Daily megestrol acetate for fertility control a clinical study

DAILY

MEGESTROL

ACETATE

FOR

A CLINICAL

F.

Maruffo**

van Nynatten** V.

*Servicio

de Tocoginecoiogia de Clinicas

STUDY

Stubrin*

C.

**Hospital

CONTROL

Casavilla* J.

B.

FERTlLlTY

P&ez**

de1 Policlfinico

de Ciudadela

“Jose’ de San Martfn”,

Buenos Aires,

Argentina

ABSTRACT Megestrol given

daily

by 41 .5%

of the

was 26%. rate

of 1.2%

bleeding

patients.

patients

(35.5%)

was preserved

which

for a total in 69.9% all

percentage

This

of 252

cycles

cycles. while

Endometrial

during

biopsies

side effect

Menstrual tests

was

cycle were

in 45 in

presecretory

119

length

studied

showed ultrastructural

showed

reasons

a pregnancy

of the treatment

function

biopsies

giving

one or more cycles

(8.5%).

Liver

liver

form was

was accepted

due to medical

3 pregnancies

most disturbing

was present

capsule

treatment

of drop-outs for

The

mg in oil

caused a discontinuation

of the normal,

12 cases.

cycles.

patterns

in 60 changes on day

cycle.

Supported

Accepted

2,938

was responsible

Amenorrhea

and were

in 4 out of

The

failure

in a dose of 0.5

during

per 100 woman-years.

(13.4%)

5 of the

(MA)

patients

patients.

Method

intermenstrual

patients

acetate

to 335

for

NOVEMBER

by Grants

publication

1972

from the Population

September

15,

VOL. 6 NO. 5

Council,

New York,

New York

1972

361

CONTRACEPTION

In order ceptives, (1).

At

this

synthetic This

to avoid

the side effects

o new method for time,

hormonal

Rude1 et al.

progestogen

This

low dose progestogen effect

cervical with

acetate,

usually

prevented

been demonstrated

Since

the first

progestogens,

with

In this

effectiveness

structural

modifications

elsewhere

(9).

cycle

this

type

paper,we

The

patients

at the

were

“Servicio

close to Buenos Aires, well

as lactating

optimal

reference

selected

Argentina. were

economic

and about

level,the

18.7%;

middle,

previous

deliveries. The

total

completed

90%

women were 74.2Yq

AND

Interference

acetate

other

synthetic

and norgestre I,

data concerning

acetate

(MA).

biopsies

will

results

the

Ultrabe reported

is made here.

METHODS

from those attending del

Women

with

the

Family

Policl&ico

Planning

de Ciudadela”

previous

septic

from the program

abortions

in order

as

to obtain

for

all

divided

of patients

only

examination

to the

three

to their

categories:

7.1%.

recruited

for

included

method was determined visit

into high,

In relation

and 15 completed

patients

patient

had a physical

a range of 18 to 37.

literate.

Fifty-six

for the trial

All

patients

socio-

low income, per cent had

was 335.

They

com-

cycles, with an average of 8.7 cycles per patient. patients completed 6 or more cycles; 98 patients

12 or more cycles

was calculated

years with were

and relatively

number

pleted a total of 2,938 One hundred ninety-one

362

and liver

to these

excluded

average age was 22.3

cohabiting

the first

its

and

fertility. The

were

and exerted secretion

type of contraceptive

clinical

of megestrol

de Tocoginecologli

mothers

this

estrogen.

cycle.

contraceptive,

are reporting

MATERIALS

Clinic

the

ovulation

noreth isterone

in endometrial

a short

during

(2,3,4,5,6).

with

of oral

acetate,

and side effects found

Only

a low dose of a

(7,8).

such as megestrol

have been used. antifertility

trial

with

contra-

in 1965

mg) and without

did not inhibit

sperm migration

oral

was started

changes in the endometrial

the hypothalamic-pituitary-ovarian

has recently

a pill

0.5

and continuously

mainly by inducing

mucus which

by conventional

of fertility

proposed using

(chloainone

compound was to be used daily

antifertility

produced

control

24 cycles.

in the study.

the initial

The

The

pregnancy

acceptability

12 months of the study.

and a complete

clinical

history

rate of the

Each taken

during

Clinic.

