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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 2821-2825
Copyright © 1997 by The Endocrine Society


Original Studies

Augmentation of Bone Mineral Density in Hirsute Women1

Samuel Dagogo-Jack, Nadia Al-Ali and Mohammed Qurttom

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


    Abstract
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Hirsutism is associated with both hyperandrogenism and oligomenorrhea or amenorrhea, which have opposing effects on bone mineral density (BMD). We tested the hypothesis that hyperandrogenism in hirsute women counteracts the osteopenic effects of menstrual dysfunction. Using dual energy x-ray absorptiometry, we measured BMD and total bone mineral content (BMC) in 32 young women referred for hirsutism. The control group consisted of 25 matched, nonhirsute women. Among the hirsute women, 21 reported regular menses, and 11 gave a history of oligomenorrhea; all members of the control group reported regular menses. Compared with controls, hirsute women had higher total BMD (1.202 ± 0.02 vs. 1.116 ± 0.02 g/cm2, P < 0.01), lumbar spine BMD (1. 183 ± 0.02 vs. 1.125 ± 0. 02 g/cm2, P < 0.01), and total BMC (2700 ± 66 vs. 2400 ± 70 g, P < 0.001). Serum total testosterone levels were similar, but androstenedione levels were higher (11.7 ± 0.80 vs. 7.9 ± 0.79 nmol/L, P < 0.005) and sex hormone binding globulin levels lower (22.0 ± 3.0 vs. 57.6 ± 8.5 nmol/L, P < 0.001) in hirsute women than controls. Oligomenorrheic hirsute women had higher BMD than nonhirsute women, although the augmentation was less pronounced than in eumenorrheic hirsute women. These results indicate that hirsutism is associated with higher bone density and mineral content, consistent with a net positive effect of hyperandrogenism on skeletal mass.


    Introduction
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
HIRSUTISM is associated with hyperandrogenism, such that even when circulating androgen levels are in the normal range, increased tissue sensitivity to androgens (or excess androgen tone) might be a mechanism for hirsutism in some women (1, 2). Hirsutism also is associated with irregular menses, and menstrual disorders (ranging in severity from subtle luteal phase defects to amenorrhea) have been associated with osteopenia (3, 4, 5, 6). Although the osteopenia in amenorrheic women can be explained by estrogen [and progesterone (7)] deficiency, the mechanism of bone loss in women with less severe, and often covert, menstrual disorders is not fully understood (3, 4, 8). Nonetheless, estrogen therapy and androgen replacement have osteoprotective effects in the appropriate clinical settings (9, 10, 11). These sex steroids interact with cognate receptors in osseous tissue (12, 13) and thereby stimulate bone formation (14, 15), although the osteoblastic effect of androgens is thought to be mediated via estrogen receptors (16).

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.


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

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 1Go). 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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Table 1. Clinical characteristics of study subjects

 
Measurement of bone density

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 {chi}-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.


    Results
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Hormonal and biochemical data

The mean serum total testosterone level (Fig. 1Go) 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. 1Go) 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. 2Go) 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 2Go).



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Figure 1. Serum total testosterone and androstenedione levels in hirsute (black bars) and nonhirsute control (white bars) women. * P < 0.01.

 


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Figure 2. Serum sex hormone binding globulin levels and body fat composition in hirsute and nonhirsute control women. * P < 0.001.

 

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Table 2. Serum biochemical characteristics of subjects

 
Bone mineral density (BMD) and content

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. 3Go) 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. 3Go). 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. 2Go), 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 3Go). Compared with nonhirsute control women, the oligomenorrheic hirsute women had higher mean values for total BMD, lumbar spine BMD, and BMC (Table 3Go). 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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Figure 3. Bone mineral density at the lumbar spine (anteroposterior projection) and total bone mineral content in hirsute and nonhirsute control women. * P < 0.01.

