Male Gonadal Disorders Flashcards
1
Q
Describe the HPG axis in the adult male
A
Hypothalamus secretes GnRH –> anterior pituitary releases FSH and LH –> FSH stimulates Sertoli cells of the testes and LH stimulates Leydig cells of the testes
Occurs once puberty starts
GnRH is a pulsatile release every 2 hours
2
Q
What is the Leydig cells function? Sertoli?
A
Leydig- testosterone synthesis, assists FSH in spermatogenesis
Sertoli- spermatogenesis and inhibin B
Inhibin B and testosterone provide negative feedback
3
Q
How does LH attach to the Leydig cells?
A
via LH receptor to stimulate uptake of cholesterol by the cellular mitochondria and initiates steroidogenesis
4
Q
Testosterone can be converted into what in the peripheral tissues?
A
Dihydrotestosterone (if 5a-reductase) or estradiol (aromatase)
5
Q
What are the effects of estradiol in males?
A
Hypothalamic/pituitary feedback
Bone resorption
Epiphyseal closure
Gynecomastia
Some vascular and behavioral effects
6
Q
What is the function of DHT in males?
A
External genitalia
Prostate growth
Acne
Facial/body hair
Scalp hair loss
7
Q
What are the effects of Testosterone?
A
Wolffian duct
Bone formation
Muscle mass
Spermatogenesis
Sexual health: libido, development and maintenance of erection, strength of erection
Mood/behavior: increases aggression, decreases anxiety/depression, provides sense of mental well-being
Improved cognition/memory
8
Q
The majority of testosteronee is synthesized in the ___ after puberty
A
testicles
9
Q
How is testosterone transported?
A
Sex hormone-binding globulin (great bounding affinity)
albumin (38%) can easily dissociate
10
Q
How is testosterone metabolized and excreted?
A
Metabolized in liver and excreted in kidneys
11
Q
What happens during male puberty?
A
Zona reticularis produces greater amounts of androgens beginning 6-8 yo
HPG axis is activated to cause sex maturation around age 9
12
Q
What are characteristics of the tanner stage of development?
A
Growth of testes and sparse pubic/axillary hair
Phallic growth: thicker pubic hair and continued testicular growth
Deepened voice, facial hair growth, prostate growth, long bone growth with eventual epiphyseal closure
Look at slides for pictures of each stage
13
Q
Stages of puberty
A
14
Q
How is testicle size measured?
A
Prader orchidometer
1-3 is prepubertal, 4-12 is pubertal, 12-25 is adult
15
Q
How could you measure testicular size if you do not have orchidometer?
A
testicular size >2.5 cm longitudinally generally indicates that the child has entered puberty
16
Q
A 6 year old male presents with his mother who is concerned about the patient’s development. She reports he has started developing pubic hair
A
Precocious puberty
17
Q
Evidence of puberty in boys before age 9
A
Precocious male puberty
18
Q
How is precocious male puberty categorized?
A
Isosexual- premature development of phenotypically appropriate secondary sexual characteristics
Heterosexual- development of secondary sexual characteristics of the opposite sex
19
Q
what are the 2 categories of isosexual precocity?
A
Gonadotropin dependent and …..
20
Q
The majority of patients will be what type of isosexual precocious male puberty?
A
Gonadotropin-dependent (central)
Can be idiopathic, hypothalamic hamartoma or other lesions, CNS tumor or inflammatory state
21
Q
What are causes of gonadotropin independent precocious puberty?
A
CAH
hcg/androgen-secreting tumor
McCune-Albright syndrome
Familial male-limited precocious puberty
Exogenous androges
22
Q
Gonadotropin-dependent precocious puberty cuase
A
Premature activation of the GnRH pulse generatory
LH/FSH levels that are inappropriately elevated for age
23
Q
Etiology of Gonadotropin-dependent precocious puberty
A
24
Q
What are historical red flags for CNS lesions precocious male puberty
A
headaches, new onset seizures, N/V, memory or personality changes, loss of balance, visual changes
25
What are PE red flags for p
26
What is the cause of gonadotropin-independent precocious puberty?
hCG secreting tumor
androgen secreting tumor
CAH
27
How is HCG related to testosterone
Activates LH receptors on the leydig cells stimulating testosterone production
Tumor locations: gonads, brain, liver, retroperitoneum, anterior mediastinum
28
What occurs in McCune Albright?
Excessive stimulation of Gsa subunit activating adenylyl cyclase resulting in steroidogenesis stimulating testosterone production
29
What is the triad of McCune Albright syndrome?
