Puberty Done by: Samir Alaidaroos,Ahmed Alamoudi,Yousef Alsawwaf Wael Bakhamees, Adel almuzaini

OBJECTIVES: Describe the normal sequence of puberty and recognize deviation from the normal. Define precocious puberty and develop an approach tohistory and physical examination. To define delayed puberty and develop an approach to history and physical examination. Appreciate the impact of delayed and precocious puberty on both the patients and their family.

Normal Puberty

Puberty The stage of physical maturation in which an individual becomes physiologically capable of sexual reproduction. Triggered by increased secretion of Luteinizing Hormone(LH). Results from changes in the hypothalamus that allow increased secretion of GnRH to stimulate secretion of LH

Phases of Puberty Adrenarche Gonadarche Stage of maturation of the cortex of adrenal glands ↑ adrenal androgens secretion  Gonadarche Earliest gonadal changes Ovaries and testes begin to grow ↑ production of sex hormones

Thelarche Pubarche First stage of secondary breast development Usually noticed as a firm, tender lump directly under the center of the nipple(papilla & areolla) Reffered as breast bud(Tanner stage 2) Pubarche First appearance of the pubic hair Results from ↑ levels androgens from adrenal glands or testes

Menarche First menstrual bleeding in females Possibility of fertility

Puberty in female: The onset of puberty in females start at age of 10-14 years old First sign of puberty is Breast development

Preadolescent. Elevation of the papilla only Female: Breast Tanner Stages Breast 1 Preadolescent. Elevation of the papilla only 2 -A small mount is formed by the elevation of the breast and papilla -Areolar diameter enlarges 3 Further enlargement of breast and areola. 4 Projection of the areola and papilla to form a secondary mound above the level of the breast 5 -Mature breast -Areola recessed to the general contour of the breast.

Other changes in female Growth spurt/Peak height velocity Female: Happens in earlier stages of puberty Average age: 12.1 Vagina Becomes thicker and duller pink in color Uterus, ovaries and follicles in the ovaries Increase in size Menstrual and fertility

Other changes in female Body shape and fat distribution: Pelvis and hip widen More fat distributed to breasts, hips, buttocks, thighs, upper arm and pubis. Body odor and acne

Hormonal Changes in female Increase in: Estrogen Prolactin Growth hormone

Puberty in Male The onset of puberty in males start at 12-16 years old The first sign of puberty is the increase of testicles size and genitalia.

Male: Genitalia Tanner Stages Genitalia 1 -The penis , testes and scrotum are of childhood size 2 -Enlargement of scrotum and testes - Scrotal skin reddens 3 -Further growth of the testes and scrotum. -Enlargement of penis, mainly in length 4 -Enlargement of penis, mainly in breadth 5 Adult genitalia

Other Changes in male Growth spurt/Peak height velocity Happens in later stages of puberty Average age: 14.1 Boys have greater velocity at the maximum pubertal growth rate Body and Facial hair Voice change Same time as growth of penis

Other changes in male Musculature and body shape Body oHeavier bones, nearly twice skeletal muscle Muscle develops mainly during the later stages of puberty odor, sweat glands, sebaceous glands and acne About the same time as facial and axillary hair growth

Hormonal Changes in male Increase in: Testosterone Growth Hormone

PRECOCIOUS PUBERTY

Patient :2732016 On examination there were no palpable masses in her abdomen. No signs of other endocrinopathies were observed. An 4 year old Saudi female presented with her mother to the outpatient endocrinology clinic complaining of ‘period-like’ light red discharge gushing out of her vagina once every three weeks for three months, her mother is concerned that her daughter is getting her period too early. The history revealed that the girl has bone pain in her limbs, and on examination multiple cafe au lait marks were observed in addition to tanner stage 1 pubic hair and tanner stage 3 breasts.

Patient :2732016

Definition Precocious puberty is defined as the onset of secondary sexual characteristics before 8 yr of age in girls and 9 yr in boys.

Classification Incomplete Complete Central (gonadotropin-dependent puberty, GDPP) Peripheral (gonadotropin- independent puberty, GIPP) Incomplete Premature thelarche Premature pubarche Depending on the primary source of hormonal production, this may be classified as

Gonadotropin-dependent precocious puberty ( GDPP):  Also known as true precocious puberty Early activation of the entire hypothalamic-pituitary-gonadal (HPG) axis Is caused by the secretion of high-amplitude pulses of gonadotropin-releasing hormone (GnRH) by the hypothalamus. Although the onset is early, the pattern and timing of pubertal events usually progresses in the normal sequence.

