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Articles by Labrie, F.
Articles by Candas, B.
The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 10 3498-3505
Copyright © 1997 by The Endocrine Society


Original Studies

Effect of 12-Month Dehydroepiandrosterone Replacement Therapy on Bone, Vagina, and Endometrium in Postmenopausal Women

Fernand Labrie, Pierre Diamond, Leonello Cusan, Jose-Luis Gomez, Alain Bélanger and Bernard Candas

Clinical Endocrine Research Unit, Laboratory of Molecular Endocrinology, CHUL Research Center and Laval University, Quebec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Prof. Fernand Labrie, Laboratory of Molecular Endocrinology, CHUL Research Center, 2705 Laurier Boulevard, Quebec, Canada G1V 4G2.


   Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
The effect of 12-month dehydroepiandrosterone (DHEA) replacement therapy has been evaluated in 14 60- to 70-yr-old women who received daily applications of a 10% DHEA cream. Vaginal epithelium maturation was stimulated by DHEA administration in 8 of 10 women who had a maturation value of zero at the onset of therapy, whereas a stimulatory effect was also seen in all three women who had an intermediate vaginal maturation index before therapy. The estrogenic effect of DHEA observed in the vagina was not observed in the endometrium, which remained atrophic in all women. Most interesting, the bone mineral density significantly increased at the hip from 0.744 ± 0.021 to 0.759 ± 0.025 g/cm2 after 12 months of treatment (P < 0.05). These changes in bone mineral density were associated with a significant 20.0% decrease (P < 0.01) in plasma bone alkaline phosphatase and a 28% decrease in the urinary hydroxyproline/creatinine ratio. A 2.1-fold increase over the control value (P < 0.01) in plasma osteocalcin was concomitantly observed. The present data describe for the first time a series of medically important beneficial effects of DHEA therapy in postmenopausal women through transformation of the precursor steroid DHEA into androgens and/or estrogens in specific peripheral intracrine tissues without significant adverse effects. The stimulatory effect on the vaginal epithelium in the absence of stimulation of the endometrium is of particular interest because it eliminates the need for progestin replacement therapy. On the other hand, the stimulatory effect on bone mineral density accompanied by an increase in serum osteocalcin, a marker of bone formation, suggests stimulation of bone formation by the androgenic action of DHEA, a finding of particular interest for both the prevention and treatment of osteoporosis.


   Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
DESPITE THE fact that the serum concentration of dehydroepiandrosterone (DHEA) sulfate (DHEA-S) in adult men and women is higher than that of any other steroid, except cholesterol, the physiological role of this adrenal steroid is little understood. Recent data, however, indicate that man, in addition to possessing a very sophisticated endocrine system, is largely dependent upon peripheral tissues for androgen and estrogen formation from the adrenal precursors DHEA-S and DHEA (1, 2, 3, 4, 5, 6). In fact, although the ovaries or testes are the exclusive sources of androgens and estrogens in lower mammals, the situation is very different in higher primates, where androgens and estrogens are in a large part or entirely synthesized locally in peripheral tissues, thus providing target tissues with the means to adjust the formation and metabolism of sex steroids according to local needs (2).

Man is thus unique, with some other primates, in having adrenals that secrete large amounts of the precursor steroids DHEA-S and DHEA, which are converted into androst-5-ene-3ß,17ß-diol and androstenedione and then into androgens and/or estrogens in peripheral intracrine tissues (1, 2, 3, 4, 5, 6). Adrenal secretion of DHEA and DHEA-S increases during adrenarche in children at the age of 6–8 yr, and maximal values of circulating DHEA-S are reached between the ages of 20–30 yr (7, 8, 9, 10). Thereafter, serum DHEA and DHEA-S levels decrease progressively. In fact, at 70 yr of age, serum DHEA-S levels have decreased to approximately 20% of their peak values, and they further decrease to only 5% by the age of 85–90 yr (7). It is remarkable that up to approximately 60% of the age-related decrease in serum DHEA-S and DHEA concentration, however, takes place before the age of 50–60 yr (71).

