Irregular menstrual cycles are a frequent source of concern for adolescents. Menstrual irregularities can be common in the first 2 years but understanding the normal menstrual cycle is important to recognize abnormalities.
Physiology: Normal Menstruation
Menarche is defined as the first episode of menstrual bleeding. The average age of menarche among all ethnicities is 12.5 years.1 There is an average of 2 years between thelarche, which is the first sign of puberty in girls, and the onset of menarche. Females most often reach menarche at Tanner stage 4 of pubertal development. The normal menstrual cycle length is 28 days ± 7 days with the menstruation lasting between 2 and 7 days. There are two distinct phases of the menstrual cycle: follicular and luteal.
The follicular phase begins with the onset of menses. By the mid-follicular phase, estradiol levels rise and lead to proliferation of the endometrium. During this phase, a dominant ovarian follicle is responsible for most of the estradiol. Stromal and epithelial cells of the endometrium proliferate with estradiol exposure. The high estradiol concentration leads to a decrease in follicle-stimulating hormone (FSH), and positive feedback to the pituitary eventually causes a burst release of luteinizing hormone (LH). The luteal phase begins with the LH surge. After approximately 36 hours of LH surge, the oocyte is released from the follicle at the surface of the ovary (ovulation). Continued exposure to LH leads to a dominant follicle becoming the corpus luteum. Corpus luteum then secretes progesterone. Progesterone will enable the differentiation of the endometrium. In the absence of fertilization, the corpus luteum involutes and stops secreting progesterone and the endometrium degenerates. Arterioles will constrict leading to hypoxia-reperfusion injury and then the lining sloughs off marking the beginning of next follicular phase.2 It can take up to 2 years from menarche to develop a mature hypothalamic-pituitary-gonadal (HPG) axis. Within 1 year, 75% of girls have a cycle between 21 and 45 days. By the fifth gynecological year, 90% of girls will have regular cycles with 75% having ovulatory cycles. Oligomenorrhea can occur in this time period.3
The basis of evaluation for patients with menstrual irregularities should start with a thorough medical history to assess the effects of each hormone. A detailed history should include the onset of pubertal development and menarche. Subsequent questions about the onset of irregular cycles, along with description of the frequency, length, and quality of the cycles and the associated symptoms are essential. If the patient has absence or cessation of menstrual cycles, the differential diagnosis depends on whether the patient has primary or secondary amenorrhea (see below). Associated symptoms such as hirsutism can suggest exposure to excess androgens (hyperandrogenism) due to conditions such as polycystic ovarian syndrome (PCOS) or congenital adrenal hyperplasia (CAH; nonclassical or simple virilizing type), whereas symptoms such as galactorrhea and headaches would point to prolactin excess due to prolactinoma. A history of congenital lymphedema and poor growth would suggest Turner's syndrome. A history of medication exposure, such as dopamine agonists or antipsychotics, should also be noted as they can affect prolactin levels.1 A history of excessive dieting and exercise should raise the suspicion for anorexia nervosa. A review to evaluate for any symptoms suggestive of systemic or illnesses involving other body systems (ie, rheumatologic or gastrointestinal illnesses) is also important as it may affect menstrual cycles. Conditions such as PCOS do have a genetic component and a family history may be informative. A detailed family history should include the fertility of the family members, age of menarche, and history of growth and pubertal development.
Physical examination should include a look for stigmata of systemic disease or dysmorphic features. Anthropometric measurements can help assess a patient's growth, body mass index, and thus identify short stature (as in patients with Turner's syndrome) and underweight status (as in patients with anorexia nervosa). Further examination should include a thorough assessment of sexual maturity, with careful attention to the distribution of excessive hair growth, male pattern balding, or acne. True hirsutism is the development of male pattern androgenized (dark and thick) hair on face, chest, back, upper arms, and thighs. A genitourinary examination includes inspection of the clitoris (to evaluate for clitoromegaly) and looking for estrogenization of the vaginal mucosa (estrogenized vaginal mucosa appears pink or pale compared to reddish nonestrogenized vaginal mucosa). Clitoromegaly can indicate congenital adrenal hyperplasia, drug-induced virilization, or disorder of sex differentiation.
Initial laboratory evaluation should include the following: human chorionic gonadotropin urine test to rule out pregnancy; complete blood count to evaluate for anemia or signs of infection/systemic inflammation; thyroid function test to evaluate for hyperthyroidism/hypothyroidism; prolactin level test to rule out hyperprolactinemia; LH, FSH, and estradiol to test the HPG axis; testosterone, sex hormone binding globulin (SHBG), and 17-hydroxyprogesterone levels to evaluate for nonclassical CAH and PCOS. Imaging studies such as a pelvic ultrasound can identify the absence of the uterus, abnormal streak ovaries such as in Turner's syndrome, or an abnormal vaginal outflow tract. The approach for evaluation of patients with irregular menstrual cycles is summarized in Figure 1.
