Androgen Disorders

OR31-1 News Summary

Low doses of anti-diabetic drug in girls with insulin resistance can prevent development of female endocrine disorder

Treating young girls who have insulin resistance with low doses of metformin, an insulin sensitizer used to treat diabetes, can avoid progression of the problem and prevent the development of Polycystic Ovary Syndrome (PCOS), an endocrine disorder that causes many troublesome symptoms, according to a new study to be presented on Friday, June 18, at The Endocrine Society’s 86th Annual Meeting in New Orleans. This study provides the first evidence, say researchers, that intervention in young children can prevent the progression to PCOS and, perhaps, reduce risks of cardiovascular disease and diabetes in such high-risk groups.

Researchers have been interested in links between early growth rates – particularly when a newborn has relatively low birth weight followed by rapid infancy weight gain – and an increased risk for obesity and adult diseases, such as diabetes. These girls often have “precocious pubarche,” which is a prepubertal symptom heralding high insulin and testosterone levels, indicative of PCOS.

In PCOS, insulin resistance leads to other hormonal abnormalities, such as elevation of male sex hormones like testosterone, which leads to the unwanted features of PCOS. These symptoms include the early appearance of pubic hair and, with the passage through puberty, an excess of body hair distributed in a male pattern, menstrual disturbances, lack of ovulation, and acne.

Dr. Lourdes Ibanez, of the University of Barcelona in Spain, and international colleagues wanted to explore this issue in a population of girls in Barcelona. These girls had a low birth weight followed by a rapid gain in infancy. They noted that this growth pattern leads to increased central body fat and insulin resistance by the age of 8 years old.

The researchers studied 28 non-obese precocious pubarche girls around the age of 8 years old who were born with a low weight and examined the effects of starting metformin before puberty. This group was randomized to receive metformin or no therapy. In a similar, but older group of 24 girls, with the average age of 13, the researchers examined the effects of discontinuing metformin therapy after 12 months and watched the metabolic results over the next six months. These post-puberty girls had also been randomized to receive metformin or no therapy for 12 months.

The researchers found that these girls with early insulin resistance were greatly helped by the treatment of metformin introduced at an early age. With the reversal of the insulin resistance, the hormone abnormalities are also reversed and there is a dramatic redistribution of body fat with reductions in the central fat and an overall return to a more normal distribution of both fat and muscle mass, and thus, potentially diminishing disease risks in adulthood. The treatment is safe and growth rates are maintained.

This study was funded by Fondo de Investigaciones de la Seguridad Social and the Instituto de Salud Carlos II in Madrid.

Androgen Disorders

P1-559

Rosiglitazone in Insulin-Resistant Women with Polycystic Ovary Syndrome: Metabolic and Ovarian Effects
Nicholas A Cataldo, Fahim Abbasi, Tracey L McLaughlin, Marina Basina, Patricia Y Fechner, Gerald M Reaven, Linda C Giudice. OB/GYN; Med; Pediatrics, Stanford Univ Med Ctr, Stanford, CA.

Polycystic ovary syndrome (PCOS) is associated with insulin resistance and hyperinsulinemia, and lowering insulinemia can reduce hyperandrogenism and promote ovulation. Rosiglitazone (ROSI) has not been extensively studied in PCOS.

In this prospective, open-label study, non-diabetic women with PCOS (1990 NICHD definition) underwent an insulin suppression test, with continuous infusion of glucose, insulin and octreotide to achieve steady-state plasma insulin (~50 mU/L) and glucose (SSPG) levels at 150-180 min (1). SSPG is an index of insulin resistance (IR) that is highly correlated with results from euglycemic-hyperinsulinemic clamp (2). Of 76 women with PCOS, 44 (58%) had SSPG >=180 mg/dL, the upper tertile of our previously reported non-diabetic adult volunteer population (3). Of these IR women, 42 had an 8-hr mixed meal profile (MP) with hourly glucose and insulin and were then randomized to ROSI 2, 4, or 8 mg daily for 12 wk, with monthly serum testosterone (T) and sex-hormone binding globulin (SHBG) and weekly progesterone levels from 4-12 wk. SSPG and MP were repeated after 12 wk.

ROSI was well tolerated, with no hepatotoxicity. SSPG and daylong insulinemia on MP declined on 8 mg ROSI by 28% and 46%, respectively (p<0.0001). On 2 mg ROSI, significantly lesser declines (by 12% and 17%) were seen. Fasting insulin declined by 40% on 8-mg ROSI. Overall, modestly improved HDL (+6%) and LDL cholesterol (-7%) and decreased blood pressure (-4%) and alanine aminotransferase (-18%) were observed on ROSI, with modest (2%) weight gain. On ROSI, mean total and free T were unchanged overall or at any dose, but SHBG rose.

Ovulation was confirmed by progesterone >=4 ng/mL in 6/15 on 2 mg, 6/11 on 4 mg, and 11/16 on 8 mg ROSI (55% overall, p=NS for dose effect). At baseline, insulin and free T levels were lower and SHBG higher in the ovulators than in non-ovulators; there was no significant difference in BMI or SSPG. On ROSI, ovulators showed a decline in total and free T, a greater SSPG decline, and lower daylong insulinemia at 12 wk than non-ovulators; both groups showed declines in daylong insulinemia.

ROSI is a promising, well-tolerated new treatment for the metabolic and ovarian abnormalities in PCOS and is most effective at 8 mg daily. In insulin-resistant women with PCOS, ROSI fails to consistently lower testosterone, but ovulation occurs on ROSI with 55% frequency and is more likely in women with lower levels of both insulin and free testosterone.

Supported by R03 HD39826 (NAC) and by Stanford GCRC.

Clinical Poster Session: Disorders of Androgen Excess in Women (11:00 AM - 12:00 PM, 2:30 PM - 3:30 PM)

Presentation Date: 6/16/2004, Time: 11:00 AM; Location: Exhibit Hall

Androgen Disorders

P1-559 News Summary

Diabetic drug shows promise for treating insulin resistance and ovarian problems of common endocrine disorder
Women with the common endocrine problem called polycystic ovary syndrome (PCOS) may benefit from a new diabetic drug, which had success in treating the metabolic and ovarian abnormalities resulting from PCOS, according to a new study to be presented on Wednesday, June 16, at The Endocrine Society’s 86th Annual Meeting in New Orleans. Of note, the drug did not cause any liver problems that have been associated with another similar drug.

