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Original Article |
Department of Endocrinology (S.D., H.B.-G., E.B., R.C., P.G., G.T.), Hôpital de La Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris; Department of Neurology (B.E., F.S.), Myological Institute, Hôpital de La Salpétrière; and Institut National de la Santé et de la Recherche Médicale U 289 and Department of Genetics, Cytogenetics, and Embryology (E.L., S.T.), Hôpital de La Salpétrière, 75 013 Paris, France
Address all correspondence and requests for reprints to: Sylvie Dejager, M.D., Ph.D., Department of Endocrinology, Hôpital de La Pitié-Salpétrière, 83 Bd de L’Hôpital, 75 013 Paris, France. E-mail: . sylvie.dejager{at}wanadoo.fr
Abstract
Our study aims to provide a comprehensive view of the endocrine features in Kennedy’s disease (KD). Twenty-two men with KD underwent detailed endocrine investigations. Clinical signs of partial androgen resistance were present in more than 80% of the patients, with gynecomastia being the most prominent. Gynecomastia was postpubertal but appeared before muscular weakness in most cases. Thirteen patients had alteration of testicular exocrine function. Hormonal profile of partial androgen resistance was present in 86% of the patients, with an elevated testosterone level in 68%. Androgen insensitivity seems to appear later in life in KD, similar to the development of neurological signs.
Although we confirm the previously reported correlation between the CAG repeat length and the early onset of the neurological disease, we describe a significant correlation between repeat length and the age of onset of gynecomastia as well as biological indexes of androgen insensitivity. This is supported by numerous in vitro data correlating variations in the CAG tract with androgen receptor activity; the longer the CAG repeats, the weaker the receptor transactivation. Ours is the first study to show such a clear and prominent pattern of androgen insensitivity in KD. In clinical practice, KD patients are often misdiagnosed as having amyotrophic lateral sclerosis. Careful examination of the endocrine component could avoid such a deleterious misdiagnosis.
KENNEDY’S DISEASE (KD) is a very rare, X-linked disease that is clinically characterized by slowly progressive muscle weakness and atrophy with onset in adult males (usually in the fourth or fifth decade). Muscle cramps may precede the onset of weakness by several years. Symptoms are related to both spinal and bulbar motor neurons involvement, including facial weakness, speech difficulty, and coarse fasciculation. KD affects 1 in 40,000 men worldwide, but remains largely under diagnosed.
Although the neurological features of the disease have been extensively described, few studies have thoroughly investigated its endocrine component (Table 1
). Nevertheless, literature usually describes KD as a nonclassic form of mild, late-onset androgen resistance. The fact that affected males exhibit mild clinical signs of androgen insensitivity, frequently quoted in reviews (1), is actually poorly documented (Table 1).
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In the normal population, the trinucleotide CAG repeats expansion (coding for polyglutamine tract) of the first exon of the AR is polymorph, with the length varying from 11–35 repeats (6). In KD, the number of the CAG repeats is further expanded, varying from 40–62 with no overlap with normal population (5). The molecular mechanism by which the increased number of CAG repeats in exon 1 of the AR gene causes the neurological disease remains unclear. However, there is now strong evidence that an increased number of CAG repeats in the coding region of exon 1 segregates with the disease phenotype; the size of CAG repeat expansion significantly influences the age of disease onset (7, 8, 9, 10), whereas no correlation between repeat length and severity of androgen insensitivity has been described.
As mentioned above, KD endocrine features have not been clearly defined in previous studies. Furthermore, the relationship between the degree of endocrine dysfunction, such as androgen insensitivity, and the number of CAG repeats in the coding region of exon 1 has been poorly investigated. Our main objective was therefore to extensively describe the endocrine characteristics of KD in a relatively large cohort of patients and to examine them in light of neurological history and molecular studies of the CAG repeats.
Patients and Methods
Between 1996 and 2001, all consecutive patients presenting with KD were referred for endocrine testing from the Department of Neurology/Myology Institute to the endocrine outpatient department at the University Hospital of La Pitie-Salpétrière in Paris.
Study population
The study population consisted of 22 consecutive KD patients from 12 families presenting with typical neurological signs, namely the progressive proximal muscle weakness, fasciculations, and atrophy associated with spinal and bulbar cord involvement.
