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Editorial |
Professor Emeritus, University of California, San Francisco
Address all correspondence and requests for reprints to: Dr. Pentti K. Siiteri, Professor Emeritus. E-mail: fhineas{at}comcast.net.
Large amounts of dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, are secreted by the adrenal glands of humans and closely related primates. Huge amounts of DHEAS are secreted by the fetal adrenal glands and converted to estrogens in the placenta during pregnancy. Soon after birth, serum DHEAS concentrations fall to low levels but rise during adrenarche around age 7–9 yr. The highest DHEAS levels occur in the early twenties and are higher than those of any other hormone. Thereafter, the DHEAS levels decline over the subsequent 5 decades. Some investigators have suggested that this decline in DHEAS is causally related to the loss of mental and physical capabilities in aging humans. Is DHEA the Ponce de Leon hormone? Despite much effort, a definitive answer to this question has yet to be found.
DHEA and Androgen Production
The early history of the steroid hormones was brilliantly recorded in 1959 by Louis F. Fieser and his wife Mary (1). I will quote pertinent facts from chapter 16, titled "Androgens." Butenandt reported the isolation of 15 mg of a potent androgen, androsterone (A), from 15,000 liters of male urine in 1931. A few years later he isolated the much weaker androgen, DHEA, and determined its chemical structure. The low potency and same A ring structure found in cholesterol suggested that DHEA might be formed in the adrenals rather than the testes. Supporting evidence came when Fieser and his associates found 88 mg/liter of DHEA in the urine of a woman with an adrenal tumor. However, interest in DHEA subsided when Lacquer reported the isolation of testosterone (T) from steer testes in 1935 (1).
Zimmerman devised a colorimetric method for measuring urinary 17-ketosteroids consisting primarily of A and its 5-ß epimer, etiocholanolone (E). Although useful for diagnosis of adrenal tumors, it provided little insight into the causes of hirsutism in women. Elucidation of the causes of this vexing problem awaited the availability of tritium and carbon-14-labeled steroids and liquid scintillation counters for their measurement in the late 1950s. Dr. Howard Taylor recruited an organic chemist, Seymour Lieberman, to join his Department of Obstetrics and Gynecology at the College of Physicians and Surgeons, Columbia University. Lieberman soon confirmed the wisdom of this novel arrangement by attracting a large group of faculty and fellows to study the production and metabolism of the steroid hormones. An early study by Roberts et al. (2) provided the first definitive evidence for the metabolism of DHEAS to DHEA and further to the metabolites A and E in humans. After iv administration of tritium-labeled DHEAS to three individuals, about 15% of the injected radioactivity was recovered from both the sulfate and glucuronide fractions of 4-d urine collections. After extensive purification, more than 95% of the radioactivity in both fractions was identified as A and E. Together with data from many other experiments (3), a four-compartment mathematical model of DHEA metabolism evolved and was presented at the 1962 Laurentian Hormone Conference (4). The model allowed estimates of the extent of conversion of DHEAS to DHEA, the conversion of DHEA to androstenedione (A4), the interconversion rates of A4 with T, and the production rates of all four steroids (4). This intellectually and experimentally challenging accomplishment was enormously rewarding to all involved. I hasten to add that during this period the metabolic clearance rate (MCR) concept was also being developed by Tait (5).
The use of isotopic methods declined as RIA methods in commercial laboratories became available. The new methods were rapid and eliminated the need for special equipment and training. However, the inherent chemical proof of biochemical transformations using molecules labeled with isotopes first developed at Columbia was lost. Therefore, studies that depend upon recording small changes in blood steroid levels must be viewed with caution. A case in point appears in the paper by Hammer et al. (6). Experiments are described in which metabolism of DHEAS and DHEA was assessed by changes in blood metabolite levels after their administration to male subjects. Metabolism of orally administered DHEA was evidenced by increased serum levels of DHEAS, A4, estrone, and androstanediol glucuronide in blood samples collected over a 6-h period. The data was quantified by the difference in area under the curves constructed from serum concentrations in the control and treatment periods. However, no evidence for DHEAS metabolism was obtained using the same protocol except for iv administration of about one fifth as much DHEA. Separate in vitro experiments in which DHEAS was incubated with liver cells also were negative. The authors state in the abstract that "these results clearly illustrate a lack of hepatic conversion of DHEAS to DHEA, challenging the concept of free interconversion of DHEA and DHEAS." The origin or meaning of "concept of free interconversion" is not defined nor referenced so it is not clear just what the authors believe they have shown. Reference 19 in the discussion cites a 1975 study in which both labeled androgens were infused but gives no details. Reference 20 quotes a statement in a recent review by the Taits, "DHEAS has not been infused in any of the published studies to achieve equilibrium conditions." The reason why this has not been done is quite simple: it is technically impossible. The MCR of DHEAS is approximately 10 liters/24 h, whereas that of DHEA is 240-fold greater or around 2400 liters/24 h. Thus, the maximum amount of DHEAS that could be transformed to DHEA and then to metabolites during the 6-h infusion would be less than 1/5 x 240 or less than 0.1% of the metabolites derived from orally administered DHEA. Clearly, such small increases in blood steroid levels cannot be accurately measured by RIA methods. The reader is referred to the large body of work published from the Lieberman laboratory and others such as Dr. Mortimer Lipsett at the NIH in the1960s.
