Azoospermia
Encyclopedia
Azoospermia is the medical condition of a male not having any measurable level of sperm
in his semen
. It is associated with very low levels of fertility or even sterility, 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.
rather than azoospermia.
(FSH) levels are low (hypogonadotropic) commensurate with inadequate stimulation of the testes to produce sperm. Examples include hypopituitarism
(for various causes), hyperprolactinemia, and exogenous FSH suppression by testosterone
. Chemotherapy
may suppress spermatogenesis. Pretesticular azoospermia is seen in about 2% of azoospermia
.
Causes for testicular failure include congenital issues such as in certain genetic conditions (e.g. Klinefelter syndrome), some cases of cryptorchism or Sertoli cell-only syndrome
as well as acquired conditions by infection (orchitis
), surgery (trauma, cancer), radiation, or other causes. Mast cell
s releasing inflammatory mediators appear to directly suppress sperm motility
in a potentially reversible manner, and may be a common pathophysiological mechanism for many causes leading to inflammation.
Generally, men with unexplained hypergonadotropic azoospermia need to undergo a chromosomal evaluation.
done to induce contraceptive sterility. Other obstructions can be congenital (example agenesis
of the vas deferens
as seen in certain cases of cystic fibrosis
) or acquired, such as ejaculatory duct obstruction
for instance by infection.
Ejaculatory
disorders include retrograde ejaculation
and anejaculation
; in these conditions sperm are produced but not expelled.
investigation. It is established on the basis of two semen analysis
evaluations done at separate occasions (when the seminal specimen after centrifugation shows no sperm under the microscope) and requires a further work-up. The following work-up is recommended by the Canadian Urologic Association:
The investigation includes a history, a physical examination including a thorough evaluation of the scrotum and testes, laboratory tests, and possibly imaging. 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 (sulphasalazine), 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 assessed to look for genetic abnormalities.
Absence of the vas deferens may be detectable on physical examination and can be confirmed by a transrectal ultrasound
(TRUS). If confirmed genetic testing for cystic fibrosis
is in order. Retrograde ejaculation is diagnosed by examining a postejaculatory void for presence of sperm.
Low levels of LH
and FSH
with low or normal testosterone
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.
Serum inhibin-B weakly indicates presence of sperm cells in the testes, raising chances for successfully achieving pregnancy through testicular sperm extraction
(TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval [CI]: 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.
It is recommended that men primary hypopituitarism may be linked to a genetic cause, a genetic evaluation is indicated in men with azoospermia due to primary hypopituitarism. Azoospermic men with testicular failure are advised to undergo karyotype
and Y-micro-deletion
testing.
) and include the following situations: The frequency of chromosomal abnormalities is inverse proportional to the semen count, thus males with azoospermia are at risk to have a 10-15% abnormalities on karyotyping versus about <1 % in the fertile male population.
Pretesticular azoospermia may be caused by congential hypopituitarism
, Kallmann syndrome
, Prader-Willi syndrome
and other genetic conditions that lead to Gnrh or gonadotropin
deficiency.
Testicular azoospermia is seen in Klinefelter syndrome(XXY) and the XX male syndrome
. In addition, 13 % of men with azoospermia have a defective spermatogenesis that is linked to defects of the Y chromosome
. 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 (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
.
Posttesticular azoospermia can be seen with certain point mutation
s in the cystic fibrosis transmembrane conductance regulator
(CFTR) gene commonly associated with congenital vas deferens abnormalities.
Genetic counselling 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.
A major advancement in recent years has been the introduction of IVF with ICSI
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 IVF-ICSI
. Pregnancies have been achieved in situations where azoospermia was associated with cryptorchism and sperm where obtained by testicular sperm extraction
(TESE).
In men with posttesticular azoospermia a number of approaches are available. For obstructive azoospermia IVF-ICSI or surgery can be used and individual factors need to be considered for the choice of treatment. Medication may be helpful for retrograde ejaculation.
Spermatozoon
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...
in his semen
Semen
Semen is an organic fluid, also known as seminal fluid, that may contain spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...
. It is associated with very low levels of fertility or even sterility, 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.
Classification
Azoospermia can be classified into three major types as listed. Many conditions listed may also cause various degrees of oligospermiaOligospermia
Oligospermia, also oligozoospermia, refers 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 morphology and motility...
rather than azoospermia.
