Treatment of persistent pubertal gynecomastia with dihydrotestosterone heptanoate

Four boys with persistent pubertal gynecomastia were given intramuscular dihydrotestosterone heptanoate (DHT-hp) at 2 to 4-week intervals for 16 weeks. By the end of treatment, breast size in all four boys had decreased 67% to 78%. Initial plasma levels of gonadotropins, estradiol, testosterone, and dihydrotestosterone (DHT) were normal. Mean plasma DHT concentration rose with the injections of DHT-hp, and remained elevated throughout the treatment period. Estradiol, LH, FSH, and testosterone decreased during treatment, as did 24-hour urinary LH and FSH. No regrowth of breast tissue was observed 6 to 15 months after treatment, although hormone concentrations had returned to near pretreatment values by 2 months after the last injection. DHT-hp has potential to be an effective medical therapy for persistent pubertal gynecomastia.     

Pubertal gynecomastia

Gynecomastia is a benign condition in males, characterized by proliferation of glandular elements resulting in concentric enlargement of one or both breasts. During puberty, there is often a transient relative imbalance between estrogen and testosterone, leading to gynecomastia. This condition usually resolves by age 18 years when adult androgen/estrogen ratios are achieved. Laboratory evaluation should include testosterone, estradiol, and gonadotropins; karyotype should be obtained in pubertal patients with testes volumes less than 6 ml. The mainstay in treatment of pubertal gynecomastia is still sympathetic reassurance considering the benign nature of the condition. Surgical removal of the breast glandular tissue should be considered in boys who have had persistent pubertal gynecomastia and have completed or nearly completed puberty.     

Leptin levels in boys with pubertal gynecomastia

BACKGROUND: It has been reported that there is a relationship between circulating leptin and sex steroid hormones and leptin is able to stimulate estrogen secretion by increasing aromatase activity in adipose stromal cells and breast tissue. Leptin receptors have been also shown in mammary epithelial cells and it has been suggested that leptin is involved in the control of the proliferation of both normal and malignant breast cells. AIM: To investigate circulating leptin levels in boys with pubertal gynecomastia. METHODS: Twenty boys with pubertal gynecomastia who were in early puberty and had no obesity, and 20 healthy individuals matched for age, pubertal stage and body mass index (BMI) with the study group, were enrolled in the study. Body weight, height and left midarm circumference (MAC) and left arm triceps skinfold thickness (TSF) were measured and BMI was calculated. A fasting blood sample was collected and routine hormonal parameters including prolactin, beta-human chorionic gonadotropin (betaHCG), total and free testosterone, estradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, androstenedione (AS) and dehydroepiandrosterone sulfate (DHEAS) levels were studied. Serum leptin levels were analyzed using radioimmunoassay. RESULTS: The mean ages of the study and control group were not different (13.9 +/- 0.89 and 14.2 +/- 0.66, respectively). No significant difference was found for BMI, MAC and TSF values between the two groups. There was no significant difference for hormonal parameters including FSH, LH, total and free testosterone, estradiol, AS, DHEAS and estradiol/total testosterone ratio between boys with pubertal gynecomastia and the controls. Serum leptin levels were found significantly higher in the study group compared with the healthy controls (5.58 +/- 0.81 and 2.39 +/- 0.29 ng/ml, respectively; p <0.001). No correlation could be determined between serum leptin levels and hormonal parameters. CONCLUSION: The presence of higher leptin levels in boys with pubertal gynecomastia indicates that leptin may be involved in the pathogenesis of pubertal gynecomastia. The role of circulating leptin in pubertal gynecomastia is probably related to increase in estrogen and/or estrogen/ androgen ratio by the stimulating effect of leptin on aromatase enzyme activity in both adipose and breast tissues, or a direct growth stimulating effect of leptin on mammary epithelial cells, or increase in sensitivity of breast epithelial cells to estrogen with inducing functional activation of estrogen receptors by leptin in breast tissue.     

