1. PUBERTAL DISORDERS
Prof. Dr. Oya Ercan

2. Early
Timing
Delayed

3. DELAYED PUBERTY

4. Delayed Puberty * Girls >13 years ( menarche >15 )
Boys >14 years
*No sign

5. DELAYED PUBERTY HYPOGONADISM Pathologic Non-pathologic
Hypogonadotrophic Hypergonadotrophic
Pathologic Non-pathologic
Transient Permanent

6. Girls (Ovarian failure) Turner syndrome, gonadal dysgenesis/agenesis
Hypergonadodotrophic hypogonadism
(Ovarian failure)
Turner syndrome, gonadal dysgenesis/agenesis
Autoimmune ovarian failure
Type 1: Addison’s, hypoparathyroidism, mucocutaneous candidiasis
Type 2: Addison’s, autoimmune thyroid disease, Type 1 DM
Mutations in gonadotrophin and gonadotrophin receptor genes
Galactosemia
Irradiation
Chemotherapy
Infectious disease (Malaria, mumps, shigella, varicella)
Enzyme deficiency

7. Girls Hypogonadotropic hypogonadism Congenital Constitutional delay
Permanent hypogonadotropic hypogonadism
Congenital
Acquired
Tumors (craniopharyngioma)
Others CNS lesions: Travma, surgery, infections, infiltrative diseases
Temporary hypogonadotropic hypogonadism
(secondary causes)
Excessive emotional stres
Unusual physical activity
Inadequate nutritional state
Chronic disease
Systemic illness

8. BOYS Hypergonadotrophic Hypogonadism (Testicular failure)
Klinefelter and Multiple X Syndromes
Anorchia
Bilateral Cryptorchidism with Dysgenetic Testes
Torsion (bilateral)
Travma
Infection ( mumps, coxsackie )
Chemotoxicity
Irradiation
Inactivating Mutations of LH and its receptor

9. BOYS Hypogonadotrophic Hypogonadism 1- Without a permanent defect
Constitutional delay of growth and development
Systemic illness
Crohn disease
Poorly controlled DM
Systemic therapy for chronic conditions
2- Permanent defect
Isolated gonadotrophin deficiency
Multiple Pituitary Hormone Deficiency
Congenital.
Acquired
Tumors, travma, irradiation, surgery, infections, infiltrative disorders

10. Congenital Isolated Hypogonadotrophic Hypogonadism (IHH)
Absent, incomplete or arrested isosexual development
Low gonadotrophins and sex hormones
Absence of systemic disease, syndromic malformations, nutritional deprivation and other functional or anatomic pituitary abnormalities

11. Inactivating Mutations in Genes Responsible For:
Differentiation and development of GnRH synthesizing neuron
NROB1 or DAX1, CHD7, FGFR 1, FGF8
Migration of neurons that synthesize and secrete GnRH
Synthesis, release and action of GnRH
Synthesis, secretion of Gn’s

12. Migration of GnRH-synthesizing Nerve Cells
KAL-1 ®
FGFR 1
FGF 8
NELF
PROK 2
PROKR 2 ®

13. Loss of function mutations in these genes associated with abnormalities of olfaction (anosmia, hyposmia)
-Kallmann syndrome-

14. New Modulators of GnRH Synthesis and Secretion (2009)
Products of TAC3 and TACR3
Prof. Kemal Topaloğlu
-Reproductive function might recover after adolescence in both males and females

15. These are subjects with CDGD in the families of many patients with IHH
(CDGP=CDGD : Absence of micropenis and crypthorchidism, endogenous initiation of sexual maturation by age 18 yr )
These aberrations of pubertal timing are varying clinical manifestations of a broad phenotypic expression of disordered regulation of GnRH pulse generation.

16. Investigation of Delayed Puberty
For practical purposes , the complete absence of signs of puberty after 14 years requires investigation.

17. Growth rate, rate of epiphyseal maturation and rate of advance in sexual maturation have all to be considered in order to attempt to separate those children with abnormal endocrine function from those with constitutional delay of growth and puberty.

