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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2151-2156
Copyright © 1999 by The Endocrine Society

From the Clinical Research Centers

Effects of Gonadal Suppression on the Regulation of Parathyroid Hormone and 1,25-Dihydroxyvitamin D Secretion in Women1

Joel S. Finkelstein and David A. Schoenfeld

Endocrine Unit, Department of Medicine, Massachusetts General Hospital (J.S.F.), and the Department of Biostatistics, Harvard School of Public Health (D.A.S.), Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Joel S. Finkelstein, M.D., Endocrine Unit, Bulfinch 327, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: finkelstein{at}helix.mgh.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Although a causal association between estrogen deficiency and bone loss has been established for many years, the mechanism by which estrogen deficiency leads to bone loss is unclear. Estrogen deficiency could induce bone loss either by a direct effect on bone cells to modify the production of bone-resorbing cytokines or by altering the production or response to calcium regulatory hormones such as PTH and 1,25-dihydroxyvitamin D. To assess the effects of ovarian hormones on calcium regulatory hormones, we evaluated the ability of calcium to suppress PTH secretion and the ability of PTH to increase serum 1,25-dihydroxyvitamin D and whole blood ionic calcium levels in women before and after GnRH analog-induced ovarian suppression. Sixteen women with endometriosis underwent iv infusion of calcium (1.1 mg calcium gluconate/cc in 5% dextrose) at a rate of 4 cc/kg·h (n = 7) or human PTH-(1–34) (Parathar) at a dose of 0.55 U/kg·h (n = 9) before and after 6 months of suppression of ovarian function with the GnRH analog nafarelin acetate (200 µg, intranasally, twice daily). Initial infusions were performed between days 6–10 of the menstrual cycle. Serum PTH and whole blood ionic calcium levels were measured at -20, -10, and 0 min and then every 10 min for 2 h during iv calcium infusions. Whole blood ionic calcium and 1,25-dihydroxyvitamin D levels were measured every 6 h for 24 h during iv human PTH-(1–34) infusions.

Serum estradiol levels were markedly suppressed by nafarelin therapy in both groups of women. The relationship between whole blood ionic calcium and serum PTH levels was similar before and during nafarelin-induced ovarian suppression. The net change and rate of rise in serum 1,25-dihydroxyvitamin D levels in response to PTH infusion were similar before and during nafarelin therapy. Peak whole blood ionic calcium and incremental increases in ionic calcium in response to PTH were similar before and during nafarelin therapy.

Our data suggest that ovarian suppression does not alter the regulation of PTH secretion in response to calcium, the ability of PTH to stimulate 1,25-dihydroxyvitamin D formation, or the skeletal sensitivity to PTH. These findings suggest that alterations in calcium regulatory hormones by estrogen deficiency are unlikely to play a major role in the pathogenesis of estrogen deficiency bone loss.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ESTROGEN deficiency leads to bone loss in women, and estrogen replacement can prevent its development (1, 2, 3, 4, 5, 6). Even though the association between estrogen deficiency and bone loss has been established for many years (7), the mechanism by which estrogen deficiency leads to bone loss is still unclear.

Estrogen deficiency could induce bone loss by increasing the local production of bone-resorbing cytokines (8), by altering the production or tissue responses to calcium regulatory hormones, or both. Many studies have reported that serum calcium levels increase after the menopause (9). There is, however, considerable disagreement regarding the effects of estrogen on the regulation of PTH secretion by calcium, the regulation of 1,25-dihydroxyvitamin D secretion by PTH, and the sensitivity of the skeleton to PTH. Some studies have found that increases in serum calcium levels after the menopause are accompanied by a compensatory decrease in serum PTH levels, whereas other studies have found that PTH levels fail to change in response to increases in serum calcium levels after the menopause, suggesting that gonadal steroids are involved in the control of PTH by calcium (9). Serum calcium levels decrease, and serum PTH levels increase when estrogen is administered to postmenopausal women with primary hyperparathyroidism (10, 11). In studies in which the dynamic regulation of PTH has been examined, it has been reported both that estrogen reduces the set-point for PTH release by calcium (12) and that estrogen has no effect on the relationship between calcium and PTH secretion (13). It has also been reported both that estrogen increases the formation of 1,25-dihydroxyvitamin D in response to PTH (14) and that estrogen has no effect on the ability of the kidney to make 1,25-dihydroxyvitamin D in response to PTH (15, 16, 17). Similarly, some (18, 19), but not all (20), studies have reported that estrogen reduces skeletal sensitivity to PTH.

