- Email: [email protected]
Evaluation and Treatment of Menorrhagia in an Adolescent Population
Evaluation and Treatment of Menorrhagia in an Adolescent Population Gary N. Frishman, MD* From the Department of Obstetrics and Gynecology, Women and Infants’ Hospital, Brown Medical School, Providence, Rhode Island.
ABSTRACT Bleeding in adolescence is a common but, potentially, difficult condition to manage. Adolescents present with unique issues related to their age, involvement of family members, different differential diagnosis when compared to an older populations, and challenges associated with their evaluation and treatment. Journal of Minimally Invasive Gynecology (2008) 15, 682–688 Ó 2008 AAGL. All rights reserved. Keywords:
Menorrhagia; Dysfunctional uterine bleeding; Adolescent; Teenager
Bleeding in adolescence is a common but, potentially, difficult condition to manage. A questionnaire-based study of more than 1000 Swedish students (average age 16.7 years) revealed that 73% experienced at least 1 bleeding-related symptom and 37% reported heavy menstruation [1]. A total of 12.5% underwent medical treatment that included (given the European location) tranexamic acid and desmopressin in addition to oral contraceptives and progestins. Menorrhagia is defined as a menstrual blood loss of more than 80 mL [2]. However, menstrual flow is difficult to quantify especially for a teenager who may be less aware of her own body, frightened by her bleeding, or both. Furthermore, most diagnostic criteria and treatment algorithms were investigated in adults and not validated in adolescents. Adolescents bring their own distinct challenges such as the difficulty in performing an adequate physical examination without anesthesia, the potential for an incomplete history, and the possible impact of a family member being present on accuracy of the history. Furthermore, a significant percentage of menstrual bleeding in adolescents is anovulatory to start out with and full maturation of the hypothalamic-pituitary-ovarian axis typically takes up to 5 years after the start of menstruation [3]. In adolescent girls with late-onset menarche, it may take up to 12 years until they are fully ovulatory [4]. The author has no commercial, proprietary, or financial interest in the products or companies described in this article. Corresponding author: Gary N. Frishman, MD, Department of Obstetrics and Gynecology, Women and Infants’ Hospital, Brown Medical School, 101 Dudley Street, Providence, RI 02905. E-mail: [email protected] Submitted May 27, 2008. Accepted for publication August 23, 2008. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2008 AAGL. All rights reserved. doi:10.1016/j.jmig.2008.08.014
When considering their evaluation and treatment, adolescents may perceive more of an urgent need for immediate results with less of a long-term perspective compared with an older population. As such, it is critical to counsel the patient (and her family) that finding the right treatment for lasting success may take time but emphasize that if both you and they are patient, a successful outcome is almost always the result. Although some practitioners consider adolescents with abnormal bleeding to be at especially high risk of a bleeding disorder, data suggest a similar yield as in older and perimenopausal women [5]. Regardless, adolescents with Pictorial Blood Assessment Chart–documented menorrhagia were shown to perceive that their heavy flow adversely affects their quality of life [6]. Definition and Terminology A lack of agreement exists about terminology used in the description of uterine bleeding [7]. For the purposes of this review, abnormal uterine bleeding (AUB) refers to perceived abnormal or excessive menstrual or nonmenstrual blood loss. Dysfunctional uterine bleeding is a subset of AUB and consists of ovulatory bleeding that is prolonged, excessive bleeding without a pattern or any organic cause. In adolescents, anovulation accounts for 95% of all AUB [8]. Evaluation As noted earlier, obtaining a history from an adolescent may be difficult. If possible, obtain a history both with and without a parent present. Establish ground rules with all family members present about confidentiality and that you will respect the patient’s privacy. If the patient is very anxious
Frishman.
Treatment of adolescent menorrhagia
but stable, consider not performing a physical examination on the first visit or having the patient choose whether or which family member accompanies her into the room. Although no literature specifically addresses whether an adolescent would prefer a female physician for her history taking or examination, when possible, it may be worthwhile to give the patient the option of having a female practitioner obtain the history and perform the pelvic examination even if she is not going to provide the follow-up care. In a similar fashion, despite the lack of any data focusing on religious, social, or cultural mores or beliefs in this population, it logically follows to be aware and respectful of these differences and preferences as with any patient population. Anovulation is the major cause of AUB in adolescence. Although an irregular menstrual pattern usually results from anovulation and is less likely to result from a bleading disorder, it is still important to consider ruling out other causes. Serial progesterone levels or BBTs are effective, easy, and safe but typically not clinically feasible in this population. Heavy bleeding with regular cycles (menorrhagia) should lead to a thorough history, which is critical to increase the suspicion for a bleeding disorder. A significant history of easy bruising, bleeding after surgery or dental work, bleeding from the gums after brushing one’s teeth, or a positive family history should result in an extended bleeding disorder evaluation. The specificity of these findings can be strengthened by establishing whether the bruising is typically greater than 5 cm and whether medical attention was required for any bleeding from a mucous membrane. When taking a family history, in addition to asking about known bleeding disorders or bleeding associated with surgery or childbirth, it may be useful to specifically ask whether any history exists of menstrual problems that required intervention in female relatives. Despite the importance of taking this history, the presence of a family history of a bleeding susceptibility or a personal history of easy bruising is neither highly specific nor sensitive, so clinical judgment is still necessary [9]. More specific historical information includes the onset of significant menorrhagia with the start of menstruation as the chance of a bleeding disorder is greatly increased in this case [10]. In addition, menorrhagia associated with a bleeding disorder is less likely to respond to traditional hormonal medical treatment such as combined hormonal oral contraceptives or progesterone-only pills [11]. It is important to be aware that high (supraphysiologic) estrogen levels may alter hematologic factors, thus potentially resulting in a false-negative finding in a bleeding disorder evaluation. Von Willebrand disease is the single most common medical disorder associated with menorrhagia at the onset of menstruation [12]. Von Willebrand disease is present in roughly 15% of ovulatory bleeding in women of all ages. Approximately 80% of women with von Willebrand disease develop menorrhagia with up to 18% undergoing a surgical treatment during their lifetime for this [11]. It is not clear whether these data apply to all AUB. Of note, if a patient is determined to have a bleeding disorder that may be inherited,
683
