ఋతు లోపాలు Menstrual Disorders

ఋతు లోపాలు 

పౌలా K. Braverman MD మరియు లెస్లీ L. వెనుకభాగం MDకిశోర మెడిసిన్, చాప్టర్ 22, 152-164 ఓపెన్ రీడింగ్ మోడ్పరిచయంఋతు సమస్యలు శిశు సంవత్సరాల సమయంలో కొంత సమయం ఆడవారు కనీసం 75% ప్రభావితం. పునరుత్పత్తి జీవితాంతం సాధారణం స్వల్పస్రావము కాలేకపోవటము, అసాధారణ గర్భాశయ రక్తస్రావం, డిస్మెనోరియా మరియు బహిష్టుకు పూర్వ సిండ్రోమ్ ఉన్నప్పటికీ, ఈ సమస్యలు యొక్క ప్రధానమైన కారణాలు పరిపక్వత మార్చడానికి. ఈ అధ్యాయం సాంక్రమిక రోగ విజ్ఞానం, రోగలక్షణ శరీరధర్మం, మూల్యాంకనం, మరియు నిర్వహణ శిశు వయస్కుడైన రోగులలో ఈ క్లినికల్ సమస్యలు ప్రతి చర్చలు తరువాత కౌమారదశలో సాధారణ ఋతు చక్రం యొక్క సమీక్ష తో ప్రారంభమవుతుంది.సాధారణ రుతు చక్రంయునైటెడ్ స్టేట్స్ లో రజస్వల మధ్యస్థ వయస్సు అన్ని జాతులు / జాతుల అంతటా 12.4 సంవత్సరాలు, నలుపు స్త్రీలకు 12.1 సంవత్సరాలు, హిస్పానిక్ స్త్రీలకు 12.3 సంవత్సరాలు, మరియు తెలుపు స్త్రీలకు 12.6 సంవత్సరాలు. రజస్వల సాధారణంగా రొమ్ము అభివృద్ధి కోసం 4 టాన్నర్ స్టేజ్ వద్ద, 2 నుండి 3 సంవత్సరాల thelarche (అనగా, రొమ్ము జూనియర్) తరువాత సంభవిస్తుంది. ముందు thelarche అమ్మాయిల్లో తరువాత thelarche తో బాలికల కంటే రజస్వల చేయుటకు ఎక్కువ విరామం కలిగి ఉంటాయి. వయసు 15 సంవత్సరాల, అయినప్పటికీ, యునైటెడ్ స్టేట్స్ లో అమ్మాయిలు 98% రజస్వల సాధించడానికి.రజస్వల నుండి ఋతు రక్తస్రావం రెండో భాగం విరామం వ్యక్తులు అంతటా విస్తృతంగా మారుతుంది. ద్వారా రజస్వల తర్వాత 1 సంవత్సరం, అమ్మాయిలు 90% 21-45 రోజుల మరియు 2-7 రోజుల నుండి మొదలుకొని ఋతు ప్రవాహం నుండి మొదలుకొని రుతు చక్రాలను కలిగి. పరిపక్వత, ovulatory పెరుగుతుంది మరియు చక్రం వ్యవధి తగ్గిస్తుంది అని చక్రాల నిష్పత్తి. రజస్వల తరువాత మూడవ సంవత్సరంలో, చక్రాల 60-80% 21-34 రోజుల వ్యవధి ఉన్నాయి. వ్యక్తిగత మామూలు సైకిల్ పొడవు ఆరవ స్త్రీ జననేంద్రియ సంవత్సరం చుట్టూ ఏర్పాటు ఉంది. ఒక కౌమార యొక్క చరిత్ర ఆధారంగా ఋతు రక్త నష్టం కొలతలకు కష్టం మరియు సరికాని ఉంది. రోజుకు ఉపయోగిస్తారు మెత్తలు లేదా tampons సంఖ్య మరియు ప్యాడ్ తరచుదనం / Tampon మార్పులు ఋతు ఆరోగ్య ఉత్పత్తులు, రకాల మరియు ఉపయోగించిన ఉత్పత్తులను బ్రాండ్లతో, మరియు వ్యక్తిగత అసహ్యపడడము తో శిశు పరిచయాన్ని లేదా సౌకర్యం ఆధారపడి. ఎక్కువ మంది పెద్దలు పాఠశాల నియమాలు మరియు తరగతుల మధ్య పరిమిత సమయం బాహ్య పరిమితుల పెద్దల కంటే కౌమార కోసం ఋతు పరిశుభ్రత మరింత సమస్యాత్మకం అయినప్పటికీ, రోజూ మూడు నుంచి ఆరు మార్పులు రిపోర్ట్. ఋతు ప్రవాహం ముఖ్యంగా 7 రోజుల కంటే ఎక్కువ వ్యవధి ప్రవాహాన్ని సంబంధం ఉన్నప్పుడు ఋతు ఉత్పత్తులు ప్రతి 1 లేదా 2 గంటల అధిక భావిస్తారు, మార్పులు అవసరం.రుతుక్రమ లేమిప్రాథమిక రుతుక్రమ లేమి ఆ వయస్సులో జనాభా అందలి పుటలు 95-98% ద్వారా సాధించవచ్చు వద్ద రజస్వల లేకపోవడంతో నిర్వచిస్తారు. యునైటెడ్ స్టేట్స్ లో అమ్మాయిలు 95% వయస్సు 14.5 సంవత్సరాలు మరియు 98% రజస్వల చేరుకోవడానికి ఎందుకంటే వయస్సు 15 సంవత్సరాలు, ప్రాథమిక రుతుక్రమ లేమి నిర్వచించడంలో ఒక సంప్రదాయవాద మరియు సాధారణంగా ఉపయోగించే కట్ పాయింట్ 15 సంవత్సరాలు. అమ్మాయిలు వయస్సు 13 సంవత్సరాలు రొమ్ము అభివృద్ధి లేదా జఘన జుట్టు లేకపోవడం రజస్వల ఒక అవకాశం ఆలస్యం సంకేతాలు పంపుతుంది మరియు బాగా ప్రాథమిక రుతుక్రమ లేమి మూల్యాంకనం ముందు యుక్తవయస్సులో ఆలస్యం (అధ్యాయం 10) విశ్లేషణ ప్రారంభిస్తుంది.రజస్వల సాధించింది ఎవరు శిశు లో, ద్వితీయ అమెనోరియాను కనీసం మూడు వరుస సైకిళ్లను బహిష్టు లేకపోవడం లేదా సాధారణ చక్రాల స్థాపించబడింది ఉండకపోతే 6 నెలల నిర్వచిస్తారు.వ్యాధివిజ్ఞాన శరీరధర్మశాస్త్రంఅనేక సంస్థాగత వ్యవస్థలు ప్రాధమిక మరియు ద్వితీయ రుతుక్రమ లేమి కారణాలు వర్గీకరణకు సహాయం ప్రతిపాదించబడ్డాయి. క్రింద వినియోగించే వ్యవస్థ హైపోథాలమస్ పిట్యూటరీ, అండాశయం, లేదా ప్రవాహపు ట్రాక్ట్ (బాక్స్ 22-1) పుట్టిన కారణం గుర్తిస్తుంది.BOX 22-1హైపోథాలమిక్ కారణాలు•GnRH లోపం•దీర్ఘకాలిక / వ్యవస్థాగత జబ్బు•ఒత్తిడి•అధికంగా వ్యాయామం•పోషకాహారలోపం, తక్కువ శరీర కొవ్వు•ట్యూమర్•థైరాయిడ్ వ్యాధిపిట్యూటరీ కారణాలు•LH, FSH లేకపోవడంతో•పిట్యూటరీ గ్రంధి నాశనం•ట్యూమర్అండాశయ కారణాలు•బీజకోశ సంబంధ వంధ్యత్వం•అండాశయ కణజాలం నాశనం•పాలిసిస్టిక్ ఓవరీ సిండ్రోమ్•అండాశయ కణితిఅవుట్ఫ్లో ట్రాక్ట్ అసాధరణాలు•కన్నము కన్నెపొర•విలోమ యోని కుడ్యము•గర్భాశయం యొక్క అవయవ పెరుగుదల లోపము, యోనిఇతర కారణాలు•గర్భం•హార్మోన్ల ద్వారా గర్భాన్ని•పుట్టుకతో అడ్రినల్ హైపర్ప్లాసియా•అధివృక్క కణితిరుతుక్రమ లేమి డిఫరెన్షియల్ డయాగ్నోసిస్గొనడోట్రోఫిన్-విడుదల హార్మోన్ (GnRH) యొక్క అసాధారణ స్రావం అమెనోరియాను ఫలితంగా, క్రమంగా, ఫొలికల్ స్టిమ్యులేటింగ్ హార్మోన్ (FSH) మరియు luteinizing హార్మోన్ (LH) మరియు ఈస్ట్రోజెన్ మరియు ప్రొజెస్టెరాన్ అండాశయ స్రావం యొక్క పీయూష స్రావం ప్రభావితం హైపోథాలమిక్ కారణాలు. సంబంధం ఋతు చక్రం అసాధారణతలు తీవ్రమైన hypoestrogenemia తేలికపాటి luteal దశలో లోపాలు మొదలుకుని. హైపోథాలమిక్ అమెనోరియాను హైపోథాలమస్ యొక్క అనాటమీ లో ఒక నిర్మాణ లోపం కన్నా GnRH స్రావం యొక్క ఫంక్షనల్ వెలగదు ప్రతిబింబించేలా చాలా అవకాశం ఉంది.ఫంక్షనల్ హైపోథాలమిక్ అమెనోరియాను బరువు నష్టం, కఠినమైన వ్యాయామం, తీవ్రమైన లేదా దీర్ఘకాలిక అనారోగ్యం, మరియు మానసిక నిరాశగా వల్ల సంభవించి ఉండవచ్చు. ఈ పరిస్థితులు అన్ని భౌతిక లేదా మానసిక లేదో, కోర్టికోట్రోపిన్-విడుదల హార్మోన్ (CRH), క్రమంగా అడ్రినల్ గ్రంధి పూర్వ పిట్యుటరీ మరియు కార్టికోస్టెరాయిడ్స్ ద్వారా పెంచే కోర్టికోట్రోపిన్ (పూర్వ పిట్యుటరీ గ్రంధి తయారు చేయు హార్మోను) స్రావం యొక్క హైపోథాలమిక్ స్రావం పెరుగుతుంది తో శారీరక ఒత్తిడి ఉత్పత్తి. CRH als

