ANDROSTENEDIONE:
A Critical Component of the Steroid Pathways

Androstenedione is a useful aid in the diagnosis of various pathologies, including male and female infertility. This steroid hormone is the immediate precursor to testosterone and estrone in the endogenous synthetic pathways of androgens and estrogens.^1–4

Androgens are classified as C-19 steroids and are secreted by the testes, adrenals and ovaries. They have a profound influence on the development of secondary male characteristics.

Androgens vary in their biological activity. Testosterone, for example, is the principal natural androgen, with the highest degree of bioactivity. Most of its bioactivity is due to the hydroxyl group in the b position at C-17. As androstenedione is missing this hydroxyl group, its bioactivity is only about one-third that of testosterone. Nevertheless, androstenedione plays a critical role in androgenic status. In fact, in female pathological conditions involving increased androgen production by the ovaries, androstenedione and other androgenic steroids, such as dehydroepiandrosterone (DHEA), can make substantial contributions to the total circulating bioactive androgen levels.

Testosterone and estrone precursor
Androstenedione is the primary testosterone prehormone of the ovaries, while DHEA is the testosterone prehormone of the adrenals. Two known pathways exist for the formation of androgens: D⁵,D ⁴ (Figure 1). The D⁵ pathway initially transforms pregnenolone into 17-hydroxypregnenolone and then into DHEA, which is converted to androstenedione (by the 3b-hydroxysteroid dehydrogenase enzyme) and finally testosterone. This is the most active synthetic pathway of the testes and adrenal glands.

The D⁴ pathway transforms pregnenolone into progesterone, which is converted to 17-hydroxyprogesterone, which in turn gives rise to androstenedione. This pathway, occurring in the ovaries, is active mostly during the luteal phase (via progesterone), while the follicular phase is characterized by the D ⁵ pathway. Synthesis takes place in the theca cells under the influence of LH before ovulation. FSH stimulates the conversion of androstenedione to estradiol in the granulosa cells. (In the postovulatory period, LH stimulates the conversion of cholesterol to progesterone.)

Fat cells are important sites of the aromatization of androstenedione into testosterone and estrone. Sixty percent of the androstenedione produced is transformed into testosterone, although the conversion of androstenedione to testosterone is a reversible reaction.

Figure 1. Androstenedione is a chemical precursor to testosterone, estrone and estradiol via the D4 and D 5 pathways. Abnormal physiological levels of this steroid hormone are found in various pathologies, such as male and female infertility, polycystic ovary syndrome, virilization and congenital adrenal hyperplasia.

Secretion and circulatory levels
Of the androstenedione produced endogenously, the ovaries and adrenals contribute about 50 and 40 percent, respectively, with the remaining 5 to 10 percent being synthesized from DHEA. Studies on serum samples from adult laboratory volunteers using IMMULITE^® Androstenedione yielded reference limits of 0.7 – 3.6 ng/mL (2.4 – 12.6 nmol/L) in men and 0.3 – 3.5 ng/mL (1.0 – 12.2 nmol/L) in women.

Androstenedione levels exhibit diurnal variation. The highest levels are found in the morning and coincide with elevated cortisol levels. Cyclic variation is seen during the menstrual cycle, with the highest levels occurring near the midcycle. As the follicle matures, a twofold increase is achieved and maintained throughout the luteal phase.

Clinical implications
Increasing androstenedione levels are observed at the onset of puberty, but gradually begin to decline after age 30. Elevated levels in women occur in pregnancy, polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia (CAH), hirsutism, virilization, and in tumors of the adrenal glands and gonads.⁵ In addition, elevated androstenedione levels often exist in conjunction with female infertility, as excess production interferes with follicle development, ovulation and cervical mucus production.

On the other hand, decreased androstenedione levels are often observed in cases of male infertility, as insufficient levels cause a reduction in sperm count. Decreased levels are also seen in women throughout the postmenopausal period and in aging men as a result of decreased aromatization.

Androstenedione is sold without a prescription as a dietary supplement in the US and UK. As a therapeutic agent, it is described in the literature as providing beneficial effects such as increased strength, well-being, libido and quality of life, as a result of increased basal testosterone levels.^6,7 Concerns exist, however, regarding the medical consequences of its administration, since anabolic steroids can have potentially dangerous side effects, such as high blood pressure, liver damage and cancer.

New DPC assays
DPC is now offering IMMULITE^®/IMMULITE^® 1000 Androstenedione and IMMULITE^® 2000 Androstenedione, in addition to the existing Coat-A-Count^® Direct Androstenedione assay, for added laboratory efficiency and flexibility in the measurement of this pivotal steroid.

References
1. Horton R, Tate JF. Androstenedione production and interconversion rates measured in peripheral blood and studies on the possible site of conversion to testosterone. J Clin Invest 1966:45:301-33.

2. Longcope C, Kato T, Horton R. Conversion of blood androgens to estrogens in normal adult men and women. J Clin Invest 1969:48:2191-201.

3. Weinstein RL, Kelch RP, Jenner MR, Kaplan SL, Grumbach MM. Secretion of unconjugated androgens and estrogens by the normal and abnormal human testis before and after human chorionic gonadotropin. J Clin Invest 1974:53:1-6.

4. Mahesh VB, Greenblatt RB. The in-vivo conversion of dehydroepiandrosterone and androstenedione to testosterone in the human. Acta Endocrinol 1962:41:400-6.

5. Mango D, Scirpa P, Battaglia F, Tartaglia E, Manna P. Diagnostic significance of steroid hormones in patients with ovarian cancer. J Endocrinol Invest 1986:9(4):307-14.

6. Leder BZ, Leblanc KM, Longcope C, Lee H, Catlin DH, Finkelstein JS. Effects of oral androstenedione administration on serum testosterone and estradiol levels in postmenopausal women. J Clin Endocrinol Metab 2002:87:5449-54.

7. Kicman AT, Bassindale T, Cowan DA, Dale S, Hutt AJ, Leeds AR. Effect of androstenedione ingestion on plasma testosterone in young women; a dietary supplement with potential health risks. Clin Chem 2003:49:167-9.