TOPICS

Finasteride in Hidradenitis Suppurativa A “Male” Therapy for a Predominantly “Female” Disease

Birgit N. Khandalavala, MD; Melissa Voutsalath DO University of Nebraska Medical Center, Omaha, Nebraska

Disclosure: The authors report no relevant conflicts of interest


Abstract

Objective: Hidradenitis suppurativa is associated with obesity and metabolic syndrome, and a hormonal component has been implicated. Finasteride is an anti-androgenic agent used for benign prostatic hypertrophy, androgenic alopecia, and, in females, hirsutism. Finasteride is an inhibitor of type II 5 alpha-reductase that reduces dihydrotestosterone levels and appears to alter end-organ sensitivity of the folliculopilosebaceous unit. The objective is to review the use of finasteride for hidradenitis suppurativa. Design: Review of the literature. Setting: Clinical treatment of patients with hidradenitis suppurativa. Measurement/participants: Five publications described the use for hidradenitis suppurativa. Four global case reports cited 13 individual patients, four male and nine female. Females included three adolescent patients and a child aged seven with precocious puberty. In the United States, finasteride in obese male adults was mentioned to be helpful. Results: Oral finasteride, as monotherapy or additional therapy was utilized for advanced hidradenitis suppurativa. The outcomes were largely favorable, with complete resolution in three patients. A latency period was evident in a majority. Limited, or continuous use for up to six years, was detailed. Response to reintroduction was successful. A benign safety profile with excellent tolerability was described. Teratogenicity of finasteride was addressed and contraception advocated in female patients. Sexual adverse effects were not ascertained. Conclusion: In hidradenitis suppurativa, finasteride could be considered in adults of both sexes as well as in select female children and adolescents, particularly those with concurrent metabolic and hormonal alterations present. Finasteride provides another highly effective, durable, relatively safe, and inexpensive option in the treatment of hidradenitis suppurativa. (J Clin Aesthet Dermatol. 2016;9(6):44–50.)


Hidradenitis suppurativa (HS)[1],[2] is a chronic, recurrent, inflammatory disease of the skin, seen most commonly in postpubertal young adults. The presentation of HS can range from a diverse spectrum of comedones, folliculitis, and abscesses to cicatricial advanced stages with scars, extensive, disfiguring tracts, fistulas, and keloids. Intertriginous areas are most frequently affected; however, HS can involve any area of the follicle-bearing skin, including the face. The burden of disease can be significant and profound due to pain and associated psychosocial aspects with reduced quality of life.[1],[2]

The overall global prevalence rate is usually noted to be one percent.[3] The incidence is suspected to be more common and point prevalence rates of 4.1 percent have been reported in a study of young adults in Europe.[4] In a United States study, an overall annual incidence of 6.0 per 100,000 person years has been reported with the highest incidence in young women.[5 ]The disease is rare in pre-pubertal stages of childhood,6 although it has been reported in children as young as 7 to 9 years of age with precocious puberty.[6],[7] The peak age of onset is seen in the second or third decade of life.[1],[6] This is followed by a substantial decline in women after the age of 50.5 The prevalence in females is significantly higher than in males with the typical ratio of 3:1.1 The increase in incidence over the past 40 years has been particularly evident in females.[5]

The etiology of HS has not been established with certainty.[1] Defects of immunity along with chronic infection are critical components for the development and persistence of the disease. Scheinfeld[2] summarizes the pathophysiology as a reaction pattern of the skin, dependent on the patient’s inherent and specific risk factors in a setting of predisposing genetic factors and inflammation.

Currently, HS is considered to be a disease of follicular pathology rather than the previous concept of an inflammatory or infectious process of the apocrine glands.[2] The mechanism of HS begins with follicular occlusion, as the initiating event, in the folliculopilosebaceous unit (FPSU).[2] Follicular occlusion is felt to arise from an increase in ductal keratinocyte proliferation causing follicular hyperkeratosis and occlusion, with follicular rupture occurring subsequently.[8] Androgen receptors are found in the keratinocytes and mediate the effects of androgens within the FPSU.[6]

The major factors contributing to HS are smoking and obesity.[9],[10] Obesity is more common in patients with HS[9] and may affect the disease through mechanical factors and abnormal hormonal metabolism.[11]

