Clinical variability in approaches to polycystic ovary syndrome.

STUDY OBJECTIVE: The objective of this study was to evaluate methods of initial diagnosis and management of polycystic ovary syndrome (PCOS) among members of the North American Society for Pediatric and Adolescent Gynecology (NASPAG) to assess the degree of practice heterogeneity among specialist providers of adolescent care. DESIGN: Cross-sectional, anonymous, internet survey PARTICIPANTS: NASPAG membership (N = 326; Respondents = 127 (39%)) RESULTS: Percentage of respondents who incorporated specific tests at initial diagnosis was highly variable ranging from 87% (thyroid stimulating hormone) to 17% (sex hormone binding globulin). Oral contraceptives and diet modification/exercise were the most common therapies recommended by 98% and 90% of respondents respectively. CONCLUSION: Considerable practice heterogeneity was present with regards to diagnostic testing for suspected PCOS. Recommendations for first-line therapy were more consistent. Future studies should clarify the clinical utility of specific diagnostic tests for adolescents, such that selection of diagnostic testing is evidence based.

Premature thelarche in infants and toddlers: prevalence, natural history and environmental determinants.

STUDY OBJECTIVE: The aim of this study was to measure the prevalence of premature thelarche in infant and toddler girls and to determine if environmental sources of estrogen were associated with early breast development. DESIGN: Observational with mixed methods: Retrospective chart review, cross-sectional component involving an interview survey, along with longitudinal follow-up of girls with thelarche up to six months. SETTING: A general pediatric clinic within a teaching hospital located in a large Midwestern city. PARTICIPANTS: Girls, between the ages of 12 and 48 months, and their mothers, presenting for well-child care. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prevalence of premature thelarche; association of premature thelarche with selected environmental exposures. RESULTS: Among the 318 subjects, the overall prevalence of premature thelarche was measured at 4.7% (n = 15). The prevalence by race/ethnicity was 4.2% among White Non-Hispanics, 4.6% among Blacks and 6.5% among White Hispanics. The peak prevalence occurred between 12-17 months of age. All thelarche cases were Tanner stage 2. No statistically significant relationship was found between premature thelarche and environmental exposures. Upon follow-up, 44% of the cases of premature thelarche had persistent breast development. CONCLUSIONS: Our study demonstrated a higher prevalence of premature thelarche than has been previously reported. This study lacked power because of the small number of premature thelarche cases, the ubiquitous presence of environmental exposure as well as the potentially small effect of each environmental factor. Future studies need to employ a very large sample in order to accurately analyze the relationship between environmental toxicants and premature thelarche.

Early weight gain related to later weight gain in adolescents on depot medroxyprogesterone acetate.

OBJECTIVE: To examine whether early weight gain in adolescents on depot medroxyprogesterone acetate (DMPA) predicts continued excessive weight gain and identify risk factors of early weight gain. METHODS: Adolescents (n=97) initiating DMPA were eligible to participate. Height and weight were assessed at baseline and at 6, 12, and 18 months. Early weight gain was defined as more than a 5% weight gain after 6 months of DMPA use. Mean body mass index (BMI) at 6-month intervals was estimated based on early weight-gain status (5% or less gain compared with greater than 5% gain). Analysis of variance modeling was used to compare group BMI at each time point. Repeated-measures analysis of covariance modeling was used to explore the association between early weight gain and percentage change in BMI at 12 and 18 months of DMPA use. RESULTS: Twenty patients (21%) had early weight gain. Mean BMI for the 5% or less group and greater than 5% group was 23.4 and 24.5 (P=.31), 23.3 and 26.6 (P=.009), 24.2 and 28.7 (P=.007), and 25.7 and 32.1 (P=.01) at 0, 6, 12, and 18 months, respectively. Early weight gain was significantly associated with percentage change in BMI at 12 and 18 months (P<.001). No risk factors for early weight gain were identified. CONCLUSION: Adolescents who experience more than 5% weight gain after 6 months of DMPA use are at risk for continued excessive weight gain. Weight gain after 6 months on DMPA can be used to identify adolescents at risk for continued weight gain, and appropriate counseling can be done at this time point. LEVEL OF EVIDENCE: II.

