|
1. [Sexual hormones in ageing males].
[Article in German]
Kley HK, Nieschlag E, Wiegelmann W, Kruskemper HL
Aktuelle Gerontol 1976 Feb;6(2):61-7
Alterations of sexual hormones in plasma of ageing males
occur between the 50th and 60th year of life with individual
variations: 1. Decreased values of testosterone in plasma and
a poor response to gonado trophins demonstrate a diminished
synthesizing capacity of the testes in old men. 2. The
decreased testosterone plasma values are followed by an
increase in LH. The response of the anterior pituitary gland
to LH-RH stimulation in old men is normal. 3. Under
basal conditions estrone as well as estradiol plasma
concentrations increase significantly with age because of
increased conversion from androgens. 4.
Parallel to estrogen plasma values an increased
concentration of the sexual hormone binding globulin (SHBG) is
found, resulting in a steep decrease of the free (= active)
testosterone fraction. 5. Decreased
testosterone, which is more strongly bound to SHBG and
increased estrone and estradiol plasma values result in an
androgen/estrogen imbalance in old men.
2. Hypophyseal-gonadal system during male
aging.
Moroz EV, Verkhratsky NS
Arch Gerontol Geriatr 1985 Apr;4(1):13-9
The concentration of sex and gonadotropic hormones in blood
plasma of 280 reasonably healthy men aged 20-105 was
determined using radioimmunoassay kits. Compared to
men aged 20-39, the statistically significant decrease in
testosterone level was registered in men aged 55-59, the
increase in oestradiol in men aged 60-64, progesterone in men
aged 55-59, and in LH and FSH in the group aged
65-69. The reactivity of central and peripheral links of the
hypothalamic-gonadal system to direct and feed-back control
influences.
3. Age variation of the 24-hour mean plasma
concentrations of androgens, estrogens, and gonadotropins in
normal adult men.
Zumoff B, Strain GW, Kream J, O'Connor J, Rosenfeld RS, Levin
J, Fukushima DK
J Clin Endocrinol Metab 1982 Mar;54(3):534-8
The 24-h mean plasma concentrations of androgens
(dihydrotestosterone and total and free testosterone),
estrogens (estrone and estradiol), and gonadotropins (LH and
FSH) were measured in 35 healthy men, aged 21-85 yr, who were
rigorously screened to exclude factors known or suspected to
alter endocrine function. The plasma total
testosterone concentration showed a slow continuous decline
with age, decreasing about 35% between 21 and 85 yr of age;
the free testosterone level was closely correlated with that
of total testosterone over the entire observed concentration
range. The concentrations of dihydrotestosterone, estrone,
estradiol, and LH were age invariant. The
concentration of FSH showed a continuous linear increase with
age; the level at age 85 was about 2.5 times the level at age
21. The following conclusions were drawn. 1) Testosterone
secretion appears to decline slowly and continuously
throughout adult life in men. 2) Measurement of the plasma
free testosterone level adds no independent information in
healthy men, since its level is closely correlated with that
of total testosterone at all concentrations. 3) The continuous
rise with age in FSH concentration while LH is age invariant
cannot be explained by changes in testosterone or estrogen
production, but might be due to a decline of inhibin
production with age.
4. Age-related changes of plasma steroids in normal
adult males.
Drafta D, Schindler AE, Stroe E, Neacsu E
J Steroid Biochem 1982 Dec;17(6):683-7
Plasma cortisol, 17-hydroxyprogesterone (17-OH-P),
testosterone (T), 5 alpha-dihydrotestosterone (DHT, estrone
(E1) and estradiol (E2), were measured in 94 normal adult men
aged between 20-99, using RIA methods after chromatographic
separation of steroids on Sephadex LH-20 columns. All plasma
steroids except 17-OH-P, were age dependent: cortisol,
testosterone and DHT decreased significantly with age,
whereas estrone and estradiol were significantly
increased in elderly men. Cortisol, testosterone,
T/DHT ratio and estradiol levels were significantly correlated
with age. The age related changes of plasma steroids
in elderly men, were suggestive of decreased cortisol
secretion, and decreased testicular function with increased
peripheral conversion of androgens into estrogens.
Testosterone was positively correlated with its precursor
(17-OH-P) and respectively its peripheral metabolites (DHT and
E2). The negative correlation between estrone and 17-OH-P
found in elderly men, suggested that increased estrogen level
in aging males may be considered able to inhibit the
testicular androgen production.
5. Changes in the pituitary-testicular system with
age.
Baker HW, Burger HG, de Kretser DM, Hudson B, O'Connor S,
Wang C, Mirovics A, Court J, Dunlop M, Rennie GC
Clin Endocrinol (Oxf) 1976 Jul;5(4):349-72
In order to provide a comprehensive account of
pituitary-testicular function in man, 466 subjects, ranging in
age from 2 to 101 years, were studied to examine blood levels
of the pituitary gonadotrophins (LH and FSH), the sex steroids
testosterone and oestradiol, the binding capacity of the sex
hormone binding globulin (SHBG), the free testosterone and
oestradiol fractions, and the transfer constant for the
peripheral conversion of testosterone to oestradiol. The
results were compared with clinical indices of testicular
size, sexual function and secondary sex hair distribution.
Serum LH and FSH were low before puberty, increased in
pubertal adolescents to levels somewhat above those of adults
and subsequently increased progressively over the age of 40
years. Testosterone levels fell slowly after the age
of 40, while there was a slight rise in plasma oestradiol with
increasing age. FSH and testosterone showed small
seasonal variations in young adult men, the lowest values
being seen in winter. SHBG binding capacity was high
in two prepubertal boys, fell in adult men, but increased in
old age. Free testosterone and oestradiol levels fell
in old age. The metabolic clearance rates (MCR) of
testosterone and oestradiol also fell in old age, while the
conversion of testosterone to oestradiol was
increased. Many correlations were observed between
various hormonal and clincial measurements. The evidence is
consistent with a primary decrease in testicular function over
the age of 40 years.
