Precocious puberty is defined as the appearance of secondary sexual characteristics before the age of eight years in girls and nine years in boys.[1] Precocious puberty is classified as either central or peripheral precocious puberty. Central precocious puberty is gonadotropin-dependent and occurs due to early activation of the hypothalamic pituitary gonadal axis. Peripheral precocious puberty, also known as precocious pseudo puberty, is gonadotropin-independent and occurs due to excess production of sex hormones either from the gonads, the adrenal glands, ectopic or exogenous sources.
Precocious puberty is isosexual if the signs of sexual development are consistent with the phenotypic gender of the child before the earliest accepted age of sexual maturation. If the signs of sexual development are inappropriate for the patient’s gender, then it is considered contrasexual. If left untreated, precocious pseudopuberty can lead to short stature in adulthood and have psychological consequences on the individual. Therefore, early recognition and treatment of this condition are essential to reduce morbidity.
I. Girls:
Functioning follicular cysts are the most common cause of precocious pseudo puberty in girls. Functional follicular cysts secrete estrogen and can present as premature breast development. Vaginal bleeding may also occur after cysts degenerate.[2]
Ovarian tumors such as granulosa cell tumors, Sertoli/Leydig cell tumors, Leydig cell tumors, and gonadoblastoma can all result in precocious puberty. Granulosa cell tumor is the most common sex cord tumor in girls and is associated with excess estrogen production, which can lead to isosexual precocious puberty. On the other hand, gonadoblastoma, Leydig cell tumors, and Sertoli/Leydig tumors lead to excess androgen production and can present with contrasexual precocious puberty.[3][2]
II. Boys:
Leydig cell tumor is the most common testicular sex cord-stromal tumor and is associated with excess testosterone production. This condition commonly presents with asymmetric testicular enlargement and precocious puberty between the ages of six and ten years in boys.[4]
Excess hCG production from testicular tumors (embryonal cell carcinoma, choriocarcinoma) and ectopic sites (pineal gland, mediastinum, liver, retroperitoneum) can lead to isosexual precocious puberty in boys.[5]
Familial male-limited precocious puberty is a rare condition that can cause isosexual precocious pseudopuberty in boys. It presents in boys as young as two years of age with precocious puberty, symmetric testicular enlargement, and positive family history of precocious puberty in male relatives.
III. Boys & Girls:
Long-standing untreated primary hypothyroidism can present as precocious puberty in boys and girls. Girls affected by this condition present with early breast development, and galactorrhea, followed by vaginal bleeding. "Van Wyk and Grumbach syndrome" refers to the combination of primary hypothyroidism, precocious puberty, delayed bone age, and ovarian cysts in girls. In boys, primary hypothyroidism may cause premature testicular enlargement.[6][7]
McCune Albright Syndrome is a rare condition that can present with irregular café au lait spots, polyostotic fibrous dysplasia, and precocious pseudopuberty in girls. Estrogen overproduction in this condition leads to early breast development, vaginal bleeding, recurrent follicular cysts, and accelerated bone growth. At times, vaginal bleeding may precede the onset of breast development. McCune Albright syndrome can also present with endocrinopathies such as thyrotoxicosis, Cushing's syndrome, gigantism, or acromegaly.[8]
Excess adrenal production of androgens can occur secondary to congenital adrenal hyperplasia or adrenal tumors and present with isosexual precocious puberty in males and contrasexual precocious puberty in females. Excess androgen production in congenital adrenal hyperplasia can occur due to a deficiency in either 21-hydroxylase or 11-beta-hydroxylase deficiency. At times, adrenal tumors may secrete estrogen only, or both estrogen and androgens.[8]
Inadvertent exposure to androgen, estrogen, or endocrine-disrupting chemicals from exogenous sources can lead to precocious puberty in both genders and gynecomastia in males.[9] Accidental exposure to estrogens may occur in the form of creams, ointment, or oral contraceptive pills prescribed for adults. Estrogen is also present in food sources such as soy products and some folk remedies. Exposure to androgen containing topical creams can lead to virilization and precocious puberty in girls.[10] Endocrine-disrupting chemicals that interfere with the natural synthesis and function or hormones are found in pesticides, plasticizers, lavender, fennel, and tea tree oils and can also lead to precocious puberty.[11]
The incidence of precocious puberty is estimated to be between 1:5000 to 1:10,000.[12] Precocious pseudopuberty is less common than central precocious puberty. An Iranian case series estimated that 23.3 % of cases of precocious puberty are due to peripheral causes.[13] The prevalence of precocious pseudopuberty varies depending on the underlying cause. For example, non-classic congenital adrenal hyperplasia affects 0.1 % of the worldwide population and is more common in Hispanics, Mediterranean, Eastern European Jews, and Yugoslavs.[14] McCune Albright syndrome is a rare condition with a prevalence of 1/100,000 to 1/1,000,000 and is more common in females.[15] Familial male precocious puberty is also rare, with a prevalence of <1/1,000,000.[16]
Overall, precocious puberty is ten times more common in females than in males.[17] Specific causes of precocious pseudopuberty may show a sex preference. For example, McCune Albright syndrome is more common in females, while familial male precocious puberty (FMPP) only affects males.
