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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2809
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 8 3017-3023
Copyright © 2006 by The Endocrine Society

Bone Mineral Density in the Complete Androgen Insensitivity and 5{alpha}-Reductase-2 Deficiency Syndromes

Vivian Sobel, Brian Schwartz, Yuan-Shan Zhu, Juan J. Cordero and Julianne Imperato-McGinley

Division of Endocrinology, Diabetes and Metabolism (V.S., Y.-S.Z., J.J.C., J.I.-M.), Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021; and North Shore University Hospital (B.S.), Manhasset, New York 11030

Address all correspondence and requests for reprints to: Dr. Julianne Imperato-McGinley, Division of Endocrinology and Metabolism, 1300 York Avenue, New York, New York 10021. E-mail: jimperat{at}med.cornell.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Subjects with complete androgen insensitivity (CAI) and 5{alpha}-reductase-2 deficiency (5{alpha}RD-2) are natural human models to study the direct effect of androgens on bone mineral density (BMD).

Objective: The objective of this study was to test the hypothesis that androgens have a direct effect on BMD in men.

Design: This was a prospective, observational study (1989–1999) using dual energy x-ray absorptiometry.

Setting: The study was set in an outpatient specialty referral center.

Patients or Other Participants: All known subjects with these conditions (12 CAI and 16 5{alpha}RD-2) from diverse sociodemographic backgrounds were recruited for the study.

Interventions: There were no interventions.

Main Outcome Measure: Mean Z score and weight-matched Z score at lumbar spine and femoral neck for CAI and 5{alpha}RD-2 subjects were determined.

Results: Twelve CAI subjects had mean Z score at L2–L4 of –2.84 (±0.97, P < 0.001) and a mean weight-matched Z score of –2.52 (±0.94, P < 0.001). The mean Z score at the femoral neck was –1.33 (±0.91, P < 0.001) and the mean weight-matched Z score was –1.10 (±0.82, P = 0.001). Sixteen 5{alpha}RD-2 subjects had a mean Z score at L2–L4 of –0.84 (±1.29, P = 0.02) and a mean weight-matched Z score for 15 of 16 patients of –0.44 (±1.08, P = 0.14). The mean Z score at the femoral neck was 0.14 (±1.02, P = 0.58) and the mean weight-matched Z score for 15 of 16 patients was 0.49 (±0.94, P = 0.06). Therefore, in CAI subjects, BMD was significantly decreased in the spine and hip. 5{alpha}RD-2 subjects had normal BMD values.

Conclusions: 1) Androgens are of direct importance in the development and/or maintenance of BMD; and 2) testosterone and/or low levels of dihydrotestosterone appear to be sufficient for BMD development and/or maintenance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SEX STEROIDS PLAY a critical role in bone formation and growth, as well as in the maintenance of bone density throughout life. The role of androgens in the maintenance of bone density has long been debated (1).

In the current study, the specific aim was to elucidate the direct effects of the androgens, testosterone (T), and dihydrotestosterone (DHT), on bone by studying bone mineral density (BMD) in the spine and hips of subjects with androgen insensitivity and 5{alpha}-reductase-2 deficiency (5{alpha}RD-2). Androgen insensitivity, usually due to defects in the androgen receptor, is characterized by the absence or impairment of androgen action, via T and DHT, in the setting of normal to elevated male estrogen levels. Therefore, this condition is an ideal model in which to study direct androgen effects on bone in the presence of adequate levels of estrogen. In contrast, 5{alpha}RD-2 is characterized by defective production of DHT, the potent nonaromatizable androgen derived from T, as a result of mutations in the 5{alpha}-reductase-2 gene. This condition, characterized by low to low-normal levels of DHT with normal to elevated levels of T and estradiol, is one in which the direct effects of DHT on bone can be studied.


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

Informed consent was obtained from all subjects. The study participants were all in good health. They did not suffer from any chronic conditions except for hypertension (one patient), type II diabetes mellitus, and depression (one patient), and orbital rhabdomyosarcoma in late childhood (one patient). They were not being treated with corticosteroids and were all nonsmokers.

