Precocious puberty

Last updated
Precocious puberty
Other namesEarly puberty
Specialty Gynecology, andrology, endocrinology
Causes Idiopathic, brain tumor

In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. There is early development of secondary sex characters and gametogenesis also starts earlier. Precocious puberty is of two types: true precocious puberty and pseudoprecocious puberty. In a minority of children with precocious puberty, the early development is triggered by a disease such as a tumor or injury of the brain. [1]

Contents

Even when there is no underlying disease, unusually early puberty can have adverse effects on social behavior and psychological development (having more mature knowledge than one's peers, feeling inadequate, trying to attend and establish friendships with older people, depression). Affected children also face shorter adult height potential and possible lifelong health risks. Central precocious puberty can be treated by suppressing the pituitary hormones that induce sex steroid production. The opposite condition is delayed puberty. [2] [3]

The term is used with several slightly different meanings that are usually apparent from the context. In its broadest sense, and often simplified as early puberty, "precocious puberty" sometimes refers to any physical sex hormone effect, due to any cause, occurring earlier than the usual age, especially when it is being considered as a medical problem. Stricter definitions of "precocity" may refer only to central puberty starting before a statistically specified age based on percentile in the population (e.g., 2.5 standard deviations below the population mean), [4] on expert recommendations of ages at which there is more than a negligible chance of discovering an abnormal cause, or based on opinion as to the age at which early puberty may have adverse effects. A common definition for medical purposes is onset before 8 years in girls or 9 years in boys. [5]

Causes

Early pubic hair, breast, or genital development may result from natural early maturation or from several other conditions.

Central

If the cause can be traced to the hypothalamus or pituitary, the cause is considered central. Other names for this type are complete or true precocious puberty. [6]

Causes of central precocious puberty can include:

Central precocious puberty can also be caused by brain tumors, infection (most commonly tuberculous meningitis, especially in developing countries), trauma, hydrocephalus, and Angelman syndrome. [7] Precocious puberty is associated with advancement in bone age, which leads to early fusion of epiphyses, thus resulting in reduced final height and short stature. [8]

Adrenocortical oncocytomas are rare with mostly benign and nonfunctioning tumors. There have been only three cases of functioning adrenocortical oncocytoma that have been reported up until 2013. Children with adrenocortical oncocytomas will present with "premature pubarche, clitoromegaly, and increased serum dehydroepiandrosterone sulfate and testosterone" which are some of the presentations associated with precocious puberty. [9] [10]

Precocious puberty in girls begins before the age of 8. The youngest mother on record is Lina Medina, who gave birth at the age of either 5 years, 7 months and 17 days [11] or 6 years 5 months as mentioned in another report. [12]

"Central precocious puberty (CPP) was reported in some patients with suprasellar arachnoid cysts (SAC), and SCFE (slipped capital femoral epiphysis) occurs in patients with CPP because of rapid growth and changes of growth hormone secretion." [13]

If no cause can be identified, it is considered idiopathic or constitutional.

Peripheral

Secondary sexual development induced by sex steroids from other abnormal sources is referred to as peripheral precocious puberty or precocious pseudopuberty. It typically presents as a severe form of disease with children. Symptoms are usually as a sequelae from adrenal hyperplasia (because of 21-hydroxylase deficiency or 11-beta hydroxylase deficiency, the former being more common), which includes but is not limited to hypertension, hypotension, electrolyte abnormalities, ambiguous genitalia in females, signs of virilization in females. Blood tests will typically reveal high level of androgens with low levels of cortisol.

