A Case of Precocious Pseudopuberty Associated With Ovarian Follicular Cyst

A case of precocious pseudopuberty associated with a follicular cyst in the ovary is described. A five-year-and-month-old Japanese girl had breast enlargement, areolar pigmentation and intermittent genital bleeding. On laparotomy, bilateral ovarian cysts were found. The left cyst (4.0 times 4.0 times 3.5 cm) was far larger than the right (1.5 times 1.3 times 1.3). The fluid in the left cyst contained a high concentration of estrogens. Therefore, the main cause of the precocious puberty was thought to be the left cyst. It was clearly detected by ultrasonography and computed tomography only when the signs of precocious puberty were remarkable and the serum estrogen level was increased; however, the right one could not be detected throughout the observation. We consider that in the case of intermittent puberty a functioning ovarian cyst can be identified more easily when the signs of precocious puberty are remarkable and the serum estrogen level is increased.     

Treatment of autonomous ovarian follicular cyst with long-term anastrozole therapy

Functional follicular ovarian cysts are frequently reported in girls with peripheral precocious puberty (PP). These cysts are usually self-limiting and resolve spontaneously. Several drugs like antiestrogens (tamoxifen) and new aromatase inhibitors are seldom used for treatment. Here we report a girl with peripheral PP who presented with unilateral enlargement of the ovary and a recurrent autonomous ovarian cyst. No skin pigmentation or bone anomaly was noted. The patient was successfully treated with anastrozole, a highly selective aromatase inhibitor. No adverse reaction was noted. Anastrozole is a safe and tolerable drug especially used to suppress estrogen action.     

Diagnosis of Ovarian Follicular Cysts from Birth to Puberty: A Report of Twenty Cases

ABSTRACT. Twenty girls aged 1 day to 17 years have been studied for ovarian follicular cysts. Clinical features leading to the discovery of the follicular cyst were different in prepubertal girls and in girls whose cyst was discovered during puberty. Before seven years of age, four girls presented a precocious pseudopuberty where breast development was in contrast with very low pituitary gonadotropin levels; two girls in this age group were diagnosed after complaining about abdominal pain. In two cases the diagnosis was prenatal during routine ultrasonography of the mother. After ten years of age, abnormal menses (5 cases) or acute abdominal pain (5 cases) were the main clinical features. In only one case the cyst presented as an abdominal mass. Follow-up of the 20 patients showed: spontaneous disappearance of the cyst within 3 to 32 weeks in 9 cases; ovariectomy in 8 cases, due to a torsion of a large cyst (over 55 mm) in 7 children and because of the fear of a possible tumor in one; limited resection of the cyst in 4 cases. By systematic ultrasonography, discovery of an ovarian cyst as defined by a non-echogenic area over 20 mm may occur relatively often in young girls. Spontaneous disappearance is frequent when the cyst is small (under 55 mm). Torsion of large cysts remains the major complication.     

Diagnosis of ovarian follicular cysts from birth to puberty: a report of twenty cases

Twenty girls aged 1 day to 17 years have been studied for ovarian follicular cysts. Clinical features leading to the discovery of the follicular cyst were different in prepubertal girls and in girls whose cyst was discovered during puberty. Before seven years of age, four girls presented a precocious pseudopuberty where breast development was in contrast with very low pituitary gonadotropin levels; two girls in this age group were diagnosed after complaining about abdominal pain. In two cases the diagnosis was prenatal during routine ultrasonography of the mother. After ten years of age, abnormal menses (5 cases) or acute abdominal pain (5 cases) were the main clinical features. In only one case the cyst presented as an abdominal mass. Follow-up of the 20 patients showed: spontaneous disappearance of the cyst within 3 to 32 weeks in 9 cases; ovariectomy in 8 cases, due to a torsion of a large cyst (over 55 mm) in 7 children and because of the fear of a possible tumor in one; limited resection of the cyst in 4 cases. By systematic ultrasonography, discovery of an ovarian cyst as defined by a non-echogenic area over 20 mm may occur relatively often in young girls. Spontaneous disappearance is frequent when the cyst is small (under 55 mm). Torsion of large cysts remains the major complication.     