Androgen insensitivity

Twelve subjects with complete androgen insensitivity (CAI) from five kindreds, with an age range of 17–62 yr and a mean age of 35 yr were studied (Table 1Go). Seven subjects were from a known kindred in the Dominican Republic (2), two subjects were from a kindred in Mexico, and three subjects were sporadic cases from families in the United States. All 12 CAI subjects were phenotypic and psychosexual females with Tanner stage V breast development, absent to scant pubic and axillary hair, and a blind vaginal pouch (3). Two additional subjects had partial androgen insensitivity (PAI), characterized by penoscrotal hypospadias, gynecomastia, axillary and pubic hair, and minimal facial hair.


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  		TABLE 1. Characteristics of patients with CAI and 5{alpha}RD-2

 
Hormonal evaluations were consistent with the diagnosis of androgen insensitivity, demonstrating normal to elevated male levels of T, elevated male levels of estradiol, and an elevated T to DHT ratio compared with normal males, but lower than that in subjects with 5{alpha}RD-2 (3) (also see Table 2Go).


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  		TABLE 2. Plasma androgen levels

 
This condition is inherited as X-linked recessive. For the Dominican kindred, the genetic defect is a single adenine insertion in the polymorphic CAG trinucleotide region of exon 1 of the androgen receptor gene (4). The mutation results in a frame shift at amino acid 60 and premature termination of the receptor, yielding a truncated androgen receptor with loss of binding to the ligand. The other genetic defects were not characterized.

5{alpha}RD-2

Sixteen subjects with 5{alpha}RD-2 from seven different kindreds, with an age range of 15–42 yr and a mean age of 29 yr, were studied. Ten subjects were from three kindreds in the Dominican Republic (5); eight subjects came from the first and largest kindred ever described with this condition (6). Three subjects were from a previously described kindred in New Guinea (7). Two subjects were from a previously described kindred in Turkey (8), and one subject came from Jordan.

All sixteen subjects were born with severe ambiguity of the external genitalia characterized by a clitoral-like penis and pseudovaginal perineoscrotal hypospadias; profound masculinization occurred at puberty. Their hormonal profile was characterized by an elevated T, low to low-normal DHT, and an elevated T to DHT ratio (Table 2Go), as well as high urinary C19 and C21 5ß to 5{alpha} steroid ratios (9).

The condition is inherited as autosomal recessive. The genetic defect in the Dominican kindred involves a single basepair substitution, which decreases the 5{alpha}RD-2 enzymatic activity by more than 95% (10). Two other subjects from different Dominican families had single basepair mutations that have also been identified (5). The genetic defect in the New Guinean kindred is a complete gene deletion (11), and in the Turkish kindred, it is a single base deletion (adenine), resulting in a frameshift and an addition of 23 amino acids at the carboxyl terminal of the enzyme, leading to complete loss of enzymatic activity (12). The Jordanian subjects have a missense mutation (L55Q) in exon 1 of the 5{alpha}-reductase-2 gene, which results in a complete loss of enzymatic activity (13).

Gonadectomy and estrogen replacement

Two of the CAI subjects had their gonads intact at the time of the study. Ten (of 12) subjects underwent gonadectomy (Table 1Go) with a mean age at gonadectomy of 23 yr and an age range of 13–42 yr. Eight of 10 subjects were 18 yr or older at gonadectomy; seven were above the age of 20; two were ages 30 and 42.

The mean time interval from gonadectomy to the time of the study was 15 yr with a range of 5–22 yr. Seven of 10 patients who underwent gonadectomy were treated with various preparations and doses of estrogen replacement (Table 1Go). Of the other subjects, one subject was on estrogen continuously until 10 months before the study (subject 10 in Table 1Go), and two subjects were off estrogen for 12 and 15 yr (subjects 6 and 12 in Table 1Go).

None of the affected subjects with PAI or 5{alpha}RD-2 deficiency underwent gonadectomy, and consequently, none were on hormone therapy.

Hormonal levels

Plasma levels of T and DHT were determined by RIA (14). Assays were performed at or in proximity to the time of BMD assessment in all subjects except the gonadectomized CAI patients, in whom hormonal assays were performed before the time of gonadectomy. The data are presented as mean ± SD.

Bone mineral assessment method

BMD at the lumbar spine and femoral neck was determined by dual energy x-ray absorptiometry using Lunar Corporation (Madison, WI) equipment. All but one of the subjects had their BMD assessed by the same machine.

