Correlation Between Serum Levels of Insulin-Like Growth Factor 1, Dehydroepiandrosterone Sulfate, and Dihydrotestosterone and Acne Lesion Counts in Adult Women

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STUDY Correlation Between Serum Levels of Insulin-like Growth Factor 1, Dehydroepiandrosterone Sulfate, and Dihydrotestosterone and Acne Lesion Counts in Adult Women

Mark Cappel, MD; David Mauger, PhD; Diane Thiboutot, MD

Objectives: To determine if insulin-like growth factor tistical testing was conducted to determine whether IGF-1 1 (IGF-1) and androgen levels (1) correlate with the pres- or androgens had a greater effect on acne lesion counts. ence and severity of acne in adult men and women, and (2) correlate directly with each other and interact in af- Results: Dehydroepiandrosterone (DHEAS), dihydrotes- fecting acne. tosterone (DHT), and IGF-1 correlated positively with acne lesion counts in women. Androstenedione and Design: Case-control study and single-center examina- DHEAS correlated with acne lesion counts in men. Al- tion of hormone levels in a cohort of volunteers. though the age-adjusted mean serum levels of IGF-1 were higher in women with clinical acne than in women with- Setting: Academic referral center. out clinical acne, this difference did not achieve statistical significance. No difference in IGF-1 level was noted Patients: Thirty-four subjects (8 women and 8 men with in men based on the presence of clinical acne. In women clinical acne, 10 women and 8 men without clinical acne). with clinical acne, IGF-1 correlated with DHT. In men Clinical acne is defined by a history of persistent acne with clinical acne, IGF-1 correlated with DHEAS and an- (acne present on most days for several years), recent acne drostenedione. In men and women with clinical acne, the treatment, and the presence of 10 or more inflamma- effects of androgens on increased acne lesion counts were tory acne lesions and 15 or more comedones. dependent on the influence of IGF-1.

Interventions: Single visit for serum sampling. Conclusions: Increased IGF-1 levels in addition to androgens may influence acne in adult men and women. Main Outcome Measures: Serum levels of IGF-1 and While IGF-1 appears to have a stronger effect on acne in androgens were determined, adjusted for age, and com- women, androgens may play a greater role in acne for pared based on the presence or absence of clinical acne men. However, in both men and women these hor- using an analysis of covariance. Correlations between hormones are interrelated, possibly owing to reciprocal ef- mone levels and acne lesion counts were calculated within fects on hormone production. each subgroup. Correlations were also calculated between serum levels of IGF-1 and androgens. Further sta- Arch Dermatol. 2005;141:333-338

EBUM PRODUCTION IS ONE OF cumulative secretion of growth hor- the key factors in the devel- mone, which makes it more suitable for opment of acne. Maximum serum testing. One study noted elevated sebum production begins serum levels of IGF-1 in 82 women with during puberty, which coin- acne aged 20 to 25 years when compared Scides with the peaking levels of growth with 31 age-matched controls.3 hormone and insulin-like growth factor 1 Author Affiliations: (IGF-1) that occur in midpuberty.1,2 Ac- CME course available at Department of Internal cordingly, elevated levels of growth hor- www.archdermatol.com Medicine, The Medical College mone and IGF-1 may play a role in the de- of Wisconsin, Milwaukee velopment of acne. Since growth hormone Similar to that of growth hormone and (Dr Cappel); Departments of is released in intermittent secretory bursts IGF-1, the level of dehydroepiandros- Health Evaluation Sciences (Dr Mauger) and Dermatology and is thus impractical to assess by ran- terone (DHEAS), the major adrenal andro- (Dr Thiboutot), The dom serum sampling, increased levels have gen precursor, progressively increases dur- Pennsylvania State University not been directly demonstrated in pa- ing puberty. It appears to be a crucial factor College of Medicine, Hershey. tients with acne. On the other hand, IGF-1 in the initiation of sebum secretion in the Financial Disclosure: None. is relatively stable and primarily reflects prepubertal period and perhaps beyond.4

