WO2001028554A1

WO2001028554A1 - Treatment of attention deficit disorder and impaired visual-spatial function with androgen

Info

Publication number: WO2001028554A1
Application number: PCT/US2000/028926
Authority: WO
Inventors: Judith L. Ross
Original assignee: Thomas Jefferson University
Priority date: 1999-10-20
Filing date: 2000-10-19
Publication date: 2001-04-26

Abstract

The present invention relates to a method of treatment of attention deficit disorder and of visual-spatial function deficit using androgen, such as oxandrolone or testosterone.

Description

TREATMENT OF ATTENTION DEFICIT DISORDER AND IMPAIRED

VISUAL-SPATIAL FUNCTION WITH ANDROGEN

FIELD OF THE INVENTION

The present invention generally relates to the field of endocrinology and to a method of treatment of attention deficit disorder and impaired visual-spatial abilities, and more particularly, to the use of androgen to treat attention deficit disorder and impaired visual-spatial abilities in androgen-deficient states, including females with Turner syndrome or ovarian failure and males with attention deficit disorder or delayed puberty.

BACKGROUND OF THE INVENTION

Estrogen and androgens are hormones that appear to influence brain development and behavior in humans and animals. Marked cognitive and behavioral changes occur during puberty in concert with marked increases in sex hormone (estrogen and androgen) levels in females and males. The purely biological effects of estrogen and/or androgen on cognitive and behavioral changes are difficult to separate from simultaneous environmental and cultural factors.

Strong evidence implicates androgen influence on brain and behavior. The existing literature and results of the present invention support or suggest that (1) androgen (testosterone) is strongly related to the development of spatial abilities; (2) sex hormones have significant effects on brain and behavior in animal studies; and (3) the neurophysiological mechanisms for the effects of sex hormones on brain development are not yet fully known. The first line of evidence supporting an association between androgen and spatial ability relates to neuropsychological impairment of subjects with other forms of androgen deficiency. Men with untreated, congenital, hypogonadotropic hypogonadism (IHH) do not have spontaneous pubertal development and have diminished production of testosterone. They have been found to have impaired spatial ability, verbal memory and attention relative to normal controls. In contrast, men with acquired, post-pubertal hypogonadotropic hypogonadism (postpubertal testosterone deficiency) did not manifest these deficits. Men with congenital IHH treated with exogenous androgen showed improvement in their spatial abilities, with no significant change in verbal abilities. This result has led to the hypothesis that the normal, endogenous rise in androgens at puberty may play a role in increased spatial ability in males. Genetic males with testicular feminization syndrome who lack androgen receptors and cannot respond to testosterone, have diminished spatial abilities in comparison to normal males. Testosterone treatment of female-to-male transsexuals was associated with improved spatial abilities and a reduction in verbal fluency, and testosterone treatment of older men (60-75 years) resulted in improved performance in the WAIS-R block design scale. Males, in general, appear to have better spatial abilities compared to pubertal girls and women after the menopause. Spatial ability tends to regress at puberty in normal girls and male superiority in spatial ability tends to debut at the time of puberty. Testosterone levels may also influence spatial abilities in women. Girls born with androgen excess in association with congenital adrenal hyperplasia have superior spatial abilities compared to siblings. In addition, higher testosterone levels in normal women (ages 18-31 years) are correlated with superior spatial abilities. These differential findings are more consistent with a longer-term, cumulative effect of androgen (testosterone) on brain development and resulting cognition.

Animal studies have shown clear cut structural effects of androgen on subcortical nuclear regions such as the hypothalamic/preoptic area as well as forebrain regions that are related to behavior. Androgen alterations during the perinatal period and puberty influence cognitive function and behavior in animal models. Female rats from litters with a high versus low percentages of male fetuses had superior spatial skills. Administration of testosterone to newborn female rats improves their performance on a maze task whereas neonatal castration of male rats results in diminished performance compared to intact male rats. Studies in monkeys demonstrated that learning ability can be altered by perinatal hormone manipulations. Female monkeys treated with androgen had superior spatial performance, compared to untreated females, and performed at levels similar to males. Additionally, early postnatal androgen was as effective as prenatal androgen exposure. In song birds, the level of androgen influences the development of specific anatomic brain structures that are necessary for song production in the male of the species. Thus, the organizational effects of androgens appear to operate both before and after birth.

The ovaries in normal girls produce very small amounts of estrogen and possibly androgen before puberty, in levels that are difficult to measure in the usual assays. Post-mortem studies of normal ovarian development in the first 2 years of life indicate that females also appear to have increased ovarian estrogen production in the first year of life, analogous to the testosterone surge in the first 6 months of life in males. Girls with Turner syndrome (TS) would therefore lack this surge, secondary to their dysgenetic ovaries. Girls with Turner syndrome are born with dysgenetic ovaries and, therefore, lack ovarian estrogen or androgen before or at puberty. Thus, Turner syndrome represents a unique, sex hormone-deficient model in which to study the biological effects of androgen treatment on the brain and, consequently, on cognition and behavior in females.

