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Primary Amenorrhea in a Young Adult with Sickle Cell Disease: A Case Report and Brief Literature Review on Adolescent Reproductive Health and Sickle Cell Disease
J Pediatr Adolesc Gynecol (2008) 21:361e370
Case Report Primary Amenorrhea in a Young Adult with Sickle Cell Disease: A Case Report and Brief Literature Review on Adolescent Reproductive Health and Sickle Cell Disease Teresa M. Erb, MD1, Kelly Gerschultz, MD1, Melanie A. Gold, DO2, and Joseph S. Sanfilippo, MD, MBA1 1
Magee Women’s Hospital of the University of Pittsburgh Medical Center; 2Division of Adolescent Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Background Sickle Cell Disease Sickle cell disease is a chronic disease with significant morbidity and mortality in children, adolescents, and young adults. An estimated 72,000 Americans have sickle cell disease, affecting one out of every 500 African Americans and one out of every 1,000 Hispanic Americans.1 The prevalence of sickle cell trait is much higher, with approximately 8% of the African American population carrying a hemoglobin S allele.1 Sickle cell disease and the spectrum of hemoglobinopathies are autosomal recessive diseases. The spectrum of disease occurs in the following descending prevalence: sickle cell disease, sickle cell/hemoglobin C disease, and the sickle cell/b-thalassemias (sickle cell/bþ-thalassemia and sickle cell/bo-thalassemia) in which there is only one Hb A chain or no Hb A chains, respectively (See Table 1). These hemoglobinopathies range in severity from sickle cell disease and sickle cell/bo-thalassemia which have severe sequelae to sickle cell/hemoglobin C disease and sickle cell/bþthalassemia which are mild and often asymptomatic. Sickle cell disease, characterized by misshapen hemoglobin and red blood cell fragility, is due to a substitution of valine for glutamic acid at position 6 on the b-globin chain of the hemoglobin molecule. These abnormal red blood cells are prone to hemolysis and have a shortened lifespan of 12 days, in contrast to the 120-day lifespan of normal red blood cells. Chronic anemia develops, resulting in lower hemoglobin levels (6e9 g/dL), higher reticulocyte counts (5e15%), and chronic hyperbilirubinemia with
jaundice.2 These abnormal red blood cells also have a propensity to sickle when deoxygenated, particularly in inflamed or infected tissues where oxygen tension is low. Although the exact etiology of vasoocclusion in sickle cell disease is not known, sickled cells tend to aggregate and polymerize which could theoretically occlude vasculature and lead to infarction. The consequences of infarction are evident early in life, as abnormal red blood cells infiltrate the spleen causing both acute and chronic hypersplenism and eventual fibrosis and atrophy. Aside from the spleen, other organs can infarct, with the brain, bone, lungs, and kidneys being the most common sites.2 The sequelae of infarction and infection negatively impact life expectancy; individuals with sickle cell disease have a 25e30 year shorter life span compared to their healthy peers. With medical advances improving life expectancy in individuals with sickle cell disease, quality of life issues arise. For the adolescent, where peer groups are very influential, these issues include the progression though puberty, contraception, and family planning.
Address correspondence to: Teresa M. Erb, MD, Magee Women’s Hospital of the University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213; E-mail: [email protected]
Puberty Abnormalities in both growth and pubertal development have been documented in children with sickle cell disease. Puberty is defined as a period of growth in which children develop secondary sexual characteristics, ultimately reaching an adult habitus. The onset of puberty, triggered by the increase in gonadotropinreleasing hormone (GnRH) from the hypothalamus, leads to an increase in luteinizing hormone (LH) secretion from the pituitary which subsequently triggers many pubertal events. In particular, the increase in GnRH pulse amplitude and frequency is necessary for a normal pubertal process. Healthy females usually begin puberty with thelarche around the ages of
Ó 2008 North American Society for Pediatric and Adolescent Gynecology Published by Elsevier Inc.
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Table 1. Frequency of Hemoglobinopathy Genotypes and Disease Severity
Hemoglobinopathy
Genotype Frequency*
Homozygous sickle SS cell disease Sickle cell/hemoglobin SC C disease Sickle cell/bþthalassemia SA
1 in 3000
Sickle cell/bothalassemia SF
1 in 7000
Disease Severity
1 in 300
Severe
1 in 500
Mild to moderate Mild to moderate Severe
*Adapted from Serjeant et al, 1997.
8 to 13 years. Adrenarche soon follows at an average age of 11 years. Menarche usually occurs between the ages of 10 and 16.5 years, with the growth spurt reaching its maximal velocity approximately one year prior to menarche. Specifically, healthy African American females without sickle cell disease undergo thelarche, adrenarche, and menarche at the mean ages of 9.48, 9.43, and 12.06 years, respectively.3 Delayed puberty is defined as incomplete development of secondary sexual characteristics by an age greater than two standard deviations beyond the mean. Every girl who has not developed breast buds by age 13 should be evaluated for delayed puberty, and every girl who has not attained menarche by age 16 should be evaluated for primary amenorrhea. There are many etiologies of delayed puberty including constitutional delay, endocrine abnormalities, chronic illness, and idiopathic causes. A study of 74 females with pubertal delay found that 30% had constitutional delay, 26% had hypergonadotropic hypogonadism, 20% had permanent hypogonadotropic hypogonadism, 19% had functional hypogonadotropic hypogonadism, and 4% had other causes.4 Objective For years clinicians have observed differences in severity both within and between children with varying sickle cell syndromes. Considering the array of factors that influence adult size and developmental maturation of an individual, it is not surprising to find that an adolescent with sickle cell disease may display growth and pubertal delay. We will discuss the major health concerns of the pre-pubertal and pubertal adolescent with sickle cell disease, review the pertinent medical literature, and offer general management strategies for the clinician caring for the adolescent with sickle cell disease. Growth and progression of pubertal development remain paramount, while concerns regarding contraception, family planning, and preconception counseling continue to be important points of discussion. Future directions required to better understand the effect of this disease on overall adolescent health are key to clinical management.
Case Presentation K.S., a 21-year-old African American woman with sickle cell disease, presented to a gynecologic-endocrine clinic at Magee Womens Hospital, Pittsburgh, PA, for consultation regarding primary amenorrhea. She experienced thelarche at age 14 years and adrenarche at age 17 years. She denied a history of sexual activity or prior evaluation for amenorrhea. She denied a family history of sickle cell disease, delayed puberty, and any other endocrinologic diseases. K.S. had severe sickle cell disease, requiring 6 to 7 hospitalizations annually for the past 7 years. She had a mediport placed 7 years prior for chronic blood transfusions, and IV narcotic pain control. The mediport was removed one year ago when a decrease in pain crisis frequency and hemolysis episodes obviated the need for continued chronic blood transfusions. Her baseline hemoglobin is 9.5 g/dL and her last blood transfusion was approximately one year prior to presentation. Her physical exam revealed a tall, thin woman at 5’8’’ and 123 lbs. She appeared much younger than her stated age. Her general exam was otherwise unremarkable except for Tanner stage 3 for breasts and pubic hair distribution. Pertinent negative findings included no thyromegaly, hirsutism, acne, acanthosis nigricans, or clitoromegaly. Her pelvic exam was normal with a perforate hymen and no vaginal septum. A urine pregnancy test was negative, and transvaginal ultrasound revealed an anteverted uterus with normal appearing bilateral ovaries. (See Table 2 for lab values.) Review of records from a previous evaluation for primary amenorrhea at 18.5 years of age revealed Tanner stage (3-breast, 2-pubic hair), bone age of 16 years, normal karyotype, and pre-pubertal levels of FH, LH, and estradiol. The differential diagnosis for primary amenorrhea is extensive (Figure 1).5 In the case of K.S., her Table 2. Laboratory Results Obtained During the Initial Workup for K.S. Lab Test
Test result
TSH Prolactin LH FSH Estradiol Hemoglobin Hematocrit MCV RDW
1.74 3.6 7.3 7.8 !20 8.8 25.1 90.0 18.9
Normal Range 0.35e5.50 mIU/mL 3.3e26.7 ng/mL *1.0e5.9 mIU/mL *1.2e7.8 mIU/mL *10e50 pg/mL 11.6e14.6 g/dL 34.1e43.3% 82.6e97.4 fl 11.5e15.0%
TSH5thyroid stimulating hormone, LH5luteinizing hormone, FSH5follicular stimulating hormone, MCV5 mean corpuscular volume, RDW5red cell distribution width. *Normal values for pre-pubertal children.
