Zeev Harel

Supplementation with omega-3 polyunsaturated fatty acids in the management of dysmenorrhea in adolescents

OBJECTIVES The purpose of the study was to examine whether dietary supplementation with omega-3 fatty acids can relieve symptoms of dysmenorrhea in adolescents. STUDY DESIGN Forty-two adolescents with dysmenorrhea were randomly allocated to two groups. In the first group 21 girls received fish oil (1080 mg icosapentaenoic acid, 720 mg docosahexaenoic acid, and 1.5 mg vitamin E) daily for 2 months followed by a placebo for an additional 2 months. In the second group 21 girls received placebo for the first 2 months, followed by fish oil for 2 more months. The Cox Menstrual Symptom Scale was used to assess response to treatment. RESULTS There were no significant differences in the Cox Menstrual Symptom Scale between the two groups at baseline after 2 months of placebo administration. After 2 months of treatment with fish oil there was a marked reduction in the Cox Menstrual Symptom Scale from a baseline mean value of 69.9 to 44.0 (p < 0.0004). CONCLUSIONS This study suggests that dietary supplementation with omega-3 fatty acids has a beneficial effect on symptoms of dysmenorrhea in adolescents.

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.

Dysmenorrhea in Adolescents

Dysmenorrhea is the most common gynecologic complaint among adolescent females. Dysmenorrhea in adolescents is usually primary, and is associated with normal ovulatory cycles and with no pelvic pathology. In approximately 10% of adolescents with severe dysmenorrheic symptoms, pelvic abnormalities such as endometriosis or uterine anomalies may be found. Potent prostaglandins and leukotrienes play an important role in generating the symptoms of dysmenorrhea. Nonsteroidal anti‐inflammatory drugs (NSAIDs) are the most common pharmacologic treatment for dysmenorrhea. A loading dose of NSAIDs (typically twice the regular dose) should be used as initial treatment for dysmenorrhea in adolescents, followed by a regular dose until symptoms abate. Adolescents with symptoms that do not respond to treatment with NSAIDs for three menstrual periods should be offered hormonal treatment such as combined estrogen/progestin oral contraceptive pills for three menstrual cycles. Adolescents with dysmenorrhea who do not respond to this treatment should be evaluated for secondary causes of dysmenorrhea. The adolescent care providers role is to explain the pathophysiology of dysmenorrhea to every adolescent female, address any concern that the patient has about her menstrual period, and review effective treatment options for dysmenorrhea with the patient.

A Contemporary Approach to Dysmenorrhea in Adolescents

Dysmenorrhea is the most common gynecologic complaint among adolescent girls. Despite progress in understanding the physiology of dysmenorrhea and the availability of effective treatments, many adolescent girls do not seek medical advice or are undertreated.Dysmenorrhea in adolescents is usually primary (functional), and is associated with normal ovulatory cycles and no pelvic pathology. In approximately 10% of adolescents with severe dysmenorrhea, pelvic abnormalities such as endometriosis or uterine anomalies may be found. Potent prostaglandins from the second series and potent leukotrienes from the fourth series play an important role in generating dysmenorrhea symptoms.Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common pharmacologic treatment for dysmenorrhea. A loading dose of NSAIDs (typically twice the regular dose) should be used as initial treatment for dysmenorrhea in adolescents followed by a regular dose until symptoms abate. Adolescents with symptoms that do not respond to treatment with NSAIDs for three menstrual periods should be offered combined estrogen/progestin oral contraceptive pills for three menstrual cycles. Adolescents with dysmenorrhea who do not respond to this treatment should be evaluated for secondary causes of dysmenorrhea.Adolescent care providers have the important roles of educating adolescent girls about menstruation-associated symptoms, as well as evaluating and effectively treating patients with dysmenorrhea.

Adolescents: At Increased Risk for Osteoporosis?

Perhaps the most important factor in the primary prevention of osteoporosis is the attainment of an optimal peak bone during adolescence. In addition to endogenous factors, such as genetic and ethnic background, environmental factors such as dietary habits, physical activity, and sex hormone therapy, influence the accretion of bone mass during this critical period of skeletal growth. First, calcium dietary intake in adolescents is generally well less than the current recommended RDA of 1200 mg/day. Multiple studies of children and adolescents have demonstrated increases in bone mass with dietary calcium supplementation. Second, regarding physical activity, the overall impression is that a moderate amount of particularly weight-bearing exercise has a positive impact on bone. There appears, however, to be a threshold of intensity of physical activity over which a negative impact on bone occurs, particularly when the exercise is of an anaerobic nature or occurring in very thin, amenorrheic participants. Third, previous research suggests that the various forms of hormonal contraception exert differing effects on bone mass in adolescents, with levonorgestrel implants and combined oral contraceptives may be associated with a more positive effect on bone mass compared with that observed with depot medroxyprogesterone acetate. From a clinical perspective, approaches to optimizing peak bone mass in adolescents would include increasing calcium intake, whether in the form of dairy products, fortified foods, or supplements as well as encouraging participation at a moderate level, in weight-bearing exercise. Last, in adolescents with extensive risk factors and predicted long duration of use, subdermal implants or combined oral contraceptives may be the optimal hormonal methods of birth control.

