Delayed puberty pathophysiology

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

Pathophysiology

Pathogenesis

• It is absolute that delayed puberty is the result of any disturbances in hypothalamus-pituitary-gonadal (HPG) axis.
• The components of HPG axis is already well identified and oriented, but the main signal of starting the puberty is not cleared completely, yet. It is not obvious that why some children start puberty at 11 and some others start at 14.
• Intact HPG axis is the main factor that a child need to become maturated. The beginning of the pathway is with gonadotropin releasing hormone (GnRH) production from hypothalamus. Then, GnRH stimulates the gonadotropic cells in 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 postpone the puberty, 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 an specific cell line or enzyme that are responsible to produce one of sex-steroids in gonads
		Gonadal agenesis	Lack of gonads, as 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 an specific cell line or enzyme that are responsible to produce GnRH in hypothalamus
		LH and FSH deficiency	Lack or disorder of an specific cell line or enzyme that are responsible to produce 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 the activity level of them.
• Sertoli cells of testes are responsible for secreting both. During fetal life in uterus, the main primary role of antimullerian hormone is to regress the embryonic female structures (mullerian). Then, the hormone become increased after birth, decreased during childhood, and finally, inhibited by testosterone in puberty. The main role of inhibin B is to inhibit the FSH through negative feedback; it is increased in early childhood, decreased gradually in childhood, and finally increased in puberty because of FSH. It will be a good marker for spermatogenesis.
• Developing preantral granulosa cells in ovaries are in charge of production of antimullerian hormone in females, while small antral follicles inhibit follicular development through negative feedback. Antimullerian hormone is increased in early childhood and decreasing around puberty. Inhibin B, that produced and secreted by both preantral and small antral follicles, is upregulated by FSH. It will be a good marker for gonadal response to LH and FSH.

Genetics

Delayed puberty has found to be on a genetic basis, most of the times. It is assumed that the main factor in determining the puberty timing is genetic elements.

In case of constitutional delay of growth and puberty (CDGP), researchers suggested 50-75% of 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. It is not sex oriented inheritance and can be seen in all family members.

Kisspeptin system

• 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 are included kisspeptin, neurokinin B, and dynorphin A. Before the puberty begins, inhibitory dynorphine A is the dominant element; decreased by stimulatory effect of neurokinin B, when puberty started. Conclusively, kisspeptin and GnRH/LH are increased.

Kallman's syndrome 1 (KAL1)

• The KAL1 gene, also called anosmin-1, with Online Mendelian Inheritance in Man (OMIM) number of 308700 is on chromosome Xp22.3, encode an exteracellular matrix glycoprotein.
• Anosmin-1 is expressed at 5 5 weeks of gestation in forebrain area of near olfactory bulbs, stimulate the afferent fibers projections from there.
• X-linked Kallman's syndrome is directly assocaited with KAL1 deletion. It is assumed to result in an absence of olfactory fibers along with disturbed migration of GnRH neurons, supposed to form from migrated olfactory placode.
• Male patient with KAL1 mutation would have central hypogonasim and anosmia/hyposmia. Additionally, the more diseases are assumed to relate with KAL1 gene, such as midline facial defects (cleft lip and/or cleft palate), short metacarpals, renal agenesis, sensorineural hearing loss, bimanual synkinesia, 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 is on chromosome 8q12, encode a receptor tyrosine kinase protein. The FGF8 gene, also called KAL6, is on chromosome 10q24.
• FGFR1 pathway is assumed to be the main role in embryogenesis, homeostasis, and wound healing. FGF 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 are including cleft palate or lip, dental agenesis and bimanual synkinesis. Other disorders related to FGF8 are including cardiac, craniofacial, forebrain, midbrain, and cerebellar developmental abnormalities.

Heparan sulfate 6-O-sulphotransferase 1 (HS6ST1)

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

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

Gross Pathology

• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Normal timing

Approximate mean ages for onset of various pubertal changes are as follows. Ages in parentheses are the approximate 3rd and 97th percentiles for attainment. For example, less than 3% of girls have not yet achieved thelarche by 13 years of age. 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 – which does not correspond to the end of puberty – and the acquisition of fertility, as well as profound psychological modifications.

The normal variation in the age at which adolescent changes occur is so wide that puberty cannot be considered to be pathologically delayed until the menarche has failed to occur by the age of 17 or testicular development by the age of 20.

For North American, Indo-Iranian (India, Iran) and European girls

• Thelarche 10y5m (8y–13y)
• Pubarche 11y (8.5–13.5y)
• Growth spurt 10–12.5y
• Menarche 12.5y (10.5–14.5)
• Adult height reached 14.5y

For North American, Indo-Iranian (India, Iran) and European boys

• Testicular enlargement 11.5y (9.5–13.5y)
• Pubic hair 12y (10–14y)
• Growth spurt 12.5–15y
• Completion of growth 17.5

The sources of the data, and a fuller description of normal timing and sequence of pubertal events, as well as the hormonal changes that drive them, are provided in the principal article on puberty.

Evaluation

Obviously anyone who is later than average is late in the ordinary sense. There are three indications that pubertal delay may be due to an abnormal cause. The first is simply degree of lateness: although no recommended age of evaluation cleanly separates pathologic from physiologic delay, a delay of 2-3 years or more warrants evaluation.

• In girls, no breast development by 13 years, or no menarche by 3 years after breast development (or by 16).
• In boys, no testicular enlargement by 14 years.

The second indicator is discordance of development. In most children, puberty proceeds as a predictable series of changes in specific order. In children with ordinary constitutional delay, all aspects of physical maturation typically remain concordant but a few years later than average. If some aspects of physical development are delayed, and others are not, there is likely something wrong. For instance, in most girls, the beginning stages of breast development precede pubic hair. If a 12 year old girl were to reach Tanner stage 3 pubic hair for a year or more without breast development, it would be unusual enough to suggest an abnormality such as defective ovaries. Similarly, if a 13 year old boy had reached stage 3 or 4 pubic hair with testes that still remained prepubertal in size, it would be unusual and suggestive of a testicular abnormality.

The third indicator is the presence of clues to specific disorders of the reproductive system. For example, malnutrition or anorexia nervosa severe enough to delay puberty will give other clues as well. Poor growth would suggest the possibility of hypopituitarism or Turner syndrome. Reduced sense of smell (hyposmia) suggests Kallmann syndrome.

Constitutional delay

Children who are healthy but have a slower rate of physical development than average have constitutional delay in growth and adolescence. These children have a history of stature shorter than their age-matched peers throughout childhood, but their height is appropriate for bone age, and skeletal development is delayed more than 2.5 SD. They usually are thin and often have a family history of delayed puberty. Children with a combination of a family tendency toward short stature and constitutional delay are the most likely to seek evaluation. They quite often seek evaluation when classmates or friends undergo pubertal development and growth, thereby accentuating their delay.