Hyperandrogenism and Hirsutism: Understanding the Link and Its Implications

Introduction: Hyperandrogenis is, a condition characterized by the excessive production of androgens (male hormones) in women. It is a significant contributor to various clinical signs, the most notable of which is hirsutism. Hirsutism refers to the presence of excessive hair growth in women in areas that are typically associated with male hair patterns, such as the face, chest, and back. While hyperandrogenism is a primary cause of hirsutism, there are instances where hirsutism occurs in the absence of detectable hyperandrogenism, posing a diagnostic and therapeutic challenge. This article explores the relationship between hyperandrogenism and hirsutism, the mechanisms underlying androgen-induced hair growth, and the phenomenon of hirsutism in the absence of hyperandrogenism.

A brief Overview on Hyperandrogenism: Hyperandrogenism in women is primarily defined by elevated levels of androgens, such as testosterone (T), androstenedione, and dehydroepiandrosterone sulfate (DHEAS). These hormones, although more typically associated with male physiological functions, are also present in women in lower concentrations and play roles in various healthy biological processes. However, when androgen levels rise above normal, they can induce masculinizing effects in women, including hirsutism.

The causes of hyperandrogenism are diverse, but the most common is polycystic ovary syndrome (PCOS), which accounts for approximately 85% of all hyperandrogenic cases. PCOS is a complex endocrine disorder characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries. Women with PCOS often present with symptoms such as irregular menstrual cycles, acne, and hirsutism, which often begins in adolescence or early adulthood. Blood tests typically reveal elevated levels of androgens, and ultrasound imaging may show polycystic ovaries.

Other causes of hyperandrogenism include late-onset congenital adrenal hyperplasia (CAH), ovarian or adrenal tumors, and rare pregnancy-related conditions like luteoma of pregnancy. Late-onset CAH is an inherited disorder that impairs hormone metabolism, leading to excessive androgen production, which can manifest as hirsutism after puberty. Ovarian and adrenal tumors, though rare, can also secrete androgens and cause hirsutism. In such cases, accurate diagnosis is critical, as these conditions may require surgical intervention.

Androgen-Induced Hirsutism: Androgens play a fundamental role in the development and maintenance of secondary sexual characteristics, including hair growth. In women, hair follicles in areas such as the face, chest, and abdomen are more sensitive to androgens. When exposed to elevated androgen levels, these hair follicles undergo a transformation from producing fine, vellus hair to producing coarse, terminal hair, characteristic of hirsutism.

The mechanism by which androgens induce hirsutism involves the stimulation of hair follicles to enter the anagen (growth) phase of the hair cycle. Androgens bind to androgen receptors in the dermal papilla cells of the hair follicle, activating a cascade of intracellular events that result in enlargement of the hair follicle and an increase in hair growth. This process is influenced by the local concentration of androgens, the density of androgen receptors, and the activity of enzymes that convert weaker androgens into more potent ones, such as the conversion of testosterone (T) to dihydrotestosterone (DHT) by the enzyme 5-alpha-reductase.

The degree of hirsutism can vary widely among women with hyperandrogenism, depending on genetic predisposition and the sensitivity of hair follicles to androgens. Women of Mediterranean, Middle Eastern, and South Asian descent, for example, are more prone to hirsutism due to a higher density of androgen receptors in their hair follicles. Similarly, hirsutism can run in families as the genes that encode for susceptibility are passed through the generations.

Diagnosis and Management of Hyperandrogenism-Induced Hirsutism: The diagnosis of hyperandrogenism typically begins with a clinical evaluation, including a detailed medical history and physical examination. Blood tests are essential for measuring serum androgen levels, particularly testosterone and DHEAS. While DHT is the most potent androgen that causes hirsutism, it is an unstable molecule, so it is very difficult to accurately measure DHT levels in blood samples. Consequently, blood tests are done for the stable androgens T and DHEAS which can be measured much more accurately.  In cases where an underlying tumor is suspected, imaging studies such as ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) may also be done.

