Male Reproductive Endocrinology Flashcards
Androgen Regulation
- negative feedback may occur by androgens directly or after conversion to estrogen
- testosterone (from Leydig cells) primarily involved in negative feedback on LH and GnRH, whereas inhibin (from Sertoli cells) suppresses FSH secretion
Tests of testicular function
- testicular size (lower limit = 4 cm x 2.5 cm)
- LH, FSH, total, bioavailable, and/or free testosterone
• human chorionic gonadotropin (hCG) stimulation test
■ assesses ability of Leydig cell to respond to gonadotropin
• semen analysis
■ semen volume, sperm concentration, morphology, and motility are the most commonly used parameters
• testicular biopsy
■ indicated with normal FSH and azoospermia/oligospermia
Hypothalamo-pituitary-gonadal axis
E45
Hypogonadism and infertility definition
• deficiency in gametogenesis or testosterone production
Hypogonadism and infertility etiology
- causes include primary (testicular failure), secondary (hypot alamic-pituitary failure), and idiopathic
- primary hypogonadism is more common than secondary
Diagnosis of Testosterone Deficiency Syndrome aka adult onset primary hypogonadism
- requires clinical manifestations of testosterone deficiency (see sidebar) AND documented testosterone levels below local lab ranges
- rule out secondary causes
Two distinct features of primary hypogonadism
- The decrease in sperm count is affected to a greater extent than the decrease in serum testosterone level
- Likely to be associated with gynecomastia
Hypergonadotropic hypogonadism (primary) hypogonadism definition
Primary testicular failure
Inc LH and FSH, Inc FSH:LH ratio
Dec testosterone and sperm count
Two features of secondary hypogonadism
- Associated with an equivalent decrease in sperm count and serum testosterone
- Less likely to be associated with gynecomastia
Hypergonadotropic hypogonadism (primary) hypogonadism etiology
Congenital Chromosomal defects (Klinefelter’s, Noonan) Cryptorchidism Dsorders of sexual development (DSD) Bilateral anorchia (vanishing testicle syndrome) Myotonic dystrophy Mutation of FSH or LH receptor gene Disorders of androgen synthesis
Germ cell defects
Sertoli cell only syndrome
Leydig cell aplasia/failure
Infection/Inflammation
Orchitis – TB, lymphoma, mumps, leprosy
Genital tract infection
Physical factors
Trauma, heat, irradiation, testicular torsion, varicocele
Drugs
Marijuana, alcohol, chemotherapy, ketoconazole, glucocorticoid, spironolactone
Hypergonadotropic hypogonadism (primary) hypogonadism diagnosis
Tes icular size and consistency (soft/firm)
Sperm count
LH, FSH, total, and/or bioavailable testosterone
hCG stimulation (mainly used in pediatrics)
Karyotype
Hypogonadotropic hypogonadism (secondary) hypogonadism definition
Hypothalamic-pituitary axis failure
dec LH + FSH (LH sometimes inappropriately normal) dec testosterone and sperm count
Hypogonadotropic hypogonadism (secondary) hypogonadism etiology
Congenital
Kallman’s syndrome
Prader-Willi syndome
Abnormal subunit of LH or FSH
Infection
Tuberculosis, meningitis
Endocrine Adrenal androgen excess Cushing’s syndrome Hypo or hyperthyroidism Hypothalamic-pituitary disease (tumour, hyperprolactinemia hypopituitarism)
Drugs
Alcohol, marijuana, spironolactone, ketoconazole, GnRH agonists, androgen/estrogen/progestin use, chronic narcotic use
Chronic illness
Cirrhosis, chronic renal failure, AIDS
Sarcoidosis, Langerhan’s cell histiocytosis hemochromatosis
Critical illness
Surgery, MI, head trauma
Obesity
Idiopathic
Hypogonadotropic hypogonadism (secondary) hypogonadism diagnosis
Testicular sze and consistency (soft/firm)
Sperm count
LH, FSH total, and/or bioavailable testosterone
Prolactin levels
MRI of hypothalamic-pituitary region
Hypogonadism and infertility treatment
• goal: testosterone replacement (improve libido, muscle mass strength, body hair growth, bone mass)
■ IM injection, transdermal testosterone patch/gel, oral
■ side effects: acne, fluid retention, erythrocytosis, sleep apnea, benign prostatic hypertrophy, uncertain effects on cardiac events/mortality in older men
■ contraindicated if history of metastatic prostate cancer, breast cancer, severe LUTS associated with BPH, uncontrolled or poorly controlled CHF PSA>4, hematocrit >50%
■ testosterone therapy only to treat symptoms of hypogonadism, often results in decreased spermatogenesis by further suppression of hypothalamic-pituitary-gonad axis
• goal: fertility
■ Treat underlying cause
■ GnRH agonist if hypothalamic dysfunction with intact pituitary, administered SC in pulsatile fashion using an external pump
■ hCG ± recombinant follicular stimulating hormone (rFSH) in cases of either hypothalamic or pituitary lesions
■ Dopamine agonist (eg. bromocriptine, cabergoline) if prolactinoma
■ testicular sperm extraction (TESE) or microscopic sperm extraction (MICROTESE) – only if testicular tissues are not functioning
Other causes of male infertility
- hereditary disorders: Kartagener syndrome (primary ciliary dyskinesia), cystic fibrosis
- anatomy: hypospadias, retrograde ejaculation
- obstruction: vasal occlusion, vasal aplasia, vasectomy, seminal vesicle disease
- sexual dysfunction: erectile dysfunction, premature ejaculation, infrequent coitus
- surgery: TURP, radical prostatectomy, orchiectomy
Defects in androgen action etiology
- complete androgen insensitivity (CAIS)
- partial androgen insensitivity (PAIS)
- 5-α-reductase deficiency
- mixed gonadal dysgenesis
- defects in testosterone synthesis
- infertile male syndrome
- undervirilized fertile male syndrome
