Disorders of Puberty

    Last updated date: 13-Jun-2023

    Originally Written in English

    Disorders of Puberty

    Disorders of Puberty


    Puberty is the process through which reproductive capability is attained, and it consists of gonadarche and adrenarche. Breast development is the first physical sign of pubertal onset in girls, and it typically occurs between the ages of 8 and 13 years. Menarche usually happens 2 to 3 years after breast development begins. The gonadotropin-releasing hormone pulse generator in the hypothalamus controls pubertal onset; however, environmental influences such as changes in energy balance and exposure to endocrine-disrupting substances can affect the timing of pubertal onset.

    Improvements in dietary and socioeconomic conditions have been linked to a secular trend in earlier pubertal onset during the last two centuries. Precocious puberty is described as the commencement of breast growth before the age of eight years, and it can be either central or peripheral. Delayed puberty can be hypogonadotropic or hypergonadotropic, and it is described as a lack of breast growth before the age of 13 or a lack of menarche before the age of 16.

    Precocious and delayed puberty can both have a detrimental impact on self-esteem, potentially leading to psychological stress. Patients who appear with pubertal abnormalities require a thorough evaluation to discover the underlying cause and develop an appropriate treatment approach.


    Physiology of Puberty

    Physiology of puberty

    Puberty is a complicated transitional period in children that is characterized by growth acceleration and the development of secondary sexual traits. It is a time of physical and psychological growth. Several genetic, environmental, and dietary variables all have a role in the onset and course of puberty.

    Puberty is caused by the hypothalamic-pituitary-gonadal (HPG) axis being activated and maturing. The HPG axis is briefly activated before birth, resulting in enhanced synthesis of steroidal hormones. This activation may result in the development of breast tissue in females and pubic hair in males. This phenomenon, known as "mini-puberty of infancy," typically regresses during the first two years of life. Although it is thought to be harmless, there is very little knowledge on its genesis and clinical impact.

    The HPG axis then goes dormant until it is reactivated in adolescence. The pulsatile release of gonadotropin-releasing hormone (GnRH) from the brain increases the anterior pituitary gland's production of follicle stimulating hormone (FSH) and luteinizing hormone (LH). In men, FSH and LH begin spermatogenesis and the production of testosterone, whereas in females, FSH and LH initiate oogenesis and the release of estradiol. Gonadarche is the activation of the gonads.


    Hormonal and Physical Changes of Normal Development

    Puberty's physical changes are caused by gonadal sex hormone production, the commencement of which (gonadarche) signifies pubertal onset. The pulsatile release of gonadotropin-releasing hormone, which activates the hypothalamic-pituitary-gonadal (HPG) axis, causes gonadarche. Adrenarche (adrenal androgen production resulting in pubic and axillary hair, body odor, and mild acne) is a separate but usually concurrent process that does not indicate true pubertal onset in either boys or girls.

    Breast development occurs in girls at a mean age of 10 years due to increasing ovarian estradiol release (range: eight to 12 years). Menarche normally follows 2.5 years following the commencement of breast development, at an average age of 12.5 years (range: nine to 15 years) (range: nine to 15 years). The earliest indicator of genuine puberty in males is testicular expansion to at least 4 mL in volume or 2.5 cm in length, which occurs at an average age of 11.5 years (range: 9.5 to 14 years). Sexual maturity ratings, such as Tanner stages, are used to characterize physical changes, which are influenced by body habitus and demographic variables.

    From the age of four through puberty, linear growth velocity is roughly 5 cm per year, with a trough before the pubertal growth surge. Peak height velocity is achieved by girls during sexual maturity ratings 2 and 3 (mean: 8.3 cm per year, age 11 or 12 years) and by males during sexual maturity ratings 3 and 4. (mean: 9.5 cm per year, age 13 or 14 years). Girls reach the end of linear development at 15 years of age, whereas males reach the end at 17 years of age. Girls grow an average of 7 cm after menarche.


    Precocious puberty

    Precocious puberty

    Precocious puberty is recognized when secondary sexual features are observed in girls under the age of eight and boys under the age of nine. Data point to an early pubertal development tendency. In the United States, around 20% of black girls and 5% to 10% of white girls aged seven to eight years show glandular breast growth, especially if obese. In females, eight years of age is a fair limit for examination. Because pathology is more common in boys with early puberty than in girls, all pubertal boys under the age of nine should be thoroughly assessed.