All had undergone an extensive neurological evaluation (muscular testing, Walton tests) before being referred to the endocrine department.
The patients then underwent clinical and endocrine evaluation, including testis examination and prostate evaluation by ultrasound. Clinical work-up covered questions regarding their personal history as well as family history of virilization disorders, and in particular, 1) presence and age of onset of gynecomastia; 2) sexual activity and libido; 3) shaving frequency; 4) fertility and the number of children; and 5) family history of genital ambiguity, infertility, or gynecomastia.
Suspected cases of gynecomastia were confirmed by mammography (and some underwent surgery), and suspected altered fertility was confirmed by sperm counts when possible. Patients were also questioned about a family history of other endocrine or metabolic disorders.
Assays
After an overnight fast, subjects were admitted to the outpatient clinic, and all blood samples were collected between 0800 and 0900 h.
Hormones
Serum concentrations of total testosterone, estradiol (E2), dehydroepiandrosterone sulfate, FSH, LH, and prolactin (PRL) were determined by established radioimmunological methods using double antibody techniques, with intra-assay coefficients of variation (CV) less than 10%. Normal values of testosterone are 10.4–27.7 nmol/liter; normal values of E2 are 73–184 pmol/liter.
Serum LH and FSH were measured by specific RIA; the sensitivity of the assays was 1 IU/liter for LH and 0.3 IU/liter for FSH, with respective intra- and interassay CV of 2.4–3.6% and 2.7–3.4% for LH and 3.7–4% and 5–5.9% for FSH. Normal values were: FSH, 1–8 IU/liter; and LH, 2–12 IU/liter.
SHBG (normal value, 18–42 nmol/liter) was measured by an electroimmunodiffusion technique on agarose gel (Hydragel agarose sebia) with respective intra- and interassay CV of 4.2–6% and 4.8–6.2%.
Absolute values for serum testosterone were multiplied by those for LH to determine the product value, which is known as the androgen sensitivity index (ASI; Refs. 11, 12). Reported values in a normal male population in the literature were 54 IU x nmol/liter2 (range, 6.7–138.7 IU x nmol/liter2; Ref. 12). In addition, the normal values determined in 35 adult healthy males within the age range 50–65 yr were 36 IU x nmol/liter2 (range, 3.5–88 IU x nmol/liter2) in our laboratory and with the same dosage methods.
All patients also had their thyroid status assessed. TSH ultra-sensible (TSHus) was measured by RIA-gnost human TSH assay (normal range, 0.1–0.4 mIU/liter).
Dynamic tests
Two dynamic tests were performed: GnRH to assess gonadotropin responses and TRH to assess PRL and TSHus responses.
Biochemical parameters
Blood tests including hematologia, liver function tests, creatine kinase (CK), fasting glycemia, creatininemia, and uricemia were performed. Plasma glucose concentrations were determined by the glucose oxidase method (glucose analyser, Beckman Coulter, Inc., Palo Alto, CA). Normal values for CK are less than 195 IU/liter.
Lipids and lipoproteins
Venous blood samples were collected after a 12-h overnight fast and were drawn into sterile EDTA-containing tubes (Vacutainer, Becton, Dickinson and Company, Franklin Lakes, NJ). Plasma lipids were quantified on a specific supra analyser (Kone, Espoo, Finland) by usual enzymatic methods with Biomerieux kits (Biomerieux, Marcy l’Etoile, France) for total cholesterol (TC) and triglycerides (TG). High-density lipoprotein-cholesterol (HDL-C) was determined using a phosphotungstic acid/MGcl2 reagent (Boeringer Mannheim, Indianapolis, IN) to precipitate the apoprotein B-containing lipoproteins, and cholesterol was measured in the supernatant, as described above for plasma. Low-density lipoprotein-cholesterol was calculated by the Friedewald’s formula. Apoproteins A-I and B and lipoprotein (a) levels were determined with nephelometric assays (Behring BNA, Marburg, Germany) using antibodies by Behring Kits.
DNA analysis and molecular biology
DNA was extracted by standard procedures from blood samples from the 22 patients after obtaining their informed consent.
