Pathophysiology of Male Hypogonadism

Question 1

What is the primary androgen and what are its functions?

Answer 1

Testosterone

1. Differentiation of Wolffian (mesonephric) duct -> INTERNAL genitalia minus prostate
2. Growth spurt -> brain, muscle, RBCs, late growth of penis
3. Libido
4. Spermatogenesis
5. Deepening of voice

Question 2

What is dihydrotestosterone formed by and what blocks it? What actions are does it have in making the male phenotypes?

Answer 2

DHT made from 5-alpha reductase conversion of testosterone, which is blocked by finasteride.

Male phenotype:
EXTERNAL genitalia -> required for differentiation of penis, scrotum, and prostate

Male pattern body hair

Question 3

What androgens are produced in the adrenal glands and what is their relative potency?

Answer 3

DHEA - dihydroepiandosterone

Androstenedione

These are relatively weaker androgens than DHT > testosterone.

Question 4

What role does testosterone have in epiphyseal closure?

Answer 4

It leads to the closure of epiphyseal plates in puberty because estrogen is made from testosterone (requires aromatase).

Formation of estrogen closes epiphyseal plates. The estrogen is also what accounts for the bone-forming / massforming effect of testosterone.

Question 5

What hormone is primarily responsible for the volume of the testes and how?

Answer 5

Primary FSH, since the production of seminiferous tubules and their filling via Sertoli cells accounts for 85% of the volume of the testes.

However, a small amount of local testosterone from Leydig cells is also required for spermatogenesis.

Question 6

What is the pattern of secretion of GnRH and why? What drug mechanism does this explain?

Answer 6

Release of GnRH is pulsatile to stimulate secretion of FSH and LH. If GnRH secretion is continuous, the GnRH receptor rapidly downregulates and inhibits FSH and LH release.

This mechanism explains the antagonist effect of Leuprolide (GnRH agonist) when given continuously.

Question 7

How is testosterone made and what secretes it? Where is DHT made?

Answer 7

Made via the conversion of androstenedione via 17 beta hydroxysteroid dehydrogenase to testosterone.

Can be made in small part in the adrenals, but 95% of this occurs in the leydig cells which secrete testosterone.

Final conversion to DHT occurs 80% peripherally.

Question 8

How is testosterone transported and what form is readily bioavailable? How does this differ from males and females?

Answer 8

98% is transported via sex hormone binding globulin (SHBG) and albumin in both males and females

Only free and albumin-bound testosterone are bioavailable. Males have less SHBG binding and more albumin-binding relative to females -> higher circulating levels of bioavailable testosterone.

(Note: estrogen stimulates synthesis of SHBG to make this happen)

Question 9

What is the definition of male hypogonadism?

Answer 9

Inadequate gonadal function manifested by:
1. Deficiency in testosterone (i.e. decreased production or resistance to action)
or
2. Deficiency in spermatogenesis

Question 10

What are some major causes of congenital primary hypogonadism?

Answer 10

1. Klinefelter syndrome
2. Disorders of testosterone biosynthesis
3. Gonadal dysgenesis
4. Cryptorchidism

Question 11

What are some acquired causes of primary hypogonadism?

Answer 11

1. Mump orchitis in adulthood
2. Radiation / chemotherapy - germ cells are very sensitive
3. Ketoconazole
4. Testicular torsion
5. Hemochromatosis - (secondary)
6. Autoimmune damage
7. Chronic systemic diseases i.e. cirrhosis, renal failure, aids
8. Aging - decline in Leydig cell number / volume, blood supply, decreased testosterone and number of Sertoli cells

Question 12

What are the physical features of Klinefelter syndrome and what is it?

Answer 12

Syndrome of extra X chromosome

Testicular atrophy / fibrosis -> small testes (pre-pubertal size) with seminiferous tubular sclerosis and rare Sertoli cell / sperm. -> infertility

Eunuchoid body shape + gynectomastia -> feminization of features (increased estrogen to testosterone ratio, leads to decreased testosterone availability)

Disproportionately long arms / legs.

Question 13

What are the psychological features of Klinefelter? What will the FSH / LH / testosterone lab values be?

Answer 13

Developmental delay. Patients often have behavioral abnormalities leading to criminality.

FSH will be elevated -> lack of inhibin B feedback from dysgenesis of seminiferous tubules

LH will be elevated -> lack of testosterone from abnormal Leydig cells

Testosterone levels decreased

These are all common signs of primary gonadal failure.

Question 14

What is male gonadal dysgenesis and what causes it? What is the associated risk increase?

