Received: July 7, 2015
Accepted: July 8, 2015
Mediterr J Hematol Infect Dis 2015, 7(1): e2015047, DOI 10.4084/MJHID.2015.047
This article is available on PDF format at:
Vincenzo De Sanctis1, Ashraf T. Soliman2, Heba Elsedfy3, Nada A. Soliman4 and Rania Elalaily5
1 Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy
2 Department of Pediatrics, Division of Endocrinology, Alexandria University Children’s Hospital, Alexandria
3 Department of Pediatrics, Ain Shams University, Cairo, Egypt
4 Ministry of Health, Alexandria, Egypt
5 Department of Primary Health Care, Abu Nakhla Hospital, Doha, Qatar
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Dear Sir,
Today many subjects with beta thalassaemia major (β-thal)
successfully survive into adult life, due to the remarkable improvement
of medical care and better understanding of pathogenesis, clinical
manifestations and prevention of endocrine complications.[1]
However, 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.[1,2]
An
emerging endocrine disorder in young adults with β-thal is late-onset
male hypogonadism (LOH). LOH is a disorder caused by the inability of
the testes to produce the physiologic levels of testosterone and normal
number of spermatozoa as a result of a disruption of the hypothalamic-
pituitary-gonadal axis. Ten out of our 120 β-thal patients (8.3%)
developed this complication and 35% developed hypogonadotropic
hypogonadism requiring sex hormone replacement therapy.[3]
The
causes of male hypogonadism in the general population are multiple. In
β-thal hypogonadism is mainly due to iron deposition in the endocrine
glands.
Iron overload may be the result of economic circumstances
(high expense of the chelation therapy), late onset of chelation
therapy or poor compliance with treatment.
Toxicity starts when
the iron load in a particular tissue exceeds the tissue or
blood-binding capacity of iron and consequently free non-transferrin
iron appears. The ‘free iron’ is a catalyst for the production of
oxygen species that peroxidise membrane lipids of cell organelles
leading to cell destruction.[2,3]
The anterior
pituitary gland is particularly sensitive to the free radicals produced
by oxidative stresses and exposure to these radicals injures 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 decreases hormone storage
along with hypo-responsiveness to hypothalamic releasing hormones.[1] This causes:
1. Abnormalities
in the hypothalamic- pituitary growth hormone axis (defective GH
secretion in response to stimulation(40%) and GH neuro-secretory
dysfunction (up to 20%) and low insulin-like growth factor-1 (IGF-1)
synthesis in response to GH).[1]
2. Abnormalities in the hypothalamic- pituitary- gonadal axis (hypogonadotropic hypogonadism).[2]
Patients with TM have lower basal FSH and LH secretion, low LH/FSH
response to GnRH (gonadotropin releasing hormone) and low sex steroid
secretion from the gonads (testosterone). In addition, there is a
variable disturbance of the spontaneous pulsatile pattern of LH and FSH
secretion (pulsatile versus apulsatile).Those patients with pulsatile
secretion of LH/FSH have higher basal LH/FSH, GnRH stimulated LH and
FSH, lower ferritin and less organ damage (liver and heart) with better
prognosis for fertility. They display complete or partial reversibility
of hypogonadism when treated with pulsatile subcutaneous GnRH infusions
every 120 minutes for 3 months. While those with apulsatile secretion
or poor pulsatile release of LH/FSH do not respond to GnRH infusion and
have poor prognosis for fertility (V De Sanctis and AT Soliman,
personal observations)
Combined iron chelation 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 β-thal subjects. Long-term studies have shown that the
combined use of deferiprone and deferoxamine (DFO) hastens iron
chelation by rapidly reducing liver iron, serum ferritin, and
myocardial siderosis. Combined chelation therapy with deferasirox and
DFO has also been proved beneficial.[1]
What we know about fertility potential in thalassaemia? The personal experience
Histologically, a reduced number of cells and moderate siderosis of
the parenchymal cells of the anterior pituitary have been found.[2]
Testicular biopsies display various degrees of interstitial fibrosis
and hyperpigmentation of undifferentiated seminiferous tubules and a
decreased number of Leydig cells.
Virtually very little is known about spermatogenesis in (β-thal). A summary of the available findings include the followings:
A normal sperm count and motility in 45% of fully sexually mature β-thal subjects.[3]
• A
possible detrimental effect of iron chelation therapy on
spermatogenesis. Three out of four patients with serum ferritin levels
lower than 500 ng/ml had poor sperm motility.[4,5]
• A higher degree of defective chromatin packaging in β-thal subjects with low sperm concentrations.[5]
• A
low seminal plasma concentration of zinc, citric acid and prostate
specific antigen. These data suggest impaired prostatic secretion.[6]
• An increase of seminal lipo-peroxidation.[7]
• An
increase of DNA sperm damage and a negative correlation with sperm
motility. These findings suggest that iron overload predispose sperm to
oxidative injury.[8]
• These findings
indicate an increase of oxidative stress in the semen of these patients
that could contribute to the impairment of sperm motility.[6,7]
• 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 animal studies.[9]
In addition, abnormal
seminal parameters and low serum folic acid levels have been found in
subjects with thalassaemia intermedia.[10]
In
our experience, β-thal patients develop LOH in their second and third
decades of life. It is possible to induce or restore spermatogenesis
with exogenous gonadotrophins in some of them.[11]
Assisted reproductive techniques may supplementary help these patients
to overcome previously untreatable causes of male infertility.[1]
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.
Despite the fact that endocrine complications are very common in multi-transfused thalassaemia patients[1,2,12]
a recent survey conducted by the International Network of Clinicians
for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) in
2014 in Acitrezza (Catania, Italy) showed that the major difficulties
reported by hematologists or pediatricians experienced in thalassaemias
or thalassaemia syndromes in following endocrine complications were: 1)
Lack of familiarity with medical treatment of endocrine complications,
2) poor interpretation of endocrine tests and 3) lack of collaboration
and on-time consultation between thalassaemic centers supervised by
hematologists and endocrinologists
The practical objectives of ICET-A (www.endothalassemia.org)
are to encourage and guide endocrine follow up of multi-transfused
patients in developing countries, to promote and support collaborative
research in this field, to encourage and guide endocrine follow up of
multi-transfused patients, and to educate and train more
endocrinologists and other paediatricians/physicians to prevent and
improve management of the growth and endocrine complications in these
patients.[13] This is in agreement with a fundamental
requirement of medical ethics, that any progress we make in research
into growth disorders and endocrine complications in thalassaemia
should be passed on to all those suffering from such disorders.
References
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