Causes can include:

Isosexual and heterosexual

Generally, patients with precocious puberty develop phenotypically appropriate secondary sexual characteristics. This is called isosexual precocity. [16]

In some cases, a patient may develop characteristics of the opposite sex. For example, a male may develop breasts and other feminine characteristics, while a female may develop a deepened voice and facial hair. This is called heterosexual or contrasexual precocity. It is very rare in comparison to isosexual precocity and is usually the result of unusual circumstances. As an example, children with a very rare genetic condition called aromatase excess syndrome – in which exceptionally high circulating levels of estrogen are present – usually develop precocious puberty. Males and females are hyper-feminized by the syndrome. [16] The "opposite" case would be the hyper-masculinisation of both male and female patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, in which there is an excess of androgens. Thus, in the aromatase excess syndrome the precocious puberty is isosexual in females and heterosexual in males, whilst in the CAH it is isosexual in males and heterosexual in females.[ citation needed ]

Research

Although the causes of early puberty are still somewhat unclear, girls who have a high-fat diet and are not physically active or are obese are more likely to physically mature earlier. [17] [18] [19] "Obese girls, defined as at least 10 kilograms (22 pounds) overweight, had an 80 percent chance of developing breasts before their ninth birthday and starting menstruation before age 12 – the western average for menstruation is about 12.7 years." [19] In addition to diet and exercise habits, exposure to chemicals that mimic estrogen (known as xenoestrogens) is another possible cause of early puberty in girls. Bisphenol A, a xenoestrogen found in hard plastics, has been shown to affect sexual development. [20] "Factors other than obesity, however, perhaps genetic and/or environmental ones, are needed to explain the higher prevalence of early puberty in black versus white girls." [18] While more girls are increasingly entering puberty at younger ages, new research indicates that some boys are actually starting later (delayed puberty). [21] [22] "Increasing rates of obese and overweight children in the United States may be contributing to a later onset of puberty in boys, say researchers at the University of Michigan Health System." [22]

High levels of beta-hCG in serum and cerebrospinal fluid observed in a 9-year-old boy suggest a pineal gland tumor. The tumor is called a chorionic gonadotropin secreting pineal tumor. Radiotherapy and chemotherapy reduced tumor and beta-hCG levels normalized. [23]

In a study using neonatal melatonin on rats, results suggest that elevated melatonin could be responsible for some cases of early puberty. [24]

Familial cases of idiopathic central precocious puberty (ICPP) have been reported, leading researchers to believe there are specific genetic modulators of ICPP. Mutations in genes such as LIN28, [25] [26] and LEP and LEPR, which encode leptin and the leptin receptor, [27] have been associated with precocious puberty. The association between LIN28 and puberty timing was validated experimentally in vivo, when it was found that mice with ectopic over-expression of LIN28 show an extended period of pre-pubertal growth and a significant delay in puberty onset. [28]

Mutations in the kisspeptin (KISS1) and its receptor, KISS1R (also known as GPR54), involved in GnRH secretion and puberty onset, are also thought to be the cause for ICPP [29] [30] However, this is still a controversial area of research, and some investigators found no association of mutations in the LIN28 and KISS1/KISS1R genes to be the common cause underlying ICPP. [31]

The gene MKRN3, which is a maternally imprinted gene, was first cloned by Jong et al. in 1999. MKRN3 was originally named Zinc finger protein 127. It is located on human chromosome 15 on the long arm in the Prader-Willi syndrome critical region2, and has since been identified as a cause of premature sexual development or CPP. [32] The identification of mutations in MKRN3 leading to sporadic cases of CPP has been a significant contribution to better understanding the mechanism of puberty. [33] MKRN3 appears to act as a "brake" on the central hypothalamic-pituitary access. Thus, loss of function mutations of the protein allow early activation of the GnRH pathway and cause phenotypic CPP. Patients with a MKRN3 mutation all display the classic signs of CCP including early breast and testes development, increased bone aging and elevated hormone levels of GnRH and LH. [34]

Diagnosis

Studies indicate that breast development in girls and the appearance of pubic hair in both girls and boys are starting earlier than in previous generations. [18] [35] [36] As a result, "early puberty" in children as young as 8 and 9 is no longer considered abnormal, particularly with girls. Although it is not considered as abnormal, it may be upsetting to parents [21] [37] and can be harmful to children who mature physically at a time when they are immature mentally. [38]