Pretesticular azoospermia
Pretesticular azospermia is characterized by inadequate stimulation of otherwise normal testicles and genital tract. Typically, follicle-stimulating hormoneFollicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
(FSH) levels are low (hypogonadotropic) commensurate with inadequate stimulation of the testes to produce sperm. Examples include hypopituitarism
Hypopituitarism
Hypopituitarism is the decreased secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain...
(for various causes), hyperprolactinemia, and exogenous FSH suppression by testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
. Chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
may suppress spermatogenesis. Pretesticular azoospermia is seen in about 2% of azoospermia
Testicular azoospermia
In this situation 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. The condition is seen in 49-93% of men with azoospermia. Testicular failure includes absence of failure production as well as low production and maturation arrest during the process of spermatogenesisSpermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
.
Causes for testicular failure include congenital issues such as in certain genetic conditions (e.g. Klinefelter syndrome), some cases of cryptorchism or Sertoli cell-only syndrome
Sertoli cell-only syndrome
Sertoli cell-only syndrome is a disorder characterized by male sterility without sexual abnormality...
as well as acquired conditions by infection (orchitis
Orchitis
Orchitis or orchiditis is a condition of the testes involving inflammation. It can also involve swelling and frequent infection.-Symptoms:Symptoms of orchitis are similar to those of testicular torsion...
), surgery (trauma, cancer), radiation, or other causes. Mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...
s releasing inflammatory mediators appear to directly suppress sperm motility
Sperm motility
Sperm motility describes the ability of sperm to move properly towards an egg. This can also be thought of as the 'quality' of the sperm, which is a factor in successful pregnancies, as opposed to the 'quantity'. Sperm which do not properly 'swim', will not reach the egg in order to fertilize it...
in a potentially reversible manner, and may be a common pathophysiological mechanism for many causes leading to inflammation.
Generally, men with unexplained hypergonadotropic azoospermia need to undergo a chromosomal evaluation.
Posttesticular azoospermia
In posttesticular 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 posttesticular genital tracts. The most common reason is a vasectomyVasectomy
Vasectomy is a surgical procedure for male sterilization and/or permanent birth control. During the procedure, the vasa deferentia of a man are severed, and then tied/sealed in a manner such to prevent sperm from entering into the seminal stream...
done to induce contraceptive sterility. Other obstructions can be congenital (example agenesis
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...
of the vas deferens
Vas deferens
The vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....
as seen in certain cases of cystic fibrosis
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
) or acquired, such as ejaculatory duct obstruction
Ejaculatory duct obstruction
Ejaculatory duct obstruction is a congenital or acquired pathological condition which is characterized by the obstruction of one or both ejaculatory ducts. Thus, the efflux of semen is not possible....
for instance by infection.
Ejaculatory
Ejaculation
Ejaculation is the ejecting of semen from the male reproductory tract, and is usually accompanied by orgasm. It is usually the final stage and natural objective of male sexual stimulation, and an essential component of natural conception. In rare cases ejaculation occurs because of prostatic disease...
disorders include retrograde ejaculation
Retrograde ejaculation
In the human male reproductive system, retrograde ejaculation occurs when semen, which would normally be ejaculated via the urethra, is redirected to the urinary bladder. Normally, the sphincter of the bladder contracts before ejaculation forcing the semen to exit via the urethra, the path of least...
and anejaculation
Anejaculation
Anejaculation is the pathological inability to ejaculate in males, with or without orgasm.It can depend on one or more of several causes, including ':*Sexual inhibition*Pharmacological inhibition...
; in these conditions sperm are produced but not expelled.
Diagnosis and evaluation
Azoospermia is usually detected in the course of an infertilityInfertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
investigation. It is established on the basis of two semen analysis
Semen analysis
A semen analysis evaluates certain characteristics of a male's semen and the sperm contained in the semen. It may be done while investigating a couple's infertility or after a vasectomy to verify that the procedure was successful. It is also used for testing donors for sperm donation, in stud...
evaluations done at separate occasions (when the seminal specimen after centrifugation shows no sperm under the microscope) and requires a further work-up. The following work-up is recommended by the Canadian Urologic Association:
The investigation includes a history, a physical examination including a thorough evaluation of the scrotum and testes, laboratory tests, and possibly imaging. 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 (sulphasalazine), 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 assessed to look for genetic abnormalities.
Absence of the vas deferens may be detectable on physical examination and can be confirmed by a transrectal ultrasound
Medical ultrasonography
Diagnostic sonography is an ultrasound-based diagnostic imaging technique used for visualizing subcutaneous body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions...
(TRUS). If confirmed genetic testing for cystic fibrosis
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
is in order. Retrograde ejaculation is diagnosed by examining a postejaculatory void for presence of sperm.
