Follow-up Study of Adolescent Girls With a History of Premature Pubarche

JOURNAL OF ADOLESCENT HEALTH 1996;18:301-305 ADOLESCENT HEALTH BRIEF/FELLOWSHIP FORUM Follow-up Study of Adolescent Girls With a History of Premature Pubarche DAPHNE MILLER, M.D., S. JEAN EMANS, M.D., AND ISAAC KOHANE, M.D., Ph.D. A total of 37 girls with a history of benign premature pubarche were followed into puberty; a disproportionate number of girls experienced early menarche. Twentyfive had some degree of acne, 14 had hirsutism, and 5 had acanthosis nigricans. Body mass index (BMI) at initial presentation correlated with postpubertal BMI and was weakly correlated with postpubertal hirsutism. KEY WORDS: Premature pubarche Acne Menarche Hirsutism Premature pubarche (PP) in girls is defined as the appearance of pubic and/or axillary hair before 8 years of age. In some girls, PP is caused by elevated androgen levels resulting from a deficiency of an adrenal enzyme [3~-hydroxysteroid dehydrogenase (3~HSD), 21-hydroxylase (21OH), or 11~-hydroxylase (11~OH)] or, more rarely, from an adrenal or ovarian tumor (1-4). In most girls, however, PP is thought to be a benign process, termed premature adrenarche (PA), caused by early isolated maturation of the adrenal gland or increased peripheral sensitivity to adrenal hormones. Premature adrenarche is a diagnosis of exclusion and can be made definitively only with a normal adrenocorticotropic hormone (ACTH) stimulation test, because basal hormonal levels and patient phenotypes at presentation can be From the Divisions of Adolescent~Young Adult Medicine and Endocrinology, Children's Hospital, Boston; and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. Address reprint requests to L Kohane, M.D., Division of Endocrinology, Children's Hospital, 300 Longwood Ave., Boston, MA 02115. Manuscript accepted July 7, 1995. similar whether resulting from a defect in steroidogenesis or PA (2-4). At present, there is no accepted protocol for the frequency or duration of follow-up examinations for girls with premature pubarche once a tumor or adrenal defect is excluded. Ibanez et al. (5) and Hawkins et al. (6) suggested that patients may experience the more serious effects of premature adrenarche in early to midadolescence. To investigate this hypothesis, we undertook a follow-up study of a group of girls considered to have benign PP to determine the prevalence of current symptoms of hyperandrogenism and to identify factors at initial presentation that may serve as predictors for the occurrence of later symptoms. Methods To identify all girls who were seen at Children's Hospital with a diagnosis of premature pubarche (PP) who had achieved the age of 11-21 years in September 1992, the charts of patients having an ACTH stimulation test, a serum dehydroepiandrosterone sulfate (DHEAS), or a coded diagnosis of PP between 1979 and 1986 were reviewed. The minimal age of 11 years was chosen to gather data on patients who were likely to be postmenarcheal. Information obtained from the initial visit and coded for data analysis included: age, age of onset of pubarche, race, height, weight, Tanner staging (sexual maturity rating) for breast and pubic hair, bone age determined from a hand and wrist radiograph using the standards of Greulich and Pyle (7), clinical signs of hyperandrogenism (acne and hirsutism), laboratory values for adrenal hormones, and maternal height, weight and age of menarche. Body mass index (BMI) Society for Adolescent Medicine, 1996 1054-139X/96/$15.00 Published by Elsevier Science Inc., 655 Avenue of the Americas, New York, NY 10010 SSDI 1054-139X(95)00234-O

302 MILLER ET AL. JOURNAL OF ADOLESCENT HEALTH Vol. 18, No. 4 was calculated as: weight in kilograms + (square of the height in meters). Only patients considered to have premature adrenarche from the initial chart review were included in the analysis of data for follow-up into puberty defined as pubertal breast Tanner stage 2. These patients were selected after applying the following stringent exclusion criteria: (a) patients with an abnormal adrenal hormone response consistent with an enzyme deficiency in the group who had received an ACTH stimulation test; and (b) patients who presented initially with cystic acne, Tanner stage of breast development >1, clitoromegaly, or a determination of bone age that was 3 SDs greater than the mean in the