Abnormal Uterine Bleeding in Adolescents Maria C. Monge, MD Director of Adolescent Medicine Dell Children’s Medical Center UTSW-Austin Pediatrics Residency Program Lone Star Circle of Care

Disclosures I have no relevant financial disclosures.

Objectives 1. Define abnormal uterine bleeding (AUB) in an adolescent. 2.  Discuss possible etiologies of AUB in an adolescent and use these in consideration of the the initial outpatient workup of AUB. 3.  Identify initial outpatient management strategies for adolescents with AUB.

Case – Madeline

Madeline Madeline is a 12 year old who comes to your office after she felt lightheaded at school. Mom called and triage nurse said to bring her in. Mom told the nurse that Madeline has had menstrual bleeding for more than 1 week and has been feeling more tired than usual for the past month.

Madeline Review of records before she arrives Healthy, on no medications Growth and development normal 50% BMI At last WCC had not started menstruating, but had SMR3 breasts and pubic hair Family history unremarkable

NORMAL Menses

Normal Menses Menarche: 2.3y after pubertal initiation Range 1-3 years Cycle length: 21-42 days (beginning to beginning) Should be regular by 2-2.5 years Cycles outside of 20-45 days should be considered abnormal even in adolescents Duration: 3-7 days Average blood loss: 30 mL/cycle Can be 20-80mL Cycles outside of 20-45 days are statistically uncommon in adolescents and warrants evaluation. By 3rd gynecologic year, 60-80% of cycles are 21-34 days long.. Individual’s normative cycle length is established by approx 5th or 6th gyn year or by age 19-20 Typical blood loss if 30-40 ml but can be 20-80, which leads to about 10-15 soaked pads or tampons per cycle Menorrhagia is defined as prolonged (>7 days) or excessive (>80 ml) of bleeding

Normal Menses Follicular phase: pulsatile release of gonadotropin RH from Hypothal, stimulates pituitary FSH & LH release, which stimulates dev’t ovarian follicles and steroid hormone synthesis. FSH: incr # granulosa cells, promotes estrogen secretion by incr aromatase, and incr # of FSH receptors on granulosa calls. LH: stimulates ovarian theca cells to incr secretion of estrogen and androgen, which are converted to testosterone and estrogen in ovaries and peripheral tissue. Incr estrogen stimulate endometrial lining proliferation and neg feedback on FSH And pos feedback on LH. Midcycle LH surge stimulates ovulation. Luteal phase: ovarian follicle-> corpus luteum produces progesterone and sm amt estrogen. Progesterone stabilized endometrial lining and promotes growth of glandular tissue and blood vessels in preparation for fertilization. Corpus lutem deteriorates if no fertilization. Decr in progesterone and estrogen triggers sloughing of lining, and stimulates incr of LH and FSH via neg feedback. -in adolescents, the positive stimulatory feedback mechanism of estrogen on LH does not mature nor does the LH surge consistently occur until 2-5 years after menarche -as a result, 50-80% of the cycles are anovulatory and irregular during the first 2 years after menarche

Anovulatory Cycles 55-82% of adolescents take up to 24 months after menarche before having regular ovulatory cycles Adolescents with later onset of menarche have longer intervals until cycles become ovulatory Immaturity of HPO axis Having an occasional ovulatory cycle stabilizes endometrial growth and allows for complete shedding Immaturity of the HPO axis. Delayed matruation of normal negative feedback mechanism that does not allow orderly growth of endometrium and withdrawl flow before endometrium becomes excessively thickend. Increased estrogen levels do not lead to fall in FSH, therefore no suppression of estrogen and ongoing stimulation of endometrial lining. There is no progestesterone (no corpus luteum formed) therefore no local prostaglandin secretion and vasoconstriction and myometrial contractility don’t occur. Endometrium proliferates beyond estrogen’s ability to maintain its integrity. Bleeding occurs when endometrium becomes unstable and continues until estrogen-induced repair takes place. However, most with anovulatory cycles do not have DUB. Mechanism of DUB is not entirely understood Again, persistence of anovulatory cycles should prompt evaluation of things other than immatur HPO axis.