6. Androgen and estrogen production in elderly men
with gynecomastia and testicular atrophy after mumps
orchitis.
Aiman J, Brenner PF, MacDonald PC
J Clin Endocrinol Metab 1980 Feb;50(2):380-6
Gynecomastia developed in three men 1-30 yr after the
occurrence of testicular atrophy due to mumps orchitis. At the
time of study, these men were 63-68 yr of age. In these men
the mean plasma production rate of testosterone was 816
microgram/24 h, a value 20% of that found in normal elderly
men without gynecomastia. The plasma production rate of
androstenedione averaged 1317 microgram/24 h. The mean
production rates of 17 beta-estradiol and estrone in these
subjects were 33 and 48 microgram/24 h, values comparable to
those of normal young men. Extraglandular formation of
estrogen from plasma prehormones accounted for all of the 17
beta-estridiol and most of the estrone produced by these
elderly men with gynecomastia. Serum gonadotropin
concentrations were elevated in these men, probably because
plasma testosterone production rates were decreased. These
findings are consistent with the view that the capacity of
Leydig cells to secrete testosterone was impaired after mumps
orchitis in these subjects, but the capacity to form
estrogen was not similarly impaired, since most estrogen is
formed in extraglandular sites. Thus, the impairment
in Leydig cell testosterone secretion after mumps orchitis
together with the normal increase in extraglandular
aromatization that accompanies aging bring about a striking
reduction in the ratio of testosterone to estrogen production
rates, and gynecomastia may result.
7. Effects of testosterone supplementation in the
aging male.
Tenover Joyce S
Journal of Clinical Endocrinology & Metabolism 75 ( 4 ):
p 1092-1098 1992
Serum androgen levels decline with aging in normal males,
such that a significant number of men over 60 yr of age will
have a mean serum total testosterone (T) level near the low
end of the normal adult range. It is not known whether lower T
levels in older men have an effect on androgen-responsive
organ systems, such as muscle, bone, bone marrow, and
prostate, nor are there data to evaluate the relative benefits
and risks of T supplementation in older men. We assessed the
physiological and biochemical effects of T therapy in 13
healthy men, 57-76 yr old, who had low or borderline low serum
T levels ( ltoreq 13.9 nmol/L). Intramuscular testosterone
enanthate (TE; 100 mg weekly) and placebo injections were
given for 3 months each. Before treatment and at the end of
both 3-month treatment regimens, lean body mass, body fat,
biochemical parameters of bone turnover, hematological
parameters, lipoprotein profiles, and prostate parameters
(such as prostate-specific antigen (PSA)) were evaluated.
Serum T level rose in all subjects with TE treatment, such
that the lowest level of T during a week's period was 19.7 +-
0.7 nmol/L (mean +- SE). After 3 months of TE treatment, lean
body mass was significantly increased, and urinary
ydroxyproline excretion was significantly depressed. With TE
treatment, there was a significant increase in hematocrit, a
decline in total cholesterol and low density lipoprotein
cholesterol, and a sustained increase in serum PSA levels.
Placebo treatment led to no significant changes in any of
these parameters. We conclude that short term (3 months) TE
supplementation to healthy older men who have serum T levels
near or below the lower limit of normal for young adult men
results in an increase in lean body mass and possibly a
decline in bone resorption, as assessed by urinary
hydroxyproline excretion, with some effect on serum
lipoproteins, hematological parameters, and PSA. The sustained
stimulation of PSA and the increase in hematocrit that occur
with physiological TE supplementation suggest that older men
should be screened carefully and followed periodically
throughout T therapy.
8. [Endocrine environment of benign prostatic
hyperplasia--relationships of sex steroid hormone levels with
age and the size of the prostate].
[Article in Japanese]
Suzuki K, Inaba S, Takeuchi H, Takezawa Y, Fukabori Y, Suzuki
T, Imai K, Yamanaka H, Honma S
Division of Urology, Shakai Hoken Mishima Hospital.
Nippon Hinyokika Gakkai Zasshi 1992
May;83(5):664-71
To determine the influence of endocrine factors on benign
prostatic hyperplasia (BHP), the levels of three sex steroid
hormones i.e., total testosterone (Total-T), free testosterone
(Free-T) and estradiol (E2), were measured in serum of healthy
154 men. Their ages ranged from 18 to 91 years old. In 59 men,
prostatic size was estimated by digital examination and was
subdivided into three groups: smaller than or equal to walnut
size, small hen's egg size and equal to or larger than hen's
egg size. Firstly, relationships of sex hormone levels with
age were studied. There was a slight decrease in Total-T over
60 years old, a significant decrease in Free-T, and no change
in E2 with age. Thus, E2/Total-T and E2/Free-T ratio increased
significantly after middle-age. Secondly, relationships of
hormone levels with prostatic size were studied. In the larger
prostate group, a significantly lower level of Total-T and
significantly higher level of E2 were detected. But there was
no difference in Free-T. Thus, the prostatic size was
correlated positively with E2 level, E2/Total-T and E2/Free-T
ratio. These suggest that the endocrine environment tended to
be estrogens-dominant with age, in particular, after
middle-age, and that patients with large prostates have more
estrogens-dominant environments. We conclude that estrogens
are key hormones for the induction and the development of
BPH.
9. Therapeutic effects of an androgenic preparation
on myocardial ischemia and cardiac function in 62 elderly male
coronary heart disease patients.
Wu SZ, Weng XZ
Department of Internal Medicine, Beijing Red Cross Chao Yang
Hospital.
Chin Med J (Engl) 1993 Jun;106(6):415-8
The elevated estradiol/testosterone (E2/T) ratio
had been proved to be a risk factor for coronary heart disease
(CHD) in elderly men. We conducted a randomized
placebo controlled crossover study on the effects of a new
androgenic preparation "Andriol" in 62 elderly men with CHD
over a period of 2.5 months. The results showed significant
differences between Andriol- and placebo-treated groups at the
end of this period: in the former, serum T level was elevated
significantly (P < 0.001), E2 level was unchanged (P >
0.05), E2/T ratio was reduced (P < 0.05), angina
pectoris (AP) was relieved (total effective rate,
77.4%), and myocardial ischemia in ECG and Holter
recordings were improved (total effective rate, respectively
68.8% and 75%). Doppler echocardiography showed that 12
parameters of cardiac function were unchanged in both groups.