The effect of tamoxifen on sex hormone binding globulin in adolescents with pubertal gynecomastia

We investigated the relationship between sex hormone binding globulin (SHBG) and pubertal gynecomastia in 21 adolescents evaluated longitudinally. Thirteen patients were given tamoxifen treatment after grading according to the Nydick classification (group 1). Group 2 consisted of eight patients followed without treatment. Gynecomastia existed bilaterally in 15 patients. There was a statistically significant breast size reduction in both groups. There was a significant decrease in serum SHBG only in group 2. These findings suggest that serum SHBG is increased by tamoxifen treatment in male adolescents. There was a decrease in SHBG levels through the duration of follow up in patients who recovered with or without treatment. However, this decrease was statistically significant in the untreated group, but not in the tamoxifen treated group. In conclusion, we suggest that the pubertal fall in SHBG levels is attenuated by tamoxifen treatment given for pubertal gynecomastia since tamoxifen increases SHBG levels in male adolescents.     

Treatment of marked gynecomastia in puberty with tamoxifen

Based on the good results of another author 10 boys with marked pubertal gynecomastia were treated with the antioestrogen Tamoxifen (Nolvadex) at a dose of 20-40 mg/d orally for 2-12 months. In most cases the gynecomastia decreased totally, only two patients experienced palpable subareolar glandular tissue at the end of therapy. Side effects were not noted. During therapy levels of estradiol and testosteron increased, with a more pronounced elevation of estradiol. Basal values of LH and FSH remained nearly unchanged, but LH showed an increased response to LH-RH, which could be explained by the antioestrogenic effect of Tamoxifen at the hypothalamic level. The reduction of breast size in spite of increased estradiol levels on the other hand, suggests that the mean therapeutic effect of tamoxifen is through estrogen receptor blockade of breast tissue.     

Long-term follow-up of tamoxifen treatment in adolescents with gynecomastia

Ten pubertal boys treated with tamoxifen for gynecomastia for more than 3 months were evaluated after 2.5-7 years (mean 4.6 years) to determine the side effects of this therapy. We assessed the safety of long duration in adolescents with pubertal gynecomastia treated with tamoxifen. We did not find any serious side effects of tamoxifen in these patients.     

Clomiphene in the treatment of adolescent gynecomastia. Clinical and endocrine studies

Twelve boys, aged 12 to 19 years, with persistent gynecomastia were treated with the antiestrogen, clomiphene citrate, at a dose of 50 mg/day by mouth for one to three months. The mean breast size decreased by 0% to 36%, with only five boys experiencing a reduction of greater than 20%. Five boys subsequently required reduction mammoplasty. Levels of urinary gonadotropins, serum testosterone, and estradiol increased significantly during therapy. Since the ratio of testosterone to estradiol remained unchanged during treatment, the antiestrogen effects were achieved primarily at the level of breast tissue. Clomiphene citrate in a dose of 50 mg/day resulted in only small decreases in persistent pubertal gynecomastia and was not a satisfactory medical therapy for the condition.     

Normoprolactinemia in boys with marked gynecomastia

Pubertal gynecomastia normally occurs as a transient phenomenon of several months duration, whereas marked pubertal gynecomastia (more than 6 cm in diameter) may persist into aduldhood. In the present study the possible involvement of prolactin (PRL) secretion in the development of marked pubertal gynecomastia was investigated. The diurnal variations of PRL, luteinizing hormone (LH), follicle-stimulating hormone (FSH), as well as the basal values of testosterone (T) and estradiol (E₂) were determined in 5 pubertal boys with marked gynecomastia and in 5 age-matched controls. Mean age of all patients was 14.4 years. The pubertal development was classified as P 3–4.In comparison to controls, boys with marked gynecomastia revealed no differences in basal values of PRL, LH and FSH, as well as in peak values of all hormones during sleep. The response of PRL, LH and FSH to LHRH/TRH stimulation was normal for pubertal age in both groups. In comparison to controls, decreased mean plasma T levels (P<0.05) and slightly increased E₂ levels (P<0.05) were found in boys with marked gynecomastia. The E₂/T ratio was also higher in boys with gynecomastia (P<0.005).These data suggest that prolactin, a hormone which may be increased in galactorrhea, is not involved in the development of marked pubertal gynecomastia in boys. The above findings suggest that slightly elevated day-time E₂ levels may be involved in the development of female-appearing breasts in pubertal boys.     