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Fig. 1. Differential Diagnosis of Primary Amenorrhea (Adapted from Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology, (5th ed.). Philadelphia, Lippincott Williams and Wilkins, 2005.)
primary amenorrhea is due to functional hypothalamic amenorrhea as evidenced by the interruption of pubertal development (at Tanner stage 3) in conjunction with normal pelvic anatomy to pre-pubertal range gonadotropins and estradiol levels and an incongruent bone age for Tanner stage (per old records). Health Concerns for the Pre-pubertal Adolescent with Sickle Cell Disease Growth and Puberty Two major health concerns for adolescents with sickle cell disease are growth and puberty, delays in both of which have been well documented in the literature since the 1960s. Growth is delayed in children with various sickle cell syndromes with those adolescents with sickle cell disease and sickle cell/bo-thalassemia being the most significantly delayed.6e9 Weight is more affected than height,7e10 with delays becoming significant in children with sickle cell disease after 7 years of age,2,11 and peaking in the adolescent years8,11 coincident with the expected onset of pubertal development. Though sexual maturation usually progresses in an orderly fashion, it is significantly
delayed (by an average of approximately two years) in the adolescent with sickle cell disease.7e10,12e14 Conclusions regarding the etiology of growth and pubertal delay in this patient population remain mixed (see Table 3). Although authors agree that the disease’s effects on development are multi-factorial, constitutional delay secondary to nutritional deficiencies and negative energy balance has been assumed to be the main contributors to pubertal delay.9,14,15 However, there is data that implicates alterations in the hypothalamic-pituitary-end organ system as the primary cause of growth and developmental delay,11,16e18 or that extreme cases of pubertal delay are likely of an endocrinologic etiology10 with possible alterations in the hypothalamic-pituitary-ovarian axis. Conflicting Conclusions Regarding the Etiology of Delayed Growth and Puberty Energy Versus Endocrine Debate One of the largest studies on development and sickle cell disease is the Cooperative Study of Sickle Cell Disease, in which 2115 participants aged 2 to 25 years with different hemoglobinopathies were identified from fifteen US clinical centers.7 Each participant’s
Reference
Study Type, location 6
N
Age range (yr)
Hgb geno-type
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Table 3. A Comparison of Selected Publications on Growth and Pubertal Delay in Adolescents with Sickle Cell Disease
Conclusions
Comments Argue for constitutional cause based on normal configuration of growth and maturation curves. No hormonal or bone age analysis SS-specific growth curves are indicated No analysis of etiology (Authors propose multi-factorial cause)
CSSC* US
1056 (f) 1008 (m)
2e25
All types
Howard University norms for AA children
For both sexes and all Hgbopathies growth and maturation curves were significantly different from norms
Platt et al, 20007
longitudinal cohort study Jamaica
315
0e19
SS
NCHS norms
Thomas et al, 20018
longitudinal cohort study West Indies
268
0e26.5
SS (99), SC (69)
age and sex-matched, AA (100)
Growth in HgbSS boys and girls is similar to norms at birth, shows maximal lag at 10e15 years, and begins to catch up by age 18 Age at menarche is delayed by 0.5 years in SC, and 2.5 years in SS
Serjeant, 19829
longitudinal cohort study US
29 (f) 26 (m)
13e18
SS
NCHS norms
Boys & girls with Hgb SS have subnormal heights & weights and delayed sexual & skeletal maturation
Luban et al, 198410
longitudinal cohort study US
133
1e18
SS(83)All variant types (50)
NCHS norms
Phebus et al, 198611
cohort study Nigeria
2466 (f)
10e19
SS(32)
age-matched, AA & AS (2207)
Impairment in height & weight increases with age and is more pronounced in boys Age at menarche is significantly delayed in pts with Hgb SS
Modebe, 199912
cross-sectional and longitudinal cohort study Egypt
110
2e10
SS
age and sex-matched controls (200) also children with constitutional delay (30) or GH deficiency (25)
Wethers, 1984
Linear growth, growth velocity and pubertal maturation are significantly delayed in children with SS
Multi-regression analysis shows weight is dominant factor in determining age at menarche for all Hgb genotypes Authors argue against endocrine cause, but no bone age or hormonal analysis Tanner stage was appropriate for bone age (constitutional) for most children, except for those with extreme pubertal delay (suggests endocrine cause) Etiology unknown, likely multi-factorial
Argue for abnormalH-P-O axis (endocrine cause) Data obtained by questionnaire Likely multi-factorial
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Control group
cross sectional study France
8
10e12
SS
age and sex-matched controls (7)
Children with SS have evidence of excess protein, energy, and glutamine metabolism
Leonard et al, 199515
Retrospective chart review Jamaica
19 (f) 13 (m)
1e11
SS
Each patient served as their own control
Singhal et al, 199516
longitudinal cohort study Brazil
20 (f) 21(m)
2e15
SS
age and sex-matched controls (41)
Splenectomy for hypersplenism in pts with SS leads to a significant increase in height, but not weight, velocity In contrast, hx undernourished controls show an increase in both parameters after nutritional supplementation Growth velocity and z-score for growth velocity do not correlate with any element of IGF axis
Luporini et al, 199217
cross-sectionalstudy Saudi Arabia
80 (f) 80 (m)
4e50
SS
age and sex-matched controls (60)
Pts with SS show varying levels of gonadal hypofunction, abnormalities of LH, FSH, testosterone, and cortisol correlated disease severity
Suggest that hypermetabolism is etiology of pubertal and growth delays (Constitutional), but study not designed to look at this relationship Argue that accelerated linear growth is not simply due to general nutritional improvement (argue against constitutional cause) Hypothesize specific nutrient deficiency (i.e. zinc), but do not consider endocrine role
Argue against protein-caloric malnutrition as etiology of growth and pubertal delay (against constitutional delay) Hypothesize etiology is from ‘‘intrinsic factors’’ of the disease, but do not specifically propose endocrine role Several endocrine abnormalities exist (majority hypothalamic hypogonadism) Do not exclude contribution of other factors (multi-factorial)
GH5Growth hormone, IGF5 insulin like growth factor, LH5lutenizing hormoneFSH5 follicle stimulating hormone, (f)5female, (m)5male, SS5homozygous Hgb S. *Cooperative Study of Sickle Cell disease identified patients from 15 US clinical centers between 1979-1981, cross sectional data was then used for detailed data analysis.
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Soliman et al, 199613
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height, weight, and sexual maturation according to the staging system described by Tanner19 were recorded. Growth and maturation curves for each of the hemoglobinopathies demonstrated a normal configuration but with delays in growth when compared to published norms for African Americans. The author concluded that the delayed development in those with sickle cell disease represented a constitutional delay because these adolescents proceeded through puberty in an orderly progression, albeit later than their healthy peers. As developmental delay cannot always be explained by constitutional delay, other authors have explored endocrinologic etiologies. Olambiwonnu et al20 studied the growth and development of adolescents with sickle cell disease, specifically exploring the endocrinology of sexual development. Gonadotropin levels, bone age (using the Gruelich and Pyle standards21), Tanner staging, and anthropomorphic data were collected from forty children with sickle cell disease. LH concentrations were noted to be significantly higher for Tanner stage, but not for age, in the sickle cell group when compared to normal African American controls. No conclusion could be drawn from the FSH concentrations, because a poor control group was used. The authors conclude that children with sickle cell disease exhibit impaired gonadal function, as reflected by the elevation in LH levels. Likewise, they attribute the delay in bone age between the ages of 12 and 19.5 years to sex steroid deficiency, as delayed gonadal function results in delayed epiphyseal maturation. These findings, coupled with the observation of subnormal heights in children with sickle cell disease by age 7 years,7 with ultimately normal adult heights,8 led the author to conclude that the growth failure for most such children is due to a transient gonadal dysfunction and possibly even the absence of a growth spurt. These findings are in contrast to the pattern of constitutional delay, where gonadotropin levels are congruent with stage of sexual development and often low for age.22 True constitutional delay is the result of variability in the rate of maturation of the hypothalamic-pituitary-gonadal axis, while gonadal function remains intact. Further Evidence in Support of Negative Energy Balance Various data implicate a negative energy balance and/ or nutritional deficiency as the etiology of developmental delay. Salman et al14 showed that children with sickle cell disease are hypermetabolic with regard to protein, energy, and glutamine utilization, which correlates with the increased erythropoesis and cardiac workload these children demonstrate. A report by Wang et al23 demonstrated that children with sickle cell disease randomized to long-term
transfusion/chelation therapy showed significant improvement in growth when compared to the standard care group. Furthermore, chronic inflammation, malabsorbtion, anorexia, and disease severity exacerbate the negative energy balance and nutritional deficiencies in sickle cell patients. Further Evidence in Support of an Endocrine Cause Other studies argue either against a general negative energy balance16 or in favor of a primary endocrine cause17,18 for the developmental and growth delays observed. The Jamaican cohort study (Singhal et al) demonstrated that those with sickle cell disease who had a splenectomy for hypersplenism showed significant improvements in hematological indices, disease severity, and height velocity, but not in weight velocity, when compared to those with sickle cell disease who did not have a splenectomy. This is in contrast to the effect of nutritional supplementation seen in severely malnourished children, in whom an increase in weight velocity precedes an increase in height velocity, suggesting that the accelerated linear growth is not simply a consequence of a general improvement in nutritional status. The fall in body mass index observed in the first six post-operative months is consistent with this observation and argues against a general energy deficiency as the cause for the absence of a growth spurt. El-Hazmi et al18 showed that gonadal hypofunction was present in females with sickle cell disease aged 4e50 years, and that the variability of hypofunction observed correlated with disease severity. Study Limitations Small sample sizes, poorly selected control groups, and factors related to study design lead to inaccuracies when generalizing this data to all adolescents with sickle cell disease. For example in Platt’s study,7 caution should be exercised in claiming that constitutional delay is the cause for their findings, as conclusions on the progression of adolescent growth and development are best made by longitudinal rather than cross sectional data. The absence of measurements for bone age and hormonal function likewise weaken the argument that constitutional delay was the etiological factor in the growth delays observed. Failure to simultaneously assess growth parameters with Tanner staging, menarcheal status, bone age, and hormone levels, results in the lack of important information regarding the effects of the endocrine system on growth, as well as the possible effects of nutritional deficiencies and energy imbalance on pubertal development. Just as the sickle cell syndromes have varying degrees of severity, it is likely that the etiologies of developmental delay also fall into a wide spectrum.
