CASE REPORT
CLINICAL PRACTICE
Perimenstrual Fluctuations in Two Siblings With Early-Onset
Parkinson’s Disease
Fabienne S. Sprenger, MD,1,* Klaus Seppi, MD,1 Elisabeth Wolf, MD,1 Werner Poewe, MD1
Menstrual-cycle–related aggravations of parkinsonism resulting
from a transient loss of dopaminergic responsiveness in pre-
menopausal women have occasionally been reported in Parkin-
son’s disease (PD). Thus far, underlying mechanisms remain
unclear and treatment options are not well established. We pres-
ent 2 cases of premenopausal sisters with early-onset PD and
severe menstrual-cycle–related reduced responsiveness to medi-
cation.
A 45-year-old woman diagnosed with early-onset PD at the
age of 34 presented with akinetic-rigid right-sided parkinson-
ism. Initially, she was treated with pramipexole 0.35 mg three
times daily (TID), which was increased in the first 4 years to
0.7 mg once-daily (QID) and later switched to ropinirole 5 mg
QID. During the switch, the patient felt optimally controlled
when she was on pramipexole 0.7 mg twice-daily (BID) and
ropinirole 5 mg BID and subsequently refused to complete the
switch to ropinirole monotherapy. Over the following 2 years
on double-agonist therapy, the patient began to notice mild
wearing-off fluctuations approximately 3 hours after each dose.
Total daily OFF-time was <25% (according to a score of 1 in
the International Parkinson and Movement Disorder Society
[MDS]-UPDRS part IV, item 3) and disability during OFFs
was mild (according to a score of 2 in the MDS-UPDRS part
IV, item 4). At the age of 39, after 5 years of agonist treatment,
she began to experience marked reductions of drug response up
to 5 days before, during, and 3 days after menstruation. Because
of worsening of parkinsonism around period times (MDS-
UPDRS part III sum score = 25 points) the dose of ropinirole
was increased to 5 mg QID and pramipexole 0.7 mg BID was
continued. Because of consistent premenstrual aggravation of
parkinsonism, the patient was eventually put on gestagen sup-
plementation with dienogest-ethinylestradiol (75 lg) for contin-
uous use. This resulted in a marked improvement of control of
parkinsonism also perimenstrually (see Fig. 1). Though she rated
herself OFF for at least 75% of the day (according to a score of
4 in the MDS-UPDRS part IV, item 3) preceding gestagen
supplementation, this changed to <25% per day (according to a
1
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
*
Correspondence to: Dr. Fabienne S. Sprenger, Department of Neurology, Innsbruck Medical University, Anichstrasse 35, Innsbruck 6020, Austria;
E-mail: Fabienne.Sprenger@i-med.ac.at
Keywords: Parkinson’s disease, premenopausal, gestagen.
Relevant disclosures and conflicts of interest are listed at the end of this article.
Received 9 January 2014; revised 18 March 2014; accepted 11 April 2014.
Published online 19 May 2014 in Wiley InterScience (www.interscience.wiley.com). DOI:10.1002/mdc3.12036
© 2014 International Parkinson and Movement Disorder Society
doi:10.1002/mdc3.12036
score of 1 in the MDS-UPDRS part IV, item 3) after hormone
replacement.
A 46-year-old woman, the sister of case 1, was diagnosed
with early-onset PD at the age of 37. She presented with mild
bradykinesia and left-accentuated mild postural and action tre-
mor. Treatment was initiated with pramipexole 0.35 mg TID,
which was increased to 0.7 mg TID within 2 years. One year
later, levodopa/benserazide 100/25 mg QID was added
because of insufficient motor control. Within 4 weeks after
initiation of L-dopa, the patient developed disabling peak-dose
dyskinesia (according to 2 points in the MDS-UPDRS part
IV, item 1, and to 4 points in the MDS- UPDRS part IV,
item 2) and mild wearing-off motor fluctuations with a daily
off-time <25% (according to a score of 1 in the MDS-UPDRS
part IV, item 3). The addition of amantadine 100 mg QID led
to satisfactory improvement of dyskinesias, but wearing-off
fluctuations remained troublesome. The patient was eventually
reasonably well controlled after switching to L-dopa/carbidopa/
entacapone 100/25/200 mg QID and after exchanging pramip-
exole immediate release with pramipexole extended release
2.1 mg QID.
