Effect of a once weekly oral contraceptive upon gonadotrophin and gonadal steroid levels

EFFECT UPON

OF

A

ONCE

WEEKLY

ORAL

AND

GONADAL

GONADOTROPHIN

Donold

R.

Tredwoy,

Daniel

R.

Section

Jr.,

Obstetrics

University

of

of

Los Angeles,

USN*

Biology

and Gynecology

Southern

School

MC

LEVELS

M.D.

Reproductive

of

STEROID

CDR

Mishell,

of

Department

M.D.,

CONTRACEPTIVE

California

Medicine

California

90033

ABSTRACT The group

of

weekly. to

Two

each.

observed majority

in

*United Accepted

an oral

of 2.5

9 and ovulatory

were

with

its

patterns

were

determined

this

mojor

in a

R-2323,administered

mg and 5 mg weekly cycles,

progesterone

cycles

ovulatory,

steroid

progestogen,

In 20 treatment

of treatment

contraception owlation

and gonadol

receiving

dosage schedules

5 subjects

were the

gonodotrophins patients

ovulatory levels

moderately

mechanism

were

once administered

gonadotrophin were

noted

effective

of action

in

levels 14.

method is other

As of

than

inhibition.

States for

Navy

Fellow

publication

AUGUST 1974

in

June

Reproductive 7,

Biology

1974

VOL. 10 NO. 2

159

CONTRACEPTION

INTRODUCTION The development of newer methods for contraception, especially the oral use of progestogens without estrogen, has proceeded rapidly during the past few years. In an attempt to avoid the necessity of daily administration of a progestogen alone a the daily ingestion of the combined oral contraceptive for 3 weeks of each cycle, a new progestogen has been developed that has a moderately

effective

The secretion sively

effect (l-4)

studied,

of

contraceptive combination

and endogenous

action oral

has been found consistancy, inhibit ovulation. In with lower contraceptive efficacy, study was undertaken to determine progestogen

upon gonadotrophin

progestogen

estrogen

steroids production

only

once a week.

upon serum gonadotrophin (5-7)

has been exten-

that these formulations, with a high level of contrast, the daily administered progestogens do not consistently inhibit ovulation. This the effect of this once weekly administered

and gonadal

MATERIALS The

administered

contraceptive

ovarian

It

when

administered

AND

steroids.

METHODS

once weekly

is 13P-ethyl-17a-ethynylThe structure of this trienic steroid with an ethyl group in position 13 is shown in Figure 1. The three double bonds ore believed to enhance the activity of steroids in this series. In animal studies, it has been determined that the compound has a particularly powerful anti-progesterone activity with low or average estrogenic, progestomimetic and pituitary inhibitory activity (8,9). R-2323 has been shown to have moderate contraceptive effectiveness when ingested once per week in doses of 2.5 mg and 5.0 mg (10). 17-hydroxy-gona-4,9,11-t&n-3-one

(R-2323)*.

The study group consisted of 10 healthy, non-pregnant women varying in age Two groups of 5 women each from 24 to 34 years, with regular menstrual cycles. received either the 2.5 mg or 5.0 mg dosage of R-2323 once per week for 8 Serum samples were obtained daily during 1 control (pretreatment) cycle weeks. and the 2 treatment months. FSH, LH, estradiol and progesterone concentrations were measured in each serum sample by previously described techniques (11). FSH, LH and estradiol levels were determined by radioimmunoassay, and progesterone was determined It has been established that the steroids present by competitive protein binding. in oral contraceptives do not interfere significantly with these assays (12). All blood samples were allowed to clot, the serum was separated by centriSince serum samples were obtained fugation, and stored at -2oOC until assayed. throughout a cycle, the samples from each complete cycle were assayed on the An endometrial biopsy was obtained from all 2.5 mg subjects and same day. *Supplied

160

by Hoescht Pharmaceutical

Company,

Raritan,

AUGUST

New

Jersey.

1974

VOL.

lo

NO.