    Precocious puberty causes 

    Precocious puberty classifies into two major categories based on the etiology

    • Central precocious puberty (GnRH dependent)
    • Peripheral precocious puberty (GnRH independent)


    Central Precocious puberty (CPP)

    Because of the early maturation and activation of the HPG axis, this kind of premature puberty constitutes real pubertal development. In girls, the most prevalent reason is idiopathic, but in men, there is generally an underlying disease. It can be attributed to a variety of factors. Among the most important categories are

    • CNS tumors – Hypothalamic hamartoma, optic glioma, arachnoid cysts, astrocytoma, ependymoma, hydrocephalus, septo optic dysplasia, pineal tumors
    • CNS injury- head trauma, cranial irradiation, cerebral palsy, infections (Tuberculous meningitis)
    • Genetics – Loss of function mutation encoding the MRF3 (Makorin ring finger 3) gene, a gain of function mutation encoding the kisspeptin (KISS1) and its receptor (KISSR) genes
    • Syndromes – Neurofibromatosis type 1, Sturge Weber syndrome, Tuberous sclerosis
    • Environmental – internationally adopted children, withdrawal from sex steroid therapy.
    • Familial precocious puberty

    Hypothalamic hamartoma is the most prevalent type of brain lesion that causes CPP. The ectopic neuronal cells in the lesion function as a backup GnRH pulse generator. It manifests as premature puberty in infancy as early as 12 months of age. Gelastic seizures are the most common association, and they are frequently resistant to treatment. Other symptoms include cognitive, behavioral, and psychiatric issues. An increase in prevalence has been observed in internationally adopted children. The precise method is unknown, although improved nutrition and exposure to hormone disrupting substances may play a role.


    Peripheral Precocious Puberty (PPP)

    PPP is defined as the premature development of secondary sexual characteristics independent of GnRH pulsatile secretion, which occurs as a result of the creation of sex hormones from endogenous or exogenous sources. It occurs less frequently than the CPP. Some significant factors are as follows:

    • Congenital adrenal hyperplasia
    • Gonadal tumors – Sex cord-stromal tumors such as Leydig cell tumors and Sertoli cell tumors, Germ cell tumors such as dysgerminoma, teratoma, and embryonal tumors.
    • Adrenal tumors
    • Familial male-limited precocious puberty (testitoxicosis)
    • Exogenous exposure to sex steroids

    Tumors are uncommon causes of PPP. CAH, adrenal tumors, and Leydig cell tumors all have elevated androgen production. Human chorionic gonadotropin (hCG) production is enhanced in germ cell cancers, hepatoblastoma, pineal, and mediastinal tumors.

    Testitoxicosis is a rare autosomal dominant illness with a male-only clinical presentation. It is caused by a germline activating mutation of the LH receptor gene, which activates the Leydig cells and results in elevated testosterone levels.


    Precocious Puberty symptoms

    Precocious Puberty symptoms

    The appearance is typically associated with the onset of pubertal symptoms too soon. Breast growth in females and enlarged testicular volume (more than 4 ml) in males are the first clinical indications. Other indications and symptoms include accelerated linear growth, acne, muscle changes, body odor, and the development of pubic and axillary hair.

    The first step is to determine whether pubertal development occurs before the typical age of onset. Rapid puberty development, even if it begins at a normal age, is also regarded abnormal. Neurological symptoms such as headache, increased head circumference, seizures, visual and cognitive abnormalities, as well as signs of anterior and posterior pituitary deficit, should be discussed with the doctor (polyuria, polydipsia, and decreased growth velocity).

    Abdominal discomfort may be a symptom of ovarian disease. Any relevant history of head injuries, brain infections, or the use of strange lotions, medications, or diets that may have exposed them to estrogen or testosterone should be investigated. It is also critical to have a comprehensive family history on the beginning of puberty in parents and siblings, since this may indicate the likelihood of a genetic problem.

    One of the most noticeable characteristics of early puberty is the acceleration of linear growth. As a result, the exact height, weight, growth velocity (cm/year), and BMI should be recorded. Tanner staging of the breast should be performed in females, which is especially difficult in obese or overweight adolescents since it is difficult to distinguish between adipose tissue and glandular breast tissue.

    An orchidometer should be used to determine testicular volume in males. Volumes greater than 4 mL indicate pubertal development. The absence of increased testicular volume and breast growth in males and females with pubic hair and body odor may motivate further study of peripheral factors. Testicular tumors are the most frequent cause of unilateral testicular enlargement.


    Precocious Puberty diagnosis

    Initial screening tests often involve measuring bone age, LH, FSH, Testosterone, Dehydroepiandrosterone sulfate (DHEA-S), 17 OH progesterone levels, and thyroid function testing.