The up to 95% reduction in the formation of DHEA-S by the adrenals during aging results in a dramatic reduction in the formation of androgens and estrogens in peripheral target tissues, a situation that has been suggested to be associated with age-related diseases such as insulin resistance (11, 12), cardiovascular disease (13), and obesity (14, 15, 16). Moreover, low circulating levels of DHEA-S and DHEA have been observed in patients with breast (17) and prostate (18) cancer. DHEA has also been found to exert antioncogenic activity in a series of animal models (19, 20, 21). DHEA has been shown to exert immunomodulatory effects in vitro (22) as well as in vivo in fungal and viral diseases (23). On the other hand, a stimulatory effect of DHEA on the immune system has been described in postmenopausal women (24).

Among the problems associated with aging, one of the most serious is osteoporosis, which causes morbidity and mortality mainly through increased fracture rates (25). Estrogen replacement therapy commonly used against osteoporosis requires the addition of progestins to counteract the endometrial proliferation induced by estrogens. Moreover, as both estrogens and progestins are thought to increase the risk of breast cancer (26, 27), we have studied the effect of 12-month administration of DHEA to 60- to 70-yr-old women on bone mineral density (BMD) and other parameters of bone formation and turnover as well as on vaginal and endometrial histology. DHEA was administered percutaneously to avoid first passage of the steroid precursor through the liver.


   Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Subjects

Fourteen healthy 60- to 70-yr-old postmenopausal women participated in this study after internal review board approval and having given their written informed consent. The participants were nonsmokers, and their average age was 63.7 ± 0.76 yr. No subject had taken hormone replacement therapy or medication known to act on bone metabolism during the previous 5 yr. No subject was suffering from an endocrine disorder, and none was taking lipid- or glucose-lowering agents. All women had a medical history, complete physical examination, and serum biochemistry profile including lipids, complete blood count, urinalysis, and detailed serum hormone determinations during the screening phase of the protocol. The mean pretreatment serum DHEA level was 3.9 ± 0.5 nmol/L. All subjects completed a daily diary to assess dietary intake, physical activity, side-effects, and sensation of well-being. The diary completed daily by the participants showed that there was no important change in diet or physical activity during the study. Well-being was evaluated by the daily diary, which included assessment of fatigue, insomnia, tolerance to usual daily activities, tolerance to stress, and level of energy. Each individual daily diary was reviewed with the subject at each monthly visit by the nurse and the physician. Although there was no specific requirement for exercise and diet, no woman was involved in a weight loss program or was following a special diet.

Study design, treatment, and measurements

DHEA (Diosynth, Chicago, IL) was administered percutaneously once daily for 12 months in the morning as a 10% cream (10% DHEA, 29.6% ethanol, 33.4% USP purified water, 16% emulsifying wax, 10% light mineral oil, and 1% benzyl alcohol). Emulsifying wax meeting national formulary standards was purchased from Croda, Toronto, Canada. It is a waxy solid prepared from cetostearyl alcohol containing a polyoxyethylene derivative of a fatty acid ester of sorbitan. The specific characteristics of the emulsifying were a melting point of 50–54 C and a hydroxyl value of 178–192 C. Light mineral oil meeting national formulary standards was purchased from Harrisons and Crosfield (Merrimack, NH). This oil is a mixture of liquid hydrocarbons obtained from petroleum. The specific characteristics of the mineral oil used were a specific gravity of 0.818–0.880 at 25 C and a viscosity of 33.5 centistorkes at 40 C.

The DHEA cream was applied over an area of approximately 20 x 20 cm on both thighs, the application being followed by rubbing with the hand for a few seconds to optimize distribution of the cream on the skin and its absorption. Starting with 5.0 g cream, the posology was adjusted according to DHEA blood levels targeted at 20–30 nmol/L. Serum DHEA was measured once a week during the first month and then monthly in both control and DHEA-treated groups. From 3–5 g cream were usually used. As control, eight women received the placebo cream during 6 months preceding DHEA therapy, whereas seven women received the same dose of placebo cream during 6 months after cessation of DHEA. All 14 women received DHEA for 12 months.

