Male
Pseudohermaphroditism
With
Partial
Androgen
Insensitivity
Bruce S. Keenan, M.D., John L. Kirkland, M.D., Rebecca T. Kirkland, M.D., and George W. Clayton, M.D.
From the Department of Pediatrics, Division of Endocrinology, Baylor College of Medicine, Houston,
Texas
ABSTRACT. Androgen insensitivity was demonstrated in
two male siblings with partial masculinization of the external genitalia. They had a previously undescribed defect
charac-terized postpubertally by high plasma testosterone and
hiteinizing hormone concentrations with low serum follicle-stimulating hormone levels. Studies in skin fibroblasts showed normal androgen receptor affinity and capacity for
5a-dihydrotestosterone (DHT), normal nuclear retention of the receptor-DHT complex, and normal conversion of
testos-terone to DHT. Pediatrics, 59:224-231, 1977, MALE
PSEUDO-HERMAPHRODITISM, ANDROGEN INSENSITIVITY, ANDROGEN
RECEPTOR, 5a-REDUCTA5E.
demonstrated a deficiency in the cytoplasmic
5a-dihydrotestosterone (DHT) receptor protein as
the probable reason for the inability of the patient
to respond to androgens. In this communication
a familial form of male pseudohermaphroditism is
described in which androgen insensitivity was
demonstrated. Studies of testosterone and DHT
metabolism in skin fibroblasts indicated that the
androgen insensitivity was a type different from
that previously described.
MATERIALS
Androgenic steroids have been shown to play a
central role in male sexual differentiation.’
According to the model developed by Jost,
incom-plete masculinization of the external genitalia
could result from disorders of androgen
produc-tion or from decreased responsiveness to
androgens.2 The former has been exemplified by
specific enzymatic defects in steroid
biosynthe-SIS.i5 Studies of the metabolic effects of
androgens in the syndrome of testicular
feminiza-tion provided the first biochemical evidence for
androgen insensitivity in man.”
Recent studies in cultured skin fibroblasts of
certain patients with androgen insensitivity have
DHT, testosterone, 5a-androstane
3a-ol-17-one (androsterone), and androst-4-ene-3, 17-dione
were obtained from Sigma, St. Louis;
5a-andro-stane-3, 17-dione (5a-androstane-dione) was
ob-tamed from Steraloids; 1,2,4,5,6,7-3H-DHT (165
to 175 curies/mmol) was obtained from
Amer-sham-Searle; 1,2,6,7-3H-testosterone and
4-’C-DHT were obtained from New England Nuclear.
(Received January 26; revision accepted for publication April 8, 1976.)
Supported in part by Public Health Service Traineeship
Grant AM5432-10 and by grant ACS INS-27N from the American Cancer Society.
ADDRESS FOR RREPRINTS: (B.S.K.) Department of
Pedi-atrics, Baylor College of Medicine, 1200 Moursund, Houston,
Solvents for extraction and chromatography were
obtained from Matheson, Coleman, and Bell.
Thin-layer chromatography plates, 20 X 20 cm,
were obtained from E. Merck, chromatography
paper from Whatman, and Florisil from
Flori-dan.
Rabbit antisera to human luteinizing hormone
(LH) and follicle-stimulating hormone (FSH)
were obtained from the National Institutes of
Health, as were the assay standard (LER 907) and
the primary iodination standards. Antiserum to
testosterone-3-oxime-albumin conjugate was
ob-tamed from Dr. Avinoam Kowarski at the Johns
Hopkins Hospital.
Tissue culture vessels were obtained from Lux
and tissue culture media, antibiotics, and buffers
were obtained from Grand Island Biological.
