male gonadal disorders Flashcards
describe the HPG axis in the adult male
- Hypothalamus secretes GnRH, stimulating the anterior pituitary to release FSH and LH
- pulsatile release every 2 hours - FSH stimulates the Sertoli cells of the testes to regulate spermatogenesis¹ and produce inhibin B
- inhibin B provides a negative feedback - LH stimulates testosterone synthesis in the Leydig cells of the testes
- testosterone provides a negative feedback and assists FSH in spermatogenesis
describe the testosterone synthesis in the testes
- LH attaches to the Leydig cells via LH receptor which stimulates the uptake of cholesterol by the cellular mitochondria and initiates steroidogenesis
- Testosterone can be converted into Dihydrotestosterone¹ (DHT) or Estradiol
- majority of this conversion takes place in the peripheral tissues
what are the additional testosterone functions
- sexual health
- libido, development and maintenance of an erection, strength of orgasm - affects mood/behavior
- increases aggression
- decreases anxiety/depression
- provides sense of mental well-being - improved cognition/memory
95% of circulating testosterone is synthesized where? the remainder is produced by what?
in testicles
by the adrenal gland
most circulating testosterone are in what state?
bound to plasma proteins (98%)
testosterone is more commonly bound to what protein?
what is the other?
sex hormone–binding globulin (SHBG) (60%) - SHBC has a greater affinity for binding testosterone than albumin
albumin (38%)
which protein can easily dissociate from testosterone so that the testosterone can become active
albumin
testosterone is metabolized where and excreted where?
liver
kidneys
what part of the adrenal gland produces greater amounts of androgens
zona reticularis
gonadarche/sex maturation is accelerated by what two processes
activation of the HPG axis
production of GnRH, LH, FSH and testosterone
gonadarche begins at what age?
9
what is the tanner stage (male)
- Begins with growth of testes and sparse pubic/axillary hair
- Followed by phallic growth; thicker pubic hair and continued testicular growth
- Other characteristics
- deepened voice
- facial hair growth
- prostate growth
- long bone growth with eventual - epiphyseal closure
What PE assessment could be done to to assess male sexual characteristic development
testicle size - measure with a Prader orchidometer - beads labeled by volume
a pt testicles size is 2mL, what would that put them on the prader orchidometer?
prepubertal size (1-3mL)
a pt testicle size is 11mL, what would that put them on the prader orchidometer
pubertal (4-12mL)
a pt testicle size is 22mL, what would that put them on the prader orchidometer
adult (12-25mL)
you don’t have a orchidometer, how could you assess male sexual characteristic development?
Testicular size >2.5 cm longitudinally generally indicates that the child has entered puberty
what is precocious male puberty?
evidence of puberty in boys before age 9
The patients Tanner stage should be documented in all patients being assessed for precocious puberty
what are the two types of precocious male puberty. describe each
- Isosexual - premature development of phenotypically appropriate secondary sexual characteristics
- Heterosexual - development of secondary sexual characteristics of the opposite sex
what are the two subtypes of isosexual precocity? describe each
- gonadotropin-dependent [central precocious puberty (CPP)] - premature activation of the GnRH pulse generator leading to inappropriately elevated
- gonadotropin (LH/FSH) levels that are inappropriately elevated for age - gonadotropin (LH/FSH) levels for age
gonadotropin-independent - (peripheral precocious puberty) - androgens from the testis or the adrenal glands are increased, with low levels of gonadotropins
3 causes of CPP
- Idiopathic MC
- Hypothalamic hamartoma or other lesions
- CNS tumor or inflammatory state
5 causes of PPP
- Congenital adrenal hyperplasia
- hCG/androgen-secreting tumor
- McCune-Albright syndrome
- Familial male-limited precocious puberty
- Exogenous androgens
what should be excluded when trying to diagnose CPP? how would you do it?