consideration should be given to evaluating her family members. Adolescents may be taking oral contraceptives with or without their parents’ knowledge or be taking their mother’s or friend’s hormonal preparations. However, even if taken sporadically, this is an unlikely cause of heavy bleeding and very unlikely to result in multiple significant bleeding episodes. In a similar fashion, one should obtain a history concerning herbal agents or drug intake. Obtaining a menstrual and sexual activity history may be very difficult and adolescent pregnancy should always be considered as a cause of bleeding [13]. Approximately 46% of 15- to 19-year-olds in the United States have had coitus at least once with this number approaching 70% by age 19 years [14]. Although an unlikely cause of significant, much less repetitive bleeding, sexually transmitted diseases are quite common in young girls with up to 40% of sexually active adolescents being infected with human papillomavirus [15]. An adolescent’s first sexual encounter may be involuntary and, independent of this, they may be more prone to intercourse-related trauma or accidental injuries to the vagina and cervix. For 10% of women aged 18 to 24 years who had sex before age 20 years, their first intercourse was involuntary [14]. This percentage increases as the age of first intercourse decreases. Because this is likely a more physically and emotionally traumatic event, the relationship of sexual activity and the events surrounding it on both a adolescent’s bleeding and willingness to provide a history should be taken into account. Their lack of familiarity with tampon use may contribute to an injury. Although uncommon, consider gastrointestinal or rectal bleeding sources (e.g., hemorrhoids, polyps, inflammatory bowel disease). An eating disorder may lead to gastrointestinal bleeding via the use of laxatives or purging and/or result in abnormal vitamin and dietary intake leading to altered coagulation status. Table 1 shows the more common causes of AUB. As noted earlier, the presence of an adult family member in the room may influence the patient’s mannerisms and how she relates her history. Family dynamics should be observed to assess, for instance, the level of support and whether the patient appears to be attention seeking. In addition, the practitioner should attempt to speak to the patient alone to obtain additional history and observe her affect and motivation while not in the presence of a family member. The causes of abnormal uterine bleeding are listed in Table 1. Physical Examination The physical examination may be challenging in a fearful adolescent girl. In addition to vital signs, orthostatic vital signs should be considered. Body mass index should be calculated. Evidence of a bleeding disorder at other sites should be investigated including petechial hemorrhages and ecchymosis. Tanner staging of the breast and pubic hair may provide information about how far the patient has progressed through
684
Journal of Minimally Invasive Gynecology, Vol 15, No 6, November/December 2008
Table 1
Table 2
Causes of abnormal uterine bleeding
Treatment algorithm for abnormal uterine bleeding
Bleeding disorders Von Willebrand disease Idiopathic thrombocytopenic purpura Factor XI deficiency Thrombocytopenia Leukemia Pregnancy related Abortion (incomplete, complete, threatened) Ectopic pregnancy Trophoblastic disease Infections Endometritis Cervicitis Endocrinopathies PCOS CAH Androgen- or estrogen-secreting tumor Thyroid disease Trauma Uterine abnormalities Myomas Polyps Congenital anomalies Reproductive tract malignancy Anovulation endometrial hyperplasia Exogenous drugs or hormones Nongynecologic causes Factitious Gastrointestinal (e.g., hemorrhoids, IBD)
No significant anemia (Hgb .13 g/dL) Reassurance and education Consider familial issues and/or gain-seeking behavior Menstrual diary Perimenstrual nonsteroidal anti-inflammatory drugs Iron and vitamin supplementation as needed Oral contraceptives (continuous or cyclic), note: done for patient’s symptoms rather than signs Moderate anemia (Hgb 9–13 g/dL) Oral contraceptives (continuous or cyclic) Consider cascade protocol followed by traditional course Levonorgestrel-releasing intrauterine device if appropriate Cyclic progesterone treatment (medroxyprogesterone acetate 10 mg/day for 14 days every 3 months or Depo-Provera (Pfizer, New York, NY) 150 mg every 3 months) Must be willing to accept breakthrough bleeding and not be at risk for significant depression Iron and vitamin supplementation as needed Treat underlying cause (e.g., anovulation may respond to weight loss, remove any structural lesion) Significant anemia (Hgb,9 g/dL) Short-term treatment Stabilize patient with, e.g., IV fluids, transfusion as indicated IV conjugated equine estrogens (25 mg every 4 hours) as indicated Oral contraceptives cascade protocol followed by traditional course Surgical intervention with D and C if not responsive to other measures Consider trial of DDAVP Consider placement of Foley balloon or other catheter to tamponade Long-term treatment Levonorgestrel-releasing intrauterine device if appropriate GnRH agonist (Lupron Depot (TAP Pharmaceuticals Inc., Lake Forest, IL) 3.75 mg once a month) with calcium supplementation and add-back therapy as indicated Cyclic progesterone treatment (medroxyprogesterone acetate 10 mg/day for 14 days ever 3 months or Depo-Provera 150 mg every 3 months) Must be willing to accept breakthrough bleeding and not be at risk for significant depression Iron and vitamin supplementation as needed Treat underlying cause (e.g., anovulation may respond to weight loss, remove any structural lesion) If does not respond to medical therapy, consider partial endometrial ablation, uterine artery embolization (if structural defect, adenomyosis) or hysterectomy as last resort
PCOS 5 polycystic ovarian syndrome; CAH 5 congenital adrenal Hyperplasia; IBD 5 inflammatory bowel disease; DDAVP 5 1-desamino8-D-arginine-vasopressin (desmopressin).
puberty. A pelvic examination, much less a rectal examination, may be difficult to perform based on patient anxiety and, if necessary, sedation may be required. Placing the foot of the stirrups closer to the table will result in a more frog-leg position potentially facilitating examination of the genitalia. The clinical decision will have to be made whether to attempt a speculum examination. If this is the case, a smaller speculum should be used and cultures considered. The initial laboratory evaluation should almost always include a pregnancy test. A complete blood cell count with differential and platelet count ought to be obtained. Assessment of the platelet count evaluates for coagulopathies such as idiopathic thrombocytopenia. Although unusual, a patient may have heavy bleeding that is not reflected in the hemoglobin. Ordering a serum ferritin or reticulocyte count may help assess for this. A low ferritin in the presence of a normal hemoglobin suggests depleted iron stores consistent with long-term heavier menses and an elevated reticulocyte count may also point to increased blood loss. Table 2 includes a treatment algorithm for abnormal uterine bleeding. Although very uncommon, endometrial hyperplasia or more progressive endometrial disease may be present in young women [16]. To avoid a biopsy, the endometrial stripe can be imaged. On ultrasound (preferably transvaginal), if a thick stripe is present and the patient is anovulatory, a with-
D and C 5 Dilation and curettage; gnRH 5 gonadotropin-releasing hormone; Hgb 5 hemoglobin; IV 5 intravenous.
drawal bleed can be induced with progesterone after which the stripe can be reassessed. If still thick, then an endometrial biopsy should be entertained. The American College of Obstetricians and Gynecologists (ACOG) recommends consideration for endometrial assessment in adolescents, especially with a history of 2 or more years of untreated anovulatory bleeding, particularly in those who are obese [17]. If a biopsy is done, clearly specify to the pathologist why it was indicated and make sure to also request pathologic evaluation for chronic endometritis, which is typically identified by the presence of plasma cells. A Papanicolaou smear should also be considered as indicated and ACOG recommends this 3 years after beginning vaginal intercourse or at age 21 years, whichever comes first.
Frishman.
Treatment of adolescent menorrhagia
In addition to their use in assessing the endometrial stripe, imaging studies should be considered to evaluate for a structural lesion. Although potentially more cumbersome (especially in the virginal adolescent), a sonohysterogram is more sensitive than a transvaginal ultrasound which, itself, is preferred over a transabdominal scan. Although the perception exists that transvaginal ultrasound is not tolerated by adolescents, it was reported that 57% of 116 adolescents being scanned in an emergency department setting for evaluation of pelvic inflammatory disease reported this to be as comfortable as a transabdominal ultrasound and 28% preferred it secondary to the discomfort of the full bladder required for a transabdominal scan [18]. However, in a virginal and/or young patient any procedure requiring a vaginal ultrasound may be perceived as invasive and undesirable. Magnetic resonance imaging (MRI) may be helpful in obtaining additional information about anomalies, about tumors or masses, or in cases in which an ultrasound is not able to be done or is inconclusive. A high index of suspicion and consideration for a MRI should result from a pelvic mass or collection appreciated by ultrasound or pelvic examination, in primary amenorrhea in the presence of cyclic cramps, for an inconclusive ultrasound result, or a combination of these. Overall, the practitioner should take into account the level of suspicion for a specific diagnosis (e.g., strong suspicion for mullerian agenesis would warrant MRI), the patient’s profile (e.g., 12-year-old virginal girl would be a poor candidate for a transvaginal procedure), and the relative cost (MRI may be 4 times as expensive as an ultrasound) and ability to pay.
