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GE NE RAL GY NE COL OGY

Evaluation of different add-back estradiol and progesterone

treatments to gonadotropin-releasing hormone agonist

treatment in patients with premenstrual dysphoric disorderBirgitta Segebladh, MD; Anna Borgstrm, MSc; Sigrid Nyberg, PhD;Marie Bixo, MD, PhD; Inger Sundstrm-Poromaa, MD, PhD

OBJECTIVE:The aim of this study was to investigate which add-backhormone replacement therapy would be most beneficial in terms ofmood effects for patients with premenstrual dysphoric disorder who arereceiving gonadotropin-releasing hormone agonist therapy.

STUDY DESIGN:Three different add-back hormone replacement treat-ments were evaluated in a randomized, double-blinded, cross-overclinical trial in 27 patients premenstrual dysphoric disorder. The add-

back treatments consisted of 1.5 mg estradiol and 400 mg progester-one, 1.5 mg estradiol and placebo, and 0.5 mg estradiol and 400 mgprogesterone. The primary outcome measure was daily symptom rat-ings for mood and physical symptoms.

RESULTS:The highest dose of estradiol in combination with proges-

terone was associated with the most pronounced symptom recurrence,

both in comparison with a lower dose of estradiol together with pro-

gesterone and estradiol-only treatment.

CONCLUSION:Based on the findings of the present study, long-cycle

add-back treatment to avoid frequent progestagen use appears to be

most beneficial for patients with premenstrual dysphoric disorder.

Key words:add-back, estradiol, GnRH agonist, premenstrual

dysphoric disorder, progesterone, clinical trial

Cite this article as: Segebladh B, Borgstrm A, Nyberg S, et al. Evaluation of different add-back estradiol and progesterone treatments to gonadotropin-releasing

hormone agonist treatment in patients with premenstrual dysphoric disorder. Am J Obstet Gynecol 2009;201:139.e1-8.

Premenstrual dysphoric disorder(PMDD) is characterized by the cy-clic recurrence of a cluster of mainly psy-

chologic, but also physical, symptoms in

thelate luteal phase of the menstrual cy-

cle.1 The most commonly reported

symptoms are irritability, depressed

mood, mood lability, and anxiety;

PMDD has a significant impact in the

lives of approximately 3-5% of the fe-

male population of fertile age.2 Given the

observation that symptoms disappear

during spontaneous anovulatory cycles

and during gonadotropin-releasing hor-

mone(GnRH) agonist-induced anovu-

lation,3-11 it has been suggested that pro-

gesterone that is produced by the corpus

luteum is the major symptom-provok-

ing agent. However, the exact mecha-

nism by which progesterone precipitates

the symptoms of PMDD is unknown, al-

thoughinteractions with the serotonin

system12 and the GABAergic sys-

tems13-15 are plausible.

Eventhough progesterone appearsto be

the main symptom-provoking factor in

PMDD, the role of estradiol is less well

studied. Previous studies in postmeno-

pausal women have indicated that higher

doses of estradiol, when combined with

progestagens, are more symptom provok-

ing than lower doses of estradiol.16 Fur-

thermore, within individual patients with

PMDD, menstrual cycles with higher es-

tradiol levels are associated withmore pro-

nounced symptoms, and estradiol on its

own appears to be as symptomprovoking

as progesterone on its own.17,18

Today serotonin reuptake inhibitors

(SSRIs) that are used as first-line treat-ment for PMDD and their clinical ef-

fects, in particular for the psychologic

symptoms of the disorder, have been

documented thoroughly.12,19 However,

for many women, the side effects of SS-

RIs, especially the sexual dysfunction,

are intolerable.20 Decreased libido and

other side-effects are often thedirect cause

for termination of SSRI therapy, which is

reflected by the high rate of withdrawal in

clinical trials and in follow-up studies of

patients with PMDD who havebeen pre-scribed SSRIs in the clinic.12,21 Further-

From the Department of Womens andChildrens Health (Drs Segebladhand Sundstrm-

Poromaa andMs Borgstrm), Uppsala University, Uppsala, and theDepartment of Clinical

Science, Obstetrics and Gynecology (Drs Nyberg and Bixo), Ume University, Ume,Sweden.