Relationship between weight and bone mineral density in adolescents on hormonal contraception.

STUDY OBJECTIVE: Since bone loss has been observed among adolescents on depot medroxyprogesterone acetate (DMPA), a clinical population that commonly experiences weight gain, we were interested in examining the direct relationship between body weight and bone mineral density (BMD) in adolescents on DMPA as compared to those on oral contraceptive pills (OC) or on no hormonal contraception (control). DESIGN: Prospective, Longitudinal study. SETTING: Four urban adolescent health clinics in a large metropolitan area. PARTICIPANTS: Postmenarcheal girls, age 12-18 years, selecting DMPA, OC or no hormonal contraception. INTERVENTIONS: At baseline, 6, 12, 18, and 24 months, all study participants underwent measurement of weight and BMD of the hip and spine. MAIN OUTCOME MEASURES: The correlation between weight and BMD, and the correlation between change in weight and change in BMD were assessed at each time point. RESULTS: Body weight was significantly (P < 0.05) positively correlated with femoral neck BMD and spine BMD at each time point regardless of contraceptive method. Change in body weight at 12 and 24 months was highly correlated with change in femoral neck BMD (P < 0.0001) for all treatment groups. No statistically significant correlation between change in weight and change in spine BMD was seen in the DMPA, OC, or control subjects at 12 or 24 months. CONCLUSION: Weight gain on DMPA may mitigate loss of BMD among adolescent users.

Biopsychosocial variables associated with substantial bone mineral density loss during the use of depot medroxyprogesterone acetate in adolescents: adolescents who lost 5% or more from baseline vs. those who lost less than 5%.

BACKGROUND: It is unclear why some adolescents experience substantial bone mineral density (BMD) loss, while others experience a minimal decrease during depot medroxyprogesterone acetate (DMPA) use. We examined biopsychosocial factors in adolescents who experienced ≥5% BMD loss from baseline compared with adolescents who experienced <5% BMD loss during DMPA use. STUDY DESIGN: A multicenter, prospective, nonrandomized study of 181 female adolescents who initiated DMPA for contraception was conducted. BMD (by dual-energy X-ray absorptiometry) and serum estradiol were measured at initiation and every 6 months for 240 weeks of DMPA use. RESULTS: Half of participants experienced BMD loss of ≥5% from baseline at the hip, and a quarter experienced BMD loss of ≥5% at the lumbar spine (BMD substantial losers, SL). Hip and lumbar spine BMD-SL received a significantly greater number of DMPA injections than non-SL (p<.001). Decreased estradiol levels did not statistically differ between BMD loss subgroups. Hip BMD-SL had significantly lower baseline body mass index (BMI) than non-SL (p=.002), and there was an inverse relationship between weight gain and degree of BMD loss. Mean calcium intake was significantly lower (p<.05) in hip BMD-SL, and reported alcohol use was significantly higher (p<.05) in lumbar spine BMD-SL compared with non-SL. CONCLUSIONS: BMD loss of ≥5% was more common at the hip than at the lumbar spine among adolescents using DMPA. Decreased serum estradiol levels did not correlate with magnitude of BMD loss. Lower BMI and calcium intake and greater alcohol use were associated with greater BMD loss in adolescents using DMPA.

Association between bone turnover, micronutrient intake, and blood lead levels in pre- and postmenopausal women, NHANES 1999-2002.

