Delayed Puberty


Delayed Puberty is the absence of secondary sexual characteristics, of 2 standard deviations from the average age of onset of normal puberty in the population and sex to which the individual belongs.
In practical and temporal terms, for men it is at the age of 14, when the testicular volume is less than 4 ml and for women it is at the age of 13, when there is still no presence of telarquia (start of the mammary button).


Puberty is the period in which sexual maturation is completed and reproductive capacity is reached.
During puberty there is an acceleration of growth and bone age, and a maturation of the primary sexual characteristics (genitals and gonads).
Along with the secondary (pubic and axillary hair, mammary development in the girl and increased testicular volume in the boy).
Pubertal delay can be produced by two types of mechanisms: alteration in the start-up of the hypothalamus-pituitary-gonadal axis (hypogonadotrpic), or primary gonadal failure to respond to a normally functioning axis (hypergonadotrpic).
In terms of sex, delayed puberty mostly affects the male sex.
A special situation is arrested puberty, which corresponds to a group of patients who may have partial or transitory abnormalities.
That is to say, they begin puberty at a normal age, but more than five years elapse between the first pubertal sign and the complete gonadal development in men or the appearance of menarche in women.
Delayed puberty is a frequent clinical picture that occurs in 3% of the population.
In both sexes the most frequent variety is delayed puberty of the simple type, which is generally of family or idiopathic origin and is due to constitutional retardation of growth and puberty or development. 60% of cases occur in males and 30% in females.


The most frequent causes of delayed puberty are: chronic diseases, such as asthma, celiac disease, Crohn’s disease, cystic fibrosis. celiac disease, primary hypothyroidism, prolonged glucocorticoid therapy, anorexia nerves, kidney failure.
Psycho-social deprivation and excessive physical exercise, especially in gymnasts and athletes.
Tumors adjacent to the hypothalamus-pituitary axis, such as craniopharyngioma, optic glioma, germinomas, astrocytomas, pituitary tumors, including hyperprolactinemia with or without prolactinoma.
Congenital anomalies: septooptic dysplasia, congenital panhypopituitarism.
Treatment with irradiation or trauma due to: surgery or cranial trauma.
But its molecular study has allowed us to understand the complex phenomenon of puberty, among them we can mention: disorders of the hypothalamus-hypothalamus-gonadal axis (HHG axis).
Such is the case of Kallmann syndrome and congenital or acquired deficiencies of pituitary hormones, dysmorphic syndromes.
Other syndromes are Noonan and Prader-Willi syndrome and Bardet-Biedl syndrome or Moon-Lidl syndrome, Swyer syndrome (46XY), which is due to a mutation of the SRY gene which produces gonadal agenesis.
Fertile eunuch syndrome or Pasqualini syndrome is a cause of hypogonadotropic hypogonadism caused by a luteinizing hormone deficiency. It is characterized by hypogonadism with spermatogenesis.
This term is incorrect and should not be used. In fact, these patients are not really eunuchs and are usually not fertile if not treated with HCG. It is explained by the absence of the luteinizing hormone LH, its deficit or inactivation.
Abnormalities in the sex chromosomes, such as Turner and Klinefelter syndromes and other causes of gonadal insufficiency, such as gonadal agenesis-disgenesis, chemotherapy (cyclophosmamide and busulfan), primary ovarian insufficiency, autoimmune gonadal insufficiency and galactosemia, polycystic ovaries, in girls.
Disorders such as hemochromatosis and thalassemia, cryptorchidism, bilateral testicular torsion should be taken into account.

-Genetic bases:

The genotype in the alterations of the HHG axis is summarized as follows:
Hypothalamus: GnRH/migration, defects in the synthesis and release of GnRH, alterations of leptin and its receptor, alterations of transcription factors.
Hypophysis: Mutations in the GnRH receptor, alterations in development and alterations in hormonal production.
Gonads: Alterations in the FSH and LH subunits, mutations in the FSH and LH receptors, alterations in intracellular signals; alterations in function and differentiation.
Migration of neurons that produce gonadotrophin-releasing hormone (GnRH): KAL gene.
GnRH action: GnRH receptor gene
Synthesis of gonadotrophins: genes of subunits of gonadotrophin
Action of gonadotrophins: genes of the gonadotrophin receptor.
As for the defects in the migration of GnRH-producing neurons, the KAL gene is located on the X chromosome, responsible for the growth and migration of olfactory and GnRH-producing neurons.
This gene originates the phenotype of Kallmann syndrome, a hypogonadotrophic hypogonadism with anosmia or hyposmia, palatine fissure, deafness, cerebellar convulsions, short fourth metacarpal and renal agenesis, in 50% of the cases.
Mutations of the GnRH receptor gene have been found in 20% of hypogonadotrophic hypogonadisms. isolated hypogonadotrophic hypogonadism (without anosmia) is usually sporadic, or of autosomal recessive inheritance.
Most of these mutations are heterozygous and reduce both the binding of GnRH to its receptor and the activation of intracellular signals.
There is absence of pubertal development and resistance to treatment with pulsed GnRH, other mutations may give slight compromise of function.
With incomplete pubertal development phenotype (physical appearance), detectable basal gonadotrophins and modest response to pulsed GnRH.
In relation to mutations and polymorphisms in the genes of the alpha and beta subunits of gonadotrophins, it is also important.
The alpha subunit is known to be common to luteinizing hormone (LH), follicle-stimulating hormone (FSH), chorionic gonadotrophin (hCG), and thyroid-stimulating hormone (TSH).
So a mutation in this chain would have a devastating result for the patient. Mutations of the beta subunits for LH and FSH are those that are accompanied by delayed puberties.
For the beta subunit of FSH, some mutations may also cause male hypogonadism, with azoospermia and infertility and in women, primary amenorrhea and infertility.
Gene mutation of the beta subunit of LH has been described in only one male, who had normal male genitals, delayed puberty, elevated serum LH levels, and normal serum FSH.
The cases mentioned are infrequent situations, but they have allowed us to know how this chain of genes works in the development of normal puberty.
Alterations of gonadotrophin receptors at the gonadal level: serum FSH was moderately increased and serum LH was normal or moderately increased.

