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Chapter 3 Defects of Androgen Metabolism and Androgen Mediated Disease Introduction
Significant clues leading to the development of safe and effective
treatments for AGA can be found in the exploration of how androgenic
hormones act to influence other pathophysiological processes. Well described
studies have been conducted with eunuchs, pseudohermaphrodites, and others
suffering from androgen mediated disorders. Although at first glance these
disorders display many obvious differences, upon deeper exploration of the
evidence, there are striking connections which bear heavily upon the central
Castration of men and males of other species was almost certainly the
first experiment in endocrinology, and the literature on the subject is vast. In
fact, the Cumming Manuscript Collection of the New York Academy of
Medicine Library contains more than 1200 references, abstracts, and
documents concerning the early history of human castration.
The Skoptzy (meaning the castrated), also called the White Doves, were
an 18th century Christian sect, which ranged from parts of Russia into Romania
and Bessarbia, whose male members, to attain their ideal of sanctity, subjected
themselves to castration. In the early years of this sect the surgical instrument
of choice was a red-hot iron rod or poker (hence the expression baptism of
fire) ref, but other instruments included pieces of glass, razors, and knives.
When the penis and testes were removed, nails were inserted into the urethra
to avoid strictures, and such men were said to urinate while sitting or squatting.
This brutal practice was continued at least until 1927 (1).
Medical studies on these individuals were performed by at least three
groups of investigators. At the turn of the century Pittard took physical
observations of 30 Skoptzy men in 1 Romanian village and noted that, among
other curious findings, they appeared to be totally free from hair loss (1). In
1907 Tandler and Grosz examined 5 Skoptzy men in Bucharest whose average
age was 30 and who had been castrated between ages 5-21. Subsequently,
during the German occupation of Romania in the First World War Walter Koch
studied 13 Skoptzy men, all between 50 and 94 years of age.
A variety of anthropomorphic measurements were made, including a
prostate examination. Androgen action is required for the development of the
prostate gland during embryogenesis (2), and the prostate does not develop in
men with mutations that profoundly impair the function of either the androgen
receptor or of the microsomal enzyme, steroid ?4 5AR type 2. Furthermore, it
has been understood since the 19th century that BPH does not develop in
prepubertal castrates and that castration causes regression of the hyperplastic
The practice of employing eunuchs as court functionaries in China and
other oriental countries goes back into prehistory (3). The procedure by which
the Chinese court eunuchs were castrated in the late 19th century during the
Qing dynasty was described in some detail by Stent in 1878, and subsequent
descriptions by other investigators (4). However, on the basis of published
interviews of surviving eunuchs, the surgical procedure, as well as the
physiologic consequences, appear to have been essentially the same in all
cases (5). In addition to osteomalacia consistent with the kind of bone
deterioration described in post-menopausal females, gynecomastia seems to
have been a common result. Wagenseil reported that 9 of 26 subjects in his
1930 Chinese eunuch study had grossly visible breast enlargement (6). He
also found that all 26 had hypoplastic to nonexistent prostate tissue. And,
importantly, juvenile hairlines and hair density were maintained in all
Pseudohermaphrodite studies
Disorders of androgen metabolism present excellent opportunities to
develop improved understanding of the effects of androgens on human hair
cycling and hair loss. Male pseudohermaphrodites with a deficiency of the
enzyme 5AR raised as girls have also provided a unique opportunity for
evaluation of the effects of androgenic processes in determination of gender
identity. In 1979 investigators published results from their observations of 19
Dominican pseudohermaphrodites. Postpubertal psychosexual histories were
obtained from 18 of these 19 subjects. Investigators noted that, at birth, the
subjects presents with a markedly bifid scrotum that appeared labia-like. There
is a clitoris-like phallus and a urogenital sinus with a blind vaginal pouch. The
testes are in the abdomen, inguinal canal or scrotum.
However, during puberty, under the influence of normal plasma levels of
testosterone, definite virilization occurs. The voice deepens, and affected
subjects develop a muscular habitus. There is substantial growth of the phallus,
and the scrotum becomes rugated and hyperpigmented. In most subjects, the
testes descend into the scrotum if they have not already done so. There is no
gynecomastia. The subjects have erections, and there is ejaculate from the
uretrhral orifice on the perineum. They are capable of intromission but,
because of the position of the urethra, are incapable of insemination (7). These
subjects are therefore testosterone-exposed and testosterone-responsive boys
born with female-appearing external genitalia and raised as girls.