BACKGROUND: Blood lead levels (BLLs) have been shown to increase during periods of high bone turnover such as pregnancy and menopause. OBJECTIVES: We examined the associations between bone turnover and micronutrient intake with BLLs in women 20-85 years of age (n = 2,671) participating in the National Health and Nutrition Examination Survey, 1999-2002. METHODS: Serum bone-specific alkaline phosphatase (BAP) and urinary cross-linked N-telopeptides (NTx) were measured as markers of bone formation and resorption, respectively. Lead was quantified in whole blood. The association between tertiles of BAP and NTx, and BLLs was examined using linear regression with natural log transformed BLLs as the dependent variable and interpreted as the percent difference in geometric mean BLLs. RESULTS: In adjusted analyses, mean BLLs among postmenopausal women in the upper tertiles of NTx and BAP were 34% [95% confidence interval (CI), 23%-45%] and 30% (95% CI, 17%-43%) higher than BLLs among women in the lowest tertiles of NTx and BAP, respectively. These associations were weaker, but remained statistically significant, among premenopausal women (NTx: 10%; 95% CI, 0.60%-19%; BAP: 14%; 95% CI, 6%-22%). Within tertiles of NTx and BAP, calcium intake above the Dietary Reference Intake (DRI), compared with below the DRI, was associated with lower mean BLLs among postmenopausal women but not premenopausal women, although most of the associations were not statistically significant. We observed similar associations for vitamin D supplement use. CONCLUSIONS: Bone resorption and bone formation were associated with a significant increase in BLLs among pre- and postmenopausal women.

Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive injections.

BACKGROUND: Depot medroxyprogesterone acetate (DMPA) is a highly effective progestin-only contraceptive that is widely used by adolescents. We investigated bone mineral density (BMD) changes in female adolescents during and following use of this method. STUDY DESIGN: A multicenter, prospective, non-randomized observational study in 98 healthy female adolescents aged 12-18 years who initiated DMPA intramuscular injections for contraception and provided BMD data for up to 240 weeks while receiving DMPA and for up to 300 weeks after DMPA cessation. BMD at the lumbar spine (LS), total hip (TH) and femoral neck (FN) was assessed by dual-energy X-ray absorptiometry. A mixed model analysis of variance was used to examine BMD changes. RESULTS: At the time of their final DMPA injection, participants had mean BMD declines from baseline of 2.7% (LS), 4.1% (TH) and 3.9% (FN) (p<.001 at all three sites). Within 60 weeks of discontinuation of DMPA, mean LS BMD had returned to baseline levels, and 240 weeks after DMPA discontinuation, the mean LS BMD was 4.7% above baseline. Mean TH and FN BMD values recovered to baseline values more slowly: 240 weeks and 180 weeks, respectively, after the last DMPA injection. CONCLUSIONS: BMD loss in female adolescents receiving DMPA for contraception is substantially or fully reversible in most girls following discontinuation of DMPA, with faster recovery at the LS than at the hip.

A longitudinal comparison of body composition changes in adolescent girls receiving hormonal contraception.

The objective of this study was to examine body composition changes in adolescent girls initiating depot medroxyprogesterone acetate (DMPA), oral contraceptives, or no hormonal contraceptive method. At 6 months, DMPA resulted in significant increases in adiposity with concomitant decreases in lean body mass. Supplemental estrogen may lessen these DMPA effects.

Dual-energy X-ray absorptiometry diagnostic discordance between Z-scores and T-scores in young adults.

Diagnostic criteria for postmenopausal osteoporosis using central dual-energy X-ray absorptiometry (DXA) T-scores have been widely accepted. The validity of these criteria for other populations, including premenopausal women and young men, has not been established. The International Society for Clinical Densitometry (ISCD) recommends using DXA Z-scores, not T-scores, for diagnosis in premenopausal women and men aged 20-49 yr, though studies supporting this position have not been published. We examined diagnostic agreement between DXA-generated T-scores and Z-scores in a cohort of men and women aged 20-49 yr, using 1994 World Health Organization and 2005 ISCD DXA criteria. Four thousand two hundred and seventy-five unique subjects were available for analysis. The agreement between DXA T-scores and Z-scores was moderate (Cohen's kappa: 0.53-0.75). The use of Z-scores resulted in significantly fewer (McNemar's p<0.001) subjects diagnosed with "osteopenia," "low bone mass for age," or "osteoporosis." Thirty-nine percent of Hologic (Hologic, Inc., Bedford, MA) subjects and 30% of Lunar (GE Lunar, GE Madison, WI) subjects diagnosed with "osteoporosis" by T-score were reclassified as either "normal" or "osteopenia" when their Z-score was used. Substitution of DXA Z-scores for T-scores results in significant diagnostic disagreement and significantly fewer persons being diagnosed with low bone mineral density.

