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Original Studies |
Division of Endocrinology, Diabetes and Metabolism (S.D-J.), Washington University School of Medicine, St. Louis, Missouri 63110; Department of Medicine (N.A-A., M.Q.), Kuwait University (Mubarak) Hospital, Safat 13110, Kuwait
Address correspondence and requests for reprints to: Samuel Dagogo-Jack, MD, Division of Endocrinology, Diabetes and Metabolism, Washington University School of Medicine(Box 8127), 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: sdagogo{at}imgate.wustl.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Thus, women with hirsutism (and associated hyperandrogenism and menstrual defects) present a unique opportunity to study the net effect, in vivo, of the opposing forces of oligomenorrhea and hyperandrogenism on skeletal mass. We hypothesized that the increased androgen tone in hirsute women counteracts the osteopenic effects of anovulation and menstrual dysfunction. We have tested this hypothesis by comparing bone mineral indices in hirsute and nonhirsute women drawn from the same ethnic population.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied 32 women, mean (± SE) age 23.0 ±
0.7 yr (range 18–42 yr), referred to Kuwait University Endocrine
Clinic for evaluation of hirsutism. Hirsutism was indicated by a score
of 8 or more, and its severity was graded as mild for scores less than
10 (n = 14), moderate for scores of 10–12 (n = 13), and
severe for scores of 12 or over(n = 5), on the Ferriman and
Gallwey (17) scale. The history of hirsutism had been present for 6
months to 14 yr (mean duration 5.2 ± 0.6 yr). Based on the
findings on clinical examination, the presence of an increased LH:FSH
ratio, and positive findings on pelvic ultrasonography, a diagnosis of
polycystic ovarian syndrome (PCOS) was entertained in 10 patients. The
remainder were diagnosed with idiopathic hirsutism, based on history,
physical examination, and negative studies for PCOS or sinister causes
of hirsutism. None of the women were virilized, and none showed
clinical or biochemical evidence of hyperthyroidism, parathyroid
disease, Cushing’s syndrome, or prolactinoma. Twenty-one patients gave
a history of regular menses (defined as 4 or more monthly menstrual
episodes during the preceding six months), and 11 had a history of
oligomenorrhea (1–3 monthly menstrual episodes during the preceding
six months). Patients with a history of amenorrhea lasting 6 months or
longer were excluded from the study. The control group consisted of 25
nonhirsute (Ferriman and Gallwey score 
7) women matched in age
and other respects with the study group (Table 1
). Information regarding the predominant
mode of dressing was recorded for each subject to take account of
possible variability in sun exposure. Subjects’ recall of dairy intake
was recorded as milk equivalents per week (1 pound of cheese was
equated to 2 eight-ounce cups of milk). All study and control subjects
were ethnic Kuwaiti Arabs. Persons from migrant populations and those
who identified their ancestry as Palestinian, Saudi, Lebanese, or
other non-Kuwaiti nationalities were excluded. Patients with a history
of previous or current drug treatment for hirsutism were excluded; no
study participant was taking medications known to affect bone density;
and none were involved in regular physical exercise or weight loss
program.
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Bone mineral density (BMD), bone mineral content (BMC), and percent body fat were measured by dual energy x-ray absorptiometry (DEXA) using a LUNAR DPX machine (LUNAR, Madison, WI). Spinal BMD was assessed in the anteroposterior (AP) projection at the L2-L4 lumbar vertebral region. Total body BMD and BMC were measured from the cranial vertex to the toes using a fast acquisition mode. The coefficient of variation (CV) of 241 consecutive measurements of a spinal phanthom during the study period was less than 1.0%, without evidence of a measurement drift.
Laboratory measurements
Serum total testosterone (Orion Diagnostica, Espoo, Finland) and androstenedione (Johnson & Johnson Diagnostics, Amersham, UK) were measured in-house, using commercial radioimmunoassay (RIA) kits, as were sex hormone binding globulin (SHBG)(Orion Diagnostica) and prolactin (Sorin Biomedica, Saluggia, Italy), using immunoradiometric assay (IRMA) kits. Serum intact parathyroid hormone was measured using IRMA, and 25-hydroxyvitamin D3 was measured by competitive protein binding assay. The lower limit of detection for the testosterone RIA was 0.1 nmol/L, and between- and within-batch CVs were less than 8%. The lower detection limit for the androstenedione RIA was 0.08 nmol/L, with CVs of less than 7%. The SHBG assay had a detection limit of 0.5 nmol/L, a within-batch CV of 4.9%, and a between-batch CV of 8.3%. Serum free thyroxine, FSH, and LH were measured with Amerlex RIA kits and TSH with an IRMA kit; all kits were supplied by Johnson & Johnson Diagnostics. Blood chemistries were analyzed on a routine multichannel analyzer.
