Download Neurons containing POMC and NPY mRNA also express Ob

Gonadal function and
Fertility issues in Thalassaemia
3rd Pan-European Conference on
Haemoglobinopathies & Rare Anaemias
Limassol, 24 – 26 October 2012
Nicos Skordis, MD
Makarios Hospital, Nicosia
The Thalassaemia map
? Original sin
AnteroVentral PeriVentricular nucleus
Leptin acts on hypothalamic neurons expressing its receptor (Ob-R).
Neurons containing POMC and NPY mRNA also express Ob-R mRNA, and
both POMC and NPY mRNA are regulated by leptin.
Changes in the synthesis and/or release of these or other hypothalamic
peptides could then act at GnRH neurons to affect GnRH release.
Leptin levels in patients with Thalassaemia
10
9
8
7
6
5
4
3
2
1
0
12
10
8
thal
control
6
4
thal
control
male
female
Del Giudice BrJ Haematology 1999
2
0
male
female
children
Vlachopapadopoulou E. Ann Clin Ped Un Ath 2004
Sexual Complications in Thalassaemia
1. Delayed puberty : Lack of pubertal development
( girls by 13 yr, boys 14 yr )
2. Arrested puberty : Lack of pubertal progression
for longer than 12 months with reduced growth
velocity
3. Primary Hypogonadism : Total absence of
pubertal development by the age of 16 yrs
4. Secondary Hypogonadism : Gonadal failure
after puberty has been completed
35
30
De Sanctis, 2002
Male Hypogonadism
Sec. Amenorrhea
Prim. Amenorrhea
Diabetes Mellitus
Hypothyroidism
Impaired OGGT
Hypoparathyroidism
25
20
15
10
5
0
45
40
35
30
25
20
15
10
5
0
Toumba M,PER
Skordis
N. PER 2007
2007
Short stature
Hypogondism F
Hypogonadism M
DM + IGT
Hypothyroidism
HypoPTH
Endocrine events and development of
secondary sexual characteristics
Endocrine event
Sexual maturation
Increased GnRH increased LH/FSH
Increased steroid production
Oestrogen secretion
Testosterone secretion
FSH secretion
Adrenal androgen secretion
Sex Steroid and GH secretion
Oestrogen withdrawal
Induction of LH surge
~3-4 years
Breast development
Penile and scrotal development
Testicular enlargement
/follicular development
Pubic and axillary hair
Growth acceleration
Menarche (anovulatory)
Ovulatory menstrual cycles
Distribution of body iron at post-mortem in TM in pre-chelation
Skeletal muscle
Testes
Kidney
Heart
Adrenal
Salivary gland
Minimum
Maximum
Thyroid
Pancreas
Liver
Parathyroid
0
2
4
6
Fe % d.w.
TM = thalassaemia major; d.w. = dry weight.
Adapted from Modell B, Mathews R. Birth Defects Orig Artic Ser. 1976;12:13.
8
Normalization of total body iron load with very
intensive combined chelation reverses cardiac and
endocrine complications of Thalassaemia major
Farmaki K. Br J Haematol. 2010
1. 39 patients with abnormal glucose metabolism, 44% normalized.
2. 18 on thyroxin for hypothyroidism, 10 were able to discontinue,
and 4 reduced their thyroxin dose.
7/14 hypogonadal males on testosterone therapy,
stopped treatment - one male became father
19 females, who were hypogonadal on DFO
monotherapy, six were able to conceive.
Acute effects of blood transfusion on pituitary gonadal
axis and sperm parameters in adolescents and young men
with Thalassaemia major: a pilot study
Soliman A. Fertility Sterility , 2012
• Total sperm count increased significantly
from 57.8 to 166 million/mL, and rapid
progressive sperm motility increased from
20.6 to 79.7 %
• Blood transfusion is associated with
significant acute enhancement ??
