Precocious Puberty. Dr. Abdulmoein Eid Al-Agha Consultant, Pediatric Endocrinologist, King Abdul Aziz University Hospital, Jeddah, Saudi Arabia

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1 Precocious Puberty Dr. Abdulmoein Eid Al-Agha Consultant, Pediatric Endocrinologist, King Abdul Aziz University Hospital, Jeddah, Saudi Arabia

2 Discussion points When to say this child is having Precocious puberty (what is the age limits in both sexes) Types of precocious puberty Etiology Biochemical & Radiological investigations Management Who should be treated! Treatment options

3 Puberty Puberty (Latin pubescere, to be covered with hair) The stage between the onset of secondary sexual characteristics and the completion of physical maturity The period in which reproductive capability is attained,manifested by spermatogenesis in males & ovulation in females

4 Puberty BRAIN NEUROTRANSMITTERS HYPOTHALAMUS GnRH PITUITARY GLAND LH / FSH GONADS TESTOSTERONE / E2 ACTIVIN INHIBIN

5 Puberty Normal age girls: 9-13 y (mean age =11 years) boys: y (mean age =13 years) primates puberty process happened very quickly within 28 days Humans puberty on hold for a longer period ( 12 y)

6 Puberty in girls Psychological / emotional changes Stages of normal puberty Thelarche Adrenarche / Pubarche Menarche Pelvic U/S changes of puberty ovarian volume and follicular size uterus to cervix ratio endometrial echo

7 Skeletal changes in girls Widening of pelvis and carrying angle Major increase in BMD Increased adipose tissue with typical female distribution 95% of growth happened < menarche Menarche usually by age yr Increased in muscle bulk but not to same extent as males

8 Somatic changes pubic & axillary hair acne Puberty perspiration and characteristic body odour (release of volatile acids= glutaric acid) oily skin and hair All these changes happen due to increased adrenal androgens which are formed equally in both males and females Adrenal androgens androstenedione, DHEA, DHEAS

9 Definition of PP In girls, defined as onset of puberty breast enlargement before age of 8 years In boys, defined as onset of puberty before age of 9 years

10 Definition!! Recently, many data suggest that girls seen in sample of pediatric practices from across the United States are developing pubertal characteristics at younger ages. Practitioners may need to revise their criteria for referral of girls with precocious puberty, with attention to racial differences!!

11 Why there is secular trend toward earlier puberty, especially in girls!!! Why percentage of girls with precocious puberty rose from 2.5% in 1969 to 10% in 1990s!!! 1. Increasing % of obesity in girls 2. Environmental estrogen

12 The Hazards of Environmental Estrogens World and I magazine; 10/1/2001; Trankina, Michele L.

13 The Hazards of Environmental Estrogens Over the past 10 years, many synthetic compounds and plant products present in the environment have been found to affect hormonal functions in various ways Premature puberty was traced to consumption of beef, and dairy products containing high concentrations of estrogen. Another study from Puerto Rico revealed higher concentrations of phthalate--a xenoestrogen present in certain plastics--in girls who showed signs of early puberty, compared with controls. estrogen-like substances in the plastic wrap used on sandwiches for kids' lunches.

14 It may be that excess of body fat and the exposure to estrogenic substances operate together to hasten puberty. Body fat is one site of endogenous estrogen synthesis. Exposure to environmental estrogens may add just enough exogenous hormone to exert the synergistic effect necessary to bring on puberty, much like the last drop of water that causes the bucket to overflow!!!!!!! World and I magazine; 10/1/2001; Trankina, Michele L.

15 Revised Definitions in girls Europe USA Precocious < 8 6 0r 7 < Early Normal > 10 > 9 For boys, USA & Europe have same definition!!

