Paul J. Turek M.D.

"Infertility may now be beget sterility"

I. INTRODUCTION

Fertility, similar to other bodily functions, is the concerted action of numerous processes
that result in normal quality sperm. As molecular genetics has advanced, so has our knowledge
about the genetics of male infertility. Most recently, it has become obvious that more men may
have a genetic basis for infertility than was previously thought. Genetics may contribute to
infertility by acting at a variety of physiologic levels including hormonal balance, sperm
production and sperm motility. An understanding of the genetic basis for reproductive failure is
essential to treat and counsel infertility patients. Although treatments of genetically-caused
infertility are limited, we are now able to bypass the infertility effects with technology. Because
of this, it is important to be conversant in genetic issues to better inform patients (a) about their
conditions and (b) about the risks of possible transmission to their offspring.
II. BASIC GENETICS 101
The appreciation of genetic factors as arbiters of disease has existed for centuries. There
are talmudic references to exemptions from circumcision in families of bleeders. Gregor Mendel
in 1865 proposed several germinal ideas about heredity from his work with garden peas. These
ideas are now established laws of heredity and guide modern research. He proposed the concept
of "hereditary factors" and "units of inheritance" that we now understand to be genes. He outlined
the concept that these units can assort and segregate independently, thus leading to mutations and
evolution.
To begin, DNA consists of base pairs of amino acids. Genes are segments or sequences of
base pairs that make sense enough to form a protein after the processes of transcription and
translation. There are approximately 50,000-100,000 genes in the human genome. Approximately
3,000 genes have known associations with disease; thus, it is assumed that at 3-6% of the
genome has undergone mutations. Mutations are stable alterations in DNA that can be passed to
offspring. When they occur in somatic cells of the body, they affect only that individual. When
they occur in the sex cells or gametes, they can be inherited by offspring. Recognized genetic
defects are generally divided into three categories.
Remember, mutations are common and necessary for evolution. When mutations cause
hereditary variation that is clinically noticable, then it is called disease.
The smallest of these are point mutations in single genes which generally follow the rules of
mendelian genetics and are usually acquired and transmitted in one of 4 basic patterns: autosomal
dominant or recessive, or X-linked dominant or recessive. Chromosomal disorders describe
shifts in whole segments of chromosomes and are classified as either structural (deletions,
duplications) or numerical (aneuploidy, triploidy). Polygenic or multifactorial genetic defects
are not well understood, but may be from several abnormalities in many genes from various
chromosomes. In addition, the environment may influence whether or not polygenic diseases are
expressed.

III. HUMAN GENETICS 102

Human cells contain 46 chromosomes (23 pairs) consisting of a pair each of 22
autosomes and 1 pair of sex chromosomes. This is the diploid state found in all
somatic cells. Germ cells like sperm and oocytes contain only 23 chromosomes and
are therefore termed haploid. When two gametes merge during fertilization, each
gamete contributes to the normal, diploid embryo. When somatic cells replicate
within the body, the process is termed mitosis; no reduction in chromosome number
occurs. However, when the sex gametes (sperm and oocytes) are formed from their
precursors, the replication process involves an extra cell division that reduces
the number of chromosomes from 46 to 23. Subsequently, a typical mitotic step
occurs so that a single, initially diploid cell produces 4 haploid progenitors.
This sex cell replication pathway is termed meiosis. The maturation process that
the newly minted haploid spermatids undergo to become sperm is termed spermiogenesis
it does not involve any nuclear replication. The Y chromosome is a small, but
intensely studied chromosome that is known to carry the genes that determine both
testis development and spermatogenesis (Figure 1). It has 60 million base pairs
and consists of a long arm (Yq) and a short arm (Yp). On the short arm can be
found the gene for Testis Determining Factor (TDF) and on the long arm, one or
more genes that may control spermatogenesis, termed AZF genes (Azoospermia factor).
The long arm (Yq) of the Y chromosome has recently become the focus of renewed
interest as it is now recognized that 7% of oligospermic and 15% of azoospermic
men may harbor a small gene deletion on this arm. A exact relationship between
the gene, its protein product and spermatogenesis is still unclear.

