. Testicular azoospermia is seen in

(XXY) and the

XX male syndrome XX male syndrome, also known as de la Chapelle syndrome, is a rare congenital intersex condition in which an individual with a 46, XX karyotype (otherwise associated with females) has phenotypically male characteristics that can vary among case ...

. In addition, 13% of men with azoospermia have a defective spermatogenesis that is linked to defects of the

Y chromosome The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abse ...

. Such defects tend to be de novo micro-deletions and affect usually the long arm of the chromosome. A section of the long arm of the Y chromosome has been termed

Azoospermia Factor 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 ...

(AZF) at Yq11 and subdivided into AZFa, AZFb, AZFc and possibly more subsections. Defects in this area can lead to oligospermia or azoospermia, however, a tight genotype-phenotype correlation has not been achieved. Spermatogenesis is defective with gene defects for the

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...

. Post-testicular azoospermia can be seen with certain point

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

s in the

cystic fibrosis transmembrane conductance regulator Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene. Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wit ...

(CFTR) gene commonly associated with congenital vas deferens abnormalities.

Genetic counselling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease; t ...

is indicated for men with genetic causes of azoospermia. In terms of reproduction, it needs to be considered if the genetic defect could be transmitted to the offspring.

BRD7

BRD7 Bromodomain-containing protein 7 is a protein that in humans is encoded by the ''BRD7'' gene. Interactions BRD7 has been shown to interact with IRF2 and HNRPUL1. Azoospermia BRD7 protein is a transcription regulator that is normally highly e ...

, a

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

regulatory protein, is normally highly expressed in the

testis A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...

. Absent or reduced expression of BRD7 protein was observed in the testes of azoospermia patients exhibiting

arrest. Homozygous knockout mice 'BRD7''(-/-)are

infertile Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...

and have higher levels of

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

and

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

in their

germline In biology and genetics, the germline is the population of a multicellular organism's cells that pass on their genetic material to the progeny (offspring). In other words, they are the cells that form the egg, sperm and the fertilised egg. They ...

cells.

Gene polymorphisms

The human breast cancer susceptibility gene 2 (''

BRCA2 ''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...

'') is employed in

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...

. A common

single nucleotide polymorphism In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...

in ''BRCA2'' is associated with idiopathic

with azoospermia. Four genes involved in DNA double-strand break repair and chromosome synapsis (''TEX11'', '' TEX15'', ''

MLH1 DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 h ...

'' and ''

MLH3 DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the ''MLH3'' gene. Function This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic in ...

'') have key roles in genomic integrity,

meiotic recombination Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryo ...

and

gametogenesis Gametogenesis is a biological process by which diploid or haploid precursor cells undergo cell division and differentiation to form mature haploid gametes. Depending on the biological life cycle of the organism, gametogenesis occurs by meiotic d ...

. Polymorphisms in these genes were tested for associations with male infertility. Single nucleotide polymorphisms in two of these genes (''TEX11'' and ''MLH3'') were found to be associated with male infertility involving azoospermy or

Diagnosis

Azoospermia is usually detected in the course of an

infertility Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...

investigation. It is established on the basis of two

semen analysis A semen analysis (plural: semen analyses), also called seminogram or spermiogram, evaluates certain characteristics of a male's semen and the sperm contained therein. It is done to help evaluate male fertility, whether for those seeking pregnancy ...

evaluations done at separate occasions (when the seminal specimen after centrifugation shows no sperm under the microscope) and requires a further work-up.Esteves SC, Miyaoka R, Agarwal A. An update on the clinical assessment of the infertile male. Clinics (Sao Paulo). orrected 2011;66(4):691–700. The investigation includes a history, a physical examination including a thorough evaluation of the scrotum and testes, laboratory tests, and possibly

imaging Imaging is the representation or reproduction of an object's form; especially a visual representation (i.e., the formation of an image). Imaging technology is the application of materials and methods to create, preserve, or duplicate images. ...

. History includes the general health, sexual health, past fertility, libido, and sexual activity. Past exposure to a number of agents needs to be queried including medical agents like hormone/steroid therapy, antibiotics, 5-ASA inhibitors (

sulfasalazine Sulfasalazine, sold under the brand name Azulfidine among others, is a medication used to treat rheumatoid arthritis, ulcerative colitis, and Crohn's disease. It is considered by some to be a first-line treatment in rheumatoid arthritis. It is ...