Gonadotropin-dependent precocious puberty ( GDPP): condition occurs at least 5- to 10-fold more frequently in girls than in boys Approximately 90% of sexual precocity in girls is idiopathic 75% of boys have a structural CNS abnormality

Causes: Non- CNS lesion: - Idiopathic - Genetics - Prolonged, untreated severe hypothyroidism CNS lesion: - CNS tumour - CNS irradiation hydrocephalus, cysts, trauma, CNS inflammatory disease

CNS lesion: Hypothalamic hamartomas are the most common brain lesion causing true precocious puberty. Hamartomas are non-malignant tumours of the tuber cinereum that consists of disorganized collection of neurons and glias. ectopically located neural tissue containing GnRH-secretory neurons and may function as an accessory GnRH pulse generator There is usually hypothalamic signs: diabetes insipidus hyperthermia unnatural crying or laughing(gelastic seizures) cachexia interrupting CNS inhibitory pathways to the hypothalamus usually in very young children

CNS lesion (cont.): Other tumour: astrocytoma, optic and hypothalamic glioma In optic glioma : proptosis In irradiation of brain : signs of growth hormone deficiency may present

Clinical manifestations: Begin at any age, follows the sequence observed in normal puberty In girls (physical changes): Breast enlargement comes first (often unilateral) Pubic hair may appear simultaneously but more often later Menarche is a late event (irregular cycle and usually anovulatory) The pubertal growth spurt occurs early in female puberty

Clinical manifestations (cont.): In girls (somatic changes): pubic & axillary hair acne body odour oily skin and hair

Clinical manifestations (cont.): In boys (physical changes): Testicular enlargement (unnoticed) Enlargement of penis Erections are common spermatogenesis observed as early as 5-6 yr of age Somatic changes: Axillary hair, acne, voice deepens

Clinical manifestations (cont.): In both gender (skeletal and emotional): Height, weight, and osseous maturation are advanced Without treatment, 30% early closure of the epiphyses > height less than the 5th percentile as adults Emotional and mood swings are common

Gonadotropin-independent precocious puberty ( GIPP): Independent of gonadotropin secretion and no activation of the Hypothalamic pituitary gonadal axis Also know as precocious pseudopuberty caused by excess secretion of sex hormones (estrogens or androgens) derived either from the gonads or adrenal glands or from exogenous sources

Causes of GIPP : Girls Boys Ovarian cysts Leydig cell tumour Ovarian tumours Human chorionic gonadotropin (hCG) secreting germ cell tumors Granulosa theca cell tumor Familial precocious puberty

Other causes of GIPP: Both in boys and girl: Exogenous estrogen Increase in hormones found in food Adrenal pathology ( eg: androgen-secreting tumour and CAH) Teratoma McCune-Albright syndrome

McCune-Albright syndrome McCune-Albright syndrome is a genetic disease caused by mutations in the GNAS1 gene. A small number, but not all, of the patient's cells contain this faulty gene (mosaic pattern). This disease is not inherited.

McCune-Albright syndrome  (MAS) consists of at least 2 of the following 3 features:  polyostotic fibrous dysplasia café-au-lait skin pigmentation autonomous endocrine hyperfunction which leads to precocious puberty

McCune-Albright syndrome Other possible manifestations include the following: Cushing syndrome Growth hormone (GH) excess (gigantism and acromegaly) Ovarian cysts Pituitary tumors Thyroid tumors

Peripheral type (GIPP) Central type (GDPP) Peripheral type (GIPP) H-P-G Axis Activated Suppressed LH and FSH Adult values Pre-Pubertal Sex steroids High Gonads Pubertal size Small in size (unless tumor)

Incomplete precocious puberty Definition: isolated manifestations of precocity without development of other signs of puberty. Incomplete Premature thelarche Premature pubarche

Premature thelarche Transient condition of isolated breast development that most often appears in the first 2 yr of life, often persists for 3-5 yr, and is rarely progressive mostly idiopathic  either remit spontaneously or are very slowly progressive.  no other signs of pubertal development and their growth rate is normal. Management: reassurance and monitoring regularly for any other sign of pubertal advancement

Premature pubarche Appearance of sexual hair before the age of 8 yr in girls or 9 yr in boys without other evidence of maturation Slowly progressive condition that requires no therapy

Patient :2732016 On examination there were no palpable masses in her abdomen. No signs of other endocrinopathies were observed. An 4 year old Saudi female presented with her mother to the outpatient endocrinology clinic complaining of ‘period-like’ light red discharge gushing out of her vagina once every three weeks for three months, her mother is concerned that her daughter is getting her period too early. The history revealed that the girl has bone pain in her limbs, and on examination multiple cafe au lait marks were observed in addition to tanner stage 1 pubic hair and tanner stage 3 breasts.

Patient :2732016

Investigations Bone Age 7 Years old FSH & LH Low T3%T4&TSH Normal ACTH Supressed GNRH High ESTROGEN High IGF-1

DELAYED PUBERTY

Patient :2832016 On examination, he was on the 90th percentile of height and the 50th percentile for weight, and his testes were found to be bilaterally small. His upper to lower ratio is 0.8. A 18 year old Saudi male came to the endocrinology outpatient clinic complaining of looking boyish compared to his peers. History revealed that he had never grown facial, axillary or pubic hair, his voice had not changed, and he noticed bilateral small enlargements in his nipples. His mother claimed no complications during her pregnancy of him, and that he did not miss his early developmental milestones, however she was concerned of the female figure of his body that started noticing around the age of 13.

