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Augmentation of Bone Mineral Density in Hirsute Women* - Oxford

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Augmentation of Bone Mineral Density in Hirsute

Women*

SAMUEL DAGOGO-JACK, NADIA AL-ALI,

ANDMOHAMMED QURTTOMDivision of Endocrinology, Diabetes and Metabolism (S.D-J.), Washington University School ofMedicine, St. Louis, Missouri 63110; Department of Medicine (N.A-A., M.Q.), Kuwait University(Mubarak) Hospital, Safat 13110, Kuwait

ABSTRACT

Hirsutism is associated with both hyperandrogenism and oligo- menorrhea or amenorrhea, which have opposing effects on bone min- 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, hir- sute women had higher total BMD (1.20260.02vs.1.11660.02g/cm

2,P,0.01), lumbar spine BMD (1. 18360.02vs.1.12560. 02

g/cm 2 Serum total testosterone levels were similar, but androstenedione levels were higher (11.760.80vs.7.960.79 nmol/L,P,0.005) and sex hormone binding globulin levels lower (22.063.0vs.57.668.5 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 pos- itive effect of hyperandrogenism on skeletal mass. (J Clin Endocrinol

Metab82:2821±2825, 1997)

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 se- verity from subtle luteal phase defects to amenorrhea) have progesterone (7)] deficiency, the mechanism of bone loss in women with less severe, and often covert, menstrual disor- ders is not fully understood (3, 4, 8). Nonetheless, estrogen therapy and androgen replacement have osteoprotective ef- fects in the appropriate clinical settings (9±11). These sex steroids interact with cognate receptors in osseous tissue (12,

13) and thereby stimulate bone formation (14, 15), although

via estrogen receptors (16). Thus, women with hirsutism (and associated hyperandro- genism 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.

menstrual dysfunction. We have tested this hypothesis bycomparing bone mineral indices in hirsute and nonhirsute

women drawn from the same ethnic population.

Subjects and Methods

Subjects

We studied 32 women, mean (6se) age 23.060.7 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 (n514), moderate for scores of 10±12 (n513), and severe for scores of 12 or over(n55), on the Ferriman and Gallwey (17) scale. The history of hirsutism had been present for 6 months to 14 yr (mean duration 5.260.6 yr). Based on the findings on clinical examination, the presence of an increased LH:FSH ratio, and positive findings on pelvic ultrasonography, a di- agnosis 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 thyroid disease, Cushing's syndrome, or prolactinoma. Twenty-one pa- tients 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 medica- tions known to affect bone density; and none were involved in regular physical exercise or weight loss program. Received April 7, 1997. Revision received May 29, 1997. Accepted

June 9, 1997.

Address correspondence and requests for reprints to: Samuel Washington University School of Medicine(Box 8127), 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: sdagogo@imgate.wustl.edu * This study was supported by an equipment grant from Kuwait

University Research Office.

0021-972X/97/$03.00/0Vol. 82, No. 9

Journal of Clinical Endocrinology and MetabolismPrinted in U.S.A.

Copyright © 1997 by The Endocrine Society

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Measurement of bonedensity

Bone mineral density (BMD), bone mineral content (BMC), and per- cent 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 of a measurementdrift.

Laboratory measurements

Serum total testosterone (Orion Diagnostica, Espoo, Finland) and 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 D 3 was measured by competitive protein binding assay. The lower limit of detection for the testosterone

8%. The lower detection limit for the androstenedione RIA was 0.08

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.

Statisticalmethods

Results are expressed as means6se. Continuous variables in hirsute and control women were compared using unpairedttests, and x-square used to compare BMI in control women and in subgroups of hirsute women defined by menstrual status. The Pearson product-moment cor- relation coefficient was used to assess correlations between BMD (or BMC) and other variables.Pless than 0.05 was accepted as significant.

Results

Hormonal andbiochemicaldata

0.12 nmol/L in hirsute women and 2.3060.22 nmol/L in

for total testosterone at Kuwait University Hospital, 0.3±3.0 nmol/L.) The serum androstenedione level (Fig. 1) was

11.760.8 nmol/L in hirsute women and 7.960.8 nmol/L

in controls,Pless than 0.005 (reference range 1.6±9.4 nmol/

L). The mean serum SHBG level (Fig. 2) in hirsute womenwas 22.063.0 nmol/L, comparedwith 57.668.5 nmol/L

in nonhirsute women,Pless 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 cal- cium, phosphorus, alkaline phosphatase, and intact PTH levels all were withinthe normal ranges (Table 2).