Presented at the 13th World Congress of Gynecological Endocrinology, Florence, Italy, Feb. 28-March 2, 2008.

Received Oct. 3, 2008; revised Nov. 25, 2008; accepted March 6, 2009.

Reprints: Birgitta Segebladh, MD, Department of Womens and Childrens Health, UniversityHospital, S-751 85 Uppsala, [email protected].

Funding for this research was provided by Swedish Research Council project K2008-54X-200642-01-3, Swedish Council for Working Life and Social Research project 2007-1955, theFamily Planning Foundation, Visare Norr, the Emil Andersson Foundation, and Vsternorrlandslns landsting. Orion Pharma AB supplied leuprolide acetate and estradiol/placebo gel.

0002-9378/$36.00 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2009.03.016

See Journal Club, page 221

Research www.AJOG.org

AUGUST 2009 American Journal of Obstetrics&Gynecology 139.e1
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more, SSRIs have been reported to be less

effective for the physiologic symptoms of

PMDD, such as breast tenderness and

bloating.12 It is therefore necessary to pro-

videadditional efficientand safetreatment

options for women who are unable to

comply with SSRI treatment.

Induced anovulation has long been

known to be a successful treatment for

severe premenstrual symptoms (PMS)

or PMDD.3-9,11,22 However, the useful-

ness of GnRH agonists is limited by their

hypoestrogenic side-effects, which in the

short run are experienced by the women

as vasomotor symptoms but in the longrun may lead to bone demineraliza-

tion.4,23 To eliminate these side-effects

and long-term risks, add-back with a cy-

clic combination of estradiol and proge-

stagens have been tried in several studies.

Although some authors report that the

alleviation of PMS symptoms from

GnRH analogue treatment is maintained

during estrogen and progestagen add-

back,3,4,7,23 other authors have found

women with PMS to be intolerant of

progestagens,

5,18

and no efforts havebeen made to evaluate the optimal add-

back hormone replacement therapy

(HRT) in patients with PMDD.

Hence, the aim of this randomized,

double-blind, crossover trial was to in-

vestigate which add-back HRTs would

be most beneficial for patients with

PMDD who receive GnRH agonist ther-

apy. For this purpose, we tested 3 differ-

ent add-back HRT regimens; a high dose

of estradiol-only, a high dose of estradiol

in combination with progesterone, and a

low dose of estradiol in combination

with progesterone. Also, by using pro-gesterone as addition to the estradiol

treatment, thestudy would provide valu-

able insight into the hormonal events

underlying the symptom provocation

during the menstrual cycle in patients

with PMDD. Based onthe studies in post-

menopausal women,16 we hypothesized

that a high dose of estradiol in combina-

tion with progesterone would be the most

symptom-provoking add-back treatment.

MATE R I ALS AN D METHODS

Subjects

The study was carried out at the depart-ment of Obstetrics and Gynecology of 3

different Swedish hospitals (Uppsala

University Hospital, Ume University

Hospital, and Sundsvall Hospital) be-

tween October 1, 2005, and November

30, 2006. Patients were recruited among

women who sought help for PMS at the

out-patient obstetric-gynecology wardsof the participating clinics and from ad-

vertisement in local newspapers.

Among 96 women who were screened

for the study, 47women did not meet the

inclusioncriteriaor hadan exclusioncri-terion. The remaining 49 women were

enrolled in the screening phase of the

study. Of these, 27 women fulfilled the

diagnostic criteria for PMDD during at

least 1 menstrual cycle. Hence, 27 pa-

tients with PMDD between 25 and 47

years of age who had experienced pre-menstrual mood changes for 6

months were included (Figure 1).

