Root Cause of Excess Facial Hair (Hirsutism) in PCOD

Excess facial hair growth, medically known as hirsutism, is a common and often distressing symptom for women with Polycystic Ovary Syndrome (PCOS) or Polycystic Ovarian Disease (PCOD). This unwanted hair growth occurs in a male-pattern distribution, including the face, chest, and back, which can significantly impact a woman’s self-esteem and quality of life. Understanding the biological mechanisms behind hirsutism in PCOD is crucial for effective management and treatment of this condition.

Understanding PCOD and Its Hormonal Implications

Polycystic Ovarian Disease is a complex endocrine disorder affecting approximately 8-13% of reproductive-age women worldwide. The condition is characterized by hormonal imbalances that lead to the formation of small cysts on the ovaries, irregular menstrual cycles, and various other symptoms including hirsutism.

At its core, PCOD involves dysregulation of reproductive hormones. Women with PCOD typically exhibit elevated levels of androgens, often referred to as “male hormones,” although they are present in all women in smaller amounts. The primary androgens involved in PCOD include testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS).

The ovaries and adrenal glands are the main sources of androgen production in women. In PCOD, both these glands may contribute to excess androgen production. The ovaries produce testosterone and androstenedione, while the adrenal glands produce DHEAS and androstenedione. This hormonal imbalance triggers a cascade of effects throughout the body, with hirsutism being one of the most visible manifestations.

The Biological Mechanism Behind Hirsutism in PCOD

Hirsutism in women with PCOD stems from a complex interplay of hormonal dysregulation affecting hair follicle biology. To understand this process, it’s important to first recognize the different types of hair present on the human body.

Human hair follicles can be categorized into three types: terminal (coarse, pigmented), vellus (fine, non-pigmented), and intermediate. Under normal circumstances, women have vellus hair in areas such as the face, chest, and back, while men have terminal hair in these regions. This sexual dimorphism in hair distribution is primarily regulated by androgens.

In women with PCOD, excess androgens trigger a transformation of vellus hair follicles into terminal hair follicles in androgen-sensitive areas, leading to hirsutism. This process involves several specific mechanisms:

1. Androgen Excess: The Primary Driver

The fundamental cause of hirsutism in PCOD is hyperandrogenism (excess androgens). Several factors contribute to this androgen excess:

Ovarian Dysfunction: In PCOD, the ovaries contain multiple small follicles that fail to develop properly. These immature follicles produce abnormally high levels of androgens. The thecal cells of the ovaries, which normally produce androgens that are then converted to estrogens, become hyperactive in PCOD.

Insulin Resistance and Hyperinsulinemia: Approximately 70% of women with PCOD have insulin resistance, where body cells become less responsive to insulin. To compensate, the pancreas produces more insulin, leading to hyperinsulinemia (high blood insulin levels). Elevated insulin levels stimulate the ovaries to produce more androgens and decrease the production of sex hormone-binding globulin (SHBG) in the liver.

Reduced SHBG Levels: SHBG is a protein produced by the liver that binds to sex hormones, including testosterone, reducing their bioavailability. Lower SHBG levels in PCOD result in higher free (biologically active) testosterone levels in the bloodstream.

Adrenal Contribution: The adrenal glands may also contribute to excess androgen production in some women with PCOD, particularly DHEAS.

Genetic Factors: Research suggests that genetic predisposition plays a significant role in PCOD and associated hyperandrogenism. Studies have identified several candidate genes related to androgen biosynthesis, action, and metabolism that may contribute to PCOD development.

2. Hair Follicle Sensitivity to Androgens

Not all women with elevated androgens develop hirsutism, suggesting that hair follicle sensitivity to androgens varies among individuals. This sensitivity is determined by several factors:

5α-Reductase Activity: This enzyme converts testosterone to dihydrotestosterone (DHT), a more potent androgen that directly affects hair follicles. Women with hirsutism often have increased 5α-reductase activity in their skin, particularly in facial hair follicles.

