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MINISTRY OF PUBLIC HEALTH OF UKRAINE NATIONAL PIROGOV MEMORIAL MEDICAL UNIVERSITY, VINNYTSYA CHAIR OF OBSTETRICS AND GYNECOLOGY №1 METHODICAL INSTRUCTIONS for practical lesson « Gynecological disorders of childhood and adolescence» MODULE 4: Obstetrics and gynecology TOPIC 12 I. Topic: Abnormalities of sexual development of girls. Classification, clinical picture, diagnostics and principles of treatment II. Class duration – 4 hours. III. Educational objectives: The student must know: 1. Special methods of examination in girls with abnormalities of sexual development. 2. Deontology of communication with patients with such pathology in juvenile age. 3. Estimate data of general clinical, special, hormonal, roentgenological, medical and genetic examination of girls with abnormalities of sexual development. The student must be able to: Examine of a patient with abnormalities of sexual development. Make diagnostics and treatment. Interpret data of clinical and laboratorial and instrumental examination. IV. Advice to the student. Disorders of Puberty Delayed Puberty o Delay of puberty can be caused by anatomic abnormalities, chromosomal disorders, neoplastic growths, or nutritional deficiencies. o Commonly presents as a physical delay in maturation combined with amenorrhea. o Causes of delayed puberty can be classified, based on the level of follicle stimulating hormone (FSH) present, as outlined in Table 30.5. o Hypergonadotropic Hypogonadism (High FSH) A sufficient amount of gonadotropins are present, but the end organs are not responsive and therefore do not produce sex steroids. Gonadal dysgenesis Present as phenotypic female with persistent prepubertal development. Usually lack breast development. May have some secondary sex characteristics and spontaneous menstruation. Most often associated with primary amenorrhea. Table 30.5 An Overview of Causes of Delayed Puberty FSH Level Differential Diagnosis gh >30 mIU/mL Gonadal dysgenesis syndromes: Turner's syndrome, Sweyer's syndrome Primary ovarian failure ow <10 mIU/mL Constitutional delay Intracranial neoplasms Isolated gonadotropin deficiencies Hormone deficiencies Kallmann syndrome Prader-Labhart-Willi syndrome Laurence-Moon-Biedl syndrome Chronic disease and malnutrition mal omic deformities result in normal development with primary amenorrhea. Imperforate hymen Transverse vaginal septum MГјllerian agenesis Turner syndrome (45, X) is most commonly associated with gonadal dysgenesis. Occurs in 1 in 2,000 to 2,500 born girls and is present in approximately 6% of all spontaneous abortions (3). Sweyer syndrome(46, XY) is also associated with gonadal dysgenesis, but patients often have a normal-to-tall stature. Most often related to a mutation or structural abnormality of the Y chromosome. Must remove gonads. Primary ovarian failure Ovaries develop but do not contain oocytes; may be associated with chemotherapy, radiation, galactosemia, gonadotropin resistance, autoimmune ovarian failure, or ovarian failure secondary to previous infection. Treatment involves administration of exogenous estrogen and progesterone to avoid osteoporosis and to facilitate development of secondary sexual characteristics. Hypogonadotrophic Hypogonadism (Low FSH) An insufficient level of gonadotropins is present to permit follicular development and therefore sex steroids are not produced. Chronic disease of malnutrition: Conditions including states of malnutrition, including starvation, anorexia nervosa, cystic fibrosis, Crohn's disease, diabetes mellitus, inflammatory disease, and hypothyroidism, are thought to lead to a disruption of gonadotropin-releasing hormone GnRH production, therefore resulting in pubertal delay (4). Constitutional delay: A delay in the (GnRH) pulse generator postpones the normal physiologic events of puberty. Intracranial neoplasms: Both craniopharyngiomas and pituitary adenomas may cause delayed puberty. Visual symptoms are often associated with these tumors, as is short stature and diabetes insipidus. Diagnosis is by CT or MRI of the head. Treatment includes either surgical excision or radiotherapy. Isolated gonadotropin deficiencies: often secondary to abnormalities in genes encoding proteins related to GnRH, FSH, or leutinizing hormone (LH) (3). Hormone deficiencies: Any aberration of growth hormone or thyroid hormone levels will affect puberty. Therefore, these levels should be investigated and treated appropriately. In addition, hyperprolactinemia can cause a decrease in levels of FSH and LH and thus delay puberty. Kallmann syndrome: A sporadic or X-linked syndrome with a classic triad of anosmia, hypogonadism, and color blindness. The hypothalamus cannot secrete GnRH due to dysfunction in the arcuate nucleus. Few or no secondary sexual characteristics are present. Prader-Labhart-Willi syndrome: an autosomal dominant condition associated with extreme obesity, emotional instability, and delayed puberty secondary to