CNS lesions
by history, neurologic examination, and a brain MRI with contrast
what historical red flags indicate a CNS lesion that is causing CPP
- headaches
- new onset seizures
- N/V
- memory or personality changes
- loss of balance, visual changes
PE red flags that indicate CNS lesion causing CPP
abnormal neuro exam
how does a Human chorionic gonadotropin (hCG) secreting tumor cause PPP
hCG activates the LH receptors on the Leydig cells stimulating testosterone production
common sites of tumor locations for hCG secreting tumor
gonads, brain, liver, retroperitoneum, and anterior mediastinum
an Androgen secreting tumor is found that is causing PPP, where could it be?
adrenal tumor of the zona reticularis
develop premature virilization because of excessive androgen production by the adrenal gland due to enzyme deficiency in the steroidogenesis pathway
what is this condition?
Congenital Adrenal Hyperplasia
the development of male physical characteristics in a female or precociously in a male
Virilization
how does McCune-Albright syndrome (MAS) cause PPP
Acquired mutation in the Gsα subunit activating adenylyl cyclase resulting in steroidogenesis stimulating testosterone production
McCune-Albright syndrome (MAS) is more common in who?
females
pt comes in with bone dysplasia, a cafe-au-lait, and is experiencing precocious puberty, what could be the cause of their precocious puberty?
McCune-Albright Syndrome
McCune-Albright Syndrome is associated with stimulation of other endocrine systems, such as:
thyrotoxicosis
growth hormone excess (gigantism or acromegaly)
Cushing Disease
how does familial male-limited precocious puberty cause Gonadotropin Independent Precocious Puberty - (Peripheral)
An autosomal dominant disorder caused by activating mutations in the LH receptor, leading to testosterone synthesis
what info do we need to get from their history to understand why their Precocious Male Puberty is happening
- Onset
- Progression - (rapidity of symptoms in timeframe)
- Associated symptoms
- assess for CNS disease - HA’s, changes in behavior or vision, seizures, previous hx of CNS disease or trauma - Exposures
- exogenous sex steroid exposure - Family history
- timing of pubertal onset in parents and siblings
- genetic disorders
PE when youre suspicious of precocious male puberty
- Height, weight and height velocity over last 6-12 months
- Pubic hair disbursement (often first symptom noticed)
- Testicular size
- Testicular tumor - asymetrical or unilateral testicular enlargement
- Neurologic exam - if suspicion of CPP on history
during your PE you notice that there are enlarged testicles (measuring >2.5 cm long or Prader orchidometer >4 ml). what could be the cause of their precocious puberty?
CPP; hCG secreting tumor (mild enlargement)
during your PE you notice that the testes remain small. what could be the cause of their precocious puberty?
adrenal etiologies (CAH, adrenal tumor), familial male precocious puberty and exogenous androgens
you want to assess bone age of a pt. what do you order?
what 3 things are you assessing?
imaging - x-ray of left wrist and hand
- advanced bone age expected with precocious puberty
assess linear growth, skeletal maturation (bone age) and secondary sexual characteristics over the past 6 months
if you see rapid growth/change from the bone imaging, what is that indicative of?
high concentrations of sex steroids due to CPP or peripheral precocity
if you see slow change from the bone imaging, what is that indicative of?