PCOS, which is characterized by an excess of androgens, or male hormones that are produced by the ovaries, is the most common cause of irregular menstruation and of infertility that is related to a woman’s failure to ovulate each month. Fertility drugs, such as clomiphene pills or injectable hormones, are prescribed for those who wish to become pregnant, and birth control pills and anti-androgens are prescribed for those who do not.

Women with PCOS also often have a metabolic abnormality known as insulin resistance in addition to their ovarian abnormality. Insulin resistance is associated with obesity, and indeed is a more prevalent abnormality than PCOS itself. Insulin-resistant individuals must either produce extra insulin to meet their body’s needs, or else they develop diabetes. Excess insulin may cause the ovaries to produce excess androgens and stop maturing eggs for ovulation.

Medications called insulin sensitizers, which reduce insulin resistance, are now available to treat diabetes. One of these, metformin, has been extensively studied in PCOS and is generally, but not consistently effective both in reducing excess androgens and in promoting ovulation and regular cycles. A second group of insulin sensitizers is the thiazolidinediones, often called glitazones. The first member of this family, troglitazone, was found to be effective for PCOS, but it has been removed from the market because of liver toxicity. Rosiglitazone is a newer member of this drug family. It has not yet been extensively studied in PCOS, but it has not caused liver problems.

Dr. Nicholas A. Cataldo and colleagues at Stanford University Medical Center in Stanford, Calif., wanted to investigate the effects of Rosiglitazone on PCOS. Three doses of the drug were assigned at random and given for 12 weeks to 42 women with both PCOS and insulin resistance. More than half of these women in the study ovulated while taking rosiglitazone, and levels of insulin resistance and circulating insulin fell. Androgen levels fell in some, but not all, of the women who ovulated. Small, favorable effects on cholesterol levels were also found.

This work is promising, note researchers, because it points to the use of a new group of drugs, the glitazones, in an off-label context for the treatment of PCOS. Women with this highly prevalent disorder have greater risks of non-reproductive disease, including diabetes and atherosclerosis, which result from their insulin resistance. Others have found that glitazones can reduce the development of diabetes and atherosclerosis. It is speculative, they add, that these benefits may extend to women with PCOS, and this question will need to be answered by future studies.

The study was funded by the National Institutes of Health.

Androgen Disorders

P1-568

The Prevalence of Polycystic Ovary Syndrome in Mexican-American Women
Mark O Goodarzi, Manuel J Quinones, Huiying Yang, Ricardo Azziz, Jerome I Rotter, Willa A Hsueh. Med, Univ of California Los Angeles; Med Genet; Ob and Gyn, Cedars-Sinai Med Ctr, Los Angeles, CA.

The prevalence of PCOS is generally estimated at 5-7% of women of reproductive age. Of note, studies regarding the prevalence of PCOS in the U.S. have largely been confined to non-Hispanic White or Black women. Given that Mexican-Americans have a high prevalence of insulin resistance and the highest age-specific prevalence of the Metabolic Syndrome, we sought to determine the prevalence of PCOS in this ethnic group. We hypothesized that given the high incidence of insulin resistance in Mexican-Americans, these women would be at increased risk for PCOS. We administered a questionnaire to 108 Mexican-American women, mean age 34.5 ± 8.3 and mean BMI 29.6 ± 8.0 kg/m2. These women were on average insulin resistant as reflected by a mean HOMA-IR of 4.1 ± 2.9 mmol × L-1 × mIU × mL-1. Criteria suggestive of PCOS consisted of the presence of both 1) menstrual abnormalities = self-report of irregular menses and 2) hyperandrogenism = report of hirsutism, acne, or alopecia. Using this definition 17% of the women were classified as having possible PCOS. Of note, of the 18 subjects classified as possibly having PCOS, only four (22%) reported hirsutism. This may reflect a low expression of hirsutism in Mexican-American women or cultural indifference to hirsutism leading to low self-reporting. Based on this questionnaire, up to 17% of Mexican-American women may have PCOS, higher than the prevalence reported in unselected White or Black women in the U.S. (~6.5%). Because Mexican-Americans have a higher burden of insulin resistance than non-Hispanic Whites or Blacks, we would expect them to have a higher incidence of PCOS, and these preliminary results are in accord with these expectations. As PCOS predisposes to development of type 2 diabetes mellitus, and possibly cardiovascular disease, a better understanding of PCOS and its component phenotypes in Mexican-American women is urgently needed.[table1]

Clinical Poster Session: Disorders of Androgen Excess in Women (11:00 AM - 12:00 PM, 2:30 PM - 3:30 PM)

Presentation Date: 6/16/2004, Time: 11:00 AM; Location: Exhibit Hall

Mexican-American women may have higher rate of common endocrine disorder that can lead to diabetes and heart disease

Researchers have found that Mexican-American women may have a much higher prevalence of a common endocrine problem, called polycystic ovary syndrome (PCOS), than non-Hispanic women, according to a new study being presented Wednesday, June 16, at The Endocrine Society’s 86th Annual Meeting in New Orleans. As PCOS may increase the risk of diabetes and coronary heart disease, this health burden may represent a significant public health problem for Mexican-American women, in particular.

PCOS is the most common endocrine disorder in women of reproductive age, affecting five to seven percent of such women. It is a leading cause of infertility and is also associated with excessive amounts of male hormones that manifest as facial hair, scalp hair loss, and acne.

Recent research suggests that women with PCOS may have an increased risk of developing diabetes mellitus and coronary heart disease, which highlights the need for an improved understanding of this common disorder. In many women with PCOS, the ability of the hormone insulin to move sugar into cells for use as fuel is impaired – called insulin resistance. Insulin resistance is a precursor for diabetes and possibly heart disease.