hypothalamic dysfunction (4). Laurence-Moon syndrome: a rare autosomal disorder associated with retinitis pigmentosa, hypogonadism, and spastic paraplegia (4). Bardet-Biedl syndrome: a rare autosomal recessive disorder associated with retinitis pigmentosa, hypogonadism, and postaxial polydactyly (4). Eugonadism (Normal FSH) In cases of eugonadism, the hypothalamic-pituitary-gonadal axis remains intact, and delay of puberty presents with primary amenorrhea related to anatomic abnormalities in the genitourinary tract, androgen insensitivity, or inappropriate positive feedback mechanisms. Anatomic abnormalities of the genitourinary tract resulting in primary amenorrhea: Imperforate hymen: may be evident in a neonate and may regress as the girl enters childhood. After menarche, the imperforate hymen may become evident when accumulating menstrual blood forms a hematocolpos and may present as an abdominal mass. Surgical intervention is required to incise the hymen and allow stored debris to escape. Transverse vaginal septum: due to failure of canalization of mГјllerian tubules and the sinovaginal bulb, leaving a membrane present. May be associated with urinary tract abnormalities as well. If the membrane is thin, it can be incised and dilated. If it is thick, surgical excision with a split thickness skin graft may be required. MГјllerian agenesis: failure of the mГјllerian tract to develop results in a blind vaginal pouch without uterus or fallopian tubes present. Ovaries are present and function normally and, therefore, puberty progresses as usual with primary amenorrhea as a presenting complaint. This must be distinguished from androgen insensitivity, as described later. One-third of these patients have associated urinary tract anomalies, and 12% have skeletal anomalies. A neovagina can be created by progressive dilation or surgery. Vaginal atresia: The lower vagina is replaced by fibrous tissue; differentiated from mГјllerian agenesis by the presence of normal uterus and fallopian tubes. Androgen insensitivity: discussed later under male feminization. Karyotype XY males present as phenotypic females with a blind vaginal pouch secondary to an insensitivity of circulating androgens. Other causes of primary amenorrhea with eugonadism include anovulation, androgen producing adrenal disease, and polycystic ovarian syndrome. Precocious Puberty o Precocious puberty is a rare condition that occurs in only 1 of 10,000 girls (5). o Defined as evidence of secondary sexual characteristics, including breast or pubic hair development at an age more than 2.5 standard deviations below the mean (5). o According to a recent study, such findings should be investigated in African American girls under age 6 and Caucasian girls under age 7 (6). o Characteristic accelerated growth velocity in combination with rapid bone growth and maturation can result in short adult stature (7). o Common causes of precocious puberty can be divided into GnRH-dependent disorders, or true or central precocious puberty, versus GnRH-independent disorders, or pseudoprecocious puberty. o Central Precocious Puberty Most commonly idiopathic; secondary sexual characteristics progress in normal sequence but more rapidly than in normal puberty, and may fluctuate between progression and regression. Related to premature development of the hypothalamic-pituitary axis and is therefore GnRH-dependent, but the initiating cause is unknown (5). May be transmitted in an autosomal recessive fashion, so check family history. Often ovarian follicular cysts are present due to elevated levels of LH and FSH (5). Other causes of central precocious puberty involve central nervous system disease: Disease often involves areas surrounding the hypothalamus; mass effect, radiation, or ectopic GnRH secreting cells are thought to cause premature activation of pulsatile secretion of GnRH from the hypothalamus. Diagnosis by CT or MRI of the head; history may be significant for headache, mental status changes, mental retardation, dysmorphic syndromes, along with the premature development of secondary sexual characteristics. Treatment should be directed at the underlying cause; the location of many of such tumors makes resection difficult, and, as a result, chemotherapy or radiation may be involved. GnRH agonist administration can result in a short burst of gonadotropin release followed by down-regulation and desensitization resulting in an overall decrease in the level of circulating gonadotropins. Follow estradiol levels to make appropriate dose adjustments (8). o Pseudoprecocious Puberty Premature development of secondary sexual characteristics occurs by a GnRH-independent mechanism. Differential diagnosis includes estrogen-secreting tumors, benign follicular ovarian cysts, McCune-Albright syndrome, Peutz-Jeghers syndrome, adrenal disorders, and primary hypothyroidism. Estrogen secreting ovarian tumors Granulosa cell tumors (60%): usually >8 cm in size; 80% are palpable on abdominal examination; others