Introduction

Menarche is defined as the first menstrual period in a female adolescent. Menarche typically occurs between the ages of 10 and 16, with the average age of onset being 12.4 years.[1] The determinants of menarcheal age are continuously being researched; however, socioeconomic conditions, genetics, general health, nutritional status, exercise, seasonality, and family size are thought to play a role. 

Menarche tends to be painless and occurs without warning. The first cycles are usually anovulatory with varied lengths and flow. Menarche signals the beginning of reproductive abilities and is closely associated with the ongoing development of secondary sexual characteristics.[2]

Issues of Concern

Menarche occurs in the setting of a maturing hypothalamic-pituitary-ovarian (HPO) axis and relies on the following processes: normal hypothalamic and pituitary function, normal female reproductive anatomy, normal nutrition, and the general absence of other intervening chronic illnesses. It is a marker of normal female reproductive health and wellness. Most females recognize menarche as their body’s critical declaration of fertility. The absence of normal menstrual periods, not related to pregnancy, is termed amenorrhea. Primary amenorrhea is the complete absence of menstruation by 15 years of age. Secondary amenorrhea is the cessation of menstruation for three months or more after it has started.[3]

Of specific concern is when menarche occurs too early, too late, or not, as these scenarios have future adverse outcomes. Menarche is considered early if it occurs before or at ten years of age and late if it occurs at or later than 15 years of age.[4]

Cellular

Numerous studies have shown the kiss1 gene, which produces kisspeptin, and its receptor G protein-coupled receptor 54 (GPR54) necessary for normal reproductive function. Kisspeptin and GPR54 are expressed in hypothalamic gonadotropin-releasing hormone (GnRH) neurons. The hypothalamic kiss1 system relays metabolic information to the gonadotropic axis. Circulating estradiol activates kisspeptin, which in turn activates GnRH neurons. Puberty is initiated when GnRH is secreted in a pulsatile manner by hypothalamic neurons.[5]

A single nucleotide polymorphism on chromosome 6, LIN28B, has been found to be associated with earlier menarche.[6]

Development

GnRH neurons are found in the olfactory pit at post-conception week six, then migrate via the forebrain to the hypothalamus by week nine. The pituitary begins to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the fetal circulation by week 12, with LH and FSH reaching peak levels at midgestation, around 20-24 weeks. LH and FSH levels are low at birth but begin to increase upon withdrawal of placental estrogens.[7] As previously discussed, pulsatile release of GnRH, and thus, LH and FSH, is necessary for puberty and menarche. The onset of female puberty is marked by thelarche (breast budding), which typically occurs after eight years of age. Thelarche is followed by pubarche (pubic hair development), growth spurt, and finally, menarche.

Menarche occurs 2-3 years after thelarche and six months after peak height velocity (PHV) is achieved. PHV is defined as the highest velocity observed during the pubertal growth spurt.[8] Menarche most commonly occurs in sexual maturity rating (SMR), or Tanner stage, IV. It is abnormal for menarche to occur before the appearance of secondary sexual development. Sexual abuse, genital trauma, tumors, or bleeding disorders should be considered in the differential diagnosis of prepubertal females who experience vaginal bleeding.

By 15 years of age, approximately 98% of females will have undergone menarche, signaling the maturation of the adolescent female body. Menarche is commonly associated with the ability to ovulate and reproduce; however, the onset of menarche does not guarantee either ovulation or fertility. Menstrual cycles are frequently irregular during adolescence, particularly during the interval from the first to the second cycle.[9] Immaturity of the HPO axis during the early years after menarche results in anovulation and irregular cycles, which can range from short cycles (< 20 days) to long cycles (> 45 days). By the third year after menarche, 60-80% of menstrual cycles are 21 to 34 days long, as is typical of an adult cycle. In girls who undergo early menarche, 50% of cycles are ovulatory in the first year, and nearly all are ovulatory by the fifth year post menarche. In contrast, it takes approximately 8 to 12 years for all cycles to be ovulatory in girls who experience a later onset of menarche.[10]

Menarche is considered early if it occurs before or at ten years of age and late if it occurs at or later than 15 years of age.[4] Menarche is also deemed to be delayed if there is more than a three-year lapse between the onset of thelarche and the first menses. 

The age at which a female experiences menarche is variable, with both genetic and environmental factors such as socioeconomic status, family life, race, exercise, and diet playing a role. Several studies have shown there to be an ethnic-racial difference in menarche onset. In one study, black girls experienced menarche three months earlier than white girls, suggesting race is an independent factor of menarcheal timing. This finding may reflect genetic factors, as black girls presented with higher insulin response to glucose challenges and increased free IGF1, which are associated with skeletal and sexual maturation.[11] 

Organ Systems Involved

In addition to the female reproductive organs (ovaries, fallopian tubes, uterus, and vagina), menarche is influenced by complex hormonal interactions involving the hypothalamus, pituitary gland, and ovaries. The adrenal glands, thyroid, and pancreas have also been shown to play a role in menarche. Thyroid hormones are necessary for normal menses, and their deficiency or excess can inhibit menarche or lead to abnormalities in existing menstrual patterns. Abnormally elevated insulin or adrenal androgens can affect normal ovarian estrogen production and decrease pituitary production of LH. The hormone leptin also appears to play a role in maintaining normal menstrual cycles.[12]

Function

Menarche is an indicator of the onset of fertility and reproductive ability, and its absence should signal the provider to evaluate for pathology.

