Delayed puberty

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Delayed puberty is almost always due to physiologic exaggerated prolongation of puberty timing in boys and girls, a condition called “constitutional delay of growth and puberty (CDGP)“. Delayed puberty sometimes has other pathophysiologies, such as hypergonadotropic hypogonadism, permanent hypogonadotropic hypogonadism, and functional hypogonadotropic hypogonadism. Delayed puberty is the result of disturbances in hypothalamus–pituitary–gonadal (HPG) axis. Genetic basis plays an important role in delayed puberty. 50-75% of cases of constitutional delay of growth and puberty (CDGP) have a positive family history of delayed puberty. 25 various genes in 3 different groups of Kallman syndrome related genes, hypothalamus–pituitary–gonadal (HPG) axis related genes, and obesity related genes, have been associated with puberty. Microscopic evaluation of ovaries in a patient with delayed puberty may reveal the presence of normal cuboidal epithelium. Delayed puberty must be differentiated from other diseases that cause latency in secondary sexual characteristics development, such as constitutional delay of puberty, hypopituitarism, and chromosomal abnormalities. The Chromosomal abnormalities include Turner’s syndrome, Klinefelter’s syndrome, and Noonan’s syndrome. The incidence of delayed puberty (hypogonadotropic hypogonadism) is approximately 1-10 cases per 100,000 individuals worldwide. The prevalence of delayed puberty is not known. Delayed puberty commonly occurs in children under 15 years of age and also occurs in individuals of all races equally. Delayed puberty (constitutional delay of growth and puberty) is seen more in boys. Physical examination is usually remarkable for delayed growth spurt along with small testicular size (less than 4 mL or 2.5 cm) in more than 14 years old boys and thelarche stage 0-1 in more than 13 years old girls. Laboratory findings consistent with the diagnosis of delayed puberty include first line and second line tests. First line tests are complete blood count, erythrocyte sedimentation rate, creatinine, electrolytes, bicarbonate, alkaline phosphatase, albumin, thyrotropin, free thyroxine, luteinizing hormone (LH), follicle stimulating hormone (FSH), insulin-like growth factor (IGF-1), and testosterone. In case of specific familial disorders, some especial laboratory tests may be needed. Second line tests are gonadotropin releasing hormone (GnRH), human chorionic gonadotropin (hCG), inhibin B, prolactin, and growth hormone (GH) tests. The mainstay of medical therapy for delayed puberty is sex hormone replacement therapy. The various formulations of estrogen, progesterone, and testosterone are used in both genders.

Studying the archaic humans in Pleistocene (i.e., greater than 10,000 years ago), it assumed that puberty was correlated with productivity in females. The age of menarche was between 7 and 13 years. Researchers have found that in a Turkana boy (from the species of Homo erectus) from 1.6 million years ago, the puberty was earlier than today humans; however, their final height was more than modern humans. The discovery and growth of agriculture in the archaic world is the main reason for delaying puberty age, through a negative impact on child growth. Agricultural communities in contrast with hunter-gatherer communities experienced the tougher lifestyle and rose with many nutrition deficits that may lead to their delayed puberty. Regarding that lifestyle was growing and the complexity of societies was increasing in the past, the process of becoming an adult from a child was prolonged which resulted in delayed puberty.

Delayed puberty is almost always due to physiologic exaggerated prolongation of puberty timing, a condition called constitutional delay of growth and puberty (CDGP). Another forms of the disease include hypergonadotropic hypogonadism, permanent hypogonadotropic hypogonadism, and functional hypogonadotropic hypogonadism.

Delayed puberty is the result of disturbances in hypothalamus–pituitary–gonadal (HPG) axis. Genetic basis plays an important role in delayed puberty. 50-75% of constitutional delay of growth and puberty (CDGP) have positive family history of delayed puberty. 25 various genes, in 3 different groups of Kallmann syndrome related genes, hypothalamus–pituitary–gonadal (HPG) axis related genes, and obesity related genes, play roles in delayed puberty. On gross pathology, lack of testicular enlargement in boys or breast development in girls is characteristic finding of delayed puberty. Microscopic evaluation of ovaries in a patient with delayed puberty may reveal the presence of normal cuboidal epithelium. The ovary has some dense fibrous tissue, about 0.4 mm thick band, in the cortex. The band is extended under the tunica albuginea, devoid of follicles. Under the fibrous band there will be numerous small follicles. These follicles consist of primordial (51%), intermediary (42%), and primary (7%) follicles.  

Delayed puberty may be caused by endocrine or genetic causes, that hypothalamus–pituitary–gonadal (HPG) axis disorders and Kallmann syndrome are the most causes, respectively. There are various genes that may be related to delayed puberty, among which the kisspeptin system genes (KISS1 and KISS1R) are the most important genes.

Delayed puberty must be differentiated from other diseases that cause latency in secondary sexual characteristics development, such as constitutional delay of puberty, hypopituitarism, and chromosomal abnormalities. Chromosomal abnormalities are Turner’s syndrome, Klinefelter’s syndrome, and Noonan’s syndrome.

The incidence of delayed puberty (hypogonadotropic hypogonadism) is approximately 1-10 cases per 100,000 individuals worldwide.The prevalence of delayed puberty is not known. Prevalence of puberty disorders is about 3,000 cases per 100,000 individuals worldwide. Regarding the definition of delayed puberty, the disease commonly occurs in children under 15 years of age. Delayed puberty usually occurs in individuals of all races, equally. Definite diagnosis upon the mean age of puberty onset in any specific societies can help to reduce the effects of ethnicity on delayed puberty epidemiology. Boys are more commonly affected by delayed puberty (constitutional delay of puberty) than girls.

The most potent risk factor in the development of delayed puberty is hypothalamus–pituitary–gonadal (HPG) axis disturbance. Other risk factors are genetic, endocrinologic, and environmental; which may disturb the HPG axis.

According to the US Preventive Services Task Force (USPSTF), screening for delayed puberty is not recommended.

The symptoms of puberty usually develop between 8 and 13 in girls and between 9 and 14 in boys, and start with symptom of breast development in girls and testicular enlargement in boys. If the testicular enlargement or breast development has not occurred at an mean age of puberty in population plus 2-2.5 standard deviation (SD), it will be called delayed puberty. The mean age is depend on various factors, such as race, nutrition, and also socioeconomic status. Recently, the puberty onset age is decreasing in US and other countries. The main complications of delayed puberty are osteoporosis, psychological problems, polycythemia, and irritation from hormonal gels and patches. The major determinant of delayed puberty prognosis is underlying co-morbidity, not the disease itself. Constitutional delay of growth and puberty (CDGP) has an excellent prognosis. The puberty and final height in these patients will occur normal in the future, without any hormone replacement. 

The hallmark of delayed puberty is lack of testicular enlargement in boys or breast development in girls, in specific stage of life. The age, in which secondary sexual characteristics are checked, is 2-2.5 SD more than the standard population average age of puberty onset. The age is 14 for boys and 13 for girls, on average. A positive family history of delayed puberty is strongly associated with delayed puberty. The most common contributing symptom of delayed puberty is anosmia or hyposmia. Less common symptoms of delayed puberty are including the symptoms related to its underlying diseases.

Patients with delayed puberty usually appear normal. Physical examination of patients with delayed puberty is usually remarkable for delayed growth spurt along with small testicular size (less than 4 mL or 2.5 cm) in more than 14 years old boys and thelarche stage 0-1 in more than 13 years old girls. Testicular size is identified by length of the longest axis or by its volume using the Prader orchidometer. Thelarche stage is determined by use of Tanner staging system. The lack of pubic or axillary hairs and also primary amenorrhea on physical examination is highly suggestive of delayed puberty.