16 Types

17 Types Central, True, GnRH dependent 89-98% of cases (major type) Periphral, Pseudo, GnRH Independent % of cases (not major type) Mixed type Started with peripheral with 2ry. activation of central Isolated Forms Thelarche Adrenarche

18 Central type Peripheral type H-P-G axis Activated axis suppressed LH & FSH Adult values Pre-pubertal Sex steroids High High Gonads Pubertal size Small in size (unless tumor)

19 Etiology

20 Central, True, GnRH dependent Etiology Idiopathic most girls ( 90 %) Secondary most boys ( 70-80%)

21 Etiology of CPP CNS disorders Hypothalamic Hamartoma Glioma (NF-1) Astrocytoma Craniopharyngioma Ependymoma, germinoma, CNS radiation therapy Post trauma (surgery)

22 Etiology of CPP Inflammation (Brain abscesses) Neurological & mental retardation Hydrocephalus prolonged sex steroid exposure associated with peripheral puberty Prolonged primary hypothyroidism ( -TSH stimulates FSH, LH, Prl)

23 Etiology of peripheral type Gonadial: McCune-Albright, tumour, cyst Adrenal: Virilising CAH, tumours Ectopic: hcg secreting tumours Germinoma, Hepatoblastoma Exogenous source of hormone Familial male dependent (Testotoxicosis) Chronic primary hypothyroidism ( -TSH stimulates testicular enlargement)

24 Autonomous gonad steroid production McCune Albright syndrome germ line activating mutations of the FSH receptor Familial male dependent precocious puberty activating mutation of the LH receptor The mutation is inherited in an autosomal dominant fashion, although sporadic cases can occur.

25 Examples of some cases

26 Six year old girl presented with bilateral breast enlargement & axillary hair for last six months, progressive in nature. On examination, she had B2PH3. Her investigations showed suppressed LH/FSH with high estardiol level and high serum inhibin. What is most likely diagnosis? What further investigations needed to be done?

27 Diagnosis: Granulosa cell ovarian tumor

28 Three years old young child presented with 2 day history of menstruation with no any other signs of puberty. No previous similar history, no history of medications nor any trauma. On examination, she was looking well, no systemic findings with weight and height on 10th.percentile and she was having Tanner stage of B2PH1.there was one large Cafeau-lait macule What is the most likely diagnosis? Mention 4 important investigations Mention 3 modalities of treatment?

29 McCune - Albright syndrome Affects both sexes Gonad autonomy (Autonomous gonad steroid production) Happen more commonly in girls In girls, the presenting feature is often menses with / without Thelarche Menses usually happen < 2-3 yrs of age Activating mutation within exon 8 of Gs gene GNAS 1 on 20q13.2,results in increased activity of the Gs protein & camp in the affected endocrine tissue

30 McCune-Albright Syndrome

31 Abnormalities in McCune-Albright syndrome Endocrine problems Precocious Puberty ++++ Goiter / Hyperthyroidism +++ Acromegaly / Gigantism ++ Cushing s syndrome + Hyperprolactinemia + Hypophosphatemic rickets +

32 Abnormalities in McCune-Albright syndrome Non-endocrine Cafe-au-lait spot ++++ Fibrous dysplasia of bone ++++ Facial asymmetry ++ Elevated hepatic transaminases ++ G.I polyposis + Cardiomyopathy + Arrhythmias +

33 McCune-Albright syndrome Estradiol level may be normal or high depending on the stage of development of follicular cyst Menstrual flow represents estrogen withdrawal following regression of large follicular cyst Basal and stimulated levels of LH / FSH are supressed in early stage After many cycles of cysts appearance and regression,maturation of Hypothalamic function develop (2ry. central precocious puberty)

34 Treatment Sequential removal of ovarian cyst Complete removal of ovaries 17 - Medroxyprogestrone (Provera) Estrogen antagonists (Tamoxifen) Aromatase inhibitors Cyproterone Acetate (Androcur) LHRH agonist (central stage)

35 Two years old toddler brought by her parents, complaining of bilateral breast bud for the last 2 months with no other relevant history or examination findings? What further important history and examination you need to confirm? Mention 3 important investigations? What is the most likely diagnosis?

36 Isolated form of pubertal development Premature Thelarche Premature Adrenarche Premature Pubarche

37 Premature Thelarche Premature breast enlargement with absence of growth spurt Bone age is not accelerated Pre pubertal pelvic U/S findings Onset between 6 m to 4 y of age Increased sensitivity of the breast tissue to low levels of sex steroids Benign nature & need no therapy

38 Eight year old brought by her mother because of smelly body odor. On examination, she was having hairy lips, hyperpigmentations, hoarse voice and acne. Her bone age was advanced? What is the most likely diagnosis? Mention important 5 investigations? Mention how to treat this girl?