Menstruation is the monthly shedding of the functional layer of the uterine endometrial lining that occurs when ovulation is not followed by fertilization. It occurs approximately every 28 days, ranging from every 21 to 45 days, with a mean cycle interval of 32.2 days in the first gynecologic year. Most menstrual periods last between three and seven days, with menses lasting more than ten days considered abnormal.[13] 

Mechanism

Puberty is initiated when GnRH is secreted in a pulsatile manner by hypothalamic neurons. This pulsatile release of GnRH allows pituitary gonadotrophs to release LH and FSH. LH begins androstenedione production in ovarian theca cells, while FSH allows aromatase in follicular cells to synthesize estradiol. An increase in serum estradiol allows breast tissue to enlarge and influences linear bone growth and epiphyseal fusion, playing a significant role in the pubertal growth spurt. 

One year before breast budding, higher peaks of LH are seen exclusively during sleep, caused by an increasing pulse amplitude of GnRH release. When breast budding occurs, LH peak amplitude increases 10-fold, and FSH pulse amplitude doubles. Progression of puberty from Tanner stage II to III is marked by a further increase in LH pulse amplitude a 20 to 40 fold increase from prepubertal levels, reflecting the rise of estradiol levels, which have now become detectable at all hours. Upon advancement to Tanner stage IV, LH and FSH pulses become diurnal and gradually mature to the adult pulsation pattern.[14]

Menarche occurs near the end of Tanner stage IV after a year-long rise in daily estradiol output. High estradiol levels at this time exert negative feedback on the gonadotropic axis to suppress it, leading to cyclic estrogen levels and uterine bleeding.[15] At the time of menarche, positive estradiol feedback on the axis is not yet established; therefore, ovulation rarely occurs. Uterine bleeding occurs with varying cyclicity until the mechanism of estrogen-induced LH surge is mature and ovulatory cycles occur. This process generally takes a year or more after menarche to become fully established. 

Related Testing

In patients with normal anatomy and delayed development, evaluating ovarian and pituitary hormones, including androgens, can assist in a diagnosis. Pituitary tumors, most often adenomas, can be associated with elevated prolactin levels and physical findings such as galactorrhea, headaches, visual changes, and amenorrhea. In primary amenorrhea, estradiol levels help measure ovarian function. If estradiol levels are low, reflexive testing of FSH and LH will differentiate between primary ovarian failure (FSH/LH elevated) and secondary ovarian failure (FSH/LH low or unmeasurable, pituitary failure).[16]

If there is evidence of hirsutism or acne on an exam, testing androgen levels, including free and total testosterone, DHEA-S, and 17-hydroxyprogesterone, can help rule out androgen-secreting tumors and congenital adrenal hyperplasia as a cause. Androgen levels may also be used to rule out or confirm a diagnosis of polycystic ovary syndrome (PCOS). It should be noted that the absence of menarche can also occur due to pregnancy, and ruling out pregnancy is essential in the evaluation.

Pathophysiology

Early Menarche

• Causes
  • Earlier onset of menarche was seen in girls surrounded by stressful family environments, those in foster care, and those living with a stepparent. This is explained through differing lifestyle and psychological factors. Additionally, those raised in urban environments experience menarche at an earlier age when compared to those raised in rural settings.[17]
  • Adolescent girls from families of high socioeconomic status (SES) experience menarche at an earlier age when compared to girls from families of a lower SES.[18]
  • Studies have shown that girls who consumed more animal protein and less vegetable protein between the ages of three to five experienced earlier menarche.[19] 
  • Multiple studies have shown that girls who have an overweight or obese BMI undergo menarche at an earlier age. One such study stated that girls who started menarche at an early age were 1.7 times more likely to have an overweight or obese BMI.[20] Additionally, one study found a positive correlation between the consumption of sugar-sweetened beverages and the onset of menarche. It was reported that girls who consumed more than 1.5 sugar-sweetened beverages per day experienced menarche approximately 2.7 months earlier than girls who consumed less than two sugar-sweetened beverages per week.[21] 
  • Formula feeding during early infancy has also been researched as a potential factor responsible for early menarche.[22]

