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Estrogen Replacement Therapy in a Man with Congenital Aromatase Deficiency: Effects of Different Doses of Transdermal Estradiol on Bone Mineral Density and Hormonal Parameters

Department of Internal Medicine, University of Modena, 41100 Modena, Italy

Address all correspondence and requests for reprints to: Prof. Cesare Carani, Cattedra di Endocrinologia, Dipartimento di Medicina Interna, Via del Pozzo 71, 41100 Modena, Italy. E-mail: andrologia{at}unimo.it

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The effects of different doses of transdermal estradiol (TE) on bone mineral density (BMD) in a man with aromatase deficiency were evaluated. The study protocol was divided in the following four phases: phase 1, before estradiol treatment; phase 2, 50 µg TE twice weekly for 6 months; phase 3, 25 µg TE twice weekly for 9 months; and phase 4, 12.5 µg TE twice weekly for 9 months. X-rays of hands, legs, and pelvis were performed, and BMD of the lumbar spine, hormonal parameters (LH, FSH, testosterone, and estradiol), and markers of bone turnover were determined during each phase.

BMD in phase 1 was 0.933 g/cm² and increased to 1.051 and 1.173 g/cm² after 4 and 7 months of TE, respectively. In phase 3, BMD reached the maximum value (1.275 g/cm²). In phase 4, BMD decreased to 1.180 g/cm² and was 1.029 g/cm² at the end of the study protocol. A bilateral necrosis of femoral heads was also detected by x-ray films.

In phase 1 serum testosterone was in the normal range, whereas serum estradiol was undetectable. During the 24-month period of treatment with TE (phases 2–4), estradiol was directly related to the amount of TE, whereas LH was inversely related to estradiol serum levels. Estradiol and gonadotropins reached optimal values only in phase 3, when FSH also was near normal; serum testosterone concentrations were normal in phases 3 and 4.

This study confirms the role of estrogens in achieving and maintaining bone mineral content in the human male, providing further clinical tools useful in the management of bone loss in aromatase deficiency in the male. We suggest that the adequate substitutive dose of TE for maintaining both bone mass and normal estradiol serum levels in adult men with aromatase deficiency may be 25 µg twice weekly (0.47 µg/kg weekly).

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE PREVENTION of bone loss by estrogen replacement therapy in postmenopausal women has been well established (1, 2). Most important, recent studies have suggested that the current recommended estrogen doses may be higher than required to maintain bone mass and decrease risk of fractures in women over 65 yr of age (3, 4, 5), thus raising the question of whether a minimal amount of endogenous estrogen may have a role in the skeletal health of postmenopausal women.

In contrast, the precise role of estrogen in human male physiology remains unknown. Crucial new tools became available when the first descriptions of young men affected with congenital estrogen deficiency were reported (6, 7, 8, 9). Taken together, these findings suggest that epiphyseal closure does not develop without the action of estrogen even in the male, and that androgen alone is not sufficient to promote normal skeletal mineralization, because severe osteoporosis was reported in all three patients described to date (6, 8, 9).

It is a matter of debate whether the effects of sex steroids on bone mineralization in the male are mediated by testicular androgens or by the action of estrogens derived from the aromatization of androgens (10). Evidence is now available that gonadal failure is associated with a decrease in bone mass in both sexes (1, 2, 11, 12, 13, 14), and the general acceptance that androgens maintain bone mass in the male as well as estrogens do in the female continues to be the prevailing view among physicians, although recent studies argue against such an idea (6, 7, 8, 9, 15).

In 1997 Carani et al. demonstrated the efficacy of transdermal estradiol (TE) to obtain the closure of epiphyses in a man with a homozygous inactivating mutation of the P-450 aromatase gene (8). Furthermore, an increase in bone mineral density (BMD), evaluated only at the lumbar spine, was also described in that short-term study (8). In a long-term study, using conjugated estrogens, Bilezikian et al. presented their 3-yr experience with treatment of an aromatase-deficient man, demonstrating the increase in BMD in both trabecular and cortical bones (9).

The request is now to plan further studies to determine the minimal and optimal dosage of estrogen replacement therapy for the management of aromatase-deficient adult men. The present study was designed to address this question, with particular regard to bone mineralization, by using different doses of TE in a man who has been reported previously to have a homozygous point mutation in exon 9 of the P-450 aromatase gene leading to a single base pair change at position 1094 with no enzyme activity (8).

	Subjects and Methods

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Case report

The study was performed on a male subject affected by severe aromatase deficiency, who has been reported previously (8). The patient came to our attention when he was 31 yr old because of persistent linear growth and infertility (8). At physical examination he was 187 cm in height, with a upper to the lower segment ratio of 0.85. Eunuchoid body proportions and genu valgum were also present. The parents were consanguineous; the mother was 162 cm in height, and the father 170 cm. The patient’s parental target height was 172.5 cm (16). At the age of 18 yr he was 170 cm in height, and he had been growing at 31 yr of age (at the time of first admission) when his bone age was still 14.8 yr.