NOVEMBER

1972

VOL.

6 NO.

5

CONTRACEPTION

The

progestogen

soft gelatin patients told

capsules

started

to take

nation

the treatment

the

intermenstrual

used in this trial

(17 alpha

capsules

bleeding

every

on the

The

antifertility per

patient

by excluding

solution

of MA

0.5

mg in

day

of the

menstrual

The

cycle

and were

ond not to stop in case amenorrhea

All

the

effect

as pregnancies failure

fifth

continuously

occurred.

2 months during

was an oil

acetoxy-6-methyl-6-dehydroprogesterone).

patients

treatment

physical

or exami-

period.

was evaluated

100 woman-years

had a complete

by determining

those pregnancies

the

This rate

of experience.

pregnancy

rate

was adjusted

due to irregular

intake

for

of the

capsules. Endometriol treatment

and

cycle.

biopsies

were

performed

biopsies

were

obtained

in 12 cases between

fixed

in 5%

buffered

glutaraldehyde

Tissues were

for electron and

liver

microscopy.

Liver

serum transaminases

were

function

performed

on 20 patients

tests,

after

6 cycles the

of

8th and

and embedded

bilirubin,

alkaline

on 60 patients

during

10th

in Epon

phosphatase

the

first

3 cycles.

RESULTS Effectiveness There occurred method

was a total

in the failure,

pregnancy

rate

pregnancy

rate,

woman-years. term , healthy Side

first

2 in the was 6.1

In addition, 5th and the other

per

excluding All the babies.

due to patient there in the

100 woman-years

those

women

of experience.

cases due to patient

becoming

failure;

pregnant

these

all

were 3 pregnancies due to 7th cycle. Thus,the overall The

failure,

during

corrected

was 1 .2 per

treatment

delivered

100 full-

Effects Intermenstrual

of cycles making the

of 15 pregnancies

9 cycles.

with

a total

of 29%

percentages

a total

were:

of 15.2%

was severe

enough

longest patients

during

period

of cycles 8.2%

(Table

with IMB.

45 patients

I).

One

1 or more cycles

of amenorrhea

1972

During

treatment

the

first

(BTB) was 13.5%

of cycles with

to cause

discontinued

NOVEMBER

(IMB).

bleeding

of cycles

Amenorrhea amenorrhea

Bleeding

breakthrough

IMB. with

Between

the

BTB and 7%

with

nineteen

for a total

of 252

in 2 women

percentage

spotting

6th and

This irregularity in the (13.4%) to discontinue

hundred

occurring

6 cycles,the and with

12th

16%, cycles,

spotting,

making

menstrual treatment.

patients

(35.5%)

cycles

(8.5%).

was 10 cycles.

cycle

had The Three

for this reason.

VOL. 6 NO. 5

363

CONTRACEPTION

TABLE

364

I.

NUMBER OF PATIENTS AND CYCLES WITH AMENORRHEA

NO. OF CYCLES

NO. OF PATIENTS

1

54

54

2

36

72

3

12

36

4

9

36

5

2

10

6

4

24

10

2

20

119

252

NOVEMBER

TOTAL CYCLES

1972

VOL.

6 NO.

5

CONTRACEPTION

Libido.

One

hundred

libido at some time

during

and the

patients

given

remaining

as the

reason for

Alopecia. reason

for

reason

for

Nervous

patients

drop-out

(38%) complained

Sixty-two

did not notice

Alopecia

interrupting

twenty-eight

the treatment.

(18%)

of reduced

had increased Loss of

any modification.

libido

libido

was

in 7 cases (2.1%).

was significant

in 4 women and was given

as their

the treatment.

Disturbances.

drop-out

in

Irritability,

12 women

Gastrointestinal.

The

depression

and headache was the

(3.5%).

most frequent

symptoms were

nausea and epi-

gastralgia. Breast tenderness a small

Tenderness.

occurred

fibroadenoma

logic

pattern.

in 62

(18%)

Changes

which

in

IUDs;

(32%)

were

removed

increase

reported

that

course.