A vaginal smear was obtained immediately before DHEA administration and then every 3 months during treatment as well as after cessation of treatment. The vaginal epithelium maturation value was evaluated according to the amount of parabasal, intermediate, and mature cells. Uterine biopsy with a polypropylene endometrial suction curette (Pipelle de Cormier, Unimar, Neuilly-en-Thelle, France) was performed before and after 12 months of DHEA treatment.

Sebum production was estimated with Sebutape patches (CuDerm Corp., Dallas, TX) placed on six facial areas for 1 h after careful cleaning of the skin with alcohol and drying.

Bone densitometry measurements (Hologic QDR-2000, dual energy x-ray absorptiometry bone densitometer, Waltham, MA) were carried out at 6-month intervals to evaluate BMD of both the left hip and lumbar spine. BMD was estimated in grams per cm2 at the lumbar spine level in the anterior pituitary and lateral projections (L2–L4) and at the level of the left hip. The total hip BMD was calculated as well as the Ward’s triangle BMD, which is the minimal density area located at the lower edge of the femoral neck box.

Samples of blood and urine were collected every 3 months in the morning between 0730–0800 h after a 12-h fast. Serum DHEA, LH, and FSH were measured by RIA (10, 28, 29). Urinary hydroxyproline and creatinine were both measured by colorimetric methods (30, 31), whereas alkaline phosphatase was measured by enzymatic assay (Ektachem 750 XRC analyzer, Eastman Kodak, Rochester, NY). Blood osteocalcin and bone-specific alkaline phosphatase were both measured as markers of bone formation by immunoradiometric assay [active human osteocalcin (Diagnostic Systems Laboratory, Webster, TX) and Ostase (Hybritech (San Diego, CA), respectively].

Statistical analyses of the data were performed using a univariate ANOVA for repeated measures. The normality of the residuals was tested with Shapiro-Wilk’s statistics, and the homogeneity of variances between the groups was assessed using Levene’s procedure. If one of the two basic assumptions of the ANOVA did not hold, the ANOVA was performed on the ranks instead of the original values, which corresponds to the Kruskal-Wallis nonparametric ANOVA. When the ANOVA determined a significant overall effect, treatment means were compared to the initial measurements at time zero with Fisher’s least significant difference tests. All statistics were performed using the SAS software (SAS Institute, Cary, NC). Results are reported as the mean and SE.


   Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Bone density

As presented in Table 1, total hip BMD increased significantly from 0.744 ± 0.021 to 0.753 ± 0.023 g/cm2 after 6 months of treatment (P < 0.05) and to 0.759 ± 0.025 g/cm2 after 12 months of DHEA administration (P < 0.05). On the other hand, after the 12 months of DHEA treatment, the femoral Ward’s triangle BMD increased from 0.486 ± 0.026 to 0.494 ± 0.026 g/cm2, and the lumbar spine BMD increased from 0.829 ± 0.030 to 0.839 ± 0.033 g/cm2, although these changes did not reach the level of statistical significance.


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Table 1. Effect of percutaneous administration of DHEA for 6 and 12 months on bone mineral density in total hip, Ward’s triangle, and lumbar spine (n = 14)

 
Markers of bone formation, resorption, and turnover

The serum concentration of osteocalcin, a marker of bone formation, increased from 1.16 ± 0.30 µg/L pretreatment to 1.95 ± 0.59 µg/L (P = NS), 2.28 ± 0.53 µg/L (P < 0.05), 2.49 ± 0.58 µg/L (P < 0.01; 115% over control), and 2.44 ± 0.47 (P < 0.01; 110% over control) after 3, 6, 9, and 12 months of treatment, respectively (Fig. 1). After cessation of DHEA administration, the serum levels of osteocalcin returned to pretreatment values of 1.52 ± 0.33 and 1.14 ± 0.58 µg/L at 3 and 6 months during placebo treatment; these values were not statistically different from pretreatment values (data not shown).



