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Effects of Selective Testosterone and Estradiol Withdrawal on Skeletal Sensitivity to Parathyroid Hormone in Men

Endocrine Unit (J.S.F., M.M., S.J.C., R.I.C., B.Z.L.), Department of Medicine, Massachusetts General Hospital, and Massachusetts General Hospital Biostatistics Center (H.L.), Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Benjamin Z. Leder, Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.

	Abstract

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Context: Gonadal steroid withdrawal increases bone turnover and causes bone loss in men, but the underlying mechanisms have not been defined. We previously reported that gonadal steroid deprivation increases the skeletal sensitivity to the bone resorbing properties of PTH infusion in men, but it is not known whether this effect is mediated by the absence of androgens, estrogens, or both.

Objective: The objective of the study was to determine the selective effects of testosterone and estradiol withdrawal on the skeletal sensitivity to PTH infusion in healthy adult men.

Design and Setting: We randomly assigned 58 healthy men between the ages of 20 and 45 yr to receive treatment with combinations of a GnRH analog, an aromatase inhibitor, and hormone add-back therapy to produce the following treatment groups: group 1 (testosterone and estradiol deficient, n = 16); group 2 (testosterone sufficient but estradiol deficient, n = 12); group 3 (testosterone deficient but estradiol sufficient, n = 14); and group 4 (testosterone and estradiol sufficient, n = 16). Twenty-four-hour PTH infusions were performed at baseline and after 6 wk of therapy. Serum N-telopeptide (NTX), C-telopeptide (CTX), osteocalcin (OC), and amino-terminal propeptide of type I procollagen (P1NP) were measured every 6 h during the PTH infusions.

Results: Serum testosterone levels fell into the castrate range in groups 1 and 3, whereas estradiol levels were similarly reduced in groups 1 and 2. Gonadal steroid levels in the replaced groups were unchanged from baseline. Serum NTX levels measured before PTH infusion did not change in group 4 (+T, +E) but increased significantly in all other groups. A similar pattern was observed in serum CTX, although the increase in group 2 (+T, –E) was not significant (P = 0.12). Preinfusion concentrations of both OC and P1NP fell in most groups, but these changes were significant in group 2 (+T, –E) for both OC and P1NP and group 4 (+T, +E) for P1NP only. Serum NTX and CTX increased during PTH infusions in all groups at all time points (P < 0.001). In the eugonadal group (group 4 +T+E), the increase in NTX was the same at wk 0 and 6, whereas in all the other groups, the PTH-induced increase in serum NTX was significantly greater at wk, 6 compared with wk 0. The same pattern emerged for CTX, although the difference in group 3 (–T,+E) was not significant (P = 0.12). Serum OC and P1NP levels fell during PTH infusions in all groups and at all time points (P < 0.001), but no significant differences were observed between wk 0 and 6 in any group.

Conclusions: These results demonstrate that the selective suppression of testosterone, estradiol, or both hormones increases the skeletal responsiveness to the bone-resorbing effects of PTH in men. These findings underscore the importance of both androgens and estrogens in male skeletal homeostasis and suggest that changes in skeletal sensitivity to PTH may play an important role in the pathogenesis of hypogonadal bone loss in men.