Prior studies regarding the prevalence of PCOS in the United States have been largely confined to non-Hispanic white or black women. No studies have evaluated how common PCOS is in Mexican-American women. This is an important question because Mexican-American women have a high prevalence of insulin resistance.

Dr. Ricardo Azziz, of Cedars-Sinai Medical Center in Los Angeles and UCLA, and colleagues surveyed 108 Mexican-American women, with the average age of 35, using a questionnaire. This questionnaire evaluated symptoms of PCOS, such as irregular menstrual periods, excess body hair, acne, or scalp hair loss. Based on the questionnaire, 17 percent of these women were classified as possibly having PCOS – a much higher percentage than non-Hispanic women, which is calculated at five to seven percent.

Additional studies that go beyond the use of the questionnaire will be undertaken to more precisely determine the prevalence of PCOS in Mexican-American women, add the researchers.

This study was funded by the National Institutes of Health

Androgen Disorders

P1-569

Oral Contraceptive Therapy Improves Mental Function in Polycystic Ovary Syndrome
Robert Krikorian, Karen Elkind-Hirsch, R Jeffrey Chang. Psychiatry, Univ of Cincinnati, Cincinnati, OH; Women’s Hlth Res Inst, Baton Rouge, LA; Reprod Med, Univ of California at San Diego, La Jolla, CA.

We report preliminary data showing the effects of oral contraceptive (OC) therapy on psychological function in young women with polycystic ovary syndrome (PCOS). Thirteen women with PCOS (M age = 24) were enrolled to either continuous or cyclic low dose OC treatment. Ten subjects completed the 48-week protocol. Assessments of mood, self-esteem, PCOS-specific concerns, and cognitive function were completed before treatment initiation and after 24 and 48 weeks of treatment. Normally cycling, healthy control subjects (n = 6; M age = 31) were evaluated at baseline only.

At baseline, there was no difference between the controls and subjects with PCOS with respect to IQ estimate or verbal memory. However, as expected, women with PCOS showed higher free androgen indices (p < .05), increased hirsutism (p < .001), and greater mood (p < .05) and self-esteem (p < .05) disturbance. After 24 weeks of treatment, decreases from baseline were observed in free androgen indices (p <.05) and hirsutism (p < .0001), that were maintained during the 48-week intervention. In addition, PCOS-specific concerns diminished, and improvements in mood (p < .09) and self-esteem (p < .05) obtained at 24 weeks persisted until termination of the protocol. There was a trend for improvement in verbal memory function at 24 weeks (p < .12), with further improvement and a highly significant effect at 48 weeks (p < .01). Overall, the beneficial treatment effects observed at 24 weeks were maintained through the 48 weeks of therapy. However, there was additional improvement in memory function between 24 and 48 weeks (Fig 1), and this could not be attributed to improved emotional functioning. These findings indicate that treatment of PCOS in young women produces positive psychological effects in concert with reduction of hirsutism and male hormone levels. The greater enhancement of memory function suggests the possibility of a direct cerebral effect of normalization of reproductive hormone levels in addition to the presumed psychological effects of altered appearance on mood and self-esteem.[figure1]

Clinical Poster Session: Disorders of Androgen Excess in Women (11:00 AM - 12:00 PM, 2:30 PM - 3:30 PM)

Presentation Date: 6/16/2004, Time: 11:00 AM; Location: Exhibit Hall

Androgen Disorders

P1-569 News Summary

Oral contraceptives improve memory function as well as psychological effects of common female disorder

Treatment with oral contraceptives can improve psychological function, such as mood and self-esteem, and even memory in young women with polycystic ovary syndrome (PCOS), according to a new study being presented on Wednesday, June 16, at The Endocrine Society’s 86th Annual Meeting in New Orleans. Researchers believe that improvements in mood and self esteem are linked to the reduction of excess body hair and male hormones as a result of treatment, which led to a greater sense of well being and enhanced self image. Improved memory function, however, appears to be associated with the effect of normalizing hormone levels on brain function that affected cognition and mood, a first-time finding, they add.

PCOS is the most common hormonal disturbance of young adult women. The disorder is one of the leading causes of infertility and manifests with irregular or absent periods, excess facial or body hair – called hirsutism – acne, hair loss, and obesity, leading to psychological distress and negative effects on self esteem.

Interested in the addressing the psychological effects of PCOS, Dr. Robert Krikorian, of the University of Cincinnati, and colleagues treated 13 women with PCOS – with the average age of 24 years – with low-dose oral contraceptive pills. Ten of the 13 women who began the study completed the full 48-week protocol. Mood, self-esteem, PCOS-specific concerns, and cognitive ability were evaluated before treatment was begun and after 24 and 48 weeks of treatment. The researchers also evaluated six normally cycling, healthy women – with the average age of 31 years – to contrast their scores with those of the women with PCOS before treatment.

At baseline, there was no difference between the healthy women and the women with PCOS in IQ estimate or verbal memory. However, women with PCOS had higher free testosterone indices, increased body hair, and greater disturbance of mood and self-esteem. After 24 weeks of treatment, decreases were observed in free testosterone levels and hirsutism, and these decreases were maintained throughout the 48-week intervention. In addition, PCOS-specific concerns decreased, and improvements in mood and self-esteem seen at 24 weeks remained until the end of the study. There was a trend for improvement in verbal memory function at 24 weeks, with further improvement and a highly significant effect at 48 weeks.

Overall, these findings highlight the beneficial emotional effects of normalizing reproductive hormones, say researchers. The beneficial treatment effects observed at 24 weeks were maintained through the 48 weeks of therapy. However, there was additional improvement in memory function between 24 and 48 weeks, and this could not be attributed to the improvement in mood, which did not continue to improve after 24 weeks. The finding of improved memory function is significant because memory deficiency generally is not recognized as a component of PCOS. The researchers conclude that it will be important to duplicate this finding in controlled studies and with alternative forms of treatment.

This study was supported, in part, by Pfizer.

