DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

MINUTES OF THE SPECIAL EMPHASIS PANEL ON
HORMONE THERAPY FOR COOLEY'S ANEMIA


June 3, 1997


The meeting of the Special Emphasis Panel on Hormone Therapy for Cooley's Anemia was
convened on June 3, 1997, at 8:00 A.M., at the Royal Sonesta Hotel, Cambridge,
Massachusetts.  In accordance with Public Law 92-463, the entire meeting was open to the
public (8:00 A.M. to 4:00 P.M.).  Alan R. Cohen, M.D. presided as Chair.


PANEL MEMBERS (see attached Panel roster)

Dr. Alan R. Cohen (Chair), Ms. Sherry Bush, Dr. Vincenzo De Sanctis, Dr. Patricia J. Giardina,
Dr. Maria I. New, Dr. Nancy F. Olivieri, Dr. John B. Porter, Dr. Elliott Vichinsky, and Dr. Beatrix
Wonke.


MEMBERS OF THE PUBLIC PRESENT

Mr. Ralph Cazzetta (Cooley's Anemia Foundation), Dr. Nursen Gurtunca (University of
Witwatersrand, Johannesburg, South Africa), Ms. Susan Kurth, R.N. (Children's Hospital,
Boston), Dr. Duru Malyali (TADAD, Istanbul, Turkey), Dr. Janet Poole (University of
Witwatersrand), Ms. Angela Sabatino, R.N. (Cornell Medical Center), Ms. Juliana Shen, R.N.
(Cornell Medical Center), and Dr. Michael Wajnrajch (Cornell Medical Center).


FEDERAL EMPLOYEES PRESENT

Alan Levine, Ph.D., NHLBI, NIH 
Helena O. Mishoe, Ph.D., NHLBI, NIH


OPEN MEETING

I.  Call to order

Dr. Alan Levine called the meeting to order with a statement of the purpose of the meeting. 
Clinical advances in the treatment of Cooley's anemia have helped to substantially increase the
life expectancy of patients.  The patients of today represent the first generation of adult
thalassemics.  As patients enter puberty, they begin to experience a variety of endocrine
abnormalities, presumably the result of anemia and tissue iron deposition from the chronic
transfusion therapy.  During the past decade hormone replacement or supplemental therapy has
become part of the medical management of thalassemia.  This Special Emphasis Panel has the
task of assessing the current state of hormone therapy for treating endocrine abnormalities and
to determine whether research opportunities now exist for studying (1) the mechanisms for
delayed sexual development, infertility, and osteoporosis in Cooley's anemia patients and (2) the
role of hormone therapy and its long-term effects in the treatment of these endocrine disorders,
and (3) the psychological impact of hormone therapy on self-esteem, body image, social
relations, and sexuality.


Il.  Review of Confidentiality and Conflict of Interest Procedures

Dr. Levine explained policies and procedures regarding confidentiality and avoidance of conflict
of interest.  Panel members signed the requisite forms.


Ill. Presentations

Mr. Ralph Cazetta, a member of the public and himself a Cooley's Anemia patient, addressed the
panel and provided the members with an important context in which to place the endocrine
problems that affect nearly all adolescent and adult patients with thalassemia major.  Mr.
Cazetta, the Director of Patient Services of the Cooley's Anemia Foundation, emphasized that as
a child he had a profound need to feel accepted by his peers, to be able to participate in the
same activities as his peers, to grow and mature at the same pace as his peers, to develop
meaningful relationships with peers and especially members of the opposite sex, to bear
children, and to be a productive member of the community.  Dr. Nancy Olivieri provided an
overview of iron in endocrine organs and impairment of growth, and sexual development.  She
noted that deferoxamine therapy to remove excess iron has no effect on the poor pubertal growth
and sexual development.  Dr. Elliott Vishinsky discussed the natural history of endocrinopathies
in hemoglobin E-beta-thalassemia.  Dr. Vincenzo De Sanctis discussed the effects of chelation
therapy on growth and endocrine complications in a large group of Italian patients.  Dr. Beatrix
Wonke discussed hormone replacement therapy and fertility and Dr. John Porter presented data
on the treatment of osteoporosis in thalassemia.  Dr. Maria New and her colleagues presented
their findings on diabetes in thalassemia. The final presentation and video shown by Ms. Sherry
Bush emphasized the psychosocial impact of hormone therapy in the thalassemia patient.  A
letter from Ms. Lorraine Alessi-Schiano, a parent of a thalassemia patient, detailing their
experiences during childhood and puberty, was shared with the Panel.


