During the follicular phase, release of GnRH stimulates the pituitary to secrete FSH and LH, which then stimulate ovarian estrogen secretion ultimately inducing endometrial proliferation. With the start of each menstrual cycle, FSH stimulates several follicles to mature over a two-week period. Only one follicle becomes dominant, however, during a cycle. These follicles produce estrogen, which enters the bloodstream and reaches the uterus where it stimulates the endometrial cells to reproduce, therefore thickening the walls.

Estrogen levels reach their peak around the 14th day of the cycle. As estrogen levels peak, the pituitary gland releases increased amounts of LH. Ovulation occurs about 12 hours after the midcycle surge in LH. The luteal phase follows ovulation, and the corpus luteum secretes progesterone and estrogen. Progesterone inhibits endometrial proliferation and induces glandular changes. Without fertilization, the corpus luteum regresses, resulting in a decrease in progesterone and estrogen, and shedding of the endometrium (menses) 14 days after ovulation.

Anovulatory cycles are common in the first 2 years after menarche because of the immaturity of the HPO axis₅,₇. Anovulation also can occur in a variety of pathological conditions. In anovulatory cycles, the follicular growth occurs with the stimulation from FSH; however, due to lack of LH surge, ovulation fails to occur. Consequently, no corpus luteum is formed and no progesterone is secreted. The endometrium continues its proliferative phase excessively. When the follicle involutes, estrogen levels drop and its withdrawal bleeding occurs. Most anovulatory cycles are regular with normal bleeding; however, the unstable proliferative endometrium can shed irregularly, resulting in prolonged heavy bleeding.

The adolescents have amenorrhea, dysmenorrhea, premenstrual syndrome and abnormal uterine bleeding as the common types of menstrual disorders which are dealt in detail below.

Abnormalities of the pituitary and hypothalamus and other endocrinopathies (thyroid disease and Cushing syndrome) may present with pubertal delay and low gonadotropin levels. Amenorrhea may be caused by problems at the pituitary gland, such as congenital hypopituitarism, tumor (pituitary adenoma), or infiltration (hemochromatosis). Prolactinoma is the most common pituitary tumor. They present with galactorrhea, headache, visual fields cuts, and amenorrhea. Elevated prolactin levels are characteristic. Craniopharyngioma is another tumor of the sella turcica that affects hypothalamic-pituitary function, presenting with pubertal delay and amenorrhea.

Other disorders associated with galactorrhea and amenorrhea include hypothyroidism, breast stimulation, stress associated with trauma or surgery, and certain drugs (phenothiazines, opiates). Hypergonadotropic hypogonadism is caused by primary ovarian failure associated with elevated gonadotropin levels. An elevated FSH will establish the diagnosis.

Turner syndrome may cause ovarian failure and a lack of pubertal development. It is the commonest chromosomal abnormality causing gonadal failure and primary amenorrhea₉. Females with this syndrome have streak gonads, absence of one of the X chromosomes, and inadequate levels of estradiol. They do not initiate puberty or uterine development. It is characterized by short stature, webbed neck, widely spaced nipples, shield chest, high arched palate, congenital heart disease, renal anomalies, and autoimmune disorders (thyroiditis, Addison disease). It may not be diagnosed until adolescence, when pubertal delay and amenorrhea occur together.

Hypogonadotropic hypogonadism is caused by hypothalamic dysfunction or pituitary failure. Low or normal levels of LH and FSH will be present, and decreased estradiol levels may be present. Ovarian failure resulting from autoimmune disorders or exposure to radiation or chemotherapy may also cause amenorrhea with pubertal delay. Hypothalamic abnormalities associated with pubertal delay include Kallmann syndromes and others. This is associated with anosmia.

In a pubertal female, pregnancy should be ruled out if there is sexual exposure and amenorrhea. Depot medroxyprogesterone (Depo-Provera), levonorgestrel implants (Norplant); and sometimes post-pill amenorrhea also occurs. Uterine synechiae (Asherman syndrome) should be suspected in amenorrheic patient with a history of abortion, dilation and curettage, or endometritis.

Sheehan syndrome (pituitary infarction) is suggested by a history of intrapartum bleeding and hypotension in parous women. Anatomical abnormalities such as imperforate hymen, transverse vaginal septum, agenesis of the vagina may also present with amenorrhea.

Ovarian failure, prolactinomas, thyroid disease, and stress, athletes (excessive exercise), eating disorder (anorexia nervosa) may cause amenorrhea after normal pubertal development. Polycystic ovarian disease may also present with amenorrhea.

Management of amenorrhea includes restoring ovulatory cycles if possible in the adolescent with constitutional delay and anovulation, replacing estrogen when necessary, reassurance to alleviate the tremendous anxiety of the patients, and re-evaluation. Many of the treatment methods require surgery (for ovarian cysts or uterine problems) or specific therapies. Not all conditions can be treated, but any underlying condition that is treatable should be treated.