BMD results are reported as Z scores, compared with current instrument-specific and age- and sex-related normative data. Normative data were provided by the Lunar Corporation. Z scores represent the number of SD values by which a given result differs from the mean value for men or women of equal age. As weight has been shown to be proportionally related to BMD (15), BMD was also expressed as a weight-matched Z score, or the number of SD values of a given BMD value from the sex-, age-, and weight-matched mean value. The weight-matched Z scores correct for the influence of weight differences on BMD. The Student’s t test was used to test for statistical significance. A P value less than 0.05 was considered statistically significant.


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

Nine subjects with androgen insensitivity before gonadectomy had a mean T level of 797.2 (normal range for males 300–800 ng/dl), a mean DHT level (for eight subjects) of 36.1 ng/dl (normal range 30–80 ng/dl), and a T to DHT ratio of 24.2 (normal 8–17) (Table 2Go).

The 16 subjects with 5{alpha}RD-2 had mean T level of 903.2 ng/dl, a mean DHT level of 22.9 ng/dl, and a T to DHT ratio for 16 subjects of 43.7 (Table 2Go).

BMD measurements

The 12 subjects with CAI (Fig. 1Go) had a mean BMD at L2–L4 of 0.891 (±0.118 SD) g/cm2 resulting in a mean Z score of –2.84 (±0.97, P < 0.001) and a weight-matched Z score of –2.52 (±0.94, P < 0.001), both significantly lower than male reference standards and in the osteoporotic range (Table 3Go). The mean BMD at the femoral neck was 0.883 (±0.121) g/cm2 with a mean Z score of –1.33 (±0.91, P < 0.001) and a mean weight-matched Z score of –1.10 (±0.82, P = 0.001), both in the osteopenic range (Table 4Go).


Figure 1
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  		FIG. 1. A comparison of weight-matched Z scores at the L2–L4 spine between normal males, subjects with 5{alpha}RD-2, subjects with CAI, and subjects with PAI. Subjects with CAI are either pregonadectomy (AI PG), on estrogen replacement (AI on E2), or off estrogen replacement (AI off E2).

 

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  		TABLE 3. BMD at L2–L4 spine (compared to a reference male population)

 

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  		TABLE 4. BMD at the femoral neck (compared to reference male population)

 
A subgroup analysis performed on the seven subjects with CAI taking estrogen replacement postgonadectomy revealed a mean BMD at L2–L4 of 0.934 (±0.110) g/cm2 resulting in a mean Z score of –2.50 (±0.95, P < 0.001), which was in the osteoporotic range. The weight-matched Z score for L2–L4 was –2.15 (±0.87, P = 0.001), which was in the severely osteopenic range. The mean BMD at the femoral neck was 0.891 (±0.109) g/cm2 with a mean Z score of –1.20 (±0.69, P = 0.004), which was in the osteopenic range and a mean weight-matched Z score of –0.96 (±0.66, P = 0.009) (Table 5Go).


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  		TABLE 5. BMD in CAI subjects on estrogen (compared to reference male population)

 
When the BMD of the patients with CAI was compared with female reference standards, the mean Z score at L2–L4 was –2.37 (±0.96, P < 0.001), with a weight-matched Z score at L2–L4 of –2.48 (±0.88, P < 0.001), both in the osteopenic range. The mean Z score for females at the femoral neck was –0.65 (±1.00, P = 0.045), and the mean weight-matched Z score for females was –0.82 (±0.91, P = 0.013).

The two androgen-resistant patients with intact gonads, who were continuously exposed to endogenous estrogen de facto, were osteoporotic with Z scores at L2–L4 of –3.07 and –3.35 respectively, and weight-matched Z scores at L2–L4 of –2.20 and –2.52 compared with male standard values. The Z scores of –2.92 and –3.02, using female normative data, were similarly low. At the femoral neck, the Z scores of –1.18 and –1.93 were consistent with osteopenia when compared with male standards. The femoral neck male weight-matched Z scores were –0.53 and –1.36, and the Z scores were –0.05 and –1.19 when using female standards.

Two patients with PAI had Z scores at L2–L4 of –0.3 and –1.39 respectively, and weight-matched Z scores of 0.69 and –0.56, within the normal range when compared with male reference standards. At the femoral neck, the Z scores for the PAI patients were 0.78 and –0.12, and the weight-matched Z scores were 1.47 and 0.46, also within the normal range.