	Introduction

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ACUTE GONADAL STEROID withdrawal leads to high turnover bone loss and increases the risk of osteoporotic fracture in men (1). Whereas the precise mechanisms involved in this process are incompletely understood, one mechanism that has received attention involves the interaction among gonadal steroids, PTH, and the stimulation of osteoclastic bone resorption. We previously reported that biochemical markers of bone resorption increase more rapidly in men infused with PTH after they have been rendered hypogonadal via GnRH analog therapy (2). It remains unclear, however, whether this increased skeletal responsiveness to PTH is due to the absence of androgens, estrogens, or both. Given the increased focus on and better understanding of the importance of estrogens in male skeletal physiology and the maintenance of normal bone turnover in men (3), we wanted to assess the differential impact of these two classes of sex steroids in mediating the effect of PTH. Specifically, we infused human PTH-(1–34) for 24 h in eugonadal men aged 20–45 yr. After this infusion, subjects began GnRH analog and aromatase inhibitor therapy and were randomized to receive no hormonal add-back therapy (–T, –E), add-back hormonal therapy with testosterone and estradiol (+T, +E), add-back therapy with testosterone alone (+T, –E), or add-back therapy with estradiol alone (–T, +E). Serum levels of biochemical markers of bone turnover and ionized calcium were measured every 6 h during both the wk 0 infusion and the postintervention infusion. By comparing the response to PTH administration before and after these hormonal manipulations, we were able to assess the individual effects of testosterone and estradiol in mediating the increase in skeletal sensitivity to PTH observed in hypogonadal men.

	Subjects and Methods

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Study subjects

Seventy-seven men between the ages of 20 and 45 yr were recruited using advertisements in accord with institutional guidelines for clinical studies. All subjects were required to have normal concentrations of serum testosterone, thyroid-stimulating hormone level, serum prostate-specific antigen, and serum calcium as well as no laboratory evidence of renal or hepatic dysfunction. Subjects were excluded from participation if they had any history of congenital or acquired bone disease (osteomalacia, vitamin D deficiency, hyperparathyroidism, Paget’s disease), recent fracture or immobilization, hyperthyroidism, cardiopulmonary disease, malignancy, benign prostatic hyperplasia, major psychiatric disease, or drug or alcohol abuse. Subjects were also excluded if they were using any drug known to interact with the study medications or any drug known to affect bone turnover markers (such as anticoagulants, gonadal steroids, glucocorticoids, anticonvulsants, suppressive doses of thyroxine, lithium, bisphosphonates, calcitonin, or sodium fluoride). Because the goal of this study was to determine the effects of specific hormonal milieus on skeletal sensitivity to PTH, it was predetermined that we would not use data from men who were noncompliant with their add-back hormone therapy (serum testosterone or estradiol levels more than 2 SD below the mean of the entire study population on visit 3). Thus, bone turnover markers were not analyzed on the samples from those men (n = 6). An additional 12 men did not receive their second PTH infusion because they withdrew from the study due to the side effects of the study medications (usually hot flashes) or other reasons. One additional subject was excluded from analysis due to acute liver inflammation found at visit 1 (not apparent at screening), leaving 58 men who form the basis of this report (43 Caucasian, four Hispanic, six African/African-American, four Asian, and one Native American). The Human Research Committee of Partners HealthCare Systems approved the study, and all subjects provided written informed consent.

Protocol

The pharmacological model we used to create the groups of selective or combined gonadal steroid hormone deficiency was similar to that used in previous studies reported by our group and others (4, 5). Specifically, subjects were randomized by computer-generated cards to one of four treatment groups (Fig. 1). Subjects in group 1 received goserelin acetate (Zoladex; AstraZeneca, Wilmington, DE) 3.6 mg by sc injection every 3 wk plus anastrozole (Arimidex; AstraZeneca) 1 mg by mouth daily for 6 wk, rendering them both testosterone and estrogen deficient (–T, –E). Subjects in group 2 received goserelin plus anastrozole plus transdermal testosterone (Androgel; Solvay, Marietta, GA) 5 g/d applied daily for 6 wk, rendering them testosterone sufficient and estrogen deficient (+T, –E). Subjects in group 3 received goserelin plus anastrozole plus transdermal estradiol (Vivelle; Novartis, Basil, Switzerland) 0.0375-mg patch applied twice weekly for 6 wk, rendering them testosterone deficient and estrogen sufficient (–T, +E). Subjects in group 4 received goserelin plus anastrozole plus transdermal testosterone plus transdermal estradiol, rendering them both testosterone and estrogen sufficient or eugonadal (+T, +E).

