17{alpha}-Hydroxylase Deficiency: 1963–1966

Edward G. Biglieri

General Clinical Research Center, University of California, San Francisco, California 94110

Address all correspondence and requests for reprints to: Edward G. Biglieri, General Clinical Resarch Center, Ward 5B, 1001 Potrero Avenue, Box 1353, San Francisco, California 94110.


    Introduction
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 Introduction
 References
 
IT WAS the best of times, and with a pinch of serendipity the identification of the 17{alpha}-hydroxylase deficiency type of congenital adrenal hyperplasia was revealed in 1963–1966.

The patient was referred by a colleague who was faced with a 35-yr-old female with hypertension and well-documented hypokalemia. She was admitted to the Clinical Study Center at San Francisco General Hospital with a presumptive diagnosis of primary aldosteronism. On admission her history was filled with observations and symptoms, in retrospect suggesting what was later to be attributed to her hormonal abnormalities.

She was the product of a full-term normal pregnancy and weighed 7 pounds at birth. She was often ill with several episodes of bronchitis before 5 yr of age. At the age of 5 yr she was hospitalized for an influenza-like syndrome. Both her mother and an 11-month-old sibling died of presumably the same illness.

At the age of 9 yr, she again was hospitalized because of a high fever and a loss of consciousness caused by a severe upper respiratory infection. Intravenous glucose promptly restored consciousness, but hypoglycemia was not documented. A similar episode occurred 1 yr later. Following a tonsillectomy, she remained hospitalized for a week because of persistent nausea and vomiting.

At the age of 16 yr she was 5 feet 3 in. in height and had not menstruated. Debilitating upper respiratory infections occurred throughout her adult life. In college and nursing school she was often called a walking culture media. At 17, a skull film showed no abnormalities and she had grown 4 in. in height. Still, she had had no menses nor had pubertal secondary sex changes appeared.

Between the ages of 17 and 24 yr, her blood pressure was frequently measured and elevated but no treatment was given. Levels ranged between 140/100 and 180/110 mmHg. Premarin was administered for 3 months (at the age of 24 yr) without any changes except for some vaginal spotting. At the age of 26 yr she was 5 feet 91/2 in. tall. At the age of 27 yr, her blood pressure was 180/120 mmHg, with negative tests for pheochromocytoma and normal intravenous pyelogram. At the age of 30 yr, systolic blood pressure was often greater than 200 mmHg. At the age of 34 yr, episodes of marked muscle weakness occurred, and low plasma potassium levels were indicated by electrocardiography. Numbness and tingling in the extremities had been noted for many years. A positive Trousseau’s sign was frequently elicited during blood pressure measurements.

When first seen, she was 35 yr of age with a blood pressure of 220/140 mmHg. A Trousseau’s sign was elicited. The skin was smooth with fine wrinkles at the corners of the mouth and eyes and with fawn-colored freckles in the malar areas. Axillary and pubic hairs were absent and breasts were pubertal. Funduscopic examination revealed arteriolar narrowing and arteriovenous nicking but no hemorrhages or exudates. No abdominal bruits were present. Gynecological examination revealed small clitoris and labia, the vagina was pink and nonestrogenized, and the cervix was small (1 cm diameter). A tubular structure was felt in the area of the uterus, and no ovaries were palpated. A vaginal smear showed no estrogen effect.

The first laboratory studies were essentially normal except for the presence of hypokalemia (2.7 mm/L) and alkalosis (CO2 29–32 mm/L, pH 7.52). The genotype was 46XX.

The initial measurements of urinary steroids were curious; tetrahydro-11-deoxycortisol and tetrahydrocortisone measured by the Porter-Silber chromogen technique were not detected. A cortisol secretory rate was not measurable. Urinary aldosterone was less than 1 mg/24 h, and the secretion rate was 10 mg/24 h. One persistent and at first puzzling determination was that l7-keto-steroids were the only steroid measured with a value of 5 mg/24 h. Initially, this value was thought to be an interfering chromogen because the usually clear blue color of the ketosteroid reaction was a muddy brown. Was it some other steroid? This early clue was found to be caused by the large amounts of metabolites of corticosterone because specific measurements of individual ketosteroids were extremely low. With this constellation of clinical findings and virtually no steroids measured by the then-current techniques, we began our odyssey into steroid biosynthesis.

Could this be a unrecognized form of congenital adrenal hyperplasia—but without virilization or mascularization? There obviously was a deficiency of17{alpha}-hydroxylase because the levels of cortisol were absent. This deficiency could account for her poor response to treatment for infections and could have been implicated in the death of her mother and sibling. Her ACTH levels were elevated.

Nondetectable levels of urinary pregnanetriol indicated an absence of production of 17{alpha}-hydroxyprogesterone ({Delta} 4 steroid). However, plasma progesterone and urinary pregnanediol levels were increased.

The lack of sexual development, eunuchoid appearance, and the lack of an estrogen effect suggested that 17{alpha}-hydroxylase had other activities—17-20 lyase (desmolase). The sex steroids (estrogen and testosterone) require this activity to form both gonadal estrogen and adrenal androgens. A deficiency of this activity was further demonstrated by low to absent levels of urinary dehydroepioandrostendione ({Delta} 5 steroid), androsterone, and etiocholandelone ({Delta} 4 steroid); low plasma testosterone and androstenedione levels; and reduced amounts of biologically active estrogens. LH and FSH were elevated. This led to the postulation that 17{alpha}-hydroxylase has two functions: [17{alpha}-hydroxy/17-20 lyase].

