Early menstrual cycles tend to be anovulatory

J Clin Endocrinol Metab. 2013 Sep; 98(9): 3572–3583.

Abstract

Context:

Adolescents are at high risk for menstrual dysfunction. The diagnosis of anovulatory disorders that may have long-term health consequences is too often delayed.

Evidence Acquisition:

A review of the literature in English was conducted, and data were summarized and integrated from the author's perspective.

Main Findings:

Normal adolescent anovulation causes only minor menstrual cycle irregularity: most cycles range from 21–45 days, even in the first postmenarcheal year, 90% by the fourth year. Approximately half of symptomatic menstrual irregularity is due to neuroendocrine immaturity, and half is associated with increased androgen levels. The former is manifest as aluteal or short/deficient luteal phase cycles and usually resolves spontaneously. The latter seems related to polycystic ovary syndrome because adolescent androgen levels are associated with adult androgens and ovulatory dysfunction, but data are sparse. Obesity causes hyperandrogenemia and, via unclear mechanisms, seems to suppress LH; it may mimic polycystic ovary syndrome. The role of pubertal insulin resistance in physiological adolescent anovulation is unclear. High-sensitivity gonadotropin and steroid assays, the latter by specialty laboratories, are necessary for accurate diagnosis of pubertal disorders. Polycystic ovaries are a normal ultrasonographic finding in young women and are associated with nearly 2-fold increased anti-Müllerian hormone levels. Oral contraceptives are generally the first-line treatment for ongoing menstrual dysfunction, and the effects of treatment are similar among preparations.

Conclusions:

Menstrual cycle duration persistently outside 21–45 days in adolescents is unusual, and persistence ≥ 1 year suggests that disordered hypothalamic-pituitary-gonadal function be considered. Research is needed on the mechanisms and prognosis of adolescent anovulation.

It is well-known that adolescents have greater menstrual irregularity (unpredictability) and less frequent menstrual cycles during the early postmenarcheal years than do adults while mature ovulatory regularity develops (1–4). However, there is a widespread misconception that any degree of menstrual irregularity is acceptable. Consequently, disorders with long-term health consequences that may underlie adolescent anovulation are often overlooked at a critical developmental stage. The purpose of this article is to review adolescent anovulation with an emphasis on maturational, rather than pathological, mechanisms and their clinical implications.

Normal Versus Abnormal Adolescent Anovulation

Menstrual irregularity is virtually always the result of anovulatory cycles. However, the converse is not true—monthly menstrual regularity does not necessarily indicate underlying regular ovulatory cyclicity.

Within 1 year of menarche, menstrual regularity approximates adult standards in most girls, although there is considerable variation in the time it takes for menstrual cyclicity to mature (1, 4, 5). Average menstrual cycle length is 21–45 days in 75% of girls 1 year postmenarche, and 5% more fall within these bounds each of the next 3 years (1, 2). During the first 2 postmenarcheal years, about half of menstrual cycles are anovulatory, but half of these anovulatory cycles are 21–45 days in length (2, 6, 7). Thus, normal menstrual frequency is much greater than ovulatory frequency. By 5 gynecological years, 95% of menstrual cycles last 21–40 days, and about 75% of cycles are ovulatory; over the next several years the mature menstrual pattern is established with approximately an 80% ovulatory rate (2, 3, 7). Earlier age of menarche is associated with earlier than average ovulatory maturation, and late maturation the opposite (3).

The greater regularity of menses than of ovulation in adolescents is partly related to the presence of aborted or immature ovulatory cycles, which are difficult to identify. Documentation of ovulation is ordinarily based on a significant basal body temperature rise (averaging 0.35°C), which requires serum progesterone to reach ≥ 2.5–4.0 ng/mL (8, 9), or on the serum progesterone level itself. Serum progesterone rises ≥ 0.5 ng/mL (1.6 nm) with development of the preovulatory follicle and exceeds 2.0 ng/mL upon corpus luteum formation after ovulation; however, mature corpus luteum function requires demonstration of a midluteal level > 3.0–5.0 ng/mL (3, 8, 10–12). A preovulatory follicle can form without clearly ovulating or generating a mature corpus luteum; this seems to occur commonly in the months before (13, 14) and after (3) menarche, resulting in aluteal or short/inadequate luteal phase cycles.