Treatment depends on the cause. The commonest cause of secondary amenorrhoea is pregnancy and this should always be excluded. Easing up on excessive exercise and eating a proper diet may bring on periods in teen athletes.

Polycystic ovary syndrome (PCOS) may respond to weight loss, and recently there has been interest in the use of insulin-sensitizing agents, e.g. metformin. Clomiphene citrate is the first choice to induce ovulation. Other methods include exogenous gonadotropin, human purified FSH, ovarian wedge resection, and ovarian drilling. For those who are not hirsute, and do not desire pregnancy, an intermittent progestin (eg, medroxyprogesterone acetate 5 to 10 mg/day po for 10 to 14 days) or oral contraceptives are used to reduce the increased risk of endometrial hyperplasia in PCOS patients.

Hypothyroidism is treated with levothyroxine. Hyperprolactinaemia often responds to bromocriptine. Prolactinomas will commonly shrink with medical therapy, but large tumours may need surgery. Other tumours of the pituitary, hypothalamus, ovary, and adrenal glands usually require surgery. Some genital tract malformations are also treated by surgery, e.g. haematocolpos. Hypothalamic amenorrhoea is treated with pulsatile GnRH. Amenorrhoea secondary to pituitary disease (excluding prolactinomas) are treated with gonadotrophins. Glucocorticoids should be used only for documented adrenal hyperfunction or enzyme defects in the steroidogenic pathway.

All women with low oestrogen levels should be considered for oestrogen replacement especially for prevention of osteoporosis. An adequate intake of calcium (1500 mg/day) and vitamin D (400 IU/day) is also advisable.

Lower abdominal pain is usually cramping or colicky but may be a dull constant ache and radiate to the lower back or legs and there is general malaise as well. The pain may start a few hours prior to or with menses, tends to peak after 24 hours, and usually subsides after 2 days. Sometimes endometrial casts (membranous dysmenorrhea) or clots are expelled. Headache, nausea, constipation or diarrhea, and urinary frequency are common; vomiting occurs occasionally. On examination the vital organs are normal. The pelvic organs are normal in primary dysmenorrhea.

Secondary dysmenorrhea usually develops years after menarche and can occur with anovulatory cycles and this may be associated with uterine and pelvic pathology such as intrauterine contraceptive device (IUCD), endometriosis, pelvic inflammatory disease (PID), cervical stenosis, a submucosal fibroid or an endometrial polyp, etc.The pain occurs when the uterus attempts to expel tissue through the os. The pain of secondary dysmenorrhea often begins 1-2 weeks prior to menses and persists until a few days after the cessation of the bleeding.

In case of primary dysmenorrhea, a woman should be assured that her reproductive organs are normal. Many do not need medications, but for women with significant problems, the most effective drugs are prostaglandin synthetase inhibitors (eg, ibuprofen, mefenamic acid) as the pain is caused by prostaglandins induced contraction of the uterus during ovulatory cycles. Prostaglandin synthetase inhibitors are effective in approximately 80% of cases₁₁,₁₂. A drug may be more effective if started 24 to 48 h before and continued 1 or 2 days after menses begins. If pain continues to interfere with normal activity, suppression of ovulation with low-dose combined oral contraceptive pill is effective. For the patient with primary dysmenorrhea who has no contraindications to combined pills or who desires contraception, the pill is the agent of choice. More than 95% will have relief with the pills₁₃.

If nonsteroidal anti-inflammatory drug (NSAID) fails, oral contraceptive pills can be used for 3-6 months. Antiemetics may be used, if there is nausea and vomiting. Adequate rest, sleep, hot fomentation, acupuncture and regular exercise may help in some women. In case of secondary dysmenorrhea, the first line of treatment is medical (eg, prostaglandin synthetase inhibitors, oral contraceptives, danazol, progestins). The treatment of the specific underlying disorder is very important. If possible, the underlying disorder or anatomic abnormality is corrected, thus relieving symptoms. Dilation of a narrow cervical os may give 3 to 6 months of relief (and allows diagnostic curettage if needed). Other surgical measures (e.g. myomectomy, polypectomy, or dilation and curettage) may be needed in some patients. But these are usually not required for adolescent girls. Presacral neurectomy and division of the sacrouterine ligaments may help selected patients.

Cyclic hormonal fluctuations seem to be an important cause. One clue to the cause may be traced to fluctuations of serotonin, a brain neurotransmitter that is thought to play a crucial role in mood states, especially depression. Insufficient amounts of serotonin may contribute to other symptoms of PMS, such as fatigue, food cravings and sleep problems. Few patients with severe PMS have undiagnosed depression. Stress also may aggravate some of the symptoms, but alone is not a cause. Some symptoms have been linked to low levels of vitamins and minerals. Eating a lot of salty foods, which may cause fluid retention, and drinking alcohol and caffeinated beverages also may cause mood and energy level disturbances.