Bone dysplasia, cafe-au-lait skin pigmentation, precocious puberty
30
What is the cause of familial male-limited precocious puberty?
Autosomal dominant disorder caused by activating mutations in the LH receptors, leading to testosterone synthesis
31
What should we ask about precocious male puberty?
Onset
Progression
Associated symptoms: assess for CNS disease--> HA, changes in behavior or vision, seizures, previous hx of CNS disease or trauma
Exposures to exogenous sex steroid exposure
Family history: timing of pubertal onset in parents and siblings, genetic disorders
32
What are components of physical exam for precocious puberty?
Height, weight, and height velocity over last 6-12 months (will grow faster than should with activation of Hbg axis)
Pubic hair disbursement
Testicular size
Testicular tumor
Neurologic exam- if suspicious of CPP on history
## Footnote
Palpate testicles for tumor and work up if present
Neurologic particularly if enlarged testicles, increases suspicion
33
When would you see an enlargement of testicles with precocious male puberty
CPP, hCG secreting tumor
34
What precocious puberty disorders would cause the testes to remain small?
Adrenal etiologies, familial male precocious puberty, and exogenous androgens
35
What imaging can be performed for precocious male puberty?
Imaging to assess bone age of left wrist and hand
Advanced bone age is expected with precocious puberty
## Footnote
Testosterone causes maturation of the bone
36
What would cause rapid growth/change in linear growth, skeletal maturation and secondary sexual characteristics over the past 6 months?
high concentrations of sex steroids due to CPP or peripheral precocity
37
If there is a slow change in growth with minimal or no change of breast, pubic hair, or genital development, what is more likely to be occuring?
Benign pubertal variant with low sex steroid concentrations
38
What is initial laboratory evaluation of precocious male puberty?
Serum testosterone: elevated in all cases
Serum LH and FSH levels: increased in CPP and low/normal in peripheral
39
in addition to initial testing If thinking hCG tumor, what would you order?
serum hCG
40
If thinking CAH/adrenal tumors, what lab testing will you order after initial testing?
DHEA, 17a-hydroxyprogesterone
41
When would you order GnRH-analogue stimulation test?
To differentiated CPP from peripheral etiologies
Rise in LH indicates CPP
Lack of rise in LH in peripheral etiologies
## Footnote
If you have a question whether HPA axis is elevated
42
How would you rule out LH/Gsa mutation?
Genetic testing
43
What imaging evaluation should be done if increase in LH/FSH to rule out tumor?
MRI brain to rule out CNS lesion with CPP or elevated hCG
CT chest/abdomen with contrast to rule out hCG tumor or mediastinum, liver, or peritoneum
US of testicles
44
How is a patient with CPP and known tumor managed?
Sent to neurosurgery
45
How is a patient managed with CPP and idiopathic CPP?
Given leuprolide for chronic stimulation of GnRH receptors to lead to desensitization of receptor and decreased release of LH/FSH after 2 weeks
## Footnote
Will have immature closure of growth plates
46
What are effects of long acting GnRH agonists?
halts early pubertal development, delays bone maturation to prevent early epiphyseal closure and increase final height
47
How is gonadotropin independent managed?
tumors-surgical removal
exogenous steroids-remove source
CAH- suppress androgen production with glucocorticoids
McCune-Albright- combination of androgen receptor antagonist (spironolactone) with aromatose inhibitors
Alternative: steroid synthesis inhibitor- ketoconazole but requires high dosing leading to a risk of hepatotoxicity
Goal of treatment: halt futher sexual development and prevent premature closure of epiphyseal plates
## Footnote
aromatase prevents conversion of testosterone to estradiol
48
Lack of testicular enlargement by age 14 or incomplete genital growth within 5 years of initial signs of puberty
delayed male puberty
49
What are categories of delayed puberty
primary hypogonadism
secondary hypogonadism
50
what is primary hypogonadism
hypergonadotropic hypogonadism secondary to primary gonadal failure
51
What is secondary hypogonadism?
constitutional delay of growth and puberty
functional hypogonadotropic hypogonadism cuased by systemic illness or malnutrition
hypogonadotropic hypogonadism caused by genetic or acquired defects in the hypothalamic pituitary region
52
what historical factors are important to delayed male puberty
Absent or slow progressing signs of puberty and linear growth
nutritional status: improper food intake, intense exercise
congenital abnormalities: altered sense of smell- associated with Kallmann syndrome, microphallus, cryptoorchidism, synkinesia (associated with Kallmann syndrome), renal agenesis
Neurologic symptoms: headache, visual disturbances, dyskinesia, seizures, and intellectual disability
family history of delyaed/absent puberty "late bloomer" indicated CDGP
## Footnote
Kallmann syndrome- causes delay of growth in puberty
synkinesia- inability to control involuntary movement
cryptorchidism- testicles do not descend by 12 months of age, problem because can cause testicular cancer
53
What phsycial exam factors should be included in assessment of delayed male puberty?
height/arm span: suggests delayed epiphyseal closure due to hypogonadism if arm span exceeds height by >5 cm
secondary sexual characteristics rated on tanner staging
testicle size measured with a prader orchidometer: prepubertal sizes are 1-3 mL, testicular size <2.5 cm longitudinally
54
What are initial assessments of delayed male puberty?