While obesity is a measure of global adiposity using the body mass index, the constellation of metabolic syndrome and increased truncal adiposity has recently been found to be highly and disproportionately prevalent in the HS cohort.[12],[13] In Gold’s study of 366 patients in the US population, 50.6 percent were found to have metabolic syndrome.[13] More profound metabolic abnormalities, including higher rates of glucose intolerance, were found in HS patients with metabolic syndrome compared to those without HS, leading to the speculation that metabolic syndrome is the primary pathology rather than the result of HS.[13] Obesity and metabolic syndrome are well known to be associated with hyperinsulinemia and other hormonal alterations that include hyperandrogenism and polycystic ovary syndrome (PCOS).[14],[15] Hyperinsulinemia produces hyperandrogenism by either a stimulant effect on ovarian androgen secretion or directly by reducing serum sex hormone-binding globulin and plays a pivotal role in the etiology of PCOS.[14] In female patients with HS, a higher prevalence of PCOS and insulin resistance have been noted.[16]

Androgens have been suggested to play a substantial role in HS,[6] which has been described as an androgen-dependent condition.17 This association has been suggested by the age distribution,[1],[6] precipitating factors,[18] as well as improvement with systemic anti-androgens therapy.[19–21] The bioactive androgen in the hair follicles is dihydrotestosterone (DHT),15 which has greater potency due to its higher affinity and slower dissociation. Testosterone has to be converted into DHT by 5 alpha-reductase, which is present in the skin as well as other tissues. There are two isoenzymes of 5?-reductase. The type 2 isoenzyme has 20 times greater affinity for testosterone than type 1. The type II 5?-reductase isoenzyme is found in the prostate, seminal vesicle, epididymis, liver, and hair follicles, while the type I 5?-reductase is present in both hair follicles and apocrine glands.[15] The activity of 5?-reductase is insulin-like growth factor-1 dependent, and during puberty there is an increased physiological signaling of growth hormone, insulin, and insulin-like growth factor-1 mediated through the insulin receptor.[22] Puberty has been described as a period of transient insulin resistance, and obesity is felt to enhance the physiological changes and often promotes earlier onset of puberty.[23] HS has been reported as the presenting symptom of precocious puberty.[6] Normal androgen levels are low prior to adrenarche and start rising around age 8.5 Clinical evidence of hyperandrogenism is usually absent in HS, and more often, results revealed no difference in plasma testosterone or dehydroepiandrosterone levels between female patients with hidradenitis.[10] Due to a lack of a conclusive correlation with biochemical hyperandrogenism and a consistent response with more global anti-androgen therapy, a local androgen effect has been postulated.[10],[24] Genetically determined local activity of 5?-reductase is felt to determine the skin sensitivity.[5] Unlike in HS, hirsutism in females is caused by systemic hyperandrogenism as well as localized skin sensitivity to androgens.[5] The degree and distribution of hirsutism is directly correlated to the presence and activity of 5?-reductase in the skin.[5] Hence, medications that target this enzyme action would benefit both conditions since they share a common pathophysiology at the follicular level.

The effective and durable treatment of HS continues to be confounding and challenging. Diverse definitive treatment strategies include both medical and surgical interventions, but well-supported evidence for any treatment modality is not available.[25] Anti-androgens comprise another modality for patients with treatment failure and evidence currently indicates a role for consideration in select women.[26] In a study of 64 female patients,[21] comparing anti-androgen therapy to antibiotics, use of cyproterone acetate, oral birth control pills, spironolactone, either alone or in combination, was noted to be superior to the use of antibiotics. This led the authors to recommend consideration of hormonal manipulation in all women with HS. Cyproterone acetate, however, is not available in the United States. In their clinical practice, Margessson and Danby27 describe the frequent use of hormonal treatment to have a good response. In female patients they have used drospirenone containing oral contraceptives and spironolactone, and in male patients, dutasteride.[27] Similar regimens and results were conveyed in a review of 350 patients.[2] The authors review the use of finasteride for HS in the current literature.

METHODOLOGY

A systematic search of the PubMed, EMBASE, and Cochrane databases was performed and reference lists of review articles were searched using Medical Subject Headings (MeSH) and the following keywords: “hidrandenitis” “suppurativa,” “acne inversa,” “Verneuil disease,” “antiandrogens,” “finasteride,” and “hormonal treatment.” Five publications were found describing the clinical use of finasteride in patients with documented HS.