Thus, at birth the defect is limited to incomplete differentiation of the
male external genitalia; masculinization of the internal structures is normal.
Especially noteworthy were the findings that at puberty, virilization occurs with
the exception of a scanty or absent beard, lack of temporal recession of
hairline, and a small to absent prostate. These among other facts led McGinley
Because of the virilization at puberty, and despite marked ambiguity of
the external genitalia at birth, they hypothesized that the affected individuals
would not have a disorder of T biosynthesis. The male puberty without breast
development and with complete spermatogenesis also precluded a defect due
to impaired androgen action. These investigators proposed, rather, that the
abnormality was due most likely to a defect in the metabolism of T at the target
tissue, that is, biotransformation of T to 5aDHT by the enzyme 5AR (8).
To define a defect in 5AR activity, these investigators measured plasma
T and 5aDHT levels in four affected males by a double isotope derivative
technique. In the affected males the plasma T concentration ranged from 470
to 960 ng per 100 mL, which was within the normal male range of 300 to 1200
ng per 100 mL (8). However, DHT concentrations were 16, 17, 21, and 29 ng
per 100 mL, which were below the normal male range of 40 to 80 ng per 100
mL. The ratio of plasma T to DHT in normal males was approximately 14/1, and
in the affected males it was approximately 40/1 (8).
In two affected males, the percentage conversion of T to 5aDHT was
measured during continuous infusion of radioactive T. The percentage
conversion was 0.48 and 0.85, and was approximately one-sixth of the reported
The above assays reflect a defect in 5a reduction resulting in the
decreased conversion of T to DHT. From the clinical presentation of
ambiguous external genitalia with normal male internal structures and the
biochemical data demonstrating ?4-steroid 5a-reductase deficiency with
decreased DHT formation, the investigators hypothesized that during
embryogenesis, and again at puberty, both T and DHT are necessary for
complete male external differentiation and development (9). T secreted in utero
by the testes acts directly on the Wolfian ducts to cause differentiation to the
vas deferens, epididymis, and seminal vesicles; but in the urogenital sinus and
urogenital tubercle, T functions as a prehormone, where its conversion to DHT
results in differentiation of the external genitalia and prostate. The anabolic
events at puberty, in particular the increase in muscle mass, the growth of the
phallus and scrotum, and the voice change, appear to be mediated by T and
occur in the affected males (10). Importantly, however, prostate growth, facial
hair, temporal recession of the hairline, and acne do not occur all of which
As noted, during their prepubertal period, the individuals affected by this
disorder of androgen metabolism were raised as females. However, they
began to realize they were different from other girls in the village between 7
and 12 years of age, when they did not develop breasts, when their bodies
began to change in a masculine direction and when masses were noted in the
inguinal canal or scrotum. For these subjects, the change to a male-gender
role primarily occurred either during puberty or in the post-pubertal period,
after the subjects became convinced they were men, and thus, began
experiencing sexual interest in women. Of the 18 subjects, 17 had successfully
changed to a male-gender identity and 16 to a male-gender role.
This paper suggests that when the sex of rearing is contrary to the
testosterone-mediated biologic sex, the biology prevails if the normal androgen-
induced activation of puberty is permitted to occur. Eighteen subjects were
unambiguously raised as females, yet despite the female assignment of
rearing, 17 subjects changed to a male-gender identity and 16 to a male-
gender role during or after puberty. Thus, it appears that the extent of
androgen (i.e. testosterone) exposure has far more effect in determining male-
gender identity than does either phenotype at birth, or gender assignment
during prepubertal rearing. It must also be noted that those effected by this
disorder present a complete absence of any signs of AGA.
Botanicals and Anabolic Steroid Usage “A third clue”
Androgens secreted or administered in abnormally large amounts can
cause development of male characteristics in the female and precocious sexual
development in the male. Conversely, hypogonadism of the male (inadequate
testicular function) leads to retarded sexual development and retention of
feminine bodily characteristics (eunuchoidism), which can sometimes be
remedied by administration of androgenic steroids.