The criteria for abnormal menstrual regularity in adolescents and adults differ in some respects (1, 4, 15–17, 132). Table 1 categorizes these, incorporating recently developed international terminology for abnormal uterine bleeding (AUB). The main difference is the shifting definition of oligomenorrhea (infrequent AUB) with gynecological age; it is defined during the first postmenarcheal year as having fewer than 4 periods, and changes gradually; the adult criterion (missing more than 3 periods yearly) becomes applicable at 5 postmenarcheal years.

Table 1.

Classification of AUB

As symptomatic menstrual irregularity persists for 1 to 2 years, actuarial risk for ongoing menstrual dysfunction rises from approximately 54% to approximately 62% (18). In a population-based study, 51% of girls who became oligo-amenorrheic at 15 years after initially menstruating regularly remained so at 18 years (19).

In summary, normal adolescent anovulatory cycles cause only minor menstrual irregularity, particularly after the first postmenarcheal year. It is not appropriate to dismiss abnormal degrees of menstrual cyclicity in adolescents (“symptomatic anovulation”; Table 1) as “physiological” variations of normal. Evaluation is suggested when abnormal menstrual function persists ≥ 1 year or is associated with other symptoms or signs, eg, hirsutism, galactorrhea.

Endocrine Mechanisms of Adolescent Anovulation

Normal pubertal maturation requires a series of neuroendocrine maturational steps, which go awry in anovulatory girls. Neuroendocrine puberty begins with hypothalamic GnRH secretion during slow-wave sleep, which is mirrored by sleep-related gonadotropin secretion (Figure 1A) (20). The onset is somewhat more closely related to radiographic bone age than chronological age, as if neuroendocrine maturation and skeletal maturation have common determinants (21, 22). With continuing GnRH stimulation, pituitary gonadotropes and ovarian follicles become increasingly more sensitive to respective stimulation by GnRH and gonadotropins (Supplemental Figure 1, published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org) (23). Gonadotropin secretion seems to become cyclic from the onset of ovarian function (22). Puberty becomes clinically apparent as thelarche when ovarian secretion sustains estradiol levels > 10 pg/mL (22, 24). Increasing GnRH secretion is successively associated with waning sensitivity to estradiol negative feedback, more robust and sustained gonadotropin secretion, and the selection of a dominant follicle that becomes a preovulatory follicle > 10 mm generating sufficient female hormone levels, principally estradiol, to exert positive feedback on gonadotropes (23, 25–27).

Twenty-four-hour premenarcheal and postmenarcheal serum LH patterns in normal and hyperandrogenic girls. Significant pulses are designated by asterisks. A, Normal premenarcheal pubertal girl. Note sleep-related increase in LH. B, Normal postmenarcheal girl in early follicular phase of the menstrual cycle. Note nocturnal slowing of LH pulses. C, Hyperandrogenic premenarcheal girl. In the rare girl in whom hyperandrogenism is detected before menarche, LH elevation is most remarkable during sleep. D, Hyperandrogenic postmenarcheal girl. LH levels and pulse frequency are high. Note the absence of normal postmenarcheal nocturnal slowing, as is typical after an anovulatory cycle; LH levels tend to fall with sleep and to be highest midday. Note that both hyperandrogenic girls have higher, but not necessarily elevated, LH levels. [Modified and reproduced from D. Apter et al.: Accelerated 24-hour luteinizing hormone pulsatile activity in adolescent girls with ovarian hyperandrogenism: relevance to the developmental phase of polycystic ovarian syndrome. J Clin Endocrinol Metab. 1994;79:119–125 (84), with permission. © The Endocrine Society.]

Most cycles through the second postmenarcheal year are immature, with long follicular phases and failure to form a preovulatory follicle that secretes sufficient estradiol to elicit a mature LH surge (Supplemental Figure 1), resulting in aluteal or short/inadequate luteal phase menstrual cycles (Supplemental Figure 2) (3, 13, 23, 28). These long anovulatory cycles are associated with increasing testosterone (T) levels (6, 28, 29). In a study of schoolgirls identified as having oligomenorrhea, 57% had frankly elevated T levels (30).

With maturity of the ovulatory cycle, sleep augmentation of gonadotropins reversibly recedes. Critical luteal phase hormone levels, principally progesterone, inhibit GnRH/LH pulse frequency and increase LH pulse amplitude with a small net suppression of the mean LH level, particularly during sleep (31–35). Nocturnal slowing of LH pulse frequency persists into the early follicular phase of the subsequent cycle as a remnant of these progesterone-related changes (Figure 1B) (33, 36–38) and is not apparent in the early follicular phase after anovulatory cycles (Figure 1D) (39, 40).

