EXPERT ANALYSIS FROM AAP 2017

CHICAGO (FRONTLINE MEDICAL NEWS)Not only do you need to know the normal features of adolescent menstruation to identify what’s abnormal, but you also need to teach your patients what’s typical, according to S. Paige Hertweck, MD, chief of gynecology at Norton Children’s Hospital in Louisville, Ky.

“Remember to use the menstrual cycle as a vital sign,” Dr. Hertweck told attendees at the American Academy of Pediatrics annual meeting. “Even within the first year of menarche, most girls have a period at least every 90 days, so work up those who don’t.”

The median age of menarche is 12.4 years, typically beginning within 2-3 years of breast budding at Tanner Stage 4 breast development, she said. By 15 years of age, 98% of girls have begun menstruation.

Girls’ cycles typically last 21-45 days, an average of 32.2 days during their first year of menstruation, with flow for 7 days or less, requiring an average of 3-6 pads and/or tampons per day. Dr. Hertweck recommends you write down these features of normal menstruation so that your patients can tell you when their cycle is abnormal or menses doesn’t return.

“Cycle length is more variable for teens versus women 20-40 years old,” she said. However, “it’s not true that ‘anything goes’ for cycle length” in teens, she added. “Cycles that are consistently outside the range of 21-45 days are statistically uncommon.” Hence the need to evaluate causes of amenorrhea in girls whose cycles exceed 90 days.

Possible causes of amenorrhea include pregnancy, polycystic ovary syndrome, thyroid abnormalities, hyperprolactinemia, primary ovarian insufficiency, or hypogonadal amenorrhea, typically stimulated by the first instance of anorexia, Crohn’s disease, celiac disease, or a gluten intolerance.

Primary amenorrhea

Dr. Hertweck listed five benchmarks that indicate primary amenorrhea requiring evaluation. Those indicators include girls who have no menarche by age 15 years or within 3 years of breast budding, no breast development by age 13 years, or no menses by age 14 years with hirsutism or with a history of excessive exercise or of an eating disorder.

You can start by examining what normal menstruation relies on: an intact central nervous system with a functioning pituitary, an ovarian response, and a normal uterus, cervix, and vagina. You should check the patient’s follicle-stimulating hormone, thyroid-stimulating hormone, and prolactin levels to assess CNS functioning, and estradiol levels to assess ovarian response. A genital exam with a pelvic ultrasound can reveal any possible defects in the uterus, cervix, or vagina.

The presence of breasts without a uterus indicates normal estrogen production, so the missing uterus could be a congenital defect or result from androgen insensitivity, Dr. Hertweck explained. In those without breasts, gonadal dysgenesis or gonadal enzymatic deficiency may explain no estrogen production. If the patient has both breasts and a uterus, you should rule out pregnancy first and then track CNS changes via FSH, TSH, and prolactin levels.

Premature ovarian insufficiency

Approximately 1% of females experience premature ovarian insufficiency, which can be diagnosed as early as age 14 years and should be suspected in a patient with a uterus but without breasts who has low estradiol levels, CNS failure identified by a high FSH level, and gonadal failure.

Formal diagnosis requires two separate instances of FSH elevation, and chromosomal testing should be done to rule out gonadal dysgenesis. You also should test the serum anti-Müllerian hormone biomarker (readings above 8 are concerning) and look for two possible causes. The FMR1 (Fragile X) premutation carrier status could be a cause, or presence of 21-hydroxylase and/or adrenal antibodies indicate autoimmune polyglandular syndrome.

Catching premature ovarian insufficiency early enough may allow patients to preserve some fertility if they still have oocytes present. Aside from this, girls will need hormone replacement therapy to fulfill developmental emotional and physical needs, such as bone growth and overall health. Despite a history of treating teens with premature ovarian insufficiency like adults, you should follow the practice guidelines specific to adolescents by the American College of Obstetricians and Gynecologists committee opinion statement ( Obstet Gynecol. 2014;123:193-7 ).