Almost all prior studies of the effects of estrogen on the regulation of or the response to calcium regulatory hormones have involved oral administration of exogenous estrogen. The physiological relevance of these studies is difficult to determine because orally administered estrogen affects serum 1,25-dihydroxyvitamin D levels differently than endogenously secreted or topically administered estrogens (9). To circumvent this important potential limitation of prior studies, we investigated the effects of iv calcium administration on the secretion of PTH and the effects of iv PTH infusion on serum 1,25-dihydroxyvitamin D and whole blood ionic calcium levels in young, normally cycling women before and after 6 months of gonadal suppression induced by administration of a long-acting GnRH analog.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

Sixteen women (aged 21–44 yr) with symptomatic, laparoscopically proved endometriosis were studied. All women had ovulation documented by a luteal phase serum progesterone level greater than 5 ng/mL during the cycle before the protocol was begun. All women had normal serum calcium, inorganic phosphate, alkaline phosphatase, bilirubin, creatinine, T4, TSH, and PRL levels. Women with medical disorders or taking medications known to affect bone or mineral metabolism were excluded. If women were taking oral contraceptives or danazol, these medications were discontinued for at least 2 months before the start of the study. If women were taking GnRH analogs, these medications were discontinued for at least 9 months before the start of the study. The study was approved by the human research committee at Massachusetts General Hospital, and all women gave written informed consent.

Protocol

The women were admitted to the General Clinical Research Center at Massachusetts General Hospital between days 6–10 of their menstrual cycles. Women were randomly assigned by computer-generated cards to receive either a 2-h iv infusion of calcium (1.1 mg calcium gluconate/cc in 5% dextrose) at a rate of 4 cc/kg·h (n = 7) or a 24-h infusion of human (h) PTH-(1–34) (Parathar, Rhone-Poulenc Rorer, Inc., Collegeville, PA) at a dose of 0.55 U/kg·h (n = 9). Serum PTH and whole blood ionic calcium levels were measured at -20, -10, and 0 min and then every 10 min for 2 h (or until the ionic calcium level exceeded 1.5 mmol/L) during iv calcium infusions. Whole blood ionic calcium and 1,25-dihydroxyvitamin D levels were measured every 6 h for 24 h during iv hPTH-(1–34) infusions. After the calcium or hPTH-(1–34) infusions were completed, women were begun on the GnRH analog nafarelin acetate (Synarel, G.D. Searle & Co., Chicago, IL) at a dose of 200 µg, intranasally, twice daily for 6 months. If serum estradiol levels were not suppressed below 40 pg/mL after 3 months, the dose of nafarelin was increased by 200–400 µg/day. Women were evaluated by a research dietitian and asked to maintain a calcium intake of approximately 1200 mg/day through diet and/or calcium carbonate supplements. Six months after starting nafarelin therapy, women were readmitted to the General Clinical Research Center for a repeat iv infusion of either calcium or hPTH-(1–34) at a dose and rate identical to those used in their initial infusions.

Biochemical assays

Serum intact PTH and 1,25-dihydroxyvitamin D levels were measured using commercial kits (Nichols Institute Diagnostics, San Juan Capistrano, CA). Serum estradiol (21) was measured by RIA. All samples for PTH and 1,25-dihydroxyvitamin D for a given subject were analyzed in the same assay. Serum total calcium and inorganic phosphate levels were determined by autoanalyzer. Whole blood ionized calcium levels were measured in lithium heparin syringes using a NOVA calcium electrode. The intra- and interassay coefficients of variation were 3% and 6%, respectively, for PTH and 10% and 14% for 1,25-dihydroxyvitamin D.

Data analysis

Preinfusion serum calcium, inorganic phosphate, estradiol, PTH, and 1,25-dihydroxyvitamin D levels were compared at baseline and after 6 months of nafarelin therapy using paired t tests. The relationship between whole blood ionic calcium levels and the log of the serum PTH levels before and during GnRH analog therapy was assessed using a mixed model ANOVA. In this model, the fixed effects were period calcium and a calcium-period interaction. The random effects were a patient effect, a period effect, a calcium effect, and a calcium-period interaction. This model is similar to fitting a line for each patient in each period (i.e. before and during GnRH analog administration) and testing for a difference in slopes and intercepts using a paired t test. Serum ionic calcium and 1,25-dihydroxyvitamin D levels during iv hPTH-(1–34) infusion were expressed as absolute levels and incremental changes from baseline. Rates of change in serum 1,25-dihydroxyvitamin D levels were determined by calculating the slopes of the relationship between time and serum 1,25-dihydroxyvitamin D levels for each woman. Peak ionic calcium and 1,25-dihydroxyvitamin D levels, incremental changes in ionic calcium and 1,25-dihydroxyvitamin D levels, and the rates of change in 1,25-dihydroxyvitamin D levels in response to PTH infusions were compared before and after nafarelin administration using paired t tests. All data are expressed as the mean ± SD unless indicated otherwise. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
iv calcium infusions