Although the traditional age cut off for precocious puberty is eight years for girls and nine years for boys, data from European studies indicate an overall decline in the age of onset of puberty in the past few decades.[18] A trend towards an earlier onset of puberty has been attributed to genetic factors, obesity, and exposure to endocrine-disrupting chemicals. For example, menarche has been observed to occur earlier in girls with high body mass index, low birth weight, and whose mothers had early menarche. A significant racial variation in the age of onset of pubertal changes has also been observed in multiple studies. For example, cross-sectional studies conducted in the US indicate than African American girls tend to experience puberty earliest, followed by Hispanic and then Caucasian girls.
A multicenter study involving subjects in San Fransisco, New York, and Cincinnati also confirmed this finding. They also found that breast development is present in 23 % in African Americans, 15% in Hispanics, and 10% of White race girls between the ages of 7 to 8 years.[19] Similarly, testicular enlargement occurs approximately one year earlier in African American boys (mean age 9.14 years) compared to White race (10.14 years) and Hispanic (10.04) boys.[1] Due to observed racial differences in the mean age of puberty, the Lawson Wilkins Pediatric Endocrine Society (LWEPS) recommends evaluation if breast development or pubic hair appears before the ages of seven in Caucasian girls and six years in African American girls.
Normal Puberty
Puberty is the transition of a child to sexual maturity and is marked by activation of the hypothalamic-pituitary-gonadal axis. A surge in the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the pituitary to increase its secretion of follicular stimulating hormone (FSH) and luteinizing hormone (LH). An increase in the basal levels of FSH and LH leads to activation of gonads, and an event referred to as "gonadarche," which is the main event in puberty. Activation of the gonads leads to an increase in the secretion of sex hormones, estrogen in girls, and testosterone in boys. In girls, an increase in estradiol leads to breast development (thelarche), an increase in bone mineral density, linear skeletal growth (growth spurt), and eventually epiphyseal fusion, which leads to the cessation of linear growth. The peripubertal rise of FSH also causes an increase in uterine volume and growth of ovarian follicles, which leads to cyclical ovulation and menstruation (menarche). "Adrenarche" occurs due to a pubertal increase in the secretion of adrenal androgens-dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS). Adrenarche manifests as an increase in pubic and axillary hair growth ("pubarche"), acne, and adult-type body odor. Other pubertal changes include an increase in the secretion of growth hormone and weight and body composition changes.[20]
In girls, breast budding (Thelarche) is the first detectable secondary sexual characteristic. However, pubarche is the initial manifestation in 15% of girls.[21] On average, menarche occurs two years after thelarche.[22] A peak in height velocity leads to a growth spurt, which occurs before menarche at approximately 12 years of age in girls. In boys, the first detectable sign of puberty is testicular enlargement, defined as a testicular diameter of >2.5 cm or testicular volume of >4 mL. Penile growth and pubarche occur approximately six months after testicular enlargement. Growth spurt in boys occurs later compared to girls at an average age of 14 years.
Precocious Pseudopuberty
In precocious pseudopuberty, the excess secretion of sex hormones occurs from the gonads, adrenal glands, ectopic or exogenous sources. This process does not depend on the activation of the hypothalamic-pituitary-gonadal axis and is associated with suppressed levels of GnRH, FSH, and LH. The exact pathophysiology varies depending on the underlying disorders:
The histopathology differs depending on the underlying cause:
History
The first step of approaching precocious puberty is to elicit a detailed history and conduct a comprehensive physical exam. History taking should begin by inquiring about the age of onset of signs of sexual development. Generally, the threshold for evaluating pubertal signs is eight years in girls and nine years in boys.