METHODS
Metabolic Studies
The patients were hospitalized on a metabolic
ward. A diet constant in daily intake of nitrogen
and phosphorus was given during a balance
period of four to five days. Foods of known
composition were weighed and the nitrogen and phosphorous content estimated from the portions ingested. While continuing the same diet during
the ensuing five or six days, testosterone
propionate was given intramuscularly in a dose of
25 or 100 mg daily. Twenty-four-hour urine
collections were obtained for the measurement of
nitrogen and phosphorous excretion. Ingested
nitrogen and phosphorous were within 1% of the
mean each day of the study.
. Clinical Studies
FSH and LH were measured by the method of
Midgley. Testosterone was measured by the
method of Tremblay et al.,’ using a specific
antibody in place of testosterone binding
globu-lin. Estrone (E,) and estradiol-17$ were measured
by the method of Wu and u’
. In addition, 17-ketosteroids were measured by
the method of Callow et al.12;
17-hydroxycorti-coids were measured by the method of Glenn and
Nelson.’ Nitrogen was measured by the method
of Minari and ‘ Inorganic phosphate
was measured by the method of Fiske and
Subba-row.’ Creatinine was measured on a Technicon
auto-analyzer.
Bone age was estimated by the method of
Gruelich and Pyle.uui
Fibroblast Studies
Fibroblasts were grown in serial subculture
from skin explants obtained either by punch
biopsy or at the time of a surgical procedure.
Minimum essential medium (MEM) containing
10% fetal calf serum, penicillin (50tg/ml),
strep-tomycin (50 U/mi), and kanamycin (50tg/ml)
was used. For some studies, fibroblasts which had
been kept frozen under liquid nitrogen in MEM
with 8% dimethyl sulfoxide were used aftec
thawing and reestablishing growth. Cultures were
maintained at 37C in an atmosphere of 10%
carbon dioxide and 90% air.
Informed consent was obtained from the
patient or parents for all of the above studies.
5a-Reductase Assay-Monolayer cultures in
150
x
15-mm Petri dishes were washed withHank’s Balanced Salt Solution to remove dead
cells and tissue culture medium. Then 10 ml of
MEM without fetal calf serum, containing
65
x
10-s M 1,2,6,7-3H-testosterone were addedand incubation carried out at 37C in 10% carbon
dioxide and 90% air. At the end of the incubation
period the medium was aspirated and saved while
the cells were analyzed for DNA content.
After adding ‘C-DHT fo,r recovery, the
medium was extracted once with 25 volumes of
dichlormethane. The extract was dried and
chro-matographed on silica gel thin-layer plates using a
chloroform to ether ratio of 160:40 (v/v). Areas
corresponding to DHT and androsterone and
5a-androstanedione were eluted and counted in a
liquid scintillation counter. In a few experiments
DHT was separated from androsterone by paper
chromatography using a hexane to methanol to
water ratio of 100:90: 10; androstenedione was
further purified by acetylation and
rechromatog-raphy in the same thin-layer system; and
testoste-rone was separated from 5a-androstanediols by
paper chromatography using a heptane to
benzene to methanol to water ratio of 33:66:80:20
(
no 5$-reduced compounds have been isolatedfrom fibroblasts incubations with testosterone).
The counts of each compound were corrected for
recovery of ‘4C-DHT and total expressed as
picomols of 5a-reduced product generated per
hour per microgram of DNA, i.e., the sum of
5a-DHT, androsterone, and
5a-androstane-3,17-dione. The amount of 5a-androstanediol
forma-tion was uniformly less than 5% of total
5a-reduced products and therefore was not included
in the measurement.
Androgen Receptor Assay-We used a
modifi-cation of the one previously reported.’ In this
instance, incubations were carried out in
150
x
15-mm Petri dishes in MEM without fetalcalf serum, containing various concentrations of
carbon dioxide and 90% air. At the end of the
incubation the plates were transferred to a 4C
room on a bed of ice. The media were aspirated
and saved. The cells were washed with ice-cold
buffer containing 20 mM of tris HC1; 1 mM of
magnesium sulfate and 0.32 M of sucrose, pH 7.5.
