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An overview of male infertility
provided by Stephen Shaban MD.
Male Infertility --- Overview
Approximately 15% of couples attempting their first
pregnancy meet with failure. Most authorities define these
patients as primarily infertile if they have been unable
to achieve a pregnancy after one year of unprotected
intercourse. Conception normally is achieved within twelve
months in 80-85% of couples who use no contraceptive
measures, and persons presenting after this time should
therefore be regarded as possibly infertile and should be
evaluated. Data available over the past twenty years
reveal that in approximately 30% of cases pathology is
found in the man alone, and in another 20% both the man
and woman are abnormal. Therefore, the male factor is at
least partly responsible in about 50% of infertile
couples.
Important issues related to the evaluation of the male
factor include the most appropriate time for the male
evaluation, the most efficient format for a comprehensive
male exam, and definition of rationale and effective
medical and surgical regimens in the treatment of these
disorders. It is extremely important in the evaluation of
infertility to consider the couple as a unit in evaluation
and treatment and to proceed in a parallel investigative
manner until a problem is uncovered. It has been shown
that the longer a couple remains subfertile, the worse
their chance for an effective cure. Many couples
experience significant apprehension and anxiety after only
a few months of failure to conceive. Unduly prolonged
unprotected intercourse should not be advocated before a
workup of the man is instituted. Initial screening of the
man should be considered whenever the patient presents
with the chief complaint of infertility. This initial
evaluation should be rapid, non-invasive and cost
effective. Of interest is the fact that pregnancy rates of
up to 50% have been reported when only the woman has been
investigated and treated even when the man was found to
have moderately severe abnormalities of semen quality.
MALE REPRODUCTIVE PHYSIOLOGY
The Hypothalamic-Pituitary-Gonadal Axis
The hypothalamus is the integrative center of the
reproductive axis and receives messages from both the
central nervous system and the testes to regulate the
production and secretion of gonadotropin releasing
hormone (GnRH). Neurotransmitters and neuropeptides
have both inhibitory and stipulatory influence on the
hypothalamus. The hypothalamus releases GnRH in a
pulsatile nature which appears to be essential for
stimulating the production and release of both
luteinizing hormone (LH) and follicle stimulating hormone
(FSH). Interestingly and paradoxically, after the
initial stimulation of these gonadotropins, the exposure
to constant GnRH results in inhibition of their release.
LH and FSH are produced in the anterior pituitary and are
secreted episodically in response to the pulsatile release
of GnRH. LH and FSH both bind to specific receptors on the
Leydig cells and Sertoli cells within the testis.
Testosterone, the major secretory product of the testes,
is a primary inhibitor of LH secretion in males.
Testosterone may be metabolized in peripheral tissue to
the potent androgen dihydrotestosterone or the potent
estrogen estradiol. These androgens and estrogens act
independently to modulate LH secretion. The mechanism of
feedback control of FSH is regulated by a Sertoli cell
product called inhibin. Decreases in spermatogenesis are
accompanied by decreased production of inhibin and this
reduction in negative feedback is associated with
reciprocal elevation of FSH levels. Isolated increased
levels of FSH constitute an important, sensitive marker of
the state of the germinal epithelium.
Prolactin also has a complex inter-relationship with
the gonadotropins, LH and FSH. In males with
hyperprolactinemia, the prolactin tends to inhibit the
production of GnRH. Besides inhibiting LH secretion and
testosterone production, elevated prolactin levels may
have a direct effect on the central nervous system. In
individuals with elevated prolactin levels who are given
testosterone, libido and sexual function do not return to
normal as long as the prolactin levels are elevated.
The Testes
Leydig; Cells
Testosterone is secreted episodically from the
Leydig cells in response to LH pulses and has a
diurnal pattern, with the peak level in the early morning
and the trough level in the late afternoon or early
evening. In the intact testis, LH receptors decrease or
down-regulate after exogenous LH administration. Large
doses of GnRH or its analogs can reduce the numbers of LH
receptors and therefore inhibit LH secretion. This has
been applied clinically to cause medical castration in men
with prostate cancer. Estrogen inhibits some enzymes in
the testosterone synthetic pathway and therefore directly
effects testosterone production. There also appears to be
an intratesticular ultra short loop feedback such that
exogenous testosterone will override the effect of LH and
inhibit testosterone production. In normal males, only 2%
of testosterone is free or unbound. 44% is bound to
testosterone-estradiol-binding globulin or TeBG, also
called sex hormone-binding globulin. 54% of testosterone
is bound to albumin and other proteins. These
steroid-binding proteins modulate androgen action. TeBG
has a higher affinity for testosterone than for estradiol,
and changes in TeBG alter or amplify the hormonal milieu.