Androgen Receptor Expression: The density and sensitivity of androgen receptors in hair follicles influence how strongly they respond to circulating androgens. Studies have shown that hirsute women may have increased androgen receptor expression in hair follicles.

Ethnic and Genetic Variations: Hair follicle response to androgens varies significantly across different ethnic groups. For example, women of Mediterranean, Middle Eastern, and South Asian descent tend to have more pronounced hirsutism with similar androgen levels compared to women of East Asian or Northern European descent.

3. The Hair Growth Cycle Alterations

Hair growth follows a cyclical pattern consisting of three phases: anagen (growth phase), catagen (transitional phase), and telogen (resting phase). Androgens influence this cycle in several ways:

Prolonged Anagen Phase: Androgens extend the anagen phase in androgen-dependent areas, resulting in longer, thicker terminal hairs.

Increased Hair Follicle Size: Under androgen stimulation, hair follicles enlarge, producing thicker hair shafts.

Increased Pigmentation: Androgens stimulate melanocyte activity in hair follicles, leading to darker hair.

Vellus-to-Terminal Transformation: The most significant effect is the conversion of vellus (fine, light) hair to terminal (coarse, dark) hair in androgen-sensitive regions.

Molecular Pathways in Androgen-Induced Hirsutism

At the molecular level, androgens affect hair follicles through complex signaling pathways:

Androgen Receptor Activation: When androgens bind to their receptors in hair follicle cells, they form an androgen-receptor complex that translocates to the nucleus.

Gene Transcription: In the nucleus, this complex binds to specific DNA sequences called androgen response elements (AREs), regulating the transcription of target genes.

Growth Factor Production: Androgen signaling stimulates the production of growth factors such as insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-β), and vascular endothelial growth factor (VEGF), which promote hair follicle growth and development.

Dermal Papilla Signaling: Androgens particularly affect the dermal papilla, a crucial component of the hair follicle that regulates hair growth. Androgen-activated dermal papilla cells release paracrine factors that stimulate the proliferation and differentiation of follicular keratinocytes.

Wnt/β-catenin Pathway Activation: Recent research has implicated the Wnt/β-catenin signaling pathway in androgen-mediated hair growth, suggesting that androgens activate this pathway to promote hair follicle development.

Insulin Resistance: A Key Player in PCOD-Related Hirsutism

Insulin resistance deserves special attention as it forms a critical link between metabolic dysfunction and hyperandrogenism in PCOD. Here’s how insulin resistance contributes to hirsutism:

Direct Stimulation of Androgen Production: Insulin acts as a co-gonadotropin, directly stimulating ovarian theca cells to produce androgens by enhancing the activity of cytochrome P450c17α, a key enzyme in androgen biosynthesis.

Reduction in SHBG Production: Elevated insulin levels suppress hepatic production of SHBG, increasing free testosterone levels in circulation.

Enhanced 5α-Reductase Activity: Insulin may upregulate 5α-reductase activity, increasing the conversion of testosterone to the more potent DHT in skin and hair follicles.

IGF-1 System Effects: Insulin increases bioavailability of insulin-like growth factor-1 (IGF-1) by reducing IGF binding protein-1 (IGFBP-1) production. IGF-1 can stimulate ovarian androgen production and may directly affect hair follicle growth.

Hypothalamic-Pituitary Effects: Insulin resistance may disrupt normal hypothalamic-pituitary-ovarian axis function, contributing to abnormal gonadotropin secretion patterns seen in PCOD.

The relationship between insulin resistance and hyperandrogenism creates a vicious cycle: insulin resistance leads to compensatory hyperinsulinemia, which stimulates ovarian androgen production, which in turn can worsen insulin resistance through various mechanisms.

Inflammatory Processes in PCOD-Related Hirsutism

Emerging research suggests that chronic low-grade inflammation plays a significant role in PCOD pathophysiology, potentially contributing to hirsutism through several mechanisms:

Oxidative Stress: Women with PCOD often exhibit increased oxidative stress markers, which can disrupt normal ovarian function and contribute to hyperandrogenism.