RESULTS

Clinical use and outcomes in HS. Finasteride was reported as monotherapy, an additive therapy in 13 patients globally, or, as an adjunctive therapy in the United States, in male patients.[2],[24],[28–30] The first report in the literature was from England in 1999 and consisted of two cases of protracted and recalcitrant HS. A 56-year-old man with severe perianal disease experienced significant improvement within a month on finasteride and a 55-year-old postmenopausal diabetic woman showed improvement in three months of therapy. The dose of finasteride was 5mg/day, and no side effects were noted after the duration of nine months and three months, respectively, with dramatic improvement of HS.28 The subsequent case series from India29 described seven patients ranging in age from 16 years to 36 years, with five female and two male cases who had failed previous antibiotic therapy. This included a 16-year-old adolescent girl. All other patients were adults, but younger than 40 years of age. Patients presented with moderate-to-severe disease and were treated with the 5mg/day dose of finasteride as monotherapy. Other medications were withheld. Within 2 to 8 weeks of therapy, the authors reported no new lesions or some improvement. After exclusive finasteride therapy of 6 to 16 months, the medication was discontinued for a month following healing. Pregnancy was ruled out before and during treatment. The patients were followed up for 8 months to 2 years subsequently. Recurrences occurred in two patients within a month of discontinuation and patients were retreated with monotherapy finasteride with favorable outcomes. Additional interventions were used as needed for the flares; however, 6 of the 7 patients continued to improve significantly and three patients progressed to complete healing. Two patients, followed for more than one year showed prolonged remissions of 8 to 18 months.

Adverse effects in one male patient consisted of prolonged pruritus leading to discontinuation of therapy, but could not be confirmed as due to the medication. In two female patients, breast enlargement and premenstrual tenderness was noted, which persisted for a year in one case. Finasteride was effective irrespective of duration or extent of the disease and was considered to have a disease-modifying potential.[29] In the third single case report from Spain, a 28-year-old man who had previously failed antibacterial and biologic therapy with extensive disease, including atypical facial involvement, was treated with 5mg/day of finasteride. After a year of treatment, nearly full remission and no new lesions were reported. Monitoring included a spermiogram. The onset and course of improvement, as well as timing of discontinuation and subsequent follow-up and results were not provided; however, no adverse effects were noted.[30]

Randhawa et al[24] from Canada most recently described the use of finasteride as adjunctive therapy for the treatment of HS in children and adolescents exclusively. A case series of three female pediatric patients included one at age seven, with precocious puberty. A 15-year-old female adolescent patient, with a known history of precocious puberty at age six, was started on 5mg/day finasteride after unsuccessful treatment of HS for eight years. After three months, finasteride was increased to 10mg/day and used in conjunction with other treatment modalities, resulting in clinical improvement with a reduction in frequency and severity of flares. Other medications were stopped and withheld, except for three brief and less intense flares requiring only antibiotics. The patient continued treatment for six years until the time of report, on monotherapy. Another 15-year-old female patient with PCOS and a year-long history of severe HS requiring surgical drainage and intravenous antibiotic was not successful with treatment with isotretinoin, erythromycin estolate, and oral contraceptives. Five mg/day finastride with erythromycin estolate and oral contraception resulted in diminished and less frequent recurrences over the next 2.5 years of follow-up. The patient continued to be on the medication at the time of publication.[24]

The third patient was a seven-year-old girl with a one-year history of HS with frequent flare-ups occurring every few weeks to months. She was treated with oral erythromycin with no improvement. Combination of topical clindamycin phosphate, benzoyl peroxide gel, oral trimethoprim, and 1.25mg/day finasteride led to minimal improvement after nine weeks. Increasing the dosage of finasteride to 2.5mg/day followed by another increase to 5mg/day after three months resulted in improvement. Trimethoprim was slightly increased; topical clindamycin phosphate was used as needed. Within one year, there was remarkable improvement of symptoms with few recurrences. Treatment was continued for three years.[24] In a review of 350 patients in the United States, Scheinfeld2 mentions that he has found finasteride to be helpful as an adjunctive therapy for obese male patients on tumor necrosis factor ?-blockers or antibiotics. No details of specific outcomes, dosage, or response were available.[2]