Precocious puberty caused by a suprasellar arachnoid cyst. Analysis of 6 cases

The authors report 6 cases (4 girls and 2 boys) with central precocious puberty associated with a suprasellar arachnoid cyst. Precocious puberty is rarely the presenting sign of arachnoid cysts. It was characterized by early onset, patent symptoms and frequent association (3 of 6 cases) with growth hormone deficiency. The latter represents a further risk of short stature. Evolution of precocious puberty varied from one case to another, without any relation with the quality of control of the arachnoid cyst and associated hydrocephalus. Half-yearly follow-up of height and bone age allowed for deciding a suppressive treatment of precocious puberty and a substitutive growth hormone therapy when needed.     

Ovarian function in girls with McCune-Albright syndrome

We measured plasma estradiol levels and ovarian volumes in eight girls with precocious puberty due to McCune-Albright syndrome. Six girls had gonadotropin-independent ovarian estrogen secretion and two girls had pubertal gonadotropin levels. Mean ovarian volume in all patients was significantly greater than in normal prepubertal girls. Mean ovarian volumes of the girls with McCune-Albright syndrome overlapped the range found in girls with idiopathic central precocious puberty or central precocious puberty associated with central nervous system lesions. However, the degree of asymmetry between the right and left ovaries was significantly greater in girls with McCune-Albright syndrome. Asymmetry was due, for the most part, to the presence of large solitary cysts in the larger of the two ovaries. In the six girls with McCune-Albright syndrome and gonadotropin-independent precocious puberty, both mean ovarian volume and the degree of asymmetry between the right and left ovaries were significantly correlated with plasma estradiol. Serum follicle-stimulating hormone bioactivity was increased in two patients but did not vary with ovarian cyst size. Thyroid-stimulating hormone levels were normal but serum prolactin was slightly elevated in one of the six girls with gonadotropin-independent precocious puberty. Fluctuation in the size of unilateral ovarian cysts appears to result in changes in the plasma estradiol level, leading to advancement and spontaneous regression of secondary sexual characteristics and menses in girls with McCune-Albright syndrome. The cause of the cyst formation is unknown but may be related to periodic elevation of as yet undefined serum factors such as follicle-stimulating hormone bioactive substances.     

Pubertal development in patients with McCune-Albright syndrome or pseudohypoparathyroidism

Gain or loss of function mutations of the GNAS1 gene lead to McCune-Albright syndrome (MAS) or pseudohypoparathyroidism Ia (PHP-Ia), respectively. Patients with MAS, caused by a post-zygotic missense mutation leading to constitutive activation of Gs alpha, suffer from gonadotropin-independent precocious puberty, and delayed or incomplete sexual development and reproductive dysfunction is found in women with PHP-Ia, an inherited disorder caused by deficient expression or function of the Gs alpha protein. In females with MAS, 50% developed precocious puberty by the age of 4 years, the remaining between 4 and 8 years. Peripheral precocious puberty is often atypical and characterized by alternate periods of rapid progression and regression of pubertal development; menstrual bleeding may occur before breast development. Ovarian cyst growth and regression is often described as a sign of ovarian follicle hyperactivation. Notwithstanding this clinical heterogeneity, a subset of patients with MAS develop relentlessly progressive precocious puberty ultimately resulting in premature epiphyseal fusion and reduced adult stature. Long-term information on reproductive function has been obtained in females: some patients had regular menses without ovarian cysts on pelvic US scan, whereas others were oligomenorrheic and showed recurrent ovarian cysts. In males with MAS, precocious puberty occurred in three patients between 4 and 9 years of age. In one patient, long-term follow-up demonstrated normal plasma testosterone and gonadotropin values at the age of 17 years. On testicular sonography, multiple hyperechogeneic spots were found in both testicles (snow-storm appearance). Female patients with PHP-Ia were oligomenorrheic or amenorrheic; more than half had delayed or incomplete sexual development, They were mildly hypoestrogenic with normal to slightly elevated serum gonadotropin levels. These clinical and biochemical findings indicate partial resistance of the theca and granulosa cells of the ovary to gonadotropins due to deficient Gs alpha activity. Responsiveness might be sufficient to promote some degree of follicular development and steroid secretion, but insufficient to induce ovulation     

The endocrine spectrum of intracranial cysts in childhood and review of the literature