39 Premature Adrenarche Occurs when the adrenal side of puberty is turned on prematurely in the absence of gonadal activation Premature appearance of pubic and axillary hair, acne, body odor & oily skin Idiopathic

40 Premature Adrenarche Elevated adrenal androgens Normal LH / FSH & gonadal steroids Need to exclude late-onset CAH Need to exclude adrenal tumours Need to exclude PCOS

41 Diagnostic work-up

42 Evaluation of Precocious Puberty History physical examination Growth percentiles Calculation of target height Bone Age assessment Predicted adult height (PAH) Basal LH, FSH and sex steroids GnRH stimulation test

43 History Age when secondary sexual development were noted What features are present? Order of appearance of secondary features Is it usual sequence or not? Virilization symptoms Pubic/ axillary hair Body odor Breast enlargement Vaginal discharges & menarche Cyclical mood changes

44 History Evidence of recent growth acceleration Family history of early puberty Age of parent puberty Past history of adoption or early weight gain History of medications

45 Examination Tanner staging Degree of Virilization Clitromegaly in girls indicate abnormal androgen Visual field assessment & fundoscopy Abdominal masses Skin (café-au-lait patches in McCune Albright syndrome, NF) Assessment of height and height velocity

46 Clinical Measurements Standing height (Harpenden stadiometer) BMI Growth velocity (growth spurt) MPH Tanner staging of pubertal development Bone age (assessed by endocrinologist) PAH

47 Tanner Staging

48 Laboratory Studies Sex steroid levels Basal LH, FSH GnRH stimulation test A definitive CPP diagnosis is confirmed by a brisk rise in LH minutes after infusion of GnRH (100 mcg), which is more than the rise in FSH. No increase in LH and FSH after infusing GnRH suggests precocious pseudo-puberty. Pre-pubertal girls with premature Thelarche sometimes show an exaggerated rise in FSH after GnRH. FSH predominant response An FSH rise more than the LH rise does not indicate CPP

49 hcg hepatoblastoma, germinoma 17 OHP &11DOC CAH Thyroid tests are not a routine requirement

50 A radiograph of the hand and wrist to determine bone age is a quick and useful means to estimate the likelihood of precocious puberty and its speed of progression Bone Age

51 Imaging Studies MRI Brain Perform an MRI after hormonal studies (GnRH test) to confirm a CPP diagnosis. Ask the radiologist to do a high-resolution study focusing on the hypothalamic-pituitary area. The younger girls with CPP, the greater the chance of finding CNS pathology girls younger than 6 y. For boys younger than 9 years, the incidence of CNS findings is much higher than in girls, and MRI should be part of the evaluation.

52 In recent years, MRI has become the imaging method of choice in the assessment of CPP MRI now allows the identification of previously unseen intracranial abnormalities in CPP, thus reducing the number of cases previously considered to be 'idiopathic.'

53 Pelvic ultrasound Ultrasound is unnecessary for girls with a definite diagnosis of CPP. If performed, however, ultrasound usually shows bilaterally enlarged ovaries, often with multiple small follicular cysts, and an enlarged uterus with an endometrial stripe. Pelvic ultrasound is essential when precocious pseudopuberty is suspected (based on examination or hormone levels) because an ovarian tumor or cyst may be detected. U/S Testes Adrenal U/S

54 Treatment

55 Why do we need to treat?? Main problems (Boys) eventual short stature psychological issues aggressiveness inappropriate libido Main problems (Girls) eventual short stature psychological issues inability to cope with menstruation risk of child abuse

56 Goals of treatment Decrease the progression of pubertal changes Decrease bone maturation Increase the predicted final adult height Psychosocial and behavioral therapy

57 Modalities of treatment CPP Surgical Care When CPP is caused by a CNS tumor other than a Hamartoma, perform a resection to the extent possible without impinging on vital structures such as the optic nerves. Radiation therapy often is indicated if surgical resection is incomplete. Unfortunately, removal of the tumor rarely causes regression of precocious puberty. Medical Care Gonadotropin-releasing hormone (GnRH) agonists

58 Do All Idiopathic Central Precocious Puberty Require Gonadotropin-Releasing Hormone Agonist Treatment?

59 Important questions prior starting GnRHa How early is the onset of puberty? How much advancement of the bone maturation? What is the predicted adult height (PAH)? Comparison of PAH to MPH? How fast the progression of physical changes? GnRH stimulation test?

