Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA
Author to whom correspondence should be addressed at: Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, 1014 Salk Hall, Pittsburgh, PA 15261, USA. Tel.: +1 412 441 4229/+1 412 383 7312; Fax: +1 412 624 1850; E-mail: gavaler{at}pitt.edu/judygavaler{at}comcast.net
(Received 8 March 2005; first review notified 22 April 2005; accepted in revised form 2 May 2005)
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ABSTRACT |
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INTRODUCTION |
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The upper USDA recommendation for alcoholic beverage consumption for adult women of all ages has been 1 drink per day or 7 total weekly drinks (TWD), while in men the upper limit has been 2 drinks per day or 14 TWD (USDA, 1995). These levels have remained unchanged for years (Gomberg, 1944
; Dufour, 1999
; Blow and Barry, 2002
; Register et al., 2002
). One must wonder, however, what methods were used to determine these drinking limit recommendations in either gender; this is an important question because these recommended limits are viewed by the public as being safe.
In evaluating what may be an acceptable level of alcohol consumption for women, it is to be noted that women cannot be viewed as a homogeneous group. Specifically, PMP women and women with cyclic ovarian function differ substantially in the neuroendocrine control of hormone production. Thus, in terms of what may be an acceptable drinking level, PMP women need to be considered separately from women with cyclic ovarian function (Gavaler, 1990; McCoy, 2002
).
In PMP women the hypothalamicpituitarygonadal axis is no longer intact because the ovaries can no longer respond (natural menopause), or are absent (bilateral ovariectomy performed at time of hysterectomy). It is important to note that women who have undergone a hysterectomy alone or with the removal of a single ovary still experience a natural menopause.
Further, PMP women are estrogen deficient by definition in the PMP state. Estrogen is produced by the conversion of androgens primarily of adrenal cortex origin by CYP19 (aromatase). This enzyme converts testosterone to estradiol (E2) and androstenedione to estrone. Further, it is particularly important to note that the activity of CYP19 is increased by alcohol consumption, increased age, in PMP women as compared to younger women, and by obesity (Hemsell et al., 1974; Bird et al., 1978
; Crilly et al., 1979
; Longcope et al., 1980
; Meldrum et al., 1981
; Ginsburg, et al., 1996
; Djordjevic et al., 1998
). In addition, alcohol-induced hormonal changes vary as an effect of race and ethnicity (Gavaler et al., 2002
).
The decreased estrogenization of the PMP state originally led to the use of estrogen replacement therapy in PMP women. Thus, if acceptable drinking levels increase circulating E2 concentrations levels among PMP women can be viewed as being beneficial up to a point in alcohol consumption, then that point of alcohol consumption at which the maximum benefit occurs becomes an issue to be determined in PMP women from all racial and ethnic groups. The maximum benefit would be the level of alcohol consumption at which no further increase in E2 levels can be detected. E2 has been selected as the estrogen to be examined because E2 exerts a greater biologic effect than estrone due to the higher binding affinity of E2 to estrogen receptor binding sites (Schutt and Cox, 1972; Rosenblum et al., 1993
). Further, it is important to emphasize that identifying the alcohol consumption level of maximum benefit in E2 concentrations is particularly important as the practice of prophylactic bilateral ovariectomy is increasing (Conklin et al., 1996
: Kontoravdis et al., 1996
; Gavaler, 2004
), while the use of previously conventional estrogen replacement therapy has diminished substantially (Austin et al., 2003
; Hersh et al., 2004
).
The goal is to assess the possibility that an acceptable drinking level for PMP women may be lower than the USDA level of alcohol consumption for women as a group of 1 drink per day or a total of 7 drinks per week by examining statistically at what level of alcohol consumption no further benefit or increase in E2 levels can be identified.