 

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Table 3. Bone mineral density (BMD) and bone mineral content (BMC) of hirsute and nonhirsute women in relation to menstrual history

 

    Discussion
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
This study shows that bone mineral content and BMD are higher in women with hirsutism than in matched, nonhirsute control women. The degree of hirsutism was mild or moderate [Ferriman and Gallwey score <12 (17)] in 27 of the 32 women (84%) and severe in the remainder (16%). None of the hirsute women showed clinical evidence of virilization, 21 (66%) were having regular menstrual periods at the time of study, and only 10 patients met strict criteria for diagnosis of PCOS (18). As a group, the hirsute women had elevated serum androstenedione levels with normal total testosterone and decreased serum SHBG levels, indicating that their serum free testosterone levels also were probably elevated. Thus, the majority of the patients in this study had a presentation similar to that of the typical patient with simple idiopathic hirsutism (19). Our findings show that mild to moderate degrees of hyperandrogenism (without clinical evidence of virilization) are, nonetheless, associated with augmentation of BMD and bone mineral content in hirsute women. The majority of women with hirsutism have increased skin sensitivity to androgens (19, 20), and the results of the present study suggest that androgen sensitivity in hirsute women probably extends to extracutaneous, skeletal sites that express androgen receptors (13, 15).

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.


    Acknowledgments
 
We thank Jane Keuss for secretarial assistance.


    Footnotes
 
1 This study was supported by an equipment grant from Kuwait University Research Office. Back

Received April 7, 1997.

Revised May 29, 1997.

Accepted June 9, 1997.


    References
 Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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  4. Boyden TW, Pamenter RW, Grosso D, Stanforth P, Rotkis T, Wilmore JH. 1982 Prolactin responses, menstrual cycles, and body composition of women runners. J Clin Endorinol Metab. 54:711–714.[Abstract]
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  6. Drinkwater BL, Brummer B, Chestnut CH III. 1990 Menstrual history as a determinant of current bone density in young athletes. JAMA. 263:545–548.[Abstract]
  7. Prior JC. 1990 Progesterone as a bone-trophic hormone. Endocr Rev. 1:386–398.
  8. Marcus R, Cann C, Madvig P, et al. 1985 Menstrual function and bone mass in elite women distance runners: endocrine and metabolic features. Ann Intern Med. 102:158–163.
  9. Ettinger B, Genant HK, Cann CE. 1987 Postmenopausal bone loss is prevented by treatment with low-dosage estrogen with calcium. Ann Intern Med. 106:40–45.
  10. Finkelstein JS, Klibanski A, Neer RM, et al. 1989 Increases in bone density during treatment of men with idiopathic hypogonadotrophic hypogonadism. J Clin Endocrinol Metab. 69:776–783.[Abstract]
  11. Finkelstein JS, Klibanski A. 1990 Effects of androgens on bone metabolism. In: Nieschlag E, Behre HM, eds. Testosterone: action, deficiency, substitution. Berlin: Springer-Verlag;204–218.
  12. Eriksen EF, Colvard DS, Berg NJ, et al. 1988 Evidence of estrogen receptors in normal human osteoblast-like cells. Science. 241:84–86.[Abstract/Free Full Text]
  13. Orwoll ES, Stribrska L, Ramsey EE, Keenan EJ. 1991 Androgen receptors in osteoblast-like cell lines. Calcif Tissue Int. 49:183–187.[Medline]
  14. Snow GR, Anderson C. 1986 The effects of 17 beta-estradiol and progestagen on trabecular bone remodeling in oophorectomized dogs. Calcif Tissue Int. 39:198–205.[Medline]
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  16. Smith EP, Boyd J, Frank GR, et al. 1994 Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med. 331:1056–1061.[Abstract/Free Full Text]
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  22. Prezelj J, Kocijancic A. 1994 Antiandrogen treatment with spironolactone and linestrenol decreases bone mineral density in eumenorrheic women with androgen excess. Horm Metab Res. 26:46–48.[Medline]
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  26. Prezelj J, Kocijancic A. 1993 Bone mineral density in hyperandrogenic amenorrhea. Calcif Tissue Int. 52:422–424.[CrossRef][Medline]
  27. Di Carlo C, Shoham Z, MacDougall J, Patel A, Hall MJ, Jacobs HS. 1992 Polycystic ovaries as a relative protective factor for bone mineral loss in young women with amenorrhea. Fertil Steril. 57:314–319.[Medline]
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