of sperm parameters and increased
concentrations of serum T, LH, FSH, and IGF-1
Goddess of Fertility
Dionysus
Chalcolithic Fertility Goddess
Cyprus 3000-2500 BCE Limestone
Fertility in Cypriot Thalassaemic women
Skordis N, Ped Endocr Rev 2004
Endocrine status
Number
Total Number
Children
Normal
Menses
72
Primary
Secondary
Αmenorrhea Αmenorrhea
11
17
100
35 % of women older than 20 years
161
Outcome of
362 pregnancies in 316 women
53
40
3
266
Full term
Pre term
Abortions
Singleton
340
Twin
20
Triple
2
Stillbirth
Update on fertility in Thalassaemia major
359 successful pregnancies Skordis N. PER 2004
• Absence of any deleterious effect on the
course of Thalassaemia
• Safety of the pregnancy
• Spontaneous fertility can occur in well
chelated and transfused patients
• Ovarian function is well preserved in women
suffering primary or secondary amenorrhea
as they become able to conceive following a
closely monitored stimulation therapy
Fertility and Pregnancy in
Thalassemia Major
SUSAN M. TUCK, JAN 2006
Over the last 15 years, 22 women with TM
have completed 29 pregnancies
The major pre-pregnancy issues, medications, and
pregnancy care are reviewed
Experience suggests that, with proper care
and guidance, pregnancies among women
with Thalassaemia major are practical and
can have successful outcomes.
Current perspectives of fertility and pregnancy in Thalassaemia.
Bajoria R, Chatterjee R Hemoglobin. 2009
Pregnancies following ART in 11 TM women
Pregnancy is
feasible and safe
in women with TM with
normal resting cardiac performance
and optimized iron overload
in specialist centers under
a multi disciplinary team
Pregnancy and beta-thalassemia: an Italian multicenter experience.
Origa R, Haematologica. 2010
46 women with TM (58 pregnancies)
11 women with TI (17 pregnancies)
Pregnancy was safe in most women with TM or TI
However, women with TI who had never previously
been transfused or who had received only minimal
transfusion therapy were at risk of severe alloimmune
anemia if blood transfusions were required during
pregnancy
Cardiac monitoring during pregnancy
in 44 pregnancies in 35 women with TM from
1997 to 2009
Echocardiograms were performed before
pregnancy, at first, second, third trimester and
after labour
Kypris L et al. 2011
No significant cardiac complications were
encountered
Pregnancy can be safe for cardiac function in
women with TM provided they have started
early on proper treatment and have a normal
resting cardiac performance
1. Pregnancy is safe
2. No severe obstetric complications
3. No deleterious effects of pregnancy on the course of
Thalassaemia
4. Women with Primary or Secondary Amenorrhea preserve
their Ovarian function and therefore Induction of Ovulation
can be easily achieved
5. ? The incidence of preterm labour and growth restriction
Issues
• Medical history
• Emotional dilemmas
• Legal issues
• Ethical issues
Evaluation of Eligibility
1. Cardiac function: ECG, Echo
2. Liver function tests, Ultrasound
3. Vessels: Clotting factors, Doppler
4. Endocrine: Hypothalamic – Pituitary –
Gonadal axis Thyroid, Calcium - OGTT
5. Viral infections: HBV, HCV, HIV
6. Iron status
7. Genetic counseling – Partner’s carrier
status and fertility
Management during pregnancy
1.
2.
3.
4.
5.
Maintenance of Hb level at 10 gr/dl
Frequent low volume blood transfusions
Serial Ultrasound to monitor fetal growth
Regular cardiac monitoring
Assessment of endocrine function, OGTT
Multidisciplinary approach by all specialist
involved in the medical care of
Thalassaemic women
stated simply
1. The desire of Thalassaemic women to achieve
motherhood should be recognized, respected and
approached with special caution and sensitivity by
all physicians involved in their medical care
2. Ambitions of this sort pose numerous medico legal
and ethical issues that need to be addressed
prudently if the patients' quality of life is to be
optimized
3. Should balance improvement in the quality of life
of the woman and the safety of her life
Induction of ovulation
• Primary Amenorrhea
• Secondary Amenorrhea
• Oligomenorrhea
• Normal Menstrual function who fail
to conceive
• Planned pregnancy where both partners are
Thalassaemics
two significant risks
• Powerful drugs - growth of two or more follicles,
with risk of twin or triplet pregnancy
• Ovarian Hyperstimulation Syndrome –
enlarged ovaries - fluid retention with bloating,
breathlessness and nausea. Although uncommon ,
serious cases require hospitalization and would be
particularly complicated to manage in a patient
already unwell with Thalassaemia.