The symptoms vary from woman to woman and from cycle to cycle. In many, symptoms are significant but brief and not disabling; in others, normal functioning is disturbed. Symptoms last a few hours to few days, usually disappearing when menses begins. In some, they may persist through and after menses. Sometimes, when menstruation begins significant dysmenorrhea can occur and is more common among adolescents and tends to diminish with age.

The most common complaints are mood alteration and irritability, nervousness, agitation, anger, crying spells, insomnia, difficulty in concentrating, lethargy, depression, and severe fatigue. Fluid retention may cause edema, transient weight gain, oliguria, and breast fullness and pain. Neuro-vascular symptoms include headache, vertigo, syncope, paresthesias of the extremities, easy bruising, and palpitation. Epilepsy may be aggravated. Gastro-intestinal symptoms include abdominal bloating, constipation, nausea, vomiting, and appetite changes and food cravings. Joint or muscle pain and backache may occur. Acne and aggravation of other skin disorders may also occur. Most women with PMS experience only a few of these problems. For some the problems are severe enough to affect their daily routines and activities. The symptoms usually disappear as the menstrual period begins. There are no unique physical findings or laboratory tests to positively diagnose PMS.

If the PMS symptoms are seriously affecting patients' health and daily activities, it needs treatment. Managing PMS with lifestyle changes can be tried. If the emotional disturbance remains limited to the mood fluctuations, it can be controlled with proper diet (e.g. low fats, high protein), taking adequate rest and sleep. Psychological counseling may help. Some times the syndrome is accompanied by episodes of epileptic fit and lowered blood sugar. Such patients should be treated with appropriate medical therapy. Symptomatic treatment is often useful. Reducing salt and salty foods and using a diuretic, starting just before symptoms are expected may relieve fluid retention. Counseling may help the woman cope with PMS, and her activities can be modified to reduce stress. Smaller, more frequent meals may reduce bloating and the sensation of fullness. Foods rich in calcium and foods high in complex carbohydrates (fruits, vegetables) are useful. Avoiding caffeine and alcohol is sometimes helpful.

Common medications for PMS include nonsteroidal anti-inflammatory drugs (NSAIDs), hormones, and antidepressants. The use of antidepressants may be limited to the two weeks before menstruation begins.Hormonal therapy is effective in some patients. Oral contraceptives; progesterone for 10 to 12 days premenstrually; a long-acting progestin (e.g., medroxyprogesterone acetate 200 mg IM every 2 to 3 monthly); or a gonadotropin-releasing hormone agonist with low-dose estrogen-progestin “add-back” therapy to eliminate cyclic changes can be used. Benzodiazepine may be used for irritability, nervousness, especially if patients cannot alter their stressful environ. Selective serotonin reuptake inhibitors (eg, fluoxetine 20 mg orally daily, sertraline 50 mg daily) are the most effective drugs in the management of psychologic and physical premenstrual symptoms₁₄. Aerobic activity, brisk walking, cycling, swimming can help improve overall health and alleviate symptoms such as fatigue and a depressed mood. Deep-breathing exercises to help reduce headaches, anxiety or insomnia. Calcium, magnesium, vitamin B-6, vitamin E are also known to be effective in soothing the symptoms of PMS.

The causes that can give rise to abnormal uterine bleeding vary based on the age and reproductive status of the patient. The differential diagnoses in adolescents with abnormal uterine bleeding are extensive and there are many causes (Table 3). The usual causes of abnormal uterine bleeding in an adult female are much different from the usual causes in an adolescent.

Figure 4

Table 3: Selected causes in abnormal uterine bleeding in adolescents (Modified from Kilbourn and Richards22.)

Structural pathology such as benign pelvic lesions and malignancy and pregnancy related disorders like ectopic pregnancy, gestational trophoblastic disease are uncommon in adolescents.

All adolescents with menorrhagia severe enough to require hospitalization or significantly reduce hemoglobin levels (to <10 g/dL) should undergo evaluation for coagulopathy. Von Willebrand's disease, a defect in platelet adhesion and a deficiency of factor VIII, is the most common bleeding disorder, affecting about 1% of the population. Diseases causing thrombocytopenia include idiopathic thrombocytopenic purpura, leukemia, and aplastic anemia. In adolescents, the prevalence of a primary coagulation disorder requiring hospitalization for abnormal uterine bleeding ranges from 3% to 20%(₂₃).

