The role of sex steroids in the regulation of insulin sensitivity and serum lipid concentrations during male puberty: a prospective study with a P450-aromatase inhibitor

Wickman, Sanna; Saukkonen, Tero; Dunkel, Leo

doi:10.1530/eje.0.1460339

Cited by 40 publications

(34 citation statements)

References 37 publications

(30 reference statements)

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“…Recent studies by Dunkel and co-workers [6][7][8] in Finland showed results generally consistent with our observations. The authors compared the effect of letrozole plus testosterone to testosterone alone in treating boys with delayed puberty.…”

Section: Discussionsupporting

confidence: 93%

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Letrozole Significantly Improves Growth Potential in a Pubertal Boy With Growth Hormone Deficiency

et al. 2005

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ABSTRACT. Clinical experience with using an aromatase inhibitor to suppress estrogen production during puberty for improvement of growth potential in adolescents with short stature is limited. This report documents treatment of such a patient with a combination of growth hormone and letrozole, a third-generation aromatase inhibitor. Our case demonstrates a favorable outcome on a short-term basis. E strogen plays a critical role for the pubertal growth spurt, skeletal maturation, and accrual and maintenance of bone mass in females as well as males. [1][2][3][4] It is now evident that gene mutations of aromatase or estrogen receptor that result in impairment of estrogen production or action have similar phenotypes, including abnormally tall stature with eunuchoid proportions, a lack of pubertal growth spurt, unfused epiphyses, and osteopenia. Aromatase, encoded by the CYP19 gene located on chromosome 15q21.2 and expressed in bones, is the key enzyme for estrogen biosynthesis. 2,4 It has been proposed that an aromatase inhibitor (AI) can be used to improve the final adult height in short pubertal boys. The hypothesis is that suppressing estrogen formation after the onset of puberty would delay the closure of the epiphyses, thus allowing for an extended period of growth without affecting the progression of androgenic development. Potential adverse effects of AIs, such as reduced bone mineral density (BMD), metabolic effects including a propensity for insulin resistance and dyslipidemia, and impairment of the hypothalamic-pituitary-gonadal axis, need to be considered. 5 To date, a couple of studies, at least in the short term, indicate that the use of an AI is safe and promising. 6-8 CASE REPORTA white male was first seen for evaluation of short stature at 14 years 8 months old. He was healthy with no other medical problems, and his birth weight and length were reported as normal. Family history was unremarkable. His father's height was 177.8 cm, and his mother's height was 162.5 cm. His midparental target height was 176.7 cm (calculated as the average of parents' heights ϩ 6.55). His initial examination revealed the following: height, 143 cm (Ͻ3rd percentile; z score Ϫ2.94); upper/lower segment ratio, 1.0; weight, 44.5 kg (11th percentile); pubic hair, Tanner II; testicular volume, 4 to 6 mL; bilateral gynecomastia. Growth hormone (GH) deficiency was diagnosed after a standard comprehensive work-up (GH peak: 6.1 ng/mL, poststimulation), and GH treatment (0.3 mg/kg per week) was initiated at 15 years. The patient responded well (Fig 1). After 14 months of GH treatment, his height increased from 144.5 to 158 cm (z score: from Ϫ2.94 to Ϫ2.04), a gain of 13.5 cm (Table 1). However, although his puberty advanced to Tanner stage IV for pubic hair and testicular volume increased to 10 mL (Tanner III), his final adult-height prediction still remained 2 SDs below his target height. Letrozole (2.5 mg/ day) was added at 16 years 2 months, when his bone age was 14 years. He was treated with the combination GH/letrozole for 17 m...

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Section: Discussionsupporting

confidence: 93%

“…5 To date, a couple of studies, at least in the short term, indicate that the use of an AI is safe and promising. [6][7][8] …”

mentioning

confidence: 99%

Letrozole Significantly Improves Growth Potential in a Pubertal Boy With Growth Hormone Deficiency

et al. 2005

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“…Letrozole reduced the fasting insulin levels and decreased high density lipoprotein (HDL) cholesterol. It remained unclear whether the reduction in HDL was related to the excessive rise in serum testosterone or to the reduction in E 2 that occurred in the letrozole-treated group (28). In adult men, most experience has been gained with anastrozole.…”