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Since both IGF-1 and DHEAS follow a similar chrono- strual cycle. Data on levels of serum androgens and tissue an- logical trend, there may be a relationship between these 2 drogen-metabolizing enzymes (5␣-reductase and 17␤- hormones. Correlations between DHEAS and IGF-1 have hydroxysteroid dehydrogenase) were previously reported in 10 been found among other groups of patients, including obese these subjects. women and normal prepubertal girls.5,6 In addition to not- ing elevated IGF-1 levels, Aizawa and Niimura3 noted el- ACNE LESION COUNT evated levels of DHEAS in postadolescent women with acne AND SERUM HORMONE LEVELS who were aged 20 to 25 years. However, DHEAS levels did not correlate with those of IGF-1. Based on clinical examination, the numbers of comedones and Several studies have shown that levels of androgens inflammatory lesions were recorded, and total acne lesions were determined. are higher in adult women with acne than in those with- Levels of IGF-1 were determined by acid ethanol extrac- out acne, yet there is little information available about tion and double antibody radioimmunoassay with intra-assay the correlation of androgen levels with acne lesion counts and interassay variance of 3.0% and 6.0%, respectively.11 Since in adults. In women in their 20s with acne, free testos- IGF circulates as a complex with binding proteins that inhibit terone levels correlated with the number of pustules, but its interaction with IGF-1 receptors, IGF binding protein 3 no correlations were noted between levels of androgens (IGFBP-3) was also determined from banked serum from the and acne lesions in men.7 In preadolescent and adoles- female subjects. Levels of IGFBP-3 were also measured via double cent girls, elevated DHEAS levels have also been corre- antibody radioimmunoassay with an intra-assay variance of 3.4% 12 lated with acne severity but not with lesion counts.8,9 to 8.0% and an interassay variance of 5.3% to 6.3%. Andro- The goal of the present study is to test the following stenedione, testosterone, DHEAS, and DHT levels were determined by means of radioimmunoassay methods as previously hypotheses in adults with acne: (1) that IGF-1 levels are reported.10 elevated in patients with clinical acne; (2) that IGF-1 correlates with androgen levels; and (3) that the extent of acne (lesion counts) correlates with levels of IGF-1 and STATISTICAL ANALYSIS androgens. Statistical Analysis System version 8 (SAS Institute Inc, Cary, This study demonstrates that the number of total acne NC) was used to analyze data from the following subgroups: lesions, inflammatory lesions, and comedones each cor- all women; women with clinical acne; women without clinical related with serum IGF-1 levels in women with clinical acne; all men; men with clinical acne; and men without clini- acne. In this group, serum IGF-1 levels also correlated with cal acne. An analysis of covariance was used to compare the serum dihydrotestosterone (DHT) levels. However, the cor- age-adjusted serum hormone levels between women with relation of IGF-1 level with number of comedones and in- clinical acne and women without clinical acne. The same flammatory lesions was not independent of the effects of analysis was performed for men with and without clinical DHT. In adult women, DHEAS and DHT also correlated acne. Serum levels of IGFBP-3 were also compared between with acne lesion counts (total, inflammatory, and com- women with and without clinical acne using analysis of edone). Although the age-adjusted mean serum IGF-1 level covariance. For all 6 of the subgroups, correlation coefficients were calculated between the various hormone levels (IGF-1, was higher in women with clinical acne, this difference DHEAS, androstenedione, testosterone, and DHT) and the only approached statistical significance (P=.07). acne lesion counts (total lesions, comedones, and inflammatory lesions). METHODS In addition, correlation coefficients were calculated between the levels of various androgens and IGF-1 to determine the presence of hormone-hormone associations. When such as- SUBJECTS sociations were found, a multivariable regression analysis was used to determine if either IGF-1 or androgens independently The institutional review board of The Pennsylvania State Uni- correlated with acne lesion counts. Partial correlation coeffi- versity College of Medicine approved this study. Men and women cients were calculated between each independent variable (IGF-1 aged 18 to 45 years with and without clinical acne were re- and androgen) and the dependent variable (acne lesion count). cruited for this study. Participants were questioned about se- If either hormone had a partial correlation coefficient with a verity, duration, and prior treatment for acne. Participants were statistically significant P value, it was considered that this hor- classified as having clinical acne based on a positive history of mone exerted effects independent of the other hormone on the persistent acne (acne present on most days for several years) acne lesion count. On the other hand, if the correlation coef- and recent acne treatment and objective physical findings of a ficient P value was not statistically significant, this indicated minimum of 15 comedones and 10 inflammatory papules on that the hormone’s effect on acne lesion count was not inde- the face. One participant with a history of persistent acne and pendent of the other hormone. Any t test finding, correlation extensive comedonal acne (45 comedones) but only 8 inflam- coefficient, or multivariable regression analysis that produced matory papules was also included in the clinical acne group. a P value of .05 or lower was considered to demonstrate a sig- Participants were excluded from the study if they had re- nificant association. ceived oral antibiotics within 1 month of the study; used topi- cal acne medications such as antibiotics, benzoyl peroxide, or RESULTS tretinoin within 2 weeks prior to the study; received prior treatment with oral retinoids; had known endocrine disease such as congenital adrenal hyperplasia, polycystic ovary syndrome, A total of 34 subjects participated in the study: 8 women or adrenal or ovarian tumor; or were currently using any type with clinical acne (mean ± SD age, 31±5 years), 10 women of hormonal contraceptive, estrogens, corticosteroids, or finas- without clinical acne (age 33±7 years), 8 men with clini- teride. Women were observed in the luteal phase of their men- cal acne (age 27±7 years), and 8 men without clinical