Table 1Go shows the mean serum calcium, inorganic phosphate, PTH, 1,25-dihydroxyvitamin D, and estradiol levels determined just before the 0 and 6 month iv calcium infusions. As expected, serum estradiol levels were suppressed during nafarelin therapy (P = 0.013). There was no significant change in preinfusion whole blood ionic calcium levels or serum inorganic phosphate, PTH, and 1,25-dihydroxyvitamin D levels in response to nafarelin-induced estrogen deficiency.


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  		Table 1. Laboratory values before iv calcium infusions at baseline and after 6 months of nafarelin therapy

 
Serum PTH levels fell rapidly during iv calcium infusion (Fig. 1Go). When whole blood ionic calcium levels exceeded 1.30 mmol/L, serum PTH was suppressed to levels at or near the assay detection limit. There was no effect of GnRH analog administration on either the slope (F = 1.09; P = 0.317) or the intercept (F = 1.25; P = 0.286) of the relationship between whole blood ionic calcium and serum PTH levels before and during nafarelin-induced estrogen deficiency (Fig. 1Go). The extent of the difference in the average PTH level was 36 ± 61%, and the extent of the difference in the rate of PTH decline with increasing calcium was 20 ± 46%/U increase in calcium. When this analysis was performed, the log of PTH was linear in the calcium level.



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  		Figure 1. Mean (±SD) serum PTH levels during iv calcium infusions in women with endometriosis before (circles) and after (squares) 6 months of nafarelin administration. The PTH value before nafarelin therapy corresponding to an ionic calcium level of 1.10–1.15 mmol/L represents a single determination, so no error bar is included.

 
iv PTH infusions

Table 2Go shows the mean serum calcium, inorganic phosphate, PTH, 1,25-dihydroxyvitamin D, and estradiol levels determined just before the 0 and 6 month iv hPTH-(1–34) infusions. Once again, serum estradiol levels were suppressed during 6 months of nafarelin therapy (P = 0.012). There was a significant decrease in preinfusion serum 1,25-dihydroxyvitamin D levels in response to estrogen deficiency in this group of women (P = 0.036). Whole blood ionic calcium, serum inorganic phosphate, and serum PTH levels did not change during 6 months of nafarelin therapy.


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  		Table 2. Laboratory values before iv hPTH-(1-34) infusions at baseline and after 6 months of nafarelin therapy

 
Serum 1,25-dihydroxyvitamin D levels increased during iv hPTH-(1–34) infusion (Fig. 2Go). Although peak serum 1,25-dihydroxyvitamin D levels were higher after 24 h of iv hPTH-(1–34) administration before nafarelin therapy (Fig. 2Go), the difference was not statistically significant (P = 0.112). Moreover, the net increases (P = 0.834) and the rates of change (P = 0.181) in serum 1,25-dihydroxyvitamin D levels were similar before and after nafarelin therapy (Fig. 2Go).



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  		Figure 2. Mean (±SE) serum 1,25-dihydroxyvitamin D levels (left panel) and changes in serum 1,25-dihydroxyvitamin D levels (right panel) during iv hPTH-(1–34) infusions in women with endometriosis before (circles, solid lines) and after (squares, dashed lines) 6 months of nafarelin administration.

 
As expected, whole blood ionic calcium levels also increased during iv hPTH-(1–34) infusion (Fig. 3Go). Peak whole blood ionic calcium levels (Fig. 3Go) and incremental changes in whole blood ionic calcium levels (Fig. 3Go) in response to iv hPTH-(1–34) infusion were similar before and during nafarelin therapy.