Management of hyperandrogenism-induced hirsutism focuses on reducing androgen levels and blocking their effects on hair follicles. Oral contraceptives are often the first-line treatment, as they suppress ovarian androgen production and increase levels of sex hormone-binding globulin (SHBG), which binds to androgens, reducing their bioavailability (stops them from binding to androgen receptors on cells). Anti-androgen drug medications, such as spironolactone and cyproterone acetate, directly block androgen receptors or inhibit androgen production. Finasteride, a 5-alpha-reductase inhibitor, is another option, as it prevents the conversion of testosterone to DHT, thereby reducing the stimulatory effect of androgens on hair follicles. As blocking androgen activity can significant negative effects on the development of embryos, women using these drugs are generally required to use contraceptive methods if they are of child bearing age.

In cases of tumor-induced hyperandrogenism, surgical removal of the tumor is necessary. For women with CAH, glucocorticoid therapy can suppress adrenal androgen production. In addition to medical treatments, cosmetic approaches such as laser hair removal or electrolysis can be employed to manage the cosmetic aspects of hirsutism.

Hirsutism in the Absence of Hyperandrogenism: While hyperandrogenism is a well-established cause of hirsutism, many women with hirsutism have normal androgen levels in their blood, a condition referred to as “idiopathic hirsutism”. In these cases, the cause of hirsutism remains elusive, though androgens are still implicated as the underlying factor for the hair growth.

One possible explanation for idiopathic hirsutism is a heightened sensitivity of hair follicles to normal circulating levels of androgens. This increased sensitivity could be due to an increased density of androgen receptors in the hair follicles, or enhanced activity of enzymes within the skin that convert weak androgens to more potent forms. For example, some hair follicles may have higher levels of 5-alpha-reductase, leading to increased production of DHT locally, even when serum androgen levels are within the normal range.

Another factor contributing to idiopathic hirsutism could be variations in the local skin metabolism of androgens. Hair follicles contain enzymes that can locally modulate androgen activity, such as aromatase, which converts androgens to estrogens, potentially antagonizing the androgenic effects. Variations in the expression or activity of these enzymes could result in localized increases in androgen action, leading to hirsutism even when there is no detectable hyperandrogenism in the bloodstream.

Diagnosing idiopathic hirsutism can be challenging, as standard blood tests will not reveal any abnormalities. There are no routine tests that can be conducted on the skin to identify localized androgen activity. Tests on hirsute skin can be done experimentally as with laboratory research, but the dermatology clinic has no skin or hair follicle test available to help diagnose idiopathic hirsutism. If blood tests are negative, but the hair growth is in an obvious hirsute pattern, then androgen activity can still be concluded as the underlying problem. Some inexperienced dermatologists and endocrinologists are reluctant to prescribe anti androgen treatments when blood tests are negative. However, experts in the field will still consider such an approach despite normal blood tests so long as the hair growth clearly has a hirsute, androgen induced, pattern to it.

Conclusion: Hyperandrogenism is a common underlying cause of hirsutism, with PCOS being the most prevalent condition associated with elevated androgen levels in women. The diagnosis and management of hyperandrogenism-induced hirsutism require a thorough understanding of the underlying endocrine mechanisms and the appropriate use of diagnostic tools and therapeutic options.

Hirsutism in the absence of hyperandrogenism, or idiopathic hirsutism, presents a more complex clinical scenario, where increased sensitivity of hair follicles to normal androgen levels, or localized alterations in androgen metabolism, are likely contributors. Despite the challenges in diagnosis, recognizing the androgenic basis of hirsutism is central for effective treatment, which may involve anti-androgen medications even in the absence of overt hyperandrogenism.

The management of hirsutism, whether associated with hyperandrogenism or not, requires a personalized approach that considers the patient’s clinical presentation, underlying conditions, and treatment preferences. As research advances, a deeper understanding of the molecular mechanisms governing hair follicle sensitivity to androgens may pave the way for more targeted and effective therapies for hirsutism.

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