Delayed puberty pathophysiology

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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]

Overview

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.

Pathophysiology

Pathogenesis

• 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.

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

• 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:

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

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

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

• 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.

The major genes in delayed puberty

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	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

Kisspeptin system (KISS1R and KISS1)

• 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.
• 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.
• 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.

Kallmann syndrome 1 (KAL1)

• 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.
• 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.
• 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.

Fibroblast growth factor receptor 1 and fibroblast growth factor 8 (FGFR1 and FGF8)

• 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.
• 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.
• Dominant deletion mutation of FGFR1 gene is found to cause a 30% decrease in hypothalamic GnRH neurons. Other defects related to FGFR1 include cleft palate or lip, dental agenesis and bimanual synkinesis. Other disorders related to FGF8 include cardiac, craniofacial, forebrain, midbrain, and cerebellar developmental abnormalities.

Heparan sulfate 6-O-sulphotransferase 1 (HS6ST1)

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

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

Prokineticin 2 and prokineticin 2 receptor (PROK2 and PROKR2)

• 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.
• 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.
• 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.

Tachykinin 3 and tachykinin 3 receptor (TAC3 and TACR3)

• 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.
• 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.
• 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.
• 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.

Gonadotropin releasing hormone and its receptor (GnRH1 and GnRHR)

• The GnRH1 and GnRHR genes with OMIM numbers 152760 and 138850 are on chromosomes 8p21–8p11.2 and 4q21.2, respectively.
• 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.
• 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.
• 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.
• The other disorders that have been associated with GnRH mutation include tooth abnormal maturation and biomineralization.

Chromodomain helicase DNA-binding protein 7 (CHD7)

• 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:
  • 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.

Nasal embryonic LH-releasing hormone factor (NELF)

• 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.
• It has some relations with Kallmann syndrome.

Early B-cell factor 2 (EBF2)

• The EBF2 gene with OMIM number of 609934 is on chromosome 8p21.2; mostly expressed in mice osteoblasts and osteoclast cells.
• 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.

DSS-AHC on the X-chromosome 1 (DAX1)

• 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).
• 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.
• Another disease that can be caused by DAX1 mutation is congenital adrenal cortex hypoplasia.

Steroidogenic factor 1 (SF1)

• 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.
• It seems that other diseases can be caused by SF1 mutation, such as male pseudohermaphroditism, Denys-Drash syndrome, and also hypospadias.

Homeobox gene 1 (HESX1)

• 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.
• 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.
• 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.

LIM homeobox gene 3 (LHX3)

• The LHX3 gene, also called LIM3, with OMIM number of 600577 is on chromosome 9q34.3, mainly expressed in developing anterior pituitary gland.
• 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).
• The LHX3 gene mutation can also result in neonatal hypoglycemia, short neck with limited rotation, mild sensorineural hearing loss, skin laxity, and skeletal abnormalities.

PROP paired-like homeobox 1 (PROP1)

• 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.
• 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.
• 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.

Leptin and leptin receptor (LEP and LEPR)

• 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.
• leptin level in human beings become increased about 50% just before puberty and also during the puberty.
• Mutation in these genes may also result in disorders in hematopoiesis, angiogenesis, wound healing, and the immune or inflammatory response.

Proprotein convrtase 1 (PC1)

• 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.
• 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.

Makorin RING-finger protein 3 (MKRN3)

• 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.

Estrogen receptor α (ESR1)

• Estrogen receptor mutations are very rare, reported as a case report with delayed puberty.
• 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).
• Female mice with mutated ESR1 gene may have hypoplastic uterus plus hemorrhagic, multicystic ovary without corpus luteum; which is make them infertile.

Associated Conditions

The associated conditions that are related to delayed puberty, are as following:

Gross Pathology

• 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.

Microscopic Pathology

• 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.

References

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