group who did not undergo an ACTH stimulation test (2,8). Based on the data from previous studies (2,8), we estimated that the frequency of unidentified cases of defects in steroidogenesis in our study patients who did not receive ACTH stimulation and met the clinical criteria for inclusion in the follow-up was between 0 and 7%. Questionnaires were sent to all identified PA patients. A letter asked patients to complete the information on the questionnaire, and a stamped, addressed envelope and card with refusal checkoff were enclosed to allow patients to easily refuse participation. The principle investigator (DM) telephoned all patients for whom neither a refusal card or questionnaire was received within 1 month. The study was approved by the Children's Hospital Committee on Clinical Investigation. The questionnaire collected information on the subject's current weight and height; medical history; medications including oral contraceptives, Retin-A, Accutane, antibiotics, or other medications for acne; age of pubarche; breast development; and menarche, presence of dysmenorrhea, occurrence of irregular menses (defined as a cycle of ~ 21 days or > 40 days), and duration of menstrual flow. Patients were asked to grade the frequency of acne [never, sometimes, always (0-2)] and the severity [none, mild, moderate, severe (0-3)]. Hirsutism was graded by severity [average, more than average, much more than average (0-2)]. For those study patients who had received their medical care at Children's Hospital through puberty, follow-up information was also collected from hospital chart review including Tal~ner staging of breast and pubic hair, clitoromegaly, acne [scored using an adaptation of a system devised for boys by Lucky et al. (9)], and hirsutism [scored by Ferriman and Gallwey (10)]. Questionnaire and chart follow-up information were analyzed separately and then com- bined to obtain the most accurate data. Measurements of weight and height were taken from the most recent data point, and data on age of menarche and thelarche were taken from the recording that was closest to the reported age. Data on maternal age of menarche were taken from the questionnaire only if this information was not available in the chart. No significant differences were noted on information obtained from chart review and questiol~naire. To obtain comparative data, physicians and nurse practitioners in the Adolescent Clinic collected similar questionnaire data on adolescent girls seen for annual health care. Information on the degree of acne and hirsutism was obtained through physical examination and self-report. These two methods of data collection were not significantly different. Data from the National Center for Health Statistics were used to compare age of menarche, height, and bone age/ chronologic age of the study subjects with a large comparison group (11). Measurements of serum levels of adrenal hormones have been previously described (12). ACTH stimulation responses were interpreted using previously published standards that were derived from combining test results from both pubertal and prepubertal controls (6,13,14). Growth curves were analyzed using the SAS program, and all other statistical analyses including multivariate analysis were performed using the Macintosh JMP statistical package (SAS Institute, Cary, NC). Because not all patients could have reached the age of menarche at the time of follow-up, a binomial distribution calculation was used to look at early age of menarche in relation to NCHS data. Unless noted otherwise, all results are reported as mean +_ SD. Z scores for patients were calculated by subtracting the mean height for age and race from the actual height and then dividing that value by the SD for height for that group. Differences between group means were determined by unpaired two tailed Student's t-tests and Pearson's correlation tests. Results A total of 90 girls were identified with a diagnosis of PP between 1979 and 1986, of whom 46 were white, 34 black, 8 Hispanic, and 2 "other." These girls were initially seen in the clinic at a mean age of 6.5 _+ 1.7 years with a mean age at first sign of axillary or pubic hair of 5.6 + 1.6 years, a mean Tanner pubic hair stage of 2.3 + 0.6, bone age/chronologic age of 1.1 +

