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Letter   |    
Parity, Number of Pregnancies, and the Age of Onset of Alzheimer’s Disease
Tomasz Sobow, M.D., Ph.D.; Iwona Kloszewska, M.D, Ph.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2004;16:120-a-121. doi:10.1176/appi.neuropsych.16.1.120-a

SIR: Estrogen deprivation has been implicated as a risk factor in Alzheimer’s Disease (AD), as some epidemiological data suggest that hormone replacement therapy (HRT) can modulate the risk of the disease. However, neither endogenous sex hormone levels in postmenopausal women1 nor the lifetime exposure to estrogens measured by the length of reproductive period2 represents irrefutable factors modulating the risk or the course of cognitive decline in AD. The issue of the possible connection of endogenous estrogens and age-related cognitive decline has been raised again recently in the report of McLay et al3 who observed that nulliparity and late menopause (both understood as surrogate measures of endogenous estrogens exposure) resulted in decreased cognitive decline in non-demented women. The association between late menopause and age at onset of AD (which might represent a marker of the rate of cognitive decline) has been shown by several groups, including ours.4 In the cohort of 65 sporadic AD cases in women we were also able to show the significant negative relationship between number of pregnancies and age at onset of AD: women with more pregnancies had younger age-at-onset (Pearson's R = −0.65, p < 0.01). In the regression model including age, age at menopause, education and smoking behavior, number of pregnancies was an independent factor (rather surprisingly even stronger than the age at menopause alone) and with each pregnancy the age of onset of AD was reduced by almost three years.

The relationship between parity (or number of pregnancies) and both cognitive decline rate in non-demented women3 and the age of onset of AD4 is difficult to interpret. One possible explanation is linked to estrogens solely: estrogen levels are very high during pregnancy and drop acutely thereafter with decreased levels maintained for approximately one year; furthermore, parity influences estrogen levels later in life. Both observations are in agreement with higher lifetime exposure to estrogens in nulliparous women. Alternatively, one can reason that progestins (which levels are also elevated in pregnancy) might play an independent role and even outweigh the benefits of estrogens, that might in part explain the recently reported failure of HRT in preventing AD or mild cognitive impairment5 and puts forward a question of the conditions (mainly safety issues) of estrogens alone replacement as an AD preventing strategy. Another unsolved question is the role of different progestins in the development of the cognitive decline (e.g., 17OH-progesterone and progesterone from different sources during pregnancy, like luteal corpora or placenta) and, finally, the use of the diverse progestins in the HRT and their potential role in the dementia prevention or treatment strategies.

The results included in the letter were in part presented during the 7th World Congress of Biological Psychiatry 1—6 July, 2001 Berlin Germany

Thal LJ, Thomas RG, Mulnard R et al.: Estrogen levels do not correlate with improvement in cognition. Arch Neurol  2003; 60:209—12
[CrossRef] | [PubMed]
 
Geerlings MI, Ruitenberg A, Witteman JC et al.: Reproductive period and risk of dementia in postmenopausal women. JAMA  2001; 285:1475—81
[CrossRef] | [PubMed]
 
McLay RN, Maki PM, Lyketsos CG: Nulliparity and late menopause are associated with decreased cognitive decline. J Neuropsychiatry Clin Neurosci 2003: 15:161—167
 
Sobow TM, Kutter EP, Kloszewska I: Hormonal decline indicator in women (age at menopause) modifies age of onset in sporadic Alzheimer’s Disease. Alzheimer Rep  1999; 2:27—30
 
Shumaker SA, Legault C, Thal L et al.: Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA  2003; 289:2651—62
[CrossRef] | [PubMed]
 
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References

Thal LJ, Thomas RG, Mulnard R et al.: Estrogen levels do not correlate with improvement in cognition. Arch Neurol  2003; 60:209—12
[CrossRef] | [PubMed]
 
Geerlings MI, Ruitenberg A, Witteman JC et al.: Reproductive period and risk of dementia in postmenopausal women. JAMA  2001; 285:1475—81
[CrossRef] | [PubMed]
 
McLay RN, Maki PM, Lyketsos CG: Nulliparity and late menopause are associated with decreased cognitive decline. J Neuropsychiatry Clin Neurosci 2003: 15:161—167
 
Sobow TM, Kutter EP, Kloszewska I: Hormonal decline indicator in women (age at menopause) modifies age of onset in sporadic Alzheimer’s Disease. Alzheimer Rep  1999; 2:27—30
 
Shumaker SA, Legault C, Thal L et al.: Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA  2003; 289:2651—62
[CrossRef] | [PubMed]
 
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