Original case Ueda et al

A 50-year-old female was referred to our hospital for hypertension. She also had secondary amenorrhea.

Q What is the definition of secondary amenorrhea ?

  • Absence of menses for 3 consecutive cycles
  • or Absence of menses for 6 months
  • In a women who have previously normal menstrual cycles

She first menstruated at the age of 13, but her menstruation became sparse and stopped at the age of 18. Although estrogen-progesterone therapy was initiated, she decided to discontinue therapy at the age of 25.

Physical examination revealed a height of 167.2 cm, body weight of 61 kg, and blood pressure of 166/122 mm Hg without antihypertensive treatment. She lacked axillary and pubic hair but had normal breast development.

Laboratory test results were unremarkable except for hypokalemia (2.9 mEq/L). Computed tomography revealed bilateral adrenal hyperplasia. (Figure)

Magnetic resonance imaging revealed an atrophic uterus and ovaries (data not shown).

Q What are the causes of bilateral adrenal gland enlargement ?

  1. Cushing’s disease
  2. ACTH independent macronodular adrenal hyperplasia
  3. Congenital adrenal hyperplasia
  4. Bilateral adrenal lymphoma
  5. Infection of adrenal gland bilateral like tuberculosis or fungal
  6. Idiopathic hyperaldosteronism
  7. Bilateral adrenal carcinoma
  8. Bilateral adrenal myelolipoma
  9. Adrenal metastasis
  10. Adrenal hemorrhage
  11. primary pigmented nodular adrenal dysplasia
  1. What are your differential diagnosis at this stage ?

At this stage, the positive clinical findings are :

  1. Hypertension (we are assuming it is refractory)
  2. Hypokalemia
  3. Bilateral adrenal gland enlargement
  4. Secondary amenorrhea (?? Is it important for a 50 year old)

My first thinking would be to consider Primary hyperaldosteronism. Maybe , it is IHA (idiopathic hyperplasia of adrenals). It is not given if this women has any clinical features of Cushing’s syndrome. However, I would also screen for Cushing’s.

Q What are the investigations you would propose ?

I would first propose doing an Aldosterone/ Renin ratio. I would also consider  an overnight dexamethasone suppression test.

Q Which patients should be tested for Primary aldosteronism ?

  1. JNC grade 2 (>160) and Grade 3 (>180) hypertension
  2. Hypertension resistant to treatment with drugs
  3. First degree Relatives of Patients with PA having hypertension
  4. Hypertension with Adrenal incidentaloma
  5. Hypertension with Hypokalemia – spontaneous or Diuretic induced
  6. Early onset hypertension or CVA (<20 years)

Q Which are the endocrinal causes of hypertension ?

  1. Adrenal
    1. Cushing’s syndrome
    2. Congenital adrenal hyperplasia
      1. 17 alpha hydroxylase deficiency
      2. 11 beta hydroxylase deficiency
    3. Pheochromocytoma
    4. Primary hyperaldosteronism
  2. Insulin resistance and metabolic syndrome
  3. Acromegaly
  4. Thyroid disorders
    1. Hyperthyroidism – increase of systolic blood pressure
    2. Hypothyroidism – increase of diastolic blood pressure
  5. Hyperparathyroidism
  6. OC pills use
  7. Rare causes
    1. Glucocorticoid remediable hypertension
    2. Liddle’s syndrome
    3. 17 beta HSD deficiency- apparent minerlocorticoid excess

Q What are the differential diagnosis of hypertension with hypokalemia  ?

  1. Aldosterone producing adenoma
  2. Idiopathic hyperaldosteronism (IHA)
  3. Cushing’s syndrome
  4. Congenital adrenal hyperplasia -11 beta hydroxylase and 17 alpha hydroxylase
  5. Glucocorticoid remediable hypertension
  6. Primary adrenal hyperplasia (unilateral adrenal hyperplasia)
  7. Liddle’s syndrome
  8. Aldosterone producing adrenal carcinoma
  9. Ectopic aldosterone producing tumors
  10. Renovascular disease
  11. Patient with hypertension on diuretics
  12. Renin secreting tumors
  13. Liquorice ingestion

The results of the endocrinologic studies are shown in Table 1.

Q What is the interpretation of the Aldosterone and PRA value in this case ?