Menstrual Disorders  Download PDF

• Paula K. Braverman MD
•  and Lesley L. Breech MD

Adolescent Medicine, Chapter 22, 152-164

Introduction

Menstrual problems affect at least 75% of females at some time during the adolescent years. Although oligomenorrhea or amenorrhea, abnormal uterine bleeding, dysmenorrhea, and premenstrual syndrome are common throughout reproductive life, the predominant causes of these problems change with maturation. This chapter begins with a review of the normal menstrual cycle during adolescence, followed by discussions of the epidemiology, pathophysiology, evaluation, and management of each of these clinical issues in adolescent-aged patients.

Normal Menstrual Cycle

The median ages of menarche in the United States are 12.4 years across all races/ethnicities, 12.1 years for black females, 12.3 years for Hispanic females, and 12.6 years for white females. Menarche typically occurs 2 to 3 years after thelarche (i.e., breast budding), at a Tanner Stage of 4 for breast development. Girls with earlier thelarche tend to have a longer interval to menarche than girls with later thelarche. By age 15 years, however, 98% of girls in the United States achieve menarche.

The interval from menarche to the second episode of menstrual bleeding varies widely across individuals. By 1 year following menarche, 90% of girls have menstrual cycles ranging from 21–45 days and menstrual flow ranging from 2–7 days. With maturation, the proportion of cycles that are ovulatory increases and cycle duration shortens. By the third year after menarche, 60–80% of cycles are of 21–34 days duration. The individual's normal cycle length is established around the sixth gynecological year. Quantifying menstrual blood loss based on an adolescent's history is difficult and inexact. The number of pads or tampons used per day and the frequency of pad/tampon changes depend on the adolescent's familiarity or comfort with menstrual hygiene products, types and brands of products used, and personal fastidiousness. Most adolescents report three to six changes daily, although external constraints such as school rules and limited time between classes may make menstrual hygiene more problematic for adolescents than adults. Menstrual flow requiring changes of menstrual products every 1 or 2 hours is considered excessive, particularly when associated with flow of more than 7 days duration.

Amenorrhea

Primary amenorrhea is defined as the absence of menarche by that age at which it is achieved by 95–98% of the population. Because 95% of girls in the United States reach menarche by age 14.5 years and 98% by age 15 years, a conservative and commonly used cut-point for defining primary amenorrhea is 15 years. The absence of breast development or pubic hair by age 13 years in girls signals a likely delay in menarche and should trigger an evaluation of pubertal delay ( Chapter 10 ) well before the evaluation of primary amenorrhea.

In the adolescent who has achieved menarche, secondary amenorrhea is defined as the absence of menses for at least three consecutive cycles or for 6 months if regular cycles have not been established.

Pathophysiology

Many organizational systems have been proposed to help categorize the causes of primary and secondary amenorrhea. The system utilized below identifies the cause as originating in the hypothalamus, pituitary, ovary, or outflow tract ( Box 22-1 ). 

BOX 22-1

Hypothalamic Causes

• • 
  GnRH deficiency
• • 
  Chronic/systemic illness
• • 
  Stress
• • 
  Excessive exercise
• • 
  Malnutrition, low body fat
• • 
  Tumor
• • 
  Thyroid disease

Pituitary Causes

• • 
  Absence of LH, FSH
• • 
  Destruction of pituitary gland
• • 
  Tumor

Ovarian Causes

• • 
  Gonadal dysgenesis
• • 
  Destruction of ovarian tissue
• • 
  Polycystic ovary syndrome
• • 
  Ovarian tumor

Outflow Tract Anomalies

• • 
  Imperforate hymen
• • 
  Transverse vaginal septum
• • 
  Agenesis of uterus, vagina

Other Causes

• • 
  Pregnancy
• • 
  Hormonal contraception
• • 
  Congenital adrenal hyperplasia
• • 
  Adrenal tumor

Differential Diagnosis of Amenorrhea

Hypothalamic causes of amenorrhea result in abnormal secretion of gonadotropin-releasing hormone (GnRH) which, in turn, affects pituitary secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and ovarian secretion of estrogen and progesterone. The associated menstrual cycle abnormalities range from mild luteal phase defects to severe hypoestrogenemia. Hypothalamic amenorrhea is much more likely to reflect functional suppression of GnRH secretion than a structural defect in the anatomy of the hypothalamus.

Functional hypothalamic amenorrhea may be caused by weight loss, strenuous exercise, acute or chronic illness, and emotional upset. All of these conditions, whether physical or emotional, produce physiological stress with increases in hypothalamic secretion of corticotropin-releasing hormone (CRH), which in turn increases corticotropin (ACTH) secretion by the anterior pituitary and corticosteroids by the adrenal gland. CRH also suppresses GnRH secretion, perhaps through an increase in central nervous system levels of dopamine or endogenous opioids. As a result of the GnRH suppression, pituitary secretion of LH decreases and ovulation ceases.

Ovulation and normal menstrual function generally reflect a positive energy balance between intake and expenditure and an energy reserve in the form of body fat. When depleted energy reserves threaten the basic metabolic processes required for survival, anovulation protects the female from the added energy burden of pregnancy. Studies of athletes have shown there is a significant correlation between strenuous exercise and disruption of the menstrual cycle. Up to two-thirds of runners have been found to have anovulation or short luteal phase cycles. Exercise has also been associated with a decrease in thyroxine and increases in growth hormone (GH), testosterone, ACTH, adrenal steroids, endorphins, and melatonin. Evidence suggests that the negative energy balance of excessive exercise may be due to an increase in insulin-like growth factor binding protein-1 (IGFBP-1) and a decrease in insulin-like growth factor (IGF) activity, which contribute to suppression of GnRH.