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METHODS |
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Data collection
To ensure the accuracy of the alcohol consumption data, the demographic questionnaire included quantity/frequency questions for the last month and for several other time points, a never-ever (in the past but not currently)-now drinking item, questions about preferred beverages, and drinking situations, all of which were spread throughout the demographic questionnaire. Alcohol data from the 3-day food and beverage record was also used. At the morning clinic visit, blood specimens were obtained for hormone measurements, and questions about when the most recent drink was consumed were also asked. Together, these data sources, and contacting the participant if necessary, resulted in the need to make corrections in <5% of participants. Using the algorithm of Turner, where 1 fluid ounce (fl oz) equals 48.41 ml and contains 22.3 g of alcohol, 12 fl oz of beer, 5 fl oz of wine and 1.5 fl oz of 80-proof liquor were set to one standard serving or drink (Turner, 1990).
Hormone assays
Hormone levels were measured using radioimmunoassay kits which have been used for years in our laboratory. For E2, the intra-assay coefficient of variation (CV) was 4.1%, and the inter-assay CV was 6.6%; the detection limit was 5 pg/ml. For LH, the standard was the first IRP 68/40; for FSH the standard was the second IRP 78/459. The intra-assay CV was 3.8% for LH, and 4.7% for FSH while the inter-assay CV was 5.8% for LH, and 6.1% for FSH.
Statistical analyses
Statistical tests used included one-way analysis of variance with the Tukey multiple comparison procedure, Pearson bivariate correlation coefficients, the independent group t-test, and multiple linear regression. Logarithmic transformations were used for all hormone levels. Data are shown as the mean ± the standard error of the untransformed data, as logarithms can be difficult to interpret. A two-tailed P-value < 0.05 was considered to be statistically significant.
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RESULTS |
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DISCUSSION |
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The plateau in E2 levels with increasing categories of alcohol has now been statistically confirmed. Further, the fact that tripling of the alcohol dose above the dose shown to be acceptable is required to breach the plateau in E2 levels in PMP women finally explains certain previous clinical observations (Gavaler, 1993; Gavaler et al., 1994
). In addition, over 25 years ago when I was using a triplet-matched isocaloric liquid diet in ovariectomized rats, I could not figure out why E2 levels in the high dose animals did not differ from the middle dose animals, while the middle dose animals differed significantly from the control-fed rats. Now I know.
Together, these findings demonstrate that 5 TWD provide the maximum benefit in terms of the estrogenization of PMP women. These findings also indirectly demonstrate the need to use various methods of collecting alcoholic beverage consumption to ensure accuracy.
The vast majority of these new findings, however, have come from the data in the entire group of PMP women not treated with previously-conventional estrogen replacement, as well as in the entire group of PMP women treated with conventional oral or patch estrogen therapy (we now insist that our E2 levels are monitored regularly). The major question which must now be pursued is whether or not these findings can be replicated in the spectrum of racial and ethnic groups. We do know that among American Indian, Black, Hispanic, Jewish, White/American Indian Blend and White PMP women not treated with estrogen replacement in these analyses that significantly in higher proportions within each group who drink consume 5 TWD (P < 0.05 within each group). We know that the percentages of current drinkers differ significantly among racial and ethnic groups (P = 0.026). We also know that E2 concentrations among both drinkers (P = 0.026) and abstainers (P = 0.06) differ significantly among racial and ethnic groups. Further, among PMP women treated with conventional estrogen replacement therapy, we know that in the 124 therapeutic-responders there are significant differences among the racial and ethnic groups in E2 levels (P = 0.049 and in the proportion of drinkers (P = 0.046); we also know that among the 49 over-responders E2 levels (P = 0.051 and TWD (P = 0.047) differ significantly among racial and ethnic groups.
Clearly more research will be required to elucidate the paradoxical arithmetic decrease in E2 levels in black PMP women. A great deal more work will be required to expand these findings to apply within each racial and ethnic group analysed separately.
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ACKNOWLEDGEMENTS |
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REFERENCES |
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