Physical Exam
I. Lab Investigations
Baseline measurement of testosterone in boys and estradiol in girls should be obtained. The elevation of baseline sex hormones with suppressed gonadotropins indicates precocious pseudopuberty. A significantly elevated testosterone level indicates testicular neoplasm in boys or an adrenal source in both boys and girls. In girls, estradiol levels are interpreted with reference to the tanner stage of breast development. Estradiol levels of >20 pg/mL indicate puberty. Significantly elevated serum estradiol levels (>100 pg/mL) in a girl indicates either an estrogen secreting ovarian cyst or ovarian tumor. On the other hand, low baseline estradiol level <10 pg/ml indicates central precocious puberty.
In precocious pseudopuberty, the baseline LH and FSH levels are in the prepubertal range. Basal LH levels should be measured early in the morning. Basal LH levels < 0.2 mIU/mL indicate either precocious pseudopuberty or benign pubertal variants. Random measurements of FSH are not very useful in diagnosis. Elevated HCG levels indicate the presence of HCG secreting tumors such as embryonal cell carcinoma, choriocarcinoma, and dysgerminoma.
Measurement of serum adrenal steroid levels is useful in differentiating premature adrenarche from precocious pseudopuberty. In patients with premature adrenarche, levels of dehydroepiandrosterone sulfate (40-135 mcg/dL), testosterone (1.1-3.7 micromol/L), and 17 hydroxyprogesterone (115- 200 ng/dL) are only mildly elevated. Elevation of DHEAS and testosterone above these ranges indicate adrenal tumors or congenital adrenal hyperplasia. An elevated early morning 17 hydroxyprogesterone (> 200 ng/dL) indicates non-classical congenital hyperplasia due to 21 hydroxylase deficiency. Elevated 11 deoxy cortisol and deoxy cortisone indicate 11 B hydroxylase deficiency.[28][29][30]
Serum thyroid-stimulating hormone (TSH) concentration and free T4 levels should be checked in patients with signs and symptoms of primary hypothyroidism.
II. Radiology
Radiographs of hand and wrist should be done in cases of suspected precocious puberty to assess epiphyseal maturation. A normal or slightly delayed bone age (< 2y over chronological age) suggests benign variants such as premature thelarche or premature adrenarche. On the other hand, significantly advanced bone age (>2 standard deviations above the mean for age) indicates accelerated linear growth and precocious puberty. Rapidly progressive bone age should raise concern for congenital adrenal hyperplasia or tumors originating from the ovaries, adrenal glands, or germ cells.[31]
In girls with suspected precocious pseudopuberty, a pelvic ultrasound is essential to determine if ovarian cysts or tumors are the underlying etiology. Pelvic ultrasound is also helpful in determining the uterine length and volume, which is a good indicator of the duration of estrogen exposure.[32][33] In boys, testicular ultrasound is helpful in identifying malignancies, such as Leydig cell tumor. In patients with clinical signs or lab evidence of excess adrenal androgens, an abdominal ultrasound or computer tomography of the abdomen is recommended.
III. Other Tests
Cases of precocious pseudopuberty should be promptly referred to an endocrinologist to prevent complications. The goals of managing precocious pseudopuberty are to treat the underlying cause and block the production or response of excess sex hormones. Specific treatments depend on the cause:
Benign or Non-progressive Pubertal Variants
Benign pubertal variants represent cases of early secondary sexual development that are not progressive, have normal height velocity, and are not associated with an underlying pathological process. Most of these variants require no treatment apart from reassurance and close monitoring for signs of pubertal progression, bone age, and acceleration in height velocity.
Variants under this category include:
Central Precocious Puberty
Central precocious puberty occurs due to premature activation of the hypothalamic-pituitary-gonadal axis and can be idiopathic, genetic, or due to central nervous system lesions. Unlike peripheral precocious puberty, patients with central precocious puberty tend to follow the normal sequence of secondary sexual development. They may also have neurological signs or visual changes. Central precocious puberty is gonadotropin independent and is associated with elevated levels of the follicular stimulating hormone (FSH) and luteinizing hormone (LH). Central precocious puberty can be confirmed by a basal LH concentration of > 0.3 IU/L or an elevation of LH in response to GnRH stimulation test.[41][42]
Prognosis of McCune Albright syndrome varies depending on the severity of bone disease and the number of endocrinopathies. The outcome of non-classical congenital adrenal hyperplasia is generally favorable if glucocorticoids are administered early. However, despite treatment, many patients go on to develop short stature in adulthood. The prognosis of ovarian granulosa cell tumors depends on the stage of the disease and the presence of residual disease.[43] Similarly, Leydig tumors have an excellent prognosis and high disease-free survival rates if the condition is localized. However, metastatic disease is associated with poor outcome.[44] Cases of precocious pseudopuberty caused by exogenous hormones or endocrine-disrupting chemicals resolve spontaneously upon discontinuing exposure.