Answer 14

Mutation in SRY

Patient will have streak gonads and female type external genitalia, with Mullerian duct development

-> associated with high risk of malignant transformation of the gonads

Question 15

What is cryptorchidism and is it common? When should you act?

Answer 15

Undescended testes (unilateral or bilateral) - most common congenital male reproductive defect

-> should act if not descended by 1 year of age because it is unlikely to descend

Question 16

Other than Kallman syndrome, what other congenital conditions are associated with lack of GnRH?

Answer 16

Prader-Willi
-> both are more associated with obesity

Laurence-Moon-Biedl
-> associated with retinitis pigmentosa and polydactyly as well

Question 17

What are other common hypothalamic defects which are acquired and may cause decreased GnRH secretion?

Answer 17

Severe illness, tumors i.e. craniopharyngioma, trauma, inflammation, cranial irradiation

Most importantly: HIGH PROLACTIN LEVELS

Question 18

What other defects is Kallmann syndrome associated with?

Answer 18

Red-green color blindness, midline facial abnormalities, and sensorineural hearing loss

Also, think of the elongated body “Tall man syndrome”

Question 19

How will testosterone and LH be affected in androgen insensitivity syndrome and what are the clinical effects?

Answer 19

Testosterone increased, LH also increased

• > defective androgen receptor makes tissues less responsive to androgens.
• > Highly variable phenotype, ranging from entirely female body habitus to male with minimal virilization

Question 20

How does 5alpha reductase deficiency present? Will internal genitalia be normal?

Answer 20

Presents with ambiguous genitalia at birth. At puberty, rising testosterone levels will cause masculinization of the genitalia.

Internal genitalia will be normal (development under control of testosterone)

Question 21

What will the lab values be for 5alpha reductase deficiency?

Answer 21

Normal estrogen/testosterone levels, LH may be normal or elevated.

Main thing: Increased testosterone to DHT ratio. Testosterone levels are not high enough until puberty to stimulate the development of external genitalia (DHT has much higher affinity than T for same receptor which allows it to do dis early on)

Question 22

How does androgen abuse / exogenous androgen affect testicular function?

Answer 22

Suppression of FSH / LH by exogenous androgens leads to decreased sperm production, which can return to normal after discontinuation

Question 23

What are the differential effects of primary vs secondary hypogonadism in the first trimester?

Answer 23

Primary - can lead to a spectrum of pathology, from development of female external genital to partial virilization with hypospadias (depend on degree of T deficiency)

Secondary (problem not at the level of the testes) - Differentiation of external genitalia will be completely normal because testosterone production is driven by placental HCG in the first trimester (HCG is homologous to LH)

Question 24

What happens if androgen deficiency occurs in the third trimester in utero?

Answer 24

Male external genitalia are fully developed, but will not grow fully -> diminished penile growth (micropenis)

Question 25

What happens if androgen deficiency onsets prior to puberty?

Answer 25

Lack of virilization and Tanner development (lack of puberty), as well as development of Eunuchoid habitus (long arms / legs), poor muscle mass development / reduced peak bone mass

Question 26

What will happen if androgens are lost following puberty?

Answer 26

Secondary sex characteristics will be intact.
1. Physical - decreased bone mineral density (loss of estrogen), decreased hair, anemia (testosterone stimulates RBCs), decreased muscle and strength

2. Psychological and sexual - decreased energy, mood, libido, and fertility

Question 27

How can you tell if small testes are pre- or post-pubertal changed?

Answer 27

Pre - testes will be firm in consistency, indicates fibrosis (i.e. Klinefelter)

Post - testes will be soft in consistency, indicates new seminiferous tube loss

Question 28

What is diagnostic of a normal sample on semen analysis and what is needed to call it abnormal?

Answer 28

Normal: >20 million sperm per cc with >50% motile

Abnormal: 3 abnormal samples during a 3 month period

Question 29

What are the side effects of using testosterone to treat hypogonadism? What is the contraindication?

Answer 29

1. Acne
2. Gynecomastia (increased estrogens)
3. Testicular atrophy (from suppression of FSH/LH)
4. Polycythemia / hyperviscosity syndrome -> testosterone increased RBC mass

Contraindicated in men with KNOWN prostate cancer

Question 30

Will testosterone restore fertility?

Answer 30

NO! Need to give pulsatile GnRH to do that, since FSH is also needed to stimulate spermatogenesis.

Testosterone will just increase your libido and sexual performance, as well as bone mineral density + lean body mass