The exon 1 of the AR gene was amplified using the forward Fam (5'-TCCAGAATCTGTTCCAGAGCGTGC-3') and reverse (5'-GCTGTGAAGGTTGCT GTTCCTCAT-3') primers flanking the CAG repeat. The PCRs were prepared as follows: 50 ng DNA, 5 pmol of each primer, 2.5 mM of each dNTP, 1.5 µl 10x PCR buffer, and 0.6 U Ampli Taq Gold DNA polymerase in a final volume of 15 µl. Samples were incubated for 12 min at 95 C to activate the Taq polymerase, then for 20 sec at 94 C, 20 sec at 58 C, and 30 sec at 72 C for 35 cycles, followed by an elongation for 10 min at 72 C at the end of each PCR. The 300-bp PCR products were pooled with the GeneScan 400HD size standard and were loaded on a 4% acrylamide gel for electrophoresis (ABI Prism 377 DNA sequencer, PE Applied Biosystems, Foster City, CA). Pathological alleles were sized using GeneScan and Genotyper softwares (PerkinElmer, Wellesley, MA).
Statistical analysis
Descriptive statistics were done; mean, SD, minimum, and maximum are given for all continuous variables, and absolute numbers and percentages are given for qualitative variables. For correlation among the sizes of CAG repeats, age of onset of gynecomastia, testosterone and ASI, a Spearman’s rank Pearson’s correlation coefficient, and associated P value were calculated. P values of less than 0.05 were considered to be significant. The statistical analysis was performed with the use of JMP software (SAS Institute, Inc., Cary, NC).
Results
Clinical findings (Table 2)
The mean age of the population was 50.5 yr (range, 31–66 yr). The mean duration of the disease was 8.3 yr (range, 2–19 yr).
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Three patients were being treated for hypertension, and two others for dyslipidemia at the time of the investigations. One patient presented with subclinical hypothyroidism (caused by Isaacs syndrome), which did not require treatment at the time of the study.
Neurological findings (Table 2
)
Age of onset of muscular weakness ranged from 28–57 yr. Cramps, fasciculations, and postural tremors started either before or at the same time as muscular weakness. Muscular involvement was most pronounced proximally. Mild facial muscle weakness was observed in all cases, and bulbar involvement was observed in 10 cases. The severity of muscular deficit was highly variable (ranging from slight difficulties in climbing stairs to complete walking impairment).
Endocrine findings (Table 2)
None of the patients revealed the pattern of either complete androgen insensitivity or genital ambiguity. Penis size, prostate gland size, and hair growth were normal in all cases. None of the patients presented with hypospadias. Gynecomastia was observed in 16 of 22 cases (73%). All cases were confirmed by mammography or surgery, and none of the patients were under treatment susceptible to cause gynecomastia. Eleven of these 16 patients (69%) had developed gynecomastia before the occurrence of muscular weakness, one at the same time as muscular weakness, and three patients a few years later. Gynecomastia was postpubertal in most cases, with an age of onset younger than 20 yr in only 5 cases.
Eleven patients (50%) reported mild symptoms of hypoandrogenicity, such as decreased sexual interest, dyserection, or decreased facial hair growth with onset concomitant to or soon after muscular symptoms. Four patients reported primary sterility, which had previously been investigated between the ages of 20 and 30 yr, with semen analysis confirming severe oligoastenoteratospermia (OAT). Three other patients had acquired sterility (after fathering at least one child), confirmed on semen analysis showing OAT for two patients and azoospermia for one patient. In all cases but one, alteration of semen parameters was present before onset of muscular weakness.
Semen analysis was not available for the remaining 15 patients, although among these patients, 3 presented with testis atrophy and 3 with testis hypotrophy, also suggesting some degree of exocrine dysfunction.
Overall, 13 of 22 patients showed some evidence of testicular exocrine dysfunction.
Hormonal findings (Table 3)
Basal testosterone levels were increased in 15 of 22 cases (68%). Within this group with high testosterone levels, SHBG levels were above the normal range in eight cases and at the upper limit of normal range in four cases (Fig. 1). A highly positive correlation was found between testosterone and SHBG (r = 0.78; P < 0.01; Fig. 1). Increased basal LH level or exaggerated LH/GnRH response (
5-fold basal LH) were observed in eight cases. Selective increase of testosterone levels in the presence of normal LH levels was seen in the seven remaining cases.
