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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 658-665
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

Treatment of Isolated Hypogonadotropic Hypogonadism Effect on Bone Mineral Density and Bone Turnover

Chun-Yuan Guo, T. Hugh Jones and Richard Eastell

Departments of Human Metabolism and Clinical Biochemistry (C.-Y.G., R.E.) and Medicine (T.H.J.), University of Sheffield, Clinical Sciences Center, Northern General Hospital, Sheffield, United Kingdom S5 7AU

Address all correspondence and requests for reprints to: Prof. R. Eastell, Department of Human Metabolism and Clinical Biochemistry, Clinical Sciences Center, Northern General Hospital, Sheffield, United Kingdom S5 7AU.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Isolated hypogonadotropic hypogonadism (IHH) presents with delayed puberty in the late teens or early twenties, with a period of testosterone deficiency during active growth. The aims of the study were to determine 1) whether long term treatment of IHH results in normalization of bone density (BMD) and bone turnover, and 2) whether BMD and bone turnover respond to increasing doses of hCG. We studied 10 men, aged 26–46 yr, with IHH who were treated with hCG or testosterone esters (Sustanon) for 2–22 yr, with age at the start of treatment between 17–29 yr, and 10 age- and body weight-matched normal men as a control group. At baseline, lumbar spine, femoral neck, trochanter, and Ward’s triangle BMD values were decreased, and serum bone Gla-protein, bone alkaline phosphatase, and urinary pyridinoline, deoxypyridinoline, and N-terminal telopeptide of type I collagen were increased compared with control values (by paired t test, P = 0.02, 0.03, 0.01, 0.05, 0.002, 0.02, 0.02, 0.007, and 0.006, respectively). The age at initial therapy was significantly correlated with total body BMD (r = -0.73; P = 0.017) and lumbar spine BMD (r = -0.756; P = 0.0097). Serum free testosterone was correlated with total body and trochanter BMD (r = 0.635; P = 0.048 and r = 0.629; P = 0.05), and serum free estradiol was correlated with total body and trochanter BMD (r = 0.641; P = 0.045 and r = 0.634; P = 0.048). Six of the 10 patients were recruited for a longitudinal study in which the dose of hCG was increased monthly from 2000 IU twice per week to 6000 IU twice per week. After increasing doses of hCG, levels of serum testosterone and estradiol and total body BMD increased significantly (by paired t test P = 0.001, 0.003, and 0.01, respectively). Serum bone Gla-protein levels increased by the first month and then decreased (paired t test, corrected by Bonferroni’s method). Serum bone alkaline phosphatase and urinary N-terminal telopeptide of type I collagen/creatinine levels decreased significantly after increasing the dose of hCG. We conclude that patients with IHH who have serum testosterone within the laboratory reference range may require a higher dose of hCG to normalize BMD and bone turnover.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT IS WELL known that testosterone insufficiency is a major risk factor for male osteoporosis (1, 2, 3, 4). Although osteoporosis is more common in women, when it occurs in men there is significant morbidity (1, 5). It has been reported that men with isolated hypogonadotropic hypogonadism (IHH) of prepubertal onset have a markedly decreased bone mineral density (BMD) in both cortical and trabecular envelopes compared to age-matched controls (3). BMD fails to return to the reference range after serum testosterone levels has been maintained in the adult male reference range for at least 1 yr (6). There have been no studies to determine whether BMD returns to normal after longer term treatment in men with IHH. A recent case report showed that androgen alone is not sufficient to promote skeletal maturation and retain bone mass, and that estrogen has a pivotal role in mineralization of the skeleton in males as well as females (7). It is not clear whether estrogen plays any role in the maintenance of BMD in men with IHH.

Hypogonadism in men is usually associated with an increase in bone remodeling (4, 8, 9, 10, 11). There have been no studies to determine how bone remodeling responds to testosterone treatment and whether estrogen has a role in the treatment of IHH in men. Several bone-specific biochemical markers of turnover have recently been introduced that allow the evaluation of small changes in bone remodeling.

Bone formation may be assessed by serum bone Gla protein (BGP) (12, 13) and serum activity of bone alkaline phosphatase (BAP) (14, 15, 16). Bone resorption may be assessed by the serum activity of tartrate-resistant acid phosphatase (TRAP) (17, 18) and the urinary excretion of pyridinoline (Pyr), deoxypyridinoline (Dpyr) (19, 20, 21, 22, 23, 24), and the N-terminal telopeptide of type I collagen (NTx) (14).