Treatment Short-term Therapy In approximately 90% of cases, acute bleeding does not require surgical intervention, but can be treated with medical therapy. In a retrospective series of 61 adolescents (mean age, 13.8 6 2.1 years) with acute anovulatory uterine bleeding, only 5 (8.2%) failed medical therapy and required dilation and curettage to stop their bleeding [19] suggesting that a dilation and curettage is rarely necessary. If the bleeding appears to not have much clinical impact (e.g., by history, complete blood cell count) then simple reassurance and education may help. A menstrual calendar may facilitate the patient being able to anticipate the timing of her flow and help her quantify the amount and duration [20]. It may also serve as a baseline before treatment to help quantify the success of any intervention and to help show that most AUB will resolve spontaneously in 1 to 2 years as the patient develops ovulatory and regular menstrual cycles [21]. For moderate bleeding in a stable patient, although without any studies supporting it or safety data, a combined oral contraceptive cascade is typically successful. One monophasic 30- to 35-mg ethinyl estradiol pill is given 3 to 4 times a day until the bleeding stops. Counsel patients that this may take 2 to 3 days (with instructions to contact the office if this
685
is not the case). This regimen is then tapered sequentially, lowering the dosage by 1 pill a day every 3 to 4 days. It is important to counsel the patient that she may have a heavy flow on completely stopping the oral contraceptives and to consider offering an antiemetic with this high-estrogen regimen to minimize the risk of nausea. When prescribing oral contraceptives make sure to alert the patient and her family to not take the placebo pills. Also, confirm that the patient will have enough active pills to complete the cascade especially because some insurance companies will not routinely permit the refill of a prescription until the next anticipated dose (in the case of oral contraceptives: 1 calendar month) is needed. If the patient is not able to take, to tolerate, or willing to try oral contraceptives, oral conjugated equine estrogen can be administered (2.5 mg every 6 hours) or medroxyprogesterone acetate (20 mg every 8 hours) until the bleeding stops [22]. For women with significant severe bleeding or compromised hemodynamic stability, intravenous conjugated equine estrogens may be given (25 mg every 4 hours for 24 hours) as an effective intervention [23]. Although that landmark study did not specifically focus on a pediatric adolescent population, intravenous conjugated equine estrogens are generally accepted and were shown to decrease blood loss in adolescents including bleeding associated with pediatric scoliosis surgery [24]. Long-term Treatment For all long-term treatment, a specific plan, potentially involving contact originating from the practitioner’s office, to follow-up with the adolescent patient is important, as a young girl may be reluctant to electively call or see a physician. With both short- and long-term therapy, replenishment of iron stores (along with steps to prevent constipation if oral iron replacement is given) should be a high priority. Low-dose (%35 mg of ethinyl estradiol) oral contraceptives are typically the first-line treatment for chronic therapy of adolescents with symptoms ranging from minimal bleeding to significant anovulatory bleeding. Although some patients and their family may be uncomfortable taking oral contraceptives, appropriate counseling can usually resolve this. Adolescents with anovulatory bleeding can be advised to assess for changes in the menstrual pattern with the hope that a more regular pattern and/or a greater comfort level with menstrual flow will lead to a decrease in the perceived symptoms. A menstrual calendar may greatly help this process. Prescribing oral contraceptives in a continuous, rather than cyclic, fashion is an excellent option to suppress menses. This has the additional benefit of treating dysmenorrhea, which some patients may have as well. A survey was taken at the North American Society for Pediatric and Adolescent Gynecology concerning prescribing extended cycles of combined oral contraception [25]. It was reported that 71% of responding gynecologist stated that they prescribed continuous regimens with or without a hormone-free interval. This is
686
Journal of Minimally Invasive Gynecology, Vol 15, No 6, November/December 2008
consistent with a survey of US adolescents (age 15–19 years), which found that most would prefer to menstruate less frequently than once a month [25]. The use of either a progestin alone or combined oral contraceptive in a young peripubertal girl who has not completed puberty is safe and will not affect future fertility [26]. Hormonal treatment is often effective and is still a reasonable first-line choice for chronic therapy even if a bleeding disorder exists. Treatment can be continued until the patient desires to stop. A trial of discontinuing therapy to assess whether regular menstrual cycles have become established can be performed with follow-up treatment considered as indicated by these findings. For anovulatory women who are not candidates for, or choose to not take, an estrogen-containing product, based on progestational agents increasing clotting factor activity (and, hence, potentially treating the root cause of bleeding), cyclic progestin withdrawal therapy is appropriate. Oral medroxyprogesterone acetate at a dosage of 10 mg a day should be taken, typically, for 10 to 14 days each month. As this is not a contraceptive, contraception should be used if indicated. In cycling women, although not as effective as other therapies, progestins were shown to decrease menstrual blood flow [27]. Of note, when used in ovulatory women, progestins may contribute to breakthrough bleeding. If an anovulatory woman with continuing exposure to endogenous estrogen elects to not take any progestin-containing drugs, some degree of periodic endometrial evaluation should be performed to rule out hyperplasia. Weight loss, achieved through exercise, diet, and lifestyle changes, is perhaps the single best treatment goal for the obese anovulatory patient. Medical regimens may include metformin or drugs geared toward appetite suppression. For the adult obese anovulatory patient who is not able to lose weight and does not respond to medical therapy, heroic efforts include bariatric surgery to facilitate weight loss or ovarian drilling to induce ovulatory cycles and it remains to be seen whether these are appropriate for an adolescent population and whether this algorithm will change with the increasing rates of obesity. Although only 771 bariatric procedures were performed in 2003 in adolescents (,1% of all bariatric procedures performed nationwide) the annual population-based number of procedures in adolescents more than tripled between 1996 to 2000 and 2000 to 2003 [28]. Ergot derivatives are typically ineffective in bleeding not associated with pregnancy [29]. Nonsteroidal anti-inflammatory drugs were shown to reduce menorrhagia compared with placebo. However, they are not as effective as tranexamic acid, danazol, or a levonorgestrel intrauterine device (IUD) [30]. Although tranexamic acid is not available in the United States, patients may be able to obtain access to it. Danazol is associated with significant enough side effects such that it is rarely used. Having said that, nonsteroidal anti-inflammatory drugs can be used in conjunction with other therapies, such as combined hormonal contraception, to achieve a synergistic effect.
A medicated IUD is an excellent option to reduce bleeding. Under the section on ‘‘Pediactric Use’’ in the package insert of levonorgestrel IUD, for the Food and Drug Administration, states: ‘‘Safety and efficacy of Mirena have been established in women of reproductive age. Use of this product before menarche is not indicated’’ [31]. Although they also state that ‘‘Mirena is recommended for women who have had at least one child’’ [31], the ACOG committee opinion asserts that IUDs ‘‘should be considered as first-line choices for both nulliparous and parous adolescents’’ [32]. Of note, these patients should be screened for gonorrhea and chlamydia before placement [31]. Counseling is important and consideration should be given to recommending barrier contraception with any new partners. The levonorgestrel IUD was shown to be effective and a reasonable option even when compared with endometrial ablation with a comparable quality of life [33]. It was also shown to decrease menstrual blood loss in women with inherited bleeding disorders who had previously attempted medical therapy unsuccessfully [34]. Aminocaproic acid, an antifibrinolytic agent, was shown to decrease menstrual blood loss associated with a Lippes D IUD [35]. It was not studied in women with menorrhagia without an IUD. Desmopressin acetate is a synthetic analog of the antidiuretic hormone vasopressin. It was well established to help patients with bleeding associated with von Willebrand disease. Desmopressin acetate was shown to decrease menorrhagia associated with a copper IUD in women without a suspected bleeding disorder [36]. Desmopressin acetate was not studied for any synergistic effect on the decreased blood loss associated with a levonorgestrel IUD. Desmopressin acetate was evaluated in a prospective randomized, double-blind, crossover study in women with a prolonged bleeding time but no bleeding disorder and was found to decrease blood loss compared with placebo both by itself and with tranexamic acid [37]. The use of these agents is unclear in women with dysfunctional uterine bleeding. For long-term management of more significant bleeding, a depot preparation of either a gonadotropin-releasing hormone (GnRH) agonist (e.g., leuprolide acetate) or depomedroxyprogesterone acetate could be considered. A retrospective study compared both of these agents in young adults (average age 29 years) with cancer undergoing myelosuppressive therapy with associated thrombocytopenia [38]. The GnRH agonist treatment was more effect in preventing menorrhagia than the depo-medroxyprogesterone acetate. It is unclear whether these results can be extrapolated to adolescents with other causes of AUB. However, depo-medroxyprogesterone acetate is typically more likely to be associated with undesirable side effects such as depression, weight gain, and breakthrough bleeding such that a GnRH agonist may be preferred. Although nonevidenced based, depo-medroxyprogesterone acetate has been given more aggressively (300 mg every 2 months then 150 mg every 2 months) than the typical contraceptive dosage (150 mg every 3 months) for the purposes of producing a rapid sustained
Frishman.
Treatment of adolescent menorrhagia
amenorrhea. This may be especially useful in a patient in whom an absorption issue is suspected. When using a GnRH agonist long term, it is important to counsel the patient about adequate exercise and calcium intake based on the risk of bone loss. Add-back therapy can be used to extend the duration of treatment and minimize the associated side effects. Although norethindrone acetate (5 mg/day) with or without conjugated equine estrogens (0.625–1.25 mg/day) is an excellent regimen in adults, it may have androgenic activity that is undesirable in an adolescent girl. Options include traditional hormone replacement therapy such Combipatch 50/140 estradiol/norethindrone acetate (Novogyne Pharmaceuticals, East Hanover, NJ) or Activella .5/.1 estradiol/norethindrone acetate (Novo Nordisk FemCare AG, Princeton, NJ). No data or consensus exists on how long GnRH agonist therapy can be used in adults or adolescents with or without add-back therapy. The impact on permanent bone mineral density is also controversial [39,40]. Although off label, expensive, and not without risks, GnRH agonist therapy with add-back may be the best therapy for selected patients. If long-term treatment is likely, consideration should be given to obtaining a baseline dual-energy radiographic absorptiometry bone scan with a repeated study in 1 to 2 years. Of note, special interpretation of dual-energy radiographic absorptiometry in a pediatric population may be required and the consulting radiologist should be made aware of this [41]. When any given therapy is not effective, consideration can be given to combining medical therapies to achieve a synergistic effect. For example, the levonorgestrel-releasing IUD can be paired with progestin or combined hormonal contraceptive treatment when solo therapy fails. Uterine artery embolization can be considered as a heroic effort. Embolization was used with life-threatening bleeding at menarche [42]. In addition, prospective data documented the ability of some women to conceive after this procedure, albeit with a greater risk of adverse pregnancy outcome [43]. Although heroic, this may be a better option for women desiring future fertility than endometrial ablation or hysterectomy. Endometrial ablation is probably not a preferred option except in those who are not a candidate for a hysterectomy [44]. Hysterectomy remains the last resort and should be an exceptionally uncommon modality to treat bleeding. A well-motivated patient can usually find a lesser alternative. A study reported that only 2 of close to 100 young women with an intellectual disability required a surgical approach to manage their menstrual issues [45]. Conclusion Abnormal uterine bleeding is a common symptom for adolescent women at either the emergency department or a physician’s office. Routine evaluation should include a careful history, physical examination as indicated and permitted, and laboratory studies including a pregnancy test and com-
687
plete blood cell count. Quantifying the level of anemia and degree of bleeding along with managing expectations may lead to a more successful treatment plan that can almost always avoid surgery.