2

CONTRACEPTION

1: 0

\’ 0

AUGUST 1974

VOL. 10 NO. 2

161

CONTRACEPTION

three

of the

5.0

mg subjects,

5-7

days

after

the

fourth

tablet

of

R-2323

was

ingested. RESULTS All and

10 control

steroids

with

progesterone

to more

of R-2323 in the able

range

of the

midcycle

with

(Figure

2,

cycle cating

of both An

and

owlation

apparently peak

secretory

endometrium

owlatory

steroid

This

biopsy

During peak

treatment

was present

cycles

of the

surge

were

(Figure

other

gonadotrophin

progesterone

were

In these

ng/ml

indicating

1.5

A normal

secretory

a basili

during

an owlatory

To summarize mg per

mg per week In each additional present. with

162

these

week

of these

cycles,

5 cycles

with

The remaining

ovulation

results,

(Table

normal

in women

with 2

endometrium.

midcycle

and

absent

were

apparently

lowered

progesterone

without

estradiol

and

were

were

consistently 5,

3 treatment steroid

a non-secretory

biopsies

owlatory

6 cycles

(Figure

ovulatory

treatment

gonadotrophin

in 2 of the

1 of the

gonadotrophin

in both

ovulatory

of ovulation

and

of the

defined

A

A.H.).

cycles

in which

levels.

The

endometrium

obtained

from

with

patients

pattern.

in 2 of the

10 treatment

cycles

during

which

and 4 of the

10 treatment

cycles

during

which

progesterone there

of

had normal

steroid

was ingested,

was ingested,

in

indi-

The remaining

4 had

lack

was found

Neither

and

other

levels

J.R.).

defined

levels

endometrium,

effect.

or following

the

levels

cycle,

of a clearly

3,

cycles

normal

levels

a probable

This patient

was performed.

the

steroid

while

endometrium

showed

steroid

normal

treatment treatment

was bleeding.

of 2 women

*with

4 cycles,

some progestational

2.5

cycles

surge,

levels.

less than

biopsies

The

pattern

cycles,

control

a menstrual

a clearly

cycles

consider-

during second

absence

4 treatment and

with

8 treatment

(Figure

patient

5 mg R-2323,

treatment by normal

There

L.L.).

o midcycle

other

three.

accompanied

4,

a biopsy

with

in both

the

her

was performed.

pattern

while

the

mg

was a clearly steroid

from the

despite

a biopsy

endometrial

was obtained

other

2.5

usually

had no midcycle

after

8 cycles

in 2 of the

in which

had a proliferative

latter

occurred

were

was observed

unchanged

in 3 of the

was found

who

of

with

cycle

there

an anouvlatory

In the

were

control

performed

rise

of treatment

cycles,

progesterone

gonadotrophins

phase

FSH levels

1 subject

endometrium.

gonadotrophin levels

In

biopsy

estradiol

cycle

of the

cycle,

and

endometrial

midcycle

patients

LH.

of both

a luteal

LH and

phase

treatment

estradiol

each

10 treatment

FSH and

proliferative

progesterone that

of

and

women,

follicular

in either

D.T.).

revealed

of both

cr

patterns

peaks

During

In 5 of the

surge

suppression

5 ng/ml.

luteal

surge

ovulatory

in 5 different

fluctuation.

gonadotrophin

had normal gonadotrophin

than

once-a-week

daily

defined

cycles

midcycle

levels

indicative

was an absence

absence

of an LH

9 cycles

had

of anovulation

of a midcycle

peak,

gonadotrophin

owlatory and

LH peak. steroid

steroid

5.0

were obtained. In an

patterns

patterns

were

consistent

I).

AUGUST

1974

VOL. 10 NO. 2

CONTRACEPTION

‘I

P

R 2323

2.5 mg

DT

r

CC~NTROL--+----

Figure

AUGUST

2.

Anovulotory

gonadotrophin

receiving

2.5

daily

cycle

1974

and

VOL.

mg R-2323 days are

10 NO. 2

-

TREATMENT+

and steroid

patterns

were

in a subject

weekly.

Samples

indicated

on the abscissa,

obtained

163

CONTRACEPTION

R t #

2323

2.5 mg

JR

40-

r

is

-300

‘, p. z

-200

: =: 2 0

-

I

IO

20

I

IO

20

I

IO

100

20

~CONTROL-l~TREATMENT----i

Figure

164

3.

Ovulatory

steroid

weekly.

In the

patterns

present.

