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