Normal maturation of ovulatory function requires optimal fat stores. Undernutrition disorders are well-known to cause anovulation; the mechanisms involve deficient fat stores as an energy resource (41), leptin deficiency (42), and endorphin suppression of gonadotropin release (43, 44). Undernutrition causes reversion to the prepubertal pattern of gonadotropin release, and recapitulation of pubertal gonadotropin maturation follows replenishment of fat stores (44, 45).

Obesity, on the other hand, also appears to suppress gonadotropins independently of hyperandrogenism (46–48). This is at least in part accounted for by accelerated metabolism of LH. Overweight early pubertal girls have a blunted rise in sleep-related LH levels, whereas mean serum LH levels are similar to those of normal-weight controls (22). These findings have raised the possibility that obesity alters the diurnal rhythm at the hypothalamic level, although disrupted slow-wave sleep in obese girls remains to be explored as an explanation (20).

Androgenization appears to be a major determinant of the sexually dimorphic patterns of gonadotropin secretion (22). Prenatal virilization programs adult expression of a male pattern of gonadotropin secretion in response to GnRH so that LH pulse amplitude and the readily releasable pool of gonadotrope LH are enhanced (Supplemental Figure 3) (48, 49), whereas the capacity to develop a gonadotropin surge in response to estradiol positive feedback is precluded (50). Reduced hypothalamic progesterone receptor expression may mediate these effects (51). During puberty, biphasic effects of T on gonadotropin secretion appear. T elevation of the modest degree (approximately 3-fold) typical of polycystic ovary syndrome (PCOS) becomes capable of stimulating LH production in females by interfering with progesterone negative feedback (48, 52, 53). However, frankly virilizing levels of T suppress LH and blunt LH responses to GnRH (48).

A large population-based study showed that half of oligomenorrheic girls had significantly increased LH and androgen levels (19). A study of over 100 nonhirsute, nonobese adolescents with irregular menses indicated that 51% of the cycles were anovulatory and that anovulatory cycles were characterized by significantly higher LH and androgen levels than ovulatory cycles (29). Detailed analysis of a dozen of these anovulatory adolescents showed that anovulation arose from neuroendocrine immaturity in 7 and from androgenic ovarian dysfunction in 5 (54). The immaturity group had normal LH levels with the sleep augmentation of normal premenarcheal girls (as in Figure 1A), and the androgenic group had the LH elevation typical of hyperandrogenism, often with a sleep-related fall in LH levels (as in Figure 1D). Usually, the immaturity pattern proved to wane and the hyperandrogenism pattern to persist 2–7 years later (55, 56).

Longitudinal studies of 2 groups of unselected healthy adolescent volunteers for 3–12 years showed that adolescent serum androgen levels were preserved into adulthood (57) and that above-average levels were significantly associated with menstrual dysfunction (19) and lower fertility (57). Thus, adolescent androgen levels seem to predict adult androgen levels and anovulation, which suggests a relationship to PCOS. These studies may have underestimated the prevalence of hyperandrogenism because none measured serum free T.

Differential Diagnosis of Symptomatic Adolescent Ovulatory Dysfunction

Adolescents should undergo screening tests for pathology when menstrual dysfunction persists (Table 1). Irregular vaginal bleeding is synonymous with ovulatory dysfunction, after exclusion of pregnancy, genital tract structural disorders or trauma, or coagulopathies.

The differential diagnosis of anovulatory disorders includes congenital or acquired primary hypogonadism (ovarian insufficiency/failure; ie, hypergonadotropic hypogonadism); secondary/tertiary hypogonadism (pituitary/hypothalamic dysfunction; ie, gonadotropin deficiency/hypogonadotropic hypogonadism and the mild variant, hypothalamic amenorrhea); or disorders that secondarily affect hypothalamic-pituitary-ovarian function (eg, delayed puberty, hyperandrogenism, hyperprolactinemia, and chronic disease) (Table 2) (58). Most of these disorders predispose to long-term health disorders, particularly infertility; additionally, hypogonadal disorders are a risk factor for short stature and osteoporosis (59), and PCOS is a risk factor for diabetes mellitus and obesity-related health disorders including cardiovascular disease and cancer (60).