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  		Figure 3. Mean (±SE) whole blood ionic calcium levels (left panel) and changes in whole blood ionic calcium levels (right panel) during iv hPTH-(1–34) infusions in women with endometriosis before (circles, solid lines) and after (squares, dashed lines) 6 months of nafarelin administration.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Despite overwhelming evidence that estrogen is essential for maintaining skeletal integrity, efforts to detect estrogen receptors in cultured bone cells and efforts to demonstrate that estrogen inhibits bone resorption in vitro were initially unsuccessful (22, 23). These negative results led many investigators to assume that the effects of estrogen on bone in vivo were indirect and were mediated by effects on the secretion or the skeletal response to classic calcium regulatory hormones such as PTH and 1,25-dihydroxyvitamin D. Subsequently, estrogen receptors were found to be present on various cells in bone, including human osteoblast-like (24) and osteoclast-like (25) cells, leading to important studies suggesting that the effects of estrogen on bone remodeling may be mediated, at least in part, by local effects in bone on the production of growth factors and cytokines (8, 26). Still, effects of estrogen on calcium homeostasis and the regulation of calcium regulatory hormones could play an important role in the physiological regulation of bone remodeling (9).

Estrogen could modulate PTH secretion either by a direct effect on the parathyroid glands or by indirect effects on serum calcium, inorganic phosphate, or 1,25-dihydroxyvitamin D levels. Several studies have shown that serum calcium and inorganic phosphate levels increase with estrogen deficiency and that serum calcium and inorganic phosphate levels decrease with estrogen replacement (9, 13, 27). Preinfusion ionic calcium levels did not change significantly in response to estrogen deficiency in our study. The failure to detect a significant increase in calcium levels is probably due to the small sample size. Prior studies have found that oral estrogen administration increases serum 1,25-dihydroxyvitamin D levels (14, 15, 17, 27, 28, 29, 30, 31), whereas transdermal estrogen does not (13, 32). Two small longitudinal studies did not detect a significant change in serum 1,25-dihydroxyvitamin D levels as women traversed the menopause (33, 34), although a significant decrease in serum 1,25-dihydroxyvitamin D levels was reported in women treated with nafarelin for 6 months (34). We found a similar decrease in serum 1,25-dihydroxyvitamin D levels in one of our two groups of women treated with nafarelin. Thus, it is plausible that changes in serum calcium or 1,25-dihydroxyvitamin D levels during estrogen deficiency or replacement could produce changes in circulating PTH levels that, in turn, might affect skeletal integrity.

It is still unclear whether estrogen can alter PTH secretion directly. Using sensitive molecular techniques, expression of estrogen receptor messenger ribonucleic acid has been demonstrated in parathyroid tissue (35). Thus, it is plausible that estrogen could have a direct effect on the synthesis or secretion of PTH. In fact, in tissue harvested from hyperplastic human parathyroid glands and human parathyroid adenomas, estrogen stimulates PTH release in a dose-dependent fashion (36). Boucher et al. reported that the relationship between serum calcium and PTH levels was altered after treatment of postmenopausal women with an oral estrogen and progestegin and concluded that estrogen alters the set-point for PTH release in postmenopausal women (12). Serum 1,25-dihydroxyvitamin D levels also increased in those patients, however, which may explain the failure of PTH levels to increase normally as calcium levels fell. Similarly, Cosman et al. reported that oral estrogen administration mitigated the rise in PTH in response to hypocalcemia in postmenopausal women (14). Once again, however, interpretation of the findings is complicated by a simultaneous increase in serum 1,25-dihydroxyvitamin D levels. In contrast, Prince et al. reported that transdermal estrogen, which did not alter serum 1,25-dihydroxyvitamin D levels, did not alter the ability of iv calcium to suppress PTH secretion (13). In all of these studies, estrogen was administered exogenously, so that the physiological relevance of the findings is not clear. In our study, women were cycling normally at the time of their initial evaluations and then had suppression of ovarian hormone production. Thus, their initial evaluations were performed in the setting of physiological gonadal steroid production. Importantly, serum 1,25-dihydroxyvitamin D and inorganic phosphate, both of which may affect parathyroid function independent of calcium, did not change significantly in the women who underwent iv calcium infusions. Using this model, our data suggest that ovarian hormones do not alter the ability of calcium to suppress PTH secretion. Thus, it seems unlikely that there is a significant direct effect of estrogen on parathyroid function in women.

As with PTH, estrogen could exert direct or indirect effects on 1,25-dihydroxyvitamin D formation. Studies performed in vitro have failed to demonstrate a direct effect of estrogen on 1,25-dihydroxyvitamin D formation (37, 38). Oral estrogen administration increases serum 1,25-dihydroxyvitamin D levels in vivo, however. The effects of oral estrogen on serum 1,25-dihydroxyvitamin D levels in vivo could be due to alterations in the production of known modulators of 1,25-dihydroxyvitamin D formation, including calcium, inorganic phosphate, and PTH, or in the sensitivity of the kidney to these factors.