No age reliably separates normal from abnormal processes in children, but the following age thresholds for evaluation are thought to minimize the risk of missing a significant medical problem:

Medical evaluation is sometimes necessary to recognize the few children with serious conditions from the majority who have entered puberty early but are still medically normal. Early sexual development warrants evaluation because it may:

Treatment

One possible treatment is with anastrozole. GnRH agonists, including histrelin, triptorelin, or leuprorelin, are other possible treatments. Non-continuous use[ clarification needed ] of GnRH agonists stimulates the pituitary gland to release follicle stimulating hormone (FSH) and luteinizing hormone (LH).[ why? ] [41] Triptorelin depot is widely used to treat central precocious puberty (CPP) in children. [42]

Puberty blockers work by stabilizing puberty symptoms, decreasing growth velocity, and slowing skeletal maturation. [43] The outcomes of treatment are assessed in terms of height, reproduction, metabolic, and psychosocial measures. The most pronounced effects on height have been seen in children experiencing the onset of puberty before 6 years of age; however there is variability in height outcomes across studies which can be attributed to varying study designs, time of symptom presentation, and time of treatment termination. [44] A study investigating the effects of puberty blockers on reproductive health showed no significant difference in the number of irregular menstrual cycles, pregnancies, or pregnancy outcomes between women who received treatment for precocious puberty and those who opted out of treatment. [45] Individuals with precocious puberty, early adrenarche, and early normal puberty show less stress after treatment compared to individuals without preexisting developmental conditions. [46]

Blockers are also used in the treatment of central precocious puberty resulting from conditions like hypothalamic hamartomas or congenital adrenal hyperplasia, where early onset of puberty is a symptom. Additionally, puberty blockers can be prescribed for children with severe forms of idiopathic short stature, allowing for more time for growth before the closure of growth plates. [47]

In the USA, since 1993, the US Food and Drug Administration (FDA) has supported the use of puberty blockers to treat precocious puberty. [48] Currently under FDA regulation the use of puberty blockers is considered on-label for the treatment of central precocious puberty. [49] ] [50]

For years, the FDA, Endocrine Society, American Academy of Pediatrics(AAP) and many other pediatric associations have supported the use of Gonadotropin-releasing hormone analogs (GnRHas) in central precocious puberty (CPP). [51]

In 2009, the Lawson Wilkins Pediatric Endocrine Society and European Society for Pediatric Endocrinology published a consensus statement highlighting the effectiveness of Gonadotropin-releasing hormone analogs (GnRHas) in early onset central precocious puberty. [52] They confirmed that the use of Gonadotropin-releasing hormone analogs (GnRHas) has had a positive effect on increasing adult height. [52] [53] However these Endocrine Societies believe additional research should be conducted before routinely suggesting GnRHAs for other conditions. [52] There is still some uncertainty surrounding the effectiveness of GnRHas when utilized for other conditions.

Overall, puberty blockers have demonstrated an excellent safety and efficacy profile in the treatment of precocious puberty.

Side effects

The most common side effects reported include nonspecific headaches, hot flashes, and implant-related skin reactions. [54]

A systematic review of studies investigating the long-term effects of treating precocious puberty with GnRH agonists found that bone mineral density decreases during treatment but normalizes afterward, with no lasting effects on peak bone mass. [55]

Prognosis

Early puberty is posited to put girls at higher risk of sexual abuse; [19] [40] however, a causal relationship is, as yet, inconclusive. [40] Early puberty also puts girls at a higher risk for teasing or bullying, mental health disorders and short stature as adults. [19] [39] [56] Girls as young as 8 are increasingly starting to menstruate, develop breasts and grow pubic and underarm hair; these "biological milestones" typically occurred only at 13 or older in the past. African-American girls are especially prone to early puberty. [18]

