Week 4 (Men's Health) Flashcards
(157 cards)
1
Q
Development of the prostate gland
A
Starts during embryonic life, continues through the neonatal period and is completed at puberty (androgen-dependent)
The stroma influences the development of the epithelial tissue
During puberty, testosterone levels increase and the prostate begins to secrete proteins and other molecules
2
Q
3 prostate zones
A
Central/periurethral zone: 20-25% of gland; 10% of prostate cancers
Transitional zone: 5% of gland; 20% of prostate cancers
Peripheral zone: 70-75% of gland; 70% of prostate cancers
3
Q
Prostate stroma
A
Smooth muscle cells
Fibroblasts
Undifferentiated spindle cells
Collagen and ground substance
Capillary vessels, lymphatics, nerves
Skeletal muscle
4
Q
Endocrine regulation of prostate gland
A
Hypothalamic-hypophyseal-testicular axis responsible for both normal and abnormal growth of prostatic tissue
GnRH from hypothalamus causes release of LH from anterior pituitary which acts on Leydig cells of testis to produce testosterone which goes to prostatic target cell and gets converted to DHT by 5 alpha reductase
Also, androgens from adrenal come into prostatic target cell to get converted to DHT
5
Q
Benign prostatic hyperplasia (BPH)
A
New data suggest stepwise increase in prostate weight with each decade of life
BPH increases with age (rare under 30; 8% in 40s; 50% in 60s and 90% in 80s)
Histologic, not clinical diagnosis
Clinical symptoms are either obstructive or irritative
More common in AAs, less in Caucasians, and even less in Asians
BPH occurs mainly in transition zone (proximal periurethral tissues)
1/3 of men with BPH require treatment
Histologically, nodular expansion of prostatic glandular elements, stromal elements, or both
6
Q
Prostate cancer (adenocarcinoma)
A
In peripheral zone
Most common cancer in men
Second leading cause of death in men
Typically in men over 50
Most common in AAs, less common in Caucasians, uncommon in Asians
TMPRSS2-ERG fusion in 30-70% of cases
7
Q
Potential mechanism of prostate cancer carcinogenesis
A
Androgen –> androgen receptor –> TMPRSS2-ERG fusion gene –> overexpression of ERG (TF) –> carcinogenesis
8
Q
How do you diagnose prostate cancer?
A
Rectal exam or PSA screening
Prostate cancer develops mostly in peripheral zone so obstructive symptoms are rare; most are clinically indolent
9
Q
Pathology/histology of prostate cancer
A
Relatively uniform proliferation, small round glands, single cell layer, some prominent nucleoli, nuclear enlargement (macronuclei), absent basal cells, blue mucin, pink secretions, crystalloids
Perineural invasion is only diagnostic feature of adenocarcinoma: involvement of nerve fiber by chains of glands, glands invading nerve substance, glands in wreath-like arrangement around the nerve
Prostate cancer consists of malignant secretory type of epithelial cells invading stroma (and some neuroendocrine cells) but no basal cells (benign glands contain luminal secretory cells and basal cells and rare neuroendocrine cells)
10
Q
High molecular weight cytokeratin
A
Exclusively expressed in basal cells
Positive staining practically excludes diagnosis of prostate cancer (because NO basal cells in prostate cancer)
Negative staining for high molecular weight cytokeratin needs to be interpreted in context of the case
11
Q
Gleason Grading
A
Based on architecture (glandular pattern), and perceived as a continuum
Cytological features do NOT play a role in determining grade
Recognizes heterogeneity of prostate cancer
Score based on recognizing “primary” and “secondary” grade and summing the two
Grade 1: circumscribed nodule, glands uniform and round
Grade 2: glands more variable in shape, increased stroma between glands, some infiltration at periphery
Grade 3: well formed glands with infiltrative growth, may be small, angulated or compressed, cribriform architecture with round nests
Grade 4: raggedly infiltrating poorly formed glands, fused glands, complex papillary-cribriform islands
Grade 5: solid masses with no gland formation, infiltrating cords and single cells (including signet-ring cells), comedo necrosis
12
Q
Which men have better outcomes for prostate cancer?
A
Improved lifespan in men with hormone-refractory, metastatic disease (?)
Improvement in outcomes in men with localized disease
13
Q
Symptoms of prostate cancer
A
None!
Metastatic disease can present as lower back and hip pain, rectal pain
14
Q
Prostate specific antigen (PSA)
A
Glycoprotein encoded by kallikrein-3 (KLK3) gene that is secreted by epithelial cells of prostate gland
Function of PSA is to liquefy semen to promote fertility (increases sperm motility and dissolves cervical mucus)
PSA is present in small quantities in serum of healthy men
Serum PSA elevated due to many prostatic disorders (BPH, prostatitis, irritation, AND cancer)
Poor test for cancer detection, better for following tumor progression (post-treatment)
15
Q
Serum PSA for different age groups
A
40s (0-2.5)
50s (0-3.5)
60s (0-4.5)
70s (0-6.5)
16
Q
Findings on digital rectal exam (DRE) for prostate cancer
A
Nodular/indurated vs. enlarged/smooth (normal or BPH?)
17
Q
Cases for and against screening for prostate cancer
A
Pros: advanced prostate cancer is incurable; without screening, few patients are diagnosed at an early stage; metastatic prostate cancer causes significant morbidity
Cons: studies have not clearly shown that screening decreases mortality; many men with prostate cancer will die from other causes (most die WITH prostate cancer, not FROM it); prostate biopsies and treatments may cause significant morbidity
18
Q
What is recommended now for prostate cancer screening?
