Reproductive factors and clinical features of Parkinson's disease

BackgroundLiterature suggests that sex steroid hormones may modify the risk for Parkinson's disease (PD). We investigated the potential effect of reproductive factors on the clinical features of idiopathic PD (IPD) patients.MethodsAll IPD female patients admitted to and evaluated at our Institute over a 12-month period were included in the present cross-sectional study. We investigated the effect of the following parameters by multivariate linear regression analysis: age at menarche, age at menopause, length of fertile life, duration of exposure to endogenous estrogens and cumulative length of pregnancies, use of contraceptives and hormonal replacement therapy.ResultsIn total, 579 patients were evaluated and 497 reported menopause before PD onset. In this population, age at PD onset was positively associated with age at menarche and at menopause, length of fertile life and duration of estrogen exposure. Moreover, UPDRS motor score was inversely associated with age at menopause, length of fertile life and duration of estrogen exposure. Increasing age at menarche was also associated with predominant resting tremor at PD onset. In models refitted on patients with early PD (disease duration <5 years; N = 226) all the associations found were confirmed. The relationship between surrogates of estrogen exposure and UPDRS motor score actually became more significant.ConclusionsOur observations support the concept that hormonal exposure of the nigro-striatal network during life may influence its susceptibility to degenerative stimuli in later life, but the association does not seem to be unique? unidirectional. In particular, increased severity of PD signs correlates with shorter duration of estrogen exposure. The underlying mechanisms need to be clarified.     

Relationship between sex differences in onset of schizophrenia and puberty

Some neurodevelopmental hypotheses of schizophrenia have postulated that sex differences in onset of illness could be explained by sexual dimorphism in onset of puberty, suggesting that early maturation accounts for the later onset of illness in women. The objective of this study was to analyse the relationship between age of menarche and age of onset of schizophrenia in a sample of Chilean patients. The medical records of 105 schizophrenic women diagnosed according to DSM-III-R criteria were studied. In all cases age of onset (first psychotic symptoms) and age of menarche were obtained. Pearson's correlation and student's t-test were used to analyse the data. The mean age of menarche in the sample of female patients (12. 98 years, S.D.=1.49) was significantly different from that of the general population of Santiago, Chile (12.53 years, S.D.=1.32) (t=2. 38; P<0.05). The mean age of onset of schizophrenia in female patients (19.92 years, S.D.=5.13) was significantly earlier in the Chilean sample than that reported in European and North American samples (P<0.05). No differences were observed when comparing the mean age at menarche. The subtypes with the earliest onset presented the earliest age of menarche and the subtypes with the latest onsets showed the latest ages at menarche. However, no correlation was observed between the age at onset of illness and the age at menarche, both in the total sample and in the analysis by subtype. The results of this study do not support a correlation between puberty and age of onset of illness.     

育龄期起病的女性帕金森病患者的临床特点

目的调查育龄期女性帕金森病(PD)患者发病的相关影响因素。方法采用调查问卷,连续选取202例发病时处于育龄期的女性PD患者,同时收集年龄、文化程度匹配的健康女性208名进行对照比较。分别收集两组人群的年龄、月经史、生育史、自然绝经年龄、患妇科疾病、妇科手术史、贝克焦虑量表等临床资料。同时记录PD组发病年龄、病程、统一帕金森病评分量表-Ⅲ(UPDRS-Ⅲ)评分、改良Hoehn-Yahr(H-Y)分级、受经期影响的人数及临床特征。结果两组患者在痛经史、流产史、患妇科疾病及手术、焦虑情绪比较差异有统计学意义(P0.05),在初潮年龄、月经周期、是否规律、有无服用避孕药比较差异无统计学意义(P0.05);PD组已绝经88例,平均(46.8±3.0)岁,对照组已绝经93例,平均(49.6±2.9)岁,PD组绝经年龄小于对照组(P0.01);PD组有54例患者受经期影响,占26.7%,均表现为临床症状的恶化。结论绝经时间早、流产次数多、有痛经史、既往有妇科肿瘤及相关手术史可能是育龄期妇女患PD风险增多的影响因素。     

Smoking and cognitive function in Parkinson's disease.