DISCUSSION

Mechanism of action of finasteride. Finasteride is a competitive and selective inhibitor of the isoenzyme type II 5?-reductase.31 Finasteride does not have any effect on the type 1 isoenzyme unlike dutasteride.2 Finasteride does not appear to cause changes in cortisol, estradiol, prolactin, thyroid stimulating hormone, thyroxine, or cholesterol, nor the hypothalamic-pituitary-testicular-axis in males.[31],[32] It is thought that finasteride can improve symptoms in HS by decreasing local concentrations of dihydrotestosterone at the level of the hair follicle by altering end-organ sensitivity rather than a more systemic effect on circulating androgens.[29] The effects seen in hirsutism, despite increasing testosterone levels, has been felt to provide additional evidence of the more localized mechanism of action.[33] One proposal is that the effects are caused by high androgen target tissue concentration.10 An alternative proposal is that there could be an enhanced target tissue response to relatively normal androgen levels.[6 ]The precise mechanism remains speculative since it has not been confirmed conclusively in any study, and confounded by the difficulty of measuring tissue and intracellular levels of DHT, as circulating levels may not be an accurate assessment.[15]

Indications and dosage. Finasteride has been indicated for use in males for benign prostatic hyperplasia (BPH) at a dose of 5mg/day since 1992 and for androgenic alopecia since 1997, at a dose of 1mg/day.[34] In female patients, this medication has been used as an alternative agent for hirsutism at a dose of 5mg/day or 7.5mg/day.33,31 From the review, the typical dosage reported was 5mg/day of finasteride in the nine adults, as well as in the three adolescents. Recommended dosage in the pediatric population has not been described in the literature. In a case report from Brazil 1mg/day to 2mg/day finasteride was used in children and adolescents for recurrent priapism.[35] No use of finasteride in the United States, in children or adolescents, has been reported. Randhawa et al[24] empirically initiated or increased the dose based on the response of HS and weight-based dosing did not appear to have been undertaken. From the review, it could be inferred that the 5mg/day dosage has been an effective starting dose in adolescents. In hirsutism, a pilot study with 2.5mg/day was used in late adolescence.[36] In a child of age seven, a lower dosage of 1.25mg/day was started and it would seem prudent to begin with the lowest possible dose.[24] In two of the pediatric-aged girls, adjustments were made according to the response and in an adolescent, the higher dose of 10mg/day was effective. Individualization of therapy appears to be a consideration if outcomes are sub-optimal, and results of titration indicate improved outcomes.

Stage of HS at time of initial therapy. Rigorous staging of HS using the Sartorious scale[2] was not undertaken for assessment of the degree of HS. In most instances, finasteride was used with more advanced disease where multiple regimens were not successful. No documented cases were found where finasteride was introduced early in the disease in adults. In a seven-year-old child, finasteride was used within one year of the onset of HS with excellent outcomes. The use of an effective drug early in HS, presumably at the time of puberty, could have a disease modifying effect,[2] hence the promising outcome in children with earlier and continuous therapy, provides another potential avenue that can be further evaluated.[24]

Latency. The onset of improvement was seen relatively quickly in this chronic disease, within two weeks at the earliest in one case, four weeks in a majority of the cases, and within 12 weeks to 52 weeks in the remainder. Latency has been seen when finasteride is used for BPH, alopecia, and hirsutism. Results of clinical therapy take up to 3 to 6 months to manifest.[31] In hirsutism, most of the benefit occurred after six months of therapy.33 This lag period requires to be taken into account and an adequate trial period should be given before abandoning or altering therapy. However, an early response in a few weeks to months seems more likely, even with significantly advanced and protracted cicatricial disease.[29] Based on the stage of the disease, no recommendations appear evident, and it was noted that the medication did produce effects despite the advanced degree of typical or atypical involvement.[30]

Duration of treatment. Finite or continuous regimens were reported. Finite monotherapy was undertaken in the study from India and was discontinued within one month of healing.[29] Recurrences did occur within a month of treatment cessation and should be expected if treatment is withheld due to the chronic nature of HS. The other publications indicated more prolonged continuous regimens. In the pediatric case series, a minimum therapy of two years was reported in all three with an ongoing therapy of six years. This was the longest duration of treatment documented in this review. The advantages of one over the other could not be concluded. While the intermittent use was associated with prolonged remissions,[29] the continuous use was associated with reduced intensity and frequency of recurrences.[24] The advantage of withholding treatment would be cost, mitigation of side effects, and redundancy if complete recovery can be sustained. Since reintroduction of finasteride was successful, this approach could be undertaken. Given the pain and psychological aspects of the disease, a continuous therapy as seen in the three youngest patients appears feasible with good tolerance.[24] The ideal duration and type of regimen could not be elucidated from the limited data. Clear documentation of rate of improvement and progression of HS based on staging was not performed to provide more objective information.

