The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 576-578
Copyright © 1997 by The Endocrine Society
Cross Genotype Sex Hormone Treatment in Two Cases of Hypogonadal Osteoporosis
Iris Vered,
Igor Kaiserman,
Ben-Ami Sela and
Joseph Sack
Pediatric Endocrinology Unit, Institute of Endocrinology, Chaim
Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine,
Tel-Aviv University, Tel-Aviv, Israel
Address correspondence and reprint requests to: Professor Joseph Sack, Department of Pediatrics, Sheba Medical Center, Tel-Hashomer, 52621 Israel. Email: Igork@cc.huji.ac.il
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Abstract
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Background: Sex hormone deficiency is the most common cause of bone
loss. Reduced bone mass and an increased risk for osteoporotic
fractures have been described in hypogonadal subjects of both sexes. We
present here the results of treating two patients showing abnormal
sexual differentiation (an XX male and an XY female), who suffered from
bone loss related to sex hormone deficiency, with cross genotype sex
hormones.
Subjects and Methods: Patient 1 was an asymptomatic 39-yr-old XY female
with complete androgen insensitivity. Her testes had been removed, and
she later discontinued estrogen treatment. Patient 2, a 37-yr-old XX
male, had congenital adrenal hyperplasia, which led to a masculine
phenotype. He was ovariectomized and reared as a male. He was treated
with glucocorticoids but refused androgen treatment for many years. We
treated both patients with phenotypically matched sex hormones (patient
1 received conjugated estrogens 1.25 mg/day, and patient 2 received 250
mg testosterone every 4 weeks) and followed their bone mineral density
(BMD) using dual-energy X-ray absorptiometry, urine calcium, and
hydroxyproline excretion.
Results: Before treatment both patients had low sex hormones and highly
elevated gonadotropins. As a result of treatment urine hydroxyproline
excretion decreased from 45 and 26.7 mg/g creatinine to 15 and 15.9
mg/g creatinine in patients 1 and 2 respectively. In patient 1, lumbar
BMD rose from 0.912gr/cm2 to 0.976gr/cm2 and
femoral neck BMD rose from 0.716gr/cm2 to
0.836gr/cm2 after 4 years of treatment. In patient 2,
lumbar BMD rose from 0.717gr/cm2 to 0.815gr/cm2
and the femoral neck BMD rose from 0.509gr/cm2 to
0.635gr/cm2 after 27 months of treatment.
Conclusions: Phenotypically-matched sex hormone therapy in patients
with abnormal sexual differentiation is essential not only to maintain
external appearance but also for the preservation of bone mass.
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Introduction
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SEX HORMONE deficiency is the most common cause
of bone loss. Reduced bone mass and an increased risk of osteoporotic
fractures have been described in hypogonadal subjects of both sexes in
various age groups (1). Replacement of sex hormones is the treatment of
choice for hypogonadal osteoporosis, and its role in prevention of
osteoporosis has been well established (1). For obvious reasons,
hormone replacement treatment for osteoporosis in humans is usually
based on the use of sex-matched sex hormones. Thus, limited information
exists regarding the effects of cross-genotype sex hormones on human
bone.
Estrogens and androgens bind to specific nuclear receptors in the bone
cells of both sexes (2, 3). Estrogen and testosterone elicit similar
biologic responses both in cultured bone cells and in castrated animals
of both sexes. Testosterone is converted into dihydro-testosterone and
estradiol in bone (4), but the specific impact of each steroid hormone
on male or female bone is unknown.
Patients with cross-genotype sex assignment resulting from abnormal
sexual development are natural models to study the sex-specific
response of the skeleton to hormones. We had the opportunity to follow
up two patients with abnormal sexual differentiation, an XY female and
an XX male, in whom bone loss related to sex hormone deficiency was
diagnosed. We present here the clinical and laboratory data on these
patients and their responses to cross-genotype sex hormone
administration.
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Subjects and Methods
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Patient 1
Patient 1 was an asymptomatic 39-yr-old XY female,
self-referred, who was concerned about osteoporosis. Complete androgen
insensitivity had been diagnosed at age 17, when she was investigated
for primary amenorrhea. The abdominal testes were removed at age 32,
and estrogen treatment was initiated but then discontinued by the
patient after 4 months. She was a heavy smoker, and her calcium intake
was estimated at 1200 mg/day. After initial evaluation, conjugated
estrogens were prescribed (1.25 mg/day), and we followed her up for 4
yr.
Patient 2
Patient 2 was a 37-yr-old XX male, referred for evaluation of
his bone density. Congenital adrenal hyperplasia (11ß hydroxylase
deficiency) had been diagnosed at the age of 1 yr, following the onset
of pseudoprecocious puberty. He was ovariectomized and reared as a
male, but was not given glucocorticoids. At age 10 he suffered a
hypertensive crisis. At that time he was 139 cm tall, fully virilized,
hyperpigmented, with bone age over 18 yr. XX karyotype and 11
ß-hydroxylase deficiency were documented. Since then, he has been
treated with glucocorticoids, thiazide diuretics and ß-blockers.
Androgen treatment was suggested many times but refused. The patient
was a nonsmoker, and his dietary calcium intake was estimated at 500
mg/day. After initial evaluation he was given testosterone-depot
injections, 250 mg every 4 weeks, and 600 mg/day calcium supplement. He
was followed up for 27 months.
During the follow-up of these patients, serum FSH, LH, 17ß-Estradiol,
DHEAS, TSH, and T4 were measured using RIA kits (DPC, LA
Ca). Urinary hydroxyproline was measured by a refinement of a specific
assay (5), and bone mineral density was measured using dual energy
X-ray absortiometry (DXA) (LUNAR, Madison, WI). The in vivo
precision in our laboratory is 1% for L2-L4 BMD, and 1.8% for femoral
neck BMD.
