Changes in serum Vitamin A levels during and after oral contraceptive therapy

CHANGES DURING

AND

Isabel

Gal,

IN

SERUM

AFTER

ORAL

VITAMIN

L.R.C.P.,

M.D.,

L.R.C.S.,

Clinical Christine

E.

Institute

of

Queen

Research

Goldhawk

L.R.F.P.S.

L.I.

and

Gynaecology

Maternity Road,

Biol.

Assistant

Obstetrics

Charlotte’s

THERAPY

Lecturer

Parkinson,

Senior

A LEVELS

CONTRACEPTIVE

Hospital,

London,

W.6

ABSTRACT Variations and pregnant The

time

Vitamin these

interval A

levels

findings

Accepted

.1L I,Y

of

1973

for

serum

women

Vitamin

during

which

A

levels

short-term

is required

has also

been

or for

have

been determined

long-term

the

investigated.

oral

chcmges to occur The

in non-pregnant

contraceptive

teratological

therapy.

in the circulating implications

of

are discussed.

publication

VOL.

8

May

NO.

1

1,

1973

13

CONTRACEPTION

INTRODUCTION

study,

In a previous Vitamin

A during

research

into maternal

(2,3),

and

was

environment

the available

Since conducted

develop,

control.

We

ceptives

occurs

is known

can

occur

and have

the

later also

during

at

the

to normal

investigated

Nine

healthy

women

(the

long-term

range

menstrual study

or 21st

cholesterol A,

Vitamin

this method

response

of

to oral

was

A birth

contra-

menstrual

cycles

contraceptives women

for

who

were

Group).

acted

more

All

as controls

than

four

put on the subjects

pill

were

to

months for

the

in the

age

blood

day

and

the

were

and

former The

levels

have

and oml or the

study

14-17

(the

groups) and

from these

been

and

part

three

groups;

tablet-free (the

as well

as the

because

Vitamin

in the

course

were

investigated

A

is that

of oral

-

controls,

luteal

estimation

of this

-

Serum

of the

reported

day

phase

26

at

in each

contraceptive

groups).

significance

groups

occasions

7th day

samples

was included

clinical

in all

ovulatory

long-term

is an integral

investigation (5).

out

on three

control

long-term -

taken

controls,

days

estimated

the

latter

-

between

- study

was carried

were

the

phase

of treatment

metabolism

cholesterol

for both

follicular

groups),

day

sampling Samples

phase

-

camtenoid

Vitamin

A

method

for

takes

part

an

increase

contraceptive

(6). The

menstrual

control

and

long-term

groups

cycles

without

any

modification

long-term

group,

two

cases were

and

1 mg norethisterone

acetate),

2.5

mg lynestranol)

1 case,

thisterone)

14

regular

to as Study

cycle

because

in cholesterol in serum

of

early

levels

concentration,

In the

pattern

long-term

treatment

therapy

METHODS

oml

investigation.

(the

10th

Vitamin

following

AND

also to five

(referred

or treatment

and

this study

raised

years.

of the

five

with

taking

and

trial

controls, and

volunteers

had been

standard

stages

contmceptive

pregnancy.

group),

of 21-28

on day or

who

of the

A all

trend

Study

four

purposes

animals (4).

the

a similar

further

concentration

a similar of oral

which

levels

whether

A

its discontinuation,

during

of serum

that

in experimental

suggests

after

concentration

Vitamin

commencement

interval

subside

a raised

humans

or shortly

time

in the

It was suggested

(1).

to be teratogenic

MATERIAL Non-Pregnant

increase

since

regarding

to its failure,

to determine

an

therapy

important

data

pregnancy

or due

levels

we reported

contraceptive

this problem

in the

therapy,

oral

tablets

and at the

normal

in their using

1 case, Norinyl therapeutic

Minovlar

Minilyn -

1 (0.05

during

existing

(0.05

(0.05

at

least

contraceptive

methods.

mg ethinyl

mg ethinyl

mg mestranol

three estmdiol

estradiol

and

and

1 mg nore-

doses.

JULY

1973

VOL.