View larger version (15K): [in this window] [in a new window]   FIG. 1. Representation of the subject randomization. All treatments lasted 6 wk.

After the infusion was completed, a GCRC nurse administered the goserelin injection and dispensed the anastrozole tablets, testosterone gel, and estradiol patches according to the subject’s assigned group. Subjects returned to the GCRC at wk 3 to receive an additional goserelin injection and medication refills. Subjects returned at wk 6 and PTH was infused in the same manner as in the wk 0 visit. Identical blood sampling was also repeated.

Measurements

Serum testosterone was measured by chemiluminescence immunoassay (Centaur, Bayer Diagnostics, Tarrytown, NY). The sensitivity of this assay is 10 ng/dl, and the intra- and interassay coefficients of variation are 1–8 and 7–9%, respectively. Serum estradiol was measured by chemiluminescence immunoassay (Elecsys2010; Roche Diagnostics, Indianapolis, IN). The sensitivity of this assay is 20 pg/ml, and the intra- and interassay coefficients of variation are less than 5 and 4–8%, respectively. If the serum estradiol level was less than 20 pg/ml, the serum estradiol was remeasured using an ultrasensitive competitive RIA after extraction and chromatographic purification (Nichols Institute, San Juan Capistrano, CA). The sensitivity of this assay is 2 pg/ml, and the intra- and interassay coefficients of variation are 5–6 and 6–13%, respectively. Serum SHBG was measured by chemiluminescence immunoassay (Immulite; Diagnostic Products Corp. Inc., Los Angeles, CA) with intra- and interassay coefficients of variation of less than 5 and 4 .5%, respectively.

NTX was measured using a competitive inhibition enzyme immunoassay (Osteomark; Ostex International, Seattle, WA) with a sensitivity of 1 nM bone collagen equivalent and intra- and interassay coefficients of variation of 6 and 9%, respectively. CTX was measured using a double-antibody enzyme-linked immunoassay (Serum Crosslaps; Nordic Biosciences Diagnostics A/S, Herlev, Denmark) with intra- and interassay coefficients of variation of 4.7 and 13.5%, respectively. Serum OC was measured using a double-antibody immunoradiometric assay (Nichols Institute) with a sensitivity of 0.5 ng/ml and intra- and interassay coefficients of variation of 2–4 and 3–6%, respectively. Serum P1NP was measured using a RIA (Orion Diagnostica, Espoo, Finland) with a sensitivity of 2 ng/ml and intra- and interassay coefficients of variation of 5–14 and 2–3%, respectively.

Statistical analyses

All data are summarized by mean ± SD unless otherwise specified. The comparisons of baseline characteristics were performed by ANOVA, as were between-group differences in serum hormone and SHBG levels at wk 6. Within-group changes in hormone levels and bone turnover markers at time 0 (i.e. values before PTH infusion) were compared by paired t test. Within each study group, the wk 0 vs. wk 6 response to PTH infusion in each bone turnover marker was examined by the longitudinal mixed-effects model, which included the random subject level intercept, random slope over time, and time by visit (wk 0 or 6) interaction term. The change in each marker during the infusion at wk 6 was considered statistically significantly different from wk 0 if the time-by-visit interaction was different from zero. All baseline comparisons were performed by two-sided tests and the treatment effect comparisons by one-sided tests. Resulting values of P < 0.05 were considered statistically significant. All analyses were performed using SAS (version 8.2; SAS Institute, Cary, NC).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 1 shows the baseline clinical characteristics, gonadal steroid levels, SHBG levels, and baseline bone turnover markers of the study subjects. Subjects were well matched and there were no statistically significant differences between groups.