When the diagnosis of aromatase deficiency was confirmed, he was 39 yr old and his height was 190 cm (8). He started estrogen replacement therapy with a high dose of TE (Estraderm, 50 µg twice weekly) in an attempt to obtain epiphyseal closure. Six months later, the dose was reduced to 25 µg twice weekly. After 9 months of such a regimen, the patient was treated with TE (12.5 µg twice weekly) to determine whether it was as effective as the previous treatment schedules in maintaining BMD.

Study protocol

To establish the effects of different doses of TE on BMD and hormonal parameters, the patient, after giving his informed consent to the treatment, was reassessed during each of the four treatment phases of the study protocol. The four phases of the study protocol, which are shown in Fig. 1, were established accordingly to the administered dose of TE treatment as follows: phase 1, before estradiol treatment; phase 2, TE treatment (Estraderm, patch system) at the dose of 50 µg twice weekly (0.95 µg/kg weekly) for 6 months as recently reported (8); phase 3, TE treatment (Estraderm, patch system) at the dose of 25 µg twice weekly (0.47 µg/kg weekly) for 9 months; and phase 4, TE treatment (Estraderm, patch system) at the dose of 12.5 µg twice weekly (0.23 µg/kg weekly) for 9 months.

View larger version (24K): [in this window] [in a new window]   Figure 1. Design of study protocol and results. BMD is expressed as the raw data (grams per cm2), as the t score, and as the increase from baseline in the graph. X-ray films of hands and knees show the progression of epiphyseal maturation.

Biochemical measurements

Blood samples were obtained by venipuncture between 0800–0900 h after an overnight fast, and all samples were stored at -80 C until analyzed. Blood samples for biochemical measurements were collected during each phase of the study protocol (in phase 1 and at the third month of phases 2–4).

Hormonal assay

Serum LH and FSH were measured by immunofluorometric assay (Delfia kits, Pharmacia Biotech, Milan Italy) according to the instructions of the manufacturer.

Serum total testosterone was determined by RIA (Diagnostic Products, Los Angeles, CA). The inter- and intraassay coefficients of variation for testosterone were 11% and 5%, respectively. Serum estradiol was determined by immunofluorometric assay (Delfia kits). The inter- and intraassay coefficients of variation for estradiol were 5% and 6%, respectively.

Markers of bone turnover

Biochemical parameters of bone turnover were measured during each of the phases of the study protocol. Alkaline phosphatase, urinary pyridoline, serum calcium, and serum phosphorous were measured using commercially available assays.

Osteocalcin was determined by RIA (Osteocalcina Myria, Technogenetics, Italy). The inter- and intraassay coefficients of variation for osteocalcin were 6% and 4%, respectively.

Bone densitometry

BMD was assessed in phase 1, in phase 2 (after 4 months of estradiol treatment), at the beginning, and at the end of phase 3 (at the 1st and 9th months of phase 3, respectively, corresponding to the 7th and 14th months from the beginning of estradiol treatment), and in phase 4 (at the 6th and 9th months, respectively, corresponding to the 20th and 24th months from the beginning of estradiol treatment; Fig. 1).

BMD was measured at the lumbar spine (L2–L4) by dual energy x-ray absorptiometry (DPX-L, Lunar Corp., Madison, WI). Daily calibration and quality control were performed according to the manufacturer’s recommendation.

X-ray film

X-ray films of wrist, hand, distal femur, and proximal tibia were performed before and during TE treatment, as summarized in Fig. 1. X-ray films of the pelvis were performed in phases 1 and 4 (24 months after the beginning of estradiol treatment).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The BMD of the lumbar spine at baseline (phase 1) was 0.933 g/cm² (Fig. 1) and increased to 1.051 and 1.173 g/cm² after 4 and 7 months of estradiol treatment, respectively. In phase 3, BMD reached the maximum value (1.275 g/cm²) after 14 months of treatment (Fig. 1). The increase in BMD from baseline was 12.6%, 25.7%, and 36.6% after 4, 7, and 14 months of treatment, respectively. During phase 4, BMD was 1.180 g/cm² after 20 months of treatment (after 6 months of estradiol, 12.5 µg twice weekly) and decreased to 1.029 g/cm² after 24 months of treatment (after 9 months of estradiol, 12.5 µg twice weekly) with a corresponding change in the increase from baseline (26.4% and 10.1%, respectively; Fig. 1). The t scores (SD from the mean in normal young men) progressively increased from -2.07 at baseline to +0.51 at the end of phase 3. During phase 4, t scores progressively decreased to -1.34 at the end of the study protocol (Fig. 1).

Biochemical markers of bone turnover (alkaline phosphatase, urinary pyridoline, and osteocalcin) rose remarkably during phase 2 and progressively decreased during phases 3 and 4, returning to baseline values. Serum calcium and phosphorous did not change significantly throughout the study protocol (Table 1).