), alpha-blockers, 5 alpha-reductase inhibitors, chemotherapeutic agents, pesticides, recreational drugs (marijuana, excessive alcohol), and heat exposure of the testes. A history of surgical procedures of the genital system needs to be elicited. The family history needs to be assessed to look for genetic abnormalities.

Congenital absence of the vas deferens Congenital absence of the vas deferens (CAVD) is a condition in which the vasa deferentia reproductive organs fail to form properly prior to birth. It may either be unilateral (CUAVD) or bilateral (CBAVD). Signs and symptoms The vas deferens co ...

may be detectable on physical examination and can be confirmed by a

transrectal ultrasound Transrectal ultrasonography, or TRUS in short, is a method of creating an image of organs in the pelvis, most commonly used to perform an ultrasound-guided needle biopsy evaluation of the prostate gland in men with elevated prostate-specific an ...

(TRUS). If confirmed, genetic testing for

is in order. Transrectal ultrasound can also assess azoospermia caused by obstruction, or anomalies related to obstruction of the ejaculatory duct, such as abnormalities within the duct itself, a median cyst of the prostate (indicating a need for cyst aspiration), or an impairment of the seminal vesicles to become enlarged or emptied. Retrograde ejaculation is diagnosed by examining a post-ejaculatory urine for presence of sperm after making it alkaline and centrifuging it. Low levels of LH and FSH with low or normal

levels are indicative of pretesticular problems, while high levels of gonadotropins indicate testicular problems. However, often this distinction is not clear and the differentiation between obstructive versus non-obstructive azoospermia may require a testicular biopsy. On the other hand, "In azoospermic men with a normal ejaculate volume, FSH serum level greater than two times the upper limit of the normal range is reliably diagnostic of dysfunctional spermatogenesis and, when found, a diagnostic testicular biopsy is usually unnecessary, although no consensus exists in this matter." Extremely high levels of FSH (>45 ID/mL) have been correlated with successful microdissection testicular sperm extraction. Serum inhibin-B weakly indicates presence of sperm cells in the testes, raising chances for successfully achieving pregnancy through

testicular sperm extraction Testicular sperm extraction (TESE) is a surgical procedure in which a small portion of tissue is removed from the testicle and any viable sperm cells from that tissue are extracted for use in further procedures, most commonly intracytoplasmic sperm ...

(TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval I 0.56–0.74) and a specificity of 0.83 (CI: 0.64–0.93) for prediction the presence of sperm in the testes in non-obstructive azoospermia. Seminal plasma proteins TEX101 and ECM1 were recently proposed for the differential diagnosis of azoospermia forms and subtypes, and for prediction of TESE outcome. Mount Sinai Hospital, Canada started clinical trial to test this hypothesis in 2016. Primary hypopituitarism may be linked to a genetic cause. So a genetic evaluation may be done for men with azoospermia as a result. Azoospermic men with testicular failure are advised to undergo

karyotype A karyotype is the general appearance of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is disce ...

and Y-micro-deletion testing.

Treatment

Pre- and post-testicular azoospermia are frequently correctible, while testicular azoospermia is usually permanent. In the former the cause of the azoospermia needs to be considered and it opens up possibilities to manage this situation directly. Thus men with azoospermia due to hyperprolactinemia may resume sperm production after treatment of hyperprolactinemia or men whose sperm production is suppressed by exogenous androgens are expected to produce sperm after cessation of androgen intake. In situations where the testes are normal but unstimulated, gonadotropin therapy can be expected to induce sperm production. A major advancement in recent years has been the introduction of

IVF In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...

with

ICSI ICSI may refer to: * Intracytoplasmic sperm injection, a medical technique used in assisted reproduction * International Computer Science Institute, a non-profit research lab in Berkeley, California * Institute of Company Secretaries of India ...

which allows successful fertilization even with immature sperm or sperm obtained directly from testicular tissue. IVF-ICSI allows for pregnancy in couples where the man has irreversible testicular azoospermia as long as it is possible to recover sperm material from the testes. Thus men with non-mosaic Klinefelter's syndrome have fathered children using

. Pregnancies have been achieved in situations where azoospermia was associated with cryptorchism and sperm where obtained by

(TESE). In men with post-testicular azoospermia, different approaches are available. For obstructive azoospermia, IVF-ICSI or surgery can be used and individual factors are considered for the choice of treatment. Medication may be helpful for retrograde ejaculation.

References

External links

{{Male diseases of the pelvis and genitals Testicular infertility factors