Analyte Information

Reproductive

17α-Hydroxyprogesterone

Analyte Information

17α-Hydroxyprogesterone

Introduction

17α-hydroxyprogesterone (also known as 17α-OHP or 17-hydroxy-4-pregnene-3,20-dione) is a C21 steroid hormone. It is an intermediate product of sex steroid and glucocorticoid synthesis; as a hormone, 17α-OHP also interacts with progesterone receptors. The summary formula of 17 α -OHP is C21H30O3, and its structural formula is shown in the Fig.1. Its molecular weight is 330.45 Da.

Fig.1: Structural formula of 17α-hydroxyprogesterone

Biosynthesis

17α-OHP is produced mainly in the adrenal gland. As with other steroids, 17α-OHP is synthesized from cholesterol via a series of enzyme-mediated steps1-3 (Fig.2).

Fig.2: Scheme of 17α-OHP biosynthesis

The first step in this pathway is the conversion of cholesterol to pregnenolone, which is stimulated by adrenocorticotropic hormone (ACTH). Pregnenolone is subsequently converted to either progesterone or 17-hydroxypregnenolone, both of which serve as precursors of 17α-OHP. 17α-OHP may then be further converted in the adrenal glands to cortisol via a series of actions involving the 21-hydroxylase (P450c21) and 11-hydroxylase (P450c11) enzymes. In both the adrenal glands and ovaries, 17α-OHP may also be converted by 17,20-lyase (P450c17) to androstenedione, a precursor of testosterone and estradiol (Fig.3).

Fig.3: 17α-OHP as an interlink in the synthesis of adrenal hormones

Small quantities of 17α-OHP are released by the ovaries during the follicular phase of the menstrual cycle. Production increases during the luteal phase and remains constant thereafter. In the absence of fertilization, production is then greatly diminished; if fertilization does occur, production continues in the corpus luteum.

Metabolism

17α-OHP circulates in blood both in a free state, or bound to either albumin or transcortin. Its biological half-life is several minutes. It is metabolized by the liver and excreted in urine as pregnantriol.

Physiological Function

17α-OHP has no known specific physiological role except as a precursor molecule. However, it is an important link in the synthesis of adrenal hormones. A defect in enzymes involved in corticoid biosynthesis may result in an accumulation of 17α-OHP and subsequent increase in adrenal androgen levels (Fig.2,3). This excess of androgens is manifested clinically as congenital adrenal hyperplasia (CAH), also called adrenogenital syndrome in women.

Levels

17α-OHP levels are age-dependent 4-8, with peak levels reached during fetal life and in the immediate postnatal period. During the first weeks of life, serum 17α-OHP levels fall approximately 50-fold compared to cord blood values. A small, transient increase occurs in male infants 30-60 days after birth. Levels in both sexes then remain constant and low throughout childhood, and progressively increase during puberty to adult levels of about 100 ng/dL (3.03 nmol/L). As with cortisol9, serum 17α-OHP levels normally exhibit ACTH-dependent diurnal variation, with a peak in the morning and a nadir at night 7,8. In women, ovarian production of 17α-OHP increases during the luteal phase of the menstrual cycle4,10,11, leading to serum levels which are several times higher than those seen in the follicular phase. Typical 17α-OHP serum levels12 of females and males are given in table 1. For each assay, the relevant reference values are shown in the appropriate Instructions for Use (IFU).

Table 1: Typical 17α-OHP serum levels Reference interval (ng/dL) Cord blood: 900 – 5,000 Premature: 26-568 Newborn, 3 days: 7-77 Prepubertal child: 3-90 Puberty Tanner stage I, male: 3-90 I, female: 3-82 II, male: 5-115 II, female: 11-98 III, male: 10-138 III, female: 11-155 IV, male: 29-180 IV, female: 18-230 V, male: 24-175 V, female: 20-265 Adults Male: 27-199 Female Follicular phase: 15-70 Luteal phase : 35-290 Pregnancy: 200-1,200 Postmenopausal: 70 Equation for the conversion of units: 1 ng/dL x 0.03 = nmol/L

Diagnostic utility – prospects and possibilities

Determination of 17α-OHP is important mainly in the diagnosis and monitoring of congenital deficiencies of the enzyme 21-hydroxylase, which causes congenital adrenal hyperplasia. Elevated 17α-OHP levels

Elevated 17α-OHP levels are associated with the following conditions: - CAH (congenital adrenal hyperplasia, the congenital absence or deficiency of 21-hydroxylase) - NCAH (non-classical congenital adrenal hyperplasia, late-onset CAH) - other forms of adrenal hyperplasia (11-hydroxylase (P450c11), 17,20- lyase (P450c17) and 3β-hydroxysteroid dehydrogenase (3β-HSD) deficiencies) - hirsutism - female infertility

Diagnostic utility – Practical applications

Congenital adrenal hyperplasia (CAH) CAH is a family of genetic conditions affecting the adrenal glands. Typically, 17α-OHP cannot be efficiently converted to cortisol due to decreased 21-hydroxylase activity. In addition, mineralocorticoid and androgen levels may be abnormal. CAH interferes with normal growth and development in children, including that of the genitals. It affects both males and females. Measurement of 17α-OHP is used to confirm this diagnosis, along with aldosterone, cortisol, androgens (e.g. testosterone).

