The effect of an oral contraceptive on the pulmonary functions

CONTRACEPTION

THE EFFECT OF AN ON

CONTRACEPTIVE

THE PULMONARY

A.R.

FUNCTIONS

El Heneidy, Y.

Departments

ORAL

Gemei,

M.D. M.D.

A.E.

Abdel-Latif,

H.K.

Toppozoda,

M.D. M.D.

of Chest Diseases and Obstetrics University

and Gynecology,

of Alexandria, Egypt

ABSTRACT The purpose of this work was to study the shorteffects

of a combined

functions.

oral contraceptive

The study was carried

for periods ranging

(Gyn-Anovlar)

on the pulmonary

out on 106 women receiving

of obstructive

or restrictive

There was no statistically

significant

these pills.

pulmonary

dysfunction

difference

between

The present work showed that the effects

pills on pulmonary

functions

This work has been partly

AUGUST

for

1976

were

financed

publication

VOL.

fairly

14

No

was found.

users and non-

users of the pills.

Accepted

the pills

from 6 months to 8 years and the results were compared

with those of 30 normal women who never received evidence

and long-term

of combined

benign.

by the W.H .O.

June

NO.

2

2,

1976

137

CONTRACEPTION

INTRODUCTION The extensive

use of oral contraceptives

the world has focussed much attention laboratory

and clinical

These studies include general

medical

Information

studies have been performed not only the pills’

and metabolic

studies in relation

concerning

tension

phase of the menstrual hormonal

factors,

monary ventilation of progesterone

simultaneous oestrogen (DLCO)

The alterations dogs before

pulmonary

1 mg was given increase

which

subjects

in pulmonary

tensions

and prolonged

diffusing

function,

for 25 days and emboli

(8).

(5,6,7). by the

Intravenous

a small but

capacity

induced (10).

for CO

more than those of untreated

by giving

oestrogens to

When diethylstilboesterol

were released

(RL) and decrease

from peripheral

in pulmonary

veins,

compliance

animals.

that oestrogens stimulate

lung tissues and the pulmonary

Oral

hypercapnia

was found to result in

CO2

progesterone

embolism were studied

were found to obstruct the lung capillaries

an increased

injection

with

(9).

system and cause mobilisation

demonstrated

patients

syndrome,

and alveolar

were found to pass to the pulmonary

interstitial

of the

and in the luteal

intramuscular

in emphysematous

drop in the pulmonary

It has been shown in animals endothelial

Furthermore,

PC02.

of oestrogen with

in lung flow resistance

were significantly

and to

and lowering (l-3)

in 40 mg doses, was found to produce

in male and female

function

neglected.

studies in pregnancy,

response was found to be enhanced

significant

pulmonary

were rather

that hyperventilation

with hypoventilation

administration

statistically

enough,

These observations led to the view that t 4). progesterone, are responsible for changes in pul-

and alveolar

(Premarin),

the pills.

organs but also their

sex steroids on the respiratory

function

and a drop in arterial

The ventilatory

Curiously

) occur during pregnancy

in normal subiects,

and in obese patients hyperventilation

established cycle

on cases taking

on target

of oestrogens to animals.

(PACO

primarily

of women all over

and enormous numbers of

administration

of female

to pulmonary

administration

CO2

effects.

the effects

It has been well alveolar

effects

to oral contraceptive

system is mostly related experimental

by millions

on these drugs,

of hepatic capillaries.

macrophage

(1 l),

Large sized macrophages

and the trapped fibrogenic

the reticulo-

and splenic

effect

cells penetrated

the

of oestrogens was

(12). contraceptive incidence

pills have been blamed

for a possible relationship

of venous thrombosis and pulmonary

embolism

to

in pill

users (13,14).

138

AUGUST

1976

VOL. 14 NO.

2

CONTRACEPTION

The present work aimed at studying Gyn-Anovlar pregnant

on lung functions,

the short-

and long-term

and the results were compared

The present work studied the menstrual

cycle.

AND

METHODS

136 cases; they were studied

They were classified

1.