Pro-inflammatory Cytokines: Elevated levels of inflammatory markers such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) are commonly observed in PCOD. These inflammatory cytokines can interfere with insulin receptor signaling, exacerbating insulin resistance and subsequently increasing androgen production.

Immune Cell Infiltration: Studies have shown increased immune cell infiltration in polycystic ovaries, potentially disrupting normal follicular development and hormone production.

Adipose Tissue Dysfunction: Many women with PCOD have excess adipose tissue, particularly visceral fat, which acts as an endocrine organ secreting various inflammatory mediators that contribute to insulin resistance and androgen excess.

Genetic and Epigenetic Factors in PCOD-Related Hirsutism

The genetic basis of PCOD and associated hirsutism is complex and likely involves multiple genes:

Family Clustering: Studies have shown that PCOD tends to run in families, with first-degree female relatives of women with PCOD having a higher risk of developing the condition.

Candidate Genes: Various candidate genes have been implicated in PCOD pathogenesis, including genes involved in:

1. Androgen synthesis and action (CYP17, CYP11A, androgen receptor gene)
2. Insulin signaling (insulin receptor gene, IRS-1, IRS-2)
3. Gonadotropin action and regulation (FSHR, LHR, LHCGR)
4. Inflammatory processes (TNF-α, IL-6)
5. Energy metabolism (PPAR-γ, adiponectin genes)

Epigenetic Modifications: Recent research indicates that epigenetic changes, such as DNA methylation and histone modifications, may play a role in PCOD development. Environmental factors like diet, exercise, and exposure to endocrine-disrupting chemicals may influence gene expression through epigenetic mechanisms.

Developmental Programming: There is growing evidence that prenatal androgen exposure may program metabolic and reproductive abnormalities characteristic of PCOD, potentially through epigenetic modifications that persist into adulthood.

The Role of Hypothalamic-Pituitary Dysfunction

The hypothalamic-pituitary-ovarian (HPO) axis dysregulation in PCOD contributes significantly to hyperandrogenism and subsequent hirsutism:

Altered Gonadotropin Secretion: Women with PCOD typically exhibit increased luteinizing hormone (LH) pulse frequency and amplitude, while follicle-stimulating hormone (FSH) levels remain normal or low. This LH/FSH imbalance favors androgen production by ovarian theca cells.

Neuroendocrine Imbalances: Kisspeptin, neurokinin B, and dynorphin (KNDy) neurons in the hypothalamus, which regulate GnRH pulsatility, may be dysregulated in PCOD, contributing to abnormal LH secretion patterns.

Feedback Mechanisms: Normal negative feedback mechanisms regulating GnRH/LH secretion appear to be impaired in PCOD, potentially due to androgen-induced alterations in hypothalamic sensitivity to sex steroids.

Prolactin Effects: Mild hyperprolactinemia, sometimes observed in PCOD, can contribute to hypothalamic-pituitary dysfunction and may exacerbate androgen-related symptoms.

Clinical Manifestations and Diagnosis of Hirsutism in PCOD

Hirsutism in PCOD typically develops gradually and follows a male-pattern distribution, affecting androgen-sensitive areas:

Common Sites: Facial hirsutism is often most prominent on the upper lip, chin, sideburn area, and lower jaw. Other commonly affected areas include the chest (particularly around the nipples), lower abdomen, inner thighs, and lower back.

Assessment Tools: Clinicians often use the modified Ferriman-Gallwey scoring system to quantify hirsutism severity. This system assigns a score from 0 (no terminal hair) to 4 (extensive terminal hair growth) in nine body areas, with a total score of 8 or higher indicating hirsutism.

Laboratory Evaluation: Diagnostic workup typically includes measurements of total and free testosterone, DHEAS, androstenedione, 17-hydroxyprogesterone, prolactin, thyroid function tests, and sometimes a complete metabolic panel to assess insulin resistance.