-Chronic Diseases:

Malnutrition, probably due to a conservation mechanism, affects the production of insulin, insulin-like growth factor (IGF-1) and leptin and decreases levels of thyroid hormones.
In more detail, the decrease in insulin increases lipolysis and proteolysis, probably because the body seeks a form of energy source compensation.
On the other hand, if the fat tissue decreases there is less leptin, which causes delayed puberty. Decreased T3 results in decreased metabolism.

-Study and treatment:

In the study of delayed or arrested puberty, the minimum study includes the determination in blood of: thyroid hormones, LH, FSH, testosterone or estradiol.
General tests to rule out a chronic pathology, such as hemogram-VHS, PCR, renal function, plasma electrolytes and liver profile.
In general, the possibility of performing a karyotype should be considered in men and women, and in girls, uterine and ovarian ultrasound should also be performed.
In certain cases, a magnetic resonance must be requested, to rule out possible tumors, usually benign, but which may injure the pituitary gland, such as creneopharyngioma.
Once the above-mentioned pathologies have been ruled out and it is confirmed that this is a constitutional stunting of growth and puberty, a decision must be made as to whether or not treatment should be initiated.
It is usually a male schoolboy, who is very concerned because all his classmates are growing rapidly and he, in some cases, has not yet given the pubertal stretch, or changed his voice, or has a beard.
He has often had several treatments for pubertal retardation, with the idea of stimulating a hypothalamus that is probably slower and causing the onset of the hormonal changes that are characteristic of puberty, which is the pulsatile secretion of LH.
Sometimes stimulation tests with an LHRH analogue are required to differentiate between the kind of hypogonadism.
The maximum response of gonadotropins occurs about 3-4 h., after administering the analogue, while the maximum peak of gonadal secretion is detected between 8-24 h: for there to be a normal pubertal response, estradiol must be equal to or greater than 40.8 pg/ml in girls and testosterone in boys, will be equal to or greater than 90.7 ng/dl.
The treatment is maintained for about 6 months, revaluing after this period the evolution and hormonal state.
If 3-6 months after stopping treatment, spontaneous puberty does not begin or the number of gonadal steroids does not increase, a second course of treatment with a higher dose may be administered.
The size and age of both groups of children treated and untreated with testosterone, standard deviations below average, at the end of growth the size of children was very similar.
When delayed puberty is due to a cause that prevents the production of sexual steroids, it is necessary to induce puberty.
In women, puberty can be induced by various methods: conjugated estrogens of equine origin, ethinyl estradiol, beta-estradiol and progestogens, among others.
All the methods are valid according to the conditions of the patient and as long as there is a waiting time for each of the stages, to imitate normal puberty.
At present, ethinyl estradiol is the least expensive way of inducing puberty, so it is the method of choice in public service hospitals.
Basically, it must be taken into account that induction must be done imitating normal physiological puberty.
In children, masculinization with some orally administered testosterone preparations is less efficient in achieving a good amount of male hair, good muscle mass, etc.
So it is more comfortable and less expensive to administer testosterone via IM, such as propionate.
Aromatase inhibitors have been used recently as a treatment for delayed puberty.
Certain results show that inhibition of endogenous estrogens leads to an increase in LH and FSH, despite high concentrations of androgens.
This suggests that estrogen inhibition in growing adolescents leads to an increase in final size.
Not all patients with delayed puberty exploit their probable genetic potential for growth, which is why the final size of these children is a few centimetres smaller.
The young man who has reached puberty enters a new process of growth in height that lasts longer than girls.
This growth process usually lasts until 19 years of age in males, 16 in females. However, growth in height can occur until the age of 20.

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