TeBG levels are increased by estrogens, thyroid
administration and cirrhosis of the liver and may be
decreased by androgens, growth hormone and obesity. The
biological actions of androgens are exerted on target
organs that contain specific androgen receptor proteins.
Testosterone leaves the circulation and enters the target
cells where it is converted to the more potent androgen
dihydrotestosterone by an enzyme 5-alpha-reductase. The
major functions of androgens in target tissues include 1)
regulation of gonadotropin secretion by the
hypothalamic-pituitary axis; 2) initiation and maintenance
of spermatogenesis; 3) differentiation of the internal and
external male genital system during fetal development; and
4) promotion of sexual maturation at puberty.
Seminiferous Tubules
The seminiferous tubules contain all the germ cells at
various stages of maturation and their supporting Sertoli
cells. These account for 85-90% of the testicular volume.
Sertoli cells are a fixed-population of
non-dividing support cells. They rest on the basement
membrane of the seminiferous tubules. They are linked by
tight junctions. These tight junctions coupled with the
close approximation of the myoid cells of the peritubular
contractile cell layers serve to form the blood-testis
barrier. This barrier provides a unique microenvironment
that facilitates spermatogenesis and maintains these germ
cells in an immunologically privileged location. This
isolation is important because spermatozoa are produced
during puberty, long after the period of self-recognition
by the immune system. If these developing spermatozoa were
not immunologically protected, they would be recognized as
foreign and attacked by the body's immune system. Sertoli
cells appear to be involved with the nourishment of
developing germ cells as well as the phagocytosis of
damaged cells. Spermatogonia and young spermatocytes are
lower down in the basal compartment of the seminiferous
tubule, whereas mature spermatocytes and spermatids are
sequestered higher up in the adluminal compartment.
The germinal cells or the spermatogenic cells
are arranged in an orderly manner from the basement
membrane up to the lumen. Spermatogonia lie directly on
the basement membrane, and next in order, progressing up
to the lumen, are found the primary spermatocytes,
secondary spermatocytes and spermatids. There are felt to
be 13 different germ cells representing different stages
in the developmental process.
Spermatogenesis is a complex process whereby
primitive stem cells or spermatogonia, either divide to
reproduce themselves for stem cell renewal or they divide
to produce daughter cells that will later become
spermatocytes. The spermatocytes eventually divide and
give rise to mature cell lines that eventually give rise
to spermatids. The spermatids then undergo a
transformation into a spermatozoa. This transformation
includes nuclear condensation, acrosome formation, loss of
most of the cytoplasm, development of a tail and
arrangement of the mitochondria into the middle piece of
the sperm which basically becomes the engine room to power
the tail. Groups of germ cells tend to develop and pass
through spermatogenesis together. This sequence of
developing germ cells is called a generation. These
generations of germ cells are basically in the same stage
of development. There are six stages of seminiferous
epithelium development. The progression from stage one
through stage six constitutes one cycle. In humans the
duration of each cycle is approximately 16 days and 4.6
cycles are required for a mature sperm to develop from
early spermatogonia. Therefore, the duration of the entire
spermatogenic cycle in humans is 4.6 cycles times 16 days
equals 74 days.
Hormonal Control of Spermatogenesis
An intimate structural and functional relationship exists
between the two separate compartments of the testis, i.e.
the seminiferous tubule and the interstitium
between the tubules. LH effects spermatogenesis indirectly
in that it stimulates androgenous testosterone production.
FSH targets Sertoli cells. Therefore, testosterone and PSH
are the hormones that are directed at the seminiferous
tubule epithelium. Androgen-binding protein which is a
Sertoli cell product carries testosterone intracellularly
and may serve as a testosterone reservoir within the
seminiferous tubules in addition to transporting
testosterone from the testis into the epididymal tubule.