The effect of estrogen on the ability of PTH to stimulate 1,25-dihydroxyvitamin D formation has been examined in several studies. Two groups reported that the net increase in circulating 1,25-dihydroxyvitamin D levels is similar before and during oral estrogen (17) or estrogen plus progestegin (14) replacement when PTH secretion is stimulated by hypocalcemia in postmenopausal women. Because the magnitude of the changes in PTH in response to hypocalcemia varied in these studies, the groups reached differing conclusions regarding the effect of estrogen on the ability of PTH to stimulate 1,25-dihydroxyvitamin D formation (16, 19). Prince et al. found that serum PTH and 1,25-dihydroxyvitamin D levels increased similarly in pre- and postmenopausal women given a low calcium diet, and they also concluded that the ability of PTH to stimulate 1,25-dihydroxyvitamin D formation was not altered by ovarian steroids (16). When PTH was infused iv into postmenopausal women, increases in 1,25-dihydroxyvitamin D levels were similar with and without oral estrogen administration (31), even when multiple doses of PTH were administered (15). In our study, basal (preinfusion) serum 1,25-dihydroxyvitamin D levels fell after nafarelin administration in the women who received PTH infusions, but ovarian suppression did not alter the ability of PTH to stimulate 1,25-dihydroxyvitamin D formation. Overall, the data indicate that ovarian hormones do not alter the responsiveness of renal 1{alpha}-hydroxylase to PTH. Changes in serum 1,25-dihydroxyvitamin D levels during oral estrogen or GnRH analog therapy are probably due to other factors such as changes in vitamin D-binding protein.

Studies examining the effect of estrogen on PTH-induced bone resorption in humans have produced variable results. Whereas one study reported that PTH-induced increases in serum calcium and urinary hydroxyproline excretion were greater in postmenopausal than in premenopausal women (19), another study failed to find such a difference (20). Differences in age, baseline bone density, or other factors between the pre- and postmenopausal women make these studies difficult to interpret. In a separate study, PTH-induced increases in urinary hydroxyproline and deoxypyridinoline excretion were smaller in estrogen-treated postmenopausal women than in untreated postmenopausal women (18). Unfortunately, however, there was also a large (9-yr) age difference between the two groups of women in that study. We failed to find any difference in PTH-stimulated ionic calcium levels before and during GnRH analog-induced estrogen deficiency. Because our women were studied before and after 6 months of GnRH analog therapy, the only major difference between the women during each infusion period was the suppression of ovarian function. Thus, our data suggest that ovarian hormones do not affect skeletal sensitivity to PTH.

Certain limitations of our study design deserve mention. Because we only examined the effects of increasing calcium levels on PTH secretion, we could not determine the set-point for PTH release before and during ovarian suppression. In addition, although serum estradiol levels were lowered dramatically by nafarelin, it is unknown whether our results might have been altered if serum estradiol levels had been suppressed even further. Changes in serum calcium during PTH infusion reflect both bone resorption and renal tubular reabsorption of calcium, although the latter effect is quite small during short term PTH administration (39). Finally, because the number of women studied in each protocol was relatively small, minor effects of ovarian hormones on calcium regulatory hormones might have been missed, although larger, physiologically important effects would have been detectable.

In summary, we found that suppression of ovarian hormone production did not alter the ability of calcium to suppress PTH secretion, the ability of PTH to stimulate 1,25-dihydroxyvitamin D production, or the ability of PTH to stimulate calcium release in young women. These findings suggest that alterations in the regulation of calcium regulatory hormones by ovarian hormones are unlikely to play a major role in the pathogenesis of estrogen deficiency bone loss.


   Acknowledgments
 
We are indebted to G.D. Searle & Co. (Chicago, IL; formerly Syntex Laboratories, Inc., Palo Alto, CA) for supplying the nafarelin acetate (Synarel) used in this study, to Ms. Pamela Miller for performing the biochemical assays, to the nursing staff of the General Clinical Research Center at Massachusetts General Hospital for their meticulous performance of the study protocol and their dedicated care of the patients, and to Drs. Robert M. Neer and Anne Klibanski for their scientific guidance.


   Footnotes
 
1 This work was supported by NIH Grants R29-DK-43341 and RR-1066 and a NIH Clinical Associate Physician Award (to J.S.F.). Back

Received November 20, 1998.

Revised March 2, 1999.

Accepted March 8, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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