Statistical methods
Results are expressed as means ± SE.
Continuous variables in hirsute and control women were compared using
unpaired t tests, and 
-square tests were used to compare
discrete variables. Single-factor ANOVA was used to compare BMI in
control women and in subgroups of hirsute women defined by menstrual
status. The Pearson product-moment correlation coefficient was used to
assess correlations between BMD (or BMC) and other variables.
P less than 0.05 was accepted as significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mean serum total testosterone level (Fig. 1) was 2.21 ± 0.12 nmol/L in
hirsute women and 2.30 ± 0.22 nmol/L in nonhirsute controls,
P more than 0.5. (Female reference range for total
testosterone at Kuwait University Hospital, 0.3–3.0 nmol/L.) The serum
androstenedione level (Fig. 1) was 11.7 ± 0.8 nmol/L in hirsute
women and 7.9 ± 0.8 nmol/L in controls, P less than
0.005 (reference range 1.6–9.4 nmol/L). The mean serum SHBG level
(Fig. 2) in hirsute women was 22.0
± 3.0 nmol/L, compared with 57.6 ± 8.5 nmol/L in nonhirsute
women, P less than 0.001 (reference range 20- 118 nmol/L).
Vitamin D stores were at the lower limit of normal in both hirsute and
control women, but serum calcium, phosphorus, alkaline phosphatase, and
intact PTH levels all were within the normal ranges (Table 2).
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The total body BMD of hirsute women, 1.202 ± 0.016
g/cm2, was higher (P < 0.01) than that of
nonhirsute controls, 1.116 ± 0.018 g/cm2. The hirsute
group also had a higher (P < 0.001) BMC (Fig. 3) than controls (2700 ± 66 g
vs. 2400 ± 70 g). The BMD at the L2 - L4 lumbar
spine was 1.183 ± 0.02 g/cm2 for hirsute women,
compared with 1.125 ± 0.02 g/cm2 for the control
group, P < 0.01 (Fig. 3). The correlation of total BMD
with body mass index was 0.44 (P < 0.05) in the
hirsute group and 0.61 (P < 0.01) in the control
group. Although both groups were well-matched for percent body fat
(Fig. 2
), the correlation of total BMD with body fat was 0.65
(P < 0.001) in the nonhirsute control group and 0.26
(P > 0.1) in hirsute women. The same trend was seen in
the correlation of lumbar spine BMD with percent body fat: 0.49
(P < 0.02) in controls and 0.23 (P >
0.1) in hirsute women. However, the correlation of body fat with BMC
was more concordant across the two groups: 0.67 (P <
0.001) in controls and 0.49 (P < 0.02) in hirsute
women. Oligomenorrheic hirsute women tended to have lower mean values
for total BMD and lumbar spine BMD than hirsute women with regular
menses, but the differences were not statistically significant (Table 3). Compared with nonhirsute control
women, the oligomenorrheic hirsute women had higher mean values for
total BMD, lumbar spine BMD, and BMC (Table 3). There were no
significant correlations between BMD and plasma total testosterone
(r = 0.13, P > 0.5) or androstenedione (r =
0.31, P > 0.1) levels. The hirsutism score also did
not correlate significantly (r = 0.32, P > 0.05)
with plasma androstenedione level.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Increased androgen sensitivity in osseous tissue of hirsute women is the contending mechanism for our findings, especially in patients with normal levels of circulating sex steroids and SHBG. Elevated serum estradiol and estrone levels in some patients with PCOS conceivably could contribute to bone formation; however, the majority of women with PCOS have serum estradiol levels within the normal range for follicular phase of ovulatory menstrual cycles in women without PCOS (18). [Serum estrogen levels were not evaluated in the present study. In a related study (21), mean estradiol levels were not significantly different between hirsute and nonhirsute groups, but the area under the curve of multiply sampled estradiol levels was approximately 40% lower in oligomenorrheic/ amenorrheic hirsute women compared with eumenorrheic hirsute women.) Support for an androgen-mediated mechanism is provided by the observation that spironolactone treatment for 1 yr significantly decreased BMD in 15 out of 17 young women with hirsutism (22). Interestingly, a decrease in plasma androstenedione level was the only hormonal variable that significantly predicted the decrease in BMD among women in the latter study (22).