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Soliman et al13 argued for a multi-factorial cause and other studies have shown multiple factors contributing to delay. Luban et al10 in a longitudinal study of 26 boys and 29 girls with sickle cell disease noted an intact hypothalamic-pituitary axis in his cohort of subjects, with notably lower than expected gonadal end organ hormones in a minority of subjects (n 5 4). These participants demonstrated severe maturational abnormalities in both linear growth and pubertal development, hence demonstrating the obvious impact of the sex steroids in normal pubertal development and linear growth in adolescence, but not necessarily in final adult height. Likwise, Singhal et al24 reported extreme retardation of adolescent growth and development to be a harbinger of an endocrine cause. General Management Considerations Importance of Early Detection The necessity for early detection of superimposed problems of growth and pubertal development is obvious; however, the practicality of how to accomplish this remains. Singhal et al8 generated sex specific height and weight references curves for children with homozygous sickle cell disease. When compared to the standards of healthy children from the National Center for Health Statistics (NCHS) they found that while both groups exhibited similar heights and weights at birth, those with sickle cell disease quickly fell off the normative curve. Those with sickle cell disease exhibited a maximum lag at 10e15 years of age, but by age 18 years, female adolescents had caught up with NCHS standards while boys were still in the catch-up phase of growth because they were still significantly shorter than NCHS standards at 18 years of age. As growth is often delayed in children with sickle cell disease compared to children with a normal hemoglobin genotype, the authors argue that superimposed growth problems can be hard to detect without the generation of such reference curves. These researchers believe that it is not appropriate to use US standard growth charts for normal children to identify impaired growth in children with sickle cell disease. Disease-specific reference growth curves can serve as a tool to assist the clinician in the early detection of superimposed growth problems in the adolescent with sickle cell disease such as those due to suboptimal nutrition, chronic hypersplenism, and even endocrine abnormalities. The precedence for using disease specific growth charts has been similarly established for children with a genetic predisposition to growth and pubertal delay, such as Turner sydrome25 and Down syndrome. Although this study was fairly large (n ~ 100), many participants were lost to follow-up after
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reaching 14 years of age, reducing the precision of the conclusions drawn about these later ages. This is reflected by the ‘‘catch-up growth‘‘ observed in female subjects who eventually attained normal final adult heights; a finding not consistently reported in the medical literature.11 The fact that the children included in this study were selected at birth, however, reduces the selection bias often seen when studies are conducted from sickle cell disease centers, which often provide medical support to the more severely affected children and adolescents with sickle cell disease. Unfortunately, no such reference curves were derived for pubertal maturation. The lack of reference curves for Tanner staging in the adolescents with sickle cell disease can still lead to a delay in the diagnosis of superimposed problems as illustrated in our case of a 21-year-old with primary amenorrhea. Nutritional Supplements Although there are multiple theoretical benefits, there is very little data supporting the use of nutritional supplements in women, children, or adolescents with sickle cell disease and delayed development. However, several investigators have pointed to specific nutrient deficiencies that may be related to growth retardation such as zinc, folate, and vitamins A, B6, C, and E.6 A recent randomized-controlled study of zinc supplementation in children aged 4 to 10 years with sickle cell disease found that daily zinc was associated with increased linear growth.26 A similar randomized-controlled trial in adolescents aged 14e17 years found that those who received zinc had increased height, weight, and testosterone levels,21 consistent with the another study by Abassi et al.27 Other studies have implicated decreased folate levels as one of the etiologies of growth delay. However, a doubleblinded controlled trial in children with sickle cell disease, aged 6 months to 4 years, revealed no significant difference in height or weight among those who received supplementation and those who did not.28 Chronic Transfusions Aside from nutritional adjustments, it has been postulated that correction of anemia with blood transfusions might improve growth and development by decreasing energy expenditure. A recent study evaluated children aged 2e16 years who were either treated with chronic transfusions every 3e5 weeks or with standard of care. While both groups started at similar baselines, the children who were chronically transfused had significantly increased heightfor-age and weight-for-age when compared to those treated with standard of care.24 There are increased risks with blood transfusions such as infection, alloimmunization, and iron overload which must be considered. Therefore this management should be
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coordinated by an experienced hematologist or sickle cell specialist. Hormonal Management Historically, oral contraceptive use was avoided in adolescent and young adult women with sickle cell disease due to concerns about the possibility of a synergistic effect of the oral contraceptive pill on either red cell deformability or the blood-clotting mechanisms. Two prospective observational studies by Yoong et al29,30 examined red cell deformity and laboratory markers of platelet activation, thrombin generation, and fibrinolysis in women with sickle cell disease. Neither study showed a significant difference in the parameters measured among women with sickle cell disease taking combined oral contraceptives (COC), progestin-only contraceptives, or non-hormonal contraceptives. Other studies have shown that COC use, even up to 54 months, did not increase sickle cell crises or thrombotic events in comparison to a control group of sickle cell disease non-COC users and normal COC users respectively.31 Sickle cell disease is not considered a contraindication to COC use, whereas the medical sequelae of sickle cell disease, such as cerebral vascular accidents, serve as absolute contraindications to COC use.32 Some would argue that the mechanism of stroke in sickle cell disease is due to ischemia from sickling, and not thrombosis as seen in non-sickle cell disease patients, and thus do not consider this a contraindication to COC use. There are numerous non-contraceptive benefits from hormone use in this population. For example, estrogen use in the woman with sickle cell disease with functional hypothalamic amenorrhea, as in our case, may have the advantage of completing breast development and preventing the future risk of osteoporosis. Furthermore, a young woman may experience multiple psychological benefits from menstruating and developing like her peers. (COC use might also decrease anemia among women with SS disease who menstruate) There is also a relationship between DepoProvera use and a lower incidence of sickle crisis resulting from red blood cell membrane stabilization with less sickling.33,34 Case Resolution Overall therapy, hormonal or otherwise, should be individualized such that treatment is specific to the etiology of the growth and/or pubertal delay. For example, the case of K.S. clearly demonstrates evidence of functional hypothalamic amenorrhea, as she had normal height with delayed Tanner staging, primary amenorrhea, and a hormonal picture consistent with estrogen and relative gonadotropin deficiency. K.S.’s main concern was her incomplete breast development and lack of menarche. Other concerns are