Non-classical congenital adrenal hyperplasia (NCAH) NCAH is a variation of CAH that may cause noticeable changes at any time from early childhood through early adulthood, but is not immediately life- threatening. NCAH has a range of symptoms which overlap with those of other disorders, making it difficult to diagnose. NCAH may be noticed in newborn screening tests. But they do not necessarily need treatment. Some with NCAH never experience bothersome symptoms, and only those children and adults who are symptomatic should be treated.

Other forms of CAH These include 11-hydroxylase (P450c11), 17,20-lyase (P450c17) and 3β-hydroxysteroid dehydrogenase-isomerase (3β-HSD) deficiencies3,13,14. Their incidence is significantly lower than that of 21-hydroxylase deficiency. In 3β-HSD deficiency, a cause of female hirsutism, 17α-OHP production is theoretically impaired. Elevated 17α-OHP levels are presumably due to extra- adrenal conversion of precursors. The ratio of these precursors (particularly 17-hydroxypregnenolone) to 17α-OHP may be useful in diagnosis14, as well as DHEA and DHEA-S levels.

References

1. Miller W.L., Levine L.S.: Molecular and clinical advances in congenital adrenal hyperplasia, J. Pediatr., 1987, 111, 1-127. 2. Miller W.L.: Molecular biology of steroid hormone synthesis, Endocrin. Rev., 1988, 9, 295-318. 3. New M.I., Levine L.S.: Congenital Adrenal Hyperplasia, Monographs on Endocrinology, vol. 26, Springer-Verlag, Berlin, 1984. 4. Abraham G.E., Swerdloff R.S., Tulchinsky D., Hopper K., Odell W.D.: Radioimmunoassay of plasma 17-hydroxyprogesterone, J. Clin. Endocrinol., 1971, 33,42-46. 5. Sippel W.G., Dorr H.G., Bidlingmaier F., Knorr D.: Plasma levels of 17- hydroxyprogesterone, cortisol, and cortisone during infancy and childhood, Pediatr. Res., 1980, 14, 39-46. 6. Lashansky G., Saenger P., Fishman K., Gautier T., Mayes D., Berg G., Di Martino-Nardi J., Reiter E.: Normative data for adrenal steroidogenesis in a healthy pediatric population: age and sex-related changes after adrenocorticotropin stimulation, J. Clin. Endocrinol. Metab., 1991, 73, 674- 686. 7. Hughes I.A., Winter J.S.D.: The application of a serum 17OH-progesterone radioimmunoassay to the diagnosis and management of congenital hyperplasia, J. Pediatr., 1976, 88, 766-773. 8. Petersen K.E., Christensen T.: 17-hydroxyprogesterone in normal children and congenital adrenal hyperplasia, Acta Pediatr. Scand.,1979, 68, 205-211. 9. Krieger D.T.: Rhythms of ACTH and corticosteroid secretion in health and disease and their experimental modification, J. Steroid Biochem., 1975, 6, 785-791. 10. Thorneycroft I.H., Mishell D.R., Stone S.C., Kharma K.M., Nakamura R.M.: The relation of serum 17-hydroxyprogesterone and estradiol-17α during the human menstrual cycle, Am. J. Obstet. Gynecol., 1971, 111, 947-951. 11. Schoneshofer M., Wagner G.G.: Sex differences in corticosteroids in man, J Clin. Endocrinol. Metab., 1977, 45, 814-817. 12. Burtis C.A, Ashwood, E.R., Bruns, D.E.: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, Elsevier Inc., 2006, p. 2042. 13. Cara J.F., Moshang T., Bongiovanni A.M., Marx B.S.: Elevated 17- hydroxyprogesterone and testosterone in a newborn with 3-beta-hydroxysteroid dehydrogenase deficiency, New Engl. J. Med., 1985, 313, 618-621. 14. Pang S., Riddick L.: Hirsutism. IN Lifshitz F. (ed): Pediatric Endocrinology, A Clinical Guide, 2nd ed., Marcel Dekker, Inc., New York, 1990, pp. 259-291.