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Clinical Studies |
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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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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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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 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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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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Discussion |
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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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, lumbar spine L2-L4; •, femoral
neck.