Gonadal Disorders

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2 types of abnormal puberty:

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Precocious puberty

Delayed puberty

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Puberty : Definitions--

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*The process of physical changes by which a child's body matures into an adult body capable of sexual reproduction to enable fertilization.

*The period of becoming first capable of reproducing sexually marked by maturing of the genital organs, development of 2˚ sex characteristics, and in the human by the first occurrence of menstruation in the female.

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Thelarche:
Gynecomastia:
Menarche:
Amenorrhea:
Spermarche:
Pubarche:
Adrenarche:
Gonadarche:

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Thelarche: breast development in females
Gynecomastia: breast development in males
Menarche: first onset of menses
Amenorrhea: absence of menses
Spermarche: first appearance of sperm
Pubarche: pubic hair development

Adrenarche: secretion of adrenal androgens by adrenal cortex; Dehydroepiandrosterone (DHEA) and it’s sulfate DHEAS – weak androgens

Gonadarche: secretion of gonadal sex steroids (testosterone and estrogen)

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HPG axis role in puberty:

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GnRH--> gonadotrope --> LH/FSH --> gonads

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Gonadotropin action on the gonads:

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androstendione gets converted to Estradiol

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Action of testosterone:

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*Prenatal differentiation of wolfian ducts and external genitalia (IF 5α reductase is present)
*Development of male secondary characteristics (male hair distribution, penile growth, laryngeal enlargement, ↑ muscle mass)
*Causes pubertal growth spurt
*Maintains spermatogenesis in sertoli cells (paracrine effect)
↑ size and secretory activity of epidymis, vas deferens, prostate and seminal vesicles
↑ libido

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Action of estrogen:

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*Maturation and maintenance of fallopian tubes, uterus, cervix and vagina
*Development of female secondary sexual characteristics
*Breast development
*Maintains pregnancy

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Pubertal timing (ages):

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outside of 2 SDs is abnormal--precocious or delayed

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Normal Puberty: mean ages

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*Breast development/thelarche: 10.5 yrs

*First menses/menarche: 12.9 yrs White girls; 12.2 yrs African American

*Testicular enlargement: 11.5 yrs

*Peak growth velocity: 12 yrs girls boys 13.5 to 14 yrs

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Tanner Stages: Girls:

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1: Pre-pubertal
2: Breast bud
3: Further enlargement
4: Areola and papilla- secondary mound
5: Adult

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Tanner staging: Pubic hair:

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1: Pre-pubertal
2: Sparse hair along labia
3: Darker,coarser, curlier over junction of pubis bone
4: Adult type : no spread to medial thighs
5: Spread to medial thighs

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Prader Orchidometer : to assess testicular volume
(testicular enlargement is first sign of puberty in boys).

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Tanner Stage: Boys (testis and penis):

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1: Pre-pubertal (<3 cc testis;<2.5 cms)
2: Testicular enlargement (~4 cc; >2.5 cms)
3: increased length
4: increased breadth and glans
5: adult

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LH secretions related to Tanner stages:

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Stage 2: LH at night only
Stage 3/4: day and night LH

*LH heralds onset of puberty--> needed to get DHT

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Precocious puberty:

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*Central/Gonadotropin-dependent:
activation of the hypothalamic-pituitary gonadal axis (↑ LH, FSH, testosterone or estradiol)

*Peripheral/Gonadotropin-independent:
elevated sex steroids from ovary or testes
(↑ testosterone or estradiol, ↓ LH, FSH)

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Etiology of Central Precocious Puberty:

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*Hypothalamic tumors
-Hamartomas (most common organic cause)
gliomas, astrocytomas, ependymomas

*Pituitary tumors: Craniopharyngiomas

*CNS anomalies
-Static encephalopathy (hypoxia, trauma, infection)
-Hydrocephalus
-Low dose irradiation

*Idiopathic: More common in girls (most common in all kids)

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Etiology of Peripheral Precocious Puberty:
-discuss environmental causes, ovarian disorders, and testicular disorders:

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*Environment
-lavender oil, tea tree oil
-E/T creams, gels

*Ovarian disorders
-Granulosa cell tumors
-Follicular cysts
-McCune-Albright Syndrome
-Severe Hypothyroidism**

*Testicular disorders
-Familial male-limited precocious puberty
-Leydig cell tumor
-McCune-Albright Syndrome
-gonadoblastoma

