12th April 2024

Delayed puberty

Delayed puberty is defined as the development of secondary sexual features after the ages of 13 in females and 14 in males. The causes of delayed puberty are categorised into primary hypogonadism or secondary hypogonadism. Delayed puberty can also be due to functional causes such as underlying chronic disease, malnutrition or excessive exercise.

The most common cause of delayed puberty is constitutional delay in both sexes, which affects all domains. There is usually a family history of delayed puberty. Constitutional delay does not result in infertility and is not pathologic. Puberty occurs at a later age; however, its progression occurs naturally.

Primary hypogonadism (hypergonadotropic hypogonadism)

Primary hypogonadism occurs when there is a dysfunction of the gonads. Those affected either do not respond to gonadotrophins or cannot produce sex hormones. Acquired causes may be radiotherapy, chemotherapy or trauma to the gonads. Congenital primary hypogonadism occurs in conditions such as Klinefelter or Turner syndrome. The classic characteristics include a reduced level of testosterone in males and reduced levels of oestrogen and progesterone in females. As a result, gonadotrophins (LH & FSH) are markedly elevated.

Klinefelter syndrome

Klinefelter syndrome is a chromosomal disorder in which there is an extra X chromosome in a normally XY male genotype. The additional X chromosome is a result of the abnormal separation of sex chromosomes during meiosis I or II.

The additional X chromosome interrupts the normal production of testosterone in Leydig cells and inhibin in Sertoli cells. A lack of negative feedback results in an elevated level of LH and FSH. The lack of testosterone results in abnormal testes maturation, reduced sperm production and lack of development of secondary male characteristics. The additional X chromosome also results in an abnormal ratio of oestrogen to testosterone. They are at an increased risk of breast cancer and osteoporosis.

Individuals with Klinefelter syndrome typically exhibit symptoms such as tall and long legs with short torsos and broad hips. Due to the abnormal production of testosterone, they also exhibit symptoms of hypogonadism. Individuals classically have decreased facial and body hair and small testes. Those affected may have gynecomastia, and they also tend to be infertile without treatment. Other clinical features may include learning disability, delayed speech development, behavioural problems and psychosocial disorders.

It can be diagnosed with karyotyping via amniocentesis before birth or blood test after birth. Treatments include hormone therapy, such as testosterone replacement during puberty and infertility treatment. Other treatments may include speech and behavioural therapy and treating any relevant psychiatric conditions the individual may have. Individuals with Klinefelter syndrome are at a higher risk of developing type 2 diabetes, osteoporosis, cardiovascular and thromboembolic diseases, autoimmune disorders, psychiatric disorders and very rarely breast cancer.

Turner syndrome

Turner syndrome is a chromosomal disorder in a female genotype where one of the X chromosomes is completely missing or partially incomplete. The most common type of Turner syndrome has one of the X chromosomes completely missing. This is due to nondisjunction during meiosis. The next most common type is mosaicism, where some of the cells of the body have 46 chromosomes while some have 45 chromosomes. This is due to nondisjunction in mitosis after the formation of the zygote. The least common karyotype of Turner syndrome has part of one of the X chromosomes missing. A part of the X chromosome is deleted during either meiosis or mitosis.

The presence of only one complete X chromosome leads to an increased rate of loss of eggs. All the eggs are lost before puberty begins, leading to menopause prior to menarche. The ovaries are unable to develop normally and have a streak appearance. They are unable to produce sex hormones and result in primary amenorrhoea. Most females with Turner Syndrome are infertile as a result. Low levels of sex steroids lead to an elevated level of FSH and LH due to a lack of negative feedback.

The X chromosome includes genes for growth and development as well as other unidentified genes. This results in a short stature. They are also predisposed to cardiovascular defects, kidney issues, lymphatic and skeletal abnormalities and at an increased risk of type 2 diabetes mellitus. The impact on growth and development depends on the proportion of cells affected in the mosaic karyotype and the amount of X chromosome deleted in the partially absent X chromosome karyotype.

Individuals with Turner syndrome classically present with short stature (height less than 2.5 percentile with girls of the same age), webbed neck, high-arched palate, widely spaced nipples and short fourth metacarpal. Their first presentation to a clinician may be due to primary amenorrhoea. These individuals are often found with bicuspid aortic valve and, less commonly, coarctation of the aorta, both of which lead to an increased risk of aortic dilatation and dissection. They are at higher risk of developing hypothyroidism, autoimmune diseases and Crohn’s disease. Some individuals are also found with horseshoe kidney.