Menstrual cycle and bone health in adolescents.

The intriguing notion of the menstrual cycle's having an acute impact on bone metabolism is examined as an expression of estrogen changes manifest as fluctuations in calcium-regulating hormones or biomarkers of bone formation/resorption. The effects of estrogen, progesterone, androgens, and follicle-stimulating hormones on bone health are also reviewed here. To date, the balance of evidence suggests that the menstrual cycle may exert a significant effect on bone metabolism. Further research needs to be conducted, however, to define these hormonal relationships.

Bone mineral density in adolescent females using injectable or oral contraceptives: a 24-month prospective study.

OBJECTIVE: To determine whether bone mineral density (BMD) is lower in hormonal-contraceptive users than in an untreated comparison group. DESIGN: Observational, prospective cohort; 24-month duration. SETTING: Adolescent clinics in a metropolitan Midwestern setting. PATIENT(S): Four hundred thirty-three postmenarcheal girls, 12-18 years of age, who were on depot medroxyprogesterone acetate (DMPA; n = 58), were on oral contraceptives (OCs; n = 187), or were untreated (n = 188). INTERVENTION(S): Depot medroxyprogesterone acetate and OCs containing 100 microg of levonorgestrel and 20 microg of ethinyl E(2). MAIN OUTCOME MEASURE(S): Measurements of BMD at spine and femoral neck were obtained by using dual x-ray absorptiometry at baseline and 6-month intervals. RESULT(S): Over 24 months, mean percentage change in spine BMD was as follows: DMPA, -1.5%; OC, +4.2%; and untreated, +6.3%. Mean percentage change in femoral neck BMD was as follows: DMPA, -5.2%; OC, +3.0%; and untreated, +3.8%. Statistical significance was found between the DMPA group and the other two groups. In the DMPA group, mean percentage change in spine BMD over the first 12 months was -1.4%; the rate of change slowed to -0.1% over the second 12 months. No bone density loss reached the level of osteopenia. CONCLUSION(S): Adolescent girls receiving DMPA had significant loss in BMD, compared with bone gain in the OC and untreated group. However, the clinical significance of this finding is mitigated by slowed loss after the 1st year of DMPA use and general maintenance of bone density values within the normal range in the DMPA group.

DXA-generated Z-scores and T-scores may differ substantially and significantly in young adults.

Central dual-energy X-ray absorptiometry (DXA) is the gold standard for non-invasive measurement of bone mineral density (BMD). Using this value and subject demographics, DXA software calculates T-scores and Z-scores. Professional society guidelines for the management of osteoporosis are based on T-scores and Z-scores, rather than on the actual BMD value. Although one expects T-scores and Z-scores to be very similar in young men and women for any given BMD measurement, little literature exists on this issue. Our clinical experience shows that some younger adult individuals (premenopausal women and men younger than 50 yr) have larger than expected difference between their DXA T-score and Z-score. This cross-sectional study evaluates the extent of this discordance between Z-scores and T-scores in a sample of 4275 men and women aged 20-49 yr. All subjects were scanned by central DXA using equipment manufactured by GE Lunar, GE, Madison, WI, or Hologic, Inc., Bedford, MA. Significant differences between Z-scores and T-scores were seen within individuals at the lumbar spine, total hip, femoral neck, and trochanter (p value<0.001) for both DXA systems. Although these differences were less than half a standard deviation (SD) in most instances, the magnitude of difference was substantial at times, being 1 or more SD in up to 11% of cases (range: -1.95 to +1.54 SD). The smallest differences were seen at the total hip and the largest differences were seen at the femoral neck for both technologies. This is in part because there is no single standard Z-score definition, resulting in different methods of calculation across, and even within, DXA manufacturers. Standardization of Z-score definition and method of calculation is indicated. DXA Z-scores should be interpreted with caution in men and women aged 20-50 yr.