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Subject Characteristics No. Total No. of Acne Lesions P Value† Comedones P Value† Inflammatory Lesions P Value† All women 18 28 ± 5 21 ± 4 8 ± 2 Clinical acne 8 44 ± 7 .002 30 ± 6 .01 14 ± 2 Ͻ.001 No clinical acne 10 16 ± 3 13 ± 2 3 ± 1 All men 16 28 ± 6 20 ± 5 8 ± 1 Clinical acne 8 42 ± 9 .01 29 ± 9 .11 13 ± 1 Ͻ.001 No clinical acne 8 15 ± 4 12 ± 4 3 ± 1

*Unless otherwise indicated, values are given as mean ± SEM. †Unpaired t test, women or men, with vs without clinical acne.

Table 2. Age-Adjusted Serum Hormone Levels in Subjects With and Without Clinical Acne*

DHEAS, Subject IGF-1, P IGFBP-3, P ng/mL P A, ng/ml P TT, ng/dL P DHT, ng/dL P Characteristics ng/mL Value mg/mL Value (µmol/L) Value (nmol/L) Value (nmol/L) Value (nmol/L) Value All women (n = 18) 287.3 ± 14.5 5.1 ± 0.4 1486.2 ± 229.6 2.4 ± 0.3 30.0 ± 4.7 16.2 ± 1.6 (4.0 ± 0.6) (8.5 ± 1.1) (1.0 ± 0.2) (0.6 ± 0.06) Clinical acne (n = 8) 316.9 ± 20.5 .08 5.5 ± 0.6 .40 1979.9 ± 309.5 .05 3.2 ± 0.4 .02 42.9 ± 6.3 .02 19.6 ± 2.2 .06 (5.4 ± 0.8) (11.2 ± 1.4) (1.5 ± 0.2) (0.7 ± 0.07) No clinical acne (n = 10) 263.7 ± 18.2 4.8 ± 0.6 1091.3 ± 275.3 1.8 ± 0.4 19.7 ± 5.6 13.5 ± 1.9 (3.0 ± 0.7) (6.3 ± 1.4) (0.7 ± 0.2) (0.5 ± 0.07) All men (n = 16) 269.2 ± 18.2 NA 2480.3 ± 338.6 2.3 ± 0.2 473.6 ± 59.0 34.0 ± 3.0 (6.7 ± 0.9) (8.1 ± 0.8) (16.4 ± 2.0) (1.2 ± 0.1) Clinical acne (n = 8) 283.3 ± 28.2 .51 NA NA 2555.5 ± 423.7 .81 2.1 ± 0.3 .33 412.6 ± 85.8 .35 35.2 ± 4.8 .74 (6.9 ± 1.1) (7.3 ± 1.0) (14.3 ± 3.0) (1.2 ± 0.2) No clinical acne (n = 8) 255.1 ± 28.2 NA 2405.0 ± 423.7 2.6 ± 0.3 534.7 ± 85.8 32.8 ± 4.8 (6.5 ± 1.1) (9.1 ± 1.0) (18.5 ± 3.0) (1.1 ± 0.2)

