Pelvic ultrasonography in normal girls and in girls with pubertal precocity

This prospective study sought to evaluate the role of pelvic ultrasonography in differentiating between various types of pubertal precocity. A control group of 117 normal girls (aged 1.1-15.6) was studied and compared with 87 girls with premature sexual maturation (aged 1.1-9.2y). Of these patients 19 had central precocious puberty (CPP), 48 had isolated premature thelarche (IPT) and 20 had premature adrenarche (IPA) Pelvic ultrasound variables evaluated were: (i) uterus: longitudinal diameter (uterine length), cross-sectional area (CSA) and fundo-cervical ratio; and (ii) ovaries: volume and morphology. Ovarian morphology was subdivided in 6 different appearances: solid, microcystic, paucicystic, multicystic, macrocystic, and major isolated cyst. In normal control girls, uterine length and CSA increased with age, although no cut-off values could be defined between different age ranges, and they were correlated with breast stage; fundo-cervical ratio was stable through childhood and increased after age 9. Ovarian volume was significantly greater in pubertal girls with breast stage 2 than in those with only pubic and/or axillary hair. There was a clear predominance of solid ovarian appearances in the age range 2-7, with the multicystic appearance being seen only after age 7, a minority being macrocystic. After age 10 all the different patterns were observed, and after age 13 the frequency of a macrocystic pattern increased. Significantly more mature ovarian appearances were observed in subjects with breast development compared with those without, independently of the presence of pubic hair. Patients with IPT had no significant differences in pelvic ultrasound measurements when compared with age-matched controls. All the different morphological ovarian appearances were observed in IPT, in contrast to age-matched controls, where only the less mature patterns (solid, micro- and paucicystic) were seen. Patients with CPP had significantly more mature patterns of ovarian morphology compared with age-matched controls, but did not differ from pubertal pre-menarcheal controls. Those patients with IPA differed from age-matched controls only in having significantly greater uterine length and CSA. Comparison of the pelvic ultrasound parameters between patient groups (IPT, CPP, IPA) and age-matched controls revealed significantly higher values in CPP for uterine length, uterine CSA and ovarian volume. Ovarian volume was also greater in IPT than in IPA. Ovarian morphology was significantly different in patients (IPT, CPP, IPA) compared with age-matched controls, but none of the ovarian morphological appearances was exclusive to a single condition. In conclusion: (i) pelvic ultrasound parameters increase progressively from birth to maturity, but no clear cut-off values can be established between age ranges; (ii) pelvic ultrasound variables reach adult values during puberty, with differences in the timing that may reflect geographical variations; (iii) the multicystic ovarian appearance occurs just before the onset of puberty; (iv) pelvic ultrasonography cannot always differentiate clearly between different disturbances of puberty and therefore cannot supersede other observations and investigations in the evaluation of pubertal disorders; and (v) in this study we propose a more detailed pelvic ultrasound terminology that can avoid apparent confusion in defining ovarian ultrasound appearance.     

Pelvic ultrasonography in girls with precocious puberty, congenital adrenal hyperplasia, obesity, or hirsutism

Real-time ultrasonography of the pelvic organs was performed on 151 girls with various complete and incomplete forms of precocious puberty, 20 girls with congenital adrenal hyperplasia, 20 with hirsutism, 18 with obesity, and 133 age-matched normal girls. Uterine and ovarian volumes were calculated and the ovarian morphologic picture was classified as homogeneous, nonhomogeneous (less than three small cystic areas), microcystic (four or more small cystic areas less than 9 mm in diameter), follicular (at least one cystic area greater than 9 mm), and macrocystic (large cystic area greater than 20 mm). Ultrasound imaging allowed an easy distinction between true precocious puberty and premature thelarche or idiopathic premature adrenarche. It was also helpful in the diagnosis of transient sexual precocity, although in these cases the differential diagnosis of precocious puberty can be difficult. In postmenarcheal patients with congenital adrenal hyperplasia, ultrasound study showed a low uterine volume and, frequently, a macrocyst in the ovary. In hirsute girls and in a few obese patients, ovaries had an increased volume and a microcystic structure, similar to those in polycystic ovary syndrome. Pelvic ultrasonography can be useful not only in diagnosing disorders in sexual development but also for greater understanding of the pathogenesis of these and other disorders.     