minimal or no change of breast, pubic hair, or genital development - more likely to be benign pubertal variant with low sex steroid concentrations
initial labs for precocious puberty
- Serum testosterone
- increased in all cases - Serum LH and FSH levels
- elevated in CPP
- low/normal in peripheral causes - based upon DDx
- Serum hCG - elevated in hCG tumor
- Dehydroepiandrosterone (DHEA) - elevated in CAH and adrenal tumors
if the initial labs are normal, what are you ordering for precocious puberty
- 17α-hydroxyprogesterone
- elevated in CAH
- normal in other etiologies - GnRH-analogue (leuprolide) stimulation test
- differentiates CPP from peripheral etiologies
— rise in LH indicates CPP
— lack of rise in LH in peripheral etiologies
if all else fails with labs for precocious puberty, what can you order
- Genetic testing if concern for LH/ Gsα subunit mutations
- if clinical presentation is consistent with MAS
imaging evaluation of precocious male puberty
- MRI brain - r/o CNS lesion with CPP or elevated hCG
- CT chest/abdomen - r/o hCG tumor of the mediastinum, liver, or peritoneum or androgen secreting adrenal tumor
- Testicular US - Leydig-cell tumor
management for Gonadotropin-Dependent - CPP
- tx underlying cause if known
- Idiopathic CPP
- long-acting GnRH agonists - Monitor: halting of symptoms, suppression of LH/FSH/testosterone
- puberty resumes after discontinuation of the GnRH agonist
what medication causes chronic stimulation of the GnRH receptors in the pituitary leads to desensitization of the receptor and decreased release of LH/FSH
long-acting GnRH agonists
effects of LA GnRH agonists with Gonadotropin-Dependent - CPP
- halts early pubertal development
- delays bone maturation, prevent early epiphyseal closure, thus increasing final height
initial stimulation with LA GnRH agonist will do what
increase LH/FSH and sex steroid production
prolonged stimulation of LA GnRH agonist will do what
reduces LH/FSH to prepubertal levels
tx options for precocious male puberty
- Tumors - surgical removal
- Exogenous steroids - identify and remove source
- CAH - suppress androgen production with glucocorticoids
- McCune-Albright syndrome and Familial male-limited precocious puberty
- combo of androgen receptor antagonist (spironolactone) + aromatase inhibitors [anastrozole (Arimidex)] - blocks conversion of testosterone to estradiol
- Alternative: Steroid synthesis inhibitor - ketoconazole - requires high dosing leading to a risk of hepatotoxicity
- Goal: halt further sexual development and prevent premature closure of the epiphyseal plates
what is the enzyme that converts testosterone to estrogen resulting in bone maturation
aromatase
what is delayed male puberty
lack of testicular enlargement by age 14 OR incomplete genital growth within 5 years of initial signs of puberty
categories of delayed puberty
- Primary hypogonadism
- hypergonadotropic hypogonadism secondary to primary gonadal failure (15%) - Secondary hypogonadism
- constitutional delay of growth and puberty¹ (CDGP) (60%)
- functional hypogonadotropic hypogonadism caused by systemic illness or malnutrition (20%)
- hypogonadotropic hypogonadism caused by genetic or acquired defects in the hypothalamic-pituitary region (10%)
hx findings of 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, cryptorchidism
- synkinesia - associated with Kallmann syndrome
- renal agenesis - neuro symptoms
- HA, visual disturbances, dyskinesia, seizures, and intellectual disability - FHX of delayed/absent puberty - “late bloomer” - indicates CDGP
clinical assessment for delayed male puberty
- Height/arm span - arm span exceeding height by > 5 cm suggesting a delayed epiphyseal closure due to hypogonadism
- Secondary sexual characteristic rated on Tanner staging
- Testicle size measure with a Prader orchidometer - beads labeled by volume
- Prader orchidometer - Prepubertal (1 to 3 mL)
- Testicular size <2.5 cm longitudinally
initial assessments of delayed male puberty
- Xray - left hand and wrist to assess bone age
- If bone age is delayed relative to chronological age and growth velocity is normal, CDGP is the most likely etiology - Serum testosterone - low for age
- Gonadotropins
- LH/FSH elevated - primary hypogonadism/gonadal failure
- LH/FSH low for age - secondary hypogonadism
if (+) family history of delayed puberty with low LH/FSH it is most likely what?
likely CDGP
if (+) family history of delayed puberty with low LH/FSH it is most likely what?
likely CDGP
if there is - fhx of delayed male puberty, what is the next step?