The physical proximity of the Leydig cells to the
seminiferous tubules and the elaboration by the Sertoli
cells of androgen-binding protein, cause a high level of
testosterone to be maintained in the microenvironment of
the developing spermatozoa. The hormonal requirements for
initiation of spermatogenesis appear to be independent of
the maintenance of spermatogenesis. For spermatogenesis to
be maintained like for instance after a pituitary
obliteration, only testosterone is required. However, if
spermatogenesis is to be re-initiated after the germinal
epithelium has been allowed to regress completely, then
both FSH and testosterone are required.
Transport-Maturation-Storage of Sperm
Although the testis is responsible for sperm production,
the epididymis is intimately involved with the
maturation, storage and transport of spermatozoa.
Testicular spermatozoa are non-motile and were felt to be
incapable of fertilizing ova. Spermatozoa gain progressive
motility and fertilizing ability after passing through the
epididymis. The coiled seminiferous tubules terminate
within the rete testis, which in turn coalesces to form
the ductuli efferentes. These ductuli efferentes conduct
testicular fluid and spermatozoa into the head of the
epididymis. The epididymis consists of a fragile single
convoluted tubule that is 5-6 meters in length. The
epididymis is divided into the head, body, and tail.
Although epididymal transport time varies with age and
sexual activity, the estimated transit time of spermatozoa
through the epididymis in healthy males is approximately
four days. It is during the period of maturation in the
head and body of the epididymis that the sperm develop the
increased capacity for progressive motility and also
acquire the ability to penetrate oocytes during
fertilization. The epididymis also serves as a reservoir
or storage area for sperm. It is estimated that the
extragonadal sperm reservoir is 440 million spermatozoa
and that more than 50% of these are located in the tail of
the epididymis. The sperm that are stored in the tail of
the epididymis enter the vas deferens which is a muscular
duct 30-35 cm in length. The contents of the vas are
propelled by peristaltic motion into the ejaculatory duct.
Sperm are then transported to the outside of the male
reproductive tract by emission and ejaculation.
During emission, secretions from the seminal vesicles
and prostate are deposited into the posterior urethra.
Prior to ejaculation peristalsis of the vas deferens and
bladder neck occur under sympathetic nervous control.
During ejaculation, the bladder neck tightens and the
external sphincter relaxes with the semen being propelled
through the urethra via rhythmic contractions of the
perineal and bulbourethral muscles. It is true that the
first portion of the ejaculate contains a small volume of
fluid from the vas deferens which is rich in sperm. The
major volume of the seminal fluid comes from the seminal
vesicles and secondarily the prostate. The seminal
vesicles provide the nourishing substrate fructose as well
as prostaglandins and coagulating substrates. A recognized
function of the seminal plasma is its buffering effect on
the acidic vaginal environment. The coagulum formed
by the ejaculated semen liquefies within 20 to 30 minutes
as a result of prostatic proteolytic enzymes. The prostate
also adds zinc, phospholipids, spermine, and phosphatase
to the seminal fluid. The first portion of the ejaculate
characteristically contains most of the spermatozoa and
most of the prostatic secretions, while the second portion
is composed primarily of seminal vesicle secretions and
fewer spermatozoa.
FERTILIZATION
Fertilization normally takes place within the uterine
tubes after ovulation has occurred. During the menstrual
mid cycle, the cervical mucus changes to become more
abundant, thinner and more watery. These changes serve to
facilitate entry of the sperm into the uterus and to
protect the sperm from the highly acidic vaginal
secretions. Physiologic changes in the spermatozoa known
as capacitation occur within the female
reproductive tract in order for fertilization to occur. As
the sperm cell interacts with the egg, there is initiation
of new flagellar movement called hyperactive motility and
morphologic changes in the sperm that result in the
release of lytic enzymes and exposure of parts of the
sperm's structure known as the acrosome reaction.
As a result of these changes, the fertilizing sperm cell
is able to reach the oocyte, traverse it's various layers,
and become incorporated into the ooplasm of the egg.