Turner syndrome can be diagnosed with karyotyping via amniocentesis before birth or a blood test after birth. Treatments include growth hormone therapy in childhood and sex hormone replacement therapy during adolescence.

Noonan syndrome

Noonan syndrome is often referred to as the “male version” of Turner syndrome as they present very similarly; however, it is a condition that can be found in males and females. It is an autosomal dominant inherited condition and is thought to be due to mutations in the Ras/mitogen-activated protein kinase transduction pathway. Individuals, similar to Turner Syndrome have short stature, congenital heart defects, characteristic facial features and delayed puberty.

Facial features of individuals with Noonan syndrome include wide-spaced and down-slanting eyes, which are often of blue or blue-green colour. They also have low-set ears, which are rotated posteriorly. These individuals often have a small chin, which results in their faces having an inverted triangular shape. Similarly to Turner syndrome, they also have broad webbed neck. Individuals with Noonan syndrome commonly present with undescended testes and also have delayed puberty.

In contrast to Turner syndrome, the most common congenital heart defect is pulmonary stenosis. Other heart defects include pulmonary valve dysplasia, septal defects, tetralogy of Fallot and hypertrophic cardiomyopathy. Other medical conditions that may occur in Noonan syndrome include chest deformities, ophthalmic and hearing defects, coagulation abnormalities, renal and splenic abnormalities, autoimmune diseases and lymphatic system abnormalities.

Treatment focuses on treating the conditions that the individual has, as the presentation can be highly variable among individuals. The main focus of treatment is often to assess and treat cryptorchidism, congenital heart defects and developmental delay.

Secondary hypogonadism (hypogonadotropic hypogonadism)

Secondary hypogonadism occurs when there is a dysfunction in the hypothalamus or pituitary gland, leading to the inability to produce gonadotrophins (LH & FSH). It can also be caused by the suppression of the hypothalamus by high prolactin or thyroid hormone levels. Acquired causes may be due to radiotherapy/chemotherapy or trauma. Congenital causes include Kallman Syndrome and panhypopituitarism. Other causes include chronic illness, excess exercise, malnutrition, obesity, and stress, which may also lead to the dysfunction of the hypothalamus or pituitary gland.

Kallman syndrome

Kallman syndrome is a result of the failure of the migration of GnRH-secreting neurons from the olfactory epithelium to the hypothalamus during embryogenesis. This defect also leads to hyposmia or anosmia. This leads to a reduced level of GnRH and, in turn, reduced levels of gonadotrophins (LH & FSH) and sex hormones – testosterone in males and oestrogen and progesterone in females. This leads to delayed puberty or failure to complete puberty. Both underdeveloped primary and secondary sex characteristics are listed below.

Both males and females are infertile. Male patients are found with small testes (<4mL), decreased muscle mass and delayed growth spurt. Females present with a lack of breast development, delayed growth spurt, lack of pubic hair growth and primary menorrhoea.

Kallman syndrome can be diagnosed by overall reduced levels of GnRH, gonadotropins (LH& FSH), testosterone/ oestrogen and progesterone. The main treatment is hormone replacement to promote puberty and the development of secondary sexual characteristics. As these individuals are also at risk of osteopenia and osteoporosis, calcium and vitamin D supplements are also part of the management.

References

• Delayed Puberty. BMJ Best Practice. Last Reviewed 19ᵗʰ December 2023
• Lissaue, Tom, Will Carroll, Keir Shiels, and Ranj Singh. Illustrated textbook of paediatrics. Amsterdam: Elservier, 2022
• Klatt, Edward C., and Vinay Kumar. Robbins and COTRAN Review of Pathology. London: Elsevier Health Sciences, 2015
• Blevins C H, Wilson M E. Klinefelter’s syndrome BMJ 2012; 345 :e7558 doi:10.1136/bmj.e7558
• Stamou, Maria I, and Neoklis A Georgopoulos. “Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism.” Metabolism: clinical and experimental vol. 86 (2018): 124-134. doi:10.1016/j.metabol.2017.10.012
• Noonan Syndrome. BMJ Best Practice. Last Reviewed 31ˢᵗ December 2023