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] Even when there is no disease, unusually early puberty can have adverse effects on social behavior and psychological development (have a more mature knowledge than one's age, feel inadequate, try to attend and establish friendships with older people, depression), can reduce adult height potential, and may shift some 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]

Contents

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's 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]

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] [43] 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. [44] 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. [44] Studies have shown that early-maturing boys are more likely to be sexually active and are more likely to participate in risky behaviors. [45]

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). [46] 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 and in humans, 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 and it also marks the beginning of 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.

<span class="mw-page-title-main">Thelarche</span> Beginning of development of the breasts in the female

Thelarche, also known as breast budding, is the onset of secondary breast development, often representing the beginning of pubertal development. It is the stage at which male and female breasts differentiate due to variance in hormone levels; however, some males have a condition in which they develop breasts, termed gynecomastia. Thelarche typically occurs between the ages of 8 and 13 years with significant variation between individuals. However, the initial growth of breast tissue occurs during fetal development.

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">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

<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). 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">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.

<span class="mw-page-title-main">Tuber cinereum hamartoma</span> Human disease

Tuber cinereum hamartoma is a benign tumor in which a disorganized collection of neurons and glia accumulate at the tuber cinereum of the hypothalamus on the floor of the third ventricle. It is a congenital malformation, included on the spectrum of gray matter heterotopias. Formation occurs during embryogenesis, typically between days 33 and 41 of gestation. Size of the tumor varies from one to three centimeters in diameter, with the mean being closer to the low end of this range. It is estimated to occur at a frequency of one in one million individuals.

<span class="mw-page-title-main">Aromatase excess syndrome</span> Medical condition

Aromatase excess syndrome is a rarely diagnosed genetic and endocrine syndrome which is characterized by an overexpression of aromatase, the enzyme responsible for the biosynthesis of the estrogen sex hormones from the androgens, in turn resulting in excessive levels of circulating estrogens and, accordingly, symptoms of hyperestrogenism. It affects both sexes, manifesting itself in males as marked or complete phenotypical feminization and in females as hyperfeminization.

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.

<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.

References

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  29. ↑ Teles, Milena Gurgel; Silveira, Leticia Ferreira Gontijo; Tusset, Cintia; Latronico, Ana Claudia (1 October 2011). "New genetic factors implicated in human GnRH-dependent precocious puberty: The role of kisspeptin system". Molecular and Cellular Endocrinology. 346 (1–2): 84–90. doi:10.1016/j.mce.2011.05.019. PMID   21664234. S2CID   27207961.
  30. ↑ Silveira, LG; Noel, SD; Silveira-Neto, AP; Abreu, AP; Brito, VN; Santos, MG; Bianco, SD; Kuohung, W; Xu, S; Gryngarten, M; Escobar, ME; Arnhold, IJ; Mendonca, BB; Kaiser, UB; Latronico, AC (May 2010). "Mutations of the KISS1 gene in disorders of puberty". The Journal of Clinical Endocrinology and Metabolism. 95 (5): 2276–80. doi:10.1210/jc.2009-2421. PMC   2869552 . PMID   20237166.
  31. ↑ Tommiska, Johanna; Sørensen, Kaspar; Aksglaede, Lise; Koivu, Rosanna; Puhakka, Lea; Juul, Anders; Raivio, Taneli (1 January 2011). "LIN28B, LIN28A, KISS1, and KISS1R in idiopathic central precocious puberty". BMC Research Notes. 4 (1): 363. doi: 10.1186/1756-0500-4-363 . PMC   3184284 . PMID   21939553.
  32. ↑ Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, et al. (2013). "Central precocious puberty caused by mutations in the imprinted gene MKRN3". N Engl J Med. 368 (26): 2467–2475. doi:10.1056/nejmoa1302160. PMC   3808195 . PMID   23738509.
  33. ↑ Macedo DB, Abreu AP, Reis AC, Montenegro LR, Dauber A, Beneduzzi D, Cukier P, Silveira LF, Teles MG, Carroll RS, et al. (2014). "Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3". J Clin Endocrinol Metab. 99 (6): E1097–1103. doi:10.1210/jc.2013-3126. PMC   4037732 . PMID   24628548.
  34. ↑ Abreu AP, Macedo DB, Brito VN, et al. (2015). "A new pathway in the control of the initiation of puberty: the MKRN3 gene". Journal of Molecular Endocrinology. 54 (3): R131–R139. doi:10.1530/jme-14-0315. PMC   4573396 . PMID   25957321.
  35. ↑ Zukauskaite, S.; Lasiene, D.; Lasas, L.; Urbonaite, B.; Hindmarsh, P. (2005). "Onset of breast and pubic hair development in 1231 preadolescent Lithuanian schoolgirls". Archives of Disease in Childhood. 90 (9): 932–936. doi:10.1136/adc.2004.057612. PMC   1720558 . PMID   15855182.
  36. ↑ Roberts, Michelle (2005-05-15). "Why puberty now begins at seven". BBC News. Retrieved 2010-05-22.
  37. ↑ Ritter, Jim (2000-08-02). "Parents worried by girls' earlier start of puberty". Chicago Sun-Times .
  38. ↑ Diana Zuckerman (2001). "Early Puberty in Girls". The Ribbon. Cornell University Program on Breast Cancer and Environmental Risk Factors. Retrieved 18 February 2018.
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  41. ↑ Florence Comite; Cutler, Gordon B.; Rivier, Jean; Vale, Wylie W.; Loriaux, D. Lynn; Crowley, William F. (24 December 1981). "Short-Term Treatment of Idiopathic Precocious Puberty with a Long-Acting Analogue of Luteinizing Hormone-Releasing Hormone". New England Journal of Medicine. 305 (26): 1546–1550. doi:10.1056/NEJM198112243052602. PMID   6458765.
  42. ↑ Bertelloni, Silvano; Mucaria, Cristina; Baroncelli, Giampiero I.; Peroni, Diego (July 2018). "Triptorelin depot for the treatment of children 2 years and older with central precocious puberty". Expert Review of Clinical Pharmacology. 11 (7): 659–667. doi:10.1080/17512433.2018.1494569. ISSN   1751-2441. PMID   29957076.
  43. ↑ (Caspi et al.1993: Lanza and Collins, 2002)
  44. 1 2 Garn, SM. Physical growth and development. In: Friedman SB, Fisher M, Schonberg SK, editors. Comprehensive Adolescent Health Care. St Louis: Quality Medical Publishing; 1992. Retrieved on 2009-02-20
  45. ↑ Susman, EJ; Dorn, LD; Schiefelbein, VL. Puberty, sexuality, and health. In: Lerner MA, Easterbrooks MA, Mistry J., editors. Comprehensive Handbook of Psychology. New York: Wiley; 2003. Retrieved on 2009-02-20
  46. ↑ Janssen, Diederik (2021). "Puer barbatus: Precocious Puberty in Early Modern Medicine". Journal of the History of Medicine and Allied Sciences. 76 (1): 20–52. doi: 10.1093/jhmas/jraa045 . PMC   7737932 . PMID   33186444.
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