References 1. Friberg B, Orno AK, Lindgren A, Lethagen S. Bleeding disorders among young women: a population-based prevalence study. Acta Obstet Gynecol Scand. 2006;85:200–206. 2. Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood loss and iron deficiency. Acta Med Scand. 1966;180:639–650. 3. Strickland JL, Wall JW. Abnormal uterine bleeding in adolescents. Obstet Gynecol Clin North Am. 2003;30:321–335. 4. American College of Obstetricians and Gynecologists committee opinion No. 349, November 2006. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstet Gynecol. 2006;108: 1323–1328. 5. Philipp CS, Faiz A, Dowling N, et al. Age and the prevalence of bleeding disorders in women with menorrhagia. Obstet Gynecol. 2005;105: 61–66. 6. Pawar A, Krishnan R, Davis K, Bosma K, Kulkarni R. Perceptions about quality of life in a school-based population of adolescents with menorrhagia: implications for adolescents with bleeding disorders. Haemophilia. 2008;14:579–583. 7. Fraser IS, Critchley HO, Munro MG, Broder M. Can we achieve international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding? Hum Reprod. 2007;22:635–643. 8. Quint EH, Smith YR. Abnormal uterine bleeding in adolescents. J Midwifery Womens Health. 2003;48:186–191. 9. Dilley A, Drews C, Miller C, et al. Von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia. Obstet Gynecol. 2001;97:630–636. 10. Claessens EA, Cowell CA. Acute adolescent menorrhagia. Am J Obstet Gynecol. 1981;139:277–280. 11. Kouides PA. Menorrhagia from a hematologist’s point of view, part I: initial evaluation. Haemophilia. 2002;8:330–338. 12. Castaman G, Federici AB, Rodeghiero F, Mannucci PM. Von Willebrand’s disease in the year 2003: towards the complete identification of gene defects for correct diagnosis and treatment. Haematologica. 2003;88:94–108. 13. Adams Hillard PJ. Menstruation in young girls: a clinical perspective. Obstet Gynecol. 2002;99:655–662. 14. Alan Guttmacher Institute. Facts on American teens’ sexual and reproductive health. Available from: http://www.guttmacher.org/pubs/ fb_ATSRH.pdf. 15. Stat bite: HPV prevalence among sexually active females. J Natl Cancer Inst. 2007;99:1575. 16. Farhi DC, Nosanchuk J, Silverberg SG. Endometrial adenocarcinoma in women under 25 years of age. Obstet Gynecol. 1986;68:741–745. 17. American College of Obstetricians and Gynecologists practice bulletin: management of anovulatory bleeding. Int J Gynaecol Obstet. 2001;72: 263–271. 18. Bulas DI, Ahlstrom PA, Sivit CJ, Blask AR, O’Donnell RM. Pelvic inflammatory disease in the adolescent: comparison of transabdominal and transvaginal sonographic evaluation. Radiology. 1992;183:435–439. 19. Falcone T, Desjardins C, Bourque J, Granger L, Hemmings R, Quiros E. Dysfunctional uterine bleeding in adolescents. J Reprod Med. 1994;39: 761–764. 20. Janssen CA, Scholten PC, Heintz AP. A simple visual assessment technique to discriminate between menorrhagia and normal menstrual blood loss. Obstet Gynecol. 1995;85:977–982. 21. Barr F, Brabin L, Agbaje O. A pictorial chart for managing common menstrual disorders in Nigerian adolescents. Int J Gynaecol Obstet. 1999;66:51–53.
688
Journal of Minimally Invasive Gynecology, Vol 15, No 6, November/December 2008
22. Munro MG, Mainor N, Basu R, Brisinger M, Barreda L. Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial. Obstet Gynecol. 2006; 108:924–929. 23. DeVore GR, Owens O, Kase N. Use of intravenous Premarin in the treatment of dysfunctional uterine bleeding–a double-blind randomized control study. Obstet Gynecol. 1982;59:285–291. 24. McCall RE, Bilderback KK. Use of intravenous Premarin to decrease postoperative blood loss after pediatric scoliosis surgery. Spine. 1997; 22:1394–1397. 25. Gerschultz KL, Sucato GS, Hennon TR, Murray PJ, Gold MA. Extended cycling of combined hormonal contraceptives in adolescents: physician views and prescribing practices. J Adolesc Health. 2007;40:151–157. 26. Bagwell MA, Thompson SJ, Addy CL, Coker AL, Baker ER. Primary infertility and oral contraceptive steroid use. Fertil Steril. 1995;63: 1161–1166. 27. Lethaby A, Irvine G, Cameron I. Cyclical progestogens for heavy menstrual bleeding. Cochrane Database Syst Rev. 2000;(2): CD001016. 28. Tsai WS, Inge TH, Burd RS. Bariatric surgery in adolescents: recent national trends in use and in-hospital outcome. Arch Pediatr Adolesc Med. 2007;161:217–221. 29. van Eijkeren MA, Christiaens GC, Scholten PC, Sixma JJ. Menorrhagia: current drug treatment concepts. Drugs. 1992;43:201–209. 30. Lethaby A, Augood C, Duckitt K. Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev. 2002;(1): CD000400. 31. Food and Drug Administration. Available from: http://www.fda.gov/ medwatch/safety/2008/May_PI/Mirena_PI.pdf. 32. American College of Obstetricians and Gynecologists committee opinion No. 392, December 2007. Intrauterine device and adolescents. Obstet Gynecol. 2007;110:1493–1495. 33. Marjoribanks J, Lethaby A, Farquhar C. Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2006;(2). CD003855. 34. Kingman CE, Kadir RA, Lee CA, Economides DL. The use of levonorgestrel-releasing intrauterine system for treatment of menorrhagia in women with inherited bleeding disorders. BJOG. 2004;111:1425–1428.
35. Kasonde JM, Bonnar J. Aminocaproic acid and menstrual loss in women using intrauterine devices. Br Med J. 1975;4:17–19. 36. Mercorio F, De Simone R, Di Carlo C, et al. Effectiveness and mechanism of action of desmopressin in the treatment of copper intrauterine device-related menorrhagia: a pilot study. Hum Reprod. 2003;18: 2319–2322. 37. Edlund M, Blomback M, Fried G. Desmopressin in the treatment of menorrhagia in women with no common coagulation factor deficiency but with prolonged bleeding time. Blood Coagul Fibrinolysis. 2002; 13:225–231. 38. Meirow D, Rabinovici J, Katz D, Or R, Shufaro Y, Ben-Yehuda D. Prevention of severe menorrhagia in oncology patients with treatmentinduced thrombocytopenia by luteinizing hormone-releasing hormone agonist and depo-medroxyprogesterone acetate. Cancer. 2006;107: 1634–1641. 39. Divasta AD, Laufer MR, Gordon CM. Bone density in adolescents treated with a GnRH agonist and add-back therapy for endometriosis. J Pediatr Adolesc Gynecol. 2007;20:293–297. 40. van der Sluis IM, Boot AM, Krenning EP, Drop SL. de Muinck KeizerSchrama SM. Longitudinal follow-up of bone density and body composition in children with precocious or early puberty before, during and after cessation of GnRH agonist therapy. J Clin Endocrinol Metab. 2002;87:506–512. 41. Gafni RI, Baron J. Overdiagnosis of osteoporosis in children due to misinterpretation of dual-energy x-ray absorptiometry (DEXA). J Pediatr. 2004;144:253–257. 42. Bowkley CW, Dubel GJ, Haas RA, Soares GM, Ahn SH. Uterine artery embolization for control of life-threatening hemorrhage at menarche: brief report. J Vasc Interv Radiol. 2007;18:127–131. 43. Pron G, Mocarski E, Bennett J, Vilos G, Common A, Vanderburgh L. Pregnancy after uterine artery embolization for leiomyomata: the Ontario multicenter trial. Obstet Gynecol. 2005;105:67–76. 44. Zurawin RK, Pramanik S. Endometrial balloon ablation as a therapy for intractable uterine bleeding in an adolescent. J Pediatr Adolesc Gynecol. 2001;14:119–121. 45. Grover SR. Menstrual and contraceptive management in women with an intellectual disability. Med J Aust. 2002;176:108–110.