A
USPSTF gave the PSA test a “D” grade: recommends against because moderate or high certainty that service has no net benefit or that harm outweighs benefit
AUA recommendation: individualized decision; benefits and consequences should be discussed prior to testing
ACS recommendation: clinicians should provide patients with info about uncertainties, risks and potential benefits to help men make decision based on personal values
19
Q
Transrectal ultrasound-guided biopsy of the prostate
A
PNBX: prostate needle biopsy
Can find benign glands, chronic inflammation, high grade prostate intraepithelial neoplasia (HGPIN), atypical glands, adenocarcinoma
In general population, will find 17-23% men have prostate cancer
20
Q
Size/volume of prostate cancer
A
Size correlates with stage
Volume proportional to grade
High volume on biopsy predicts high volume on final pathology, but low volume on biopsy does not predict small volume on final pathology
21
Q
Prostate cancer clinical stage (TNM)
A
T1a: tumor found in <5% of TURP chips
T1b: tumor found in >5% TURP chips
T1c: tumor detected from PSA elevation
T2a: tumor involves <1/2 of one lobe
T2b: tumor involves >1/2 of one lobe but not both lobes
T2c: tumor involves both lobes
T3a: tumor extends through the capsule
T3b: tumor extends into seminal vesicles
T4: tumor extends to invade adjacent structures (bladder neck, pelvic sidewall, rectum)
22
Q
Prostate cancer risk stratification
A
Risk based on PSA, Gleason grade, clinical stage (DRE)
Low risk: PSA <10, Gleason score 6, clinical stage T1c or T2a
Intermediate risk: PSA 10-20, Gleason score 7, clinical stage T2b
High risk: PSA >20, Gleason 8-10, clinical stage T2c
23
Q
When would you do a bone scan or abdominal/pelvic CT?
A
Bone scan if PSA >10 or Gleason >8
Abdominal/Pelvic CT scan if PSA >20 or Gleason >8
24
Q
Treatment for men with localized prostate cancer
A
>90% of men have clinically localized disease
No consensus on best treatment for men with localized disease (T1-2, N0, M0)
25
Main factor to consider in management of prostate cancer
**Life expectancy**/overall **health**
Patient with long life expectancy can suffer morbidity and mortality from prostate cancer
26
Management options for prostate cancer
**Active** **surveillance**: criteria are **Gleason 6**, **T1-2a**, **PSA\<10**, significant co-morbidities, **limited life expectancy**; 3% lifetime risk of death, but 60-70% have it on autopsy; some men do not benefit from definitive treatment
**Radical** **prostatectomy**: open, laparoscopic, or robotic approaches; prostate removed (+/- pelvic lymph nodes); nerve-sparing or non-nerve sparing technique depending on tumor location, sexual function
**Radiation** **therapy**: external beam (+/- androgen deprivation therapy), brachytherapy for low-intermediate risk patients, combination for intermediate-high risk
27
Prostate cancer treatment side effects
**Sexual dysfunction**
**Urinary incontinence**
Urethral stricture
Bowel dysfunction
**Irritative bladder symptoms**
28
Castration-resistant prostate cancer (CRPC)
Previously called "hormone-refractory" or "androgen-independent"
**Do not respond** to reduction of testosterone/DHT levels
Serial rise in PSA and/or radiologic/clinical progression
29
Treatment of advanced disease
**Locally** **advanced** (T3-4): external beam **radiation** therapy plus **hormone** therapy
**Metastatic**: **hormone** therapy, **chemotherapy**
**Castration resistant prostate cancer** (CRPC): chemotherapy (**Docetaxol**), further androgen deprivation, **immunotherapy**
30
Hormone deprivation therapy
**Bilateral orchiectomy**
**GnRH agonists**/antagonists (goserelin, leuprolide): block **testosterone** **release** from testicle
**Anti-androgens** (flutamide, bicalutamide, enzalutamide): block testosterone **receptors**
**Ketoconazole**: blocks testosterone **synthesis**
**Abiraterone**: blocks enzymes involved in testosterone **synthesis** (CYP17)
31
Newly approved drugs (since 2010) for prostate cancer
**Immunotherapy**: sipuleucil T (**Provenge**)
**Androgen deprivation**: abiraterone, enzalutamide (**Xtandi, MDV3100**)
Bone loss: **denosumab**
32
Testicular cancer
Most common cancer in males **15-34**
**White** **men** get it 5x more
5 year survival rate is 92% (stage 1 \>97%!)
**Cure** rates **greater than 80%** for all stages (due to predictable pattern of spread and chemosensitivity)
(Think of it like endometrial cancer for women!)
33
Types of testicular cancer
**Germ cell tumors** (GCT): **95%**; **seminomas** most common subtype and slow growing and radiosensitive; **non-seminomatous** (choriocarcinoma (hCG), embryonal, yolk sac (AFP), teratoma) often in 20s, grow fast and spread rapidly to lymph nodes and lung
**Non-germ cell tumors**: sertoli cell, leydig cell; stromal are 4% of cancers; metastasis is rare
34
Signs and symptoms of testicular cancer
**Painless** testicular mass
10% report recent testicular trauma
**Swelling** in lower **extremities**, back pain, cough or dyspnea (advanced disease)
35
Evaluation for testicular cancer
H&P
Urinalysis, urine C&S, tumor markers (beta hCG, AFP, LDH)
Maybe: scrotal ultrasound, abdominal/pelvic CT, chest X-ray or CT, head CT
36
Management for testicular cancer
**Radical orchiectomy**
Radiotherapy
Chemotherapy
**Retroperitoneal lymph node dissection (RPLND)**
Salvage chemotherapy
Bone marrow transplant
For **localized** testicular cancer: **radical orchiectomy**, observation with CT scans every 2 months for 5 years, **RPLND**, **radiotherapy** to retroperitoneum (seminoma only) 2 cycles of BEP chemotherapy
For **metastatic** testicular cancer: **radical orchiectomy**, **radiotherapy** to retroperitoneum (seminoma only), **chemotherapy** (non-seminoma GCT), **RPLND** vs. salvage **chemo** vs. **observation**
37
TNM staging of testicular cancer
T0: no evidence of tumor (testicular scar)
Tis: intratubular germ cell neoplasia (carcinoma in situ)
**T1**: tumor confined to t**estis/epididymis**, no lymphovascular invasion, no involvement of tunica vaginalis
**T2**: **lymphovascular** invasion or extension to **tunica** **vaginalis**
**T3**: tumor invasion of **spermatic cord**
**T4**: tumor invasion into **scrotum**
N0: no LN involvement
