A L MAGOS, M BRINCAT, J W W STUDD
Abstract
The hypothesis that the many non-specific changes normally
associated with cyclical ovarian activity are the primary aetiological
factors in the premenstrual syndrome was tested by
suppressing ovulation with subcutaneous oestradiol implants.
Sixty eight women with proved premenstrual syndrome were
treated under placebo controlled conditions for up to 10 months
in a longitudinal study. Active treatment was combined with
cyclical oral norethisterone to produce regular withdrawal
periods. Symptoms were monitored with daily menstrual distress
questionnaires, visual analogue scales, and the 60 item general
health questionnaire. Of the 35 women treated with placebo 33
improved, giving an initial placebo response rate of 94%. The
placebo effect gradually waned, but the response to the active
combination was maintained for the duration of the study.
Analysis of the prospective symptom ratings showed a significant
superiority of oestradiol implants over placebo after two months
for all six symptom clusters in the menstrual distress questionnaire.
Changes seen in the retrospective assessments were less
significant but the trend was the same.
Treatment with oestradiol implants and cyclical progestogen
was well tolerated and appears to be both rational and effective
for severe cases of the premenstrual syndrome.
Introduction
All aspects of the premenstrual syndrome remain subjects of much
controversy.' Nevertheless, in the confusion concerning definition,
diagnosis, aetiology, and treatment five observations appear to be
salient. The premenstrual syndrome is associated with cyclical
ovarian activity and does not occur before puberty, during pregnancy,
or after the menopause. Menstruation itself is incidental, as
cyclical symptoms continue after hysterectomy, provided that
ovarian function is conserved.' Most healthy women report adverse
symptoms before menstruation.4 Extensive metabolic and psychological
studies have failed to find a specific abnormality in the
premenstrual syndrome.' Lastly, the condition shows a strong
response to placebo. While the factors concerned in responsiveness
to placebo are extremely complex,6 the evidence none the less
suggests a primary role for cyclical ovarian activity in pathogenesis.
That the ovarian cycle is associated with such profound effects
should not be surprising. Many physical, psychological, and
behavioural changes affecting all body systems occur during the
normal menstrual cycle. Furthermore, the premenstrual syndrome
is only one of many disorders that regularly fluctuate with ovarian
activity; examples include migraine, epilepsy, rheumatoid arthritis,
diabetes, and asthma. The corollary of considering cyclical ovarian
activity as fundamental in the aetiology of the premenstrual
syndrome is that suppression of ovulation should abolish symptoms.'
Anovulation may be achieved by subcutaneous implants of
oestradiol (Organon Laboratories)9 combined with cyclical oral
progestogen to ensure regular withdrawal periods and prevent
endometrial hyperplasia. "' The benefits of that approach have been
reported in a retrospective study." This paper presents the results of
a prospective randomised controlled study of oestradiol implants
and cyclical oral norethisterone in the management of the premenstrual
syndrome.
Patients and methods
Study design-As there is no standard treatment for the premenstrual
syndrome and the condition shows a strong response to placebo,' the study
treatment was compared against a placebo. A parallel study was appropriate,
as subcutaneous oestradiol implants are long acting preparations with
biochemical activity lasting over 12 months." We find that the therapeutic
benefit is maximal two to four months after implantation and that the
response generally wanes after five to six months, when the implant is
repeated.' Hence we planned to monitor treatment over two consecutive
implants with special emphasis on months 2-4 and 8-10. Patients were
reviewed every three months and given fresh implants when symptoms were
returning. All those who were not sterilised were advised to use nonhormonal
contraception throughout.
Patients-Women who fulfilled the following criteria were recruited from
the premenstrual syndrome clinic at Dulwich Hospital: (a) age 25-45 with
regular periods and a cycle length of 24-32 days; (b) not using drugs that
affect ovarian function; (c) not suffering from other medical or psychiatric
condition; (d) family complete; (e) normal pelvic organs on clinical
examination; (f) agreeable to treatment with hormone implants; (g) prepared
to monitor symptoms daily during the study; (h) a complaint of premenstrual
distress for at least the past six months; and (i) confirmation of the
diagnosis of the premenstrual syndrome on prospective daily symptom
rating for at least one ofthe six symptom clusters studied. Of 132 consecutive
patients referred to the clinic during the study period, 68 fulfilled these
criteria and were entered into the study.