Bone mineral density in postmenarchal adolescent girls in the United States: associated biopsychosocial variables and bone turnover markers.

PURPOSE: During adolescence, bone formation prevails over resorption, resulting in accumulation of 40% of peak bone mass throughout this time period. Although multiple studies have explored bone mass accrual during the early stages of puberty, less is known about factors that may influence bone accrual during later years of adolescence. In the present cross-sectional study we examined relationships among bone mineral density (BMD) and demographic factors, behavioral variables, and bone metabolism markers in postmenarchal adolescent girls. METHODS: The population was comprised of 389 healthy postmenarchal adolescent girls aged 11-18 years, who were recruited into a prospective study of the effect of depot medroxyprogesterone acetate (DMPA) on bone health in adolescents. At the baseline visit, investigators collected demographic, reproductive health, and lifestyle data, and performed a complete physical examination. Body mass index (BMI) was calculated. Before study initiation, BMD at the lumbar spine, total hip, and femoral neck was measured by dual-energy X-ray absorptiometry (DXA), and markers of bone metabolism (serum bone-specific alkaline phosphatase [BAP], serum osteocalcin, and urinary N-telopeptide [uNTX]) were measured. The baseline data from this study were analyzed to evaluate possible correlates of BMD in postmenarchal adolescent girls. Potential associations between BMD values and other parameters were assessed by analysis of variance and Pearson's correlation coefficient. RESULTS: Participants enrolled in the study had a mean (+/- SD) chronological age of 14.9 +/-1.7 years (range 11-18), mean gynecologic age of 39.9 +/-23.0 months (range 1-120) postmenarche, and mean BMI of 23.5 +/-4.6 kg/m(2) (range 16.0-42.2). Racial/ethnic distribution was 46% African American, 35% Caucasian, and 19% other races; 9% had previously been pregnant. Positive correlations were observed between lumbar spine BMD and chronological age (r = .301, p < .0001), gynecologic age (r = .349, p < .0001), and BMI (r = .371, p < .0001). Total hip and femoral neck BMD values were significantly higher (p < .05 and p < .05, respectively) in African American participants compared with non-African American participants. Previous history of pregnancy was significantly associated with a lower BMD at the lumbar spine (p < .0001) and the total hip (p < .01) when compared with the BMD of adolescents who had never been pregnant. Cigarette smoking and alcohol use were not associated with significant differences in BMD. Negative correlations were observed between gynecologic age and the levels of BAP (r = -.564, p < .0001), osteocalcin (r = -.349, p < .0001), and uNTX (r = -.281, p < .0001), and between lumbar spine BMD and BAP (r = -.363, p < .0001), osteocalcin (r = -.129, p < .05), and uNTX (r = -.202, p < .001) levels. CONCLUSIONS: Our data demonstrate that chronological age, gynecologic age, race/ethnicity, BMI, and previous history of pregnancy are markedly associated with BMD in postmenarchal adolescent girls. Bone accretion in the postmenarchal years continues in the face of a slowdown in bone turnover during this time period.

Depot medroxyprogesterone acetate and bone mineral density in adolescents--the Black Box Warning: a Position Paper of the Society for Adolescent Medicine.

The purpose of this Position Paper is to review the published Black Box Warning regarding depot medroxyprogesterone acetate (DMPA) and bone loss as it relates to adolescent girls. The scientific findings that prompted the Food and Drug Administration to issue the warning are reviewed and the following additional issues are considered: (1) likely low risk of fracture related to DMPA use, (2) evidence of at least partial recovery after discontinuation of the method, and (3) the need to balance the physical, social and economic cost of adolescent pregnancy versus the immediate and long-term impact of DMPA on bone. A list of clinical guidelines is included, the main recommendation of which is to continue prescription of DMPA, with counseling about the risks and benefits, in most of the adolescent population desiring to use this contraceptive method.