Body fat is a more important determinant of ovulation than body weight, with 22% the estimated minimum required to maintain regular ovulatory cycles in most adults. The average 18% body fat at menarche may contribute to the higher proportion of anovulatory cycles during the early gynecological years than thereafter. The mechanism underlying the association between body fat and ovulation appears to be leptin, which is produced in body fat and signals the brain that there are adequate energy stores. With weight loss and a decrease in body fat, there is a fall in leptin levels leading to suppression of gonadotropin secretion. Chronic suppression of the hypothalamic–pituitary axis, as in patients with anorexia nervosa or persistent, excessive exercise, is associated with severe hypoestrogenemia. In addition to anovulation, the very low estrogen levels result in an atrophic endometrium and a complete absence of breakthrough bleeding. Bone mineralization peaks during adolescence and slows or halts in the absence of estrogen. The resulting plateau in bone density may place the young woman at lifelong risk of osteoporosis and fracture.

Structural hypothalamic amenorrhea most commonly is due to Kallman syndrome or congenital GnRH deficiency ( Chapter 10 ). Other causes include hypothalamic tumors, irradiation of the central nervous system, and hypothyroidism. The menstrual abnormalities associated with hypothyroidism are due to increased hypothalamic secretion of thyroid-releasing hormone (TRH), increased prolactin, and negative feedback on GnRH.

Pituitary causes of amenorrhea include tumors, infarction, surgery, radiation, cysts, tuberculosis, sarcoidosis, replacement by fatty tissue, and rare inherited deficiencies of LH and FSH. Pituitary adenomas account for up to one-third of cases of secondary amenorrhea and, of these, half are prolactin-secreting (i.e., prolactinoma). Large prolactinomas can produce visual field cuts and headache. Most, however, are small microadenomas that present as galactorrhea and/or amenorrhea without a mass effect. Other, less common pituitary tumors are craniopharyngiomas, meningiomas, gliomas, chordomas, and metastases from other sites.

Tumors, infiltrative processes, and cysts of the pituitary or nearby tissue can decrease FSH and LH secretion by destruction of pituitary tissue and/or compression of the pituitary stalk with decreased delivery of GnRH from the hypothalamus to the pituitary. Compression can also disrupt dopaminergic regulation, resulting in hyperprolactinemia and feedback inhibition of GnRH secretion. In some cases, hyperprolactinemia presents as galactorrhea with relatively normal menses, whereas in others it presents as amenorrhea. Pituitary tumors associated with Cushing disease, hyperthyroidism, and acromegaly can cause amenorrhea but do so within a spectrum of other signs and symptoms.

Sheehan syndrome, or pituitary apoplexy, is a rare postpartum complication in which hemorrhagic shock causes infarction and necrosis of the pituitary gland, with subsequent deficiencies of one or more pituitary hormones.

Ovarian causes of amenorrhea present as hypergonadotropic hypogonadism ( Chapter 10 ) and include gonadal dysgenesis or agenesis, premature ovarian failure, and resistant ovaries. Gonadal dysgenesis and premature ovarian failure account for 30–40% and 10–28% of primary amenorrhea, respectively. Gonadal dysgenesis, or Turner syndrome ( Chapter 10 ), presents in its pure, 45,X form in 60% of cases and as genetic mosaicism in 40% of cases. Most patients with Turner syndrome have nonfunctioning ovarian streaks, pubertal delay, and primary amenorrhea. Although unusual, some patients with mosaic Turner syndrome produce sufficient estrogen to support pubertal development and menses. Rarely, a patient with mosaic Turner syndrome can become pregnant. However, even in those patients who do have functioning ovarian tissue, most experience premature menopause with accelerated follicular atresia.

Premature ovarian failure, defined as menopause before age 40 years, affects 1% of women. It presents with primary or secondary amenorrhea and elevated serum levels of LH and FSH due to hypoestrogenemia and the lack of negative feedback on the hypothalamic–pituitary axis. Although most cases are idiopathic, known causes of premature ovarian failure include radiation to the pelvis, chemotherapy, infection, trauma, and autoimmune disease. Ovarian failure is less likely in younger than in older women who are exposed to radiation or chemotherapy, perhaps because of younger and more numerous oocytes. Alkylating chemotherapeutic agents are particularly toxic to the ovary, and the use of multiple agents increases the chances for ovarian failure. Autoimmune diseases such as thyroiditis, adrenal insufficiency, and hypoparathyroidism have been associated with ovarian antibodies and lymphocytic infiltration into developing follicles. In galactosemia, metabolites of galactose impair germ cell migration to the genital ridge, resulting in premature ovarian failure. Finally, patients who are Fragile X carriers are at risk for premature ovarian failure.

It is important to recognize that elevated gonadotropins may not represent ovarian failure. Pituitary adenomas that secrete FSH and LH typically do not present with amenorrhea but, rather, with headaches and visual disturbances related to tumor growth. Patients with resistant ovaries have mutations of the gonadotropin receptor, resulting in present but unresponsive ovarian follicles and elevated serum gonadotropins. Late-onset congenital adrenal hyperplasia due to deficiency of 17-hydroxylase is manifested as amenorrhea and elevated gonadotropins in the presence of ovarian follicles ( Chapter 23 ).

Outflow tract anomalies fall into four categories: agenesis/hypoplasia, abnormal canalization, duplication of structures, and the presence of a septum within the uterine cavity or vaginal canal. Most isolated abnormalities of the Müllerian duct and urogenital sinus are polygenic, but single gene mutations have been identified for a few rare syndromes.

The clinical severity of outflow tract anomalies varies widely. A study of fertile women having laparoscopic bilateral tubal ligation performed for contraception revealed that 3% had previously unrecognized Müllerian tract anomalies. At the other extreme is Müllerian agenesis, or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, which occurs in approximately 1 per 5000 female births. MRKH syndrome is the congenital absence of the proximal vagina and, in 90% of cases, the cervix and uterus. Those cases in which a normal or rudimentary uterus is present typically have functioning endometrium with obstruction to flow due to the abnormal vaginal canal.

Imperforate hymen is probably the most common obstructive anomaly of the female reproductive tract. Familial occurrences of imperforate hymen have been reported, but most cases are isolated events. The adolescent patient with an imperforate hymen may be asymptomatic before the accumulation of concealed menstrual flow or may present with recurrent bouts of cyclical abdominal pelvic pain. A bluish, bulging hymen and a vagina distended with blood may be found on genital inspection and recto-abdominal palpation. In some cases, the vagina may be extremely large, and the condition may result in back pain, pain with defecation, nausea and vomiting, and/or difficulty with urination. In extreme cases, hydronephrosis due to mechanical obstruction of the ureters from the grossly enlarged vagina can occur.

Transverse vaginal septa are believed to arise from a failure in fusion and/or canalization of the urogenital sinus and Müllerian ducts. Approximately 46% of vaginal septa occur in the upper vagina, 40% in the middle vagina, and 14% in the lower vagina. On speculum examination, the vagina is a short, blind pouch. The septa are usually less than 1 cm thick and may extend completely or partially from one vaginal sidewall to the other. Although transverse vaginal septa often have small central or eccentric perforations, hematocolpos remains a common presenting finding. Rarely, pyohematocolpos may be caused by ascending infection through the small perforation.

Androgen insensitivity syndrome typically presents as primary amenorrhea in an adolescent who is phenotypically female and genetically male (46X,Y). Testes are present but do not descend completely and are at increased risk for malignancy. Müllerian-inhibiting substance is produced, which prevents the development of the female internal reproductive structures, including the upper vagina, cervix, and uterus. Testosterone is also produced but there is end-organ insensitivity to its effects with abnormal negative feedback and high estrogen levels due to peripheral conversion of the testosterone. Breast development is normal, pubic and axillary hair is scant, the vagina is short, and the cervix and uterus are absent. Complete androgen insensitivity is usually diagnosed during puberty when a well-developed young woman presents with amenorrhea.