Treatment-Eligible patients were treated under double blind conditions,
such that neither the patient nor the assessing physician was aware of
the allocation. Treatment was randomised by a second physician, whose
role was to dispense the appropriate implant and progestogen. Allocation
was based on random numbers, equating odd numbers with active
and even numbers with placebo treatment. Blocking in groups of 10
was incorporated to minimise imbalance in allocation. Treatment was either
a 100 mg subcutaneous oestradiol implant and 5 mg oral norethisterone for
seven days per cycle (oestradiol group) or placebo implant and 5 mg placebo,
identical in appearance with the active drug, for seven days per cycle
(placebo group). Implants were inserted deep into the subcutaneous tissue
of the anterior abdominal wall using the technique of Thom and Studd. "
The timing of tablets was adjusted individually depending on the length of
the menstrual cycle, such that the last tablet was taken two days before the
next expected period. Implants were repeated if the assessing physician
judged on interviewing the patient that symptoms were returning or had
failed to respond to the first implant.
Assessment of symptoms-Symptoms before and during treatment were
monitored using three parameters. Daily symptom ratings were obtained
using a modified Moos menstrual distress questionnaire consisting of 34
adverse symptoms in six symptom clusters (pain, concentration, behavioural
change, autonomic reactions, water retention, and negative affect) scored
daily on a scale of 0-3 (no symptoms to severe symptoms).'4 While
recognising that conclusions drawn from the analysis of symptom clusters
cannot be applied directly to isolated symptoms, this approach is appropriate
for a condition typically associated with numerous non-specific
complaints, as it reduces the need for multiple statistical testing. A 100 mm
visual analogue scale was also completed at each clinic visit to describe how
the women -had been feeling since their last attendance (O=very well to
'100=very'unwell).'5 Lastly, the 60 item general health questionnaire was
applied at each visit as a non-specific screening tool for current psychiatric
morbidity'6; a score was obtained by counting the number of items for which
morbidity was said-to be increasing. Weight, blood pressure, menstrual
pattern, changes in medication, side effects, complications, and reasons for
stopping treatment prematurely were also recorded by the assessing
physician.
Statistical methods-The total daily ratings for each of the six symptom
clusters in the menstrual distress questionnaire during the pretreatment
cycle and every second cycle after treatment (cycles 2, 4, 6, 8, and 10) were
assessed by trend analysis. '7 This provides both qualitative and quantitative
statistics concerning chronological data, in this case symptoms during the
menstrual cycle. Records were analysed provided that no more than three
days of values were missing in a cycle. Qualitative analysis of the pattern of
symptom trends before treatment was used for diagnosing the premenstrual
syndrome (eligibility criterion (i)); the syndrome was defined as a condition
associated during the menstrual cycle with (a) significant (p<005) positive
(worsening) symptom trends during the 14 days before menstruation and at
no other time in the cycle; and (b) significant (p<005) negative (improving)
symptom trends some time after the onset of menstruation and at no time
after the presence of significant positive trends (fig 1). Quantitative analysis
was used to provide three indices of the severity of symptoms before
and after treatmnent-namely, the maximum and minimum exponentially
smoothed averages;'representing peaks and troughs in symptoms, and the
mean symptom score during the cycle (fig 1). These indices were calculated
for the six symptom clusters in the menstrual distress questionnaire and for
all symptoms recorded. The.effect of treatment on these three variables was
assessed by the Kruskal-Wallis test (within groups) and, using the difference
between scores before and after treatment, Wilcoxon's rank sum test
(betweengroups).-Data fromthe visual analogue scale (without transformation)
and general health questionnaire were analysed by similar nonparametric
techniques. Other variables were assessed using one way analysis
of variance (within groups) and the unpaired t test and x2 test with Yates's
correction (between groups). All statistics were two tailed. A significant
difference was defined as p<0 05.
Power calculation-Trial size was estimated by considering that 90% of
the cases would improve with active treatment and 50% with placebo and
accepting a type I error of 5% and a type II error of 10%; with this calculation
the required number of patients in each treatment group would be 23.
Allowing for the length of the study and the pharmacokinetics of implant
treatment, we decided to continue recruitment until roughly that number of
cases had been treated for at least four months.
Results
The characteristics of the two treatment groups, including baseline scores
from the menstrual distress questionnaire, visual analogue scale, and general
health questionnaire, were similar except for a significantly higher mean
diastolic blood pressure in the placebo group (unpaired t test: df=66;
t=2-96; p<001) (table I). The average duration of follow up was also
comparable, with 5-5 (SD 3-2) and 4-9 (2-7) months respectively for the
women treated with oestradiol and placebo. There were no drop outs from
the group receiving oestradiol. Conversely, two women given placebo
stopped treatment after three months because they thought that the implant
had failed to help their symptoms, while a third failed to attend for follow up
at six months.