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IV. GENETIC DISEASES RESULTING IN INFERTILTY

This complex topic will be discussed by dividing the reproductive tract into 3
components,pretesticular, testicular and post-testicular, and examining specific
genetic abnormalities that affect each portion of the tract.

1.Genetic Conditions with Pre-Testicular Effects.

Pre-testicular effects are generally hormonal in nature, because spermatogenesis
is largely controlled by hypothalamic-pituitary axis. Several syndromes are known
to affect the hypothalamus and pituitary gland. Most of these result from single
gene deletions. Kallmans Syndrome causes male hypogonadism because of a deficiency
in hypothalamic gonadotropin-releasing hormone (GnRH). It occurs in 1/50,000
persons and is most commonly an X-linked recessive disease. The clinical features
include anosmia, facial asymmetry, color
blindness, renal anomalies and cryptorchidism. The hallmark of the syndrome is a
delay in pubertal development. Patients have severely atrophic testes (<2 cm)
with biopsies showing germ cell arrest and Leydig cell hypoplasia. Hormone
evaluation reveals a low testosterone, low LH and low FSH. These men can be
fertile when given FSH and LH. Prader-Willi Syndrome is another very rare
condition (1/20,000) characterized by obesity, retardation, small hands and feet
and hypogonadism. Again, a deficiency of GnRH is the
problem. The single gene deletion associated with this condition is on chromosome 15. Similar to
Kallmans Syndrome, spermatogenesis can be induced with exogenous FSH and LH.
Bardet-Biedl Syndrome is another rare form of hypogonadotropic hypogonadism that results
from GnRH deficiency. It is characterized by retinitis pigmentosa, polydactyly and
hypogonadism. It presents similar to Kallmans Syndrome except the patient has genetic obesity.
The hypogonadism can be treated with FSH and LH.
Sickle Cell Anemia is associated with the inheritance of B S-globin genes and is found in 1/600
Afro-americans . Men with sickle cell anemia have decreased testosterone and either increased or
decreased LH and FSH. Although high or low levels of gonadotropins would appear to implicate
very different diseases, it may be that pituitary and testicular microinfarcts from sickle disease
account for these two disparate presentations of hypogonadism.
B-Thalessemia patients have mutations in the B-globin gene that leads to an imbalance in the
alpha and beta globin composition hemoglobin. The trait is present in 3-5% of Mediterranean and
African peoples. Clinical features range from mild anemia (trait) to iron overload (major
thalessemia). Infertility may result from the deposition of iron in the pituitary gland and testis.
Cerebellar Ataxia can be associated with hypogonadotropic hypogonadism. This is a rare
condition which can result from consanguinous unions. Cerebellar involvement includes
abnormalities of speech and gait. These patients are eunichoid-looking with atrophic testis.
Hypothalamic-pituitary dysfunction is thought to cause infertility; the basis for the dysfunction
may be from pathological changes in cerebral white matter.
2.Genetic Conditions with Testicular Effects.
Conditions that directly effect the testicle tend to result from structural or numerical
chromosomal abnormalities. Unlike with pretesticular conditions that are treatable with hormone
replacement, the testicular effects are, at present, largely untreatable. Assisted reproductive
technology, however, can provide biological children for men with these conditions, but it
virtually ensure that the genetic disease will be transmitted.

