GANGGUAN PUBERTAS Dr Eka Agustia Rini Sp AK Sub Bagian Endokrinologi Ilmu Kesehatan Anak FK-UNAND / RS Dr M. Djamil Padang

PRECOCIOUS PUBERTY

Hypothalamus - Pituitary – Gonad axis

INTRODUCTION Frequency : girls > boys Epidemiology Frequency : girls > boys Girls: most have a benign central cause Boys: 50% pathologic peripheral cause.  all boys with precocious puberty should undergo detailed investigation, but in girls additional investigation can be based on the clinical impression

Profiles of Girls with Precocious Puberty (N=438) Age of onset between 7-7.9 year olds 6 year olds < 6 years old. 59.6% 22.4% 18% Etiology Gonadotropin Dependent Gonadotropin independent 97.7% 2.3% Neurogenic abnormalities (MR/CT skull) 18.4% Cisternino M, Arrigo T, Pasquino AM, et al. Etiology and Age Incidence of Precocious Puberty in Girls: A Multicentric Study. J Pediatr Endocrinol Metab. 2000;13(suppl 1):695-701

Precocious Puberty Definition Appearance of secondary sexual characteristics : boys < 9 years and girls < 8 years old (- 2SD) Sex steroid  Estrogen: female Testosterone:male

Genital, Hirsutism, acne, male habitus Effect of sex steroid Estrogen  Accelerated bone maturation and early epiphyseal fusion (tall child but short adult) Uterus, mammary gland Testosterone Genital, Hirsutism, acne, male habitus General:sexual behavior, aggressiveness

Classification GnRH dependent (central) : premature reactivation hypothalamus-pituitary-gonad axis  increased gonadotropin  increased sex steroids (dependent) Usually idiopathic GnRH independent (peripheral): autonomous sex steroid secretion,  depressing the hypothalamus-pituitary-gonad axis Usually pathologic

Classification Variant premature thelarche premature adrenarche gynecomastia

Etiology GDPP idiopathic CNS tumor non-tumor: post infection, radiation, trauma, congenital iatrogenic Delayed diagnosis of GIPP

Clinical manifestation GDPP Always isosexual Normal sequence of puberty Hormonal profile: increased gonadotropin and sex steroid

Etiology GIPP - male Isosexual adrenal: tumor, CAH testes : cell Leydig tumor, familial testotoxicosis gonadotropin-secreting tumor: non CNS: hepatoma, germinoma, teratoma CNS: germinoma, adenoma (LH secreting) heterosexual Increased peripheral aromatization

Etiology GIPP - female Isosexual) McCune Albright Severe hypothyroid heterosexual adrenal: tumor, CAH tumor ovarium: arrhenoblastoma

Mc Cune Albright Syndrome Trias Precocious puberty / endocrine hyperactivity Fibrodysplasia Café au lait

Clinical manifestation GIPP Isosexual or heterosexual (late onset CAH, tumor adrenal) Disconcordant of sexual characteristics (testes volume inappropriate with pubertal stage - smaller) Low or normal gonadotropin and increased sex steroid

Benign Premature Adrenarche self-limited condition occurring before six years of age characterized by the appearance of pubic and no further secondary sexual development. normal growth patterns

Benign Premature Adrenarche Normal bone age Slight elevation of serum DHEA Normal adrenal steroid hormone levels Normal sex hormone levels ACTH stimulation test: to exclude late-onset CAH GnRH test: prepubertal pattern Normal imaging studies No specific treatment required

Premature Adrenarche Excude virilization clitoral enlargement, advanced bone age, acne, rapid growth, and voice change. rapid progression If virilization present measure testosterone, 17-OHP and DHEA USG: adrenal or ovarian tumor 17-OHP or DHEA: CAH

Benign Premature Thelarche Isolated appearance of unilateral or bilateral breast aged 6 months to 3 years No other signs of puberty or evidence of excessive estrogen effect (thickening of the vaginal secretions or bone age acceleration). Ingestion or application of estrogen-containing compounds must be excluded as etiology