The remainder of the assay is as previously
described. The cells were transferred in
tris-sucrose into disposable glass test tubes,
centri-fuged, aspirated, resuspended in 20 mM of tris
HC1, 1.5 mM of EDTA, 0.5 M of potassium
chloride, pH 7.5, sonicated and centrifuged at
2, 100 g for 20 minutes. The supernate was
analyzed for bound radioactivity (using Sephadex
G25 to separate bound from free) and DNA
content.’8 Bound radioactivity was expressed as
mols
x
10 to 18/ng of DNA. Nonspecific bindingwas estimated from incubations in which a
250-fold excess of unlabeled DHT was included in the
medium containing H-DHT. This was
sub-stracted to give an estimate of specific binding at
each point on the saturation curve. Double
recip-rocal plots of 1 /bound radioactivity versus
1/:IH.DHT concentration in the medium were
made to determine the dissociation constant and
binding capacity of the receptor.
CASE REPORTS Case 1
The propositus (TCH No. 343-727) was born after an
uncomplicated pregnancy, labor, and delivery. Birthweight was 2,495 gm. When first seen, a female gender assignmnent was made because of perineal hyospadias, a urogenital sinus,
and a small phallus. At age 6 weeks, however, he was
reassigned as a male.
Between the ages of 3 and 13 years, four surgical
procedures were performed to correct his genital defect and
the associated cryptorchidism. The testes were examined on
one occasion and appeared grossly normal.
He was first seen at Texas Children’s Hospital at age 11. He was at that time prepubertal. By age 13, pubic hair and gynecomnastia were present. At that time a bilateral mastec-tomy was performed. At age 17 the gynecomastia recurred
and was reoperated upon. Although the distribution of pubic and axillary hair was thought to be normal at that time, his
voice had not deepened and no facial hair was present. There
was no increase in height after age 13. At age 18 a
four-month course of testosterone enanthate, 200 mg intranmscu-larly monthly, was given. No change in his secondary sexual characteristics was noted.
Admission 1-At the time of his first admission to the Clinical Research Center (CRC) he was 20 years 7 months of age. His height was 170 cm. Blood pressure was 124/76. His appearance was younger than his chronological age, partly because of the lack of temporal recession of the hairline. Skeletal and muscular proportions were masculine. The ratio
of the upper to lower body segments was 1.05. There was
minimal facial hair-shaving was done very infrequently.
There was no acne and pubic hair in a female distribution
and axillary hair were present. Both testes were in the
scrotum; the left testis measured 5.0 x 2.3 cm and the right
5.5
x
2.3 cm. Erect penile length was 1 1.5 cm. The peniswas moderately scarred but the glans and corpora were
adequate and the urethra ended just proximal to the glans. Apart from these findings and small periareolar masectomy scars, the physical examination was normal.
Initial laboratory data including hemoglobin concentra-tion, hematocrit, WBC, urinalysis, blood urea nitrogen, and serum concentrations of calcium, phosphorus, alkaline phos-phatase, sodium, potassium, chloride, and bicarbonate were all normal. Urinary 17-hydroxycorticosteroid excretion was 7.9 mg/24 hr and 17-ketosteroid excretion 17.0 mg/24 hr. Skin fibroblast karyotype was 46 XY (23 cells counted), as was that of the leukocytes.
Admission 2-At age 23, he was readmitted to the CRC for studies before and during the administration of testosterone
propionate, 100 mg/day intramuscularly (see below). His
physical examination at that time was unchanged.
Admission 3.-At age 24, he was readmitted for studies of fertility. He had been married and wished to know about the possibility of having children. Performance during inter-course was said by him to be adequate, although delayed delivery of the ejaculate to the meatus was described.
