Several findings in this study suggested a more benign PD phenotype in women compared with men. The benefits for women seemed to apply mainly to the events preceding overt PD. Firstly, women tended to be older than men at symptom onset. Secondly, women presented more often than men with a tremor dominant form of PD, which in turn was associated with a slower disease progression. Thirdly, at onset of the disease, women had higher levels of striatal dopamine binding than men. These benefits in the preclinical phase could be related to oestrogen status, because parity (number of children), age at menopause and duration of the fertile life span were all associated with a later age at onset of PD. However, women seemed to have no further advantage over men once PD had become clinically manifest. Thus the rates of disease progression—as indexed by both clinical scores and measurements of striatal dopamine binding—were comparable between men and women with overt symptoms. In the next paragraphs, we discuss these findings in more detail.
Gender differences preceding clinical PD
The 2 year difference in age at PD onset between men and women observed here is comparable with the difference found in most epidemiological studies.7
It suggests that the development of symptomatic PD is slightly delayed in women compared with men. This could be explained by higher initial striatal dopamine levels in women compared with men, as noted in this study. Those higher initial dopamine levels could delay the moment of reaching a critical threshold of striatal dopamine depletion and hence postpone the development of parkinsonian symptoms.
Several observations support this explanation. In our study, at symptom onset and throughout the course of the disease, women had 16% higher striatal [123
I]FP‐CIT binding than men. This suggests that the critical threshold of dopamine depletion at which symptoms emerge is 16% higher in women than in men. However, women become symptomatic 2 years later then men. This could be explained by a similar relative loss of dopamine required for symptom onset in men and women, but a higher initial dopamine content in women. Furthermore, healthy women have higher striatal dopamine transporter binding than healthy men.23,24,25
The gender difference in striatal dopamine transporter binding noted in our study thus appears to be physiological and not specifically PD related. This is supported by the fact that healthy women have a lower postsynaptic dopamine D2
receptor affinity than healthy men,26
probably reflecting D2
receptor downregulation induced by high presynaptic striatal dopamine levels. Animal experiments confirm a physiological gender difference: in healthy rats and MPTP lesioned mice, the density of dopamine transporters and striatal dopamine concentrations were higher in females than in males.27,28,29
Secondly, in animal studies, expression of striatal dopamine transporters appeared to be determined by oestrogen28,30
and closely paralleled the level of striatal dopamine.31
Consequently, a situation in which intracerebral oestrogen levels increase (eg, pregnancy) will lead to upregulation of striatal dopamine transporters, in turn resulting in higher striatal dopamine levels.
Although extrapolating animal data to humans requires caution, our data would fit into this concept. We found that parity—the result of pregnancy, a situation of high circulating oestrogen levels—correlated positively with age at onset, a fact not reported previously. However, a relationship between parity and PD irrespective of age at onset has been reported previously: women with PD had reduced parity compared with healthy women.32
Moreover, medical conditions leading to oestrogen depletion (eg, hysterectomy, oophorectomy or short fertile life span) increased the risk of PD20,21,33
while a reduced risk was found for postmenopausal oestrogen use, which increases cumulative oestrogen levels.16,17
Our study showed that a later menopause and a longer fertile life span—also increasing cumulative oestrogen levels—delayed the age at onset. This has not been reported previously.
Gender differences in overt PD
The rate of decline in SPECT binding did not differ between the sexes. Most other studies show rates of decline similar to ours, although not specified for gender.34,35,36,37
The results suggest that once the critical threshold of striatal dopamine depletion has been exceeded, disease progression does not differ between men and women. In other words, oestrogens may exert some form of neuroprotection in the preclinical stage of PD, or may even postpone the beginning of the degenerative process, but fail once symptoms have become clinically apparent. This idea is supported by animal work: oestrogens may protect against nigrostriatal degeneration in animal models of PD when administered prior to the insult11,12,13
but do not exert any beneficial effects when administered after nigrostriatal damage has occurred.12,13
This may help to understand the failure of oestrogen replacement therapy in slowing the progression of overt PD in women. Thus a double blind, placebo controlled study of high dose transdermal 17β‐oestradiol in postmenopausal women with PD showed no effect on motor scores.19
Furthermore, a placebo controlled, randomised, double blind trial in postmenopausal women with PD found no significant effect of orally administered oestradiol on objective and subjective parkinsonian symptoms.18
An additional explanation could be that both orally and transdermally administered oestrogens do not lead to high enough oestrogen concentrations within the blood–brain barrier to exert any effect at all.
When pointing at a variable (ie, oestrogen) as a possible aetiological factor in a disease process, one should take into account that this variable might coexist with or influence another, perhaps unknown, factor which is actually responsible for the observed effect. For example, a long fertile life span may have increased the risk of iron deficiency because of iron loss during menses and pregnancies. Iron, in turn, has been implicated as an important factor in the oxidative processes within the nigrostriatal system although its precise role remains unclear. Consequently, we cannot exclude the fact that the iron status of the women in our study could have contributed to the findings which we associated with oestrogens.
Tremor dominant patients, both men and women, were 3.6 years older at symptom onset than patients presenting with the hypokinetic‐rigid subtype of PD. The tremor dominant patient group also showed a 38% slower increase (ie, slower deterioration) in sUPDRS‐III scores, a finding consistent with previous suggestions of a more benign course for this PD subtype.37,38,39,40
I]FP‐CIT binding tended to decrease less fast in the tremor dominant patients. Together with a later onset and a more frequent onset with tremor in women, these findings suggest that women are more likely than men to acquire the benign tremor dominant PD subtype.
This study was not without drawbacks. Firstly, our department is a dedicated referral centre for patients with movement disorders, and this may have affected the basic characteristics of our study population. It would seem unlikely, however, that referral bias confounded our questions regarding the influence of gender on PD. The percentage of men and women with PD in our population was similar to population based numbers. Another issue could be that referrals from a greater distance to our clinic could have represented different (ie, more complicated) PD patients than the ones from nearby. However, we compared the patient characteristics from those referred within the area of Nijmegen with those coming from other geographical regions and did not find any significant differences. Furthermore, we analysed the SPECT results obtained from the three different hospitals located in three distant regions of the Netherlands separately, before pooling them. We found the same results for both separate and combined analyses. Therefore, we feel that the most important referral biases have been excluded. Moreover, the magnitude of this PD cohort enabled us to select many patients with a disease duration of up to 10 years but without exposure to levodopa or dopamine agonists. This created the opportunity to study the unmedicated, natural course of PD.
Secondly, oestrogen status was ascertained retrospectively, which could have introduced recall bias. However, the most important oestrogen status item, parity, is unlikely to be subject to recall bias. Finally, the oestrogen status analyses were based on a limited sample size. Therefore, extrapolating our findings to all women with PD requires caution. Nevertheless, our study may initiate important future research into the hypotheses and explanations we suggested.