8 NO.

1

CONTRACEPTION

Since

the

purpose

a special

experimental

Initially,

their

occasions

at the

additional

then

above

correlation

tablet

the

available

they

taken the

norethisterone

occurred

until

serum Vitamin

because three

the

Vitamin

Vitamin

A

chmges

month

regarding

the

ad

then

effects

after

which

had

controls.

A

all

Vitamin

discontinuation

for six cycles.

Another

woman

stopped

long-term

and

with

this

then

to

until

of two pill

of short-term,

3 mg break-

such

to be modified

on the

As a result,

among

and

because

of treatment,

had been

therapy.

levels,

and

one

continued

A

to continue increase,

requirement

This

content

case

This had

levels.

of

some

estradiol

to one an

course

suggested

mg ethinyl

showed

contraceptive

had

and

cycle

two the

contraception.

and estrogen

It was planned

levels

treatment,

one

and

for one

to pre-treatment in the

stopped

cycles

for one

levels

occurred

cases who

for three

A

returned

pill

(0.05

Minovlar. A

the

group.

cycle,

study

progestogen

factor,

study least

of oral

our previous

Gynovlor

with

own

pattern

time

of the on at

menstrual

of

of the

determined,

as their

content

effect

5 members

were

the

later

was administered

bleeding

investigate

of

intermediate

therapy

the

levels

because

contmceptives.

acetate)

for the

customary

progestogen

through

as the

acted

in the

has relatively oral

A

stages

was chosen

between

this

was to assess the

Vitamin

that

tablet

study

was designed

mentioned

begun,

contraceptive and

this

pre-treatment

advantage

Minovlar

of

method

we

two

the

cycles,

taking

gained

intermittent

Of

cases.

for

time later

the

one pill

information

oml

contraceptive

therapy. Altogether, group the

and

study

of the

we

five group.

A

Three of one

women, of

of

and at

Laboratory

Vitamin

A

modified

cycles; ad

were

18 cycles

eight

for

the

post-treatment

occasionally

long-term

cycles

from

missed at different

stages

serum.

A

carotenoid

end

Serum

whether and

study.

their

serum

end who

They

were

awaiting

had a two-week

Vitamin

A and

course

carotenoids

were

of thempy.

steroids

found

A was then checking these

VOL. 8 NO.

1

with

added

to serum

in the assayed

experiment

method by the

interfere

were

compounds

readings.

by ‘fudkin’s

was analysed

estradiol

levels

Vitamin of

estimated

synthetic

ethinyl

highest

None

of pregnancy,

Investigation

A similar

to the

1973

the

and

cholesterol

The

serum.

daily

were

to the

preparation.

trimester

experimental

carotenoids

acetate

equivalent

first

this

(8).

To establish thistetone

into

Minovlar

before,

Methods

dT;LY

determinations

in their

enrolled

tablet

assayed

end

control

Study

termination,

treated

few

33

19 treatment

cycle.

Pregnant

further

investigated

pre-treatment,

these

serum of those and

the

showed

any

which

wos

of Watson

analyses,

(9).

nore-

in concentrations receiving

result

was carried

(7),

method

compared

out

interference

this

particular

with

un-

by adding

cholesterol

with

Vitamin

the

CONTRACEPTION

RESULTS groups

showed

increased

Vitamin

therapy.

All

Mean

Vitamin

A

for

all

in

1.

A,

carotenoid

Figure

Non-Pregnant Variations of the

Table

I.

is shown The

and

of

serum Vitamin

menstrual

cycle

A statistical

mittent

levels groups

during are

oral

shown

contraceptive in gmphic

form

shown

comparison

in Table

behaviour

and

are

between

cholesterol their

levels

at different

standard

groups at different

deviations

stages

of the

in

inves-

II.

of serum Vitamin

continuous

and

as means with

thempy

for

A

and

carotenoids

individual

cases

during

short-term,

is illustrated

in

inter-

Figures

2,

3,

4. The

were

mean

similar

dividual

Vitamin

to those

readings

ment,

which

later

to those

(Fig.