Menorrhagia: heavy menstrual bleeding

Even though average blood loss is estimated at 30 mL per period, that number means little in clinical practice because patients cannot measure the actual amount of menses. Better indicators of abnormally greater flow include flow lasting longer than 7 days, finding clots larger than a quarter, changing menstrual products every 1-2 hours, leaking onto clothing such that patients need to take extra clothes to school, and any heavy periods that occur with easy bruising or with a family history of bleeding disorders.

First-line treatment for heavy menstrual bleeding in teens is hormonal contraception, either combination oral contraceptive pills, the transdermal patch, or the intravaginal ring, which can be combined with other therapies.

An alternative for those under age 18 (per Food and Drug Administration labeling) is oral tranexamic acid, found in a crossover trial with an oral contraceptive pill to be just as effective at reducing average blood loss and improving quality of life, but with fewer side effects and better compliance. Before prescribing anything for heavy menstrual bleeding, however, you must consider possible causes and rule some out that require different management.

Aside from pregnancy, one potential cause of menorrhagia is infection such as chlamydia or gonorrhea, which should be considered even in those with a negative sexual history, Dr. Hertweck said. Other possible causes include an immature hypothalamic-pituitary-ovarian axis, polycystic ovary syndrome (even with low hemoglobin), malignancy with a hormone-producing tumor, hypothalamic dysfunction (often stimulated by eating disorders, obesity, rapid weight loss, or gluten intolerance), or coagulopathy.

“Teens with menorrhagia may need to be screened for a bleeding disorder,” Dr. Hertweck said. At a minimum, she recommends checking complete blood count, ferritin, and TSH. “The most common bleeding disorders associated with heavy menstrual bleeding include platelet function disorders and von Willebrand.”

Up to half of teen girls with menorrhagia who visit a hematologist or multidisciplinary clinic receive a diagnosis of a bleeding disorder, Dr. Hertweck said. And up to half of those with menorrhagia at menarche may have von Willebrand, as do one in six adolescents who go to the emergency department because of heavy menstrual bleeding.

Von Willebrand syndrome

Von Willebrand syndrome is a deficiency or dysfunction of von Willebrand factor (vWF), a protein with binding sites for platelets, collagen, and factor VIII that “serves as a bridge between platelets and injury sites in vessel walls” and “protects factor VIII from rapid proteolytic degradation,” Dr. Hertweck said. Von Willebrand syndrome is the most common inherited congenital bleeding disorder. Although acquired von Willebrand syndrome is rare, it has grown in incidence among those with complex cardiovascular, hematologic, or immunologic disorders.

“Correct diagnosis is complex and not always straightforward,” Dr. Hertweck said, but “a positive response to questions in four categories is highly sensitive.” They are as follows:

• Menses lasting at least 7 days and interfering with a person’s daily activities.

• “History of treatment for anemia.

• Family history of a diagnosed bleeding disorder.

• History of excessive bleeding after tooth extraction, delivery, miscarriage, or surgery.

Diagnostic assays include platelet concentration of vWF antigen, an activity test of vWF-platelet binding, and factor VIII activity. However, you often need to repeat diagnostic testing because vWF antigens vary according to race, blood type, age, acute phase response, and menstrual cycle timing, Dr. Hertweck said.

“Remember to draw von Willebrand testing only during the first 3 days of the menstrual cycle when estrogen levels are at the nadir,” she said.

Because estrogen increases vWF, treatment for von Willebrand syndrome should be progestin only, either oral pills, medroxyprogesterone acetate (MPA, or Depo-Provera injections), or an etonogestrel implant.

Dr. Hertweck presented several cases of abnormal menstruation and extreme conditions such as severe menorrhagia. Outside of von Willebrand in such patients, possible platelet disorders could include Glanzmann thrombasthenia (a platelet function disorder that is caused by an abnormality in the genes for glycoproteins IIb/IIIa) and platelet storage pool disorder, both of which should be diagnosed by a hematologist.

Dr. Hertweck reported having a research grant from Merck related to contraceptive implants in adolescents.

pdnews@frontlinemedcom.com

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