No obvious side effect was found in those who took
Andriol.
10. The influence of aging on plasma sex hormones
in men: the Telecom Study.
Simon D, Preziosi P, Barrett-Connor E, Roger M, Saint-Paul M,
Nahoul K, Papoz L
Am J Epidemiol 1992 Apr 1;135(7):783-91
From April 1985 to July 1987, 1,408 healthy white men aged
20-60 years in Paris, France, recruited on an occupational
basis, underwent a physical examination and measurements of
plasma sex hormones in a cross-sectional study. Both
total testosterone and estradiol showed a significant stepwise
decrease with age (p less than 0.001) starting in the early
adult years, while estrone did not vary. These
relations of testosterone and estradiol with age remained
significant after adjustment for body mass index, subscapular
skinfold, and tobacco and alcohol consumptions, and they were
not modified by exclusion of the men who reported chronic
disease. Both the mechanism for the early decrease in
testosterone and its clinical significance merit further
investigation.
11. Serum 5alpha-dihydrotestosterone and
testosterone changes with age in man.
Lewis JG, Ghanadian R, Chisholm GD
Acta Endocrinol (Copenh) 1976 Jun;82(2):444-8
Serum 5alpha-dihydrotestosterone (DHT) and testosterone (T)
were measured in 98 normal adult men aged between 20-80 years,
separating T and DHT by thin layer chromatography and using a
sensitive and reliable radio-immunoassay. In three age groups
between 20-40, 40-60 and 60-80, the means +/- SEM for serum
DHT were 84 +/- 4, 79 +/- 3 and 67 +/- 3 (ng/100 ml)
respectively. The corresponding values for testosterone were
559 +/- 25, 491 +/- 25 and 475 +/- 28 (ng/100 ml). A
significant decrease was observed in the DHT level of the
60-80 years age group compared to either the 20-40 (P less
than 0.01) or the 40-60 (P less than 0.02) age groups.
There was a moderate decline in the testosterone level
of the 60-80 years age group compared to 20-40 years
(P less than 0.05) but there were no significant changes in
the testosterone levels between other groups.
12. Sex hormones and age: a cross-sectional study
of testosterone and estradiol and their bioavailable fractions
in community-dwelling men.
Ferrini RL, Barrett-Connor E
Am J Epidemiol 1998 Apr 15;147(8):750-4
The role of endogenous sex hormones in many diseases makes
understanding factors that influence levels of these hormones
increasingly important. This study examined age-associated
variations in total and bioavailable testosterone and
estradiol levels among community-dwelling Caucasian men in
Rancho Bernardo, California. Plasma samples obtained from 810
men aged 24-90 years in 1984-1987 were analyzed in 1993 using
radioimmunoassay. Analyses of age-hormone associations,
adjusting for weight, body mass index, alcohol ingestion,
smoking, physical activity, caffeine intake, specimen storage
time, and disease status, were undertaken. Bioavailable
testosterone and bioavailable estradiol levels decreased
significantly with age independently of covariates.
Total testosterone and estradiol levels decreased with
age only when analyses were controlled for
confounders. The importance of the age-associated
decline in endogenous sex hormone levels, particularly levels
of bioavailable testosterone and bioavailable estradiol, and
their relation to disease and function in men deserve further
research.
13. Steroid hormones, memory and mood in a healthy
elderly population.
Carlson LE, Sherwin BB
Department of Psychology, McGill University, Montreal,
Canada.
lindac@ego.psych.mcgill.ca
Psychoneuroendocrinology 1998 Aug;23(6):583-603
Men (n = 31), women estrogen-users (n = 14), and women
estrogen non-users (n = 41), whose average age was 72.1 +/-
5.6 years, were tested with a battery of psychological tests
measuring verbal memory, visual memory, concentration and
attention, language fluency and semantic memory, and mood.
Plasma levels of testosterone (T), estradiol (E2), cortisol
(CRT) and dehydroepiandrosterone-sulfate (DHEAS) were assessed
by radioimmunoassay. The ratio of DHEAS to CRT was calculated
to determine it's relationship to memory functioning. The men
had higher T and DHEAS levels than both groups of women. Women
estrogen-users had higher E2 levels than both men and estrogen
non-users and the men had higher E2 levels and a
higher DHEAS/CRT ratio than the (female) estrogen
non-users. There were no group differences in CRT
levels. Men and estrogen-users had higher total (p < .01)
and forward (p < .001) digit span scores compared with
non-users. Women estrogen-users also had higher backward digit
span scores than non-users (p < .05), while both groups of
women performed better than men on category retrieval (p <
.01). The implications of these findings with respect to
hormonal influences on memory in elderly men and women are
discussed.
14. Estrogen-androgen levels in aging men and
women: therapeutic considerations.
Greenblatt RB, Oettinger M, Bohler CS
J Am Geriatr Soc 1976 Apr;24(4):173-8
The influence of aging on serum levels of gonadotropins
(FSH and LH), testosterone and estradiol was studied in the
following groups: 4 normal men (ages 30 to 50), 38 men with
symptoms of the male climacteric (ages 51 to 84), 25 men with
relative impotence (ages 31 to 50), 10 normal women (ages 24
to 31), and 6 menopausal women (ages 58 to 76). FSH and LH
levels began to rise in men in their 40's, and the increase
became more conspicuous in the later age decades. The degree
of elevation was nowhere comparable to that observed in the
aging women. In the male, the serum testosterone levels showed
a progressive decrease from the fifth age decade onward,
whereas in the female there was an increase after the
menopause. Estradiol levels showed no significant
change in the aged male, but they were somewhat higher than in
the aged female. Exceptions to the low-testosterone and
low-gonadotropin relationship were observed in individual
cases and might be explained by relatively high estradiol
values. Proper replacement therapy by means of estrogens for
the postmenopausal female and androgens for the aging male is
often of great benefit, physically and
emotionally.