the sequelae of oligo-ovulation including unplanned pregnancy and future osteoporosis. Due to this, initial estrogen followed sequentially by progestin was the best overall treatment for K.S. Sex hormone replacement therapy is intended to mimic physiologic puberty, enhance normal growth, induce and maintain normal menstruation, as well as support normal bone maturation and calcification. There is still controversy regarding the best hormone replacement therapy for girls with hypogonadism. Standard optimal therapy begins at very low doses (2 mcg/day of ethinyl estradiol) for 6 months followed by a progressive increased in dose by 2 mcg/day every 6 months to a total of 6 mcg/day. This dose escalation is meant to prevent nausea and improve compliance, while also allowing the completion of breast development in addition to increases in linear height.35 The main reason for starting ethinyl estradiol in a low dose is to stimulate growth hormone (GH) secretion, because higher doses typically lead to GH suppression. This low dose of ethinyl estradiol is followed by higher estrogen doses with 5 mcg/day increases every 6 months to a total of 20 mcg/day. Thereafter, adding in progestin with a low dose COC can be initiated.35,36 Specifically, K.S. was started on conjugated estrogens 0.625mg once a day for 3 months, because she had already shown evidence of pubertal development and had achieved a normal adult height. This will be followed by an increase in dose to 1.25 mg once daily for a 6 month interval and it will be given at bedtime to reduce nausea. K.S. was counseled that this regimen will not prevent spontaneous ovulation, and so, if she were to become sexually active she would require further contraception. Thereafter, she will be transitioned to a lower dose COC (any regimen with 20e35 mcg of ethinyl estradiol and a progestin will suffice and the choice is usually based on insurance and cost). Additionally, a baseline dual energy X-ray absorptiometry (also known as a DEXA or bone scan) will be obtained to evaluate for osteoporosis or osteopenia as will serial scans, at 2-year intervals, to follow K.S.’s response to the initiation of estrogens. Post-pubertal Health Concerns Female adolescents with sickle cell disease who have successfully completed puberty have other health concerns. With regard to family planning, issues such as contraception and preconception counseling often arise. Medroxyprogesterone acetate (MDPA) has been purported to be the ideal contraceptive method for females with sickle cell disease.33,34 This is based on the observed reduction in both vaginal bleeding and the number of pain crises in women on MDPA.33,34 Likewise, low dose combined hormonal contraception, and progestin-only methods like the levonorgestrel intrauterine system and subdermal implant (Implanon) may be safer options than pregnancy
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given the increased risk of fetal, neonatal, and maternal morbidity and mortality of pregnancy among adolescents with sickle cell disease. In addition to educating adolescent and young women with sickle cell disease about the inherent risks associated with pregnancy, these young women must also be prepared for the social and psychological challenges that may arise when a mother with a chronic illness raises a family. Further, health care providers should discuss the options of partner screening and prenatal diagnosis with all females with sickle cell disease who are of reproductive age. Due to advances in the management of individuals with sickle cell disease, issues related to infertility will likely become a concern, as more women are surviving into adulthood and attempting to conceive. Future Directions U.S. growth and development curves for healthy children are not applicable to the adolescent with sickle cell disease, leading to the establishment of unique growth curves for this population.8 Standardized curves for pubertal maturation have not been developed but are needed to identify abnormalities at an earlier age and to expedite treatment of potential endocrine causes. Assistance in the transition from pediatric to adult care is also critical. Studies indicate that patients leave pediatric care without adequate preparation, and are transferred to the adult clinician based solely on age or pregnancy status.37 However, the patient’s readiness to transfer is not taken into consideration, leading to a loss of follow-up or increased emergency room visits once patients leave pediatric care.37 Thus, a structured approach is essential to promote optimum stability in adolescent care for the patient with sickle cell disease. A therapeutic environment should educate the adolescent on her disease process, aid her in developing life skills to effectively manage her health, and assist in a smooth transition to adult care by integrating health care and social networks such as family, school, work, the community and other health care providers. References 1. Sickle Cell Disease Guideline Panel: Sickle cell disease: screening, diagnosis, management, and counseling in newborns and infants. Clinical Practice Guideline No 6. AHCPR Pub. No. 93-0562. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services. April 1993 2. Serjeant G: Sickle-cell disease. Lancet 1997; 350:725 3. Slyper A: The pubertal timing controversy in the USA, and a review of possible causative factors for the advance in timing of onset of puberty. Clin Endocrinol 2006; 65:1 4. Sedlmeyer I, Palmert M: Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab 2002; 87:1613
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5. Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology, (5th ed.). Philadelphia, Lippincott Williams and Wilkins, 2005 6. Wethers D, Ann NY Acad Sci: Delayed growth and sexual maturation in sickle cell disease 1989; 565:137 7. Platt O, Rosenstock W, Espeland M: Influence of sickle hemoglobinopathies on growth and development. N Engl J Med 1984; 311:7 8. Thomas P, Singhal A, Hemmings-Kelly M, et al: Height and weight reference curves for homozygous sickle cell disease. Arch Dis Child 2000; 82:204 9. Serjeant G, Singhal A, Hambleton I: Sickle cell disease and age at menarche in Jamaican girls: Observations from a cohort study. Arch Dis Child 2001; 85:375 10. Luban N, Leikin S, August GA: Growth and development in sickle cell anemia. Preliminary report. Am J Pediatr Hematol Oncol 1982; 4:61 11. Phebus C, Gloninger M, Maciak B: Growth patterns by age and sex in children with sickle cell disease. J Pediatr 1984; 105:29 12. Modebe O: The effect of homozygous sickle cell disease on the age of menarche in Nigerian schoolgirls. Ann Hum Biol 1987; 14:181 13. Soliman A, elZalabany M, Amer M, et al: Growth and pubertal development in transfusion-dependent children and adolescents with thalassemia major and sickle cell disease: A comparative study. J Trop Pediatr 1999; 45:23 14. Salman E, Haymond M, Bayne E, et al: Protein and energy metabolism in prepubertal children with sickle cell anemia. Pediatr Res 1996; 40:34 15. Leonard M, Zemel B, Kawchak D, et al: Plasma zinc status, growth, and maturation in children with sickle cell disease. J Pediatr 1998; 132:467 16. Singhal A, Thomas P, Kearney T, et al: Acceleration in linear growth after splenectomy for hypersplenism in homozygous sickle cell disease. Arch Dis Child 1995; 72:227 17. Luporini S, Bendit I, Manhani R, et al: Growth hormone and insulin-like growth factor 1 Axis and growth of children with different sickle cell anemia haplotypes. J Pediatr Hematol Oncol 2001; 23:357 18. El-Hazmi M, Bahakim H: Al-Fawaz I: Endocrine functions in sickle cell anaemia patients. J Trop Pediatr 1992; 38:307 19. Tanner, et al: Growth and endocrinology of the adolescent. In: Gardner LI, editor. Endocrine and Genetic Diseases of Childhood. Philadelphia, WB Saunders, 1969, pp 19e60 20. Olambiwonnu O, Penny R, Frasier S: Sexual maturation in subjects with sickle cell anemia: Studies of serum gonadotropin concentration, height, weight, and skeletal age. J Pediatr 1975; 87:459 21. Gruelich WW, Pyle IS, editors. A Roentgenological Atlas of Skeletal Maturation of the Hand and Wrist, (2nd ed.). Stanford, Stanford University Press, 1959 22. Penny R, Guyda H, Baghdassarian A, et al: Correlation of serum follicular-stimulating hormone and luteinizing hormone as measures by radioimmunoassay in disorders of sexual development. J Clin Invest 1847; 1970:49 23. Wang W, Morales K, Scher C, et al: STOP Investigators. Effect of long term transfusion on growth in children with sickle cell anemia: Results of the stop trial. J Pediatr 2005; 147:244
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24. Singhal A, Gabay L, Serjeant G: Testosterone deficiency and extreme retardation of puberty in homozygous sickle cell disease. West Indian Med J 1995; 44:20 25. Gawlik A, Gawlik T, Augustyn M, et al: Validation of growth charts for girls with Turner syndrome. Int J Clin Pract 2006; 60:150 26. Zemel B, Kawchak D, Fung E, et al: Effect of zinc supplementation on growth and body composition in children with sickle cell disease. Am J Clin Nutr 2002; 75:300 27. Abbasi A, Prasad A, Ortega J, et al: Gonadal function abnormalities in sickle cell anemia: Studies in adult male patients. Ann Intern Med 1976; 85:601 28. Rabb L, Grandison Y, Mason K, et al: A trial of folate supplementation in children with homozygous sickle cell disease. Br J Haematol 1983; 54:589 29. Yoong W, Tuck S, Yardumian A: Red cell deformability in oral contraceptive pill users with sickle cell anaemia. Br J Haematol 1999; 104:868 30. Yoong W, Tuck S, Pasi K, et al: Markers of platelet activation, thrombin generation, and fibrinolysis in women with
31. 32. 33.