Xray: left hand and wrist, bone age delayed relative to chronological age and growth velocity is normal, CDGP is most likely etiology
serum testosterone: low for age
Gonadotropine: LH/FSH elevated; primary hypogonadism/gonadal failure
LH/FSH low for age;; secondary hypogonadism
55
what are additional considerations for delayed male puberty?
If + family history of delayed puberty with low LH/FSH likely CDGP
If - family history look for other etiologies
56
How is constitutional delay of growth and puberty managed?
reassure with f/u vs testosterone therapy considering testosterone if patients self-esteem regarding stature and/or prepubertal appearance is affected
57
If a patient has secondary hypogonadism/primary, how are you going to manage delayed male puberty?
interrupted therapy with testosterone replacement therapy after 6 months to determine whether endogenous LH and FSH has ensued
Primary hypogonadism- indefinite therapy
58
Failure of the testes to produce an adequate amount of testosterone
hypogonadism
59
What are the 3 classifications of hypogonadism?
hypergonadotropic, hypogonadotropic, both simulataneously
60
what is the cause of hypergonadotropic hypogonadism?
pathology in the testes themselves, low testosterone with high LH
61
what is the cause of hypogonadotropic hypogonadism?
insufficient hormone secretion from the pituitary/hypothalamus, low testosterone with normal/low LH
62
What is the clinical presentation of hypogonadism
severity depends on age of onset
onset beginning between 2nd-3rd month of fetal development results in ambiguous genitalia/male pseudohermaphroditism
onset of 3rd trimester leads to cryptorchidism/micropenis
63
what happens if onset after birth and before adulthood
symptoms of delayed puberty
64
what happens if onset after puberty
decreased energy, loss of libido, decreased morning erections within days-weeks of onset
loss of facial/axillary/pubic hair, decrease muscle mass, increased fat mass, and loss of bone mineral density occurs after several years of untreated disease
-decrease in frequency of shaving, hypogonadal facies- fine wrinkles with the sparse beard growth
infertility may also occur
65
What are the goals of clinical evaluation for hypogonadism?
determine onset before or after puberty
determine if normal genitalia
determine if primary or secondary
66
How is hypogonadism worked up
take fasting 8-10 am testosterone, if normal symptoms are due to something else
if low, repeat testosterone and draw LH, FSH, if LH and FSH normal secondary hypogonadism
If LH and FSH elevated, primary hypogonadism
67
how is hypogonadism treated?
manage underlying etiology
testosterone therapy if lack of puberty onset by age 14
primary testicular failure
severe hypogonadotropic hypogonadism of any etiology with serum testosterone levels less than 150 ng/mL
age related hyogonadism
68
decrease in testosterone production starting between the 4th-6th decades of life and progresses slowly with age with rate of devline greater in obese men and with chronic illness
andropause
69
What is the pathophysiology of andropause?
defects at all levels of the HPG axis leading to pulsatile GnRH secretion decrease, LH response to GnRH reduced, and testicular rresponse to LH impaired
70
How is testosterone therapy used in age related hypogonadism?
not recommended for all older men with low testosterone levels
recommended if at least 3 symptoms of androgen deficiency who have testosterone levels <200 ng/dL and benefits outweigh risk: S/s of erectile dysfunction, poor morning erection, low libido, ...
71
when is the highest and lowest LH?
8 AM-highest, 8 PM-lowest
72
When is a fasting specimen of total testosterone taken?
8-10 AM preferred
food and glucose suppresses serum testosterone concentration
repeat if first assessment is low
73
why is free testosterone assessed?
assesses amount of testosterone not bound to albumin or AHBG
inicated if abnormal total testosterone
74
What can cause abnormal sex hormone binding globulin?
Increased SHBG: age, liver disease, hyperthyroidism, anorexia, HIV and antiseizure drugs
decreased SHBG: obesity, hypothyroidism, insulin resistance, DM2, exogenous androgens/anabolic steroids, glucocorticoids, nephrotic syndrome
75
When would you take inhibin B levels?