The 16 subjects with 5{alpha}RD-2 (Fig. 1Go) had a mean BMD at L2–L4 of 1.128 (±0.151) g/cm2, resulting in a mean Z score of –0.84 (±1.29, P = 0.02) and a mean weight-matched Z score of –0.44 for 15 of 16 patients, (±1.08, P = 0.14) (Table 3Go). The mean BMD at the femoral neck was 1.086 (±0.140) g/cm2 with a mean Z score of 0.14 (±1.02, P = 0.58) and a mean weight-matched Z score for 15 of 16 patients of 0.49 (±0.94, P = 0.06) (Table 4Go).

The mean BMD values at both the lumbar spine (Table 3Go) and femoral neck (Table 4Go) were significantly lower for subjects with CAI including the subgroup on estrogen replacement therapy (Table 5Go) compared with subjects with 5{alpha}RD-2.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Some have theorized that the effect of androgens on bone density is indirect, via their peripheral conversion to estrogens and their subsequent binding to estrogen receptors. In support of this hypothesis, adult subjects with rare mutations affecting either the estrogen receptor or the aromatase enzyme, which converts androgen to estrogen, have been shown to have decreased bone density despite normal androgen levels (16, 17, 18, 19). These subjects are exceptional, however, in that they do not undergo growth plate closure due to lack of estrogen signaling. Furthermore, the importance of estrogen signaling in BMD in men does not exclude the possibility that androgens also play a role. As an example, selective androgen receptor blockade in men with prostate cancer results in significant loss of BMD, supporting the importance of direct androgen action via the androgen receptor in BMD (20, 21).

CAI, a condition due to a functionally inactivated androgen receptor, is a biological model in which to discern the direct effects of androgens on BMD. In this condition, androgen signaling is markedly decreased to absent, whereas estrogen levels are normal to elevated. If androgens play a direct role in bone density development and/or maintenance, BMD should be decreased in these patients. Conversely, if androgens affect BMD and bone strength through the indirect route, via conversion to estrogen by aromatization and activation of the estrogen receptor, subjects with this condition should have normal BMD comparable to control males. By comparing bone density in CAI subjects to that of normal males, we controlled for genotype, estrogen levels, and any androgen signaling via alternate pathways that do not use the androgen receptor. In this study of bone density in CAI subjects, female Z scores were also used for comparison.

The affected subjects are from diverse ethnic, geographic, and racial backgrounds, factors that all play a role in determining BMD. Because the normative data used to determine Z scores was from a Caucasian reference population, weight-adjusted Z scores were used to minimize potential ethnic and racial effect on BMD. Studies have demonstrated that ethnic and racial differences in BMD are, to a large extent, eliminated once adjustments for body size (particularly body weight) are made (21, 22). In fact, weight appears to be a significant determinant of BMD (23, 24, 25). Furthermore, although both the CAI and 5{alpha}RD-2 groups had a large, ethnically Dominican and racially mixed component, the BMD between the two groups, nevertheless, was significantly different.

The results indicate that BMD was substantially reduced in the CAI group compared with age- and weight-matched male standard values, implicating the androgen receptor-signaling pathway as an important factor in bone formation and/or BMD maintenance. This was further highlighted by the significant decrease in bone density present in the two subjects with intact gonads. Interestingly, when BMD in patients with CAI was compared with an age- and weight-matched female standard, despite adequate estrogen replacement, the reduction in BMD was still profound in the lumbar spine, and modest but statistically significant in the hip. The results suggest that endogenous estrogen or estrogen replacement is insufficient to overcome the lifelong deficit in androgen action.

Interestingly, in the current study, the most dramatic differences in BMD in subjects with CAI were found in the lumbar vertebrae as opposed to the hip, suggesting a particularly important role of androgens on trabecular bone.