Patient :2832016

Definition Its defined when there is no sign of pubertal development by age 13 in girls and by age 14 in boys.

Low gonadotropin secretion Types Low gonadotropin secretion (hypogonadotropic hypogonadism). High gonadotropin secretion ( hypergonadotropic hypogonadism).

Constitutional delay of growth and puberty/familial The commonest , more common in males. usually familial , having occurred in the parent or sibling of the same sex. Could be induced by dieting and excessive physical training. delayed sexual maturation , and delayed in skeletal maturity on bone age. Legs are longer in comparison to the back ( eunuchoid body habitus). The deceleration (nadir) before their pubertal growth spurt is prolonged in the affected children as opposed to their peers , this cause them to eventually reach the target height.

Hypogondatropic Hypogonadism ( Low gonadotropin secretion) Hypogondatropic Hypogonadism hinders the spontaneous entry into gonadarche , while adrenarche usually occur to some degree. During childhood and early puberty they have normal proportions and growth. When they reach adulthood enuchoid proportions may occur because their bones grow longer than normal ( Upper to lower ratio less than 0.9)

Hypogondatropic Hypogonadism ( Low gonadotropin secretion) Isolated gonadotropin deficiency e.g Kallman Syndrome. Idiopathic hypopituitarism Hypothalamic-Pituitary tumors.

Isolated gonadotropin deficiency Inability to release gonadotropins but no other pituitary abnormalities, is indicative of Isolated gonadotropin deficiency. Patients grow normally but they fail to achieve the accelerated growth characteristic of the normal growth spurt. An example is Kallmann Syndrome , this syndrome typically feature anosmia.

Hypothalamic-Pituitary tumors. CNS Tumors: Pituitary adenoma, germinoma, glioma, prolactinoma, craniopharyngioma.

Systemic medical conditions: Anorexia nervosa Athletic Amenorrhea Chronic illness Hypothyroidism.

Hypergonadotropic Hypogonadism ( High gonadotropin secretion) Characterized by elevated gonadotropin and low sex steroid levels , a result of primary gonadal failure. Associated Conditions: 1- Ovarian Failure 2- Testicular Failure

Ovarian Failure A Common cause is turner syndrome or the syndrome of gonadal dysgenesis. The karyotype is classically 45,XO. Patients with other types of gonadal dysgenesis and galactosemia, also patients treated with chemotherapy or radiation for malignancy may also develop ovarian failure.

Testicular Failure Klinfelter Syndrome ( seminiferous tubular dysgenesis) is the most common cause. Karyotype is 47,XXY. Clinical presentation: hypogonadism (small testes, azoospermia, oligospermia), gynecomastia in late puberty, Eunchoid body. Leydig cell function maybe spared, however Seminiferous tubular function is characteristically lost. LH levels may be normal or elevated , while FSH levels are unmistakably elevated

Patient :2832016 On examination, he was on the 85th percentile of height and the 50th percentile for weight, and his testes were found to be bilaterally small. His upper to lower ratio is 0.8 A 18 year old Saudi male came to the endocrinology outpatient clinic complaining of looking boyish compared to his peers. History revealed that he had never grown facial, axillary or pubic hair, his voice had not changed, and he noticed bilateral small enlargements in his nipples. His mother claimed no complications during her pregnancy of him, and that he did not miss his early developmental milestones, however she was concerned of the female figure of his body that started noticing around the age of 13.

Patient :2832016

Examination The vitals were normal. His height was 187cm, significantly taller than both his parents, and he had a tanner stage 2 penis with small testicles, in addition to tanner stage 3 breasts. He had no thyroid enlargement or ocular abnormalities. His bone age was 14.

Investigations Karyotype 47 + XXY FSH High T3%T4&TSH Normal Prolactin Low Testosterone Normal LH

IMPACT ON PATIENTS & PARENTS

The impact of Precocious puberty on both the patient and family Even when it's happening to average 12-year-olds, puberty can be a confusing time. It can be all the more stressful for younger kids with early puberty. Adolescent with Precocious puberty may go through social and emotional stress due to: Girls : 1. Short stature 2. Shyness 3. Inability to cope with menstruation and they are at risk of sexual child abuse 4. Behavioral problems

Boys : Short stature Aggressiveness and inappropriate sexual drive . Behavioral problems

The impact of delayed puberty on both the patient and family Adolescent with delayed puberty may go through social and emotional stress due to: 1. Physical appearance: - Short stature: to their lack of sexual development. - Lack secondary sexual characteristics. 2. Being bullied at school: - Reluctance to go to school - Fear of the journey to and from - Things go missing – money, school clothes, lunch boxes - Bruises and scratches.

Thank you!

Done by: Sameer Alaidroos Ahmed Al-amoudi Yousef Alsawaf Wael Bakhamees Adel Almuzaini

References UPTODATE MEDSCAPE NELSON PEDIATRICS BMJ BESTPRACTICE PROF.AGHA LECTURES ILLIUSTRATED