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sickle cell disease: effects of differing forms of hormonal contraception. Eur J Haematol 2003; 70:310 Carlone J, Keen P: Oral contraceptive use in women with chronic medical conditions. Nurse Pract 1989; 14:9 WHO medical eligibility criteria for contraceptive use, (3rd ed.). World Health Organization, 2004 de Abood M, de Castillo Z, Guerrero F, et al: Effect of Depo-Provera or Microgynon on painful crises of sickle cell anemia patients. Contraception 1997; 56:313 De Ceulaer K, Gruber C, Hayes R, et al: Medroxyprogesterone acetate and homozygous sickle-cell disease. Lancet 1982; 2:229 Spiliotis B: Growth and long-term hormone therapy. Pediatr Endocrinol Rev 2006; 1(3 Suppl):192 Rubin K: Hypogonadism in adolescent females: New insights and rationale supporting the use of physiologic regimens to induce puberty. Pediatr Endocrinol Rev 2005; 2:645 Wojciechowski E, Hurtig A, Dorn L: A natural history study of adolescents and young adults with sickle cell disease as they transfer to adult care: A need for case management services. J Pediatr Nurs 2002; 17:18
Case Report Primary Amenorrhea in a Young Adult with Sickle Cell Disease: A Case Report and Brief Literature Review on Adolescent Reproductive Health and Sickle Cell Disease Teresa M. Erb, MD1, Kelly Gerschultz, MD1, Melanie A. Gold, DO2, and Joseph S. Sanfilippo, MD, MBA1 1
Magee Women’s Hospital of the University of Pittsburgh Medical Center; 2Division of Adolescent Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Background Sickle Cell Disease Sickle cell disease is a chronic disease with significant morbidity and mortality in children, adolescents, and young adults. An estimated 72,000 Americans have sickle cell disease, affecting one out of every 500 African Americans and one out of every 1,000 Hispanic Americans.1 The prevalence of sickle cell trait is much higher, with approximately 8% of the African American population carrying a hemoglobin S allele.1 Sickle cell disease and the spectrum of hemoglobinopathies are autosomal recessive diseases. The spectrum of disease occurs in the following descending prevalence: sickle cell disease, sickle cell/hemoglobin C disease, and the sickle cell/b-thalassemias (sickle cell/bþ-thalassemia and sickle cell/bo-thalassemia) in which there is only one Hb A chain or no Hb A chains, respectively (See Table 1). These hemoglobinopathies range in severity from sickle cell disease and sickle cell/bo-thalassemia which have severe sequelae to sickle cell/hemoglobin C disease and sickle cell/bþthalassemia which are mild and often asymptomatic. Sickle cell disease, characterized by misshapen hemoglobin and red blood cell fragility, is due to a substitution of valine for glutamic acid at position 6 on the b-globin chain of the hemoglobin molecule. These abnormal red blood cells are prone to hemolysis and have a shortened lifespan of 12 days, in contrast to the 120-day lifespan of normal red blood cells. Chronic anemia develops, resulting in lower hemoglobin levels (6e9 g/dL), higher reticulocyte counts (5e15%), and chronic hyperbilirubinemia with
jaundice.2 These abnormal red blood cells also have a propensity to sickle when deoxygenated, particularly in inflamed or infected tissues where oxygen tension is low. Although the exact etiology of vasoocclusion in sickle cell disease is not known, sickled cells tend to aggregate and polymerize which could theoretically occlude vasculature and lead to infarction. The consequences of infarction are evident early in life, as abnormal red blood cells infiltrate the spleen causing both acute and chronic hypersplenism and eventual fibrosis and atrophy. Aside from the spleen, other organs can infarct, with the brain, bone, lungs, and kidneys being the most common sites.2 The sequelae of infarction and infection negatively impact life expectancy; individuals with sickle cell disease have a 25e30 year shorter life span compared to their healthy peers. With medical advances improving life expectancy in individuals with sickle cell disease, quality of life issues arise. For the adolescent, where peer groups are very influential, these issues include the progression though puberty, contraception, and family planning.
Address correspondence to: Teresa M. Erb, MD, Magee Women’s Hospital of the University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA 15213; E-mail: [email protected]
Puberty Abnormalities in both growth and pubertal development have been documented in children with sickle cell disease. Puberty is defined as a period of growth in which children develop secondary sexual characteristics, ultimately reaching an adult habitus. The onset of puberty, triggered by the increase in gonadotropinreleasing hormone (GnRH) from the hypothalamus, leads to an increase in luteinizing hormone (LH) secretion from the pituitary which subsequently triggers many pubertal events. In particular, the increase in GnRH pulse amplitude and frequency is necessary for a normal pubertal process. Healthy females usually begin puberty with thelarche around the ages of
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Table 1. Frequency of Hemoglobinopathy Genotypes and Disease Severity
Hemoglobinopathy
Genotype Frequency*
Homozygous sickle SS cell disease Sickle cell/hemoglobin SC C disease Sickle cell/bþthalassemia SA
1 in 3000
Sickle cell/bothalassemia SF
1 in 7000
Disease Severity
1 in 300
Severe
1 in 500
Mild to moderate Mild to moderate Severe
*Adapted from Serjeant et al, 1997.
8 to 13 years. Adrenarche soon follows at an average age of 11 years. Menarche usually occurs between the ages of 10 and 16.5 years, with the growth spurt reaching its maximal velocity approximately one year prior to menarche. Specifically, healthy African American females without sickle cell disease undergo thelarche, adrenarche, and menarche at the mean ages of 9.48, 9.43, and 12.06 years, respectively.3 Delayed puberty is defined as incomplete development of secondary sexual characteristics by an age greater than two standard deviations beyond the mean. Every girl who has not developed breast buds by age 13 should be evaluated for delayed puberty, and every girl who has not attained menarche by age 16 should be evaluated for primary amenorrhea. There are many etiologies of delayed puberty including constitutional delay, endocrine abnormalities, chronic illness, and idiopathic causes. A study of 74 females with pubertal delay found that 30% had constitutional delay, 26% had hypergonadotropic hypogonadism, 20% had permanent hypogonadotropic hypogonadism, 19% had functional hypogonadotropic hypogonadism, and 4% had other causes.4 Objective For years clinicians have observed differences in severity both within and between children with varying sickle cell syndromes. Considering the array of factors that influence adult size and developmental maturation of an individual, it is not surprising to find that an adolescent with sickle cell disease may display growth and pubertal delay. We will discuss the major health concerns of the pre-pubertal and pubertal adolescent with sickle cell disease, review the pertinent medical literature, and offer general management strategies for the clinician caring for the adolescent with sickle cell disease. Growth and progression of pubertal development remain paramount, while concerns regarding contraception, family planning, and preconception counseling continue to be important points of discussion. Future directions required to better understand the effect of this disease on overall adolescent health are key to clinical management.
Case Presentation K.S., a 21-year-old African American woman with sickle cell disease, presented to a gynecologic-endocrine clinic at Magee Womens Hospital, Pittsburgh, PA, for consultation regarding primary amenorrhea. She experienced thelarche at age 14 years and adrenarche at age 17 years. She denied a history of sexual activity or prior evaluation for amenorrhea. She denied a family history of sickle cell disease, delayed puberty, and any other endocrinologic diseases. K.S. had severe sickle cell disease, requiring 6 to 7 hospitalizations annually for the past 7 years. She had a mediport placed 7 years prior for chronic blood transfusions, and IV narcotic pain control. The mediport was removed one year ago when a decrease in pain crisis frequency and hemolysis episodes obviated the need for continued chronic blood transfusions. Her baseline hemoglobin is 9.5 g/dL and her last blood transfusion was approximately one year prior to presentation. Her physical exam revealed a tall, thin woman at 5’8’’ and 123 lbs. She appeared much younger than her stated age. Her general exam was otherwise unremarkable except for Tanner stage 3 for breasts and pubic hair distribution. Pertinent negative findings included no thyromegaly, hirsutism, acne, acanthosis nigricans, or clitoromegaly. Her pelvic exam was normal with a perforate hymen and no vaginal septum. A urine pregnancy test was negative, and transvaginal ultrasound revealed an anteverted uterus with normal appearing bilateral ovaries. (See Table 2 for lab values.) Review of records from a previous evaluation for primary amenorrhea at 18.5 years of age revealed Tanner stage (3-breast, 2-pubic hair), bone age of 16 years, normal karyotype, and pre-pubertal levels of FH, LH, and estradiol. The differential diagnosis for primary amenorrhea is extensive (Figure 1).5 In the case of K.S., her Table 2. Laboratory Results Obtained During the Initial Workup for K.S. Lab Test
Test result
TSH Prolactin LH FSH Estradiol Hemoglobin Hematocrit MCV RDW
1.74 3.6 7.3 7.8 !20 8.8 25.1 90.0 18.9
Normal Range 0.35e5.50 mIU/mL 3.3e26.7 ng/mL *1.0e5.9 mIU/mL *1.2e7.8 mIU/mL *10e50 pg/mL 11.6e14.6 g/dL 34.1e43.3% 82.6e97.4 fl 11.5e15.0%
TSH5thyroid stimulating hormone, LH5luteinizing hormone, FSH5follicular stimulating hormone, MCV5 mean corpuscular volume, RDW5red cell distribution width. *Normal values for pre-pubertal children.