**N1**: LN **\<2cm**
N2: LN \>2cm, and \<5cm
**N3**: LN **\>5cm**
38
RPLND templates
Multiple templates depending on **location of tumor**
New surgical techniques preserve ejaculatory function
Intraperitoneal vs. retroperitoneal
39
Chemotherapy for testicular cancer
For non-seminomatous germ cell tumors
4 cycles of **BEP** (bleomycin, etoposide, platinum) standard
70% cure rate
Patients with **elevated tumor markers after chemo** require **salvage** chemo
Patients with **normal markers but residual masses after chemo** require **surgery**
Post-chemo **RPLND**: 10% residual cancer, 45% teratoma, 45% fibrosis
40
Lower urinary tract symptoms (LUTS)
Constellation of symptoms that reflect pathological processes involving lower urinary tract (bladder, bladder outlet, prostate, or urethra)
25% of men \>40 have LUTS and prevalence increases with age (60% at 60 and 80% at 80)
Symptoms **obstructive**, **irritative**, or **both**
Not disease specific or diagnostic of BPH
41
Obstructive vs. irritative LUTS
**Obstructive**: hesitancy, slow stream, start/stop, dribbling, incomplete emptying
**Irritative**: frequency, urgency, nocturia, dysuria, possibly incontinence
42
Evaluation of LUTS
Medical history asking about other causes of voiding dysfunction and identification of complicating co-morbidities (DM, stroke, DDD)
Physical exam with DRE and neuro exam
Urinalysis, PSA in appropriate patients (serum creatinine not needed in initial evaluation)
**AUA symptom index** (mild symptoms 0-7, moderate symptoms 8-19, severe symptoms 20-35)
43
Differential diagnosis of LUTS
**UTI**
Primary **bladder dysfunction** (neurogenic bladder, bladder atony)
**Bladder neck contracture** (BNC)
Prostatic obstruction (**BPH/cancer**)
**Stricture**
**Meatal stenosis**
44
Diagnostic tests for evaluation of LUTS
**Uroflow** (ml/sec)
**Postvoid residual**
Pressure/flow studies
Urodynamics
Possibly imaging, cystoscopy
45
UF/PVR
Measures **peak flow** and **voided volume**
Can assess voiding pattern
Bladder scan to measure **residual**
46
Natural history of BPH
Starts with symptoms of **hesitancy** and **weak stream** with straining
As symptoms progress, **incomplete emptying** occurs with **increasing PVR**
High PVR may lead to **UTI** and **bladder stones**
Long-standing obstruction leads to **bladder hypertrophy** with increased urgency and **urge incontinence**
Bladder eventually becomes **atonic** with severe **urinary retention**
**Nephropathy** secondary to obstruction can lead to **renal failure**
47
Treatment options for BPH
**Watchful waiting**: for **mild** symptoms, if no complications, re-assess patient annually
**Alpha blockers**: initial medical treatment; for patients with **moderate to severe** symptoms
**5-alpha reductase inhibitors**: for patients with **large** **glands** or **hematuria** secondary to BPH
**Phytotherapy**: substances derived from **plants**; mechanism unclear (anti-inflammatory, inhibition of hormone effects on prostate growth possible)
**Surgery** (traditional, transurethral, minimally invasive)
48
Alpha1 blockers as treatment for symptomatic BPH
**Relax smooth muscle** around blood vessels and in the prostate and bladder to **allow better urine flow**
Work **quickly**--improve symptoms within **days**
Side effects: **dizziness**, orthostatic **hypotension**, fatigue, headache, retrograde ejaculation, angina in men with CAD
Doxazosin (Cardura)
Terazosin (Hytrin)
**Tamsulosin** (**Flomax**): selective for prostate smooth muscle with fewer side effects and no dose titration; **alpha-1A specific** so only acts on prostate and not on blood vessels like doxazosin or terazosin!
Alfuzosin
49
5-alpha reductase inhibitors as treatment for symptomatic BPH
Blocks conversion of testosterone to **DHT** (which is major sex hormone in prostate cells)
Results in **decrease** in prostate **size**
Work **slowly**, take **months** before improvement is noted
Side effects: impotence, decreased libido, decreased ejaculate volume, decreased PSA
**Finasteride** (Proscar)
Dutasteride
50
Combination therapy for BPH
Doxazosin plus finasteride
Very **expensive**
Assess risk of progression (with one drug) vs. side effects of 2 drugs
Studies ongoing for "step-down therapy" (start with both then discontinue the alpha blocker)
51
Phytotherapy for BPH
Substances derived from plants
Most common are **saw palmetto** and **pygeum**
52
When do you refer to urology for BPH?
**Refractory** symptoms
Hematuria, recurrent UTI, bladder stones
If patient wants **surgery**
**Urinary retention**
Complicating co-morbidities
53
Indications for surgery for BPH
Bothersome **symptoms** refractory to medications
**Obstructive nephropathy**
Recurrent UTIs
Bladder stones
Hematuria
54
Benefits of surgery for BPH
80-90% of patients report significant **symptom relief**
Minimally invasive modalities available (including office-based)
No more need for medical therapy after surgery
Side effects are mild for transurethral procedures
55
Transurethral resection of the prostate (TURP)
Resectascope inserted into **urethra**
**Loop electrocautery** used to systematically **shave tissue**
Goal is to resect adenoma down to capsule
Avoid urinary sphincter!
Gold standard for surgical treatment
Complications: bleeding, TUR syndrome (severe hyponatremia caused by absorption of fluids used to irrigate the bladder), incontinence, retrograde ejaculation
56
PVP laser prostatectomy (greenlight)
Photo-selective vaporization of the prostate (PVP)
**Laser** evaporates prostate tissue
No time limit on resection
**Very** **little** peri-operative bleeding
Catheter may be removed same day
57
Other thermotherapies for BPH
**Trans-urethral microwave therapy (TUMT)**: uses microwaves, local anesthesia, not as effective as TURP
**Trans-urethral needle ablation (TUNA)**: uses high radiofrequency waves to evaporate tissue, local anesthesia, short-term data are good
**High intensity focused ultrasound (HIFU)**: uses ultrasonic energy to heat tissue, good short-term data
58
Open prostatectomy
Reserved for **large** glands \>80g!