Ovarian Reserve Testing
(the capacity of the ovary to provide eggs that are
capable of fertilization resulting in a healthy and
successful pregnancy)
is based on indirect measures to evaluate the size
of the residual ovarian follicle pool
Antral follicle count (AFC ) reflects
the pool of primordial follicles ,
those follicles that decline with age
Reproductive aging is directly related to the
decline in the pool of these follicles
AMH : Earliest marker of change with age and has very
little intercycle and intracycle variability
AMH prevents recruitment of non-dominant follicles
Paternity in Cypriot Thalassaemics
Skordis N, Ped Endocr Rev 2004
Endocrine
Status
Normal
Number
54
Total number
Hypogonadism
4
58
20% of all men > 20 years
Children
96
Abnormal sperm concentrations , quality , motility
and morphology in males with TM
DeSanctis in Fert Ster;50:969,1988
140
Induction of spermatogenesis with hCG and hMG
120
100
80
60
40
20
0
before
HCG
HCG HMG
Endocrine complications
Primary Hypogonadism
IGTT
Secondary Hypogonadism
DM
Hypothyroidism
6
5
4
3
2
1
0
Cryopreservation - preserved by freezing - of
ejaculated semen, which can be used for insemination
or ICSI whenever pregnancy is desired
Oxidative stress and Infertility
• Induced by Reactive Oxygen Species – ROS
• Normal levels of ROS are required for sperm
physiology but excessive levels can negatively
affect sperm quality
• Contributing factor in 30 – 80 % of all cases
• The generation of ROS can be exacerbated by
environmental, infectious and life style
factors
• Oxidative stress can be measured
F
Hypothesis suggesting one of the mechanisms by which DNA damage in human spermatozoa can
increase the mutational load subsequently carried by the embryo
Aitken R J et al. Reproduction 2011;141:139-150
© 2011 Society for Reproduction and Fertility
Spermatozoal DNA damage in patients with
β- thalassaemia syndromes. - 28 patients with TM and TI
De Sanctis V Pediatr Endocrinol Rev. 2008
1.
Significantly more sperm DNA damage (mean
TUNEL=18.5%, SCSA=0.28) than controls (mean
TUNEL=11.4%, mean SCSA=0.18)
2. Negative correlation between itchromatin structure
damage and sperm concentration (r2=0.3, p<0.006).
3. There was a significant negative correlation
between serum ferritin levels and
abnormal sperm morphology - Possible
detrimental effect on spermatogenesis by
the iron chelator DFX
Sperm DNA damage in potentially fertile homozygous βthalassaemia patients with iron overload
Doreen Perera
Results
1. TM patients (median ferritin: 2251 μg/l) had more
sperm DNA damage
2. The sperm DNA damage by SCSA and TUNEL were
positively correlated
3. The age of onset of chelation and sperm DNA
damage were positively associated with both
SCSA and TUNEL
4. No other biochemical or clinical data were associated
with sperm DNA damage.
Sperm DNA damage in potentially fertile homozygous βthalassaemia patients with iron overload
Doreen Perera
Conclusions
1. The increase in sperm DNA damage and the negative
correlation between sperm motility and DNA damage
suggest that
iron overload predisposes sperm to
oxidative injury.
2. This finding has important implications in ART – ICSI
where there is increased risk of transmitting defective
DNA to the offspring
Therapeutic management of Oxidative Stress
Sperm concentartion 106/mL
Semen quality
North America
Europe
Mother,
don’t kill my sperm !
Vitamin D
Hormone (Vitamin ) D
•
•
•
•
and Reproduction
Steroidogenesis in healthy women
Higher clinical pregnancy rates in IVF
Endometriosis
Polycystic Ovary Syndrome
• Semen Quality
• Androgen status - Testosterone levels
Spermatozoal DNA damage in patients with
β- thalassaemia syndromes. - 28 patients with TM and TI
De Sanctis V Pediatr Endocrinol Rev. 2008
1. Thalassaemic patients with low sperm
concentrations were more likely to have a higher degree
of defective chromatin packaging.
2. Possible detrimental effect on spermatogenesis by
the iron chelator desferrioxamine
3. Thalassaemic patients especially those being
considered for assisted conception procedures
should be counselled accordingly
Use of laptop computers connected to internet
through Wi-Fi decreases human sperm motility and
increases sperm DNA fragmentation
Conrado Avenda Fertility and Sterility, 2012
epilogue