One woman had

the

breast

and showed a typical

histo-

of 2 to 4 pounds was observed in 33

(10%).

of the cycles, the menstrual

of the

cycles, it was shorter

cycle

length

than 23 days and

33 days. Method.

method,

One

hundred

88 (26%) other

they

preferred

conventional

want

to be bothered

and in many instances, the

reasons for

ninety-six

of them for

due to various

that

some didn’t

than of the

discontinued

patients

In 69.9%

In 14.1%

Acceptability II) and 108

An

patients treatment

loss of 2 to 4 pounds was observed

16%, it was longer

patients

their

was surgically

of Cycles.

was 23 to 33 days.

(10%)

during

in Body Weight.

patients;

Length

Twenty-nine

at some time

The

reasons. with

(58.5%)

medical

contraceptives, different

dropping

reasons

reasons given studies

out could

(Table

by the

either

pills

during

or

the trial;

not be determined

at

all. Special 1.

Studies

Endometrial

Biopsies.

treatment.

The

day 21,

while

proliferative. ined under of the

Biopsies

light the

results

the electron cells

taken

differed

On

when

day 5, the

of a presecretory

fine

showed a well-developed

endoplasmic

reticulum,

and a prominent

The

cells

tions

which

abundant

consisted

cytoplasmic

NOVEMBER 1972

mainly

of the

stromal

presence

of

were

lipid

also

of

on

typically was exam-

structure

endometrium.

biopsies

6 cycles

pattern

the tissue

granules

Golgi.

after

secretory

on day 5 of the cycle considerably

microscope. was that

in 20 patients

showed a normal

samples obtained

These

epithelial

were

microscope

of most These

increased

glycogen

showed modifica-

droplets

and more

organelles.

VOL. 6 NO. 5

365

CONTRACEPTION

w

-

d

366

(u

-

-

c-4

NOVEMBER

1972

VOL. 6 NO. 5

CONTRACEPTION

Liver

2.

Studies.

tion

studies

showed

None (serum

a normal

of the

women

developed

serum

transaminases

bilirubin,

pattern

except

for

a few

jaundice.

All

liver

and alkaline

transient

func-

phosphatase)

and nonsignificant

changes. The

liver

biopsies

by light

a great

biopsies, There

were

a normal

The

number

also

electron of

smooth

was on increase

parenchymo

microscope

in the

with

mitochondria

endoplasmic

of

the

cases studied

in 4 out

crystalline

with

reticulum

number

in all

showed,

megamitochondria

many normal-size

The

inclusions. there

presented

microscopy.

the

of

12

inclusions.

same type

was always

of

proliferated

and

peroxisomes.

DISCUSSION Megestrol more efficient Tablets

acetate

both

containing

contraception The served to

of our 2,938

deficiency,

considered,

(Pearl the

study,

only

resulting

of progesterone were

in

but

is

of ovulation.

recently

used for

pregnancy

for

higher

became

patients

which

can be attributed

with

rate

number

the

of

using

1 .2

obper

100

of pregnancies

method lower

pregnant

effective-

In 335

pregnancy

the total

rate

iseven

of 43 women

contraceptive

occurred

a corrected when

the

solution.

3 failures

However, Thisrate

21 out

in an oil

cycles,

use effectiveness

estradiol

demonstrate

mg MA

index).

to that

and as an inhibitor

(10).

investigation

perlOOwoman-years.

recent

similor agent

and ethynyl

results

dose of 0.5

throughout

method

optimal

results

woman-years 6.1

4 mg of MA

with

ness of a daily

has an action

as a progestational

wos

doses of a daily

is

much higher, MA.

In a

dose of 0.25

In a similar study using oil capsules of 0.25 mg MA there mg MA (11). were 20 pregnancies out of 152 resulting in a pregnancy rate of 13.63 per 100 woman-years method reduced

(12).

and patient the

In both

reports,

failures,

pregnancy

rate

to

same dose was used in tablets a significant

Among

have

them,

Martinez-Manautou

low

figure.

rate

of 4.5

the Zaiiartu

1.3

rate

pregnancies (14)

with

per lOOwoman-years.

of 2Ter

of pregnancies, same group

of

the dose to 0.5 solution,

(13)

due to patient the

same drug

A recent et al.

(26).

nancy

rate

of

per 100 woman-years.

VOL. 6 NO. 5

studies using

the

due to both investigators

mg.