Associated **bladder** **stones**
Very bloody **surgery**, requires inpatient stay
59
Treatment of acute retention
This is a real **emergency**!
Person **cannot pee**
Place indwelling Foley **catheter**, treat infection, start **alpha blocker**
Voiding trial in 1-2 weeks, but If fail voiding trial, teach how to catheterize themselves (CIC: clean intermittent catheterization), consider second drug vs. surgery
60
How do you evaluate a scrotal mass?
H&P
Look for pain, redness, heat, reducibility, orientation of testis, cremasteric reflex
**Transillumination**
Urinalysis, urine culture
Ultrasound
61
Differential diagnosis for scrotal mass
**Hydrocele**
Epididymal cyst (**spermatocele**)
**Varicocele**
**Epididymo-orchitis**
**Hematocele** (testicular rupture)
Testicular **torsion**
**Tumor**
**Hernia**
62
Hydrocele
Collection of **serous fluid** inside **tunica vaginalis**
Non-communicating (no fluid from abdomen?) is most common in adults
Communicating (fluid from abdomen?) is common in newborns
Excess tunica vaginalis fluid production
Treatment: observation, aspiration/sclerotherapy, scrotal repair, inguinal repair
Note: can recur after aspiration or surgical excision
63
Epididymal cyst/spermatocele
Cystic dilation of epididymis
Spermatoceles have **sperm** present
Treatment: observation vs. surgical excision
64
Varicocele
Pathologic **dilation** of the **pampiniform plexus**
**Heat** around testicle due to increased blood flow can cause **infertility**
Causes **heavy, dull** sensation
Can cause testicular **atrophy**
Found in 20% of normal men; 40% of infertile men
Treatment is surgical: open vs. lap ligation
65
Epididymo-orchitis
**Epididymitis** is most **common** inflammatory condition of scrotum
**Acute infection** can lead to sepsis
**Chronic infection**/inflammation can lead to **chronic pelvic pain syndrome**
Usually an **ascending** infection through **vas deferens**
In children, consider associated GU abnormalities
In **young** men, consider **STDs** (or UTI?)
In **older** men, consider **BPH** (or UTI?)
66
Torsion
Urologic **emergency**!
Extravaginal (neonates) or intravaginal (adults)
Associated with "bell clapper" deformity
Testicular salvage is 100% if de-torsed in **6 hours** or less
Need to go to **OR**, but can try manual de-torsion (under local anesthetic)
67
Testicular rupture
AKA **hematocele**
Rupture of **tunica albuginea** leads to **extrusion** of **seminiferous tubules** and **blood**
Important to repair in order to preserve testicular function, decrease complications such as fistula formation and anti-sperm antibodies resulting in infertility
Associated with **trauma**
Requires **emergent** scrotal exploration with **repair** or **orchiectomy**
68
In what percent of couples is male factor the primary or contributing cause of failure to conceive?
**50%!**
69
How long do fever or viremia affect testes function for?
**3 months** after systemic illness
70
Important clinical history for male infertility workup
**Undescended testes**
**Post-pubertal mumps** (because pre-pubertal mumps doesn't affect testes, just parotid gland)
YV plasty (of foreskin??)
**RPLND**
**Diabetes** and **hypertension** (can cause impotence, retrograde ejaculation)
**Medications**: sulfasalazine (decreased density, motility and morphology), cimetidine (interferes with LH secretion), nitrofurantoin (maturation arrest in rats, decreased motility in vitro), anabolic steroids
Chemo-alkylating agents (**cyclophosphamide**)
**Tamsulosin**
**Alcohol**, nicotine, marijauna suppress HPG axis
71
What to look for on physical exam when investigating male infertility
**Temporal baldness** (DHT present?)
**Gynecomastia** (excess estrogens or altered estrogen/androgen balance)
Inguinal and scrotal **scars** (hernia or spermatocelectomy)
**Testis** (volume, consistency)
**Varicocele**
**Epididymal fullness** (possible obstruction)
**Vas deferens** (feel for their presence)
DRE (**prostate** tender/boggy, SV?)
**Penis** (Peyronie's plaques, lesions, hypospadias)
72
Routine tests for infertility workup for male
Urinalysis
**Semen analysis (x2)**
FSH
LH
Testosterone
Estradiol
Prolactin
73
Semen analysis
Must do on **2 separate occasions** 3-4 weeks apart
**48-72 hours of abstinence** beforehand
Collect **post-ejaculate urine** (check for retrograde ejaculation)
**Volume**, concentration (not that relevant), **total** count (important), **motility** and **morphology**, **pH** and **fructose**
74
Where does fluid that makes up semen come from?