Androgen Disorders

P1-573

Combined Suppression Therapy for the Treatment of Hirsutism in the Polycystic Ovary Syndrome (PCOS): Clinical Predictors of Success.
Shahin Ghadir, Kelley Stephens, Ricardo Azziz. Dept of Ob and Gyn, Univ of California, Los Angeles; Dept of Ob and Gyn, Univ of Alabama at Birmingham, Birmingham, AL; Dept of Ob and Gyn, Cedars-Sinai Med Ctr, Los Angeles, CA.

Many patients with PCOS suffer from hirsutism. Few studies have addressed the outcome and factors affecting the success of the commonly utilized combination treatment with oral contraceptives and spironolactone (OC+SPA) in the treatment of hirsutism. In the present study, we assess the clinical predictors of success of treating hirsutism in PCOS using an OC+SPA preparation (1 mg ethinodiol diacetate/35 mcg ethinyl estradiol/d + SPA 200 mg/d) . All patients presenting between 10/87 and 6/02 with PCOS (ovulatory dysfunction, hirsutism and/or elevated androgens, after the exclusion of related disorders) were identified. Outcomes were ascertained by retrospective chart review. Patients seeking fertility therapy only, with inadequate follow-up (<6 mos), or poor compliance (seen at intervals of >18 mos or on meds for <80% of time) were excluded. A single observer assigned modified Ferriman Gallwey (mFG) hirsutism scores, and patients described their hirsutism as improved, worsened, or unchanged at follow-up. Included were 142 patients (age: 26.2 ± 8.3 yrs; BMI: 32.1 ± 9.7 kg/m2), 51.4% of which were obese (i.e. BMI ³ 30 kg/m2). There was a weak positive correlation between initial mFG score and BMI (r=0.22, p<0.05), but not with androgen levels. Treatment duration ranged from 6 to 155 mos.(mean = 35.4 mos.) Overall, 89.9% of the treated patients reported subjective improvement in their hirsutism. The mean mFG score following treatment was significantly lower than baseline (4.1 ± 3.6 vs. 9.9 ± 4.8, p<0.0001), with a mean difference of 59% ± 32%. Non-obese patients were more likely to experience normalization of their hirsutism (i.e. mFG of < 8) compared to their obese counterparts (90% vs. 72%, p<0.05). However, BMI did not correlate with self-reported improvement nor with the decrease in mFG from baseline. The initial mFG score was highly correlated with the absolute decrease in mFG (r=0.68, p<0.0001); alternatively total and free testosterone did not correlate with therapeutic response. These data indicate that the majority of PCOS patients who are compliant will experience an improvement in hirsutism with combination OC+SPA treatment, independent of baseline androgen levels and greater in those with more severe degrees of hirsutism. Obesity may be a negative predictor for improvement in hirsutism following treatment, and suggests the possible need for using greater doses of anti-androgens in the larger patient.. Supported by NIH grants R01-HD29364 and K24-HD01346 [RA].

Clinical Poster Session: Disorders of Androgen Excess in Women (11:00 AM - 12:00 PM, 2:30 PM - 3:30 PM)

Presentation Date: 6/16/2004, Time: 11:00 AM; Location: Exhibit Hall

Androgen Disorders

P1-573 News Summary

Birth control pills and diuretic decrease unwanted hair growth in patients with common endocrine disorders

The majority of patients with a common female endocrine disorder, called polycystic ovary syndrome (PCOS), who were treated with oral contraceptive pills and the diuretic spironolactone showed improvement in the amount of excessive hair growth, according to a new study being presented on Wednesday, June 16, at The Endocrine Society’s 86th Annual Meeting in New Orleans. Of interest, even when there was a reduction in hair growth, levels of male hormones remained unaffected.

Women with PCOS do not ovulate on a regular basis, have excessive hair growth and have high levels of male hormones, called androgens. The combination of oral contraceptive pills and a drug called spironolactone is a commonly used treatment for excessive hair growth; however, few studies have addressed the factors affecting the success of this combination. Spironolactone is a “potassium-sparing” diuretic often used to treat high blood pressure, congestive heart failure, and kidney and liver disease.

To develop more data about the use of this drug combination, Dr. Shahin Ghadir of the University of California, Los Angeles, and colleagues reviewed the charts of all patients with PCOS who were seen between October 1987 and June 2002. The examining physician had used a scale called Ferriman Gallwey (mFG) for evaluating the amount of hair growth on the patients. The patients were later asked to see if they believed that their hair growth had improved, worsened, or was unchanged at the follow-up appointment. The study included 142 patients, who were, on average, 26 years old, with a body mass index of 32.1kg/m2. Of these patients, 54 percent were obese.

The patients were treated anywhere from six months to almost 13 years, with the average patient being treated for approximately nearly three years. Nearly 90 percent of the patients who were treated with both oral contraceptives and also spironolactone noted a decrease in hair growth. The researchers observed that patients who were obese actually showed less of an improvement in their loss of excessive hair growth, suggesting to them that possibly larger doses of medications would be necessary to achieve the same outcomes as the non-obese group.

What did show to be very significant, however, was that the more hair growth the patient experienced at the initial assessment, the better the results were at the end of treatment. Male hormones, such as testosterone, were also measured in these patients, but the treatment did not have any effect on these levels.

Androgen Disorders

P2-560

Mortality in Klinefelter Syndrome. A Danish Registry Study.
Anders B Bojesen, Svend Juul, Niels Birkebaek, Jens S Christiansen, Claus H Gravholt. Med Dept M, Endocrinology and Diab, Aarhus Univ Hosp, Aarhus Hosp; Dept of Epidemiology and Social Med, Aarhus Univ; Pediatric Dept A, Aarhus Univ Hosp, Skejby Hosp, Aarhus, Denmark.