Normally the production of both hormones by the ovaries increases significantly throughout puberty, until adult levels are reached. Androgens are also produced by the adrenal gland before puberty in the process of adrenarche which commences at age 6 to 8 and is independent of gonadal development. Adrenarche (part of adrenal development) occurs normally in girls with Turner syndrome. Androgen levels are apparently similar in girls with Turner syndrome and normal girls before puberty. However, commencing with puberty, in normal girls, functioning ovaries then produce 25-50% of total circulating androgens. Thereafter (after age 10), androgen levels are decreased in Turner syndrome girls compared to age-matched normal girls. The principal androgen, testosterone, can act directly on the brain or can be converted (aromatized) peripherally and in the brain to estrogen (estradiol). The absence of ovarian function and therefore production of estrogen and androgen in girls with Turner syndrome may alter normal brain and behavior development, function, or both. Thus girls with Turner syndrome represent an excellent model for examining the effects of low dose androgen replacement therapy in childhood. Additionally girls with Turner syndrome have well documented nonverbal learning disabilities, impaired attention and visual spatial abilities. In the present invention, these deficits improve with oxandrolone or testosterone (androgen) treatment in these girls. In the present invention, androgen treatment has cumulative, positive effects on attention and some aspects of visual-spatial function. The current invention has a number of novel features, which represent improvements over the current treatments for attention deficit. The current invention also involves a method of treatment for cognitive dysfunction in any female with ovarian dysfunction.

An additional population that may benefit is boys with attention deficit- hyperactivity disorder (ADHD). This diagnosis is made more commonly in boys. Improvement in at least a subset of boys occurs in association with puberty. Thus introduction of low doses of a safe oral androgen, oxandrolone or testosterone, would be of potential benefit in this population.

Currently available treatment for attention deficit disorder includes medications which are stimulants and amphetamine derivatives, such as methylphenidate (Ritalin), magnesium pemoline (Cylert), dextroamphetamine (Dexedrine), and a variety of tricyclic antidepressants. As stimulants, these drugs must be closely monitored and dosage must be carefully regulated to avoid side effects, such as nervousness or insomnia. Additionally, such stimulants have a tendency to lose their effectiveness over time. Long-term use of such drugs in children has been associated with attenuated growth, including effects upon height and weight gain. The present invention, however, represents a novel approach for treatment of cognitive dysfunction in humans and in other mammals.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide a method of treating attention deficit in a mammal, comprising administering a physiologically effective amount of androgen to said mammal.

It is a further object of the present invention to provide a method of treating attention deficit in a mammal, comprising administering a physiologically effective amount of androgen to said mammal, where said androgen is oxandrolone or testosterone.

It is another object of the present invention to provide a method of treating visual-spatial function deficit in a mammal, comprising administering a physiologically effective amount of androgen to said mammal.

It is a further object of the present invention to provide a method of treating visual-spatial function deficit in a mammal, comprising administering a physiologically effective amount of androgen to said mammal, where said androgen is oxandrolone or testosterone. It is another object of the present invention to provide a method of treating attention deficit in a human with Turner syndrome, comprising administering a physiologically effective amount of androgen to said human.

It is a further object of the present invention to provide a method of treating attention deficit in a human with Turner syndrome, comprising administering a physiologically effective amount of androgen to said human, where said androgen is oxandrolone or testosterone.

It is another object of the present invention to provide a method of treating visual-spatial function deficit in a human with Turner syndrome, comprising administering a physiologically effective amount of androgen to said human. It is a further object of the present invention to provide a method of treating visual-spatial function deficit in a human with Turner syndrome, comprising administering a physiologically effective amount of androgen to said human, where said androgen is oxandrolone or testosterone.

It is another object of the present invention to provide a method of treating attention deficit in a human with ovarian dysfunction, comprising administering a physiologically effective amount of androgen to said human.

It is a further object of the present invention to provide a method of treating attention deficit in a human with ovarian dysfunction, comprising administering a physiologically effective amount of androgen to said human, where said androgen is oxandrolone or testosterone. It is another object of the present invention to provide a method of treating visual-spatial function deficit in a human with ovarian dysfunction, comprising administering a physiologically effective amount of androgen to said human.

It is a further object of the present invention to provide a method of treating visual-spatial function deficit in a human with ovarian dysfunction, comprising administering a physiologically effective amount of androgen to said human, where said androgen is oxandrolone or testosterone.

It is noted that the androgen of the present invention can be administered through a variety of methods, including but not limited to, orally, transdermally (i.e., by a patch), intranasally, intravenously, or intramuscularly.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1A. A graph showing the results of androgen treatment of girls with

Turner syndrome.

Fig. IB. A graph showing the attention results of androgen treatment of girls with Turner syndrome.