A seminal fluid specimen was obtained after four days of abstinence. Less than 1 cc of mucoid fluid containing no spermatozoa was obtained. A mo&rate number of neutro-phils was seen. Biopsy of both testes showed thickened tubular basement membranes. Sertoli cells comprised the majority of the tubular cells; few spermatogenic elements
were present. Leydig cells appeared to be normal. A
cinecystogram and retrograde urethrogram showed a small urethral diverticulum near the base of the penile shaft. Cystoscopy revealed a female urethral configuration. The lateral indentation of the prostatic lobes and the veru
montanum, normally seen even in prepubertal boys, were
absent. The father was 185 cm tall and the mother 162 cm. Each was in good health, without abnormalities. A younger brother had a similar defect in sexual differentiation. Another brother at age 19 years was 180 cm tall and had
normal sexual development. There was no known
consan-guinity.
Case 2
The second patient, TCH No. 421-779, a younger brother of the propositus, was first seen at the age of 1 day for evaluation of ambiguous external genitalia. Birthweight was 2,910 gm. The perinatal period was uneventful.
It was the decision of the parents to raise him as a male, primarily because of the fact that his affected older sibling was raised in that manner. Abnormal findings were limited to the external genitalia. The scrotum was bifid. Perineal hypospadias was present with chordee.
Laboratory data at that time included normal serum
concentrations of electrolytes and a buccal smear which was chromatin-negative. Urinary 17-ketosteroid excretion was 0.79 mg/24 hr on the third day of life.
At age 6 months, he was admitted to another hospital where a retrograde urethrogram was done. No vaginal pouch was seen. Exploration of the inguinal canals revealed two normal-appearing testes. No female internal organs were
noted.
Between the ages of 5 and 1 1 years he had three operative procedures to correct hypospadias.
When admitted to the CRC, he was 1 1 years 7 months old.
Height was 132 cm, weight was 27.3 kg, and blood pressure was 90/60. Abnormal findings were limited to the external genitalia. The left testis was high in the inguinal canal while
TABLE II
urethra and was moderately deformed. It measured 3 cm in length. He appeared to be prepubertal.
Admission laboratory data including hemoglobin
con-centration, hematocrit, blood urea nitrogen, urinalysis, serum concentrations of sodium, potassium, chloride, bicar-bonate, calcium, and phosphorus were all normal. Bone age was that of a 9-year-old and skull X-ray films were normal. Karyotype from peripheral leukocytes was 46 XY. Urinary 17-hydroxycorticosteroids were 1.0 mg/24 hr and 17-ketoste-roids were 1.33 mg/24 hr.
At age 12 he was hospitalized for further studies. At that time he was 136 cm tall and weighed 28 kg. His testes had
enlarged, the right measuring 3.0 X 1.5 cm and the left
2.5
x
1.5 cm. The scrotum was rugated and slightlypigmented. No pubic, axillary, or facial hair was present. His voice had not changed.
RESULTS. Clinical Studies
Patient l’s adolescent growth pattern was of
interest with a growth spurt of two years’
dura-tion and a growth arrest at age 13. His final height
was closer to his mother’s, while his father and
unaffected brother were
tall.
Virilization atpuberty was slow. and incomplete.
At age 24, facial hair, scalp hair, and voice were
prepubertal and sexual hair distribution was
female. Patient 2 at age 12 was still prepubertal in
appearance except for slight testicular
enlarge-ment and scrotal rugation. He showed slightly
delayed osseous maturation.
Table I shows the results of hormonal studies.
Plasma testosterone concentration in patient 1
TABLE I
CLINICAL STUDIES IN Two BROTHERS WITH PARTIAL
ANDROGEN IN5EN5ITIvrry
Clinical Data Patient Patient 2 Normal
1 ,.-_-__, Adult
Study Study Males#{176}
I 2
Age (yr) 23 11 12
LH (ng/ml, LER 907) 64.7t 17.7t - 32.8 ± 9.1
FSH (ng/ml, LER 907) lOOt 187t - 213 ± 59
Testosterone (ng/dl) 2,324 106 176 588 ± 288
Estrone (ng/dl) 23.9 - 6.8 < 5
Estradiol (ng/dl) 15.4 - < 2.3 < 5
#{176}Mean± 2 SD.
tMean of four separate determinations.