Group

A

(26 women)

Group

B

(26 women) were on the pil Is for two years. (27 women) were on the pills for four years.

3.

Group

C

4.

Group

D

5.

A control

were on the pills for six months.

(27 women) were on the pills for 6-8 of present or previous

of the same age, groups (Table

parity

the pill

and socio-economic

0.05

cases were subjected

a)

Clinical

b)

Radiological

norethisterone

examination

c)

Electrocardiographic

d)

Pulmonary

function

They had

disease,

and were

oral

oestradiol

studies:

to o preestablished

scheme,

of the chest,

study,

and

tests.

position.

with the apparatus,

Every test was performed

higher

value

of the two tests wos registered.

which

was done only for 23 cases, function

is a combined

3 mg, and ethinyl

to the following

The cases were first acquainted done in the sitting

which

acetate

study; this was done according

pulmonary

or cardiac

group as the other pill-using

users were on Gyn-Anovlar,

containing

All

pulmonary

I).

contraceptive mg.

years.

group of 30 women who never had oral contraceptives.

no evidence

All

in the first half of

into five groups as follows:

2.

Apart

and all tests were

ot least twice,

from pulmonory

all cases were subjected

and the compliance,

to the following

tests:

Lung volumes and capacities: The inspiratory

and the vital

capacity

The functional nitrogen

residual

by adding ture,

capacity (V.C.),

the R.V.

to the V.C.

i)

voluntary

A direct

method,

the expiratory

reserve volume

volume

The total

(R.V.)

was obtained

lung capacity

(T.L.C.)

by deduction

was obtained

Lung volumes were expressed at body tempera-

barometric

ventilation

(E.R.V.)

Lode’s spirometer.

(F .R .C .) was measured by the open circuit

The residual

from the F.R.C.

under the prevailing Maximal

(I .C.),

were measured by using a 9-litre

capacity

washout method.

of the E.R.V.

2.

of

those of

women. MATERIAL

1.

effects

with

pressure saturated

(M.V.V.)

using a closed circuit

was obtained spirometer

with water

vapour.

by two methods: equipped

with a

kymogroph .

AUGUST

1976 VOL. 14 NO. 2

139

CONTRACEPTION

ii)

An indirect

method,

by multiplying

first second (F.E.VT)

by a factor

the forced of 35.

expired

The higher

volume

value

after the

of M.V.V.

in

the two methods was taken.

3. Timed vital capacity:

the volume of air forcibly

one second (F.E.VT)

and three

expired

seconds (F.E.V3)

was measured after

and for the total

time using

Lode’s spirometer.

4.

lntrapulmonary

gas mixing

5. Carbon dioxide

studies:

was measured by the nitrogen

Measurements

of CO2

air were made by means of a rapid infrared The end-tidal CO2 i) ii)

point was considered

washout method.

concentration

analyzer

to represent

in the expired

(Godart

capnograph).

the alveolar

CO2.

Arterial

tension was measured by two methods:

Rebreathing

method.

Astrup’s technique.

6. Dead space and pulmonary ventilation: The respiratory ventilation

(R.M.V.)

calculated

rate (R.R.),

using the following VA =

Where

VC02

tidal

= the volume

equation VCO2

of CO2

7.

while

Arterial 40%

oxygen

oxygen,

a bicycle 8.

the remaining

Pulmonary volume

iii)

soturotion after

ergometer compliance

apparatus.

of total

the specific

performed

on 23 cases:

ventilation

i) at rest,

load maintained

ii) after

was related

5 in the control

group,

breathing using

for 3 minutes. recordings

pressure by means of Godart’s was obtained.

the

dead space (D.C.).

and iv) after exercise

was measured by the simultaneous

compliance

i.e.

(VT),

the physiological

100% oxygen,

When the lung compliance

capacity,

was

per minute.

was determined:

and the introoesophageal

(V.A.)

(ml X 0.863)

part ventilates

with 50-watt

and resting minute ventilation

(15):

expired

breathing

(T.V.)