DHEAS and Placental Estrogen Production
When Paul MacDonald and I completed our studies at Columbia, we established laboratories in the Obstetrics and Gynecology Department at Southwestern Medical School in Dallas. To determine if DHEAS is converted to estrogen during pregnancy, and we devised a more accurate and less tedious experimental design in which DHEAS labeled with carbon-14 was injected together with tritium labeled estradiol. This approach allowed a precise estimate of the extent of conversion of precursor to product simply by comparing the isotope ratios in the purified product with that of the injected mixture of tracers (7). Our first positive results were published in a companion paper (8). Experiments in women with molar pregnancies were positive, but the extent of conversion of DHEAS to estradiol varied considerably. We also studied three women who were pregnant with anencephalic fetuses and found little or no radioactivity in samples of cord blood obtained at delivery (9). However, unlike data from normal pregnant women, there was little difference in the specific activities with respect to tritium of estriol, estrone, or estradiol (see below). These important experiments encouraged us to proceed, as the total amount of weak beta radioactivity used in our experiments was trivial compared to the large amounts of gamma radioactivity routinely used in diagnostic tests of thyroid function. Furthermore, the biological half-life of the isotope in the steroids is the same as the parent hormone, about 1 d, since the ring structure of steroids remains intact in vivo. A review of our studies appeared in this journal in 1966 (10). The conversion of DHEAS to estradiol increases until the maximal size of the placenta is reached at about 30–32 wk gestation. We also studied the dynamics of placental utilization of DHEAS and found that the MCR of DHEAS increases from 8–10 liters/24 h to 50–100 liters/24 h during normal pregnancy (11). This increase reflects the action of placental steroid sulfatase, which allows access of DHEA to the 3ß-hydroxysteroid dehydrogenase and aromatase enzymes within the syncytiotrophoblast layer and conversion to estrone and estradiol. Frandsen and Stakemann (12) found very low estriol excretion by women who were pregnant with an anencephalic fetus and suggested that the normal fetal adrenal glands secrete a steroidal precursor for placental estriol synthesis. Our studies supported this scheme, as the tritium specific activity of estriol isolated from normal pregnant women consistently was 5- to 10-fold lower than that of estrone or estradiol. These results indicated that labeled estriol formed from DHEAS in the maternal compartment was being diluted by unlabeled estriol. We estimated that more than 100 mg/24 h of estriol was formed in the fetoplacental unit near the end of normal pregnancy. The concept of the fetoplacental unit came from studies in Diczfalusy’s (13) laboratory showing that DHEAS from the fetal adrenal glands was hydroxylated at the 16
position in the fetal liver and then aromatized to estriol in the placenta. Most of this massive amount of estriol exits the placenta into the uterine vasculature and the maternal circulation. Estriol is still considered by some to be a weak estrogen even though studies in sheep many years ago showed that it is a potent stimulator uterine blood flow (14).
Although estradiol levels in maternal blood are higher than estriol, it is bound to the much higher levels of SHBG and not available to tissues. Optimal development and growth of the fetus depends upon adequate delivery of oxygen and nutrients across the hemochorial placenta to the fetal circulation throughout gestation. Continued growth and development of the newborn infant depends upon increased blood flow to the breasts during gestation in preparation for lactation. Although studies of estriol on the breasts of pregnant woman are unlikely to be performed, its effects are clearly evident by visual inspection. Can DHEAS have a more important role in homo sapiens?
Footnotes
Abbreviations: A, Androsterone; A4, androstenedione; DHEA, Dehydroepiandrosterone; DHEAS, DHEA sulfate; E, etiocholanolone; MCR, metabolic clearance rate; T, testosterone.
Received April 18, 2005.
Accepted April 27, 2005.
References
This article has been cited by other articles:
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  R. J. Santen, H. Brodie, E. R. Simpson, P. K. Siiteri, and A. Brodie History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target Endocr. Rev., June 1, 2009; 30(4): 343 - 375. [Abstract] [Full Text] [PDF]
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