Lecture 21: Male Gonadal Disorders Flashcards
1
Q
Describe the Hypothalamus-Pituitary-Gonadal Axis in males. (HPG)
A
- Hypothalamus secretes GnRH to stimulate anterior pituitary every 2 hours (pulsatile)
- Anterior pituitary releases FSH and LH
- FSH stimulates Sertoli cells in testes to regulate spermatogenesis and produce inhibin B
- Inhibin B provides negative feedback to stop FSH.
- LH stimulates Leydig cells to produce testosterone.
- Testosterone provides negative feedback to stop LH, but assists FSH in spermatogenesis.
FSH = for sperm hormone
2
Q
What does LH allow the uptake of in Leydig cells?
A
Cholesterol, which is converted to testosterone.
3
Q
What is testosterone converted to? Where?
A
It is converted to either DHT or estradiol.
Majority of the conversion occurs in the peripheral tissues.
4
Q
What are the additional functions of testosterone?
A
- Sexual health
- Mood (increased aggression, decreased depression)
- Improve cognition/memory
5
Q
Where is the majority of testosterone produced?
A
Testicles.
5% in adrenal glands.
6
Q
What is 98% of testosterone bound to?
A
60%: Sex hormone-binding globulin (SHBG)
38%: Albumin
SHBG has a higher binding affinity.
7
Q
What is the remaining 2% of unbound testosterone for?
A
Physiologically active.
8
Q
What is unique about albumin-bound testosterone?
A
It can dissociate readily in capillaries.
9
Q
Where is testosterone metabolized/excreted?
A
Metabolized in the liver.
Excreted via the kidneys.
10
Q
What two processes begin to ramp up to initiate puberty?
A
- Adrenarche in the zona reticularis to produce androgens (6-8y)
- Gonadarche (Activation of HPG axis, around 9y)
11
Q
How do we stage male puberty development?
A
Tanner stages, beginning at 1 and ending at 5.
12
Q
What are the first signs of male puberty?
A
- Growth of testes
- Pubic/axillary hair growth
13
Q
How do we measure testicle size clinically? What qualifies as adult size?
A
Prader orchidometer, with 12-25 mL being adult size.
14
Q
If we do not have a prader orchidometer at hand, what else can suggest that a male has entered puberty?
A
Testicular size > 2.5cm longitudinally.
15
Q
What qualifies as precocious puberty?
A
Evidence of puberty in boys prior to the age of 9.
16
Q
What are the two types of precocious puberty?
A
- Isosexual: premature development of phenotypically appropriate secondary sexual characteristics.
- Heterosexual: Development of secondary sexual characteristics of the opposite sex.
17
Q
What are the two subtypes of isosexual precocity?
A
- Gonadotropin-dependent (Central precocious puberty)
- Gonadotropin-independent (Peripheral precocious puberty)
18
Q
What is the pathophysiology behind central precocious puberty? (CPP)
A
CPP is caused by a PREmature activation fo the GnRH pulse generator, causing inappropriately elevated GnRH levels.
19
Q
What is the pathophysiology behind peripheral precocious puberty?
A
Androgens from the testes or adrenal glands are increased, but gonadotropin levels are low.
20
Q
What is the MC of CPP?
A
Idiopathic
21
Q
What is the MC of peripheral precocious puberty?
A
CAH
22
Q
What is the 2nd likely etiology for CPP and what might suggest it?
A
CNS lesions.
- History red flags: HA, seizures, N/V, memory/vision changes, loss of balance, etc.
- PE red flag: abnormal neuro exam
- Imaging: Abnormal MRI brain w/ contrast
23
Q
What two tumors can cause peripheral precocious puberty?
A
- hCG tumor
- Androgen secreting tumor in the zona reticularis
24
Q
What two enzyme deficiencies in CAH typically lead to precocious puberty?
A
- 21-hydroxylase
- 11-hydroxylase
25
What syndrome more common in females can lead to peripheral precocious puberty in males? How?
McCune-Albright syndrome (MAS)
A mutation in the activation of adenylyl cyclase results in testosterone production.
26
What triad of findings suggests McCune Albright?
1. Bone dysplasia
2. Cafe-au-lait skin pigmentation
3. Precocious puberty
27
What autosomal dominant disorder can lead to peripheral precocious puberty?
Familial male-limited precocious puberty, which results in LH activation errors, causing testosterone synthesis.
28
What simple and exogenous way can males enter precocious puberty?
