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Report of a workshop: Interaction between oral contraceptives and essential dietary nutrients
REPORT OF A WORKSHOP: INTERACTION
BETWEEN ORAL CONTRACEPTIVES
ESSENTIAL
DIETARY
Helmut Mueller, John J. Schrogie,
AND
NUTRIENTS
M.D. M. D.
National
Center for Population Research Institute of Child Health and Human Development Bethesda, Maryland
Accepted
for publication
September 27,
1971
CONTRACEPTION
A number oral
of
recent
contraceptive
a lesser
degree,
animals
and humans.
vitamin
BT2
relative
vitamin
of
stances
of vitamin
plasma
amino
importance.
which
have a marginal
Child
July
28,
Bethesda,
Maryland.
On
the
basis
populations tryptophan mately
75%
nutrients
of all
is too
cytes);
of
for
their
or tryptophan
small
is uncertain. Froportion
tryptophan fact,
ment of oral
*See
224
of
attached
studies
the
existing
serum
varies
40%
and essential
of
on the
intake.
the oral
basis of
The
effect
to be more common, users
tested.
of different
methodologies
in selected of
tissue
metabolites
and by means of acid
or
contraceptive tryptophan
users. brain
folic
requiring
Possible sarotonin
significance
essential results
(plasma,
status: erythro-
tests using
histidine
pathways,
respectively.
of
these
has been observed decrease
of
pro-
available
depressbn;
is useful
obser-
in a
in serotonin
decrease
and mental
Bo therapy
on
in approxi-
vitamin-dependent
loading
and subsequent
that vitamin
levels
location,
nutritional
compartments
anemia
acid
various
pyridoxine-dependent
oxygenase of
research.
oral contraceptives
assessing
or physiological
know-
and
contraceptive-using
These
standard
megaloblostic
body of
on the other
for
of
Heolth,
nutrients
being observed
Data
Institute of
geographical of
such generalizations.
have suggested
of
Institutes
that
contraceptive-associated
list
National
to survey
Regulating
National
it appears
may lead to depletion
several
met at the
data presented,
the folic
public
populations
by the Fertility
Research,
further
However,
of oml
convened
Population
for
determination
duced by induction
experts*
for
In many cases the biochemical vations
be paid to those
and priorities
formation;
these sub-
may have widespread
directions
levels
to assess
changes in the of
about
to permit
vitamin
quantitative
enzymes
of
was asked
contraceptive
limited
acid,
and an apparent
role
steroids
appears
are based on a number measurement
group
and dietary
metabolism
in
folic
status.
Center
effect
of
with
the fundamental
contraceptive
The
status
A and copper
of
and to
acids
levels
may be interrelated
none to more than
studied.
mcioeconomic
vitamin
of
Bo,
and amino
of
of the
in from
zinc
influences
vitamin
reduced
should
Development
The
important
acid,
include
such findings
a group
ledge on the interaction make recommendations
of
attention
Branch,
and Human
are decreased
levels
nutritional
1971,
folic
copper,
Because
Particular
Evaluation
Health
BT2,
Bg which
acids.
of
observed
biochemistry,
health
On
have suggested
vitamin
increased
in nutritional
Methods
A,
The effects
and zinc,
deficiency
pattern
publications
drugs on the metabolism
in the
in treat-
depression.
participants.