The paper chromatography systems used for isolating steroids consistently revealed a single ultraviolet-absorbing spot that was the only one seen, which did not have a running rate of known steroids. Thus, it was called the mysteroid–possibly unique for this patient. It had some indication by microqualitative tests that it had hydroxyl groups and had an unsaturated double bond. We harvested this material, and when we had sufficient quantities, the powder was sent to Dr. T. Gallagher at Sloan-Kettering for identification. The answer—caffeine! This was a shock and embarrassment. It was then that the mystery was solved. This spot was never seen in urine specimens sent to us from when she was at college, but appeared only when she was hospitalized. Because of religious convictions, coffee was not taken at college or at home. However, in the Clinical Study Center, it was "the only ’tolerable’ liquid drink available," according to the patient.

The other major steroid pathways of steroidogenesis are the 17-deoxy in the zona fasciculata and the aldosterone pathway in the zona glomerulosa. In the 17-deoxy pathway, the potent mineralocorticoid deoxycorticosterone (DOC) is produced along with corticosterone, 18-hydroxydeoxycorticosterone and 18-hydroxycorticosterone. All have mineralocorticoid properties. In large quantities, corticosterone could modulate ACTH release in the pituitary.

At that time there was no assay for DOC, its secretory rate, or its tetrahydro metabolite. However, a developed assay for corticosterone secretion rate demonstrated a marked elevation at 112–124 mg/h (n = 0.9–4.0). Tritium-labeled DOC was available, but standards for its metabolites were nonexistent. To develop chromatograph systems to isolate tetrahydrodeoxycorticosterone (THDOC) for calculating the DOC secretion rate and measurement of its urinary metabolite, we had to make our own THDOC. Through an unusual series of fortuitous conversations, I was informed that Viadril (Pfizer and Co., New York) (a product that was considered candidate for use as an intravenous anesthetic agent) was pure dihydro-DOC.

We accumulated many milligrams of this material. With the consent of an adrenalectomized and oophorectomic woman, 20 mg were administered orally, and a 24-h urine was collected. Liver conversion of dihydro-DOC to THDOC was complete, and the only steroid to be found in the urine was THDOC, almost a lifetime supply. After purification and random labeling with tritium, we had our labeled THDOC tracer to complete our DOC studies; 24-h urinary THDOC levels were 500 mg/24 h (n = 9–25), and the secretory rate was 4.0 mg/24 h (n = 0.05–0.160). All steroids of the 17-deoxy pathway were elevated and driven by ACTH. The hypertension and potassium wasting could now be explained.

Because aldosterone was virtually absent by measurement of the 18-glucuronide, tetrahydroaldosterone, and secretory rate, it was important that plasma renin activity be assayed. An elaborately prepared plasma sample was sent to Ann Arbor, MI. The result indicated major suppression. The explanation for the reduced production was the mineralocorticoid action of DOC. Treatment would be similar to that of other forms of congenital adrenal hyperplasia, namely the administration of glucocorticoids to suppress ACTH release. Doses are usually small (10–20 mg cortisol, 0.25–1.0 mg dexamethasone). Initial treatment must be carefully monitored. In this index case, dexamethasone 2 mg/day produced rapid suppression of ACTH and reduction of DOC. With no mineralocorticoid and a markedly suppressed renin-aldosterone system, marked natriuresis, weight loss, hypotension, and hyperkalemia (6.7 mm/L) occurred within 48 h. Treatment with fludrocortisone was required during this early period. Levels of corticosterone and DOC are usually not reduced into the normal range when blood pressure is restored to normal values. Along with a return of aldosterone production, mineralocorticoid action is sufficient. At the time the original paper was written and the patient had been on dexamethasone therapy for 3 months, aldosterone was still virtually absent. Restoration of plasma renin activity and aldosterone production occurred after 1 yr of therapy. This is not unlike the recovery of the renin-angiotensin system after the removal of an aldosterone-producing adenoma.

The index case had no radiographic evidence of osteoporosis even after a lifetime of estrogen deficiency. Calcium and GH levels were normal. The use of estrogen must be decided on an individual basis. This patient elected not to take cyclical estrogen therapy because she felt that the psychological changes would be too difficult. However, it is recommended.



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Figure 1. Biosynthetic pathways in adrenal cortex. The elevations of 21-deoxycortisol in four of our cases is not explained.

 

    Acknowledgments
 
Assays not developed in my laboratory were generously performed, and I gratefully acknowledge the assistance of colleagues in different areas of steroid chemistry but with mutual curiosity. Without their talents, the faithful formulation of this deficiency would await another time: R. Underwood (progesterone), C. Lloyd (androstenedione and testosterone), S. Ulick (THaldo), R. Rivera (DHEA, etiocholanolone, androsterone, prenanetriol, pregnanediol), A. Paulsen (biologically active estrogens), E. Gold (ACTH), J. W. Conn (plasma renin activity), G. Grodsky (hGH), R. Havel (free fatty acids, glycerol), and T. Gallagher (caffeine).

Received February 21, 1996.

Revised July 1, 1996.

Accepted July 1, 1996.


    References
 Top
 Introduction
 References
 

  1. Biglieri EG, Herron MA, Brust N. 1966 17-hydroxylation in man. J Clin Invest. 45:1946–1954.[Medline]
  2. New MI. 1970 Male pseudohermaphroditism due to 17{alpha}-hydroxglase deficiency. J Clin Invest. 49:1930–1941.[Medline]
  3. Yanase T, Simpson ER, Waterman MR: 1990 17{alpha}-hydroxylase/17-20-lyase deficiency: from clinical investigation to molecular definition. Endocr Rev. 12:91–108.[Medline]




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