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Klinefelters Syndrome is the most common genetic reason for azoospermia. accounting for
14% of cases. It has a classic triad: small, firm testes, gynecomastia, and azoospermia. In this
abnormality of chromosomal number, 90% of men carry an extra X chromosome (47 XXY) and
10% of men are mosaic with a combination of XXY/XY. Paternity with this syndrome is rare, but
more likely in the mosaic form of the disease. Testes biopsies show sclerosis and hyalinization.
Hormones usually demonstrate a decreaed testosterone and frankly elevated LH and FSH. This
syndrome may present with increased height, decreased intelligence, varicosities, obesity,
diabetes, leukemia, increased likelihood of extragonadal germ cell tumors and breast cancer (20x
higher than normal males).
XYY Syndrome is another abnormality of chromosomal number that can result in infertility.
Typically, men with 47, XYY are tall and 2% exhibit aggressive, often criminal behavior.
Hormone evaluation reveals an elevated FSH and normal testosterone and LH. Semen analyses
show either severe oligospermia or azoospermia. Testis biopsies demonstrate maturation arrest or
Sertoli cell-Only syndrome.
XX Male Syndrome presents as a male with azoospermia. Typically, there is normal male
external and internal genitalia. Patients usually present with gynecomastia at puberty. Hormone
evaluation shows elevated FSH and LH and low or normal testosterone. Testis biopsy reveals an
absence of spermatogenesis with hyalinzation, fibrosis and Leydig cell clumping. The most
obvious explanation is that the SRY or Testis Determining Region is translocated from the Y to
the X chromosome so that testis differentiation is present. However, the Azoospemia gene (AZF)
is not similarly translocated, resulting in azoospermia.
Noonans Syndrome presents phenotypically as a male Turners syndrome (45, X0). However,
the karyotype is normal 46, XY and the chromosomal abnormality not yet identified. Typically,
these men have dysmorphic features like webbed neck, short stature, low set ears and wide set
eyes. At birth, 75% will have cryptorchidism that limits fertility in adulthood. If testes are fully
descended, then fertility is possible and likely.
Immotile Cilia Syndrome is a heterogeneous group of disorders in which sperm motility is
reduced or absent. The sperm defects are from abnormalities in the motor apparatus or axoneme
of sperm and other ciliated cells. Various defects in the dynein arms cause deficits in ciliary and
sperm activity. Kartageners Syndrome is a subset of this disorder that presents with the triad of
chronic sinusitis, bronchiectasis and situs inversus. Most immotile cilia cases are diagnosed in
childhood due to respiratory and sinus difficulties. Cilia present in the retina and ear may also be
defective and lead to retinitis pigmentosa and deafness in Ushers Syndrome. Men with immotile
cilia characteristically have necrospermia or completely nonmotile but viable sperm in normal
numbers. Depending on the ciliary defect, there can be some sperm motililty and forward
progression. Sperm nuclear material is thought to be unaffected. Serum hormones are normal as is
the testis biopsy. The Hypo-osmotic Sperm Swelling Test can determine whether non-motile
sperm are viable and may help these men to conceive.
The Azoospermia Gene. It has recently been discovered that approximately 10-15% of men with
azoospermia will have structural changes in the Y chromosome. This idea was originally
postulated in 1976 based on small structural changes in the Y chromosome seen on karyotyping.
This led to the concept that an azospermic factor (AZF) existed and its absence or mutation
accounted for the azoospermia. Since then, an explosion in molecular genetics technology has
allowed far more sophisticated analysis of the Y chromosome. Presently, the DAZ (Deleted in
Azoospermia) region is the most likely candidate gene and is the subject of intense study at UCSF
by Dr. Renee Reijo. The exact function of these genes in spermatogenesis is not clear, as the gene

products are only beginning to be recognized. It is expected, however, that men who acquire or