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Figure 1. Effect of DHEA administered percutaneously up to 12 months on serum concentrations of osteocalcin.

 
In parallel with the above-indicated effects on serum osteocalcin, the serum concentration of bone alkaline phosphatase decreased from 16.5 ± 1.3 µg/L (pretreatment) to 14.4 ± 0.9 µg/L (P < 0.05), 14.9 ± 0.7 µg/L (P = NS), 13.0 ± 0.9 µg/L (P < 0.01), and 13.2 ± 1.0 µg/L (P < 0.01) after 3, 6, 9, and 12 months of treatment (Fig. 2). The values observed 3 and 6 months after cessation of DHEA treatment were not significantly different from those measured pretreatment or after 6 months of DHEA treatment, although they suggest a trend toward a return to pretreatment values. The urinary hydroxyproline/creatinine ratio, a marker of bone resorption, decreased from 24.0 ± 1.7 µmol/mmol creatinine at pretreatment to 20.6 ± 1.4 (P < 0.05) and 17.2 ± 0.93 µmol/mmol creatinine (P < 0.01) after 3 and 6 months of DHEA treatment, respectively. After 9 and 12 months of treatment, the urinary hydroxyproline/creatinine ratio was decreased at 18.4 ± 0.9 (P < 0.01) and 19.0 ± 1.3 (P < 0.0l) µmol/mmol, respectively (Fig. 3). Total serum alkaline phosphatase decreased from 92.4 ± 6.9 U/L at pretreatment to 84.6 ± 4.1 (P = NS), 82.6 ± 4.1 (P < 0.05), 74.9 ± 4.1 (P < 0.01), and 77.1 ± 4.8 U/L (P < 0.01) at 3, 6, 9 and 12 months, respectively (Table 2).



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Figure 2. Effect of DHEA administered percutaneously up to 12 months on serum concentrations of bone alkaline phosphatase.

 


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Figure 3. Effect of DHEA administered percutaneously up to 12 months on the hydroxyproline/creatinine urinary excretion ratio.

 

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Table 2. Effect of 12-month percutaneous administration of DHEA to 60- to 70-yr-old women on plasma alkaline phosphatase, SHBG, and DHEA concentrations

 
Vaginal cytology

Vaginal cytology was examined as specific parameter of the estrogenic action of DHEA. Before treatment, 10 women had a completely atrophic vaginal smear exclusively composed of parabasal cells (Fig. 4, A and B, for example). In 8 of these 10 women, during DHEA treatment the vaginal cytology was converted into a pattern typical of that in normal cycling women, showing mainly the presence of superficial pyknotic cells (Fig. 5, A and B, for example). In 2 of the 10 women with a zero maturation index value at the start of treatment, no significant change in the cytological maturation value was observed up to 12 months of treatment (Fig. 6A). In the 3 women who had a maturation value between 1–40 at the start of treatment, stimulation was also observed, and the cytology became typical of the normal reproductive range in all of them at 3 months, the first measurement after the start of DHEA administration (Fig. 6B). In the last 2 women, the maturation value was already in the normal range for women of reproductive age before treatment, and it remained unchanged during treatment (Fig. 6B).



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Figure 4. A, Atrophic vaginal smear with numerous parabasal cells in a 65-yr-old woman before starting treatment with DHEA (x100). B, Atrophic vaginal smear with numerous parabasal cells in a 65-yr-old woman before starting treatment with DHEA (x400).

 


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Figure 5. A, Vaginal smear from the same patient as Figs. 4A after 12 months of DHEA treatment, showing superficial pyknotic cells (x100). B, Vaginal smear from the same patient as Fig. 4B after 12 months of DHEA administration, showing superficial pyknotic cells at larger magnification (x400).