Abbreviations: A, androstenedione; DHEAS, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; IGF-1, insulin-like growth factor 1; IGFBP-3, IGF binding protein 3; NA, not applicable; TT, total testosterone. *Values are given as mean ± SEM. Reference ranges are as follows: IGF-1, 90-780 ng/mL, depending on age; IGFBP-3, 1.19-6.02 mg/mL, depending on age and sex; DHEAS for men, 1500-4500 ng/mL (4.1-12.2 µmol/L); DHEAS for women, 1000-3600 ng/mL (2.7-9.8 µmol/L); A for men, 0.5-2.0 ng/mL (1.8-7.0 nmol/L); A for women, 0.4-2.4 ng/mL (1.4-8.4 nmol/L); TT for men, 250-900 ng/dL (8.7-31.2 nmol/L); TT for women, 20-80 ng/dL (0.7-2.8 nmol/L); DHT for men, 30-85 ng/dL (1.0-2.9 nmol/L); DHT for women, 4-22 ng/dL (0.1-0.8 nmol/L).

acne (age 34±7 years). Table 1 lists the range of the vari- CORRELATION OF SERUM HORMONE LEVELS ous acne lesion counts in the patient subgroups and de- AND ACNE LESION COUNTS tails a significant difference in lesion counts between subjects with and without clinical acne. In the all-women group, IGF-1, DHEAS, and DHT levels correlated with total acne lesions, comedones, and in- SERUM HORMONE LEVELS flammatory lesions. Androstenedione and testosterone levels correlated with inflammatory lesions in this group The age-adjusted mean hormone levels were deter- as well. In women with clinical acne, IGF-1 levels cor- mined in each subgroup based on sex and the presence related with total acne lesions, comedones, and inflam- or absence of clinical acne (Table 2). While women with matory lesions (Table 3). clinical acne had elevated IGF-1 and DHT levels com- In the all-men group, DHEAS and androstenedione lev- pared with women without clinical acne, this difference els correlated with total acne lesions and comedones, with only approached statistical significance (P=.08 and P=.06, the exception of a lack of correlation between andro- respectively). No statistically significant difference in stenedione and comedones. In men with clinical acne, IGF-1 level was noted in men. No differences were noted DHEAS and androstenedione correlated with total acne in IGFBP-3 levels based on the presence of clinical acne lesions and comedones. No correlation between IGF-1 in women. and acne lesions was noted in men (Table 3). Androstenedione, testosterone, and DHEAS levels were significantly greater in the women with clinical acne than CORRELATION OF SERUM IGF-1 in women without clinical acne, as previously reported.10 WITH OTHER ANDROGENS On the other hand, men did not have a significant difference in androgen levels based on the presence of clinical Statistically significant correlations were found between acne (Table 2). These data are reiterated herein to pro- IGF-1 and certain androgens in the all-women group, vide a framework for demonstrating the correlation be- women with clinical acne, and men with clinical acne tween serum hormone levels and acne lesion counts. (Table 4). In the all-women group, IGF-1 correlated with

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 3. Serum Hormones and Correlation With Various Acne Lesion Counts in Patient Subgroups*

Total No. No. of No. of of Acne Lesions, Comedones, Inflammatory Lesions, Subgroup Hormone Correlation Coefficient Correlation Coefficient Correlation Coefficient Women All women IGF-1 0.60† 0.58‡ 0.50‡ DHEAS 0.67† 0.58‡ 0.72§ Androstenedione 0.51‡ NS ࿣ 0.63‡ Testosterone NS ࿣ NS ࿣ 0.55‡ DHT 0.71§ 0.65† 0.67† Women with clinical acne IGF-1 0.88† 0.77‡ 0.74‡ Men All men DHEAS 0.78‡ 0.76‡ NS ࿣ Androstenedione 0.72‡ NS ࿣ NS ࿣ Men with clinical acne DHEAS 0.79‡ 0.76‡ NS ࿣ Androstenedione 0.72‡ 0.70‡ NS ࿣