Patients with precocious puberty may encounter different complications, depending on the primary diagnosis:
Patients with precocious pseudopuberty should be offered psychological and emotional support as the physical changes of puberty may lead to emotional distress. Affected patients are often subjected to higher societal expectations based on their physical maturity rather than their age. Parents and teachers, therefore, need to be counseled and reminded to maintain age-appropriate expectations. Patients who experience early puberty may start engaging in risk-taking behavior (drugs, alcohol use, ad sexual activity) at an earlier age and require age-appropriate sex education.
Patients with precocious pseudopuberty are usually seen initially by a primary care physician or pediatrician. All physicians should be aware of the physiological pubertal changes, their normal sequence, and the age cutoff for considering pubertal changes as precocious. The onset of puberty before the age of six years in African American girls, seven years in caucasian girls, and nine years in boys should be evaluated thoroughly for precocious puberty.[45] [Level 5] Cases of precocious pseudopuberty should be promptly identified and referred to a pediatric endocrinologist for further management to prevent the development of short stature in adulthood.
Although primarily managed by an endocrinologist, patients often require interprofessional care. Consultations with oncology are required in cases of precocious puberty due to malignancy. Referral to surgery may be required for surgical excision of an underlying adrenal, ovarian, or testicular tumor. A referral to urology may be required due to the proximity of the gonads to the genitourinary system. Patients with McCune Albright syndrome may require referral to orthopedics to correct bone deformities due to fibrous dysplasia. Patients with precocious pseudopuberty can develop depression or behavioral disorders, which may require consultation with a psychiatrist and a child psychologist. Interdisciplinary collaboration is important for optimal patient outcomes in precocious pseudopuberty.
[1] | Carel JC,Léger J, Clinical practice. Precocious puberty. The New England journal of medicine. 2008 May 29; [PubMed PMID: 18509122] |
[2] | Dhivyalakshmi J,Bhattacharyya S,Reddy R,Arulselvi KI, Precocious pseudopuberty due to ovarian causes. Indian pediatrics. 2014 Oct [PubMed PMID: 25362018] |
[3] | Marx SJ, Hyperplasia in glands with hormone excess. Endocrine-related cancer. 2016 Jan [PubMed PMID: 26407873] |
[4] | García González M,Casal-Beloy I,Somoza Argibay I,Dargallo Carbonell T, Atypical presentation of Leydig cell tumour in three prepubertal patients: diagnosis, treatment and outcomes. Journal of pediatric endocrinology & metabolism : JPEM. 2019 Apr 24 [PubMed PMID: 30875329] |
[5] | Gattuso G,Casanova M,Biassoni V,Terenziani M,Schiavello E,Sironi G,Collini P,Pallotti F,Morosi C,Massimino M, Precocious pseudopuberty, a paraneoplastic manifestation: a report of 2 cases. Tumori. 2020 May 28 [PubMed PMID: 32462993] |
[6] | Baranowski E,Högler W, An unusual presentation of acquired hypothyroidism: the Van Wyk-Grumbach syndrome. European journal of endocrinology. 2012 Mar [PubMed PMID: 22170796] |
[7] | Cabrera SM,DiMeglio LA,Eugster EA, Incidence and characteristics of pseudoprecocious puberty because of severe primary hypothyroidism. The Journal of pediatrics. 2013 Mar; [PubMed PMID: 23196132] |
[8] | Haddad NG,Eugster EA, Peripheral precocious puberty including congenital adrenal hyperplasia: causes, consequences, management and outcomes. Best practice & research. Clinical endocrinology & metabolism. 2019 Jun [PubMed PMID: 31027974] |
[9] | Henley DV,Lipson N,Korach KS,Bloch CA, Prepubertal gynecomastia linked to lavender and tea tree oils. The New England journal of medicine. 2007 Feb 1; [PubMed PMID: 17267908] |