Laboratory findings consistent with the diagnosis of delayed puberty include first line and second line tests. First line tests are complete blood count, erythrocyte sedimentation rate, creatinine, electrolytes, bicarbonate, alkaline phosphatase, albumin, thyrotropin, free thyroxine, luteinizing hormone (LH), follicle stimulating hormone (FSH), insulin-like growth factor (IGF-1), and testosterone; In case of specific familial disorders, some especial laboratory tests may be needed. These laboratory tests are including anti-gliadin antibody and anti-tissue transglutaminase antibody (i.e., Celiac disease diagnosis) or anti-neutrophil cythoplasmic antibodies (i.e., inflammatory bowel disease diagnosis). Second line tests are gonadotropin releasing hormone (GnRH), human chorionic gonadotropin (hCG) test, inhibin B, prolactin, and growth hormone (GH) tests.

There are no ECG findings associated with delayed puberty.

An X-ray may be helpful in the diagnosis of delayed puberty. Findings on an X-ray are specific to measuring bone age. Bone age may be used to predict the children final adult height. Studies have shown that there is strong association between bone age and the initiation of puberty in boys involved in developmental disorders. If the difference between measured bone age and chronological age is more than 2 years, it will strongly diagnostic of constitutional delay of growth and puberty (CDGP).

There is limited role for CT scan to measure the bone age more precise.

Brain MRI may be helpful in the diagnosis of delayed puberty. Findings on MRI suggestive of delayed puberty include hypothalamo–pituitary lesions, aplasia of olfactory bulb and/or sulci (Kallmann syndrome), optic nerve compression (pituitary adenoma), and inner ear abnormalities (CHARGE syndrome). Showing the aplasia of olfactory bulbs and/or sulci in MRI, it is assumed as differentiation of Kallmann syndrome from isolated hypogonadotropic hypogonadism, in patient without smelling problems or hard to evaluate.

There are no ultrasound findings associated with delayed puberty. It may be used to evaluate the gross anatomy of gonads.

There are no other imaging findings associated with delayed puberty.

Karyotyping is used to diagnose delayed puberty caused by chromosomal disorders, such as Turner syndrome and Klinefelter syndrome. University of Pennsylvania Smell Identification Test (UPSIT), consist of microencapsulated odorants released by scratching standardized odor-impregnated questionnaires, is used to detect hyposmia or anosmia in Kallmann syndrome.

The main pharmacological medical therapy for delayed puberty is sex hormone replacement therapy. The aim of treatment is to stimulate the puberty onset and to merge the secondary sexual characteristics in patients. The various formulations of estrogen, progesterone, and testosterone are used in both genders for medical therapy of delayed puberty. Other types of treatments are include low-dose oxandrolone, dihydrotestosterone (DHT), and kisspeptin agonist.

The mainstay of treatment for delayed puberty is medical therapy. Surgery is usually reserved for patients with either pituitary tumors, hypothalamus hamartomas, and Turner syndrome. There are two procedures for excision of pituitary tumors, including endoscopic transsphenoidal surgery and craniotomy. In presence of Y chromosome the chance of becoming malignant is higher in Turner syndrome, oophorectomy (even salpingo-oophorectomy) has to be done urgently. 

There are no established measures for the primary prevention of delayed puberty.

Effective measures for the secondary prevention of delayed puberty include timely diagnosis and hormone replacement therapy in order to prevent osteoporosis and short adult height and salpingo-oophorectomy in Turner syndrome to prevent ovarian malignancy. 

There are limited data about cost-effectiveness of therapy in delayed puberty. The main part of the economic burden of delayed puberty is because of its various and specific blood tests, such as hormone assay. The main treatment for the patients with short stature is growth hormone (GH), thus, the potential cost of treating all eligible children with growth hormone (GH) is approximately $40 billion dollars.  

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Studying the archaic humans in Pleistocene (i.e., greater than 10,000 years ago), it assumed that puberty was correlated with productivity in females. The age of menarche was between 7 and 13 years. Researchers have found that in a Turkana boy (from the species of Homo erectus) from 1.6 million years ago, the puberty was earlier than today humans; however, their final height was more than modern humans. The discovery and growth of agriculture in the archaic world is the main reason for delaying puberty age, through a negative impact on child growth. Agricultural communities in contrast with hunter-gatherer communities experienced the tougher lifestyle and rose with many nutrition deficits that may lead to their delayed puberty. Regarding that lifestyle was growing and the complexity of societies was increasing in the past, the process of becoming an adult from a child was prolonged which resulted in delayed puberty.

Theories of puberty

Granville Stanley Hall[1] 1844-1924

Biogenetic psychologic theory

• First psychologist that describe the puberty and adolescence scientifically. • Describes the period as “storm and stress” period. • A new birth, “for the higher and more completely human traits are now born” • The period is corresponding to the last stage of development- Maturity.

Sigmund Freud[2] 1856-1939

Psychoanalytic theory

• This stage of life could be seen phylogenetically. • The developmental stages of psychosexuality are completely defined by genetic factors and are not dependent to the environmental issues. • A holistic pathway influenced by social, emotional, and also behavioral situations.

Eduard Spranger[3] 1882-1963

Philosophy of culture theory

• Describes the adolescence period and puberty as a distinct stage of life with its specific characteristics. • The puberty is the age that disorganized mental structure of the child transits to maturity. • The “dominant value direction” of the adolescent would be the main personality identifier.

Otto Rank[4] 1884-1939

Independence theory

• Criticize the major role of sexuality, and suggested “will” as the main controller of sexuality. • The main part of puberty is to change from dependence to independence. • Beginning of the puberty, the adolescent start to struggle with dependency, both externally (parents, society, and laws) and internally (cravings as instinctual urges). • No need to externally limit or inhibit sexualism, through which the adolescent is finding independence in front of biological needs’ dominance.

Leta Hollingworth[5] 1886-1939

Continuity of development theory

• Believes that puberty is based on continuity and progresses gradually, not through distinct stages. • Biological and social changes during puberty are not correlated.

Anna Freud[6] 1895-1982

Defense mechanism theory

• The most important factor in the formation of person’s character is puberty. • Normal progression may encounter the obstacle, in which id (superego) is overriding the ego. • The defense mechanisms of ego against id are the main determinant of puberty process and outcome.

Jean Piaget[7] 1896-1980

Cognitive theory

• The main step in puberty is growing of logical thinking. • The final stage of egocentrism happens at puberty, transitioning from childhood to adulthood.

Erik Erikson[8] 1902-1994

Identity development theory

• Assumes that the most important issue during the period of adolescent is identity crisis. • The adolescent has to find the identity, himself/herself, through evaluating the capabilities and weaknesses, and also the way they can be used. • In a person fails to find a stable identity, it may lead him/her to self-doubt and role confusion.

Roger Barker[9] 1903-1990

Somatopsychological theory

• Evaluates the influence of physiological changes on behavior by puberty. • These changes are in body dimensions and hormonal secretion, that experience accelerated speed during adolescence. • These physical changes allow the adolescents to present in adult communities, and therefore improving behaviors and beliefs.

James Marcia[10] 1930s-Now

Identity status theory

• Describes identity as “an internal, self-constructed, dynamic organization of drives, abilities, beliefs and individual history”. • The more the person is going through puberty, the more he/she stabilizes the identity.