Table 2.

Major Pathological Causes of Adolescent Anovulation

The most common of these disorders are delayed puberty, which affects 2.5–5.0% of adolescents (61), and PCOS, which affects 6–15% of reproductive-age women (60). Maturational dysfunction plays a major role in the former and a controversial role in the latter.

Delayed puberty is usually due to a “constitutionally” extreme variant of the normal physiological gonadotropin deficiency of childhood but may be caused by chronic endocrine, metabolic, or systemic disorders, as well as by hypogonadism (61). Any disorder that retards growth retards the onset of puberty to approximately the extent indicated by bone age. Constitutional delay of puberty has a strong familial basis: 50–75% have a family history of delayed puberty. Constitutional delay seems over-represented in families with idiopathic hypogonadotropic hypogonadism or hypothalamic amenorrhea cases, so rare variants in genes underlying these conditions appear to contribute to the etiology (40, 62).

PCOS accounts for 72–84% of chronic hyperandrogenism in adults (63, 64). Functional ovarian hyperandrogenism is usually the source of the androgen excess (65, 66). This ovarian dysfunction is unique: it appears to be intrinsic (67) and is characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation (GnRH agonist or human chorionic gonadotropin testing) and/or subnormal suppression of plasma T upon adrenal suppression by dexamethasone (66). Experimental evidence indicates that ovarian androgenization may account for anovulation and polycystic ovaries (65, 68). The cause of PCOS is unknown, but considerable evidence suggests that it arises as a complex trait with contributions from both heritable and nonheritable intrauterine and extrauterine factors, among which insulin resistance and obesity are most common (69, 70).

Internationally sanctioned diagnostic criteria for PCOS have evolved beyond the syndrome described by Stein and Leventhal (71, 72). “Rotterdam criteria“ are the broadest, recognizing all combinations of otherwise unexplained clinical or biochemical hyperandrogenism, evidence of anovulation, and a polycystic ovary (73), whereas Androgen Excess-PCOS Society criteria recognize only hyperandrogenic combinations (74). PCOS phenotypes in diminishing order of specificity, hyperandrogenism, and insulin resistance (75–77) are: 1) hyperandrogenic oligo-anovulation and a polycystic ovary (“classic” phenotype); 2) hyperandrogenic oligo-anovulation (National Institutes of Health [NIH] criteria) (78); 3) hyperandrogenism and a polycystic ovary (“ovulatory PCOS”); this permits diagnosis in women with cutaneous or metabolic manifestations who lack anovulatory symptoms (74), which controversially permits PCOS diagnosis in apparently normal females with a polycystic ovary and mild hirsutism or subclinical hyperandrogenemia (79); and 4) oligo-anovulation and a polycystic ovary; this low-specificity phenotype is particularly controversial; the extent to which it results from undetected ovarian hyperandrogenism is unclear.

The diagnosis of PCOS in adolescence is additionally controversial, primarily because of 3 questions. How can one determine whether adolescent hyperandrogenemia is due to PCOS or is the consequence of physiologically prolonged anovulatory cycles? Is the correlation between adolescent and adult androgen levels and menstrual patterns sufficiently high that adolescent hyperandrogenic anovulation accurately predicts adult PCOS? And is the polycystic ovary normal in adolescents?

It has been suggested that, to avoid overdiagnosis, PCOS only be diagnosed in adolescents with ≥ 2-year persistence of hyperandrogenism, anovulatory menstrual pattern, and ovarian size > 10 cc (80). This proposal has received qualified reproductive endocrinology endorsement (60).