Patients who were included met the

criteria for PMDD diagnosis, which was

defined in the Diagnostic and Statistical

Manual of Mental Disorders, 4th edi-

tion. Diagnosis was based on daily, pro-

spective symptom ratings on the cyclicity

diagnoser (CD)scale during 1-2 cycles

before inclusion.6 Patients who were se-

verely disabled by their PMDD symp-

toms whofulfilled PMDD criteria duringthe first screening cycle were not re-

quired to score symptoms for 1 cycle.

TheCD scale consists of 8 negative mood

parameters (depression, fatigue, irrita-

bility, anxiety, mood swings, affect labil-

ity, difficulties in concentrating, andsleeping disturbances), 3 positive mood

parameters (interest in usual activities,

cheerfulness, energy), and 4 somatic

symptoms (food cravings, bloating,

breast tenderness, and menstrual bleed-

ing). The CD scale is a Likert scale thatranges from 0-8, with 0 as complete ab-

sence of a particular symptom and 8 as

the maximal severity of the symptom. In

addition, the CD scale contains a score

for measuring the every-day social func-

tioning and work performance, for

which each score corresponds to a cer-

tain degree of impact. Patients were con-

sidered to have PMDD if they had a clin-

ically relevant 100% increase in at least 5

symptoms during 7 premenstrual days,

compared with 7 mid-follicular days,that were associated with a clinically sig-

FIGURE 1

Flow-chart of the study

PMDD, premenstrual dysphoric disorder.

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nificant social and occupational impair-

ment. The threshold score for impact on

daily life was set at a score of 4 for 2

days during the luteal phase. This score

corresponded to avoidance of social in-

teraction. All patients displayed at least 1

week of sparse symptoms (scores 2)in

the mid-follicular phase.

The exclusion criteria were ongoing

treatment with any hormonal com-

pounds, ongoing treatment with benzo-

diazepines or other psychotropic drugsincluding SSRI and the presence of any

ongoing psychiatric disorder. The pres-

ence of psychiatric disorders was evalu-

ated by a structured psychiatric inter-

view, the Swedish version of Mini

International Neuropsychiatry Inter-

view, which is based on the Diagnostic

and Statistical Manual of Mental Disor-

ders, 4th editionandInternational Statis-

tical Classification of Diseases and Health-

related Problems, revision 10.24 Subjects

who previously had used SSRI treatmentwere allowed to participate in this study.

All subjects had negative pregnancy test

results.

The women gave written informed

consent before inclusion in the study.

The study procedures were in accor-

dance with ethical standards for hu-

man experimentation, and the Inde-

pendent Research Ethics Committee,

Uppsala University, and the Medical

Products Agency in Sweden approvedthe study.

Study design

The effect of 3 different add-back HRTs

in combination with leuprolide acetate

on daily symptoms was evaluated in a

randomized, double-blinded, cross-over

design (Figure 2). Leuprolide acetate

(Enanton Depot; Orion Pharma, Espoo,

Finland) was given openly in a dose of

3.75 mg as a first subcutaneous injection,

followed 1 month later by a subcutane-

ous injection of 11.25 mg, with an effect

that lasted for the remaining 3 months ofthe study.

During the first month of leuprolide

acetate treatment, no add-back HRT was

given. The start of add-back HRT coin-

cided with the second leuprolide acetate

injection and was administered during

three 28-day cycles (Figure 2). The add-

back treatments consisted of continuous

daily transdermal administration of es-

tradiol gel (Divigel; Orion Pharma) with

a vaginal progesterone (Progesteron

MIC 400 mg; Apoteket Production &Laboratories, Malm, Sweden) or pla-

cebo addition during the last 14 days of

each treatment cycle. The different treat-

ment cycles were (1) 1.5 mg estradiol gel

once daily in combination with 400 mg

vaginal progesterone once daily during

the last 14 days of the study cycle

(1.5E2P), (2) 1.5 mg estradiol gel once

daily in combination with placebo once

daily during the last 14 days of the study

cycle (1.5E2-only), and (3) 0.5 mg estra-

diol gel once daily in combination with400 mg vaginal progesterone once daily

during the last 14 days of the study cycle

(0.5E2P).