Introduction: Klinefelter syndrome (KS) is the most prevalent sex chromosome disorder, affecting approximately one in every 600 men. Hypogonadism is frequent and many patients, but not all, receive testosterone treatment. Neither the consequences of long-term hypogonadism, nor the consequences of long-term treatment with testosterone in KS are well known. This study describes the mortality in the known Danish population of men suffering from KS through the years 1973 to 2000.
Materials and methods: We used Danish registries, covering the whole nation, to create a cohort including all men diagnosed with KS and an age-matched control group. From the Danish Cytogenetic Central Registry data on 859 KS-subjects were extracted. Data on 4295 age-matched control subjects were extracted from the Danish Central Office of Civil Registration. Death diagnoses were then extracted from the Danish Cause of Death Registry. Total risk time for the cohort was 73,001 person-years. Death diagnoses were available on 122 KS-subjects and 483 control-subjects. Risk of dying was calculated using stratified Cox regression analysis. P values less than 0.05 were considered significant.
Results: Hazard ratio (HR) of dying from all causes was 1.40, p = 0.002. We found an increased mortality risk from: infectious diseases (HR = 3.45, p = 0.019), neurological diseases (HR = 3.27, p = 0.017), heart diseases (HR = 1.42, p = 0.026), lung diseases (HR = 2.83, p < 0.001) and urinary tract diseases (HR = 3.72, p =0.010). Subdividing infectious diseases, heart diseases and lung diseases, we found an increased risk of dying from: septicemia (HR = 4.36, p = 0.03), pulmonary heart diseases (HR = 4.17, p = 0.002), pneumonia (HR = 2.08, p = 0.009), and non-asthmatic obstructive airway diseases (HR = 3.72, p = 0.002).
Conclusions: Men diagnosed with Klinefelter syndrome have a 40 percent increased mortality risk. Whether the increased risk is a consequence of long-term untreated hypogonadism, long-term testosterone treatment, the syndrome per se or other factors is presently unknown.

Clinical Poster Session: Androgen Disorders in Men & Women (11:00 AM - 12:00 PM, 2:30 PM - 3:30 PM)

Presentation Date: 6/17/2004, Time: 11:00 AM; Location: Exhibit Hall

Androgen Disorders

P2-560 News Summary

Men with chromosome disorder have two-year decrease in life expectancy

Researchers found that men suffering from a male sex chromosome syndrome have a reduced life expectancy of two years compared to men without the problem, according to a new study being presented on Thursday, June 17, at The Endocrine Society’s 86th Annual Meeting in New Orleans.

Klinefelter syndrome (KS) is the most common sex chromosome disorder in men. It affects one in every 600 men. Symptoms include infertility, hypogonadism, or low production of male sex hormones, increased height, small testicles and decreased verbal intelligence compared to normal men. For most men suffering from the syndrome, the symptoms are mild and, consequently, they are not diagnosed unless they want to have children.

A few cases are diagnosed in childhood, mainly because of learning disabilities and behavioral problems. Many myths exist about the disorder. Much of the current knowledge about KS is based on follow-up studies on the few percent diagnosed in childhood. To learn more about the death rate and the diseases leading to death in men suffering from KS, Dr. Anders B. Bojesen and colleagues at Arhus University Hospital in Aarhus, Denmark, conducted an epidemiological study including all the men and boys diagnosed with KS in Denmark. They compared findings of 859 men diagnosed with KS to 4,295 age-matched men randomly selected.

Information from the control group was randomly collected from the Danish Central Office of Civil Registration. Death diagnoses for both groups were then extracted from the Danish Cause of Death Registry. Death diagnoses were available on 122 men with KS and 483 controls.

Researchers found that Klinefelter syndrome was associated with 2.1 years loss of life span. Furthermore, they found that the main causes of death in KS are the same as for normal men, such as cardiovascular diseases, cancers and respiratory diseases. However, those with KS face an increased risk of dying from infectious diseases, neurological diseases, cardiovascular diseases, lung diseases and urinary tract diseases compared to the control group.

Whether the increased risk is a consequence of long-term hypogonadism, the syndrome itself, or other factors, such as socioeconomic status, is unknown, researchers said. The results from this study, they add, may help doctors focus their attention on associated diseases in Klinefelter syndrome, but also in the counseling the patient or the parents of a boy with the disorder.

The study was supported by the Danish Health Research Council.

Androgen Disorders

P2-562

Use and Abuse of Anabolic Steroid Hormones and Body Shaping Drugs by High School Athletes and Non-Athletes.
Linn Goldberg, Diane L Elliot, David P MacKinnon, Esther L Moe, Wendy McGinnis, Andrew Cleary, Kuehl S Kuehl. Med, Oregon Hlth & Sci Univ, Portland, OR; Psych, Arizona State Univ, Tempe, AZ.

Background. Hormone abuse, especially intake of anabolic steroids (AS) and use of other athletic enhancing and body shaping drugs (AEBSD) have been reported by adolescents. It is presumed that those participating in school sports are at greater risk for using these drugs. Purpose. To assess use of anabolic steroid, including androstenedione (AS), with and without the use of other AEBSD among high school athletes and non-athletes.
Methods. Male and female students (N= 4111) from 13 high school districts in Oregon, completed questionnaires during the fall 2000-2001 school year. Lifetime use of AS and other AEBSD (amphetamines, methamphetamines, pseudoephedrine, and diet pills) were recorded. Students indicated personal use by estimating the number of times they took the drug(s) on a continuum, from no use to >40 lifetime uses. Results. Overall, self-report of lifetime AS use was 4.5%, without a difference between athletes (4.6%) and non-athletes (4.5%). Male AS use (6.1%) was more than double female use (2.6%) (p<.001). Lifetime use of other AEBSD was 25.7%, with more than one out of 10 students reporting “heavy” use (>12 times use/lifetime). When AS was combined with other AEBSD, 27.2% of students reported use, with over 11% indicating heavy use. More non-athletes used other AEBSD (28.8%) compared to 20.4% athlete users (p<.001); with a greater percentage of non-athletes (12.1%) reporting “heavy” use as compared to 7.5% of athletes indicating heavy use. Among non-athletes, more adolescent females (34.3%) used other AEDBSD than males (22.9%) (p<.001), although among athletes, the gender differences were not as great; 23.2% female use v 17.9% male use (p= .012). Higher reported grade point average (GPA) was inversely related to AS and AEBSD use (p<.001), with 14.4% of those with 2.0 GPA reporting heavy use compared to 8.1% reporting heavy use among 4.0 GPA students. For AS use, students with GPAs of 2.5 or below used steroids at a lifetime rate of 6.0%, compared to a rate of 3.5% among students with GPAs of 3.0 or higher. Conclusions. There is widespread use of AS and AEBSD among high school students, with AS use occurring more often among males, without differences between athletes and non-athletes. Unlike typical substances of abuse other AEBSD use is significantly higher among adolescent females than males. Although sports may have a protective effect for male and female use of certain AEBSDs, athlete participation does not deter AS use. Supported by The National Institute on Drug Abuse, National Institutes of Health. Grant # DA-12018 to Dr. Goldberg.