Flowsheet for evaluation of patients with irregular menstrual cycles.
Primary Amenorrhea: Definition and Causes
Primary amenorrhea is defined by chronological criteria as a lack of uterine bleeding by age 14 years if the patient has no other secondary sexual characteristics or by age 16 years despite having normal secondary sexual characteristics.1
Absence of Secondary Sexual Characteristics
Turner's syndrome. Turner's syndrome occurs in 1 of every 2,500 to 3,000 live births.4 This syndrome is characterized by the absence of one X chromosome. Major areas of concern in this syndrome include growth failure, cardiovascular disease, and gonadal failure.
The syndrome represents a wide spectrum of chromosomal abnormalities, the most common of which is the classic Turner's syndrome with 45X karyotype. Less common is the mosaic Turner's syndrome with mosaic sex chromosome such as 45X/46XX, 45X/46XY.
These patients may present with primary amenorrhea secondary to ovarian failure. Laboratory findings in these patients show elevated gonadotropin levels along with low estradiol levels. To establish a diagnosis of Turner's syndrome, a standard karyotype is required.
A consistent finding in Turner's syndrome is short stature. Height typically plots less than 5% on National Standard for Health Statistics (NCHS)/Centers for Disease Control (CDC) growth chart for girls, and the average adult height of those with Turner's syndrome is usually 20 cm below the mean for the general population.5 Of note, however, those with mosaic Turner's syndrome or significantly tall parents, can potentially have height measurements plot on the growth curve (between the 5% and 95% range), but appear short for the family (below mid-parental height).5 Characteristic physical findings include congenital lymphedema, low posterior hair line, webbed neck, prominent ears, high-arched palate, micrognathia, broad chest, cubitus valgus, multiple pigmented nevi, abnormal finger nails, intestinal telangiectasia, and hypoplastic nipples.4 Cardiovascular anomalies are common including bicuspid aortic valve and coarctation of the aorta. Renal anomalies occur in one-third to one-half of girls with Turner's syndrome, with monosomic patients at greater risk. The most common anomaly is a horseshoe kidney.6 Patients are also at risk for osteopenia.4
Recommendations for hormone replacement include cyclical estrogen and progestin. This is typically initiated as a low-dose estrogen therapy by oral or transdermal route at age 12 years, adding progestin once there is breakthrough bleeding or when the patient reaches an adult estrogen dose, which is typically deferred for 2 years after the start of estrogen.7,8
Acquired ovarian failure. Acquired ovarian failure is a rare cause of amenorrhea, usually secondary to an autoimmune condition. This can occur as part of a polyglandular syndrome. There are two main types of this syndrome—the autoimmune polyglandular syndrome type 1 (APS 1) and type 2 (APS 2). APS 1 consists of autoimmune adrenalitis, hypoparathyroidism, and mucocutaneous candidiasis. Ovarian failure has been associated with 60% of people with this APS syndrome.1 APS 2 consists of Addison disease associated with hypothyroidism or type 1 diabetes. Approximately 10% of these patients can have hypergonadotrophic hypogonadism.9
Presence of Secondary Sexual Characteristics
Anomalies of the outflow tract. Normal menses requires a patent outflow tract, which is established in-utero. The tract is formed from the midline fusion of the paired mullerian ducts to form the uterus, fallopian tubes, cervix, and upper one-third of the vagina. The urogenital sinus develops into the urethra and the lower two-thirds of the vagina.10
An imperforate hymen is a cause of outflow obstruction and is noted as a bluish bulging mass at the entrance of the vagina. To treat and to establish a normal menstrual flow, a cruciate incision is usually performed. Another example of outflow obstruction is the presence of a transverse vaginal septum; this is caused by the failure of the vaginal plate to fuse and dissolve as it meets the mullerian duct, which makes the upper one-third of the vaginal canal. Resection of the septum is the definitive treatment in this case.6
Mullerian agenesis (or Mayer-Rokitansky-Kuster-Hauser syndrome) is a congenital anomaly of the genitourinary tract that can also lead to outflow tract obstruction. This condition is caused by failure of the mullerian ducts to develop, resulting in uterine agenesis and hypoplasia of the upper one-third of the vaginal wall. These patients can also present with renal and skeletal anomalies. They often present in adolescence with primary amenorrhea, will have normal female external genitalia, and a pelvic ultrasound shows an absent uterus. Treatment requires a multidisciplinary team approach, including urology, endocrinology, and psychology.11