Madeline On arrival to office -- History In the midst of her 3rd menstrual period First one about 4 months ago and was light, lasted 5 days; Second one about 2 months ago and was moderate flow lasting 7 days Started 8 days prior Soaking pads every 1-2 hours

How do you quantify bleeding? Proposed screening questions Period lasting > 7 days Feeling of “flooding” or “gushing” most cycles Activities limited by periods Bleeding “problem” after dental extraction, surgery or delivery/miscarriage Family history of bleeding disorder Teenagers (well, probably all women) are bad at quantifying blood loss. 1 drop = hemorrhaging

Madeline – Additional details ROS: feeling tired, maybe easy bruising but not sure, no acne or hirsuitism Medications: None Family History: Mom menarche age 13 and was irregular for 1-2 years Social history: Lives with Mom, in 6th grade, has a boyfriend but no sex, no trauma, no foreign bodies in vagina Healthy. No PMx. No meds.

Differential diagnosis

Differential for abnormal bleeding Anovulatory uterine bleeding Vaginal, cervical or uterine carcinoma, sarcoma, polyps Endocrine disorders Cervical hemangioma Bleeding disorders Congenital uterine abnormalities Pregnancy-related complications Vaginal lacerations, trauma Infection Hormonal contraception Endometriosis Use of IUDs Foreign body Medications Pregnancy related: threatened, spontaneous, incomplete, or missed abortion, ectopic, complications of TABs Infection: PID, endometritis, cervicitis, vaginitis Bleeding disorders: thrombocytopenia (ITP, leukemia, aplastic anemia, chemotherapy), clotting disorders (vWD) Endocrine: hypo- or hyperthyroidism, adrenal disease, hyperprolactinemia, PCOS, ovarian failure Medications: hormonal contraception (esp POPs), anticoagulants, platelet inhibitors, androgens, spironolactone, antipsychotics ANOVULATORY BLEEDING IS DIAGNOSIS OF EXCLUSION

What is on our differential for Madeline? Systematic approach Consider pertinent history and physical

What is on our differential for Madeline? Systematic approach Prolactinoma Thyroid Disease Cushings, CAH PCOS, Anovluation, Pregnancy, POI, Trauma, Infection, Polyp Bleeding Disorder

Exam considerations

Exam Key points Vitals , Height, Weight, BMI Features of endocrinopathies Androgen excess Cushingoid Thyroid Other signs of bleeding GU exam Minimum is external Pelvic exam-most girls who have used tampons can tolerate a 1 finger digital exam to check for foreign bodies Turner’s, ED, FAT, PCOS Acne, hirsuitism, clitoromegaly Petechiae, bruising External- look for clitoromegaly, evidence of trauma/lacerations

Madeline - Exam Vital Signs: BP 98/66 HR 72 T 98.4 BMI 75th% Gen: slightly pale and anxious-appearing Neck: no thyroid enlargement CV: soft SEM at RUSB Chest: SMR4 breast Abd: soft, NT/ND, no striae GU: SMR 4 pubic hair, external exam without evidence of trauma, +bleeding from vagina Skin: no hirsuitism, acne, acanthosis, petechiae, bruising Key points on exam: Vitals, BMI, height – Turners, thin/obese with ED, FAT, PCOS Obvious evidence of endocrinopathy – androgen excells, acne, hirsuitism, clitoromegaly, cushingoid, thyroid Other signs of bleeding, petechiae, bruising External genital exam – clitoromegaly, lacerations Pelvic exam- most girls who have used tampons can tolerate a 1 finger digital exam to check for foreign bodies

Any changes to the differential? Anything move up or down the list?

Laboratory evaluation

Laboratory Evaluation CBC with differential B-hcg (sensitive urine or serum) TSH, free T4 Type and Screen FSH, LH, prolactin, free/total T, DHEA-S PT/PTT, von Willebrand panel GC/CT testing Note, certain labs need to be drawn prior to starting hormonal agents and prior to transfusion if applicable.