Several esters of testosterone are commonly used by injection for this
purpose. Many orally active analogs of testosterone are also available in which
activity is greatly enhanced, and often the ratio of androgenic activity to
anabolic activity is shifted markedly in favor of the latter.
This ratio primarily determines the therapeutic value of these compounds
as anabolic agents. They are used together with growth hormone to promote
growth in children in whom physical development is retarded. They are also
used to promote physical recovery from debilitating diseases. Their reported
use by some athletic competitors in sports has been decried.
It has been anecdotally reported that prostate enlargement and
premature hair loss for males genetically susceptible to baldness can be
ameliorated by the herb Saw Palmetto Berry Extract (60-320 mg per day).
Increased levels of DHT in steroid users have been implicated in the
pathogenesis of these conditions. These reports initially led us to consider the
potential efficacy of this, and other botanicals, in the treatment of androgenetic
Pathophysiology of Benign Prostatic Hyperplasia Causes, incidence, and risk factors:
Benign prostatic hyperplasia (BPH), a non-malignant abnormal
enlargement of the prostate gland, affects almost all men to some degree as
they age and can cause a significant disruption of lifestyle due to urinary
outflow obstructive and irritative symptoms. This disorder shares a remarkable
degree of hormonal processes with AGA. It has also been shown responsive to
drugs and agents used to treat AGA. BPH is characterized by large, discrete
nodules formed in the periurethral region of the prostate. These nodule may
narrow the urethra sufficiently to case full or partial obstruction.
An accumulation of estrogen in the aging prostate, along with increased
conversion of testosterone to its more active metabolite, dihydrotestosterone
(DHT), seems to induce this aberrant hyperplasia. Fatty acid deficiencies, zinc
deficiency, and amino acid deficiencies may also contribute to the disease
The specific etiology of BPH is unknown. However, it has been noted
that eunuchs, (individuals born male who have been castrated), do not develop
this disorder. Furthermore, after castration, benign prostatic hyperplasia has
Since the presence of normal testicular function appears to be
necessary for the development of BPH, it is believed that the hyperplastic
tissue metabolizes the androgenic hormones differently than normal prostate
tissue. Although by definition this tissue is benign, progressive growth of the
tumor may cause significant obstruction of the urethra and interfere with the
The incidence of BPH increases with advancing age. BPH is so
common, that it is believed all men will develop benign prostatic hyperplasia if
they live long enough. Some degree of BPH is present in 80% of all men over
40 years old and this figure increases to 95% of all men 80 years old (figure
Figure 14: Incidence of histological BPH increases as a male ages.
Symptoms:
Less that half of all men with BPH show any symptoms of the disease,
which may include urinary hesitancy, weak urine stream, nocturia, pain on
urination, hematuria, urinary retention, and increased urinary frequency.
Signs and tests:
A digital rectal exam will reveal an enlarged, soft prostate. Urine flow rate
may be measured (men with BPH have a rate less than 10 ml per second).
Post-void residual volume may be measured. An IVP (Intravenous Pyelogram)
may be done to confirm the diagnosis or look for blockage. Urinalysis may be
useful in order to check for blood or infection. Urine should be cultured if signs
of infection are present. Prostatic-specific antigen blood test has also become
part of the diagnostic standard of care. And finally, a cystoscopy should be
done based on significant positive findings with less invasive tests.
Treatment:
The choice of an appropriate treatment is based on the severity of
symptoms, the extent to which they affect lifestyle, and the presence of any
other medical conditions. Treatment options include watchful waiting, various
drug therapies aimed at decreasing the size of the prostate or reducing the
severity of symptoms, and several surgical methods to remove or compress the
Medications: Alpha 1 blockers
Current medical therapy may involve a trial use of alpha 1-blockers (doxazosin,
prazosin, and terazosin), which are also used to treat hypertension. Peripheral
vasodilation is the primary mechanism of action of alpha1-blockers. They
inhibit post-synaptic alpha1-receptors on smooth muscle of veins and arteries.