However, limitations to these proposed criteria are apparent from further considerations. Table 3 shows data on adolescent PCOS (diagnosed on the basis of otherwise unexplained hyperandrogenemic AUB without regard to lengthy persistence or polycystic ovaries) in relation to reference groups of nonhirsute eumenorrheic adolescent (≥1 y postmenarcheal) and adult subjects with ultrasonographically normal ovaries (66, 79, 81, 82). The clinical picture in these adolescent PCOS patients is indistinguishable from that in adult PCOS patients. Progressive hirsutism may constitute clinical evidence of hyperandrogenism (80) and help distinguish PCOS from physiological anovulation; hirsutism was present in half our PCOS patients (adolescents, 57%; adults, 51%). Obesity is another PCOS risk factor (19), yet 26% of our adolescents were nonobese. Most importantly, the unique PCOS-type of functional ovarian hyperandrogenism is full-blown in adolescent PCOS, similar to adults (Table 3) (82, 83). (Ovarian function is also similar in adolescent and adult volunteers, with the exception of a fall in serum anti-Müllerian hormone [AMH] and a rise in FSH with reproductive aging). Eight percent of the adolescent PCOS group was documented to have functional ovarian hyperandrogenism within 1 year of menarche (1 with primary amenorrhea) and another 8% during the second postmenarcheal year. The neuroendocrine features in adolescent PCOS are also identical to those seen in adult women with PCOS (84). These data are compatible with the concept that adolescent PCOS is a congenital or early developmental defect in ovarian function that becomes fully expressed upon perimenarcheal achievement of a mature level of hypothalamic-pituitary-ovarian function.

Table 3.

Comparison of Normal Postmenarcheal and PCOSa Adolescents (Ages 11.1–17.9 y) and Adults (Ages 18.0–39.9 y)b

Appropriate criteria for polycystic ovaries in adolescence are unclear. Traditional adolescent criteria have been volume > 10.8 cc (in the absence of a follicle > 10 mm) or ≥ 10 follicles (2–9 mm) in the maximum ultrasonographic plane (the abdominal technique necessary in virginal adolescents does not permit counting total antral follicles) (81). About half of healthy adolescent volunteers meet these criteria (81), whereas one-third of adolescent PCOS do not (Table 3). Furthermore, adolescent polycystic ovary morphology varies significantly over time (56, 85). The Rotterdam criteria for an adult polycystic ovary are volume > 10cc (with no follicle > 10 mm) or total antral follicle count ≥ 12 small follicles per ovary (86). However, the normal adult parameters fall with age, particularly follicle counts, which current technology reveals to exceed Rotterdam criteria in about one-half of normal 20 to 30 year olds (87, 88). Most polycystic ovaries in healthy young women are functionally normal; others are associated with nearly 2-fold elevated AMH (which indexes growing follicle number) or steroidogenic abnormalities, which have been respectively postulated to predict a prolonged reproductive lifespan or a relationship to PCOS (79).

The above considerations suggest that the combination of PCOS risk factors and AUB may facilitate the documentation of hyperandrogenemia and permit PCOS diagnosis by NIH criteria within 1 year of the last menstrual period. Waiting ≥ 2 years to diagnose and treat PCOS in such cases may unnecessarily delay treatment and recognition of comorbidities and increase the possibility of lost follow-up.

Insulin resistance is present in about 25% of PCOS adolescents, judging from the prevalence of metabolic syndrome (89–92), but in perhaps 50% judging from euglycemic clamp data (93). Most studies indicate that the insulin resistance is disproportionate to the degree of obesity, the prevalence of which approximates 35–80% (70, 89, 90, 94).

PCOS ovaries function as if sensitive to the hyperinsulinemia that compensates for the tissue-selective insulin resistance of PCOS (65, 95). T formation by steroidogenic cells is stimulated by insulin, an effect mediated by an adipogenic transcription factor (KLF15) (96, 97). In addition, insulin-resistant hyperinsulinism also seems to be related to anovulation in PCOS: ovulatory women with PCOS are less insulin-resistant than anovulatory PCOS (97, 98). Weight loss (99, 100) or drugs that lower insulin levels (101–103) improve ovulation and ovarian dysfunction.

Normally, insulin resistance and compensatory hyperinsulinemia peak in midpuberty and wane thereafter (104–107), in parallel with GH production (108, 109). The waning insulin resistance as puberty progresses generally parallels improvement in menstrual regularity. Nonfasting measures of insulin resistance have not been examined in relation to physiological adolescent anovulation independently of androgen levels (19).

Obesity may itself be a common unrecognized cause of adolescent ovulatory dysfunction (19, 48). Obesity seems to disrupt ovulatory cyclicity by suppressing gonadotropins and by increasing insulin resistance. Obesity also can raise androgen levels (66): adipocyte type 5 17β-hydroxysteroid dehydrogenase, an enzyme that is up-regulated by insulin, forms T from circulating androstenedione; the expression of this enzyme in sc fat correlates with body mass index and falls with weight loss in simple obesity. Thus, simple obesity may cause the PCOS picture.

