Perimenstrual Fluctuations in Two Siblings With Early‐Onset Parkinson's Disease

Menstrual‐cycle–related aggravations of parkinsonism resulting from a transient loss of dopaminergic responsiveness in premenopausal women have occasionally been reported in Parkinson's disease (PD). Thus far, underlying mechanisms remain unclear and treatment options are not well established. We present 2 cases of premenopausal sisters with early‐onset PD and severe menstrual‐cycle–related reduced responsiveness to medication.

A 45‐year‐old woman diagnosed with early‐onset PD at the age of 34 presented with akinetic‐rigid right‐sided parkinsonism. 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 supplementation with dienogest‐ethinylestradiol (75 μg) for continuous 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 score of 1 in the MDS‐UPDRS part IV, item 3) after hormone replacement.

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).

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 tremor. 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 pramipexole 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 deterioration 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), accompanied 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 supplementation with dienogest‐ethinylestradiol (75 μg) 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 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 Moreover, 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 administration.2 Also, in postmenopausal women, estrogen‐replacement therapy appears to reduce motor disability in patients with motor fluctuations and dyskinesias.3, 4, 5 Remarkably, in this population, withdrawal of hormone replacement therapy may result in worsening of parkinsonian symptoms.6 However, in a prospective 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 fluctuations and fluctuations in estrogen or progesterone.7 Nevertheless, 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 requirement, or proneness to dyskinesias in women, compared to men.8, 9, 10, 11 The improvement of perimenstrual aggravation of motor symptoms with dienogest‐ethinylestradiol supplementation in our cases also suggests that low estrogen levels somehow contributed to reduced responsiveness to dopaminergic treatment during menses. An explanation for the delayed appearance, 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 conclusion, 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 perimenstrual loss of dopaminergic responsiveness in premenopausal women with PD.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (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

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 lecture fees from Medtronic. W.P. has received consultancy and lecture fees from Astra Zeneca, Teva, Novartis, GSK, Boehringer‐Ingelheim, UCB, Orion Pharma, and Merck Serono in relation to clinical drug development programs for PD.