IV.     The following future research efforts emerged for NHLBI consideration.

1. Natural History:  A prospective, longitudinal study is needed to define the natural history of
endocrinopathies in thalassemia.  Such a study would help clarify the relative contributions of the
primary hemolytic anemia and the secondary iron overload to the endocrine abnormalities. 
Particular attention should be paid to patients with E-beta- thalassemia who may have a unique
set of risk factors such as diet and for whom normative data should be carefully collected.  The
increasing proportion of patients in the United States with hemoglobin E-beta-thalassemia and
related syndromes make this group a particularly important part of such studies.

2.  Deferoxamine and Bone Toxicity:  The potential toxicity of deferoxamine on bone growth and
development requires further investigation.  The precise role of the chelator in the bone
abnormalities seen particularly in pre-pubertal patients with thalassemia requires definition, and
the possible contribution of growth hormone therapy to the detrimental effects of deferoxamine
needs further study.

3. Predicting and Detectinq Endocrine Damage:  Studies are needed to define the role of tissue
imaging in the detection and monitoring of endocrine disorders. The relative values of tissue
imaging, tissue iron determinations and other markers of iron overload should be assessed in
regard to their value in predicting or detecting endocrine damage.

4. Fertilityv and Pregnancy:  Issues regarding fertility and pregnancy are particularly important as
the life span of patients with thalassemia increases. Specific issues include defining the rate of
infertility, identifying regimens of hormonal therapy to induce fertility, and studying the outcome of
pregnancy. Additional areas of investigation related to pregnancy include the study of the effect
of pregnancy on iron overload and related organ function, the safety of deferoxamine use during
pregnancy (and, conversely, the dangers of stopping chelation therapy during pregnancy), and
the outcome of infants born to parents with thalassemia after hormonal therapy (e.g., growth and
development, neuropsychologic findings, etc.).

5. Hormonal Replacement Therapy:  Studies are needed to assess the role of hormonal
replacement therapy in thalassemia patients with delayed puberty.  The studies would address
the appropriate timing of, and criteria for, hormonal replacement therapy, the application of new
treatments such as transdermal patches, and cellular and biochemical measures of hormonal
replacement therapy.

6. Osteoporosis:  Osteopenia and osteoporosis have been identified as common complications
of thalassemia that may contribute substantially to the morbidity of the disease.  Investigations in
these areas could be divided into three parts. Phase I studies would identify the optimal methods,
such as bone density scans and histomorphometry, to investigate bone abnormalities.  Phase ll
studies would evaluate the extent of the clinical problem in patients with thalassemia while Phase
lll studies would address possible therapies and the monitoring of any intervention. In addition,
studies of bone disease should look at other possible genetic predeterminants such as vitamin D
receptors that may interact with thalassemia in causing significant bone disease.  The role of
bone disease in thalassemia major and thalassemia intermedia should be compared using
cellular and biochemical markers.

7. Diabetes:  Diabetes remains a particularly important endocrine disorder in thalassemia. 
Suggested studies include definition of the proper monitoring of insulin and glucose
dysregulation, study of the optimal time of intervention, and comparison of various agents in
regard to their ability to prevent or delay insulin dependency.  In addition, the possible
contribution of intensive iron chelation therapy to the reversal of early diabetes should be
investigated.

8. Psychosocial Issues:  Psychosocial issues are an extremely important component of virtually
all endocrine abnormalities associated with thalassemia. The study of these disturbances goes
hand-in-hand with the investigation of etiologies and therapies. In particular, studies are needed
to define the relationship between endocrine problems, self-esteem and compliance with
chelation therapy.  In addition, the impact of delayed growth and sexual development on
psychosocial functioning should be explored.  Cultural and psychological issues affecting
compliance with iron chelation therapy and hormonal replacement therapy require definition.  The
effect of hormonal replacement therapy, pregnancy and other therapeutic and natural events
related to endocrine disorders in thalassemia should be assessed in regard to their effect on
overall psychosocial function including self-esteem, employment, education, etc.


ADJOURNMENT

The meeting was adjourned at 4:00 P.M. on June 3, 1997.


CERTIFICATION

We hereby certify that the foregoing minutes are accurate and complete.




  Alan R. Cohen, M.D.                     Alan S. Levine, Ph.D.
  Chairman                                      Executive Secretary
  Special Emphasis Panel on           Special Emphasis Panel on 
  Hormone Therapy for                    Hormone Therapy for
  Cooley's Anemia                           Cooley's Anemia   
.