10/12- Disease of Male Reproduction Flashcards
What is seen here?
- Red arrow
- Yellow arrow
- Blue arrow
- Green arrow
- 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
What are Sertoli cells?
- Function
- Hormones produced
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
How do levels of plasma testosterone change over life?
- 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
T/F: Aging is associated with decreased T in healthy males
False
Describe steroidogenesis?
- Cholesterol = initial substrate
- Binds LDL cholesterol receptor or produced endogenously
- StAR
- Pregnenolone
Done in the fetal Leydig cell
What are typical testicular steroid secretion rates?
- Testosterone: 7 mg/day
- DHT: 560 ug/d (+ some peripheral conversion)
- E2: 21 ug/d (+30 ug/d from peripheral conversion of testosterone)
Describe the different types/forms of testosterone in regards to total levels?
Which form(s) is/are bioavailable?
- SHBG bound (54%)
- Albumin bound (44%)
- Free (2%)
Bioavailable:
- Free
- Albumin bound
These 2 forms bind the AR receptor in the target tissue
What are effects of T/DHT-AR on the human body?
- 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
What are some Androgen Insensitivity Syndromes?
Symptoms
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
_____ is essential for the development of the male sexual phenotype during embryologic development
AR (androgen receptor) signaling is essential for the development of the male sexual phenotype during embryologic development
What is seen in SRD5-2 deficiency?
At birth:
- Lack of phallus
- Bifid scrotum
- External female genitalia
At puberty:
- Develop phallus
- Phenotype becomes male in adulthood
Why do SRD5-2 deficient people have female phenotype at birth?
How do they undergo near normal puberty?
- DHT is essential for virilization of external genitalia (and the prostate)
- Pubescent changes depend on testosterone, not DHT
What are abnormalities of the adult phenotype in SRD5-2 deficient individuals?
- Lack of male pattern baldness
- Lack of body hair (facial and pubic hair present
- Small prostate
What happens when there is a lack of testosterone production during the 2nd half of fetal devo and 1st year of life?
Testosterone at this stage is responsible for growth of penis and descent of testicles
- Micropenis/cryptorchidism
What is the phenotype of estrogen insenstivity and aromatase deficiency syndromes?
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
Epidemiology of Hypogonadism
- Prevalence
- 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%)
What are signs and symptoms of androgen deficient states?
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
What is eunucoidism?
- 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)
What is Kallmann’s syndrome?
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)
Describe the evaluation of hypogonadism
- 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
What are causes of primary testicular failure?
- 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
What are causes of secondary testicular deficiency?
(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)
What are causes of tertiary testicular deficiency?
- 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
What are the expected effects of:
- Testosterone
- DHT
- E2
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
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
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
What is erectile dysfunction (ED)?
Inability to reach an erection sufficient to complete sexual intercourse
T/F: Sexual dysfunction prevalence increases with age?
True
- Mostly due to rising rates of moderate/complete ED
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)
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
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
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
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
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)
How is ED diagnosed?
- Secondary Sexual Characteristics
- Pulses and sensation
- Testicular size
- Anatomy of the penis (r/o Peyronie’s)
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
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
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
Pathogenesis of gynecomastia?
Useful to think of an altered estrogen/androgen ratio at the level of the breast as the cause of the gynecomastia
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)
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
Drug induced gynecomastia can occur with what drugs?
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
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
