Download An overview of male reproduction in thalassaemia

An overview of male reproduction
in thalassaemia
Vincenzo De Sanctis 1, Ashraf Soliman 2, Mohamed Yassin 3
1
2
Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, 44121 Ferrara, Italy
Departments of Pediatrics and 3 Hematology, Hamad Medical Center (HMC), Doha, Qatar
An overview of male reproduction in thalassaemia
Failure of pubertal growth, delay or absence of sexual development, infertility and sexual dysfunction due to hypogonadism and defective spermatogenesis are well recognized disturbances among male patients with thalassaemia major
( -thal). These problems are attributed mainly to the damage caused by chronic anaemia and deposition of iron in the
pituitary gland and testicles. In our experience, more and more adult thalassemic patients in their second and third decade
of life with the prospect of marriage wish to know their ability to father a child. It is possible to induce or restore spermatogenesis with exogenous gonadotrophins. Although knowing the importance of good compliance with treatment, clinicians have to consider the possibility that overzealous desferrioxamine treatment may adversely affect spermatogenesis
and/or sperm function. Much progress has been achieved in the field of male infertility in both diagnostics and treatment.
Assisted reproductive techniques may further help these patients to overcome previously untreatable causes of male infertility. This is not a comprehensive review of male fertility problems in thalassaemia. However, it is a short contribution
written by pediatric endocrinologists and haematologist with a great interest in the subject and actively involved in the
management of male infertility in -thal subjects.
Key words: Thalassaemia, Hypogonadism, Iron overload, Chelation therapy, Spermatogenesis, Fertility in males.
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Today many patients with thalassaemia major
( -thal) successfully survive into adult life, due
to remarkable improvement of medical care and
to a better understanding of pathogenesis, clinical manifestations and prevention of endocrine
complications (1-5). Despite the improvement
of the treatment, the involvement of the
endocrine system still burdens the life of these
patients. In fact, several studies have reported
that as many as 51% to 66% of patients may
have pubertal failure, sexual dysfunction and
infertility, due to hypogonadism (1-5).
The causes of male infertility in general population are multiple while in -thal are classically
considered to be the result of iron deposition in
the endocrine glands (4).
Iron overload may be the result of economic circumstances (expense of the chelation therapy),
late onset of chelation therapy or poor compliance with treatment (6). Toxicity starts when the
iron load in a particular tissue exceeds the tissue
or blood-binding capacity of iron, and free nontransferrin iron appears. The ‘free iron’ is a catalyst of the production of oxygen species that
damage cells and peroxidize membrane lipids
leading to cell destruction (7). Other possible
causes of hypogonadism in -thal include liver
disorders, chronic hypoxia and associated
endocrine complications, such as diabetes (8).
This is not a comprehensive review of male fertility problems in thalassaemia. It is not meant to
be. However, it is a short contribution written by
pediatric endocrinologists and haematologist
with a great interest in the subject and actively
involved in the management of male infertility in
-thal subjects.
Endocrine control of pubertal
development in males
Pubertal development is the result of increasing
release of GnRH by the hypothalamus, which
stimulates the pituitary to release both gonadotropins LH and FSH. The gonadotropins stimulate the gonads (testis) to develop and produce
the sex steroids (testosterone) (Figure 1). FSH
stimulates the seminiferous tubules to produce
sperms. LH stimulates specialized cells in the
testes called Leydig cells to secrete the male hormone, testosterone (9). The rate of LH secretion is
influenced by the amount of testosterone circulat-
Figure 1.
Gonadotrophin secretion and feeback control in males.
ing in the blood. FSH secretion is controlled by
inhibin. The rate of inhibin secretion is governed
by the amount of sperm being made by the seminiferous tubules (9, 10).
Besides producing the male characteristics,
testosterone enhances the production of sperm.
Two important negative feedback loops exist to
regulate the secretion of gonadotropins.