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The mean ASI (LH x testosterone multiplication product) in our population was 166 IU x nmol/liter2 (range, 20.3–364 IU x nmol/liter2). This result is far above the normal range, whether one takes into account the mean reported in a control group of 53 fertile Caucasian men (54 IU x nmol/liter2; range, 6.7–138.7 IU x nmol/liter2; Ref. 12) or the mean found in our laboratory in healthy control men (36 IU x nmol/liter2; range, 3.5–88 IU x nmol/liter2). Furthermore, ASI was more than 120 IU x nmol/liter2 in 14 of 22 cases (64%).
E2 levels were normal except in two patients in whom they were slightly increased (205.5 and 201.8 pmol/liter). FSH was increased in five cases. Responses of FSH to LHRH were normal. Some patients, despite severe semen abnormalities, had normal basal FSH. Among patients who did not undergo semen analysis, three had mildly elevated FSH levels.
PRL levels were normal in all cases, as well as the other endocrine parameters: thyreotrope axis, corticotrope axis, GH, IGF-I, and the 
-subunit (data not shown).
In summary, 19 of 22 patients (86.4%) presented biological signs of partial androgen insensitivity, including an association of 1) elevated testosterone, associated with high inappropriate SHBG and/or LH levels in 15 cases, and 2) testosterone in the upper normal range, associated with explosive response of LH to GnRH in four cases. Additionally, gynecomastia was present in two of the three remaining patients, despite hormonal findings not reflecting androgen insensitivity.
Biological analysis
Glycemia was in the normal range in all cases (mean, 5.6 ± 0.61 mmol/liter) as well as uricemia (mean, 204 ± 123 µmol/liter). CK was greatly increased in all of the subjects (mean 
10 times the normal value, 1431 IU/liter; range, 400-6912 IU/liter). Liver enzymes were slightly elevated in 17 cases, mainly in patients with high levels of CK, probably in relation with the muscular involvement.
Hematologia was normal, with in particular a mean hematocrite value of 42% (± 4).
TC was above 6.45 mmol/liter in 15 of 22 cases (68%) with associated increased TG levels in 9 cases. HDL-C was normal in all patients, with no value less than 0.90 mmol/liter. Apolipoprotein B was elevated in 12 cases (mean, 1.30 ± 0.27 g/liter; range, 0.81–1.86 g/liter). Lipoprotein (a) was above 35 mg/dl in 5 cases. Altogether, lipid abnormalities are frequent in this population with only four patients having normal lipid findings. Among the patients with dyslipidemia, only two were treated (with fibrates) at the time of the analysis, but they were not normalized (Table 4).
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KD was genetically confirmed in all patients. The number of CAG repeats in exon 1 of the AR ranged from 40–51 (Table 2). Family history of female carriers of affected men was found in 13 of 22 patients.
Correlation between phenotype and genotype (Figs. 2 and 3)
The relationship between the number of CAG and age of onset of gynecomastia was studied. Interestingly, an increased number of CAG was found to be associated with a lower age of onset of gynecomastia (Fig. 2; r = -0.51; P = 0.02, one-sided). Furthermore, a similar and consistent relationship was found between the degree of endocrine dysfunction (biological indexes of androgen insensitivity) and the number of CAG repeats: the longer the CAG, the more marked the androgen insensitivity. Namely, the correlation coefficients for SHBG and ASI were r = 0.41 and r = 0.51, respectively, with P values of 0.03 and less than 0.01 (Fig. 3). Correlation between testosterone levels and the number of CAG repeats followed the same pattern, without reaching significance level (r = 0.3; P = 0.09).
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Discussion
Since the first description of the disease by Kennedy over 30 yr ago (1968), there have been few detailed descriptions of the endocrine features of SBMA (13). It was only in 1991 that La Spada et al. (14) identified the AR mutation as being responsible for the disease. In all, only about 50 cases, including brief endocrine descriptions, have been reported worldwide with usually less than eight patients per publication (Table 1).
Ours is the first study in which a relatively large cohort of patients with KD underwent a systematic and comprehensive endocrine characterization.