The risk of dementia among Parkinson's disease (PD) patients is greatly elevated compared to controls, yet little is known about determinants of cognitive function among PD patients. We assessed the relation between cigarette smoking prior to disease onset and later cognitive function among PD patients (n = 286) and age- and sex-matched controls (n = 1144) participating in the Nurses' Health Study and Health Professionals Follow-up Study. Both groups completed telephone-administered assessments of cognitive function. We used linear regression to calculate mean differences in cognitive test scores across smoking categories, adjusted for age, education, sex, age at onset of PD, and years since diagnosis. PD patients scored significantly worse on all tests than their matched controls. In analyses only among PD cases, but not among controls, current smokers at PD onset scored worse than never smokers on the Telephone Interview for Cognitive Status (difference = -0.82, 95% CI: -1.33, -0.30, P = 0.002) as well as on a global score combining results of all tests (difference = -0.36, 95% CI: -0.72, 0.01, P = 0.06). This difference was equivalent to the difference in global score observed among controls approximately 10 years apart in age. Analyses of pack-years of smoking prior to disease onset gave similar results. These findings, nested in prospective cohort studies, suggest that cigarette smoking prior to disease onset is associated with worse cognitive function in PD.     

S18Y polymorphism in the UCH-L1 gene and Parkinson's disease: evidence for an age-dependent relationship.

We studied the relationship between Parkinson's disease (PD) and the S18Y polymorphism in the UCH-L1 gene and the effect on this relationship of age at onset, smoking, and pesticides. Patients requested free health coverage for PD to the Mutualité Sociale Agricole (MSA), the French health insurance organization for people whose work is related to agriculture. Controls requested reimbursement of health expenses to the MSA. A maximum of three controls were matched to each case. Analyses included participants with both parents born in Europe. There were no differences in S18Y genotypes between patients (n = 209; 67% SS, 32% SY, 1% YY) and controls (n = 488; 66% SS, 30% SY, 4% YY). The relationship between PD and S18Y was modified by age at onset (P = 0.03). The Y allele was inversely associated with PD for patients with onset before 61 years (odds ratio [OR] = 0.53; 95% confidence interval [CI], 0.29-0.99); there was no association for older patients (62-68 years: OR = 1.21; 95% CI, 0.67-2.20; >68 years: OR = 1.24; 95% CI, 0.67-2.31). Among patients, Y carriers had a later onset than noncarriers (P = 0.04). These findings were not modified or confounded by smoking and pesticides. In this community-based case-control study, carriers of the Y allele were at decreased risk of developing PD at a young age, independently of pesticides and smoking.     

Influence of coffee drinking and cigarette smoking on the risk of primary late onset blepharospasm: evidence from a multicentre case control study

Prior coffee and smoking habits were investigated in a multicentre case control study involving 166 patients presenting with primary late onset blepharospasm (BSP), 228 hospital control patients with primary hemifacial spasm and 187 population control subjects from five Italian centres. Information on age at disease onset, smoking and coffee drinking status at the reference age and average number of cups of coffee drunk/cigarettes smoked per day reached high and similar test-retest reproducibility in case and control patients. Unadjusted logistic regression analysis yielded a significant inverse association of prior coffee drinking and cigarette smoking with case status for the control groups. After adjustment for age, sex, referral centre, disease duration, years of schooling and ever coffee drinking/cigarette smoking, as appropriate, the smoking estimate lacked significance whereas the association of coffee intake and BSP did not (cases vs hospital control patients: OR 0.37 (95% CI 0.20 to 0.67); cases vs population control subjects: OR 0.44 (95% CI 0.23 to 0.85)). The strength of the inverse association between BSP and coffee intake tended to increase with the average number of cups drunk per day. There was a significant correlation between age of BSP onset and number of cups per day (adjusted regression coefficient 1.73; p = 0.001) whereas no correlation was found with number of packs of cigarettes per day. Coffee drinking may be inversely associated with the development of primary BSP and this association may partly depend on the amount consumed.     

Earlier puberty as a predictor of later onset of schizophrenia in women.

OBJECTIVE: The aim of this study was to determine whether puberty plays a mediating role in onset of schizophrenia. The hypothesis was that there is an inverse relation between age at puberty (menarche) and age at onset in women. METHOD: Competent and consenting individuals with DSM-IV-defined schizophrenia or schizoaffective disorder and their mothers underwent a 45-minute interview to ascertain age at first odd behavior, age at first psychotic symptoms, age at first hospitalization, and ages at various indices of puberty. Information about substance use, head injury, perinatal trauma, and first-degree family history of schizophrenia was also obtained. RESULTS: In the women (N = 35), the earlier the age at menarche, the later the ages at both the first psychotic symptoms and the first hospitalization. There was no significant association between puberty and onset in the men (N = 45). Other than gender, none of the examined variables played a role in the interaction of puberty and onset of illness. CONCLUSIONS: In women, early puberty (whether through hormonal or social influence) was associated with later onset of schizophrenia. This effect was not found in men; in fact, the trend was in the opposite direction.     