ABSTRACT Bleeding in adolescence is a common but, potentially, difficult condition to manage. Adolescents present with unique issues related to their age, involvement of family members, different differential diagnosis when compared to an older populations, and challenges associated with their evaluation and treatment. Journal of Minimally Invasive Gynecology (2008) 15, 682–688 Ó 2008 AAGL. All rights reserved. Keywords:
Menorrhagia; Dysfunctional uterine bleeding; Adolescent; Teenager
Bleeding in adolescence is a common but, potentially, difficult condition to manage. A questionnaire-based study of more than 1000 Swedish students (average age 16.7 years) revealed that 73% experienced at least 1 bleeding-related symptom and 37% reported heavy menstruation [1]. A total of 12.5% underwent medical treatment that included (given the European location) tranexamic acid and desmopressin in addition to oral contraceptives and progestins. Menorrhagia is defined as a menstrual blood loss of more than 80 mL [2]. However, menstrual flow is difficult to quantify especially for a teenager who may be less aware of her own body, frightened by her bleeding, or both. Furthermore, most diagnostic criteria and treatment algorithms were investigated in adults and not validated in adolescents. Adolescents bring their own distinct challenges such as the difficulty in performing an adequate physical examination without anesthesia, the potential for an incomplete history, and the possible impact of a family member being present on accuracy of the history. Furthermore, a significant percentage of menstrual bleeding in adolescents is anovulatory to start out with and full maturation of the hypothalamic-pituitary-ovarian axis typically takes up to 5 years after the start of menstruation [3]. In adolescent girls with late-onset menarche, it may take up to 12 years until they are fully ovulatory [4]. The author has no commercial, proprietary, or financial interest in the products or companies described in this article. Corresponding author: Gary N. Frishman, MD, Department of Obstetrics and Gynecology, Women and Infants’ Hospital, Brown Medical School, 101 Dudley Street, Providence, RI 02905. E-mail: [email protected] Submitted May 27, 2008. Accepted for publication August 23, 2008. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2008 AAGL. All rights reserved. doi:10.1016/j.jmig.2008.08.014
When considering their evaluation and treatment, adolescents may perceive more of an urgent need for immediate results with less of a long-term perspective compared with an older population. As such, it is critical to counsel the patient (and her family) that finding the right treatment for lasting success may take time but emphasize that if both you and they are patient, a successful outcome is almost always the result. Although some practitioners consider adolescents with abnormal bleeding to be at especially high risk of a bleeding disorder, data suggest a similar yield as in older and perimenopausal women [5]. Regardless, adolescents with Pictorial Blood Assessment Chart–documented menorrhagia were shown to perceive that their heavy flow adversely affects their quality of life [6]. Definition and Terminology A lack of agreement exists about terminology used in the description of uterine bleeding [7]. For the purposes of this review, abnormal uterine bleeding (AUB) refers to perceived abnormal or excessive menstrual or nonmenstrual blood loss. Dysfunctional uterine bleeding is a subset of AUB and consists of ovulatory bleeding that is prolonged, excessive bleeding without a pattern or any organic cause. In adolescents, anovulation accounts for 95% of all AUB [8]. Evaluation As noted earlier, obtaining a history from an adolescent may be difficult. If possible, obtain a history both with and without a parent present. Establish ground rules with all family members present about confidentiality and that you will respect the patient’s privacy. If the patient is very anxious
Frishman.
Treatment of adolescent menorrhagia
but stable, consider not performing a physical examination on the first visit or having the patient choose whether or which family member accompanies her into the room. Although no literature specifically addresses whether an adolescent would prefer a female physician for her history taking or examination, when possible, it may be worthwhile to give the patient the option of having a female practitioner obtain the history and perform the pelvic examination even if she is not going to provide the follow-up care. In a similar fashion, despite the lack of any data focusing on religious, social, or cultural mores or beliefs in this population, it logically follows to be aware and respectful of these differences and preferences as with any patient population. Anovulation is the major cause of AUB in adolescence. Although an irregular menstrual pattern usually results from anovulation and is less likely to result from a bleading disorder, it is still important to consider ruling out other causes. Serial progesterone levels or BBTs are effective, easy, and safe but typically not clinically feasible in this population. Heavy bleeding with regular cycles (menorrhagia) should lead to a thorough history, which is critical to increase the suspicion for a bleeding disorder. A significant history of easy bruising, bleeding after surgery or dental work, bleeding from the gums after brushing one’s teeth, or a positive family history should result in an extended bleeding disorder evaluation. The specificity of these findings can be strengthened by establishing whether the bruising is typically greater than 5 cm and whether medical attention was required for any bleeding from a mucous membrane. When taking a family history, in addition to asking about known bleeding disorders or bleeding associated with surgery or childbirth, it may be useful to specifically ask whether any history exists of menstrual problems that required intervention in female relatives. Despite the importance of taking this history, the presence of a family history of a bleeding susceptibility or a personal history of easy bruising is neither highly specific nor sensitive, so clinical judgment is still necessary [9]. More specific historical information includes the onset of significant menorrhagia with the start of menstruation as the chance of a bleeding disorder is greatly increased in this case [10]. In addition, menorrhagia associated with a bleeding disorder is less likely to respond to traditional hormonal medical treatment such as combined hormonal oral contraceptives or progesterone-only pills [11]. It is important to be aware that high (supraphysiologic) estrogen levels may alter hematologic factors, thus potentially resulting in a false-negative finding in a bleeding disorder evaluation. Von Willebrand disease is the single most common medical disorder associated with menorrhagia at the onset of menstruation [12]. Von Willebrand disease is present in roughly 15% of ovulatory bleeding in women of all ages. Approximately 80% of women with von Willebrand disease develop menorrhagia with up to 18% undergoing a surgical treatment during their lifetime for this [11]. It is not clear whether these data apply to all AUB. Of note, if a patient is determined to have a bleeding disorder that may be inherited,
683
consideration should be given to evaluating her family members. Adolescents may be taking oral contraceptives with or without their parents’ knowledge or be taking their mother’s or friend’s hormonal preparations. However, even if taken sporadically, this is an unlikely cause of heavy bleeding and very unlikely to result in multiple significant bleeding episodes. In a similar fashion, one should obtain a history concerning herbal agents or drug intake. Obtaining a menstrual and sexual activity history may be very difficult and adolescent pregnancy should always be considered as a cause of bleeding [13]. Approximately 46% of 15- to 19-year-olds in the United States have had coitus at least once with this number approaching 70% by age 19 years [14]. Although an unlikely cause of significant, much less repetitive bleeding, sexually transmitted diseases are quite common in young girls with up to 40% of sexually active adolescents being infected with human papillomavirus [15]. An adolescent’s first sexual encounter may be involuntary and, independent of this, they may be more prone to intercourse-related trauma or accidental injuries to the vagina and cervix. For 10% of women aged 18 to 24 years who had sex before age 20 years, their first intercourse was involuntary [14]. This percentage increases as the age of first intercourse decreases. Because this is likely a more physically