From **seminal vesicles** (basic, thick)
From **prostate** (acidic, thin)
75
WHO semen parameters
**Volume** 1.5cc
Normozoospermia: normal specimen, **\>15 million/mL**, \>39 million total
Progressive **motility 32%**
Morphology, strict **4%**
76
Oligozoospermia
**Low concentration** of sperm
77
Asthenozoospermia
**Low motility**
78
Teratozoospermia
**Low** normal **morphology**
79
Azoospermia
**No sperm**
Note: one common cause is maturation arrest
80
Contributions to semen
**65%** from **seminal vesicles** (thick, basic)
30-35% from **prostate** (thin, acidic)
3-5% from **vas deferens** (note: so after vasectomy, can't tell just from ejaculate)
81
When to use certain ultrasounds
**Scrotal ultrasound**: epididymal or **testicular** masses, testicular pain, hydrocele, trauma, testicular size and internal pathology, varicocele (position)
**Transrectal ultrasound (TRUS)**: good for imaging **prostate** and **seminal vesicles**; for low volume azospermia, abnormal DRE, retrograde ejaculation, EDO, hematospermia or pyospermia
**Renal ultrasound**: congenital absence of vas deferens (CAVD), 20% ipsilateral anephric, SV pathology
82
Causes of male factor infertility
**Varicocele** (heated sperm so don't work; affects both testes because septum is thin)
**Azoospermia** (obstructed vs. non-obstructed)
Endocrine
Genetic
Acquired
Ejaculatory
**Spinal cord injury**
Inflammation
83
Varicocelectomy
**Embolization** vs. **surgery**
Reverses damage to testes
40-70% pregnancy rates
However, not always effective
84
Endocrine causes of male infertility
**Kallman's syndrome**: **hypogonadotropic** **hypogonadism** (lack of secondary sexual characteristics), **anosmia**
**Hyperprolactinemia**: **low testosterone**, low LH, erectile dysfunction
85
Ejaculatory duct obstruction
**Low volume, fructose negative, acid pH**
Azoospermia or severe oligospermia
Trans-urethral resection of the ejaculatory duct (**TURED**): better success in patients with partial obstruction; complications include urine reflux (SV-itis), retrograde ejaculation, external sphincter injury
86
Congenital bilateral absence of vas deferens
**CABVD**
80% of those with CABVD have detectable mutations in the **CFTR** locus (**2** mild mutations or 1 mild and 1 severe)
87
Nonobstructive azoospermia and severe oligospermia
12% of azoospermic and 7% of oligospermic men have **abnormal** **karyotype** (translocation and inversions; Klinefelter Syndrome, 46XX male from translocation but have SRY gene; structural Y chromosome abnormalities)
3% of severely oligospermic men have **chromosomal translocations**
88
Klinefelter's Syndrome
**47XXY** from non-disjunction in meiosis
10% mosaic; 11% of azoospermic men
**Hypergonadotropic hypogonadism** with **small testes**
Breast cancer and extragonadal NSGCT
Fertility can lead to 47 XXY or 47 XXX
89
Y chromosome microdeletions
**AZFa**: proximal; azoospermia, poor prognosis
**AZFb**: central; azoospermia, poor prognosis
**AZFc**: distal; azoospermia or severe oligospermia, normal clinical findings and normal FSH
90
Acquired causes of male infertility
**Surgical**: infuinal hernia with or without mesh; hydrocelectomy, spermatocelectomy
Infectious: **mumps**, **epididymitis**
**Traumatic**
**Hypertension** and **diabetes**: erectile dysfunction and retrograde ejaculation
**Spinal cord injury**
91
What can cause retrograde ejaculation?
**Diabetes**
**Alpha blockers**
**Transurethral resection of the prostate** (TURP)
92
Spinal cord injury and infertility
Level of injury
Time from injury
Complete vs. incomplete
Autonomic dysreflexia (risk at T6 and above--HTN, bradycardia, sweating, chills, headache, stroke, seizure and death; pretreat with Nifedipine)
Vibratory stimulation (to induce emission)
Electro-ejaculation (testis cancer, sympathectomy) better interrupted current, less sv exposure
Fluid intake
Alkalinization
Sympathomimetics
93
Inflammation and infertility
SA: **WBCs** vs. immature sperm
Reactive oxygen species (**ROS**)
Not necessarily infection
**Pain, voiding dysfunction**
Activation, oxidative stress
Get cultures
Antibiotics, antioxidants
**SCSA** (sperm chromatin structure assay): 2 theories of DNA damage (intratesticular as part of spermatogenesis and damage from ROS and failure of antioxidant system)
94
Corpus cavernosa
2 cylindrical **smooth muscle** pouches that relax and fill with blood to cause an erection
**Cavernosal nerve** is stimulated which causes **cavernosal artery** to open up
95
How does the cavernosal nerve cause the corpus cavernosum to relax?
Cavernosal nerve is **NANC** nerve (nonadrenergic, noncholinergic) and secretes **NO** gas
**NO is** formed in **terminal** of nerve using **O2**, **L-arginine**, and **PnNOS** --\> NO diffuses into corpus cavernosum and acts on **guanyl cyclase** to create **cGMP** --\> cGMP causes **relaxation** of **smooth muscle** of corpus cavernosum
Later, phosphodiesterase (**PDE**) breaks down cGMP
96
Nerves for erection and ejaculation
Erection: **cavernous** **nerve** (autonomic, **parasympathetic**)
Ejaculation (and orgasm): **pudendal** **nerve** (somatic)
Note: can have erection but not ejaculation and vice versa
Note: **emission** is an autonomic (**sympathetic**) nerve?
97
Penile vasculature
Blood goes from **aorta** to **common iliac** to **internal iliac** to **internal pudendal** to **common penile** artery which **trifurcates** into:
**Dorsal artery** (top of penis)
**Cavernosal arteries** (go to cavernosa--achieve erectile response)
**Urethral artery** (bottom of penis, in corpus spongiosum)
98
5 phases of penile erection
1) **Blood** **flow** through **pudendal** **artery** increases (note: blood flow can increase 40-50x within a few seconds of cavernosal nerve stimulation)
2) **Squeeze** cavernosal artery shut and **intracorporeal pressure increases**
3) **Plateau** of blood flow and pressure
4) **Ischial** **cavernosus** muscles squeeze and shoot intracorporeal **pressure** **up** even though no blood flow in
5) **PDE** works to **break down cGMP** and relax smooth muscle resulting in **decrease in pressure** (still no blood flow)
99
How much blood flow does flaccid vs. erect penis get?
