fertility in thalassemia sylvia titi singer, md thalassemia center ucsf benioff children’s...
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Fertility in Thalassemia
Sylvia Titi Singer, MDSylvia Titi Singer, MD
Thalassemia CenterThalassemia Center
UCSF Benioff Children’s Hospitals UCSF Benioff Children’s Hospitals
Oakland, CAOakland, CA
June 2014June 2014
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
Why is it more relevant?
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
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
Iron
Pituitary MRI Imaging
Signal intensity reduction, Using GRE T2*-weighted pituitary-to-fat signal intensity ratio
Normal
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 Womenmethods 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)
Normal
Low 25 30 35 40 450
10
20
30
40
50
AF
CAge (years)
Follicles are low but present in the majority of thalassemia women
Represents low FSH/LH stimulation, but more accurate
AFC>12-15Good potential
Thal
AMH (anti Mullerian Hormone) A good indication of ovarian reserve in thalassemia
25 30 35 40 450
50
100
150
Age (years)
AM
H p
M
Conclusion:Most women have preserved ovarian functionPremature decline in function in women >33-35 years
Thalnormal
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 count (mill/ml)
motility PituitaryIron(R2)
LIC(mg/gdw)
LICPast
range
Ferritin(ug/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 depende
nt
2-7 (?)
<150
*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) up to 12-15 years
ICSI-Intra Cytoplasmatic Sperm Injection to overcome low sperm count
Injection of a single sperm directly into egg
ICSI
What can Men do to Preserve Fertilityand 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 messageWomen: 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-oxidantsHematologist: Discuss fertility issues/ preservation Referral to specialist
Reproductive Endocrinology, and Reproductive Endocrinology, and Urology Urology
UCSF Medical CenterUCSF Medical CenterMarcelle Cedars, MD Marcelle Cedars, MD James Smith, MDJames Smith, MDDeborah Trevithick PNPDeborah Trevithick PNP
Pediatric Clinical Reasearch Center Pediatric Clinical Reasearch Center (PCRC) and thalassemia clinical team at (PCRC) and thalassemia clinical team at CHRCOCHRCO Olivia vega, Nancy Sweeters, Annie HigaOlivia vega, Nancy Sweeters, Annie Higa Elliott Vichinsky, MD, Dru Foote, PNPElliott Vichinsky, MD, Dru Foote, PNP
Ash Lal, MDAsh Lal, MD
Cooley’s Anemia Foundation
Patients and families