15. The effect of testosterone aromatization on
high-density lipoprotein cholesterol level and postheparin
lipolytic activity.
Zmuda JM, Fahrenbach MC, Younkin BT, Bausserman LL, Terry RB,
Catlin DH, Thompson PD
Department of Medicine, Miriam Hospital, Providence,
RI.
Metabolism 1993 Apr;42(4):446-50
Stanozolol, an oral 17 alpha-alkylated androgen, increases
hepatic triglyceride lipase activity (HTGLA) and decreases
high-density lipoprotein cholesterol (HDL-C) levels, whereas
intramuscular testosterone has comparatively little effect.
In the present study, we tested the hypothesis that
aromatization of androgen to estrogen blunts the lipid and
lipase effects of exogenous testosterone. Fourteen
male weightlifters received testosterone enanthate (200 mg/wk
intramuscularly), the aromatase inhibitor testolactone (250 mg
four times per day), or both drugs together in a randomized
cross-over design. Serum testosterone level increased
during all three drug treatments, whereas estradiol level
increased only with testosterone alone (+47%, P < .05),
demonstrating that testolactone effectively inhibited
testosterone aromatization. Testosterone decreased
HDL-C(-16%, P < .05), HDL2-C(-23%, NS), and apoprotein
(apo) A-I (-12%, P < .05) levels, effects that were
consistently but not significantly greater with simultaneous
testosterone and testolactone administration (HDL-C, -20%;
HDL2-C, -30%; apo A-I, -15%; P < .05 for all). In contrast,
both testosterone regimens decreased HDL3-C levels by 13% (P
< .05 for both). HTGLA increased 21% during testosterone
treatment and 38% during combined testosterone and
testolactone treatment (P < .01 for both). Lipoprotein
lipase activity (LPLA) increased only during combined
testosterone and testolactone treatment (+31%, P < .01),
suggesting that estrogen production may counteract the effects
of testosterone on LPLA. Testolactone alone had little effect
on any lipid, lipoprotein, apoprotein, or lipase
concentration.
16. Evidence that brain aromatization regulates LH
secretion in the male dog.
Worgul TJ, Santen RJ, Samojlik E, Irwin G, Falvo RE
Am J Physiol 1981 Sep;241(3):E246-50
A variety of data suggest an independent role for androgens
and estrogens in the regulation of luteinizing hormone (LH)
secretion in the male. Estrogens, in the male are
primarily derived from testicular androgens that are
aromatized both in peripheral tissues and in the CNS.
Our prior data suggested a pharmacologic regimen that blocked
CNS aromatization without lowering peripheral estrogen or
testosterone levels. Such experimental conditions would permit
assessment of the relative roles of CNS versus peripheral
aromatization in the regulation of LH secretion. We utilized
this regimen (aminoglutethimide, a potent aromatase inhibitor,
and hydrocortisone) in seven adult male dogs for 14 days.
Plasma LH rose to castrate levels, 450% above control values
on days 7 and 14. These LH increments stimulated similar rises
in androstenedione, testosterone, and dihydrotestosterone. In
contrast, plasma estrone and estradiol concentrations remained
constant. The induction of castrate LH levels without a
concomitant fall in peripheral androgens or estrogens is best
explained by a block of central aromatization and thus a
reduction in local hypothalamic concentrations. We
conclude that aromatization in the CNS rather than peripheral
tissues is the more important site with respect to LH negative
feedback in the male dog.
17. Origin of estrogen in normal men and in women
with testicular feminization.
MacDonald PC, Madden JD, Brenner PF, Wilson JD, Siiteri
PK
J Clin Endocrinol Metab 1979 Dec;49(6):905-16
The purpose of this study was to quantify the various
sources of estrone (E1) and 17 beta-estradiol (E2) production
in normal men and in women with testicular feminization. The
mean production rate of E1 in four young adult men was 58
micrograms/24 h, while that of E2 was 44 micrograms/24 h. In
these men, E1 production could be accounted for totally by
extraglandular formation through 1) aromatization of
plasma androstenedione, 2) conversion of E2 which was formed
from the aromatization of plasma testosterone, and 3)
conversion of secreted E2. In these men, only 12 micrograms or
less of E2 production could not be accounted for by
extraglandular formation from plasma C19 precursors, and is
presumed to have arisen by testicular secretion. In
six women with testicular feminization, the mean production
rate of E1 was 99 micrograms/24 h, while that of E2 was 77
micrograms/24 h. The amount of E2 production that
arose by glandular secretion could be computed in four of
these women and was considerably greater than that found in
the young adult men. In these women with testicular
feminization, an average of 44 micrograms/24 h E2 could not be
accounted for by extraglandular formation and is presumed to
have arisen by testicular secretion. The mean plasma
production rate of testosterone in the normal men was 5.7
mg/24 h, while that in the women with testicular feminization
was 8.3 mg/24 h. However, the range of plasma production rates
of testosterone in the women with testicular feminization was
large (1.3--17.0 mg/24 h).
18. Familial gynecomastia with increased
extraglandular aromatization of plasma
carbon19-steroids.
Berkovitz GD, Guerami A, Brown TR, MacDonald PC, Migeon
CJ
J Clin Invest 1985 Jun;75(6):1763-9
We evaluated a family in which gynecomastia occurred in
five males in two generations. In each affected subject,
gynecomastia and male sexual maturation began at an early age.