Defects in androgen action clinical features
depends on age of onset
Effects of testosterone deficiency throughout development
First Trimester in utero - Incomplete virilization of external genitalia (ambiguous genitalia) Incomplete development of Wolffian ducts to form male internal genitalia (male pseudohermaphrodism)
Third Trimester in utero - Micropenis, Cryptorchidism (failure of normal testicular descent)
Prepuberty - Incomplete pubertal maturation (high pitch voice, sparse pubic + axillary hair, absence of facial hair) Eunuchoidal body habitus (greater growth of extremity long bones relative to axial bones) Poor muscle development, reduced peak bone mass
Postpuberty - Decrease in energy, mood, and libido Fine wrinkles in corners of mouth and eyes Decrease in pubic/axillary hair, hematocrit, muscle mass, strength, and BMD
Defects in androgen action treatment
appropriate gender assignment in the newborn
- hormone replacement or supplementation
- psychological support
- gonadectomy for cryptorchidism (due to increased risk for testicular cancer)
- reduction mammoplasty for gynecomastia
Infertility definition
Infertility: failure of a couple to conceive after 12 mo of regular intercourse without use of contraception in women <35 yr of age; after 6 mo of regular intercourse without use of contraception in women ≥35 yr
Infertility history and P/E
History • Partner status re: infertility • Length of time for attempt to conceive • Prior successes with other partners • Ejaculation problems • Frequency of interco rse • Prev Surg, Med Hx, STI Hx • Hx orchitis? Cryptorchidism? • Hx toxic exposure? • Medications • Alcohol and illicit drug use • Heat exposure: bath, sauna, whirlpool • Smoking
P/E • General (height, weight, gynecomastia, masculine) • Testicular size and consistency • Varicocele? • Pituitary disease? • Thyroid disease?
Infertility investigations
Should be considered for couples unable to conceive after 12 mo of unprotected and frequent intercourse. Consider earlier evaluation if suggestive medical Hx and physical, and in women ≥35 yr of age
• Semen analysis x 2 (sperm count, morphology, motility) • Scrotal/testicular U/S (look for varicocele) • Blood work: LH, FSH, testosterone, prolactin, thyroid function tests, DNA fragmentation of sperm, karyotype, Y chromosome deletion • Test female partner
Infertility treatment
- No specific therapy for majority of cases
- Treat specific causes
- Consider: intrauterine insemination, IVF, therapeutic donor insemination, testicular aspiration of sperm, adoption
Gynecomastia definition
- true gynecomastia refers to benign proliferation of the glandular component of the male breast, resulting in the formation of a concentric, rubbery, firm mass extending from the nipple(s)
- pseudogynecomastia or lipomastia refers to enlargement of soft adipose tissue, especially seen in obese individuals
Gynecomastia etiology for physiologic and pathologic
Physiologic
• puberty
• elderly (involutional)
• neonatal (maternal hormone)
Pathologic
• endocrinopathies: primary or secondary hypogonadism, hyperthyroidism, extreme hyperprolactinemia, adrenal disease
• tumours: pituitary, adrenal, testicular, breast, ectopic production of hCG
• chronic diseases: cirrhosis, renal, malnutrition (with refeeding)
• drugs: estrogens and estrogen agonists, spironolactone, ketoconazole, cimetidine, digoxin, chemotherapy, marijuana, alcohol
• congenital/genetic: Klinefelter’s syndrome, androgen insensitivity other: idiopathic (majority of gynecomastia is classified as idiopathic), familial
DOC TECH Drugs Other Congenital Tumour Endocrine CHronic disease
Gynecomastia pathophysiology
• hormonal imbalance due to increased estrogen activity (increased production, or increased availability of estrogen precursors for peripheral conversion to estrogen) or decreased androgen activity (decreased androgen production, binding of androgen to sex hormone binding globulin SHBG), or androgen receptor blockage)
Gynecomastia history and physical exam
- recent change in breast characteristics
- trauma to testicles
- mumps
- alcohol and/or drug use
- FHx
- sexual dysfunction
• signs of feminization
• breast
■ rule out red flags suggesting breast cancer: unilateral, eccentric, hard or fixed mass, skin dimpling or retraction, and nipple discharge or crusting
■ gynecomastia occurs concentrically around nipple, is not fixed to underlying tissue
• genito-urinary exam
• stigmata of liver or thyroid disease
Gynecomastia investigations
- laboratory: serum TSH, PRL, LH, FSH, testosterone, estradiol, LFTs creatinine, hCG (if hCG is elevated need to locate the primary tumour)
- CXR and CT of chest/abdomen/pelvis (to locate neoplasm)
- testicular U/S to rule out testicular mass
- MRI of hypothalamic-pituitary region if pituitary adenoma suspected
Gynecomastia treatment
initial observation for most men with gynecomastia
• medical
■ correct the underlying disorder, discontinue responsible drug
■ androgens for hypogonadism
■ anti-estrogens: tamoxifen has most evidence for benefit
■ aromatase inhibitors: less evidence of benefit as compared to anti-estrogens
• surgical
■ usually required for macromastia, gynecomastia present for >1 yr (fibrosis is unresponsive to medication), or failed medical treatment and for cosmetic purposes
Pubertal gynecomastia age, prognosis and approach
- This benign condition peaks between 13-14 years of age and spontaneously regresses in 90% of cases within 2yr
- Waiting is often the best approach
Occurrence of Gynecomastia
3 Peaks
Infancy 60-90%
Puberty 4-69%
Ages 50-80 24-65%