Abbreviations: DHEAS, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; IGF-1, insulin-like growth factor 1; NS, not significant. *Androgen–acne/IGF-1 correlation coefficients were reported for each of the subgroups only if determined to be significant (PՅ.05). †P value, .001-.01. ‡P value, .01 to .05. § PϽ.001. ࿣P Ͼ.05.

as seen in Table 4. In the all-women group, IGF-1 cor- Table 4. Correlation of IGF-1 With Serum Androgens related with DHEAS and DHT. A multivariable regression analysis demonstrated that the partial correlations IGF-1 Correlation of DHEAS and DHT with total lesions and with inflam- Subgroup Correlative Androgen Coefficient matory lesions were each independent of IGF-1 Women (Table 5). However, the partial correlations of DHEAS All women DHEAS 0.54* and DHT with comedones were dependent on the ef- DHT 0.75† Women with clinical acne DHT 0.76* fects of IGF-1. In women with clinical acne, IGF-1 correlated with DHT. The multivariable regression analysis Men showed that the partial correlation of IGF-1 with com- All men No androgens Men with clinical acne DHEAS 0.86‡ edones and the partial correlation of IGF-1 with inflam- A 0.82‡ matory lesions were each dependent on the correlation of IGF-1 with DHT. In contrast, IGF-1 correlated with Abbreviations: A, androstenedione; DHEAS, dehydroepiandrosterone; total lesions independently of its correlation with DHT. DHT, dihydrotestosterone; IGF-1, insulin-like growth factor 1. In the all-men group, no correlation of IGF-1 with se- *P value, .01-.05. †PϽ.001. rum androgens was noted. In men with clinical acne, ‡P value, .001-.01. IGF-1 correlated with DHEAS and androstenedione. The multivariable regression analysis demonstrated that the partial correlations of DHEAS and androstenedione with total lesions and comedones were dependent on the cor- DHEAS (r=0.54; PϽ.05) and DHT (r=0.75; PϽ.001). In relation of these androgens with IGF-1 (Table 5). women with clinical acne, only DHT correlated with serum IGF-1 (r=0.76; PϽ.05). In the all-men group, neither DHEAS nor androstenedione correlated with IGF-1. COMMENT On the other hand, in men with clinical acne, DHEAS and androstenedione levels correlated with IGF-1 (r=0.86; Sebum production is a major factor in the pathogenesis PϽ.01 and r=0.82; PϽ.01, respectively) (Table 4). of acne. Growth hormone and IGF-1 may play roles in sebaceous gland physiology as evidenced by the expression DETERMINATION OF THE INDEPENDENT of receptors for growth hormone and IGF-1 on human se- EFFECTS OF EITHER IGF-1 OR SERUM baceous glands and in sebocytes.13,14 Studies of the ex- ANDROGENS ON ACNE LESION COUNTS pression of growth hormone and IGF-1 receptors in human sebaceous glands and analysis in rat preputial glands The data in Table 3 demonstrate that IGF-1 and andro- suggest that these factors stimulate sebocyte differentia- gens each correlated with various acne lesion counts in tion and proliferation.13,15 Clinically, in teenaged to middle- the subgroups. Because of the potential for a joint influ- aged patients with acromegaly, sebum excretion rate cor- ence of IGF-1 with an androgen, a multivariable regres- relates positively with the output of growth hormone by sion analysis was performed when a significant correla- the pituitary.16,17 Aizawa and Niimura3 reported that IGF-1 tion was noted between IGF-1 and a particular androgen levels were significantly higher in 20- to 25-year-old women

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 5. Multivariable Regression Analysis Indicating Partial Correlation Coefficients of Hormones With Acne Lesion Counts*

Subgroup Hormone Pair† Total Lesions‡ Comedones Inflammatory Lesions‡ Women All women DHEAS 0.53§ NS 0.54 ࿣ IGF-1 NS NS NS All women DHT 0.52§ NS 0.45§ IGF-1 NS NS NS Women with clinical acne DHT NS NS NS IGF-1 0.78§ NS NS Men All men NA NA NA NA NA NA NA NA Men with clinical acne DHEAS NS NS NS IGF-1 NS NS NS Men with clinical acne A NS NS NS IGF-1 NS NS NS