18. Pelvic ultrasound assessment
Unfortunately, there is no equivalent examination in males. Ovarian maturation continues throughout childhood and as the ovarian morphology reflects pulsatile Gn secretion, this examination can be used to distinguish constitutional delay from complete hypogonadotrophic hypogonadism. The examination may also be useful in the diagnosis of Turner’s syndrome and gonadal dysgenesis.

19. Serum sex steroid measurements:
These have little use in the investigation of delayed puberty. In order to be useful, serum testosterone in males in early puberty needs to be measured from samples in the early hours of the morning although in girls in early puberty, measurement of serum estradiol during the daytime is more appropriate than the measurement of testosterone in boys.

20. Serum gonadotrophin measurements:
Basal serum Gn is useful in the diagnosis of gonadal failure. After the age of 10 years, both LH and FSH concentrations are markedly elevated in gonadal failure.

21. GnRH Test
GnRH test has no use in the investigation of delayed puberty. Such a test is inappropriate in that Gn release is tested at the pituitary rather than the hypothalamic level.
Spontaneous Gn secretion

22. hCG Test:
Serum testosterone concentrations before and after hCG offers a method of distinguishing between constitutional delay of growth and puberty and complete hypogonadotrophic hypogonadism in the majority of cases.

23. Serum prolactin:
Prolactinomata are a rare cause of delayed puberty. However, this diagnosis will be missed unless serum PRL measurements is undertaken.

24. Neuroradiology:
Tms of the hypothalamo-pituitary region may present as an evolving endocrinopathy of which the loss of Gn and GH are early in the sequence of the development of panhypopituitarism.

25. Chromosomes: Turner syndrome GI function:
red cell folate
anti-gliadin ab coeliac
anti-endomysium ab
inflammatory bowel disease: radiology ,endoscopy

26. CDGP:
Stature reduced for chronological age but appropriate for pubertal development and bone maturation.
Family history of delayed puberty
Much more common in boys than girls

27. Idiopathic Hypogonadotrophic Hypogonadism:
Normal height
Arrested epiphyseal maturation at approximately 13 years
(+) anosmia (Kallmann’s syndrome)
Colour blindness
Cryptorchidism boys
micropenis

28. Sex steroids in boys and girls
hCG in boys
Not less than 2 years (puberty induction)

29. EARLY PUBERTY

30. Classification GnRH-dependent GnRH-independent GnRH-driven Peripheral
Central Precocious pseudo
True puberty

31. Early Puberty Normal Consonance Idiopathic central precocious puberty
Central precocious puberty secondary to Hypothalamo-pituitary tumours and infections
Raised intracranial pressure
Cranial irradiation
Gonadotrophin-independent precocious puberty(Testotoxicosis)

32. Loss of consonance (pseudopuberty)
Hypothalamo-pituitary endocrinopathy
Cushing’s Disease
Adrenal Disorders
Cushing’s syndrome
Congenital adrenal hyperplasia
Primary tumours
Gonadal Disorders
Mc Cune- Albright syndrome
Primary Hypothyroidism
Isolated Premature Thelarche

33. Etiology FEATURES CENTRAL PRECOCİOUS PUBERTY THELARCHE Age of onset
< 8 years
< 2 years
Pubic and axillary hair
Progressive development
Absent
Menses
As in normal puberty
Usually absent
Skeletal maturation
Advanced
Appropriate
Growth velocity
Accelerated
Normal
Growth prognosis
Compromised
Duration of condition
Continues as adult sexual maturation
Usually resolves after a few years, always by 8 years of age
Prognosis for fertility
May be compromised
Breast development
Progressive development
Minor (Usually B2 or B3 cycling at approximately 6 week intervals

34. Mc Cune-Albright Syndrome
Activating mis-sense mutation in the gene for the α subunit of Gs.
Mosaic distribution of cells with mutation
Polyostotic fibrous dysplasia
Café au lait spots
Endocrinopathy
gonads
adrenal cortex
thyroid
pituitary gland
parathyroid gland
“G protein stimulation as if trophic hormones were present.”

35. Testotoxicosis
Activating mutation of the LH receptor