    The age of the bones is a preliminary screening test. If the bone age is older (by more than two standard deviations) than the chronological age, more testing should be performed. Hormonal testing distinguishes between peripheral and central causes. CPP is indicated by a baseline prepubertal LH level greater than 0.3 IU/L. Levels less than 0.3 are indicative of secondary causes or benign variations. If there is a strong suspicion of central causes, the gold standard GnRH stimulation test should be performed.

    Because this test is not accessible in the United States, the GnRH agonist is used instead. FSH levels are only of limited use. Extremely high levels of estradiol in females or testosterone in males, together with reduced LH and FSH, indicate peripheral precocity. Adrenal androgens, such as dehydroepiandrosterone sulfate (DHEA S), can be used to distinguish between testicular and adrenal sources of androgens.

    Human chorionic gonadotropin (hCG) levels in boys should be taken into account. Some germ cell tumors produce hCG, which stimulates the LH receptors and causes testosterone synthesis to rise.

    In PPP instances, pelvic ultrasonography identifies ovarian tumors or cysts in females, whereas testicular ultrasonography detects nonpalpable Leydig cell tumors in males. To rule out a hypothalamic lesion, magnetic resonance imaging should be performed in all cases with CPP, especially in men. It should also be explored in females who exhibit early pubertal changes (less than 6 years of age).


    Precocious puberty Treatment 

    central precocious puberty

    Central precocious puberty

    The decision to treat is influenced by the child's age and the course of puberty. Consider therapy if the child's symptoms are fast increasing or if bone age is greatly advanced. The primary aims of therapy are to maintain adult height and to relieve the related psychological stress. GnRH agonists are the gold standard of treatment.

    Long and short-acting GnRH agonists are available in a variety of formulations (intranasal, intramuscular, and subcutaneous). The formulation is chosen based on the preferences of the patient and the practitioner. The most prevalent in the United States is leuprolide acetate. It is a depot injection that is given every three months.

    GnRH agonist treatment is usually regarded as safe, with no severe adverse effects observed. Local skin responses (intramuscular soreness, sterile abscesses) and post-menopausal symptoms are the most prevalent side effects (hot flushes). While on medication, pubertal development, growth velocity, and skeletal maturation must be monitored on a regular basis.


    Peripheral Precocious puberty

    The treatment is aimed at removing the source of the sex steroids. Surgery is recommended for gonadal and adrenal tumors. Exogenous sources of sex steroids should be avoided if they are discovered. Glucocorticoids are used to treat classic congenital CAH. Blocking estrogen production with aromatase inhibitors (anastrozole, letrozole) and selective estrogen selective receptor modulators provides some relief in McCune-Albright syndrome (tamoxifen). 

    The best therapy for family male-limited precocious puberty is unknown, however a combination of an androgen antagonist (spironolactone) and an aromatase inhibitor is preferred (anastrozole, testolactone).


    Delayed puberty

    Delayed puberty

    Puberty that occurs later in life is referred to as delayed puberty. This means that a child's outward indicators of sexual maturity do not present until she is 12 years old in females and 14 years old in boys. Breast or testicle development, pubic hair growth, and voice changes are examples of this. These are referred to as secondary sexual traits.

    Functional hypogonadotropic hypogonadism is a common cause of delayed puberty in both boys and females. This is a transitory clinical condition caused by many pressures to the body, such as chronic disorders such as severe persistent asthma, sickle cell anemia, cystic fibrosis, or ulcerative colitis. Any cause of dietary insufficiency should be considered.

    While eating disorders are more common in women, it would be incorrect to discount them in men. The physician should also look into any possible extrinsic reasons of malnutrition, such as the patient's social environment at home. Psychological reasons in developing teenagers must also be studied, since they typically connect with the symptoms indicated above. Panhypopituitarism is a less common form of congenital hypogonadotropic hypogonadism. However, this usually leads in growth hormone deficit as well, and should be examined if a patient presents with extreme low stature at a young age.


    Delayed Puberty in Males

    A major reason of pubertal delay in boys is a constitutional delay in puberty and growth (CDPG). When the rate of growth slows, CDPG occurs. The patients are mostly healthy adolescent guys who seem young for their age. They are of average size at birth. Their pace of growth, however, diminishes at the age of 3 to 6 months. When the patients reach the age of three or four, they will be growing below but parallel to the third percentile line.