:1:
Mean of two separate determinations.was 6 SD above the mean for adult males. Despite
this, serum LH concentration was approximately
2 SD above the mean for adult males in our
laboratory and in others using a similar
meth-od.1920 Serum FSH was abnormally low, while
estrone and estradiol concentrations were in the
adult female range. The same relative
concentra-tions of LII and FSH were seen on two occasions,
one year apart.
Patient 2, on the other hand, had a plasma
testosterone concentration compatible with
mid-adolescence,21 despite his prepubertal
ap-EFFECT OF TESTOSTERONE PROPIONATE ON NITROGEN AND PHOSPHATE EXCRETION
Days Patient 1
Urinary Nitrogen
(gin/24 hr)
Patie nt 2
Urinary Nitrogen Urinary Phosphate
-gm/24 hr gm/gm of
Creatinine
,-mg/24 hr mg/gin of
Creatinine
Control Period
1 13.0 8.42 16.9 625.6 1,256
2 15.4 8.39 14.5 652.5 1,131
3 13.2 3.97 12.4 405.8 1,264
4 15.3 4.51 18.1 396.9 #{149} 1,594
5 - 5.58 15.2 468.4 1,276
Mean ± SEM 14.2 ± 0.7 6.17 ± 1.0 15.4 ± 2.3 509.8 ± 54 1,304 ± 7.7
1 15.0
Testosterone Propionate
7.01 15.9 540.0 1,224
2 11.9 5.68 14.0 495.2 1,220
3 14.5 7.31 16.0 603.2 1,323
4 14.3 2.38 14.7 460.0 2,840
LH
Control
FSH
Testosterone
:::::::::::::::::::::::::::::
,yean
. .-........ .- ....... ...r .#{149}
x,e,,’
...‘
.‘. . ... . . ... . . .. . . . ... . . ....... .v .‘.. . ‘ . ‘ .. . . ....‘ . . . . ... . ..
. I. ..
. . . . .v . . #{149}.. ‘ . ‘ . .‘ ... . . ... ... . . . .%. . . . ... . . ... . . . ... ___‘“_&_&_
120
110
100
90
Fig. 1.Effect of testosterone propionate administration on serum LH and FSH concentrations. Shaded area, norm ± SD for adult males; open circles, 25 mg/day in patient 1;closedcircles, 100 mg/day in patient 1; dashedlines, 25 mg/day in patient 2.
r’..
w
-J
E
0’ C
200
180
160
140
120
100
80
60
40
20
Control
123456789
DAYS
123456789
DAYS
‘;
‘:
pearance. LH and FSH concentrations were also
compatible with early to mid-adolescence.”
Testosterone Propionate Administration
Urinary excretion of nitrogen and phosphate
was studied during a control period and during
daily intramuscular administration of testosterone
propionate. Neither patient had a urinary
nitrogen response (Table II). In patient 1, plasma
testosterone increased from 2,324 ng/dl to 3,123
ng/dl, while in patient 2 it rose from 198 ng/dl to
2,234 ng/dl.
Serum concentrations of LH and FSH were
measured during the same study periods. As
shown in Figure 1, testosterone propionate (25
mg/day) did not cause a significant change in LH
for patient 1. The LH values in patient 2 were too
low to interpret. FSH concentration was in the
prepubertal range for patient 1 and decreased
during testosterone administration. FSH
suppres-sion was also seen in patient 2.
A large dose of testosterone propionate, 100
mg/day for five days, was given to patient 1
during a second study period. Although FSH
concentration decreased, LH was not
signifi-cantly different after five doses (Fig. 1). Plasma
testosterone concentration increased from 2,290
ng/dl to 5,934 ng/dl during this period.