Exogenous androgen exposure like testosterone cream.
29
What historical findings are important to know for suspected puberty issues?
* Onset
* Progression
* Assess CNS disease
* Exposures
* Family history of puberty onsets/conditions
30
If a patient presents with enlarged testes, what are the more likely etiologies?
* CPP
* hCG tumor (mild)
31
If a patient presents with small testes but precocious puberty, what are the more likely etiologies?
* Adrenal etiologies
* Familial male precocious puberty
* Exogenous androgens
32
What finding could suggest testicular tumor?
Asymmetry or unilateral testicular enlargement
33
What imaging should be ordered for suspected precocious puberty?
Left wrist and hand XRAY to assess bone age.
34
What is being assessed in an XRAY of the left hand and wrist?
* Linear growth
* Skeletal maturation/bone age
35
What are the two lab tests we should order for initial evaluation of suspected precocious puberty? Expected results?
* Serum testosterone: elevated in all types.
* Serum LH/FSH: only elevated in CPP.
36
What secondary lab tests would be elevated in precocious puberty? What etiologies are they linked to?
* Serum hCG elevated in hCG tumor
* DHEA elevated in CAH or adrenal tumor
* 17a-hydroxyprogesterone elevated in CAH
37
What test can we run to differentiate CPP from peripheral? What result indicates CPP?
GnRH analogue (Leuprolide) stimulation test.
Rise in LH when administered indicates CPP.
38
What genetic testing would we run for precocious puberty?
LH/GS-alpha subunit mutation test if we suspect McCune Albright.
39
After we get our XRAY, what other imaging modalities might we use for evaluating precocious puberty? What do they rule out?
* MRI brain: r/o CNS lesion with CPP or if theres elevated hCG.
* CT Chest/Abd: r/o hCG tumor or adrenal tumors.
* Testicular US: r/o Leydig-cell tumors
40
How do we treat CPP?
* Treat underlying cause (if tumor)
* Idiopathic requires long-acting GnRH agonists.
41
Describe the MOA of a long-acting GnRH agonist.
Initially, LH/FSH secretion will increase.
However, long-term use will result in densensitization of the receptors, reducing them to prepubertal levels. (Takes about 2 weeks to do so)
42
What are the effects of long-acting GnRH agonists?
* Halts early pubertal development
* Delay bone maturation
* Prevent early epiphyseal closure, increasing final height.
43
How is leuprolide administered?
Depot injections every 1, 3, or 6 months
44
What is the alternative to leuprolide?
Histrelin SQ implant annually.
45
How do we treat peripheral precocious puberty?
* Tumor excision
* Removal of exogenous steroids
* Glucocorticoids to suppress CAH
46
How do we treat McCune Albright syndrome and Familial male-limited precocious puberty?
Combination of androgen receptor antagonists (spironolactone) with aromatase inhibitors (anastrozole) to prevent the conversion of testosterone to estradiol.
Alternative: steroid synthesis inhibitor (ketoconazole)
47
What is the risk with using ketoconazole to treat something like MAS?
You may require high dosages, which can induce hepatoxicity.
48
What qualifies as delayed male puberty?
Lack of testicular enlargement by age 14 OR incomplete genital growth within 5 years of puberty onset.
49
What are the two categories of delayed male puberty?
* Primary hypogonadism
* Secondary hypogonadism
50
What is the primary cause of delayed puberty?
Secondary hypogonadism secondary to constitutional delay of growth and puberty (CDGP)
51
What are the 6 MCC of delayed puberty?
1. CDGP
2. Systemic disorders
3. CNS tumors and treatment
4. Hypothalamic-pituitary causes (Low gonadotropins)
5. Gonadal causes (High gonadotropins)
6. Androgen insensitivity
52
What congenital abnormalities suggest Kallman syndrome?
* Altered sense of smell
* Synkinesia
53
What does a family history of delayed/absent puberty suggest?
CDGP
54
What are the congenital abnormalities that may suggest delayed puberty?
* Altered sense of smell
* Microphallus
* Cryptorchidism (increased risk of testicular cancer)
* Synkinesia
* Renal agenesis
55
What wingspan difference suggests a delayed epiphyseal closure secondary to hypogonadism?
Wingspan exceeding height by 5 cm
56
What testicle size might suggest delayed puberty?
* 1-3 mL using a prader orchidometer.
* < 2.5cm longitudinally
57
What would our initial assessment for delayed puberty involve?