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Results
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Patient 1
Patient 1 was 181 cm tall, a slender female, weighing 67 kg, with
well-developed breasts, scanty pubic and axilary hair, and normal
external genitalia.
Her initial laboratory tests revealed normal kidney and liver
functions, normal blood count, and normal levels of serum calcium,
phosphorus, alkaline phosphatase, PTH, and thyroid hormones. Serum
gonadotropins were elevated (FSH 40 IU/L, LH 46 IU/L), while 17-ß
estradiol (<20 pg/mL) and testosterone (0.1 ng/mL) were below the
normal range. DHEAS was mildly elevated (3.6 µg/mL, normal <3).
Table 1
presents the decrease in urine calcium and
hydroxyproline with estrogen therapy. Bone density in the lumbar spine
and proximal femur was originally lower than expected for a female of
that age. Fig. 1 presents the bone mineral density (BMD) at
1 yr intervals up to 4 yr after the estrogen treatment was started. As
can be seen, the lumbar spine density rose from 0.912
gr/cm2 (81% of young normal mean) to 0.976
gr/cm2 (84%) and the femoral neck bone density rose from
0.716 gr/cm2 (78% of young normal mean) to 0.836
gr/cm2 (85%).
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Figure 1. The bone mineral density of patient 1 during
4 yr of treatment with estrogen.  , lumbar spine L2-L4; •, femoral
neck.
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Patient 2
Patient 2 was a 137 cm tall male, weighing 67 kg, with little
facial hair, feminine hair distribution, small penis, and empty
scrotum. His initial laboratory tests revealed normal kidney and liver
functions, normal blood count, and normal levels of serum calcium,
phosphorus, alkaline phosphatase, PTH, and thyroid hormones. The
gonadotropins were high (FSH 40.4 IU/L, LH 27.7 IU/L), 17-ß estradiol
(<20 pg/mL), testosterone (<0.1 ng/mL) and DHEAS (<0.05 pg/mL) were
very low. Compound S was adequately suppressed (0.1 µg/L). Table 1
presents the changes in urine calcium and hydroxyproline with
testosterone therapy. Bone mineral density at the lumbar spine and
proximal femur was markedly decreased at baseline and increased at both
sites during the 27 months of therapy. Fig. 2 presents the
bone mineral density up to 27 months after the initiation of
testosterone treatment. As can be seen, the lumbar spine density rose
from 0.717 gr/cm2 (58% of young male normal mean) to 0.815
gr/cm2 (66%), and the femoral neck bone density rose from
0.509gr/cm2 (51% of young male normal mean) to 0.635
gr/cm2 (59%).
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Figure 2. The bone mineral density of patient 2
during 27 months of treatment with testosterone. , lumbar spine
L2-L4; •, femoral neck.
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Discussion
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The aim of this study was to learn about the effects of
cross-genotype sex hormone treatment in human subjects. Both estrogens
and androgens elicit similar biological responses in bone cells and in
animal models (2, 3, 4). Both affect bone cell proliferation and alkaline
phosphatase production (6, 7), increase type I collagen mRNA (6),
decrease PTH-stimulated PGE2 production (8, 9), decrease
cAMP production (6, 10), increase mRNA for TGF-ß (11, 12), and
inhibit the increase in bone turnover and the resultant bone loss in
castrated male rats (13).
In human subjects, the anabolic steroid nandrolone seems to increase
bone mass in osteoporotic post-menopausal women (14), and in one
case-controlled study there was a lower, albeit nonsignificant, risk
for hip fracture in post-menopausal women taking anabolic steroids
(15). Bone mass was maintained in young women treated with danazol for
endometriosis despite a low-estrogen state (16), and male to female
transsexuals treated with estrogens and antiandrogens showed suppressed
bone turnover and normal bone mass compared with age-matched healthy
males (17).
We present here two cases of cross-genotype sex assignment who
were not treated with sex hormones following gonadectomy. Both showed
accelerated bone resorption and compromised bone density. The first
patient, a genetic male with feminine phenotype resulting from lack of
testosterone receptor activity, responded well to estrogen with a
resultant increase in bone density. Thus, we might assume she had
active estrogen receptors. The importance of the estrogen receptor in
the male is demonstrated by the findings that lack of estrogen activity
in the male, secondary to a defective estrogen receptor, leads to
decreased mineral density and skeletal maturity even if testosterone
concentration is normal (18).
The second patient, a genetic female with masculine phenotype caused by
increased adrenal androgens, had a low bone density because of lack of
estrogen (ovariectomy), and the suppression of adrenal androgens as
well as the glucocorticoid treatment. Treatment with testosterone was
successful in increasing bone density. This could be because of a dual
sensitivity of the bone steroid receptor to both estrogen and
testosterone or because of aromatization of testosterone to estradiol.
The latter is supported by findings that P450 aromatase deficiency can
lead to a dissociation between skeletal growth and the accretion of
bone density and mass (19). The lack of in situaromatization in the male results in tall stature, delayed
epiphyseal closure, and osteoporosis.
In both our patients, phenotype-matched sex hormone therapy
resulted in an increase in bone density. We assume that in both sexes
it is probably the estrogen that causes a favorable effect on bone
density when administered as conjugated estrogen or derived from
testosterone by aromatization.
In conclusion, long-term, phenotype matched, sex hormone treatment is
recommended in castrated patients with abnormal sexual differentiation,
not only for sexual appearance and function, but also to preserve
skeletal integrity. Thus, even patients who are not interested in
therapy for external sexual appearance should be advised to continue
treatment to maintain normal bone density.
Received July 17, 1996.
Revised September 16, 1996.
Accepted September 24, 1996.
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Abstract
Introduction