Differential Diagnosis: Other causes of hirsutism, such as congenital adrenal hyperplasia, Cushing’s syndrome, androgen-secreting tumors, and certain medications, must be excluded before attributing hirsutism to PCOD.

Management Approaches for PCOD-Related Hirsutism

Understanding the biological mechanisms behind hirsutism in PCOD is crucial for developing effective treatment strategies, which generally fall into the following categories:

Lifestyle Modifications

Weight Management: Even modest weight loss (5-10% of body weight) in overweight women with PCOD can reduce insulin resistance, restore ovulation, and improve androgen levels, potentially reducing hirsutism.

Dietary Interventions: Low-glycemic-index diets may improve insulin sensitivity and reduce androgen levels. Some research suggests anti-inflammatory diets may also be beneficial.

Regular Physical Activity: Exercise improves insulin sensitivity independent of weight loss and may directly reduce androgen levels.

Stress Management: Chronic stress can exacerbate hormonal imbalances in PCOD through activation of the hypothalamic-pituitary-adrenal axis. Stress reduction techniques such as mindfulness meditation may be helpful.

Pharmacological Interventions

Oral Contraceptives: Combined oral contraceptives (COCs) containing ethinyl estradiol plus a progestin with anti-androgenic properties (such as cyproterone acetate, drospirenone, or dienogest) reduce ovarian androgen production, increase SHBG levels, and decrease free testosterone.

Anti-androgens: Medications such as spironolactone, flutamide, and finasteride block androgen action at the tissue level. Spironolactone, which blocks androgen receptors and inhibits 5α-reductase activity, is most commonly used.

Insulin Sensitizers: Metformin improves insulin sensitivity, potentially reducing hyperinsulinemia and consequently decreasing ovarian androgen production. Thiazolidinediones (e.g., pioglitazone) may have similar effects but are less commonly used.

GnRH Agonists: These medications suppress ovarian androgen production by inhibiting gonadotropin release but are typically reserved for severe cases due to side effects and cost.

5α-Reductase Inhibitors: Finasteride inhibits the conversion of testosterone to DHT, particularly useful for women with demonstrated increased 5α-reductase activity.

Cosmetic Approaches

Temporary Hair Removal Methods: Shaving, waxing, depilatory creams, and threading provide temporary relief from unwanted hair.

Permanent and Semi-Permanent Methods: Electrolysis offers permanent hair reduction through destruction of individual hair follicles. Laser hair removal and intense pulsed light (IPL) therapy provide long-term reduction by targeting melanin in hair follicles, though multiple sessions are typically required.

Topical Treatments: Eflornithine cream (Vaniqa) inhibits ornithine decarboxylase in hair follicles, slowing facial hair growth when used regularly.

Emerging Research and Future Directions

Recent advances in understanding the pathophysiology of PCOD and hirsutism are opening new therapeutic avenues:

Androgen Synthesis Inhibitors: Selective inhibitors of enzymes involved in androgen biosynthesis, such as CYP17 inhibitors, are being investigated for their potential in treating hyperandrogenism.

Anti-inflammatory Approaches: Given the role of chronic inflammation in PCOD, anti-inflammatory agents may hold promise. Preliminary studies with omega-3 fatty acids, vitamin D supplementation, and statins have shown some benefit.

Microbiome Interventions: Emerging research suggests that gut microbiome dysbiosis may contribute to PCOD pathophysiology. Probiotics and prebiotics that modulate the gut microbiome are being studied as potential adjunctive treatments.

AMPK Activators: Compounds that activate AMP-activated protein kinase (AMPK), such as berberine, may improve metabolic parameters and potentially reduce androgen levels in PCOD.

Novel Insulin Sensitizers: New insulin-sensitizing agents without the side effects of current medications are under investigation.

Epigenetic Modifiers: As understanding of epigenetic changes in PCOD grows, interventions targeting these modifications may become possible.

Psychological Impact and Holistic Management

The psychological impact of hirsutism in women with PCOD is often substantial and should not be overlooked:

Body Image Concerns: Hirsutism can significantly affect body image and self-perception. Studies consistently show higher rates of body dissatisfaction among women with PCOD-related hirsutism.