Figure 2 shows the changes in hormone levels between wk 0 and 6. The wk 6 serum testosterone levels in the subjects assigned to groups 1 and 3 were dramatically lowered into the castrate range (P < 0.001 for both groups vs. wk 0). Specifically, the serum testosterone levels fell from 505 ± 47 to 36 ± 4 ng/dl in group 1 and from 421 ± 35 to 33 ± 3 ng/dl in group 3. The serum testosterone levels did not change in the subjects assigned to groups 2 and 4. Furthermore, the wk 6 mean serum testosterone levels in groups 1 and 3 were highly statistically different from those in groups 2 and 4 (P < 0.001 for all comparisons). The mean serum testosterone levels in group 1 were not different from those in group 3 nor were the levels different in subjects in group 2 vs. group 4.

View larger version (17K): [in this window] [in a new window]   FIG. 2. Mean (±SEM) serum gonadal steroid hormone levels at wk 0 and 6. *, P 0.001, compared with wk 0.

Mean serum SHBG levels remained constant in all groups except for an increase from 23.3 ± 2.2 to 27.4 ± 3.8 nmol/liter in group 3 (P = 0.019). At wk 6, there were no significant between-group differences in SHBG levels (P = 0.952).

Baseline bone turnover markers

Figure 3 shows the serum NTX and CTX measured before PTH infusion at wk 0 and 6. No significant changes were seen in the eugonadal group in either marker. Serum NTX increased from 18.7 ± 6.7 to 22.7 ± 7.5 nmol/liter in group 1 (–T, –E) (P < 0.001), from 18.0 ± 4.2 to 21.2 ± 7.3 nmol/liter in group 2 (+T, –E) (P = 0.011), and from 18.6 ± 2.4 to 20.9 ± 6.1 nmol/liter in group 3 (+T, –E) (P = 0.045).

View larger version (15K): [in this window] [in a new window]   FIG. 3. Baseline (pre-PTH infusion) mean (±SEM) serum NTX and CTX concentrations at wk 0 and 6. *, P 0.001, compared with wk 0. #, P < 0.05, compared with wk 0.

Figure 4 shows the serum OC and P1NP measured before PTH infusion at wk 0 and 6. Serum OC decreased significantly in group 2 (+T, –E) only (from 13.0 ± 4.8 to 11.5 ± 4.1 ng/ml, P < 0.001). Serum P1NP decreased in both groups 2 (from 59.8 ± 21.7 to 48.5 ± 18.8 ng/ml, P = 0.018) and 4 (from 58.2 ± 23.3 to 54.7 ± 19.2 ng/ml, P = 0.024).

View larger version (16K): [in this window] [in a new window]   FIG. 4. Baseline (pre-PTH infusion) mean (±SEM) serum OC and P1NP concentrations at wk 0 and 6. *, P 0.001, compared with wk 0. #, P < 0.05, compared with wk 0.

Figure 5 shows the PTH-induced increases in NTX and at wk 0 and 6, whereas Fig. 6 shows the difference in the response to PTH between these two time points. Serum NTX and CTX increased during PTH infusions in all groups at all time points (P < 0.001). In the eugonadal group (group 4, +T+E), the PTH-induced increases in NTX and CTX were the same at wk 0 and 6. In all other groups, the changes in NTX were significantly greater at wk 6, compared with wk 0. Specifically, the difference in the NTX response to PTH between wk 0 and 6 was 6.0 ± 5.9 nmol/liter in group 1 (–T, –E) (P < 0.001), 5.0 ± 9.0 nmol/liter in group 2 (+T, –E) (P = 0.011), and 3.7 ± 9.2 nmol/liter in group 3 (–T, +E) (P = 0.045). Similar findings were observed in serum CTX, although the changes in group 3 (–T, +E) were not statistically significant. The difference in the PTH-induced CTX response between wk 0 and 6 was 0.61 ± 0.32 ng/ml in group 1 (–T, –E) (P < 0.001), 0.46 ± 0.70 ng/ml in group 2 (+T, –E) (P = 0.004), and 0.19 ± 0.41 ng/ml in group 3 (–T, +E) (P = 0.124).