• After studying the archaic humans in Pleistocene (i.e., greater than 10,000 years ago), it was assumed that puberty was correlated with productivity in females. The age of menarche was between 7 and 13 years.
• Researchers have found that in a Turkana boy (from the species of Homo erectus) from 1.6 million years ago, the puberty was earlier than today humans; however, their final height was more than modern humans.
• The discovery and growth of agriculture in the archaic world is the main reason for delaying puberty age, through a negative impact on child growth. Agricultural communities in contrast with hunter-gatherer communities experienced a tougher lifestyle and rose with so many nutrition deficits; that may lead to their delayed puberty.
• On the other hand, the more crowded life of agricultural communities, compared with hunter-gatherers, made them more vulnerable to infections, especially zoonoses. Therefore, child mortality rate was raised and conclusively the puberty age was delayed, based on “life history theory“.
• As the lifestyle was improving and the complexity of societies was increasing in the past, the process of becoming an adult from a child was prolonged which resulted in delayed puberty.
• Over the last 150 years, the menarche age has lowered, due to the improvement of hygiene, nutrition, and infection control. On the other hand, the role of adolescents in society and concluded expectations are increased; therefore, the maturation necessitated so many qualifications to gather and is delayed more and more. Nowadays, it is the first time in our history that biological maturation becomes well preceded from social maturation. It may encounter the adolescents to much more pressure, need to reevaluate the place of adolescents in modern life.
• In 1904, Hall described the puberty as “storm and stress” period. The stage assumed to consist of oppositional and emotionally labile characteristics in adolescents. The future adulthood life quality is significantly related to and also influenced from this period outline.
• In 1958, Anna Freud showed that some biological and physiological changes during the puberty are the main factors contributing to “storm and stress“.
• In 1999, Bogin demonstrated that in human beings the time of maturation and puberty is later than other apes; which is due to more complicated childhood growth process. The suggested age of maturation in chimpanzee was 3 years earlier than humans.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Delayed puberty is almost always due to physiologic exaggeration of the prolongation of puberty timing; a condition called constitutional delay of growth and puberty (CDGP). Other forms of delayed puberty include hypergonadotropic hypogonadism, permanent hypogonadotropic hypogonadism, and functional hypogonadotropic hypogonadism.

• Delayed puberty may be classified according to etiology into 4 subtypes which includes:^[1]
  • Constitutional delay of growth and puberty (CDGP)
  • Hypergonadotropic hypogonadism
  • Permanent hypogonadotropic hypogonadism
  • Functional hypogonadotropic hypogonadism
• The most common subtype of delayed puberty, constitutional delay of growth and puberty (CDGP), has no pathological etiology and is completely physiologic.
• Other subtypes of delayed puberty are classified upon the serum levels of sex hormones and also gonadotropins.
• The complete classification of delayed puberty is as follows:

Delayed puberty classification

LH, FSH, and GnRH plasma level

Normal

Abnormal

Constitutional delay of growth and puberty (CDGP)

LH and FSH increased GnRH increased

LH and FSH decreased GnRH decreased

LH and FSH decreased GnRH decreased (transient)

Hypergonadotropic hypogonadism (primary hypogonadism)

Permanent hypogonadotropic hypogonadism (secondary hypogonadism)

Transient hypogonadotropic hypogonadism (functional hypogonadism)

​ Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Delayed puberty is the result of disturbances in hypothalamus-pituitary-gonadal (HPG) axis. Genetics plays an important role in the development of delayed puberty. In case of constitutional delay of growth and puberty (CDGP), 50-75% of patients have a positive family history of delayed puberty. About 25 various genes, in 3 different group of Kallmann syndrome-related genes, hypothalamus–pituitary–gonadal (HPG) axis related genes, and obesity-related genes play roles in delayed puberty. On gross pathology, lack of testicular enlargement in boys or breast development in girls is the characteristic finding of delayed puberty. Microscopic evaluation of ovaries in a patient with delayed puberty may reveal the presence of normal cuboidal epithelium; the ovary has some dense fibrous tissue, about 0.4 mm thick band, in the cortex. The band is extended under the tunica albuginea, devoid of follicles. Under the fibrous band, there will be numerous small follicles. These follicles consist of primordial (51%), intermediary (42%), and primary (7%) follicles.

• Delayed puberty is the result of disturbances in hypothalamus–pituitary–gonadal (HPG) axis.
• The components of HPG axis are already well identified and oriented, but the main signal of starting puberty is not completely understood. It is not understood why some children start puberty at 11 and some others later.
• Intact HPG axis is the main factor required for the development of maturation in a child. The beginning of the pathway is with gonadotropin releasing hormone (GnRH) production from the hypothalamus. Then, GnRH stimulates the gonadotropic cells in the anterior pituitary gland, producing luteinizing hormone (LH) and follicle stimulating hormone (FSH). Finally, LH and FSH stimulate the gonads maturation to produce the sex-steroids, firing the puberty process.
• Every single failure in the mentioned pathway could lead to delayed puberty. The failure may be congenital or acquired during the life.^[1]

Group	Form of disease	Disease	Pathogenesis
Primary hypogonadism	Congenital	Chromosomal abnormality	Lack or disorder of a specific cell line or enzyme that is responsible for producing one of the sex-steroids in gonads
		Gonadal agenesis	Lack of gonads, as a main source of sex-steroids
	Acquired	Any external stress to the gonadal tissues	Destruction of gonadal cell line, responsible for producing and secreting sex-steroids
Secondary hypogonadism	Congenital	GnRH deficiency	Lack or disorder of a specific cell line or enzyme that is responsible for producing GnRH in hypothalamus
		LH and FSH deficiency	Lack or disorder of a specific cell line or enzyme that is responsible for producing LH or FSH in pituitary gonadotropic cells
	Acquired	Any external stress to the hypothalamus or anterior pituitary	Destruction of hypothalamus or anterior pituitary cell line, responsible for producing and secreting GnRH, LH, or FSH

• Antimullerian hormone and inhibin B are two glycoproteins that are secreted from gonads and can reflect their activity level. Their plasma level changes reflect the puberty status in children, as follows:^[2]

Sex	Hormone	Source of secretion	After birth	Childhood	Puberty	Function
Boys	Antimullerian hormone	Sertoli cells of testes	↑	↓	↓	Female structures (mullerian) regression Inhibited by testosterone in puberty
	Inhibin B	Sertoli cells of testes	↑	↓	↑	Inhibit the FSH through negative feedback Marker of spermatogenesis
Girls	Antimullerian hormone	Granulosa cells of preantral follicles in ovary	↑	↑	↓	Marker for the assessment of follicular pool
	Inhibin B	Both preantral and small antral follicles in ovary	↓	↓	↑	Marker of gonadal response to LH and FSH

• Genetics plays an important role in delayed puberty. It is assumed that the main factor in determining puberty timing is genetic elements.^[3]

• In case of constitutional delay of growth and puberty (CDGP), 50-75% of patients have a positive family history of delayed puberty.^[4]

• It is thought that CDGP is inherited in an autosomal dominant pattern, with or without the effects of complete penetrance.
• Delayed puberty is not a sex oriented inheritance and can be seen in all family members.^[5]