Pelvic ultrasonography: Early differentiation between isolated premature thelarche and central precocious puberty

We examined 55 girls with isolated premature thelarche between the ages of 0.3 and 7.3 years (group A), 20 children with central precocious puberty between 2.1 and 7.7 years of age and 101 age-matched controls. The children with precocious puberty were divided according to distribution of pubic hair into group B (Tanner stages PH1, B2–3;n=11), representing an early stage of the disorder, and group C (stages PH2–3, B3–4;n=9), representing an advanced stage. Uterine and ovarian volumes were measured sonographically, peak serum levels of luteinizing hormone and folliclestimulating hormone were determined after intravenous administration of luteinizing hormone-releasing hormone. The mean uterine and ovarian volumes were significantly greater in children with precocious puberty than in controls (group B: uterine volume: 3.8±2.0 ml vs 0.9±0.3 ml for controls,P<0.001; ovarian volume: 2.2±1.3 ml vs 0.6±0.2 ml for controls,P<0.01; group C: uterine volume: 8.0±4.4 ml vs 1.0±0.3 ml for controls,P<0.01; ovarian volume: 2.6±1.3 ml vs 0.4±0.1 ml,P<0.01). No significant differences were found between children with premature thelarche and the control group. As a diagnostic method for the early detection of central precocious puberty, ultrasound measurement of uterine volume had a sensitivity and specificity of 100% (cut-off value, 1.8 ml), while ultrasound determination of ovarian volume had a sensitivity of 82% and a specificity of 95% (cut-off value, 1.2 ml). In contrast, as a diagnostic criterion the ratio of levels of luteinizing hormone to follicle-stimulating hormone as determined following stimulation with luteinizing hormone releasing hormone had a sensitivity of 33% and a specificity of 100% (cut-off value, 1.0). Conclusion: ultrasonographic measurement of uterine and ovarian volume offers a reliable means of distinguishing between isolated premature thelarche and early stages of central precocious puberty.     

Studies of gonadotrophin pulsatility and pelvic ultrasound examinations distinguish between isolated premature thelarche and central precocious puberty

We have studied the pulsatile secretion of gonadotrophins at night and made ovarian ultrasound examinations in three girls with central precocious puberty and three with isolated premature thelarche. The three girls with precocious puberty had well-defined pulsatile secretion of LH and FSH with LH predominating, as would be expected in normal puberty. Pulsatile secretion of gonadotrophins was also seen in girls with premature thelarche but the pattern was reversed. In girls with precocious puberty, large multicystic ovaries and large uteri were seen on ultrasound examination, whereas girls with isolated premature thelarche had small uteri and ovaries with less than four cysts up to 15 mm in diameter. These data provide the key to understanding the aetiology of isolated premature thelarche.Abbreviations GnRH gonadotrophin releasing hormone - LH luteinising hormone - FSH Follicle stimulating hormone - SDS standard deviation score     

A comparison of patients with premature thelarche and idiopathic true precocious puberty in the initial stage of illness

A comparative study of patients with premature thelarche and patients with idiopathic true precocious puberty was conducted. The age at the first visit tended to be lower for those with precocious puberty. In comparison with normative data for children, the frequency of low birthweight and small for date (SFD) status was greater in the 55 patients with premature thelarche, but SFD was also frequent in the 18 patients with precocious puberty. The height, weight and Kaup's index were all within the normal range for these two groups. The ratios for bone age/chronologic age and bone age/height age tended to be high in both groups. In the patients with premature thelarche, the blood luteinizing hormone (LH) level showed a normal response, and the blood follicle stimulating hormone (FSH) level a hyper-response, to stimulation with luteinizing hormone-releasing hormone (LH-RH). In contrast, both the blood LH and FSH levels showed a normal response to LH-RH stimulation in most of the patients with precocious puberty, and a hyper-response was rare among them. Although the blood estradiol (E2) level was higher in patients with precocious puberty than in those with premature thelarche, about 50% and 90% of the patients in the respective groups had normal levels. These results suggest that normal responses of blood LH and excessive responses of blood FSH to LH-RH loading may be useful in some patients for diagnosing premature thelarche at an early stage.     

Role of pelvic ultrasonography in the diagnosis, therapeutic indications and surveillance of central precocious puberty

The use of pelvic ultrasonography was evaluated as a diagnostic and follow-up tool in girls with precocious puberty. Before treatment 23 of 33 patients with central precocious puberty presented an increased size of the uterus. In 10 cases with prepubertal size of the uterus, the precocious puberty was only beginning or of mild severity. During treatment with a LHRH analogue, changes in uterine size were slow in spite of a satisfactory and rapid control of estrogen secretion. At onset of treatment, transient ovarian cysts were seen in 2 patients. In our experience, pelvic ultrasonography did not provide significant information on the control of the disease by LHRH analogue therapy. Of 16 girls with presumed premature thelarche, 3 presented signs of estrogenic stimulation of the uterus. It remains a useful technique to rule out the presence of ovarian cysts or tumors at time of diagnosis.     