and emotionally traumatic event, the relationship of sexual activity and the events surrounding it on both a adolescent’s bleeding and willingness to provide a history should be taken into account. Their lack of familiarity with tampon use may contribute to an injury. Although uncommon, consider gastrointestinal or rectal bleeding sources (e.g., hemorrhoids, polyps, inflammatory bowel disease). An eating disorder may lead to gastrointestinal bleeding via the use of laxatives or purging and/or result in abnormal vitamin and dietary intake leading to altered coagulation status. Table 1 shows the more common causes of AUB. As noted earlier, the presence of an adult family member in the room may influence the patient’s mannerisms and how she relates her history. Family dynamics should be observed to assess, for instance, the level of support and whether the patient appears to be attention seeking. In addition, the practitioner should attempt to speak to the patient alone to obtain additional history and observe her affect and motivation while not in the presence of a family member. The causes of abnormal uterine bleeding are listed in Table 1. Physical Examination The physical examination may be challenging in a fearful adolescent girl. In addition to vital signs, orthostatic vital signs should be considered. Body mass index should be calculated. Evidence of a bleeding disorder at other sites should be investigated including petechial hemorrhages and ecchymosis. Tanner staging of the breast and pubic hair may provide information about how far the patient has progressed through
684
Journal of Minimally Invasive Gynecology, Vol 15, No 6, November/December 2008
Table 1
Table 2
Causes of abnormal uterine bleeding
Treatment algorithm for abnormal uterine bleeding
Bleeding disorders Von Willebrand disease Idiopathic thrombocytopenic purpura Factor XI deficiency Thrombocytopenia Leukemia Pregnancy related Abortion (incomplete, complete, threatened) Ectopic pregnancy Trophoblastic disease Infections Endometritis Cervicitis Endocrinopathies PCOS CAH Androgen- or estrogen-secreting tumor Thyroid disease Trauma Uterine abnormalities Myomas Polyps Congenital anomalies Reproductive tract malignancy Anovulation endometrial hyperplasia Exogenous drugs or hormones Nongynecologic causes Factitious Gastrointestinal (e.g., hemorrhoids, IBD)
No significant anemia (Hgb .13 g/dL) Reassurance and education Consider familial issues and/or gain-seeking behavior Menstrual diary Perimenstrual nonsteroidal anti-inflammatory drugs Iron and vitamin supplementation as needed Oral contraceptives (continuous or cyclic), note: done for patient’s symptoms rather than signs Moderate anemia (Hgb 9–13 g/dL) Oral contraceptives (continuous or cyclic) Consider cascade protocol followed by traditional course Levonorgestrel-releasing intrauterine device if appropriate Cyclic progesterone treatment (medroxyprogesterone acetate 10 mg/day for 14 days every 3 months or Depo-Provera (Pfizer, New York, NY) 150 mg every 3 months) Must be willing to accept breakthrough bleeding and not be at risk for significant depression Iron and vitamin supplementation as needed Treat underlying cause (e.g., anovulation may respond to weight loss, remove any structural lesion) Significant anemia (Hgb,9 g/dL) Short-term treatment Stabilize patient with, e.g., IV fluids, transfusion as indicated IV conjugated equine estrogens (25 mg every 4 hours) as indicated Oral contraceptives cascade protocol followed by traditional course Surgical intervention with D and C if not responsive to other measures Consider trial of DDAVP Consider placement of Foley balloon or other catheter to tamponade Long-term treatment Levonorgestrel-releasing intrauterine device if appropriate GnRH agonist (Lupron Depot (TAP Pharmaceuticals Inc., Lake Forest, IL) 3.75 mg once a month) with calcium supplementation and add-back therapy as indicated Cyclic progesterone treatment (medroxyprogesterone acetate 10 mg/day for 14 days ever 3 months or Depo-Provera 150 mg every 3 months) Must be willing to accept breakthrough bleeding and not be at risk for significant depression Iron and vitamin supplementation as needed Treat underlying cause (e.g., anovulation may respond to weight loss, remove any structural lesion) If does not respond to medical therapy, consider partial endometrial ablation, uterine artery embolization (if structural defect, adenomyosis) or hysterectomy as last resort
PCOS 5 polycystic ovarian syndrome; CAH 5 congenital adrenal Hyperplasia; IBD 5 inflammatory bowel disease; DDAVP 5 1-desamino8-D-arginine-vasopressin (desmopressin).
puberty. A pelvic examination, much less a rectal examination, may be difficult to perform based on patient anxiety and, if necessary, sedation may be required. Placing the foot of the stirrups closer to the table will result in a more frog-leg position potentially facilitating examination of the genitalia. The clinical decision will have to be made whether to attempt a speculum examination. If this is the case, a smaller speculum should be used and cultures considered. The initial laboratory evaluation should almost always include a pregnancy test. A complete blood cell count with differential and platelet count ought to be obtained. Assessment of the platelet count evaluates for coagulopathies such as idiopathic thrombocytopenia. Although unusual, a patient may have heavy bleeding that is not reflected in the hemoglobin. Ordering a serum ferritin or reticulocyte count may help assess for this. A low ferritin in the presence of a normal hemoglobin suggests depleted iron stores consistent with long-term heavier menses and an elevated reticulocyte count may also point to increased blood loss. Table 2 includes a treatment algorithm for abnormal uterine bleeding. Although very uncommon, endometrial hyperplasia or more progressive endometrial disease may be present in young women [16]. To avoid a biopsy, the endometrial stripe can be imaged. On ultrasound (preferably transvaginal), if a thick stripe is present and the patient is anovulatory, a with-
D and C 5 Dilation and curettage; gnRH 5 gonadotropin-releasing hormone; Hgb 5 hemoglobin; IV 5 intravenous.
drawal bleed can be induced with progesterone after which the stripe can be reassessed. If still thick, then an endometrial biopsy should be entertained. The American College of Obstetricians and Gynecologists (ACOG) recommends consideration for endometrial assessment in adolescents, especially with a history of 2 or more years of untreated anovulatory bleeding, particularly in those who are obese [17]. If a biopsy is done, clearly specify to the pathologist why it was indicated and make sure to also request pathologic evaluation for chronic endometritis, which is typically identified by the presence of plasma cells. A Papanicolaou smear should also be considered as indicated and ACOG recommends this 3 years after beginning vaginal intercourse or at age 21 years, whichever comes first.
Frishman.
Treatment of adolescent menorrhagia
In addition to their use in assessing the endometrial stripe, imaging studies should be considered to evaluate for a structural lesion. Although potentially more cumbersome (especially in the virginal adolescent), a sonohysterogram is more sensitive than a transvaginal ultrasound which, itself, is preferred over a transabdominal scan. Although the perception exists that transvaginal ultrasound is not tolerated by adolescents, it was reported that 57% of 116 adolescents being scanned in an emergency department setting for evaluation of pelvic inflammatory disease reported this to be as comfortable as a transabdominal ultrasound and 28% preferred it secondary to the discomfort of the full bladder required for a transabdominal scan [18]. However, in a virginal and/or young patient any procedure requiring a vaginal ultrasound may be perceived as invasive and undesirable. Magnetic resonance imaging (MRI) may be helpful in obtaining additional information about anomalies, about tumors or masses, or in cases in which an ultrasound is not able to be done or is inconclusive. A high index of suspicion and consideration for a MRI should result from a pelvic mass or collection appreciated by ultrasound or pelvic examination, in primary amenorrhea in the presence of cyclic cramps, for an inconclusive ultrasound result, or a combination of these. Overall, the practitioner should take into account the level of suspicion for a specific diagnosis (e.g., strong suspicion for mullerian agenesis would warrant MRI), the patient’s profile (e.g., 12-year-old virginal girl would be a poor candidate for a transvaginal procedure), and the relative cost (MRI may be 4 times as expensive as an ultrasound) and ability to pay.