The testosterone negative feedback loop is established in fetal life and inhibits hypothalamic and
pituitary production of GnRH and LH. InhibinB, produced by the Sertoli cell, exerts inhibitory
effects on FSH secretion from the pituitary gland,
however this negative feedback loop is only
established at around puberty (10).
Any disruption of this system or dysfunction of
its components may lead to infertility (11).
The physical changes
of puberty
Timing of puberty is the result of both genetic
constitution and environmental influences.
Chronic systemic diseases are often associated
with delayed puberty (3, 9).
The initial physical sign of puberty is testicular
enlargement. At birth testes measure about 1 ml,
during the following 2-3 months volume increases
to 2 ml, and then decreases again around 6 months
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V. De Sanctis, A. Soliman, M. Yassin
An overview of male reproduction in thalassaemia
Table 1.
Pubertal assessment according to Tanner.
Penile development
Growth of pubic hair
P1: Prepubertal
PH1: Prepubertal
P2: Early puberty
(enlargement of scrotum and testes,
4-5 ml, little or no enlargement of penis)
PH2: Early puberty
(sparse growth)
P3: Mid puberty
(enlargement of penis and further
growth of testes, 8-12 ml, and scrotum)
PH3: Mid puberty
(hair extends over the pubic junction)
P4: Advanced puberty
(enlargement of penis in length
and breadth. Increased pigmentation
of scrotal skin and enlargement
of testicles, 15-25 ml)
PH4: Advanced puberty
(hair corresponds to adult growth
but less extensive)
P5: Adult
PH5: Adult
of life. These changes are due to an increase followed by a decrease of androgens during early
infancy. Few changes occur until age 11-12 years,
when the first signs of puberty develop with an
increase in testes volume (3-4 ml) (Table 1). The
maximum increase, about 4 ml per year, occurs at
a bone age of about 13-14 years. Some children
reach complete sexual development in less than 2
years, while others require more than 4 years (9).
Testes enlargement is mainly due to the increase
in volume and tortuosity of seminiferous tubules. Spermatogenesis commences during puberty and continues throughout life and until old
age (12, 13).
The assessment of testicular volume is done
using Prader’s orchidometer (Figure 2). This is a
series of plastic ellipsoids ranging from a volume
of 1 ml to 25 ml. The testis, held longitudinally
between thumb and index finger, is compared
with the ellipsoid with the same volume (14).
Physiology of testicular function
The testes fulfil two tasks: steroidogenesis and
spermatogenesis. Steroidogenesis takes place in
the Leydig (interstitial) cells, situated between
the seminiferous tubules. Spermatogenesis takes
place in the germinal epithelium of these tubules.
The germ cells undergo various stages of development from spermatogonia before spermatozoa
(mature sperm) reach maturation (Figure 3).
This process takes about 60 days to be produced
and another 10-14 days for them to pass through
the epididymis and vas deferens (12, 13).
Disorders of pubertal development
and iron overload
On average puberty starts at approximately 11
years in boys, with 99% showing a testicular
volume of 4 ml or greater by the age of 14 years
(9, 14).
Delayed puberty is defined as the complete lack
of pubertal development in boys by the age of 14
and hypogonadism is defined as the absence of
testicular enlargement (less than 4 ml) by the age
of 16 years. Also, a pubertal arrest may result in
hypogonadotropic hypogonadism after some
spontaneous development (15, 16).
Hypogonadotropic hypogonadism, which still
remains the commonest endocrinopathy in
patients with thalassaemia major, has been
proven to be the result of hemosiderosis of the
gonadotroph cells of the pituitary gland (17-19).
An emerging endocrine disorder in young adult
-thal subjects is late-onset male hypogonadism
(LOMH). LOMH is a disorder caused by the
inability of the testes to produce physiologic levels of testosterone and the normal number of
spermatozoa as a result of a disruption of the
hypothalamic- pituitary-gonadal axis (De Sanctis
el al., personal observations).
Figure 2.
Prader’s orchidometer.
Figure 3.