Isosexual precocious puberty

Isosexual precocious puberty refers to the appearance of phenotypically appropriate secondary sexual characteristics before age 8 years in girls and before 9 years in boys. Isosexual precocity may be categorized into several subgroups depending upon etiology and clinical course: true and complete isosexual precocity refers to early activation of the intact hypothalamic-pituitary-gonadal axis; pseudo-isosexual precocity is due to sex steroid production which is independent of hypothalamic-pituitary regulation; incomplete forms of isosexual precocity include premature thelarche and premature adrenarche. Etiologic, diagnostic and therapeutic considerations are discussed.     

Management of central isosexual precocity: diagnosis, treatment, outcome

The diagnosis of central isosexual precocity, a condition much more common in girls than in boys, is currently viewed as a spectrum of disorders between isolated premature thelarche and borderline early puberty. In some countries, a trend may be seen toward onset of puberty at earlier ages. Integration of the clinical findings with bone age, pelvic echography, and hormonal data as well as follow-up ascertainment of progression of development is critical to define which patients should be proposed for therapy. The use of long-acting forms of gonadotropin-releasing hormone (GnRH) agonists may not be indicated in slowly progressive variants or borderline early puberty because they do not affect final height. Preservation of height potential is particularly obvious in precocious puberty starting at young ages. In some selected patients, associated growth hormone therapy may increase adult height but further studies are warranted. The psychosocial and behavioral correlates of precocious puberty are an important and under investigated area.     

小于2岁婴幼儿乳房早发育临床随访研究

目的：了解小于2岁婴幼儿乳房发育的临床现况及转归,分析影响乳房消退的相关因素。方法：分析2009年10月至2010年9月间因乳房早发育来我院内分泌科就诊的863例2岁以下患儿临床及实验诊断资料并进行纵向随访研究。结果：小于2岁单纯乳房早发育患儿中绝大多数（89.3%）在3周岁内消退,乳房消退平均年龄为17±6月龄;小部分（10.7%）反复或持续增大,3岁后仍不消退,极少数转变为中枢性性早熟。初诊时乳房Tanner分期和基础E2值升高与否是影响乳房消退的独立危险因素。结论：小于2岁婴幼儿乳房早发育在临床并不少见,大多呈自限性病程,3周岁内可消退,但对2岁以上乳房增大持续不消退者要定期随访。     

Massive breast enlargement in an infant girl with central nervous system dysfunction

A 6-month-old female is described who presented with severe idiopathic macromastia. The breast enlargement began at 2 months of age and progressed such that subtotal mastectomies were necessary at 23 months. Extensive hormonal evaluation prior to surgery revealed no evidence of estrogenization or precocious puberty. There was no galactorrhea. A breast biopsy showed immature mammary tissue. In vitro analysis of the patient's serum using a mouse mammary thymidine incorporation assay revealed similar mitogenic activity in the patient's serum compared to adult controls. Post surgical follow up of this patient, 3.5 years later, has revealed no breast enlargement, precocious sexual development, or growth acceleration. Of interest, however, she has manifested an idiopathic degenerative neurologic condition characterized by psychomotor delay, ataxia, and seizures. Remarkably, hormone studies at age 5.5 years showed an exaggerated gonadotrophin response to intravenous gonadotrophin releasing hormone and prepubertal estrogen levels. While this case may represent an extraordinary example of idiopathic premature thelarche, the severe nature of this infant's macromastia in association with neurologic dysfunction and increased gonadotrophins suggests that central nervous system factors were etiologic.     

Premature Thelarche–Natural History and Sex Hormone Secretion in 68 Girls

ABSTRACT. Data obtained during long-term follow-up of 68 girls with premature thelarche were analysed. In 85 % onset was before the age of 2 years, in 30.8 % being present at birth. In 44.1 % there was a regression after 3^2/12±2^8/12 12years (SD). Basal levels of plasma FSH and response to LH-RH were significantly higher than prepubertal controls (1.93± 1.56 vs. 0.8±0.1 mU/ml and peaks 12.3±5.4 vs. 7.9±1.0 mU/ml respectively; p <0.001). Twenty-seven of 52 patients tested had increased plasma estradiol and in 27 of 40 patients tested, urocytograms or vaginal smear showed estrogenization. Basal levels of LH and response to LH-RH were prepubertal. The girls with premature thelarche were significantly taller than normal controls of the same age ( p <0.001). These results suggest that premature thelarche is an incomplete form of precocious sexual development probably due to derangement in the maturation of the hypothalamo-pituitary-gonadal axis which results in a higher than normal secretion of FSH, as well as a defect in the peripheral sensitivity to the sex hormones.     