include arrhenoblastomas, thecomas, lipid cell tumors, teratomas, or choriocarcinomas. Diagnose by sonography, manage surgically with adjuvant chemotherapy, if indicated, and follow by estradiol levels. Benign follicular ovarian cysts Most common form of estrogen-secreting masses in children May require a diagnostic laparoscopy versus exploratory laparotomy to differentiate from a malignant tumor. Removal of the cyst may be therapeutic. McCune-Albright syndrome Triad: cafГ© au lait spots, polyostotic fibrous dysplasia, and cysts of skull and long bones; precocious puberty is present in 40% (9). Sexual precocity results from recurrent follicular cyst. Removal of cyst is not helpful. Aromatase inhibitors (i.e., testolactone) may help symptoms. Evaluate with serial pelvic sonograms to detect the presence of gonadal tumors. Peutz-Jeghers syndrome Commonly characterized by mucocutaneous pigmentation and GI polyposis Also associated with rare sex cord tumors, including epithelial tumors of the ovary, dysgerminomas, or Sertoli-Leydig cell tumors, whose estrogen secretion may result in feminization and incomplete sexual precocity Girls with Peutz-Jeghers syndrome should be screened with serial pelvic sonograms. Adrenal disorders Some adrenal adenomas have been noted to secrete estrogen alone and may therefore give rise to sexual precocity. Primary hypothyroidism Characterized by premature breast development and galactorrhea without an associated growth spurt Key points in evaluation and management of precocious puberty Perform a detailed evaluation with Tanner staging. Laboratory data should include LH, FSH, estradiol, progesterone, 17-hydroxyprogesterone, DHEA, DHEAS, TSH, T4, hCG (5). A GnRH stimulation test would provide a definitive diagnosis of central precocious puberty (5). Obtain an x-ray to determine bone age. Head CT or MRI can rule out an intracranial mass. Abdominal/pelvic ultrasound can be used to evaluate the ovaries (5). Goals for management include maximizing adult height and delaying maturation until a normal age of puberty. Treat the intracranial, ovarian, or adrenal pathology if present and attempt to reduce associated emotional problems (8). Male Feminization o Genetic males (XY) undergo feminization related to androgen insensitivity. o Complete androgen insensitivity, or “testicular feminization” (10). Transmitted in a maternal X-linked recessive fashion Pathophysiology: Androgen presence is unable to induce the Wolffian duct to mature and, as a result, seminal vesicles, vas deferens, and epididymis do not form. AntimГјllerian hormone is present so mГјllerian duct formation remains inhibited such that uterus, cervix, and fallopian tubes do not form either. The resulting phenotype is female, with a vagina derived from the urogenital sinus that ends in a blind pouch, and testes that often descend through the inguinal canal. Clinical presentation: primary amenorrhea, Tanner stage V breast development, scant axillary and pubic hair Management: gonadectomy is recommended secondary to an increased incidence of malignancy; exogenous estrogen therapy is also recommended. o Incomplete androgen insensitivity (10) Less common with presentation ranging from near complete masculinization to near complete failure or virilization. As minimal sensitivity to androgens is present, the Wolffian duct system develops to some extent, although spermatogenesis usually remains absent. Physical exam may include a range of clitoromegaly or ambiguous genitalia. Sex assignment depends on the degree of masculinization present; if a male sex assignment is made, caution should be taken because gynecomastia may occur during puberty, if androgen receptor presence is inadequate. o 5-alpha reductase deficiency is a condition in genotypic males (XY) who are phenotypically female in the prepubertal state and become phenotypic men at puberty. No breast development is present, which distinguishes this condition from androgen insensitivity. Normal testicular function is present. Female Virilization o Genetic females (XX) are exposed to increased androgen levels that lead to inappropriate virilization, most often an indicator of organic disease in girls. o Virilizing congenital adrenal hyperplasia (CAH): most commonly associated with deficiency of 21-hydroxylase, an autosomal recessive disorder. Many present as the newborn girl with ambiguous genitalia and possible associated salt-wasting due to mineralocorticoid deficiency. Virilization may also be delayed until later childhood, related to androgen excess at that time (11). o Cushing's disease: may result from an adrenal carcinoma and may manifest as growth failure, with or without virilization, obesity, striae, or moon facies. o Ovarian tumors: arrhenoblastoma is the most common virilizing ovarian tumor. Others include lipoid cell tumor and gonadoblastoma. VIII. Premature Thelarche Definition: bilateral breast development without other signs of sexual maturation in girls before age 8 (12). Commonly occurs by age 2 and is rare after age 4. The etiology behind premature thelarche is unclear, but an exogenous estrogen source must be excluded. Not known to be associated with central nervous system pathology and is not known to be a familial condition. The mechanism is thought to be related to a temporary activation of the hypothalamic-pituitary-gonadal axis with increased FSH secretion (12). Upon finding during physical examination, precocious puberty must be ruled out: o Document the appearance of the vaginal mucosa, breast size, and presence or absence of a pelvic mass on pelvic/rectal examination. o Determine bone age with radiographic imaging; should be within normal range in premature thelarche and advanced in precocious puberty. o Pelvic sonography should demonstrate a normal prepubertal uterus. o Plasma estrogen levels may be mildly elevated, but dramatic elevations suggest another etiology. Stimulated responses of LH and FSH may be obtained and are both generally elevated in precocious puberty, whereas only stimulated FSH is elevated in premature thelarche (12). Also, review recently used medications and topical creams as application of topical conjugated estrogens (Premarin) for longer than 2 to 3 weeks, which may result in breast changes. Prognosis: In idiopathic cases, a regression in breast enlargement often occurs after a few months but may persist for several years. In approximately 50% of patients, breast development can last 3 to 5 years. V. Self-assessment tasks: 1. What is premature development? 2. Methods of diagnostics of premature sexual development. 3. Make a plan to treat the patient with premature sexual development. 4. What is sexual development delay? Clinical picture. 5. Methods of diagnostics and treatment of syndrome of sexual development delay. AMENORRHOEA Amenorrhoea is the absence of menstruation; it is a symptom, not a disease and is often physiological, as in pregnancy. The term primary amenorrhoea refers to a patient of any age who has never menstruated. Secondary amenorrhoea refers to cessation of the periods after menstruation has been established. Amenorrhoea may be classified as: Physiological • before puberty • during pregnancy • during lactation • after the menopause Pathological uterine lesions ovarian lesions pituitary disorders disorders of other endocrine glands psychiatric illness and emotional stress severe general illness drugs following surgical operations or radiotherapy. PHYSIOLOGICAL AMENORRHOEA BEFORE PUBERTY Menstruation normally begins between the ages of 11 and 14, but this will be affected by heredity and the nutritional state of the patient. Oestrogenic activity of the ovary begins some years before the menarche, but at first the oestrogen levels are not usually sufficient to promote adequate endometrial development to cause bleeding when oestrogen levels are reduced. DURING PREGNANCY Amenorrhoea lasts through pregnancy and beyond during lactation. Until the 12th week of pregnancy there is a decidual space between the decidua capsularis (the decidual layer that covers the ovary after fertilization), the decidua vera (the decidual layer that lines the uterus after fertilization) and the fetal sac. Although in theory bleeding may occur from the decidual space, such bleeding should be regarded as being potentially pathological, with partial separation of embryonic attachments. DURING LACTATION The average time between delivery and the first subsequent period is 10—12 weeks in those patients who do not breast-feed their infants, whereas in those who do, it depends on the duration of the breast-feeding. Ovulation may start again at about the same time. During lactation prolactin is secreted in large amounts by the anterior lobe of the pituitary gland and there is partial, but not complete, suppression of secretion of luteinizing hormone, so that ovarian follicles may mature but fail to rupture. AFTER THE MENOPAUSE Examination of the ovaries of a woman who is well past the menopause shows no active Graafian follicles. Cessation of oestrogen production from the ovary is temporarily associated with overproduction of gonadotrophic hormone from the pituitary gland. PATHOLOGICAL AMENORRHOEA UTERINE LESIONS In general uterine causes of amenorrhoea are rare. Amenorrhoea occurs when the uterus is rudimentary and only represented by a nodule of fibromuscular tissue at the top of the vagina. In such cases the vagina may also be absent, but the ovaries and the secondary sexual characteristics are usually normal. Failure of canalization of the cervix or vagina can lead to haematomeira and haematocolpos respectively. Except with these severe congenital defects of the uterus it is rare for amenorrhoea to be due to uterine hypoplasia. If there is any endometrium present it will respond to stimulation by oes-trogens. Removal of the endometrium by excessive curettage or endometrial ablation may result in obliteration of the uterine cavity. Destruction of the endometrium by