The alveolar

VA was expressed as percentage R.M.V.,

volume

were determined.

of tidal

compliance

to the functional Pulmonary

5 in group A,

residual

compliance

was

4 in group B,

3 in group C and 6 cases in group D. The results were statistically to compare

by the computer;

1.10

analysed

using the standard

(Student)

t-test

the data of the four groups on the pills with those of the control P values of less than 0.05

were considered

AUGUST

statistically

1976

group,

significant.

VOL. 14 NO.

2

CONTRACEPTION

RESULTS The results of the clinical subject

of o separate

revealed

article.

no abnormalities

study are not discussed here,

Radiologic

that deserve

II,

and comparison

of the results of I .C.,

E .R .V.,

the four groups on the pills with those of the control significant

be the

investigations

mention.

The mean values of the lung volumes and capacities Table

and will

ond electrocardiographic

are presented V.C.

in

and T .L.C.

group revealed

in

no statistically

differences.

Table

III shows the results of the ventilatory

values of T.V., and M.V.V.,

R.R.,

R.M.M.,

VA/Vt,

studies; when comparing

intrapulmonary

we found no statistically

significant

gas mixing,

differences

between

the

F.E.V. the groups

on the pills and the controls. Table end-forced CO2

IV shows the results of CO

CO2,

tension

mean expired

(PaC02),

C02,

studies.

a l2 veolar

and the arterial-alveolar

of the four groups on Gyn-Anovlor

The results of end-tidal

CO2

tension

CO2

(PACO2),

tension

showed no statistically

gradient

significant

C02,

arterial (a-APC02) differences

from those of the controls.

Table

I:

Mean

Control

Age

Mean P Mean

Group

Group

C

D

29.0 (k5.9) > 0.05

31 .o (*

6.5) so.05 5.47

represent

parity

B

(*2.06) ‘0.05

brackets

and

Group

::“,

P Figures within

oge

A

1 (f

Controls

of

Group

28.8 (*4.6)

Parity

values

< 0.05

standard deviation.

31.7 (‘3.1) ‘0.05 5.60 (*1.62) PO.05 P = Comparison

35.1 (*4.2) so.05

($6) <0.05 with

(5% level).

AUGUST

1976 VOL. 14 NO. 2

141

CONTRACEPTION

Table

I.C.

Mean

II:

(ml)

E.R.V.

results

of

V.C.

(ml)

Group

Group

Group

A

B

C

D

1924

1949

1938

(5243)

(h340)

(5 316)

970 (+ 235)

R.V.

R.V.

(ml)

(ml)

T.L.C.

2906

2977

2854

(*400)

(+ 327)

(* 359)

(+

(+

142

98.7

99 10.1)

9;.3)

lnspiratory

I.C.

=

capacity, =Total

> 0.05

11 .7)

(+ K)

2066

2012

2109

2138

2988

(+ 257)

(+240)

(* 395)

(+ 259)

1033

1042

1121

1096

1091

(f 103)

(’ 122)

(+209)

(*241.7)

(‘1166)

(+ *39.8)

(*

(*

(*

(*

97.9 Z)

17.4)

Y79.7)

t:::,

3966

3910

4011

4018

3936

(h299.3)

(k316.4)

(* 379)

(+ 380)

(2 336)

92.4

92.6

6.7)

(+

3.5)

capacity,

96.5

3.97)

(f

26.3

25.8

F.R.C.

100 (f

11.7)

(*245)

(%)

Vital

(5:;)

2900

(*

P

1038 (+296)

(+ 296)

(%ofpredicted)

R.V./I.L.C.

1941 (* 340)

2933

(*

T.L.C.

983 (*294)

(% of predicted)

T.L.C.

1951 (k 261 .4)

(+320.6)

(* (ml)

capacities

Group

(% of predicted)

F.R.C.

and

Group

1012

(ml)

volumes

Control

(+263) V.C.

lung

E.R.V.

= Functional

(*

5.5)

27.7 (*

= Expiratory residual

96.0 (*

7.6)

(+

26.7

5.4)

(*

R.V.