Abbreviations (alphabetic):
CHD7: Chromodomain helicase DNA-binding protein 7 gene, DAX1: DSS-AHC on the X-chromosome 1, EBF2: Early B-cell factor 2 gene, FGF8: Fibroblast growth factor 8 gene, FGFR1: Fibroblast growth factor receptor 1 gene, FSH: Follicle stimulating hormone, GnRH: Gonadotropin releasing hormone, GnRH1: Gonadotropin releasing hormone 1 gene, GnRHR: Gonadotropin releasing hormone receptor gene, GPR54: G protein-coupled receptor-54 gene, HESX-1: Homeobox gene 1, HPG axis: Hypothalamus-pituitary-gonadal axis, HS6ST1: Heparan sulfate 6-O-sulphotransferase 1 gene, KAL1: Kallmann syndrome 1 gene, LEP: Leptin gene, LEPR: Leptin receptor gene, LH: Luteinizing hormone, LHX3: LIM homeobox gene 3, NEC1: Neuroendocrine convertase 1, NELF: Nasal embryonic LH-releasing hormone factor gene, NK3R: Neurokinin 3 receptor gene, NKB: Neurokinin B gene, NR0B: Nuclear receptor 0B, NR5A1: Nuclear receptor 5A1, OMIM: Online Mendelian Inheritance in Man, PC1: Proprotein convertase 1, PROK2 : Prokineticin 2 gene, PROKR2: Prokineticin 2 receptor gene, PROP-1: PROP paired-like homeobox 1, RPX: Rathke pouch homeobox, SF-1: Steroidogenic factor 1, TAC3: Tachykinin 3 gene,TACR3: Tachykinin 3 receptor gene,

Groups	Gene	Other name(s)	OMIM number	Chromosome	Function	Other related disorders
Kallmann syndrome and Isolated hypogonadotropic hypogonadism[6]	KAL1	KAL1, anosmin-1	308700	Xp22.3	Migration of GnRH neurons Olfactory bulb development	Midline facial defects (cleft lip and/or cleft palate) Short metacarpals Renal agenesis Sensorineural hearing loss Bimanual synkinesis Oculomotor abnormalities Cerebellar ataxia
	FGFR1	KAL2	136350	8q12	Embryogenesis Homeostasis Wound healing Olfactory bulb differentiation and development GnRH neurons migration and function	Cleft palate or lip Dental agenesis Bimanual synkinesis
	PROKR2	KAL3	607123	20p13	Neuroendocrine system (arcuate nucleus, olfactory tract, and suprachiasmatic nucleus) Olfactory bulb development Gonadal development GnRH increase	Fibrous dysplasia Sleep disorder Severe obesity Synkinesis Epilepsy
	PROK2	KAL4	607002	3p21.1
	CHD7	KAL5	608892	8q12.1	Olfactory bulb development	CHARGE syndrome: Colobomata Heart anomalies Choanal Atresia Retardation Genital anomalies Ear anomalies
	FGF8	KAL6	600483	10q24	Primary generation of neural tissue Olfactory bulb differentiation and development GnRH neurons migration and function	Cardiac developmental abnormalities Craniofacial developmental abnormalities Forebrain developmental abnormalities Midbrain developmental abnormalities Cerebellar developmental abnormalities
	GPR54	KISS1R	604161	19p13.3	Regulation of GnRH secretion	–
	KISS1	KISS1, kisspeptin1	603286	1q32	Sexual maturation and HPG activation with pulsatile GnRH	–
	HS6ST1	–	604846	2q21	Extracellular sugar modifications FGFR–FGF interactions modulator Anosmin-1 interaction with cell membrane	–
	TAC3	NKB	162330	12q13–q21	HPG axis function Stabilize development during puberty Fetal gonadotropins secretion GnRH secretion regulation	Micropenis Cryptorchidism
	TACR3	NK3R	152332	4q25
	GnRH1	–	152760	8p21–8p11.2	One of the most important elements in HPG axis	Teeth abnormal maturation and biomineralization
	GnRHR	–	138850	4q21.2	Gonadal normal functions	Atrophic gonads along with low LH/FSH and sex hormones Sexual puberty disturbance Inability to conceive Failure to impact from exogenous GnRH
	NELF	–	608137	9q34.3	Modulating neuron migration in developmental process Olfactory axons and also GnRH neurons functions	–
	EBF2	–	609934	8p21.2	Effective role in HPG axis	–
HPG axis development	DAX1	NR0B	300473	Xp21.2	Increased expression during the spermatogenesis and steroidogenesis Both sertoli and leydig cells Peak expression during puberty	Congenital adrenal cortex hypoplasia
	SF-1	NR5A1	184757	9q33.3	Mainly expressed in sertoli and leydig cells Plays an important role in steroidogenesis and spermatogenesis Dominantly expressed by leydig cells in puberty	Male pseudohermaphroditism Denys-Drash syndrome Hypospadias
	HESX-1	RPX	601802	3p14.3	Pituitary development Midfacial differentiation Mutation may lead to pituitary hypoplasia	Septooptic dysplasia Reduced prosencephalon Anophthalmia Microphthalmia Defective olfactory development Rathke pouch bifurcations Abnormalities in the corpus callosum, hippocampus, and septum pellucidum
	LHX3	LIM3	600577	9q34.3	Development of pituitary gland and its hormone secretion	Neonatal hypoglycemia Short neck with limited rotation Mild sensorineural hearing loss Skin laxity Skeletal abnormalities
	PROP-1	–	601538	5q35.3	Developing anterior pituitary gland Gonadotrophs Tthyrotrophs Somatotrophs Lactotrophs Low LH and FSH delay the puberty	Thyroid dysfunctions Growth retardation Libido/Lactation problems
Obesity related hypogonadotropic hypogonadism	LEP	OB	164160	7q32.1	Modulation of body weight Beginning the puberty Recombinant leptin injection in female mice result in puberty Increased about 50% just before puberty and also during the puberty	Hematopoiesis disorders Angiogenesis disorders Wound healing disorders Immune or inflammatory response disorders
	LEPR	OBR	601007	1p31.3
	PC1	NEC1	162150	5q15	Regulates neuroendocrine pathway Proopiomelanocortin (POMC) cleavage Processing proinsulin and proglucagon in pancreas.	Extreme childhood obesity Abnormal glucose homeostasis Hypocortisolism Elevated plasma proinsulin, and also POMC

• The GPR54 gene, also called KISS1R, with Online Mendelian Inheritance in Man (OMIM) number of 604161 is on chromosome 19p13.3. The KISS1 gene, also called kisspeptin1, with OMIM number of 603286 is on chromosome 1q32.
• The GnRH secretion has to be pulsatile to stimulate gonadotropins. In regulation of GnRH secretion, kisspeptin and the related G-protein coupled receptor (KISS1R or GPR54) have key roles. Kisspeptins are encoded by KISS1 gene, neuropeptides secreted from hypothalamus nuclei. It is found that patients with idiopathic hypogonadotropic hypogonadism have KISS1 receptor (GPR54) inactivating gene mutations.^[7][8]
• By the time of puberty, the KISS1 genes become activated through neuroanatomical and functional changes from environmental triggers, critical for brain sexual maturation and HPG activation with pulsatile GnRH.^[9]
• Along HPG axis neurons, gamma-aminobutyric acid is inhibitory and glutamate is excitatory neurotransmitters. In related KNDy neurons in arcuate nucleus, the materials secreted include kisspeptin, neurokinin B, and dynorphin A. Before puberty begins, inhibitory dynorphin A is the dominant element; decreased by stimulatory effect of neurokinin B, when puberty started. Conclusively, kisspeptin and GnRH/LH are increased.^[10]

• The KAL1 gene, also called anosmin-1, with OMIM number of 308700 is on chromosome Xp22.3, encode an extracellular matrix glycoprotein.
• Anosmin-1 expressed at five weeks of gestation in forebrain area near olfactory bulbs, stimulate the afferent fibers projections.^[11]
• X-linked Kallmann syndrome is directly associated with KAL1 deletion which results in an absence of olfactory fibers along with disturbed migration of GnRH neurons.^[12]
• Male patients with KAL1 mutation would have central hypogonadism and anosmia/hyposmia. Additionally, more diseases are assumed to be related to KAL1 gene, such as midline facial defects (cleft lip and/or cleft palate), short metacarpals, renal agenesis, sensorineural hearing loss, bimanual synkinesis, oculomotor abnormalities, and cerebellar ataxia.^[13]