The ratio of the concentration of plasma estradiol-17 beta to
that of plasma testosterone was elevated in each affected
subject. In the three siblings with gynecomastia, the transfer
constant of conversion of androstenedione to estrone (i.e.,
the fraction of plasma androstenedione that was converted to
estrone as measured in the urine) was 10 times that of normal
persons. The transfer constant of conversion of testosterone
to estradiol-17 beta in the one subject studied also was 8-10
times that of normal men, whereas the transfer constants of
conversion of estrone to estradiol-17 beta and of estradiol-17
beta to estrone were normal. Despite the elevation in
extraglandular aromatase activity, there was a normal response
of the hypothalamic-pituitary axis to provocative stimuli.
This is the second documentation of gynecomastia that is
associated with increased extraglandular aromatase activity,
and the first time that the defect was found to be familial
with a probable X-linked (or autosomal dominant, sex limited)
mode of inheritance.
19. The pharmacokinetics of intravenous
testosterone in elderly men with coronary artery
disease.
White CM, Ferraro-Borgida MJ, Moyna NM, McGill CC, Ahlberg
AW, Thompson PD, Chow MS, Heller GV
University of Connecticut School of Pharmacy, Hartford,
USA.
J Clin Pharmacol 1998 Sep;38(9):792-7
Intracoronary testosterone injections have recently been
shown to possess coronary vasodilating effects. The same may
be true for intravenous testosterone, but the pharmacokinetic
and hemodynamic aspects need exploration before pharmacologic
studies can begin. This trial determined the pharmacokinetic
and hemodynamic properties of 300 microg of testosterone given
intravenously. Degree of testosterone aromatization to 17-beta
estradiol after exogenous administration and overall patient
tolerability also were evaluated. Eleven elderly men with
coronary artery disease participated in the study and were
given 300 microg of testosterone intravenously over 10
minutes. Serum blood concentrations of testosterone and
17-beta estradiol were measured at baseline and then
periodically. Testosterone serum concentrations were stripped
and fit to a two-compartment model for all patients. The
volume of distribution (Vdarea) was 80.36 +/- 24.51 L, and the
elimination half-life was 55.93 +/- 23.06 minutes. No
hemodynamic differences or side effects were noted.
The serum concentrations of 17-beta estradiol were
significantly increased from baseline beginning 5 minutes
after infusion to the end of the study (180 minutes after
infusion).
20. Testosterone pharmacokinetics after application
of an investigational transdermal system in hypogonadal
men.
Yu Z, Gupta SK, Hwang SS, Kipnes MS, Mooradian AD, Snyder PJ,
Atkinson LE
ALZA Corporation, Palo Alto, California 94303-0802,
USA.
J Clin Pharmacol 1997 Dec;37(12):1139-45
This open-label, randomized, placebo lead-in,
three-treatment crossover study in 19 hypogonadal men (27-82
years of age) evaluated dose proportionality of serum
testosterone concentrations with application of one or two
investigational transdermal testosterone systems for
application to the arm or torso. Testosterone in vivo kinetics
profiles were determined using DeMonS, a recently developed
numerical deconvolution method that estimates drug absorption
at different time intervals and/or drug disposition model
parameters. After application of the investigational
transdermal systems, the mean serum testosterone,
dihydrotestosterone, estradiol, and free testosterone
concentrations were elevated to normal levels.
Treatment allowed approximation of the normal circadian
pattern of endogenous testosterone secretion, and the increase
in serum testosterone concentrations was proportional to the
surface area of systems applied. The investigational
transdermal system provided effective testosterone replacement
therapy as judged by pharmacokinetic parameters.
21. The effect of supraphysiologic doses of
testosterone on fasting total homocysteine levels in normal
men.
Zmuda JM, Bausserman LL, Maceroni D, Thompson PD
University of Pittsburgh Medical Center, PA 15213, USA.
Atherosclerosis 1997 Apr;130(1-2):199-202
Elevated total homocysteine (tHcy) levels are associated
with increased risk for atherosclerotic cardiovascular
disease. tHcy levels are higher in men than in women, and
estrogen replacement therapy may reduce tHcy levels in
postmenopausal women. The effect of androgenic hormones on
tHcy levels in men has not been examined. The present study
determined the effect of supraphysiologic doses of
testosterone, with or without its aromatization to estradiol,
on fasting tHcy levels in 14 normal male weightlifters aged
19-42 years. Subjects received testosterone-enanthate (200
mg/week intramuscularly), the aromatase inhibitor,
testolactone (1 g/day orally), or both drugs together in a
crossover design. Each treatment lasted 3 weeks and each
treatment was separated by a 4-week washout. Both testosterone
regimens increased serum testosterone levels, whereas
estradiol increased only during testosterone alone.
Mean tHcy levels were not significantly altered when
testosterone was given alone or together with testolactone.
Testolactone did not significantly influence tHcy levels. We
conclude that short-term, high-dose testosterone
administration does not affect fasting tHcy levels in normal
men.
22. [Therapeutic efficacy of testolactone
(aromatase inhibitor) to oligozoospermia with high
estradiol/testosterone ratio].
[Article in Japanese]
Itoh N, Kumamoto Y, Maruta H, Tsukamoto T, Takagi Y, Mikuma
N, Nanbu A, Tachiki H
Department of Urology, Sapporo Medical College.
Nippon Hinyokika Gakkai Zasshi 1991
Feb;82(2):204-9
To our knowledge, the action of estradiol which is produced
from testosterone by aromatase on human spermatogenesis has
not been fully clarified. In oligozoospermia, with high values
of E2/T ratio, it is considered that the role of estradiol is
suppressive to spermatogenesis. In this study, alteration of
spermatogenesis was evaluated when serum estradiol levels were
decreased by suppression of aromatase activity. Nine male
infertile patients were treated with testolactone (Teslac: 1.0
g/day, for 3 months), one of the aromatase inhibitors. Four of
them had an increase in sperm count (more than 10 x 10(6)/ml
relative to base line). In endocrinological findings, serum
estradiol levels and E2/free T ratio were significantly
decreased after treatment. Serum free testosterone levels were
significantly increased in all cases, presumably from
decreased sex hormone binding globulin (SHBG) levels. These
findings suggested the effectiveness of the administrated
aromatase inhibitor. In particular four patients whose sperm
counts were improved after testolactone treatment had high
values of basal serum estradiol levels and E2/free T ratio
before treatment, and these values were normalized after
treatment. In conclusion we suggest that an aromatase
inhibitor may be effective to male infertile patients with
high serum estradiol levels.