Increased Cortisol Levels in Aging and Alzheimer's Disease in Postmortem Cerebrospinal Fluid

The hypothalamo-pituitary-adrenal (HPA) axis is activated during aging and even more so in dementia. Increased levels of corticosteroids may be neurotoxic. Therefore we have investigated cortisol levels in cerebrospinal fluid (CSF) of Alzheimer patients and controls. Ventricular postmortem CSF was collected from clinically and neuropathologically well-defined Alzheimer patients (n = 26) and control subjects (n = 21). In the group of Alzheimer patients the mean CSF total cortisol level was 83% higher than that in the controls. In presenile Alzheimer patients (< 65 years of age; n = 13) the CSF-cortisol level was 5 times higher than that of presenile controls (n = 7). In contrast, senile Alzheimer patients (n = 13) and controls of over 65 years of age (n = 14) did not show a significant difference in CSF-cortisol levels. The presence or absence of a difference in the cortisol-CSF levels in, respectively, presenile or senile Alzheimer patients as compared to controls was due to the 3.5-fold rise of CSF-cortisol in control subjects over 65 years of age as compared with controls under 65 years of age. The CSF-cortisol levels in presenile and senile Alzheimer patients were similar. No significant correlation was observed in the Alzheimer patients between age of onset of the dementia and CSF cortisol levels or duration of Alzheimer's disease and CSF cortisol levels. The finding that in senile Alzheimer patients cortisol levels were similar to those of unaffected age-matched controls does not seem to support the cortisol neurotoxicity hypothesis. On the other hand, it should be noted that postmortem ventricular CSF cortisol levels were found to be 13–16 times higher than lumbar puncture CSF cortisol levels of ambulatory patients. This means that the ventricular CSF levels probably reflect the reaction of the HPA-axis to the process of dying rather than the basal levels of this system. The exact consequences of elevated HPA-axis activity for the human brain should be studied in more detail.     

Relationship between eye symptoms and blepharospasm: a multicenter case-control study.

Although patients with primary blepharospasm (BSP) commonly report experiencing ocular symptoms before the onset of orbicular spasms, the precise frequency and pathogenic role of this subjective ocular discomfort are poorly understood. We conducted a multicenter case-control study to investigate symptoms related to disorders of the anterior segment of the eye, administering a questionnaire to 165 patients with BSP and 180 age- and gender-matched control patients with hemifacial spasm. On a validation sample, our questionnaire yielded high accuracy in detecting eye diseases (predominantly, dry eye syndrome) using detailed ophthalmological examination as the criterion. Logistic regression analysis indicated a significant association between ocular symptoms at disease onset and BSP. Ocular symptoms starting in the year preceding disease onset (short-latency symptoms) showed a stronger association with BSP than ocular symptoms occurring earlier in time (long-latency symptoms). The association was stronger when short-latency symptoms developed from 40 to 59 years of age, whereas this was not observed for long-latency symptoms. Our findings support the view that eye symptoms associated with BSP result from eye diseases and may be involved in the pathogenesis of BSP. The differential risk of developing BSP, based on age at onset of ocular symptoms, suggests that age and eye diseases may interact in giving rise to BSP.     

Menarche, oral contraceptives, pregnancy and progression of disability in relapsing onset and progressive onset multiple sclerosis

Female gender and hormones have been associated with disease activity in multiple sclerosis (MS). We investigated age at menarche, use of oral contraceptives and pregnancy in relation to progression of disability in relapsing onset and progressive onset MS. We conducted a cross-sectional survey among individuals with MS, registered by the Flemish MS Society in Belgium. A time-to-event analysis and Cox proportional hazard regression were performed with time to Expanded Disability Status Score (EDSS) of 6 (requires a cane) as outcome measure. Hazard ratios for the time from onset and the time from birth were adjusted for age at onset and immunomodulatory treatment. Data on 973 women with definite MS were collected. In the relapsing onset group, women with at least two pregnancies had a reduced risk to reach EDSS 6 compared with nulliparous women. In the progressive onset group, later age at menarche was associated with a reduced risk to reach EDSS 6, whereas oral contraceptive use was associated with a higher risk of reaching EDSS 6. Our study corroborates the association of pregnancies with a reduced progression of disability in relapsing onset MS. In progressive onset MS, a slower progression was found in women with a later onset of menarche and a more rapid progression occurred when women reported the use of oral contraceptives.     

