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Six-Year Results of Spironolactone and Testolactone Treatment of Familial Male-Limited Precocious Puberty with Addition of Deslorelin after Central Puberty Onset

Developmental Endocrinology Branch, National Institute of Child Health and Human Development (E.W.L., J.J., K.M.B., G.B.C.), and the Department of Radiology (S.C.H.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Ellen Leschek, M.D., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: ellen_leschek{at}nih.gov

	Abstract

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Short term treatment with spironolactone, testolactone, and, after the onset of central puberty, deslorelin can normalize the rate of growth and bone maturation in boys with familial male-limited precocious puberty. To test the hypothesis that this treatment can achieve long term normalization of the growth and development of these children, we examined the growth rate, bone maturation rate (change in bone age/change in chronological age), and predicted adult height of 10 boys who were treated with spironolactone (5.7 mg/kg·day) and testolactone (40 mg/kg·day) for at least 6 yr. Deslorelin (4 µg/kg·day) treatment was initiated 2.6 ± 1.3 yr after beginning spironolactone and testolactone treatment.

The growth rate normalized within 1 yr of starting treatment and remained normal during the next 5 yr of treatment (P < 0.001). The rate of bone maturation normalized during the second year of treatment and remained normal thereafter (P < 0.001). Predicted height increased from 160.7 ± 14.7 centimeters at baseline to 173.6 ± 10.1 centimeters after 6 yr of treatment (P < 0.05 during the fourth through the sixth year of treatment compared to baseline).

We conclude that long term treatment with spironolactone, testolactone, and, after central puberty, deslorelin normalizes the growth rate and bone maturation and improves the predicted height in boys with familial male-limited precocious puberty. The ultimate effect of this approach on adult height will require further study.

	Introduction

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FAMILIAL male-limited precocious puberty (FMPP; also termed testotoxicosis) is a LH-releasing hormone (LHRH)-independent form of precocious puberty (1, 2, 3, 4, 5) resulting from an activating mutation of the LH receptor (6). The mutation either occurs de novo or is inherited in an autosomal dominant fashion. Affected males usually begin pubertal development by 1–3 yr of age, which leads to rapid growth and bone maturation, progressive virilization, and, ultimately, premature epiphyseal fusion and adult short stature.

Five approaches to the treatment of this disorder have been attempted. Long-acting LHRH agonist has proven ineffective as a sole agent (2, 7). Two patients treated with medroxyprogesterone acetate and one patient treated with cyproterone have been described (2, 8). Decreased growth velocity and lowering of testosterone levels were observed in these three patients, but the available data are not sufficient to evaluate the long term effects of these agents on growth and development.

Two other therapies have been shown to be effective in the treatment of FMPP. The first, ketoconazole (9, 10, 11), inhibits several biosynthetic steps in the production of both adrenal and gonadal steroids (9, 12, 13), and serum testosterone levels can be monitored to assess efficacy. However, despite treatment with ketoconazole, patients ultimately undergo an escape phenomenon (secondary central precocious puberty), resulting in the need for additional therapy with LHRH agonist (11). In addition, ketoconazole hepatotoxicity (14, 15) is a recognized adverse effect (16). Ketoconazole hepatotoxicity is idiosyncratic (15).

The second therapeutic regimen that has been shown to be effective in FMPP is the combination of spironolactone (an antiandrogen that antagonizes androgen at the receptor level), testolactone (an aromatase inhibitor that blocks the conversion of androgen to estrogen), and, once secondary central puberty has started, deslorelin (a LHRH agonist) (17, 18). This combination includes an aromatase inhibitor because of the critical role of estrogen in promoting epiphyseal fusion (19, 20). As with ketoconazole, LHRH agonist therapy is required once central puberty begins. Unlike ketoconazole, this drug regimen has little or no effect on the serum testosterone level, and therefore, efficacy must be assessed by monitoring growth, bone maturation, virilization, and sexual behaviors. No serious adverse effects have been observed with any of the medications in this regimen.