A reduction in BMD in human subjects with CAI has also been suggested by several studies, with only two studies having more than a few subjects (26, 27, 28, 29). Bertelloni et al. (28) studied 10 patients with CAI and found that both areal and volumetric BMD, which adjusts BMD for bone size, were significantly reduced in these patients when compared with a control group, as well as to standardized data from normal males and females. However, in this study, seven of 10 of the patients were less than 18 yr old and prepubertal or peripubertal (mean age for all patients, 13.7 yr). Gonadectomy was performed in seven of the 10 patients at ages 1.2–18 yr (mean age at gonadectomy, 10.9 yr), and all were on hormone replacement therapy. A larger study by Marcus et al. (29) included 28 women with androgen insensitivity (22 complete and six high-grade partial) recruited from a national androgen insensitivity support group. Because all subjects were recruited from an androgen insensitivity support group, none of them were biochemically or genetically confirmed to have androgen insensitivity. Furthermore, in some cases, the degree of androgen insensitivity was rated by the patients and not verified by their physicians.

The Marcus study (29) compared BMD at the lumbar spine and proximal femur to age-specific normative female values. Although 18 of the 22 subjects were postpubertal, the average age of gonadectomy in this study was 15 yr, 8 yr younger than the mean age at gonadectomy in the current study. Lumbar spine BMD was significantly reduced in subjects with CAI compared with female controls, whereas average spine and hip BMD values did not differ from normal in those with partial androgen insensitivity. A significantly greater deficit in BMD was found in those women who were noncompliant with hormone replacement therapy, such that in the noncompliant hormone replacement therapy group hip as well as spine BMD was significantly reduced. Importantly, when BMD measurements were adjusted for size, subnormal BMD was observed at both the hip and spine, even for the estrogen-compliant group, in keeping with the findings of the current study.

In our study, all but two of the CAI patients underwent gonadectomy well after the time of puberty (average age of 23 yr), allowing for pubertal bone acquisition, growth, and growth plate closure. Despite this fact, BMD was still significantly reduced. Furthermore, in the two adult subjects aged 17 and 21 with intact gonads, BMD was also markedly reduced, yielding Z scores at L2–L4 of –3.07 and –3.35. These findings suggest that intact gonads during the time of pubertal development or thereafter do not establish and/or maintain BMD in patients with CAI. Furthermore, subjects who were taking hormone replacement therapy also had significantly reduced BMD when compared with standard values. Therefore, our data are very suggestive of a direct role for androgens in development and/or maintenance of BMD.

Our study was limited by a small number of subjects; however, these genetic conditions are rare, and in comparison to similar studies, the study size was substantial. The limitations of the use of areal BMD with respect to the influence of bone size on the measurement of BMD must also be acknowledged (30). A more qualitative assessment of BMD in these patient populations in future studies would yield interesting and useful information on the effects of androgens on both trabecular and cortical bone density and structure.

Our study findings are supported by animal data. Studies of BMD in the androgen-resistant (Tfm) male mouse, due to a single base deletion of the androgen receptor gene leading to a 90% reduction of androgen receptor mRNA (31), have shown that trabecular BMD and structure are diminished compared with Tabby control mice (32). In addition, cortical BMD is diminished when compared with normal male mice from the C57BL/6J strain (32). T replacement after orchidectomy has no effect on trabecular or cortical bone structure. It also had less of an effect on trabecular BMD when compared with T replacement in orchidectomized control animals, suggesting the importance of androgen-receptor mediated androgen action on bone in this animal model (32). In the androgen receptor knock-out mouse (33), both cortical and trabecular bone mass are reduced compared with male controls. The bone loss is only partially prevented by treatment with aromatizable T, suggesting that androgens acting directly through the androgen receptor play an essential role in normal bone formation and remodeling (34).

The role of DHT in maintaining bone strength and BMD was assessed in this study, using the model of inherited 5{alpha}RD-2, in which lifelong levels of DHT fall in the low to low-normal range and the T to DHT ratio is high. In these individuals, there was no significant reduction in BMD compared with standardized male values, suggesting either that T and/or low levels of DHT from 5{alpha}RD-1 are sufficient for normal BMD. Other studies assessing the effect of DHT on bone in men by using the 5{alpha}-reductase-2 inhibitor, finasteride, have demonstrated no significant effect of decreased levels of DHT on BMD (35, 36, 37). Furthermore, 5{alpha}-reductase-1 produces approximately 30% of DHT in the serum, accounting for most of the circulating DHT in 5{alpha}RD-2 subjects (38). It should also be noted that bone cells from both humans and animals appear to express predominantly the type 1 5{alpha}-reductase (39). Therefore, local and circulating DHT production by 5{alpha}-reductase-1 could play a role in bone homeostasis. In addition, the elevated levels of T in 5{alpha}RD-2 subjects, accounted for by DHT regulation of LH secretion (40), may also be a contributing factor.

