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Original Studies |
Veterans Affairs Medical Center and Department of Medicine, Stanford University (R.M., D.L.), Palo Alto, California 94304; Department of Medicine, University of California-San Diego School of Medicine (D.L.S.), La Jolla, California 92093; Department of Medicine Columbia University College of Physicians and Surgeons (E.S.), New York, New York 10032; Department of Medicine, University of Chicago School of Medicine (M.E.), Chicago, Illinois 60637; and Indiana University (C.A.Q.), Indianapolis, Indiana 46285
Address all correspondence and requests for reprints to: Robert Marcus, M.D., GRECC 182-B, Veterans Affairs Medical Center, 3801 Miranda Avenue, Palo Alto, California 94304.
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Abstract |
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Introduction |
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The syndrome of androgen insensitivity (AIS), previously known as testicular feminization, offers a unique opportunity to evaluate the consequences of a total or near-total lack of androgen action. AIS is caused by mutations in the androgen receptor producing impaired to complete lack of response to endogenous and exogenous androgens (18). Individuals with complete AIS possess a normal male 46,XY genotype and functioning testes (19, 20). They are phenotypic females who undergo normal breast development at puberty (if testes are in situ), but have complete absence of androgen-dependent body hair and Müllerian duct structures in most cases. Consequently, patients with complete AIS experience life-long amenorrhea. Beginning at the onset of puberty, those with gonads in situ have high serum concentrations of both testosterone and estradiol (21, 22) that persist until surgical gonadectomy, which is undertaken eventually in all patients to prevent gonadal malignancy. Individuals with partial forms of AIS show variable degrees of virilization and sexual ambiguity, but even in the face of complete lack of androgen response, some anthropometric features, such as height and the dimensions of bone and teeth, are intermediate between typical male and female patterns (20).
To date, relatively little information has been published on the skeletal consequences of complete androgen insensitivity. Affected mice with this condition showed impaired long bone growth, possibly related to low circulating concentrations of insulin-like growth factor I (23). However, cancellous bone volume and density were similar to those in normal littermates, a finding attributed by the researchers to high serum estrogen concentrations. In humans, the results of isolated case reports and small series (24, 25, 26) indicate a high prevalence of low bone mineral density at clinically relevant sites, i.e. lumbar spine and proximal femur, but it is difficult in those reports to distinguish the effects of androgen resistance from those of estrogen lack. Our research group evaluated the skeletal mineralization status of a group of women with complete and high grade partial AIS to determine the effects of androgen resistance and exogenous estrogen on bone mass.
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Subjects and Methods |
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Attendees at annual gatherings of a national AIS support group were recruited by newsletter before their 1997 (San Diego, CA) and 1998 (Chicago, IL) meetings. Arrangements were made for volunteers to complete a standardized questionnaire and undergo measurement of height, weight, and BMD at the time of these meetings. Of approximately 70 North American women who received the initial mailing, 28 agreed to participate. Those who were unable to attend the meetings completed the study protocol at a medical center near their home. Each participant gave written informed consent, and the protocol was approved by the Administrative Panel on Research with Human Subjects, Stanford University. For minor children, written consent was provided by a parent or legal guardian, with assent by the child.
Questionnaires
Adult participants self-completed a questionnaire that covered medical history, health habits, calcium and other dietary supplements, and environmental exposures. Questions concerning the diagnosis and severity of AIS included the age at which diagnosis was established, the age at gonadectomy, and the chronology and consistency of exogenous estrogen therapy following surgery. Exogenous estrogen use was summarized in consecutive 3-yr intervals after gonadectomy and addressed the preparation, dose, and frequency of administration of prescribed estrogen as well as the participant’s own assessment of her compliance with medication during that interval. Minor participants were administered the same questionnaire by a single member of the research group.
Each participant’s exposure to exogenous estrogen was rated on a four-point scale: excellent, adequate dose, promptly initiated, missed a few days only; good, occasional missed dose, less than 1 yr hiatus between surgery and initiation of treatment; fair, took more than 75% of prescribed medication but admitted long delays in onset and/or prolonged interruptions in treatment; and poor, several years of no estrogen treatment.