Hyperandrogenism as a cause of amenorrhea or oligomenorrhea is discussed in Chapter 23 . Conditions associated with hyperandrogenism include polycystic ovary syndrome (PCOS), ovarian or adrenal tumors that produce androgens, congenital adrenal hyperplasia, and Cushing disease. PCOS is the most common endocrine disorder in women of reproductive age and accounts for more than 90% of adolescent hyperandrogenism. Late-onset congenital adrenal hyperplasia (CAH), or 21-hydroxylase deficiency, is an autosomal recessive disorder that typically presents during adolescence as amenorrhea or oligomenorrhea, hirsutism, and often virilization. Androgen-producing tumors are rare in adolescents but should remain in the differential diagnosis, especially in cases of amenorrhea associated with the rapid onset of hirsutism or virilization.

Evaluation

The evaluation of an adolescent with amenorrhea begins with a thorough developmental and sexual history. The history should identify the ages of thelarche (i.e., onset of breast development), pubarche (i.e., onset of pubic hair development), and menarche; menstrual pattern; timing of first and last sexual intercourse; height and weight progression along established growth curves; eating and exercise patterns; weight fluctuations; signs of hyperandrogenism; galactorrhea; pelvic pain; known genitourinary anomalies; and history of chronic illness.

The physical examination should include the stages of breast and pubic hair development; the determination of body mass index (BMI) from the height and weight; skin examination for acne and hirsutism; ophthalmological examination; thyroid palpation; breast examination for galactorrhea; abdominal examination for masses; and pelvic examination for hymenal patency (i.e., insertion of a moist cotton swab into the vagina and/or bimanual examination); mucosal estrogenization; clitoral size; and outflow tract anatomy. A well-estrogenized mucosa should appear pink and moist, as compared with the red, thin mucosa of hypoestrogenemia.

Patients who cannot tolerate bimanual examination or recto-vaginal examination and those in whom the examinations are inconclusive should have pelvic ultrasonography performed to identify developmental anomalies and/or genital tract obstruction. Ultrasound also allows measurement of the endometrial stripe, which is an index of estrogen stimulation of the endometrium, and identification of ovarian cysts or masses ( Chapter 23). Ultrasound can be performed by transabdominal, transvaginal, and/or transperineal approaches. The latter can be helpful in young adolescents who cannot tolerate the transvaginal study. Magnetic resonance imaging (MRI) of the pelvis and/or abdomen is an excellent modality for further defining the presence of a vaginal septum, uterine remnant, streak gonads, and renal anomalies. MRI of the sella with and without contrast is the preferred modality for evaluating a suspected prolactinoma.

Nearly all adolescents with primary or secondary amenorrhea warrant a qualitative test for human chorionic gonadotropin (HCG) to exclude pregnancy, even if sexual activity is denied, and measurement of serum prolactin and TSH levels. Signs of hyperandrogenism on physical examination should be explored with measurement of serum free and total testosterone, dehydroepiandrosterone-sulfate (DHEAS), FSH, LH, and perhaps 17-hydroxyprogesterone ( Chapter 23 ). Adolescents with suspected but undiagnosed systemic illness should have a complete blood count, erythrocyte sedimentation rate, serum electrolytes, glucose, blood urea nitrogen (BUN), creatinine, liver function tests, total protein, albumen, and TSH.

Serum FSH and LH levels will help differentiate hyper- from hypogonadotropic hypogonadism ( Chapter 10 ). Elevated levels in a patient with primary amenorrhea and no history of radiation, chemotherapy, or autoimmune disease suggest gonadal dysgenesis and should trigger chromosomal analysis. If chromosomes are normal, serum levels of anti-ovarian antibodies should be measured. Low levels of FSH and LH in a patient with primary or secondary amenorrhea indicate hypogonadotropic hypogonadism due to decreased function at the hypothalamic or pituitary level. If there is no evidence of underlying systemic illness or other endocrine disorder, evaluation for Kallman syndrome should be pursued by formal olfactory testing, genetic and endocrine consultation, and head MRI.

As noted in Chapter 10 , the assessment of pituitary function in an adolescent with primary amenorrhea in the setting of delayed puberty can be particularly difficult. Low or normal levels of serum GH and its mediators, IGF-1 and IGFBP-3, may reflect GH deficiency, malnutrition, low body weight, or constitutional delay of puberty. In adolescents with severe hypogonadotropic hypogonadism, GnRH stimulation testing by an endocrinologist can help determine whether anterior pituitary function is appropriate for the level of pubertal development.

Management

The management of primary or secondary amenorrhea depends on the adolescent's physical and psychosocial maturation as well as the underlying pathology. The major decisions are about hormonal therapy in patients with hypothalamic, pituitary, and ovarian causes, and about surgery in patients with outflow tract anomalies.

Hormonal therapy is indicated for all adolescents with ovarian failure. Those with primary amenorrhea who are pre-pubertal or in early puberty should be managed with low-dose estrogen replacement to stimulate maturation, followed by maintenance estrogen and progesterone, usually in the form of combination oral contraceptive pills (OCPs) containing 20–30 mcg estradiol or equivalent. Patients with secondary amenorrhea due to ovarian failure do not require titration of the estrogen dose and can begin maintenance therapy with low-dose OCPs.

Adolescents with primary or secondary amenorrhea due to hypothalamic suppression can be challenged with oral progesterone 10 mg daily for 5 days. Withdrawal bleeding in response to the progesterone challenge indicates an intact outflow tract that has been primed by estrogen. The adolescent with persistent amenorrhea who responds to the challenge should repeat the 5-day course every 3 months to prevent chronic endometrial hyperplasia, which is a risk factor for endometrial cancer. The adolescent who does not respond to the challenge either has insufficient estrogen to induce a proliferative endometrium or has an outflow tract abnormality.

The most common dilemma in the management of adolescents with amenorrhea is the use of hormone replacement therapy (HRT) in those with functional suppression of GnRH secretion. Although some studies suggest that bone density in adolescent athletes with hypothalamic amenorrhea may be protected by HRT with combined estrogen-progestin OCPs, current evidence does not support its use in adolescents with amenorrhea due to anorexia nervosa. Management should instead focus on weight gain and the maintenance of sufficient body fat to support menses ( Chapter 35 ).

Patients with amenorrhea due to medication-induced hyperprolactinemia usually can be managed conservatively, with continuation of the responsible medication if it is considered important for overall physical and psychosocial health. Serum prolactin levels < 100 ng/ml can be monitored every 3 to 6 months, whereas those over 100 ng/dl generally warrant further evaluation with either head MRI or discontinuation of the medication responsible for the increase. Levels of 100–200 ng/dl in patients who are not on medications associated with hyperprolactinemia usually indicate pituitary microadenomas that do not require treatment unless breast discomfort develops or the patient wishes to conceive. In these cases, the usual treatment is a dopamine agonist such as bromocriptine. Levels > 200 ng/dl are associated with pituitary adenomas that are likely to produce other symptoms, such as headache or visual field cuts. Surgery, often with adjunctive radiation therapy, is indicated for these patients.

Surgery is indicated to correct imperforate hymen, transverse vaginal septum, and some cases of Müllerian aplasia. The correction of imperforate hymen can be performed at any age but is often delayed until early puberty when the estrogen effect on the mucosa facilitates a good repair. Puncture of an imperforate hymen without definitive repair can result in bacterial infection of an inadequately drained fluid collection and should be avoided. The level and thickness of a transverse vaginal septum should be determined by MRI prior to surgery to help plan the procedure.