    The patient will continue to have a decreased development velocity (2 to 4 cm/year) and pubertal delay when their male counterparts go through puberty and a growth spurt. The growth spurt occurs in typical boys at a testicular capacity of 10 ml, which is between Tanner stages 3 and 4. (usually ages 13 to 15). Boys with CDPG and delayed puberty have a later growth spurt, usually between the ages of 15 and 17.

    When the patient hits puberty, his catch-up growth will continue until he achieves his estimated goal height, which may not occur until he is 17 or 18 years old. The patient's bone age will be 2 or more years older than his chronological age; the bone age will also coincide with his present height. Typically, history will indicate a "late bloomer" sibling or parent.

    For example, the father may not have had a growth spurt until he was 15 or 16 years old. CDPG is typically an exclusion diagnosis. However, distinguishing between CDPG and hypogonadotropic hypogonadism is sometimes challenging.

    Although brain tumors such as adenomas and craniopharyngiomas are uncommon causes of hypogonadotropic hypogonadism, they are a more prevalent cause of pubertal delay in boys than girls. Such masses impair the HPG axis, resulting in a reduction in sex hormones downstream. When a youngster complains of headaches, dizziness, vomiting, or abnormalities in vision, a cranial mass should be suspected.

    Hypergonadotropic hypogonadism, on the other hand, occurs when there is a primary gonadal failure. Because testosterone levels are low, GnRH, LH, and FSH levels rise. The cause of hypergonadotrophic hypogonadism might be acquired or congenital. Acquired reasons include radiation to the testes for cancer, surgery for cryptorchism or torsion, or infection with mumps, such as orchitis.

    Klinefelter syndrome is the most prevalent congenital type of primary gonadal insufficiency in boys. Klinefelter syndrome is caused by sex chromosomal aneuploidy, which most usually results in a 47, XXY karyotype. Tall height, excessively long limbs, eunuchoid body habitus, gynecomastia, and neurological or behavioral disorders are common in patients. The characteristic indication, however, is tiny (less than 4 ml) yet solid testes, which frequently results in infertility owing to oligospermia or azoospermia.


    Delayed Puberty in Females 

    Delayed Puberty in Females

    Females are less likely to have a genetic delay in puberty and development. When it does occur, the family history usually includes a "late bloomer" sibling or parent. Females, on the other hand, have a substantially higher prevalence of functional hypogonadotropic hypogonadism. It frequently occurs as a result of illnesses that diminish total body fat, such as anorexia nervosa or severe activity in females. Both entail a large reduction in calories, which reduces the body's leptin levels and results in gonadotropin insufficiency.

    Reduced LH and FSH release, along with reduced body fat, suppresses estrogen synthesis and secretion, postponing puberty. Although Kallman syndrome can induce delayed puberty in girls, it is extremely rare and more prevalent in males. This is due to the fact that KS is an X-linked recessive genetic condition that can potentially be autosomal dominant.

    Hypergonadotropic hypogonadism in females is caused by primary ovarian failure and can be acquired or congenital. Receiving radiation therapy for the treatment of tumors and malignancies is one of the acquired causes. Autoimmune ovarian damage might possibly result in hypergonadotrophic hypogonadism.

    Turner syndrome (TS) must be considered when hypergonadotropic hypogonadism is accompanied with low stature. Turner syndrome is caused by a partial or full lack of one X chromosome, resulting in the 45, X karyotype. Patients with nuchal translucency, cystic hygroma, or lymphedema may appear in infancy. A webbed neck, large chest with widely spread nipples, and low height are other common clinical characteristics.


    Delayed Puberty symptoms

    Delayed Puberty symptoms

    When patients and their families present with concerns about pubertal delay, obtaining a thorough history is critical. 

    The clinician should initially ask if the kid or caregivers have seen any indicators of puberty, such as breast development, testicular enlargement, body odor, axillary hair, pubertal hair, or acne. It is necessary to distinguish between the occurrences of adrenarche and puberty. A comprehensive examination of all systems from head to toe will aid in ruling in or ruling out the causes of pubertal delay. Fatigue or weight loss may indicate a chronic disease such as sickle cell anemia, depression, or malnutrition. A young kid with headaches and poor vision should be evaluated for a brain mass.


    Delayed Puberty diagnosis

    Before ordering labs and imaging, the child's estimated goal height should be plotted based on the biological parents' adult heights. It is critical to examine the patient's development curves, which should be based on proper age, gender, height, weight, and BMI. If there are several data points on the curves, any changes in pattern or velocity may be significant.

