serum testosterone levels have multiple negative

systemic effects, including increased rates of car-

diovascular disease, dyslipidemia, diabetes, meta-

bolic syndrome and osteoporosis as well as all-cause

mortality.

5,6

Testosterone in the bloodstream is bound mostly

to sex hormone-binding globulin and to a lesser

extent to albumin and corticosteroid-binding glob-

ulin. Only about 1% to 2% of testosterone is unbound

or free and, thus, biologically active. Sex hormone-

binding globulin increases with age and inhibits

testosterone function. Numerous studies show that

TST is effective for increasing serum testosterone

with correlated clinical improvement in quality of

life, weight and waist circumference.

12,13

The ADAM

and more recently the qADAM

questionnaires have been used to assess subjective

symptoms of hypogonadism. Yamaguchi et al noted

that patients treated with at least 6 months of

TST showed improved ADAM scores.

Taylor and

Levine reported improved ADAM scores in hypo-

gonadal men treated with CC.

The selective estrogen receptor modulator CC

effectively treats male hypogonadism by indirectly

increasing serum testosterone and increasing the

ratio of testosterone to estradiol.

18,19

While CC is

not FDA (Food and Drug Administration) approved

for hypogonadism, it has been used off label for

many years. Side effects are typically minor and

may include nausea, dizziness, weight gain and

±uid retention. Improvement in serum testosterone

is achieved by inhibiting the negative feedback of

estradiol to the hypothalamic-pituitary-gonadal axis

at the level of the hypothalamus. Subsequent release

of luteinizing hormone and follicle-stimulating hor-

mone from the anterior pituitary results in greater

stimulation of Leydig cells, which produce the

anabolic hormone testosterone.

Recent evidence

suggests that CC may be an appropriate alternative

treatment for male hypogonadism because it is

safe,

affordable and effective

22,23

for improving

serum testosterone levels.

Testosterone injections have been used for many

years but this modality often generates serum

testosterone with peak and trough values above and

below the normal range, respectively, with unclear

effects of how these ±uctuations affect satisfaction.

Preparations such as testosterone gels provide a

more stable level of serum testosterone. We per-

formed a cross-sectional, retrospective comparison

of hypogonadal symptoms in men using CC, and

testosterone gels and injections, and in men not on

TST. We hypothesized that men on CC for symp-

tomatic hypogonadism would be as satis²ed (ac-

cording to qADAM scores) with therapy as those

on testosterone gels or injections despite varying

serum total testosterone levels.

MATERIALS AND METHODS

After receiving approval from the Baylor College of

Medicine institutional review board we administered

the qADAM questionnaire

14,15

to all men who presented

with symptoms of hypogonadism. qADAM consists of the

10 questions of the original ADAM questionnaire

with

yes and no answers replaced by a Likert scale of 1 to 5 in

which 5 represents the absence of a given symptom and

1 represents maximal symptoms. qADAM was devised to

better quantify improvement in hypogonadal symptoms

when full symptom resolution is not achieved. qADAM

scores range from 10 to 50 with a lower score indicating

more severe hypogonadal symptoms. All questions were

weighted equally and no threshold score has been noted

to accurately diagnose hypogonadism.

Using

retrospective

cross-sectional

design

analyzed data based on treatment regimen, including CC,

and testosterone gels and injections as well as no TST

in eugonadal men who served as controls. Treatment

regimens included CC (25 mg orally once daily), testos-

terone gels (Testim

1% or AndroGel

1.62% 2 to 4 pumps

per day) and testosterone injections (testosterone cypio-

nate 100 to 200 mg once weekly intramuscularly

) in men

treated for symptomatic hypogonadism, de²ned as total

testosterone less than 300 ng/dl and 3 or fewer positive

symptoms on ADAM.

14,15

All men who had a testosterone

level measured while on treatment and who completed

the ADAM questionnaire were included in analysis.

Treatment ef²cacy was evaluated by pretreatment

and posttreatment serum testosterone levels. Posttreat-

ment values were determined at the same visit that

qADAM

was

completed.

Testosterone

and estradiol

were measured by radioimmunoassay using the Access

2 Immunoassay System. Testosterone levels were drawn

before 10 a.m. in men younger than 40 years, and between

9 a.m. and 5 p.m. in men older than 40 years. Since

variability in serum testosterone in men on testosterone

injections makes the timing of blood draws dif²cult,

samples were collected during the scheduled patient

followup visit with no special concern for the timing of

the last injection. Variability in levels was obviated by

the random nature of the draw and the number of pa-

tients surveyed. An equal number of men on each treat-

ment regimen were age matched to eliminate the

confounding effect of age on hypogonadal symptoms.

Data were analyzed using Excel

and Minitab

16.

All values are shown as the median

IQR. The

Mann-Whitney test was used to evaluate differences in

medians between groups with p

0.05 considered statis-

tically signi²cant.

RESULTS

We reviewed the charts of 1,150 men on TST, of

whom 93 on CC (31), testosterone injections (31) and

testosterone gels (31) were age matched (see table).

We also age matched 31 men not on TST. There

was no difference in median age between men on

CC, testosterone injections, testosterone gels and

controls (40.9, 40.5, 43.9 and 40.5 years, respec-

tively, p

0.05). Median testosterone increased from

876

TESTOSTERONE SUPPLEMENTATION VERSUS CLOMIPHENE CITRATE FOR HYPOGONADISM