Pulsatile secretion of luteinizing hormone and sleep-related gonadotropin rhythms in girls with premature thelarche

The concentrations of LH, FSH and PRL were determined in serum samples obtained at night in 1–2 h intervals as well as at 15 min intervals during a 3 h period between 9 and 12 p.m. and 9 and 12 a.m. in three girls with premature thelarche, who had not developed further signs of precocious puberty for more than 18 months.A sleep-dependent LH and FSH increase was documented in all of them with a predominance of FSH secretion during sleep and after LHRH stimulation. In all three girls an episodic pattern of LH was found during sleep. In daytime minor fluctuations of LH secretion were found in two patients whereas in one patient an episodic LH pattern was demonstrable with minor peak values as during sleep.Normal PRL secretion during sleep as well as after TRH stimulation excludes a permissive role of this hormone in premature thelarche.We conclude that in girls with isolated premature thelarche a matured hypothalamo-pituitary gonadotropin axis is active comparable to normal pubertal children.     

Precocious, early and fast puberty in males with Chiari I malformation

Type I Chiari malformation is a disorder characterized by a displacement of the cerebellar tonsils through the foramen magnum into the upper cervical spinal canal and, contrary to type II Arnold-Chiari malformation, without the presence of myelomeningocele. As described in the literature, patients suffering from Arnold-Chiari malformation with myelomeningocele can frequently present with precocious puberty, whereas only one report shows an association between Chiari I malformation and early puberty. We describe three young males--8.8, 9.4 and 10.4 years old--who were diagnosed with precocious, early and fast puberty associated with type I Chiari malformation. In patients 2 and 3, the reason for diagnostic management recommendation was a rapid progression of pubertal development over one year. None of the patients manifested hypophyseal-hypothalamic axis dysfunction other than sexual precocity. Neurological and ophthalmological examinations were normal in all patients. Our data show that type I Chiari malformation can be considered one of the possible causes for precocious, early and accelerated puberty in male patients, suggesting the need to carry out brain nuclear magnetic resonance imaging in order to investigate the presence of this malformation.     

Premature Thelarche in Later Childhood Demonstrates a Pubertal Response to GnRH Stimulation Test at One Year after Breast Development

Premature thelarche in later childhood (such as at 5–7 yr of age) is not always easy to distinguish from GnRH-dependent precocious puberty. In this study, a GnRH stimulation test was performed on 21 girls from 5 to 7.5 yr of age with early breast development. In 8 of 11 girls within 1 yr after thelarche, i.e., breast development, the GnRH stimulation test showed a prepubertal response, and in all 10 girls at more than 1 yr after breast development, the GnRH stimulation test showed a pubertal response. In observations of 4 girls with a prepubertal response, the GnRH stimulation test showed to a pubertal response by 1 yr or more after breast development in 3 of 4 the girls. These results indicate the possibility that almost all cases of breast development in later childhood consist of premature thelarche and that premature thelarche in later childhood may easily lead to early puberty at 1 yr or more after breast development. Careful observations are therefore recommended for at least 1 yr, even if early breast development is considered to be associated with premature thelarche in later childhood.     

PUBERTAL DEVELOPMENT IN THE PRADER-LABHART-WILLI SYNDROME

ABSTRACT. The sexual maturation in the Prader-Labhart-Willi (PLW) syndrome was investigated in 14 patients, 10 females and 4 males. A wide variability in the pattern of pubertal development was found including delayed puberty in 5 patients and normal puberty in 4 patients; sexual precocity was also observed in 5 patients, true precocious puberty in one patient and incomplete sexual precocity in the form of precocious pubarche in 4 patients. In 5 patients, 3 of them with precocious pubarche, the appearance of the pubertal signs was followed by a delay or arrest in their future development. An LH-RH stimulation test was performed in 11 patients. In the 6 patients who eventually developed normal puberty, the basal levels and the peak responses of both LH and FSH were within the range of those observed in normal controls of the same pubertal stage. In 4 patients showing marked delay or arrest of puberty, the basal levels were normal or low and the responses of LH and FSH to LH-RH were blunted. Priming with repeated LH-RH stimulation in one of the male patients led to an augmented LH response, suggesting a hypothalamic hypogonadotrophism. It is concluded that the lack of uniformity in the pattern of sexual maturation in the PLW syndrome is due to a variability in the location and extent of a hypothalamic lesion, which may comprise an active process continuing beyond the perinatal period.     