Daily symptom ratings-Six of the 91 (6 6%) menstrual distress questionnaires
in the oestradiol group and eight of the 81 (9 9%/o) in the placebo group
were inadequate for analysis. Symptoms generally improved at the start of
treatment with both oestradiol and placebo, as denoted by a fall in peak and
mean daily ratings (figs 2 and 3). While the benefits of active implants
were sustained, resulting in a significant improvement in all symptom
clusters during treatment (Kruskal-Wallis tests: df=5; 12 9<X'<40S5;
00001<p<0-05), the placebo response tended to wane during the study
period and the overall effect was not statistically significant for any of the
clusters (Kruskal-Wallis tests: df=5; 1 l<X2<9-0; p>01). Changes in
trough symptom scores were variable after both treatments (fig 4), a
significant and maintained reduction occurring only for negative affect after
oestradiol implants (Kruskal-Wallis test: df=5; j'=11-9; p<005). Comparison
of the two treatments showed superiority of the active combination
over placebo at all times and for all variables (table II). The improvement in
total scores in the menstrual distress questionnaire were consistantly
significant after the first two months of the study for peak and mean daily
symptom ratings (Wilcoxon's rank sum tests: 0-001 <p<0-05). Differences
in the minimum exponentially smoothed average were smaller and reached
significance only at four months (Wilcoxon's rank sum test: p<001).
Individual comparisons of the six symptom clusters showed that the efficacy
of oestradiol applied to all complexes, with greatest benefit on pain,
autonomic reactions, water retention, and negative affect (for example,
Wilcoxon's rank sum tests 0O001<p<Ol at four months for maximum
exponentially smoothed average and mean daily ratings). Once more
changes in the minimum exponentially smoothed average generally failed to
reach the 5% level of significance compared with placebo.
Visual analogue scale-Irrespective of the treatment all but four women
reported an improvement in symptoms throughout the study, scores on the
visual analogue scale being reduced by on average 41-54o (table III). The
exceptions included two members of the oestradiol group (one at six months
and one at nine months) and two treated with placebo (both at three
months). Overall, the reductions in visual analogue scores were significant
for both oestradiol (Kruskal-Wallis test: df=3; x2-=503; p<0001) and
placebo (Kruskal-Wallis test: df=3; x2=55 6; p<0001). Although active
treatment was associated with the greater fall in visual analogue scores at all
times, the large interpatient variability in measurements and the relatively
small number of observations later in the study meant that the comparison
with placebo failed to reach statistical significance (Wilcoxon's rank sum
tests: p>O-1).
General health questionnaire-Similar results were obtained from analysis
of the 60 item general health questionnaire. Both treatments were followed
by significant reductions in scores early on, but by nine months results in the
placebo group were worse than before treatment (table III). Nevertheless,
the treatment effects were not significantly different because of the large
scatter of the data (Wilcoxon's rank sum tests: p>0. 1).
Other variables-Of the women who had tried conventional treatments,
30 out of 30 receiving oestradiol and 27 out of 32 (84-4%) placebo considered
implants to be more effective (Yates's X2 test: df= 1; x'= 1-92; p<02). The
average number ofimplants dispensed during the study was similar for both
treatment groups, being 2-1 (SD 0-51) for oestradiol and 2-0 (0-48) for
placebo. For the 67 women who had more than one implant during the study
the average interval between implants was 5-6 (SD 1 -6) and 5-0 (1-6) months
for oestradiol and placebo respectively (unpaired t test: df=65; t= 15;
p<O2). There were no significant changes in weight or blood pressure
during the study.
Side effects-Both treatments were well tolerated and side effects were
usually mild and transient. Most common complaints in the oestradiol and
placebo groups included mastalgia (nine and two cases respectively), nausea
(three and four), weight gain (five and none), and headache (two and three).
Menstrual pattern remained unchanged or improved for most women. In
particular, there was a tendency for period pain and flow to decrease with
active treatment. Onlv two women receiving oestradiol and four placebo
reported episodes of irregular bleeding.
Discussion
Several important observations are evident from our study.