• Outcomes
  • Early menarche has been associated with physical and psychosocial problems, including anxiety and depression, earlier sexual intercourse, substance use, and suicidal behavior. These outcomes may be attributed to adolescent girls associating negative physical and psychological changes with menstruation reflecting misconception, ignorance, and the fear of being different from peers.[23] 
  • Substantial evidence from multiple countries suggests that girls who undergo menarche at an early age are more vulnerable to early pregnancy, sexually transmitted infections, and sexual violence.[24] 
  • Early menarche can lead to premature fusion of the epiphyseal growth plates, subsequently leading to a final adult height that is shorter than the potential genetic height.[25]
  • Undergoing menarche at an early age leads to an increased prevalence of hypercholesterolemia in adulthood, ultimately leading to a higher risk of developing cardiovascular diseases such as hypertension, coronary heart disease, and stroke. Studies have also shown there to be an increased risk of developing metabolic syndrome and type 2 diabetes mellitus.[22] 
  • Higher bone mineral density of the lumbar spine and femoral neck in older age has been seen in girls who underwent menarche at an early age, explained by the prolonged lifetime exposure to the protective effects of endogenous estrogens.[26]
  • Studies have shown that girls who experience early menarche have a 23% higher risk of developing breast cancer than girls who experience delayed menstruation. This is enhanced by the observation that early menarche is accompanied by abdominal-type obesity and thus higher circulating levels of insulin, testosterone, and insulin-like growth factor 1, which in turn acts as growth factors for mammary tissue proliferation and are likely to promote mammary gland carcinogenesis.[27]

Late Menarche

Primary amenorrhea is the term used to describe the absence of menarche in an adolescent female who has not reached menarche by age 15 or who has not done so within three years of thelarche.

• Causes
  • Menarche can be delayed in adolescents with very low body mass due to starvation, malabsorption, or an eating disorder such as anorexia nervosa. It is estimated that minimum body fat of 17% is necessary for menarche, with 22% body fat required for maintaining regular menses.[28]
  • Menarche, on average, occurs later in athletes than in the general population, suggesting that intense exercise of at least two hours per day delays puberty and, therefore, menarche.[29]
  • Additional studies have shown that the presence of older sisters in the household is associated with a later onset of menarche.[30]
  • Menarche can be delayed in normal developing females due to abnormalities of the female genitourinary tract. Females with an imperforate hymen may present with delayed menarche and often have a history of recurrent cyclic abdominal or pelvic pain. On exam, these patients may present with a palpable lower abdominal mass and often have a bulging, bluish-colored hymen.[31]
  • The absence of a normal uterus or vagina due to Mullerian agenesis, or Mayer-Rokitansky-Kuster-Hauser syndrome, has an incidence of approximately 1/4500 females and often goes undiagnosed until a patient presents with an absence of menarche. Other complex hormonal abnormalities such as androgen insensitivity syndrome can present with external female development and primary amenorrhea. Abnormal development of female gonads due to Turner syndrome also can lead to ovarian agenesis and absent menses.[32]

• Outcomes
  • Delayed menarche has been shown to lead to decreased mineral density in the forearm, spine, and proximal femur, resulting in osteoporosis and an increased risk of fractures later in life.[33]
  • Late menarche may be positively associated with the risk of developing Alzheimer disease.[2]

Clinical Significance

While there is a set window of time for which menarche should begin, there is variation within that window with many different causes. As previously discussed, a girl's socioeconomic status, diet, activity, and genetics can play a role in when she begins puberty and menarche. It is crucial to educate prepubertal girls and their guardians on the progression of puberty and the development of the menstrual cycle. It is essential to talk openly about the subject and dispel any fears or misinformation the child may have. Clinicians should convey that females will begin to menstruate approximately 2-3 years after breast development begins and that menstruation is a normal part of development. Girls should be instructed on the use of feminine products and what is considered normal menstrual flow. This should be a collaborative educational effort between the patient, guardian, and clinician. 

Menstrual abnormalities that require further evaluation:[34]

• Absence of menarche within three years of thelarche
• Absence of menarche by 14 years of age with signs of hirsutism
• Absence of menarche by 14 years of age with a history or exam suggestive of excessive exercise or eating disorder
• Absence of menarche by 15 years of age

Anatomical problems leading to amenorrhea can typically be diagnosed by a thorough history, a careful visual exam of the external genitalia, and a manual exam of the reproductive organs of the adolescent female patient. Clinicians should take a history in private and maintain confidentiality whenever possible. It is also important to explain the physical exam in detail and provide a chaperone during the exam. 

Clinically, it is essential to know that both sexual abuse and childhood physical abuse can trigger early menarche. Screening for sexual abuse is an important aspect of general pediatric practice, but many pediatricians lack a consistent approach to patient evaluation. Menarche may provide clinicians with an opportunity to discuss the topic of sexual initiation and screen for past abuse. As a healthcare provider, noting the presence of early menarche when in combination with other physical or behavioral signs and symptoms should prompt one to obtain a more detailed history.[35]