23. Familial effects on plasma sex-steroid content
in man: testosterone, estradiol and Sex-hormone-binding
globulin.
Meikle AW, Stanish WM, Taylor N, Edwards CQ, Bishop CT
Metabolism 1982 Jan;31(1):6-9
We investigated whether familial factors influence the
plasma content of sex-steroids and sex-hormone-binding
globulin (SHBG) in 98 adult males of 66 families. They had no
apparent endocrine dysfunction, The 0800-1100 hr plasma levels
of testosterone, 5 alpha-dihydrotestosterone (DHT),
estradiol-17 beta (E2) and estrone (E1) were measured by
radioimmunoassay. The free fractions of E2 and testosterone
were determined by equilibrium dialysis, and binding capacity
of SHBG was also calculated. The data were analyzed by
analysis of variance. We observed that the differences in the
plasma content of testosterone (p = .02). SHBG binding
capacity (p = 0.1), and E2 (p = 0.3), free E2 index (p = .05)
were all substantially less variable within groups of brothers
than among non-brothers. The variability of the plasma
concentration of DHT, free testosterone and E1 was not
significantly less within brothers than among non-brothers.
The correlation between either plasma testosterone content (r
= .14) or SHBG binding capacity (r = .12) and percent of ideal
body weight was not significant statistically. Age had no
effect on the results. Our data suggest that genetic
and/or environmental factors may affect the plasma content of
testosterone, E2 and SHBG
24. Conversion of androgens to estrogens in
cirrhosis of the liver.
Gordon GG, Olivo J, Rafil F, Southren AL
J Clin Endocrinol Metab 1975 Jun;40(6):1018-26
The contribution, by peripheral conversion, of
androstenedione and testosterone to the circulating estrogens
was determined in men with cirrhosis of the liver. The
conversion ratio of androstenedione to estrone, estradiol and
testosterone and the conversion ratio of testosterone to
estrone (but not estradiol) and androstenedione were
significantly increased. The plasma concentrations of
androstenedione and testosterone were increased and decreased
respectively; the mean plasma concentration of androstenedione
being similar to that found in normal women. The metabolic
clearance rate of androstenedione was not altered in cirrhosis
although the metabolic clearance rate of testosterone was
decreased. The production rate of androstenedione was elevated
while that of testosterone was reduced. The instantaneous
contribution of plasma androstenedione to estrone and
estradiol was increased in cirrhosis as was the contribution
of testosterone to estrone (but not to estradiol). Thus the
increased estradiol levels in cirrhosis result, in large part,
from increased peripheral conversion from the androgens. The
percent contribution of plasma testosterone to plasma
androstenedione was decreased although the absolute amount
derived by conversion was normal. The percent contribution of
plasma androstenedione to plasma testosterone was increased
sevenfold in cirrhosis. The fraction of the daily
androstenedione production derived from the plasma
testosterone pool was not significantly altered. However, a
significant fraction of the daily production rate of
testosterone was derived from androstenedione. Thus, 15% of
the circulating testosterone is not secreted but is derived by
peripheral conversion from androstenedione. Normal levels of
gonadotropins were found in cirrhosis.
25. Alteration in the plasma testosterone:
estradiol ratio: an alternative to the inhibin
hypothesis.
Sherins RJ, Patterson AP, Brightwell D, Udelsman R, Sartor
J
Ann N Y Acad Sci 1982;383:295-306
The data suggest that in the absence of the testis: (1)
testosterone can maintain both FSH and LH concentrations
chronically within the physiological range; (2) that
estradiol preferentially suppresses plasma LH concentration,
indicating that the androgenic component of testosterone
modulates FSH secretion; and (3) that
subphysiological testosterone concentrations accompanied by
physiological estradiol levels permit FSH to escape to
midcastrate levels while maintaining LH concentration at
intact levels. An alteration in the testosterone: estradiol
ratio can account for a selective FSH elevation when
testosterone production is low. The data provide an
alternative explanation for the inhibin phenomenon.
26. Which testosterone replacement therapy?
Cantrill JA, Dewis P, Large DM, Newman M, Anderson DC
Clin Endocrinol (Oxf) 1984 Aug;21(2):97-107
Three different forms of testosterone (T) replacement
therapy were compared; they were the intramuscular injection
of mixed testosterone esters 250 mg; the subcutaneous
implantation of 6 X 100 mg pellets of fused testosterone; and
the oral administration of testosterone undecanoate (TU) 80 mg
twice daily. Six hypogonadal males were treated with oral TU
for an eight week period, during which time serial serum
hormonal estimations were performed over 10 h at the
initiation and after four and eight weeks of therapy. Serum T
levels showed marked variability both between subjects and
within the same subject on different occasions. We attribute
this to variability in absorption of TU, which is formulated
in oleic acid. The overall mean T level calculated from the
areas under the profiles of TU was 12.0 nmol/l. Hormone
responses to injected T esters were studied in nine
hypogonadal males. Serum T rose to supraphysiological peak
concentrations (mean 71 nmol/l) 24-48 h after an injection,
followed by an exponential decay to reach baseline
concentrations after 2-3 weeks. The overall calculated mean T
level in subjects receiving testosterone esters 250 mg every
three weeks was 27.7 nmol/l. Subcutaneous implantation of
testosterone in six hypogonadal men produced a gradual rise in
serum T followed by a slow decline, with T levels remaining
within the normal range for 4-5 months. The calculated overall
mean T level over 21 weeks after implantation was 17.0 nmol/l.