8.1) 27.3

4.7)

reserve volume,

capacity,

94.1

7.8)

(riV.C.

= Residual

4.4) =

volume,

lung capacity.

of all results

of pill

users as compared to those of controls.

AUGUST

1976

VOL.

14 NO.

2

CONTRACEPTION

Table

T.V.

III:

Mean

Group

Group

Group

A

B

C

D

515 65.9)

2.8)

(*856)

l

( 780)

515

50.9)

(f

2.0)

(f

8665 (* 1005)

(+ D.S./T.V.

2:;)

(*

35.4

(%) (+

3.8)

8376

8563 (+980)

5364

5230

(rt733)

(*714.5)

(S ::;,

(k

(*

35.9 (+

4.5)

9290

5711 P680) 63.8

6.2)

(*

36.6

4.2)

2.0)

(3 1060)

63.4

3.7) 35.5

(*

17.0

1 .67)

63.6

(%)

(h 45.0)

16.3 (f

1.7)

(*1170)

5317 ( l 1400)

520

71 .4)

16.0

16.7

5366

(ml)

(+

41.9)

(f

8374

(ml)

529

520 (f

16.8

(Breath/min)

VA/W

studies

Group

(f

V.A.

ventilatory

Group

(ml)

R.M.V.

of

Control

(f R .R.

results

4.1) 36.2

(*

6.08)

(*

4.0)

Distribution N2 washout time

FEV Total

F.E.V.,

time

(min)

2.18 (*

0.41)

(f

:::,

5.9)

(“h>

2.18)

11.9)

{%ofpredicted)

Z2)

$8)

(*

:::)

(3

volume,

(+

12.0)

= Respiratory

11.4)

rate,

F.E.V.

=Maximol

(f

z)

(f

(*

97.2

2.94)

12.4)

5.3)

(f

2.7) 81 .6

(5

11.5)

R.M.V.

= Resting minute ventila-

ventilation, D .S. = Dead space, =F.E.V. after one second, F.E.V.3

no statistical

differences

from those of the controls

Figures within

brackets

VOL.

(*

;:;6) 79.3

6.9)

89.5

12.0)

M.V.V.

1916

81 .O

97.6

2.5)

(’

3 seconds,

represent

(f

92.8 (*

Vt =Total F.E.V.1

AUGUST

(f

(*

85.2

87.0 (*

15.1)

R.R.

3.5) 97.9

tion, VA = Alveolar ventilation, F.E.V. = Forced expired volume, after

(*

81 .3

6.1)

(% 7::)

93.5 (f

=Tidal

23, 2)

82.0 (*

88.0

(L/min) (*

T.V.

(‘t

99.3 (f

M.V.V.

(*

83.8 (f

M.V.V.

0.63)

(sec.)

(%)

F.E.V.3

2.28 (*

voluntary

ventilation.

=

Results showed

at the 5% level.

standard deviations.

14 NO. 2

143

CONTRACEPTION

Table

End-Tidal

PAC02

of

CO2

studies

Group

Group

Group

Group

A

B

C

D

4 4.89 0.36)

4 4.96 0.4)

4 X5)

4 Z8)

(S2)

5.06 4 0.43)

(t X3)

4 Z9)

4 z::,,

(Z:,,

CO2 (%) (* 0.29) 3.05

(t Z2)

4 0.31) 3.02

4 0.37) 2.97

(S4)

CO2

(%)

(mm Hg)

PoCO2

results

Group

(%)

Mean expired

Mean

Control

CO2

End-Forced

IV:

(mm Hg)

i) Rebreath ing

33.8

39.19

33.85

33.7

33.4

p2.59)

& 2.6)

4 2.83)

4 2.5)

(+1.95)

55.9

36.69

36.84

36.6

36.3

(k2.7)

42.27)

4 2.4)

~2.4)

(*2.1)

technique ii) Astrup’s

a-APC02

(mm Hg)

PAC02

= Alveolar

Arterial-Alveolar P > 0.05 Figures

Toble results

37.4

37.4

37.4

42.2)

k2.7)

(*2.4)

(* ::;)

(+ 3.47 1 .85)

(* 3.53 1 .34)

4 Z5)

(Z)

CO2 tension, of pill

PaC02

144

CO2 tension,

a-APC02

=

users OS compared to those of controls. standard deviations.