View larger version (15K): [in this window] [in a new window]   FIG. 5. Mean (±SEM) PTH-induced increase in serum NTX and CTX at wk 0 and 6. *, P 0.001, compared with wk 0. #, P < 0.05, compared with wk 0.

View larger version (10K): [in this window] [in a new window]   FIG. 6. Mean (±SEM) difference in the PTH-induced increase in serum NTX and CTX between wk 0 and 6. *, P 0.001, compared with wk 0. #, P < 0.05, compared with wk 0.

View larger version (16K): [in this window] [in a new window]   FIG. 7. Mean (±SEM) PTH-induced change in serum OC and P1NP at wk 0 and 6.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Whereas intermittent sc administration of PTH increases bone mass in men (21), continuous infusion of PTH potently activates bone resorption (2) and inhibits osteoprotegerin and stimulates receptor activator of nuclear factor-ß ligand expression in vitro (22, 23). In women, estrogen deficiency increases skeletal sensitivity to the bone-resorbing actions of PTH, thereby promoting bone loss after menopause (24, 25, 26). In men, we previously reported that combined androgen and estrogen withdrawal increases the skeletal responsiveness to the bone-resorbing effects of PTH infusion (2). This study now further confirms this finding and demonstrates that both androgens and estrogens are independently involved in this process (although the effect of selective androgen deficiency on CTX was not statistically significant). Furthermore, the results suggest that whereas there may be a limited additive effect of combined gonadal steroid deprivation, compared with the selective deprivation of androgens or estrogens individually, there does not appear to be any synergy between the two states of hormonal deprivation.

We also found that whereas PTH infusion decreases biochemical markers of bone formation, there was no difference in the magnitude of this decrease in subjects after androgen, estrogen, or combined gonadal steroid withdrawal. The acute effect of PTH to decrease markers of osteoblast function has been described previously in men and women (2, 25, 26) and contrasts with the effect of long-term daily intermittent PTH administration to increase markers of bone formation (27, 28). Because there was no differential effect on bone formation in the subjects before or after hormonal manipulation, it is difficult to interpret the physiologic significance of the reduction. Similarly, the reduction of the pre-PTH infusion OC and P1NP levels between wk 0 and 6 in group 2 (+T, –E) is of unclear significance but may represent the importance of estrogens in inhibiting osteoblast apoptosis (29, 30, 31).

Several limitations of this study deserve mention. First, because the hormonal manipulations were acute, it is unclear whether long-term gonadal steroid deficiency would have the same effects on PTH sensitivity. Additionally, changes in biochemical markers of bone turnover provide only indirect data concerning the changes in osteoblastic and osteoclastic activity, whereas a more direct assessment would require an invasive study design and would likely be prohibitive in this healthy population. Finally, because we studied young men, it is unknown whether older men would respond in the same manner.

We conclude that selective suppression of androgen or estrogen production increases the skeletal responsiveness to the bone-resorbing properties of PTH in men. These findings underscore the importance of both androgens and estrogens in male skeletal homeostasis and suggest that changes in skeletal sensitivity to PTH may play an important role in the pathogenesis of hypogonadal bone loss in men. Further study is necessary to better assess the cellular and molecular mechanisms that underlie this novel observation.

	Acknowledgments

 
We thank the nurses and staff of the Mallinckrodt General Clinical Research Center for the care of the study volunteers and Carrie Whelan of the GCRC core lab.

	Footnotes

 
First Published Online December 13, 2005

Abbreviations: CTX, C-telopeptide; NTX, N-telopeptide; OC, osteocalcin; P1NP, amino-terminal propeptide of type I procollagen.

This work was supported by National Institutes of Health Grants K23-RR16310 (to B.Z.L.), K24-DK02759 (to J.S.F.), and Massachusetts General Hospital Clinical Research Center Grant RR-1066.

The authors report no disclosures.

Received November 15, 2005.

Accepted December 6, 2005.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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