Treatment Short-term Therapy In approximately 90% of cases, acute bleeding does not require surgical intervention, but can be treated with medical therapy. In a retrospective series of 61 adolescents (mean age, 13.8 6 2.1 years) with acute anovulatory uterine bleeding, only 5 (8.2%) failed medical therapy and required dilation and curettage to stop their bleeding [19] suggesting that a dilation and curettage is rarely necessary. If the bleeding appears to not have much clinical impact (e.g., by history, complete blood cell count) then simple reassurance and education may help. A menstrual calendar may facilitate the patient being able to anticipate the timing of her flow and help her quantify the amount and duration [20]. It may also serve as a baseline before treatment to help quantify the success of any intervention and to help show that most AUB will resolve spontaneously in 1 to 2 years as the patient develops ovulatory and regular menstrual cycles [21]. For moderate bleeding in a stable patient, although without any studies supporting it or safety data, a combined oral contraceptive cascade is typically successful. One monophasic 30- to 35-mg ethinyl estradiol pill is given 3 to 4 times a day until the bleeding stops. Counsel patients that this may take 2 to 3 days (with instructions to contact the office if this
685
is not the case). This regimen is then tapered sequentially, lowering the dosage by 1 pill a day every 3 to 4 days. It is important to counsel the patient that she may have a heavy flow on completely stopping the oral contraceptives and to consider offering an antiemetic with this high-estrogen regimen to minimize the risk of nausea. When prescribing oral contraceptives make sure to alert the patient and her family to not take the placebo pills. Also, confirm that the patient will have enough active pills to complete the cascade especially because some insurance companies will not routinely permit the refill of a prescription until the next anticipated dose (in the case of oral contraceptives: 1 calendar month) is needed. If the patient is not able to take, to tolerate, or willing to try oral contraceptives, oral conjugated equine estrogen can be administered (2.5 mg every 6 hours) or medroxyprogesterone acetate (20 mg every 8 hours) until the bleeding stops [22]. For women with significant severe bleeding or compromised hemodynamic stability, intravenous conjugated equine estrogens may be given (25 mg every 4 hours for 24 hours) as an effective intervention [23]. Although that landmark study did not specifically focus on a pediatric adolescent population, intravenous conjugated equine estrogens are generally accepted and were shown to decrease blood loss in adolescents including bleeding associated with pediatric scoliosis surgery [24]. Long-term Treatment For all long-term treatment, a specific plan, potentially involving contact originating from the practitioner’s office, to follow-up with the adolescent patient is important, as a young girl may be reluctant to electively call or see a physician. With both short- and long-term therapy, replenishment of iron stores (along with steps to prevent constipation if oral iron replacement is given) should be a high priority. Low-dose (%35 mg of ethinyl estradiol) oral contraceptives are typically the first-line treatment for chronic therapy of adolescents with symptoms ranging from minimal bleeding to significant anovulatory bleeding. Although some patients and their family may be uncomfortable taking oral contraceptives, appropriate counseling can usually resolve this. Adolescents with anovulatory bleeding can be advised to assess for changes in the menstrual pattern with the hope that a more regular pattern and/or a greater comfort level with menstrual flow will lead to a decrease in the perceived symptoms. A menstrual calendar may greatly help this process. Prescribing oral contraceptives in a continuous, rather than cyclic, fashion is an excellent option to suppress menses. This has the additional benefit of treating dysmenorrhea, which some patients may have as well. A survey was taken at the North American Society for Pediatric and Adolescent Gynecology concerning prescribing extended cycles of combined oral contraception [25]. It was reported that 71% of responding gynecologist stated that they prescribed continuous regimens with or without a hormone-free interval. This is
686
Journal of Minimally Invasive Gynecology, Vol 15, No 6, November/December 2008
consistent with a survey of US adolescents (age 15–19 years), which found that most would prefer to menstruate less frequently than once a month [25]. The use of either a progestin alone or combined oral contraceptive in a young peripubertal girl who has not completed puberty is safe and will not affect future fertility [26]. Hormonal treatment is often effective and is still a reasonable first-line choice for chronic therapy even if a bleeding disorder exists. Treatment can be continued until the patient desires to stop. A trial of discontinuing therapy to assess whether regular menstrual cycles have become established can be performed with follow-up treatment considered as indicated by these findings. For anovulatory women who are not candidates for, or choose to not take, an estrogen-containing product, based on progestational agents increasing clotting factor activity (and, hence, potentially treating the root cause of bleeding), cyclic progestin withdrawal therapy is appropriate. Oral medroxyprogesterone acetate at a dosage of 10 mg a day should be taken, typically, for 10 to 14 days each month. As this is not a contraceptive, contraception should be used if indicated. In cycling women, although not as effective as other therapies, progestins were shown to decrease menstrual blood flow [27]. Of note, when used in ovulatory women, progestins may contribute to breakthrough bleeding. If an anovulatory woman with continuing exposure to endogenous estrogen elects to not take any progestin-containing drugs, some degree of periodic endometrial evaluation should be performed to rule out hyperplasia. Weight loss, achieved through exercise, diet, and lifestyle changes, is perhaps the single best treatment goal for the obese anovulatory patient. Medical regimens may include metformin or drugs geared toward appetite suppression. For the adult obese anovulatory patient who is not able to lose weight and does not respond to medical therapy, heroic efforts include bariatric surgery to facilitate weight loss or ovarian drilling to induce ovulatory cycles and it remains to be seen whether these are appropriate for an adolescent population and whether this algorithm will change with the increasing rates of obesity. Although only 771 bariatric procedures were performed in 2003 in adolescents (,1% of all bariatric procedures performed nationwide) the annual population-based number of procedures in adolescents more than tripled between 1996 to 2000 and 2000 to 2003 [28]. Ergot derivatives are typically ineffective in bleeding not associated with pregnancy [29]. Nonsteroidal anti-inflammatory drugs were shown to reduce menorrhagia compared with placebo. However, they are not as effective as tranexamic acid, danazol, or a levonorgestrel intrauterine device (IUD) [30]. Although tranexamic acid is not available in the United States, patients may be able to obtain access to it. Danazol is associated with significant enough side effects such that it is rarely used. Having said that, nonsteroidal anti-inflammatory drugs can be used in conjunction with other therapies, such as combined hormonal contraception, to achieve a synergistic effect.
A medicated IUD is an excellent option to reduce bleeding. Under the section on ‘‘Pediactric Use’’ in the package insert of levonorgestrel IUD, for the Food and Drug Administration, states: ‘‘Safety and efficacy of Mirena have been established in women of reproductive age. Use of this product before menarche is not indicated’’ [31]. Although they also state that ‘‘Mirena is recommended for women who have had at least one child’’ [31], the ACOG committee opinion asserts that IUDs ‘‘should be considered as first-line choices for both nulliparous and parous adolescents’’ [32]. Of note, these patients should be screened for gonorrhea and chlamydia before placement [31]. Counseling is important and consideration should be given to recommending barrier contraception with any new partners. The levonorgestrel IUD was shown to be effective and a reasonable option even when compared with endometrial ablation with a comparable quality of life [33]. It was also shown to decrease menstrual blood loss in women with inherited bleeding disorders who had previously attempted medical therapy unsuccessfully [34]. Aminocaproic acid, an antifibrinolytic agent, was shown to decrease menstrual blood loss associated with a Lippes D IUD [35]. It was not studied in women with menorrhagia without an IUD. Desmopressin acetate is a synthetic analog of the antidiuretic hormone vasopressin. It was well established to help patients with bleeding associated with von Willebrand disease. Desmopressin acetate was shown to decrease menorrhagia associated with a copper IUD in women without a suspected bleeding disorder [36]. Desmopressin acetate was not studied for any synergistic effect on the decreased blood loss associated with a levonorgestrel IUD. Desmopressin acetate was evaluated in a prospective randomized, double-blind, crossover study in women with a prolonged bleeding time but no bleeding disorder and was found to decrease blood loss compared with placebo both by itself and with tranexamic acid [37]. The use of these agents is unclear in women with dysfunctional uterine bleeding. For long-term management of more significant bleeding, a depot preparation of either a gonadotropin-releasing hormone (GnRH) agonist (e.g., leuprolide acetate) or depomedroxyprogesterone acetate could be considered. A retrospective study compared both of these agents in young adults (average age 29 years) with cancer undergoing myelosuppressive therapy with associated thrombocytopenia [38]. The GnRH agonist treatment was more effect in preventing menorrhagia than the depo-medroxyprogesterone acetate. It is unclear whether these results can be extrapolated to adolescents with other causes of AUB. However, depo-medroxyprogesterone acetate is typically more likely to be associated with undesirable side effects such as depression, weight gain, and breakthrough bleeding such that a GnRH agonist may be preferred. Although nonevidenced based, depo-medroxyprogesterone acetate has been given more aggressively (300 mg every 2 months then 150 mg every 2 months) than the typical contraceptive dosage (150 mg every 3 months) for the purposes of producing a rapid sustained
Frishman.
Treatment of adolescent menorrhagia
amenorrhea. This may be especially useful in a patient in whom an absorption issue is suspected. When using a GnRH agonist long term, it is important to counsel the patient about adequate exercise and calcium intake based on the risk of bone loss. Add-back therapy can be used to extend the duration of treatment and minimize the associated side effects. Although norethindrone acetate (5 mg/day) with or without conjugated equine estrogens (0.625–1.25 mg/day) is an excellent regimen in adults, it may have androgenic activity that is undesirable in an adolescent girl. Options include traditional hormone replacement therapy such Combipatch 50/140 estradiol/norethindrone acetate (Novogyne Pharmaceuticals, East Hanover, NJ) or Activella .5/.1 estradiol/norethindrone acetate (Novo Nordisk FemCare AG, Princeton, NJ). No data or consensus exists on how long GnRH agonist therapy can be used in adults or adolescents with or without add-back therapy. The impact on permanent bone mineral density is also controversial [39,40]. Although off label, expensive, and not without risks, GnRH agonist therapy with add-back may be the best therapy for selected patients. If long-term treatment is likely, consideration should be given to obtaining a baseline dual-energy radiographic absorptiometry bone scan with a repeated study in 1 to 2 years. Of note, special interpretation of dual-energy radiographic absorptiometry in a pediatric population may be required and the consulting radiologist should be made aware of this [41]. When any given therapy is not effective, consideration can be given to combining medical therapies to achieve a synergistic effect. For example, the levonorgestrel-releasing IUD can be paired with progestin or combined hormonal contraceptive treatment when solo therapy fails. Uterine artery embolization can be considered as a heroic effort. Embolization was used with life-threatening bleeding at menarche [42]. In addition, prospective data documented the ability of some women to conceive after this procedure, albeit with a greater risk of adverse pregnancy outcome [43]. Although heroic, this may be a better option for women desiring future fertility than endometrial ablation or hysterectomy. Endometrial ablation is probably not a preferred option except in those who are not a candidate for a hysterectomy [44]. Hysterectomy remains the last resort and should be an exceptionally uncommon modality to treat bleeding. A well-motivated patient can usually find a lesser alternative. A study reported that only 2 of close to 100 young women with an intellectual disability required a surgical approach to manage their menstrual issues [45]. Conclusion Abnormal uterine bleeding is a common symptom for adolescent women at either the emergency department or a physician’s office. Routine evaluation should include a careful history, physical examination as indicated and permitted, and laboratory studies including a pregnancy test and com-
687
plete blood cell count. Quantifying the level of anemia and degree of bleeding along with managing expectations may lead to a more successful treatment plan that can almost always avoid surgery.
