Male Repro Tract Pathology

Question 1

GDPP

Answer 1

Gonadotropin-dependent premature puberty
Due to early maturation of the hypothalamic pituitary gonadal axis
More than 80% idiopathic
Almost all idiopathic cases are in girls

Question 2

Causes of GDPP

Answer 2

Idiopathic
CNS lesions – hamartomas
Other CNS tumors – astrocytoma, ependymoma, pinealoma, optic and hypothalamic glioma
CNS irradiation, hydrocephalus, cysts, trauma, inflammatory disease, congenital midline defects
Previous excess steroid exposure
Primary hypothyroidism – regresses with thyroxine therapy

Question 3

What is a genetic cause of GDPP premature male puberty?

Answer 3

Gain of function mutations in Kisspeptin 1 gene and KISS-1R

Loss of function mutations in MKRN3

Question 4

GIPP

Answer 4

Gonadotropin-independent premature puberty
Due to excess secretion of sex hormones derived from gonads or adrenal glands, exogenous sources of steroids, or ectopic production of gonadotropin from a germ cell tumor
May be genre appropriate or inappropriate

Question 5

Isosexual GIPP

Answer 5

Leydig cell tumors
Human chorionic gonadotropin (hCG) secreting germ cell tumors
Dysgerminomas to embryonal cell carcinoma and choriocarcinoma

Question 6

What can cause familial male limited premature puberty?

Answer 6

Activating mutation in LH receptor gene

Rare

Question 7

What are some adrenal pathologies that may lead to premature puberty?

Answer 7

Androgen secreting tumors
Enzymatic defects and adrenal steroid biosynthesis – 11 beta hydroxylase deficiency, 3B-HSD deficiency, hexose 6 phosphate DH deficiency, PAPSS2 deficiency
Estrogen secreting tumors
Androgen and estrogen secreting tumors

Question 8

What are some other causes of premature male puberty?

Answer 8

Exogenous estrogen
Pituitary gonadotropin secreting tumors
McCune Albright syndrome - rare, triad of peripheral premature puberty, cafe au lait skin pigmentation and fibrous dysplasia of bone

Question 9

What causes incomplete premature puberty?

Answer 9

Due to increased adrenal androgen production

Isolated male hormone mediated sexual characteristics (pubic/axillary hair, acne, and apocrine odor)

Question 10

What labs should you do to evaluate premature male puberty?

Answer 10

Basal LH levels, if elevated –> GDPP

If not elevated stimulated with GnRH agonist –> elevated LH and FSH means GDPP, lack of significant increase means GIPP

Question 11

What should you do if you have determined GDPP with initial labs?

Answer 11

Get a pituitary MRI
Measure estradiol, testosterone, TSH, free T4
GH if prior cranial irradiation

Question 12

What should you do if you have determined GIPP with initial labs?

Answer 12

Get testosterone, estradiol, LH, FSH, cortisol and DHEA, DHEAS, 17-hydroxyprogesterone, hCG
If hCG elevated and tumor in mediastinum a karyotype for Klinefelter syndrome recommended for mediastinal germanium
Testicular ultrasound

Question 13

Treatment for GDPP

Answer 13

Direct therapy toward underlying pathology for identifiable CNS lesions
Exception – benign hypothalamic hamartoma
Majority require treatment with GnRH agonist – Leuprolide

*Primary goal is to achieve normal adult height –> DO NOT treat to address perceived psychosocial consequences

Question 14

How should GDPP be followed?

Answer 14

Measure LH and sex steroid levels prior to 2nd or 3rd monthly doses or after change in dose
Measure bone age every 6-12 months
Success can be measured by performing a diagnostic GnRH agonist stimulation test
Continue treatment until 12 years of age or however long desired
Normal puberty returns on average 17 months after stopping therapy

Question 15

Treatment fro GIPP

Answer 15

Requires addressing the underlying cause
Tumors require surgery
Radiation and chemo may be necessary depending on the site and histological type
Identify and remove exogenous steroid sources
Glucocorticoids for congenital adrenal hyperplasia
Anti-androgens with aromatase inhibitor if needed for McCune Albright syndrome
Familial male limited premature puberty treated with spironolactone (anti-androgen) and testolactone (aromatase inhibitor)
Ketoconazole - androgen inhibitor

Question 16

Delayed male puberty

Answer 16

Usually the result of inadequate gonadal secretion, most often caused by defective gonadotropin secretion (LH and FSH) from anterior pituitary d/t defective GnRH from hypothalamus

Question 17

Klinefelter syndrome

Answer 17

XXY [male]
Testicular atrophy, eunuchoid body shape, tall, long extremities, gynecomastia, female hair distribution
May present with developmental delay
Presence of inactivated X chromosome (Barr body)

Question 18

Primary hypogonadism

Answer 18

Low testosterone and/or sperm with high LH and FSH, consider karyotype for Klinefelter’s

Question 19

Secondary hypogonadism

Answer 19

Low testosterone and/or sperm with low or inappropriately normal LH and FSH
Needs pituitary work up, prolactin, iron, other pituitary hormones, MRI if indicated