CLINICAL FINDINGS
History
The cornerstone of the evaluation of infertile man is a
careful history and physical examination. Specific
childhood illnesses should be sought including
cryptographies, post pubertal mumps orchitis and
testicular trauma or torsion. Precocious puberty may
indicate the presence of an adrenal-genital syndrome,
whereas delayed puberty may indicate Klinefelter's
syndrome or idiopathic hypogonadism. Prenatal exposure to
diethylstilbesterol should be ascertained because this may
cause an increased incidence of epididymal cysts or a
slightly increased frequency of cryptorchidism. A detailed
history of exposure to occupational and environmental
toxins, excessive heat, or radiation should be elicited.
Cancer chemotherapy has a dose-dependent and potentially
devastating effect on the testicular germinal epithelium.
The drug history should be reviewed for anabolic steroids,
cimetidine, and spironolactone which can effect the
reproductive cycle. Medications like sulfasalazine and
nitrofurantoin may effect sperm motility. Illicit drugs
and excessive alcohol consumption are associated with a
decrease in sperm count and hormonal abnormalities.
Previous medical and surgical diseases and their treatment
may occasional compromise reproductive function. Men with
unilateral undescended testes will have overall semen
quality of considerably less than normal. Previous
surgical procedures such as bladder neck operations or
retroperitoneal lymph node dissection for testicular
cancer may cause retrograde ejaculation or absent
emission. Diabetic neuropathy may result in either
retrograde ejaculation or impotence.
Both the vas deferens and the testicular blood supply
can easily be injured during hernia repair. In patients
with cystic fibrosis, the vas deferens or epididymis and
seminal vesicles are usually absent. Any generalized fever
or illness can impair spermatogenesis. The ejaculate may
be affected for three months after the event, as
spermatogenesis takes about 74 days from initiation to the
appearance of mature sperm. There is also a variable
transport time in the ducts. Sometimes events that have
occurred in the previous 3-6 months are extremely
important. Sexual habits including frequency of
intercourse, frequency of ejaculation, use of coital
lubricants and the patient's understanding of the
ovulatory cycle should be discussed. Previous infertility
evaluation and treatment and the reproductive history from
previous marriages should be ascertained. A history of
recurrent respiratory infections and infertility may be
associated with the immotile cilia syndrome, in which the
sperm count is normal but the spermatozoa are completely
non-motile due to ultrastructural defects. Kartagener's
syndrome, which is a variant of immotile cilia syndrome,
consists of chronic bronchiectasis, sinusitis, situs
inversus and immotile spermatozoa. In Young's syndrome,
also associated with pulmonary disease, the cilia
ultrastructure is normal but the epididymis is obstructed
due to inspissated material, and these patients present
with azoospermia. Loss of libido associated with
headaches, visual abnormalities and galactorrhea may
suggest a pituitary tumor. Other medical problems that
have been associated with infertility include thyroid
disease, seizure disorders, and Liver disease.
Interestingly it is not the seizure disorder itself that
causes infertility but it is the typical treatment of it
with Dilantin (phenytoin). Dilantin decreases FSH. Chronic
systemic diseases such as renal disease and sickle cell
disease are associated with abnormal reproductive hormonal
parameters.
Physical Examination
During the physical examination, particular attention
should be paid to discerning features of hypogonadism.
Typically this would be viewed as poorly developed
secondary sexual characteristics, eunuchoidal skeletal
proportions i.e. arm span two inches greater than height,
ratio of upper body segment (crown to pubis) to lower body
segment (pubis to floor) less than 1, and the lack of
normal male hair distribution ie. sparse axillary, pubic,
facial, and body hair in conjunction with lack of temporal
hair recession. One should be on the lookout also for
infantile genitalia ie. small penis, testes, and prostate
with under-developed scrotum. One may see a diminished
muscular development and mass.
A careful examination of the testes is an essential
part of the examination. Normal adult testes are on the
average about 4.5 cm long and 2.5 cm wide with a mean
volume of about 20 cc. A caliper or orchidometer may be
used to measure testicular size. If the seminiferous
tubules were damaged before puberty, the testes are small
and firm. With postpubertal damage, they are usually small
and soft.