After inclusion, patients were assigned

to the 3 different treatments in a se-

quence that was determined by a com-

puterized random-number generator (6different sequences). The order of study

medication was randomized in blocks of

6. Randomization code was prepared by

Apoteksbolaget Production & Laborato-ries (Stockholm, Sweden); allocation

was implemented by the use of num-

bered containers. During the study, the

subjects and study personnel were not

informed about the order of treatments.

Randomization codes were kept secret at

the Pharmacy at Uppsala University

Hospital until completion of the study.Apoteksbolaget Production & Labora-

tories (the National Corporation of Swed-

ish Pharmacies; Malm, Sweden) pre-

pared the identically looking progesterone

and placebo vagitories. Double-dummy

packing of estradiol gel was made by Apo-

teksbolaget Production & Laboratories

(Stockholm, Sweden). Patients applied 2

different estradiol gels every day. During

the1.5-mgestradiolcycles,1packageof1.0

mgestradiol and1 packageof 0.5 mgestra-

diolwereapplied.Duringthe0.5-mgestra-diol cycle, 1 package of 0.5 mg estradiol

FIGURE 2

Schematic diagram of the study design

GnRH, gonadotropin-releasing hormone;HRT, hormone replacement therapy.


TABLE

Demographic data of the studygroup (n 27)

Variable

Studygroup(n 27)

Age (y)a 39.3 4.9...........................................................................................................

History of premenstrualsymptoms (y)a

12.3 6.7

...........................................................................................................

Body mass index(kg/m2)a

24.9 3.3

...........................................................................................................

Parity (n)a 1.7 1.4...........................................................................................................

University/collegeeducation (n)

21 (77.8%)

...........................................................................................................

Employed (n) 23 (85.2%)...........................................................................................................

Married/cohabiting (n) 24 (88.9%)...........................................................................................................

Smoker (n) 3 (11.1%)...........................................................................................................Previous psychiatrichistory (n)

5 (18.5%)

...........................................................................................................a Data are given as mean SD.

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and a placebopackage(similar size andap-

pearance as the 1.0 mg package) were ap-

plied.Packing ofprogesterone andplacebo

vagitories were also made by Apoteksbo-

laget Production & Laboratories (Stock-

holm, Sweden). Compliance was assessed

by counting the remaining vagitories and

gel patches at each visit.

We chose to administer progesteronevaginally to avoid firstpassagemetabolism

in the liver and formation of progesterone

metabolites, which aremore abundant af-

ter oral administration.25 By a vaginal ad-

ministration, the serum concentrations of

progesterone and its metabolites would

better mimic values that areseen during

the normal menstrual cycle.25

The primary outcome was the mean

daily symptom ratings made on the CDscale during the last 10 days of each

treatment cycle. On completion of the

study, the patients were allowed to

continue medication or to pursue in-

dependent treatment with their own

physicians.

StatisticsEstimated power for the studywas based

on the study of Bjorn et al.

16

The studyhad an 80% power to detect a difference

FIGURE 3

Negative mood during add-back hormone replacement therapy to GnRH agonist

Mean SEM daily symptom ratings on a 9-point cyclicity diagnoser (CD) scale of irritability, anxiety, depressed moods, and impact on daily life during

the last 10 days of each treatment cycle in 27 patients with PMDD. Treatments consisted of leuprolide acetate only, leuprolide acetate with add-back

of 1.5E2P, 0.5E2P, and 1.5E2-only, respectively. During the first treatment cycle, the 2-way analysis of variance revealed significant differences between

the add-back hormone replacement therapy regimens (premenstrual irritability scores, F[3,26] 5.69 [P .001]; anxiety scores, F[3,26] 4.50;

[P .01]; depression, F[3,26] 6.00 [P .001]; mood swings, F[3,26] 3.72 [P .05]; and impact on daily life scores, [F3,26] 3.64 [P

.05]). Post-hoc analyses are given in the Figure. Triple asterisksdenote P .001, Tukey Honestly Significance Test.