*Don't memorize all of these*

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Etiology of Peripheral Precocious Puberty:
-discuss hCG secreting tumors and Adrenal disorders:

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*hCG-secreting tumors
-Dysgerminoma
-Teratoma
-Chorioepithelioma
-Choriocarcinoma
-Hepatoblastoma

*Adrenal disorders
-Adrenal adenoma
-Adrenal carcinoma
-CAH
-Premature Adrenarche

*Don't memorize all of these*

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Severe hypothyroidism effect on puberty:

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-High TSH --> binding to FSH receptor (remember they have a common alpha subunit) in ovary --> increased estradiol secretion --> breast development

-TSH can also bind to receptors in testicles to stimulate inhibin and spermatogenesis

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Central Precocious Puberty:

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*Thelarche < 8 y.o. in girls
*Testicular enlargement < 9 years in boys.
*1/5000 to 1/10,000 children
*10-23x more common in girls than boys
*Etiology:
Girls: Idiopathic (70-90%)
Boys: CNS lesions (60-94%)

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Schematic of early puberty in females:

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Schematic of early puberty in males:

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*Male with central precocious puberty with sixth nerve palsy secondary to intracranial astrocytoma
*Right eye is esotropic
*The kid is muscular
*Thin scrotum

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*Thelarche and vaginal bleeding at 2 ½ yrs
A. At 3½ years , BA 7 yrs
B. At age 5 8/12 yrs
C. At age 8 years – BA 14 yrs
*Final adult height: 142 cms ( 56” or 4’8”)

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Dx of CPP:

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*GnRH level? a very short half-life of 2-5 mins and is confined in the hypothalamic-portal circulation.
*Old test: GnRH stimulation testing: gold standard (LH predominant response)

*Current test: Serum LH by ICMA test >0.3 IU/L is consistent with central puberty

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McCune Albright Syndrome:

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*peripheral precocious puberty, café-au-lait spots and firbous dysplasia of bones

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McCune Albright Syndrome

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*McCune Albright Syndrome
*increased sex steroids
*low LH/FSH

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Pathophysiology of MAS:

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*Mutation in the Gsα gene that occurs early in embryogenesis ( somatic or post-zygotic)

*Results in constitutive activation of adenylyl cyclase in multiple affected tissues

*Unregulated hormone production independent of the normal stimulatory factors from the hypothalamus or pituitary gland.

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*Large penis noted at 6 wks
*Pubic hair at 6-9 months
*At 18 months
*Tanner 4 penis, 3 pubic hair, and testicular volume 3cc
husky voice
muscular
*Low LH/FSH, High testosterone

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Familial Male-Limited Precocious Puberty AKA Testotoxicosis

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Familial Male-Limited Precocious Puberty AKA Testotoxicosis:

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*Presentation
-Typically at ≤ 4 years old
-Signs of puberty, rapid virilization and growth acceleration

*History
-Frequently a positive family history of FMPP

*Low LH/FSH, High testosterone
*Penis is more advanced than testicles
*Male-only counterpart of McCune-Albright (McA happens in both sexes)...LH receptor is mutated.

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Pathogenesis of testitoxicosis:

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*Normal Production
LH-->Leydig cell receptor--> adenyl cyclase stimulated  testosterone

*Mutations
Constitutively active Leydig cell receptor--> adenyl cyclase stimulated--> testosterone

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Leydig Cell Hyperplasia in testitoxicosis

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Treatment for Precocious puberty:

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*Central Precocious Puberty: GnRH agonist

*Tumors (testicular/ovarian): surgery, chemotheraphy

*McCune Albright Syndrome: Tamoxifen (estrogen antagonist)

*Familial male limited precocious puberty/Testotoxicosis: anti-androgen or aromatase inhibitors

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Why do we use GnRH agonists to treat central precocious puberty?

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*1978 study--Belchetz cut out the hypothalamus of monkeys and gave a steady concentration of GnRH --> low LH/FSH

*When he have GnRH in a pulsatile manner --> high LH/FSH

*Therefore, we give a continuous GnRH agonist to kids with CPP, which keeps LH/FSH low in them.

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Treatment for CPP?

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*GnRH agonist
*Treatment of choice since 1981
*Continuous administration suppresses FSH and LH levels and inhibits gonadal activity (by a desensitization mechanism).

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Example of GnRH agonists we use?