 


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Figure 6. Effect of percutaneous administration of DHEA up to 12 months (13 women) followed by 6 months of placebo (5 women) on vaginal cytological maturation. In A, the 10 women had a zero maturation value at the start of treatment. The stimulation can be seen in 8 women at the first measurement during treatment. In B, on the other hand, 3 women had intermediate maturation values of their vaginal cytology, whereas 2 had normal maturation values before starting DHEA treatment. Different symbols represent individual women.

 
Endometrial histology

Considering the major concern related to the stimulatory effect of estrogens on endometrial proliferation with the related risk of endometrial carcinoma (32, 33), an endometrial biopsy was performed before starting treatment and after 12 months of DHEA administration. As shown in Fig. 7, the endometrial atrophy seen in all women at the start of treatment remained unaffected by 12 months of DHEA administration.



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Figure 7. Atrophic endometrium after 12 months of DHEA treatment in a representative 65-yr-old woman (x100).

 
Sebum secretion

As skin sebaceous glands are known to contain all the steroidogenic enzymes that catalyze the transformation of DHEA into the androgen DHT (34, 35, 36, 37), and androgens are the main stimulators of sebaceous gland activity (38, 39, 40, 41), we have measured the effect of DHEA treatment on sebum secretion. As measured by the Sebutape technique at six facial sites, percutaneous administration of DHEA led to a comparable 66–79% stimulation (P < 0.01) of sebum secretion after 3, 6, 9, and 12 months of treatment (Fig. 8). Sebum secretion had returned to pretreatment values 3 months after cessation of DHEA therapy (data not shown).



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Figure 8. Effect of percutaneous administration of DHEA for 6 and 12 months on the sebum secretion index measured with the Sebutape technique on six facial areas at the indicated time intervals.

 
Serum SHBG

Serum SHBG levels, on the other hand, decreased from 65 ± 9.8 nmol/L pretreatment to 52.7 ± 5.6 (P < 0.01), 51.7 ± 5.3 (P < 0.01), 51.9 ± 7.1 (P < 0.01), and 53.5 ± 6.2% (P < 0.05) after 3, 6, 9, and 12 months of DHEA treatment, respectively, with a return to pretreatment values at 3 and 6 months of placebo administration.

Secondary effects

Two women presented a slight increase in facial hair growth on the upper lip, and two other women developed slight acne during treatment. Well-being and an increase in energy were reported in 80% of women.


   Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
The present study describes for the first time a series of medically important beneficial effects of DHEA administered for 12 months to postmenopausal women. Possibly the most important effect is the DHEA-induced stimulation of BMD. The relatively rapid change in BMD is accompanied by an increase in the value of a marker of bone formation, namely the serum osteocalcin concentration, whereas a decrease in bone resorption reflected by a decrease in urinary hydroxyproline excretion was observed in parallel. In addition, the estrogenic stimulation of vaginal cytology in the absence of any sign of stimulatory effect on the endometrium is of potentially major interest for the prevention and management of menopause. Our data also confirm the beneficial effects of DHEA on well-being and energy reported previously (42).

As far as serum lipids are concerned, we observed a small, but not statistically significant, decrease in serum triglycerides, cholesterol, and lipoprotein components up to 12 months of percutaneous administration of DHEA (43). Our data certainly suggest that DHEA treatment has no deleterious effects; rather, they show a trend toward positive effects on the serum lipid and lipoprotein profiles, although a larger cohort of subjects is needed to reach definitive conclusions. On the other hand, it should be mentioned that conjugated equine estrogens raise triglyceride levels and show a deterioration of the insulin response (44, 45). In fact, our data show an inhibitory effect of DHEA treatment on fasting blood glucose and insulin levels (43), thus suggesting an advantageous effect over that of equine estrogens on glucose metabolism.

