10/12- Disease of Male Reproduction Flashcards
1
Q
What is seen here?
- Red arrow
- Yellow arrow
- Blue arrow
- Green arrow
A
- Red arrow: Leydig cells
- Yellow arrow: Basement membrane
- Blue arrow: Sertoli cells
- Green arrow: Germ cells
From outside to insider, germ cells:
- Spermatogonia
- Spermatocytes
- Spermatids
- Spermatozoa
2
Q
What are Sertoli cells?
- Function
- Hormones produced
A
Function:
- Provide structural support
- Produce important hormones:
- Anti-Mullerian hormone (AMH)
- Inhibin and Activin: secreted after puberty; work together to regulate FSH secretion
- Estradiol: aromatase from SCs converts testosterone to estradiol to direct spermatogenesis
3
Q
How do levels of plasma testosterone change over life?
A
- Starts ~ 8 wks of gestation
- During fetal life, levels increase to near adult male levels (directing male sexual organ development)
- Drop at birth
- Rise throughout puberty
- Peaks in early adulthood
4
Q
T/F: Aging is associated with decreased T in healthy males
A
False
5
Q
Describe steroidogenesis?
A
- Cholesterol = initial substrate
- Binds LDL cholesterol receptor or produced endogenously
- StAR
- Pregnenolone
Done in the fetal Leydig cell
6
Q
What are typical testicular steroid secretion rates?
A
- Testosterone: 7 mg/day
- DHT: 560 ug/d (+ some peripheral conversion)
- E2: 21 ug/d (+30 ug/d from peripheral conversion of testosterone)
7
Q
Describe the different types/forms of testosterone in regards to total levels?
Which form(s) is/are bioavailable?
A
- SHBG bound (54%)
- Albumin bound (44%)
- Free (2%)
Bioavailable:
- Free
- Albumin bound
These 2 forms bind the AR receptor in the target tissue
8
Q
What are effects of T/DHT-AR on the human body?
A
- Stimulation of erythropoiesis
- Enlargement of larynx, thickening of vocal cords
- Bone: BMD, peak bone mass, long bone growth
- Body composition, strength, muscle mass
- Hair growth and devo of mail hair distribution
- Genital appearance and spermatogenesis
- Cognitive function, mood, sexual function
9
Q
What are some Androgen Insensitivity Syndromes?
Symptoms
A
Complete androgen insensitivity
- Female external phenotype
- Lack axillary and pubic hair (androgen receptor dependent)
- Retained testes
- Blind ending vagina
- No uterus
Incomplete androgen insensitivity
- Phenotype varies from infertility to gynecomastia and various degrees of hypospadias
Minimal androgen insensitivity
10
Q
_____ is essential for the development of the male sexual phenotype during embryologic development
A
AR (androgen receptor) signaling is essential for the development of the male sexual phenotype during embryologic development
11
Q
What is seen in SRD5-2 deficiency?
A
At birth:
- Lack of phallus
- Bifid scrotum
- External female genitalia
At puberty:
- Develop phallus
- Phenotype becomes male in adulthood
12
Q
Why do SRD5-2 deficient people have female phenotype at birth?
How do they undergo near normal puberty?
A
- DHT is essential for virilization of external genitalia (and the prostate)
- Pubescent changes depend on testosterone, not DHT
13
Q
What are abnormalities of the adult phenotype in SRD5-2 deficient individuals?
A
- Lack of male pattern baldness
- Lack of body hair (facial and pubic hair present
- Small prostate
14
Q
What happens when there is a lack of testosterone production during the 2nd half of fetal devo and 1st year of life?
A
Testosterone at this stage is responsible for growth of penis and descent of testicles
- Micropenis/cryptorchidism
15
Q
What is the phenotype of estrogen insenstivity and aromatase deficiency syndromes?
A
Female hormones do play role in male sexual development
- If no aromatase, no production of estradiol
Results in:
- Tall stature; vertical growth continues into 30s, unfused epiphyses
- Genu valgum (knock-kneed)
- Osteoporosis
- Eunuchoid proportions of the skeleton
- Increased adiposity
- Acanthosis nigricans, insulin resistance
- NASH
Sometimes:
- Oligozoospermia
- Cryptorchidism
- Increased volume of testes
- Changes in sexual behavior
16
Q
Epidemiology of Hypogonadism
- Prevalence
A
- 39% of population > 45 yo have lower testosterone than normal
- Diagnosis is made based on low T and symptoms (sexual, decreased strength, psychological) it was much lower in 40-70 yo pop
- Only a minority of men with hypogonadism are treated (5-10%)
17
Q
What are signs and symptoms of androgen deficient states?