60 Important questions prior starting GnRHa Is the child also deficient in GH? Has psychosocial well-being been compromised? Is treatment likely to improve the quality of life? Are the anticipated gains worth the potential expense & complications of therapy?

61 Very important issue is the distinction between the non progressive forms of CPP with respect to auxological effects on growth and whether there is need to start treatment!

62 GnRH agonists First reported in 1981 The treatment of choice of CPP Alteration of peptide sequence of native GnRH with more potency, affinity to the receptors Acts continuously with down regulation of GnRH receptors

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64 GnRH agonist Daily S/C preparation Desoriline 4-8 ug/kg/d Busereline 20-40ug/kg/d leuprolide ug/kg/day Nafarelin(intranasal) ug/kg/day Depot-preparations Leuprorelin acetate (Lupron) 0.3 mg / kg (7.5 mg) Tryptorelin (Decapeptyl) ug/kg Goserelin (Zoladex)

65 Response to therapy Suppression of endogenous LH / FSH should be confirmed by GnRH test after 3m and then bi-annually Testosterone and E2 with in 1-2 Wk Regression of Pubertal changes

66 Adverse effects Anaphylactic reactions: angioedema, urticaria Local skin reactions : redness,swelling, itchiness and sterile abscesses Flare up phenomena initial activation of HPG axis with worsening of symptoms Under treatment Results in stimulation rather suppression of central axis

67 Final Height After GnRHa Treatment for Central Precocious Puberty Bone age (BA) and chronological age (CA) at start of treatment, as well as BA advance at cessation of treatment, were the most important variables influencing height gain in multiple regression analysis. BA advance at start of treatment was most important in simple correlation. In girls, GnRHa treatment seems to restore FH into the target range. A younger age and advanced bone age at start of treatment are associated with more height gain from GnRHa treatment.

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69 Treatment - Conclusion 1) The use of long-acting (GnRH) agonists may not be indicated in slowly progressive variants or borderline early puberty because they do not affect final height. 2) Preservation of height potential is particularly obvious in precocious puberty starting at young ages. 3) In some selected patients, associated growth hormone therapy may increase adult height but further studies are warranted.

70 Combined use of GH& GnRHa It appears that patients with CPP who grow poorly during GnRHa therapy may have alterations in their GH-IGF-I axis. This may be attributable to an exaggerated and sustained decrease in the secretion of GH with the withdrawal of sex steroids after the GnRHa therapy has been initiated. Treatment to slow skeletal maturation in the face of suppressed GH secretion will still result in compromised adult height. This has led some investigators to speculate that at least a subset of patients with CPP would benefit from the addition of GH therapy to the GnRHa treatment.

71 The results of such treatment first were reported in 1991 by Oostdijk et al in a study of 3 girls with growth velocities less than the 25th percentile for chronologic age after 3 years of treatment with deslorelin. Treatment with GH was then started, and after 18 months of combination therapy, all the girls' predicted adult heights had improved (statistical analysis not published). Since then, additional studies have addressed the question of whether combination therapy improves the predicted adult height in children with idiopathic CPP. Pediatrics;1999; Pescovitz, Ora Hirsch

72 Effects of combined Gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty Pucarelli I,et.al J Pediatr Endocrinol Metab Sep;16(7):

73 Combined use of GH& GnRHa CONCLUSIONS The primary goal of GnRHa therapy in CPP is to maintain normal height potential, It is disturbing that not all patients attain adult heights that are within their genetic target ranges. The effect of GnRHa therapy on the growth axis still is not completely clear, but it is apparent that some children have significant deceleration of their growth velocity, sometimes in association with decreases in GH and IGF-I levels, during treatment. In fact, decreased secretion of IGF-I may even occur in treated patients with normal growth.