Clinical symptoms of partial androgen insensitivity
Nineteen of the 22 patients (86%) in our study showed some clinical signs of partial androgen insensitivity; the most common feature was gynecomastia, present in 16 of 22 cases (73%), followed by undermasculinization, testicular hypotrophy, or reduced fertility. There were no cases of genital ambiguity or hypospadias. Gynecomastia probably resulted from the lack of the normal inhibitory action of androgens on breast tissue proliferation rather than from an increase in estrogen levels, a mild case of which was observed in only two patients.
Testicular exocrine dysfunction was common, present to some extent in 13 of our 22 patients. Severe semen abnormalities (OAT or azoospermia) were confirmed in the seven patients who had previously undergone sperm counts because of infertility. Reduced testis size was observed in the six remaining patients for whom sperm count was not justifiable on ethical grounds. OAT can be regarded as a good index of testicular dysfunction and androgen insensitivity, because spermatogenesis is highly androgen-dependent. Infertility due to azoospermia has been reported to be the only consistent feature of partial androgen resistance (1, 2, 12).
It is important to point out that the endocrine symptoms can precede the onset of the neurological symptoms, and thus the diagnosis of KD, by several years. Although the age of onset of gynecomastia was highly variable, ranging from 12–57 yr, gynecomastia appeared before muscular weakness in many cases. Six of the seven patients with OAT had altered sperm counts before development of muscular weakness.
Both the onset of semen degradation and gynecomastia became discernible later in adulthood. Several men had fathered at least one child before being diagnosed with OAT. This confirms that, unlike other AISs, the mild androgen insensitivity in KD is not a fixed feature of the disease but rather slowly progressive like the neurological symptoms. The delayed development of both androgen insensitivity and motor neuron degeneration may reflect a progressive AR dysfunction rather than a fixed deficit, supporting the hypothesis of a regulatory defect of the AR in this disorder (15). One exception has recently been reported (16): an 11-year-old Japanese boy with undermasculinized genitalia and an abnormally expanded CAG repeat. This raises the possibility that susceptibility to androgen-related disorders by other genetic and/or environmental factors is increased with expanded CAG (16).
Hormonal profiles in KD, although of obvious interest, have rarely been described in the literature (Table 1). Furthermore, these few descriptions fail to reveal any consistent pattern. Few studies (about 10 published cases) reported increased levels of LH associated with normal testosterone levels (17, 18, 19, 20). Mariotti et al. (21) found normal plasma levels of LH and FSH in all but one of the 15 patients studied. Igarashi et al. (8) found elevated testosterone levels in 3 of 15 patients, but LH was not assessed. Curiously, increased testosterone levels have rarely been reported (21). One study even reported some cases of decreased testosterone levels with normal LH levels (22).
In patients with AIS, the typical hormonal profile usually associates normal or elevated testosterone levels with elevated or nonsuppressed LH levels. E2 levels are often increased due to aromatization of testosterone to E2. SHBG is one of the few reliable biological markers for androgen sensitivity. SHBG, which is normally increased by E2 and decreased by androgen, is therefore usually elevated in AIS.
The typical pattern of AIS was frequently found in our KD patients; high testosterone levels associated with inappropriately high SHBG levels were present in 12 cases. The strong positive correlation observed between testosterone and SHBG is in contrast to what is known in a normal male population (Fig. 1). High testosterone levels with relative LH hyperresponsiveness to GnRH were present in 12 cases. Exaggerated response of LH to GnRH despite normal testosterone level, which was present in four cases, has been considered as an interesting sign of partial androgenoresistance (23). This enhanced response could reflect a greater stock of LH due to a lack of direct pituitary suppressive effect of testosterone, thus being a sign of androgen resistance at the pituitary level. Sobue et al. (24) found a reduced suppressive effect of administration of synthetic androgens on testosterone, LH, and FSH levels in patients with KD compared with male controls, which indicates an attenuated effect of androgen at the pituitary level in this disease. ASI was markedly increased in 14 cases (64%), the mean being more than twice that determined in control groups from previous studies (11, 12). This distinctively high value again reflects the presence of partial androgen resistance in our KD population.