To determine whether long term treatment with spironolactone, testolactone, and deslorelin (after central puberty has begun) is effective in sustaining normalization of growth and bone maturation, we studied growth and bone maturation in 10 boys treated with spironolactone and testolactone for at least 6 yr. Growth velocity and bone maturation returned to prepubertal levels during the first year of therapy and stayed there for the duration of treatment. Predicted height appeared to improve progressively throughout the treatment period.

	Subjects and Methods

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Patients (Table 1)

The 10 boys with FMPP had a known activating mutation of the LH receptor (D578G, substitution of aspartic acid by glycine at position 578 of the LH receptor). They ranged in age from 2.3–5.6 yr at the start of therapy, and their bone ages ranged from 4–13.5 yr. The duration of symptoms before starting therapy ranged from 0.5–2.6 yr. Bone age advancement at the onset of therapy was 1.7–8.9 yr. Deslorelin was started at chronological age 4.7–9.5 yr (bone age, 10–15.5 yr), between 0.2–4.2 yr after starting spironolactone and testolactone treatment. Seven of the 10 patients had acne at baseline, and 7 of the 10 parents reported frequent spontaneous erections and behaviors thought to reflect puberty, such as acting-out and wide fluctuations in mood.

The protocol was approved by the Institutional Review Board of the NICHD. Informed consent was obtained from the parents, and assent was obtained from the older children. Pretreatment growth velocity was determined over an interval of 3–12 months. Height was measured at 0800 h (the average of 10 stadiometer heights). Bone age was determined by the method of Greulich and Pyle, interpreted by a single radiologist who was unaware of the patient’s treatment (21). The rate of bone maturation was calculated by dividing the interval change in bone age by the interval change in chronological age. Predicted height was determined by the Bailey-Pinneau method (22). Testicular volume was measured at each visit by Prader orchidometer (23) and testicular ultrasound, and pubic hair stage was assessed by the method of Tanner (24). Gonadotropin levels were measured 30 and 15 min before and immediately before a 100-µg iv bolus injection of LHRH (gonadorelin) and at 15, 30, 45, 60, 90, and 120 min thereafter.

Spironolactone was given daily in two oral doses. The dose was 1.5 mg/kg·day during the first 1–2 weeks, 3.0 mg/kg·day during the second 1–2 weeks, and 5.7 mg/kg·day thereafter. Testolactone was initially administered in four divided doses, which was later changed to three doses (20 patient-yr, four times daily; 40 patient-years, three times daily). Testolactone therapy was started at 20 mg/kg·day during the first 1–2 weeks and increased every 1–2 weeks to 30 mg/kg·day and then 40 mg/kg·day. LHRH analog (deslorelin, D-Trp⁶-Pro⁹-Des-Gly¹⁰-LHRH ethylamide) was started at the onset of secondary central precocious puberty at a dose of 4 µg/kg·day administered each evening. The decision to start LHRH agonist was based on both clinical evidence of central puberty (an acute increase in the signs and symptoms of puberty) and a LHRH test that was either frankly pubertal or approaching a pubertal response (Table 2). Doses of medications were adjusted at 6-month intervals.

LH, FSH, and testosterone were measured by RIA (Hazleton Laboratories, Vienna, VA), as previously described (25, 26).

Statistical analysis

All data are expressed as the mean ± SEM. Changes with treatment were evaluated by ANOVA for repeated measures. Data at individual time points during treatment were compared to pretreatment values using two-tailed paired Student’s t test with the Bonferroni adjustment for multiple comparisons.

	Results

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Growth rate, bone maturation, and predicted height

After 1 yr of treatment, growth rate decreased from 16.1 ± 1.1 cm/yr to 7.5 ± 0.6 cm/yr (P < 0.005; Fig. 1a). During the subsequent 5 yr of treatment, growth rate normalization was maintained (P < 0.005 vs. pretreatment). Similarly, growth velocity SDS decreased from 6.9 ± 1.0 to 1.1 ± 0.4 (P < 0.005; Fig. 1b) after 1 yr of treatment and continued to be significantly lower during the next 5 yr of treatment (P < 0.005 vs. pretreatment).