Clinical Poster Session: Androgen Disorders in Men & Women (11:00 AM - 12:00 PM, 2:30 PM - 3:30 PM)

Presentation Date: 6/17/2004, Time: 11:00 AM; Location: Exhibit Hall

Androgen Disorders

P2-562 News Summary

High school boys more prone to anabolic steroid use but high school girls are heavier users of other body-shaping, athletic-enhancing drugs

High school girls, including athletes and non-athletes, use more body-shaping and athletic-enhancing drugs than high school boys, according to a study of Oregon teens being presented on Thursday, June 17, at The Endocrine Society’s 86th Annual Meeting in New Orleans. In addition, the study found that the national rise in anabolic steroid use may be driven more by non-athletes than athletes and boys more than girls.

Dr. Linn Goldberg, of the Oregon Health and Science University in Portland, and colleagues assessed more than 4,100 students from 13 school districts in Oregon. Students answered a survey on their lifetime use of anabolic steroids and other athletic-enhancing and body-shaping substances, including amphetamines, methamphetamines, pseudoephedrine (Sudafed®), and diet pills, and the number of times theses substance were used. The scale ranged from “no use” to “over 40 times use.”

Overall, 4.5 percent of students admitted to using anabolic steroids, with no significant difference between athletes, at 4.6 percent use, and non-athletes, at 4.5 percent use. Male use of anabolic steroids was more than double female use – 6.1 percent vs. 2.6 percent, respectively.

Use of other athletic-enhancing and body-shaping drugs was 25.7 percent, with more than one out of 10 students reporting “heavy” use, characterized by greater than 12 times use in their lifetime. More non-athletes used these other athletic-enhancing and body-shaping drugs compared to athletes – 28.8 percent vs. 20.4 percent, respectively. In addition, a greater percentage of non-athletes – at 12.1 percent – reported “heavy” use of these other drugs compared to 7.5 percent of athletes.

Including both athlete and non-athlete girls, high school females used more of the body-shaping and athletic-enhancing substances than boys. Grade point average had an inverse relationship to substance use. That is, the higher the self-reported grade point average, the lower the drug use.

The researchers believe they uncovered two new and significant trends. First, there appears to be an increase in use of anabolic steroids among high school non-athletes, which may be driving the recent national increases in steroid use among teens. Second, while high school females usually use less alcohol and other drugs, their use of body-shaping and athletic-enhancing drugs are greater than that of their male high school counterparts, and this extends to both athletes and non-athletes.

Because Oregon teen drug use mirrors the national rates of substance use, say researchers, these findings also suggest there may be 427,000 male and 182,000 female high school steroid users, based on the approximately 14 million high school students in the United States. Use of athletic and body shaping substances, they add, may involve nearly 2 million high school students.

This study was funded by the National Institute on Drug Abuse.

P2-564

Prevalence of Hypogonadism in Men with Type 2 Diabetes Mellitus.
Dheeraj Kapoor, Hazel Aldred, Kevin Channer, Thomas Hugh Jones. Ctr for Diab and Endocrinology, Barnsley District Gen Hosp, Barnsley, UK; Cardiol, Royal Hallamshire Hosp; Acad Unit of Endocrinology, Univ of Sheffield, Sheffield, UK.

Men with Type 2 diabetes mellitus have lower androgen levels than nondiabetic men. Studies have also shown that low serum testosterone levels in men predict the future development of Type 2 diabetes as well as insulin resistance. It has also been demonstrated that low levels of circulating androgens are associated with coronary artery disease, dyslipidaemia, hypertension and visceral obesity. The purpose of this study was to determine the prevalence of hypogonadism in a population of men with Type 2 diabetes.
This study was approved by the Barnsley District General Hospital ethics committee. 300 male patients above the age of 30 [ Mean age 58 ] with Type 2 diabetes registered with the diabetes centre at Barnsley District General Hospital have been recruited. Patients with elevated CRP [greater than 10 milligrames / litre] were excluded. Blood was taken between 8 and 10am and analysed for levels of total testosterone, SHBG and HbA1c. Body mass index and waist hip ratio were recorded. Obesity was defined as a body mass index of >30 and or waist hip ratio of >0.95. 16.33% had total testosterone <7.5 nanomoles / litre with 49.66% had total testosterone <12 nanomoles / litre.
Serum testosterone levels were significantly lower in men with obesity [p<0.05]. Of the hypogonadal men, 31% had elevated LH/ FSH indicating primary testicular failure and 69% had normal LH/ FSH indicating mixed primary and secondary failure or secondary failure. Comparing patients with good diabetic control HbA1c less than 7% [n=157] with those with inadequate control HbA1c greater than 7% [n =143], testosterone levels [less than 12 nanomoles / litre] were significantly lower in the group with poor control [p <0.05] .
This study shows that there is a high prevalence of hypogonadism in men with Type 2 diabetes. This finding suggests that men with Type 2 diabetes should be routinely screened. The fact that low testosterone levels are associated with poor control implies that testosterone may be involved with the degree of insulin sensitivity. However it is uncertain whether hypotestosteronaemia contributes to impaired glucose tolerance or is the result of insulin resistance. Further studies to answer these questions are underway.