[10] | Martinez-Pajares JD,Diaz-Morales O,Ramos-Diaz JC,Gomez-Fernandez E, Peripheral precocious puberty due to inadvertent exposure to testosterone: case report and review of the literature. Journal of pediatric endocrinology [PubMed PMID: 23426834] |
[11] | Breil T,Yakovenko V,Inta I,Choukair D,Klose D,Mittnacht J,Schulze E,Alrajab A,Grulich-Henn J,Bettendorf M, Typical characteristics of children with congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: a single-centre experience and review of the literature. Journal of pediatric endocrinology & metabolism : JPEM. 2019 Mar 26 [PubMed PMID: 30817301] |
[12] | Partsch CJ,Sippell WG, Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens. Human reproduction update. 2001 May-Jun; [PubMed PMID: 11392376] |
[13] | Rohani F,Salehpur S,Saffari F, Etiology of precocious puberty, 10 years study in Endocrine Reserch Centre (Firouzgar), Tehran. Iranian journal of reproductive medicine. 2012 Jan; [PubMed PMID: 25242967] |
[14] | Binay C,Simsek E,Cilingir O,Yuksel Z,Kutlay O,Artan S, Prevalence of nonclassic congenital adrenal hyperplasia in Turkish children presenting with premature pubarche, hirsutism, or oligomenorrhoea. International journal of endocrinology. 2014; [PubMed PMID: 24778650] |
[15] | Dumitrescu CE,Collins MT, McCune-Albright syndrome. Orphanet journal of rare diseases. 2008 May 19; [PubMed PMID: 18489744] |
[16] | Cornacchia MA,Bhushan S,Arguello R, A Case of Familial Male-Limited Precocious Puberty in a Child With Klinefelter Syndrome. Journal of the Endocrine Society. 2018 Oct 1; [PubMed PMID: 30283825] |
[17] | Kaplowitz P, Clinical characteristics of 104 children referred for evaluation of precocious puberty. The Journal of clinical endocrinology and metabolism. 2004 Aug; [PubMed PMID: 15292280] |
[18] | Mul D,Fredriks AM,van Buuren S,Oostdijk W,Verloove-Vanhorick SP,Wit JM, Pubertal development in The Netherlands 1965-1997. Pediatric research. 2001 Oct; [PubMed PMID: 11568291] |
[19] | Biro FM,Galvez MP,Greenspan LC,Succop PA,Vangeepuram N,Pinney SM,Teitelbaum S,Windham GC,Kushi LH,Wolff MS, Pubertal assessment method and baseline characteristics in a mixed longitudinal study of girls. Pediatrics. 2010 Sep; [PubMed PMID: 20696727] |
[20] | Borgström B,Fridström M,Gustafsson B,Ljungman P,Rodriguez-Wallberg KA, A prospective study on the long-term outcome of prepubertal and pubertal boys undergoing testicular biopsy for fertility preservation prior to hematologic stem cell transplantation. Pediatric blood & cancer. 2020 Jul 10 [PubMed PMID: 32649054] |
[21] | Susman EJ,Houts RM,Steinberg L,Belsky J,Cauffman E,Dehart G,Friedman SL,Roisman GI,Halpern-Felsher BL, Longitudinal development of secondary sexual characteristics in girls and boys between ages 91/2 and 151/2 years. Archives of pediatrics [PubMed PMID: 20124146] |
[22] | Biro FM,Huang B,Crawford PB,Lucky AW,Striegel-Moore R,Barton BA,Daniels S, Pubertal correlates in black and white girls. The Journal of pediatrics. 2006 Feb; [PubMed PMID: 16492435] |
[23] | Goyal A,Malhotra R,Khadgawat R, Precocious pseudopuberty due to virilising adrenocortical carcinoma progressing to central precocious puberty after surgery. BMJ case reports. 2019 Mar 12 [PubMed PMID: 30862670] |
[24] | Lane LC,Flowers J,Johnstone H,Cheetham T, Adult height in patients with familial male-limited precocious puberty and the role of an aromatase inhibitor in patient management. Journal of pediatric endocrinology & metabolism : JPEM. 2018 Apr 25 [PubMed PMID: 29654692] |
[25] | Hoseinpour MJ,Ghanbari A,Azad N,Zare A,Abdi S,Sajadi E,Abbaszadeh HA,Farahani RM,Abdollahifar MA, Ulmus minor bark hydro-alcoholic extract ameliorates histological parameters and testosterone level in an experimental model of PCOS rats. Endocrine regulations. 2019 Jul 1 [PubMed PMID: 31517633] |
[26] | Looijenga LHJ,Kao CS,Idrees MT, Predicting Gonadal Germ Cell Cancer in People with Disorders of Sex Development; Insights from Developmental Biology. International journal of molecular sciences. 2019 Oct 10 [PubMed PMID: 31658757] |