74 Conclusions The published studies do suggest a real benefit from adding GH to GnRHa therapy in children with suboptimal growth during GnRHa therapy. However, the studies have been small and have not all included control groups, and that the sole study that followed the subjects to adult heights found only a modest improvement. Studies in short normal children and GH-deficient children who are treated with a combination of GH and GnRHa to improve adult heights have yielded encouraging, yet somewhat limited, results as well Combination therapy could be a viable treatment option in some children with CPP, but additional studies are needed before widespread clinical use outside of a research setting can be recommended.

75 GnRH antagonist act by competitive binding to the pituitary GnRH receptors, thereby preventing the action of endogenous GnRH - theoretically offering a more direct and dose-dependent treatment The antagonist available today in Germany is a concomitant in assisted reproduction with only 1-3 days duration. long-acting depot preparations of other GnRH antagonists are in developing phase

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78 GnRH antagonist Antagonists such as Abarelix-Depot bind to GnRH receptors and turn them off, causing an immediate and complete decline in sex hormones production to the level of medical castration. The immediate suppression of the pituitary achieved by GnRH antagonists without an initial stimulatory effect is the main advantage of these compounds over the agonists. The main disadvantages of the antagonists are that they are expensive

79 Other Medications!!

80 Cyproterone Acetate (Androcur) in the Treatment of Precocious Puberty CPA was found effective in persistently suppressing pituitary gonadotropic secretion when administered orally at a dose of 50 mg bid. After the introduction of gonadotropic analogues (GnRHa) for treatment of central precocious puberty, short term use of CPA was found useful to counteract the initial initial 'flare-up' of the pituitary-gonadal axis, followed by a reduced luteinising hormone secretion by desensitization of pituitary GnRH receptors Other indications for CPA treatment during childhood and adolescence, congenital adrenal hyperplasia Acne Hirsuitism

81 Treatment of peripheral type Medical therapy Medroxyprogestrone acetate (Provera) Ketoconazole Aromatase enzyme inhibitors (testolctone) Androgen antagonists Surgical treatment of underlying pathology if present

82 Medroxyprogestrone acetate (Provera) Before availability of GnRH agonists, this category was the mainstay of therapy. Progestin work by providing feedback suppression of pituitary Gonadotropin secretion. They lack significant androgenic or estrogenic activity. Not expensive treatment Can stop menstruations, but has no much role in improvement of PAH Can be a good choice to those who present late

83 Medroxyprogestrone acetate (Provera) Structurally similar to glucocorticoid Progestational agent which suppresses gonadotrophin Useful in the treatment of both types Effective in halting the advancement of secondary characters in both sexes Effective in preventing menstruation No effects on bone maturation Dose : mg/m2 IM q2wk

84 ketoconazole Anti-fungal with side effect of the inhibition of both steroidogenesis and testosterone synthesis at 17,20 Lyase step Dose mg/day Suppression happen with in 48 h Potential hepatotoxic

85 Aromatase Inhibitors Aromatase enzyme converts Androstedione to estrone Testosterone to estradiol Decreasing level of estradiol and receptor affinity has major rule in decreasing bone maturation and give more chance of delayed epiphysis closure in both sexes Many researches going on currently, to use of this category in those with advanced bone age and short stature to improve PAH, especially those with verilizing CAH, who present late with precocious puberty & advanced bone age

86 First generation Aromatase Inhibitors Testolactone Second generation Formastine, Plomestane, Atamestane, Minamestane, Exemastane Third generation Anastrazole (Arimidex) Letrazole (Femara)

87 Aromatase Inhibitors Testolactone (Teslac) is a competitive steroidal aromatase inhibitors Combined with Spirinolactone is useful in treatment of familial Testotoxicosis Dose 20 mg/kg/day initially then 40 mg/kg/day divided into 4 doses

88 Anti - Androgens 1. Intra Adrenal blockage of androgen production Ketoconazole Blocks adrenal steroid production at several enzymatic steps Considered to be reversible medical adrenalectomy 2. Peripheral blockage of androgen action Anti- Androgens: Spirinolactone (aldactone) Cyproterone acetate (Androcur) Finasteride = 5 - reductase enzyme inhibitor Androgen receptor-blockers: Flutamide

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