Abbreviations: A, androstenedione; DHEAS, dehydroepiandrosterone; DHT, dihydrotestosterone; IGF-1, insulin-like growth factor; NA, not applicable; NS, not significant. *Significance (PϽ.05) means that the hormone’s effect on acne is independent of the other hormone; nonsignificance means that the hormone’s effect on acne is dependent on the other hormone. †The “Hormone Pair” column denotes the androgen that correlates with IGF-1 for the corresponding subgroup as seen in Table 4. The multivariable regression analysis compares IGF-1 and the corresponding androgen in relation to one another. ‡Reported number values represent partial correlation coefficients. §P value, .01-.05. ࿣P value, .001-.01

with acne than in controls: 6 women with acne had IGF-1 when compared with controls in women in their 20s with levels higher than the normal range. Since growth hor- acne but not in men.7 In the present study, DHEAS levels mone stimulates IGF-1 production, it was hypothesized were significantly higher in an older group of adult women that these findings reflected an increased growth hor- with acne than in those without acne, but again not in men mone secretion in women with acne. (Table 2). Since adrenal androgens (such as DHEAS) are Our study, performed in older women (mean±SD age, the major contributors to circulating androgens in women 33±6 years) supports the findings that IGF-1 levels are and girls, it seems logical that the presence of acne relates higher in adult women with acne than in those without to serum DHEAS levels more in women than in men. Since acne. However, these differences did not achieve statis- androgen levels are much lower in women, other hor- tical significance, perhaps owing to our small sample size. mones such as IGF-1 or growth hormone could have a As in the case of serum androgens that were previously greater effect on acne in women than in men. reported in these patients, the mean IGF-1 levels were In both men and women, DHEAS correlated with all within the reference range in both groups with the ex- acne lesion counts (total, comedo, and inflammatory). ception of 1 woman (age 42 years) in the clinical acne Although there was no significant difference in the age- group (IGF-1 level, 437 ng/mL).10 Furthermore, in the adjusted mean serum levels of DHEAS in men with and present study, IGF-1 level correlated with total acne count, without clinical acne, a significant correlation of DHEAS comedone count, and inflammatory lesion count in adult with acne lesion counts was observed within the all- women. This correlation between IGF-1 and total acne men group and men with clinical acne, which suggests lesion count was especially strong in women with clini- that the extent of acne (as indicated by lesion counts) cal acne (r=0.88; P=.004). In men, however, there were directly correlates with serum DHEAS level in both men no significant differences in serum levels of IGF-1 based and women (Table 3). on the presence of clinical acne and no correlation of Numerous studies point to an interrelationship be- IGF-1 with acne lesion counts (Table 3). tween IGF-1, insulin, and androgens. These relationships These and previous data imply that IGF-1 or another are complex and not completely understood. They are best factor with a direct relationship to IGF-1 (such as growth exemplified in women with polycystic ovary syndrome, hormone) plays a role in acne in women. It appears that which is characterized by insulin resistance leading to hy- even normal serum IGF-1 levels may contribute to acne perinsulinemia, hyperandrogenemia, and increased acne. in women. Based on the strong correlation of IGF-1 lev- Insulin at high levels, as found in insulin-resistant sub- els and acne lesion counts in women with clinical acne, jects, can interact with the IGF-1 receptor. In addition, some it is possible that these women are more sensitive to varia- studies have demonstrated elevated IGF-1 levels in women tions in serum IGF-1 levels, whereas the putative effects with polycystic ovary syndrome.19 of IGF-1 on sebaceous glands in men may be masked by Increasing levels of serum