Adolescent gynecomastia. Differential diagnosis and management

Gynecomastia signifies a transient or permanent disturbance in steroid hormone physiology and occurs when the male breast is exposed to a decreased ratio of androgen to estrogen. This article discusses pubertal and pathologic gynecomastia, diagnostic approach, and treatment.     

Gynecomastia: review

Gynecomastia is a common clinical condition consisting of a benign proliferation of male breast glandular tissue. It may be an incidental finding on routine examination or may present as an acute, unilateral or bilateral, painful tender mass beneath the areolar region. Most cases of gynecomastia have no known cause, especially in patients presenting in adolescence. An imbalance in the ratio of estrogen to androgen tissue levels is postulated as a major cause in the development of gynecomastia. Endocrine investigations may include the measurement of serum testosterone, estradiol, gonadotrophin, prolactin and thyroid function tests, but not all patients with gynecomastia require extensive laboratory analysis. There are three management considerations for gynecomastia: observation, drug therapy and surgery (mastectomy). Surgical removal is recommended: if a trial of medical therapy is unsuccessful; if no regression is present after 1 year observation; if the condition worsens; if psychosocial problems rise due to gynecomastia and in patients after completing pubertal period.     

Pubertal growth and development in cystic fibrosis: a retrospective review

AIM: Normal growth patterns are seen throughout the first decade in children with cystic fibrosis (CF). Growth in the second decade is, however, less satisfactory and may reflect pubertal delay. This study was performed to assess the extent of pubertal delay, to examine factors that influence the timing and magnitude of the pubertal growth spurt, and to establish whether the final height for most CF patients differed significantly from the normal population. METHODS: Thirty subjects (16 male) attending a single centre were studied. Peak height velocity (PHV), final height and ages when achieved were compared with population norms. Outcome data were correlated with disease severity using Shwachman and Chrispin-Norman scores and forced expiratory volume in 1 s. RESULTS: PHV was significantly later in both genders in this CF population compared with Tanner and Whitehouse standards: boys 14.6 y (95% confidence interval (95% CI) 12.4-16.8, p < 0.01) and girls 12.6 y (95% CI 10.5-14.7, p < 0.01). Mean PHV was also lower in both genders (boys 7.7 cm y(-1) and girls 6.4 cm y(-1), both p<0.001). However, final heights did not differ significantly from Freeman standards (height standard deviation scores: males--1.2, females--0.1); 52% of final heights equalled or exceeded the mid-parental centile. CONCLUSION: CF patients showed suboptimal PHVs with a later pubertal growth spurt influenced by disease severity, but eventually achieved a normal final height.     

The incidence of pubertal gynecomastia in boys living in the Ankara region

The incidence of pubertal gynecomastia was determined in 646 Turkish boys in Ankara. A marked increase in the incidence was observed at Pubertal Stage 4 (60.2%) and age 14 years (61.1%). The incidence of gynecomastia during puberty at various pubertal stages and ages was 34.6%. Although the incidence of unilateral gynecomastia was 19.6%; there was no difference between right or left involvement.     

Somatic puberty development in girls

In 142 Swiss girls of the First Zurich Longitudinal Study. The somatic pubertal development between 9 and 18 years is described. The mean chronological age at the onset of the pubertal growth spurt was 9.6 years (standard deviation 1.2 years). The peak of the pubertal growth spurt (peak height velocity: PHV) was reached at a mean age of 12.2 years (SD 1.0). The development of pubic hair started at a mean age of 10.4 years (SD 1.2), breast development at 10.9 years (SD 1.2) and the development of axillary hair at 12.0 years (SD 1.1). Menarche occurred 2.7 years (SA 1.1) after the initiation of pubic hair development and 2.2 years (SD 1.1) after the breast development had started. Menarche was noted at a mean age of 13.4 years (SA 1.1). At menarche the mean height was 156.9 cm (SD 6.3), the mean weight 45.5 kg (SD 6.8) and the mean bone age (according to Greulich and Pyle) 12.6 years (SD 0.8). With the onset of menarche 95.3% (SD 1.7) of adult height were reached; the corresponding remaining height gain was 7.8 cm (SD 2.8). Acne was observed in 81% and striae in 41% of the girls by 18 years.     

