Delayed puberty overview

# Overview
Delayed puberty is almost always due to physiologic exaggerated prolongation of puberty timing in boys and girls, a condition called "constitutional delay of growth and puberty (CDGP)". Delayed puberty sometimes has other pathophysiologies, such as hypergonadotropic hypogonadism, permanent hypogonadotropic hypogonadism, and functional hypogonadotropic hypogonadism. Delayed puberty is the result of disturbances in hypothalamus-pituitary-gonadal (HPG) axis. Genetic basis plays an important role in delayed puberty. 50-75% of cases of constitutional delay of growth and puberty (CDGP) have a positive family history of delayed puberty. 25 various genes in 3 different groups of Kallman syndrome related genes, hypothalamus-pituitary-gonadal (HPG) axis related genes, and obesity related genes, have been associated with puberty. Microscopic evaluation of ovaries in a patient with delayed puberty may reveal the presence of normal cuboidal epithelium. Delayed puberty must be differentiated from other diseases that cause latency in secondary sexual characteristics development, such as constitutional delay of puberty, hypopituitarism, and chromosomal abnormalities. The Chromosomal abnormalities include Turner's syndrome, Klinefelter's syndrome, and Noonan's syndrome. The incidence of delayed puberty (hypogonadotropic hypogonadism) is approximately 1-10 cases per 100,000 individuals worldwide. The prevalence of delayed puberty is not known. Delayed puberty commonly occurs in children under 15 years of age and also occurs in individuals of all races equally. Delayed puberty (constitutional delay of growth and puberty) is seen more in boys. Physical examination is usually remarkable for delayed growth spurt along with small testicular size (less than 4 mL or 2.5 cm) in more than 14 years old boys and thelarche stage 0-1 in more than 13 years old girls. Laboratory findings consistent with the diagnosis of delayed puberty include first line and second line tests. First line tests are complete blood count, erythrocyte sedimentation rate, creatinine, electrolytes, bicarbonate, alkaline phosphatase, albumin, thyrotropin, free thyroxine, luteinizing hormone (LH), follicle stimulating hormone (FSH), insulin-like growth factor (IGF-1), and testosterone. In case of specific familial disorders, some especial laboratory tests may be needed. Second line tests are gonadotropin releasing hormone (GnRH), human chorionic gonadotropin (hCG), inhibin B, prolactin, and growth hormone (GH) tests. The mainstay of medical therapy for delayed puberty is sex hormone replacement therapy. The various formulations of estrogen, progesterone, and testosterone are used in both genders.

# Historical Perspective
Studying the archaic humans in Pleistocene (i.e., greater than 10,000 years ago), it assumed that puberty was correlated with productivity in females. The age of menarche was between 7 and 13 years. Researchers have found that in a Turkana boy (from the species of Homo erectus) from 1.6 million years ago, the puberty was earlier than today humans; however, their final height was more than modern humans. The discovery and growth of agriculture in the archaic world is the main reason for delaying puberty age, through a negative impact on child growth. Agricultural communities in contrast with hunter-gatherer communities experienced the tougher lifestyle and rose with many nutrition deficits that may lead to their delayed puberty. Regarding that lifestyle was growing and the complexity of societies was increasing in the past, the process of becoming an adult from a child was prolonged which resulted in delayed puberty.

# Classification
Delayed puberty is almost always due to physiologic exaggerated prolongation of puberty timing, a condition called constitutional delay of growth and puberty (CDGP). Another forms of the disease include hypergonadotropic hypogonadism, permanent hypogonadotropic hypogonadism, and functional hypogonadotropic hypogonadism.

# Pathophysiology
Delayed puberty is the result of disturbances in hypothalamus-pituitary-gonadal (HPG) axis. Genetic basis plays an important role in delayed puberty. 50-75% of constitutional delay of growth and puberty (CDGP) have positive family history of delayed puberty. 25 various genes, in 3 different groups 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 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.

# Causes
Delayed puberty may be caused by endocrine or genetic causes, that hypothalamus-pituitary-gonadal (HPG) axis disorders and Kallmann syndrome are the most causes, respectively. There are various genes that may be related to delayed puberty, among which the kisspeptin system genes (KISS1 and KISS1R) are the most important genes.

# Differentiating Delayed puberty from Other Diseases
Delayed puberty must be differentiated from other diseases that cause latency in secondary sexual characteristics development, such as constitutional delay of puberty, hypopituitarism, and chromosomal abnormalities. Chromosomal abnormalities are Turner's syndrome, Klinefelter's syndrome, and Noonan's syndrome.

# Epidemiology and Demographics
The incidence of delayed puberty (hypogonadotropic hypogonadism) is approximately 1-10 cases per 100,000 individuals worldwide.The prevalence of delayed puberty is not known. Prevalence of puberty disorders is about 3,000 cases per 100,000 individuals worldwide. Regarding the definition of delayed puberty, the disease commonly occurs in children under 15 years of age. Delayed puberty usually occurs in individuals of all races, equally. Definite diagnosis upon the mean age of puberty onset in any specific societies can help to reduce the effects of ethnicity on delayed puberty epidemiology. Boys are more commonly affected by delayed puberty (constitutional delay of puberty) than girls.

# Risk Factors
The most potent risk factor in the development of delayed puberty is hypothalamus-pituitary-gonadal (HPG) axis disturbance. Other risk factors are genetic, endocrinologic, and environmental; which may disturb the HPG axis.

# Screening
According to the US Preventive Services Task Force (USPSTF), screening for delayed puberty is not recommended.