Age of puberty and the risk of multiple sclerosis: a population based study

Background and purpose:  Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Given a potential role for sex hormones in MS, we have investigated whether or not the age of puberty influences the risk of developing MS in a population-based cohort.
Methods:  We identified 5493 MS index cases and 1759 spousal controls with age of puberty information from the Canadian Collaborative Project on Genetic Susceptibility to MS. Age of puberty was compared between index cases and controls, and any effect of age of puberty on the age of onset of MS was also investigated.
Results:  There were no significant differences between male index cases and controls with respect to age of puberty, P  =   0.70. However, a significant difference was observed between female index cases and female controls, with average age of puberty being 12.4 and 12.6 years respectively, P  =   0.00017, providing a relative risk decrease of 0.9 per year increase of age of puberty. There was no effect of the age of puberty on the age of MS onset in either sex.
Conclusions:  Earlier age at menarche increases the risk of MS in women. Whether this association is a surrogate for a disease causative factor or directly involved in MS disease aetiology needs to be uncovered.     

Postmenopausal estrogen replacement therapy and risk of AD: a population-based study

OBJECTIVE: To study the association between estrogen replacement therapy in postmenopausal women and AD using a case-control design. BACKGROUND: Studies of the effect of estrogen therapy on the risk of AD have been limited and have yielded conflicting results. METHODS: Case patients were all postmenopausal women who developed AD in the quinquennium 1980 through 1984 in Rochester, MN (n = 222). One control subject from the same population and free of dementia was matched to each case patient by age (+/-3 years) and length of enrollment in the records-linkage system (n = 222). Estrogen exposure was defined as any form of estrogen (oral, parenteral, topical, suppository) used for at least 6 months after the onset of menopause and before the onset of AD (or corresponding year in the matched control subject). Information on dose and duration of use was abstracted. Consistent with the matched design, analyses entailed conditional logistic regression. RESULTS: AD patients and control subjects had identical age at menarche (median: 13.0 versus 13.0 years) and age at menopause (median: 50.0 versus 50.0 years). The frequency of estrogen use was higher among control subjects than AD patients (10% versus 5%; odds ratio = 0.42; 95% confidence interval 0.18 to 0.96; p = 0.04). There was a significant trend of decreasing odds ratios with increasing duration of use. The inverse association between estrogen therapy and AD remained significant after adjustment for education and age at menopause. CONCLUSION: These results from a population-based study suggest that estrogen replacement therapy is associated with a reduced risk of AD in postmenopausal women.     

Glutathione-S-transferase-1 and interleukin-1beta gene polymorphisms in Japanese patients with Parkinson's disease.

We studied genetic polymorphisms in the glutathione-S-transferase-1 (GST-1) gene region and the interleukin-1beta (IL-1beta) promoter region in patients with Parkinson's disease (PD, n = 361), as well as controls (n = 257). Although we have confirmed the previous results, in a larger sample, that the IL-1beta genotype has affected the age at onset of PD patients, no contribution of the GST-1 gene polymorphism was observed in the allele frequency or the onset age of the disease in Japanese persons.     

Onset of epilepsy and menarche—Is there any relationship?

PURPOSE: Women with epilepsy have increased frequency of reproductive health problems compared to women without epilepsy. In puberty, reproductive hormonal changes during sexual maturation may affect epilepsy and induce the debut of seizures as indicated in some studies. On the other hand, epileptic activity affects sex hormone function, which may induce alterations in pubertal endocrine maturation and thereby menarche age. We wanted to investigate the relation between epilepsy and menarche age in a larger population of female epilepsy patients. METHODS: A retrospective, questionnaire study of a cohort of 265 female outpatients from three Norwegian hospitals and 142 controls, aged 18-45 years was conducted. Parameters regarding epilepsy and reproductive health issues were registered. Perimenarche was defined as 2 years before and 2 years after the year of menarche. RESULTS: There was a significantly higher frequency of patients with epilepsy debut between 10 and 18 year compared to 0-9 years (p<0.01). There was, however, no significant difference in occurrence of epilepsy debut in the perimenarche period compared to the 5 year periods before and after perimenarche, and no significant difference in epilepsy debut in the year of menarche compared to the 5 years before or after. Menarche age was not significantly different in those with epilepsy debut before or after menarche. Epilepsy type (idiopathic generalised or partial) did not influence the menarche age. CONCLUSIONS: The study did not confirm the former observations of clustering of epilepsy debut at menarche or in the perimenarche period or alterations in menarche age in girls with epilepsy. However, onset of epilepsy is more frequent in the adolescent years (10-18), than in childhood (0-9).     

