Delayed Puberty

Introduction

Delayed puberty is defined clinically by the absence or incomplete development of secondary sexual characteristics bounded by an age at which 95 percent of children of that sex and culture have initiated sexual maturation. However, there are wide ranges within and across populations as to the order and temporal sequences that occur during puberty, especially in girls. In girls, this is due in part to the fact that some features of early sexual maturation (pubic hair, axillary hair and odor, and acne) are manifestations of adrenal activity (adrenarche), which typically occurs about six months after the start of true puberty (ie, ovarian maturation, heralded by breast development). Hence, some girls have early breast development, but little else for some time, whereas others follow the typical sequencing of events as described by Tanner’s pioneering work quite precisely.

Causes

The most common cause of delayed puberty is a functional defect in production of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This may be due to physiologic individual variation, known as constitutional delay of growth and puberty, or other functional defects, such as undernutrition or chronic illness. The GnRH deficiency leads to defective secretion of gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) from the anterior pituitary, which results in inadequate steroid secretion by the gonads. Other causes of delayed puberty include a variety of hypothalamic, pituitary, and gonadal disorders.

Differential Diagnosis

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.

Drugs

Anabolic steroids:

Testosterone (Delatestryl, Depo-Testosterone)

The depot preparation of testosterone is available as enanthate or cypionate salt. It is available in a multiuse vial for intramuscular injection. Transdermal preparations are available and have been used successfully in this context, although no established protocols are available

Epidemiology

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.

Natural Progression

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.

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.

Possible Complications

The main complications of delayed puberty are osteoporosis, psychological problems, polycythemia, and irritation from hormonal gels and patches.

Possible 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.

Prognosis

The major determinant of prognosis in delayed puberty 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 normally in the future even without any hormone replacement therapy.

Patients with benign co-morbidity induced delayed puberty, like delayed puberty due to lifestyle disorders (malnutrition or excessive exercise) or mild chronic diseases, can completely gain their normal puberty characteristics after suitable treatment of underlying diseases.

Permanent causes of delayed puberty, such as idiopathic hypogonadotropic hypogonadism, genetic diseases, chromosomal disorders (e.g., Turner’s syndrome or Klinefelter’s syndrome), or pituitary surgical procedures (e.g., craniopharyngioma treatment) need lifelong hormone replacement therapy.

Primary Prevention

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

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.

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.

Signs or 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.

Studies

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Number of studies: 2

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Completed

Number of studies: 7

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Enrolling by Invitation

Number of studies: 0

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Not Yet Recruiting

Number of studies: 0

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Recruiting

Number of studies: 3

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Results Available

Number of studies: 1

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Results Not available

Number of studies: 13

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Suspended

Number of studies: 0

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Terminated

Number of studies: 1

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Withdrawn

Number of studies: 0

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Types

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.

Typical Test

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.

References:

https://www.uptodate.com/contents/approach-to-the-patient-with-delayed-puberty#H17171410
https://www.wikidoc.org/index.php/Delayed_puberty_medical_therapy
https://patient.info/doctor/delayed-puberty
https://www.ncbi.nlm.nih.gov/books/NBK544322/
https://clinicaltrials.gov/

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