* XRAY L hand/wrist
* Serum testosterone (low)
* Gonadotropin levels
58
What XRAY findings suggest CDGP?
* Bone age delayed relative to actual age.
* Normal growth velocity.
59
If a patient presents with delayed puberty and has an elevated FSH/LH, what etiology does that suggest? Decreased?
* Elevated: Primary hypogonadism or gonadal failure.
* Decreased: Secondary hypogonadism.
60
If a patient has suspected CDGP, what is the treatment?
* Reassurance with f/u
* Testosterone therapy (if patient's self-esteem is affected)
61
How do I treat primary and secondary hypogonadism?
* Primary: Indefinite testosterone replacement.
* Secondary: Testosterone replacement for 6mo, then interrupt to check endogenous secretion of FSH/LH.
62
Adding what medication can help increase adult height for those with delayed puberty?
Aromatase inhibitor like anastrozole.
63
What is hypogonadism?
Failure of the testes to produce adequate testosterone
64
What are the 3 classifications of hypogonadism?
* Hypergonadotrophic: pathology of the testes resulting in low testosterone but high LH.
* Hypogonadotrophic: insufficient secretion from hypothalamus/pituitary, resulting in low testosterone and low LH.
* Both
65
If hypogonadism presents early on in the fetus, such as by the 2nd month, what might occur to the fetus' gonads?
* Ambiguous genitalia
* Male pseudohermaphroditism
66
If hypogonadism occurs in a fetus late in gestation, such as the 3rd trimester, what might it affect?
* Cryptorchidism
* Micropenis
67
How does an adult that went through delayed puberty untreated often present?
* Decreased energy/libido
* Decreased morning wood
* Loss of pubic/axillary
* Decreased muscle mass
* Increased fat mass with bone mineral density decreases
* Possible infertility
68
What are the 3 goals of a clinical evaluation for hypogonadism?
1. Determine if S/S occurred prior to or post puberty.
2. Determine if patient has normal genitalia.
3. Determine if hypogonadism is primary or secondary.
69
What is the first step in evaluating hypogonadism?
Morning total testosterone
70
If a patient presents with low morning testosterone levels, what is the next step?
* Draw it 2x more.
* Draw LH and FSH levels.
71
If a patient presents with low total testosterone and normal/low LH/FSH, what is the suspected etiology?
Secondary hypogonadism
72
If a patient presents with low total testosterone but elevated FSH/LH, what is the suspected etiology?
Primary hypogonadism
73
What are the indications for testosterone replacement therapy?
* Lack of puberty by age 14 (delayed puberty)
* Primary testicular failure/hypergonadotrophic hypogonadism
* Severe hypogonadotrophic hypogonadism (Secondary) with total testerone < 150 ng/mL
* Age-related hypogonadism
74
What is andropause?
Decrease in testosterone production usually between 40-60, greatest in obese and chronically ill men.
Everything in the HPG axis becomes slowly impaired.
75
When should you test for low testosterone levels?
Only when symptoms are present
76
For age-related hypogonadism, when is testosterone replacement therapy indicated?
* 3+ androgen deficiency symptoms
* Testosterone < 200 ng/dL
* Benefits outweigh risk
77
What are the androgen deficiency symptoms?
* ED
* Poor Morning wood
* Low libido
* Depression
* Fatigue
* Inability to perform vigorous activity
78
When is testosterone generally the highest?
8-10AM
79
If a fasting morning testosterone is low, what should we do?
Repeat it
80
If we have a persistently low morning testosterone, what test can we order to further evaluate it?
Free testosterone
| Should be linear. If not, possible abnormal function or abnormal SHBG.
81
What hormones does SHBG bind to?
* Testosterone
* DHT
* Estradiol
82
When do we order a SHBG test?
* Suspected abnormality in testosterone binding to SHBG coexists with hypogonadism.
* No free testosterone assay available.
83
What is the primary cause of elevated SHBG?
Age
84
What is the primary cause of decreased SHBG?
Obesity
85
What does high LH suggest? High FSH?
* Elevated LH: Primary hypogonadism
* Elevated FSH: Damage to seminiferous tubules
| Normal/low of both with low T indicates secondary hypogonadism
86
When is an Inhibin B test ordered? What interpretation are we looking for?
Suspicion of damage to Sertoli cells.
Decreased would mean damage to the seminiferous tubules.
87
When is a semen analysis indicated?
Infertility
88
What does a normal semen analysis often exclude at the same time?
Gonadal dysfunction.
