Menstruation Disorders in Adolescents 

Updated: Apr 09, 2019
Author: Kirsten J Sasaki, MD; Chief Editor: Andrea L Zuckerman, MD 

Overview

Background

In adolescents, disorders of menstruation may present as abnormal uterine bleeding (AUB). Broadly understood, AUB includes the following:

  • Absence of bleeding
  • Irregular bleeding
  • Abnormally heavy bleeding
  • Bleeding in between periods

Amenorrhea, or absent menstruation, can be either primary or secondary. Primary amenorrhea is defined as either (a) the lack of menstruation by the age of 15 years (or within 3 years of thelarche) with otherwise normal pubertal development or (b) the lack of secondary sexual characteristics by the age of 13 years.[1] Secondary amenorrhea is defined as the lack of menses for 6 months, though it is uncommon even in adolescents to lack menses for more than 3 months.

AUB, according to the International Federation of Gynecology and Obstetrics (FIGO) system, is determined on the basis of four parameters: frequency, regularity, duration, and volume.[2]  The 2018 revision of this system includes intermenstrual bleeding. Causes of AUB can be classified according to the PALM-COEIN system, in which the acronym PALM represents structural causes (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia) and the acronym COEIN represents nonstructural causes (coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not otherwise classified).[2]

Once a woman has begun menarche, there are multiple menstrual disorders that can occur. These presentations may also be associated with painful menses, known as dysmenorrhea.

Menstrual disorders in adolescents do mirror some common menstrual disorders in adults, but amenorrhea, systemic bleeding disorders, abnormal bleeding due to exogenous hormones, and sexually transmitted infections (STIs) are more common in this population. Using a systematic approach to evaluating this population will help the general practitioner diagnose and treat most of the common causative conditions. Consultation with a specialist may be necessary for complex cases or unusual disorders that are not regularly treated in a general practice.

For patient education resources, see the Women's Health Center and Pregnancy Center, as well as Amenorrhea, Vaginal Bleeding, Female Sexual Problems, Birth Control Overview, and Birth Control Methods.

Pathophysiology

To determine what constitutes a disorder of menstruation, one must first have a clear understanding of normal menstruation.

Puberty involves the maturation of the neuroendocrine system and requires multiple steps to achieve completion. The hypothalamus begins to secrete gonadotropin-releasing hormone (GnRH), and as secretion continues, the pituitary gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and ovarian follicles become more sensitive to stimulation.

Increases in GnRH pulsatility lead to gonadotropin secretion, eventually leading to selection of a dominant follicle. As the follicle grows, it produces estrogen, which in turn provides positive feedback on the gonadotropins to cause an LH surge and thus ovulation. In regard to the endometrium, during ovulatory menstrual cycles, the dominant follicle secretes estradiol, which causes the endometrium to proliferate, and prepare for potential implantation.

After ovulation, a corpus luteum develops as the granulosa cells become luteinized. The corpus luteum secretes progesterone, which transitions the endometrium into a more stable environment for possible implantation. Without implantation of an embryo, the corpus luteum involutes; this involution leads to falling progesterone and estradiol levels and thus to shedding of the endometrium as it loses its blood supply.

If any of the above steps is disrupted, menarche and the menstrual cycle may not occur or may occur irregularly and result in absent or abnormal menses.

In the United States, the median age of menarche is 12.43 years, with only 10% of females menstruating at 11 years and 90% by 13.75 years.[3] Non-Hispanic blacks demonstrate an earlier median age of menarche, 12.06 years, compared with 12.55 years for non-Hispanic whites.

Menarche usually occurs when females have Tanner stage IV breast and pubic hair development[4] ; the average interval from the development of breast buds to the onset of menarche is 2-3 years. In the first years after menarche, anovulatory cycles are more common and may constitute 50% of cycles. Nevertheless, most cycles are still between 21 and 45 days and last between 2 and 7 days (mean, 5 days).[5, 6]

The age of menarche is associated with the length of time needed to achieve regular ovulatory cycles. A younger age of menarche is associated with more than 50% ovulatory cycles after 1 year, whereas a later onset of menarche is not associated with fully ovulatory cycles for 8-12 years.[7]

Finally, in a normal menstrual cycle, a female will lose about 30-40 mL of blood or use approximately three to six pads or tampons each day.[1] Loss of more than 80 mL of blood or bleeding that persists for longer than 7 days is an indication of abnormal menstrual flow.[8]

Etiology

Primary amenorrhea

The most common causes of primary amenorrhea are ovarian insufficiency, müllerian agenesis, and hypogonadotopic hypogonadism.[9] Pregnancy must also be considered, in that ovulation and intercourse can occur before the onset of menarche.

