SECONDARY

AMENORRHOEA

AFTER ORAL CONTRACEPTIVES FOLLOW-UP

- TREATMENT AND

Rodney P. Shearman Department of Obstetrics and Gynaecology University of Sydney, 2006, Australia

ABSTRACT

Clinical data are presented on 103 patients with secondary amenorrhaea of more than 12 months duration developing after treatment with oral cantmceptives. Four appeared to have a premature menopause; two so far, have radiological evidence of pituitary turnour; in the remainder the level of disturbance was apparently the hypothalamus. The only common abnormality on physical examination was galactorrhoea, which was present in 23 women. Thirty patients had a history of persistent menstrual irregularity before taking oral contraceptives, while five more had had previous episodes of menstrual irregularity. Sixty-eight had a history of regular menstruation before treatment. Twenty-six of 61 treated patients conceived as a result of treatment. Thirty-five underwent spontaneous cure, and in a further 12 patients,owlatory menstruation returned after induced pregnancy. However, 31 had persistent amenorrhoea, and amenorrhoea returned in a further 14 after induced pregnancy.

Accepted

for publication

December

3,

1974

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INTRODUCTION Earlier with oral secondary history reports from this department amenorrhoea (1,2,3). Uncertainty have described durotion a series after of patients and of

of at least 12 months

stopping effects

contraceptives

remains about the frequency modifying

natural

of this condition

and about the possible

induced ovulation This reference effects

and pregnancy. the findings menstrual of spontaneous in 103 patients history, cure, with particular with oral and

paper presents previous prospects

to their

length of treatment menstrual pattern.

contraceptives,

response to treatment,

of induced pregnancy

on the subsequent METHODS

All oral

103 patients

were referred duration, last patient

for investigation appeared after

of secondary

amenorrhoea time

of more than 12 months contraceptives. 1972; in December parity Tables

which

they stopped taking the longest pattern, and

The

in this series was seen for the first is 18 months, menstrual The previous

the minimum length

period of follow-up

period of followup length of subsequent I-III.

now more than 10 years. of treatment, amenorrhoea

at presentation,

type of oral contraceptive,

to the time of presentation

are shown in

TABLE Cycle Cycle before and pority

I before treatment Parity before Treatment

Treatment

Cycle Regular Irregular Irregular

length days months

Number

of patients 73 21 9 (5) *

Parity

Number

of patients 81 16 6 103

26-35 l-3

No pregnancies 1 pregnancy 2 or more

3 months or more Tota I

103

* 3 patients spontaneous patients

had a history return

of 12-18

months

secondary

omenorrhoea

with

to regular regular

cycles before starting cycles followed

oral contraceptives.

TWO

had initially

by irregular

periods and hot flushes

before starting

oral contraceptives.

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TABLE II Length of treatment and of subsequent omenorrhoea at presentation

Length

of Treatment

Length

of Subsequent Amenorrhoea

Months 3-6 7-12 13-24 25-36 37 or more

Number 19 13 40 22 9 -

of Patients

Months 12-23 24-35 36 or more

Number 76 15 12

of patients

103 -

Total

103 -

TABLE III Type of oral contraceptive

Type
Unknown Combined Combined Sequen tia Pi I I (19-nor gestogen) gestogen)

Number

of Patients 9 a4 2 8

Pi I I (17-acetoxy

I
Total

103

No patient gave a history tives. Seven were

had clinical mildly

evidence both before

of contributing and after

organic with - i.e.,

disease. oral

Two

of hot flushes,

treatment

controcepof cloudy

hirsute,

and 23 had galactorrhoea

the secretion

of true and copious milk, secretion from the breost.

not just the ability

to express a small amount

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Each patient up x-rays of the skull

was euthyroid, and pituitory

while

initial

and,

where appropriate, in all but 2 patients.

follawTwo

fosso were normal of pituitary

wamen so far have radiological has been necessary

evidence

tumour and hypophysectomy

in one of these. RESULTS

Potential standardised On days 2,3 ganadotrophins.

ovarian This

responsiveness stimulation i.u.

was studied

in 84 potienk urinary

by o for 8 days. is injected

gonadotrophin and 4, 5000

test (4) augmented

by assay of endogenous oestrogens

test is based on assay of total of pregnant day. This

mare serum gonadotrophin

intramuscularly as o single dose foch potency 0s 225 i.u. of Pergonal . TABLE

has about the same bialogicol

IV stimulation test of Patients

Response to gonadotrophin Response

Number

Nil Normal Excessive Tota I

12 (4) + 53 C(ll) 84 *

+ *

Four with Eleven

premature

menopause before starting treatment had high levels This by induced.