When

the

rate

had

pregnancy

with

(15)

other

chlormadinone

lOOwoman-years.

of 9.3

1972

Foss

of previous et al.

rate

NOVEMBER

The

of an oil

nancy

1 .l

number

by increasing

instead

been a number

a pregnancy

excluding

total

to 4.42.

There mg obtained dex,

increase

the

was considered.

failure,

was 0.2,

using50

CA

acetate

0.5

But the corrected

and dose obtained

study with

progestogens.

obtained

pg norgestrel

in-

an extremely a pregnancy a total

preg-

had a preg-

367

CONTRACEPTION

Recently, 15,939

cycles

Scharff with

ber of pregnancies the

same drug

Index

of

Pearl

Index

(16)

d-norgestrel.

was 4.4

and the

and dose studied

1.05

per

100

to be

Index

norgestrel, data

prevention

becoming

pregnant

a large gators

ent

educated

medical

for

For total o 50.4%

43%

the

drop-out

46%

(11).

durations relation

368

of

Index

acetate

for and

acetate.

of these

These

drugs for the

accidental

The

cycle

patients

one

possibilities

of

of treatment. stopped

due

on the

treatment

and

motivotion

by including

economic index,

where

those

the

have

investi-

standards

of the

government is quite

For these

is

differ-

reasons, we

people

consider

cases who

for

reasons of the

the

the

drop-

treatment

people

growth.

therefore,

only

the

personality

of the

of countries We,

separate

to unknown

low natality

demographic

those

should

discontinue

religious very

attitude.

showed (13)

potients

with

wide

ore

officially

it more valid discontinue

to

treat-

of the

trial.

to duration

figures.

11%

trial

(14).

With With

from treatment

acetote of these

In our opinion, of the

is a very

by Scharff

with

high

index

norgestrel;

of

he obtained

(16).

withdrew

variation

of 48.5%

reported

variable and

norethisterone

The

incidence

figure

of drop-outs

10.2%

152

our

to the

studies was

MA,

the

pregnancies

Pearl

studies, the

7th

of the

depending

a high

with

drop-outs,

incidence Other

using

a Pearl

reasons.

similar

of drop-out

the

of drop-outs

and the

with

acceptability

withdrawal,

the

megestrol

other

cases who

to the

policy,

in o contraceptive

ment

for total

of contraception.

half

cultural,

our figures

the

obtained

norethindrone

13 for

acceptability,

trials

due

countries

evaluate

than

percentages

in different

compare

for

after

from the

as motivation,

from other

num-

mg norethindrone,

progestogens,

and

cycles

method

The

a contraceptive

cannot

more

the

In Argentina,

against

and

most unsatisfactory

decline

reasons

variation as well

0.35

total

Kesserii

12 cycles.

causes.

patients.

acetate

early

investigation,

due to medical

nonmedical

different

as in most of the

in the

In considering out

cycles

woman-yeors

woman-years

was the

apparently

completing

was 0.9.

completing

for the

(19).

as well

occurred

In our

with 100

megestrol

In our trial, pregnancies

before

trial

of pregnancy

index

With

100

women

Index

5,000

(17). per

chlormadinone

that

than

1,969

Pearl

(18).

was 2 per

4 for

indicated

1.3

from

The

more

of 0.6

In a comparative pregnancies

data

corrected

woman-years

was found

and a corrected

total

collected

30 ug

(e.g.,

(NEA)

0.5

the

oil

(12).

was 24%

percentages acceptability

mg CA, the solution In another and with

percentage

of 0.5 0.5

mg CA,

moy be due to the should

mg

short trial,

be expressed

different in

one year).

NOVEMBER

1972

VOL. 6 NO. 5

CONTRACEPTION

The

most disturbing

so important

by itself

intercourse

and was the

percentage

of cycles

Our

results

found IMB

et al.

declines

to 6%.

pill

IMB

had

menstrual women (This the

Almost

receiving drug

frequency

He

spotting

found

after

6th

the

same drug to 26.4%).

in the

norgestrel

in other

women

(13.4%).

cycle

previous

to about in 2.5%

a greater

5th

one-half

of

frequency

a conventional study

(ll),

in 25%

inter-

of the

receiving

In subsequent

except

(14)

Morthez-

incidence

of those

mg.)