The aims of the present study were to determine 1) whether long term treatment of IHH results in normalization of BMD and bone turnover, 2) the BMD and bone turnover responses to increasing doses of hCG, and 3) whether estradiol plays any role in bone metabolism in men with IHH.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Cross-sectional study

Ten Caucasian men with IHH, aged 26–46 yr (mean, 34; SD, 6) and weighing 66–104 kg (mean, 85.7; SD, 15.4) at the time of the study, were recruited (Table 1Go). Patients were diagnosed by clinical features and biochemical testing (testosterone, pituitary hormones, and LH-releasing hormone stimulation test; Table 1Go). Computerized axial tomography of the pituitary was normal on initial presentation of each subject. All patients presented with delayed puberty. Two patients had Kallmann’s’ syndrome-associated anosmia with IHH, 7 had idiopathic IHH, and 1 had posttraumatic IHH. The patient with posttraumatic IHH presented at age 18 yr with delayed puberty and had a history of head injury at age 12 yr. The range of the initial age at starting treatment was 17–28 yr (mean, 23; SD, 4). The duration of treatment was 2–22 yr (mean, 10; SD, 6). Over the previous 2 yr, 7 patients were treated with hCG, 2 with testosterone esters (Sustanon), and the other 1 with hCG in the first 6 months, then with Sustanon for the next 18 months (Table 1Go). The doses of hCG ranged from 2000–4000 IU twice per week, and the dose of Sustanon ranged from 125–250 mg every 2 weeks depending on the level of serum testosterone. Blood samples were taken within 1–3 days after hCG injection. Our previous study showed that hCG therapy resulted in less day to day variation in testosterone levels than exogenous testosterone therapy and in some patients induces a normal or near-normal diurnal variation in testosterone production (25). The range of median serum testosterone levels in the last 2 yr was 11.6–29.0 nmol/L (male reference range, 9.4–37.0; Table 1Go). The interval between serum testosterone measurements was 1–4 months over the 2-yr period. When all available data on testosterone measurements were evaluated for the past 2 yr (a total of 141 determinations of testosterone), abnormally low levels of testosterone (<9.4 nmol/L) were found in 11 of 141 (7.8%) determinations. The reason for low levels of testosterone was that some blood samples were taken immediately before hCG or Sustanon injections or the subjects missed an injection before their routine clinic appointments. Ten healthy men, aged 27–47 yr (mean, 34.6; SD, 7.2) yr and weighing 70–98 kg (mean, 82; SD, 11.4), were recruited as controls. Age and body weight in patients and controls were individually matched (±2 yr and ±9 kg).


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  		Table 1. Age, diagnosis, duration of treatment, testosterone, and therapies over previous 2 yr and pretreatment tests

 
Longitudinal study

Six of the 10 patients were recruited for an escalating dose study. All 6 patients were treated with hCG. The doses of hCG from all 6 patients were reduced to 2000 IU twice per week for 1 month and then baseline blood and 24-h urine samples were taken and BMD measurements were made. After baseline samples were collected, the doses of hCG were increased to 3000 IU twice per week for 1 month, 4000 IU twice per week for 1 month, 5000 IU twice per week for 1 month, and finally, 6000 IU twice per week for 1 month. Two of the 6 patients remained on 5000 IU twice per week for 2 months in the last 2 months. Blood and 24-h urine samples were collected at the end of every month, and BMD measurements were repeated at the end of last month in the longitudinal study.

No test subject had any of the following diseases that are known to affect bone metabolism: diseases of the thyroid, parathyroid, adrenals, kidney, or liver; hypothalamus-pituitary tumors; diabetes mellitus; or history of fracture in the last year. No test subject had taken any medication that could cause bone loss within the last 2 yr. All subjects gave written informed consent, and the study was approved by the ethical committee of the Northern General Hospital (Sheffield, UK).