The treatment of Müllerian aplasia begins with patient and family counseling about the cause and consequences of the anomaly. First and foremost is reassurance about female gender, both genetically and phenotypically. Although nonsurgical and surgical options exist for creating a vaginal canal, cervical and uterine dysgenesis is incompatible with successful pregnancy. In general, all techniques to establish a vagina should be delayed until mid to late adolescence when the patient can share in the decision about whether, when, and how to proceed. The nonsurgical method is considered first-line therapy and involves the use of vaginal dilators to apply progressive pressure against the vaginal dimple with gradual invagination of the mucosa. Recent studies demonstrate that 85–90% of patients achieve a functional vagina with this method. For those patients in whom dilators are unsuccessful, surgery can be considered. However, the patient and family must understand that most surgical interventions require the postoperative utilization of dilators.

Abnormal Uterine Bleeding

Abnormal uterine bleeding refers to the prolonged, acyclical, or heavy flow of blood and/or tissue from the endometrial cavity. Although most vaginal bleeding is of uterine origin, other causes should be considered, such as cervicovaginal trauma or mass ( Box 22-2 ). When there is no identifiable structural, infectious, or hemostatic cause, the term dysfunctional uterine bleeding (DUB) applies. During early adolescence, most abnormal uterine bleeding meets the definition of DUB and reflects the irregular endometrial sloughing that accompanies anovulatory cycles. 

BOX 22-2

Outflow Tract

• • 
  Trauma
• • 
  Foreign body
• • 
  Tumor
• • 
  Cervical polyp
• • 
  Uterine myoma
• • 
  Intrauterine device
• • 
  Uterine carcinoma

Ovarian Causes

• • 
  Tumor
• • 
  Cyst

Anovulation

• • 
  Pituitary abnormalities
• • 
  Hypothalamic abnormalities
• • 
  Immaturity of the hypothalamic–pituitary axis
• • 
  Androgen excess
• • 
  Thyroid disease

Hematological Conditions

• • 
  Thrombocytopenia
• • 
  Clotting disorders
• • 
  Platelet disorders
• • 
  Anticoagulant medications

Pregnancy

• • 
  Ectopic
• • 
  Molar
• • 
  Miscarriage

Infection

• • 
  Sexually transmitted infections
• • 
  Pelvic inflammatory disease

Hormonal Contraception

Differential Diagnosis of Abnormal Uterine Bleeding

Abnormal uterine bleeding typically is described in terms of its duration, quantity, and the interval between bleeding episodes. Menorrhagia refers to bleeding that lasts > 7 days or is > 80 ml in quantity. Menometrorrhagia is heavy, prolonged bleeding that occurs at irregular intervals. Polymenorrhea occurs at regular but short intervals of < 21 days.

Epidemiology

Most abnormal uterine bleeding during adolescence is DUB associated with anovulatory cycles. Less common causes include pregnancy, hormonal contraception, pelvic inflammatory disease (PID), bleeding disorders, hypo- or hyperthyroidism, PCOS, trauma, and congenital anomalies of the outflow tract. Unlike adults, endometrial cancer is an extremely rare cause of abnormal uterine bleeding in adolescents. A study of girls presenting with menorrhagia at menarche revealed that 45% had systemic bleeding dyscrasias. Platelet function disorders, including von Willebrand disease, were particularly common and probably are under-recognized in young adolescents with menorrhagia. Although von Willebrand disease is considered the most common inherited bleeding abnormality among females, with an overall prevalence of 1.3% in a heterogeneous population of U.S. children and adolescents, several studies suggest that other platelet function disorders may be responsible for many cases of unexplained menorrhagia. There is some evidence that menorrhagia associated with platelet dysfunction is more common in black than white females.

Pathophysiology

Anovulatory DUB in most adolescents is due to delayed maturation of the normal negative feedback mechanisms along the hypothalamic–pituitary–ovarian axis. The gradual rise in estrogen does not suppress FSH secretion, resulting in ongoing estrogen secretion by the ovaries and endometrial proliferation in response to the estrogen. In the absence of progesterone, which normally is increased in the luteal phase of the cycle, the thickening endometrium becomes increasingly unstable and disorganized shedding begins. Although immaturity accounts for most DUB during the first 1–2 years following menarche, it is unlikely beyond this point. Other causes of anovulation, such as PCOS, should always be considered if the DUB persists.

Pregnancy is always in the differential diagnosis of abnormal uterine bleeding, and a qualitative urine pregnancy test should be performed in nearly all patients. Consultation with an obstetrician is recommended for any pregnant patient who is bleeding and is essential if the bleeding is associated with abdominal pain or hemodynamic instability. The differential diagnosis includes threatened or spontaneous abortion, ectopic pregnancy, PID, and gestational trophoblastic disease.

von Willebrand disease is highly variable in severity and age at diagnosis. In many cases, menorrhagia at menarche is the first manifestation. Normally, platelets adhere to damaged blood vessels in a process mediated by the binding of von Willebrand factor (vWF) to a glycoprotein complex on the platelet membrane. In von Willebrand disease, underproduction or dysfunction of the vWF component of the Factor VIII molecule is associated with abnormal platelet adhesion at sites of vascular injury, reduced Factor VIII levels, and/or qualitative defects in Factor VIII activity. Patients with von Willebrand disease tend to have predominantly quantitative (Types I and III) or qualitative (Type II) defects of vWF, with Type I accounting for 70% of cases.

Evaluation

The evaluation of an adolescent with abnormal uterine bleeding should begin with characterization of the bleeding pattern. Specific information should include age at menarche; cycle length (i.e., day 1 of bleeding to day 1 of next bleeding episode), duration of bleeding; and quantity of bleeding (i.e., number of saturated tampons or sanitary napkins per 24 hours). Other information on history should include age at onset of sexual activity, history of sexually transmitted infections (STIs), condom use, new sexual partners within the past 3 months, contraception, past history of nonvaginal bleeding or bruising, family history of bleeding disorders, and current medications.

The physical examination should focus, first and foremost, on establishing hemodynamic stability through the evaluation of supine, sitting, and standing blood pressure and heart rate. Mucous membranes and skin should be examined for pallor, petechiae, ecchymoses, hirsutism, acne, and acanthosis nigricans. Lymphadenopathy and hepatosplenomegaly should be noted, and a new flow murmur on cardiac examination might suggest anemia. External genitalia should be examined for clitoromegaly, congenital anomalies of the introitus, and evidence of trauma. If DUB is likely and the patient is not sexually active, speculum examination is usually unnecessary. In other cases, however, it should be performed to inspect the cervix and vaginal canal and to collect samples for STI testing.

Pelvic ultrasonography is often performed to delineate anatomy when a structural anomaly is suspected, to assess the thickness of the endometrial stripe, to determine whether a pregnancy is intrauterine, or to determine whether hematocolpos or a uterine clot is present. Even when DUB has been heavy and prolonged, a thickened endometrial stripe is usually visualized. A uterine clot suggests that distention of the uterine cavity is interfering with myometrial contraction and hemostasis.

If the cause of abnormal bleeding remains uncertain, laboratory testing should include pregnancy testing (i.e., qualitative urine human chorionic gonadotropin [HCG]); STI testing of sexually active patients; measurement of serum TSH level and often serum androgen levels; CBC with platelet count; and prothrombin time and partial thromboplastin time. For patients in whom von Willebrand disease is suspected, the following laboratory studies should be ordered: Factor VIII activity, vWF antigen level, ristocetin cofactor activity, and multimeric analysis. The Platelet Function Analyzer (PFA-100), which is now available in many institutions, screens for acquired platelet disorders (e.g., aspirin-induced), von Willebrand disease, and some of the more complex inherited causes of platelet dysfunction. Tests of platelet aggregation represent the next level of evaluation but are laborious, costly, and not readily available in many institutions. In addition, interpretation of the results can be difficult because they are affected by hemolysis, lipemia, thrombocytopenia, and certain medications.

