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]


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.



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

Sex Hormone Source of secretion After birth Childhood Puberty Function
Boys Antimullerian hormone Sertoli cells of testes
Inhibin B Sertoli cells of testes
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


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

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


Isolated hypogonadotropic hypogonadism[6]

KAL1 KAL1, anosmin-1 308700 Xp22.3
FGFR1 KAL2 136350 8q12
PROKR2 KAL3 607123 20p13
PROK2 KAL4 607002 3p21.1
CHD7 KAL5 608892 8q12.1
FGF8 KAL6 600483 10q24
GPR54 KISS1R 604161 19p13.3
  • Regulation of GnRH secretion
KISS1 KISS1, kisspeptin1 603286 1q32 -
HS6ST1 - 604846 2q21 -
TAC3 NKB 162330 12q13–q21
TACR3 NK3R 152332 4q25
GnRH1 - 152760 8p21–8p11.2
  • One of the most important elements in HPG axis
GnRHR - 138850 4q21.2
NELF - 608137 9q34.3 -
EBF2 - 609934 8p21.2
  • Effective role in HPG axis
HPG axis development DAX1 NR0B 300473 Xp21.2
SF-1 NR5A1 184757 9q33.3
HESX-1 RPX 601802 3p14.3
LHX3 LIM3 600577 9q34.3
PROP-1 - 601538 5q35.3
Obesity related

hypogonadotropic hypogonadism

LEP OB 164160 7q32.1
LEPR OBR 601007 1p31.3
PC1 NEC1 162150 5q15

Kisspeptin system (KISS1R and KISS1)

Kallmann syndrome 1 (KAL1)

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

Heparan sulfate 6-O-sulphotransferase 1 (HS6ST1)

Prokineticin 2 and prokineticin 2 receptor (PROK2 and PROKR2)

Tachykinin 3 and tachykinin 3 receptor (TAC3 and TACR3)

Gonadotropin releasing hormone and its receptor (GnRH1 and 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 and leptin receptor (LEP and LEPR)

Proprotein convrtase 1 (PC1)

Makorin RING-finger protein 3 (MKRN3)

Estrogen receptor α (ESR1)

Associated Conditions

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
Gonadal dysgenesis
• Testicular agenesis
Trauma/Testicular torsion
Chemotherapy/Radiation therapy
Mumps, coxsackie
• Autoimmune oophiritis
• Autoimmune orchitis
5-alpha reductase deficiency
Lyase deficiency
Congenital lipoid adrenal hyperplasia
Androgen insensitivity
• Sertoli cell only syndrome (Del Castillo syndrome)
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
Cystic Fibrosis
Inflammatory bowel disease
Celiac disease
Juvenile rheumatoid arthritis
Anorexia nervosa/Bulimia
Sickle cell disease
Chronic renal disease
Diabetes mellitus
Growth hormone deficiency
Cushing syndrome
• Excessive exercise

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


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