April 1996 FOLLOW-UP STUDY OF PREMATURE PUBARCHE 303 Table 1. Binomial Calculations Representing the Probability of Observing the Number of Cases of Early Menarche Found in the Present Sample of Black and White Girls With Premature Adrenarche, Under the Null Hypothesis that this Sample Is Representative of the General Population Probability Probability No. of PA girls % Girls Reaching of Sample No. of PA Girls % Girls Reaching of Sample Reaching Menarche Before Findings, Reaching Menarche Before Findings, Menarche Age 10 Years in Given Menarche Age 11 Years in Given Before Age 10 the NCHS Population Before Age 11 the NCHS Population Sample n Years Population Proportions Sample n Years Population Proportions Black 14 3 0.2% ~.0001 Black 14 5 4.0% ~.0001 White 18 2 0.2%.0006 White 18 4 0.8% <.0001 Total 32 5 0.2% ~.0001 Total 32 9 4.0%* ~.0001 * 4.0% was used for the total population estimate, because it provides a more conservative test than either the white population estimate or the average of the black and white estimates. 0.3, BMI of 17.8 _+ 2.9, and mean Z score for height of +0.5 _+ 1.3. Of these, 19 patients had ACTH stimulation tests done either at presentation or sometime in the ensuing 10 years. Mean age at ACTH testing was 9.2 + 3.3 years. Four patients, all white, had test results consistent with 21OH deficiency, and one had results consistent with 3[~HSD. Fourteen patients had normal responses. Of the 90 patients initially studied, 37 patients considered to have benign premature pubarche were followed into puberty. Of the initial 90, 6 refused follow-up and 40 patients were lost to follow-up (letters returned or the addresses or telephone numbers were unknown 6-13 years after initial evaluation). Seven for whom postpubertal data were available were excluded from data analysis because they met the exclusion criteria or had abnormal ACTH stimulation results. Of the 37 patients ultimately included in the follow-up group, 23 returned the study questionnaires, 11 were assessed by chart review and questionnaire, and 14 were assessed by chart review alone. The 37 patients were not different from the remainder of the initial study population regarding presenting data. Mean age at follow-up was 14.6 _+ 2.9 years. Mean BMI was 23.1 +_ 4.8 and was not significantly different among ethnic groups. A total of 25 had some degree of acne, 14 had hirsutism, 5 had acanthosis nigricans, and 3 had postpubertal onset of clitoromegaly. Of the 30 postmenarcheal patients, 4 had irregular menses and 9 had dysmenorrhea. White patients reported increased severity of acne (p =.0009) and hirsutism (p =.05) compared with the black study patients, and no other significant differences were noted between the two groups. In the subset of black and white girls, 5 of 32 had menarche before age 10 years, and 9 of 32 had menarche before age 11 years (Table 1). Using a binomial distribution calculation, we found that the hypothesis that the proportion of our study population with early menarche was equal to that of the general population (11) was highly unlikely. This was true of both black and white patients, as well as the combined population. Furthermore, the mean age of menarche for study patients (11.0 _+ 1.6 years) was significantly lower than the mean maternal age of menarche (11.9 + 1.7 years) (p =.04). Postpubertal data on age of menarche, age of thelarche, hirsutism, acne, dysmenorrhea, irregular menses, clitoromegaly, acanthosis nigricans, and BMI were assessed using multivariate analysis to identify any significant relationships among variables for follow-up of study girls. An older age of menarche was correlated with irregular menses (r =.23, p =.009) and severity of ache (r =.26, p =.008). Irregular menses and severity of acne were also directly correlated (r =.41, p =.002). Hirsutism was correlated with the presence of acne (r =.30, p =.002) and acanthosis nigricans (r =.17, p =.02). The data gathered at initial presentation were correlated with postpubertal follow-up data to identify any relationships that were significant and that might predict postpubertal outcomes. A higher BMI at presentation correlated with a higher postpubertal BMI (r =.31, p =.001). Initial BMI was weakly correlated with increased severity of hirsutism (r =.14, p =.04). Weight for height age did not correlate with hirsutism for all girls, but there was a correlation between presenting weight for height age and postpubertal hirsutism in black girls (r =.80, p = 0.02). There was also a correlation between later age of occurrence of PP and post-pubertal hirsutism (r =.42, p = 0.026). Patients completing the questionnaire were examined against a comparison group of 40 clinic patients with similar ethnicity and age (53% white, 30% black,