Androgen insensitivity. Androgen insensitivity is a disorder caused by an X-linked androgen receptor defect. In-utero, the genetic 46, XY male does not respond to androgens and appears as a phenotypic female. The typical presentation is primary amenorrhea in a phenotypic female or bilateral inguinal swelling in a girl infant. There are three different categories of this condition: complete androgen insensitivity, partial androgen sensitivity, and mild androgen insensitivity.12
Patients with complete androgen insensitivity have spontaneous breast development. This development occurs secondary to the conversion of androgen to estrogens in the adipose tissue. The Sertoli cells of the male gonads are functional in this condition, and these cells produce anti-mullerian hormone, which causes the uterine structures to regress and therefore the uterus and upper part of the vagina fail to develop. Abdominal ultrasound demonstrates a blind vaginal pouch, gonads either within the abdomen or inguinal canal, and absent uterus. There is an increased risk of malignant transformation (germ cell tumors) in these gonads later in life and hence the current recommendation is to remove the gonads; however, timing may be individualized.13
Patients with partial androgen insensitivity present with a variety of phenotypes depending on the residual androgen receptor function. Those patients with mild androgen insensitivity usually have normal male development until puberty. At that time, they are at increased risk for development of gynecomastia and infertility.
Menstrual Irregularities: Definition and Causes
Oligomenorrhea is defined as fewer than eight cycles per year after 2 years of menarche.3 Ovarian insufficiency or hyperandrogenism, hypothalamic-pituitary axis disorder, and prolactin excess can lead to this presentation. In the first 2 years after menarche, this pattern is most commonly secondary to immaturity of the HPG axis.
Menorrhagia is defined as prolonged (>7 days) or excessive (>80 mL/day) uterine bleeding at regular intervals. The most common etiology is an immature HPG axis. These findings can also be seen with underlying bleeding abnormalities such as a coagulation defect, thrombocytopenia, or platelet dysfunction.1
Secondary amenorrhea is defined as absence of a menstrual cycles for 90 days after a woman has had regular periods for at least 6 months.3 The most common cause of secondary amenorrhea is pregnancy, so this should always be ruled out first. Other differentials to consider include structural lesions, endocrinopathies, and chronic inflammatory lesions. Acquired ovarian failure should also be considered.
Dysfunctional Uterine Bleeding
Abnormal uterine bleeding (AUB) is defined as excessive menstrual flow, cycles occurring more frequently than every 21 days or less frequently than every 45 days, and intermenstrual or breakthrough bleeding. There are several possible etiologies for AUB, including pregnancy, thyroid disorders, or PCOS. However, the diagnosis of dysfunctional uterine bleeding is generally accepted when all other possible etiologies have been ruled out, and the most common cause in adolescence is anovulation. Primary goals are to prevent complications such as anemia. Treatment options include combined oral contraceptives, progestins, and nonsteroidal anti-inflammatory drugs.14
Etiology of Menstrual Irregularities
Hypogonadotropic hypogonadism is defined as hypogonadism (low estrogen) due to low secretion of gonadotropin-releasing hormone and thus low secretion of LH and FSH. This can be permanent or transient.
Patients with anorexia nervosa or excessive exercise develop transient hypothalamic dysfunction and fall under this category. Multiple studies have shown that these patients have lower gonadotropin levels secondary to extreme weight loss.15 Low energy availability can lead to metabolic derangements, including hypoglycemia, hypoinsulinemia, and sick euthyroid syndrome, along with suppression of leptin levels. Leptin has been shown to be an important factor for menstruation, correlating with adequate body fat.16 Those with decreased body fat have a loss of LH pulsatility and thus loss of normal menstruation.1
Thyroid dysfunction can cause dysregulation of normal menses. Elevation in thyrotropin-releasing hormone (which can be seen in primary hypothyroidism) leads to an increase in prolactin secretion, which leads to irregular menstrual cycles.17 Hyperthyroidism has also been shown to lead to oligomenorrhea, which can progress to amenorrhea.18 Associated symptoms of hypothyroidism include cold intolerance, fatigue, dry skin, and constipation. Associated symptoms of hyperthyroidism include palpitations, heat intolerance, frequent bowel movements, and weight loss. Treatment of the underlying etiology will help improve the menstrual disturbances.