Benign Premature Thelarche Normal growth rate and bone age Normal levels of gonadotropins and estradiol USG: normal ovaries, prepubertal uterus Usually resolves spontaneously and requires no treatment re-evaluation at intervals of 6-12 months to ensure that premaure thelarche is not the beginning of isosexual precocious puberty

Gynecomastia Breast enlargement in males common in teenage years, lasting 2 years differentiate with obese boys lipomastia no mammae disk Pathological causes must be sought

Pubertal Gynecomastia Incidence: 50-60% of boys during early adolescence breast tissue usually asymmetric and often tender. If history and physical examination, including palpation of the testicles, are unremarkable, reassurance and periodic reevaluation are all that is necessary. Most cases resolve in one to two years.

Gynecomastia Drugs sex steroids, hCG, psychoactive (phenotiazine), antituberculosis, testosterone antagonist (ketoconazole, cimetidine, spironolactone) Malnutrition Idiopathic (most common) Tumor producing disease hepatoma, adrenal, testes, LH and hCG producing tumors

Pubertal Gynecomastia Familial gynecomastia X-linked recessive trait or a sex-limited dominant trait unless associated with hypogonadism no further evaluation in an otherwise normal boy If severe, gynecomastia  cosmetic surgery. Pathologic gynecomastia Klinefelter's syndrome: high risk for breast cancer prolactin-secreting adenomata

Pubertal Gynecomastia Pathologic gynecomastia hormone-secreting tumors (testes, hepatoma), cirrhosis, hypo- and hyperthyroidism. Drug induced (marijuana, phenothiazines, opiates, amphetamines, digitalis, estrogens, ketoconazole, spironolactone, isoniazid, tricyclic antidepressants, cimetidine, etc). If worsens and associated with psychologic morbidity  bromocriptine, tamoxifen reduction mammoplasty rarely indicated.

Diagnostic work up Gonadotropin dependent or independent? Etiology?

Hypothalamus GnRH (-) Pituitary LH/FSH Gonad E2 or T H-P-G axis

(-) Hypothalamus GnRH Primary Pituitary LH/FSH Sex steroid  Gonad Sex steroid  H-P-G axis in GDPP

(-) Hypothalamus GnRH Pituitary LH/FSH Sex steroid  Gonad Extra Gonadal PRIMARY Sex steroid  H-P-G axis in GIPP

Diagnostic work up History age of onset, progressivity, family history, growth, symptoms extragonadal cause (adrenal), CNS complaints, gelactic laughter (hamartoma), previous history: encephalitis, meningitis TB Physical examination pubertal stage, signs of virilisation, height, testes size (small indicative of perpheral cause), CNS signs, skin (acne, café au lait),

Diagnostic work up Laboratory gonadotropin, bHCG, 17-OHProgesterone (CAH), cortisol (Cushing syndrome, adrenal tumor) Imaging Bone age, pelvic ultrasound, skull x-ray, CT/MRI, bone survey (McCune Albright),

Therapy According to the etiology GDPP idiopathic: GnRH agonis GIPP : medroxy-progesteron, ketoconazole, dll Variant: observation

Prognosis According to etiology GDPP idiopathic: GnRH agonis Final height = potential genetic height Preserved fertility Psychosocial minimal, regression of secondary sex GIPP : medical Potential genetic height  Regression of secondary sex  

Conclusion Not all pubertal disorders are pathologic Early increase of sex steroid should be thoroughly investigated GnRH agonist = drug of choice for GDPP

DELAYED PUBERTY

Definisi Pubertas terlambat bila tidak adanya tanda-tanda pubertas laki-laki pada usia 14 tahun perempuan pada usia 13 tahun Klasifikasi hipergonadotropik hipogonadism hipogonadotropik hipogonadism Ammenorrhoe primer Ammenorrhoe sekunder

hipogonadism Hipergonadotropik (-) Hipotalamus LHRH LH/FSH Hipofisis Target Organ (gonad) Primary defect Sex Steroid

Hipergonadotropik hipogonadism Dengan kelainan kromosom Dysgenesis gonad Sindrom Turner Pure gonadal dysgenesis Sindrom Klinefelter Androgen Insensitivity Syndrome *