look for other etiologies
- pituitary hormone deficiencies, malnutrition, hyperprolactinemia, chronic diseases, CNS disorders
- Imaging (CT/MRI) of suspected tumors
management for delayed male puberty
- presumed constitutional delay of growth and puberty
- reassurance with f/u vs. testosterone therapy
— consider testosterone if patients self-esteem regarding stature and/or prepubertal appearance is affected - Testosterone replacement therapy
- Secondary hypogonadism - interrupted therapy after 6 months to determine whether endogenous LH and FSH secretion has ensued
- Primary hypogonadism - indefinite therapy - Adding an aromatase inhibitor may allow attainment of greater final adult height
a failure of the testes to produce an adequate amount of testosterone
Hypogonadism
3 classifications of Hypogonadism
- hypergonadotropic (primary)
- pathology in the testes themselves
- low testosterone with high LH - hypogonadotropic (secondary/tertiary)
- insufficient hormone secretion from the pituitary/hypothalamus
- low testosterone with normal/low LH - both simultaneously
presentation of hypogonadism is dependent upon what 3 things
- age of onset
- severity of testosterone deficiency
- both testosterone and spermatogenesis are affected
Onset of Hypogonadism beginning between the 2nd-3rd month of fetal development would later develop what?
ambiguous genitalia/male pseudohermaphroditism
Onset of hypogonadism during 3rd trimester of fetal development would later develop what?
defects in testicular descent leading to cryptorchidism as well as micropenis
Onset of Hypogonadism after birth and before adulthood would present how?
Symptoms of delayed puberty
Hypogonadism Onset after puberty would present how?
- Decreased energy, loss of libido, decreased morning erections within days-wks 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
Goals of clinical evaluation of hypogonadism
- determine if s/s indicate that onset was before or after puberty
- determine if patient has normal genitalia
- determine if hypogonadism is primary or secondary
management of hypogonadism
- Address underlying etiology if applicable
- Testosterone Therapy Indications
- lack of puberty onset by age 14
- primary testicular failure (hypergonadotropic hypogonadism)
- severe hypogonadotropic hypogonadism of any etiology with serum testosterone levels less than 150 ng/mL
- age-related hypogonadism
what is “andropause”
a decrease in testosterone production starting between the 4th-6th decades of life and progresses slowly with age
Andropause has a greater rate in who?
obese men and those with chronic illness
pathophys of Age Related Hypogonadism
defects at all levels of the HPG axis:
1. pulsatile GnRH secretion diminishes
2. LH response to GnRH is reduced
3. testicular response to LH becomes impaired
what is likely the main cause of declining androgen levels
testis dysfunction
when should screening for age related hypogonadism occur?
utilized only when symptoms are present
tx for Age Related Hypogonadism
Testosterone therapy
1. recommended if at least 3 symptoms of androgen deficiency who have testosterone levels <200 ng/dL and benefits outweigh risk
- S/S: erectile dysfunction, poor morning erection, low libido, depression, fatigue, and inability to perform vigorous activity
Testosterone therapy is not recommended for who with those experiencing hypogonadism?
all older men with low testosterone levels
goal of therapy for testosterone therapy
development or maintenance of secondary sexual characteristics and increased libido, muscle strength, fat-free mass, and bone density
total testosterone includes what?
includes both protein bound and unbound
normal value based upon sex and age
Diurnal variation of total testosterone is based upon what?
pulsatile LH release
8 AM - highest levels
8 PM - lowest levels
what is preferred when collecting total testosterone
Fasting specimen between 8-10 AM preferred
- food and glucose suppresses serum testosterone concentration
- Repeat if first assessment is low
Assesses amount of testosterone not bound to albumin or SHBG
Free Testosterone
indication for collecting Free Testosterone
abnormal total testosterone
in most cases, free testosterone will have what relationship with total testosterone.
if it does not follow that normal relationship, what would that indicate?
linear correlation to total testosterone
consider abnormality in function or level of SHBG
a suspected abnormality in testosterone binding to SHBG coexists with hypogonadism
free testosterone assay isn’t readily available
what are you ordering?
Sex-Hormone Binding Globulin
Sex-Hormone Binding Globulin binds to 3 sex hormones:
- testosterone
- dihydrotestosterone
- estradiol (estrogen)
increased SHBG indicates?
age, liver disease, hyperthyroidism, anorexia, HIV and antiseizure drugs
decreased SHBG indicates?
obesity, hypothyroidism, insulin resistance, DM2, exogenous androgens/anabolic steroids, glucocorticoids, nephrotic syndrome
you want to evaluate low testosterone levels, what else could you order to do so?