Gynecomastia is a consistent feature of a feminizing
state. Men with congenital hypogonadism may have
associated midline defects such as anosmia, color
blindness, cerebellar ataxia, hair lip, and cleft palate.
Hepatomegaly may be associated with problems of hormonal
metabolism. Proper neck examination may help rule out
thyromegaly, a bruit or nodularity associated with
disease. Neurologic exam should test the visual fields and
reflexes.
Irregularities in the epididymis suggest a previous
infection and possible obstruction. Examination may reveal
a small prostate with androgen deficiency or slight
tenderness (bogginess) in men with prostatic infection.
Any penile abnormalities like hypospadias, abnormal
curvature, phimosis, should be looked for. The scrotal
contents should be carefully palpated with the patient in
both the supine and standing positions. Many varicoceles
are not visible and may only be discernible when the
patient stands or performs the Valsalva maneuver.
Varicoceles can often result in a smaller left testis, and
a discrepancy in size between the two testes should arouse
suspicion. Both vas deferens should be palpated, as 2% of
infertile men have congenital absence of the vasa and
seminal vesicles.
PRE-TESTICULAR CAUSES OF INFERTILITY
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Hypothalamic disease |
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Isolated
gonadotropin deficiency (Kallmann's syndrome) |
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Isolated
LH deficiency ("Fertile eunuch") |
| |
Isolated
FSH deficiency |
| |
Congenital
hypogonadrotropic syndromes |
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Pituitary disease |
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Pituitary
insufficiency (tumors, infiltrative processes,
operation, radiation) |
| |
Hyperprolactinemia |
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Hemochromatosis |
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Exogenous
hormones (estrogen-androgen excess, glucocorticoid
excess, hyper and hypothyroidism). |
HYPOTHALAMIC DISEASE
Kallmann's syndrome which is an isolated
gonadotropin (LH and FSH) deficiency occurs in both a
sporadic and familial form and although uncommon i.e. 1 in
10,000 men, it is second to Klinefelter's syndrome as a
cause of hypogonadism. The syndrome is often associated
with anosmia, congenital deafness, hair lip, cleft palate,
craniofacial asymmetry, renal abnormalities, color
blindness. The hypothalamic hormone GnRH appears to be
absent. If exogenous GnRH is administered, both LH and FSH
are released from the pituitary. Except for the
gonadotropin deficiency, anterior pituitary function is
intact. The syndrome appears to be inherited either as an
autosomal recessive trait or an autosomal dominant trait
with incomplete penetrance. The differential diagnosis
should include delayed puberty. Kallmann's syndrome
distinguishing features though are testes less than 2 cm
in diameter and positive family history with the presence
of anosmia. "Fertile eunuch" are individuals with
isolated LH deficiency. They have eunuchoid
proportions with variable degrees of virilization and
gynecomastia. They characteristically have large testes
and semen containing a few sperm. Plasma FSH levels are
normal but both the serum LH and testosterone
concentrations are low normal. The cause appears to be a
partial gonadotropin deficiency in which there is adequate
LH to stimulate testosterone production with resultant
spermatogenesis but insufficient testosterone to promote
virilization. In isolated FSH deficiency which is
rare, patient's are normally virilized and have normal
testicular size and baseline levels of LH and
testosterone. Sperm counts range from O to a few sperm.
Serum FSH levels are low and do not respond to GnRH
stimulation. Congenital hypogonadotropic syndromes
are associated with secondary hypogonadism and a multitude
of other somatic findings. Prader-Willi syndrome is
characterized by hypogonadism, hypomentia, hypotonia at
birth and obesity. Laurence-Moon-Bardet-Biedel syndrome is
an autosomal recessive trait characterized by mental
retardation, retinitis pigmentosa, polydactyly and
hypogonadism. These syndromes are felt to be due to a
defect in hypothalamic deficiency of GnRH.