Cross-section of human testis
in an young adult
(from: Reproductive Biology and
Endocrinology 2003, 1:107, mod.)
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There are 2 types of male hypogonadism, regardless of age of onset. Primary; involves testicular
failure that results in low testosterone levels,
impairment of sper-matogenesis, and elevated
gonadotropin levels. Secondary; results from
central defects of the hypothalamus or pituitary
and is associated with low- to- normal gonadotropin levels (LH and FSH) and low testosterone
levels (20-27).
The anterior pituitary gland is particularly sensitive to the free radicals produced by oxidative
stresses and exposure to these radicals injurious
to the gland. Magnetic resonance imaging (MRI)
shows that even a modest amount of iron deposition within the anterior pituitary can interfere
with its function. Excess iron deposition in the
anterior pituitary leads to degranulation of the
adenohypophysis and decreased hormone storage with ensuing hypogonadism due to pituitary
hyporesponsiveness to gonadotrophin releasing
hormone (4, 17-19).
Histologically a reduced number of cells and
moderate siderosis of the parenchymal cells of
the anterior pituitary have been found. Testicular
biopsies show various degrees of interstitial
fibrosis and hyperpigmentation of undifferentiated seminiferous tubules and a decreased number
of Leydig cells (4, 28).
Genotype differences may influence the patient’s
susceptibility to hypogonadotropic hypogonadism, possibly as a result of differences in the
amounts of blood transfused and/or their vulnerability to free radical damage. The pituitary damage is rarely reversible (29).
When hypogonadism develops before the age of
puberty, the manifestations are those of impaired
puberty:
• small testes and phallus;
• scanty pubic and axillary hair;
• disproportionately long arms and legs (from
delayed epiphyseal closure);
• persistently high-pitched voice.
When hypogonadism develops after the age of
puberty, some signs and symptoms are suggestive of male hypogonadism, while others are less
clearly associated. The patient presents with:
• very small, soft or shrinking testes;
• loss of libido and activity;
• decreased spontaneous erections or impotence;
• reduced muscle bulk and strength
• reduction of seminal fluid or aspermia (24-27);.
The history and the physical examination
The cornerstone of the evaluation of infertile
man is a careful history including the current
problem/complaint, age, occupation, previous
seminal analysis findings, any associated medical
complication such as diabetes, smoking, alcohol
and caffeine consumption (24-27).
In the physical examination particular attention
should be paid to:
1. Vital signs, body height and weight (BMI),
arm-span, secondary sexual characters, and
examination of thyroid gland.
2. Features of hypogonadism: Complete or partial development of secondary sexual characteristics (penis length, distribution of body
hair, including beard growth, axillary hair
and pubic hair).
3. Testicular size: Failure of one or both of the
testes to descend into the scrotum or damage
to the testicles, such as by injury or after a
mumps infection, may reduce sperm production. Because approximately 85% of testicular
mass consists of germinal tissue, a reduced
germinal cell mass would be associated with a
reduced testicular size and a soft consistency.
4. Presence of varicocele: Varicocele which is
varicosity of the veins around the testes can
occasionally cause infertility.
5. Presence of gynaecomastia: It may be the result
of medications, genetic disorders, hyperprolactinemia, or chronic liver disorders.
Hormonal measurements
Hormonal screening can be limited to the determination of serum concentrations of follicle stimulating hormone (FSH), luteinising hormone
(LH), testosterone (T), TSH and prolactin. A low
testosterone level is one of the best indicators of
hypogonadism of hypothalamic or pituitary origin (24-27). Low LH and FSH values concurrent
with low testosterone levels indicate hypogonadotropic hypogonadism (24-27). Elevated FSH
and LH values help to distinguish primary testicular failure (hypergonadotropic hypogonadism)
from secondary testicular failure (hypogonadotropic hypogonadism) (Figure 4). An elevated FSH level associated with small, atrophic
testes implies irreversible infertility (24-27).