View larger version (25K): [in this window] [in a new window]   Figure 1. Growth velocity (a), growth velocity SD score (b), bone maturation (c), and predicted height (d) during 6 yr of treatment in 10 patients with FMPP. Values are the mean ± SEM.

Predicted height appeared to increase progressively after the first year of treatment. By the fourth, fifth, and sixth years, it had increased from 160.7 ± 4.6 cm (pretreatment) to 169.6 ± 2.8 cm (fourth year; P < 0.025 vs. pretreatment), 171.3 ± 3.0 cm (fifth year; P < 0.01 vs. pretreatment), and 173.6 ± 3.2 cm (sixth year; P < 0.005 vs. pretreatment; Fig. 1d).

Gonadotropins and sex steroids

Peak LHRH-stimulated LH levels at the start of treatment (7.2 ± 1.5 IU/L) were in the prepubertal range in all subjects (Fig. 2). By 5 and 6 yr of treatment, all of the boys had entered central puberty, and their baseline and stimulated gonadotropin levels were maintained in the prepubertal range by the administration of deslorelin.

View larger version (23K): [in this window] [in a new window]   Figure 2. Peak LH level during 6 yr of treatment in 10 patients with FMPP before and after initiation of LHRH analog treatment.

View larger version (17K): [in this window] [in a new window]   Figure 3. Testosterone levels during 6 yr of treatment in 10 patients with FMPP. Values are the mean ± SEM.

Rarely, gastrointestinal upset was noted with testolactone administration. This resolved spontaneously in all cases without any reduction in medication dose. Electrolytes remained normal in all patients throughout the study. No hepatic, renal, or hematological abnormalities were noted during the study. Patients and parents were instructed to withhold medications during gastrointestinal illnesses to prevent hyponatremia.

Clinical characteristics

Seven of the 10 boys had acne that had improved by the 6-month visit after starting spironolactone and testolactone. Two of the four boys whose parents complained of aggressive behavior before treatment had improved behavior within 6 months of starting treatment.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Short term treatment with spironolactone, testolactone, and deslorelin has been shown previously to normalize the rate of growth and bone maturation and to improve signs and symptoms of early puberty in patients with FMPP (17, 18). We have now demonstrated that these effects are sustained during long term treatment in 10 patients for at least 6 yr. In addition, predicted adult height appears to increase progressively after the first year and attains statistical significance after 4 yr (compared to the predicted height before treatment). Further, no significant adverse effects were observed during the long term administration of these drugs.

Some baseline variability exists among the patients studied in this series. Some boys had more advanced development than others when treatment was initiated. In addition, despite the fact that all of the boys had the same LH receptor mutation, the onset and rate of pubertal progression before treatment varied among boys with FMPP. Despite this variability, the patients in this series experienced significant and sustained improvement in growth velocity, bone maturation, and predicted height.

The rarity of FMPP has resulted in a paucity of data concerning the treatment of this disorder (17, 18), and the current report, as far as we are aware, describes both the largest group of patients and the longest duration of treatment for which comprehensive results are available. This report demonstrates that long term treatment is safe and provides continued normalization of growth rate and bone maturation and sustained improvement of predicted height. Short term treatment of FMPP with ketoconazole and LHRH analog (11) had similar effects, but there are no long term data documenting its continued benefit and safety. In addition, one patient with FMPP developed severe hepatotoxicity while undergoing treatment with ketoconazole (16).

Long term treatment with spironolactone, testolactone, and deslorelin safely normalizes the rate of growth and bone maturation and improves predicted height in boys with FMPP. The effect of this treatment regimen on final adult height will require further study as the patients in this series complete their growth.

	Footnotes

 
Current address: Eli Lilly & Co., Lilly Research Laboratories, Indianapolis, Indiana 46285.

Received March 4, 1998.

Revised September 30, 1998.

Accepted October 12, 1998.

	References

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