[27] | Haddad N,Eugster E, An update on the treatment of precocious puberty in McCune-Albright syndrome and testotoxicosis. Journal of pediatric endocrinology [PubMed PMID: 17663289] |
[28] | Armengaud JB,Charkaluk ML,Trivin C,Tardy V,Bréart G,Brauner R,Chalumeau M, Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. The Journal of clinical endocrinology and metabolism. 2009 Aug; [PubMed PMID: 19454583] |
[29] | Rosenfield RL, Clinical review: Identifying children at risk for polycystic ovary syndrome. The Journal of clinical endocrinology and metabolism. 2007 Mar; [PubMed PMID: 17179197] |
[30] | Livadas S,Dracopoulou M,Dastamani A,Sertedaki A,Maniati-Christidi M,Magiakou AM,Kanaka-Gantenbein C,Chrousos GP,Dacou-Voutetakis C, The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. Clinical endocrinology. 2015 Apr; [PubMed PMID: 25041270] |
[31] | Creo AL,Schwenk WF 2nd, Bone Age: A Handy Tool for Pediatric Providers. Pediatrics. 2017 Dec; [PubMed PMID: 29141916] |
[32] | de Vries L,Horev G,Schwartz M,Phillip M, Ultrasonographic and clinical parameters for early differentiation between precocious puberty and premature thelarche. European journal of endocrinology. 2006 Jun; [PubMed PMID: 16728550] |
[33] | Badouraki M,Christoforidis A,Economou I,Dimitriadis AS,Katzos G, Evaluation of pelvic ultrasonography in the diagnosis and differentiation of various forms of sexual precocity in girls. Ultrasound in obstetrics [PubMed PMID: 18951545] |
[34] | Root AW, Precocious puberty. Pediatrics in review. 2000 Jan; [PubMed PMID: 10617758] |
[35] | Papanikolaou A,Michala L, Autonomous Ovarian Cysts in Prepubertal Girls. How Aggressive Should We Be? A Review of the Literature. Journal of pediatric and adolescent gynecology. 2015 Oct; [PubMed PMID: 26228588] |
[36] | Nunez SB,Calis K,Cutler GB Jr,Jones J,Feuillan PP, Lack of efficacy of fadrozole in treating precocious puberty in girls with the McCune-Albright syndrome. The Journal of clinical endocrinology and metabolism. 2003 Dec; [PubMed PMID: 14671160] |
[37] | Mieszczak J,Lowe ES,Plourde P,Eugster EA, The aromatase inhibitor anastrozole is ineffective in the treatment of precocious puberty in girls with McCune-Albright syndrome. The Journal of clinical endocrinology and metabolism. 2008 Jul; [PubMed PMID: 18397987] |
[38] | Feuillan P,Calis K,Hill S,Shawker T,Robey PG,Collins MT, Letrozole treatment of precocious puberty in girls with the McCune-Albright syndrome: a pilot study. The Journal of clinical endocrinology and metabolism. 2007 Jun; [PubMed PMID: 17405850] |
[39] | Eugster EA,Rubin SD,Reiter EO,Plourde P,Jou HC,Pescovitz OH, Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. The Journal of pediatrics. 2003 Jul; [PubMed PMID: 12915825] |
[40] | Leschek EW,Flor AC,Bryant JC,Jones JV,Barnes KM,Cutler GB Jr, Effect of Antiandrogen, Aromatase Inhibitor, and Gonadotropin-releasing Hormone Analog on Adult Height in Familial Male Precocious Puberty. The Journal of pediatrics. 2017 Nov; [PubMed PMID: 29144249] |
[41] | Kaplowitz P,Bloch C, Evaluation and Referral of Children With Signs of Early Puberty. Pediatrics. 2016 Jan; [PubMed PMID: 26668298] |
[42] | Houk CP,Kunselman AR,Lee PA, Adequacy of a single unstimulated luteinizing hormone level to diagnose central precocious puberty in girls. Pediatrics. 2009 Jun; [PubMed PMID: 19482738] |
[43] | Schumer ST,Cannistra SA, Granulosa cell tumor of the ovary. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003 Mar 15; [PubMed PMID: 12637488] |
[44] | Featherstone JM,Fernando HS,Theaker JM,Simmonds PD,Hayes MC,Mead GM, Sex cord stromal testicular tumors: a clinical series--uniformly stage I disease. The Journal of urology. 2009 May; [PubMed PMID: 19286222] |
[45] | Kaplowitz PB,Oberfield SE, Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics. 1999 Oct; [PubMed PMID: 10506238] |