To the Editor: The Journal should be congratulated for publishing the preliminary work of Anne L. Hoff, Ph.D., et al. (1). However, I suggest that there are methodological flaws in the study design as well as erroneous conclusions drawn from inaccurate data in the report. It is well known that the temporal association of neuropsychiatric testing with documentation of the phases of the menstrual cycle phase is vital if valid conclusions are to be drawn concerning the hormonal milieu and its association with cognitive abilities (2–5). Unfortunately, the authors failed to do so.

It is also well known that the adult brain has tremendous neural plasticity, and manipulation of hormones results in significant improvements in various cognitive domains (6). In the study by Dr. Hoff et al., estrogen and progesterone levels were measured on a weekly basis for 4 weeks. The resulting data were then averaged. One can wonder whether these results were statistically significant, given the large variations during women’s menstrual cycles; the range of estradiol has been reported as 50–600 pmol (Canada) or 40–260 pg/ml (U.S.) (7). More important, however, is the fact that not all estrogens are equal. Comparing endogenous estrogen with conjugated equine estrogen is not scientifically valid, since the human radioimmunoassay for 17β-estradiol does not measure levels of estrone sulfate, equilin sulfate, 17α-dihydroequilin sulfate, equilin, equilenin, 17β-dihydroequilin, or 17β-dihydroequilenin, which are all metabolic products of conjugated equine estrogen (7).

The same holds true for ethinyl estradiol, which is the synthetic estrogen found in most oral contraceptives. Taking oral contraceptives usually results in ovarian suppression; thus, there is no production of 17β-estradiol, the most prevalent endogenously produced estrogen. Thus, one has to question the measurement of 17β-estradiol in the women who were taking oral contraceptives. None of your readers would measure an imipramine level in a patient taking fluoxetine; however, measuring 17β-estradiol in patients taking oral contraceptives is its psychiatric equivalent and is therefore inaccurate.

Another methodological flaw in the study by Dr. Hoff et al. is apparent in the authors’ progesterone measurement. This arises because endogenous (ovarian-produced) progesterone has a chemical structure different from that of the synthetic progestins used in hormone-replacement therapy (medroxyprogesterone) and oral contraceptives (norethindrone). Consequently, a measurement for endogenously occurring progesterone will not give meaningful values in women who are taking synthetic progestins, which are of a different chemical structure and would not be measured in an assay for endogenous progesterone (8).

In conclusion, because of the methodological problems and questionable significance of the serum assays, the conclusions of Dr. Hoff et al. cannot be justified. There is also the element of the duration of illness affecting cognition, which the authors do acknowledge. The examination of hormone levels performed by radioimmunoassay in the psychiatric population is long overdue. Although this work is needed, it requires rigorous protocols with temporally associated neuropsychiatric testing in populations experiencing similar endogenous hormonal milieus.