Classification of AIS grade
Each woman or her physician rated her degree of androgen
insensitivity on a 1–7 scale using the pictorial grading system
described by Quigley et al. (20), where grade 7 refers to
complete AIS (Table 1
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BMDs at the lumbar spine and femoral neck were determined by dual energy x-ray absorptiometry (DXA). Ten women underwent DXA examination at the time of their AIS support group meeting. Six women were examined at the University of California-San Diego in September 1997 using Hologic, Inc., equipment (QDR 1000, Hologic, Inc., Bedford, MA; supervised by D.S.). Four women underwent DXA examination at the University of Chicago in September 1998 using Lunar Corp. equipment (Lunar Corp., Madison, WI; supervised by M.F.). Twelve women underwent DXA examinations at their local institutions. In each case, the accuracy and completeness of the report were verified by telephone contact with the densitometry laboratory director. Two participants each underwent the study protocol at the Columbia University (ES), Indiana University (CQ), and Palo Alto Veterans Affairs (RM) Medical Centers. Of the 28 subjects, 20 were studied with Hologic, Inc., and 8 with Lunar Corp. equipment.
Bone mineral results are reported here as BMD z-scores compared to current instrument-specific NHANES-congruent age-related normative data for females. Normative data z-scores represent the number of SDs by which a given result differs from the nominal age-related mean value. A value at the age-predicted mean would have a z-score value of 0. BMD, in grams per cm2, is calculated by dividing the estimated mineral content of a region of interest by the area of that region. Thus, BMD is an areal measurement, not a true volumetric density, and is subject to error when measurements are made in individuals who are particularly tall or short (27). Therefore, as the distribution of heights of the study subjects was skewed toward tall stature, we calculated an additional variable, bone mineral apparent density (BMAD), which largely corrects for the confounding effects of bone size. BMAD has been described and validated previously in our laboratory (27, 28). Age-specific BMAD z-scores were calculated using normative data that we have generated in-house and published in part (29).
For attendees at the San Diego, Chicago, Indianapolis, New York, and Palo Alto bone density laboratories, height and weight were measured with wall-mounted stadiometers and balance beam or electronic scales. For the women who obtained BMD measurements privately, all but two of the individual laboratory directors confirmed that measurements were made in the laboratory at the time that bone density examination was obtained.
Data handling and analysis
Data were entered into the StatView V statistical software
package (SAS Institute, Inc., Cary, NC). Group z-score
results for the study cohort were compared to a value of zero using
one-sample t tests. Analyses were two-tailed, and
P < 0.05 was designated as the criterion for
significance. The z-scores for individual subjects were obtained from
the densitometer-specific normative databases published by the
manufacturers. In general, we compared study results to normative
female databases. However, because some gender-specific skeletal
characteristics may reflect the function of genes and factors that are
related to chromosomal complement rather than to sex steroid hormones,
we also made some comparisons against normative male standards.
Descriptive data are presented in Table 2
as the mean ± SD or ranges, and z-scores
are presented in the text as the mean ± SEM
and in the figures as box plots (see Fig. 1 for explanation).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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); 5 of the 24 adult women (20.8%) in
the total cohort exceeded 6 ft in height. Of the 18 adult women with
complete AIS, 7 (38.8%) exceeded approximately 5 ft, 11 in. in height
(180 cm), and 2 women were more than 6 ft tall. One of 6 women with
partial AIS was 5 ft, 10 in. in height, and another was 6 ft tall. Gonadectomy and estrogen replacement status
The average age at gonadectomy was 15.4 yr for the complete AIS
group and 14.0 for the partial AIS group (Table 3). Two participants with complete AIS
(aged 12 and 14 yr) had not yet undergone gonadectomy. All subjects but
1 initiated estrogen replacement within the first several months after
surgery. One individual began estrogen replacement the following year.