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Fig. 1. Differential Diagnosis of Primary Amenorrhea (Adapted from Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology, (5th ed.). Philadelphia, Lippincott Williams and Wilkins, 2005.)
primary amenorrhea is due to functional hypothalamic amenorrhea as evidenced by the interruption of pubertal development (at Tanner stage 3) in conjunction with normal pelvic anatomy to pre-pubertal range gonadotropins and estradiol levels and an incongruent bone age for Tanner stage (per old records). Health Concerns for the Pre-pubertal Adolescent with Sickle Cell Disease Growth and Puberty Two major health concerns for adolescents with sickle cell disease are growth and puberty, delays in both of which have been well documented in the literature since the 1960s. Growth is delayed in children with various sickle cell syndromes with those adolescents with sickle cell disease and sickle cell/bo-thalassemia being the most significantly delayed.6e9 Weight is more affected than height,7e10 with delays becoming significant in children with sickle cell disease after 7 years of age,2,11 and peaking in the adolescent years8,11 coincident with the expected onset of pubertal development. Though sexual maturation usually progresses in an orderly fashion, it is significantly
delayed (by an average of approximately two years) in the adolescent with sickle cell disease.7e10,12e14 Conclusions regarding the etiology of growth and pubertal delay in this patient population remain mixed (see Table 3). Although authors agree that the disease’s effects on development are multi-factorial, constitutional delay secondary to nutritional deficiencies and negative energy balance has been assumed to be the main contributors to pubertal delay.9,14,15 However, there is data that implicates alterations in the hypothalamic-pituitary-end organ system as the primary cause of growth and developmental delay,11,16e18 or that extreme cases of pubertal delay are likely of an endocrinologic etiology10 with possible alterations in the hypothalamic-pituitary-ovarian axis. Conflicting Conclusions Regarding the Etiology of Delayed Growth and Puberty Energy Versus Endocrine Debate One of the largest studies on development and sickle cell disease is the Cooperative Study of Sickle Cell Disease, in which 2115 participants aged 2 to 25 years with different hemoglobinopathies were identified from fifteen US clinical centers.7 Each participant’s
Reference
Study Type, location 6
N
Age range (yr)
Hgb geno-type
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Table 3. A Comparison of Selected Publications on Growth and Pubertal Delay in Adolescents with Sickle Cell Disease
Conclusions
Comments Argue for constitutional cause based on normal configuration of growth and maturation curves. No hormonal or bone age analysis SS-specific growth curves are indicated No analysis of etiology (Authors propose multi-factorial cause)
CSSC* US
1056 (f) 1008 (m)
2e25
All types
Howard University norms for AA children
For both sexes and all Hgbopathies growth and maturation curves were significantly different from norms
Platt et al, 20007
longitudinal cohort study Jamaica
315
0e19
SS
NCHS norms
Thomas et al, 20018
longitudinal cohort study West Indies
268
0e26.5
SS (99), SC (69)
age and sex-matched, AA (100)
Growth in HgbSS boys and girls is similar to norms at birth, shows maximal lag at 10e15 years, and begins to catch up by age 18 Age at menarche is delayed by 0.5 years in SC, and 2.5 years in SS
Serjeant, 19829
longitudinal cohort study US
29 (f) 26 (m)
13e18
SS
NCHS norms
Boys & girls with Hgb SS have subnormal heights & weights and delayed sexual & skeletal maturation
Luban et al, 198410
longitudinal cohort study US
133
1e18
SS(83)All variant types (50)
NCHS norms
Phebus et al, 198611
cohort study Nigeria
2466 (f)
10e19
SS(32)
age-matched, AA & AS (2207)
Impairment in height & weight increases with age and is more pronounced in boys Age at menarche is significantly delayed in pts with Hgb SS
Modebe, 199912
cross-sectional and longitudinal cohort study Egypt
110
2e10
SS
age and sex-matched controls (200) also children with constitutional delay (30) or GH deficiency (25)
Wethers, 1984
Linear growth, growth velocity and pubertal maturation are significantly delayed in children with SS
Multi-regression analysis shows weight is dominant factor in determining age at menarche for all Hgb genotypes Authors argue against endocrine cause, but no bone age or hormonal analysis Tanner stage was appropriate for bone age (constitutional) for most children, except for those with extreme pubertal delay (suggests endocrine cause) Etiology unknown, likely multi-factorial
Argue for abnormalH-P-O axis (endocrine cause) Data obtained by questionnaire Likely multi-factorial
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Control group
cross sectional study France
8
10e12
SS
age and sex-matched controls (7)
Children with SS have evidence of excess protein, energy, and glutamine metabolism
Leonard et al, 199515
Retrospective chart review Jamaica
19 (f) 13 (m)
1e11
SS
Each patient served as their own control
Singhal et al, 199516
longitudinal cohort study Brazil
20 (f) 21(m)
2e15
SS
age and sex-matched controls (41)
Splenectomy for hypersplenism in pts with SS leads to a significant increase in height, but not weight, velocity In contrast, hx undernourished controls show an increase in both parameters after nutritional supplementation Growth velocity and z-score for growth velocity do not correlate with any element of IGF axis
Luporini et al, 199217
cross-sectionalstudy Saudi Arabia
80 (f) 80 (m)
4e50
SS
age and sex-matched controls (60)
Pts with SS show varying levels of gonadal hypofunction, abnormalities of LH, FSH, testosterone, and cortisol correlated disease severity
Suggest that hypermetabolism is etiology of pubertal and growth delays (Constitutional), but study not designed to look at this relationship Argue that accelerated linear growth is not simply due to general nutritional improvement (argue against constitutional cause) Hypothesize specific nutrient deficiency (i.e. zinc), but do not consider endocrine role
Argue against protein-caloric malnutrition as etiology of growth and pubertal delay (against constitutional delay) Hypothesize etiology is from ‘‘intrinsic factors’’ of the disease, but do not specifically propose endocrine role Several endocrine abnormalities exist (majority hypothalamic hypogonadism) Do not exclude contribution of other factors (multi-factorial)
GH5Growth hormone, IGF5 insulin like growth factor, LH5lutenizing hormoneFSH5 follicle stimulating hormone, (f)5female, (m)5male, SS5homozygous Hgb S. *Cooperative Study of Sickle Cell disease identified patients from 15 US clinical centers between 1979-1981, cross sectional data was then used for detailed data analysis.
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Soliman et al, 199613
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height, weight, and sexual maturation according to the staging system described by Tanner19 were recorded. Growth and maturation curves for each of the hemoglobinopathies demonstrated a normal configuration but with delays in growth when compared to published norms for African Americans. The author concluded that the delayed development in those with sickle cell disease represented a constitutional delay because these adolescents proceeded through puberty in an orderly progression, albeit later than their healthy peers. As developmental delay cannot always be explained by constitutional delay, other authors have explored endocrinologic etiologies. Olambiwonnu et al20 studied the growth and development of adolescents with sickle cell disease, specifically exploring the endocrinology of sexual development. Gonadotropin levels, bone age (using the Gruelich and Pyle standards21), Tanner staging, and anthropomorphic data were collected from forty children with sickle cell disease. LH concentrations were noted to be significantly higher for Tanner stage, but not for age, in the sickle cell group when compared to normal African American controls. No conclusion could be drawn from the FSH concentrations, because a poor control group was used. The authors conclude that children with sickle cell disease exhibit impaired gonadal function, as reflected by the elevation in LH levels. Likewise, they attribute the delay in bone age between the ages of 12 and 19.5 years to sex steroid deficiency, as delayed gonadal function results in delayed epiphyseal maturation. These findings, coupled with the observation of subnormal heights in children with sickle cell disease by age 7 years,7 with ultimately normal adult heights,8 led the author to conclude that the growth failure for most such children is due to a transient gonadal dysfunction and possibly even the absence of a growth spurt. These findings are in contrast to the pattern of constitutional delay, where gonadotropin levels are congruent with stage of sexual development and often low for age.22 True constitutional delay is the result of variability in the rate of maturation of the hypothalamic-pituitary-gonadal axis, while gonadal function remains intact. Further Evidence in Support of Negative Energy Balance Various data implicate a negative energy balance and/ or nutritional deficiency as the etiology of developmental delay. Salman et al14 showed that children with sickle cell disease are hypermetabolic with regard to protein, energy, and glutamine utilization, which correlates with the increased erythropoesis and cardiac workload these children demonstrate. A report by Wang et al23 demonstrated that children with sickle cell disease randomized to long-term
transfusion/chelation therapy showed significant improvement in growth when compared to the standard care group. Furthermore, chronic inflammation, malabsorbtion, anorexia, and disease severity exacerbate the negative energy balance and nutritional deficiencies in sickle cell patients. Further Evidence in Support of an Endocrine Cause Other studies argue either against a general negative energy balance16 or in favor of a primary endocrine cause17,18 for the developmental and growth delays observed. The Jamaican cohort study (Singhal et al) demonstrated that those with sickle cell disease who had a splenectomy for hypersplenism showed significant improvements in hematological indices, disease severity, and height velocity, but not in weight velocity, when compared to those with sickle cell disease who did not have a splenectomy. This is in contrast to the effect of nutritional supplementation seen in severely malnourished children, in whom an increase in weight velocity precedes an increase in height velocity, suggesting that the accelerated linear growth is not simply a consequence of a general improvement in nutritional status. The fall in body mass index observed in the first six post-operative months is consistent with this observation and argues against a general energy deficiency as the cause for the absence of a growth spurt. El-Hazmi et al18 showed that gonadal hypofunction was present in females with sickle cell disease aged 4e50 years, and that the variability of hypofunction observed correlated with disease severity. Study Limitations Small sample sizes, poorly selected control groups, and factors related to study design lead to inaccuracies when generalizing this data to all adolescents with sickle cell disease. For example in Platt’s study,7 caution should be exercised in claiming that constitutional delay is the cause for their findings, as conclusions on the progression of adolescent growth and development are best made by longitudinal rather than cross sectional data. The absence of measurements for bone age and hormonal function likewise weaken the argument that constitutional delay was the etiological factor in the growth delays observed. Failure to simultaneously assess growth parameters with Tanner staging, menarcheal status, bone age, and hormone levels, results in the lack of important information regarding the effects of the endocrine system on growth, as well as the possible effects of nutritional deficiencies and energy imbalance on pubertal development. Just as the sickle cell syndromes have varying degrees of severity, it is likely that the etiologies of developmental delay also fall into a wide spectrum.