Low Vitamin D Status Among Obese Adolescents: Prevalence and Response to Treatment

PURPOSE To explore the prevalence of low vitamin D status among obese adolescents and to examine the effect of current management of low vitamin D status in these patients. METHODS A retrospective chart review of obese adolescents who had been screened for vitamin D status by serum total 25-hydroxyvitamin D (25(OH)D) level. Vitamin D deficiency was defined as 25(OH)D level of <20 ng/mL, vitamin D insufficiency as 25(OH)D level of 20-30 ng/mL, and vitamin D sufficiency as 25(OH)D level of >30 ng/mL. Adolescents with vitamin D deficiency were treated with 50,000 IU of vitamin D once a week for 6-8 weeks, whereas adolescents with vitamin D insufficiency were treated with 800 IU of vitamin D daily for 3 months. Repeat 25(OH)D was obtained after treatment. RESULTS The prevalence rate of low vitamin D status among 68 obese adolescents (53% females, 47% males, age: 17 ± 1 years, body mass index: 38 ± 1 kg/m(2), Hispanic: 45%, African American: 40%, Caucasian: 15%) was 100% in females and 91% in males. Mean (±SE) 25(OH)D level was significantly higher in summer (20 ± 8 ng/mL) than in spring (14 ± 4 ng/mL, p < .02), and significantly lower in winter (15 ± 7 ng/mL) than in fall (25 ± 15 ng/mL, p < .05). Although there was a significant (p < .00001) increase in mean 25(OH)D after the initial course of treatment with vitamin D, 25(OH)D levels normalized in only 28% of the participants. Repeat courses with the same dosage in the other 72% did not significantly change their low vitamin D status. CONCLUSIONS Increased surveillance and possibly higher vitamin D doses are warranted for obese adolescents whose total 25(OH)D levels do not normalize after the initial course of treatment.

Dysmenorrhea in adolescents and young adults: from pathophysiology to pharmacological treatments and management strategies.

Background: Dysmenorrhea is the most common gynecologic complaint among adolescent and young adult females. Dysmenorrhea is usually primary and is associated with normal ovulatory cycles and with no pelvic pathology. In ∼ 10% of females with severe dysmenorrhea symptoms, pelvic abnormalities such as endometriosis or uterine anomalies may be found. Objective: To review the current knowledge regarding the pathophysiology of dysmenorrhea, as well as review pharmacological treatments and strategies for management of dysmenorrhea in adolescent and young adult females. Methods: Review of original articles on dysmenorrhea that have been published in the medical literature. Results/conclusions: Potent prostaglandins and potent leukotrienes play an important role in generating primary dysmenorrhea symptoms. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common pharmacologic treatment for dysmenorrhea. A loading dose of NSAIDs (typically twice the regular dose) should be used as initial treatment for dysmenorrhea, followed by a regular dose until symptoms abate. Adolescents and young adults with symptoms that do not respond to treatment with NSAIDs for three menstrual periods should be offered hormonal treatment such as combined estrogen/progestin oral contraceptive pills (OCPs) for three menstrual cycles. If dysmenorrhea does not improve within 6 months of treatment with NSAID and OCPs, a laparoscopy is indicated to look for endometriosis. The goal of pharmacological treatment for endometriosis is to block its abnormal positive feedback loop. The abnormal loop consists of high local levels of estrogen in the lesions, which induce transcription of COX-2 and synthesis of prostaglandin E2. This results in further expression and activity of aromatase and a further increase in estrogen.

Long-term alterations in growth hormone and insulin secretion after temporary dietary protein restriction in early life in the rat

