PANCE Blueprint Endocrinology (7%)

Hypogonadism (Lecture)

Patient will present as → a 25-year-old male who is being seen for an immigration physical. On physical examination, you note delayed secondary sexual characteristics - childlike voice, bilateral gynecomastia, minimal axillary hair, small testes 3 MLS, and a small penis ( < 1 cm). The patient is normotensive (BP 110/70), weight 74.8kg, height 160.7 cm, BMI 29. When questioned, he reports a lack of early morning erection. No history of tiredness or blurred vision. Laboratory investigation reveals a 9 am testosterone 2.8 nmol/L (8-30), LH 37 U/l, FSH 30.1 U/l, Prolactin - 96 mIU/L, 9 am cortisol - 374 nmol/L, T4 13.19 pmol/L, and  TSH 1.3 mU/L. A chromosomal analysis reveals a 47 XXY, compatible with Klinefelter’s syndrome. MRI of the pituitary demonstrates a small pituitary, no mass lesion seen.

A failure of the gonads, testes in men and ovaries in women, to function properly. Production of a man's testosterone and a woman's estrogen are inhibited

  • If the onset is before puberty, growth and sexual development may be affected
  • After puberty, there may be sexual difficulties, reduced fertility, and absence of menstruation

Male hypogonadism

Decrease in effective testosterone levels as a result of

  • Decreased free concentration - often a result of decreased production (Leydig and pituitary dysfunction), also result of increased synthesis of SHBG
  • Decreased activity at receptor - often a result of androgen receptor deficiency

May be primary or secondary or age-related

Primary hypogonadism (testicular dysfunction) is a result of a decrease in testicular testosterone secretion and/or a decrease in spermatogenesis with an associated increase in gonadotropin levels as in Klinefelter syndrome, cryptorchidism, and following orchitis, testicular trauma, chemotherapy, and irradiation.

Primary hypogonadism / hypergonadotropic hypogonadism - ↓ function of Leydig cells - results in ↓ testosterone synthesis

  • Etiologies include alcoholic liver disease and damage to Leydig cells as a result of trauma, toxins, inflammation, and irradiation
  • Klinefelter syndrome, orchitis, congenital or acquired anorchia, testicular maldescent, testicular tumors
Secondary hypogonadism (pituitary and/or hypothalamus dysfunction) is due to hypothalamic-pituitary dysfunction, which results in a decrease in testosterone levels and/or spermatogenesis with gonadotropin levels that are subnormal or inappropriately within the normal range.

Secondary hypogonadism / hypogonadotropic hypogonadism: ↓ function of hypothalamus/pituitary - results in ↓ LH and FSH synthesis and consequent ↓ testosterone synthesis

  • Craniopharyngioma
  • Pituitary adenoma


• Total testosterone (early morning 8-10 AM) • LFTs, sHBG • Free testosterone (Calculated)

Cause and target organ damage

• LH/FSH • Prolactin • Iron studies • Semen analysis • DEXA bone scan • Genetic testing

Imaging: MRI of pituitary and Ultrasound of testes

Testosterone replacement therapy is indicated when patients have symptoms and signs of hypogonadism and serum testosterone levels that are consistently subnormal with levels of <250 ng/dl.

  • In patients with hypogonadotropic or secondary hypogonadism, chorionic gonadotropin and/or GnRH therapy can optimize spermatogenesis, whereas, generally in patients with primary hypogonadism, subnormal spermatogenesis and infertility are irreversible.

Nonpharmacologic therapy

  • Weight reduction, especially when it appears to be a major factor underlying male hypogonadism
  • Discontinuation of anabolic steroids, CNS-active medications, and narcotic abuse
  • Surgery or radiation therapy for patients with a pituitary functioning or non-functioning tumor with visual field abnormality and headaches who are not candidates for further medical therapy or have been unsuccessfully treated with medication
  • Surgery indicated for chronic gynecomastia and, occasionally, in cases with recent-onset gynecomastia that has not responded to testosterone replacement therapy

Chronic therapy testosterone formulations may include:

  • Depo-Testosterone 150 to 200 mg is injected intramuscularly every 2 weeks
  • Testosterone adhesive patch (Androderm) delivers 2.5 or 5 mg of testosterone when applied nightly to the back, abdomen, upper arms, or thighs. Serum testosterone levels rise to within normal range in a few hours after application and, thereafter, are relatively stable. Daily doses of up to 10 mg may be necessary
  • Testosterone gel - The gel is applied daily in the morning by hand over the shoulder, upper arms, or abdomen
  • Testosterone pellets: 3 to 6 pellets of testosterone each containing 75 mg of testosterone are surgically inserted subcutaneously every 3 to 6 months and provide relatively stable serum testosterone levels


Monitoring should be done two to three months after the initiation of treatment and after changing a dose. When the dose appears to be stable, monitoring every 6 to 12 months should suffice

  • Depo-testosterone: Serum testosterone should be measured midway between injections in men who are receiving testosterone enanthate or cypionate, and the value should be mid-normal, eg, 500 to 600 ng/dL. The dose should be reduced if higher values are obtained
  • Transdermal: The serum testosterone can be measured at any time in men who are using any of the transdermal preparations, with the recognition that the peak values occur six to eight hours after application of the patch
  • Gel: two serum testosterone measurements before making dose adjustments. The therapeutic goal should be a testosterone value well within the normal range (400 to 700 ng/dL [13.9 to 24.3 nmol/L])

osmosis Osmosis
Question 1
A 57-year-old male with a history of metabolic syndrome, obesity, sleep apnea, chronic back pain, presents to clinic with decreased libido, erectile dysfunction, and depression which have been going on for about 6 to 12 months. He has two biological children and reports no prior infertility and went through puberty normally. He is on chronic narcotic medications for his back pain. His sleep apnea is not currently treated as he doesn’t like to use machines while sleeping. Which laboratory findings would be characteristics of secondary hypogonadism?  
Normal gonadotropins (LH/FSH) and normal testosterone
High gonadotropins and low testosterone
High gonadotropins and high testosterone
Low gonadotropins and low testosterone
Low gonadotropins and high testosterone
Question 1 Explanation: 
Low testosterone with uncompensated (low) gonadotropins would suggest secondary hypogonadism (pituitary and/or hypothalamus dysfunction). Low testosterone with elevated gonadotropins would suggest primary hypogonadism (testicular dysfunction).
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References: Merck Manual · UpToDate

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