Metabolism. The mean bioavailability is 63 to 65 percent from a single dose, and daily dosing is accumulative by 50 percent.[31] The mean half-life is 4.8 to 6 hours. The drug is largely excreted unchanged in the fecal material. Finasteride is chiefly metabolized in the liver to 17-carboxylic acid by CYP3A4 isoenzymes. The metabolite is mainly excreted in feces (57%) and in the urine (39%). The effect of liver disease on pharmacokinetics is not known.[31] In chronic kidney disease no adjustment of the dose is required.[31] Drug interactions are theoretical, even with prolonged use, making this a safe combination with other pharmaceutical therapies including antibiotics,[31] and was certainly well evident in this report.[24]

Side effects and safety profile. Finasteride has a long history of safety in men with BPH. The side effects are relatively benign and transient and comparative to placebo.[37] The long-term use in males has been associated with relatively minor adverse effects and most frequently due to sexual dysfunction.31 Effects are known to be reversible.[38] In two cases of azoospermia, discontinuation resulted in reversal of the condition.[39] There was no effect on the hypothalamic-pituitary-gonadal axis; however, a slight effect was noted in serum prostate-specific antigen (PSA) in young men with the 1mg/day dose.[32] The major adverse effects seen in general use in more than 10 percent of patients are orthostatic hypotension, dizziness, decreased libido, impotence, and weakness.[40] Edema, drowsiness, skin rash, gynecomastia, decreased ejaculate volume, and dyspnea may be seen in 2 to 10 percent. The one instance of discontinuation in a male patient due to pruritus could not be confirmed by a challenge,[29] and the usual incidence is less than one percent, along with other side effects. While sexual adverse effects are rare, in April 2012, the United States Food and Drug Administration (FDA) required a label change that would include the 1mg/day finasteride dose (Propecia) label to include libido disorders, ejaculation disorders, and orgasm disorders that continue after discontinuation of the drug. A revision of the 5mg/day finasteride (Proscar) label included decreased libido that continues after discontinuation of the drug. Both medication labels now include description of reports of male fertility and/or poor semen quality that normalizes after drug discontinuation.[41] This review involved only four males with detailed records, three of whom were younger in age. None of the patients were noted to have sexual side effects. One patient did have a spermiogram done and the authors were cognizant of the potential for adverse effects and expressed concern about the sparse safety data in younger patients.30 In men over the age of 50, there appears to be an increased risk of high-grade prostate cancer. Though the medication has been used off-label for chemoprevention for prostate cancer, this indication has not been approved by the FDA for cancer prevention following review of these concerns.[31] Although no causal link has been established, in men, counseling and appropriate monitoring would appear to be indicated, after making an informed decision.

Besides the general adverse effects, in females, the major concern is teratogenicity and breast tenderness and enlargement. Finasteride is contraindicated in pregnancy and is categorized as pregnancy risk X due to the potential to cause feminization of the male fetus.[31] This drug is not indicated for use in reproductive aged females,[31] and pregnant women need to avoid physical contact with the medication. Due to this risk, women who were planning a pregnancy were excluded.[29] In the case reports, all women at risk of pregnancy, were cautioned and often treated in combination with oral contraceptives or other contraceptive options to prevent pregnancy if indicated.[29],[24] In one case series, regular tests for pregnancy were undertaken prior to and during treatment[29] and may be required if contraception cannot be guaranteed. Routine recommendations to ensure compliance with birth control are not indicated.[15] Aside from the risk of teratogenicity, finasteride has not been associated with abnormal systemic hormonal changes in women that would impair future childbearing by preventing ovulation or other reproductive dysfunction.[15] The use of finasteride, if properly administered, could be preferable in young women, particularly given the much more significant and protracted side effects of some of the other modalities.[29] The use of finasteride with oral birth control for hirsutism has been more effective than monotherapy with finasteride; a similar benefit could be evident in HS. In addition, finasteride does not have any drug interaction with birth control, hence no additional methods for prevention of pregnancy are needed, despite the enhanced risk of teratogenicity.[31] The documentation did not include the presence or degree of hirsutism in any of the female patients, although some were noted to have PCOS.[24] The combined use of oral contraception would be advantageous for those patients with HS who have hirsutism and metabolic abnormalities concomitantly. Two women experienced breast tenderness and enlargement, which, although persistent in one for a year, did resolve, and confirms the benign profile associated with finasteride.