Clinical Poster Session: Androgen Disorders in Men & Women (11:00 AM - 12:00 PM, 2:30 PM - 3:30 PM)

Presentation Date: 6/17/2004, Time: 11:00 AM; Location: Exhibit Hall

Androgen Disorders

P2-564 News Summary

Men with type-2 diabetes should have testosterone levels evaluated

Many men with type-2 diabetes – also known as adult onset diabetes – have low testosterone levels in their blood, according to a new study being presented on Thursday, June 17, at The Endocrine Society’s 86th Annual Meeting in New Orleans. The researchers believe there is good evidence that these diabetic men should routinely be checked for testosterone deficiency and considered for testosterone replacement therapy, which can prevent heart and other problems.

People with type-2 diabetes are at risk of heart disease as well as vascular disease. Dr. T. Hugh Jones, of the Barnsley District General Hospital in Barnesley, United Kingdom, and colleagues have previously shown that low testosterone levels are associated with coronary heart disease, and testosterone replacement can lead to improvement in blood flow through diseased arteries in the heart.

Therefore, these researchers wanted to determine the prevalence of low testosterone levels, also known as hypogonadism, in men with type-2 diabetes. They evaluated 300 men over the age of 30 – with the average age of 58 years – who had type-2 diabetes. They found that 17 percent of the men had very low levels of testosterone, and another 32 percent had low normal levels.

The researchers note that this finding is not new, but it emphasizes the issue that many physicians do not check the testosterone status of their diabetic patients. They add that testosterone may be involved with the degree of insulin sensitivity in diabetic men. However, it is uncertain whether low testosterone contributes to impaired glucose tolerance or is the result of insulin resistance. They are conducting additional studies to answer these questions.

This study was funded by Barnsley District General Hospital NHS Trust of Barnsley and Royal Hallamshire Hospital in Sheffield, United Kingdom.

Androgen Disorders

P2-571

Low DHEAS, but Not Free Testosterone, Is Associated with Low Sexual Interest in Young, Non Health Seeking Women
Susan R Davis, Sonia L Davison, Susan Donath, Robin Bell. Ob and Gyn, Monash Univ, the Jean Hailes Fdn; Biochemistry, Monash Univ, Clayton, Australia.

Background and aims: Testosterone (T) therapy improves sexual function in pre and postmenopausal women with low sexual desire1;2. However, a relationship between endogenous androgens and sexuality has not been systematically examined in healthy women. Our aim was to explore whether amongst women in the community, those with low scores on a validated sexual questionnaire have differing androgen levels to those with higher scores and if so, to develop a working definition of androgen insufficiency.
Methods: 1432 women, aged 18 to 75 years were recruited randomly from the Victorian community via electoral roles over 15 months. Each gave a morning blood sample and completed questionnaires on the same day. Premenopausal women had blood drawn after cycle day 8 and pre menstruation. Sexuality was evaluated by the validated Profile of Female Sexual Function (PFSF) and sex steroids were measured using sensitive assays. To specifically investigate the contribution of androgens to each PFSF domain we separately analysed women <45years as the range of androgen levels was greatest in this group. For all analyses involving free T we excluded users of the oral contraceptive pill.
Results: 1250 women (~ 90% of the study population) gave responses to the PFSF. The 7 domains of the PFSF were not normally distributed, with a significant proportion of women reporting very low levels of sexual desire and arousal (15% had scores < 10 on a scale 0-100). Increasing age was associated with lower domain scores (p<0.001). For women <45 years, being in the lowest 10th centile for DHEAS, but not freeT, made an independent contribution to the risk of having a domain score for desire and arousal below the 10th centile (p=0.03 and 0.047 respectively). There was no independent contribution of either free T / DHEAS for a low score for sexual responsiveness, orgasm or pleasure. Serum DHEAS and freeT were highly correlated (r=0.55,p<0.001).
Conclusions: In this randomly recruited population of non-health seeking women we found a significant proportion reported little or no sexual desire or arousal. We found that low DHEAS makes an independent contribution to low levels of sexual interest, but not of sexual behaviour, in young women. DHEAS is the most abundant sex steroid and is an important prescursor for intracellular androgen production. We propose that DHEAS is a useful marker of low androgen status, although it may not be the effector at the tissue level that influences sexual interest. This study was supported by the NHMRC Centre of Clinical Research Excellence at the Jean Hailes Foundation #219279.

Clinical Poster Session: Androgen Disorders in Men & Women (11:00 AM - 12:00 PM, 2:30 PM - 3:30 PM)

Presentation Date: 6/17/2004, Time: 11:00 AM; Location: Exhibit Hall

Androgen Disorders

P2-571 News Summary

Low sexual interest in young women can be identified by sex hormone DHEA

Women under 45 with low libido may benefit from testosterone supplements; however, they cannot necessarily be identified by measuring blood testosterone, according to a new study to be presented on Thursday, June 17, at The Endocrine Society’s 86th Annual Meeting in New Orleans. DHEA sulphate, a sex hormone, appears to be a more important marker of low libido compared with testosterone. Researchers also found that low sexual desire and arousal are common in women.

DHEA sulphate is the most abundant sex hormone in the female circulation and provides a major source for the production of testosterone in cells. Researchers believe that DHEA sulphate is a useful marker for the determination of low androgen status. Androgens are hormones that produce male characteristics. The most well known of these is testosterone. Testosterone is made by the ovaries. About half of the testosterone the ovaries make is from the hormone DHEA sulphate, which is produced by the adrenal glands. DHEA sulphate is also converted into testosterone in other parts of the body, such as the skin and hair follicles.

Dr. Susan Davis, of the Jean Hailes Research Unit and Monash University in Clayton, Australia, and colleagues sought to determine whether women who had low libido also had low levels of testosterone or DHEA sulphate. They wanted to know whether measuring low testosterone levels could identify women with low libido who might benefit from testosterone therapy.

They recruited 1,423 women randomly from the community to participate. They were aged 18 to 75 years and lived in urban, suburban, and rural regions. Researchers found that there was a strong relationship for women under 45 years old between having scores for desire and arousal in the lowest 10 percent possible and also having low DHEA sulphate in the lowest 10 percent of the group. Although multiple factors contribute to sexual interest, the researchers demonstrated that having a low DHEA sulphate makes an independent prediction of having low levels of sexual desire, arousal, and responsiveness. They did not find a relationship between any of the hormones and orgasm or pleasure, or between blood testosterone measurement and sexual questionnaire scores.