OCTOBER
1971 VOL. 4 NO. 4
CONTRACEPTION
On a more theoretical level, oral contraceptives may influence the formation of melanin and catecholamines by their influence on the folate-controlled, biopterine-dependent sequence of tyrosine metabolism leading to changes in skin pigmentation or cardiovascular dynamics, respectively. The low serum folate, elevated plasma homocystine levels and intravascular coagulation observed in cases of homocystinuria might represent a syndrome analogous to the problem of thromboembolism in oral contraceptive users. It was judged by the group that present knowledge of these metabolic abnormalities in oral contraceptive users does not warrant a recommendation for large-scale dietary supplementation at the present time. However, it was recommended that the problem be investigated comprehensively, with emphasis on nutrition surveys, to determine the prevalence and incidence of these effects in larger populations as well as on studies in animal models to improve understanding of the effects observed. Correlations between recognized adverse effects observed in oml contraceptive users and nutritional status should be investigated. A corollary of the program of investigation should include evaluation of the effects of the steroids on the quantity and quality of milk produced by nursing mothers using oral contraceptives for the prevention of further pregnancies. Other populations warranting particular attention are those women who become pregnant after discontinuation of oral contraceptives as well as those women resuming contraception after a pregnancy. Adverse effects resulting from drug-nutrient intemctions are likely to be amenable to practical preventive and corrective therapy and offer a unique opportunity for the study and control of adverse drug reactions. In addition, further exploration of oral contraceptive-nutrient interactions may form the basis for a more unified understanding of the pa&genesis of the presently bewildering spectrum of seemingly unrelated adverse effects attributed to these drugs.
OCTOBER
1971
VOL.
4 NO.
4
22s
CONTRACEPTION
Fertility
Regulating Center
National
Institute
PLANNING
of
SESSION:
Methods
Evaluation
for Population
Research
Child
Health
ORAL
CONTRACEPTIVES
ROSTER John
J.
Schrogie,
Chief,
Fertility for
National
Institute
and
Chairman
Evaluation
Population Human
Child
AND
VITAMINS
J.
Professor
and Choirman
McGanity,
Obstetrics
Health
of Obstetrics
University
of
Galveston, Dr.
M.D.
Arnold
of Clinic01
Oncology
Advisor
Division
of
Oncology
Pan American
of Wisconsin
Madison,
Wisconsin
C.E.
of
Director
David
B.
Director St.
Division School
Coursin,
Lancaster, 0.
St.
Boniface Boniface,
Executive
Secretary Institute
Rockville
Bethesda,
R.
Streiff,
of
Department New 1249 New
226
York
M.D. of
Medical
Science
Building
Medicine
Room M419 of
Gainesville,
Florida Florida
32601
17604 Mueller,
M.D.
Msficer of
Nutrition
Executive
20014
Fertility
Methods Center
Pike
Maryland
Leonard
Professor
Canada
Professor
National
Evalu&ion
for
Population Institute
and Human A.
Hospital
Manitoba,
Kline
American 9650
General
Assistant
University
Hospital
Lee
M.D.
Hematology
Hematology,
M.D.
Pennsylvanio
20037
Shojania, of
Orgonization
N.W.
D.C.
St.
Helmut Dr.
Street,
Majid
Richard 35233
of Research
Joseph’s
Surveillance
Health
of Medicine
South
Alabama
School
77550
Nutrition
23rd
Director
Medicine
7thAvenue
Birmingham,
A.
M.D.
of Alabama
525
in
Washington,
and
Nutrition
of
University 1919
Jr.,
Medicine
Deportment
School
53706
Butterworth,
Professor
Medical
8, Gynecology
Medical
Schaefer
R.
Rofessor University
Texas Texas
Raymond
Clinical
M.D. of
and Gynecology
Department
Development
Brown,
Development
William
Branch
Research
of
Human
PARTICIPANTS
Regulating
Methods Center
M.D.,
OF
and
Branch
Luhby,
Regulating
Branch Research
of Child
Health
Development
M.D.
Pediatrics of
Pediatrics
Medical
College
5th Avenue York,
New
York
lOc(L9
OCTOBER
1971
VOL. 4 NO. 4
CONTRACEPTION
SELECTED REFERENCES
Aly,
H.E.,
Donald, 86 metabolism.
Oral contraceptives E.A. and Simpson, M.H.: Amer. J. of Clin. Nutrition 24:25r7, 1971.
Baumblatt, M.J. and Winston, 1970, p. 832.
F.:
Pyridoxine
and the pill.