1). Statistical

between

the

controls,

the

analysis

Individually, Vitamin

A,

but

limited

number

to this

difference. Variations

A.

From all

long-term these

and

differences

Pregnant

levels

studied,

highest

post-treatment

statistically

stages.

levels

After

had

A

not

cycles

inverse

significant

relationship

this

values

trend.

levels

were

of the study

contributed

with

Vitamin

observed

group,

with

The

probably

show any correlation

cholesterol

mean levels

was highly

reciprocate

carotenoid

not

to the

pretreatment

II).

to show an

did

similar

a three-month

subsided

levels

in-

of treat-

discontinuation

showed

to their

(Table

tended

did

cases

cycles

in the

but

none

of

significant.

the

short-term

oml

contraceptive

increased

from a mean

pre-treatment

pg/lOO

ml of serum.

Although

of 50.0

After

in Vitamin cycles

some outstanding

cholesterol

in the

were

values

3 and 4).

returned

group of

Study

During levels

carotenoids

three

treatment

study

observation

initial

Individual A

of the

Close

in the

Vitamin

treated

cycle

1).

(Figs.

completely

mean

and

early

difference

and

combined

groups

level

group’s not

of the

in the the

group

study

cycles

of cases

fluctuations

in the

the serum the

treatment (Fig.

was observed.

but had

untreated

first

group

at a raised trend

observed

interval,

of the

in the

long-term

extreme

settled

fluctuations level

levels

revealed

a declining

tablet-free

A

of the

of therapy,

statistical to interpret,

16

A the

Study

stages tigation

levels

analysis partly

was of only because

borderline

of the

small

administration, value

of 35.6

serum Vitamin pg

this was an increase These

significance. number

of cases

to a mean of 69

studied,

JlJLY

per

findings

1973

A

level

cent, are

and partly

VOL.

a

difficult because

8 NO. 1

CONTRACEPTION

LONG-TERM

GROUP

60 CONTROL

GROUP

40

NON

PREGNANT

STUDY

GROUP

7;’ 60r

60

PREGNANT

r

GROUP

40

20

0 PRE -TREATMENT STAGE

Figure

1.

Mean

serum Vitamin

at various

JIiLY

1973

VOL.

8 NO. 1

POST-TREATMENT STAGE

A

stages of the

levels

for

the

groups

investigation.

17

Treatment cycles

Study Grovp (5) Pre-treat. cycles

Group (4)

Long-term

(9)

ContrQls

GROUP

_

I

f

kl1.8

A83.5

l38.8 *11.4

*71.2

k18.8

43.6

282.6 141.9

46.7

285.1

151.3

*16.1

k82.6 *29.8

*12.0

61.3

Q6.9

+10.9

63.6

57.2

274.1

251.3 140.1

kl3.6

ti2.5

k6.0

*21.3

69.7

34.8

I

’

186.8

*78.7

272.4

I

253.5 139.5

126.8

k37.3

245.3 148.5 *30.8

ti9.5

256.7

i93.4

GO.9

98.0

ti4.6

Ill - Day 26

--l-l

SAMPLE

AND CHOLESTEROL CYCLE

102.3

*24.4

130.1

GO.7

148.9

h8.6

63.0

+29.5

*14.5

I

126.4

A 1 CAROT.

II - Day 14

55.6

30.1

263.6

*13,7

98.5

*.0

34.0

-3.5

261.6

147.6

58.7

*12.9

*13.9

k71.0

ti5.5

*11.41 60.1

45.9

WT.

SAMPLE

254.9 I

I

125.4

CAROT . CHOLESTt iJ9/ l&l ml

I - Day 5

41.4

100 ml

A

SAMPLE

LEVELS OF SERUM VITAMIN A, CAROTENOIDS AT VARIOUS STAGES OF THE MENSTRUAL

P9/

VIT.