The dominant estrogen used for replacement was conjugated equine
estrogens (Premarin). In 10 instances estrogen was
initiated at higher than standard replacement doses (0.9 or 1.25
mg/day), although 4 patients, including 2 14-yr-old and 1 11-yr-old
girls, began at a 0.3-mg daily dose, which was later increased in 3 of
them.
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Women with partial AIS had average z-scores for both lumbar
spine and hip BMD that did not differ significantly from zero,
indicating no deficit in BMD in that group compared with age-specific
normative values. For those with complete AIS, the average lumbar spine
BMD z-score of -1.08 was significantly lower than zero
(P = 0.0003), but values at the hip did not differ
significantly from zero (Fig. 2). Among
18 adults with complete AIS, 2 met WHO criteria for osteoporosis at the
lumbar spine (t score, less than -2.5), and 1 met this
criterion for the femoral neck (30). An additional 8 women met WHO
criteria for osteopenia (t score, less than -1.0) at the
spine, as did 6 women at the femoral neck (Table 3).
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We considered it likely that skeletal deficits would be
exaggerated in women whose adherence to estrogen replacement was poor.
We therefore analyzed BMD separately for adult women who had shown
excellent or good compliance (designated compliant) and for women whose
compliance had been fair or poor (designated noncompliant). At the
lumbar spine, both compliance groups had BMD z-scores significantly
below zero; the BMD z-score of noncompliant women (mean ±
SEM, -2.15 ± 0.15) was significantly lower than that
of the compliant group (-0.75 ± 0.28; Fig. 3). At the femoral neck, only the
noncompliant group showed an average BMD z-score that was significantly
lower than zero (-0.95 ± 0.40). When the lumbar spine BMD of the
estrogen-compliant group was compared to normative male standards, the
average z-score was almost 2 SD below the mean for
age-matched males (-1.81 ± 0.36; P <
0.0001).
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Bone mineral apparent density
In the estrogen-compliant group in which the average uncorrected
femoral neck BMD z-score did not differ from zero, the calculated BMAD
z-score was significantly lower than normal (z = -1.38 ±
0.28; P = 0.017; Fig. 4).
Similarly, the significant deficit shown in lumbar spine BMD z-score
for this group was magnified for BMAD (z = -1.3 ± 0.43;
P < 0.01).
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No significant associations were observed between bone mass measurements and self-reported calcium intake, tobacco or alcohol use, or habitual physical activity. Six women with complete AIS reported having experienced a fracture in the past. Three of these women reported multiple (n = 3–6) fractures. All of these appeared to have been the consequence of some degree of trauma. No relationship of fracture history to bone mass was observed.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase, which converts
testosterone to dihydrotestosterone. In that report, average spine and
femoral neck z-scores for the AIS patients were reduced at -2.8 and
-1.33, respectively, whereas those for the 5-reductase-deficient
patients were -0.84 and 0. 14, respectively. In that analysis, AIS
z-scores were compared to male normative data, with results very
similar to those of the present study. Schwartz et al. (31)
concluded that deficiency of a single androgen (dihydrotestosterone)
does not substantially affect BMD, whereas loss of all direct androgen
action (AIS) does. Although our finding that even estrogen-compliant women with complete AIS have subnormal spine BMD is compatible with the idea that skeletal acquisition and maintenance requires the independent participation of androgens, other possible interpretations require consideration. The most obvious of these concerns the adequacy of estrogen exposure. If removal of the gonads is delayed until puberty or later, adolescent girls with AIS will probably be exposed to very high concentrations of endogenous estrogen (21). However, after orchidectomy, exposure to estrogen may be insufficient to maintain bone mass, because of either delayed initiation or poor compliance with estrogen therapy. It is also possible that higher doses of estrogen may be necessary to maintain BMD in younger individuals with AIS than the typical replacement regimens used to prevent bone loss in the early postmenopausal period. In this study, women rated as having been poorly compliant with estrogen therapy showed significantly lower BMD than those with good or excellent compliance ratings. However, even those women who promptly started and fastidiously maintained estrogen replacement showed a significant deficit in lumbar spine BMD and in both lumbar and femoral BMAD.