**Flaccid: 1-2 cc/min**
**Erect: 90 cc/min**
100
Medical factors associated with ED
Age
**Diabetes**
Depression
**Hypertension**
High cholesterol
Surgery or injury to pelvic region
**Medications**: antihypertensives, antidepressants
Chronic illness: ischemic heart disease, CRF, alcohol
101
Venous leakage as a cause of impotence
**Venous leakage** (corporal veno-occlusive mechanism) is **most common** cause of impotence
**Tunica albuginea** (muscle layers) must have sufficient **stiffness** to **compress venules** penetrating it so venous outflow is blocked
**PDE-5 inhibitors** block PDE, enhance cGMP and enhance activity of smooth muscle (good treatment!)
102
Erectile dysfunction and cardiovascular disease
ED is associated with **hypertension**, **high cholesterol**, **heart disease**
ED can be another **sign** of cardiovascular disease
103
Vasorelaxing substances
**Alpha blockers**
**PGE-1** (stimulates cGMP)
**PDE inhibitor**
104
PDE-5 inhibitors
These drugs only work if you have **had stimulation** of cavernosal nerve leading to NO production, leading to cGMP
If take drug and then are NOT sexually stimulated, nothing will happen
More drug will give you higher concentration but SAME halflife (won't have erection for way longer or anything)
PDE receptors located everywhere (even PDE-5), and **cross-reactivity** accounts for side effects
**Sildenafil (Viagra)**
**Vardenafil**
**Tadalafil (Cialis)**: longest halflife (17.5 hours)
105
Why don't you want to give PDE-5 inhibitor to someone on nitrates?
PDE-5 inhibitor contraindicated with nitrates because nitrates relax vascular system also, and combination can cause **hypotension**
106
Other therapies for impotence
Intracorporeal **injections**
Medicated urethral system for erections (**MUSE**)
**Mechanical** therapy
**Surgery** (semi-rigid vs. inflatable implants)
107
Germ cell tumor
**95%** of **testicular** cancers are germ cell tumors (GCT)
**Seminoma**: can be **mixed** with other GCT types or can be **pure** seminoma; may or may not have elevated hCG
108
Non-seminomatous germ cell tumors (NSGCT)
**Choriocarcinoma**: markedly elevated **hCG**; usually presents as small or even non-palpable primary tumor with **soft tissue** and **brain metastasis** secondary to hematogenous spread
**Embryonal**: most **aggressive** form; when present with teratoma referred to as **teratocarcinoma**
**Yolk sac**: leads to elevated **AFP**
**Teratoma**: technically **non-malignant** form (does not invade) but **grows rapidly** and can compress vital structures (bowel, renal, venous); note both immature and mature teratomas are worrisome unlike in women where mature teratomas are benign
109
Non-germ cell tumors
**Stromal tumors** are **4%** of testicular cancers
(**sertoli** cell vs. **leydig** cell tumors)
**Sertoli cell tumor**: usually found incidentally on ultrasound; rarely invade or metastasize
**Leydig cell tumor**: excretion of **estrogen** can lead to gynecomastia, loss of libido or ED; rarely invades or metastasizes
**Metastasis** to testicles is **rare**
110
Seminal vesicle
Gland responsible for the **majority** of the ejaculate **volume**
Note: ejaculatory duct is tube formed when vas deferens and seminal vesicle join
111
Transrectal ultrasound (TRUS)
Excellent imaging modality for **prostate** and **seminal vesicles**
112
Process of getting an erection
1) 2 paired **cavernosal nerves** from S2-S4 of spinal cord) stimulated
2) This causes **smooth** **muscle** of cavernosal **arterioles** and **corporal** **tissue** to **relax**
3) Blood **pools** in corpora cavernosa
4) Increase in **intracorporeal** **pressure** which passively **shuts off veins** (under tunica albuginea) exiting corpora
Note: process of trapping blood within corporal bodies is **passive** just due to high ICP within corporal bodies
113
Which cells make Mullerian Inhibiting Factor (MIF; MIS)?
**Sertoli cells** make MIS
114
Male testicles
**15-25mL** in volume
Contain **seminiferous tubules**, which contain developing germ cells
**Interstitial** tissue consists of **Leydig cells**, mast cells, macrophages, nerves, blood and lymph vessels
Ductuli efferentes lead from rete testis to epididymis
115
What is needed for spermatogenesis?
**Sertoli cells**
Local **testosterone** (from **leydig** cells)
Note: **can't give exogenous testosterone** though because need **local stimulation** and **LH and FSH** to cause testosterone induction
116
What do you give a man with low FSH who wants to be fertile?
Give **FSH** **alone** for **qualitative** spermatogenesis
Give **FSH** and **testosterone** for **quantitative** increase in spermatogenesis
117
Why do you remove gonads in people with gonadal dysgenesis syndromes?
Higher **risk for cancer** in gonadal dysgenesis syndromes
Note: leave gonads in through puberty in androgen insensitivity syndrome because they produce enough testosterone to be converted to estrogen by aromatase in order to have the person go through "normal female puberty" but then remove the testes after puberty
118
What happens if you get androgen deficiency at different stages of development/life?