Though boys face fewer problems from early puberty than girls do, early puberty is not always positive for boys. Early sexual maturation in boys can be accompanied by increased aggressiveness due to the surge of pubertal hormones. [57] Because they appear older than their peers, pubescent boys may face increased social pressure to conform to adult norms; society may view them as more emotionally advanced, although their cognitive and social development may lag behind their physical development. [57] Studies have shown that early-maturing boys are more likely to be sexually active and are more likely to participate in risky behaviors. [58]

History

Pubertas praecox is the Latin term used by physicians from the 1790s onward. Various hypotheses and inferences on pubertal (menstrual, procreative) timing are attested since ancient times, which, well into early modernity were explained on the basis of temperamental, humoral and Jungian "complexional" causes, or general or local "plethora" (blood excess). [59] Endocrinological (hormonal) theories and discoveries are a twentieth-century development.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Gonadotropin-releasing hormone</span> Mammalian protein found in Homo sapiens

Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.

Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormonal signs that puberty has begun. In the United States, girls are considered to have delayed puberty if they lack breast development by age 13 or have not started menstruating by age 15. Boys are considered to have delayed puberty if they lack enlargement of the testicles by age 14. Delayed puberty affects about 2% of adolescents.

Adrenarche is an early stage in sexual maturation that happens in some higher primates, typically peaks at around 20 years of age, and is involved in the development of pubic hair, body odor, skin oiliness, axillary hair, sexual attraction/sexual desire/increased libido and mild acne. During adrenarche the adrenal glands secrete increased levels of weak adrenal androgens, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione (A4), but without increased cortisol levels. Adrenarche is the result of the development of a new zone of the adrenal cortex, the zona reticularis. Adrenarche is a process related to puberty, but distinct from hypothalamic–pituitary–gonadal axis maturation and function.

Pubarche refers to the first appearance of pubic hair at puberty. It is one of the physical changes of puberty and can occur independently of complete puberty. The early stage of sexual maturation, also known as adrenarche, is marked by characteristics including the development of pubic hair, axillary hair, adult apocrine body odor, acne, and increased oiliness of hair and skin. The Encyclopedia of Child and Adolescent Health corresponds SMR2 with pubarche, defining it as the development of pubic hair that occurs at a mean age of 11.6 years in females and 12.6 years in males. It further describes that pubarche's physical manifestation is vellus hair over the labia or the base of the penis. See Table 1 for the entirety of the sexual maturity rating description.

Gonadarche refers to the earliest gonadal changes of puberty. In response to pituitary gonadotropins, the ovaries in females and the testes in males begin to grow and increase the production of the sex steroids, especially estradiol and testosterone. The ovary and testis have receptors, follicle cells and leydig cells, respectively, where gonadotropins bind to stimulate the maturation of the gonads and secretion of estrogen and testosterone. Certain disorders can result in changes to timing or nature of these processes.

Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. To distinguish it from other forms of hypogonadotropic hypogonadism, Kallmann syndrome has the additional symptom of a total lack of sense of smell (anosmia) or a reduced sense of smell. If left untreated, people will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably are infertile and are at increased risk of developing osteoporosis. A range of other physical symptoms affecting the face, hands and skeletal system can also occur.

Xenoestrogens are a type of xenohormone that imitates estrogen. They can be either synthetic or natural chemical compounds. Synthetic xenoestrogens include some widely used industrial compounds, such as PCBs, BPA, and phthalates, which have estrogenic effects on a living organism even though they differ chemically from the estrogenic substances produced internally by the endocrine system of any organism. Natural xenoestrogens include phytoestrogens which are plant-derived xenoestrogens. Because the primary route of exposure to these compounds is by consumption of phytoestrogenic plants, they are sometimes called "dietary estrogens". Mycoestrogens, estrogenic substances from fungi, are another type of xenoestrogen that are also considered mycotoxins.

<span class="mw-page-title-main">Gonadotropin-releasing hormone agonist</span> Drug class affecting sex hormones

A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.