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Soliman et al13 argued for a multi-factorial cause and other studies have shown multiple factors contributing to delay. Luban et al10 in a longitudinal study of 26 boys and 29 girls with sickle cell disease noted an intact hypothalamic-pituitary axis in his cohort of subjects, with notably lower than expected gonadal end organ hormones in a minority of subjects (n 5 4). These participants demonstrated severe maturational abnormalities in both linear growth and pubertal development, hence demonstrating the obvious impact of the sex steroids in normal pubertal development and linear growth in adolescence, but not necessarily in final adult height. Likwise, Singhal et al24 reported extreme retardation of adolescent growth and development to be a harbinger of an endocrine cause. General Management Considerations Importance of Early Detection The necessity for early detection of superimposed problems of growth and pubertal development is obvious; however, the practicality of how to accomplish this remains. Singhal et al8 generated sex specific height and weight references curves for children with homozygous sickle cell disease. When compared to the standards of healthy children from the National Center for Health Statistics (NCHS) they found that while both groups exhibited similar heights and weights at birth, those with sickle cell disease quickly fell off the normative curve. Those with sickle cell disease exhibited a maximum lag at 10e15 years of age, but by age 18 years, female adolescents had caught up with NCHS standards while boys were still in the catch-up phase of growth because they were still significantly shorter than NCHS standards at 18 years of age. As growth is often delayed in children with sickle cell disease compared to children with a normal hemoglobin genotype, the authors argue that superimposed growth problems can be hard to detect without the generation of such reference curves. These researchers believe that it is not appropriate to use US standard growth charts for normal children to identify impaired growth in children with sickle cell disease. Disease-specific reference growth curves can serve as a tool to assist the clinician in the early detection of superimposed growth problems in the adolescent with sickle cell disease such as those due to suboptimal nutrition, chronic hypersplenism, and even endocrine abnormalities. The precedence for using disease specific growth charts has been similarly established for children with a genetic predisposition to growth and pubertal delay, such as Turner sydrome25 and Down syndrome. Although this study was fairly large (n ~ 100), many participants were lost to follow-up after
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reaching 14 years of age, reducing the precision of the conclusions drawn about these later ages. This is reflected by the ‘‘catch-up growth‘‘ observed in female subjects who eventually attained normal final adult heights; a finding not consistently reported in the medical literature.11 The fact that the children included in this study were selected at birth, however, reduces the selection bias often seen when studies are conducted from sickle cell disease centers, which often provide medical support to the more severely affected children and adolescents with sickle cell disease. Unfortunately, no such reference curves were derived for pubertal maturation. The lack of reference curves for Tanner staging in the adolescents with sickle cell disease can still lead to a delay in the diagnosis of superimposed problems as illustrated in our case of a 21-year-old with primary amenorrhea. Nutritional Supplements Although there are multiple theoretical benefits, there is very little data supporting the use of nutritional supplements in women, children, or adolescents with sickle cell disease and delayed development. However, several investigators have pointed to specific nutrient deficiencies that may be related to growth retardation such as zinc, folate, and vitamins A, B6, C, and E.6 A recent randomized-controlled study of zinc supplementation in children aged 4 to 10 years with sickle cell disease found that daily zinc was associated with increased linear growth.26 A similar randomized-controlled trial in adolescents aged 14e17 years found that those who received zinc had increased height, weight, and testosterone levels,21 consistent with the another study by Abassi et al.27 Other studies have implicated decreased folate levels as one of the etiologies of growth delay. However, a doubleblinded controlled trial in children with sickle cell disease, aged 6 months to 4 years, revealed no significant difference in height or weight among those who received supplementation and those who did not.28 Chronic Transfusions Aside from nutritional adjustments, it has been postulated that correction of anemia with blood transfusions might improve growth and development by decreasing energy expenditure. A recent study evaluated children aged 2e16 years who were either treated with chronic transfusions every 3e5 weeks or with standard of care. While both groups started at similar baselines, the children who were chronically transfused had significantly increased heightfor-age and weight-for-age when compared to those treated with standard of care.24 There are increased risks with blood transfusions such as infection, alloimmunization, and iron overload which must be considered. Therefore this management should be
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coordinated by an experienced hematologist or sickle cell specialist. Hormonal Management Historically, oral contraceptive use was avoided in adolescent and young adult women with sickle cell disease due to concerns about the possibility of a synergistic effect of the oral contraceptive pill on either red cell deformability or the blood-clotting mechanisms. Two prospective observational studies by Yoong et al29,30 examined red cell deformity and laboratory markers of platelet activation, thrombin generation, and fibrinolysis in women with sickle cell disease. Neither study showed a significant difference in the parameters measured among women with sickle cell disease taking combined oral contraceptives (COC), progestin-only contraceptives, or non-hormonal contraceptives. Other studies have shown that COC use, even up to 54 months, did not increase sickle cell crises or thrombotic events in comparison to a control group of sickle cell disease non-COC users and normal COC users respectively.31 Sickle cell disease is not considered a contraindication to COC use, whereas the medical sequelae of sickle cell disease, such as cerebral vascular accidents, serve as absolute contraindications to COC use.32 Some would argue that the mechanism of stroke in sickle cell disease is due to ischemia from sickling, and not thrombosis as seen in non-sickle cell disease patients, and thus do not consider this a contraindication to COC use. There are numerous non-contraceptive benefits from hormone use in this population. For example, estrogen use in the woman with sickle cell disease with functional hypothalamic amenorrhea, as in our case, may have the advantage of completing breast development and preventing the future risk of osteoporosis. Furthermore, a young woman may experience multiple psychological benefits from menstruating and developing like her peers. (COC use might also decrease anemia among women with SS disease who menstruate) There is also a relationship between DepoProvera use and a lower incidence of sickle crisis resulting from red blood cell membrane stabilization with less sickling.33,34 Case Resolution Overall therapy, hormonal or otherwise, should be individualized such that treatment is specific to the etiology of the growth and/or pubertal delay. For example, the case of K.S. clearly demonstrates evidence of functional hypothalamic amenorrhea, as she had normal height with delayed Tanner staging, primary amenorrhea, and a hormonal picture consistent with estrogen and relative gonadotropin deficiency. K.S.’s main concern was her incomplete breast development and lack of menarche. Other concerns are