There are multiple ways of categorizing the causes of primary amenorrhea. One method is to group the causes according to the levels of gonadotropins and ovarian production of hormones, as follows[10] :

Another common way of organizing the multiple causes of primary amenorrhea is to categorize them on the basis of the absence or presence of breasts and a uterus, as follows:

  • Breasts present, uterus present - Hypothalamic dysfunction; pituitary lesion; PCOS; ovarian insufficiency
  • Breasts present, uterus absent - Müllerian agenesis; complete androgen insensitivity
  • Breasts absent, uterus present - Hypogonadotropic hypogonadism; gonadal dysgenesis/agenesis
  • Breasts absent, uterus absent - Enzyme deficiency (ie, 17,20-desmolase deficiency); agonadism

This categorization generally excludes etiologies associated with ambiguous genitalia, hyperandrogenism, and Cushing syndrome.[11]

Yet another method of categorizing the etiologies of primary amenorrhea involves evaluating the components of the hypothalamic-pituitary-ovarian (HPO) axis as well as the uterus and other endocrine disorders that could affect menstruation, as follows:

  • I. Anatomic defects - Müllerian agenesis ( Mayer-Rokitansky-Kuster-Hauser syndrome); complete androgen insensitivity syndrome; imperforate hymen; transverse vaginal septum
  • II. Primary hypogonadism - Gonadal dysgenesis: Turner syndrome (45,X), Swyer syndrome (46,XY); gonadal agenesis
  • III. Hypothalamic causes - Dysfunctional (stress, exercise, diet, eating disorders); Kallmann syndrome
  • IV. Pituitary causes - Tumors ( prolactinoma, other hormone-secreting tumors)
  • V. Other endocrine gland disorders - Adrenal (adult onset adrenal hyperplasia, Cushing syndrome); thyroid disease; ovarian tumors
  • VI. Multifactorial/other causes - PCOS; constitutional delay

Regardless of the manner in which one wishes to organize the causes of primary amenorrhea, evaluation of such a patient should always include certain key elements (see Presentation and Workup).

Abnormal uterine bleeding

Structural pathology is a rarer cause of abnormal bleeding in adolescents than in adults, accounting for less than 10% of abnormal bleeding in the adolescent population.[10] The most common causes of AUB in adolescents include ovulatory dysfunction, commonly due to immaturity of the HPO axis and PCOS, coagulopathy, pregnancy, and pelvic infections.[10, 12, 6]

Ovulatory dysfunction

Ovulatory dysfunction is the most common cause of AUB in adolescents. As noted (see Pathophysiology), cycles are not consistently ovulatory for the first few years after menarche, especially if menarche occurs at a later age. During this time, the most common cause of irregular menstrual cycles is immaturity of the HPO axis, but additional etiologies should be considered, including pregnancy, PCOS, hypothyroidism, hyperprolactinemia, and functional hypothalamic dysfunction.

During anovulatory cycles, an oocyte is not released, and without the formation of a corpus luteum, progesterone is not produced. This results in endometrial proliferation from unopposed estrogen with fragile blood vessels. The endometrium irregularly outgrows its blood supply, thus leading to unpredictable, erratic,[13] and sometimes heavy and prolonged bleeding.[14]

Polycystic ovary syndrome

PCOS is the most common endocrine disorder, with a prevalence of 6-10%.[15] It is also the most common cause of irregular menstrual bleeding, oligomenorrhea, or amenorrhea, associated with hyperandrogenism.[16]

Oligomenorrhea is defined as menstrual cycles occurring more than 35 days to 3 months apart. In adolescents, oligomenorrhea may be extended to cycles that last longer than 45 days until 2-3 years after menarche, though cycles extending past 35 days may be an early indicator of irregular menstrual cycles.[17] Patients with PCOS often have few, irregular, and at times heavy cycles throughout the year.