<span class="mw-page-title-main">Familial male-limited precocious puberty</span> Medical condition

Familial male-limited precocious puberty, often abbreviated as FMPP, also known as familial sexual precocity or gonadotropin-independent testotoxicosis, is a form of gonadotropin-independent precocious puberty in which boys experience early onset and progression of puberty. Signs of puberty can develop as early as an age of 1 year.

The gonadotropin-releasing hormone receptor (GnRHR), also known as the luteinizing hormone releasing hormone receptor (LHRHR), is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is the receptor of gonadotropin-releasing hormone (GnRH). Agonist binding to the GnRH receptor activates the Gq/11 family of heterotrimeric G proteins. The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate.

<span class="mw-page-title-main">Kisspeptin</span> Mammalian protein

Kisspeptins are proteins encoded by the KISS1 gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis. Kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone (GnRH) at puberty, the extent of which is an area of ongoing research. Gonadotropin-releasing hormone is released from the hypothalamus to act on the anterior pituitary triggering the release of luteinizing hormone (LH), and follicle stimulating hormone (FSH). These gonadotropic hormones lead to sexual maturation and gametogenesis. Disrupting GPR54 signaling can cause hypogonadotrophic hypogonadism in rodents and humans. The Kiss1 gene is located on chromosome 1. It is transcribed in the brain, adrenal gland, and pancreas.

<span class="mw-page-title-main">Histrelin</span> Chemical compound

Histrelin acetate, sold under the brand name Supprelin among others, is a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with added potency. When present in the bloodstream, it acts on particular cells of the pituitary gland called gonadotropes. Histrelin stimulates these cells to release luteinizing hormone and follicle-stimulating hormone. Thus it is considered a gonadotropin-releasing hormone agonist or GnRH agonist.

<span class="mw-page-title-main">KiSS1-derived peptide receptor</span> Mammalian protein found in Homo sapiens

The KiSS1-derived peptide receptor is a G protein-coupled receptor which binds the peptide hormone kisspeptin (metastin). Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues. Activation of the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell.

Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles in a male. In response to the signals, the gonads produce hormones that stimulate libido and the growth, function, and transformation of the brain, bones, muscle, blood, skin, hair, breasts, and sex organs. Physical growth—height and weight—accelerates in the first half of puberty and is completed when an adult body has been developed. Before puberty, the external sex organs, known as primary sexual characteristics, are sex characteristics that distinguish males and females. Puberty leads to sexual dimorphism through the development of the secondary sex characteristics, which further distinguish the sexes.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.

Gonadotropin-releasing hormone (GnRH) insensitivity also known as Isolated gonadotropin-releasing hormone (GnRH)deficiency (IGD) is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.

Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

Puberty blockers are medicines used to postpone puberty in children. The most commonly used puberty blockers are gonadotropin-releasing hormone (GnRH) agonists, which suppress the natural production of sex hormones, such as androgens and estrogens. Puberty blockers are used to delay puberty in children with precocious puberty. They are also used to delay the development of unwanted secondary sex characteristics in transgender children, so as to allow transgender youth more time to explore their gender identity. The same drugs are also used in fertility medicine and to treat some hormone-sensitive cancers in adults.

<span class="mw-page-title-main">Premature thelarche</span> Medical condition

Premature thelarche (PT) is a medical condition, characterised by isolated breast development in female infants. It occurs in females younger than 8 years, with the highest occurrence before the age of 2. PT is rare, occurring in 2.2-4.7% of females aged 0 to 2 years old. The exact cause of the condition is still unknown, but it has been linked to a variety of genetic, dietary and physiological factors.

The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Indications for bicalutamide include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.