Management

When there is an identifiable cause for abnormal uterine bleeding, such as PID, that problem obviously should be treated. The more difficult management decisions pertain to DUB and patients with bleeding dyscrasias. In these situations, hemodynamic status and hemoglobin level often dictate treatment ( Box 22-3 ). It is very important to note that the management of abnormal uterine bleeding in adolescents is quite different than in older adults. Unlike adults in whom persistent or uncontrolled uterine bleeding commonly leads to dilatation and curettage (D&C), this is rarely required in adolescents and should be considered only when the options, discussed later, fail. 

BOX 22-3

Mild: Hemodynamic Stability and Hemoglobin > 11 g/dl

• • 
  Menstrual calendar.
• • 
  Iron supplementation.
• • 
  Consider combined OCP.
• • 
  Re-evaluate in 1–3 months.

Moderate: Hemodynamic Stability and Hemoglobin > 9 g/dl

• • 
  Menstrual calendar.
• • 
  Iron supplementation.
• • 
  Combined OCP containing ≥ 30 mcg ethinyl estradiol, one tablet every 6 hours until bleeding stops or up to 4 days, followed by taper to one tablet every 8 hours for 2–3 days, one tablet every 12 hours for 2 days, one tablet (i.e., active hormone tablet in packet, not placebo-week tablet) daily for 2–3 weeks. Then discontinue pills for 1 week to allow withdrawal bleed, followed by OCP cycles for 3–6 months.
• • 
  Re-evaluate in 1–3 months.

Severe: Hemodynamic Instability and Hemoglobin < 9 g/dl

• • 
  Hospitalization for intravenous fluids and/or transfusion.
• • 
  Iron supplementation.
• • 
  Combined OCP, as noted above. If bleeding does not slow significantly with two doses, add the following to the oral contraceptive regimen: conjugated estrogen 25 mg intravenously every 4–6 hours until bleeding stops or up to 4 doses.
• • 
  Dilatation and curettage if bleeding persists.
• • 
  Combined OCP cycles for 3–6 months.

Management of Dysfunctional Uterine Bleeding (DUB)

The stable adolescent with mild DUB and a normal hemoglobin level can be observed without treatment. The patient should record bleeding on a menstrual calendar, call immediately if flow increases or new symptoms develop, and schedule a follow-up visit within 1–3 months if bleeding stops or remains mild and intermittent. Hormonal therapy with a combined estrogen-progestin OCP can be initiated in those adolescents who are troubled by the bleeding, even if scant. In most cases, mild anovulatory DUB stops with the OCP and regular withdrawal bleeding during the placebo week of the pill cycle is established. After 3–6 months of regular menses on the pill, a trial without it can be considered.

The stable adolescent with mild-moderate anemia (i.e., hemoglobin level > 9.0 g/dl) should be managed with combined estrogen-progestin therapy for at least 3–6 months, as outlined in Box 22-3 . Emergent care is essential for the unstable patient, and prompt inpatient care is recommended for the patient with a hemoglobin level < 9.0 g/dl who continues to have heavy bleeding. Of note, the initial hemoglobin and hematocrit values may be falsely elevated in an unstable patient and may decrease significantly with fluid resuscitation. Patients requiring the combined OCP several times daily for acute control of bleeding often benefit from the simultaneous administration of an anti-emetic to control the nausea associated with high-dose estrogen. Once the oral contraceptive is reduced to the maintenance dose of one pill daily, oral iron replacement therapy (i.e., 60 mg elemental iron orally three times daily) should be started for all patients with anemia and continued for at least 8 weeks.

Hormonal therapy for an adolescent with DUB usually consists of estrogen and progestin, administered as a monophasic combined OCP. Estrogen facilitates hemostasis and endometrial healing. Progestin halts endometrial proliferation and stabilizes the endometrial lining. Once the bleeding has stopped, the oral contraceptive should be continued as one pill daily until there is significant improvement in the hemoglobin level or for a minimum of 3 weeks to allow endometrial repair. At that point, the pill is stopped for 1 week and a withdrawal bleed occurs. The patient should be warned that this withdrawal bleed is likely to be heavy but painless and limited in duration, secondary to the endometrial proliferation induced by the high-dose estrogen during the initial phase of treatment. The oral contraceptive should then be cycled for 3–6 months according to the usual pill pack instructions to allow the endometrium to heal completely. Extended hormone replacement for up to 3 months prior to a withdrawal week is an option but is more likely to be associated with unpredictable breakthrough bleeding due to the prolonged endometrial stimulation and proliferation.

Norethindrone acetate or medroxyprogesterone acetate are progestin-only alternatives that can be used for the control of bleeding in patients who cannot tolerate estrogen or for whom it is contraindicated. Acutely, the progestin may be required in higher dosage and should be administered orally or intramuscularly. Once the bleeding stops, the progestin should be continued as a daily pill, a long-acting intramuscular injection (i.e., depot medroxyprogesterone acetate), or a progestin-containing intrauterine device (IUD).

Intravenous estrogen is available for patients who cannot tolerate or continue to bleed on the OCP. Of note, progestin should be administered with the estrogen to stabilize the endometrial lining. Conjugated estrogen in a dose of 25 mg intravenously every 4–6 hours is administered for a maximum of four doses. When the bleeding is controlled, the estrogen and progestin should be continued as the OCP as noted previously and in Box 22-3 . Rarely, transfusion of packed red blood cells is required for patients with severe anemia that has developed quickly. Most adolescents in whom the anemia has developed gradually, even if severe, are hemodynamically stable and do not require transfusion.

Other treatment modalities can be utilized as adjuncts to hormonal therapy for the acute management of severe or prolonged DUB, such as methergine or misoprostol, which stimulate uterine contraction. Antifibrinolytic therapy aids in preventing dissolution of clot and is commercially available in the United States as Amicar (aminocaproic acid). In patients with von Willebrand disease, an infusion of vWF-rich Factor VIII (i.e., Humate P) may be necessary acutely. These patients may also benefit from long-term use of the combined OCP therapy because the estrogen component of the pill increases vWF and Factor VIII levels.

Adolescents with von Willebrand disease or other causes of platelet dysfunction and those with the hemophilia gene who experience recurrent menorrhagia despite hormonal therapy may benefit from desmopressin (DDAVP) administered as a highly concentrated nasal spray (Stimate). DDAVP is a synthetic analog of antidiuretic hormone that increases vWF and Factor VIII levels, as well as platelet adhesion to vessel walls. The usual dose of Stimate is one puff in each nostril for the first 1–3 days of menses, and weights should be monitored daily because of the antidiuretic effect. Oral antifibrinolytic therapy may be considered for those patients who do not respond to Stimate. However, frequent, high dosing is typically required for oral antifibinolytic medications, with associated gastrointestinal side effects and low patient adherence to the regimen.

Primary Dysmenorrhea

Definitions

• Dysmenorrhea: Painful menstruation.
• Primary dysmenorrhea: Painful menstruation with no apparent pelvic pathology. This chapter focuses on primary dysmenorrhea.
• Secondary dysmenorrhea: Painful menstruation caused by pelvic pathology, such as endometriosis, outflow tract obstruction, or PID. Chapter 23 discusses secondary dysmenorrhea.

Epidemiology

Dysmenorrhea is the most common cause of missed school and work time by females, estimated at more than 140 million lost hours per year. Dysmenorrhea of varying severity accompanies 20–90% of adolescent menstrual cycles. The prevalence of primary dysmenorrhea increases with adolescent gynecological age (i.e., time since menarche) due to its association with ovulatory cycles (see following discussion), peaks at age 17 years, and decreases with parity. Severe dysmenorrhea that significantly interferes with function 1–3 days per month affects 5–42% of adolescents and is more likely be primary than secondary in origin.