As mentioned above, DHEA is well known to be transformed into both androgens and estrogens in peripheral tissues (2, 3, 5, 6). Despite the marked fall in endogenous androgens in women during aging, the use of androgens in postmenopausal women has been limited mainly because of the fear of an increased risk of cardiovascular disease, as based upon older studies showing an unfavorable lipid profile with androgen treatment. Recent studies, however, have shown no significant effect of combined estrogen and androgen therapy on the serum levels of cholesterol, triglycerides, high density lipoproteins (HDL), low density lipoproteins (LDL), and the HDL/LDL ratio compared to that of estrogen alone (46). In agreement with these observations, our data show that DHEA, a compound with a predominantly androgenic influence, has apparently no deleterious effect on the serum lipid profile (43). Similarly, no change in the concentrations of cholesterol, its subfractions, or triglycerides from those after treatment with estradiol alone has been observed after 6 months of therapy with estradiol plus testosterone implants (47). It should be mentioned that a study in man has shown an inverse correlation between fetal serum DHEA-S and low density lipoproteins (48). More recently, a correlation has been found between low serum testosterone and DHEA levels and increased visceral fat, a parameter of higher cardiovascular risk (16).

Administration of testosterone in moderate doses leading to plasma testosterone levels in the physiological range has even been found to induce a decrease in plasma triglyceride and cholesterol levels, a reduction in abdominal adipose cell LPL activity, as well as an increased lipolytic responsiveness of adipocytes to norepinephrine (49, 50, 51). The percutaneous administration of testosterone in men with abdominal obesity led to decreased plasma triglycerides, cholesterol, and fasting blood glucose levels as well as decreased diastolic blood pressure. Such data indicate an improvement by androgens in the risk factors for cardiovascular disease (49).

Although the maximal 4.1% and 6.6% decreases in serum cholesterol observed at 6 months in our study did not reach the level of significance, possibly due to the small number of subjects (43), such changes are comparable to the 2.8% decrease in serum cholesterol observed after 1 yr of replacement therapy with Premarin and Provera (52). Such changes are also in agreement with the 3% decrease in total serum cholesterol achieved with percutaneous 17ß-estradiol (Estrogel) and Utrogestan (28) and the 5.5% inhibition of the same parameter after treatment with Premarin and Utrogestan (28). It should also be mentioned that the serum lipid levels in our cohort of subjects were within the normal range at the start of therapy, whereas it is recognized that the beneficial effects of replacement therapy with Premarin/Provera depend upon the initial serum lipid values (53). As HDL cholesterol appears to remain stable during the menopausal period, whereas LDL cholesterol increases (54), our data showing a trend for decreased LDL levels (43) might represent another positive effect of DHEA treatment.

Although androgens are gaining increased recognition for their specific beneficial effects in postmenopausal women, virilizing effects are observed with the use of testosterone (55, 56). As examples of the beneficial effects of androgens, BMD measured in the lumbar spine, femoral trochanter, and total body was increased more by estrogen plus testosterone implants than by estradiol alone over a 24-month period (57). Moreover, in established osteoporosis, anabolic steroids have been reported to help prevent bone loss (58). Similarly, sc estradiol and testosterone implants have been found to be more efficient than oral estrogen in preventing osteoporosis in postmenopausal women (59). Although the difference has been attributed to the different route of administration of estrogen, the cause of the difference could well be the action of testosterone. Androgen therapy, as observed with nandrolone decanoate, has been found to increase vertebral BMD in postmenopausal women (60). The present data indicate a significant increase in BMD in the hip as soon as 6 months after the initiation of the treatment. The total improvement over the 12 months reaches 2.0%. An increase, although not yet significant at the 12th month of treatment, was also observed in the hip Ward’s triangle and the lumbar spine. Based upon our results in the rat, it is likely that the important stimulatory effect observed on bone formation in the present group of women treated with DHEA is due to the conversion of DHEA into androgens.