advanced pelvic tuberculosis is not now seen in the UK, although such cases still occur in some developing countries. OVARIAN LESIONS Primary amenorrhoea occurs with ovarian dysgenesis. Secondary amenorrhoea may be caused by failure of the ovarian enzyme systems necessary for the production of oestrogens. There is a spectrum of such disorders, of which the polycystic ovary (Stein—Lev enthal) syndrome is the one most commonly recognized. In this disorder, secondary amenorrhoea is associated with bilateral enlargement of the ovaries, which contain multiple small follicular cysts in a dense stroma. Many of these patients are obese, and have an excessive growth of facial and body hair. The secretion of FSH is within the normal range but the LH level may be raised producing a reversed FSH/LH ratio of 1:3. The serum testosterone may also be raised. Some oestrogen is produced, but not enough to cause uterine bleeding. Because of the enzyme block increasing levels of one of the precursors of oestrogen, androstenedione, a weak androgen, is found in the follicular fluid and in the blood plasma; this may explain the hirsuties. A surprising thing about this condition is that a fairly extensive wedge-resection of both ovaries is often followed by a return of normal menstruation and even pregnancy. However, such surgical treatment is not now usually employed, because ovulation and menstruation can usually be induced with clomiphene. Secondary amenorrhoea from ovarian failure may occur without evident cause. The serum level of oestrogens is low, while the level of gonado-trophins is raised, hence the disorder is sometimes called hypergonadotrophic amenorrhoea. If ovarian laparoscopic biopsy shows that follicles are present the term resistant ovary syndrome is used, and in such cases ovulation may sometimes be induced with clomiphene, or with LH-RH (GnRH). Absence of ovarian follicles leads to premature ovarian failure (premature menopause). However, ovarian biopsy is not always conclusive, as only a small part of the ovary is examined, and both spontaneous and induced ovulation may unexpectedly occur. Hormone replacement therapy will be required to avoid immediate and long-term menopausal symptoms and sequelae. Inflammatory disease or neoplasms of the ovaries do not cause amenorrhoea. PITUITARY DISORDERS Pituitary infantilism Rare cases of pituitary infantilism (Levi-Lorain syndrome) occur; the cause is unknown. The patients are of child-like stature and proportions, with primary amenorrhoea. Secretion of FSH is absent or low, and no oestrogens are found in the urine. Ischaemic necrosis of the pituitary gland This was originally described by Simmonds, but is often known as Sheehan's disease. It is the result of thrombosis of the pituitary blood vessels after profound hypotension and hypovolaemia, most commonly caused by severe postpartum haemorrhage. The production of gonadotrophic, thyro-trophic and adrenotrophic hormones ceases, or is very inadequate. The patients are lethargic, gain weight and have a low metabolic rate, hypotension and amenorrhoea. Treatment with hormones is disappointing. Thyroxine and cortisone are usually given. Oestrogens may produce cyclical bleeding, but this can only be of psychological benefit. Methyltestosterone has also been given for its anabolic effect. Adenoma of the anterior lobe of the pituitary gland (prolactinoma) This may cause an excessive secretion of prolactin and consequent amenorrhoea. The tumour may be very small and difficult to demonstrate by computerized tomography or even magnetic resonance imaging. Hyperprolactinaemia may be diagnosed if the prolactin level exceeds 1000 mIU/L. Stress can cause a temporary increase in secretion of prolactin. Galactorrhoea can occur. If the tumour is large enough it may press on the optic nerves causing diminished vision at the edges of the visual fields. The other cells of the pituitary are usually unaffected. If a specific tumour is found it is treated by radiotherapy or surgery, but if no tumour is evident bromocriptine will inhibit the output of prolactin. DISORDERS OF OTHER ENDOCRINE GLANDS Adrenal gland The adrenogenital syndrome is caused by either a tumour or hyperplasia of the adrenal cortex. There is excessive production of androgens and the urinary excretion of oxosteroids is increased. The symptoms and signs are those of virilism, with deepening of the voice, hirsuties, acne, amenorrhoea and enlargement of the clitoris. In Cushing's syndrome, hyperplasia (or less commonly a tumour) of the adrenal cortex produces an excess of glucocorticoids which stimulate the conversion of protein into carbohydrate. These patients have amenorrhoea, hypertension, poly-cythaemia, osteoporosis and diabetes; the abdomen often shows striae like those of pregnancy. Amenorrhoea occurs in advanced cases of Addi-son's disease when adrenal tissue is deficient. Thyroid gland Amenorrhoea may occur in either myxoedema or hyperthyroidism, if they are severe. Pancreas