Male Hypogonadism, Infertility & Gynecomastia

The male axis and how it fails

Division of labor. Pulsatile GnRH drives LH and FSH. LH acts on Leydig cells to produce testosterone, and the very high intratesticular testosterone concentration is essential for spermatogenesis. FSH acts on Sertoli cells, which make androgen-binding protein and inhibin B and nurture developing germ cells. Testosterone, partly after aromatization to estradiol, suppresses LH; inhibin B selectively suppresses FSH.

Reading the labs. Low testosterone with high LH and FSH means testicular (primary) failure; low testosterone with low or inappropriately normal LH and FSH means hypothalamic–pituitary (secondary) failure. Germ and Sertoli cells are more fragile than Leydig cells, so isolated tubular damage raises only FSH (lost inhibin B).

Causes of hypogonadism

Klinefelter syndrome (47,XXY). The most common chromosomal cause of male hypogonadism, affecting about 1 in 500–1,000 males, from meiotic nondisjunction. Seminiferous tubules hyalinize (azoospermia, low inhibin B, high FSH) and Leydig cells function poorly (low testosterone, high LH). High LH increases aromatization, so estradiol is relatively high and gynecomastia is common. Patients are tall with long legs, small firm testes, sparse body hair, frequent learning or language difficulties and a Barr body. Risks include male breast cancer, mediastinal germ cell tumors, SLE and osteoporosis. Microdissection testicular sperm extraction with ICSI can still allow paternity.

Other primary causes. Mumps orchitis follows parotitis by several days in postpubertal males, causing painful swelling and later atrophy; bilateral disease impairs fertility. In cryptorchidism, higher temperature damages germ cells (high FSH, usually normal testosterone) and germ cell tumor risk rises; orchiopexy at 6 to 12 months of age (by 18 months at the latest) improves fertility and permits self-examination but does not erase the tumor risk. Alkylating agents (cyclophosphamide, procarbazine), cisplatin and radiation cause azoospermia, so sperm should be banked before treatment.

Secondary causes. Hyperprolactinemia (prolactinoma) suppresses GnRH; opioids and glucocorticoids, including Cushing syndrome, blunt GnRH and LH; in obesity, adipose aromatase raises estradiol (suppressing LH) and low SHBG lowers total testosterone; hemochromatosis deposits iron in pituitary gonadotrophs. Check prolactin, iron studies and pituitary MRI as indicated.

Exogenous androgens. Testosterone or anabolic steroids suppress LH and FSH, so intratesticular testosterone collapses even while serum androgen activity is high, producing testicular atrophy and oligo- or azoospermia. Other effects include acne, erythrocytosis, lower HDL, gynecomastia from aromatization, and hepatotoxicity with 17α-alkylated oral agents. Spermatogenesis can take months to recover after stopping.

A man with hypogonadotropic hypogonadism who wants children needs hCG (LH activity) with or without FSH, or clomiphene; testosterone would further suppress spermatogenesis.

Male infertility

Approach. Infertility is failure to conceive after 12 months of regular unprotected intercourse; a male factor contributes in about half of couples, and semen analysis is the first test. Mechanisms fall into four groups.

Varicocele. Dilation of the pampiniform plexus feels like a bag of worms, enlarges on standing or Valsalva and collapses when supine. About 90% are left-sided because the left gonadal vein drains into the left renal vein at a right angle. Lost countercurrent cooling raises scrotal temperature and lowers sperm count, motility and morphology; it is the most common correctable cause of male infertility. A right-sided varicocele, or one that does not collapse supine, prompts imaging for a retroperitoneal or renal mass.

Y-chromosome microdeletions. Deletions in the azoospermia factor regions (AZFa, AZFb, AZFc) of Yq cause nonobstructive azoospermia or severe oligospermia with normal testosterone, often high FSH and small-normal testes. Sperm can sometimes be retrieved, mainly with AZFc deletions, but any son conceived by ICSI inherits the deletion. Karyotype and microdeletion testing are recommended in nonobstructive azoospermia.

Congenital bilateral absence of the vas deferens. Present in nearly all men with cystic fibrosis and in otherwise healthy men with CFTR mutations. Because the seminal vesicles are also hypoplastic, the ejaculate is low in volume, acidic and fructose-negative. Testes, testosterone and gonadotropins are normal, so sperm can be retrieved surgically for ICSI; the partner should be tested for CFTR mutations.

Primary ciliary dyskinesia. Autosomal recessive defects of axonemal dynein arms (for example, DNAH5) paralyze cilia and flagella: normal sperm counts with immotile sperm, chronic sinusitis, otitis, bronchiectasis and situs inversus in about half (Kartagener syndrome). Nasal nitric oxide is low, and affected women have subfertility and more ectopic pregnancies.

Retrograde ejaculation. Erection is parasympathetic (pelvic splanchnic nerves), emission sympathetic (hypogastric nerve) and ejaculation somatic (pudendal nerve). If the α1-controlled bladder neck fails to close during emission, semen enters the bladder: diabetic autonomic neuropathy, α1-blockers such as tamsulosin, TURP, retroperitoneal lymph node dissection and spinal cord injury are typical causes. Sperm appear in post-ejaculatory urine, and sympathomimetics such as pseudoephedrine may restore antegrade ejaculation.

Gynecomastia

Definition and mechanism. Benign proliferation of glandular ductal and stromal tissue forming a rubbery, often tender, concentric subareolar disc, usually bilateral. The common denominator is a higher estrogen:androgen ratio from more estrogen production or aromatization, less androgen production or action, or higher SHBG, which binds testosterone more tightly than estradiol. Pseudogynecomastia is subareolar fat without a glandular disc. Breast cancer is instead usually unilateral, hard, eccentric and fixed, with nipple retraction or bloody discharge.

Physiologic peaks. Newborns (maternal and placental estrogens; fades within weeks), puberty (transient relative estrogen excess; usually regresses within about 2 years) and older age (falling testosterone, more adipose aromatase, higher SHBG).

Pathologic causes. Cirrhosis reduces hepatic clearance of androstenedione, leaving more for peripheral aromatization, and raises SHBG; spironolactone often adds to it. Hyperthyroidism raises SHBG and aromatase activity. CKD impairs Leydig cells. Refeeding after starvation and any form of hypogonadism, including Klinefelter syndrome, can cause it. Leydig cell tumors secrete estradiol and testosterone; Sertoli cell tumors, as in Peutz–Jeghers syndrome, can overexpress aromatase; and hCG from testicular germ cell tumors (choriocarcinoma) or from lung and liver cancers drives Leydig-cell estradiol production.

Drugs by mechanism.

• Androgen receptor blockade: spironolactone, cimetidine, flutamide, bicalutamide
• Less androgen made or activated: ketoconazole, GnRH analogs such as leuprolide, 5α-reductase inhibitors (finasteride, dutasteride)
• Estrogen-like activity or estrogen source: estrogens, digoxin, aromatizable anabolic steroids
• Gynecomastia-sparing swaps: eplerenone instead of spironolactone, famotidine instead of cimetidine