LH/FSH
high/low basal LH indicates?
high - primary hypogonadism
normal/low - secondary hypogonadism
high/low basal FSH indicates?
increase - damage to the seminiferous tubules
normal/low - secondary hypogonadism
Indicated when suspicion of damage to Sertoli cells
what lab are you getting? a low reading indicates?
inhibin B
decreased when there is damage to the seminiferous tubules
if infertility is suspected, what are you ordering?
Semen Analysis
Most often a normal semen analysis excludes gonadal dysfunction
what makes a semen analysis sufficient enough to diagnosis disturbance of testicular function
At least 3 semen samples should be examined over a 2- to 3-month interval
Collection after 2 to 7 days of sexual abstinence with examination occurring within 1 hour after collection
Sperm maturation cycle requires how long?
appx 3 months
factors that can lower semen counts
fever, trauma, drug exposure, recent ejaculation
when is testicular bx indicated?
hypogonadal men with normal-sized testes and azoospermia to distinguish between spermatogenic failure and ductal obstruction
Harvesting of sperm for ICSI (intracytoplasmic sperm injection)
enlargement of the male breast resulting from excess estrogen action and is usually the result of an increased estrogen/androgen ratio
Gynecomastia
True gynecomastia is associated with ?
glandular breast tissue that is >4 cm in diameter and often tender
ddx for Gynecomastia
Pseudogynecomastia - excessive adipose tissue
Breast cancer
physiology of Gynecomastia
- Newborn - transplacental transfer of maternal and placental estrogens
- During puberty (age 10-14) - high ratio of estrogen to androgen in early stages of puberty
- Aging - increase in fat tissue and increased aromatase activity (leading to increased estradiol)
(Normal physiologic gynecomastia)
Pathology of Gynecomastia
increased aromatase activity
drugs (20% cases)
causes/etiology of Gynecomastia
- testicular or hCG tumors
- gonads, brain, liver, retroperitoneum, and anterior mediastinum - adrenal tumors
- chronic liver disease
- malnutrition
- hyperthyroidism
- familial gynecomastia
clinical findings/hx for Gynecomastia
- onset, progression, pain/tenderness, location (bilat/unilateral)
- pain/tenderness = in adolescents; absent in adults - (+) nipple sensitivity
- drug hx
- PMH
- assess for liver and kidney disease, hyperthyroidism, hypogonadism
PE of gynecomastia
breast exam: seated and supine
1. Tissue consistency
- breast tissue = glandular, tender
- fatty tissue = diffuse, nontender
2. Location
- breast tissue: subareolar, symmetrical, bilateral and tender (early on)
- malignancy: unilateral, nontender and offset from areola
3. assessment of virilization
- testicular examination & measurement
- secondary sexual characteristics
4. Abdominal exam
- adrenal mass, hCG secreting mass of the liver, retroperitoneum,
Red flags for breast malignancy indicating need for imaging:
new onset or rapid unilateral growth
non-tender tissue
fixed mass lateral to areola
management for Gynecomastia
- Pubertal - reassurance - symptoms will resolve within 1-2 yr
- consider medical therapy if patient’s mental health is affected - Drug induced - discontinue therapy (if appropriate) and monitor for improvement in symptoms (it may take several months)
- Androgen deficiency - testosterone therapy
- hCG tumor - imaging (CT/MRI) and refer to general surgeon
- Aromatization
- assess for Sertoli and adrenal tumors - Other causes of gynecomastia (present <12 months)
- observe x 3 months
— no regression: begin 9-12 months of medical therapy - selective estrogen receptor modulator (tamoxifen), aromatase inhibitor [anastrozole (Arimidex)] - Surgical correction for persistent or severe symptoms > 12 months
indications of testosterone therapy
- low testosterone levels resulting in features of androgen deficiency
- benefits only proven in documented androgen deficiency, as demonstrated by testosterone levels that are well below the lower limit of normal
- does not restore fertility
schedule of testosterone therapy
III
what testosterone therapy is injectable
what is the regimen
how does it affect testosterone levels
Testosterone enanthate and T. cypionate
1. 24 hrs after administration - testosterone levels rise into the high-normal, then gradually decline into the hypogonadal range over the next 2 weeks.