Intracranial cysts (ICC) may cause a wide spectrum of endocrinological disorders. We evaluated 27 patients who were diagnosed with ICC during investigation for neuroendocrine dysfunctions and reviewed the relevant literature. The types of ICC in the patients were arachnoid cysts (n = 13); Rathke cleft cysts (n = 7); pineal cysts (n = 5); an ependymal cyst (n = 1) and a cavum septum pellucidum cyst (n = 1). The neuroendocrine dysfunctions of the patients were obesity (n = 7), isolated growth hormone deficiency (n = 6), central precocious puberty (n = 6), multiple pituitary hormone deficiency (n = 3), central diabetes insipidus (n = 1), growth hormone deficiency and central precocious puberty (n = 1), obesity and galactorrhea (n = 1), obesity and hypogonadotropic hypogonadism (n = 1) and growth hormone neurosecretory dysfunction (n = 1). Only three patients, who had arachnoid cysts, showed neurologic symptomatology. Although three patients underwent surgery, no improvements in endocrinological dysfunctions were observed. ICC should be considered when evaluating patients with endocrinological problems and patients with coincidental ICC should be recommended for follow-up.     

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.     

外周性性早熟患儿的病因及预后随访

目的：探讨外周性性早熟的病因及预后。方法：应用简化的促性腺激素释放激素（GnRH）激发试验测定卵泡刺激素（FSH）及黄体生成素（LH）、雌二醇（E2）水平,并采用B超检查及骨龄检测等方法对125例外周性性早熟患儿进行病因诊断。随访病例102例,随访时间3个月至7.5年。结果：125例患儿的病因分布为：摄入外源性性激素80例,卵巢囊肿11例,McCune Albright 综合征11例,先天性肾上腺皮质增生症（CAH）5例,卵巢畸胎瘤、男性化肾上腺肿瘤、女性化肾上腺肿瘤、垂体柄肿瘤各1例,另有14例患儿病因尚不能确定。预后：摄入外源性性激素者随访72例,均在1～6个月性征消退;11例卵巢囊肿患儿中,8例1~4个月性征自行消退,但其中1例2年3个月后转为中枢性性早熟;1例囊肿切除术后性征消退;卵巢畸胎瘤者术后性征消退;McCune Albright 综合征及CAH者治疗后临床症状减轻,7例转为中枢性性早熟;2例肾上腺肿瘤术后性征消退;1例垂体柄肿瘤术后1年死亡。结论：外周性性早熟病因多样,详细的病史、体检、辅助检查有助于早期明确诊断,不同病因预后不同。     

Pubertas praecox in McCune-Albright syndrome--case report and review of the literature

A patient is presented with the syndrome of polyostatic fibrous dysplasia and precocious puberty (PP). The endocrinopathy in McCune-Albright-syndrome (MAS) has formerly been ascribed to a central (hypothalamic) origin. In this patient the PP was caused by a luteinized follicular cyst, suggesting autonomous hyperfunction of this gland. High serum estradiol levels returned to normal after cystectomie. The review of the literature suggests the peripheral origin of PP to be more frequent in younger age groups (under 6 years). It appears possible that peripheral hypersecretion of sexual steroids may cause a rise of gonadotropins secondarily followed by true PP in older children provided such longstanding hypersecretion leads to a generalized maturation of the body including skeletal maturation. Treatment in pseudoprecocious puberty seems to be not effective with LH-RH-analogues. Cyproteroneacetate alone or in combination with a LH-RH analogue gave the impression of being more successful. Cystectomy can lead to a cure but a recurrence of ovarian cysts is possible. A combination of surgical and drug therapy may be beneficial under these circumstances. Until now there is no sufficient treatment for polyostotic fibrous dysplasia.     

Recurrent ovarian cyst and mutation of the Gsα gene in ovarian cyst fluid cells: what is the link with McCune-Albright syndrome?*

Isolated peripheral precocious puberty due to recurrent ovarian cysts evokes a McCune-Albright syndrome (MAS). This syndrome associates endocrine dysfunction such as precocious puberty, polyostotic fibrous dysplasia, and ‘’café-au-lait“ skin lesions. We report the case of a 3-y-old girl who presented with peripheral puberty with extremely elevated oestradiol level, low LH and FSH levels, and an ovarian cyst that quickly resolved. Skeletal X-rays were normal and she had no café-au-lait spots. GnRH analogue treatment was ineffective. A second ovarian cyst appeared and was completely drained under ultrasonographic guidance. Molecular biological analysis performed on fluid cells revealed the Arg201→His mutation of the Gsa gene described in MAS. Percutaneous aspiration of simple ovarian cyst to detect‘’MAS” mutation is of interest in the diagnosis of recurrent ovarian cyst.     