androgens appear to cor- the overriding effects of higher serum androgen levels. relate with a rise in IGF-1 level. For example, when Serum DHEAS levels correlate with the presence of acne DHEAS was administered to postmenopausal women, in prepubertal children and in adolescent girls aged 14 to IGF-1 level also increased.20 Similarly, when oophorec- 17 years.9,18 Levels of DHEAS were significantly elevated tomized women were given testosterone, a linear in-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 crease occurred in the IGF-1–IGFBP-3 ratio but not a de- Acknowledgment: We thank Jan Light, LPN, Jolene Spon- crease in IGFBP-3 levels.21 These findings suggest that hower, MA, and Chris Hamilton, BS, for assistance with increasing serum androgens may directly stimulate pro- patient recruitment and the technical aspects of the study. duction of IGF-1. Conversely, IGF-1 may also stimulate DHEAS produc- REFERENCES tion by the adrenal gland or even within the skin itself. In- sulin-like growth factor 1 has been shown to play a major 1. Rosenfield RL, Deplewski D. Role of androgens in the developmental biology of role in promoting and maintaining the expression of ste- the pilosebaceous unit. Am J Med. 1995;98:80S-88S. roidogenic enzymes that are responsible for converting cho- 2. Cara JF, Rosenfield R, Furlanetto R. A longitudinal study of the relationship of lesterol into steroid precursors for the synthesis of DHEAS plasma somatomedin-C concentration to the pubertal growth spurt. Am J Dis 22 Child. 1987;141:562-564. and androgens. Steroidogenic enzymes are expressed in 3. Aizawa H, Niimura M. Elevated serum insulin-like growth factor-1 (IGF-1) levels human sebaceous glands where they may play a role in lo- in women with postadolescent acne. J Dermatol. 1995;22:249-252. cal androgen production.23 Also, IGF-1 can induce 5␣- 4. Stewart ME, Downing DT, Cook JS, Hansen JR, Strauss JS. Sebaceous gland reductase in human skin fibroblasts, leading to an in- activity and serum dehydroepiandrosterone sulfate levels in boys and girls. Arch 24 Dermatol. 1992;128:1345-1348. creased conversion of testosterone to DHT. In the present 5. De Pergola G, Cospite M, Giagulli V, et al. Insulin-like growth factor-1 (IFG-1) study, levels of DHEAS and androstenedione correlate with and dehydroepiandrosterone sulphate in obese women. Int J Obes Relat Metab those of IGF-1 in men with clinical acne, which supports Disord. 1993;17:481-483. the hypothesis that IGF-1 may play a role in stimulating 6. Guercio G, Rivarola M, Chaler E, Maceiras M, Belgorosky A. Relationship be- the activity of steroidogenic enzymes. In women, DHT cor- tween the growth hormone/insulin-like growth factor-1 axis, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal girls. J Clin Endocri- relates with acne lesions and with IGF-1. A high correla- nol Metab. 2003;88:1389-1393. tion exists between DHT and IGF-1 in women with clini- 7. Schmidt J, Lindmaier A, Spona J. Endocrine parameters in acne vulgaris. Endo- cal acne, suggesting that IGF-1 may influence DHT through crinol Exp. 1990;24:457-464. stimulation of 5␣-reductase (Table 4). 8. Lucky AW, Biro FM, Huster GA, Leach AD, Morrison JA, Ratterman J. Acne vulgaris in premenarchal girls. Arch Dermatol. 1994;130:308-314. Despite these correlations, the data from our study dem- 9. Lucky AW, Biro FM, Simbartl LA, Morrison JA, Sorg NW. Predictors of severity onstrate that IGF-1 and androgens can act independently of acne vulgaris in young adolescent girls: results of a five-year longitudinal study or dependently on acne lesion counts, depending on the J Pediatr. 1997;130:30-39. patient group or subgroup. For example, androgens exert 10. Thiboutot D, Gilliland K, Light J, Lookingbill D. Androgen metabolism in seba- independent effects of IGF-1 in the all- women and all- ceous glands from subjects with and without acne. Arch Dermatol. 