Firstly, even carefully selected women suffering from the premenstrual
syndrome usually show a significant response to placebo,
certainly early in treatment. The immediate response to placebo in
our study was 94%, all but two of the 35 women receiving a placebo
implant reporting improvement during the first three months. This
is much higher than the often quoted 50-60% and, indeed, larger
than the maximum rate reported (89%). The duration of the
response varied, but on average the daily symptom ratings, which
are generally considered to be the most accurate index of symptoms,
returned to pretreatment scores by six months. The response to the
subsequent placebo implant appeared to be weaker and of shorter
duration (figs 2-4). Though the "surgical" nature of the treatment
may in some way account for such a potent placebo response, we
must assume that psychosocial factors play an important part in this
condition. Many of these patients admit to problems with personal,
family, and sexual relationships in particular, and it is this aspect of
their distress that we believe responds to placebo.
Despite the extent of the placebo response, subcutaneous
oestradiol implants with cyclical oral norethisterone proved to be
the progestogen. Controlled studies have failed to find that
norethisterone, or indeed other progestogens, are successful for
any but isolated symptoms of the premenstrual syndrome.' Conversely,
implants of 100 mg oestradiol have been shown to be
highly effective in the management of the syndrome. Though the
retrospective ratings (visual analogue and general health questionnaire
scores) failed to distinguish between the treatments, their
infrequent application necessarily means that they represent the
weakest index of treatment effect. Conversely, the improvement
seen in daily symptom ratings with oestradiol was statistically
superior after the first two months, and this difference applied to all
symptom clusters. To our knowledge this is the first treatment
subjected to a large scale controlled study to have been found to be
successful in relieving the typical complaints of the syndrome. Our
results support those of the pilot retrospective study, which, in
addition, showed that the treatment was well tolerated after
prolonged use." In that study lower doses of oestradiol were
generally dispensed after the initial 100 mg pellet without loss of
effect, and this is to be recommended in the long term to avoid
hyperoestrogenaemia.
We attribute the efficacy of our treatment to suppression of
cyclical ovarian activity by the oestrogen rather than any effect of
contraceptive-though not immediately, as pregnancies may occur
during the first six months.' We have also found that follicular
activity and luteinisation continue in some cases during the first few
months (unpublished observations). Incomplete suppression of
ovulation early on may partly explain the inferior response at two
months.
Ovulation may be suppressed by other therapeutic manoeuvres.
The combined oral contraceptive pill may not only be contraindicated
in this age group but, though the definitive study has still
to be done, is probably effective in only half or so of cases.' The
reason may be that the benefits of anovulation secondary to the
oestrogen component are negated by progestogenic side effects
which are similar to the typical complaints of the premenstrual
syndrome.''" Furthermore, the cyclical nature of the pill regimen
is itself associated with hormonal swings. Crystalline implants of
"natural" oestradiol not only provide a continuous source of
oestrogen but do not have the potential cardiovascular complications
of "synthetic" oestrogens; implants are already widely and
safely used for the treatment of climacteric complaints.'9 Giving
norethisterone for a shorter duration each cycle may account for the
better tolerance with our treatment, though we have seen women
who are extremely sensitive to progestogen. Such patients may
improve with reduced dosage or other progestational agents.
Ovarian function may also be inhibited by danazol. Recent trials
have reported favourably on certain symptoms (D H Gilmore et al,
paper presented to 11th World Congress of Gynecology and
Obstetrics, West Berlin, 1985). Danazol, however, appears to be
poorly tolerated and is associated with a considerable drop out rate
because of androgenic and other side effects. Gonadotrophin
releasing hormone agonist has been used to produce reversible
"medical ovariectomy" and relief of premenstrual distress but, as
pointed out by the authors, the low levels of oestradiol release
induced precludes its long term use.-' Oestradiol implants are both
well tolerated and also maintain plasma oestrogen concentrations in
the normal to high follicular range."
In conclusion we have shown that subcutaneous implants of
oestradiol combined with cyclical oral norethisterone is of definite
benefit for the premenstrual syndrome. Taken in conjunction with
the degree of placebo responsiveness shown by these patients, we
hypothesise that the primary event in this condition is ovarian
activity with its associated physical, psychological, and behavioural
changes, which, in this group ofwomen, are amplified secondary to
psychosocial factors or as yet undetermined central mechanisms.
Despite arguments about the importance of"reproductive biology"
in the genesis of psychiatric morbidity2' 2 there seems little doubt
that the hormonal and other changes associated with the ovarian
cycle have profound effects on both the soma and the psyche, effects
that may logically be controlled by manipulating ovulation.