MEAN

TABLE

CONTRACEPTION

TABLE

Ii

STATISTICAL ANALYSIS BETWEEN THE MEAN VITAMIN A LEVELS OF THE GROUPS AND BETWEEN VARIOUS STAGES OF INVESTIGATION OF THE STUDY GROUP

_ NO. OF CYCLES CONTROL

GROUP

33

NO. OF ASSAYS 95

MEAN VITAMIN A -f S.D. 42.8 *13.0

\

18

45

62.6/ *14.2

GROUP

33

95

42.8 *13-o

STUDY GROUP (Treatment cycles)

19

46

58.7 > k13.3

5

15

33.9 *12.7

19

46

58.7 > l13.3

8

23

46.2 > *11.8

33

95

42.8 f13.0

8

23

46.2 l11.8

LONG-TERM

CONTROL

STUDY

GROUP

GROUP

PRE-TREATMENT CYCLES TREATMENT

CYCLES

POST-TREATMENT CYCLES CONTROL

GROUP

6.2


3.8


x0.3 1.1

STUDY GROUP (Post-treatment cycles)

.II-LY

1973

VOL.

8 n-0.

1

>0.2

19

CONTRACEPTION

VITAMIN (crq./lOO

A ‘.

ml.1

.,

&/

.-

.-4 ‘,

.-

:

:

R ,’ :

I/ 8

’

:

: i

--•

300

CAROTENOIDS cJLg./rOOml.1 i 0

”

25

”

5

_

14

25

”

5

”

(4

26

u-l-

2.

Short-term contraceptive

20

14 b,

”

25

5 1

14

”

26

2nd

5 1

”

U

MMVOFCVCLE

3rd

PO5T~lR~~~MENT

T%F

Figure

”

5

thempy

using different

types of oral

tablets.

JULY

1973

VOL.

8 NO. 1

CONTRACEPTION

JI’LY

1973

Figure

3.

Intermittent

Figure

4.

Continuous

VOL. 8 i’i0. 1

contraceptive

contraceptive

therapy.

therapy.

21

CONTRACEPTION

of the this

physiologically

stage

declining

of pregnancy

trend

in the

serum

Vitamin

A

concentration

at

(TO). DISCUSSION

This elevated

study

Vitamin

A

the

study

of the

that

group

have

condition

circulating

would

also

the

of

on the serum

that

questions

Vitamin

The

are

that

and

some

cycles,

though ovulation

Vitamin or other

human

may

be due

to the

with

fetal

against Moya in the

22

that

experiments

some of the and

fact

Thomdike

feto-placental

have either

form,

have

harmful (20) unit.

factors Similar

fat

of Vitamin Until

supplementary

these

excess in the

of normal It clarify

Vitamin

have

also

phenomenon,

administration

(13-16)

Vitamin

A

interferes

not protected

environment are

been

JULY

which

A metabolism.

is apparently substances

investi-

menstrual

this question.

risk in the conception

the

at the

is doubtful

for this

could

maternal

soluble

stages with

or recurs

level.

maternal

fetus

early

stages of the

to that

responsible

affect

observations

the

CI connection

o temtological

present

demonstrated,

That

is enhanced.

during

ct raised

or soon after,

that

some

A.

is highly

storage

A

have

contraceptives

The human

(1,ll)

is suppressed

are

preparations

shown

(17,18).

the

levels

pattern

and at

revealed

utilisation

throw

Vitamin

studies

During

(12).

changes

before,

these

A

a similar

metabolic

studies

sex hormones

development

pill

the It

in the

might

to restrict

could

ovulation

non-suppressant

of synthetic

Animal

the

taking

contraceptives.

Vitamin

until

in an exaggerated

oral

oral

chronically

often

occur

circulating either

A

in the

interruption.

which

to Vitamin

cycles

A showed

on ovulatory

Recent

in the

stopping

whether

of

therapy

using

are

changes

in independent

post-treatment

or after serum

a study

observed

is required

the

women

it seems to be advisable

interval

gation,

behavior

clinical

Vitamin

taking

whether

cent

of Resides

as improvement

occasional

per

encountered.

of the

excess

by women

therapy,

of carotenoid

to women

in the

ony

contraceptive

solved,

fluctuations

commencement

but

oral

whether

contraceptive

conversion

A administration

of treatment fact

during or the

since only

a decline

the

the

level.