Hipergonadotropik hipogonadism Tanpa kelainan kromosom kongenital gangguan biosintesis steroid adrenal (P450c17,P450scc,3bHSD) dan gonad (17-KS, P450 aromatase) anorchia, ovary resistant syndrome, LH resistance didapat radiasi, chemotherapy, proses autoimun

hipogonadism Hipogonadotropik (-) Hipotalamus LHRH Primary defect LH/FSH Hipofisis (-) Target Organ (gonad) Sex Steroid

Hipogonadotropik hipogonadism Constitutional delay Kelainan Susunan Syaraf Pusat Tumor (craniopharyngioma, germinoma, optic glioma, histiocytosis X) Struktural (mid line defect) Sindrom Kallmann hipopituitarism idiopathic pasca tindakan (radiasi, khemoterapi inflamasi, infiltrasi - hemosiderosis)

Hipogonadotropik hipogonadism Penyakit kronis endokrin, malnutrisi/anorexia nervosa, kelainan sistemik Aktivitas fisik berlebihan Sindrom-sindrom Prader-Willi; Laurence-Moon-Biedl

Hypothalamic and pituitary causes of pubertal failure-low gonadotrophins Congenital defects Kalmann syndrome Congenital adrenal hypoplasia Septoptic dysplasia Development defect of pituitary Tumors, direct effects or following radiotherapy or surgery Haemochromatosis

Italian Working Group on Endocrine Complication in non-endocrine diseases, 1993

Delayed puberty in Thalassamia patient Italian Multicenter Thalassemia study 1993, (29 centers), 3092 patients : Puberty failure: males 41 % females 39,5 % All patient with hemachromatosis need periodic careful endocrine evaluation

Tatalaksana Anamnesis Pemeriksaan fisik Pemeriksaan penunjang Terapi

Anamnesis Riwayat perkembangan pubertas di dalam keluarga Data pertumbuhan & perkembangan Riwayat penyakit/pengobatan dahulu Fungsi penciuman

Pemeriksaan fisik Pemeriksaan fisik secara umum Pemeriksaan neurologis (funduskopi) d Antropometri (TB, BB, rasio segmen atas dan bawah, rentang lengan) Status pubertas Stigmata suatu sindrom (pendek, obese, retardasi mental, webbed neck dll)

Pemeriksaan Penunjang Pencitraan: usia tulang, CT scan/MRI kepala & USG genitalia interna (atas indikasi), Hormonal (basal/ uji GnRH) LH,FSH,Prolactin, Estrogen atau testosterone Dan lain-lain analisis kromosom (atas indikasi) uji fungsi penciuman

Psychological distress? Pubertal Delay Any signs of puberty? YES Psychological distress? NO Check height, FSH/LH, T4/TSH, Prolactin, Karyotype (girls) YES NO Low FSH/LH High FSH oxandrolone / sex steroids GnRh / sex steroids sex steroids Monitor growth & pubertal progress

Hormonal replacement Discrepancies exist concerning the age of initiation dosage Some authors : postponing treatment until the age when arrested sexual maturation in easily diagnosed Early treatment supporters: Insist on the psychological benefits treatment Sexual development should be induce at an appropriate age

Recommended hormone replacement When to wait watchfully and when to test and refer are part of the art of medicine Female patients chronological age > 13-14 years bone age > 11 years Male patients chronological age > 14-15 years bone age > 12 years

Hormonal replacement Females : start ŵ estrogen 0,25 mg daily (6-9 months) after 9 MOs cyclic therapy ŵ estrogen for 1st 21 days Males: testosterone enanthate 50 mg IM/ monthly after 6-9 MOs, dose gradually increased to 200 mg/3 weeks (2-3 years)

KESIMPULAN Pubertas berlangsung menurut stadium, umur tertentu Pubertas harus selalu menjadi perhatian orangtua / tenaga kesehatan Setiap tenaga kesehatan dapat mendeteksi kelainan pubertas secara dini dan segera melakukan rujukan