Bilateral established necrosis of femoral heads was evident in phase 1, and no modifications were recorded thereafter.

As shown in Table 1, at baseline (phase 1) serum testosterone levels were in the normal range, whereas serum estradiol levels were undetectable. Six months of treatment with high dose TE (phase 2) resulted in a remarkable decrease in serum testosterone below the normal range with a corresponding increase in serum estradiol above normal values. Serum testosterone and estradiol levels returned to the normal range during phases 3 and 4. Serum FSH levels were above the normal range at baseline, and LH was normal (phase 1). Serum LH and FSH levels fell below normal values in response to high doses of estradiol in phase 2. LH returned to the normal range during phase 3, and FSH was slightly above normal. LH rose to high normal values, and FSH rose to above normal values during phase 4.

No side-effects, notably gynecomastia and loss of libido, were reported by the patient during throughout the study protocol.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Up until now only two men affected with congenital aromatase deficiency have been reported (7, 8). We present the results of treatment with various doses of TE on BMD and hormonal parameters in a man with aromatase deficiency. The data document an improvement in BMD at the lumbar spine during phases 2 and 3. BMD reached a maximum value during phase 3, when the patient was administered 25 µg TE twice weekly, but decreased during phase 4 when a lower dose was given, suggesting that this last regimen was not sufficient to preserve the bone mass previously achieved, and that the effect on BMD is probably dose dependent. This finding is also reinforced when hormonal parameters are taken into account. In fact, LH, estradiol, and testosterone levels were all in the normal range in phases 3 and 4, reaching the optimal values only in phase 3 when FSH was also near normal.

Before this study, the efficacy of estrogen treatment in improving BMD in an aromatase-deficient man had been well documented by the only long-term study by Biliezikian et al. (9), in which increasing doses of conjugated estrogens (from 0.3–0.75 mg/day) during the first 12 months and the final dose of 0.75 mg/day for the subsequent 2 yr have been used. That treatment also resulted in an increase in serum estradiol levels above the normal range, whereas gonadotropin serum levels remained near the normal range (9, 17, 18).

The challenge is to establish the minimum effective dose of estrogen for long-term treatment in men lacking aromatase activity. The subject reported here is important, because the schedule of treatment in this rare condition is poorly defined, and better understanding should lead to an improvement in clinical management. We evaluated BMD at the lumbar spine and hormonal parameters during each phase of the study protocol according to the dose administered, keeping in mind that normal serum concentrations of estradiol, testosterone, and gonadotropins as well as the absence of undesirable side-effects are also goals of the treatment. The possibility of using a transdermal patch instead of a pill could be useful in clinical practice according to the patients’ preferences, which also have to be taken into account.

A strict correlation between serum estradiol and BMD in men was shown in elderly men (19) and as well as adult men (20). A direct effect on BMD due to estrogen treatment was also demonstrated in male to female transsexuals (21, 22) and in both eugonadal men with osteoporotic fractures (23) and men affected by idiopathic osteoporosis (24).

It remains a matter of debate whether the lack of aromatase activity causes the bilateral necrosis of femoral heads. The patient never underwent corticosteroid therapy, and there were no other predisposing factors. Osteoporosis is not a common cause of osteonecrosis of the femoral head in men (25), even if both conditions may be associated in some circumstances (26, 27). The pathogenesis of necrosis of the femoral head remains controversial (28, 29), although ischemic events are a possible cause of osteonecrosis (30, 31). Recently, the effect of estrogens on vascular cells and tissues is largely emphasized (32), and it is only possible to speculate that the congenital lack of estrogen activity on the bone microcirculation of the femoral head may act as a permissive factor for injuries.

Morishima et al. (7) showed fused proximal femoral epiphyses with iliac unossified apophyses in their patient with a bone age of 14 yr before estrogen treatment. Here, the authors report a modest delay of epiphyseal closure of distal femur and proximal tibia compared with that of the hand and wrist. In general, it is not an unusual finding in normal growth, and it may be simply a casual and independent finding. Few data on the progress of skeletal maturation at different sites are available from the literature in health and disease (33), and longitudinal bone growth remains a poorly understood process (34, 35).

In conclusion, by our experience we suggest that the adequate replacement dose for maintaining both bone mass and normal estradiol serum levels in adult men with aromatase deficiency may be 25 µg twice weekly (0.47 µg/kg weekly) TE. Of course, reports of other male subjects affected with aromatase deficiency would provide further elucidations of the pathophysiology of this rare disease and its effective pharmacological treatment. Unanswered questions remain. Whatever the clinical usefulness of estrogen treatment may be, it remains unknown whether a strategy that attempts to restore and maintain the estrogen milieu will improve both the survival and quality of life of men with aromatase deficiency (36). Again, it has not been precisely identified at what age estrogen replacement therapy has to be started.

Received August 2, 1999.

Revised November 9, 1999.

Accepted January 20, 2000.

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