the sequelae of oligo-ovulation including unplanned pregnancy and future osteoporosis. Due to this, initial estrogen followed sequentially by progestin was the best overall treatment for K.S. Sex hormone replacement therapy is intended to mimic physiologic puberty, enhance normal growth, induce and maintain normal menstruation, as well as support normal bone maturation and calcification. There is still controversy regarding the best hormone replacement therapy for girls with hypogonadism. Standard optimal therapy begins at very low doses (2 mcg/day of ethinyl estradiol) for 6 months followed by a progressive increased in dose by 2 mcg/day every 6 months to a total of 6 mcg/day. This dose escalation is meant to prevent nausea and improve compliance, while also allowing the completion of breast development in addition to increases in linear height.35 The main reason for starting ethinyl estradiol in a low dose is to stimulate growth hormone (GH) secretion, because higher doses typically lead to GH suppression. This low dose of ethinyl estradiol is followed by higher estrogen doses with 5 mcg/day increases every 6 months to a total of 20 mcg/day. Thereafter, adding in progestin with a low dose COC can be initiated.35,36 Specifically, K.S. was started on conjugated estrogens 0.625mg once a day for 3 months, because she had already shown evidence of pubertal development and had achieved a normal adult height. This will be followed by an increase in dose to 1.25 mg once daily for a 6 month interval and it will be given at bedtime to reduce nausea. K.S. was counseled that this regimen will not prevent spontaneous ovulation, and so, if she were to become sexually active she would require further contraception. Thereafter, she will be transitioned to a lower dose COC (any regimen with 20e35 mcg of ethinyl estradiol and a progestin will suffice and the choice is usually based on insurance and cost). Additionally, a baseline dual energy X-ray absorptiometry (also known as a DEXA or bone scan) will be obtained to evaluate for osteoporosis or osteopenia as will serial scans, at 2-year intervals, to follow K.S.’s response to the initiation of estrogens. Post-pubertal Health Concerns Female adolescents with sickle cell disease who have successfully completed puberty have other health concerns. With regard to family planning, issues such as contraception and preconception counseling often arise. Medroxyprogesterone acetate (MDPA) has been purported to be the ideal contraceptive method for females with sickle cell disease.33,34 This is based on the observed reduction in both vaginal bleeding and the number of pain crises in women on MDPA.33,34 Likewise, low dose combined hormonal contraception, and progestin-only methods like the levonorgestrel intrauterine system and subdermal implant (Implanon) may be safer options than pregnancy
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given the increased risk of fetal, neonatal, and maternal morbidity and mortality of pregnancy among adolescents with sickle cell disease. In addition to educating adolescent and young women with sickle cell disease about the inherent risks associated with pregnancy, these young women must also be prepared for the social and psychological challenges that may arise when a mother with a chronic illness raises a family. Further, health care providers should discuss the options of partner screening and prenatal diagnosis with all females with sickle cell disease who are of reproductive age. Due to advances in the management of individuals with sickle cell disease, issues related to infertility will likely become a concern, as more women are surviving into adulthood and attempting to conceive. Future Directions U.S. growth and development curves for healthy children are not applicable to the adolescent with sickle cell disease, leading to the establishment of unique growth curves for this population.8 Standardized curves for pubertal maturation have not been developed but are needed to identify abnormalities at an earlier age and to expedite treatment of potential endocrine causes. Assistance in the transition from pediatric to adult care is also critical. Studies indicate that patients leave pediatric care without adequate preparation, and are transferred to the adult clinician based solely on age or pregnancy status.37 However, the patient’s readiness to transfer is not taken into consideration, leading to a loss of follow-up or increased emergency room visits once patients leave pediatric care.37 Thus, a structured approach is essential to promote optimum stability in adolescent care for the patient with sickle cell disease. A therapeutic environment should educate the adolescent on her disease process, aid her in developing life skills to effectively manage her health, and assist in a smooth transition to adult care by integrating health care and social networks such as family, school, work, the community and other health care providers. References 1. Sickle Cell Disease Guideline Panel: Sickle cell disease: screening, diagnosis, management, and counseling in newborns and infants. Clinical Practice Guideline No 6. AHCPR Pub. No. 93-0562. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services. April 1993 2. Serjeant G: Sickle-cell disease. Lancet 1997; 350:725 3. Slyper A: The pubertal timing controversy in the USA, and a review of possible causative factors for the advance in timing of onset of puberty. Clin Endocrinol 2006; 65:1 4. Sedlmeyer I, Palmert M: Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab 2002; 87:1613
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5. Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology, (5th ed.). Philadelphia, Lippincott Williams and Wilkins, 2005 6. Wethers D, Ann NY Acad Sci: Delayed growth and sexual maturation in sickle cell disease 1989; 565:137 7. Platt O, Rosenstock W, Espeland M: Influence of sickle hemoglobinopathies on growth and development. N Engl J Med 1984; 311:7 8. Thomas P, Singhal A, Hemmings-Kelly M, et al: Height and weight reference curves for homozygous sickle cell disease. Arch Dis Child 2000; 82:204 9. Serjeant G, Singhal A, Hambleton I: Sickle cell disease and age at menarche in Jamaican girls: Observations from a cohort study. Arch Dis Child 2001; 85:375 10. Luban N, Leikin S, August GA: Growth and development in sickle cell anemia. Preliminary report. Am J Pediatr Hematol Oncol 1982; 4:61 11. Phebus C, Gloninger M, Maciak B: Growth patterns by age and sex in children with sickle cell disease. J Pediatr 1984; 105:29 12. Modebe O: The effect of homozygous sickle cell disease on the age of menarche in Nigerian schoolgirls. Ann Hum Biol 1987; 14:181 13. Soliman A, elZalabany M, Amer M, et al: Growth and pubertal development in transfusion-dependent children and adolescents with thalassemia major and sickle cell disease: A comparative study. J Trop Pediatr 1999; 45:23 14. Salman E, Haymond M, Bayne E, et al: Protein and energy metabolism in prepubertal children with sickle cell anemia. Pediatr Res 1996; 40:34 15. Leonard M, Zemel B, Kawchak D, et al: Plasma zinc status, growth, and maturation in children with sickle cell disease. J Pediatr 1998; 132:467 16. Singhal A, Thomas P, Kearney T, et al: Acceleration in linear growth after splenectomy for hypersplenism in homozygous sickle cell disease. Arch Dis Child 1995; 72:227 17. Luporini S, Bendit I, Manhani R, et al: Growth hormone and insulin-like growth factor 1 Axis and growth of children with different sickle cell anemia haplotypes. J Pediatr Hematol Oncol 2001; 23:357 18. El-Hazmi M, Bahakim H: Al-Fawaz I: Endocrine functions in sickle cell anaemia patients. J Trop Pediatr 1992; 38:307 19. Tanner, et al: Growth and endocrinology of the adolescent. In: Gardner LI, editor. Endocrine and Genetic Diseases of Childhood. Philadelphia, WB Saunders, 1969, pp 19e60 20. Olambiwonnu O, Penny R, Frasier S: Sexual maturation in subjects with sickle cell anemia: Studies of serum gonadotropin concentration, height, weight, and skeletal age. J Pediatr 1975; 87:459 21. Gruelich WW, Pyle IS, editors. A Roentgenological Atlas of Skeletal Maturation of the Hand and Wrist, (2nd ed.). Stanford, Stanford University Press, 1959 22. Penny R, Guyda H, Baghdassarian A, et al: Correlation of serum follicular-stimulating hormone and luteinizing hormone as measures by radioimmunoassay in disorders of sexual development. J Clin Invest 1847; 1970:49 23. Wang W, Morales K, Scher C, et al: STOP Investigators. Effect of long term transfusion on growth in children with sickle cell anemia: Results of the stop trial. J Pediatr 2005; 147:244
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24. Singhal A, Gabay L, Serjeant G: Testosterone deficiency and extreme retardation of puberty in homozygous sickle cell disease. West Indian Med J 1995; 44:20 25. Gawlik A, Gawlik T, Augustyn M, et al: Validation of growth charts for girls with Turner syndrome. Int J Clin Pract 2006; 60:150 26. Zemel B, Kawchak D, Fung E, et al: Effect of zinc supplementation on growth and body composition in children with sickle cell disease. Am J Clin Nutr 2002; 75:300 27. Abbasi A, Prasad A, Ortega J, et al: Gonadal function abnormalities in sickle cell anemia: Studies in adult male patients. Ann Intern Med 1976; 85:601 28. Rabb L, Grandison Y, Mason K, et al: A trial of folate supplementation in children with homozygous sickle cell disease. Br J Haematol 1983; 54:589 29. Yoong W, Tuck S, Yardumian A: Red cell deformability in oral contraceptive pill users with sickle cell anaemia. Br J Haematol 1999; 104:868 30. Yoong W, Tuck S, Pasi K, et al: Markers of platelet activation, thrombin generation, and fibrinolysis in women with
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sickle cell disease: effects of differing forms of hormonal contraception. Eur J Haematol 2003; 70:310 Carlone J, Keen P: Oral contraceptive use in women with chronic medical conditions. Nurse Pract 1989; 14:9 WHO medical eligibility criteria for contraceptive use, (3rd ed.). World Health Organization, 2004 de Abood M, de Castillo Z, Guerrero F, et al: Effect of Depo-Provera or Microgynon on painful crises of sickle cell anemia patients. Contraception 1997; 56:313 De Ceulaer K, Gruber C, Hayes R, et al: Medroxyprogesterone acetate and homozygous sickle-cell disease. Lancet 1982; 2:229 Spiliotis B: Growth and long-term hormone therapy. Pediatr Endocrinol Rev 2006; 1(3 Suppl):192 Rubin K: Hypogonadism in adolescent females: New insights and rationale supporting the use of physiologic regimens to induce puberty. Pediatr Endocrinol Rev 2005; 2:645 Wojciechowski E, Hurtig A, Dorn L: A natural history study of adolescents and young adults with sickle cell disease as they transfer to adult care: A need for case management services. J Pediatr Nurs 2002; 17:18