Madeline - Results CBC: Hemoglobin 10.4 g/dL, remainder normal Urine hcg: negative TSH: 255 mIU/L, T4 0.5 mcg/L Von Willebrand Panel: VW Factor 90% (50-160 normal) Factor XIII 142% (70-170 normal)

A note about VWF screening Many factors impact VWF levels Ideal to test off of hormones or on Day 7 of placebos VWD <30% activity now considered diagnostic 30-50% is “low von Willebrand factor” Consider screening as not uncommon in adolescents with menorrhagia Estimates vary widely in literature with many suffering from selection bias ?10% of women with menorrhagia will have vwd as cause. Stress (traumatic blood draw), exercise, inflammation, hormones MANY other factors impact VWF levels Samples not kept at the correct temperature can lead to false positives or negatives--beware the send out! Elevated levels are associated with: Inflammation Hormones (including pregnancy and OCPs) Stress (ie traumatic blood draw) Exercise Decreased levels are associated with: Blood type O Hypothyroidism

Role of imaging? Consider if: Unable to do pelvic exam Prolonged bleeding despite treatment Pelvic mass or uterine anomaly suspected

Next steps? Stop bleeding Treat underlying condition (if applicable)

Key points for all patients All patients should keep a menstrual calendar Ensure iron stores are addressed, even if Hgb normal. Patients typically need several months of oral iron to replete stores Patients may prefer a mobile app, of which there are many free ones.

Hormonal Treatment of bleeding

Recommended choice of OCPs Off-label use Monophasic Potent progestin Norgestrel (0.3mg) Ex. Lo/Ovral, Low-Ogestrel, Cryselle Levonorgestrel (0.15mg) Ex. Nordette, Levlen, Levora, Portia Note: Naming brand names does not imply endorsement of a particular product

Treatment depends on current bleeding and Hgb Mild Menses slightly prolonged or cycle slightly more frequent Normal hemoglobin This can be distressing to patients and families May observe for several cycles Iron supplementation Naproxen or Ibuprofen Anti-prostaglandins have been reported to decrease blood loss May consider treatment with OCP or progestin Continue treatment for 3-6 months. If chose to treat with OCPs, 1 pill daily for 21 days followed by 1 week of placebo or continuous pills if prefer.

Treatment depends on current bleeding and Hgb Moderate Menses >7d or cycle frequency <3 weeks and mild anemia (Hgb 10-11g/dL) If patient not bleeding significantly at time of visit and is not already on hormonal therapy can start with 1 pill daily If patient with moderate bleeding at time of visit, 1 pill BID until bleeding stops, then daily for total of 21 days Continue cyclic pills or may do continuous Follow Hgb as needed Consider continuing pills at least until Hgb normal (min 3-6 months) Note, important to give clear instructions and even consider diagraming pills; will need more than 1 pack at a time!!

Treatment depends on current bleeding and Hgb Severe Ongoing heavy bleeding with moderate anemia (Hgb 8-10g/dL) If bleeding is slowing and Hgb >9 g/dL Can start with BID pills (see moderate) If bleeding not slowing 1 pill q6h for 2-4 days prn anti-emetic 2h before pill 1 pill q8hx 3 days 1 pill q12h for at least 2 weeks Follow serial Hgb closely Consider inpatient admission if concern for patient/family reliability Watch for bleeding, if persists, may need BID hormonal pills and eliminate pill free interval until Hgb has returned to normal Once Hgb normal, use regular or extended cycle OCPs for at least 6 months

Treatment depends on current bleeding and Hgb Severe Ongoing heavy bleeding, Hgb ≤ 7g/dL, Orthostatic vital signs Admit for inpatient management Notes Decision to transfuse not based solely on number Most patients can be managed with OCPs D&C rarely indicated IV estrogen only in severe acute hemorrhage, when patient NPO or critical care needed. Seems to increase clotting at level of capillaries.

What if patient has contraindication to estrogen? Medroxyprogesterone Short courses in mild bleeding Cyclic therapy if need ongoing Norethindrone acetate Cyclic therapy Continuous menstrual suppression LNG-IUS Definitely consider consultation -Can also consider in patients/parents not willing/wanting to do OCPs.

Indications for referral

When should referral be considered? To ER Symptomatic anemia Vital sign abnormalities To Adolescent Medicine/Reproductive Endocrinology OCP complications or decisions Bleeding difficult to control (breaking through) Secondary cause identified Note, can always contact for advice in interim

Take home points

Conclusions Remember what is “normal” Differential broad History is important Menstrual history as a “vital sign” CBC to guide treatment Different treatment options exist

Thank you! Contact information: Maria C. Monge, MD Director of Adolescent Medicine UTSW-Austin Pediatrics Residency Program 312-498-3470 mcmonge@hotmail.com