• The FGFR1 gene, also called KAL2, with OMIM number of 136350 found on chromosome 8q12, encodes receptor tyrosine kinase protein. The FGF8 gene, also called KAL6, is found on chromosome 10q24.
• FGFR1 pathway is assumed to play the main role in embryogenesis, homeostasis, and wound healing. FGF8 critical role in primary generation of neural tissue has been established by so many researchers.^[14]
• On the other hand, interaction between FGFR1, FGF8, and heparan sulfate helps olfactory bulb to become differentiated and developed, also facilitates GnRH neurons migration and function.^[15]
• Dominant deletion mutation of FGFR1 gene is found to cause a 30% decrease in hypothalamic GnRH neurons.^[16] Other defects related to FGFR1 include cleft palate or lip, dental agenesis and bimanual synkinesis.^[13] Other disorders related to FGF8 include cardiac, craniofacial, forebrain, midbrain, and cerebellar developmental abnormalities.

• The HS6ST1 gene with OMIM number 604846 on chromosome 2q21, has some functions in extracellular sugar modifications; but has been found mutated in hypogonadism.^[17]

• The modifications of heparan sulfate polysaccharides in extracellular matrix have some roles in FGFR–FGF and also anosmin1–cell membrane interactions.^[18][19]
• This gene has been found mutated in both Kallmann syndrome and idiopathic hypogonadism, with various course and timing or GnRH deficiencies.^[17]

• The PROK2 and PROKR2 genes, also called KAL4 and KAL3, with OMIM numbers of 607002 and 607123 on chromosomes 3p21.1 and 20p13, respectively. They are believed to be cause of Kallmann syndrome.
• PROKR2, a G protein coupled receptor (GPCR), has a major role in olfactory bulb development; the mutation may lead to severe gonadal atrophy.^[20]
• In prokineticin system, there are two receptors (PROKR1 and PROKR2) and two ligands (PROK1 and PROK2). PROK1 and its receptor (PROKR1) have some roles in gastrointestinal system motility. However, PROK2 and PROKR2 are parts of neuroendocrine system, located in arcuate nucleus, olfactory tract, and suprachiasmatic nucleus.^[21]
• It seems that mutated versions of PROK2 and PROKR2 could lead to decrease GnRH production and hypogonadism. Other disorders caused by their mutations include fibrous dysplasia, sleep disorder, severe obesity, synkinesis, and epilepsy.^[22]

• The TAC3 and TACR3 genes, also called neurokinin B (NKB) and neurokinin 3 receptor (NK3R), with OMIM numbers of 162330 and 152332, are on chromosomes 12q13–q21 and 4q25, respectively.^[23]
• Normal function of TAC3/TACR3 system is necessary for an intact HPG axis and also its development during puberty. TAC3/TACR3 system disturbance is known to cause micropenis and also cryptorchidism in males, showing the major role in fetal gonadotropins secretion.^[24]
• TACR3 encoded protein (NK3R) is GPCR, initially produced in central nervous system. The major mechanism, through which the mutated gene may lead to neuroendocrine disturbance and delayed puberty, is not completely discovered.^[25]
• TAC3 encoded protein (NKB) is produced in arcuate nucleus of hypothalamus and play an important role in GnRH secretion. Parallel to that, kisspeptin is also produced and secreted in arcuate nucleus, where both of them are inhibited by estrogen. It may be considered that kisspeptin and NKB have same roles in diverting negative feedback from sex hormones to GnRH. Their mutation is related with hypogonadism.

• The GnRH1 and GnRHR genes with OMIM numbers 152760 and 138850 are on chromosomes 8p21–8p11.2 and 4q21.2, respectively.^[26]
• In HPG axis, GnRH is one of the most effective elements; therefore, its defect could directly influence the axis and slow down its progress. Mutated gene in mice make them sexually infantile, infertile, and with low sex hormones and gonadotropins.^[27]
• The GnRHR gene is also responsible for gonadal normal functions, its mutation could lead to hypogonadism and delayed puberty. It seems that the mutation has other outcomes, such as atrophic gonads along with low LH/FSH and sex hormones, sexual puberty disturbance, inability to conceive, and resistance from exogenous GnRH. ^[28]
• Variable expressivity in these genes could cause spectrum of symptoms, from fertile eunuch syndrome and partial idiopathic hypogonadotropic hypogonadism to complete GnRH resistance (i.e., characterized by cryptorchidism), microphallus, very low LH/FSH, and delayed puberty.^[29]
• The other disorders that have been associated with GnRH mutation include tooth abnormal maturation and biomineralization.^[30]

• The CHD7 gene, also called KAL5, with OMIM number 608892 is found on chromosome 8q12.1.
• The main result of the CHD7 gene mutation is autosomal dominant CHARGE syndrome; combination of hypogonadism and Kallmann syndrome, which includes:^[31]
  • Colobomata
  • Heart anomalies
  • Choanal Atresia
  • Retardation
  • Genital anomalies
  • Ear anomalies
• Screening for CHD7 gene is recommended in patients with hypogonadism or Kallmann syndrome with specific features, such as semicircular canals hypoplasia or aplasia, dysmorphic ears, and deafness.

• The NELF gene with OMIM number 608137 on chromosome 9q34.3 is found mostly in nervous tissues specifically during fetal development. It has also been found in olfactory bulb and pituitary LH releasing cells.
• The most common function is in olfactory axons and also GnRH neurons, before and during neuron migration in developmental process.^[32]
• It has some relations with Kallmann syndrome. ^[33]

• The EBF2 gene with OMIM number of 609934 is on chromosome 8p21.2; mostly expressed in mice osteoblasts and osteoclast cells.^[34]
• The gene is believed to have an effective role in HPG axis. In mutated version, it can cause defect in the axis, leading to secondary hypogonadism.^[35]

• The DAX1 gene, also called nuclear receptor 0B (NR0B), with OMIM number of 300473 on chromosome Xp21.2, mostly expressed in all members of HPG axis (hypothalamus, pituitary, and gonads).^[36]
• During the spermatogenesis and steroidogenesis, it seems that both sertoli and leydig cells have increased expression of DAX1 gene. It is assumed that during puberty, the peak expression of DAX1 occurred.^[37]
• Another disease that can be caused by DAX1 mutation is congenital adrenal cortex hypoplasia.^[38]

• The SF1 gene, also called nuclear receptor 5A1 (NR5A1), with OMIM number of 184757 on chromosome 9q33.3, has some roles in reproduction, steroidogenesis, and sexual differentiation.
• It is mainly expressed in sertoli and leydig cells, plays an important role in steroidogenesis and spermatogenesis. The SF1 is believed to experience increase in expression during childhood into adolescence, become dominantly expressed by leydig cells in puberty.^[37]
• It seems that other diseases can be caused by SF1 mutation, such as male pseudohermaphroditism, Denys-Drash syndrome, and also hypospadias.^[39]

• The HESX1 gene, also called Rathke pouch homeobox (RPX), with OMIM number of 601802 is on chromosome 3p14.3, starts to express during embryogenesis and help the formation of Rathke pouch and anterior pituitary.^[40]
• The main function of HESX1 gene is pituitary development and also midfacial differentiation. Mutation may lead to pituitary hypoplasia and decreased level of all anterior pituitary hormones.^[41]
• Other disorders resulting from HESX1 mutation include septooptic dysplasia, reduced prosencephalon, anophthalmia, microphthalmia, defective olfactory development, Rathke pouch bifurcations, and also abnormalities in the corpus callosum, hippocampus, and septum pellucidum.^[40]

