8 Pathogenesis and Classification of Female Pattern Hair Loss

Sara Wasserbauer

Summary

Female hair loss is a multifactorial disease, abounding with concomitant factors and mimics. With roughly 21 million women experiencing hair loss in the United States alone, and up to 80% of women experiencing noticeable hair loss by the age of 60 years, it is a significant problem that demands dedicated hair loss physicians. Most experts now agree that, unlike male pattern hair loss, androgens may not be the primary etiologic factor, other genetic and androgenetic influences are certainly present. Thus the term “female pattern hair loss” or “female hair loss” is preferred over “androgenetic alopecia.”

The histologic and clinical presence of miniaturization of the hair follicle is diagnostic of both female and male pattern hair loss (FPHL and MPHL; Fig. 8.1). In both cases, the anagen phase of the follicle is shortened, the hair has less time to grow, and thus the resulting hair fiber grows shorter and thinner in caliber.¹ However, miniaturization in female patients seems to be more widespread and less concentrated in specific areas. Women with FPHL tend not to experience discrete areas of baldness. Rather, most women experience a diffuse central miniaturization (with or without parietal involvement) with or without hairline preservation (i.e., the “Christmas tree pattern”).² Less likely is a “male pattern” with miniaturization at the frontotemporal corners and vertex, and this pattern is more closely associated with an actual hyperandrogenetic or unopposed androgen state.

8.2 Genetics in Development of Female Pattern Hair Loss

An autosomal dominant pattern with incomplete penetrance fits most cases of MPHL, so it is tempting to look for a genetic inheritance pattern for hair loss in women. According to an early study by Smith and Wells, 54% of women with FPHL have a male first-degree relative older than 30 years with androgenetic alopecia and 23% of women with FPHL have a female relative older than 30 years with androgenetic alopecia.³ Women younger than 50 years with “diffuse hair loss” have also been noted to have “hair thinning” or MPHL in at least 50% of their mothers and brothers, respectively. Differences in genetic expression and thus the response to hormonal influences may account for the male:female discrepancies.³ Racial factors also seem to point to a strong genetic component, with at least one study by Sim et al showing women of European ancestry with higher prevalence of FPHL than Korean women.⁵

However, genetics with a Mendelian pattern of inheritance definitely cannot account for the development of FPHL. Many of the studies regarding genetics are observational and not necessarily predictive. Both affected and unaffected patients note lack of similarity to family members. Initial studies linking a single variation on the CYP17 gene to both polycystic ovary syndrome (PCOS) and MPHL development led to the hypothesis that PCOS was the phenotypic equivalent of MPHL.6 Unfortunately, genes implicated in the development of both PCOS and MPHL—both conditions associated with progressive miniaturization and pattern hair loss—do not cosegregate with the phenotype in question, and thus cannot be relied upon to pinpoint the primary genetic defect.⁷

Furthermore, genotypic analysis looking for associations between FPHL and six common sex steroid hormone receptors demonstrated no correlation.⁸ More recent study suggests that some women who have FPHL (and other signs of increased androgen effects) demonstrate increased sensitivity to androgens, perhaps involving increased expression of the androgen receptor gene. In genetically susceptible patients, lower estrogen-to-testosterone ratios (when both are within normal range) may be the trigger for the development of FPHL.⁹ As a result of these and other studies, it is clear that while a genetic link exists, the complex mode of inheritance for this common disorder needs more study to be completely elucidated.

8.3 The Evidence for Hormones in the Pathogenesis of Female Pattern Hair Loss

FPHL is at least partly influenced by androgens, although hair loss in women is influenced by many other factors. Conditions in which androgen excess is a primary abnormality almost always have a component of scalp alopecia.¹⁰ PCOS is a clear example of this and patients may present with additional evidence of androgen excess in the form of acne, irregular menses, weight gain, hirsutism, and difficulty with conception (Table 8.1). Abnormal androgen levels are not predictive of female hair loss risk. Many patients with obvious miniaturization and clinical presentations consistent with FPHL have androgen levels, including testosterone and dehydroepiandrosterone sulfate, within the normal range.¹¹ Furthermore, a full range of hormones apart from androgens has been implicated in women’s hair loss including estrogens, prolactin, thyroid hormone, cortisol, growth hormone, and melatonin.

Table 8.1 Signs and symptoms of a female hyperandrogenetic state

Of the hormones implicated in FPHL, testosterone’s effects can be the easiest to see, particularly in those patients who choose to use exogenous testosterone supplementation. It is a common to see clinically significant hair loss (often in the “male” pattern of hair loss, i.e., in the frontotemporal corners and vertex) resulting within a few years of supplementation even at low doses. Testosterone alone has been shown to suppress growth of hair follicles in vitro.¹² Paradoxically, short-term use in women for the treatment of hypoactive libido may result in increased hair growth in unwanted areas (face, axillae, etc., where dihydrotestosterone (DHT) is stimulatory rather than inhibitory) in addition to the scalp.¹³ If high testosterone levels are suspected clinically, the levels should be measured with a serum assay (non-analog) and any level that seems incongruous with the clinical presentation should prompt repeating the test. Even low testosterone values should be considered suspect if standardized testing strategies are not used.¹⁴