Cushing syndrome can also lead to irregular menses. Studies indicate that the elevated cortisol inhibits gonadotropin release at the hypothalamic level.19 Associated signs and symptoms include poor growth, excessive weight gain unexplained by dietary intake, easy bruising, muscle weakness, hypertension, violaceous striae, and round facies. Surgery or medical therapy is often necessary to resolve the underlying etiology of the Cushing syndrome.
Hyperprolactinemia can be secondary to structural lesions such as adenomas. Pituitary stalk disruption can also lead to decreased dopamine secretion. Dopamine normally suppresses prolactin release; therefore, when the pituitary stalk is disrupted, the patient develops hyperprolactinemia. Excess prolactin leads to reduced LH-pulse frequency and LH responsiveness to estrogen.20 Treatment is a dopamine agonist such as cabergoline or bromocriptine.
Polycystic Ovarian Syndrome
PCOS is the most common metabolic disorder in women of reproductive age. Irregular menses, elevated androgens, and insulin resistance characterize PCOS. Little information is published about the diagnosis and treatment of adolescents with PCOS.
There are several criteria used for the diagnosis of PCOS. The most widely accepted criteria used in adolescents are the National Institutes of Health criteria. According to these criteria, PCOS is characterized by (1) anovulation or oligo-ovulation, (2) clinical or biochemical signs of hyperandrogenism, and (3) exclusion of hyperprolactinemia, thyroid disease, congenital adrenal hyperplasia, and Cushing syndrome.21 It is currently recommended to wait until 2 years after menarche to investigate and/or make a diagnosis of PCOS to allow the HPG axis time to mature.
Hirsutism is hair growth that is more abundant, darkly pigmented, and localized in a male pattern. This is a clinical manifestation of hyperandrogenism and is often noted in patients with PCOS. Scoring for hirsutism in females is based on the Ferriman-Gallwey system. A score of <8 is considered normal. Other signs of hyperandrogenism include acne and male pattern balding. As for menstrual irregularities, females may present with oligomenorrhea, secondary amenorrhea, or dysfunctional uterine bleeding. Polycystic ovaries identified on a pelvic ultrasound are defined as 12 or more follicles measuring 2 to 9 mm or increased ovarian volume in adult women. It is more difficult to use these criteria in adolescent females, as these ovarian changes can be normal physiological changes seen during pubertal development.
The pathophysiology of PCOS has not been fully characterized. Many patients have evidence of abnormal LH secretion in which they have higher serum concentrations and increased frequency and amplitude of LH pulses.1 A significant percentage of patients with PCOS display insulin resistance. The combination of insulin resistance and increased LH secretion appears to stimulate ovarian androgen production. In addition, elevated insulin levels inhibit hepatic synthesis of sex hormone binding globulin (SHBG).22 These changes result in increased bioavailability of free androgens. Excess androgen production in PCOS patients has been shown to cause premature ovarian follicle arrest leading to anovulation and menstrual irregularities.22 Thus, the combination of elevated LH, hyperinsulinemia, and excess ovarian androgen production gives rise to the PCOS phenotype of oligoovulation/anovulation and hyperandrogenism.
Therefore, laboratory testing would reveal elevated free testosterone, low SHBG level, and elevated LH to FSH ratio (although this last component is not needed for diagnosis in adolescents). Testing for other disorders described in the diagnostic criteria is normal. Treating PCOS in adolescents is important beyond relieving its symptoms because without treatment there is an increased risk of developing infertility, endometrial hyperplasia and carcinoma, type 2 diabetes mellitus, metabolic syndrome, and possibly cardiovascular disease.23 Available treatment options include oral contraceptive pills and metformin.1
Oral contraceptive pills lower androgens by suppressing ovarian production of androgens and increasing SHBG. Metformin improves insulin sensitivity and lowers insulin resistance that contributes to the anovulation that occurs in PCOS.24 Anti-androgen therapy is used to improve hirsutism and acne.
The conditions that lead to menstrual abnormalities are variable and are reviewed in this article. A detailed history and physical examination remain key in the evaluation to determine the etiology and thus the best intervention for each condition. A referral to endocrinology would be recommended for those who have a history of primary amenorrhea with a lack of sexual characteristics by age 14 or 16 years despite having normal secondary sexual characteristics, or those who do not normalize their menstrual cycles 2 years after menarche and who have clinical signs of hyperandrogenism.
- Lifshitz F. Pediatric Endocrinology. 5th ed. New York, NY: Informa Healthcare USA, Inc; 2007.
- Deligeoroglou E, Tsimaris P, Deliveliotou A, Christopoulos P, Creatsas G. Menstrual disorders during adolescence. Pediatr Endocrinol Rev. 2006;3(suppl 1):150–159.