Section: Discussionmentioning

confidence: 99%

Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism

Loves¹,

Ruinemans-Koerts²,

Boer³

2008

European Journal of Endocrinology

122

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Objective: Isolated hypogonadotropic hypogonadism (IHH) is frequently observed in severely obese men, probably as a result of increased estradiol (E 2 ) production and E 2 -mediated negative feedback on pituitary LH secretion. Aromatase inhibitors can reverse this process. This study evaluates whether letrozole once a week can normalize serum testosterone in severely obese men and maintain its long term effect. Design: Open, uncontrolled 6-month pilot study in 12 severely obese men (body mass indexO 35.0 kg/m 2 ) with obesity-related IHH and free testosterone levels !225 pmol/l, treated with 2.5 mg letrozole once a week for 6 months. Results: Six weeks of treatment reduced total E 2 from 123G11 to 58G7 pmol/l (P!0.001, meanG S.E.M.), and increased serum LH from 4.4G0.6 to 11.1G1.5 U/l (P!0.001). Total testosterone rose from 5.9G0.5 to 19.6G1.4 nmol/l (P!0.001), and free testosterone from 163G13 to 604G 50 pmol/l (P!0.001). Total testosterone rose to within the normal range in all subjects, whereas free testosterone rose to supraphysiological levels in 7 out of 12 men. The testosterone and E 2 levels were stable throughout the week and during the 6-month treatment period. Conclusion: Letrozole 2.5 mg once a week produced a sustained normalization of serum total testosterone in obese men with IHH. However, free testosterone frequently rose to supraphysiological levels. Therefore, a starting dose !2.5 mg once a week is recommended.European Journal of Endocrinology 158 741-747

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“…Although only short-term follow-up is still available, these controlled clinical trials have provided a good safety profile for treatment with aromatase inhibitors. No adverse effects have been demonstrated on glucose, plasma lipid concentrations, and insulin sensitivity (20,23), spermatogenesis (24), and cognitive function (25). Additionally, aromatase inhibitors did not induce detrimental effects on bone mineral density (19,20,26).…”

Section: Discussionmentioning

confidence: 93%

Combined treatment with GH and anastrozole in a pubertal boy with Cushing's disease and postsurgical GH deficiency

Boronat

Marrero²,

López-Plasencia³

et al. 2012

European Journal of Endocrinology

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Growth failure is a characteristic manifestation of pediatric Cushing's disease. Catch-up growth is usually incomplete after cure of the disease, and final height is often compromised. Possible mechanisms for this phenomenon include postoperative persistence of GH hyposecretion and absence of retardation of bone maturation in spite of GH deficiency. This report describes the outcome in the case of a boy with Cushing's disease for whom GH replacement therapy was combined with anastrozole, an aromatase inhibitor, in order to delay skeletal maturation and extend the available time for linear growth. The case of a 14 years 4-months-old pubertal male (Tanner stage III) with GH deficiency after successful surgical treatment of Cushing's disease is presented. His height was 147.2 cm (K2.34 SDS), and his midparental target height 171.2 cm (K0.95 SDS). Bone age was 13.5 years and predicted adult height 163.2 cm (K2.2 SDS). Combined treatment was administered for 2.5 years. GH was maintained up to age 18 years. Anastrozole induced a substantial deceleration of bone age. Near-final height at 18 years was 169.5 cm (K1.07 SDS). Puberty progressed normally. Compared with population reference data, bone mineral density before GH plus anastrozole treatment was K4.07 SDS in the lumbar spine and K1.85 SDS in the femoral neck. These measures increased to K1.95 and K0.89 SDSs respectively, at 18 years, when GH was discontinued. Combined treatment with GH and aromatase inhibitors could be a therapeutic alternative to improve the stature of pubertal boys with Cushing's disease and postsurgical GH deficiency.

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The role of sex steroids in the regulation of insulin sensitivity and serum lipid concentrations during male puberty: a prospective study with a P450-aromatase inhibitor

Cited by 40 publications

References 37 publications

Letrozole Significantly Improves Growth Potential in a Pubertal Boy With Growth Hormone Deficiency

Letrozole Significantly Improves Growth Potential in a Pubertal Boy With Growth Hormone Deficiency

Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism

Combined treatment with GH and anastrozole in a pubertal boy with Cushing's disease and postsurgical GH deficiency

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