Numerous demographic, dietary, and hormonal factors influence the accrual of bone mass. To ensure a valid comparison between hirsute and nonhirsute subjects, the present study attempted to control as many of these variables as was clinically possible. All subjects were recruited from the same ethnic group, and all were well-matched with regard to age, percent body fat, sun exposure (as deduced from mode of dressing), level of physical activity, and parity. The hirsute women reported less dairy consumption than did nonhirsute women, but serum calcium, phosphorus, vitamin D, and PTH levels were similar in both groups. In any case, the lower intake of dairy products by the hirsute women should have decreased, not increased, their BMD. Notably, low vitamin D levels have previously been reported in the Arabian Gulf region (23). Within the same ethnic group, however, genetic and familial factors play a role in determining the distribution and density of body hair (19) as well as accrual of bone mass (24). It was not possible to specifically assess the influences of genetic and familial factors on hair pattern and bone mass in the present study.
The higher bone density and mineral content of hirsute women was observable at all skeletal sites. The subset of oligomenorrheic hirsute women who tended to have lower BMD and BMC than their eumenorrheic counterparts showed the greatest disparity at the lumbar spine. However, this trend did not reach statistical significance, and the hirsute women, regardless of menstrual status, accrued greater BMD and BMC than did women in the control group. In both the hirsute and control groups, BMD was correlated with BMI, but the hirsute women showed no correlation between percent body fat and BMD, and a weaker correlation between body fat and BMC, than did controls. The reasons for the latter findings are unclear, but may well be related to differential effects of hyperandrogenism on musculoskeletal and soft tissue body composition (25).
Our finding of higher indices of bone mass in women with hirsutism is in accord with previous reports (26, 27). However, our data showing statistically similar BMD in oligomenorrheic and eumenorrheic hirsute women is in apparent discord with the results of Castelo-Branco and colleagues (21), who found a significantly lower lumbar spine BMD in hirsute women with irregular menses, compared with those with regular cycles. The discrepancy between our findings and those of the previous report may be the result of selection bias: Castelo-Branco and colleagues (21) combined amenorrheic women (with documented serum estradiol deficiency) and those with oligomenorrhea in one group, whereas none of our oligomenorrheic patients had complete cessation of menses. It is likely, therefore, that the inclusion of women with prolonged periods of amenorrhea and hypoestrogenism accounts for the subgroup differences between our study and the previous one. Consistent with our findings though, Castelo-Branco and colleagues (21) showed that the absolute values for BMD in hirsute women with amenorrhea-oligomenorrhea, as well as androstenedione levels in the entire hirsute group, were higher than those of nonhirsute women.
Estrogens coregulate the peripubertal surge in bone formation and eventual attainment of peak bone mass in young women (28), such that conditions associated with hypoestrogenism often result in bone loss (4, 5, 6). The effect of androgens or estrogen/ androgen balance (29) on the female skeleton is not as well studied as is that of estrogens. Our findings and other reports (21, 26, 27) indicate that women with hirsutism have higher BMD than nonhirsute controls, probably through an osteogenic effect of hyperandrogenism. The differing magnitudes of augmentation of BMD in eumenorrheic hirsute women vs. oligomenorrheic/amenorrheic hirsute women with reduced levels of integrated estrogen secretion (21) suggest that the effects of androgen excess on female skeletal mass might be additive to those of estrogens.
In conclusion, the collective data from our study and from other reports (21, 26, 27) indicate that hyperandrogenism overrides the osteopenic effects of oligomenorrhea, amenorrhea, and/or hypoestrogenism in hirsute women. Because hirsutism is a disorder of young women, many of whom may not yet have attained peak bone mass (28), prolonged antiandrogen therapy that decreases BMD (22) may interfere with the accrual of peak bone mass, with possible untoward consequences (30). Thus, the necessity for and duration of such systemic therapy, especially in eumenorrheic young women with simple hirsutism, should be carefully considered.
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Acknowledgments |
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Footnotes |
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Received April 7, 1997.
Revised May 29, 1997.
Accepted June 9, 1997.
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