Estrogens have a mixed effect on FPHL, through several possible mechanisms. It has been shown that estrogen (likely the alpha form) causes the hair cycle to prematurely enter catagen and maintain telogen, albeit reversibly.¹⁵ Other studies show 17-beta estradiol (through the alpha estrogen receptor pathway) may be a direct inhibitor of 5-alpha reductase at higher concentrations and that 17-alpha estradiol prevents additional testosterone availability by promoting the conversion of testosterone to other less potent androgens.^16,17 Thus, the presence of estrogen prevents additional DHT action on the dermal papilla, and through these mechanisms, treatment with estrogen may help either return to or keep the hair follicle in the anagen phase of the hair cycle. Progesterone also inhibits DHT synthesis in the dermal papilla on par with finasteride. This helps explain why women in their mid-40s start to exhibit signs of hair loss and why there is a spike in the incidence of FPHL in postmenopausal women (since at that time progesterone and estrogen levels drop, and follicle-stimulating hormone and luteinizing hormone levels rise).¹⁸ Treatment with 5-alpha reductase inhibitors such as finasteride and cyproterone acetate (also known as cyproterone acetate, also an androgen blocker) can be helpful for some women with FPHL but is not universally effective. Current data present a mixed picture and there are still no studies on the side effect profile in women.¹⁹

The hormones implicated in hair loss may not themselves have a direct effect. The explanation may lie in the higher (up to five times) concentrations of aromatase expressed in the follicles of women versus men.²⁰ Aromatase leads to conversion of testosterone and androstenedione to the less potent estrogen, estradiol, and estrone instead of DHT, thus sparing the dermal papillae from its miniaturizing effects. An example of the role of aromatase in hair loss is in the population of women treated with tamoxifen and/or aromatase inhibitors (anastrozole, letrozole, or exemestane)—usually for hormone receptor positive (HR+) breast cancers. Over the course of their treatment with aromatase inhibitors, these women predictably experience hair thinning and develop FPHL. Other enzymes have been implicated in this same sort of hormone conversion. These include STS, 17-beta-HSD, 3-beta-HSD, 3-alpha-HSD, and type II 5-alpha reductase. All have varying expression and activity levels within the dermal papilla of hair follicles depending on the body site and within the scalp, potentially accounting for many of the variations in hair loss patterning. So it stands to reason that the levels of different hormones by themselves will not fully elucidate the pathogenic cause of FPHL.

Women’s scalps also exhibit higher levels of sex-hormone–binding globulin, which means female scalps are exposed to lower levels of potent androgens since the androgens themselves remain bound. Evidence for the role of sex hormone binding globulin (ShBG) includes the study that showed that lower levels of ShBG are associated with diffuse hair loss in young women.21 There is no absolute diagnostic testing standard to measure aromatase, ShBG, or even 5-alpha reductase levels; so, clinical application of these principles remains in our future as clinicians. A complete laboratory panel for evaluating the female patient with FPHL should be designed to examine the factors we know to be important (Table 8.2).

Table 8.2 Recommended blood tests for evaluation of FPHL

8.4 Confounding Factors in Determining the Pathogenesis of Female Pattern Hair Loss

FPHL is most likely exacerbated by a number of factors including stress and stress hormones, chronic illnesses, surgery, medications (too numerous to list), and a low protein diet. Vitamin B12 and vitamin D deficiencies can also play a role in accelerating hair loss.²² Heat (straightening, curling, or drying), chemicals (perms and coloring), and traction (pulling, plucking, extensions, or tight hairstyles) are all long-term risks for damaging hair, especially if done daily, and can imitate or aggravate FPHL. Smoking, strict vegetarianism, and severe weight loss are definitely correlated with poor hair growth and should be avoided. Since hair loss in a female likely involves a combination of etiologies, the initial history will take longer than that in a male patient and should include all of the aforementioned contributory factors (Table 8.3).

Table 8.3 Factors to include in patient history when evaluating female pattern hair loss

Two of these factors are worth specific mention, as they can often either mimic or coexist with FPHL. Low iron, as measured by a serum ferritin <70 ng/mL and hypothyroidism (even when adequately treated) can have a particularly devastating effect and if not already known should be screened for routinely in alopecic female patients.

8.5 Classification of Female Pattern Hair Loss

Several systems for classification of female hair loss have been proposed. The most familiar is the Norwood/Ludwig scale proposed in 1977, followed by the Savin scale proposed in 1994 and the Cohen Hair Loss Severity scale in 2004. Other scales include the Olsen scale and the Ebling-Rook scale. The Ludwig scale is simple in that it has three classifications of FPHL severity based on overall visual exam. Its major contribution is the recognition of the pattern of preservation of the frontal hairline when compared to MPHL and the lack of complete alopecia (exceedingly rare) that Hamilton had included in his original grading scale for women. Nearly all patterns of the Ludwig scale show visually significant hair loss over the same area of scalp (i.e., the top) with a side part, and thus do not allow for a fully descriptive classification. Despite this, it continues to be widely used in teaching texts for pattern hair loss in women (Fig. 8.2).

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