There are multiple diagnostic criteria for PCOS, including those of the National Institute of Health, the Rotterdam Consensus Criteria, and those of the Androgen Excess Society. They all include two of three different criteria in some combination, as follows[18, 19, 20, 21] :

  • Hyperandrogenism (either clinical or laboratory)
  • Oligoamenorrhea or amenorrhea
  • Polycystic ovaries on pelvic ultrasonography (US)

The diagnosis may be more challenging to make in adolescents, in that anovulatory cycles and acne are more common among this age group. Consequently, some have recommended that all of the Rotterdam criteria—including laboratory evidence of hyperandrogenism or progressive hirsutism, and not only acne—must be present for a diagnosis of PCOS in adolescents.[17]

Obesity is commonly associated with PCOS, because insulin resistance plays a role in the central pathophysiology of the disease,[16] but as many as 20% of adults with PCOS are not obese.[18]  Metabolic syndrome is also common in PCOS adolescents,[22] which places these individuals at increased risk for cardiovascular disease and diabetes.

Additional causes should be considered in an adolescent with hirsutism and irregular menstrual bleeding, including congenital adrenal hyperplasia and ovarian and adrenal tumors. These can be ruled out by means of blood tests (see Workup).

Finally, endometrial malignancy, though rare in women younger than 40 years, should also be on the differential diagnosis for adolescents with irregular menses. Farhi et al presented a case series of 10 young women, the youngest of which was 15 years of age, all diagnosed with endometrial adenocarcinoma.[23] The most common presentation was irregular menses.

Heavy menstrual bleeding

AUB–heavy menstrual bleeding (HMB), formerly referred to as menorrhagia, is defined as blood loss exceeding 80 mL or bleeding that lasts longer than 7 days each menstrual cycle. Because objective evaluation of blood loss via the alkaline hematin method is cumbersome, AUB-HMB is often defined subjectively as excessive menstrual bleeding, even though subjective assessments of blood loss have been demonstrated to be largely inaccurate.[8]

Pictorial blood assessment charts have demonstrated high sensitivity and specificity for identifying HMB.[24] AUB-HMB can be due to uterine structural causes (eg, fibroids or adenomyosis), systemic or iatrogenic causes, and (especially important in adolescents) systemic bleeding disorders. As many as 19% of adolescents who are admitted with AUB have an underlying bleeding disorder,[25, 26] and when menorrhagia occurred from the onset of menarche, 65% of women had a bleeding disorder.[25]

Von Willebrand disease, factor deficiencies, and platelet abnormalities are the most common causes of bleeding disorders in the adolescent population, with von Willebrand disease being the most common inherited bleeding disorder.[27] Von Willebrand disease is an autosomally inherited bleeding disorder with three types and various degrees of severity. It is due to either a quantitative or a qualitative deficiency in von Willebrand factor, a protein involved in platelet adhesion.

Because menstrual bleeding is controlled by the formation of a platelet clot, HMB since menarche may be the presenting symptom in as many as 53% of patients with von Willebrand disease.[28] The prevalence is 0.8-1.3% in the general population[29] and 13-20% in those with menorrhagia.[30, 31]

The most common form of von Willebrand disease, type 1, is autosomal recessive, accounts for 70% of cases, and presents with a milder bleeding tendency as compared with the other types.[27] In addition to HMB, symptoms include epistaxis, bleeding after dental procedures, postoperative bleeding, and joint bleeding.[32]

The American College of Obstetricians and Gynecologists (ACOG) has recommended initial screening in patients with HMB since menarche[12] as well as a history of excessive bleeding (including frequent gum bleeding) and more than two episodes of epistaxis per month or frequent bruising.[33]

Another screening tool, specifically for adolescents, includes a history of menses longer than 7 days, a “flooding” or “gushing” sensation, bleeding through a pad or tampon in 2 hours, a history of anemia, a family history of a bleeding disorder, or a history of a bleeding disorder after a hemostatic challenge, such as a tooth extraction or delivery.[34]

Intermenstrual bleeding

As the name indicates, AUB–intermenstrual bleeding (IMB), previously referred to as metrorrhagia, is defined as bleeding in between periods. Common causes in adolescents include the following:

  • Pregnancy
  • STIs
  • Iatrogenic etiologies from administration of exogenous steroids, including oral contraceptive pills

Pregnancy, including ectopic pregnancy, can present with irregular uterine bleeding or amenorrhea.