- Rosenfield RL, Cooke DW, Radovick S. Puberty and its disorders in the female. In: Sperling MA, ed. Pediatric Endocrinology. Philadelphia, PA: Elsevier; 2014:569–663.
- Bondy CATurner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007;92(1):10–25. doi:. doi:10.1210/jc.2006-1374 [CrossRef]
- Bertapelli F, Barros-Filho Ade A, Antonio MA, Barbeta CJ, de Lemos-Marini SH, Guerra-Junior G. Growth curves for girls with Turner syndrome. BioMed Res Int. 2014;2014:687978. doi:. doi:10.1155/2014/687978 [CrossRef]
- Marsh CA, Grimstad FW. Primary amenorrhea: diagnosis and management. Obstet Gynecol Surv. 2014;69(10):603–612. doi:. doi:10.1097/OGX.0000000000000111 [CrossRef]
- Levitsky LL, Luria AH, Hayes FJ, Lin AE. Turner syndrome: update on biology and management across the life span. Curr Opin Endocrinol Diabetes Obes. 2015;22(1):65–72. doi:. doi:10.1097/MED.0000000000000128 [CrossRef]
- Gravholt CH. International Turner Syndrome Consensus Group. Clinical Practice Guideline for the care of girls and women with Turner syndrome: proceedings from the 2016 Cinicnnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017;177:G1–G70. doi:. doi:10.1530/EJE-17-0430 [CrossRef]
- Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg?Clin Exp Immunol. 2004;137(2):225–233. doi:. doi:10.1111/j.1365-2249.2004.02561.x [CrossRef]
- Styne DM, Grumback MM. Pediatric disorders of sex development. In: Melmed S, Polonsky KS, Larsen PR, Kronenburg H, ed. Williams Textbook of Endocrinology. 13th ed. Philadelphia, PA: Elsevier; 2016:893–963.
- Styne DM, Melvin M. Physiology and disorders of puberty. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 13th ed. Philadelphia, PA: Elsevier; 2016:1074–1218.
- Hughes IA, Werner R, Bunch T, Hiort O. Androgen insensitivity syndrome. Semin Reprod Med. 2012;30(5):432–442. doi:. doi:10.1055/s-0032-1324728 [CrossRef]
- Oakes MB, Eyvazzadeh AD, Quint E, Smith YR. Complete androgen insensitivity syndrome--a review. J Pediatr Adolesc Gynecol. 2008;21(6):305–310. doi:. doi:10.1016/j.jpag.2007.09.006 [CrossRef]
- Deligeoroglou E, Karountzos V, Creatsas G. Abnormal uterine bleeding and dysfunctional uterine bleeding in pediatric and adolescent gynecology. Gynecol Endocrinol. 2013;2(1):74–78. doi:. doi:10.3109/09513590.2012.705384 [CrossRef]
- Litt IF, Glader L. Anorexia nervosa, athletics, and amenorrhea. J Pediatr. 1986;109(1):150–153. doi:10.1016/S0022-3476(86)80597-2 [CrossRef]
- Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351(10):987–997. doi:. doi:10.1056/NEJMoa040388 [CrossRef]
- Koutras DA. Disturbances of menstruation in thyroid disease. Ann N Y Acad Sci. 1997;816:280–284. doi:10.1111/j.1749-6632.1997.tb52152.x [CrossRef]
- Benson RC, Dailey ME. The menstrual pattern in hyperthyroidism and subsequent posttherapy hypothyroidism. Surg Gynecol Obstet. 1955;100(1):19–26.
- Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD, et al. Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels. J Clin Endocrinol Metab. 1998;83(9):3083–3088. doi:10.1210/jcem.83.9.5084 [CrossRef].
- Fourman LT, Fazeli PK. Neuroendocrine causes of amenorrhea--an update. J Clin Endocrinol Metab. 2015;100(3):812–824. doi:. doi:10.1210/jc.2014-3344 [CrossRef]
- Brook CGD, Clayton P, Brown R. Brook's Clinical Pediatric Endocrinology. 6th ed. Chichester, UK: Wiley-Blackwell; 2009. doi:10.1002/9781444316728 [CrossRef]
- Nestler JE, Powers LP, Matt DW, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72(1):83–89. doi:. doi:10.1210/jcem-72-1-83 [CrossRef]
- Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab. 2006;91(2):492–497. doi:. doi:10.1210/jc.2005-1666 [CrossRef]
- Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011;7(4):219–231. doi:. doi:10.1038/nrendo.2010.217 [CrossRef]