References

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  2. ↑ Howard, S. R.; Dunkel, L. (2018). "The Genetic Basis of Delayed Puberty" (PDF). Neuroendocrinology. 106 (3): 283–291. doi:10.1159/000481569. PMID   28926843. S2CID   4772278.
  3. ↑ Klein, D. A.; Emerick, J. E.; Sylvester, J. E.; Vogt, K. S. (November 2017). "Disorders of Puberty: An Approach to Diagnosis and Management". American Family Physician. 96 (9): 590–599. PMID   29094880.
  4. ↑ precocious+puberty at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  5. ↑ "default - Stanford Children's Health". www.stanfordchildrens.org. Retrieved 2021-02-16.
  6. ↑ David Gardner, Dolores Shoback. Basic And Clinical Endocrinology. McGraw-Hill Medical; 2011. 9th Edition. Pg. 550
  7. ↑ Dickerman, R. D.; Stevens, Q. E.; Steide, J. A.; Schneider, S. J. (2004). "Precocious puberty associated with a pineal cyst: is it disinhibition of the hypothalamic-pituitary axis?". Neuro Endocrinology Letters. 25 (3): 173–175. PMID   15349080.
  8. ↑ Kumar, Manoj; Mukhopadhyay, Satinath; Dutta, Deep (2015-01-15). "Challenges and controversies in diagnosis and management of gonadotropin dependent precocious puberty: An Indian perspective". Indian Journal of Endocrinology and Metabolism. 19 (2): 228–235. doi: 10.4103/2230-8210.149316 . PMC   4319262 . PMID   25729684.
  9. ↑ Subbiah, Sridhar; Nahar, Uma; Samujh, Ram; Bhansali, Anil (May 2013). "Heterosexual precocity: rare manifestation of virilizing adrenocortical oncocytoma". Annals of Saudi Medicine. 33 (3): 294–297. doi:10.5144/0256-4947.2013.294. ISSN   0256-4947. PMC   6078526 . PMID   23793435. So far, in the pediatric age group, only three cases of functioning adrenocortical oncocytoma have been reported. We report a case of functioning adrenocortical oncocytoma in a 3 1/2-year-old female child who presented with premature pubarche, clitoromegaly, and increased serum dehydroepiandrosterone sulfate and testosterone. She was managed successfully with right adrenalectomy, and the tumor histology was consistent with adrenal oncocytoma.
  10. ↑ Santos-Silva, Rita; Bonito-Vítor, Artur; Campos, Miguel; Fontoura, Manuel (2014). "Gonadotropin-Dependent Precocious Puberty in an 8-Year-Old Boy with Leydig Cell Testicular Tumor". Hormone Research in Paediatrics. 82 (2): 133–137. doi:10.1159/000358084. ISSN   1663-2818. PMID   24862970. S2CID   9961260.
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  14. ↑ Masse, R. J.; Shaw, P. J.; Burgess, M. (2008). "Intracranial choriocarcinoma causing precocious puberty and cured with combined modality therapy". Journal of Paediatrics and Child Health. 29 (6): 464–467. doi:10.1111/j.1440-1754.1993.tb03022.x. PMID   8286166. S2CID   21886832.
  15. ↑ Antoniazzi, F.; Zamboni, G. (2004). "Central precocious puberty: current treatment options". Paediatric Drugs. 6 (4): 211–231. doi:10.2165/00148581-200406040-00002. PMID   15339200. S2CID   21330464.
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  17. ↑ (Tanner, 1990).
  18. 1 2 3 4 Kaplowitz, P. B.; Slora, E. J.; Wasserman, R. C.; Pedlow, S. E.; Herman-Giddens, M. E. (2001). "Earlier onset of puberty in girls: relation to increased body mass index and race". Pediatrics. 108 (2): 347–353. doi:10.1542/peds.108.2.347. PMID   11483799.
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  21. 1 2 Cooney, Elizabeth (2010-02-11). "Puberty gap: Obesity splits boys, girls. Adolescent males at top of the BMI chart may be delayed". NBC News. Archived from the original on January 11, 2016. Retrieved 2010-05-22.
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