Lancet,
and vitamin
April
18,
Biochemistry and pathology of tryptophan metabolism and its Brown, R.R.: regulation by amino acids, vitamin B6, and steroid hormones. Amer. J. of Clin. Nutrition 24:243, 1971, Craft,
I.L., Wise, I., acid utilization.
Jr., and Briggs, M.H.: Oral contraceptives Amer. J. Obstet. Gynec. 108:1120, 1970.
and amino
Kahn,
S.B.,Fein, S., Rigberg, S. and Brodsky, I. : Correlation of Folate metabolism and socioeconomic status in pregnancy and in patients taking oral contraceptives. Amer. J. Obstet. Gynec. 108:931, 1970.
Luhby, A.L., Brin, M., Gordon, M., Davis, P., Murphy, M. and Spiegel, H.: Vitamin B6 metabolism in users of oml contraceptive agents. I. Abnormal urinary xanthurenic acid excretion and its correction by pyridoxine. Amer. J. of Clin. Nutrition 24:684, 1971. McLean, F.W., Heine, M.W., Held, B. and Streiff, R.R.: Relationship the oral contraceptive and folic acid metabolism. Amer. J. Obstet. 104:745, 1969. Necheles, T.F. and Snyder, L.M.: iated with oral contraceptive Price,
Streiff,
Malabsorption of folate palyglutamates assoctherapy. New Eng. J. of Med. 282:858, 1970.
Thornton, M.J. and Mueller, H .M.: J.M., using steroid hormones for ovulation control. 20:452, 1967.
The influence Rose, D.P.: Sci . 31-265, 1966. R. R. 214:105,
ond oral contraceptives.
J.
Amer.
Med.
Clin.
Assoc.
1970.
Schenker, J.G., Heilerstein, copper and zinc levels 22:229, 1971.
OCTOBER
Tryptophan metabolism in women Amer. J. of Clin. Nutrition
of oestrogens on tryptophan metabolism in man.
: Folate deficiency
between Gynec.
1971
VOL.
S., Jungreis, E. and Polishuk, W.Z.: in patients taking oral contraceptives.
4 NO. 4
Serum Fertil. Steril.
“27
BETWEEN ORAL CONTRACEPTIVES
ESSENTIAL
DIETARY
Helmut Mueller, John J. Schrogie,
AND
NUTRIENTS
M.D. M. D.
National
Center for Population Research Institute of Child Health and Human Development Bethesda, Maryland
Accepted
for publication
September 27,
1971
CONTRACEPTION
A number oral
of
recent
contraceptive
a lesser
degree,
animals
and humans.
vitamin
BT2
relative
vitamin
of
stances
of vitamin
plasma
amino
importance.
which
have a marginal
Child
July
28,
Bethesda,
Maryland.
On
the
basis
populations tryptophan mately
75%
nutrients
of all
is too
cytes);
of
for
their
or tryptophan
small
is uncertain. Froportion
tryptophan fact,
ment of oral
*See
224
of
attached
studies
the
existing
serum
varies
40%
and essential
of
on the
intake.
the oral
basis of
The
effect
to be more common, users
tested.
of different
methodologies
in selected of
tissue
metabolites
and by means of acid
or
contraceptive tryptophan
users. brain
folic
requiring
Possible sarotonin
significance
essential results
(plasma,
status: erythro-
tests using
histidine
pathways,
respectively.
of
these
has been observed decrease
of
pro-
available
depressbn;
is useful
obser-
in a
in serotonin
decrease
and mental
Bo therapy
on
in approxi-
vitamin-dependent
loading
and subsequent
that vitamin
levels
location,
nutritional
compartments
anemia
acid
various
pyridoxine-dependent
oxygenase of
research.
oral contraceptives
assessing
or physiological
know-
and
contraceptive-using
These
standard
megaloblostic
body of
on the other
for
of
Heolth,
nutrients
being observed
Data
Institute of
geographical of
such generalizations.
have suggested
of
Institutes
that
contraceptive-associated
list
National
to survey
Regulating
National
it appears
may lead to depletion
several
met at the
data presented,
the folic
public
populations
by the Fertility
Research,
further
However,
of oml
convened
Population
for
determination
duced by induction
experts*
for
In many cases the biochemical vations
be paid to those
and priorities
formation;
these sub-
may have widespread
directions
levels
to assess
changes in the of
about
to permit
vitamin
quantitative
enzymes
of
was asked
contraceptive
limited
acid,
and an apparent
role
steroids
appears
are based on a number measurement
group
and dietary
metabolism
in
folic
status.