STIs—specifically, those caused by Chlamydia trachomatis, Trichomonas vaginalis, herpes simplex virus (HSV), human papillomavirus (HPV), and Neisseria gonorrhoeae —are more common in adolescents. One survey demonstrated that among female adolescents aged 14-19 years, 24% had evidence of one of the above infections. Risk factors for STI include the following:

  • Age less than 25 years
  • Multiple partners
  • Early age of sexual activity
  • Inconsistent condom use
  • Alcohol or drug consumption

Common symptoms include vaginal discharge, dysuria, and genital lesions. STIs can also cause irregular vaginal bleeding due to inflammation of the genital tract,[35] including the cervix and endometrium, which can be fragile and shed irregularly.[14]

Exogenous hormone administration, in the form of combined estrogen-progestin contraceptives, administered orally or transdermally, or progestin-only contraceptives (eg, depot medroxyprogesterone acetate, the etonogestrel implant, and the levonorgestrel-releasing intrauterine device [IUD]), can cause intermenstrual and irregular bleeding patterns.

Unscheduled bleeding is common during the first months after initiation of combined estrogen-progestin methods, and it will generally resolve after the first three cycles.[36] Unscheduled bleeding rates may be higher in those taking lower-dose pills (eg, 20 µg ethinyl estradiol) than in those taking higher-dose pills (eg, 30-35 µg).[37]

Progestin-only regimens are commonly associated with unscheduled bleeding, which may continue throughout the entire use of the medication. Although almost 50% of women will be amenorrheic after 12 months of depot medroxyprogesterone use, irregular bleeding during the first several months is common. The etonogestrel implant is associated with up to a 15% discontinuance rate due to irregular bleeding issues.[38] The levonorgestrel-releasing IUD is associated with irregular bleeding and spotting in the first 3-6 months after placement.

Finally, the nonhormonal copper IUD is associated with heavier periods and irregular bleeding during the first few months after placement, but the heavier bleeding improves over time, whereas the irregular bleeding generally does not.[39]

Dysmenorrhea

Dysmenorrhea may be either primary or secondary. Primary dysmenorrhea occurs in the absence of any identifiable pathology and is attributed to the production of prostaglandins during the menstrual cycle. Secondary dysmenorrhea occurs when there is an identifiable pelvic or hormonal pathology causing pain.

The most common gynecologic causes of secondary dysmenorrhea are endometriosis and pelvic inflammatory disease (PID). Endometriosis occurs when endometrial glands and stroma implant outside of the uterus, most commonly in the peritoneal cavity but also in the gastrointestinal (GI) tract, urinary tract, and lung. PID is a polymicrobial infection that is 10 times more common in adolescents than in adults.[10]

 

Presentation

History

Primary amenorrhea

It is recommended to start an evaluation for primary amenorrhea if a female with normal secondary sexual characteristics has failed to menstruate by the age of 15 years or within 3 years of breast budding (thelarche).[1] Another indication of delayed puberty, and cause for workup, is lack of breast development by the age of 13 years.

The evaluation should start with a thorough history to assess for any history of vaginal bleeding, development of other secondary sexual characteristics, or evidence of excess androgens, such as hirsutism or increased muscle mass. A review of systems should include any changes in weight, stress or activity level, headaches, visual disturbances, or milk production.

The past medical history should include questions about childhood health or chronic illness, as well as use of any medications, including metoclopramide and antipsychotic agents. The family history should include any history of delayed puberty or premature ovarian failure.

Abnormal uterine bleeding

Evaluation of abnormal uterine bleeding (AUB) should commence with a thorough history that includes, including age of menarche, menstrual bleeding patterns (eg, number of cycles over the past 12 months), duration and severity of menstrual flow, and pelvic pain associated with the cycle.

Some adolescents may find the creation of a menstrual calendar or diary helpful for identifying menstrual patterns.[14] Because every woman changes her pad or tampon differently, it may be difficult at times to establish the presence of heavy menstrual flow; in such cases, it may be helpful to ask about use of overflow pads or multiple pads or about disruption of daily activity as a result of menstrual flow.