Androgen Metabolism in Skin Fibroblasts
Incubation of cultured fibroblasts of inguinal
skin of patient 1 with 1,2,6,71Htestosterone at
1.5 nM resulted in 50. 1% conversion to ‘H-DHT
in 20 minutes. Other metabolites measured
included androstenedione, 0. 1%, and
androste-rone, 0.2%. The remainder was testosterone. The
activity of 5a-reductase, measured at 65 nM Of
testosterone, was high when compared to foreskin
fibroblasts (Table III). A normal inguinal skin
fibroblast incubation had an activity of 5.88
pm/gig of DNA/hr.
Androgen receptor activity was also studied in
these fibroblasts. The dissociation constant and
binding capacity of this receptor for :IH..DHT
were within the range observed for normal
foreskin fibroblasts (Table III) and for cells of
other origins.’ Each observation noted in Table
III represented a saturation analysis using six to
eight monolayer cultures. Several different
TABLE III
ANDROCEN RECEPTOR FUNCTION IN SKIN FIBROBLASTS
Study Patient 1 Controls
Mean Range No. of
Observations
5a-reductase (pmol/hr/ig of DNA) 17.5 5.62 3.75 to 7.80 6
Androgen-receptor whole
Kd (M x 10”) 0.93t 0.78 0.33 to 1.50
.
9
Bmax (m X 10 “/g of DNA) 294t 768 173 to 2,583 9
Nuclear retention of androgen receptor
(m X 10”/sg of DNA)
66 (17 to 97) 94 29 to 105 5
#{176}Normative data primarily abstracted from previous report; data include foreskin fibroblasts. Kd dissociation constant; Bmax = total capacity of the receptor system.
t
Mean of two determinations.:1:
Range of five observations.this work. As has been reported elsewhere,’ no
trend with serial subcultures was observed.
Nuclear retention of the DHT-receptor
com-plex was measured following incubations with 1.5
nM of 3H-DHT. The mean value and range
observed for five separate series of experiments
with the patient’s cells was similar to that
observed in foreskin fibroblasts (Table III).
DISCUSSION
Defects in the differentiation of the male
external genitalia and the later expression of
secondary sexual characteristics may be classified
in respect to the production and action of
testic-ular androgens. Heritable disorders characterized
by absence of a specific enzymatic step in the
biosynthesis of testosteone associated with male
pseudohermaphroditism have been well
de-scribed.’5 More recently, classification of
disor-ders of the peripheral action of androgens, long
known to be a cause of male
pseudohermaphro-ditism,6 7has begun. Thus, a familial defect in
Sa-reductase, believed to be the first step in
testoste-rone action, has been described by Walsh et al.22
and Imperato-McGinley et al.23 Deficiency of the
cytosol receptor for 5a-DHT has been shown to
be associated with some instances of complete
androgen insensitivity or testicular feminization
l7 while other patients, clinically
indis-tinguishable, have normal cytosol and nuclear
binding of 5a-DHT.2
The affected siblings in this family had male
pseudohermaphroditism with partial
masculini-zation of the external genitalia and no gross
evidence of Mullerian structures or a vagina.
Marked gynecomastia, requiring two surgical
procedures, was present in patient 1. At puberty
further development of the penis occurred, but
the
eventual size was abnormally small. Theprostate was not detectable and complete
matu-rational arrest of spermatogenesis and a female
urethral configuration were demonstrated. The
voice remained high-pitched, shaving was
infre-quent, and acne never developed by age 24.
These
findings in the presence of an abnormallyhigh plasma testosterone concentration in the
adult patient 1 suggested partial androgen
insen-sitivity as the cause. This was further supported
by the failure of high doses of testosterone
propionate to depress serum LH or change
urinary nitrogen and phosphorus excretion. Lee et
20
have
shown that doses of testosterone as lowas 12.5 mg/day will cause approximately a 50%
drop in serum LH concentration in normal males
within four to five days. Significant decreases in
nitrogen and phosphorus excretion have been
shown to occur on such doses during this period in
normal adult males.25 Our data indicated a
signif-icant rise in plasma testosterone during each
study. Variations in urinary nitrogen excretion
even under carefully controlled balance
condi-tions make precise quantitation of responsiveness
to androgens impossible. The data in these
patients can, however, be taken to indicate a
degree of androgen resistance.