Hormonal studies and physical maturation in adolescent gynecomastia

As part of a 3-year longitudinal study of lipid and hormonal changes during puberty, 536 boys aged 10 to 15 years were prospectively followed every 6 months to assess development of gynecomastia. The overall prevalence of gynecomastia in the 377 with complete data was 48.5% (51% of white subjects and 46% of black subjects). In the majority of subjects, gynecomastia developed during mid-puberty. Gynecomastia was bilateral in 55% of subjects, on the left side in 19%, and on the right in 26%. Gynecomastia was documented for only one visit in the majority of subjects. When subjects were matched at the onset of gynecomastia for race, visit number, and pubertal rating, there were no significant differences between those with or without gynecomastia in serum estradiol level, testosterone level, estrogen/testosterone, ratio, or dehydroepiandrosterone-sulfate level. However, free testosterone level, weight, and Quetelet index were all significantly lower, and the testosterone-estrogen binding globulin level was significantly greater, in those with gynecomastia. We conclude that approximately half of adolescent boys have transient gynecomastia, usually lasting less than 1 year; those with gynecomastia enter mid-puberty at an earlier age, have a lower Quetelet index, and have lower serum free testosterone levels.     

Plasma testosterone and estrogens in pubertal gynecomastia

Plasma levels of testosterone, estrone, and estradiol were measured in healthy males of all developmental stages and compared to the values of adolescents suffering from gynecomastia. There was no difference between normals and patients in their testosterone and estrogen levels, and no imbalance of the testosterone-estrogen ratio was observed in pubertal gynecomastia.Supported by Deutsche Forschungsgemeinschaft, SFB 51.     

Quality of life after growth hormone therapy and induced puberty in women with Turner syndrome

OBJECTIVE: To evaluate health-related quality of life (HRQoL) in young women with Turner syndrome (TS) after long-term growth hormone (GH) therapy and induced puberty and to analyze whether HRQoL was influenced by auxologic parameters, pubertal development, or subjective parameters. STUDY DESIGN: The study group comprised 49 women with TS, mean (standard deviation) age 19.6 (+/-3.0) years, all former participants of 2 GH studies, > or =6 months after GH discontinuation. Puberty was induced by estrogen treatment, at mean age 12.9 (+/-1.1) years. HRQoL was measured by self-reports of the 2 generic questionnaires, SF36 and TAAQOL. As an additional source of information on HRQoL, we applied parental proxy reports. RESULTS: HRQoL of the women with TS was normal. Remarkably, the women with TS had higher HRQoL scores on some of the scales, including "social functioning" and "role-emotional." Satisfaction with height and breast development had a positive influence on several HRQoL scales. CONCLUSIONS: The young women with TS who reached normal height and had age-appropriate pubertal development reported normal HRQoL. The relatively high scores on some of the HRQoL scales can be explained by an estrogen effect or by a possible response shift, indicating a different internal reference in women with TS. We hypothesize that GH and estrogen treatment positively influenced HRQoL in young women with TS.     

Prediction of Pubertal Growth at Start of Estrogen Replacement Therapy in Turner Syndrome

In estrogen replacement therapy in Turner syndrome, there is no report which recommends the timing of the start of estrogen therapy in relation to height or adult height prediction. We have established a prediction model for pubertal growth (height difference from the start of estrogen therapy until adult height) at the start of estrogen replacement therapy. Twenty-seven Turner girls without spontaneous puberty were divided into two groups according to birth years; Group I consisted of 16 patients born from 1980–1989 and Group II consisted of 11 patients born before 1980. Using clinical characteristics from Group I, stepwise multiple regression analysis taking pubertal growth as an independent factor, and chronological age, bone age (TW2 RUS method standardized for Japanese children), height and height SDS as dependent factors revealed following formula (p<0.001, R2=0.737): (pubertal growth) = – 1.01x (Chronological age at start of E) – 0.326x (height at start of E) – 1.779x (bone age at start of E) + 90.997. Predicted adult height was obtained by adding predicted pubertal growth to height at the start of estrogen therapy. The mean absolute difference between real adult height (tallest height after height velocity less than 1 cm/yr) and predicted adult height was 1.6 ± 0.9 cm (0.3–2.8 cm) in Group I. When this prediction model was applied to Group II, The mean absolute difference between real adult height and predicted adult height was 1.0 ± 0.7 cm (0.1–2.0 cm). A prediction model for pubertal growth at start of estrogen therapy in Turner syndrome was obtained. Using this prediction model, the timing of the start of estrogen therapy can be decided in consideration of the patient’s desired adult height.     