V shows the mean volues of arterial room air,

room air were analysed,

40%

oxygen saturation. significant

No statistically

significant

and non-users

of the oral contraceptive.

differences

were

and the controls.

VI shows the mean values of pulmonory

compliance.

When the

and 100% oxygen and on exercise

no statistically

found between the groups using the pills Table

= Arterial

gradient.

brackets represent

at rest breathing

breathing

37.8 (* 1 .8)

CO2 tension

of all results within

37.1 (* 1 .8)

differences

AUGUST

compliance

and of specific

were found between users

1976

VOL. 14 NO.

2

CONTRACEPTION

Table

Resting,

V:

Mean

results

of

Control

Group

Group

A

02

Group

saturation

Group

Group

C

D

B

breathing 95.0

96.3

(*0.80)

(+O.w)

a) Room air

b) 40%

Exercise,

1l I) 97.9

97.4

97.6

(51.44)

(*0.97)

98.2

97.9

97.9

(*?$l)

(* 0.40)

@0.63)

(*0.62)

(*0.5)

(%O)

b2.3)

94.5

94.1

(* 1.77)

(* 1.55)

94.3

l

brackets

95.9 4

97.7

of all results of pill

Figures within

96.2 (*0.83)

(*0.80)

(* 1 74)

P >0.05

75.9 (+ 1 .3)

97.5

breothing

room air

~

(10.94)

oxygen

c) lOO% oxygen

users as compared

represent

Table

VI:

93.8

data

Group A

702 (* 186)

98.1

to those of controls.

Compliance

Group (ml)

(*l.O)

standard deviations.

Control

Volume

arterial

Group B

629 (*171)

Group C

537 (*

70)

Group D

710 (5

42)

638 (*

98)

Pressure (cm H20) (*:::6) Compliance

(L/cm

Specific

0.133 (*

H2G) compliance

>

0.05

AUGUST

0.019)

0.009)

of all results of pill

(*Z)

0.130 (*

0.063 (*

P

(*?R)

0.019)

0.127 (*0.02)

0.067 (IfI 0.013)

(zt:::,)

0.129

0.128

(iO.009)

(*0.008)

0.066

0.064

0.066

(*0.006)

(*O.OOl)

(*0.006)

users as compared

1976 VOL. 14 NO. 2

,:::,,

to those of controls,

CONTRACEPTION

DISCUSSION Study of the possible rather

neglected.

example, PC02

of oral contraceptives

studies were performed

a study was done on the effects

(7),

and another on the effect

compliance effect

effects

Few relevant

and airway

resistance

lorge number of short-

that neither Anovlar)

short-

ventilation,

alveolar

Moreover,

no striking

users and non-users were within

CO2 tensions

differences

in pulmonary

was absolutely

ethinyl

pulmonary

testosterone,

the ethinyl

no evidence

ethinyl

oestrogen of Gyn-Anovlar

which

were found between

the specific

prevents

PC02.

the respiratory

an ethinyl

produced neither Winter

and airway

resistance

preparation

there

compliance

is no evidence and airway

thot these might be affected pulmonary

a study performed l.c.,

may explain nor a drop

2) an oestrogen

(C-Quens).

but they did not mention

They

found

the duration

of the steroids.

Although

1) Increased

This

of 9 normal women before and

and 3) a sequential

3) Diminished

stimulant

(16) compared the lung

(1 mg diethyfstilbestrol)

Several

to

the synthetic

group.