References 1. Friberg B, Orno AK, Lindgren A, Lethagen S. Bleeding disorders among young women: a population-based prevalence study. Acta Obstet Gynecol Scand. 2006;85:200–206. 2. Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood loss and iron deficiency. Acta Med Scand. 1966;180:639–650. 3. Strickland JL, Wall JW. Abnormal uterine bleeding in adolescents. Obstet Gynecol Clin North Am. 2003;30:321–335. 4. American College of Obstetricians and Gynecologists committee opinion No. 349, November 2006. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstet Gynecol. 2006;108: 1323–1328. 5. Philipp CS, Faiz A, Dowling N, et al. Age and the prevalence of bleeding disorders in women with menorrhagia. Obstet Gynecol. 2005;105: 61–66. 6. Pawar A, Krishnan R, Davis K, Bosma K, Kulkarni R. Perceptions about quality of life in a school-based population of adolescents with menorrhagia: implications for adolescents with bleeding disorders. Haemophilia. 2008;14:579–583. 7. Fraser IS, Critchley HO, Munro MG, Broder M. Can we achieve international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding? Hum Reprod. 2007;22:635–643. 8. Quint EH, Smith YR. Abnormal uterine bleeding in adolescents. J Midwifery Womens Health. 2003;48:186–191. 9. Dilley A, Drews C, Miller C, et al. Von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia. Obstet Gynecol. 2001;97:630–636. 10. Claessens EA, Cowell CA. Acute adolescent menorrhagia. Am J Obstet Gynecol. 1981;139:277–280. 11. Kouides PA. Menorrhagia from a hematologist’s point of view, part I: initial evaluation. Haemophilia. 2002;8:330–338. 12. Castaman G, Federici AB, Rodeghiero F, Mannucci PM. Von Willebrand’s disease in the year 2003: towards the complete identification of gene defects for correct diagnosis and treatment. Haematologica. 2003;88:94–108. 13. Adams Hillard PJ. Menstruation in young girls: a clinical perspective. Obstet Gynecol. 2002;99:655–662. 14. Alan Guttmacher Institute. Facts on American teens’ sexual and reproductive health. Available from: http://www.guttmacher.org/pubs/ fb_ATSRH.pdf. 15. Stat bite: HPV prevalence among sexually active females. J Natl Cancer Inst. 2007;99:1575. 16. Farhi DC, Nosanchuk J, Silverberg SG. Endometrial adenocarcinoma in women under 25 years of age. Obstet Gynecol. 1986;68:741–745. 17. American College of Obstetricians and Gynecologists practice bulletin: management of anovulatory bleeding. Int J Gynaecol Obstet. 2001;72: 263–271. 18. Bulas DI, Ahlstrom PA, Sivit CJ, Blask AR, O’Donnell RM. Pelvic inflammatory disease in the adolescent: comparison of transabdominal and transvaginal sonographic evaluation. Radiology. 1992;183:435–439. 19. Falcone T, Desjardins C, Bourque J, Granger L, Hemmings R, Quiros E. Dysfunctional uterine bleeding in adolescents. J Reprod Med. 1994;39: 761–764. 20. Janssen CA, Scholten PC, Heintz AP. A simple visual assessment technique to discriminate between menorrhagia and normal menstrual blood loss. Obstet Gynecol. 1995;85:977–982. 21. Barr F, Brabin L, Agbaje O. A pictorial chart for managing common menstrual disorders in Nigerian adolescents. Int J Gynaecol Obstet. 1999;66:51–53.
688
Journal of Minimally Invasive Gynecology, Vol 15, No 6, November/December 2008
22. Munro MG, Mainor N, Basu R, Brisinger M, Barreda L. Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial. Obstet Gynecol. 2006; 108:924–929. 23. DeVore GR, Owens O, Kase N. Use of intravenous Premarin in the treatment of dysfunctional uterine bleeding–a double-blind randomized control study. Obstet Gynecol. 1982;59:285–291. 24. McCall RE, Bilderback KK. Use of intravenous Premarin to decrease postoperative blood loss after pediatric scoliosis surgery. Spine. 1997; 22:1394–1397. 25. Gerschultz KL, Sucato GS, Hennon TR, Murray PJ, Gold MA. Extended cycling of combined hormonal contraceptives in adolescents: physician views and prescribing practices. J Adolesc Health. 2007;40:151–157. 26. Bagwell MA, Thompson SJ, Addy CL, Coker AL, Baker ER. Primary infertility and oral contraceptive steroid use. Fertil Steril. 1995;63: 1161–1166. 27. Lethaby A, Irvine G, Cameron I. Cyclical progestogens for heavy menstrual bleeding. Cochrane Database Syst Rev. 2000;(2): CD001016. 28. Tsai WS, Inge TH, Burd RS. Bariatric surgery in adolescents: recent national trends in use and in-hospital outcome. Arch Pediatr Adolesc Med. 2007;161:217–221. 29. van Eijkeren MA, Christiaens GC, Scholten PC, Sixma JJ. Menorrhagia: current drug treatment concepts. Drugs. 1992;43:201–209. 30. Lethaby A, Augood C, Duckitt K. Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev. 2002;(1): CD000400. 31. Food and Drug Administration. Available from: http://www.fda.gov/ medwatch/safety/2008/May_PI/Mirena_PI.pdf. 32. American College of Obstetricians and Gynecologists committee opinion No. 392, December 2007. Intrauterine device and adolescents. Obstet Gynecol. 2007;110:1493–1495. 33. Marjoribanks J, Lethaby A, Farquhar C. Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2006;(2). CD003855. 34. Kingman CE, Kadir RA, Lee CA, Economides DL. The use of levonorgestrel-releasing intrauterine system for treatment of menorrhagia in women with inherited bleeding disorders. BJOG. 2004;111:1425–1428.
35. Kasonde JM, Bonnar J. Aminocaproic acid and menstrual loss in women using intrauterine devices. Br Med J. 1975;4:17–19. 36. Mercorio F, De Simone R, Di Carlo C, et al. Effectiveness and mechanism of action of desmopressin in the treatment of copper intrauterine device-related menorrhagia: a pilot study. Hum Reprod. 2003;18: 2319–2322. 37. Edlund M, Blomback M, Fried G. Desmopressin in the treatment of menorrhagia in women with no common coagulation factor deficiency but with prolonged bleeding time. Blood Coagul Fibrinolysis. 2002; 13:225–231. 38. Meirow D, Rabinovici J, Katz D, Or R, Shufaro Y, Ben-Yehuda D. Prevention of severe menorrhagia in oncology patients with treatmentinduced thrombocytopenia by luteinizing hormone-releasing hormone agonist and depo-medroxyprogesterone acetate. Cancer. 2006;107: 1634–1641. 39. Divasta AD, Laufer MR, Gordon CM. Bone density in adolescents treated with a GnRH agonist and add-back therapy for endometriosis. J Pediatr Adolesc Gynecol. 2007;20:293–297. 40. van der Sluis IM, Boot AM, Krenning EP, Drop SL. de Muinck KeizerSchrama SM. Longitudinal follow-up of bone density and body composition in children with precocious or early puberty before, during and after cessation of GnRH agonist therapy. J Clin Endocrinol Metab. 2002;87:506–512. 41. Gafni RI, Baron J. Overdiagnosis of osteoporosis in children due to misinterpretation of dual-energy x-ray absorptiometry (DEXA). J Pediatr. 2004;144:253–257. 42. Bowkley CW, Dubel GJ, Haas RA, Soares GM, Ahn SH. Uterine artery embolization for control of life-threatening hemorrhage at menarche: brief report. J Vasc Interv Radiol. 2007;18:127–131. 43. Pron G, Mocarski E, Bennett J, Vilos G, Common A, Vanderburgh L. Pregnancy after uterine artery embolization for leiomyomata: the Ontario multicenter trial. Obstet Gynecol. 2005;105:67–76. 44. Zurawin RK, Pramanik S. Endometrial balloon ablation as a therapy for intractable uterine bleeding in an adolescent. J Pediatr Adolesc Gynecol. 2001;14:119–121. 45. Grover SR. Menstrual and contraceptive management in women with an intellectual disability. Med J Aust. 2002;176:108–110.