The total testosterone level should be drawn
between 7:00 am and 11:00 am, as it is highest
at this time of day. The American Association of
Clinical Endocrinologists identifies a total testosterone level below 200 ng/dL as low, while The
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An overview of male reproduction in thalassaemia
hypogonadism. MRI may also quantify the pituitary iron deposition (17-19).
Figure 4.
Hormonal assessment im
primary and secondary
hypogonadism.
Endocrine Society identifies 300 ng/dL as the
threshold (30).
The diagnostic value of prolactin measurement is
extremely low in men with semen abnormalities
unless these are associated with decreased libido,
erectile dysfunction, and evidence of hypogonadism. Prolactin measurement is warranted in
patients with low serum testosterone levels without
an associated increase in serum LH levels (24-27).
Magnetic Resonance Imaging (MRI)
MRI of the pituitary-to-fat signal intensity ratios
and the pituitary height and volume are significantly lower in -thal with hypogonadotropic
Macroscopic variables
Macroscopic variables are volume, pH, coagulation, liquefaction, color and viscosity (Table 2).
Table 2.
Macroscopic parameters of the semen analysis.
Parameters
Normal values
pH
7.8
Coagulation/liquefaction
Coagulates and liquefies within 20 mins
at room temperature
Colour
Whitish-gresy; pearl-white
Viscosity
4 mm threading
Table 3.
Lower reference limits (5 centiles and their 95% confidence intervals) for semen
characteristics (from: WHO manual for Semen Analysis, 5th Edn, 2010).
th
Parameter
Semen volume (mL)
Total sperm number (106 per ejaculate)
Semen analysis
Although semen analysis is not a test of fertility,
a carefully performed semen analysis is a highly
predictive indicator of the functional status of the
male reproductive hormonal cycle, spermatogenesis and the patency of the reproductive tract.
The World Health Organization Laboratory Manual
for Examination of Human Semen and SemenCervical Mucous Interactions is highly recommended for technical details (31). In the detection of
male factor fertility problems, basic semen analysis using the WHO criteria is a sensitive test (sensitivity of 89.6%, i.e. it is likely to detect nine out
of ten men who have ‘true’ semen abnormality),
but it has poor specificity (an abnormal test result
does not always mean there is a true semen abnormality). Analysis of repeat semen samples provides greater specificity in identifying semen
abnormalities; a single-sample analysis will falsely
identify about 10% of men as abnormal, but
repeating the test reduces this to 2% (31).
Lower reference limit
1.5 (1.4-1.7)
39 (33-46)
Sperm concentration (106 per mL)
15 (12-16)
Total motility (progressive and non-progressive, %)
40 (38-42)
Progressive motility (%)
32 (31-34)
Vitality (live spermatozoa, %)
58 (55-65)
Sperm morphology (normal forms, %)
4 (3.0-4.0)
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Microscopic variables
The microscopic parameters assess spermatogenesis (Table 3).
The minimum number of specimens to define
good or poor quality of semen is three samples
over a 6-8 week interval with a consistent period
of abstinence of 2-3 days.
A repeat semen analysis should be requested
after two to three months, bearing in mind that a
complete spermatogenesis cycle lasts for 74 days.
Classical semen analysis, which includes sperm
concentration, motility and morphology, gives
an approximate evaluation of the functional
competence of spermatozoa.
• Low numbers of sperms and poor sperm
movement can have an impact on fertility.
• Abnormally shaped sperms can also result in
failure to conceive.
• Abnormal level of white blood cells could
indicate an infection.
The fertilizing potential of sperm depends not
only on the functional competence of spermatozoa but also on sperm DNA integrity. Sperms
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Rivista Italiana di Medicina dell’Adolescenza - Volume 10, n. 2, 2012
with compromised DNA integrity, regardless of
the degree of DNA damage, appear to have the
capacity to fertilize oocytes at the same rate as
normal sperm. However, the embryos produced
by fertilization of an oocyte with DNA damaged
sperm can not develop normally (32) . Therefore,
the evaluation of sperm DNA integrity, in addition to routine sperm parameters, could add further information on the quality of spermatozoa
and improved predictive values could be
obtained from validated sperm DNA fragmentation assays. The most commonly used techniques
to assess sperm DNA integrity are the TUNEL and
sperm chromatin structure assays (SCSA) (32).