Pathophysiology

Primary dysmenorrhea is caused by hypercontraction of the myometrium, tissue ischemia, and hypersensitivity of pain nerve terminals in the uterine cavity. The underlying mechanism involves the endometrial production and secretion of prostaglandin F ₂ alpha (PGF ₂ α) and prostaglandin E ₂ (PGE ₂ ) during menses. PGF ₂ α is primarily responsible for the symptoms of dysmenorrhea, producing the uterine contractions and ischemia as well as mediating pain sensation. Endometrial levels of PGF ₂ α and PGE ₂ are higher in the secretory than proliferative phase of the menstrual cycle, supporting the association of primary dysmenorrhea with ovulatory cycles; are highest in the first two days of flow, explaining why dysmenorrhea is more severe in the beginning than end of menses; and are higher in women with than without dysmenorrhea. Although serum levels of PGF ₂ α and PGE ₂ are not increased during menstruation, studies have demonstrated that intravenous infusion of PGF ₂α induces systemic symptoms similar to those that are associated with primary dysmenorrhea (e.g., headache, nausea, vomiting, backache, diarrhea, dizziness, and fatigue). The causative role of prostaglandins is further supported by consistent evidence demonstrating the effectiveness of prostaglandin synthetase inhibitors (i.e., NSAIDs) in the treatment of primary dysmenorrhea.

Evaluation

Key questions to ask the adolescent with dysmenorrhea include the following: Did the pain begin with menarche? Was the pain as severe when it began as it is now? Does the pain occur only during menstruation? Menstrual duration, flow, and interval should be reviewed, along with changes in cycle pattern over time. The effect of dysmenorrhea on the adolescent's function should be discussed in detail, including missed school and decreased social involvement. Those adolescents who have tried NSAIDs without success should be asked when they begin the medication. NSAIDs are most effective when begun with or shortly before the onset of pain because their primary mechanism of action is to decrease endometrial production of prostaglandins.

The history should also include questions about sexual activity, STIs, and sexual risk behaviors (e.g., number of lifetime partners, new partner within the past 3 months, non-use of condoms). A thorough review of systems is important because of the many non-gynecological conditions that can cause pelvic pain ( Box 22-4 ). The psychosocial history should include questions about stress, substance abuse, and cigarette smoking, which has been specifically associated with dysmenorrhea. 

BOX 22-4

• • 
  Gastrointestinal disorders
• • 
  Inflammatory bowel disease
• • 
  Irritable bowel syndrome
• • 
  Constipation
• • 
  Lactose intolerance
• • 
  Musculoskeletal pain
• • 
  Inflammatory process
• • 
  Trauma
• • 
  Tumor
• • 
  Cystitis
• • 
  Ureteral obstruction
• • 
  Calculi
• • 
  Psychogenic disorders
• • 
  History of abuse

Non-Gynecological Causes of Pelvic Pain

Pelvic examination generally can be deferred in the adolescent with probable primary dysmenorrhea who denies history of sexual intercourse. The insertion of a moistened cotton swab into the vaginal canal can help rule out a hymenal abnormality or vaginal septum, and recto-abdominal examination can help identify a mass when bimanual vaginal examination is difficult. Laboratory testing is unnecessary in the adolescent with probable primary dysmenorrhea. If the history or physical examination suggests that the dysmenorrhea is secondary to organic pathology, the specific condition that is suspected should guide testing ( Chapter 23 ).

Management

First- and second-line therapies for primary dysmenorrhea are NSAIDs and OCPs, respectively. Clinicians should explain that primary dysmenorrhea is normal but uncomfortable and that the symptoms can be controlled. Many studies have demonstrated that adolescents typically know little about effective treatment options for dysmenorrhea, and even those who use NSAIDs typically do not begin them before the onset of pain.

NSAIDs are divided into several groups, including salicylic acids, acetic acids, propionic acids, fenamates, benzenesulfonamides, furanones, and oxicams. Those that are best-studied and most widely used for the treatment of dysmenorrhea are the propionic acids (e.g., ibuprofen, naproxen) and fenamates (e.g., mefenamic acid). Mefenamic acid may be advantageous in some clinical situations because it competes with prostaglandins for binding sites, thus antagonizing prostaglandin action as well as inhibiting prostaglandin synthesis. The typical dosing patterns of commonly used NSAIDS are shown in Table 22-1 . 

Table 22-1

NSAID Regimens for Dysmenorrhea

NSAID	First Dose (mg)	Subsequent Dose (mg)
Ibuprofen	400–600	400 every 4–6 hours or 600 every 6 hours
Naproxen	500	250 every 6–8 hours
Naproxen sodium	550	275 every 6–8 hours or 550 every 12 hours
Mefenamic acid	500	250 every 6 hours

NSAIDs should be started either with the onset of pain if it precedes menses or with the first sign of menstruation. There is no proven advantage to starting prior to the onset of menses in an individual whose pain begins after the onset of bleeding. NSAIDs typically are needed for only 1–3 days and are associated with minimal side effects when used in the recommended doses. Each formulation should be tried for two or three menstrual cycles, and a 6-month trial with at least two different formulations is recommended before deciding that NSAIDs are ineffective.

Hormonal therapy can be added to NSAIDs for patients with ongoing discomfort or can be used alone for patients who do not tolerate NSAIDs or derive no benefit from them. OCPs have been shown to decrease symptoms in more than 90% of patients with primary dysmenorrhea. The mechanisms of action include the inhibition of ovulation and the development of an atrophic endometrium, with resultant decreases in prostaglandins and menstrual flow. The patient should be counseled that maximal effect may be delayed for several cycles. If dysmenorrhea persists on the 28-day cycle of the usual OCP pack, the patient can skip the placebo pills and take only the hormone-containing pills for up to 3 months before allowing 7 days without hormones for a withdrawal bleed. Progestin-only methods, such as injectable depot medroxyprogesterone acetate (Depo-Provera) and the levonorgestrel-releasing intrauterine system (Mirena), also are effective for the treatment of dysmenorrhea.

Some studies suggest that oral supplementation with vitamin B ₁ , magnesium, and vitamin E may be helpful in the management of dysmenorrhea. GnRH agonists may be needed for the control of dysmenorrhea secondary to endometriosis but rarely are indicated for primary dysmenorrhea.

Premenstrual Syndrome

Definitions

• Premenstrual dysphoric disorder (PMDD) is defined by the Diagnostic and Statistical Manual of Mental Health Disorders , 4th edition (DSM-IV-TR) according to the criteria noted in Box 22-5 . The symptoms of PMDD are more severe than those of PMS and predominantly affect mood. 
  BOX 22-5

  • I 
    In most menstrual cycles in the past year at least five of these symptoms (including at least one of the symptoms in category A) were present for most of the time 1 week before menses, began to remit within a few days after the onset of the follicular phase (menses), and were absent in the week after menses.
    • A 
      Principal Symptoms
      • 1 
        Markedly depressed mood, feelings of hopelessness or self-deprecating thoughts
      • 2 
        Marked anxiety, tension
      • 3 
        Marked affective lability (i.e., feeling suddenly sad or tearful)
      • 4 
        Persistent and marked anger or irritability or increased interpersonal conflicts
    • B 
      Other Symptoms
      • 1 
        Decreased interest in usual activities such as friends and hobbies
      • 2 
        Subjective sense of difficulty in concentrating
      • 3 
        Lethargy, easy fatigability, or marked lack of energy
      • 4 
        Marked change in appetite, overeating, or specific food cravings
      • 5 
        Hypersomnia or insomnia
      • 6 
        A subjective sense of being overwhelmed or out of control
      • 7 
        Other physical symptoms (e.g., breast tenderness, bloating, weight gain, headache, joint or muscle pain)
  • II 
    The symptoms markedly interfere with work, school, usual activities, or relationships with others.
  • III 
    Symptoms are not merely an exacerbation of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder (although it may be superimposed on any of these disorders).

  Criteria I, II, and III are confirmed by prospective daily ratings for at least two consecutive symptomatic menstrual cycles.

  DSM-IV-TR Criteria for the Diagnosis of PMDD

  Adapted from: American Psychiatric Association. Diagnosis and Statistical Manual of Mental Disorders, 4th edition. DSM-IV-Text Revision. DSM-IV-TR. Washington, D.C. American Psychiatric Association, 2000.
• Premenstrual syndrome (PMS) a constellation of predictable physical, cognitive, affective, and behavioral symptoms that occur cyclically, beginning with ovulation, continuing during the luteal phase of the menstrual cycle, and quickly resolving with menstruation. To date, there is no universally accepted definition or set of diagnostic criteria for PMS.