Pubertal development in the Prader-Labhart-Willi syndrome.

The sexual maturation in the Prader-Labhart-Willi (PLW) syndrome was investigated in 14 patients, 10 females and 4 males. A wide variability in the pattern of pubertal development was found including delayed puberty in 5 patients and normal puberty in 4 patients; sexual precocity was also observed in 5 patients, true precocious puberty in one patient and incomplete sexual precocity in the form of precocious pubarche in 4 patients. In 5 patients, 3 of them with precocious pubarche, the appearance of the pubertal signs was followed by a delay or arrest in their future development. An LH-RH stimulation test was performed in 11 patients. In the 6 patients who eventually developed normal puberty, the basal levels and the peak responses of both LH and FSH were within the range of those observed in normal controls of the same pubertal stage. In 4 patients showing marked delay or arrest of puberty, the basal levels were normal or low and the responses of LH and FSH to LH-RH were blunted. Priming with repeated LH-RH stimulation in one of the male patients led to an augmented LH response, suggesting a hypothalamic hypogonadotrophism. It is concluded that the lack of uniformity in the pattern of sexual maturation in the PLW syndrome is due to a variability in the location and extent of a hypothalamic lesion, which may comprise an active process continuing beyond the perinatal period.     

Tamoxifen treatment in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome and peripheral precocious puberty

Patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) can be classified as types 1 or 2, according to the presence or not of ovarian failure. We report a 5 year-old girl with BPES and large multicystic ovaries who developed peripheral precocious puberty with thelarche (Tanner stage III) and pubarche (Tanner stage II). Pelvic ultrasound revealed pubertal uterus and enlarged multicystic ovaries. Fibrous dysplasia and McCune-Albright syndrome were ruled out. Treatment with an estrogen antagonist was started (tamoxifen, 10 mg/day), achieving regression of thelarche. Tamoxifen treatment was stopped at 10-(7/12) years, and growth velocity and skeletal maturation rate returned to normal. No treatment-associated adverse effects were observed.     

Breast contact thermography for differentiation between premature thelarche and true precocious puberty

Breast contact thermography was used to differentiate between premature thelarche and true precocious puberty. The technique was applied to 10 girls with premature thelarche, 12 with precocious puberty and 105 controls (Tanner B1-5). In controls, the scores attributed to the maturative thermographic signs correlated with breast development stages. In premature thelarche thermographic signs of vascularization were always absent, while in precocious puberty they were always observed, although in some cases unilaterally. The thermographic index (higher total score between the two breasts) ranged from 0 to 3 in girls with premature thelarche and from 4 to 10 in girls with precocious puberty. The thermographic pattern in premature thelarche was similar to that in prepubertal girls and did not progress in two girls who were repeatedly examined. We emphasize the useful role of contact thermography in evaluating pubertal breast development and in differentiating between premature thelarche and true precocious puberty.Abbreviations BCT breast contact thermography - TI thermographic index - B breast development stage - F fundus - N nipple - A areolar zone - V vascular growth pattern     

Sexual precocity and its treatment

Background

Puberty is a complex and dynamic period in development during which individuals transition from the juvenile to adult state. Regulated by multiple genetic and endocrine controls, it is characterized by somatic growth and sexual maturation. Sexual precocity is defined as the appearance of secondary sexual characteristics before the lower limit of the normal age for pubertal onset.

Data sources

Based on recent publications and the experience with the disease of our group, we reviewed the normal timing and order of puberty, the definition of sexual precocity, the classification of sexual precocity, the differential diagnosis of sexual precocity, variations in pubertal development, the diagnosis of sexual precocity, and the treatment of sexual precocity.

Results

Sexual precocity can be classified as either gonadotropin-releasing hormone (GnRH)-dependent or GnRH-independent. Regardless of the etiology, sexual precocity causes increased height velocity, somatic development, and skeletal maturation, which may have profound physical and psychological implications.

Conclusions

The treatment of sexual precocity is focused on its cause and must address both its psychosocial and clinical implications. For GnRH-dependent precocious puberty, GnRH agonists are the main pharmacological agents used. Alternatively, the treatment of disorders causing GnRH-independent sexual precocity is directed toward the underlying abnormality.     

Sexual precocity: sex incidence and aetiology.

The aetiology of 197 girls and 16 boys presenting with sexual precocity was reviewed. Ninety one girls and four boys had central precocious puberty (M:F 23:1); a cause was identified in all the boys but in only six girls. All boys with precocious puberty need detailed investigation; in girls investigation should be based on clinical findings, particularly the consonance of puberty.