GnRH, gonadotropin-releasing hormone.Segebladh.Evaluation of add-backtreatments forpatientswith PMDD. Am J Obstet Gynecol 2009.



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in 1.0 scale-step on the CD scale, with a

standard deviation of 1.1.

Analysis of efficacy was conducted by

2-way analysis of variance (ANOVA)

with repeated measures. By using this

analysis, it is possible to compare repeti-

tive measures within individual subjectsand to use them as their own controls.

Because of the cross-over design, only

symptom scores during the progester-

one/placebo addition during the last 10

days of each treatment cycle were used;

the first 18 days of each treatment cycle

were considered to be wash-out phases.

Daily symptom ratings on the CD

scale were analyzed by ANOVA with

treatment (3 different HRTs) and day

(10 days of progesterone/placebo addi-

tion), as within subject variables. When-ever the ANOVA indicated a main effect

of treatment, post hoc tests by Tukey

Honestly Significance Test were made to

elucidate the effect of the treatments.

Occasional missing values were substi-

tuted by interpolation.

All values in the text and Tables are

displayed as mean SEM, unless other-

wise stated. The SPSS statistical package

(SPSS Inc, Chicago, IL) was used for all

analyses.A probability value of

.05wasconsidered significant.

Results

Twenty-seven patients with PMDD were

included in the clinical trial. Two patients

(7.4%) dropped out of the study, both be-

cause of adverse side-effects from GnRH

agonist treatment (sweating and head-

ache). One of these dropouts completed 2

treatment cycles and has been kept in the

analyses as far as possible. Consequently,

25patientscompleted thestudy (Figure1).Demographic data of the study group is

presented inTable 1.Seven women (25.9

%) had used SSRI previously, and 8

women (29.6 %) previously had used

herbal products for their PMS. Five pa-

tients prematurely terminated the use of

the progesterone/placebo vagitories dur-

ing1ofthetreatmentcycles,evenlydistrib-

uted between the 3 treatments. Only days

when progesterone or placebo treatment

was actually administered have been usedin the analyses.

Despite of the 18-day wash-out phase

during each treatment cycle, significant

cross-over effects were evident in all

rated negative mood symptoms (cut-off

for significant cross-over,P .1; irrita-

bility,P .005; anxiety, P .072; de-

pression,P .098; mood swings, P

.064; impact on daily life,P .001). For

this reason, the results on negative mood

symptoms are given only for the firsttreatment cycle (as a parallel study). No

cross-over effects or order effects were

evident for physical symptoms (bloating,P .30; breast tenderness,P .80). Re-

sults for physical symptoms thus com-

prise the entire 3 treatment cycles.

Negative mood symptoms

During the first treatment cycle, the

2-way ANOVA revealed significant dif-

ferences between the add-back HRT reg-

imens (premenstrual irritability scores,F[3,26] 5.69 [P .001]; anxiety

scores, F[3,26] 4.50 [P .01]; depres-

sion, F[3,26] 6.00 [P .001]; mood

swings, F[3,26] 3.72 [P .05]) andimpact on daily life scores (F3,26 3.64

[P .05];Figure 3).

Results of the post hoc tests of treat-

ment effects are given in Figure 3. Ac-

cording to the post-hoc tests, 1.5E2P in-

duced significantly more pronounced

symptoms than did 1.5E2-only (irritabil-ity scores,P .001; anxiety, P .001;

mood swings,P .001; depression,P

.001; impact on daily life,P .001).

Likewise, according to the post-hoc

tests, treatment with 1.5E2P resulted in

increased scores of anxiety, depression,

and impact on daily life, compared with

0.5E2P (anxiety,P .001; depression,P

.001;Figure 3).

Finally, anxiety scores and ratings of

impact on daily life were also increased

during treatment with 0.5E2P, comparedwith 1.5E2-only (Figure 3).