Methods

Serum levels of total and free testosterone (TT and FT), total and free estradiol (TE2 and FE2), intact PTH, BGP, BAP, and TRAP; urinary excretion of Pyr, Dpyr, and NTx; and BMD in total body, lumbar spine, and hip were measured in all test subjects. The Pyr, Dpyr, and NTx excretions were expressed by the ratio to 24 h urinary creatinine (Cr) excretion (Pyr/Cr, Dpyr/Cr, and NTx/Cr). Serum levels of TT, FT, and TE2 were determined by RIA using commercially available kits (Coat-A-Count, Diagnostic Products Corp., Los Angeles, CA), and FE2 was measured by equilibrium dialysis (Nichols Institute Diagnostics, San Juan Capistrano, CA). Serum intact PTH was measured by immunoradiometric assay, using a commercial available Allegro INTACT PTH kit (Nichols Institute Diagnostics). The intraassay coefficient of variation was 4%, and the interassay coefficient of variation was 6%. Serum BGP levels were measured by commercial available kits using an immunoradiometric assay (CIS Bio International, France). The overall intra- and interassay coefficients of variation were 4% and 6%, respectively. Serum BAP activity was measured by wheat germ lectin assay (12, 13, 26), with intra- and interassay coefficients of variation of 3% and 5%, respectively. Serum TRAP activity was measured by enzyme assay (18), with intra- and interassay coefficient of variation of 2% and 4%, respectively. All blood samples were taken in the fasting state between 0900–1000 h. Urinary Pyr and Dpyr were measured in 24-h urine collections by high performance liquid chromatography (20). The intra- and interassay coefficients of variation were 7% and 9%, respectively. NTx were measured in the 24-h urine collections by enyzme-linked immunosorbent assay (Ostex International, Seattle, WA); the intra- and interassay coefficients of variation were 5% and 7%, respectively. BMD in total body, lumbar spine, and hip was measured by DXA (Lunar DPX, Lunar Corp., Madison, WI). The precision of the BMD measurement was 1%, 1%, and 3%, respectively, in total body, lumbar spine, and femoral neck. The phantom scans were made using an aluminum spine phantom provided by Lunar, and they were performed over the same time period as the patient scans. The coefficient of variation for the phantom scans was 0.67%. The mean slope and the SE of the line for the phantom scans during the study period were 0.0000089 and 0.0000091. This estimate for the slope does not differ from zero.

In the cross-sectional study, BMD and biochemical markers of bone turnover in patients and controls were compared by one-sample t test. BMD was adjusted by age (Z-score) to determine the relationship to age of initial therapy, duration of treatment, and sex hormones. In the longitudinal study, the areas under the curves for the changes in TT, FT, TE2, and PTH were calculated to determine whether the changes from baseline were different from zero. Repeated measures ANOVAs and one-sample t test with Bonferroni’s correction were used to compare the changes in biochemical markers of bone turnover between different time points. Three of the six above biochemical markers of bone turnover (serum BGP and BAP and urinary NTx/Cr) were measured in the longitudinal study.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Cross-sectional study

Serum levels of sex hormone and intact PTH in the patients did not differ from those in paired controls. Serum BGP levels (P = 0.002), serum activity of BAP (P = 0.02), and 24-h urinary excretion of Pyr/Cr (P = 0.02), Dpyr/Cr (P = 0.007), and NTx/Cr (P = 0.006) were increased, whereas BMD at the lumbar spine (P = 0.02), femoral neck (P = 0.03), trochanter (P = 0.01), and Ward’s triangle (P = 0.05) was decreased in patients compared with control values (Fig. 1Go).



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  		Figure 1. Comparison of BMD and biochemical markers of bone turnover between patients and age-matched controls. The Z scores were derived from the controls. The reference range is defined as a Z-score between +2 and -2 (area between dotted lines).

 
The age at initial therapy was significantly correlated with total body BMD (r = -0.73; P = 0.017) and lumbar spine BMD (r = -0.756; P = 0.0097) after age and body weight adjustment (Fig. 2Go). Linear regression analysis showed that total body BMD would be a Z-score of -2 if the age at starting treatment was 24 yr (y = 9.762 - 0.487x), whereas lumbar spine BMD would be a Z-score of -2 if the age at starting treatment was 21 yr (y = 6.372 - 0.303x). BMD at the total body and trochanter was positively correlated with serum FT and FE2 after log transformation of hormone data (Table 2Go). There was a significant positive correlation between serum testosterone and estradiol levels (TT vs. TE2, r = 0.90 and P < 0.001; FT vs. FE2, r = 0.92 and P < 0.0001). No correlation was found between duration of treatment and bone density or bone turnover. There were no significant correlations between biochemical markers of bone turnover and serum sex hormone levels or between BMD and either age or body weight in either group.



