Patient J

The following is adapted from a case presented in the New England Journal of Medicine.
New England Journal of Medicine (2016) "Case 32-2016--A 20-Year-Old Man with Gynecomastia" 375: 1567-1579

The patient came to the hospital for a routine annual examination to establish adult care. He reported a 3-year history of bilateral breast enlargement, with no nipple discharge.

…Approximately 4 years before this evaluation, increased thirst and fluid consumption and frequent urination (four to five times during the day and up to three times each night) had developed. The patient’s parents reportedly worried that he might have diabetes, but a urinary glucose screen was negative and further evaluation was not pursued.

What is the term for excessive urine production?


Why does hyperglycemia (in diabetes mellitus) cause increased frequency of urination?


What sensors are responsible for promoting thirst?


In recent months, the frequency of urination had decreased and thirst was normal. He also reported a several-year history of blurred vision, which had been corrected with glasses; he had no diplopia and had occasional headaches after exertion. Puberty was reportedly normal. Approximately 8 months before this presentation, the frequency of shaving decreased from weekly to every 2 weeks.

On examination, the patient appeared young for his age, with minimal facial hair. The blood pressure was 98/62 mm Hg; the other vital signs were normal. The height was 179 cm, the weight 85 kg, and the body-mass index (the weight in kilograms divided by the square of the height in meters) 26.5. Both breasts were enlarged, with no nipple retraction, masses, or discharge. The testicles were small (approximately 2.5 cm in length).

This patient has gynecomastia, which refers to non-cancerous breast enlargement that occurs in a male. Male breast tissue has receptors for both estrogen and testosterone.  Gynecomastia is caused by a change in the ratio of estrogen to testosterone:  estrogen stimulates breast growth, while testosterone inhibits breast growth. Gynecomastia may transiently occur in newborns, during puberty, or in old age as a result of normal fluctuations of estrogen and testosterone.  However in this case, it appears to be due to a pathological process causing lower than normal secretion of testosterone.

What about this patient's presentation suggests that there is lower than normal secretion of testosterone?


Below is the doctor's comment:

Two striking features of this young man’s presentation are gynecomastia and decreased testicular volume. Gynecomastia is most often caused by an increase in the action of estrogen relative to that of testosterone.  The presence of both gynecomastia and decreased testicular volume narrows the differential diagnosis to disorders that would produce both effects — primary or secondary gonadal failure.

        regulation of reproductive functionGonadal failure (also called hypogonadism) involves deficient secretion of testosterone in a man. "Primary" hypogonadism means the defect is in the testes. Note however, that testosterone secretion is regulated through the hypothalamus and anterior pituitary (see figure). The anterior pituitary secretes two gonadotropin hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) that stimulate spermatogenesis and testosterone production in the testis. Thus, secondary hypogonadism can occur when there is deficient secretion of FSH and LH.

Urinalysis was normal.  Additional diagnostic blood tests were performed.  Important test results are presented in the table below.

Patient Value
Reference Range
Sodium (mmol/L)
160 135-145
Potassium (mmol/L)
3.6 3.4-4.8
Chloride (mmol/L)
125 100-108
Fasting glucose (mg/dL)
73 70-110
Osmolality (mOsm/kg of water)
334 280-296
Testosterone (ng/dL)
<20 270-1070
Luteinizing hormone (U/L)
0.1 2-12
Follicle-stimulating hormone (U/L)
0.1 1-12

The test results show much lower than normal secretion of FSH and LH, indicative of hypogonadism due to lack of gonadotropin stimulation. This is known as hypogonadotropic hypogonadism or "secondary gonadal failure". As well, the tests show an increase in plasma osmolality.

(Osmolality, like osmolarity, is a measure of the osmotic activity of a fluid. Osmolality measures the amount of solute per kilogram of water, osmolarity measures the amount of solute per liter of water.)

One more piece of the patient's history offers an important clue that could help to discriminate among these causes of hypogonadism. That patient had a 4-year history of polyuria and polydipsia that had recently started to resolve. Diabetes mellitus was considered and ruled out; however, diabetes insipidus was not.  Diabetes insipidus is caused by a loss of the action of vasopressin on the renal collecting duct to reabsorb water.

Vasopressin is a hormone that is released at the posterior pituitary by a type of neurosecretory cell. What type of neurosecretory cell releases vasopressin?


What type of neurosecretory cell regulates hormone secretion from the anterior pituitary?


In what part of the brain are neurosecretory cells located?


What sensors regulate vasopressin release, and where are they located?


Diabetes insipidus is typically associated with increased thirst in response to rising hypertonicity. If adequate fluids are available, the serum osmolality is rarely substantially higher than the normal range. This patient’s serum sodium level and osmolality were quite high (see table above); these findings, combined with a lack of polydipsia, raise concerns about an unusual condition known as adipsic diabetes insipidus.

"Adipsic" refers to a lack of thirst. Adipsic diabetes insipidus occurs because of dysfunction in the hypothalamic osmoreceptors. The patient was found to have a germinoma (a type of tumor) which was located in the suprasellar region, that is the area of the hypothalamus directly above the pituitary gland in the sella turcica. The patient's symptoms occurred because the tumor compromised the function of various cell types located in the suprasellar region of the hypothalamus:  magnocellular cells releasing vasopressin, parvocellular cells releasing GnRH, and the hypothalamic osmoreceptors that stimulate thirst and vasopressin secretion.

The patient had surgery, followed by chemotherapy and radiation to fully eliminate the tumor. He was treated with testosterone supplementation to address his hypogonadism. His diabetes insipidus was treated with desmopressin, a vasopressin agonist that specifically binds to the V2 vasopressin receptors in the kidney.

Does vasopressin increase or decrease water reabsorption in the kidney?


How does vasopressin work in the cells of the collecting duct to change water reabsorption?


...[The patient was initially] discharged with guidelines that specified how much fluid he should drink daily, since he did not have appropriate thirst. This regimen was accompanied by frequent laboratory checks to monitor sodium levels...Partial thirst returned approximately 1 year after treatment of the germinoma; the patient began reporting a sense of thirst when he had a high-normal or slightly high sodium level, and thus he was allowed to drink in response to thirst instead of using the prescribed fluid guidelines. His sodium level is now well controlled with daily desmopressin.