A history of current or previous sexual activity should be elicited, as well as a history of any previous sexually transmitted infections (STIs) and any current vaginal discharge or dysuria. These questions should be posed in a nonthreatening, nonaccusatory manner. Relating the identification of the menstrual disorder to a possible infection may place the adolescent at ease.

All chronic medical conditions and all medications or herbal supplements should be identified. Specific inquiries should be made about the use of anticoagulants, antipsychotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and hormonal contraceptives, which can all cause irregular menses. All previous surgical procedures should be noted, and any complications (eg, postoperative bleeding) should be detailed.

Another important component of the history includes a thorough family history for bleeding disorders, especially von Willebrand disease. If a patient is taking any short-acting exogenous hormones, especially if she is doing so for contraception, it is important to ensure that these agents are being taken appropriately and consistently.

Dysmenorrhea

Dysmenorrhea can occur with regular bleeding patterns or can be associated with AUB. Primary dysmenorrhea presents with painful menses and occasionally is accompanied by nausea, vomiting, diarrhea, fatigue, and headache.[10] In secondary dysmenorrhea, the pain often precedes the onset of menses.

Endometriosis may be asymptomatic but can also cause cyclic and acyclic pelvic pain, painful menses, dysuria, dyschezia and infertility. It may be present in as many as 70% of adolescents who present with dysmenorrhea.[40]  Pelvic inflammatory disease (PID) can present with painful, irregular uterine bleeding or vaginal discharge.

Physical Examination

Primary amenorrhea

Physical examination for primary amenorrhea begins with measurement of height, weight, body mass index (BMI), and vital signs. One should also evaluate for staging of thelarche and adrenarche, as well as for signs of hyperandrogenism, including hirsutism, acne, and clitoromegaly.

Thelarche marks the beginning of breast development and includes five Tanner stages, as follows[4] :

  • Stage 1 - No palpable breast tissue
  • Stage 2 - Development of breast buds with elevation of the papilla
  • Stage 3 - Enlargement of the breast without separation of the areola
  • Stage 4 - Formation of a secondary mound, as the areola and papilla project above the breast
  • Stage 5 - Recession of the areola to the contour of the breast

Adrenarche indicates the activation of the adrenal cortex to produce androgens; it is associated with pubarche, or the development of pubic hair.

The examination should also include evaluation of physical features consistent with Turner syndrome, such as short stature, webbed neck, shield chest, and widely spaced nipples. If feasible, a genital examination should be performed to evaluate for presence of an imperforate hymen, absent or blind-ending vagina, or transverse vaginal septum, as well as the presence of a cervix, uterus and ovaries. If this is not possible, imaging can be performed to evaluate for the presence of müllerian structures.

Abnormal uterine bleeding

Physical examination for AUB should include height, weight, BMI, and vital signs. As with the examination for amenorrheic patients, one should inspect for signs of hyperandrogenism and also for indications of insulin resistance, which may suggest polycystic ovary syndrome (PCOS). If there is suspicion of a possible bleeding disorder, physical evaluation should include inspection for petechiae, skin pallor, ecchymoses, and swollen joints.

If there is concerned about possible PID, a speculum examination should be performed to inspect for discharge, and endocervical samples should be collected for detection of gonorrhea or chlamydia. Urine samples can also be tested with nucleic acid amplification if a vaginal examination is not feasible. A bimanual examination assessing for cervical motion tenderness, uterine and adnexal tenderness is also important when there is concern about possible STI.

 

Workup

Laboratory Studies

Primary amenorrhea

The laboratory workup for primary amenorrhea depends on the findings from the history and physical examination. If there is physical evidence of a blind-ending vaginal pouch, measurement of the testosterone level and karyotyping are indicated to differentiate between müllerian agenesis and complete androgen insensitivity syndrome.

If a uterus is present, basic laboratory evaluation includes a pregnancy test and levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, thyroid-stimulating hormone (TSH), and prolactin. For interpretation of FSH and LH test results, the estradiol and progesterone levels must be low. In young women with no menses, it is sometimes necessary to draw weekly estradiol and progesterone levels until they indicate that the patient is in the early follicular phase, and then draw FSH and LH levels.