A
Development before birth first trimester
- Genital Ambiguity
Development before birth third trimester/after birth minipuberty
- Micropenis
Development before puberty
- Delayed puberty
- Lack of adult male hair distribution
- Decreased muscle mass and strength + increased subcutaneous fat
- Diminished endurance
- Decreased libido, ED
- No ejaculate
- Eunuchoid skeleton
- Infertility/Azoospermia
- Eunucoidism
- Small testes
- Loss of male hair
- Gynecomastia
- Osteoporosis
- Infantile genitalia and prostate
- High pitched voice
Development after puberty
- Incomplete sexual development
- Decreased libido and ED
- Decreased frequency of shaving
- Diminished body hair
- Decreased muscle mass and strength
- Diminished endurance
- Increased fat mass
- Gynecomastia
- Osteoporosis
- Infertility
- Testicular atrophy
- Small prostate
- Height loss for minimal trauma
- Hot flashes
18
Q
What is eunucoidism?
A
- Legs disproportionately long (distance from pubic symphysis to crown of head shorter than 1/2 total height)
- Arms disproportionately long (arm span greater than one’s height)
19
Q
What is Kallmann’s syndrome?
A
Autosomal dominant mutation in KAL gene
- Results in failure of proper migration in GnRH neurons and olfactory neurons
- Isolated hypogonadotropic hypogonadism with anosmia (Testosterone deficiency)
20
Q
Describe the evaluation of hypogonadism
A
- Low TT x 2 (consider measuring BT)
If FSH/LH low/normal (2’/3’):
- PRL/pituitary panel, Iron studies
- MRI pituitary (TT under 150 pg/mL), pituitary hormone abnormalities, neurological symptoms
If FSH/LH high (1’):
- Kariotype
21
Q
What are causes of primary testicular failure?
A
- Klinefelter’s syndrome
- Orchitis (infection, radiation)
- Testicular trauma/torsion
- Autoimmune damage
- Chemotherapy (suramin, alkylating agents)
- Drugs (Ketokenazole, Spironolactone (receptor blocker), Abiraterone, alcohol, Enzalutamide
- Cryptorchidism
- LH receptor mutations (inactivating)
- Chronic diseases (CKD, cirrhosis, HIV)
- Varicocele
22
Q
What are causes of secondary testicular deficiency?
A
(Low T and low or inappropriately normal LH)
- Mass lesions (craniopharyngioma, prolactinoma, non-prolactin secreting pituitary tumors, metastatic tumors, cysts, trauma etc)
- Apoplexy/Infarction/radiotherapy
- GnRH receptor mutations, LH/FSH mutations
- Malnutrition
- Medications (GnRH agonists)
- Chronic diseases (Diabetes, Obesity, OSA, Anorexia Nervosa)
23
Q
What are causes of tertiary testicular deficiency?
A
- Aging
- Infiltrative diseases (sarcoidosis, hemochromatosis)
- Gene Mutations [Kallman’s (associated with anosmia), Kisspeptin, Kisspeptin-R, GnRH and GnRh-R mutations, NKB]
- Exogenous gonadal steroids, opiates
24
Q
What are the expected effects of:
- Testosterone
- DHT
- E2
A
T (either directly or indirectly through aromatization to estradiol)
- Penis maturation
- More …
DHT
- Hairline recession
- Growth of the prostate
E2
- Shedding of sc fat
- Achievement of adult bone phenotype
- Regulating insulin sensitivity
- Libido
25
Symptoms/signs of androgen deficiency occurring prior to vs. after puberty are similar except for what:
A. Decreased or absent libido
B. Decreased muscle mass and strength
C. Eunuchoid skeleton
D. Osteoporosis
E. Diminished body hair
Symptoms/signs of androgen deficiency occurring prior to vs. after puberty are similar except for what:
A. Decreased or absent libido
B. Decreased muscle mass and strength
**C. Eunuchoid skeleton**
D. Osteoporosis
E. Diminished body hair
26
JH, a 15.5 y/o male presents with lack of sexual development. Which of the following findings would provide an etiology for his androgen deficiency?
A. A eunuchoid skeleton
B. A very small prostate
C. Anosmia
D. Small testes
E. A low serum testosterone level
JH, a 15.5 y/o male presents with lack of sexual development. Which of the following findings would provide an etiology for his androgen deficiency?
A. A eunuchoid skeleton
B. A very small prostate
**C. Anosmia**
D. Small testes
E. A low serum testosterone level
27
What is erectile dysfunction (ED)?
Inability to reach an erection sufficient to complete sexual intercourse
28
**T/F**: Sexual dysfunction prevalence increases with age?
True
- Mostly due to rising rates of moderate/complete ED
29
What are risk factors for ED?
- Age
- Poor physical and psychological health
- Lifestyle factors (i.e. sedentary)
- Obesity
- Cigarette smoking
- Alcohol misuse
- Recreational drug use (eg, marijuana and heroin)
30
What are organic causes of ED?
- **Vasculogenic**: Cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, OSA, obesity
- **Neurogenic**:
* Central: Spinal cord or brain injuries, Parkinson disease, Alzheimer disease, multiple sclerosis, Stroke.