Bone mineral density (BMD)and content

The total body BMD of hirsute women, 1.20260.016

g/cm 2

1.11660.018g/cm

2 .Thehirsutegroupalsohadahigher(P, The BMD at the L2 - L4 lumbar spine was 1.18360.02 g/cm 2 2 forthe control group,P,0.01 (Fig. 3). The correlation of total BMD 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 spine BMD with percent body fat: 0.49 (P,0.02) in controls and 0.23 (P.0.1) in hirsute women. However, the correla- tion 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

TABLE 1.Clinical characteristics ofstudy subjects

Hirsutism Control

Number 32 25

Age (yr) 23.060.7 24.460.7

Kuwaiti 32 25

Nulliparous 30 23

Eumenorrheic 21 25

Oligomenorrheic 11 0

BMI (kg/m

2 ) 28.661.1 26.261.2

Body Fat(%) 4661.6 4461.7

Traditional attire 20 16

Western attire 12 9

Dairy intake

a ,24oz./week 22 9 $24 oz./week 10 16 a

Expressed in milk equivalents.

FIG. 1. Serum total testosterone and androstenedione levels in hir- sute (black bars) and nonhirsute control (white bars) women. *P, 0.01.

2822 DAGOGO-JACKET AL.

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BMD than hirsute women with regular menses, but the dif- ferences were not statistically significant (Table 3). Com- pared with nonhirsute control women, the oligomenorrheic hirsute women had higher mean values for total BMD, lum-

0.13,P.0.5) or androstenedione (r50.31,P.0.1) levels.

The hirsutism score also did not correlate significantly (r5

0.32,P.0.05) with plasma androstenedione level.

Discussion

This study shows that bone mineral content and BMD are control women. The degree of hirsutism was mild or mod- erate [Ferriman and Gallwey score,12 (17)] in 27 of the 32 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 se-

rum free testosterone levels also were probably elevated.Thus, the majority of the patients in this study had a pre-

sentation similar to that of the typical patient with simple idiopathic hirsutism (19). Our findings show that mild to idence of virilization) are, nonetheless, associated with aug- mentation of BMD and bone mineral content in hirsute women. The majority of women with hirsutism have in- creased 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, es- pecially in patients with normal levels of circulating sex steroids and SHBG. Elevated serum estradiol and estrone levels in some patients with PCOS conceivably could con- tribute 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 hir- sute and nonhirsute groups, but the area under the curve of multiply sampled estradiol levels was approximately 40% FIG. 2. Serum sex hormone binding globulin levels and body fat com- position in hirsute and nonhirsute control women. *P,0.001. TABLE 2.Serum biochemical characteristics of subjects

Analyte Hirsute Nonhirsute Reference range

Calcium (mmol/L) 2.3460.02 2.3260.02 2.2±2.6

Phosphorus (mmol/L) 1.260.03 1.160.03 0.8±1.6

Alk. Phosphatase (U/L) 79646664 39±117

25-OH-vitamin D (

mg/L) 8.461.0 7.461.4 8±55

Intact PTH (pmol/L) 3.660.3 4.360.5 1.3±7.6

FIG. 3. Bone mineral density at the lumbar spine (anteroposterior projection) and total bone mineral content in hirsute and nonhirsute control women. *P,0.01. TABLE 3.Bone mineral density (BMD) and bone mineral content (BMC) of hirsute and nonhirsute women in relation to menstrual history

Hirsute womenNonhirsute

womenEumenorrheic Oligomenorrheic

Number of subjects 21 11 25

Total BMD (g/cm

2 ) 1.20460.03 a

1.19760.03

a

1.11660.02

L2-4 BMD (g/cm

2 ) 1.19960.03 a

1.15160.02 1.12560.02

BMC (g) 2718690

b

2689684

b

2400670

a

P,0.01vs.nonhirsute women.

b

P,0.001vs.nonhirsute women.

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pared with eumenorrheic hirsute women.) Support for an androgen-mediated mechanism is provided by the observa- tion that spironolactone treatment for 1 yr significantly de- creased 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 pre- (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 vari- ables 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 and parity. The hirsute women reported less dairy con- sumption 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 prod- ucts 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 fa- milial 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 hir- sute women, regardless of menstrual status, accrued greater the hirsute and control groups, BMD was correlated with BMI, but the hirsute women showed no correlation between body fat and BMC, than did controls. The reasons for the latter findings are unclear, but may well be related to dif- ferential 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, com- pared with those with regular cycles. The discrepancy be the result of selection bias: Castelo-Branco and col- leagues (21) combined amenorrheic women (with docu- mented serum estradiol deficiency) and those with oligo- menorrhea in one group, whereas none of our oligomenorrheic patients had complete cessation of men- ses. It is likely, therefore, that the inclusion of women with

prolonged periods of amenorrhea and hypoestrogenismaccounts 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 am- enorrhea-oligomenorrhea, as well as androstenedione lev- els in the entire hirsute group, were higher than those of nonhirsute women. Estrogens coregulate the peripubertal surge in bone for- mation and eventual attainment of peak bone mass in young women (28), such that conditions associated with hypoestrogenism often result in bone loss (4±6). The effect of androgens or estrogen/ androgen balance (29) on thequotesdbs_dbs17.pdfusesText_23