• The LHX3 gene, also called LIM3, with OMIM number of 600577 is on chromosome 9q34.3, mainly expressed in developing anterior pituitary gland.^[42]
• It seems that LHX3 gene function is very important in development of pituitary gland and its hormone secretion. Therefore, mutation in the gene is related to combined pituitary hormone deficiency (CPHD).^[43]
• The LHX3 gene mutation can also result in neonatal hypoglycemia, short neck with limited rotation, mild sensorineural hearing loss, skin laxity, and skeletal abnormalities.^[42]

• The PROP1 gene with OMIM number of 601538 is on chromosome 5q35.3, with a main rule in developing anterior pituitary gland and also proper development of gonadotrophs, thyrotrophs, somatotrophs, and lactotrophs.^[44]
• When PROP1 gene become inactivated through mutation, patient may experience deficiency in LH, FSH, GH, TSH, and prolactin serum levels. Lack of LH and FSH would prevent the patient entering the puberty.^[45]
• Regarding the gene function in different cell types of pituitary, it can be concluded that the PROP1 gene mutation can lead to thyroid dysfunctions, growth retardation, and libido/lactation problems.

• The LEP and LEPR genes, also called OB and OBR, with OMIM numbers of 164160 and 601007 are on chromosomes 7q32.1 and 1p31.3, respectively; both of them have major roles in modulation of body weight.
• These genes are believed to carry the message of beginning the puberty, recombinant leptin injection in female mice may result in puberty and also cure their maturation problems.^[46]
• leptin level in human beings become increased about 50% just before puberty and also during the puberty.^[47]
• Mutation in these genes may also result in disorders in hematopoiesis, angiogenesis, wound healing, and the immune or inflammatory response.

• The PC1 gene, also called neuroendocrine convertase 1 (NEC1), with OMIM number of 162150 is on chromosome 5q15, mainly regulates neuroendocrine pathway.
• PC1 gene has the dramatic role of proopiomelanocortin (POMC) cleavage. On the other hand, they help processing proinsulin and proglucagon in pancreas.^[48]
• There is assumed relationship between PC1 gene mutation and hypogonadotropic hypogonadism along with extreme childhood obesity, abnormal glucose homeostasis, hypocortisolism, elevated plasma proinsulin, and also POMC concentrations.^[49]

• Newly discovered MKRN3 gene has a role in ubiquitination and cell signaling. The gene family proteins are majorly expressed in fetal brain during development, especially in arcuate nucleus.
• It seems that the gene amplification is on its peak after birth, gradually declined by the time, and finally raised again when puberty begins. Therefore, it is believed to be one of the factors of starting the puberty, along with kisspeptins and neurokinin B.^[50]

• Estrogen receptor mutations are very rare, reported as a case report with delayed puberty.^[51]
• Estradiol effects on breast maturation and also presents a negative feedback to hypothalamus and pituitary, by means of estrogen receptor α (encoded by ESR1 gene).^[52]
• Female mice with mutated ESR1 gene may have hypoplastic uterus plus hemorrhagic, multicystic ovary without corpus luteum; which is make them infertile.^[53]

The associated conditions that are related to delayed puberty, are as following:^[1]

Associated conditions

Primary hypogonadism

Secondary hypogonadism

Functional hypogonadism

• Turner syndrome • Noonan syndrome • Fragile X syndrome • Cryptorchidism • Gonadal dysgenesis • Testicular agenesis • Trauma/Testicular torsion • Chemotherapy/Radiation therapy • Mumps, coxsackie • Galactosemia • Autoimmune oophiritis • Autoimmune orchitis • 5-alpha reductase deficiency • Lyase deficiency • Congenital lipoid adrenal hyperplasia • Androgen insensitivity • Sertoli cell only syndrome (Del Castillo syndrome)

• Astrocytoma • Germinoma • Glioma • Craniopharyngioma • Prolactinoma • Langerhans cell histiocytosis • Rathke pouch cyst • Kallmann syndrome • Isolated hypogonadotropic hypogonadism • HPG axis development • Obesity and hypogonadotropic hypogonadism • Prader-Willi syndrome • Bardet-Biedl syndrome • CHARGE syndrome • Gaucher disease • Post central nervous system Infection • Septo-optic dysplasia • Congenital hypopituitarism • Chemotherapy/Radiation therapy • Trauma

• Cystic Fibrosis • Asthma • Inflammatory bowel disease • Celiac disease • Juvenile rheumatoid arthritis • Anorexia nervosa/Bulimia • Sickle cell disease • Hemosiderosis • Thalassemia • Chronic renal disease • AIDS • Diabetes mellitus • Hypothyroidism • Hyperprolactinemia • Growth hormone deficiency • Cushing syndrome • Excessive exercise • Malnutrition

• On gross pathology, lack of testicular enlargement in boys or breast development in girls is the characteristic finding of delayed puberty.
• The time to examine these developments is 2-2.5 standard deviations of age more than the standard population mean.

• On microscopic histopathological analysis, the main finding is lack of differentiation of gonadal cells; the characteristic finding of delayed puberty.
• Microscopic evaluation of ovaries in a patient with delayed puberty may reveal the presence of normal cubical epithelium. The ovary has some dense fibrous tissue, about 0.4 mm thick band, in the cortex. The band is extended under the tunica albuginea, devoid of follicles. Under the fibrous band there will be numerous small follicles. These follicles consist of:
  • Primordial follicles: Consists of oocyte in first prophase covered with simple squamous layer of pregranulosa cells (51% of all oocytes).
  • Intermediary follicles: Consists of oocyte covered with mixture of squamous and cubical cells (42% of all oocytes).
  • Primary follicles: Consists of a monolayer of cubical granulosa cells (7% of all oocytes).
• There are no follicles beyond the primary follicles in all sections.^[54]

​ Template:WS Template:WH

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Delayed puberty may be caused by endocrinologic or genetic causes. The most common endocrinologic causes of delayed puberty are hypothalamus–pituitary–gonadal (HPG) axis disorders. The most common genetic cause of delayed puberty is Kallmann syndrome. There are various genes that may be related to delayed puberty, among which the kisspeptin system genes (KISS1 and KISS1R) are the most important genes.

• Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. There are no life-threatening causes of delayed puberty, however, complications resulting from untreated delayed puberty are common.