    If more testing is required, a bone age can be used to establish the child's current growth status. An X-ray of the left wrist and hand would be used to determine bone age. An abdominal ultrasound to examine the ovaries and uterus may aid in the diagnosis of a patient with Turner syndrome who has streak gonads. An ultrasound of the testicles can aid in the diagnosis of cryptorchidism or a mass. When a brain mass, such as a craniopharyngioma, is suspected, the doctor should conduct a brain MRI.

    A provider may also opt to include laboratory testing to assess a child's pubertal state. Serum LH, FSH, estradiol in females, and total testosterone in males are common tests to include. Additional labs should be ordered based on clinical observations and usually include a complete blood count, a full metabolic panel, free T4 and thyroid-stimulating hormone for thyroid function, and erythrocyte sedimentation rate for chronic inflammatory diseases.

    If a patient has galactorrhea and delayed puberty, a prolactin level and an assessment for a prolactinoma are required. Some doctors may add tests for adrenarche, such as DHEA-S, to the access for adrenarche. Insulin-like growth factor 1 (IGF-1) testing is required if panhypopituitarism or growth hormone insufficiency is a concern. In the future, a pediatric endocrinologist may decide to undertake a GnRH stimulation test, although this is generally not included in the first screening for delayed puberty. Finally, if a syndrome is suspected, karyotype testing should be considered. 


    Delayed Puberty Treatment 

    • Constitutional Delay in Puberty and Growth (CDPG)

    Following a CDPG diagnosis, therapy is generally directed by the patient's and parents' goals. Close supervision may be warranted, particularly if puberty has begun and grownup stature is not the major concern. When puberty and growth are actual psychosocial reasons of stress and poor self-esteem in a kid, a short-course therapy with modest dosages of testosterone for males or estrogen for girls is typically begun. Bullying, poor academic performance, or pulling out of sports may prompt the provider to initiate therapy.

    Treatment can increase growth rate, sexual maturation, and mental well-being without causing substantial adverse effects or altering the eventual goal height much. There is an oral and intramuscular (IM) version of testosterone available for men with CDPD. However, because to the major adverse effect of liver damage induced by oral testosterone, the IM version is typically more suited. In females with CDPG, both oral and intramuscular estrogen are available, however oral estrogen is more commonly used as a treatment option.

    Once therapy begins, the patient must be closely observed for indicators of pubertal development, such as testicular enlargement in males or breast growth in females. After a few months of therapy, the practitioner may decide to discontinue sex-steroid medication to assess sustained pubertal growth while off therapy. Growth hormone treatment has been utilized to enhance height in individuals who are more concerned with low stature than with delayed puberty. It has not, however, been found to have a true influence on eventual adult height in adolescents with CDPG and is hence not suggested for therapy.

    • Permanent Hypogonadism

    Patients with persistent hypogonadism, whether caused by intrinsic gonadal failure or irreversible abnormalities in the HPG axis, will need a longer course of sex-steroid treatment. In males, intramuscular testosterone (IM testosterone) is the first-line therapy. A modest dosage of testosterone is begun and steadily raised over time until adult levels of testosterone are achieved. A modest dosage of oral estrogen is the standard first-line therapy in females.

    Estrogen is also gradually raised over time until breakthrough vaginal bleeding occurs, or after 12 to 24 months of therapy. Patients are then advised to begin combined estrogen and progesterone medication for typical monthly withdrawal bleeding. The shift allows the body to have more regular physiological menstrual periods. Oral contraceptives and transdermal estrogen patches combined with oral progesterone are common hormone replacement therapy.



    Puberty disorders can have a significant influence on both physical and mental well-being. Precocious puberty is defined as pubertal onset in girls before the age of eight and before the age of nine in boys. Patients with early isolated pubertal alterations, prepubertal linear growth, and no concerning neurologic symptoms have a benign developmental pattern and should be evaluated in the appropriate therapeutic setting. Most females with genuine precocious puberty, or complete activation of the hypothalamic-pituitary-gonadal axis, have an idiopathic cause, whereas boys are more likely to show detectable disease on imaging.

    Following a history and physical examination, serum follicle-stimulating hormone, luteinizing hormone, and testosterone (boys) or estradiol (girls) levels should be measured, as well as thyroid function tests and bone age radiography. Brain magnetic resonance imaging should be conducted on females under the age of six, all boys experiencing premature puberty, and youngsters experiencing neurologic symptoms. Delayed puberty is defined as the lack of breast development in girls by the age of 13 and the absence of testicular growth in boys by the age of 14 to at least 4 mL in volume or 2.5 cm in length.