Suspicion of damage to sertoli cells
if decreased there is damage to seminiferous tubules
76
If a patient comes in with infertility issues, what follow up study can you do?
semen analysis
must be done 3 times over a 2 to 3 month interval due to sperm maturation cycle of 3 months
77
What are factors that can lower semen counts?
fever, trauma, drug exposure, recent ejaculation
collection via masturbation after 2-7 days of sexual abstinence with examination occurring within 1 hour after collection
78
What is the average specimen in healthy gonadal male
SEMEN VOLUME appx 2.5 ml
sperm concentration >15 million/mL
>50% of sperm show progressive motility
>>30% with normal morphology
79
what is the indication for testicular biopsy
hypogonadal men with normal sized testes and azospermia to distinguish between spermatogenic failure and ductal obstruction
harvesting of sperm for ICSI
80
enlargement of male breast resulting from excess estrogen action and is usually the result of an increased estrogen/androgen ratio
gynecomastia
81
True gynecomastia is assoicated with ____
glandular breast tissue that is >4 cm in diameter and often tender
82
wht are differential diagnosis for gynecomastia?
pseudogynecomastia, breast cancer
83
what are normal times gynecomastia can occur
newborn: transplacental transfer of maternal and placental estrogens
during puberty, aging
84
What can cause pathologic gynecomastia?
increased aromatase activity
testicular or hCG tumors
adrenal tumors
chronic liver disease
malnutrition
...
85
20% of cases of pathologic gynecomastia are due to
drugs
86
What historical findings are important for gynecomastia?
onset, progression, pain/tenderness, location: pain/tenderness is often seen in adolescents and absent in adults
+ nipple sensitivity
+ careful drug history
+ PMH
87
what physical exam shoudl be performed on patient with suspected gynecomastia?
breast exam
....
testicular exam looking for tumor, size
secondary sexual characteristics
abdominal exam: adrenal mass, hCG secreting mass of the liver, retroperitoneum
88
What are red flags for breast malignancy?
non tender
fixed to tissue
new onset or rapid growth
89
How is gynecomastia managed?
Pubertal- reassurance, symptoms will resolve within 1-2 years
Drug induced- discontinue therapy and monitor for improvement in symptoms
androgen deficiency- testosterone therapy
hCG tumor- imaging and refer to general surgeon
90
IF gynecomastia with aromatization, what should you do?
assess for sertoli and adrenal tumors
look for other causes of gynecomastia and observe x 3 monhts for regression and treat with tamoxifen/aromatase inhibitor if no regression (must treat with medical therapy within 9-12 months)
surgical correction for persistent or severe symptoms >12 months
91
what are indications of testosterone?
low testosterone with features of androgen deficiency, benefits only proven in documented androgen deficiency as demonstrated by testosterone levels that are well below the lower limit of norma
does not restore fertility
92
What is the route of testosterone and dosing?
injectable
Within 24 hours after IM administration, testosterone levels rise and then gradually decline into hypogonadal range over the next 2 weeks
bimonthly regimen results in peaks and troughs that are accompainied by changes in mood, sexual desire, and energy level
93
how often is extra long acting testosterone dosed?
first dose is followed by 2nd dose at 4 weeks with subsequent dosease every 10 weeks
must be given in clinic
94
how is gel testosterone administered?
has to be applied daily in area not easily accessed by others
95
what are less commonly used routes of testosterone?
pellets inserted into skin, nasal gel, oral testosterone BID
96
What are goals of testosterone therapy?
restoration of testosterone into normal range
promote secondary sexual characteristics
...
97
How should testosterone therapy be monitored?
every 3-6 months monitor testosterone levels
injectable: test halfway through dosing
transdermal gels/sol: any time after patient has been on at least 1 week
gel: 1 month after initiation
bone mineral density after 1-2 years of testosterone therapy
PSA level before intiiating treatment and at 3-6 months
urologic consultation if there is an increase in serum PSA conc within 12 months of initiation of testosterone treatment or increase in PSA by >.4 ng/mL, or detection of prostatic abnormality on digital rectal exam
98
who can you not give testosterone therapy to?
hematocrit >54%
99
what are adverse effects of testosterone therapy?
injectable testosterone esters: fluctuations in mood or libido, and, rarely, cough after injections
testosterone gels: wash off every day, female partner can have increased testosterone if exposed
nasal gel: nasal irritation, epistaxis
100
what are absolute contraindications for testosterone therapy?
metastatic prostate cancer, breast cancer
prostate ndoule
PSA >.4
erythrocytosis
CHF uncontrolled
...