Very little is known about testosterone in women, although it is becoming increasing popular as a treatment for low libido in postmenopausal women. This study is important as it demonstrates that women with low libido who may benefit from testosterone therapy cannot simply be identified by measuring blood testosterone

Researchers found that after the age of 45, there was little variation in the androgen hormone level and the difference between women with low libido and not low libido was less apparent.

This research was supported by the National Health and Medical Research Council of Australia.

Androgen Disorders

P2-572

The Effect of Dehydroepiandrosterone Replacement on Mood, Memory Well-Being and Sexual Function in Hypoadrenal Women.
Ketan K Dhatariya, Glenn E Smith, K Sreekumaran Nair. Endocrine Res Unit, Mayo Clin and Foundatation, Rochester, MN.

Context:The adrenally produced sex hormone precursor dehydroepiandrosterone (DHEA) and its sulfated ester (DHEAS) are found in high levels in the circulation. They are found in very low concentrations in Addison’s disease or adrenalectomized subjects. DHEA replacement is not part of the current standard of care for hypoadrenal subjects.(1)
Hypoadrenal individuals whilst on replacement of glucocorticoid and mineralocorticoid replacement have a lower quality of life than healthy controls. (2) Previous studies of DHEA replacement in hypoadrenal subjects have shown conflicting results. (3-5)
Objective:To assess the effect of DHEA replacement on mood, memory, well being, depression and sexual health.
Design:Randomized, double-blind, placebo-controlled, cross-over study conducted between May 2002 and July 2003.
Setting:A single center study recruiting subjects from hospital held records, advertisements, and the internet.
Participants:Thirty-three hypoadrenal Caucasian women were recruited. Twenty-six women completed the whole study.
Intervention:50 mg of once daily DHEA or placebo were given for 12 weeks each, with a two week washout period between treatment phases.
Main Outcome Measures: Validated instruments were used to assess different aspects of psychological health.Cognition was assessed using the Auditory Verbal Learning Test (AVLT), Controlled Word Association Test (COWAT), and Trail Making Test (TMT). Self perception was assessed using the Memory Functioning Questionnaire (MFQ), Changes in Sexual Functioning Questionnaire (CSFQ), Health Status Questionnaire (HSQ), and the Beck Depression Inventory (BDI).
Results:General health perception improved in the women given DHEA in the second phase of the study (± SD) (-0.66 ± 0.92 vs -0.19 ± 0.83, first half vs second half, p = 0.031). There was a significant decline in arousal scores in the second phase of treatment in the 12 women given DHEA during the first phase (8.5 ± 1.98 vs 7.67 ± 2.19, p = 0.016). There was also a significant improvement in total AVLT score after the DHEA phase (51.42 ± 9.39 vs 54.87 ± 10.23, Placebo vs DHEA, 95% CI 0.63, 6.21, p = 0.03). There were no significant differences between the DHEA and placebo in any of the other measured psychological parameters.
Conclusions:This study shows that 50 mg of DHEA given for 3 months results in improvements in general health perception, arousal, and learning efficiency. Thus DHEA replacement may need to be considered for this patient population.
This work was made possible by support from the NIH GCRC grants M01-RR00585 and AG14383-05.

Clinical Poster Session: Androgen Disorders in Men & Women (11:00 AM - 12:00 PM, 2:30 PM - 3:30 PM)

Presentation Date: 6/17/2004, Time: 11:00 AM; Location: Exhibit Hall

Androgen Disorders

P2-572 News Summary

DHEA supplement is helpful in people without adrenal gland function, possibly in elderly

Researchers believe that supplementation of DHEA, a hormone secreted by the adrenal glands, is associated with a significant improvement in general health perception, sexual arousal, and learning efficiency in people without functioning adrenal glands, according to a new study to be presented on Thursday, June 17, at The Endocrine Society’s 86th Annual Meeting in New Orleans. Whether DHEA replacement should be routinely recommended for others who have low levels of DHEA, such as the elderly, say researchers, needs further study.

The adrenal gland, located above each kidney, produces three main hormones, two of which are essential for life. One hormone is called a glucocorticoid, such as cortisol, which is essential for maintaining sugar levels in the body and in managing the body’s response to stress. The other hormone is known as a mineralocorticoid, called aldosterone, which is essential in maintaining the body’s salt concentration. In people in whom the adrenal glands do not work – because they are diseased or have been removed surgically – these hormones must be replaced through supplementation to ensure the person remains well and healthy. If these are not replaced, death occurs within days. A third hormone – called dehydroepiandrosterone, or DHEA, for short, is also produced. In fact, it is produced in vast quantities, but no one knows what it does. It is not essential for life, however. Under normal circumstances, DHEA is produced in the adrenal glands, secreted into the blood, and then converted into the sex hormones testosterone and estrogen in various tissues of the body. DHEA is widely available in the United States and on the Internet as a health food supplement, yet its health benefits have yet to be fully defined.

Previous studies have been done looking at the effects of DHEA replacement in people whose adrenal glands do not work, but there have been conflicting results – with some finding that DHEA replacement makes people feel better and others saying that it does nothing at all. One consistent finding is that individuals without functioning adrenal glands have lower quality of life scores when formally tested against people whose adrenal glands are normal. In addition, aging is associated with a natural decline in DHEA levels; therefore, DHEA replacement in people over 60 may help memory, sexual function, and general well-being.

To get more answers, Dr. Ketan K. Dhatariya and colleagues, of the Mayo Clinic and Foundation in Rochester, Minn., recruited a total of 33 women whose adrenal gland either did not work or had been removed. Their ages ranged from 21–80 years old. Of the initial 33 women, 26 finished the entire study. The women underwent psychological evaluation at the beginning of the study, then took either DHEA or a placebo for 12 weeks, and then repeated the psychological assessments. After a two-week wash-out period, the participants then took the alternate drug for another 12 weeks, followed by a third assessment. When comparing scores in all three stages of the study, the researchers found that 50 mg of DHEA given once daily had measurable, ben