One patient had normal hormonal findings. Two patients, aged 63 and 58 yr, had testosterone levels in the low-normal range with normal LH level and explosive LH/GnRH. This endocrine pattern is not what would be expected in patients with androgen insensitivity but has been reported before (22). However, aging contributes to the decline in serum testosterone (25), and patients were studied at different ages and at different stages in the course of their disease. A longitudinal cohort study would be required to assess a possible change in testosterone levels in parallel with disease duration.
In view of our consistent finding of partial AIS in this population, it might be interesting to treat these patients with high doses of exogenous androgen. However, therapeutic trials of testosterone have been disappointing so far, giving inconsistent results (26). Although modest positive benefit and functional improvement have been shown in some cases, the effect may have been nonspecific. No definite conclusion can be drawn from these limited and uncontrolled trials (26, 27, 28).
Other endocrine axes were normal, with the exception of subclinical hypothyroidism in one patient caused by Hashimoto thyroiditis (untreated at the time of the study). This patient had Isaac syndrome, which associates neuromyotony and Hashimoto thyroiditis. We believe that the presence of Isaac syndrome in our study is coincidental.
No other AR mutation, including complete deletion, causes motor neuron deficiency such as in SBMA. It has been suggested that the expansion of the CAG repeats behaves as a dominant gain of function mutation so that the presence of an expanded polyglutamine tract in the protein is toxic for motor neurons (29, 30). The mechanism could be enhanced apoptosis (31). Beside this gain of function, there is a loss of AR function (20, 32). The trinucleotide CAG is located in exon 1, which encodes the transactivation domain of AR. The majority of in vitro studies have found reduced transactivation function of the mutated AR containing an increased number of CAG (33, 34, 35, 36). Butler showed that SBMA-AR was localized mainly in the cytoplasm in the form of dense aggregates (30). The AR aggregations can sequester proteins, including cofactors for AR-induced transcription, and lead to aberrant processing; additionally the homeostatic disturbances associated with aggregate formation may affect normal cell function (37, 38). Decreased AR transcriptional activation and sequestration of AR cofactors probably account for the features of mild androgen insensitivity (39). Interestingly, a wide spectrum of AR transactivation seems to exist even within the normal range of the polyglutamine tract. A relationship between the number of CAG and fertility has been described; men with short CAG repeats were found to have the highest sperm output within the normal fertile population (40). However, this relationship remains controversial, because some studies have demonstrated an impaired sperm production associated with long CAG tracts (41, 42, 43, 44), whereas others were unable to corroborate these findings (45, 46). Similarly, the recently described association of longer CAG repeats with moderate undermasculinization of the male genitalia (47) has yet to be confirmed (48). Conversely, short CAG repeats have been linked to an increased risk and an earlier age of onset of prostate cancer (49) and more recently to male pattern baldness (50). In women, CAG repeat polymorphism is linked to the intrinsic androgenic activity and influences the process leading to polycystic ovary syndrome (51, 52, 53). Therefore, AR triplet repeats within the normal range should not necessarily be regarded as a benign and silent polymorphism (47).
As reported with all expansion diseases, the longer the repeat, the earlier the onset of the neurological disease (7, 8, 9, 10). Ours is the first study to show a definite link between endocrine features and the number of CAG (Figs. 2 and 3). Previous studies have not found any clear correlation between CAG repeat length and severity of endocrine symptoms (7, 8, 9, 54). Mac Lean et al. (20) found a nonsignificant trend for an increased number of CAG associated with a younger age of onset of gynecomastia. Warner et al. (55) have suggested a possible link between the severity of neuromuscular dysfunction and some endocrine abnormalities in eight patients. In our larger cohort of patients, we found a significant correlation between the age of onset of gynecomastia and the number of CAG repeats. Consistent with these clinical findings, biological indexes of androgen insensitivity, such as ASI and SHBG, were also significantly correlated with repeat length. This relationship is in line with the reported correlation between the modulation of AR activity and the number of CAG repeats observed in the normal range (44, 47). This is also in agreement with the in vitro data, which demonstrated an inverse correlation between the number of CAG and capacity of transactivation of the AR.