Center
effect
of
with
the fundamental
contraceptive
The
status
A and copper
of
and to
acids
levels
may be interrelated
none to more than
studied.
mcioeconomic
vitamin
of
Bo,
and amino
of
of the
in from
zinc
influences
vitamin
reduced
should
Development
The
important
acid,
include
such findings
a group
ledge on the interaction make recommendations
of
attention
Branch,
and Human
are decreased
levels
nutritional
1971,
folic
copper,
Because
Particular
Evaluation
Health
BT2,
Bg which
acids.
of
observed
biochemistry,
health
On
have suggested
vitamin
increased
in nutritional
Methods
A,
The effects
and zinc,
deficiency
pattern
publications
drugs on the metabolism
in the
in treat-
depression.
participants.
OCTOBER
1971 VOL. 4 NO. 4
CONTRACEPTION
On a more theoretical level, oral contraceptives may influence the formation of melanin and catecholamines by their influence on the folate-controlled, biopterine-dependent sequence of tyrosine metabolism leading to changes in skin pigmentation or cardiovascular dynamics, respectively. The low serum folate, elevated plasma homocystine levels and intravascular coagulation observed in cases of homocystinuria might represent a syndrome analogous to the problem of thromboembolism in oral contraceptive users. It was judged by the group that present knowledge of these metabolic abnormalities in oral contraceptive users does not warrant a recommendation for large-scale dietary supplementation at the present time. However, it was recommended that the problem be investigated comprehensively, with emphasis on nutrition surveys, to determine the prevalence and incidence of these effects in larger populations as well as on studies in animal models to improve understanding of the effects observed. Correlations between recognized adverse effects observed in oml contraceptive users and nutritional status should be investigated. A corollary of the program of investigation should include evaluation of the effects of the steroids on the quantity and quality of milk produced by nursing mothers using oral contraceptives for the prevention of further pregnancies. Other populations warranting particular attention are those women who become pregnant after discontinuation of oral contraceptives as well as those women resuming contraception after a pregnancy. Adverse effects resulting from drug-nutrient intemctions are likely to be amenable to practical preventive and corrective therapy and offer a unique opportunity for the study and control of adverse drug reactions. In addition, further exploration of oral contraceptive-nutrient interactions may form the basis for a more unified understanding of the pa&genesis of the presently bewildering spectrum of seemingly unrelated adverse effects attributed to these drugs.
OCTOBER
1971
VOL.
4 NO.
4
22s
CONTRACEPTION
Fertility
Regulating Center
National
Institute
PLANNING
of
SESSION:
Methods
Evaluation
for Population
Research
Child
Health
ORAL
CONTRACEPTIVES
ROSTER John
J.
Schrogie,
Chief,
Fertility for
National
Institute
and
Chairman
Evaluation
Population Human
Child
AND
VITAMINS
J.
Professor
and Choirman
McGanity,
Obstetrics
Health
of Obstetrics
University
of
Galveston, Dr.
M.D.
Arnold
of Clinic01
Oncology
Advisor
Division
of
Oncology
Pan American
of Wisconsin
Madison,
Wisconsin
C.E.
of
Director
David
B.
Director St.
Division School
Coursin,
Lancaster, 0.
St.
Boniface Boniface,
Executive
Secretary Institute
Rockville
Bethesda,
R.
Streiff,
of
Department New 1249 New
226
York
M.D. of
Medical
Science
Building
Medicine
Room M419 of
Gainesville,
Florida Florida
32601
17604 Mueller,
M.D.