Recent findings from basic science are revealing increasing evidence of impaired neurogenesis[42] and that finasteride can involve other mechanisms besides the androgen receptor. The shrinkage of the corpora cavernosa in mice[43] and persistence effects in the prostate in male gerbils were reported.[44] In human subjects aged 40 and younger, finasteride has been associated with sexual side effects that may persist despite discontinuation of the medication. The study author advocated increased awareness of the potential serious long-term risks since finasteride has additional inhibitory effects on the production of neuro-active steroids.[42] Safety in the pediatric population. Safety in the pediatric population has not been determined and is unknown, and besides the risk of teratogenicity, finasteride could potentially affect male fertility. At the 1mg/day dose used for up to eight years in both girls and boys from a case series of 57 patients with androgenic alopecia,[45] the only adverse effect was one male patient with temporary sexual dysfunction that did not persist even though the medication was continued.[46] With 1mg/day orally twice a day in a study group of five children and adolescents, no side effects were documented with a duration of treatment up to 31 months.[35]

Comorbid conditions. This review confirmed that all reported use of finasteride was in post-pubertal patients, and included those with precocious puberty, obesity, diabetes, and PCOS, and included one early postmenopausal but diabetic woman.[28] Due to the lack of documentation of concomitant hirsutism reported in any of the female cases, additional benefit could not be determined. The favorable outcomes seen may be reflective of the benefit of finasteride in this cohort and the selection of the appropriate patients based on metabolic and hormonal abnormalities reported.

CONCLUSION

In a chronic and challenging disease such as HS, the need for effective and durable, yet safe and tolerable, therapy is imperative since no single modality has shown significant sustained benefits.[2] Cost and availability are additional determinants of treatment. While complete resolution is often not possible, remissions and decrease in the frequency and extent of lesions is the foremost therapeutic goal.

Anti-androgens appear to have a useful role in achieving these objectives in HS. The use of finasteride as monotherapy or adjunctive therapy has recently been reported with encouraging and remarkable results that have included complete remission. Finasteride appears to have a disease-modifying potential. Use was detailed in a range of nine adult patients, and four female youths, but not in male children or male adolescents. So far, finasteride has been introduced mainly in moderate to later stages and found to be effective irrespective of the duration or advancement of the disease. Since cases consisted of treatment failures and advanced disease, the effect on progression of early disease could not be assessed. Greater benefits may be seen if used prior to cicatricial progression. Improvement was noted within a few weeks to months in most and is reflective of the latency of clinical action of finasteride. Intermittent or continuous regimens have been described. Recurrences should be expected after treatment cessation, and reintroduction is possible with good outcome. Optimal timing of initiation of treatment, dosage, titration, duration, or discontinuation remains undefined. Adverse effects were benign and relatively few, with excellent tolerance, even in children, which is of particular importance given the high discontinuation rates and complications of both medical and surgical therapies. Complications of long-term use in younger patients are unknown since finasteride has chiefly been used in older patients. In male patients, serious sexual side effects have been reported to be persistent, requiring recent additional changes to the medication label. Risks of potential teratogenicity in female patients must be communicated and the use of birth control addressed in women of reproductive age. In female patients, in the presence of insulin resistance and PCOS that is often associated with hirsutism, the use of finasteride could have additional benefits. The cost advantage of a generic medication as seen in this global distribution is certainly another advantage. There are no additional costs incurred due to monitoring.

With the increasing incidence of obesity and its associated comorbidities that often include hormonal and metabolic abnormalities, finasteride for HS could be a useful adjunct or alternative pharmaceutical option. The judicious and selective use of finasteride appears to be a sustainable, cost-effective, and safe medical option and could be considered more often in adults of both sexes and potentially in post-pubertal females of the pediatric population.

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