Androgen deficiency during **early embryogenesis**: **ambiguous genitalia**
Androgen deficiency **post-natally but pre-pubertally**: eunuchoidal, **hypogonadal** male, prepubertal testes (\<4cc), increased body fat, osteopenia, gynecomastia
Androgen deficiency **post-pubertally**: **hypogonadal** male, decreased libido, ED, decreased muscle strength/mass, decreased body hair, decreased well-being/energy, mood changes, osteopenia, increased abdominal fat, gynecomastia
119
Pre-pubertal hypogonadism
**Small testes**, phallus and prostate
**Scant** pubic and axillary hair
**Eunuchoidal** proportions
**Reduced** **musculature**
**Gynecomastia**
Persistently **high-pitched voice**
120
Eunuchoidal proportions
**Arm** span 2cm **greater** than **height**
Heel to pubis 2cm greater than crown to pubis
**"Female"** stature of **longer legs than torso**
In male, eunuchoidal proportion may indicate **prepubertal** **onset** of hypogonadism
Note: **testosterone** makes men's **legs shorter** (or torso longer)
121
Hormone levels in male hypogonadism for different reasons
**Hypothalamic-pituitary** hypogonadism: **"inappropriately normal" or low FSH/LH**, low T
**Gonadal dysfunction** hypogonadism: **high FSH/LH**, low T
**Defects in androgen action** hypogonadism: **high LH, normal FSH**, normal/**high T**
122
Causes of primary testicular failure (which leads to hypogonadism)
Congenital: **Klinefelter's syndrome** and variants, cryptorchism, anorchia, myotonia dystrophica, **androgen resistance syndromes**, androgen biosynthesis defects and **5 alpha reductase deficiency**
Acquired: orchitis (mumps, leprosy, AIDS, others), **trauma**, torsion, surgery, irradiation, cancer **chemotherapy** and other toxins, idiopathic
123
Causes of hypogonadotropic hypogonadism
Congenital: **Kallman's syndrome**, congenital adrenal hypoplasia, septo-optic dysplasia, steroid sulfatase deficiency, Prader-Willi syndrome, GnRH receptor mutations
Acquired: **pituitary** **tumors** (prolactinomas and others), **craniopharyngioma**, germinoma, granulomatous diseases (**TB,** sarcoid, histiocytosis), autoimmune hypophysitis, trauma, surgery, irradiation, weight loss, AIDS
124
Mixed primary and secondary causes of male hypogonadism
Acute or chronic illness
**Aging**
Hemochromatosis
**HIV** and associated diseases
**Obesity**
**Diabetes mellitus**
Idiopathic
125
Kallman's Syndrome
**Hypogonadotropic hypogonadism** with **anosmia**
**Decreased synthesis of gonadotropin** in anterior pituitary
**Anosmia**, lack of seconday sexual characteristics
**Eunuchoidism** with low LH and FSH, cryptorchidism, cleft palate or lip, congenital **deafness**, prepubertal testes
Increase LH and FSH after GnRH treatment
126
Klinefelter's Syndrome
**XXY male**
**Primary hypogonadism** (**dysgenesis** of **seminiferous tubules** and **abnormal leydig cell** function)
Varying degrees of hypogonadism
Gynecomastia, eunuchoid body, small firm testes (atrophy), azoospermia (infertility), decreased pubic hair and decreased penis size in some
Elevated FSH and LH
127
Disorders of sexual development and function by defect and gender
**Central** (hypothalamus/pituitary): Kallman's syndrome
**Gonadal**: Female: gonadal failure/**agenesis** in XX, gonadal agenesis XY (**Swyer's syndrome** with no uterus, **Turner's syndrome XO**, mullerian agenesis; Male: **Klinefelter's syndrome XXY**
**Hormones**: androgen insensitivity, 5 alpha reductase deficiency, congenital adrenal hyperplasia (17 alpha hydroxylase deficiency is feminizing)
128
Target organs of testosterone
Brain: **libido**, **aggression** cognition
Male sex organs: **penile** **growth**, **spermatogenesis**, **prostate** growth and function
**Muscle**: increase in strength and volume
Kidney: stimulation of **erythropoietin** production
Bone marrow: **stimulate stem cells**
Bone: **accelerated linear growth**, closure of epiphyses
Skin: hair growth, **balding**, sebum production
Liver: synthesis of **serum proteins**
129
Why do men get more testosterone deficiency as they age?
**Decreasing testosterone** and **increasing SHBG**?
130
Testosterone free and bound
**1-2%** of testosterone is **free** (unbound)
**30-50%** is **bound to albumin** with low affinity (free and albumin bound T are bioavailable)
**40-50%** is bound to **SHBG** (not bioavailable)
131
Androgen deficiency and body composition
Hypogonadal men, or men who have had orchiectomy have **decreased bone density**
Androgen deficiency is associated with:
**Increase** in **body fat**
**Decrease** in **"fat free mass"**
**Decrease** in **muscle protein synthesis**
Note: **testosterone** **replacement** returns body composition to **normal** (increases muscle mass and decreases fat mass)
132
Risk factors for osteoporosis and fractures in men
**Age \>65**
Previous fracture
Falls
Low or declining BMD
Low body weight (BMI \<25)
10% weight loss after age 50
Certain medications
Sedentary lifestyle
Low calcium and vitamin D intake
Excessive **alcohol**
**Smoking**
Medical conditions
Hypogonadism
133
Testosterone treatment of hypogonadal men
**Improves** **libido** and erectile function (due to increase in libido, not direct effect on erection physiology) in many
Improves **mood**
Increases **muscle** size and strength
Increases **bone mineral density** and may decrease risk of fracture (although this hasn't been tested)
134
Aging and testosterone physiology
With age:
**SHBG increases**
**Free** and bioavailable **T decreases**
**Total T decreases**
135
Presentation of androgen deficiency in aging men
**Decreased libido, erectile dysfunction**
**Gynecomastia**
Decreased facial and body **hair**
Decreased **energy** and work capacity
136
Testosterone and RBC mass
Testosterone stimulates **erythropoetin** to **increase hematocrit**
High hematocrit may be **thrombogenic** though
137
Administration of testosterone treatment
**Injectable**
Transdermal **gel**, **patch**
**Transbuccal**
**Implants** (in buttcheek)
138
What can happen if you give too large a dose of testosterone?
Can actually get **gynecomastia** because aromatase is activated and can convert testosterone to estrogen
139
Risks of testosterone replacement
**Testicular atrophy** and **infertility** are common (usually reversible after stopping treatment)
**Sleep apnea**
**Acne**
Skin reactions with patch
Gynecomastia rare, usually reversible
CAD (no evidence?)
Lipids (oral, but maybe not injectible?)
Erythrocytosis
Fluid retention rare
BPH rare
Prostate cancer theoretical but not proven
Hepatotoxicity with oral agents (not used commonly in US)
140
Contraindications to testosterone replacement therapy
**Absolute** contraindications: **prostate** cancer, **breast** cancer, **hematocrit \>55%**
**Relative** contraindications: untreated **sleep apnea**, severe **obstructive** symptoms of **BPH**, advanced **CHF**, **hematocrit \>52%**
141
How can men get increased levels of estradiol or estrone?