Diagnostic Evaluation of Symptomatic Adolescent Ovulatory Dysfunction

The first step in the diagnostic workup for hypothalamic-pituitary-ovarian-reproductive tract axis disturbances is to rule out chronic disorders or localizing findings by history, physical, and gynecological (110) examination and a chronic disease test panel (complete blood count, erythrocyte sedimentation rate, comprehensive metabolic and celiac panels, IGF-I, and thyroid function tests) (58). Aspects that deserve emphasis in adolescents follow.

Sexual immaturity and bone age retardation characterize delayed puberty. Gonadotropin levels must be interpreted in relation to bone age. Until the bone age reaches 11 years, neuroendocrine puberty may not have begun, so the hypergonadotropism of primary hypogonadism may not be manifest. On the other hand, until the bone age reaches 13 years, constitutionally delayed puberty may be impossible to distinguish from idiopathic hypogonadotropic hypogonadism. Immature breast development is itself a bioassay for hypoestrogenism.

In sexually mature adolescents with AUB, pregnancy test and assays of serum gonadotropins, prolactin, estradiol, and T are first-line studies. Progestin challenge is an alternate way to assess adequacy of estrogenization (withdrawal bleeding indicates estradiol averaging ≥ 40 pg/mL [111] in the absence of hyperandrogenism [112] or pregnancy). Hematological disorders must be considered for excessive bleeding (17, 113).

Biochemical confirmation of hyperandrogenemism is preferable to only clinical evidence of hyperandrogenism and is more sensitively detected by serum free T than total T because SHBG levels are significantly decreased in obese, insulin-resistant, and/or hyperandrogenic individuals (114). PCOS is ordinarily diagnosed by excluding the most common or other serious hyperandrogenic conditions: nonclassic congenital adrenal hyperplasia, hyperprolactinemia, and virilizing tumor (73). The extent of screening and the approach to further evaluation for rare conditions, eg, cortisol excess, differs among practices (114).

It is exceedingly important that high-sensitivity, high-specificity (“pediatric”) hormone assays be used for these purposes. The multichannel platform assays now commonly used by hospital laboratories are excellent for gonadotropin, SHBG, and dehydroepiandrosterone sulfate assays, but most of these methods are not accurate or well-standardized for other sex steroid assays (114, 115). Total T, free T (calculated from total T and SHBG data), and estradiol measurements should be performed by specialty laboratories with well-defined reference intervals. It is anticipated that the increasingly widespread use of tandem mass spectrometry methods will improve access to reliable and accurate steroid assays. Although our limited data show no significant difference between adolescent and adult baseline free T (Table 3), volunteers' free T levels tend to fall 0.09 pg/mL yearly from 1 year postmenarche over the reproductive years (11.1–39.9 y; P = .09).

GnRH agonist testing may prove helpful in the diagnosis of hypogonadotropic hypogonadism (22, 49). Brain magnetic resonance imaging is advisable in most hypothalamic-pituitary dysfunction. This includes hypothalamic amenorrhea, which is a diagnosis of exclusion although the various stress-related forms usually have tell-tale behavioral and psychological characteristics (116).

Pelvic ultrasonography is indicated for evaluating genital tract anatomy and screening for ovarian tumors. It currently plays only a secondary role in the diagnosis of PCOS, however.

Although polycystic ovaries usually are a normal variant, pelvic ultrasonography is useful in the PCOS workup to rule out tumoral hyperandrogenism and to allay the anxieties that arise when pronouncing a diagnosis that involves ovarian “cysts.” Very high AMH levels, above the range for normal-variant polycystic ovaries, are specific but insensitive for PCOS (79).

Although PCOS is ordinarily a diagnosis of exclusion, ovarian function testing usually can provide specific evidence of the unique functional ovarian hyperandrogenism (Table 3). Eighty percent of PCOS patients have elevated T after adrenocortical function is suppressed by dexamethasone, and two-thirds have a characteristic 17-hydroxyprogesterone hyper-responsiveness to GnRH agonist (66). Most PCOS women with normal ovarian androgenic function had no identifiable source of androgen other than obesity. Thus, simple obesity may be a distinct, potentially reversible cause of the PCOS picture; these cases typically have mild hyperandrogenemia and normal LH, AMH, and ovarian size (66, 79).