  1. The aldosterone is mentioned as pg/ml. We need to convert it to ng/dl for interpretation of Aldosterone: renin ratio. For this we divide the value by 10.
  2. Here the ratio is around 90 : 1 . Ratio more than 20:1 is suggestive of Hyperaldosteronism.
  3. So in conclusion she has have hyperaldosteronism

Q What is the interpretation of her cortisol values ?

  1. Cortisol value baseline itself is low.
  2. ACTH is also elevated
  3. Cortisol post ACTH stimulation is also inadequate

In conclusion there is cortisol deficiency.

Q What is your diagnosis based on this data ?

  1. Patient has a low cortisol and high aldosterone
  2. She also has bilateral adrenal enlargement
  3. I am inclined to think in line of CAH. As discussed previously it could be
    1. 17 alpha hydroxylase deficiency
    2. 11 beta hydroxylase deficiency

Q Which test will help differentiate the two causes of CAH ?

  1. I would go for a 17 hydroxyprogesterone. The value of 17 OHP would be expected to be high in case of 11 beta hydroxylase and low in case of 17 alpha hydroxylase deficiency .
  2. Also DHEAS, testosterone and androstenedione will be low in 17 alpha hydroxylase while high in 11 beta hydroxylase.
  3. Seeing the values of DHEAS etc, we are probably dealing with a case of 17 alpha hydroxylase deficiency.

Although her ACTH level was high, the cortisol and dehydroepiandrosterone sulfate (DHEA-S) levels were low. Further investigation revealed markedly elevated pregnenolone, progesterone, deoxycorticosterone, and corticosterone levels, but androstenedione was not detected. We performed a rapid ACTH stimulation test and a 1-mg dexamethasone suppression test . Rapid ACTH stimulation increased the levels of steroid hormones upstream of 17 alpha-hydroxylase (e.g., pregnenolone and progesterone), but the cortisol response was slight and hormones downstream of 17,20-lyase (e.g., DHEA-S) were completely unresponsive. Overnight 1-mg dexamethasone normalized her ACTH level (20.5 pg/mL) and potassium (5.1 mEq/L), and suppressed hormones upstream of 17 alpha-hydroxylase.

A urine steroid profile analysis was performed according to the method previously reported. In brief, the method comprised enzymatic hydrolysis of 0.2 mL urine, extraction, derivative formation, purification, gas chromatography-mass spectrometory-selected ion monitoring mode analysis, and quantification. The results are consistent with a diagnosis of 17OHD (Fig 2). Although the basal serum aldosterone level was elevated and regulated in an ACTH-dependent manner as shown in Table 1, we observed low urine metabolites (Ms) of aldosterone (glucuronides of tetrahydroaldosterone and aldosterone). Based on these findings together, we diagnosed her with 17OHD.

Q Is aldosterone levels elevated in 17 alpha hydroxylase deficiency ?
It may or may not be elevated. Because of increased metabolites of the mineralocorticoid pathway the renin may be suppressed (which is seen in this case) and the aldosterone may also be suppressed because of the low renin. The increase blood pressure is because of the metabolites upstream to aldosterone having minerocorticoid activity which are

  1. 11 deoxycorticosterone
  2. Corticosterone
  3. 18 hydroxycorticosterone

Q What happens to the sexual development in 17 alpha hydroxylase deficiency in males and females ?

Both would be hypogonadal.

Females (46 XX)

  1. Primary amenorrhea
  2. Absent secondary sexual characteristics

Males (46 XY)

  1. female external genitalia
  2. Absence of mullerian structures but presence of wolffian structures.
  3. They will be reared as girls

Genetic testing was performed to confirm the diagnosis, and 2 distinct previously reported mutations were detected in the CYP17A1 gene. One was c985_987delTACinsAA at exon 6, and the other was R416C at exon 8. Although her parents’ DNA could not be analyzed, we diagnosed her with 17OHD due to the compound heterozygosity of these 2 mutations.

Q What would be the treatment of this condition ?


After daily administration of 0.5 mg dexamethasone, her ACTH level and PAC declined, and her hypokalemia improved. Her blood pressure, however, remained elevated.


  1. 17 alpha hydroxylase deficiency generally presents in females with hypogonadism , hypotension and hypokalemia during puberty, however mild cases can present at a much later age.
  2. Aldosterone levels are not often elevated in patients with 17 alpha hydroxylase because of suppressed renin. This increased blood pressure is because of other steroids upstream having mineralocorticoid activity.

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