ABSTRACT: Protein malnutrition early in life stunts subsequent physical growth in both humans and rats, but the mechanism(s) is unknown. To test the hypothesis that temporary early life dietary protein restriction produces long-term alterations in the growth hormone (GH) neuroendocrine axis, we examined the effects of 3 wk of exposure to dietary protein restriction in male rats postweaning (3–6 wk of age) on spontaneous and GH-releasing factor (GRF)-stimulated GH secretion at 12 wk of age. In comparison to rats weaned onto a normal diet (23% protein), rats weaned onto a low (4%) protein diet failed to catch up growth when transferred to the normal diet between 6 and 12 wk of age. Spontaneous 6-h GH secretory profiles of adult rats fed the low protein diet early in life showed a 41% reduction in mean GH peak amplitude and a significant suppression in overall mean 6-h plasma GH concentrations (37.5 ± 4.5 versus 56.9 ± 5.9 μ g/L; p < 0.02). The magnitude of the GH response to 1 μ g of rat GRF(1–29)NH2 i.v. challenge was augmented during the GH trough period in these rats (165.7 ± 30.4 versus 43.9 ± 17.6 μ g/L;p < 0.01). Although basal plasma IGF-I levels and glucose tolerance of protein-deprived rats were normal at 12 wk of age, the insulin response to ip glucose was severely blunted [insulin integrated area under the curve: 303.0 ± 32.7 versus 778.3 ± 105.0 pmol/L/75 min; p < 0.01]. These results demonstrate that temporary protein malnutrition early in life 1) blunts spontaneous pulsatile GH secretion, 2) augments GH responsiveness to GRF challenge, and 3) reduces the insulin secretory response to glucose in adulthood. Our findings suggest that dietary protein in early life is an important determinant for CNS control of GH secretion as well as for the development of pancreatic β-cell sensitivity to glucose. Such alterations in the GH neuroendocrine axis, together with the subnormal insulin secretion, likely contribute to the lack of catch-up growth in this model.

Depo-provera in adolescents: Effects of early second injection or prior oral contraception

PURPOSE To examine the effects of an early second injection or prior use of oral contraceptive pills (OCP) on side effects of Depo-Provera during the early months of use in adolescents. METHODS Thirty-six girls, gynecologic age 4.2 +/- 0.3 years, and body mass index (BMI) 23.2 +/- 0.8, received the currently recommended injection of 150 mg every three months. Twenty-seven girls (gynecologic age 3.9 +/- 0.5 years, BMI 24.0 +/- 0.8) received the second injection six weeks after the first injection. Fifteen girls (gynecologic age 5.0 +/- 0.5, BMI 25.4 +/- 1.3) switched directly from an OCP to Depo-Provera. The patients were periodically assessed by their care providers. RESULTS Early administration of the second injection of Depo-Provera did not alter the bleeding episodes, onset of bleeding, or total days of bleeding (14.3 +/- 3.7 vs. 17.1 +/- 4.0, p = 0.62) during the three months interval following injection, compared with the standard second injection interval. Moreover, an excessive BMI gain (BMI increase 0.99 +/- 0.22 vs. 0.40 +/- 0.14, p = 0.03) was observed in these girls. Girls who switched directly from OCP showed no difference in the rate of BMI gain when compared to those not previously on OCP (BMI increase 0.38 +/- 0.3). Bleeding duration of these girls, however, was markedly reduced; the total number of days of bleeding was 5.7 +/- 1.9 (p = 0.0003) during the first three month interval, and 5.7 +/- 2.3 (p = 0.019) during the three month period following the second injection. This reduction did not persist beyond the first six months. CONCLUSIONS Early second Depo-Provera injection does not alter the experience of menstrual abnormalities, and predisposes to greater weight gain; OCP use prior to Depo-Provera results in a decrease in the duration of bleeding with no change in the weight gain rate.

Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture.

OBJECTIVE: Depot medroxyprogesterone acetate (DMPA) reversibly reduces bone mineral density. To estimate the extent to which DMPA might increase fracture risk, we undertook a retrospective cohort study of fractures in DMPA users and users of non-DMPA contraceptives, using the General Practice Research Database. METHODS: Eligible women were aged younger than 50 years at the qualifying first contraceptive prescription. The DMPA users were classified by DMPA exposure (cumulative and time of last dose) based on prescription records. All incident fractures were included; fracture incidence and risk factors before starting contraceptive use (DMPA or other) also were estimated. RESULTS: We identified 11,822 fractures in 312,395 women during 1,722,356 person-years of follow-up. Before contraceptive use started, DMPA users had higher fracture risk than nonusers (incidence rate ratio 1.28, 95% confidence interval [CI] 1.07–1.53). After DMPA started, crude fracture incidence was 9.1 per 1,000 person-years for DMPA users and 7.3 for nonusers (crude incidence rate ratio 1.23, 95% CI 1.16–1.30). Fracture risk in DMPA users did not increase after starting DMPA (incidence rate ratio after or before 1.08, 95% CI 0.92–1.26). There was little confounding by age or other factors that could be measured. Fracture incidence was 9.4 per 1,000 person-years in low-exposure DMPA users, and 7.8 per 1,000 in high-exposure DMPA users. The DMPA users had higher fracture risk than nonusers at the start of contraceptive use, with no discernible induction period. CONCLUSION: Although DMPA users experienced more fractures than nonusers, this association may be the result of confounding by a pre-existing higher risk for fractures in women who chose DMPA for contraception. LEVEL OF EVIDENCE: II