# Natural History, Complications, and Prognosis
The symptoms of puberty usually develop between 8 and 13 in girls and between 9 and 14 in boys, and start with symptom of breast development in girls and testicular enlargement in boys. If the testicular enlargement or breast development has not occurred at an mean age of puberty in population plus 2-2.5 standard deviation (SD), it will be called delayed puberty. The mean age is depend on various factors, such as race, nutrition, and also socioeconomic status. Recently, the puberty onset age is decreasing in US and other countries. The main complications of delayed puberty are osteoporosis, psychological problems, polycythemia, and irritation from hormonal gels and patches. The major determinant of delayed puberty prognosis is underlying co-morbidity, not the disease itself. Constitutional delay of growth and puberty (CDGP) has an excellent prognosis. The puberty and final height in these patients will occur normal in the future, without any hormone replacement.

# Diagnosis

## History and Symptoms
The hallmark of delayed puberty is lack of testicular enlargement in boys or breast development in girls, in specific stage of life. The age, in which secondary sexual characteristics are checked, is 2-2.5 SD more than the standard population average age of puberty onset. The age is 14 for boys and 13 for girls, on average. A positive family history of delayed puberty is strongly associated with delayed puberty. The most common contributing symptom of delayed puberty is anosmia or hyposmia. Less common symptoms of delayed puberty are including the symptoms related to its underlying diseases.

## Physical Examination
Patients with delayed puberty usually appear normal. Physical examination of patients with delayed puberty is usually remarkable for delayed growth spurt along with small testicular size (less than 4 mL or 2.5 cm) in more than 14 years old boys and thelarche stage 0-1 in more than 13 years old girls. Testicular size is identified by length of the longest axis or by its volume using the Prader orchidometer. Thelarche stage is determined by use of Tanner staging system. The lack of pubic or axillary hairs and also primary amenorrhea on physical examination is highly suggestive of delayed puberty.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of delayed puberty include first line and second line tests. First line tests are complete blood count, erythrocyte sedimentation rate, creatinine, electrolytes, bicarbonate, alkaline phosphatase, albumin, thyrotropin, free thyroxine, luteinizing hormone (LH), follicle stimulating hormone (FSH), insulin-like growth factor (IGF-1), and testosterone; In case of specific familial disorders, some especial laboratory tests may be needed. These laboratory tests are including anti-gliadin antibody and anti-tissue transglutaminase antibody (i.e., Celiac disease diagnosis) or anti-neutrophil cythoplasmic antibodies (i.e., inflammatory bowel disease diagnosis). Second line tests are gonadotropin releasing hormone (GnRH), human chorionic gonadotropin (hCG) test, inhibin B, prolactin, and growth hormone (GH) tests.

## Electrocardiogram
There are no ECG findings associated with delayed puberty.

## X-ray
An X-ray may be helpful in the diagnosis of delayed puberty. Findings on an X-ray are specific to measuring bone age. Bone age may be used to predict the children final adult height. Studies have shown that there is strong association between bone age and the initiation of puberty in boys involved in developmental disorders. If the difference between measured bone age and chronological age is more than 2 years, it will strongly diagnostic of constitutional delay of growth and puberty (CDGP).

## CT scan
There is limited role for CT scan to measure the bone age more precise.

## MRI
Brain MRI may be helpful in the diagnosis of delayed puberty. Findings on MRI suggestive of delayed puberty include hypothalamo-pituitary lesions, aplasia of olfactory bulb and/or sulci (Kallmann syndrome), optic nerve compression (pituitary adenoma), and inner ear abnormalities (CHARGE syndrome). Showing the aplasia of olfactory bulbs and/or sulci in MRI, it is assumed as differentiation of Kallmann syndrome from isolated hypogonadotropic hypogonadism, in patient without smelling problems or hard to evaluate.

## Ultrasound
There are no ultrasound findings associated with delayed puberty. It may be used to evaluate the gross anatomy of gonads.

## Other Imaging Findings
There are no other imaging findings associated with delayed puberty.

## Other Diagnostic Studies
Karyotyping is used to diagnose delayed puberty caused by chromosomal disorders, such as Turner syndrome and Klinefelter syndrome. University of Pennsylvania Smell Identification Test (UPSIT), consist of microencapsulated odorants released by scratching standardized odor-impregnated questionnaires, is used to detect hyposmia or anosmia in Kallmann syndrome.

# Treatment

## Medical Therapy
The main pharmacological medical therapy for delayed puberty is sex hormone replacement therapy. The aim of treatment is to stimulate the puberty onset and to merge the secondary sexual characteristics in patients. The various formulations of estrogen, progesterone, and testosterone are used in both genders for medical therapy of delayed puberty. Other types of treatments are include low-dose oxandrolone, dihydrotestosterone (DHT), and kisspeptin agonist.

## Surgery
The mainstay of treatment for delayed puberty is medical therapy. Surgery is usually reserved for patients with either pituitary tumors, hypothalamus hamartomas, and Turner syndrome. There are two procedures for excision of pituitary tumors, including endoscopic transsphenoidal surgery and craniotomy. In presence of Y chromosome the chance of becoming malignant is higher in Turner syndrome, oophorectomy (even salpingo-oophorectomy) has to be done urgently.

## Primary prevention
There are no established measures for the primary prevention of delayed puberty.

## Secondary prevention
Effective measures for the secondary prevention of delayed puberty include timely diagnosis and hormone replacement therapy in order to prevent osteoporosis and short adult height and salpingo-oophorectomy in Turner syndrome to prevent ovarian malignancy.

## Cost-effectiveness of therapy
There are limited data about cost-effectiveness of therapy in delayed puberty. The main part of the economic burden of delayed puberty is because of its various and specific blood tests, such as hormone assay. The main treatment for the patients with short stature is growth hormone (GH), thus, the potential cost of treating all eligible children with growth hormone (GH) is approximately $40 billion dollars.