Fertility in Thalassemia

1. Fertility in Thalassemia Sylvia Titi Singer, MD Thalassemia Center UCSF Benioff Children’s Hospitals Oakland, CA June 2014

2. 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?

3. 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 notseem 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

4. Topics to discuss • Causes of infertility • Measures to predict fertility status • Fertility preservation and treatment/intervention options • Planning pregnancy

5. Causes of infertility

6. The Reproductive System and Hypogonadism • Hypogonadism: Diminished activity of the gonads Testes or ovaries • Reduced sex hormone synthesis: Testosteroneestrogenand impaired gamete (eggs or sperm) production • Depending on the degree of severity, may result in infertility

7. 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? Pituitary-Gonadal Axis and Iron Iron ? Iron

8. 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

9. 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

10. Measurements of reproductive potential

11. 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

12. Ultrasound for Follicle Count (AFC) AFC>12-15 Good potential Normal Thal Low • Follicles are low but present in the majority of thalassemia women • Represents low FSH/LH stimulation, but more accurate

13. AMH (anti Mullerian Hormone) A good indication of ovarian reserve in thalassemia Thal normal Conclusion: • Most women have preserved ovarian function • Premature decline in function in women >33-35 years

14. Preventionand Intervention Options

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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)

21. 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

22. Iron load and sperm analysis *Has a child

23. 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

24. 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 Treatments for Male Infertility ICSI

25. 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

26. 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

27. 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