Social Anxiety and Avoidance: Many women with hirsutism experience social anxiety and may avoid social situations, potentially leading to isolation.

Depression and Reduced Quality of Life: Research indicates higher rates of depression and reduced quality of life scores in women with hirsutism.

Psychological Support: Cognitive-behavioral therapy, support groups, and sometimes pharmacological treatment for anxiety or depression may be beneficial components of a comprehensive management approach.

A holistic management approach addressing both the biological mechanisms and psychological aspects of hirsutism in PCOD is essential for optimal outcomes. This approach should be personalized, taking into account the severity of symptoms, patient preferences, reproductive goals, and associated metabolic abnormalities.

Conclusion

Hirsutism in PCOD represents a complex manifestation of underlying hormonal and metabolic dysregulation. The primary driver is hyperandrogenism, stemming from ovarian dysfunction, insulin resistance, reduced SHBG levels, and potentially increased 5α-reductase activity and androgen receptor sensitivity in hair follicles. Genetic factors, inflammatory processes, and hypothalamic-pituitary dysfunction further contribute to this multifaceted condition.

Understanding these intricate biological mechanisms provides the foundation for targeted therapeutic approaches. Effective management typically involves a combination of lifestyle modifications, pharmacological interventions targeting specific pathways in the pathophysiology, cosmetic hair removal methods, and psychological support. As research continues to unravel the complexities of PCOD and associated hirsutism, new therapeutic targets and more personalized treatment approaches are likely to emerge.

For women living with PCOD-related hirsutism, knowledge of the underlying causes can be empowering, helping them work with healthcare providers to develop optimal management strategies that address both the physical manifestations and psychological impact of this challenging condition.

FAQs

Q: What is the main cause of facial hair growth in women with PCOD? A: The primary cause is excess androgens (male hormones) such as testosterone and DHEAS. In PCOD, both the ovaries and adrenal glands produce abnormally high levels of these hormones, which stimulate terminal hair growth in androgen-sensitive areas like the face.

Q: How does insulin resistance contribute to hirsutism in PCOD? A: Insulin resistance leads to high insulin levels (hyperinsulinemia), which directly stimulates the ovaries to produce more androgens. Insulin also decreases production of sex hormone-binding globulin (SHBG) in the liver, resulting in higher levels of free testosterone in the bloodstream that can affect hair follicles.

Q: Is hirsutism in PCOD hereditary? A: There is a strong genetic component to both PCOD and hirsutism. Women whose female relatives have PCOD or hirsutism are more likely to develop these conditions. Additionally, ethnic background influences hair follicle sensitivity to androgens, with women of Mediterranean, Middle Eastern, and South Asian descent being more prone to hirsutism.

Q: Can weight loss reduce facial hair growth in PCOD? A: Yes, weight loss of even 5-10% in overweight women with PCOD can significantly improve insulin sensitivity, reduce androgen levels, and subsequently decrease hirsutism. This is often the first-line recommendation for overweight women with PCOD-related hirsutism.

Q: How long does it take for treatments to reduce facial hair in PCOD? A: Most pharmacological treatments for hirsutism (such as oral contraceptives or anti-androgens) take at least 6-12 months to show significant results. This is because they can only affect new hair growth, while existing terminal hairs complete their growth cycle, which can last several months.

Q: Can PCOD-related hirsutism be completely cured? A: Rather than a “cure,” hirsutism in PCOD is typically managed as a chronic condition. With appropriate treatment, symptoms can be significantly reduced or controlled, but they may return if treatment is discontinued, especially if the underlying hormonal imbalances persist.

Q: Are there any natural remedies that effectively treat PCOD-related hirsutism? A: While some natural approaches may help manage PCOD and potentially reduce hirsutism, scientific evidence for most is limited. Lifestyle modifications like weight management, regular exercise, and a low-glycemic diet have the strongest evidence for improving hormonal profiles in PCOD.