PITUITARY DISEASE
Pituitary insufficiency may result from tumors,
infarctions, iatrogenic causes like surgery and radiation
or one of several infiltrative processes. If pituitary
insufficiency occurs prior to puberty, growth retardation
associated with adrenal and thyroid deficiency is the
major clinical presentation. Hypogonadism that occurs in a
sexually mature male usually has its origin in a pituitary
tumor. Decreasing libido, impotence and infertility may
occur years before symptoms of an expanding tumor i.e.
such as headaches, visual abnormalities, or
thyroid/adrenal hormone deficiency. Once an individual has
passed through normal puberty, it takes a long time for
secondary sexual characteristics to disappear unless
adrenal insufficiency is present. The testes will
eventually become small and soft. The diagnosis is made by
low serum testosterone levels with low or low normal
plasma gonadotropins concentrations. Depending on the
degree of panhypopituitarism, plasma corticosteroids will
be reduced with plasma TSH and growth hormone levels.
Hyperprolactinemia can cause both reproductive
and sexual dysfunction. Prolactin-secreting tumors of the
pituitary gland whether from a microadenoma (less than 10
mm) or a macroadenoma, can result in loss of libido,
impotence, galactorrhea, gynecomastia and alter
spermatogenesis. Patients with a macroadenoma usually
first present with visual field abnormalities and
headaches. They should undergo CT or MRI scanning of the
pituitary and laboratory testing of anterior pituitary,
thyroid and renal function. These patients have low serum
testosterone levels but basal serum levels of LH and FSH
are either low or low normal and reflect an inadequate
pituitary response to depressed testosterone.
Approximately 80% of men with hemochromatosis
have testicular dysfunction. Their hypogonadism may be
secondary to iron deposition in the liver or may be
primarily testicular as a result of iron deposition in the
testes. Iron deposits have also been found in the
pituitary, implicating this gland as the major site of
abnormality.
With regard to the role of exogenous hormones,
adrenocortical tumors, Sertoli cell tumors,
interstitial cell tumors of the testes may all at
times be estrogen-producing. Hepatic cirrhosis is
associated with increased endogenous estrogens. Estrogens
act primarily by suppressing pituitary gonadotropin
secretion, resulting in secondary testicular failure.
Androgens can also suppress pituitary gonadotropin
secretion thereby leading to secondary testicular failure.
The current use of anabolic steroids by certain
athletes may result in temporary sterility. Endogenous
androgen excess may be due to an androgen-producing
adrenocortical tumor or testicular tumor but more likely
to congenital adrenal hyperplasia. As a consequence of
this disease, the production of androgenic steroids by the
adrenal cortex is increased, resulting in premature
development of secondary sexual characteristics and
abnormal phallic enlargement. The testes failed to mature
because of gonadotropin inhibition and are
characteristically small. In the absence of precocious
puberty, the diagnosis is extremely difficult since
excessive virilization is difficult to detect in an
otherwise normally sexually mature man. Careful laboratory
evaluation is essential. Infertility caused by documented
congenital adrenal hyperplasia is treatable with
corticosteroids. Physicians have used corticosteroids in
individuals with idiopathic infertility, but unless these
abnormalities can be documented, steroid therapy has no
place.
Sometimes glucocorticoid excess (prednisone
usage) is exogenous in the therapy of ulcerative colitis,
asthma, or rheumatoid arthritis. The result is decreased
spermatogenesis. The elevated plasma cortisone levels
depress LH secretion and can cause secondary testicular
dysfunction. Correction of the glucocorticoid excess
results in improvement in spermatogenesis. Hyper
and hypothyroidism can alter spermatogenesis.
Hyperthyroidism effects both pituitary and testicular
function with alterations in the secretion of releasing
hormones and increased conversion of androgens to
estrogens.
TESTICULAR CAUSES OF INFERTILITY
|
- Chromosomal
abnormalities (Klinefelter's syndrome, XX disorder
(sex reversal syndrome), XYY syndrome) |
|
- Noonan's syndrome (male
Turner's syndrome) |
|
- Myotonic dystrophy |
|
- Bilateral anorchia
(vanishing testes syndrome) |
|
- Sertoli-cell-only
syndrome (germinal cell aplasia) |
|
- Gonadotoxins (drugs,
radiation) |
|
- Orchitis |
|
- Trauma |
|
- Systemic disease (renal
failure, hepatic disease, sickle cell disease) |
|
- Defective androgen
synthesis or action |
|
- Cryptorchidism |
|
- Varicocele |
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