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-In the U.S., Leuprorelin (Lupron) and Histrelin

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Dosages and costs of GnRH agonist treatment?

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histrelin is a continuous subdermal med--no shots; implant lasts about a year. Maybe longer.

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Delayed puberty definition:

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*Absence of thelarche (breast bud) at 13 yrs of age in girls

*Absence of testicular enlargement at 14 yrs of age in boys

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Classification of delayed puberty:

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*Constitutional delay in growth and puberty (CDGP)
*Hypogonadotropic hypogonadism
*Hypergonadotropic hypogonadism
*Genetic defects of the Hypothalamic-pituitary axis

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Differential diagnosis of delayed puberty:

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hypergonadotropic--no negative feedback AKA 1˚ gonadal failure

hypogonadotropic AKA 2˚ gonadal failure

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Schematic of the hypothalamic-pituitary-gonadal axis in a normal patient and in the setting of primary and secondary hypogonadism:

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CDGP:

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*Delay in onset of puberty
*Usually shorter than peers
*NORMAL growth velocity
*Positive family history of pubertal delay in a parent

*Adrenarche (pubic hair) is characteristically delayed along with gonadarche (breast bud/testicular enlargement)

*TREATMENT: Reassurance or short course of testosterone enanthate or cypionate--> 2˚ sex traits.

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Define Hypogonadotropic hypogonadism:

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Absent or decreased ability of the hypothalamus to secrete GnRH or the pituitary gland to secrete LH and FSH

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Causes of Hypogonadotropic hypogonadism:

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*CNS disorders:
-Tumors (CRANIOPHARYNGIOMA ): most common
-Acquired CNS d/o: TB, sarcoid, trauma
-Congenital disorders: Septo-optic dysplasia (absent septum pellucidum)
-Irradiation: e.g. ( CNS leukemia requiring 18-Gy dose radiation

*Genetic defects of the hypothalamic-pituitary axis
A. Isolated gonadotropin deficiency: Kallmann’s syndrome
B. Multiple pituitary hormone deficiency
C. Miscellaneous: Prader-Willi syndrome, chronic disease, anorexia nervosa, hypothyroidism

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Why can hypothyroidism cause hypogonadotropic hypogonadism?

How can it also lead to precocious puberty?

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*TRH and TSH levels will rise; thus raising PRL levels, which suppress LH/FSH.

*High TSH can cross react and stimulate the LH/FSH receptors in the ovary/testicle (alpha subunit)

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3 labs to get when someone presents with delayed penile growth (case was a 20 year old with 3.5cm penis and 2cc testes)

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LH
FSH
Testosterone
*Turns out case guy had a FGFR1 mutation

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Genes involved in pubertal development:

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Don't need to memorize; just be aware of the mutations out there.

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Hypergonadotropic hypogonadism:

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implies that hypothalamic pituitary component of pubertal signalling has been activated through lack of negative feedback that is normally exerted by actions of sex steroids.

*Males
A. Klinefelter’s syndrome
B. Other forms of primary testicular failure
(chemotherapy and radiation to testicles)
C. Anorchia (no testes) or cryptorchidism (undescended)

*Females
A. Turner’s syndrome
B. Other forms of primary ovarian failure (chemotherapy, radiation to ovaries, autoimmune oophoritis)

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*Seminiferous tubular dysgenesis AKA Klinefelter!!!!!!
*Some have Leydig cell problems, need testosterone replacement

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Klinefelter’s syndrome:

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*Most common form of primary testicular failure
*Incidence: 1:800- 1,000
*Physical exam: decreased upper:lower segment ratio, small, firm testes, developmental delay, learning disability
*Leydig cell function is less affected than seminiferous tubule function
*Aka syndrome of seminiferous tubule dysgenesis

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Treatment for Klinefelter:

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Treatment : Testosterone preparations: depot IM injections vs. gel (look out for that gel!)

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Turner’s syndrome:

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*Syndrome of gonadal dysgenesis
*45 X or mosaicism (45X, 46XX, 45X, 47XXX, etc)
*“streak gonads” – fibrous tissue without germ cells

*Features: short stature (most common), bicuspid aortic valve ( most common cardiac defect)

*No estrogen, high FSH

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Turner syndrome

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Physical stigmata of Turner syndrome (diagram):

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turner

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Treatment for Turner syndrome:

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Growth hormone for short stature
Estrogen for pubertal induction