Onset of dementia is associated with age at menopause in women with Down's syndrome

Women with Down's syndrome experience early onset of both menopause and Alzheimer's disease. This timing provides an opportunity to examine the influence of endogenous estrogen deficiency, indicated by age at menopause, on risk of Alzheimer's disease. A community-based sample of 163 postmenopausal women with Down's syndrome, 40 to 60 years of age, was ascertained through the New York State Developmental Disability service system. Information from cognitive assessments, medical record review, neurological evaluation, and caregiver interviews was used to establish ages for onset of menopause and dementia. We used survival and multivariate regression analyses to determine the relation of age at menopause to age at onset of Alzheimer's disease, adjusting for age, level of mental retardation, body mass index, and history of hypothyroidism or depression. Women with early onset of menopause (46 years or younger) had earlier onset and increased risk of Alzheimer's disease (AD) compared with women with onset of menopause after 46 years (rate ratio, 2.7; 95% confidence interval [CI], 1.2-5.9). Demented women had higher mean serum sex hormone binding globulin levels than nondemented women (86.4 vs 56.6 nmol/L, p = 0.02), but similar levels of total estradiol, suggesting that bioavailable estradiol, rather than total estradiol, is associated with dementia. Our findings support the hypothesis that reductions in estrogens after menopause contribute to the cascade of pathological processes leading to AD.     

Minor physical anomalies in childhood and adolescent onset schizophrenia

A modified version of the Waldrop scale (WS) was used to assess the prevalence of minor physical anomalies in schizophrenic patients (n = 71) and healthy controls (n = 65). The mean total WS score was 3.32 (SD 1.98) for the schizophrenic patients, significantly higher than that for the controls (2.19, SD 1.18). Minor physical anomalies were compared between two schizophrenic groups, divided on the basis of age at onset, early onset schizophrenia (EOS, onset under age 18 years) group and late onset schizophrenia (LOS, onset at or above age 20 years) group. The mean total WS score was 3.92 (SD 1.86) in the EOS group, significantly higher than the 2.59 (SD 1.79) in the LOS group. Minor physical anomalies are an indirect index for early prenatal central nervous system (CNS) maldevelopment; the present study indicated association between minor physical anomalies and EOS, thus a relationship between early prenatal CNS maldevelopment and EOS. These results support the hypothesis that EOS constitutes a subset of schizophrenia in which neurodevelopmental damage is largely involved.     

Female reproductive cycle and obsessive-compulsive disorder

BACKGROUND: The aim of our study was to assess whether there is a relationship between reproductive cycle events and the initiation or changes in symptoms of obsessive-compulsive disorder (OCD). METHOD: Forty-six female outpatients meeting DSM-IV criteria for OCD completed a semistructured interview at our OCD unit to assess the relationship between reproductive cycle events and OCD. Dates of data collection were from January 2001 to December 2003. RESULTS: In our sample, OCD onset occurred in the same year as menarche in 22% (N = 10), at pregnancy in 2% (N = 1), at postpartum in 7% (N = 3), and at menopause in 2% (N = 1). Worsening of preexisting OCD was reported by 20% of patients (9/45) at premenstruum, 8% (1/12) at pregnancy, 50% (6/12) at postpartum, and 8% (1/12) at menopause. The number of premenstrual mood symptoms, which included anxiety, irritability, mood lability and depressed mood, was associated with both premenstrual worsening of OCD (OR = 5.1, p < .01) and onset or worsening of OCD at postpartum (OR = 2.7, p < .05). Patients with an onset or worsening of OCD at postpartum also more frequently reported pre-menstrual worsening of OCD and previous history of major depressive disorder, including postpartum depression (p < or =.05 for all). CONCLUSION: In a substantial number of patients, the onset or worsening of OCD was related to reproductive cycle events, especially at menarche and postpartum. Certain women with OCD seem to be vulnerable to worsening of OCD at different reproductive periods that imply hormonal fluctuations, and premenstruum and post-partum were the 2 reproductive events with a greater vulnerability. Those patients whose OCD symptoms appeared to be related to reproductive events also exhibited a greater history of mood symptoms (premenstrual depression and major depressive episodes).     

Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects

OBJECTIVE: The authors conducted a prospective study of neurodegenerative and vascular dementia in Belgium. Strict diagnostic inclusion criteria were used to include well defined patients and controls. The results of apolipoprotein E (APOE) genotype effect on risk and clinical characteristics are presented. METHODS: APOE genotyping was performed in patients with probable Alzheimer's disease (AD) (n=504), frontotemporal dementia (FTD) (n=47), vascular dementia (VaD) (n=152), mixed dementia (n=132), mild cognitive impairment (MCI) (n=44), Parkinson's disease (PD) (n=30), dementia with Lewy bodies (DLB) (n=17), and multisystem atrophy (MSA)/progressive supranuclear palsy (PSP) (n=12). RESULTS: The APOE allele frequencies of this Belgian control population (epsilon 2: 6.9%; epsilon 3: 76.2%; epsilon 4: 16.9%) did not differ from those reported for other white populations. AD, MCI, and mixed dementia patients had higher APOE epsilon 4 (32.9%, 38.6%, and 28.4% respectively) and lower APOE epsilon 3 (62.2%, 53.4%, and 66.3%) frequencies compared with controls, whereas only AD and mixed dementia patients had lower APOE epsilon 2 frequencies (4.9% and 5.3%). Apart from a borderline significant different distribution of APOE allele frequencies in VaD patients compared with controls, no other differences were detected. The influence of APOE epsilon 4 on clinical features of dementia was limited to lower age at onset in AD patients and a less pronounced negative correlation between age at onset and number of epsilon 4 alleles in MCI and mixed dementia patients. CONCLUSIONS: This study confirmed the risk association between APOE epsilon 4 and AD. The observation that APOE epsilon 4 is associated with mixed dementia reflected the role of AD in the aetiopathogenesis of this condition. Although MCI is an aetiologically heterogeneous syndrome, the increased APOE epsilon 4 frequencies indicated that a large proportion of the MCI patients included in the study might be predisposed to develop AD.     

The relation between menarche and the age of first symptoms in a multiple sclerosis cohort

BACKGROUND: Previously, multiple sclerosis (MS) has been thought to be associated with changes in hormone levels. This study investigates the association between the age of menarche and the age of onset of the first symptoms of MS. METHODS: A complete list of patients diagnosed with MS in the province of Newfoundland and Labrador was constructed. The age of menarche for our entire relapsing remitting female MS (RRMS) population was requested by mailout survey. Age of symptom onset was ascertained by chart review. RESULTS: A 74% rate of return on the survey results was obtained (150 RRMS patients). A linear regression model demonstrated that the age of first symptoms increased by 1.16 years as the age of menarche increased by one year (R2 = 0.69, P = 0.04). Another analysis showed that the average age of first symptoms for women with reported menarche from 10 to 12 years was 28.96 years compared with 31.83 years for a reported menarche from 13 to 15 years, a significant difference (P = 0.047, t-test). CONCLUSIONS: This study suggests that menarche may be related to the pathogenesis of MS.     

Age of menarche and schizophrenia onset in women

OBJECTIVE: The "estrogen hypothesis" posits that this hormone serves as a protective factor in the development of schizophrenia. If true, then it is expected that the earlier the age of menarche, the later the onset of schizophrenia (as has been reported by some investigators). This study attempts to replicate this relationship in a sample of women with schizophrenia and schizoaffective disorder. METHOD: Self-report menarche age, clinical status, and onset of disorder were collected in a sample of 68 women (55 diagnosed with schizophrenia and 13 with schizoaffective disorder). RESULTS: Menarche age and schizophrenia onset were not negatively correlated as would be predicted by the estrogen hypothesis. Two clinical measures, however, did correlate with age of menarche as predicted. Higher negative symptom scores (total SANS) and greater functional impairment (lower GAF) were reported in subjects who reported a later age at menarche. CONCLUSION: This study suggests that an earlier age at menarche might predict improved clinical outcome after schizophrenia onset (in support of the estrogen hypothesis). Our data, however, do not support Cohen et al.'s findings regarding the relationship between age at menarche, and the timing of the onset of the disorder. Further investigations regarding the relationship between estrogen and schizophrenia development in women are needed. It is suggested that other developmental factors, both biological and psychosocial, might play a crucial role in both the age at onset and the outcome of the disorder in women.