Low levels of LH
LH
LH, Lh, or lh may stand for:*Laurel and Hardy*Leasehold *Left-handed or left hand*Letterhead, the heading at the top of a sheet of letter paper*lh, a digraph for many languages...
and FSH
FSH
FSH may refer to:* Follicle-stimulating hormone* Fox Sports Houston, a regional Fox Sports Net affiliate station for the Houston, Texas area* Facioscapulohumeral muscular dystrophy* International Civil Aviation Organisation code for Flash Airlines...
with low or normal testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
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.
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
Testicular sperm extraction is the process of removing a small portion of tissue from the testicle under local anesthesia and extracting the few viable sperm cells present in that tissue for the purpose of intracytoplasmic sperm injection...
(TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval [CI]: 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.
It is recommended that men primary hypopituitarism may be linked to a genetic cause, a genetic evaluation is indicated in men with azoospermia due to primary hypopituitarism. Azoospermic men with testicular failure are advised to undergo karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
and Y-micro-deletion
Y chromosome microdeletion
Y chromosome microdeletion is a family of genetic disorders caused by missing gene in the Y chromosome. Many men with YCM exhibit no symptoms and lead normal lives. However, YCM is also known to be present in a significant number of men with reduced fertility...
testing.
Genetic causes of azoospermia
Genetic factors can cause pretesticular, testicular, and posttesticular azoospermia (or oligospermiaOligospermia
Oligospermia, also oligozoospermia, refers 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 morphology and motility...
) and include the following situations: The frequency of chromosomal abnormalities is inverse proportional to the semen count, thus males with azoospermia are at risk to have a 10-15% abnormalities on karyotyping versus about <1 % in the fertile male population.
Pretesticular azoospermia may be caused by congential hypopituitarism
Hypopituitarism
Hypopituitarism is the decreased secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain...
, Kallmann syndrome
Kallmann syndrome
Kallmann syndrome is a genetic disorder marked by anosmia and hypogonadism - the decreased functioning of the glands that produce sex hormones. Abnormalities in various genes may cause a defect in the hypothalamus, causing a deficiency of gonadotropin-releasing hormone ; this in turn causes...
, Prader-Willi syndrome
Prader-Willi syndrome
Prader–Willi syndrome is a rare genetic disorder in which seven genes on chromosome 15 are deleted or unexpressed on the paternal chromosome...
and other genetic conditions that lead to Gnrh or gonadotropin
Gonadotropin
Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. This is a family of proteins, which include the mammalian hormones follitropin , lutropin , placental chorionic gonadotropins hCG and eCG and chorionic gonadotropin , as well as at least two...
deficiency.
Testicular azoospermia is seen in Klinefelter syndrome(XXY) and the XX male syndrome
XX male syndrome
XX male syndrome is a rare sex chromosomal disorder. Usually it is caused by unequal crossing over between X and Y chromosomes during meiosis in the father, which results in the X chromosome containing the normally-male SRY gene...
. In addition, 13 % of men with azoospermia have a defective spermatogenesis that is linked to defects of the Y chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
. 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 (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
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
.
Posttesticular azoospermia can be seen with certain point mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator is a protein that in humans is encoded by the CFTR gene.CFTR is a ABC transporter-class ion channel that transports chloride and thiocyanate ions across epithelial cell membranes...
(CFTR) gene commonly associated with congenital vas deferens abnormalities.
Genetic counselling 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.
Treatment
Pre- and post-testicular azoospermia a 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 with ICSI
Intracytoplasmic sperm injection
Intracytoplasmic sperm injection is an in vitro fertilization procedure in which a single sperm is injected directly into an egg.-Indications:...
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 IVF-ICSI
Intracytoplasmic sperm injection
Intracytoplasmic sperm injection is an in vitro fertilization procedure in which a single sperm is injected directly into an egg.-Indications:...
. Pregnancies have been achieved in situations where azoospermia was associated with cryptorchism and sperm where obtained by testicular sperm extraction
Testicular sperm extraction
Testicular sperm extraction is the process of removing a small portion of tissue from the testicle under local anesthesia and extracting the few viable sperm cells present in that tissue for the purpose of intracytoplasmic sperm injection...
(TESE).
In men with posttesticular azoospermia a number of approaches are available. For obstructive azoospermia IVF-ICSI or surgery can be used and individual factors need to be considered for the choice of treatment. Medication may be helpful for retrograde ejaculation.