Epidemiology

An estimated 70–90% of women experience some pre-menstrual symptoms. The 3–8% of these women who describe the symptoms as severe enough to affect quality of life probably represents the subgroup with PMDD. More than 200 symptoms have been described in the literature, the most common of which are listed in Box 22-6. At least one premenstrual symptom is reported by 50–100% of adolescents, and 14–89% of adolescents describe their symptoms as moderate to severe. There is a higher concordance of PMS among monozygotic than dizygotic twins, and a maternal history of PMS increases the likelihood of its development. The prevalence of PMS increases with advancing age beyond 30 years. 

BOX 22-6

Emotional Symptoms

• • 
  Irritability
• • 
  Depression
• • 
  Fatigue or lethargy
• • 
  Anger/argumentative
• • 
  Insomnia or hypersomnia
• • 
  Mood lability
• • 
  Anxiety
• • 
  Poor concentration
• • 
  Confusion
• • 
  Tearfulness
• • 
  Social withdrawal

Physical Symptoms

• • 
  Headaches
• • 
  Swelling: legs or breasts; breast tenderness
• • 
  Increased appetite
• • 
  Food cravings
• • 
  Weight gain
• • 
  Sense of abdominal bloating
• • 
  Fatigue
• • 
  Muscle and joint aches and pain

Symptoms Associated with PMS and PMDD

Pathophysiology

PMS probably represents an interaction between sex steroids and central neurotransmitters. There is some evidence supporting reduced serotonergic function in the luteal phase of the menstrual cycle and alteration in the response of the gamma aminobutyric acid (GABA) receptor complex. Although serotonergic dysregulation is the most plausible theory, variable response to selective serotonin reuptake inhibitors (SSRIs) implies the involvement of other factors. Estrogen, progesterone, and testosterone levels are normal, but women with PMS/PMDD may be more vulnerable to the normal cyclical fluctuations in serum levels of these hormones. Current evidence does not support associations of PMS with prolactin, growth hormone, thyroid hormone, adrenal hormones, luteinizing hormone (LH), follicle-stimulating hormone (FSH), antidiuretic hormone, insulin, zinc, vitamin A, vitamin E, thiamine, magnesium, or pyridoxine.

Evaluation

There are no universally accepted findings on physical examination or laboratory evaluation that establish a diagnosis of PMS or PMDD. Important findings on history are as follows: (1) symptoms occur in the luteal phase and resolve within a few days of menses; (2) symptoms recur over at least three menstrual cycles and cannot be explained by other physical or psychological problems; and (3) symptoms are severe enough to disrupt normal activities. PMS and PMDD can be exacerbated by and/or exacerbate (i.e., menstrual magnification) co-existing psychiatric or medical conditions such as seizures, migraine headaches, irritable bowel syndrome, asthma, and allergies.

Management

A stepwise approach to the management of PMS and PMDD is outlined in Box 22-7 . For adults with severe symptoms, SSRIs are considered first-line therapy. Placebo-controlled studies have demonstrated improvements in both physical symptoms and mood with fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and venlafaxine. Unlike depression, the symptoms of PMS and PMDD typically improve within 24–28 hours of initiating therapy. Furthermore, the medications appear to be equally effective when used either continuously or only during the luteal phase (i.e., the 14 days following ovulation). Low-dose therapy is usually sufficient, and intermittent use has not been associated with symptoms of SSRI withdrawal. It is important to note that fluoxetine is the only SSRI approved for use in adolescents < 18 years of age. Studies suggest more variable effectiveness with the continuous or intermittent use of alprazolam, which affects the GABA receptor complex; clomipramine, which is a nonselective serotonin receptor agonist; and buspirone, which is a partial serotonin receptor agonist. 

BOX 22-7

Step 1a: Mild-moderate symptoms:

• • 
  Complex carbohydrates, aerobic exercise, calcium supplementation, and possibly magnesium or chasteberry fruit.

Step1b: Physical symptoms predominate:

• • 
  Spironolactone, oral contraceptive, Depo-Provera, NSAIDs.

Step 2: Mood symptoms predominate:

• • 
  SSRI or an anxiolytic medication.

Step 3: No response to Steps 1 or 2:

• • 
  Gynecological consultation about GnRH agonists.

Approach to the Treatment of PMS and PMDD

Adapted from: American College of Obstetricans and Gynecologists: Premenstrual syndrome. ACOG Practice Bulletin #15. Washington, D.C., American College of Obstetricians and Gynecologists, April, 2000; and Johnson SR: Premenstrual syndrome, premenstrual dysphoric disorder, and beyond: A clinical primer for practitioners. Obstet Gynecol 2004;104:845–859.

Studies exploring the use of OCPs for PMS or PMDD have yielded inconsistent results. A double-blind, placebo-controlled study of an oral contraceptive containing drospirenone and ethinyl estradiol 30 mcg in women with PMDD demonstrated improvement in a few physical symptoms. Another study of a newer formulation containing drospirenone and ethinyl estradiol (20 mcg) daily for 24 days and nonactive pills for 4 days (24/4 regimen) rather than the usual 21/7, showed improvement in both mood and physical symptoms. Generally, OCPs can be considered if the symptoms are primarily physical.

Other regimens to suppress ovulation can also be considered, such as continuous use of oral contraceptives for 3 months and the injectable depot medroxyprogesterone acetate (Depo-Provera). GnRH has been shown to be effective in adult women for the treatment of PMS and PMDD but is associated with severe hypoestrogenemia and increased risk of osteoporosis. GnRH with add-back estrogen-progestin therapy can be considered in adults when other modalities have failed but is rarely indicated for adolescents with PMS or PMDD. Spironolactone may help reduce premenstrual breast tenderness, bloating, or weight gain from fluid retention in some patients. Similarly, NSAIDs may help control some physical symptoms. Evidence remains limited regarding the use of mineral supplementation, herbal preparations, and dietary manipulation.

One of the most promising interventions is calcium (1200 mg/day) in the form of calcium carbonate, which has been reported to reduce physical and emotional symptoms in a well-designed, multicenter study. A prospective case-control study, nested in the Nurses' Health Study II, demonstrated that the risk of developing PMS was reduced among women with high intake of calcium and vitamin D. Magnesium supplementation (200 to 400 mg/day) has been noted in some studies to reduce negative mood and water retention, but the mechanism of action is not understood and data are limited.

Placebo-controlled trials have demonstrated the possible effectiveness of chasteberry; ginko leaf extract for breast tenderness, fluid retention, and mood; and carbohydrates for the control of food craving and mood. The mechanism of action for the latter may involve an increase in tryptophan, which is a precursor to serotonin. Evidence is limited regarding the effectiveness of pyridoxine (vitamin B ₆ ) and vitamin E.

Major Points

• • 
  All patients with amenorrhea should be evaluated to determine pubertal staging and the presence of normal genital anatomy.
• • 
  During adolescence, eating disorders and excessive exercise are common causes of secondary amenorrhea.
• • 
  PCOS should be considered in the differential diagnoses of both amenorrhea and abnormal uterine bleeding.
• • 
  Anovulation is the most common cause of abnormal uterine bleeding in adolescents.
• • 
  Inherited bleeding disorders should always be considered in adolescents with heavy or prolonged uterine bleeding that began with menarche.
• • 
  Endometrial prostaglandins are responsible for the uterine contractions, tissue ischemia, and stimulation of endometrial pain nerve terminals of primary dysmenorrhea.
• • 
  Adolescents with dysmenorrhea who do not respond to medical therapy should be evaluated for endometriosis or outflow tract anomalies.
• • 
  Most menstruating adolescents have at least one pre-menstrual symptom.
• • 
  The diagnoses PMS and PMDD depend on recurrence over at least three cycles with adverse effects on school, work, and social function.