FIGURE 4

Cross-over effects that depended on the first used add-back treatment

Summarized negative mood symptoms throughout the study course, depending on with which

treatment the subjects started. Each pointrepresents the group mean SEM of the last 10 days

of each treatment cycle. Patients with premenstrual dysphoric disorder who started with 1.5E2P

continued to display higher negative mood ratings throughout the study, compared with subjects

who started with 1.5E2-only (F[2,26] 5.73;P .01). During the gonadotropin-releasing hormone

(GnRH) cycle, there was no difference between groups in summarized negative mood symptoms.CD, cyclicity diagnoser.

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Cross-over effects on negative

mood symptoms

Cross-over effects were seen among the 6

different sequences of treatment.Figure

4 displays summarized negative mood

symptoms throughout the study course,which depended on with which treat-

ment the subjects started. When data are

analyzed depending on the first-used

add-back treatment, it is evident that

subjects who started with 1.5E2P contin-

ued to display higher negative mood rat-

ings throughout the study, compared

with subjects who started with 1.5E2-

only (F[2,26] 5.73;P .01; posthoc

tests revealed that the difference between

1.5E2-only as first cycle and 1.5E2P as

first cycle wassignificant with a probabil-ity value of .01). During the GnRH cycle,

there was no difference among groups in

summarized negative mood symptoms.

Similarly, no differences in pretreatment

ratingswere found among these 3 groups

(data not shown).

Physical symptoms

Physical symptom scores were con-

stantly very low throughout the study

course. Nevertheless, the 2-way ANOVA

revealed significant differences in breasttenderness (F[3,26] 7.67; P .001)

and bloating (F[3,26] 13.30;P .001;

Figure 5). The 1.5E2P and 0.5E2P treat-

ments caused increased ratings of bloat-

ing and breast tenderness, in comparison

to 1.5E2-only(difference between 1.5E2P

and 1.5E2-only, P .05, respectively;difference between 0.5E2P and 1.5E2-

only,P .001, respectively).

Adverse events

Eight patients(29.6 %) reported vegetative

symptoms duringthe study, and7 patients

(25.9%) reported recurrent mood symp-

tomsduringthestudy course.Five patients

(18.5%) complained of headache/mi-

graine, and 2 patients (7.4 %) reported

sleeping disturbances. Two patients (7.4

%) had complaints of nausea.

COMMENT

Theprimary aimof thepresent study was

to evaluate which add-back HRT would

be most beneficial for patients with

PMDD. The highest dose of estradiol in

combination with progesterone was as-

sociated with the most pronounced

symptom recurrence, both in compari-

son with a lower dose of estradiol in

combination with progesterone and es-tradiol-only treatment. Hence, the most

beneficial add-back HRT consisted of es-

tradiol-only treatment. Because estra-

diol-only add-back is not feasible, long-

cycle treatment with progestagen addi-

tion every third month could be an

alternative. Previous studies in post-

menopausal women have indicatedthat 14 days of progestagen treatment

every third month is sufficient to ob-

tain endometrial safety.26 If the patient

with PMDD wishesto maintain regularmenstrual bleedings, the lowest possi-

ble estradiol dose should be used. Pre-

vious studies have indicated that low-

dose HRT is sufficient for the

alleviation of menopausal symptoms

and maintenance or improvement of

bone density.27

According to our results, PMDDsymptoms are not caused only by pro-

gesterone fluctuation, but also the serum

concentration and/or dose of estradiol

and the estradiol/progesterone ratio

might impact on symptom provocation.