The findings of our study suggest the importance of androgens in BMD development and/or maintenance. When put in the context of past studies that support the important role of estrogen in BMD maintenance in men, they lead to the conclusion that both androgens and estrogens play a role in male bone development and/or maintenance, and that perhaps the actions of androgens and estrogens in this scenario are complementary. They also demonstrate that estrogen levels in males are not wholly sufficient for BMD development and/or maintenance. Theoretically, it is possible that androgens affect the laying down of the bony matrix during childhood and puberty upon which estrogen then acts throughout adulthood. Consequently, without the structural architecture that is dependent upon adequate androgen stimulation in men, estrogen action is impaired. Therefore, in the model of CAI, lack of androgen stimulation during puberty leads to inadequate bone formation, which cannot be salvaged by administration of estrogen later in adulthood (i.e. by hormone replacement therapy after gonadectomy).

In summary, assessment of BMD values in patients with CAI and 5{alpha}RD-2 suggests that androgens are of direct importance in building and/or maintaining BMD via androgen receptor signaling. Furthermore, the presence of T and/or low levels of DHT is sufficient for this to occur.


   Footnotes
 
This research was supported by the Weill Medical College General Clinical Research Center Grants M01 RR00047 and R01 HD09421 from National Institutes of Health.

Disclosure statement: The authors have nothing to disclose.

First Published Online May 30, 2006

Abbreviations: BMD, Bone mineral density; CAI, complete androgen insensitivity; DHT, dihydrotestosterone; PAI, partial androgen insensitivity; 5{alpha}RD-2, 5{alpha}-reductase-2 deficiency; T, testosterone.

Received December 22, 2005.