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  		Figure 2. Relationship between the age at initial therapy and total body BMD (y = 9.762 - 0.487x; r = -0.73; P = 0.01), age at initial therapy and lumbar spine BMD (y = 6.372 - 0.303x; r = -0.76; P = 0.0097)

 

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  		Table 2. Correlations between BMD (Z score) and other parameters

 
Longitudinal study

Serum TT, FT, TE2, and PTH levels increased significantly after increasing the dose of hCG. The areas under the curve of changes in TT, FT, TE2, and PTH were all greater than zero (by one-sample t test, P < 0.01 for all measurements; Fig. 3Go). Serum BGP levels increased significantly at the end of the first month and then decreased gradually. The decrease was significant at the end of the last month compared with baseline (by one-sample t test with Bonferroni’s correction). Serum BAP levels did not change significantly until the last month of treatment. Urinary NTx/Cr levels decreased significantly in the last 3 months of treatment (Fig. 4Go). BMD of the total body increased significantly during the 4-month period (by one-sample t test, P = 0.01). The mean total body bone mineral content (grams) increased 3.4% (95% confidence interval, 1.2–5.7%). A mean increase of 4.7% (1.6–7.9%) in lean total body mass was found in the six patients. There was no significant change in body weight, except in one patient who lost 14 kg due to a reducing diet. BMD at the lumbar spine, femoral neck, and trochanter increased in all patients except the patient who was receiving the reducing diet (Fig. 5Go). There was no correlation between mean BMD and rate of change in BMD in the six patients. We did not find a correlation between the changes in sex hormones and the change in BMD.



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  		Figure 3. Changes in serum levels of sex hormones and PTH in response to treatment with hCG. The area under the curve was calculated to compare with the baseline. The area between dotted lines represents the reference range. By one-sample t test, P < 0.01 for all measurements.

 


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  		Figure 4. Changes in biochemical markers of bone turnover in response to treatment with hCG. Repeated measures ANOVA was significant for all three markers (P < 0.05). *, By one-sample t test with the Bonferroni correction, P < 0.05.

 


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  		Figure 5. Changes in BMD in response to treatment with hCG. The patient with decreased BMD at the lumbar spine and femoral neck lost 14 kg in 4 months. By one-sample t test, P < 0.05 for total body BMD.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
It is unclear whether BMD and bone turnover related to hypogonadism can be restored to normal after long term adequate androgen replacement therapy. Isolated gonadotropin deficiency of prepubertal onset is an uncommon disorder, hence the small cohort of patients in this study. We found that BMD and bone turnover in patients with IHH did not normalize despite serum TT levels that had been maintained within the male reference range for at least 2 yr. The finding of low BMD in IHH patients who have been receiving long term therapy in the present study is consistent with previous studies (3, 6). Prior studies on bone turnover in men with hypogonadism have not been consistent in their findings. In a histomorphometric study, Finkelstein et al. (6) showed that seven of the nine patients with IHH had a low bone turnover, whereas the other two patients had normal or high bone turnover. In another histomorphometric study, Jackson et al. (8) reported that bone turnover was increased significantly in men with hypogonadism-induced osteoporosis compared with that in either men with idiopathic osteoporosis or postmenopausal women. In the same study, bone turnover decreased after testosterone treatment. In studies of biochemical markers of bone turnover, increased serum BGP levels have been reported in men after castration (10) and in men with significantly decreased serum testosterone levels resulting from GnRH agonist administration for 1 yr (11).

The reason for these different findings is not clear. The decreased BMD and increased bone turnover in the present study may indicate that even though serum testosterone levels are within the normal range, they are too low to maintain normal bone metabolism. In patients 5, 8, and 10, serum TT and FT levels were below the male reference range or at the lower limit at the time when samples were taken. Blood samples were taken immediately before Sustanon or hCG injection in the three patients. Patients 5 and 8 were treated with Sustanon, and patient 10 was taking hCG. The serum TT and FT levels only can represent the testosterone levels when blood samples were taken in these patients and do not indicate whether there is adequate tissue androgenization. Currently, there is no known marker of this parameter over a period of time. Furthermore, serum TT and FT levels in the patient group were not significantly decreased compared with those in the control group.