If the FSH is elevated, primary hypogonadism is likely, and karyotyping should be performed to determine whether there is evidence of Turner syndrome (45,X or 45,X/46,XX mosaic) or Swyer syndrome (46,XY). If the FSH is low or normal, the cause is likely hypothalamic, and further workup may include imaging of the head if no obvious cause (eg, stress- or exercise-induced hypothalamic dysfunction) is identified.

If the prolactin level is elevated, it is important to make sure that it was obtained in the fasting state without any recent nipple stimulation; if it was not, it may have to be repeated. If the prolactin level remains elevated and there is no recent medication use, including psychotropic medications to explain the elevation, magnetic resonance imaging (MRI) of the pituitary should be performed to evaluate for a pituitary microadenoma or adenoma.

With signs of hyperandrogenism, serum testosterone, dehydroepiandrosterone sulfate (DHEA-S), and 17-hydroxyprogesterone (17-OHP) levels should be checked to rule out an ovarian or adrenal tumor or congenital adrenal hyperplasia.

Abnormal uterine bleeding

Laboratory evaluation for abnormal uterine bleeding (AUB) should include a pregnancy test, a complete blood count (CBC), TSH levels, testing for gonorrhea and chlamydia, and screening for bleeding disorders when indicated.[12] In high-risk individuals, testing for HIV, syphilis, and hepatitis B and C should be considered as well.

For those with irregular bleeding patterns, measurement of hormone values (eg, estradiol, FSH, LH, and prolactin) may be indicated. Again, for proper interpretation of these values, they should be obtained in the early follicular phase; if menses are irregular, weekly estradiol and progesterone levels can be obtained until they are sufficiently low, at which point LH and FSH can be added. If there is concern about insulin resistance or metabolic abnormalities, one may consider performing a 2-hour glucose tolerance test, as well as fasting lipid levels.

If androgen excess is noted, or as part of an initial screen, one should consider evaluating free and total testosterone levels, DHEA-S, and 17-OHP. Screening for bleeding disorders includes CBC with platelets, coagulation studies, and, if there is concern about possible von Willebrand disease, von Willebrand-ristocetin cofactor activity, von Willebrand factor antigen, and factor VIII level.

Imaging Studies

Diagnostic imaging for primary amenorrhea, like the laboratory workup, depends on the findings from the history and physical examination.

Imaging studies for AUB generally begin with transvaginal ultrasonography (US). Imaging is not necessary in all patients, but it is recommended if abnormal findings (eg, an enlarged uterus) are noted on physical examination or if symptoms continue despite treatment in a patient with normal physical findings. Further evaluation may include hysterosonography or hysteroscopy[12] ; some patients may require laparoscopy, especially if a diagnosis of endometriosis is under consideration.

 

Treatment

Management of Primary Amenorrhea

Treatment of amenorrhea depends upon the identified cause. The following is a brief description of treatment options.

In cases of müllerian agenesis, counseling is warranted to discuss the diagnosis with the patient and the family; this should include a discussion of future fertility options, including use of a gestational carrier, and sexual relationships. Treatment includes nonsurgical and surgical creation of a neovagina, as well as general gynecologic examinations to evaluate for vaginal stricture and stenosis.[41]

For androgen insensitivity syndrome, complete gonadectomy may be performed after the patient has completed puberty to prevent gonadal neoplasia, for which the patient is at increased risk.[42] In this case, use of a donor egg versus use of a gestational carrier may be discussed.

Anatomic defects, such as imperforate hymen or transverse vaginal septum, are treated with a surgical procedure to create a patent outflow tract. Usually, a successful, normal pregnancy and delivery can be anticipated.

For primary hypogonadism, if it is due to premature ovarian failure, treatment should include a discussion of hormone therapy, and additional assessment may be required, including testing for a premutation in the FMR1 gene.[43] A donor egg can be utilized, with normal delivery expected.

In cases of functional hypothalamic amenorrhea, gaining weight and reducing exercise levels will likely result in resumption of menses.[44]

Polycystic ovary syndrome (PCOS) is treated essentially as it would be in the context of abnormal uterine bleeding (AUB; see below).

