Androstenedione (A4) is an androgenic steroid hormone, often called a “pro-hormone,” that is naturally present in all females. Its primary role is not to exert a strong biological action itself but to serve as a crucial intermediate compound in the body’s system of hormone production. While A4 is structurally classified as an androgen, or “male” hormone, it is a necessary precursor for the synthesis of both more potent androgens and the main female hormones, estrogens. This dual conversion function is necessary for maintaining overall hormonal health in women.
Production and Hormonal Conversion
The synthesis of androstenedione in females occurs primarily in two distinct glandular locations: the adrenal glands, which sit atop the kidneys, and the ovaries. In healthy, premenopausal women, approximately half of the circulating androstenedione originates from the adrenal glands, with the remaining half being produced by the ovaries.
This production process is regulated by signals from the brain. The adrenal component is influenced by Adrenocorticotropic Hormone (ACTH), while the ovarian component is stimulated by Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH).
Once released into the bloodstream, androstenedione acts as a metabolic stepping stone, converting into its end-product hormones in various peripheral tissues, including the liver, fat cells, and skin. One pathway involves its conversion into the more potent androgen, testosterone, which contributes to female libido and bone and muscle maintenance. The other critical pathway involves aromatization, where the enzyme aromatase transforms androstenedione into estrone, a form of estrogen.
A4 provides almost all of the body’s estrone and roughly half of the total circulating testosterone in females. This dual conversion is particularly significant after menopause. When the ovaries’ production of estradiol decreases dramatically, estrone production from the peripheral conversion of A4 becomes the primary source of estrogen.
Natural Fluctuations in Healthy Females
The concentration of androstenedione in the blood changes throughout a woman’s life and across the span of a single menstrual cycle. Generally, the levels of androstenedione are highest during a woman’s reproductive years, often peaking in her twenties. Following this peak, there is a gradual decline in the circulating levels of androstenedione and other androgens as a woman ages.
Within the menstrual cycle, androstenedione levels show significant variation tied to ovarian activity. Concentrations are generally lowest during the early follicular phase, which is the beginning of the cycle. The levels then increase substantially, reaching their highest point around the time of ovulation and remaining elevated through the luteal phase. This reflects hormone production from the ovarian follicle and subsequent corpus luteum.
After natural menopause, the ovarian contribution of androstenedione production decreases, though the adrenal glands continue their secretion. Despite this shift, the levels of androstenedione continue to decline with age. Concentrations in women one decade post-menopause are roughly half of those in premenopausal women.
Symptoms and Causes of Elevated Levels
When androstenedione levels become excessively high, the increased precursor is converted into higher amounts of potent androgens like testosterone, leading to clinical signs of hyperandrogenism. The most common manifestations of this excess androgen exposure are dermatological, affecting hair follicles and oil glands.
Symptoms of Hyperandrogenism
- Hirsutism: Characterized by the growth of coarse, dark hair in a male-pattern distribution, such as on the chin, upper lip, chest, and abdomen.
- Acne and Oily Skin: Resulting from androgens stimulating the sebaceous glands to produce excessive sebum.
- Alopecia: Female-pattern hair thinning, often presenting as a loss of density on the scalp.
- Menstrual Irregularities: Elevated androgen levels can disrupt the normal ovulatory cycle, resulting in infrequent periods (oligomenorrhea) or the complete absence of periods (amenorrhea).
The most frequent underlying medical cause of elevated androstenedione is Polycystic Ovary Syndrome (PCOS), which is responsible for the majority of hyperandrogenism cases in reproductive-aged women. In PCOS, the ovaries often overproduce androgens, including A4. This complex endocrine disorder often involves insulin resistance, which further exacerbates ovarian androgen production.
Adrenal gland disorders are another group of causes, including congenital adrenal hyperplasia (CAH), a genetic condition that causes a defect in adrenal enzyme function, leading to a buildup of androgen precursors. In rare instances, adrenal or ovarian tumors can also secrete high and rapidly rising levels of A4. The rapid onset of severe symptoms like clitoral enlargement, deepening of the voice, or increased muscle mass (virilization) can be a warning sign of an androgen-secreting tumor.
Diagnosis and Treatment Approaches
The medical evaluation for suspected androstenedione imbalance begins when a woman presents with clinical symptoms of hyperandrogenism. Laboratory testing involves a blood draw to measure the level of A4, along with other key hormones like total testosterone and DHEA-S. These measurements help determine the source of the excess androgen production—whether ovarian or adrenal. The timing of the blood test may be specified, particularly in premenopausal women, for the most accurate interpretation.
Imaging studies, such as a pelvic ultrasound, are often performed to examine the ovaries for the characteristic appearance associated with PCOS. If an adrenal cause is suspected, especially with very high androgen levels or rapidly progressing symptoms, imaging like a CT or MRI of the adrenal glands may be ordered to rule out a tumor. The overall management strategy focuses on treating the specific underlying cause of the elevated A4.
For Polycystic Ovary Syndrome, treatment often includes lifestyle changes, such as weight loss and regular exercise, to improve insulin sensitivity. Medications may include oral contraceptives to regulate menstrual cycles and suppress ovarian androgen production, or anti-androgen drugs to directly block the effects of androgens at the tissue level. In cases of adrenal tumors, surgical removal is the standard treatment, which typically resolves the hormonal excess.