What we know about fertility
potential in thalassaemia?
The personal experience
Virtually very little is known about spermatogenesis in ( -thal).
In summary, we found:
• A normal sperm count and motility in 45% of
fully sexually mature -thal subjects (33)
• A possible detrimental effect of iron chelation
therapy on spermatogenesis. Three out four
patients with serum ferritin levels lower than
500 ng/ml had poor sperm motility (34)
• A higher degree of defective chromatin packaging in -thal subjects with low sperm concentrations (32)
• A low seminal plasma of zinc, citric acid and
prostate specific antigen. These data suggest
an impaired prostatic secretion (35)
• An increase of seminal lipoperoxidation.
These findings indicates an increase of oxidative stress in the semen of these patients that
could contribute to the impairment of sperm
motility (36)
• An increase of DNA sperm damage and a
negative correlation with sperm motility.
These findings suggest that iron overload predispose sperm to oxidative injury (32)
• Blood transfusion is associated with significant acute enhancement of sperm parameters
and increased concentrations of serum T, LH,
FSH, and IGF-1. These “acute” effects on
spermiogenesis are reached by an unknown
mechanism and suggest a number of pathways that need further human and/or experimental studies (5)
• Abnormal seminal parameters and low serum
acid folic levels have been found in subjects
with thalassaemia intermedia (37).
Iron chelation therapy
Combined therapy (use of two chelators on the
same day), may induce negative iron balance and
may reverse hypogonadism and endocrine complications in severe iron overloaded -thal subjects (38-40). Long-term studies have shown that
deferiprone and deferoxamine (DFO) have
shown to accelerate iron chelation by rapidly
reducing liver iron, serum ferritin, and myocardial siderosis.Combination chelation therapy
with deferasirox and DFO has also been shown
beneficial (39).
Counselling
Sometimes certain ‘lifestyle’ factors may be
responsible for poor semen quality. For example
obesity, alcohol abuse, use of anabolic steroids,
extreme sports and increase in scrotal temperature through thermal underwear, sauna or hot
tub use or occupational exposure to heat sources.
A considerable number of drugs can also affect
the spermatogenesis (41).
Hormonal treatment
Hormonal treatment of pubertal disorders in thalassaemia is a complex issue due to the many
associated complications. Therefore, each patient
has to be assessed individually. Collaboration
between endocrinologists and other doctors is
critical (42).
The treatment of delayed or arrested puberty,
and hypogonadotrophic hypogonadism depends
on factors such as age, severity of iron overload,
damage to the hypothalamo-pituitary-gonadal
axis, chronic liver disease, and the presence of
psychological problems resulting from hypogonadism (43).
Although thalassaemics who fail to enter puberty
or whose puberty is arrested before complete sexual maturation has occurred are considered to be
sterile for life, we found that this is not necessarily
true and that gonadotropin treatment (hCG and
hMG) can achieve spermatogenesis (44, 45).
Because of advances in fertilization and sperm
banking technologies, all subjects, even those
with extremely low sperm counts and motility,
should be considered candidates for sperm cyropreservation (33).
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An overview of male reproduction in thalassaemia
For delayed puberty in males, low dosages of
intramuscular depot-testosterone esters (25 mg)
are given monthly, at a bone age of about 12
years, for 6 months to stimulate growth velocity.This is accompanied by only an early pubertal
development. In patients with hypogonadism
therapy can continued and the dose increased to
100 mg/mo. until the growth rate begins to
wane.The fully virilising dose is 75-100 mg of
depot-testosterone esters every 10 days administered intramuscularly or 100 mg/m² twice a
month. (46). The same effects can be achieved
with topical testosterone gel.