Accepted May 23, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C 2004 Androgens and bone. Endocr Rev 25:389–425[Abstract/Free Full Text]
  2. Imperato-McGinley J, Ip NY, Gautier T, Neuweiler J, Gruenspan H, Liao S, Chang C, Balazs I 1990 DNA linkage analysis and studies of the androgen receptor gene in a large kindred with complete androgen insensitivity. Am J Med Genet 36:104–108[CrossRef][Medline]
  3. Imperato-McGinley J, Peterson RE, Gautier T, Cooper G, Danner R, Arthur A, Morris PL, Sweeney WJ, Shackleton C 1982 Hormonal evaluation of a large kindred with complete androgen insensitivity: evidence for secondary 5{alpha}-reductase deficiency. J Clin Endocrinol Metab 54:931–941[Medline]
  4. Zhu YS, Cai LQ, Cordero JJ, Canovatchel WJ, Katz MD, Imperato-McGinley J 1999 A novel mutation in the CAG triplet region of exon 1 of androgen receptor gene causes complete androgen insensitivity syndrome in a large kindred. J Clin Endocrinol Metab 84:1590–1594[Abstract/Free Full Text]
  5. Cai LQ, Zhu YS, Katz MD, Herrera C, Baez J, DeFillo-Ricart M, Shackleton CH, Imperato-McGinley J 1996 5{alpha}-Reductase-2 gene mutations in the Dominican Republic. J Clin Endocrinol Metab 81:1730–1735[Abstract]
  6. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE 1974 Steroid 5{alpha}-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 186:1213–1215[Abstract/Free Full Text]
  7. Imperato-McGinley J, Miller M, Wilson JD, Peterson RE, Shackleton C, Gajdusek DC 1991 A cluster of male pseudohermaphrodites with 5{alpha}-reductase deficiency in Papua New Guinea. Clin Endocrinol (Oxf) 34:293–298[Medline]
  8. Akgun S, Ertel NH, Imperato-McGinley J, Sayli BS, Shackleton C 1986 Familial male pseudohermaphroditism due to 5-{alpha}-reductase deficiency in a Turkish village. Am J Med 81:267–274[CrossRef][Medline]
  9. Imperato-McGinley J, Peterson RE, Gautier T, Sturla E 1979 Male pseudohermaphroditism secondary to 5{alpha}-reductase deficiency—a model for the role of androgens in both the development of the male phenotype and the evolution of a male gender identity. J Steroid Biochem 11:637–645[CrossRef][Medline]
  10. Thigpen AE, Davis DL, Gautier T, Imperato-McGinley J, Russell DW 1992 Brief report: the molecular basis of steroid 5{alpha}-reductase deficiency in a large Dominican kindred. N Engl J Med 327:1216–1219[Medline]
  11. Zhu YS, Katz MD, Imperato-McGinley J 1998 Natural potent androgens: lessons from human genetic models. Baillieres Clin Endocrinol Metab 12:83–113[CrossRef][Medline]
  12. Can S, Zhu YS, Cai LQ, Ling Q, Katz MD, Akgun S, Shackleton CH, Imperato-McGinley J 1998 The identification of 5{alpha}-reductase-2 and 17ß-hydroxysteroid dehydrogenase-3 gene defects in male pseudohermaphrodites from a Turkish kindred. J Clin Endocrinol Metab 83:560–569[Abstract/Free Full Text]
  13. Wigley WC, Prihoda JS, Mowszowicz I, Mendonca BB, New MI, Wilson JD, Russell DW 1994 Natural mutagenesis study of the human steroid 5{alpha}-reductase 2 isozyme. Biochemistry 33:1265–1270[CrossRef][Medline]
  14. Peterson RE, Imperato-McGinley J, Gautier T, Sturla E 1977 Male pseudohermaphroditism due to steroid 5-{alpha}-reductase deficiency. Am J Med 62:170–191[CrossRef][Medline]
  15. Glauber HS, Vollmer WM, Nevitt MC, Ensrud KE, Orwoll ES 1995 Body weight versus body fat distribution, adiposity, and frame size as predictors of bone density. J Clin Endocrinol Metab 80:1118–1123[Abstract]
  16. Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER 1997 Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 337:91–95[Free Full Text]
  17. Bilezikian JP, Morishima A, Bell J, Grumbach MM 1998 Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 339:599–603[Free Full Text]
  18. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K 1995 Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 80:3689–3698[Abstract]
  19. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS 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]
  20. Diamond T, Campbell J, Bryant C, Lynch W 1998 The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: longitudinal evaluation and response to intermittent cyclic etidronate therapy. Cancer 83:1561–1566[CrossRef][Medline]
  21. Ross PD, He Y, Yates AJ, Coupland C, Ravn P, McClung M, Thompson D, Wasnich RD 1996 Body size accounts for most differences in bone density between Asian and Caucasian women. The EPIC (Early Postmenopausal Interventional Cohort) Study Group. Calcif Tissue Int 59:339–343[CrossRef][Medline]
  22. Bhudhikanok GS, Wang MC, Eckert K, Matkin C, Marcus R, Bachrach LK 1996 Differences in bone mineral in young Asian and Caucasian Americans may reflect differences in bone size. J Bone Miner Res 11:1545–1556[Medline]