with

gross cycle irregularity

Twelve strong ovarian Fift)rthree level.Ninteen 50 pg

showed no response to this dose. and two of these patients evidence of premature Eight treated

Four of these,

of gonodotrophins, presumptive biopsy

complained

of hot flushes.

menopause has been confirmed of endogenous with clomiphene

in two women.

had law levels defined

gonadatrophins; oestrogens

seven of these were subsequently had a normal of at least 15 pg

and had ovulation in urinary

response,

as an increase

per 24 hours and less than 50 pg response, This

per 24 hours obove the basal of more thon

had on excessive

this being on increase IV).

per 24 hours above the basal level. ovaries

has been shown to indicate

the presence of polycystic

(5) (Table

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luteinising

The response of serum luteinising hormone to an introvenous bolus of hormone releasing hormone to one patient is shown in Figure 1.

LHRH

20&gI./.

Jl
0 30 60 TIME

90

120

(minutes)

Figure 1. Serum LH after intro venous administration of LHRH. had shown a normal response to gonadotrophin stimulation. Results of treatment

This potient

The only treatment relevant is induction of ovulation. It is our practice to attempt ovulation induction only in those women currently concerned by infertility, Sixty-one patients hove been treated, all initially with clomiphene citmte. Thirty-four appeared to ovulate, and twenty-four pregnancies in twentytwo patients resulted. Seven patients who failed to respond to clomiphene were treated with human pituitary gonadotrophins. All ovulated and there were 6 pregnancies in 4 patients. The results are wmrnarised in Table V.

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TABLE Results

V.

of treatment Clomiphene citrate Human pituitary gonadotrophin (HPG)

Number Number

of patients of patients ovulating

61

apparently Number

34

of patients 22 * 4+

conceiving

2 patients

conceived

twice

+2
with

patients

conceived

twice

with

clomiphene

gonadotrophins

Results

of FoIIow-UD These are summarised in Table Vi. Ninety-three patients have been between

followed

up,

the length pregnancy

of follow-up Amenorrhoea in a further

from initial persists 14.

presentation

varying

18 months
after

and 10 years. stil I persisting patients

in 31 patients

and recurred of secondary

induced

The longest episode

amenorrhoea

is 132 months. have undergone menstrual spontaneous after cure, induced and a further pregnancy. 12

Thirty-one have had restoration

of normal

pattern

Two patients

are currently

pregnant,

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TABLE

VI

Follow-up Results Number of Patients

Lost to follow-up Persistence Spontaneous Spontaneous Recurrence Currently of amenorrhoea cure cure after induced after pregnancy induced pregnancy

10 31 35 12 * 14* 2

of amenorrhoea pregnant

* Two patients pregnancy

hod recurrence

of amenorrhoea

after

first

induced

and spontaneous

cure after

second induced

pregnancy.

DISCUSSION It is still not possible to be absolutely amenorrhoea. sure what role the oral At least 6 patients contraceptives

play in the genesis of secondary reasons for amenorrhoea, of pituitary found oral tumaur. patients in other

had coincidental from that to

4 because of presumed premature of these 2 conditions secondary belief at this centre with

menopause and 2 because is no different unrelated

The incidence Our earlier patients with

amenorrhoea

contraceptives. (6). While

(3) that the incidence of oral contraceptive omenorrhoea

of galactorrhoea on subsequent intake are over could be

in these patients analysis represented

indicated

a causal connection a history with secondary

was not supported

in our total

patients of patients.

(6), this

due to bias in referral While causality.

prospective

study of patients (7) found

discontinuing of patients later. of 0.7%.

the pill

gives an index oral in

of the frequency contraceptives

of this problem, still

such studies that 0.8%

by themselves

do not prove definite et al.(8)

Larsson-Cohn

discontinuing Pettersson

had omenorrhoea population

six months

o study of a separate

found a figure

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The only reliable his colleagues stopping with loss. studied (9).

comparative

studies

seem to be those of Fries often

and

They indicate

that the genesis of amenorrhoea multifactorial, menstrual in 16%of causal association irregularity

in patients

oral contraceptives results indicate

is frequently a probable

being associated or weight oral women

a high risk status Their (8). Thirty-four

such as previous amenorrhoea

between

contraceptives

and secondary

amenorrhoeic

patients

had persistently

irregular

cycles

before

taking

oral

contraceptives, by chance. (see Table prior I), Five

and this is probably of the remaining While

a greater

proportion

than would menstrual

be expected irregularity history caution

23 had prior

episodes of menstrual therefore, to exercise

but 68 of the 103 women had an impeccable it may be reasonable, for patients with a history

to treatment. with

in using oral contraceptives patients previously

of irregular

menstruation,

regular

cycles are not immune to this complication. had taken the pill for only 3 to 6 months. between duration of