Msficer of
Nutrition
Executive
20014
Fertility
Methods Center
Pike
Maryland
Leonard
Professor
Canada
Professor
National
Evalu&ion
for
Population Institute
and Human A.
Hospital
Manitoba,
Kline
American 9650
General
Assistant
University
Hospital
Lee
M.D.
Hematology
Hematology,
M.D.
Pennsylvanio
20037
Shojania, of
Orgonization
N.W.
D.C.
St.
Helmut Dr.
Street,
Majid
Richard 35233
of Research
Joseph’s
Surveillance
Health
of Medicine
South
Alabama
School
77550
Nutrition
23rd
Director
Medicine
7thAvenue
Birmingham,
A.
M.D.
of Alabama
525
in
Washington,
and
Nutrition
of
University 1919
Jr.,
Medicine
Deportment
School
53706
Butterworth,
Professor
Medical
8, Gynecology
Medical
Schaefer
R.
Rofessor University
Texas Texas
Raymond
Clinical
M.D. of
and Gynecology
Department
Development
Brown,
Development
William
Branch
Research
of
Human
PARTICIPANTS
Regulating
Methods Center
M.D.,
OF
and
Branch
Luhby,
Regulating
Branch Research
of Child
Health
Development
M.D.
Pediatrics of
Pediatrics
Medical
College
5th Avenue York,
New
York
lOc(L9
OCTOBER
1971
VOL. 4 NO. 4
CONTRACEPTION
SELECTED REFERENCES
Aly,
H.E.,
Donald, 86 metabolism.
Oral contraceptives E.A. and Simpson, M.H.: Amer. J. of Clin. Nutrition 24:25r7, 1971.
Baumblatt, M.J. and Winston, 1970, p. 832.
F.:
Pyridoxine
and the pill.
Lancet,
and vitamin
April
18,
Biochemistry and pathology of tryptophan metabolism and its Brown, R.R.: regulation by amino acids, vitamin B6, and steroid hormones. Amer. J. of Clin. Nutrition 24:243, 1971, Craft,
I.L., Wise, I., acid utilization.
Jr., and Briggs, M.H.: Oral contraceptives Amer. J. Obstet. Gynec. 108:1120, 1970.
and amino
Kahn,
S.B.,Fein, S., Rigberg, S. and Brodsky, I. : Correlation of Folate metabolism and socioeconomic status in pregnancy and in patients taking oral contraceptives. Amer. J. Obstet. Gynec. 108:931, 1970.
Luhby, A.L., Brin, M., Gordon, M., Davis, P., Murphy, M. and Spiegel, H.: Vitamin B6 metabolism in users of oml contraceptive agents. I. Abnormal urinary xanthurenic acid excretion and its correction by pyridoxine. Amer. J. of Clin. Nutrition 24:684, 1971. McLean, F.W., Heine, M.W., Held, B. and Streiff, R.R.: Relationship the oral contraceptive and folic acid metabolism. Amer. J. Obstet. 104:745, 1969. Necheles, T.F. and Snyder, L.M.: iated with oral contraceptive Price,
Streiff,
Malabsorption of folate palyglutamates assoctherapy. New Eng. J. of Med. 282:858, 1970.
Thornton, M.J. and Mueller, H .M.: J.M., using steroid hormones for ovulation control. 20:452, 1967.
The influence Rose, D.P.: Sci . 31-265, 1966. R. R. 214:105,
ond oral contraceptives.
J.
Amer.
Med.
Clin.
Assoc.
1970.
Schenker, J.G., Heilerstein, copper and zinc levels 22:229, 1971.
OCTOBER
Tryptophan metabolism in women Amer. J. of Clin. Nutrition
of oestrogens on tryptophan metabolism in man.
: Folate deficiency
between Gynec.
1971
VOL.
S., Jungreis, E. and Polishuk, W.Z.: in patients taking oral contraceptives.
4 NO. 4
Serum Fertil. Steril.
“27