  23. Cheung EY, Ho AY, Lam KF, Tam S, Kung AW 2005 Determinants of bone mineral density in Chinese men. Osteoporos Int 16:1481–1486[CrossRef][Medline]
  24. Tuck SP, Pearce MS, Rawlings DJ, Birrell FN, Parker L, Francis RM 2005 Differences in bone mineral density and geometry in men and women: the Newcastle Thousand Families Study at 50 years old. Br J Radiol 78:493–498[Abstract/Free Full Text]
  25. Valero C, Zarrabeitia MT, Hernandez JL, Zarrabeitia A, Gonzalez-Macias J, Riancho JA 2005 Bone mass in young adults: relationship with gender, weight and genetic factors. J Intern Med 258:554–562[CrossRef][Medline]
  26. Mizunuma H, Soda M, Okano H, Kagami I, Miyamoto S, Ohsawa M, Ibuki Y 1998 Changes in bone mineral density after orchidectomy and hormone replacement therapy in individuals with androgen insensitivity syndrome. Hum Reprod 13:2816–2818[Abstract/Free Full Text]
  27. Soule SG, Conway G, Prelevic GM, Prentice M, Ginsburg J, Jacobs HS 1995 Osteopenia as a feature of the androgen insensitivity syndrome. Clin Endocrinol (Oxf) 43:671–675[Medline]
  28. Bertelloni S, Baroncelli GI, Federico G, Cappa M, Lala R, Saggese G 1998 Altered bone mineral density in patients with complete androgen insensitivity syndrome. Horm Res 50:309–314[CrossRef][Medline]
  29. Marcus R, Leary D, Schneider DL, Shane E, Favus M, Quigley CA 2000 The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome. J Clin Endocrinol Metab 85:1032–1037[Abstract/Free Full Text]
  30. Seeman E 2001 Clinical review 137: Sexual dimorphism in skeletal size, density, and strength. J Clin Endocrinol Metab 86:4576–4584[Free Full Text]
  31. Gaspar ML, Meo T, Bourgarel P, Guenet JL, Tosi M 1991 A single base deletion in the Tfm androgen receptor gene creates a short-lived messenger RNA that directs internal translation initiation. Proc Natl Acad Sci USA 88:8606–8610[Abstract/Free Full Text]
  32. Vandenput L, Swinnen JV, Boonen S, Van Herck E, Erben RG, Bouillon R, Vanderschueren D 2004 Role of the androgen receptor in skeletal homeostasis: the androgen-resistant testicular feminized male mouse model. J Bone Miner Res 19:1462–1470[CrossRef][Medline]
  33. Yeh S, Tsai MY, Xu Q, Mu XM, Lardy H, Huang KE, Lin H, Yeh SD, Altuwaijri S, Zhou X, Xing L, Boyce BF, Hung MC, Zhang S, Gan L, Chang C 2002 Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues. Proc Natl Acad Sci USA 99:13498–13503[Abstract/Free Full Text]
  34. Kawano H, Sato T, Yamada T, Matsumoto T, Sekine K, Watanabe T, Nakamura T, Fukuda T, Yoshimura K, Yoshizawa T, Aihara K, Yamamoto Y, Nakamichi Y, Metzger D, Chambon P, Nakamura K, Kawaguchi H, Kato S 2003 Suppressive function of androgen receptor in bone resorption. Proc Natl Acad Sci USA 100:9416–9421[Abstract/Free Full Text]
  35. Matzkin H, Chen J, Weisman Y, Goldray D, Pappas F, Jaccard N, Braf Z 1992 Prolonged treatment with finasteride (a 5{alpha}-reductase inhibitor) does not affect bone density and metabolism. Clin Endocrinol (Oxf) 37:432–436[Medline]
  36. Amory JK, Watts NB, Easley KA, Sutton PR, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL 2004 Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 89:503–510[Abstract/Free Full Text]
  37. Matsumoto AM, Tenover L, McClung M, Mobley D, Geller J, Sullivan M, Grayhack J, Wessells H, Kadmon D, Flanagan M, Zhang GK, Schmidt J, Taylor AM, Lee M, Waldstreicher J 2002 The long-term effect of specific type II 5{alpha}-reductase inhibition with finasteride on bone mineral density in men: results of a 4-year placebo controlled trial. J Urol 167:2105–2108[CrossRef][Medline]
  38. Schwartz JI, Van Hecken A, De Schepper PJ, De Lepeleire I, Lasseter KC, Shamblen EC, Winchell GA, Constanzer ML, Chavez CM, Wang DZ, Ebel DL, Justice SJ, Gertz BJ 1996 Effect of MK-386, a novel inhibitor of type 1 5{alpha}-reductase, alone and in combination with finasteride, on serum dihydrotestosterone concentrations in men. J Clin Endocrinol Metab 81:2942–2947[Abstract]
  39. Issa S, Schnabel D, Feix M, Wolf L, Schaefer HE, Russell DW, Schweikert HU 2002 Human osteoblast-like cells express predominantly steroid 5{alpha}-reductase type 1. J Clin Endocrinol Metab 87:5401–5407[Abstract/Free Full Text]
  40. Canovatchel WJ, Volquez D, Huang S, Wood E, Lesser ML, Gautier T, Imperato-McGinley J 1994 Luteinizing hormone pulsatility in subjects with 5-{alpha}-reductase deficiency and decreased dihydrotestosterone production. J Clin Endocrinol Metab 78:916–921[Abstract]




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