Delayed puberty may be caused by:^[1]

• Mumps
• Cryptorchidism
• Turner syndrome
• Testicular trauma
• Testicular torsion
• Sickle cell disease
• Thalassemia
• Kallmann syndrome
• Isolated hypogonadotropic hypogonadism
• Hypothalamus-pituitary-gonadal (HPG) Axis development disorder
• Obesity and hypogonadotropic hypogonadism
• Cystic fibrosis
• Asthma
• Inflammatory bowel disease
• Celiac disease
• Diabetes mellitus
• Excessive exercise
• Malnutrition

Less common causes of disease name are including:^[1]

• Noonan syndrome and related disorders
• Fragile X premutation
• Gonadal dysgenesis
• Vanishing testes syndrome
• Coxsackie virus
• Galactosemia
• Autoimmune oophiritis
• Autoimmune orchitis
• 5-alpha reductase deficiency
• 17,20-lyase deficiency
• Congenital lipoid adrenal hyperplasia
• Androgen insensitivity
• Sertoli cell only syndrome (Del Castillo syndrome)
• Astrocytoma
• Germinoma
• Glioma
• Craniopharyngioma
• Prolactinoma

• Langerhans cell histiocytosis
• Rathke pouch cyst
• Prader-Willi syndrome
• Bardet-Biedl syndrome
• CHARGE syndrome
• Gaucher disease
• Post central nervous system infection
• Septo-optic dysplasia
• Congenital hypopituitarism
• Chemotherapy
• Radiation therapy
• Juvenile rheumatoid arthritis
• Anorexia nervosa

• Bulimia
• Hemosiderosis
• Chronic renal disease
• AIDS
• Hypothyroidism
• Hyperprolactinemia
• Growth hormone deficiency
• Cushing syndrome

Delayed puberty is caused by a mutation in the following genes:^[2]

• Kisspeptin system (KISS1R and KISS1)
• Kallmann syndrome 1 (KAL1)
• Fibroblast growth factor receptor 1 (FGFR1)
• Fibroblast growth factor 8 (FGF8)
• Heparan sulfate 6-O-sulphotransferase 1 (HS6ST1)
• Prokineticin 2 (PROK2)
• Prokineticin 2 receptor (PROKR2)
• Tachykinin 3 (TAC3)
• Tachykinin 3 receptor (TACR3)
• Gonadotropin releasing hormone (GnRH1)
• Gonadotropin releasing hormone receptor (GnRHR)
• Chromodomain helicase DNA-binding protein 7 (CHD7)
• Nasal embryonic LH-releasing hormone factor (NELF)
• Early B-cell factor 2 (EBF2)
• DSS-AHC on the X-chromosome 1 (DAX1)
• Steroidogenic factor 1 (SF1)
• Homeobox gene 1 (HESX1)
• LIM homeobox gene 3 (LHX3)
• PROP paired-like homeobox 1 (PROP1)
• Leptin (LEP)
• Leptin receptor (LEPR)
• Proprotein convrtase 1 (PC1)
• Makorin RING-finger protein 3 (MKRN3)
• Estrogen receptor α (ESR1)

Cardiovascular	CHARGE syndrome
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Chemotherapy
Ear Nose Throat	Mumps, Rathke pouch cyst, CHARGE syndrome, Septo-optic dysplasia
Endocrine	Isolated hypogonadotropic hypogonadism, Hypothalamus–pituitary–gonadal (HPG) Axis development disorder, Diabetes mellitus, Congenital lipoid adrenal hyperplasia, Androgen insensitivity, Sertoli cell only syndrome (Del Castillo syndrome), Craniopharyngioma, Prolactinoma, Prader-Willi syndrome, Bardet-Biedl syndrome, CHARGE syndrome, Congenital hypopituitarism, Hypothyroidism, Hyperprolactinemia, Growth hormone deficiency, Cushing syndrome
Environmental	Excessive exercise, Chemotherapy, Radiation therapy
Gastroenterologic	Inflammatory bowel disease, Celiac disease
Genetic	Turner syndrome, Kallmann syndrome, Cystic fibrosis, Noonan syndrome, Fragile X premutation, Vanishing testes syndrome, Galactosemia, 5-alpha reductase deficiency, 17,20-lyase deficiency, Congenital lipoid adrenal hyperplasia, Androgen insensitivity, Sertoli cell only syndrome (Del Castillo syndrome), Prader-Willi syndrome, Bardet-Biedl syndrome, Gaucher disease
Hematologic	Sickle cell disease, Thalassemia, Langerhans cell histiocytosis, Hemosiderosis, AIDS
Iatrogenic	Chemotherapy, Radiation therapy
Infectious Disease	Mumps, Coxsackie virus, AIDS
Musculoskeletal/Orthopedic	Juvenile rheumatoid arthritis
Neurologic	Astrocytoma, Glioma, Post central nervous system infection
Nutritional/Metabolic	Malnutrition, Obesity, 5-alpha reductase deficiency, Anorexia nervosa, Bulimia
Obstetric/Gynecologic	Hypothalamus–pituitary–gonadal (HPG) Axis development disorder, Isolated hypogonadotropic hypogonadism
Oncologic	Astrocytoma, Germinoma, Glioma, Craniopharyngioma, Prolactinoma
Ophthalmologic	Bardet-Biedl syndrome, CHARGE syndrome, Septo-optic dysplasia
Overdose/Toxicity	No underlying causes
Psychiatric	Anorexia nervosa, Bulimia
Pulmonary	Asthma, Cystic fibrosis
Renal/Electrolyte	Congenital lipoid adrenal hyperplasia, Chronic renal disease
Rheumatology/Immunology/Allergy	Autoimmune oophiritis, Autoimmune orchitis, Langerhans cell histiocytosis, Juvenile rheumatoid arthritis
Sexual	AIDS
Trauma	Testicular trauma
Urologic	Cryptorchidism, Testicular torsion, Gonadal dysgenesis, Vanishing testes syndrome, Germinoma, CHARGE syndrome
Miscellaneous	Excessive exercise

List the causes of the disease in alphabetical order.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Delayed puberty must be differentiated from other diseases that cause latency in secondary sexual characteristics development, such as constitutional delay of puberty, hypopituitarism, and chromosomal abnormalities. Chromosomal abnormalities are Turner’s syndrome, Klinefelter’s syndrome, and Noonan’s syndrome.

• Delayed puberty must be differentiated from other diseases that cause latency in secondary sexual characteristics development, such as constitutional delay of puberty, hypopituitarism, and chromosomal abnormalities. Chromosomal abnormalities are Turner’s syndrome, Klinefelter’s syndrome, and Noonan’s syndrome.^[1]

Diseases		Laboratory Findings					Physical examinations				Other Findings
		GnRH	LH	FSH	Estradiol	Testosterone	Lack of secondary sexual characteristics	Amenorrhea	Webbed neck	Final height
Delayed puberty	Primary hypogonadism	↑	↑	↑	↓	↓	+	+	–	↓	–
	Secondary hypogonadism	↓	↓	↓	↓	↓	+	+	–	↓	–
Constitutional delay of puberty		Normal	Normal	Normal	Normal	Normal	+	+	–	Normal	• Normal puberty, finally
Hypopituitarism		↑	↓	↓	↓	↓	+	+	–	↓	–
Turner’s syndrome		↓	↑	↑	↓	–	+	+	+	↓	• Bicuspid aortic valve
Klinefelter’s syndrome		↓	↑	↑	–	↓	+	–	–	Normal	• Testicular dysgenesis
Noonan’s syndrome		↓	↑	↑	–	↓	+	–	+	Normal	• Mitral valve prolapse
Outflow tract obstruction (imperforate hymen or transverse vaginal septum)		Normal	Normal	Normal	Normal	Normal	–	+	–	Normal	• Imperforate hymen • Perirectal mass • Bulging hymen with hematocolpos
Mayer-Rokitansky-Kuster-Hauser syndrome		Normal	Normal	Normal	Normal	Normal	–	+	–	Normal	• Variable absence of Mullerian structures in pelvic ultrasound

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

The incidence of delayed puberty (hypogonadotropic hypogonadism) is approximately 1-10 cases per 100,000 individuals worldwide.The precise prevalence of delayed puberty is not known. The whole puberty disorders prevalence is about 3000 cases per 100,000 individuals worldwide. Delayed puberty is a condition commonly seen in children under 15 years of age. Delayed puberty usually occurs in individuals of all races. A definite diagnosis of the mean age of puberty onset in any specific societies can help to reduce the effects of ethnicity on delayed puberty epidemiology. Boys are more commonly affected by delayed puberty (constitutional delay of puberty) than girls.