**Testicular leydig or sertoli cell tumor**
**Testicular germ cell tumor**
**Adrenocortical tumor**
**hCG** producing tumor (lung, HCC, renal cell carcinoma) bc hCG acts like LH to increase T which increases E?
Increased **aromatase** **activity** (pathologic or physiologic if adipose tissue and advancing age)
**Drugs** can **displace** estradiol and estrone from SHBG causing **increased free estrogen**
Medications: **cimetidine**, GnRH agonists, **spironolactone**
142
Somatic tissues affected by androgen and estrogen
**Androgen**: muscle, larynx, beard, distribution of sexual hair, bone and cartilage, nervous system, heart, **RBCs**
**Estrogen**: breast, uterus, adipose-tissue distribution, heart and vascular endothelium, bone and cartilage, nervous system
143
Treatment and care of transgender patients
Hormonal treatment and living as desired gender for at least 1 year prior to surgery
**MTF** hormones: **estradiol** (oral, patch, parenteral); **antiandrogens** (spironolactone, cyproterone acetate), **5 alpha reductase inhibitor** (finasteride), **GnRH agonist**
**FTM** hormones: **testosterone** (parenteral, transdermal)
Note: prior hormone effects on skeleton and vocal cords cannot be reversed (MTF can't get higher voice, need speech therapy)
144
Monitoring hormone therapy in transgender MTF
Measure serum T and E every **3 months**
Serum T should be \<55ng/dL
Serum E shouldn't be above physiological range, should be \<200pg/ml
If on **spironolactone**, check **K+** and other electrolytes every 2-3 months over first year
Routine **cancer** **screening**
**BMD** testing at baseline if risk factors for osteoporosis
Note: estrogen treatment confers risk of thromboembolic disease, macroprolactinoma, liver dysfunction, breast cancer, CAD, CVD, migraines
145
Monitoring hormone therapy in transgender FTM
Measure serum T every **2-3 months**
For injections, measure level **midway** **between** **injections** (if \>700 or \<350 then adjust dose)
Measure **estradiol** during **first 6 months** or until no uterine bleeding for 6 months (estradiol should be \<50)
Measure CBC and LFT every 3 months for first year then 1-2 times per year
If cervical or mammary tissue present then perform **cancer screening**
Note: testosterone treatment confers risk of breast cancer, uterine cancer, erythrocytosis, liver dysfunction
146
Nervous system in sexual response
ANS: **parasympathetic** (pelvic splanchnic: inferior hypogastric from pelvic plexus S2,3,4) and **sympathetic** (sacral splanchnic: lower thoracic, upper lumbar)
Motor/sensory: **pudendal** nerve S2,3,4
147
4 stages of sexual response in women
1) **Excitement**: breast/genital vasocongestion (labio majora/minora, clitoris), vaginal lubrication, uterus pulls away from bladder, cervix pulls away from vagina, vagina lengthens
2) **Plateau**: clitoris retracts under clitoral hood, outer 1/3 of vagina swells, Bartholin's glands secrete mucous in introitus
3/4) **Orgasm/resolution**: sphincter surrounding meatus of urethra closes (sympathetic), contraction of vagina and uterus, dilation of cervix (spinal cord reflex via pudendal nerve), oxytocin released
148
4 stages of sexual response in men
1) **Excitement**: penile erection, scrotal vasocongestion and tensing, testicular elevation
2) **Plateau**: pre-ejaculatory secretion form bulbourethral glands
3/4) **Orgasm/resolution**: emission (sympathetic) is movement of ejaculate into prostatic urethra via peristaltic contractions of vas deferens, seminal vesicles, prostatic smooth muscle, sphincter muscles of urethra close; ejaculation (spinal cord reflex via pudendal nerve) is semen expelled from urethra, ischiocavernosis, bulbospongiosis, pelvic floor muscles contract, oxytocin released (may be important mediator of ejaculation)
149
Basson's sexual response cycle for women
Intimacy --\> intimacy needs stimuli --\> sought stimuli processed --\> arousal --\> sexual desire continue --\> positive physical and emotional outcome --\> intimacy
150
Classifications for female sexuality disorder
Symptoms must be **persistent** or **recurrent**, and must cause **personal distress**
Sexual **desire** disorder
Sexual **arousal** disorder
**Orgasmic** disorder
Sexual **pain** disorders (dyspareunia, vaginismus, noncoital)
151
Conditions associated with sexual pain
**Superficial**: vestibulodynia, vulvodynia, chronic vulvar dermatoses, condylomas, other derm condition
**Deep**: endometriosis, pelvic congestion syndrome, interstitial cystitis, uterine retroversion, uterine leiomyomas, adenomyosis, PID, pelvic adhesive disease, ovarian remnant syndrome, IBS, h/o sexual abuse
152
Male sexual dysfunction
Hypoactive sexual desire disorder (**reduced libido**)
**Erectile disorder/dysfunction**
**Premature ejaculation**
**Orgasmic disorder**
153
Treatment for premature ejaculation
**SSRI**
**Topical anesthetic**
**Condom**
**Squeeze techniques** (squeeze tip of penis)
154
Peyronie's Disease
Acquired **plaque-induced penile deformity** (curvature, indentation or hour glass shape)
3.2% prevalence
Pain with erection, ED, difficulty with intercourse
Usually secondary to **trauma** with bleeding, inflammation and fibrosis
13% regress, 40% progress and 47% no change
155
Histology of prostate cancer
**Normal** prostate glands are **large**, **irregular** and have **2 cell layers** (inner layer is luminal secretory cells and outer layer is basal cells)
**Prostate** **cancer** glands are **smaller** and **homogeneous** with **one single layer of cells**
156
Renal cell carcinomas that are malignant
**Clear cell** carcinoma: chicken wire pattern
**Papillary cell** carcinoma: multifocal, hemorrhage/necrosis, psammoma bodies, foamy macrophage; type 1 more benign looking and type 2 more malignant looking
**Chromophobe** RCC: solitary, solid, central fibrosis, clear cell boundary, pale flocculent cytoplasm, perinuclear halo, variable cell size
157
Renal cell carcinomas that are benign
**Oncocytoma**: mahogany brown, central stellate scar, sheet or island of cells, loose edematous stroma, no mitosis