Management of Abnormal Uterine Bleeding

Polycystic ovary syndrome

Treatment of PCOS depends on the patient’s goals, as follows:

  • For patients who wish to conceive, clomiphene citrate is the first-line treatment, followed by gonadotropins [18]
  • For those who are not attempting to conceive, a combined oral contraceptive pill (COCP) is usually the first line of treatment, provided that there are no contraindications; COCPs are therapeutic for multiple reasons, including regulating menstrual cycles, suppressing ovarian and adrenal androgen production and increasing circulating levels of sex hormone binding globulin, thus lowering the levels of free testosterone in the serum [15]

In addition to these treatment options, lifestyle modifications are recommended for overweight and obese PCOS patients so as to decrease their risk for cardiovascular disease, diabetes, and metabolic syndrome.[18, 45, 19]

Metformin has also been demonstrated to decrease ovarian androgen production and insulin levels, and it may improve ovulation rates; however, it is not currently approved for treatment of PCOS-related menstrual dysfunction. It may be used to delay the development of diabetes in those with impaired glucose tolerance, but is not as effective as lifestyle modifications.[45]

For patients with hirsutism, multiple treatment options are available. A multitiered approach is often necessary, combining cosmetic procedures with medications such as COCPs and antiandrogens (eg, spironolactone, flutamide and finasteride).[18]  When antiandrogen medications are being used, it is important to use contraceptives as well because the antiandrogens are teratogenic.

Heavy menstrual bleeding

First-line therapy for AUB–heavy menstrual bleeding (HMB) often includes nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and mefenamic acid. They have been demonstrated to decrease menstrual blood loss in comparison with placebo; they decrease prostaglandin levels, which are increased in women with AUB-HMB.[46]

Additional treatment options include hormone therapy with COCPs, as well as the use of progestin-only medications, including pills, medroxyprogesterone acetate, and the etonogestrel implant (especially if there are contraindications for COCP therapy).[47]

Another progestin-only option is the levonorgestrel-releasing intrauterine device (IUD),[48, 49] which has been demonstrated to decrease menstrual blood loss to a greater extent than NSAIDs, COCPs, or antifibrinolytic agents do.[50] Although most of the studies on IUDs have been performed in women at least 18 years of age, this is an appropriate form of contraception in adolescents[51]  and thus may be an option for treatment of AUB-HMB.

A nonhormonal pharmacologic option that has been demonstrated to decrease HMB in adults is the use of antifibrinolytic drugs, such as tranexamic acid[52] ; however, these agents are not currently approved for use in adolescents.

Coagulopathy

If a patient is diagnosed with von Willebrand disease, one should seek consultation with a hematologist in order to optimize the treatment regimen. Possible medical options include antifibrinolytic agents, COCPs, and progestin-only contraceptives.[34] Additional nonhormonal treatment options include desmopressin acetate and recombinant factor VIII.[32]

Intermenstrual bleeding

If a patient is taking a short-acting hormone, it is important to counsel her about proper administration of the medication. It is also important to provide counseling about what she may expect in terms of bleeding patterns, especially during the first few months of use. If a patient was recently started on contraceptives, unscheduled bleeding is common in the first 3 months, and in many cases, all that is needed is reassurance.

If irregular bleeding persists and the adolescent is taking a low-dose COCP (eg, < 20 µg ethinyl estradiol), the intermenstrual bleeding (IMB) may resolve if the estrogen dose is increased.[37] Depending on when the bleeding occurs during the cycle, she may benefit from increasing either the progestin level or the estrogen support in her formulation.[53]

For patients who are taking progestin-only formulations, bothersome unscheduled bleeding can often be treated by administering NSAIDs or by providing brief estrogen supplementation with COCPs, provided that no contraindications exist.[54]

Management of Dysmenorrhea

Primary dysmenorrhea

First-line therapy for primary dysmenorrhea consists of NSAIDs, which inhibit prostaglandin synthesis and lead to less vigorous uterine contractions.[55] Improvement may occur if regularly scheduled doses are started 1-2 days before anticipated menses. If improvement is not seen after three menstrual cycles, a trial of oral contraceptive pills for three menstrual cycles may be offered.

Secondary dysmenorrhea

Secondary dysmenorrhea is less likely to respond to NSAIDs than primary dysmenorrhea is.[10]

Endometriosis

NSAIDs are a common first-line treatment for endometriosis, though there is no current evidence that these agents reduce endometriosis-related pain.[56] Oral contraceptives, progestins, androgens, and gonadotropin-releasing hormone (GnRH) agonists are the mainstays of medical therapy.