After 6 years of antiparkinsonian treatment, the patient began
to experience perimenstrual episodes of pronounced deteriora-
tion of motor symptoms (especially tremor) with motor OFF-
time occupying more than 75% of waking day (according to a
score of 4 in the MDS-UPDRS part IV, item 3, and to an
OFF-sum-score of 35 in the MDS-UPDRS part III), accompa-
nied by depressive symptoms with suicidal thoughts and panic
attacks. These deteriorations, which started approximately
2 days before menstruation and lasted up to 2 days after
menstruation, caused regular consultations of our outpatient
clinic. This patient was eventually put on gestagen supplementa-
tion with dienogest-ethinylestradiol (75 lg) for continuous use,
resulting in a reduction of perimenstrual OFF-time from
approximately 75% per day (according to a score of 4 in the
MDS-UPDRS part IV, item 3) to <25% per day (according to
a score of 1 in the MDS-UPDRS part IV, item 3) without any
125

CASE REPORT
Figure 1 Diaries of case I (A and B) and II (C and D) showing OFF time before (A and C) and while being on dienogest-ethinylestradiol
supplementation (B and D).
change in dopaminergic treatment (see Fig. 1). OFF-period
related depression and suicidality also subsided.
In 2012, at the age of 46, the patient was genetically tested
and a homozygous mutation in the intron 6 of the PARK2
gene (c.734 + 1G>A) was found.
Menstrual-cycle–related fluctuations in idiopathic PD were
first described by Quinn and Marsden in 1986. Similar to our
finding, they reported a subjective deterioration of parkinsonism
beginning approximately 5 days before and lasting until 2 days
after the onset of menses in 11 of 12 female patients.1 More-
over, Thulin et al. found, in up to 75% of women with PD, a
worsening of parkinsonian symptoms during menses, even if the
menstrual cycle was induced by exogenous hormone adminis-
tration.2 Also, in postmenopausal women, estrogen-replacement
therapy appears to reduce motor disability in patients with
motor fluctuations and dyskinesias.3–5 Remarkably, in this pop-
ulation, withdrawal of hormone replacement therapy may result
in worsening of parkinsonian symptoms.6 However, in a pro-
spective study including 10 premonopausal women with an
average age of 42 and disease duration of 6 years, there seemed
to be no correlation between severity of menstrual-related fluc-
tuations and fluctuations in estrogen or progesterone.7 Never-
theless, there is evidence that estrogen might influence PD
symptoms and explain gender-specific differences in PD, such as
the lower prevalence of PD in females, lower L-dopa require-
ment, or proneness to dyskinesias in women, compared to
men.8–11 The improvement of perimenstrual aggravation of
126 MOVEMENT DISORDERS CLINICAL PRACTICE
23301619, 2014, 2, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mdc3.12036, Wiley Online Library on [18/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Perimenstrual Fluctuations in Early-Onset PD
motor symptoms with dienogest-ethinylestradiol supplementa-
tion in our cases also suggests that low estrogen levels somehow
contributed to reduced responsiveness to dopaminergic treat-
ment during menses. An explanation for the delayed appear-
ance, by approximately 6 years, of these periodic changes of
parkinsonism might be the gradual decline of ovarial activity
during the fourth decade. Because estrogen signaling seems to
be altered in parkin-related PD patients, this might be a target
for future therapeutic strategies in this patient population.12
However, the mechanism by which estrogen influences the
dopamine system in the short run is still unknown. In conclu-
sion, these two cases demonstrate that hormone replacement by
continuous use of a conventional birth control pill can be a
treatment option for symptoms caused by a transient perimen-
strual loss of dopaminergic responsiveness in premenopausal
women with PD.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Exe-
cution; (2) Statistical Analysis: A. Design, B. Execution,
C. Review and Critique; (3) Manuscript: A. Writing of the
First Draft, B. Review and Critique.
F.S.S.: 1A, 1B, 1C, 3A
K.S.: 1A, 1B, 3B
E.W.: 1A, 1B, 3B
W.P.: 1A, 1B, 3B
doi:10.1002/mdc3.12036

Sprenger et al.
Disclosures
Funding Sources and Conflicts of Interest: The authors
report no sources of funding and no conflicts of interest.
Financial Disclosures for previous 12 months: F.S.S. has
received traval grants from AOP-Orphan and Abbvie. K.S. has
received honoraria for speaking and consulting from Novartis,
Boehringer Ingelheim, Lundbeck, Schwarz Pharma, UCB
Pharma, and GlaxoSmithKline (GSK). E.W. has received lec-
ture fees from Medtronic. W.P. has received consultancy and
lecture fees from Astra Zeneca, Teva, Novartis, GSK, Boehrin-
ger-Ingelheim, UCB, Orion Pharma, and Merck Serono in
relation to clinical drug development programs for PD.
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CASE REPORT
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