* Peripheral: diabetic neuropathy, post radical pelvic surgery, pelvic radiotherapy
- **Changes in penile/cavernous anatomy**: Peyronie's disease, cavernous fibrosis, penile fracture
- **Endocrine**: Hypogonadism, hyperprolactinemia, hyper- and hypothyroidism, hyper- and hypocortisolism
- **Medications**: Antihypertensives, antidepressants, antipsychotics, antiandrogens, recreational drugs
- **Systemic diseases**: liver, renal, respiratory failure
31
What are psychogenic causes of ED?
- **Predisposing factors**: traumatic past experiences, strict upbringing, inadequate sex education, anxiety, depression
- **Precipitating factors**: relationship problems, stress, family social pressures, major life events, such as childbirth, loss of a job, divorce, death in the family, physical or mental health problems
32
ED is a risk factor for what?
**Coronary artery disease**
- New incident CAD developed in 11% of men over the 10 yr follow up period
33
What are drugs that contribute (?? or cure??) ED?
**Central nervous system acting agents**
- anti-depressants (SSRI’s 15-80%), antipsychotics (risperidone, olanzapine), methadone, heroin, cocaine, nicotine, alcohol
**Antiarrhythmics**
- Digoxin, Amiodarone
**Antiandrogens**
- (spironolactone, ketoconazole, abiraterone, GnRH agonists, 5a reductase inhibitors, cimetidine)
**Antihypertensives**
- beta blockers (0.5%), Thiazide, CCB, Clonidine
**Chemotherapeutic agents**
- cychophosphamide, busulfan
34
Evaluation of ED?
- Presence of spontaneous erections
- Gradual vs. sudden onset of the condition
- Relevant drug history
- Past medical and surgical disorders to evaluate general health and presence of conditions associated with ED
- Standardized questionnaires : International Index of Erectile Function (IIEF) and the Sexual
- Health Inventory for Men (SHIM)
- Interview partner (very useful)
35
How is ED diagnosed?
- Secondary Sexual Characteristics
- Pulses and sensation
- Testicular size
- Anatomy of the penis (r/o Peyronie's)
36
What labs should be run with ED?
- How to treat if hypogonadism?
- Glucose and lipid profiles
- CMP, TSH
- Total testosterone
* If hypogonadism, treat with TRT
37
What is gynecomastia?
- Pseudogynecomastia/lipomastia?
**Gynecomastia**: enlargement of the glandular and stromal contents of the male breast
- May be manifestation of life-threatening underlying disease
- Can be painful
- Frequently cosmetic concern
**Pseudogynecomastia/lipomastia**: breast enlargement caused by an increase in adipose tissue
38
Gynecomastia facts
- Unilateral or symmetric?
- Relation to areola
- Discharge?
- Signs of possible malignancy
- Can be unilateral or asymmetrical
- Concentric in relationship to the areola and the consistency is moderately firm
- Rarely, one can express a milky discharge
_Possible malignancy:_
- Presence of blood in the discharge
- Skin dimpling
- Nipple retraction
- Harder consistency or axillary adenopathy
39
Pathogenesis of gynecomastia?
Useful to think of an altered estrogen/androgen ratio at the level of the breast as the cause of the gynecomastia
40
What are physiological causes of gynecomastia?
- **Neonatal** (initial 2 mo of life): caused by the passage of maternal hormones across the placenta during delivery); transient
- **Pubertal**: caused by normal hormonal imbalances between testosterone and estrogen that commonly occurs at the beginning of puberty (95% transient)
41
What are non-physiologic causes of gynecomastia?
**Neoplasms secreting estrogens or hCG**
- Adrenal and Leydig cell tumors
- hCG-producing (especially testis and lung)
- Sertoli cells
**Increased Aromatization T-\> E**
- Aromatase excess syndrome
- Drugs
- Alcoholic cirrhosis
- Aging
- Obesity
- Hyperthyroidism
**Exposure to exogenous estrogens**
- Gender dysphoria
- PCa treatment
- Partner vaginal cream
**Increased estrogen production**
- Puberty
- Refeeding gynecomastia
**Absolute or relative deficiency of androgens**
- Hypogonadism (all 1ary and 2ary causes)
- Aging
- Renal failure dialysis
- Hepatic cirrhosis
- HIV
- Prostate Cancer
42
Drug induced gynecomastia can occur with what drugs?
43
What are the most common causes of gynecomastia in the clinical setting?
- **Puberty** (25%)
- **Drugs** (25%)
- Not detectable (25%)
- Dirrhosis (8%)
- 1' hypogonadism (8%)
Then:
- Testicular tumor
- 2 hypogonadism
- Hyperparathyroidism
- CKD
44
Diagnosis of gynecomastia?
**History/PE:**
- For how long it has been present, tenderness, sign symptoms of known conditions associated with gynecomastia, medication history
- Glandular consistency, features of cancer to r/o
- Degree of virilization, secondary sexual development
**Labs:**
- CMP
- TSh, T, E2, LH, FSH, hCG, PRL
**US/Mammogram**
- Only if clinically suspected
- US testicles or adrenal CT