Unexpectedly, we found a particularly high frequency of lipid abnormalities in our KD population. Only 4 patients had completely normal lipid findings, whereas 15 patients (68%) had a marked elevation of TC (>6.45 mmol/liter). This number is in deep contrast with the known incidence of hypercholesterolemia in the French population (17% of the adult population has a TC >6.45 mmol/liter). However, most patients did not report family history of either dyslipidemia or coronary artery disease and did not present any condition that may cause secondary dyslipidemia. Lipid abnormalities have already been described in case reports of KD (55, 56, 57, 58, 59). A high incidence of hyperlipoproteinemia has also been reported in patients with amyotrophic lateral sclerosis (60). To date, there is no explanation for this high frequency of lipid disturbances found in KD, which warrants continued investigation. Recently, lower levels of HDL-C have been associated with short CAG repeats in healthy men (61). Short CAG repeats thus appeared to put men at increased risk for developing coronary heart disease. This is in good agreement with our results, because none of the KD patients had low levels of HDL-C (mean, 1.36 mmol/liter), and none had coronary heart disease.
In conclusion, our findings show partial AIS as being a consistent feature of KD in a large cohort having undergone a thorough endocrine investigation. In addition, clinical and biological indexes of androgen insensitivity were related to the number of CAG repeats in the AR.
In view of our consistent finding of partial AIS in this population, one might think it interesting to treat these patients with high doses of exogenous androgen. More information in properly designed placebo-controlled trials should be forthcoming.
The recent development of a transgenic model of SBMA (transgenic mice expressing highly expanded repeat AR and developing many of the motor symptoms) will provide a useful tool for testing future therapeutic strategies (62).
The high frequency and clear pattern of endocrine abnormalities, coupled with the fact that they often precede neurological symptoms, should help clinicians avoid the misdiagnosis of KD with other degenerative diseases such as amyotrophic lateral sclerosis (63).
Acknowledgments
We acknowledge and thank Felicity Neilson for critical reading of this manuscript and for helpful discussions and Dr. Françoise Wright for analyzing hormonal parameters and for kindly providing control group data.
Footnotes
Abbreviations: AIS, Androgen insensitivity syndrome; AR, androgen receptor; ASI, androgen sensitivity index; BMI, body mass index; CK, creatine kinase; CV, coefficient(s) of variation; E2, estradiol; HDL-C, high-density lipoprotein-cholesterol; KD, Kennedy’s disease; OAT, oligoastenoteratospermia; PRL, prolactin; SBMA, spinal and bulbar muscular atrophy; TC, total cholesterol; TG, triglycerides; TSHus, TSH ultra-sensible.
Received March 6, 2002.
Accepted May 13, 2002.
References
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  L. E. Rhodes, B. K. Freeman, S. Auh, A. D. Kokkinis, A. La Pean, C. Chen, T. J. Lehky, J. A. Shrader, E. W. Levy, M. Harris-Love, et al. Clinical features of spinal and bulbar muscular atrophy Brain, October 21, 2009; (2009) awp258v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
 |
|
 S. T. Page, J. K. Amory, and W. J. Bremner Advances in Male Contraception Endocr. Rev., June 1, 2008; 29(4): 465 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
 |
|
 A M Solomon and P M G Bouloux Modifying muscle mass - the endocrine perspective. J. Endocrinol., November 1, 2006; 191(2): 349 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
N. Atsuta, H. Watanabe, M. Ito, H. Banno, K. Suzuki, M. Katsuno, F. Tanaka, A. Tamakoshi, and G. Sobue Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients Brain, June 1, 2006; 129(6): 1446 - 1455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yu, N. Dadgar, M. Albertelli, A. Scheller, R. L. Albin, D. M. Robins, and A. P. Lieberman Abnormalities of Germ Cell Maturation and Sertoli Cell Cytoskeleton in Androgen Receptor 113 CAG Knock-In Mice Reveal Toxic Effects of the Mutant Protein Am. J. Pathol., January 1, 2006; 168(1): 195 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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M. Zitzmann, M. Depenbusch, J. Gromoll, and E. Nieschlag Prostate Volume and Growth in Testosterone-Substituted Hypogonadal Men Are Dependent on the CAG Repeat Polymorphism of the Androgen Receptor Gene: A Longitudinal Pharmacogenetic Study J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2049 - 2054. [Abstract] [Full Text] [PDF]
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