1999;135: 1041-1045. men groups. However, in men and women with clinical 11. Nichols Institute Diagnostics. IGF-1 by Extraction: Radioisotopic Assay Manual. acne, IGF-1 appears to play a greater role. For example, in San Juan Capistrano, Calif: Nichols Institute Diagnostics; 1995. men with clinical acne, neither androgens nor IGF-1 ex- 12. Hossenlopp P, Seurin D, Segovia B, Portolan G, Binoux M. Heterogeneity of insulin- erted effects independent of one another. Moreover, in like growth factor binding proteins between structure and affinity. Eur J Biochem. 1987;170:133-142. women with clinical acne, IGF-1 actually acted indepen- 13. Rudman S, Philpott M, Thomas G, Kealey T. The role of IGF-1 in human skin and dently of androgens (Table 5). its appendages: morphogen or mitogen? J Invest Dermatol. 1997;109:770- The effects of hormones on the skin are complex and 777. not well understood. Our study suggests that in adult 14. Oakes S, Haynes K, Waters M, Herington A, Werther G. Demonstration and lo- women, serum levels of IGF-1 in addition to androgens calization of growth hormone receptor in human skin and skin fibroblasts. J Clin Endocrinol Metab. 1992;75:1368-1373. may influence acne. Despite there being a correlation of 15. Deplewski D, Rosenfield RL. Growth hormone and insulin-like growth factors acne with elevated IGF-1 and DHEAS, it would be diffi- have different effects on sebaceous cell growth and differentiation. Endocrinology. cult to use these hormones as laboratory markers of adult 1999;140:4089-4094. acne in the clinical setting because levels are usually within 16. Burton J, Libman L, Cunliffe WJ, Wilkinson R, Hall R, Shuster S. Sebum excretion in acromegaly. Br Med J. 1972;1:406-408. the normal range. Undoubtedly, these hormones have im- 17. Goolamali S, Burton J, Shuster S. Sebum excretion in hypopituitarism. Br J portant effects in other organ systems in the adult in ad- Dermatol. 1973;89:21-24. dition to effects in the skin, and therefore nonspecific in- 18. Aizawa H, Nakada Y, Niimura M. Androgen status in adolescent women with acne hibition of hormone synthesis could have undesirable vulgaris. J Dermatol. 1995;22:530-532. effects. However, our data provide a rationale for the fur- 19. Giudice L. Growth factor action on ovarian function in polycystic ovary syndrome. Endocrinol Metab Clin North Am. 1999;28:325-333. ther study of androgen, IGF-1, and growth hormone re- 20. Genazzani A, Stomati M, Strucchi C, Puccetti S, Luisi S, Genazzani A. Oral de- ceptor activity in the sebaceous gland. In the future, it hydroepiandrosterone supplementation modulates spontaneous and growth hor- may be possible to down-regulate or block receptor sig- mone-releasing hormone-induced growth hormone and insulin-like growth fac- naling in a tissue-specific manner to decrease the pro- tor-1 secretion in early and late postmenopausal women. Fertil Steril. 2001; 76:241-248. pensity for acne. 21. Azziz R, Deal CL, Potter HD, Gargosky SE, Rosenfeld RG. Regulation of extrago- nadal insulin-like growth factor-binding protein-3 by testosterone in oophorec- Accepted for Publication: June 7, 2004. tomized women. J Clin Endocrinol Metab. 1994;79:1747-1751. Correspondence: Diane Thiboutot, MD, Department of 22. Pham-Huu-Trung M, Villette J, Bogyo A, Duclos J, Fiet J, Binoux M. Effects of Dermatology, HU 14, The Pennsylvania State Univer- insulin-like growth factor 1 (IGF-1) on enzymatic activity in human adrenocor- tical cells: interactions with ACTH. J Steroid Biochem Mol Biol. 1991;39:903- sity College of Medicine, 500 University Dr, Hershey, PA 909. 17033 ([email protected]). 23. Thiboutot D, Jabara S, McAllister J, et al. Human skin is a steroidogenic tissue: Funding/Support: This study was supported by Na- steroidogenic enzymes and cofactors are expressed in epidermis, normal sebo- tional Institutes of Health (NIH) grant NIH K08 AR046766 cytes, and an immortalized sebocyte cell line (SEB-1). J Invest Dermatol. 2003; 120:905-914. (Dr Thiboutot) and NIH General Clinical Research Cen- 24. Horton R, Pasupuletti V, Antonipillai I. Androgen induction of steroid 5␣- ter grants M01 RR010732 and C06 RR016499 to The reductase may be mediated via insulin-like growth factor 1. Endocrinology. 1993; Pennsylvania State University College of Medicine. 133:447-451.

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