Fertility in Thalassemia

Sylvia Titi Singer, MD

Thalassemia Center
UCSF Benioff Children’s Hospitals
Oakland, CA
June 2014
 Why is it more relevant?
Prime goal:
– Seeking better quality of life
 Employment, marriage, family
 Want to have advance information,
planning
– Currently: infrequent open
discussion of the topic
– Insufficient information
 Difficult to plan
 increased anxiety, disappointment
 Affecting relationships, self image, QOL
 Thalassemia Fertility Issues
 Iron-induced hypogonadism: A most common
endocrinopathy in thalassemia: 23-55%
 Even with presumed adequate chelation-
hypogonadism and infertility are common
– LIC of at 3-9 mg/gr does not seem to eliminate
reproductive problems
– Iron induced oxidative stress- probably a significant
cause of infertility in thalassemia

 Still, consistent chelation since young age -

maintains hormonal secretion and fertility
 Topics to discuss
 Causes of infertility

 Measures to predict fertility status

 Fertility preservation and

treatment/intervention options

 Planning pregnancy
Causes of infertility
 The Reproductive System and
Hypogonadism
 Hypogonadism: Diminished
activity of the gonads
Testes or ovaries

 Reduced sex hormone

synthesis: Testosterone
estrogen and impaired
gamete (eggs or sperm)
production

 Depending on the degree of

severity, may result in
infertility
Pituitary-Gonadal Axis and Iron

Iron
 Pituitary gland very
sensitive to iron
deposition/injury

 Iron causes pituitary cell

damage: reduced hormone
synthesis, including LH/FSH

 Low or absent stimulation

of gonads: Low Estrogen or
testosterone

 Additional direct effect of

? iron/oxidative injury on
ovaries and testes?
Iron
 Pituitary MRI Imaging

Normal
Signal intensity reduction,
Using GRE T2*-weighted
pituitary-to-fat signal
intensity ratio
Iron overload
• Pituitary iron deposition: mostly not reversible
• True Pituitary volume loss
 Women
 Low LH/FSH  low estrogen:
• Primary/Secondary
amenorrhea (no menses) or
irregular menstrual cycle
• Common need for hormonal
treatment for ovulation
induction and pregnancy
 Secondary effects of low
estrogen
• low bone density
• Fatigue, mood swings
Measurements of reproductive
potential
 Fertility Measures Women
methods for Ovarian Reserve Testing (ORT)

Trans-vaginal Ultrasound: size and number of follicles

(developing eggs) in the ovaries, named AFC = Antral
Follicle Count.
• Affected by LH/FSH -low if  pituitary iron
• Helps assessing chance of response to ovulation
induction.
AMH a hormone secreted by the ovaries (blood test)
•A low level of AMH suggests that the ovary may be
depleted of eggs
•Not LH/FSH dependent , therefore, a good prediction of
ovarian follicle pool for thalassemia women
Ultrasound for Follicle Count (AFC)
50 AFC>12-15
Normal Good potential
40
Thal
30

A FC
20

10

0
25 30 35 40
Low4 5
A g e (y e a rs )

 Follicles are low but present

in the majority of thalassemia
women
 Represents low FSH/LH
stimulation, but more accurate
 AMH (anti Mullerian Hormone)
A good indication of ovarian reserve in thalassemia

150
Thal
normal
100
AMH pM

50

0
25 30 35 40 45
Age (years)

Conclusion:
 Most women have preserved ovarian function
 Premature decline in function in women >33-35 years
 Prevention
and Intervention Options
 Interventions/Treatments
 Inquire early about
– Referral to reproductive endocrinologist
– Follow hormone levels and ovarian
reserve to predict fertility status:
 LH/FSH, estrogen, AMH levels, AFC

– Egg freezing options

– Information on process/cost
 Thalassemia team to incorporate in
comprehensive care plan
 Pregnancy and Thalassemia
 A practical option with intensive care and ovulation
induction therapy
 Over 450 pregnancies reported (Major and
Intermedia)
 50-75% pregnancies occurred in females with
amenorrhea, required hormonal treatment for
ovulation induction.
 Most report term delivery of normal babies
 Higher rate of:
– Premature labor
– Low birth weight (~8%)
– No increase in birth defects
 Pre-pregnancy recommendations
Pregnancy
– Increased cardiac effort
– Increased iron load
– Risk of cardiac failure
 Liver iron: If > 15 mg/gdw  delay conception
 T2* MRI: If<10 ms  delay
 Resting and stress echo
 Hep C positive: counseling on transmission risk
 Chelation issues
 Most don’t chelate 1st trimester
 Need to chelate! Avoid late pregnancy cardiac issues
 Pregnancy Course:
summary of recent reports