In women with evidence of ovulation, abnormal uterine bleeding should prompt suspicion of benign pelvic lesions. Hypothyroidism is an uncommon, although important, cause of metrorrhagia or menorrhagia even in adolescents. In about 25% of cases of menstrual abnormalities, an organic or pathologic etiology such as pregnancy complications, neoplasm, infection, or disease conditions such as a coagulation disorder can account for the abnormality₂₄.

The term DUB describes the syndrome of abnormal menstrual patterns caused by hormonal imbalances. In majority of cases, it is secondary to anovulation, which is more common at the extremes of reproductive age. Patients with anovulatory cycles typically do not experience premenstrual tension syndrome-breast discomfort, increased mucoid vaginal discharge, or premenstrual cramping and bloating-characteristic of ovulatory cycles (Table 4). The most common causes of anovulatory cycles include polycystic ovary syndrome (PCOS), hypothalamic amenorrhea, premature ovarian failure, and hyperprolactinemia₂₅. Approximately 90% of cases in nonpregnant adolescents are secondary to DUB ₂₆. DUB may also occur with ovulatory cycles as a result of insufficiency of the corpus luteum (luteal phase defect). Periods are usually regular in timing but duration of menses is increased. This is less common in adolescents than in adult women.

The following information is useful to determine whether the bleeding is ovulatory or anovulatory in nature and, therefore, helps in the proper management (Table 4).

Figure 5

Table 4: Characteristics of ovulatory and anovulatory menstrual cycles

In rare cases, coagulation disorders may be the cause of heavy bleeding₂₇. Heavy bleeding can eventually lead to iron deficiency anaemia₂₈. These include diseases that affect platelet number or function (such as idiopathic thrombocytopenic purpura, von Willebrand's disease, or leukemia), as well as disruption of intrinsic coagulation factors (hereditary coagulopathies, hepatic or renal failure). Medications such as aspirin or warfarin may also contribute to the problem of bleeding. Phenytoin, phenothiazines, steroids, tricyclic antidepressants, and lithium may also contribute to abnormal menses.

Age of menarche, detailed description of the pattern of bleeding (the frequency, duration, and severity of flow), current medications or hormonal contraceptives, previous gynecologic history, family history, desire for contraception, sexual history, likelihood of pregnancy, and the presence of chronic medical problems, risk factors for sexually transmitted diseases, and tobacco use are all important aspects of the patient's history. It is also crucial to determine if the bleeding is acyclic or cyclic, the latter being more consistent with ovulation.

Evidence of androgen excess (hirsutism, acne, etc.), evidence of hypo or hyperthyroidism, thyromegaly, presence of galactorrhea (hyperprolactinemia) and many other physical findings may help arrive at a diagnosis.Evidence of liver disease, eating disorders, and coagulopathies should be sought for in adolescents. Although a thorough pelvic examination is essential in older women; it is rarely needed in the adolescents. In young women during the 5 years following menarche and women with breakthrough bleeding who are using hormonal contraceptives, an internal examination is not necessary except if there is contact bleeding or if the possibility of an STD cannot be excluded₇,₃₁,₃₂.

In most cases, investigation is limited to a complete blood cell count (Table 5). Abnormal leukocyte count may indicate leukemias. The level of hemoglobin will signify the severity of the menorrhgia and also guide for the urgency of the treatment. Sexually active adolescents who have abnormal uterine bleeding should have a urine or serum pregnancy test. Other tests are done only if indicated by the history and physical findings. Diagnostic tests for systemic diseases such as hypothyroidism, hyperthyroidism, renal disease, malnutrition, etc., may be used as clinically indicated₃₃.

Figure 6

Table 5: Laboratory and imaging studies for abnormal uterine bleeding inadolescents

Testing for sexually transmitted diseases may be indicated in sexually active adolescents. Adolescents who are not pregnant do not require additional workup. In this group, if a cause is not uncovered during the evaluation described earlier, a diagnosis of dysfunctional uterine bleeding is assumed, and treatment may be prescribed accordingly. Von Willebrand's disease should be suspected with excessive bleeding at menarche and quantitative or functional assays for von Willebrand's factor, bleeding time, etc, are helpful in diagnosing it. Coagulation studies (PT/PTT) and platelet count are helpful in cases of thrombocytopenias.

Ultrasound may be useful in some to ascertain the normalcy of the reproductive organs and therefore valuable in some adolescents but invasive diagnostic modalities like D & C, hysteroscopy and Pap smears are not applicable to the adolescents unlike older women in whom these are sometimes very useful.

In polycystic ovary syndrome, a properly timed LH: FSH ratio (> 2:1) is usually present, along with clinical and/or laboratory findings of hyperandrogenism (elevated free testosterone levels) and chronic anovulation (in the absence of secondary causes such as hyperprolactinemia, adult-onset congenital adrenal hyperplasia, and neoplasm).