2. bimonthly regimen therefore results in peaks and troughs in testosterone levels that are accompanied by changes in a patient’s mood, sexual desire, and energy level
what testosterone therapy is injectable LA? describe the regimen/dosing
Aveed - testosterone undecanoate)
1. First dose is followed by 2nd dose at 4 wks with all subsequent doses occurring every 10 wks
2. Requires in office administration followed by 30-minute observation
3. Provider must have completed training via AVEED® Risk Evaluation and Mitigation Strategy (REMS) Program
which testosterone therapy is in gel and solution form? describe the regimen
Gel (AndroGel, Testim, and Fortesta) and Solution (Axiron)
1. Gel - applied daily to area not easily accessed by others
2. Testosterone levels should normalize within a month and remain steady throughout 24 hours
- Adjust the dose if needed based on testosterone level monitoring
what are the other routes of testosterones that are used less frequently
- Pellets (Testopel)
- 3-6 pellets surgically inserted q 3-6 months into the buttocks, lower abdominal wall, or thigh - Nasal gel (Natesto)
- new to market
- TID dosing - Oral testosterone undecanoate (Jatenzo)
- BID dosing
management for testosterone therapy
- Evaluate patient 3–6 months after treatment initiation and then annually
- Check hematocrit at baseline, at 3–6 months and then annually.
- Measure bone mineral density of lumbar spine and/or femoral neck after 1–2 years of testosterone therapy in hypogonadal men with osteoporosis
- men >40 y/o + PSA >0.6 ng/mL = digital rectal examination and check PSA level before initiating treatment, at 3–6 months
- urologic consultation (if needed)
- Evaluate formulation-specific adverse effects at each visit
injectable testosterone should monitor their serum testosterone when?
midway between injection
transdermal gels/sol testosterone should monitor their serum testosterone when?
any time after pt has been on tx for at least 1 wk
nasal gel testosterone should monitor their serum testosterone when?
periodically 1 month after initiation
pt on testosterone therapy has a hematocrit >54%, what is the next step
- stop therapy until hematocrit decreases to a safe level
- evaluate for hypoxia and sleep apnea
- reinitiate therapy with a reduced dose.
when if urologic consultation needed when on testosterone therapy
- An increase in serum PSA concentration >1.4 ng/mL within any 12-month period of testosterone treatment.
- A PSA velocity >0.4 ng/mL per year using PSA level after 6 months of testosterone administration as reference (applicable only if PSA data are available for a period exceeding 2 years).
- Detection of a prostatic abnormality on digital rectal examination.
Conditions in Which Testosterone Administration is Associated with Very High Risk of Serious Adverse Outcomes:
Breast cancer
Metastatic prostate cancer
Conditions in Which Testosterone Administration is Associated with Moderate to High Risk of Adverse Outcomes:
Undiagnosed prostate nodule or induration
PSA >4 ng/mL (>3 ng/mL in individuals at high risk for prostate cancer, such as blacks and men with first-degree relatives who have prostate cancer)
Erythrocytosis (hematocrit >50%)
Severe lower urinary tract symptoms associated with benign prostatic hypertrophy as indicated by the American Urological Association/International prostate symptom score >19
Uncontrolled or poorly controlled congestive heart failure
what are the endocrine society’s guidelines
- avoid testosterone replacement in patients with mild vague symptoms and borderline/low testosterone on only one occasion
- “trial” therapy should be avoided
- testosterone therapy suppresses the pituitary-testicular axis
- testosterone therapy suppresses spermatogenesis and decreases testicular size