Fig. 1C. A graph showing the visual-spatial results of androgen treatment of girls with Turner syndrome.

Figs. 1A, IB, and 1C indicate a cumulative, positive effect of androgen treatment in girls with Turner syndrome. Treatment effects were greatest at the end of the 2-year treatment interval.

DETAILED DESCRIPTION

The results of the present invention are demonstrated in the data as shown in Figs. 1A, IB, and 1C. The improvement increased with increasing duration of treatment.

Oxandrolone (Anavar), is manufactured by Biotechnology General Corporation (Iselin, NJ). It is a nonaromatizable androgen and is given orally as a single daily dose. Side effects of the drug are few. The dosage used in the patients represented in the graphs of Figs. 1A, IB, and 1C was 0.06 mg/kg/day.

In Fig. 1A, the graph shows the results of androgen treatment of girls with Turner syndrome. During the four-year treatment period, the attention deficit and visual-spatial deficit of subjects and the control group are measured. The subjects treated with androgen and the subjects not treated with androgen are compared to the control group in the percentage of the attention deficit and visual-spatial deficit. While both non-androgen and androgen-treated begin year 0 at a level above 40% relative to controls, the rate of increased attention and visual-spatial improvement grows faster in the treated group. Moreover, the androgen-treated group demonstrates a significantly higher overall percentage of attention and visual-spatial capability than the non-androgen treated group.

In Fig. IB, the graph shows only the attention results of androgen treatment of girls with Turner syndrome. During the four-year treatment period, the attention deficit of the subjects and the control group are measured. Similar to Fig. 1A, the subjects treated with androgen and the subjects not treated with androgen are compared to the control group, but this time the comparison is only in the percentage of the attention deficit.

In Fig. 1C, the graph shows only the visual-spatial results of androgen treatment of girls with Turner syndrome. During the four-year treatment period, the visual-spatial deficit of the subjects and the control group are measured. The subjects treated with androgen and the subjects not treated with androgen are compared to the control group, but this time the comparison is only in the percentage of the visual- spatial deficit. Additional data were obtained as a blinded study of the particular treatment group of each Turner syndrome subject ([A] oxandrolone plus growth hormone, [B] growth hormone alone. Results from the year 1 minus baseline visit and year 2 minus baseline for Turner syndrome (groups A and B) are presented below: This analysis excluded subjects with VIQ less than 70. Each Turner syndrome and control subject is seen yearly for a total of 4 years. An ANOVA was performed, comparing the delta for year 2 for the Turner A and Turner B groups. A. COMPARISON OF BASELINE TURNER (A AND B)

TABLE Al : AGE AND IQ RESULTS

TABLE A2: VISUAL-SPATIAL/VISUAL-MOTOR TEST RESULTS: Year 1 minus the baseline and ear 2 minus the baseline

^♦positive number for delta implies better score at year 1 or 2, compared to baseline

TABLE A2: ATTENTION TEST RESULTS: Year 1 minus the baseline and year 2 minus the baseline

^ΛTOVA = Test of Variables of Attention, omission errors, Lower number indicates fewer errors * positive number for delta implies better score at year 1 or 2, compared to baseline

TABLE A3: EXECUTIVE FUNCTION TEST RESULTS: Year 1 minus the baseline and year 2 minus the baseline

The results presented include many variables. Nonetheless, the two groups were wel matched for age and socioeconomic status (SES). In summary, girls with Turner syndrome treated with the androgen oxandrolone appear to have significant improvement in selected cognitive domains after two but not one year of treatment. The domains include visual-spatial function, attention as related to distractibility on the WISC/R, executive function and math achievement. These results represent a potential benefit associated with 2 years of oxandrolone treatment.

Claims

I CLAIM:

1. A method of treating attention deficit in a mammal, comprising administering a physiologically effective amount of androgen to said mammal.

2. The method of Claim 1, where the androgen is oxandrolone or testosterone.

3. A method of treating visual-spatial function deficit in a mammal, comprising administering a physiologically effective amount of androgen to said mammal.

4. The method of Claim 3, where the androgen is oxandrolone or testosterone.

5. A method of treating attention deficit in a human with Turner syndrome, comprising administering a physiologically effective amount of androgen to said human.

6. The method of Claim 5, where the androgen is oxandrolone or testosterone.

7. A method of treating visual-spatial function deficit in a human with

Turner syndrome, comprising administering a physiologically effective amount of androgen to said human.

8. The method of Claim 7, where the androgen is oxandrolone or testosterone.

9. A method of treating attention deficit in a human with ovarian dysfunction, comprising administering a physiologically effective amount of androgen to said human.

10. The method of Claim 9, where the androgen is oxandrolone or testosterone.

11. A method of treating visual-spatial function deficit in a human with ovarian dysfunction, comprising administering a physiologically effective amount of androgen to said human.

12. The method of Claim 11, where the androgen is oxandrolone or testosterone.