Intraduct Papillomatosis of the Breast in a Peripubertal Male

A 13-year-old boy presented with right-sided gynecomastia. Histological examination of the excised specimen revealed distention of ducts by papillary configurations of proliferating epithelium. The boy had no known family history of breast disease and physical examination revealed minor dysmorphic features, but a karyotype was normal. The possible relationship of this lesion to other proliferative lesions described in the pubertal male breast is discussed.     

雌激素替代诱导Turner综合征患儿乳房和子宫发育临床观察

目的　观察以雌激素替代诱导Turner综合征患儿乳房和子宫发育进程的规律,探究获得模拟正常青春发育进程的疗效与雌激素剂量和疗程的关系。方法　2005年1月至2015年12月期间,对就诊于中山大学附属第一医院儿科57例无青春发育或发育停滞的Turner综合征患儿,按国际指南方案治疗,以雌激素小剂量开始,逐步递增。回顾性分析雌激素剂量调节方案与乳房Tanner分期和子宫发育进程的关系。结果　57例Turner综合征患儿开始雌激素替代治疗年龄为15.00（14.25,16.87）岁,追踪时间2.07（0.62,3.06）年。（1）乳房发育：追踪年限内达到B2、B3、B4和B5期所需时间分别为0.29 （0.25,0.33）,0.75 （0.46,1.08）,2.20 （0.92,3.08）和3.67 （1.71,4.44）年。（2）子宫发育：雌激素替代治疗前,Turner综合征患儿子宫容积0.51（0.14,0.86） mL,长径1.89（1.23,2.18） cm。替代后乳房达B2期时,雌激素剂量≤0.5 mg/d组与＞0.5 mg/d组的子宫容积和长径差异无统计学意义。B3期时,雌激素≥1.0 mg/d组的子宫参数均大于雌激素＜1.0 mg/d组。B4期时,雌激素≥1.5 mg/d组的子宫容积较＜1.5 mg/d组子宫容积大。结论　Turner综合征患儿接受雌激素替代治疗后,乳房发育进程可接近正常。子宫发育随乳房Tanner分期进展。在乳房发育达B2期后,子宫发育进程对雌激素依赖性增加。雌激素替代治疗时,起始可予小剂量,达B2期后可适当加大剂量并递增,以加速子宫发育。     

Parental diabetes, pubertal stage, and extreme obesity are the main risk factors for prediabetes in children and adolescents: a simple risk score to identify children at risk for prediabetes

Objectives:  The current worldwide increase of prediabetes defined as impaired fasting glucose or impaired glucose tolerance and type 2 diabetes mellitus (T2DM) coincides the increase of obesity. However, it is unclear that which children have an increased risk and should be screened for prediabetes.
Methods:  We studied 437 overweight children and adolescents to identify risk factors for prediabetes. A risk score for prediabetes was calculated using logistic regression. This score was examined in a second, independent cohort of 567 overweight children and adolescents. History of T2DM in parents and grandparents, degree of overweight, age, pubertal stage, birth weight, hypertension, dyslipidemia, acanthosis nigricans, and abdominal obesity were considered as potential risk factors.
Results:  The frequency of prediabetes was 6% in sample 1 and 17% in sample 2. The strongest association was observed for history of parental diabetes with an adjusted odds ratio (aOR) of 9.5 [95% confidence interval (CI) 2.5–36.4] in sample 1 and 6.3 (95% CI 3.7–10.7) in sample 2, followed by pubertal stage with an aOR of 5.5 (95% CI 0.7–45.4) in sample 1 and 6.2 (95% CI 2.4–15.6) in sample 2, and by extreme obesity with an aOR of 5.0 (95% CI 1.7–15.3) in sample 1 and 3.3 (95% CI 2.0–5.4) in sample 2.
Conclusions:  The main risk factors for prediabetes were parental diabetes, pubertal stage, and extreme obesity. Screening for prediabetes seems meaningful in subjects with either a parental history of diabetes or a combination of extreme obesity and pubertal stage and detected nearly 90% of the overweight children and adolescents with prediabetes.