At baseline, total body BMD was not decreased significantly compared with the control value. Our linear regression showed that BMD at total body and lumbar spine would be less than a -2 Z-score if the age of initial therapy was greater than 24 and 21 yr, respectively, compared with that in age-matched healthy subjects. Eight of the 10 patients were 19–25 yr old, and 1 was 17 yr old at the initiation of treatment. There may be a critical period of skeleton response to sex hormones during development. This finding underlines the importance of starting treatment early to optimize bone mineralization. However, we did not find a correlation between the BMD at any skeletal site and the duration of treatment in our patients. Apart from late treatment, a further possibility to explain this phenomenon is a genetic one, although no such factors have previously been identified. Serum FT and FE2, rather than TT and TE2, were correlated with total body and trochanter BMD in the present study. This finding shows that the serum FT and FE2 are more valuable than serum TT and TE2 to evaluate the relationship between sex hormone levels and BMD in patients with IHH.

Our longitudinal study showed a response of total body BMD and bone turnover in patients with IHH to high dose administration of hCG even though serum testosterone had previously been maintained within the reference range. The increase in total body BMD was 4–5.6% in 4 months. This response seems to support the hypothesis that total body BMD was more sensitive to sex steroid replacement than skeletal sites in trabecular bone in patients with IHH. We observed a mean change of 4.7% in lean total body mass in our six patients. It is possible that change in body composition caused by testosterone may affect the estimate of total body BMD. Lumbar spine, femoral neck, and trochanter BMD increased by 4 months in five of the six patients; the patient who did not gain bone lost 14 kg in weight.

Bone formation decreased significantly at the end of the study, whereas bone resorption decreased within 2 months of starting high dose hCG treatment. The response of serum BGP levels to the administration of hCG was biphasic in these patients. It has been reported that testosterone can stimulate the activity of bone formation over 6 months in healthy men (27). Our data show that the response of bone formation to testosterone in men with IHH is dependent on dose, time course, or, possibly, serum estrogen levels. Serum PTH levels increased significantly in the present study; this is consistent with a previous report (27). The increased PTH was possibly due to the decreased serum calcium level, which, in turn, resulted from decreased bone turnover. Decreased serum calcium has been reported in healthy men receiving high dose testosterone treatment even though the reason for decreased serum calcium was unclear in this study (27). Decreased 24-h urinary calcium levels were found in a similar study in which healthy men were given high dose testosterone as a male contraceptive (28).

Estrogen can inhibit bone turnover in women and has proven to be a major protective factor for female osteoporosis. We found a significant correlation between serum estradiol and testosterone levels, although the levels of both testosterone and estradiol in patients were not significantly decreased compared with those in paired controls in a cross-sectional study. In the longitudinal study, serum estradiol levels were increased in parallel with serum testosterone levels after increasing the hCG dose. The stimulation of estradiol levels during hCG therapy is probably due to the induction of testicular aromatase activity as well as some peripheral aromatization of testosterone (29, 30, 31). There was a positive correlation between total body BMD and serum estradiol levels in our cross-sectional study. This may indicate that estrogen has a protective role in men and implies that hCG may be a better treatment than exogenous testosterone for men with IHH with respect to bone integrity. It is not clear whether the protective role of estrogen in men is accounted for by synergy between estrogen and testosterone or whether they are independent of each other. It has previously been suggested that the effects of androgen deficiency on bone are related to low estrogen levels, presumably due to the reduced amount of testosterone available for peripheral conversion to estradiol by aromatization (32). Because serum estradiol levels were markedly elevated in response to hCG administration, it is difficult to determine whether the changes in bone density and bone turnover in our patients were due to the increases in testosterone, estradiol, or both.

We conclude that patients with IHH receiving long term therapy have increased bone turnover and decreased BMD, especially at trabecular bone sites. Both bone turnover and BMD responded well to the administration of high dose hCG. Biochemical markers of bone turnover may have a value in assessing adequate tissue androgenization. Estrogen may play an important role together with androgen to normalize bone turnover in men with IHH. This study underlines the importance of starting treatment early to optimize bone development.


   Acknowledgments
 
We are grateful to Esther Carlton of Nichols Institute for measurements of serum free estradiol, and Ostex International (Seattle, WA) for the NTx kits supplied free of charge. We thank Mrs. A. Johnson and Mrs. S. Bowles and Mr. A. Milne for BMD measurements.

Received July 9, 1996.

Revised October 2, 1996.

Accepted October 6, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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