Serum oestradiol (E2) levels remained within the
normal male range throughout the study periods on both TU and
T implant therapy but showed a supraphysiological peak (mean
347 pmol/l) 24-48 h after a T injection. 5
alpha-dihydrotestosterone (DHT) levels appeared to parallel
those of T on the three forms of therapy, with DHT:T ratios
being highest for TU therapy. This was also true for the
target organ metabolite 5 alpha-androstane-3 alpha,17
beta-diol. At the doses studied drug costs were similar for T
implantation (every 5 months) and T ester injections (every 3
weeks), but were 7-8 times higher for TU (80 mg twice a day).
We conclude that T implantation remains overall the most
physiological form of androgen replacement therapy, is
generally well accepted and attended by few side effects; TU
may have a useful role in the initial phases of therapy.
27. Conversion of androgens to estrogens in
idiopathic hemochromatosis: comparison with alcoholic liver
cirrhosis.
Kley HK, Niederau C, Stremmel W, Lax R, Strohmeyer G,
Kruskemper HL
J Clin Endocrinol Metab 1985 Jul;61(1):1-6
Hypogonadism is common in patients with some liver
diseases, such as idiopathic hemochromatosis (IHC) and
alcoholic cirrhosis (AC). However, gynecomastia, a typical
feature in AC, does not occur in IHC. To determine the
hormonal basis for this difference, the following parameters
were determined in patients with IHC and AC as well as in
normal men: plasma concentrations of androgens and estrogens,
metabolic clearance and production rates of androstenedione
and testosterone, and the contribution of peripheral
conversion of androstenedione and testosterone to the
circulating estrogens. Severe impotence in both patients with
IHC and those with AC was associated with more than 50%
reduction in plasma testosterone. The reduction was due to 63%
and 70% decreases in testosterone production in IHC and AC,
respectively. The MCRs were less affected in IHC and AC (19%
and 37% reductions, respectively). In IHC, the fall in
testosterone concentrations was accompanied by decreased
production and plasma concentrations of androstenedione, a
precursor for estrogen synthesis. In contrast, production and
plasma concentrations of androstenedione were significantly
increased in AC. Patients with IHC had estradiol und estrone
levels similar to those in normal men (mean +/- SD, 16.2 +/-
4.6 vs. 20.3 +/- 3.7 pg/ml; P = NS), whereas in AC, estradiol
and estrone were significantly elevated (38.0 +/- 5.3 and 68.5
+/- 17.2 pg/ml, respectively). In IHC, sex hormone-binding
globulin levels were in the same range as in the normal men,
whereas sex hormone-binding globulin was increased in AC. In
IHC, the instantaneous contribution of plasma androstenedione
to estrone and estradiol was normal, whereas that of plasma
testosterone to plasma estrogens was decreased by about 50%.
In contrast, in AC, the instantaneous contribution of plasma
androstenedione to estrogens was greatly enhanced, and that of
testosterone was in the normal range. Since the MCRs of
androgens and the conversion ratios of androgens to estrogens
indicate normal peripheral metabolism of sex hormones in IHC,
decreased androgen formation implies decreased testicular
synthesis. This was confirmed by a significantly decreased LH
level in IHC (5.5 +/- 1.9 vs. 10.5 +/- 3.1 mU/ml in normal
men), indicating pituitary failure. In AC, however, increased
LH (20.0 +/- 2.7 mU/ml) may be indicative of primary
testicular failure. These results confirm clinical features of
hypogonadism and normal estrogenic activity in patients with
IHC.
28. Sublingual administration of
testosterone-hydroxypropyl-beta-cyclodextrin inclusion complex
simulates episodic androgen release in hypogonadal men.
Stuenkel CA, Dudley RE, Yen SS
Department of Reproductive Medicine, School of Medicine,
University of California-San Diego, La Jolla 92093.
J Clin Endocrinol Metab 1991 May;72(5):1054-9
In search of a more physiological testosterone (T)
replacement therapy for hypogonadal states, we evaluated an
inclusion complex of T with 2-hydroxypropyl-beta-cyclodextrin
(HPBCD). HPBCD enhances T solubility and absorption, but HPBCD
is not absorbed. Five hypogonadal men (mean age, 32.4 +/- 2.3
yr) with serum T levels below the normal range were treated in
two separate experimental phases with either a 2.5- or 5.0-mg
tablet of sublingual (SL) T-HPBCD three times daily for 7
days. Acute pharmacodynamic changes were monitored at baseline
and 10, 20, and 40 min and 1, 1.5, 2, 3, 4, and 8 h after
administration of the first dose. At the 5-mg dose, a maximal
concentration (Cmax) of T (85.4 +/- 11.0 nmol/L) was achieved
in 20 min (63 +/- 24-fold increase), followed by a rapid
decline to below the normal range (less than 12 nmol/L) at 2
h, with an estimated half-life of decline of 1.87 +/- 0.19 h.
The dihydrotestosterone (DHT) Cmax (4.1 +/- 0.5 nmol/L)
occurred at 32 +/- 5 min (8.9 +/- 1.3-fold increase) and
declined to below the normal range (less than 1.2 nmol/L)
after 3 h. The integrated 8 h value for the ratio of T/DHT was
10.0 +/- 1.1, which fell within the normal range. The
increment in androstenedione paralleled that in T, and the
Cmax (6.8 +/- 0.9 nmol/L) was reached in 24 +/- 4 min (2.3 +/-
0.6-fold increase). Compared to baseline, the Cmax was
significantly greater for T (P less than 0.005), DHT (P less
than 0.0005), and androstenedione (P less than 0.005).
Both estradiol (E2) and estrone (E1) remained in the
normal range (less than 200 pmol/L), although the Cmax for E1
was significantly greater than baseline (P less than
0.05). Serum LH levels were suppressed (19.0 +/-
2.6%) at 2 h (P less than 0.05), without a significant change
in FSH. During 7 days of treatment, there was no cumulative
increase in basal T, DHT, and E2 levels or further decline in
LH or FSH levels. There was no change in sex hormone-binding
globulin levels. Similar results were observed with the 2.5-mg
dose, suggesting that the capacity of SL absorption may be
limited to a certain dose of T-HPBCD. The fluctuations in T
after SL administration of T-HPBCD resemble endogenous
episodic secretion. We conclude that T, complexed with
HPBCD, is rapidly absorbed by the SL route and quickly
metabolized without sustained elevations of DHT or
E2.