304 MILLER ET AL. JOURNAL OF ADOLESCENT HEALTH Vol. 18, No. 4 17% hispanic). The study group had a significantly younger age of thelarche (9.8 + 1.6 vs. 10.9 + 1.7 years; p =.02), an increased frequency of acne (2.0 + 0.6 vs. 1.4 + 0.6; p =.002), increased severity of acne (1.3 ± 0.9 vs. 0.5 + 0.6; p =.001), and increased frequency of acne treatment (26% vs. 3%; p --.004). Acne severity and frequency were significantly higher for whites (p =.008 and p =.0001, respectively). There was no difference in the incidence of irregular menses between study and comparison groups (13% vs. 14%); the study group had a lower incidence of dysmenorrhea (20% vs. 61%, p --.003). Discussion Recent studies of girls with PP have suggested that a small number have partial adrenal enzyme deficiencies, but that the majority have benign premature pubarche, caused by early maturation of the adrenal gland or increased peripheral sensitivity to adrenal hormones (3-5,15). Little information on the natural history of this condition has been available to aid the clinician in the follow-up of U.S. girls once they are diagnosed with benign PP. In our series of girls with mixed ethnicity, we observed that a disproportionate number of black and white girls experienced an early menarche in comparison to the NCHS population. The mean age of menarche of the patients was also significantly earlier than their mother's age of menarche. However, the subset of 17 girls with a normal or late menarche had an increased incidence of acne and hirsutism compared to a group of adolescent clinic patients. It is important to note that we chose the minimal age of 11 years for study patients before initiating data collection, to ensure that most patients were postpubertal. Because we have potentially excluded some patients with very early menarche who had only reached the age of 9 or 10 years at the time of the study, the mean age of menarche for study girls might be lower if all known postmenarcheal patients were included. The mean age might also be higher if the outcome of all study patients were determined at age 18 years. Although the number reporting irregular menses in study group was comparable with that of the comparison population, menstrual irregularity in the study group was significantly related to severity of acne. This suggests that irregularity was more likely to be experienced by patients with hyperandrogenism. Irregular menses and severity of acne were correlated with older age at menarche. The positive relationship between irregular menses and older age of menarche cannot be attributed to the fact that menstrual cycles are often irregular in the first few years after menarche, because the mean age of follow-up was 16.7 years and all had reached menarche at least 21/2 years earlier. Our study suggests that although all girls with early development of sexual hair should be followed into midadolescence so that hyperandrogenism can be appropriately evaluated and treated, girls with higher BMI or weight for height age at initial diagnosis warrant particularly close follow-up. Once hirsutism becomes significant, it is difficult to reverse. Accordingly, evidence of increasing hirsutism, acne, or irregular menses in a girl with a history of early development of sexual hair may warrant a more complete evaluation including ACTH stimulation test (if not already done) and assessment of the possibility of polycystic ovary syndrome. This study has a number of important limitations. Only 24% (n = 9) of the patients in our follow-up group received ACTH stimulation tests, leaving the possibility that others of the remaining 28 patients may have had undiagnosed 21OH or 3~HSD deficiency which accounted for their symptoms. Using strict criteria to eliminate patients with excessive symptoms of hyperandrogenization at initial presentation from follow-up data should have lessened the prevalence of patients with defects in steroidogenesis. Follow-up 6-13 years after initial identification required that either the patient return to the endocrine clinic after the age of 11 years or