Treatment with estrogens is known to decrease the value of the markers of bone resorption, namely urinary hydroxyproline, total and free pyridinoline and deoxypyridinoline cross-links, and N-telopeptides of type I collagen as well as serum C-terminal cross-linked collagen telopeptide (61). A close correlation is observed among the various markers of bone resorption, especially between pyridinoline and deoxypyridinoline and between pyridinoline and free cross links (61). Of particular interest is the present observation of a marked increase in the concentration of serum osteocalcin, a well recognized marker of bone formation. This unique effect of DHEA may be particularly important for postmenopausal women, because it raises the hope of regaining at least partially the bone lost during the peri- or postmenopausal years, whereas estrogens can only decrease the rate of bone loss and are unable to recuperate the bone lost before the start of therapy (62, 63).

It is clear from the present observation of an inhibitory effect of DHEA on serum SHBG levels and a stimulation of sebum secretion that DHEA possesses a predominantly androgenic activity, whereas the stimulation of vaginal cytology is a typical estrogenic effect. In fact, it is well known that increased androgens reduce whereas increased estrogens stimulate serum SHBG concentrations in women (64). As mentioned above, the androgenic activity of DHEA, well demonstrated on sebum production and on serum SHBG levels, is probably responsible for the increased concentration of serum osteocalcin and increased BMD observed in the present study.

The androgenic component of DHEA should also be useful in reducing hot flushes in postmenopausal women. In fact, androgen therapy is known to be successful in reducing hot flushes in hypogonadal men (65). Moreover, the addition of androgens has been found to be effective in relieving hot flushes in women who had unsatisfactory results with estrogen alone (66). There is also much evidence that androgens make an important contribution to libido and sexuality in women (67). Although the number of women in the present study was limited, and the questionnaire on sexual activity was not extensive, there was no clear indication, except anecdotal, of increased libido after DHEA treatment. Well-being, however, was increased in 80% of the women. Similarly, in a recent study, well-being was improved in 82% of the women, whereas no effect was reported on libido during DHEA administration (42). Well-being included increased energy, better ability to handle stress, improved quality of sleep, and feeling of relaxation (42). In agreement with our findings after DHEA therapy, the benefits of androgens added to estrogen or hormone replacement therapies have been described on general well-being, energy, mood, and general quality of life (68, 69).

It should be mentioned that measurement of circulating levels of testosterone and estradiol have limited value in the assessment of androgenic and estrogenic activities in peripheral tissues (2, 4, 70, 71). In fact, the concentrations of serum testosterone and estradiol in the blood predominantly reflect testicular and ovarian androgen and estrogen secretion, respectively. In postmenopausal women, on the other hand, almost all active sex steroids are made locally in peripheral tissues (2, 4). The circulating levels of the adrenal C19 steroids are the parameters directly reflecting the level of precursor sex steroid secretion by the adrenals. However, the most reliable parameters of the total androgenic impact on the organism are the serum concentrations of the metabolites of androgens, especially the glucuronide derivatives of androstane-3{alpha},17ß-diol, androstane-3ß,17ß-diol, and androsterone as well as androsterone sulfate (2, 10). The interpretation of these measurements of circulating androgen metabolites, however, must take into account the fact that each cell and tissue synthesizes its own androgens and/or estrogens from DHEA or DHEA-S according to the level of expression of the steroidogenic enzymes in each peripheral intracrine tissue (2) and that the circulating levels of the resulting androgen metabolites represent the sum of the contribution of all cells and tissues that independently release different amounts of the steroid metabolites in the circulation.

The present data clearly suggest the interest of a new approach to hormone replacement therapy with potentially improved efficacy and tolerance. It is possible that DHEA replacement therapy could not only correct, but also prevent, the multiple problems associated with menopause, a phenomenon preceded and accompanied by the decreased formation of both androgens and estrogens during aging in women.

Received November 18, 1996.

Revised March 17, 1997.

Revised May 28, 1997.

Accepted June 27, 1997.


   References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 

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