A were

none

observed

with

of

cycles

mean

to investigate

harm,

years

that

are

mean

was 46.3

of Vitamin

tissues,

levels the

treatment

contraceptives,

epithelial

altered

showed

of the

In some cases,

is without

of the

than group

pre-treatment

has been

to establish

mechanism

is impaired

these

A

A during

carotenoids

suggestive A

Vitamin

level

A

study,

higher

levels

be advisable

childbearing

be important

or storage light

Vitamin

cent

their

of oral

nails

still

Vitamin

long-term

mean

above

on the

skin and

their

the

effects

effect

hair,

per

of the

A intoxication.

It would

throughout

and

serum

In CI previous

no pathological

side

a beneficial of the

level

per cent

Vitamin

that

was 77.5

mean

controls

reported

contraceptives. raised

cases

increases,

suggest

finding

contraception.

the

was 73.2

From the symptoms

pill

pill

of the

considerable

could

our previous

of oral

In this study, than

these

course

level

controls. higher

confirms

in the

(19).

freely made

1973

AS

transmitted in an ex-

VOL. 8 NO. 1

CONTRACEPTION

perimental when

study

study

also

liver

Vitamin

(22).

The

maternal

A

liver

concerned the

gmdually

Vitamin

A decreases

during

Vitamin

first

of pregnancy,

could

interfere This

from

A

study

subsequent

the

supports

a treatment-free

interval

this

in the

in the

first the

trimester

needs

may

still

be taking

pill,

However,

conjecture

there

12th

it would

of oral

week in-

during

or may

in our

female

protection the not yet

is a possibility

as shown

that

the

further

is that

discontinuation

with

ml by the

the

During

of pregnancy

is a physiological

contmceptive

our

established,

of pregnant

oral

of pregnancy,

yet

environment.

levels

changes,

of

susceptible

contraceptive

Compared

ml,

hormonal

effect

is not

maternal

decline

pattern.

previous

oml

20.3pg/lOO

physiological

between

the

in certain

the

effects.

stage

thempy,

in both

that

pregnant

be advisable

contmceptive

group,

to have

tablets

and

pregnancy.

Nevertheless, any

a woman

at

and

of other

fetal

gestation

teratological

teratology

p&O0

trimester

as regards

its delayed

levels

with

first

of

contraceptive

hazard

3rd trimesters.

of 40

at 6 weeks result

importance

2nd and level

this

A or is the Its

recovered

the

ml

Whether

vestigation.

Vitamin

levels

serum

(10).

raised

in human

non-pregnant

the

or soon after,

A

maternal

to 36 pg/lOO

be fully

during,

Vitamin

A

increases

trimester

of

oml

observed

a possible

Vitamin

women against

discussed

raised

average

drop

we

about

population’s of pregnancy

occur

role

increases

12 weeks

were

unit,

A sepamte

studies.

and suggested

conception

(21).

pregnancy

first

following

in independent

materno-fetal

embryo

in early in the

is that

(l),

human

the

A concentration

communication

the

in the

per cent

findings

Vitamin

A

reaches

therapy

by 26

A environment

should

pregnancy,

contraceptive

fetal

Although

are

readily

of

previous

individuals,

Vitamin

A

of these

increases

Vitamin

therapy.

of

that

importance

In our

transfer Vitamin

concentration

serum and

altered

and

that

indicated

corresponding

we

on the

it was found

our observations

recommendation

on the

length

indicate of this

the

interval

need

for

large-scale

studies

before

is suggested.

ACKNOWLEDGEMENTS This

work

Our

thanks

R.A.M.

Burt for We

also

.lU,Y

has been

the

are

due

their

1973

VOL.

to

help

wish to thank volunteers

supported

Professor

8

kindly

NO.

Medical

C.J.

Research

Dewhurst,

Mr.

Council. S.

Campbell

and

Mrs.

and encouragement.

Mrs.

who

by the

Finella

Tapping

participated

1

for

her farreaching

in this study.

assistance,

and

CONTRACEPTION

REFERENCES 1.

Gal, I., Parkinson, C. and Craft, I.: human plasma Vitamin A levels. &it.

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