The alpha1-receptors are also abundant in the smooth muscle of the bladder
neck and prostate. Antagonism of these receptors causes relaxation of the
bladder muscle, which then results in increased urinary flow rates and relief of
These medications may be useful in the treatment of BPH because they
relax the muscles of the bladder neck, allowing easier urination. Of the people
treated with alpha 1-blocker medications, 74 percent reported an improvement
Finasteride
This drug has recently been approved for treatment of BPH. Finasteride
lowers prostate hormone levels, thus reducing the size of the prostate. This
drug has been shown to increase the urine flow rate and decrease the
symptoms of BPH. It may take up to 6 months before one notices a significant
improvement in symptoms. However, potential side effects related to use of
finasteride include decreased sex drive (3.3%) and impotence (2.5 - 3.7%).
Finasteride and BPH
The development of the human benign prostatic hyperplasia clearly
requires a combination of testicular androgens and aging. Although the role of
androgens as the causative factor for human benign prostatic hyperplasia is
debated, they undoubtedly have at least a permissive role. The principal
prostatic androgen is DHT. Although not elevated in human benign prostatic
hyperplasia, DHT levels in the prostate remain at a normal level with aging,
despite a decrease in the plasma testosterone. DHT is generated by reduction
As mentioned earlier, two isoenzymes of 5alpha-reductase have been
discovered. Type 1 is present in most tissues of the body where 5alpha-
reductase is expressed and is the dominant form in sebaceous glands. Type2
5AR is the dominant isoenzyme in genital tissues, including the prostate.
Finasteride is a 5AR inhibitor that has been used for the treatment of BPH. At
doses prescribed clinically, its major effect is through suppression of type 2
5alpha-reductase, as it has been shown to have a much lower affinity for the
type 1 isoenzyme. Finasteride suppresses DHT by about 70% in serum and by
as much as 85-90% in the prostate. The remaining DHT in the prostate is likely
Two large international multicenter phase III trials have been published
documenting the safety and efficacy of finasteride in the treatment of human
benign prostatic hyperplasia (13). Combining these two studies, randomized,
controlled data are available for 12 months. Noncontrolled extension of these
data from a subset of patients, who elected to continue drug treatment for 3, 4
or 5 years, are also available. These studies demonstrate that long-term
medical therapy with finasteride can reduce clinically significant endpoints
such as acute urinary retention or the need for surgery. According to the
meta-analysis of six randomized clinical trials with finasteride, finasteride is
most effective in men with clinically hyperplastic prostates. A more effective
dual inhibitor of type 1 and 2 human 5AR may lower circulating DHT to a
greater extent than finasteride and show advantages in the treatment of human
benign prostatic hyperplasia and other disease states that depend on DHT.
Clinical evaluation of potent dual 5alpha-reductase inhibitors may help define
the relative roles of human type 1 and 2 5alpha-reductase in the
pathophysiology of benign prostatic hyperplasia and other androgen-
Finasteride has recently been reformulated from 5 mg
(Proscar™/indication BPH) to 1 mg dosage (Propecia™/indication AGA) after
it was discovered, quite by accident, that individuals being treated for BPH with
finasteride were showing an abatement of hair loss associated with AGA (14).
Other Medications
Antibiotics may also be prescribed to treat chronic prostatitis, which
commonly accompanies BPH. Some men note symptom relief after a course of
Surgery:
Surgery is usually indicated for men with symptoms of incontinence,
hematuria, urinary retention, and recurrent UTIs. The choice of a specific
surgical procedure is usually based on the severity of symptoms and the size
Surgical treatment options include transurethral resection of the prostate
(TURP), transurethral incision of the prostate (TUIP), and open prostatectomy.
Various studies are underway to evaluate the effectiveness of other treatments,
such as hyperthermia, thermal therapy, prostatic stents, and hormonal therapy.
Conclusions
Several lines of evidence examined in this chapter have converged to
support the view that both circulating testosterone and the modifying enzyme,
5AR, have profound effects on androgen metabolism and provide insight into
the role of these compounds in hair loss. First, the absence of circulating
testosterone (and therefore, DHT) in males castrated prior to puberty has been
shown to prevent AGA in later life, suggesting that this metabolism is key to the
pathogenesis of male pattern hair loss. Secondly, in a group of male
pseudohermaphrodites with inherited defects in the 5AR gene, the inability to
convert circulating testosterone to its active metabolite, DHT, also led to the
preservation of the juvenile hair line. These two examples demonstrate that
whether the disturbance in androgen metabolism results from either the
absence of substrate (T), active metabolite, DHT, or dysfunction of the enzyme
5AR, at least one phenotypic consequence is consistent and reproducible -
terminal hair density as well as juvenile hairlines remain intact in such
In contrast, a third and critical observation was noted in bodybuilders
who were self-administering anabolic steroids that excessive levels of
circulating T and therefore DHT had the opposite effect of the first two
examples – that of acceleration of hair loss due to upregulation of the hormonal
Collectively, these lines of converging evidence pointed to a common
theme among disorders resulting from dysregulation of the conversion of T to
DHT, and led the author to the central hypothesis of this dissertation.