(250 mg Delalutin),

changes in these parameters,

failed

hyperventilation

and Sullivan

or

progestogens

He suggested that

of 1) a progestogen

pulmonary

thus

and no restrictive

and dehydroprogesterone,

also contains

in our series.

lung camp ?iance,

of administration

Furthermore,

compliance

after the administrotion no significant

pulmonary

compliance

may be extended to include

why this combined oral contraceptive volumes,

(Gyn-

The values of lung compliance

of the alveolar

progestogens

of Tyler

PC0

pill

(7) found that the synthetic

nortestosterone

suggestion

in the alveolar

in a

oxygen saturation.

of hyperventilation

Tyler

and lowering

group in synthetic

This

functions

The present work showed

and arterial

to the F.R.C.,

dysfunction.

produce hyperventilation effects.

users.

normal (18).

Our study revealed obstructive

on alveolar

Our aim was to study the

pulmonary

of accepted normal for women (17).

was related

was for

on lung volumes,

on lung volumes and capacities,

and arterial

the lower limit

steroids

use of an oestrogen-progestogen

effects

of this oral contraceptive.

when the compliance obtained

on different

and long-term

nor long-term

produced significant

progestogens

synthetic

in nine women (16).

of a combined oral contraceptive

reasonobly

of synthetic

of certain

on lung functions

on human subjects;

in animals

functions

in our laboratory 2) Diminished

M.V.V.,

that synthetic

resistance

female hormones affect

in humans,

yet an evidence

the

exists

(10).

were found changed in normal pregnancy, (2).

F.R.V.,

4) Shortening

in

These were: V.C.,

F.R.C.,

R.V.

of the N2 washout time,

andT.L.C., 5) Diminished

6) Increased R.M.V. caused by augmentation F.E.V.1 and F.E.V.3, and R.R., 7) Increased D.S./T.V. ratio, and 8) Diminished alveolar

of both T.V. and arterial

PCO2.

146

AUGUST

1976

VOL.

14 NO.

2

CONTRACEPTION

The reasons for the difference contraceptive

therapy

as elevation

on pulmonary

of the diaphragm

have no respiratory The serum level

effect

oral contraceptive

levels

of oestrogens or progestogens

None

medication

pulmonary

emboli.

Pulmonary

function

pulmonary D.S./T.V.

ratio

of repeated

pulmonary

The

evidence

possible thrombogenic

arterial a-A

of repeated

of interstitial findings

used when the body weight do not necessarily

Therefore,

if any

value

in the early

in this condition saturation

gradient

(22).

radiologic,

pulmonary

are

and tension, The electro-

in the diagnosis

electrocardiographic

embolism.

in the literature

This does not

about the pills as

is considered

for 21 days alternating thot oral contraceptives

seem to have no cumulative

fibrosis.

fibrogenic (25),

with

electrocardiographic in animals

far exceed

(12)

those in the pills

2) The changes that occur

and 3) Combined

in

oral contraceptives

seven doys of no medication.

are inactivated

or

This is not contradictory

effects

used in animals

apply to humans,

evidence

The data which

radiologic,

pulmonary

of pulmonory

ore taken

combined

occur

functions.

agents.

1) The doses of oestragens

animals

oxygen

PC02

The present work showed no clinical,

because:

use.

’

rise in the

that commonly

(24) are also of great value

to the data available

to the experimental

pill

3)

(19)

embolism.

function

evidence

pregnancy

in pulmonary

main findings

In the present work we found no clinical,

physiologic

emboli

studies have a striking

and increased

(23) and chest radiogram

seem contradictory

during

illness during

diminished

cardiogram

or pulmonary

steroids seem to

they would only be small repeated

thromboembolism. changes,

immensely

Trophoblast

from an acute occurred,

restrictive

female

and oral factors,

steroids of pregnancy,

for some changes

phenomena

of repeated

increased

(20).

embolic

diagnosis

to natural

does not result in a significant

(21) may be responsible

of our cases suffered

pulmonary

of pregnancy

1) Mechanical

2) Synthetic

contrary

hormones increases

while

in pregnancy

the effects include:

in pregnancy,

stimulant

of female

between functions

and excreted

There

ropidly,

is

and they

effects.

the present study provided,

oral contraceptives

on lung functions

showed that the effects

were foirly

of

benign.

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