One could argue that typical replacement doses of estrogen might not fully compensate for a lack of periodic surges in circulating estradiol normally observed during midfollicular and luteal phases of the menstrual cycle. However, this concept may be countered by our results in women with partial AIS. In these subjects, no detectable BMD deficits were observed despite the fact that their hormone exposure postgonadectomy was similar to that of the complete AIS women, and they, too, experienced no phase-specific surges in estrogen. It is also possible that as yet undefined alterations in the overall hormonal and growth factor milieu of patients with AIS could underlie their observed skeletal deficits.
The superior BMD of subjects with partial relative to complete AIS suggests a somewhat protective effect of the limited degree of androgen responsiveness of those with partial AIS. Thus, with deference to the possibilities outlined above, we consider it likely that the lack of a direct skeletal action of androgen underlies at least part of the bone mineralization deficits observed in women with complete AIS.
These results provide yet another illustration of the importance of considering bone mass measurements in relation to skeletal size. In this study, adjustment for body size was necessitated by a skewing of heights toward tall stature, an observation that has been made previously and has been suggested to reflect some process attributable to a stature-determining function of the Y chromosome. Although deficits in BMD were relatively modest and confined to the spine in estrogen-compliant women, BMAD size adjustment revealed that low bone mass in AIS women is both more severe and more generalized than would otherwise have been evident.
The clinical significance of skeletal deficits in AIS women is not clear. Bone density deficits of 1 SD are associated with a 2- to 3-fold long-term increase in fracture risk. Six of the 22 (27%) women with complete AIS in this study had sustained at least 1 fracture in the past, and 3 women had suffered multiple fractures. None of these appeared to be a fragility fracture. It is now clear that even traumatic fractures occur with greater frequency in adolescents with lower bone mass. Of the 6 women with a previous fracture, 3 met WHO criteria for osteopenia, and 3 had apparently normal BMD. The expected annual fracture incidence in the United States is 3% for girls 6–16 yr of age (32), and 27% of girls have sustained at least one fracture before age 16 yr (33). Given such a high prevalence of fracture in the normal population, it is clear that the present small study lacks sufficient power to permit conclusions regarding an excessive fracture rate.
Some limitations to this study warrant mention. Despite the fact that this sample of women with AIS is the largest to have been reported, it remains fairly small, so that power to identify low order associations is severely constrained. The study group was a convenience sample of patients with AIS, and we cannot know whether the observed results are generalizable to the rest of the AIS population. An additional issue concerning this group of women also warrants comment. The average age at gonadectomy, close to 15 yr, reflects standard practice in the 1970s that was substantially replaced in the 1980s by a tendency to remove the gonads during infancy for girls in whom an early diagnosis was made. Girls with AIS managed during the 1980s and 1990s with early gonadectomy will probably have been exposed to considerably less estrogen before puberty than most of our study subjects, whose gonads remained in situ until completion of puberty. Although it is not possible to generalize based on the small number of pubertal girls with AIS included in this study, it is of interest that the girl who had undergone gonadectomy in infancy and had not yet received estrogen had a rather low lumbar spine z-score. In the absence of clear guidelines for the timing and dosage of pubertal hormone replacement therapy in girls with AIS, whose needs may differ from those of other hypogonadal teens (such as those with Turner syndrome), it is important to monitor these girls for skeletal milestones, such as the pubertal growth spurt, adult height, and bone mineralization.
Received July 28, 1999.
Revised November 2, 1999.
Accepted November 19, 1999.
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References |
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1(1) procollagen and transforming growth factor-ß steady state
messenger ribonucleic acid levels in human osteoblast-like osteosarcoma
cells. Endocrinology. 128:2723–2730.[Abstract]
-Reductase deficiency and complete androgen insensitivity:
natural models to suggest a direct role for androgens on bone density
in men [Abstract OR23–1]. Proc of the 81st Annual Meet of The
Endocrine Society, 1999.
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