COCPs decrease pain as compared with placebo, and in patients who experience pain during withdrawal bleeding, pain reduction has been demonstrated with continuous oral contraceptives.[57] Progestins, administered orally and subcutaneously, provide pain relief and offer benefit equivalent to that of GnRH agonists, with fewer side effects.[58]

GnRH agonists do provide effective relief of endometriosis-related pain, but they have significant side effects, including osteopenia, vaginal dryness and hot flashes. If these agents are used for longer than 6 months, add-back therapy should be initiated.[59]

Pelvic inflammatory disease

Treatment of pelvic inflammatory disease (PID) consists of antibiotics (given orally or intravenously, depending on the patient’s clinical presentation and findings) and, potentially, drainage of an abscess or surgical intervention. In view of the known sequelae of untreated PID, it is recommended that all sexually active women presenting with lower abdominal or pelvic pain with no other identifiable etiology, or cervical motion, uterine or adnexal tenderness be empirically treated for PID.[60, 61]

 

Medication

Medication Summary

Medications used in the management of menstrual disorders depend on the type of disorder and the etiology of the disorder.

Estrogen and progestin combination

Class Summary

In patients with secondary amenorrhea who have a completely normal physical examination, medroxyprogesterone can be used to diagnose anovulation as the cause of amenorrhea (progesterone challenge test). Estrogens are effective in controlling acute, profuse bleeding. Estrogen also induces formation of progesterone receptors, making subsequent treatment with progestins more effective.

Ethinyl estradiol and a progestin derivative (Ovral, Ortho-Novum, Ovcon, Genora)

Combination pills of estrogen and progesterone in varying doses are used in the management of DUB. 21-day or 28-day cycles are used. Reduces secretion of LH and FSH from pituitary by decreasing amount of GnRH

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Class Summary

These agents block formation of prostacyclin, an antagonist of thromboxane, which is a substance that accelerates platelet aggregation and initiates coagulation.

Naproxen (Aleve, Anaprox, Naprosyn)

For relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Mineral Supplements

Class Summary

These agents are used to provide adequate iron for hemoglobin synthesis and to replenish body stores.

Iron sulfate (Feosol, Feratab, Fer-Iron, Slow-FE)

A nutritionally essential inorganic substance.

Progestins

Class Summary

These agents inhibit secretion of pituitary gonadotropins, which subsequently cause endometrial thinning.

Etonogestrel implant (Nexplanon)

Etonogestrel reduces secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH), which in turn inhibits endometrial proliferation.

Levonorgestrel (Mirena)

Levonorgestrel reduces secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH), which in turn alters the endometrium.

Medroxyprogesterone acetate (Depo-Provera)

Progestin therapy in adolescents produces regular cyclic withdrawal bleeding until maturity of positive feedback system is achieved. Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. Typically does not stop acute bleeding episode but produces a normal bleeding episode following withdrawal.

Gonadotropin releasing hormone agonists

Class Summary

Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Leuprolide acetate (Eligard, Lepron Depot)

Works by reducing concentration of GnRH receptors in the pituitary via receptor down regulation and induction of postreceptor effects, which suppress gonadotropin release. After an initial gonadotropin release associated with rising estradiol levels, gonadotropin levels fall to castrate levels, with resultant hypogonadism. This form of medical castration is very effective in inducing amenorrhea, thus breaking ongoing cycle of abnormal bleeding in many anovulatory patients. Because prolonged therapy with this form of medical castration is associated with osteoporosis and other postmenopausal side effects, many practitioners add a form of low-dose hormonal replacement to the regimen. Because of the expense of these drugs, they usually are not used as a first line approach but can be used to achieve short-term relief from a bleeding problem, particularly in patients with renal failure or blood dyscrasia.

Antidiabetic agents, biguanine

Metformin (Fostamet, Glucophage, Glumetza, Riomet)

Metformin has been demonstrated to decrease ovarian androgen production and insulin levels, and it may improve ovulation rates; however, it is not currently approved for treatment of PCOS-related menstrual dysfunction. Metformin in many, but not all, studies successfully treated hirsutism in patients with PCOS secondary to insulin resistance. Not effective if patient does not have insulin resistance.