We thank all our colleagues who helped in the premenstrual syndrome
clinic, including Laila Hanna, Tim O'Dowd, Maggie Blott, and Julia
Montgomery. We are also grateful to Linda Abbott and Trish Waghorn,
whose administrative and secretarial work was essential; and, finally, to
Sister P A Fryer and other members of the nursing staff who prepared the
implant sets for the clinic. This work was supported by a grant from King's
Voluntary Research Trust.
References
I Magos AL, Studd JWW. The premenstrual syndrome. In: Studd JWW, ed. Progress in obstetics
and naecolorj. Vol 4. Edinburgh: Churchill Livingstone, 1984:334-50.
2 Magos AL, Studd JWW. PMS-a new approach to cause and cure. Contemporay Obserics and
Gywcology 1984;24:85-91.
3 Backstrom T, Boyle H, Baird DT. Persistence of symptoms of premenstrual tension in
hysterectomized women. BrJObset Gynaecol 1981;88:530-6.
4 Taylor JW. The timin of menstruation-related symptoms assessed by a daily symptom rating
scale. Acia PsychiasrScand 1979;60:87-105.
5 Mattson B, von Schoultz B. A comparison between lithium, placebo and a diurectic in
premenstrual tension. Acwa PsychiaarScand 1974;255(suppl):75-84.
6 Grunbaum A. The phcebo concpt in medkine and psychiatry. PsycholMed 1986;16:19-38.
7 Magos Al, Studd JWW. Effects of the menstrual cycle on medical-disorders. BrJ Hosp Med
1985,33:68-77.
8 Studd JWW. Premeasne tension syndrome. BrMedJ 1979;i:410.
9 Greenblatt RB, Asch RH, MSahesh VB, Bryner JR. Implantation of pure crystalline pellets of
estradiol for conception control. AmJ Obst Gynecol 1977;127:520-4.
10 Studd JWW, Thom MH. Oestrogens and endometrial cancer. In: Studd JWW, ed. Progress in
obstetnrcsand gnaeceidag. \'ol 1. Edinburgh: Churchill l.ivingstone, 1981:182-98.
11 Magos AL, Collins WP, Studd JWW. M n t of the premenstrual syndrome by
subcutaneous implants of oestradiol. journal of Psychosomatic Obsttics and Gynaecologv
1984;3:93-9.
12 ThomMH, Cqlins WP, Studd JWW. Hormonal profiles in postmenopausal women after therapy
with subcutaneous implants. BrJ7 Obsm Gynoecol 1981;88:426-33.
13 Tlon MH, Studd JWW. Practical procedures-hormone implantation. Br Med _ 1980;280:
848-50.
14 MoosAR. Typology ofmenstrual cycle symptoms. Amj Obstet Gynecol 1969;103:390-402.
15 Maxwell C. Sensitivity and accuracy of the visual anaiogue scale: a psycho-physical classroom
experiment. BrJ7 Ci Phor}acol 1978;6:15-24.
16 Goldberg DP, Kay C,Thompson L. Psychiatric morbidity in general practice and the community.
PsycholMed 1976;6:565-9:
17 Magos AL, Studd JWW Assessment ofmenstrual cycle symptoms by trend analysis. Am7Obsws
Gynecol(in press).
18 Hammarback S, Backstrom T, Holst J, von Schoultz B, Lyrens S. Cyclical mood changes as in the
premenstrual tension syndrome during sequential estroeprogestagen poatmenopausal replhement therapy. Acta Obsiet Gywcol Scand 1985;64:393-7.
18& Magos AL, Brewster E, Singh R, O'Dowd T, Brincat M, Studd JWW. The effects of
norethisterone in postmenopausal women on oestrogen replacement therapy: a model for the
premenstrual syndrome. BrJ Obstet Gyaecol (in press.J
19 Studd JWW. Hormone implats in the climacteric syndrome. In: Campbel S, ed. The managementofthemenopsenadposmenopausalyears. London: MTPPress, 1976:383-5.
20 Muse KN, Cetel NS, Futterman LA, Yen SSC. The premenstrual syndrome: effects of "medical
ovariectomy."NEgl Med 1984;311:1345-9.
21 Jenkins RJ, Clare AW. Women and mental illness. BrMedJ 1985;291:1521-2.
22 Studd JWW, Brincat M, Magos A, Montgomery J. Women and mental illness. Br Med J 1986;292:201.
(Acceped30April 1986)