References
1. Wilson JD ; Roehrborn C Long-term consequences of castration in men: lessons from the Skoptzy and the eunuchs of the Chinese and Ottoman courts. J Clin Endocrinol Metab, 84(12):4324-31 1999 2. Tandler, Julius and Siegfried Grosz: "Über den Einfluß der Kastration auf den Organismus. III. Die Eunuchoide", Archiv für Entwicklungsmechanik der Organismen 29 (1910), 290 - 324 3. Mary M. Anderson, Hidden Power: The Palace Eunuchs of Imperial China, (Buffalo NY: Prometheus, 1990), 15-18, 307-11 4. Yi, Uch'ol. "Koryo sidae uihw'an gwan e tachayo" [An examination of the eunuchs in the Koryo Dynasty]. Sahak yon'gu , 1 (1958): 18-45. 5. Li, Zhi'an. "Qiexue yu Yuandai chaozheng" [Keshiq and Yuan court administration]. Zhongguo shi yanjiu, 1990.4 (1990): 111-17. 6. Wittfogel, Karl A. and Feng, Chia-sheng. History of Chinese Society: Liao . Philadelphia: American Philosophical Society, 1949 7. Imperato-McGinley J ; Gautier T ; Peterson RE ; Shackleton C The prevalence of 5 alpha-reductase deficiency in children with ambiguous genitalia in the Dominican Republic. J Urol, 136:867-73 1986 8. Imperato-McGinley J ; Gautier T ; Zirinsky K ; Hom T ; Palomo O ; Stein E ; Vaughan ED ; Markisz JA ; Ramirez de Arellano E ; Kazam E Prostate visualization studies in males homozygous and heterozygous for 5 alpha-reductase deficiency. J Clin Endocrinol Metab, 75:1022-6 1992
9. Imperato-McGinley J ; Shackleton C ; Orlic S ; Stoner E C19 and C21 5 beta/5 alpha metabolite ratios in subjects treated with the 5 alpha-reductase inhibitor: comparison of male pseudohermaphrodites with inherited 5 alpha-reductase deficiency. J Clin Endocrinol Metab, 70:777-82 1990 10. Imperato-McGinley J ; Gautier T ; Peterson RE ; Shackleton C The prevalence of 5 alpha-reductase deficiency in children with ambiguous genitalia in the Dominican Republic. J Urol, 136:867-73 1986 11. Herdt GH ; Davidson J The Sambia "turnim-man": sociocultural and clinical aspects of gender formation in male pseudohermaphrodites with 5-alpha-reductase deficiency in Papua New Guinea. Arch Sex Behav, 17:33-56 1988 12. Janknegt RA ; Chapple CR Efficacy and safety of the alpha-1 blocker doxazosin in the treatment of benign prostatic hyperplasia. Analysis of 5 studies. Doxazosin Study Groups. Eur Urol, 24:319-26 1993 13. Kaplan SA ; Olsson CA Patient satisfaction with finasteride in the treatment of symptomatic benign prostatic hyperplasia. Clin Ther, 18:73-83 1996 14. Kaufman KD Finasteride, 1 mg (Propecia), is the optimal dose for the treatment of men with male pattern hair loss [letter; comment] Arch Dermatol, 135:989-90 1999
Max-Planck-Institut Ökonomik Universitäten und regionales Wirtschaftswachstum Group Entrepreneurship, Growth and Public Policy Universitäten und regionales Wirtschaftswachstum Eine stille und praktisch unbemerkte Veränderung hat die Wirtschaftspolitik ergriffen. Wäh-rend sich die Sicherung von Wirtschaftswachstum und die Schaffung von Arbeitsplätzen bis-her auf fiskalische
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