Endocrine Management Aspects of Symptomatic Adolescent Anovulation

In some cases, treatment of the underlying cause has the potential to normalize ovulatory function, eg, prolactinoma, nonclassic congenital adrenal hyperplasia. Otherwise, treatment depends greatly on whether the adolescent is sexually immature or mature.

Sexually immature girls with hypogonadism require hormone replacement therapy that preserves growth potential. Two controlled studies have shown that this is possible using very low, marginally feminizing estrogen doses starting as young as 11–12 years of age (117, 118). Transdermal estradiol is a convenient, physiological form of therapy that appears to impose no cardiovascular risk and optimizes bone health (119–121). Consistent with current guidelines (122), we start hypogonadal girls on a transdermal patch delivering 25 μg daily for 1 week monthly; then we gradually increase the cycle duration (to 3 wk) at 6-month intervals to reach an adult dose (100 μg) at 3 years. Constitutionally delayed girls are started at 25 μg 2–3 weeks monthly and usually require no more than 6–12 months of treatment. Cyclic progestin is added for 7–10 days during the latter portion of the estrogen replacement cycle after 2 years of estrogen therapy or when unpredictable bleeding occurs.

Monophasic estrogen-progestin combined oral contraceptive (COC) pills administered cyclically (3 wk per month) are the usual first-line treatment for AUB in sexually mature girls. COC benefits include improvement of endometrial hyperplasia, dysmenorrhea, hyperandrogenemia, acne, and hirsutism (114). Overall, they carry about a 4-fold increased risk of venous thromboembolism in first-time users; this risk decreases with duration of use and decreasing estrogen dose but is less than that of pregnancy (123–125). This risk may be slightly higher in COCs containing the antiandrogenic/antimineralocorticoid progestin drospirenone in comparison to the biochemically androgenic levonorgestrel or other progestins; however, this assessment may represent differential prescribing to the obese PCOS population. Although COCs containing ≤ 20 μg ethinyl estradiol pose little cardiovascular risk, they may inadequately promote normal accrual of bone mass (126) and may be less effective in controlling irregular menstrual bleeding, particularly in obese hyperandrogenic girls, than those containing 30–35 μg ethinyl estradiol. Girls with heavy AUB may require 3- to 4-fold higher estrogen doses (113).

Options to prevent endometrial hyperplasia are cyclic progestin (eg, micronized progesterone 100–200 mg daily for 7–10 d every 2–3 wk) for those opposed to COCs or progestin-only contraceptives where COCs are risky, but both less reliably control menses or androgen excess.

Obesity sometimes causes AUB, and obesity and insulin resistance are frequent comorbidities. Lifestyle modification with diet and exercise counseling is paramount, but sustained weight loss is difficult to achieve (127, 128). Well-controlled studies indicate that metformin therapy offers no advantage over lifestyle modification as regards weight, menstrual frequency, or ovulation (60, 129, 130); abnormal glucose tolerance is the only clear indication for metformin.

COCs should not be given indefinitely for unexplained AUB. Withdrawal for diagnostic purposes should be coupled with contraceptive counseling.

Need for Clinical Research

Adolescents are at high risk for menstrual dysfunction, which may have long-term health consequences. Clinical research is vital to better understand the natural history of well-characterized adolescent anovulation and the normal and abnormal physiology of adolescent menstrual cycles (unknowns include the effects of estrogen and progesterone on the development of central nervous system rhythmicity [diurnal, cyclic, sleep-related], relationship of pubertal insulin resistance to physiological anovulation, and effects of obesity on the hypothalamic-pituitary-gonadal axis). Normative data for new tests are critical to such studies. Clinical research would be facilitated if it were more widely recognized that normal adolescents, as part of a vulnerable population, have a condition potentially approvable for research under federal regulations 45CFR46.406/21CFR50.53 (131).

Supplementary Material

Acknowledgments

The critical review and helpful suggestions of Drs Randall B. Barnes, David Cooke, Paula J. Adams Hillard, Dorit Koren, Natalie Shaw, and Christine Yu are appreciated.

The author's research was supported in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health (NIH) through cooperative agreement U54-041859, as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research, HD-39267;, and RR-00055; and UL1RR024999 from the National Center For Research Resources. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Center For Research Resources or the NIH.

Disclosure Summary: The author has no conflicts of interest to declare.

Footnotes

Abbreviations:

AMHanti-Müllerian hormoneAUBabnormal uterine bleedingCOCcombined oral contraceptivePCOSpolycystic ovary syndrome.

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