Arachnoid cysts in childhood with endocrinological outcomes

Arachnoid cysts are mainly manifested with the consequent neurological disorders. Even though these cysts may interfere in many systems due to their localizations, there is little information concerning their involvement in endocrinological disorders. We emphasize endocrinological functions together with cyst localizations and neurological disorders in childhood. A total of 50 patients diagnosed with arachnoid cysts were screened for cyst localizations, neurological symptoms and endocrinological outcomes evaluated by pubertal and growth status and hypothalamopituitary insufficiency. We investigated the interactions of these parameters. Arachnoid cysts were localized mostly in the middle fossa (54%) and posterior fossa (26%). Middle fossa cysts had a strong predilection for male gender (66.7% male) and left hemispheric dominancy (77%). We detected growth hormone deficiency in six patients, obesity in six patients and central precocious puberty in one patient; cysts were in the temporal area in three of the obese cases. All patients in our study had normal levels of cortisol, thyroid hormones and prolactin. In pediatric patients with arachnoid cysts, endocrinological follow-up is crucial as neurological outcomes and further evaluations are needed, mainly to confirm pubertal and growth status.     

Precocious puberty in children with tumours of the suprasellar and pineal areas: organic central precocious puberty

During the past 11 y, 115 children younger than 8/9 y of age (female/male) with tumours of the suprasellar or pineal areas were followed in our clinic to study the incidence of precocious puberty. In addition, type of central lesion, clinical characteristics and gonadotropic secretion were studied in order to elucidate the different mechanisms of gonadal activation. A control group of 21 patients with idiopathic precocious puberty and a control group of 10 age-matched patients with suprasellar tumours without precocious puberty were also studied. Precocious puberty associated with organic central lesions was found at diagnosis in 30 patients (26%), in 9 out of 48 patients with glial cell tumours (18.7%), 6 out of 9 patients with germ cell tumours (66.6%), 11 out of 11 patients with hypothalamic hamartomas (100%) and in 4 out of 4 patients with subarachnoid cysts or arachnoidocele (100%). Precocious puberty was not found in any of 36 patients with craniopharyngioma. With the exception of one patient with pineal germinoma, all lesions were localized to the suprasellar area. In all patients with hypothalamic hamartoma, precocious puberty was diagnosed before 4 y of age, while in most patients with the other lesions, it was diagnosed after this age. Height SDS, weight increase and advancement of bone age were similar in both idiopathic and organic central precocious puberty. Maximal LH responses to GnRH in idiopathic and organic central precocious puberty were similar except for germ cell tumours. Patients with suprasellar tumours without precocious puberty had lower maximal LH (but not FSH) responses to GnRH, with the exception of germ cell tumours. In the latter, elevation of serum beta-hCG indicates that this gonadotropin was responsible for gonadal stimulation. In hypothalamic hamartomas, the prepubertal hiatus in the activity of the GnRH pulse generator was absent. The mechanism of this failure in the inactivation of GnRH is unknown. Data suggest that in glial cell tumours and in subarachnoid cysts, an unknown factor, probably secreted by the tumours, advances the tempo of GnRH maturation. Therefore, the aetiology of organic central precocious puberty is multiple and is directly related to location and type of lesion. CONCLUSION: This clinical information suggests that the onset of puberty is not the result of the disruption of a putative pulse generator inhibitory influence but the consequence of secretion of stimulatory substances by the lesions.     

Ovarian follicle cysts and precocious puberty

A "transient" precocious puberty with ovarian follicular cysts was observed in four girls. Each girl presented with several successive and transient episodes of development of secondary sex characters: breast development, areolar pigmentation, brown abdominal median line were the clinical signs of oestrogen secretion. At the time of referral, plasma and urinary gonadotropins levels were low in the prepubertal range while plasma oestradiol concentrations were elevated, in the pubertal range. At this time, as well as during each episode of "pubertal" development, the gonadotropins response to GnRH stimulation was blunted. In contrast, a prepubertal or pubertal response was observed when the clinical symptoms of estrogenization had resumed. Ultrasonography showed one or several ovarian follicular cysts. In two cases, the treatment with the GnRH agonist, D-TRP 6 GnRH [Decapeptyl (R)], was successful, suggesting a central dysfunction     

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.     