 90% result in successful delivery

- High incidence of twins
 7% had a spontaneous miscarriage
 65-75% required hormone induced ovulation
 60-70% were delivered by Cesarean section
 ~25-30% born premature (30-36 wks)
 Mean Hb kept at 11.2 g/dL
 Ferritin increased 1460 to 2690
 Pregnancy Course:
recent reports-Cont.

 Mean age for pregnancy 24 to 29.5 years old

 Overall cardiac function remained stable: EF 63 61%
 Limited information on pre/post T2*
 90% of those with high glucose pre pregnancy
developed gestational diabetes, 7% developed glucose
intolerance
 No reports of thrombotic cases while pregnant
 Splenectomized women received Aspirin during
pregnancy
 Men
 Low pituitary LH/FSH:
– Low testosterone
– Low sperm count (Oligospermia)
 Higher sperm DNA damage

 Secondary effects of low

testosterone:
– Fatigue
– Low bone density
– Less muscle mass
– Delay/low secondary sexual
characteristics
– Low Libido (sexual drive)
 Thalassemia Male Fertility
 Less is known compare to women
 Only a few reports of TM males fathering children
(more on pregnant TM women)
 Spermatogenesis more sensitive to iron damage than
ovarian follicle pool
 Generally, Male infertility: significant effect of
oxidative damage  affects sperm integrity
 Iron-induced oxidative injury likely a
significant role in thalassemia sperm
production
 Iron load and sperm analysis
Age Sperm motility Pituitary LIC LIC Ferritin
count Iron (mg/ Past (ug/L)
(mill/m (R2) gdw) range
l)
26 178 75 13.5 (nl) 6 5.4-8.2 634(670-
1100)
26 0 0 17 (high) 23 11-24 4290
(3000-4900)
28* 11 37 - 8.2 7-14 1965
(1524-4000)
nl >20 >50 Age 2-7 <150
dependent (?)

*Has a child
Methods to assess/ increase Male Fertility
 Conventional sperm test (count, motility, volume )
 Sperm DNA fragmentation test -correlates with
fertility
 Stimulate own testosterone and therefore more
sperm production.
– HCG: Human chorionic gonadotropine– mimics LH
(can add FSH)
– Clomid (Clomiphene): Also stimulates endogenous
testosterone and sperm synthesis
 Recommended ~6 months prior to plan for a child
 Treatments for Male Infertility
Significant Advances in methodology
to overcome male infertility:
 Sperm Freezing (cryopreservation) ICSI
up to 12-15 years
 ICSI-Intra Cytoplasmatic Sperm
Injection to overcome low sperm
count
 Injection of a single sperm directly
into egg
 What can Men do to Preserve Fertility
and Know your options?

 Maintain low iron levels from early childhood

 Keep normal levels of vitamins C and E, Zinc
(protective !)
 Supplement with anti-oxidants !

Assess fertility potential:

– Sperm analysis including DNA integrity
– When to change from testosterone to HCG or Clomid
– Special infertility treatments
– sperm freezing
– ICSI
 Take home message
Women: Lower follicle than nl count but still present
 Need more aggressive early screening and intervention
 Younger age better chances for a successful response to
hormonal stimulation (don’t wait for late 30s…)
Men: Spermatogenesis very sensitive to oxidative stress
 Consider early sperm freezing
 HCG treatment

Both:
• Keep normal levels of Vitamins C and E, Zinc
• Supplement with anti-oxidants
Hematologist: Discuss fertility issues/ preservation
 Referral to specialist
 Reproductive Endocrinology, and Urology
UCSF Medical Center
Marcelle Cedars, MD
James Smith, MD
Deborah Trevithick PNP

Pediatric Clinical Reasearch Center (PCRC)

and thalassemia clinical team at CHRCO
Olivia vega, Nancy Sweeters, Annie Higa
Elliott Vichinsky, MD, Dru Foote, PNP
Ash Lal, MD

 Cooley’s Anemia Foundation

 Patients and families