For anxiety and depressive symptoms,

there was a dose-dependent increase in

symptom recurrence when estradiol

doses were increased. This findingis in

line with a study by Schmidt et al18 in

which both estradiol and progesterone,

when given on their own, induced recur-rence of symptoms in patients with

PMDD that was treated with GnRH ag-

onist. However, our finding is partly at

odds with Mortola et al3 who, in a small

double-blind cross-over study, foundthat an add-back combination of conju-

gated equine estrogen and medroxypro-

gesterone acetate was superior to conju-

gated equine estrogen only and

medroxyprogesterone acetate only. Pre-

vious studies in postmenopausal women

have indicated that higher doses of estra-diol, when combined with progestagens,

are more symptom provoking than

lower doses of estradiol.16 Within indi-

vidual patients with PMDD, menstrual

cycles with higher estradiol levels are as-

sociated with more pronounced symp-

toms.17,28 Furthermore, our finding is in

line with a number of clinical trials of

combined oral contraceptives for

PMDD in which an oral contraceptive

that contained 20 g ethinylestradiol in

combination with drospirenone hasbeen shown to be efficient for

FIGURE 5

Physical symptoms during add-back hormonereplacement therapy to GnRH agonist

Mean SEM daily symptom ratings on a 9-point cyclicity diagnoser (CD) scale of bloating and

breast tenderness during the last 10 days of each treatment cycle in 27 patients with premenstrual

dysphoric disorder. Treatments consisted of leuprolide acetate only, leuprolide acetate with add-back

of 1.5E2P, 0.5E2P, and 1.5E2-only, respectively. The 2-way analysis of variance revealed significant

differences between add-back hormone replacement therapy regimens in breast tenderness (F[3,26]

7.67;P .001) and bloating (F[3,26] 13.30; P .001). Post-hoc analyses are given. The

single asteriskdenotesP .05, Tukey Honestly Significance Test; the triple asterisksdenoteP

.001, Tukey Honestly Significance Test.GnRH, gonadotropin-releasing hormone.




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PMDD,29,30 whereas the 30 g ethi-

nylestradiol and drospirenone combina-

tion has not.31

The major weakness of our study is the

cross-over design that resulted in signif-

icant carry-over effects between the dif-

ferent add-back therapies. The majorreason that a washout cycle was not in-

cluded in the study design was that it

would increase the study length and thus

increase the risk for drop-outs and time-effects. Furthermore, because we only

planned to use the last 10 days of each

treatment cycle, we had anticipated that

the estradiol-only days of each treatment

cycle would be a sufficient washout from

progesterone, which clearly turned out

not to be the case. Because of the carry-

over effects, we could use only the firstcycle of treatment, which resulted in a

substantially smaller number of subjects

who could be evaluated. However, the

carry-over effects occurred only in psy-

chologic symptoms, not in physical

symptoms; physical symptoms are eval-

uated in the intended sample.

When data were analyzed according to

which add-back treatment had been

given during the first add-back cycle, it

was clear that subjects who started with a

higher dose of estradiol in combinationwith progesterone continued to display

increased symptom ratings throughout

the study, compared with subjects who

started with estradiol-only. Hence, thosewho experienced the most severe symp-

toms during the first add-back cycle con-

tinued to do so throughout the study,

whereas those who experienced minute

symptoms during the first add-back cy-

cle continued to experience low levels of

symptom recurrence during the next cy-

cles. Previous studies have indicated thatpatients with PMDD display an abnor-

mal central nervous system response to

normal hormone fluctuations18,32,33; ac-

cording to our findings, such abnormal

responses may persist over time or in-

duce expectations or alternatively sensi-

tize subjects to a certain degree of symp-

tom recurrence in subsequent cycles.

Thus, it is possible that a certain hor-

mone provocation (being positive or

negative) may leave residual traces and

vulnerabilities that might alter the futureresponse to ovarian hormones.

As opposed to negative mood symp-

toms, experiences of physical symptom

were not carried over between treatment

cycles. This finding implies that the

wash-out phases that were used for the

study were sufficient in terms of hor-

mone clearance and that very subtlechanges in hormone levels may induce

detectable changes in physical com-

plaints within an individual subject.

Based on the findings of the present

study, long-cycle add-back treatment toavoid the frequent use of progestagens

appears to be most beneficial for patients

with PMDD. PMDD symptoms are af-

fected by the progesterone addition, but

the estradiol dose appears to influence

symptom expression as well. f

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