• The incidence of delayed puberty (hypogonadotropic hypogonadism) is approximately 1-10 cases per 100,000 individuals worldwide.
• Idiopathic hypogonadotropic hypogonadism is responsible for approximately 10% of delayed puberty in boys.
• Klinefelter’s syndrome (hypergonadotropic hypogonadism) accounts for 5-10% of delayed puberty in boys.^[1]

• The prevalence of delayed puberty is unknown.
• Prevalence of puberty disorders is about 3000 cases per 100,000 individuals worldwide.^[2]
• The prevalence of primary amenorrhea in the US is < 0.1%.^[3]

• The case-fatality rate of delayed puberty is approximately zero. There is no reported case of mortality due to delayed puberty.

• Delayed puberty is commonly seen in children under 15 years of age.

• Delayed puberty usually affects individuals of all races.
• Different races have different puberty onset ages; menarche occurs in African-American girls at age (12.2 yrs) earlier than White girls (12.9 yrs), which is because of body mass index (BMI) difference between races.^[4]
• A definite diagnosis of the mean age of puberty onset in any specific societiy can help to reduce the effects of ethnicity on delayed puberty epidemiology.

• Boys are more commonly affected by delayed puberty (constitutional delay of puberty) than girls.^[5]
• The boy to girl ratio is approximately 2 to 1 in constitutional delay of puberty.

• Although there is a difference between the age of puberty onset in developed and developing countries, epidemiology of delayed puberty is same.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

The most potent risk factor in the development of delayed puberty is hypothalamus–pituitary–gonadal (HPG) axis disturbance. Other risk factors include genetic, endocrinologic, and environmental which may disturb the HPG axis.

• The most potent risk factor in the development of delayed puberty is hypothalamus–pituitary–gonadal (HPG) axis disturbance.
• Other risk factors are including genetic, endocrinologic, and environmental which may disturb the HPG axis.

• Common risk factors in the development of delayed puberty may be genetic, endocrinologic, and environmental.
• Common risk factors in the development of delayed puberty include:
  • Family history of delayed puberty^[1]
  • Genetics^[2]
  • Chromosomal disorders
  • Eating disorders
  • Chronic illnesses
  • Malnutrition
  • Excess exercise
  • Acquired gonadal disorders^[3]
  • Pituitary surgery prior to puberty^[4]
  • Chemotherapy
  • Radiation therapy^[5]
  • Sickle cell disease
  • Hemosiderosis

• Less common risk factors in the development of delayed puberty include:
  • Congenital pituitary structural abnormalities
  • Congenital testicular disorders
  • Adrenal hypoplasia^[6]
  • Histiocytosis
  • Sertoli Cell only Syndrome (Del CastillonSyndrome)^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

According to the US Preventive Services Task Force (USPSTF), screening for delayed puberty is not recommended.

• According to the US Preventive Services Task Force (USPSTF), screening for delayed puberty is not recommended.
• Although there are not any recommended screening protocols to screen children with a delayed puberty, short stature and a poor growth rhythm at the beginning of secondary school entry should warrant review by a family practitioner.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

The symptoms of puberty usually develop between ages 8 to 13 in girls and 9 to 14 in boys and start with breast development in girls and testicular enlargement in boys. If the testicular enlargement or breast development has not occurred at a mean age of puberty in population plus 2-2.5 standard deviation (SD), it will be called delayed puberty. The mean age depends on various factors, such as race, nutrition, and also socioeconomic status. Recently, the age of onset of puberty is decreasing in the US and other countries. The main complications of delayed puberty are osteoporosis, psychological problems, polycythemia, and irritation from hormonal gels and patches. The major determinant of delayed puberty prognosis is underlying co-morbidity, not the disease itself. Constitutional delay of growth and puberty (CDGP) has an excellent prognosis. The puberty and final height in these patients will be normal in the future, without any hormone replacement therapy.

• The symptoms of puberty usually develop between ages 8 to 13 in girls and ages 9 to 14 in boys and start with breast development in girls and testicular enlargement in boys.
• If the testicular enlargement or breast development has not occurred at a mean age of puberty in population plus 2-2.5 SD, it will be called delayed puberty. The mean age depends on various factors, such as race, nutrition, and also socioeconomic status. Recently, the age of onset of puberty is decreasing in the US and other countries.
• If left untreated, all of the patients with a constitutional delay of puberty and growth may progress to develop normal puberty and growth.
• All patients with delayed puberty have to be precisely monitored until normal puberty and growth become accomplished. It may take about 2-5 years. Final height can be measured by adding or subtracting 2.5 inches to the average height of parents. On average, puberty is accompanied by gaining 25 cm of height in girls and 30 cm in boys.

Delayed puberty in boys is identified as:^[1]

• No sign of testicular enlargement by 14 years of the age

OR

• No pubic hair by 15 years of age

OR

• No penis and testicles development to adult type 5 years after onset of puberty

Delayed puberty in girls is identified as:^[1]

• No signs of breast development by 14 years of age

OR

• No pubic hair by 14 years of age

OR

• No breast development to adult type 5 years after onset of puberty

OR

• No menstruation by 16 years of age

Approximate mean ages for onset of various pubertal changes are as follows:

Developmental changes during puberty in girls occur over a period of 3-5 years, usually between 9 and 14 years of age. They include the occurrence of secondary sex characteristics beginning with breast development, the adolescent growth spurt, the onset of menarche (not correspond to the end of puberty), and the acquisition of fertility, as well as profound psychological modifications.^[2]

• Thelarche: 10 years and 5 months of age
• Pubarche: 11 years of age
• Growth spurt: 10-12.5 years of age
• Menarche: 12.5 years of age
• Adult height reached: 14.5 years of age

• Testicular enlargement: 11.5 years of age
• Pubic hair: 12 years of age
• Growth spurt: 12.5–15 years of age
• Completion of growth: 17.5 years of age

Osteoporosis

• Lack of estrogen and other sex steroids can lead to decreasing bone mineralization and osteoporosis.^[3]
• The amount of bone mass gained during puberty is the key determinant factor in development of osteoporosis.^[3]
• If left untreated, patients with delayed puberty attain normal sexual maturation but will experience a decreased peak bone mass .^[4]

Psychological problems^[5]

• Delayed puberty may threaten the final height and also adult phenotype.
• Delayed or absent secondary sexual characteristics may affect a person’s self-esteem and interpersonal relationships.
• Patients with a disease resulting in anorchia have to be counseled about testicular prosthesis.

Polycythemia

• The use of testosterone in the treatment of delayed puberty can cause RBCs overproduction which can lead to increased hematocrit.

Irritation from gels and patches

• Therapeutic hormonal gels and patches that are frequently used in delayed puberty can cause allergic reactions and irritation.

• The major determinant of prognosis in delayed puberty is underlying co-morbidity, not the disease itself.
• Constitutional delay of growth and puberty (CDGP) has an excellent prognosis. The puberty and final height in these patients will occur normally in the future even without any hormone replacement therapy.
• Patients with benign co-morbidity induced delayed puberty, like delayed puberty due to lifestyle disorders (malnutrition or excessive exercise) or mild chronic diseases, can completely gain their normal puberty characteristics after suitable treatment of underlying diseases.
• Permanent causes of delayed puberty, such as idiopathic hypogonadotropic hypogonadism, genetic diseases, chromosomal disorders (e.g., Turner’s syndrome or Klinefelter’s syndrome), or pituitary surgical procedures (e.g., craniopharyngioma treatment) need lifelong hormone replacement therapy.^[6]

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