89
What is the criteria for an abnormal semen analysis?
At least 3 semen samples studied for 2-3 months since sperm takes 3 months to mature.
90
How quickly must semen analysis be performed?
Within 1 hour of collection.
91
What are the two indications for a testicular biopsy?
1. Hypogonadal men with normal-sized testes and azoospermia to distinguish between spermatogenic failure vs ductal obstruction.
2. Harvesting of sperm for ICSI.
92
What is gynecomastia?
Enlargement fo the male breast dt excess estrogen.
Glandular breast tissue > 4cm in diameter and is tender upon palpation.
93
What is the cause of pathologic gynecomastia?
Increased aromatase activity.
94
For gynecomastia, when is pain/tenderness of the breast MC age-wise?
Usually only painful/tender in adolescents.
95
Describe breast tissue that is normal vs malignant.
Normal: subareolar, symmetrical, bilateral, tender (early on)
Malignant: Unilateral, non-tender, offset from areola.
96
What are the 3 red flags on a clinical breast exam that warrant further investigation?
* New onset or rapid unilateral growth.
* Non-tender mass
* Fixed mass lateral to areola.
97
What are the 4 primary causes of gynecomastia? Treatment?
Pubertal: reassurance, self-resolving in 1-2yrs.
Drug-induced: stop taking drug and monitor.
Androgen deficiency: Testosterone replacement
hCG tumor: MRI/CT and refer to surgery
98
If high levels of estradiol are present with normal testosterone, what is the suspect etiology and treatment?
Assess for Sertoli and adrenal tumors.
Refer to surgery once MRI/CT obtained.
99
If a patient with gynecomastia shows no improvement after 9-12 months, what is the treatment? What if its been 12+ months?
* Selective estrogen receptor modulator (tamoxifen)
* Aromatase inhibitor (anastrozole)
12+ months = surgery
100
What drug schedule is testosterone replacement?
Schedule III
101
What can testosterone not restore?
Fertility.
102
What are the 2 week versions of testosterone injections called?
* Testosterone enanthate
* Testosterone cypionate
103
What is the long-acting testosterone injection called? What counseling/precautions are required?
Testosterone undecanoate.
* 1 dose and then 2nd dose in 4 weeks.
* 10 weeks per dose afterwards.
* All doses must be given IN OFFICE with provider monitoring for 30 mins and completing REMS.
104
What other routes can testosterone be administered?
* Gel
* Solution
* Pellets (into your butt, lower abd wall, or thighs)
* Nasal gel
* Oral (decanoate)
105
What are the goals of testosterone replacement therapy?
* Restore levels to normalish
* Promote development and maintenance of secondary sexual characteristics and normal sexual function.
* Build/sustain normal bone/muscle mass
* Psychosocial adjustment for teens
106
How often do we measure people being given testosterone injections?
Midway between injections.
107
How often do we measure patients being given testosterone gel/solution?
Anytime after 1 week of therapy.
108
How often do we measure patients being given nasal gel testosterone?
After 1 month of therapy.
109
What CBC measurement would indicate us to stop testosterone therapy?
Hematocrit > 54%
Evaluate for hypoxia and sleep apnea.
110
After 1 year of testosterone therapy in hypogonadal males, what bones do we measure and why?
Bone mineral density in lumbar and femur.
Osteoporosis
111
If a patient is over 40 and has an elevated PSA, what do we need to check and when?
* DRE and PSA check prior to starting testosterone.
* 3-6 months 2nd check.
112
What 3 findings would indicate a need for urologic consultation for a patient on testosterone therapy?
1. Increase in serum PSA > 1.4 within a 12 month period.
2. PSA velocity > 0.4 annually after at least 6 months of testosterone therapy.
3. Prostatic abnormality on DRE.
113
What formulation specific adverse effects should we ask patients on testosterone therapy EVERY VISIT?
* Injection: Mood fluctuations or cough post injection.
* Gels: Wash site after application to make sure it doesn't get onto others.
* Nasal gel: nasal irritation or epistaxis.
114
What two conditions are associated with extremely high risk of adverse effects if given testosterone?
* Metastatic prostate cancer
* Breast cancer
115
What are the 4 guidelines by the endocrine society regarding testosterone replacement therapy?
1. Avoid in patients with mild vague symptoms or only a one-time low reading.
2. Avoid trial therapy.
3. Therapy suppresses pituitary-testicular axis.
4. Therapy suppresses spermatogenesis and decreases testicular size.