Nineteen There is no valid therapy

of the patients evidence

in this series of subsequent

of a relationship amenorrhoea.

and the likelihood No positive

significance with complication

can be read into the data in Table the statement (10). be expected that sequential Th e incidence

III except are not taken by

to indicate associated Australia. With menopause, findings in the figure

disagreement with this

preparations

of types of tablets

these patients

are what would

from the sales of various

compounds in

the exception the level indicate with

of the 4 patients ovaries

with (Table

coincidental

premature of This is

of disturbance polycystic that the level

is not ovarian. cf disturbances of oral

both the frequency is hypothalamic.

compatible

IV) and the response shown

to be expected from the site of action The data permit treated had patients, only a chance effect restoration real difficulty by 2 patienk. followed clomiphene, recurrence with restoration

contraceptives. Of 61

some conclusions

to be reached about prognosis. Induced pregnancy following pregnancy

only 26 have conceived. on ultimate prognosis; of ovulatory of giving The first

appears to have 12 patients The very is illustrated

cycles and 14 recurrence prognosis

of amenorrhoea. level with

an accurate

at an individual induced

of these had one pregnancy of amenorrhoea. by spontaneous conceived treatment

clomiphene rather and had course sooner

by recurrence

A second pregnancy with

was induced with

this was followed of amenorrhoea. conceived of ovulatory

cure and pregnancy clomiphene

than she wished. clomiphene,

The second patient during

She did not respond to the second treatment with HPG

and then had spontaneous

periods. available for follow-up, the amenorrhoea persists in 31.

Of 93 patients While

some of this group may undergo spontaneous

cure in the future,

many of

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these have already 11 years secondary experienced

more than 4 years amenorrhoea cure, is 72 months. works with

secondary

amenorrhoea, interval

and 1 of them has who have of amenorrhoea

to date. the longest

Of the 35 patients preceding

spontaneous

we have observed Science to do justice

concepts of averages variety

which

are far too general life (11).

to the subjective

of an individual

REFERENCES

1.

Shearman, Lancet ii:

R.P.

Amenorrhoea (1966).

after

treatment

with

oral

contraceptives.

1110-1111 R. P. with R.P.

2.

Shearman, treatment

Investigation oral

and treatment Lancet

of amenorrhoea i: 325-326 after ii: with

developing

after

contraceptives. secondary

(1968). oral contraceptive

3.

Shearman, therapy

Prolonged

amenorrhoea Lancet

- natural R. P.

and unnatural Diagnostic Br. med. J. R. I. (1966). I.D.

history.

64-66

(1971).

4.

Shearman,

ovarian ii:

stimulation

heterologous

gonadotrophin. 5. Shearman, Gynec. 6. R.P.

1115-1116

(1964). polycystic ovary. Obstet.

and Cox, 21: l-33

The enigmatic

Surv. R.P. oral

Shearman, between J. Obstet.

and Smith, Br.

Statistical 79: 654-656

analysis (1972).

of relationship and galactorrhoea.

contraceptives,

secondary

amenorrhoea

Gynaec. U.

Comm.

7.

Larsson-Cohn, combined (1969). oral

The length

of the first treatment.

three

menstrual

cycles after stand. 48: 416-422

contraceptive

Acta obstet.

gynec.

8.

Pettersson, amenorrhea 117: 80-86 H.,

F.

,
1.

Fries,

H.

and Nillius,

5. J.

Epidemiology rates. Amer.

of secondary J. Obstet. Gynec.

Incidence

and prevalence

(1973). Nillius, 11. S. J. and Pettersson, loss. F. Epidemiology of etiology J. Obstet. of secondary special Gynec. regard 118: 473-479

9.

Fries,

amenorrhea. (1974).

A retrospective and weight

evaluation

with

to psychogenic

factors

Amer.

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1975 VOL. 11 NO. 2

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10.

Macleod, Amer. J.

S. C., Obstet.

Parker, Gynec.

A.S.

and Per/in,

I.A. (1970).

The oversuppression

syndrome.

106: 359-364

11.

Jung,

C. G.

Memories, p. 17.

Dreams and Reflections.

Collins

and Routledge,

London 1963,

132

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