A large pedigree with similar physical findings
and LH, FSH, and testosterone concentrations
has
recently been described by Wilson et al.26; theinheritance pattern was compatible with an
X-linked recessive trait. Although Wilson et al.
5a-reductase deficiency, other studies regarding the
peripheral action of testosterone were not carried
out, and the nature of their defect(s) remains
unknown.
Several
additional
findings in these patientsmay be explained by an abnormally high plasma
estradiol concentration. These include
gyneco-mastia, the low serum FSH concentration, and
the early cessation of growth observed in patient
4. Further suppression of FSH by testosterone
propionate administration may also be explained
by conversion to estradiol.
Early steps in the mechanism of action of
testosterone are believed to include conversion of
testosterone to 5a-DHT by 5a-reductase, binding
of DHT to a receptor protein, and the retention of
the DHT-receptor complex by nuclear
chroma-tin. Production of messenger RNA and/or cell
proliferation are believed to follow this initial
sequence.
Thus, the fibroblasts from patient 1 were
studied with respect to these early steps. The
activity of 5a-reductase was above that measured
in foreskin fibroblasts. The affinity of the receptor
for DHT as indicated by the dissociation constant
was in the range observed in normals. Androgen
insensitivity in these patients clearly was not due
to 5a-reductase deficiency or altered affinity of
the androgen receptor for DHT.
The total capacity of the receptor system in
this syndrome was in the lower part of the range
observed for normals. However, the amount of
DHT-receptor complex retained by the nuclei
was close to the mean value observed in normals.
The range of normal for total number of receptor
sites is so wide as to make it difficult to determine
whether a value in the lower range, as seen in
patient 1, represents a partial deficiency. The
work of Meyer et a!. suggested that much of
variability observed is due to clonal variation.27
Nevertheless, it would be expected that a
signifi-cant reduction in total receptor activity would be
reflected in a corresponding reduction in nuclear
retention of the steroid-receptor complex. Such a
reduction was not observed in this case.
IMPLICATIONS
Two findings seemed to separate this group of
patients from others reported. First, although
these patients showed evidence of androgen
insensitivity in several respects, the skin fibroblast
studies indicated that the early steps in
testoste-rone action within the cell were intact. Secondly,
the serum FSH concentration was abnormally
low while LH and testosterone were elevated. In
patients with complete testicular feminization
LH concentration has been elevated and FSH
normal or elevated.2829 As more is elucidated
about the effects of androgens in fibroblasts and
their underlying mechanisms, the biochemical
defect in this syndrome may be elucidated.
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ACKNOWLEDGMENTS
We wish to express our special thanks to Ms. Elaine Potts for her assistance in the dietary aspects of the metabolic balance studies.
We are indebted to Dr. Avinoam Kowarski, Department of Pediatrics, Johns Hopkins Hospital, for computer pro-grams used for radioimmunoassay and double isotope calcu-lations.
Plasma estrogen determinations were carried out in the laboratory of Paige K. Besch, Ph.D., Department of
Obstet-rics and Gynecology, Baylor College of Medicine.
DYING
Traditionally the person best protected from death was the one whom
society had condemned to die. Society felt threatened that the man on Death
Row might use his tie to hang himself. Authority might be challenged if he took
his life before the appointed hour. Today, the man best protected against
setting the stage for his own dying is the sick person in critical condition.
Society, acting through the medical system, decides when and after what
indignities and mutilations he shall die.
I. ILLICH
(Medical Nemesis, 1975)