Q: How does facial hair in PCOD differ from normal facial hair in women? A: Normal female facial hair is typically fine, light-colored vellus hair. In PCOD, excess androgens transform these vellus hairs into thick, dark terminal hairs in a male-pattern distribution, affecting areas like the upper lip, chin, jawline, and neck.

Q: Can stress worsen hirsutism in women with PCOD? A: Yes, chronic stress can exacerbate hormonal imbalances in PCOD by activating the hypothalamic-pituitary-adrenal axis, potentially increasing adrenal androgen production. Stress management techniques may help as part of a comprehensive treatment approach.

Q: Is it safe to use hair removal creams and other cosmetic methods alongside medical treatments for PCOD-related hirsutism? A: Most cosmetic hair removal methods are safe to use alongside medical treatments for hirsutism. In fact, a combination approach is often recommended, where medical treatments address the underlying hormonal causes while cosmetic methods provide immediate symptomatic relief.

Bibliography

1. Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, Lizneva D, Natterson-Horowtiz B, Teede HJ, Yildiz BO. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016;2:16057. doi: 10.1038/nrdp.2016.57.
2. Rosenfield RL, Ehrmann DA. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocr Rev. 2016;37(5):467-520. doi: 10.1210/er.2015-1104.
3. Escobar-Morreale HF, Carmina E, Dewailly D, Gambineri A, Kelestimur F, Moghetti P, Pugeat M, Qiao J, Wijeyaratne CN, Witchel SF, Norman RJ. Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2012;18(2):146-70. doi: 10.1093/humupd/dmr042.
4. Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016;106(1):6-15. doi: 10.1016/j.fertnstert.2016.05.003.
5. Randeva HS, Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, Lehnert H. Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev. 2012;33(5):812-41. doi: 10.1210/er.2012-1003.
6. Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr Rev. 2015;36(5):487-525. doi: 10.1210/er.2015-1018.
7. Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E; American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE); Androgen Excess and PCOS Society. American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society Disease State Clinical Review: Guide to the Best Practices in the Evaluation and Treatment of Polycystic Ovary Syndrome – Part 1. Endocr Pract. 2015;21(11):1291-300. doi: 10.4158/EP15748.DSC.
8. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364-379. doi: 10.1016/j.fertnstert.2018.05.004.
9. Mihailidis J, Dermesropian R, Taxel P, Luthra P, Grant-Kels JM. Endocrine evaluation of hirsutism. Int J Womens Dermatol. 2017;3(1 Suppl)
10. . doi: 10.1016/j.ijwd.2017.02.007.
11. Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, Welt CK; Endocrine Society. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565-92. doi: 10.1210/jc.2013-2350.
12. Fraison E, Kostova E, Moran LJ, Bilal S, Ee CC, Venetis C, Costello MF. Metformin versus the combined oral contraceptive pill for hirsutism, acne, and menstrual pattern in polycystic ovary syndrome. Cochrane Database Syst Rev. 2020;8(8)
13. . doi: 10.1002/14651858.CD005552.pub3.
14. Fernandez RC, Moore VM, Van Ryswyk EM, Varcoe TJ, Rodgers RJ, March WA, Moran LJ, Avery JC, McEvoy RD, Davies MJ. Sleep disturbances in women with polycystic ovary syndrome: prevalence, pathophysiology, impact and management strategies. Nat Sci Sleep. 2018;10:45-64. doi: 10.2147/NSS.S127475.
15. Schmidt TH, Shinkai K. Evidence-based approach to cutaneous hyperandrogenism in women. J Am Acad Dermatol. 2015;73(4):672-90. doi: 10.1016/j.jaad.2015.05.026.
16. Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med. 2005;353(24):2578-88. doi: 10.1056/NEJMcp033496.
17. Martin KA, Anderson RR, Chang RJ, Ehrmann DA, Lobo RA, Murad MH, Pugeat MM, Rosenfield RL. Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(4):1233-1257. doi: 10.1210/jc.2018-00241.