Treatment of hypogonadotropic hypogonadism
may be initiated for 2 purposes: androgenization
and/or induction of fertility. It is known that
hCG binds to Leydig cell LH receptors and stimulates the production of testosterone.
Male patients with onset of hypogonadotropic
hypogonadism before completion of pubertal
development may have testes generally smaller
than 5 ml and usually require therapy with both
hCG and human menopausal gonadotropin (or
FSH) to induce spermatogenesis. The initial regimen of hCG is usually 1,000 to 2,000 IU administered intramuscularly two times a week. The
clinical response is monitored, and testosterone
levels are measured every 2 to 3 months. Dosage
adjustments of hCG may be needed to determine
an optimal schedule.
The disadvantages of hCG include the need for
more frequent injections and the greater cost.
Larger testis volume is a useful prognostic indicator of response (44). If the patient is fully virilized
and 8-12 months of hCG therapy have not led to
the production of sperm, then FSH therapy should
be initiated (44). FSH is available as human
menopausal gonadotropin (hMG). Sperm banking
procedures, even in subjects with reduced sperm
count and motility is recommended (33). Once a
pregnancy has occurred, the FSH therapy can be
stopped and spermatogenesis can be maintained
with hCG alone. Men with arrested puberty or
with postpubertal, acquired hypogonadotropic
hypogonadism may initiate and maintain production of sperm with hCG therapy only (47).
Infertility
In presence of infertility, the male and female
partners are evaluated to determine the cause
and best treatment options. Infertility is defined
69
by the World Health Organization as the “inability
of a sexually active, non-contracepting couple to
achieve pregnancy in one year”. Although no universally accepted consensus exists between specialties on the management of infertility, several
algorithms have been devised to provide an initial assessment of the infertile male (48).
Today new assisted reproductive techniques
(ART) offer hopes to many couples (22-27):
• intra-uterine insemination is used for mild
male factor infertility problems;
• intracytoplasmic sperm injection (ICSI) as a
management for severe male factors or for
recurrent unexplained failed in vitro fertilization (IVF) cycles (25). ICSI is a procedure that
is performed in conjunction with IVF. With
ICSI, a single sperm from the male partner is
injected directly into a woman's egg (oocyte) in
the laboratory. The pregnancy rate with ICSI is
approximately 20% to 40% per cycle (22-24).
• adoption is offered for cases with recurrent
unexplained failed IVF cycles and donor
insemination for azoospermia;
• testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) has been
used in patients with Klinefelter syndrome
and azoospermia (49). No case report in thalassaemia are available in literature but at our
knowledge this is a procedure suggested by
some Experts in reproductive thechniques in
patients with azoospermia and arrested
puberty.
International guidelines are required to assist these
patients because it is widely accepted that infertility and involuntary childlessness, and the decision
to engage with assisted reproduction technology
services as a patient, donor or surrogate can entail
wide-ranging psychosocial issues (50).
In conclusion, failure of pubertal growth, delay or
absence of sexual development, infertility and sexual dysfunction due to hypogonadism and defective spermatogenesis are well recognized disturbances among male patients with thalassaemia
major. These problems are attributed mainly to
the damage caused by chronic anaemia and iron
deposition in the pituitary gland and testicles. At
present, one of the major problems dealing with
adult patients with beta-thalassemia are “fertility”
and “osteoporosis”. In our experience, more and
more adult thalassemic patients in their second
and third decades of life, with the prospect of marriage, wish to know their ability to father a child.
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Rivista Italiana di Medicina dell’Adolescenza - Volume 10, n. 2, 2012
It is possible to induce or restore spermatogenesis
with exogenous gonadotrophins in some of them.
Clinicians should recognize that both big iron
overload (defective chelation) and overzealous use
of desferrioxamine may adversely affect spermatogenesis and/or sperm function. Much progress has
been achieved in the field of male infertility, both
in the diagnostics and treatment aspects. Assisted
reproductive techniques may supplementary help
these patients to overcome previously untreatable
causes of male infertility.
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