In the second cycle,

first

in a subject

treatment

receiving

2.5

mg R-2323

cycle, no midcycle LH surge was a midcycle surge took place.

AUGUST 1974

VOL. 10 NO. 2

CONTRACEPTION

TABLE

ANOVULATORY

LH AND

IN 20 R-2323

I

PROGESTERONE

PATTERNS

TREATED CYCLES

ANOVULATORY PATTERN (Progesterone) (LH)

R-2323 DOSAGE (Once-A-Week)

2.5

mg

5

5.0

mg

6 _-____ Total

11

2 4 -----.6

During treatment cycles with both doses of R-2323, examination of the cervical mucus consistently demonstrated a progestational effect. This effect was present even when the gonadotrophin and steroid patterns were consistent with ovulation. DISCUSSION The results of this study show considerable differences in effects on endogenous gonadotrophin and gonadal steroid secretion between different women receiving the same dosage. In the majority of cycles with both dosage schedules of the once-a-week progestogen, R-2323, owlatory steroid levels were found (Table I, Figures 3 and 4). Those steroid patterns were found both with and without discernable midcycle gonadotrophin surge (Table I .)

Other investigators have reported the presence of normal owlatory steroid patterns in urine and serum without the presence of a midcycle gonadotrophin surge in women ingesting low doses of progestogen daily (2,13,14). In the study of Larsson-Cohn et al. (14), in which no midcycle LH surge occurred during treatment with O.-of norethindrone daily, the mean LH secretion was not significantly different from the mean level during the follicular phase of normal Nevertheless, the concentration of urinclry estrogens and plasma procycles. gesterone were similar to normal ovulatory cycles. Conception occurred in 2 cycles with this gonadotrophin and steroid pattern. These investigators postulated that since the minimum secretion of LH necessary to produce owlation is not known, perhaps small changes in LH are sufficient to induce ovulation, or a surge of shorter duration, not observed with once daily sampling.

AUGUST

1974

VOL. 10 NO. 2

165

CONTRACEPTION

5.0 mg

R 2323

01, , I

IO

,

,

,

,

,

,

,

,

20

30

I

IO

20

30

I

IO

1

,

20

30 I

t

-

too -

40

E .

T ,” a z

200

20

,

0 IO C

4.

Ovulatory

20

30

CONTROL+-

gonadotrophin

5 mg R-2323

166

y

100

IO

Figure

1 ;

r! f

5 f 2 a .

I E

300

30

I

IO

20

30

I

IO

TREATMENT

and steroid

20 ------

patterns

0

30

in a subject

receiving

weekly.

AUGUST

1974

VOL.

10 NO.

2

CONTRACEPTION

5.0 mg

R 2323

i

IO

20

IO

I

20

30

AH

40

50

CCONTROL-l~TREATMENT----i

Figure

5.

Anovulatory 5 mg R-2323

gonadotrophin

stead of cyclically

AUGUST 1974

since

VOL. 10 NO.

and steroid

The treatment

weekly.

2

the

patient

patterns

in a subject

days cre listed was amenorrheic

receiving

consecutively during

in-

therapy.

167

CONTRACEPTION

A similar mechanism probably takes place with this progestogen administered once weekly. Since ovulation probably occurs much mOTe frequently than conception during treatment with this formulation, its main contraceptive mechanism of action is probably other than inhibition of ovulation, possibly increasing viscosity of cervical mucus. The higher dosage, 5.0 mg of R-2323, inhibits ovulation to a greater extent than the lower dosage, and clinical effectiveness of the higher dosage is apparently greater than the lower dosage (10). Thus far, it appears that only those steroid contraceptive formulations which consistently inhibit ovulation, such as the combination oral steroid and the high dose injectable progestogen, are nearly completely effective in preventing pregnancy. All other formulations, such as the one studied here, as well as daily administered progestogens, have lesser degrees of clinical effectiveness.

ACKNOWLEDGEMENTS was supported by grants

This investigation the

Hoechst

the

Contraceptive

by the Council,

Pharmaceutical

Development

International New

Company. Research

Committee

York,

New

This

from

work

Program

on Contraception

The

Ford

Foundation

was undertaken sponsored

and

as part

of

and coordinated

Research

of

The

Population

York.

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169