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inherit these gene deletions will certainly pass them on to offspring if assisted reproductive
technology is used to achieve biologic pregnancies.
3. Genetic Conditions with Post-Testicular Effects.
The post-testicular portion of the reproductive tract includes the epididymis, vas deferens,
seminal vesicles and associated ejaculatory apparatus. Genetic conditions in these organs are
mainly of polygenic or multifactorial nature. This discussion will exclude conditions that present
with ambiguous genitalia or intersex.
Cystic Fibrosis is the most common, fatal autosomal recessive disorder in the U.S. It is
associated with more than 600 possible genomic mutations. The disease is associated with fluid
and electrolyte abnormalities (abnormal chloride-sweat test) and presents with chronic lung
obstruction and infections, pancreatic insufficiency and infertility. Interestingly, 98% of men with
cystic fibrosis (CF) have wolffian duct abnormalities: the body and tail of the epididymis, vas
deferens, seminal vesicles and ejaculatory ducts are atrophic, fibrotic or completely absent. Serum
hormones and spermatogenesis are usually normal. Most afflicted patients die in their twenties of
pneumonia or related problems. Gene therapy is being actively applied to this disease. A blood
test for CF genetic mutations is available.
Congenital Absence of the Vas Deferens (CAVD) accounts for 1-2% of all cases of infertility
and up to 5% of azoospermic men. On physical examination, no palpable vas deferens is observed
on one or both sides. Similar to CF, the rest of the wolffian duct system may also be abnormal
and unreconstructable. Recently, this disease has been demonstrated to be a form fruste of CF.
However, the vast majority of these men fail to demonstrate any symptoms of CF. In cases of
bilateral vasal absence, 65% of patients will harbor a detectable CF mutation. In addition, 15% of
these men will have renal malformations, most commonly unilateral renal agenesis. In patients
with unilateral CAVD, the incidence of detectable CF mutations is generally lower, and that of
renal agenesis approaches 40%. Serum hormones are normal as is spermatogenesis. Epididymal
sperm aspiration is very effective in procurring sperm from these men for use with IVF since
virtually all of these men will have an intact caput epididymis (Figure 2).
Youngs Syndrome presents with the clinical triad of chronic sinusitis, bronchiectasis and
obstructive azoospermia. The obstruction is located in the epididymis, usually near the junction
the caput and corpus. Since obstruction may not occur until after puberty, fertility is possible in

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some patients. The pathophysiology of the condition is unclear but may involve abnormal ciliary
function or abnormal mucus quality and slugding within the epididymis. Serum testosterone, FSH
and LH are normal, as are the testis biopsies . Reconstructive surgery can be attempted but
usually meets with lower success rates than observed with other obstructed conditions.
Idiopathic Epididymal Obstruction is a relatively uncommon, but well-recognized condition
found in otherwise healthy azoospermic men. It is sucessfully treated with epididymovasostomy.
There is recent evidence linking this condition with CF: in one series, 37% of men so
obstructed were seen to harbor a CF gene mutation. This implies that up to one-half of patients
with idiopathic obstruction at the level of the epididymis may in fact have a genetic predisposition
or reason for the problem.
Myotonic Dystrophy is the most common reason for adult-onset muscular dystrophy. This
usually presents with cataracts, muscle atrophy, and various endocrinopathies. Most men with this
condition are noted to have testis atrophy but fertility has been reported. Infertile men may have
elevated FSH and LH with low or normal testosterone and testis biopsies show seminferous
tubule damage in 75% of cases.
Adult Polycystic Kidney Disease is an autosomal dominant disorder associated with numerous
cysts of the kidney, liver, spleen, pancreas, epididymis seminal vesicle and testis. Disease onset
usually occurs in the 3rd or 4th decade with symptoms of abdominal pain, hypertension and renal
failure. Ten-40% of patients will also have cerebral berry aneurysms. Infertility with this disease
is usually secondary to obstructing cysts in the epididymis or seminal vesicle. Serum hormones
are normal and spermatogenesis is undisturbed.
V. CONCLUSIONS
1. Infertility can be caused genetic conditions, many of which have other implications for
the health of the patient or for offspring.
2. These diseases can have pre-testicular, testicular and post-testicular effects on fertility.
3. Molecular genetics is a rapidly growing field that may help explain many of what are
now considered idiopathic cases of male infertility.
4. Most genetic causes of infertility can be bypassed if spermatzoa are being produced
with assisted technologies. However, it is critical that appropriate genetic
counseling be given to couples who seek biological pregnancies.