Self-reported physical activity and bone mineral density in urban adolescent girls.

BACKGROUND: This observational study aimed to examine the prevalence of activities of daily living, as well as the impact of leisure time activities, on bone mineral density in urban adolescent girls. METHODS: Patients completed a 23-item physical activity questionnaire at baseline, recording time spent in various activities in the previous 7 days. In addition to leisure time activities, activities of daily life were also considered. Activities were characterized and scored by metabolic intensity (METPA) and mechanical strain on bone (MECHPA). The METPA score for each activity is the product of the metabolic intensity of the activity and the time spent in the activity. The MECHPA score estimates the mechanical strain on bone from ground reaction forces. The logged scores were divided into quartiles with the lowest quartile as the reference group. RESULTS: Four hundred fifty-five females (ages 12-18 years) completed the survey (62% black and 38% non-black). The log of the overall METPA score was a significant predictor of bone mineral density (i.e. higher METPA score predicted a higher bone mineral density, P = 0.03). A MECHPA score in the highest quartile was associated with a higher bone mineral density (P < 0.05) when compared to the other MECHPA quartiles. CONCLUSIONS: In this population of urban adolescent girls, activities of daily living were reported with a higher frequency than sports activities. Results indicated a positive association between the time spent in metabolically intense activities and bone mineral density. There also appears to be a threshold effect for the relationship between activities with the highest mechanical strain and bone mineral density.

Weight gain in obese and nonobese adolescent girls initiating depot medroxyprogesterone, oral contraceptive pills, or no hormonal contraceptive method.

OBJECTIVE: To examine weight changes in a large cohort of obese and nonobese adolescent girls initiating depot medroxyprogesterone acetate (DMPA), an oral contraceptive (OC), or no hormonal contraceptive method (control). DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 450 adolescent girls, aged 12 to 18 years, who attended 4 urban health clinics and selected DMPA, OC, or control. Data collection occurred at baseline and at 6, 12, and 18 months; consisted of structured interview and measurement of height and weight; and occurred from April 19, 2000, through September 26, 2003. MAIN OUTCOME MEASURE: Weight was examined as mean change over 18 months and actual weight at each study visit. On the basis of preliminary analyses, we stratified the sample according to baseline obesity status (nonobese, body mass index [calculated as weight in kilograms divided by the square of height in meters] < 30; obese, body mass index > or =30). RESULTS: Adolescent girls who were obese at initiation of DMPA gained significantly more weight than did obese girls starting OC or control (P<.001 for both). At 18 months, mean weight gain was 9.4, 0.2, and 3.1 kg for obese girls receiving DMPA, receiving OC, and control, respectively. Weight gain in obese girls receiving DMPA was also greater than weight gain in all nonobese categories (4.0 kg, DMPA; 2.8 kg, OC; 3.5 kg, control; P<.001). A significant interaction (P = .006) between length of time receiving DMPA and weight gain was evident for obese subjects. CONCLUSIONS: Over 18 months, DMPA use was associated with increasing rates of weight gain in obese subjects. The potential contribution to severe obesity in this population is concerning.

Depot medroxyprogesterone acetate: implications for weight status and bone mineral density in the adolescent female.

Depot medroxyprogesterone acetate (DMPA) is an effective and easy-to-use contraceptive method for adolescents. However, recent literature suggests that overweight teens may be at increased risk for weight gain while on this contraceptive method, and decreases in bone mineral density have been documented in adolescents on DMPA, particularly with longer duration of use. Consideration of this new literature on DMPA and its implications for clinical practice must be done in the context of the United States having the highest adolescent pregnancy rate in the industrialized world. Hence, potential DMPA risks need to be weighed against the risk of unintended pregnancy in an adolescent.