A Case of Atypical McCune-Albright Syndrome with Vaginal Bleeding

Background

McCune-Albright syndrome (MAS) is a rare non-inherited disorder characterized by the clinical triad of precocious puberty, cafe-au-lait skin lesions, and fibrous dysplasia of bone.

Case Presentation

We report a girl with MAS, presenting initially with vaginal bleeding at the age of 17 months. Ultrasonography revealed unilateral ovarian cysts and ureteral and ovarian enlargement. Considering the clinical and paraclinical findings, the patient diagnosed as a case of gonadotropin-independent precocious puberty was treated with medroxy-progestrone acetate (MPA) for three months. During the follow up, recurrent episodes of bleeding, ovarian activation and cyst formation, as well as breast size development were reported. At the age of 5.5 years, fibrous dysplasia was detected, which in coexistence with precocious puberty confirmed the diagnosis of MAS. The patient had no cafe-au-lait skin macles during follow up.

Conclusion

Considering that clinical manifestations of MAS appear later in the course of recurrent periods of ovarian activation and cyst formation, a careful clinical observation and follow up of patients is necessary and the diagnosis of MAS must be kept in mind in cases with gonadotropin-independent precocious puberty.     

The NIH experience with precocious puberty: diagnostic subgroups and response to short-term luteinizing hormone releasing hormone analogue therapy

Between 1979 and 1983, 129 children (95 girls) with precocious puberty were referred to the National Institutes of Health and received treatment for at least 6 months with the long-acting LHRH analogue D-Trp6-Pro9-NEt-LHRH. The majority (107 of 129) of the children had central precocious puberty mediated by activation of the hypothalamic-pituitary-gonadal axis in association with hypothalamic hamartomas (24 of 107) or other central nervous system lesions (21 of 107), or idiopathic precocious puberty (62 of 107). Hypothalamic hamartomas or other central nervous system lesions were a frequent cause of central precocious puberty in girls (27 of 87), but idiopathic precocious puberty was still the most frequent diagnosis (63%). Idiopathic precocious puberty was uncommon in boys (6%). The patients with peripheral precocious puberty included six girls with McCune-Albright syndrome and six boys with familial male precocious puberty. These children had peripheral sex steroid secretion in the absence of hypothalamic-pituitary-gonadal axis maturation. The children with combined peripheral and central precocious puberty included nine children with congenital adrenal hyperplasia and one girl with a virilizing adrenal tumor. In the patients with central precocious puberty or combined peripheral and central precocious puberty, LHRHa therapy caused suppression of gonadotropin and sex steroid levels (P less than 0.001), stabilization or regression of secondary sexual characteristics, and decreases in growth rate and in the rate of bone age maturation (P less than 0.005). Patients with peripheral precocious puberty, however, had no significant change in gonadotropin or sex steroid levels, growth rate, or the rate of bone age maturation, and no improvement in secondary sexual characteristics. Thus, LHRHa is an effective treatment of central precocious puberty and combined peripheral and central precocious puberty, but is ineffective in the therapy of peripheral precocious puberty.     

Central precocious puberty: Evaluation by neuroimaging

To evaluate the incidence of abnormal intracranial findings in children with central precocious puberty, 62 children (51 girls, 11 boys) were examined by computerized tomography and/or magnetic resonance imaging (MRI) of the brain. Forty-four had normal examinations; 18 (11 girls, 7 boys) showed intracranial pathologies, including hamartoma of the tuber cinereum (8 cases), parenchymal loss (3 cases), hypothalamicchiasmatic lesions (2 cases), lesions of the corpus callosum (2 cases), suprasellar cyst (1 case), and pineal cyst and mesiotemporal sclerosis (1 case each). Based on the correlation between the clinical and the imaging results of this series, the authors recommend MRI as the imaging method of choice in the investigation of precocious puberty.     

Precocious puberty and pineal cyst — an uncommon association

We present a five year old boy with central precocious puberty and pineal gland cyst on neuroimaging. This association is uncommon and highlights the role of pineal gland in puberty.