they voluntarily answer a questionnaire. This could potentially have introduced some bias into the follow-up population, in that girls with more severe postpubertal symptoms may have been more likely to pursue continued medical care. However, the patients in the follow-up population had the same ethnicity, age of onset of pubarche, and presenting laboratory data as the initial study group, which is also comparable to that of populations described in earlier studies (1-3,8,13). Including only patients who had achieved the age of 11 years clearly underestimated the number of adolescents who will eventually develop signs of hyperandrogenism. Because some of these younger study patients had not yet reached menarche, the opportunity for correlating age of menarche to signs of hyperandrogenism was reduced. The comparison group was small and may have reduced the power in this study. Follow-up into puberty of 37 patients with a history of benign PP suggested that these girls have a higher incidence of acne and hirsutism than the

April 1996 FOLLOW-UP STUDY OF PREMATURE PUBARCHE 305 comparison population. Further studies of girls with benign PP are needed to clarify the preliminary results of this report, but clinicians need to maintain vigilance for androgen excess states occurring in early to midadolescence to assure adequate evaluation and discussion of therapeutic options. The authors thank the staff of the endocrine laboratory, Joan Mansfield, M.D., and Elizabeth Woods, M.D., M.P.H., for study design and reading the manuscript; Estherann Grace, MD, and other members of the Adolescent Practice for collecting control data; Terry Fenton, Ph.D., and Alicia Schrier, M.S., for statistical help; and the Endocrine Department for allowing their patients to be contacted for this study. This research was supported in part by Project MCJ-MA259195 from the Maternal and Child Health Bureau (Title V, Social Security Act), Health Resources and Services Administration, Department of Health and Human Services at Children's Hospital, and Department of Health and Human Services Training Grant 5T35-7552-08 at Harvard Medical School. The study was presented at the Society for Adolescent Medicine meeting, Los Angeles, March 1994. References 1. Temeck J, Pang S, Nelson C, et al. Genetic defects of steroidogenesis in premature pubarche. J Clin Endocrinol Metab 1987;64:609-17. 2. Siegel S, Finegold D, Urban M, et al. Premature pubarche, etiological heterogeneity. J Clin Endocrinol Metab 1992;74: 239-47. 3. Oberfield S, Mayes D, Levine L. Adrenal steroidogenic function in a black and Hispanic population with precocious pubarche. J Clin Endocrinol Metab 1990;70:76-82. 4. Balducci R, Boscherini B, Mangiantini A, et al. Isolated precocious pubarche: An approach. J Clin Endocrinol Metab 1994; 79:582-9. 5. lbanez L, Potau N, Virdis R, et al. Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1993;76:1599-1603. 6. Hawkins L, Chasalow F, Blethen S. The role of adrenocorticotropin testing in evaluating girls with premature adrenarche and hirsutism/oligomenorrhea. J Clin Endocrinol Metab 1992; 74:248-53. 7. Greulich W, Pyle S. Radiographic atlas of skeletal development of hand and wrist. Stanford, CA: Stanford Press, 1959. 8. Morris A, Reiter E, Geffner M, et al. Absence of nonclassical congenital adrenal hyperplasia in patients with precocious adrenarche. J Clin Endocrinol Metab 1989;69:709-15. 9. Lucky A, Biro F, Huster G, et al. Acne vulgaris in early adolescent boys. Arch Dermatol 1991;127:210-2. 10. Ferriman D, Gallwey J. Clinical assessment of body hair growth in a woman. J Clin Endocrinol Metab 1961;21:1440-7. 11. Data from National Center for Health Statistics: Age at menarche, United States. Vital Health Stat 1973;133:2-3. 12. Emans SJ, Grace E, Fleischnick E, et al. Detection of late-onset 21-hydroxylase deficiency congenital adrenal hyperplasia in adolescents. Pediatrics 1983;72:690-5. 13. Granoff A, Chasalow F, Blethen S. 17-Hydroxyprogesterone responses to adrenocorticotropin in children with premature adrenarche. J Clin Endocrinol Metab 1985;60:409-15. 14. Endocrine Sciences. Pediatric steroid profiles for the evaluation of defects in steroid biosynthesis. May 1991. 18418 Oxnard St, Tarzana, CA 91356 15. Ibanez L, Virdis R, Potau N, et al. Natural history of premature pubarche. An auxological study. J Clin Endocrinol Metab 1992;72:254-7.