29. The association of hyperestrogenemia with
coronary thrombosis in men.
Phillips GB, Pinkernell BH, Jing TY
Department of Medicine, Columbia University College of
Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center,
New York, NY, USA.
Arterioscler Thromb Vasc Biol 1996
Nov;16(11):1383-7
Both hyperestrogenemia and hypotestosteronemia have
been reported in association with myocardial infarction (MI)
in men. It was previously observed that the serum
testosterone concentration correlated negatively with the
degree of coronary artery disease (CAD) in men who had never
had a known MI. The present study investigated the
relationship of sex hormone levels to the thrombotic component
of MI by comparing these levels in 18 men who had had an MI
(ie, thrombosis) and 50 men with no history of MI (ie, no
thrombosis) whose degree of CAD was in the same range. The
mean degree of CAD, age, and body mass index in these two
groups was not significantly different. The mean serum
estradiol level in the men who had had an MI (38.5 +/- 8.8
pg/mL) was higher (P = .002) than the level in the men who had
not had an MI (31.9 +/- 7.1 pg/mL). The mean levels of
testosterone, free testosterone, sex hormone-binding globulin,
insulin, dehydroepiandrosterone sulfate, cholesterol, HDI,
cholesterol, and systolic and diastolic blood pressure did not
differ significantly. Estradiol was the only variable
measured that showed a significant relationship to MI (P <
.003 by multivariate logistic regression). These findings
suggest that hyperestrogenemia may be related to the
thrombosis of MI.
30. Lower androgenicity is associated with higher
plasma levels of prothrombotic factors irrespective of age,
obesity, body fat distribution, and related metabolic
parameters in men.
De Pergola G, De Mitrio V, Sciaraffia M, Pannacciulli N,
Minenna A, Giorgino F, Petronelli M, Laudadio E, Giorgino
R
Institute of Medical Clinic, Endocrinology and Metabolic
Disease, University of Bari, School of Medicine, Italy.
Metabolism 1997 Nov;46(11):1287-93
The purpose of this study was to examine the relationships
between androgenic status and plasma levels of both
prothrombotic and antithrombotic factors in men, irrespective
of obesity, body fat distribution, and metabolic parameters.
Sixty-four apparently healthy men, 40 with a body mass index
(BMI) greater than 25 kg/m2 (overweight and obese [OO]) and 24
non-obese controls with a BMI less than 25, were selected and
evaluated for (1) plasma concentrations of plasminogen
activator inhibitor-1 (PAI-1) antigen, PAI-1 activity,
fibrinogen, von Willebrand factor (vWF) antigen, vWF activity,
and factor VII (FVII) as the prothrombotic factors; (2) plasma
levels of tissue plasminogen activator (TPA) antigen, protein
C, and antithrombin III as the antithrombotic factors; (3)
fasting plasma concentrations of insulin and glucose and the
lipid pattern (triglycerides [TG] and total and high-density
lipoprotein [HDL] cholesterol) as the metabolic parameters;
and (4) free testosterone (FT), dehydroepiandrosterone sulfate
(DHEAS), and sex hormone-binding globulin (SHBG) serum levels
as the parameters of androgenicity. Body fat distribution was
evaluated by the waist to hip ratio (WHR). In OO and non-obese
subjects taken together, plasma levels of PAI-1 antigen,
fibrinogen, and FVII were inversely associated with FT (r =
.255, P < .05, r = -3.14, P < .05, and r = -.278, P
<.05, respectively), and the negative relationships of both
fibrinogen and FVII with FT were maintained after stepwise
multiple regression analysis. Plasma concentrations of PAI-1
antigen and PAI-1 activity were also negatively correlated
with SHBG (r = -.315, P < .05 and r = -.362, P < .01,
respectively), and these associations held irrespective of the
other parameters investigated. None of the antithrombotic and
fibrinolytic factors were independently related to serum
androgen levels. Subjects with a BMI higher than 25 kg/m2 had
higher plasma concentrations of PAI-1 antigen, PAI-1 activity,
and fibrinogen as compared with non-obese controls (P <
.001, P < .001, and P < .01, respectively). In addition,
in OO and control subjects as a whole, multiple stepwise
regression analysis showed that the associations of BMI with
PAI-1 activity, fibrinogen, vWF antigen, and vWF activity were
independent of any other metabolic and hormonal parameters.
Plasma concentrations of PAI-1 antigen, PAI-1 activity, and
fibrinogen were also directly correlated with WHR in all
subjects taken together, irrespective of the other parameters
investigated. Evaluation of antithrombotic factors showed that
OO subjects had higher TPA plasma concentrations than
non-obese controls (P < .001), whereas protein C and
antithrombin III did not differ in the two groups. TPA was
also directly correlated with BMI (r = .415, P < .001) and
WHR (r = .393, P < .001) in all subjects. The
results of this study indicate that (1) men with lower FT
serum levels have higher fibrinogen and FVII plasma
concentrations, and those with lower SHBG serum levels also
have higher levels of PAI-1 antigen and activity; (2)
irrespective of other factors, obesity per se may account for
higher concentrations of PAI-1, fibrinogen, and vWF; (3)
plasma levels of PAI-1 (antigen and activity) and fibrinogen
correlate independently with WHR; and (4) among the
investigated antithrombotic factors (TPA antigen, protein C,
antithrombin III), only TPA antigen plasma concentrations are
higher in men with abdominal obesity. Thus, because of
the increase in several prothrombotic factors, men with
central obesity, particularly those with lower androgenicity,
seem to be at greater risk for coronary heart disease
(CHD). Apparently, this risk is not counteracted by a
parallel increase in plasma concentrations of antithrombotic
factors.
|