15.2%.

et al.

cycle, the using

5%

to

mg CA.

of treatment

in only

The

29%

In another

dose of 0.25

sexual

Zaiiartu 0.5

treatment

cycle

CA but

from

studies.

the

was not

with

receiving

After

d-norgestrel

to be present

hemorrhage

interfered

and dose found

first

or

dropped using

the

of treatment.

in a reduced

Kesserii

in 45

(14.5

present

The

drop-out

found

3 cycles

of spotting

IMB.

frequently

of the women

cases with

NEA,

CA.

15%

all

was used

receiving

declines

first

the

wos

very

for

to those

with

during

spotting

last

IMB

5 cycles

wos the

reason

in about

(13)

in thext

effect

bleeding

main

similar

symptom

Manautou

the

with

are thus

this

side

but

in those

MA.

cycles,

patients

reported

a lower

frequency

of cycles

and BTB

in 3.3%

of

IMB.

of cycles

(17).

study,

Amenorrhea

was a relatively

it was present

at some time

corresponding found l-l

with

.7%

were

to 8.5% low

of all

the

amenorrheic

of cycles

.

similar

with

oil

capsules

results

with

cycles

(11,15).

MA,

Other turbances, sidered in

reported

but

side

in only

treatment

were

variation

in the

in part

patient

about

spontaneous

way

different

for

the

with

(15).

Other 4 patients,

and reduction

of subjective

symptoms

their ore tabulated.

frequency

1972 VOL. 6 NO. 5

were

were

were

for

libido.

in different

discon-

was discontinued

a cause

stopping

The

with great

trials

If one deliberately will

similar of short

nervous

symptoms

to be associated in

with 25-35

on excess

treatment were

thought

the data were collected. symptoms,

These

are

lasted

are

study

between

there

comment

therefore, symptoms

symptoms

were

15.2%

wos normal.

findings

In another

to produce

especial

present

length

progestagens,

in figure

3 patients.

These

cycles

and headache. and,

cycle

(12),

of cycles

These

in only

23 days.

7%

when

those

as MA

amenorrhea

effect

drop-out

had a tendency

deserve

reported

In our

patients, thon

as well

found

side

of the

different

are higher

of cycles.

menstrual

than

72.4%

treatment

frequency

complaints

NOVEMBER

reason

Gastrointestinal

alopecia,

to the

(12),

which

2 cases.

14%

This

shorter

depression

(3.6%).

same drug

50 pg norgestrel

trial

to be due to the

treatment

due

with

effects

the

of the

cycles,

norgestrel

reported

(69.9%)

norgestrel

irritability,

12 women

with

figures the

using

complication.

in 34.6%

These of all

(16)

CA

were

mg MA

treatment

own results.

cycles

In o comparative

days.

(17)

our

cycles

of 0.5

2.4%

and was the

of the

to those

cycles.

(14) with

1 or 2 cycles

74.1%

the (13), Scharff

Kessert’

and Zaiiortu

In most of the Only

all

cycles.

more in accordance mostly

of

doses of CA

common but transient during

be higher

than

is probably asks the if

only

369

CONTRACEPTION

The with

liver

mild

in contrast with

function

alterations with

the

conventional

Those

facts

is responsible with

for

Study

of

features

These

changes

liver

consisted

most of the

Challenge

This

with

cases

finding

is

by many investigators

cases developed

component

of the

jaundice.

combined

steroids

a low dose of CA to women

of pregnancy

Our menstrual

findings of MA

cycle

drug. to

patients

was well

appearance

of a great

In another to induce

on the

of the

tolerated

to our

is an effective an advantage

by

were

not reported.

On

which

was responsible

irregular

the

due to very for

structure

of the

contrary,

this

frequent a high

percentage

our

re-

normal that

has the

irregularities, of patients

the

action

endometrium

steroids,

into

results

the

of

provided

found

fertilized

in our ovum.

use of a low dose

administration especially

such as thrombosis

therapy

menstrual

were

low dose of

some light

Its continuous

contraceptive

the

contraceptive

otherwise

complications

(23).

on day 5 of the

factor,

we can conclude

pills

megamitochondria

changes that

bring found

in the

method.

of

changes.

and dissociated

nidation

Severe

number

suggest

pattern

12 cases,

conventional

CA,similar

of a cervical

over combined

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