Amenorrhoea may occur in severe or badly controlled diabetes. PSYCHIATRIC ILLNESS AND EMOTIONAL STRESS The hypothalamus controls the output of gonado-trophins from the pituitary gland, and higher centres in the brain affect the function of the hypothalamus. Starting a new job, being away from home for the first time or emigration are examples of stressful conditions which may cause amenorrhoea until social readjustment has been made. Sudden bad news or severe emotional distress may have the same effect. The periods are likely to return spontaneously and reassurance is all that is required, but the possibility of some other coincidental cause such as pregnancy must not be forgotten. Amenorrhoea accompanies anorexia nervosa. The girl is often rejecting the imagined burdens of maturity, and the refusal of food is intended to stop progress from childhood to womanhood. Psychiatric help is necessary, and restoration of a diet with adequate proteins and vitamins. GENERAL ILLNESS AND WEIGHT-LOSS Menstrual function may be temporarily suppressed during or after any severe illness, or during a chronic illness such as chronic renal disease. Secondary amenorrhoea occurs with starvation. This was seen in the inmates of concentration camps during World War II, although other severe psychological stresses were also present. A less severe example is found in ballet dancers and other young women who strive to maintain a slight, slim figure by strict dieting. Amenorrhoea is common and periods return when a more reasonable body mass is restored. Strenuous and continued exercise with diet restriction, such as in preparation for a major athletic season, may often lead to amenorrhoea. This is usually reversed when body mass is allowed to return to a normal level. DRUGS Amenorrhoea sometimes occurs after stopping oral contraception; it can continue for some months. Spontaneous return of menstruation is to be expected within 6 months, but in a few cases treatment by induction of ovulation with clo-miphene or gonadotrophins is required. This type of amenorrhoea is more common in women who had irregular periods before starting oral contraception, and some of them are merely reverting to their previous menstrual pattern. The possibility that the amenorrhoea is due to pregnancy must not be forgotten. Prostaglandin inhibitors occasionally cause amenorrhoea. SURGICAL OPERATIONS OR RADIOTHERAPY Obviously, amenorrhoea will follow hysterectomy or removal of both ovaries. The ovaries may also be suppressed by pelvic irradiation for malignant disease. Amenorrhoea can also be obtained by laser ablation of the endometrium, by cryosurgery or by removal of the endometrium with a resecto-scope. INVESTIGATION AND TREATMENT PRIMARY AMENORRHOEA If a girl has not begun to menstruate by the age of 17, investigation is advised. The management of these cases calls for some discretion; to subject an embarrassed young woman to a barrage of investigations is not always helpful. Some or all of the following may be required, but the more invasive, such as examination under anaesthesia or laparos-copy, should not be made until the other tests show that they are essential. Stature and body form Dwarfism may be the result of some long-standing metabolic disorder; for example, renal disease, a malabsorption syndrome or lack of growth hormone, as in pituitary infantilism. In such cases amenorrhoea is a small part of a wider problem. In some cases of gonadal dysgenesis (Turner's syndrome) the patients are of short stature, but in others (simple gonadal dysgenesis) the patients tend to be tall. Webbing of the neck or wide carrying angles at the elbows suggest Turner's syndrome. Patients with the adrenogenital syndrome may be short and muscular with hirsuties. Breast and pelvic examination If breast development has taken place there must have been some oestrogenic activity, and in such cases it is possible that there is some abnormality of the lower genital tract such as haematocolpos causing cryptomenorrhoea, or a rudimentary uterus. A special problem is testicular feminization. In these cases the breasts are well formed, but the vagina may be short and the uterus is absent. There may be a family history of the disease. The diagnosis rests on the discovery that the patient is chro-matin negative, XY. Patients without breast development are likely to have gonadal dysgenesis, and for such cases chromosomal analysis is essential. There will also be absence of breast development in cases of pituitary infantilism. Hormone assays The essential distinction to be made is between cases of hypothalamic or pituitary failure, in which the levels of FSH, LH and oestrogens will be low. When the ovary fails to respond, the level of both gonadotrophins will be high and that of oestrogens low. Chromosomal studies In all cases of primary amenorrhoea in which the diagnosis is not clinically certain a full chromosomal analysis should be carried out to exclude a congenital abnormality such as 46 XY in a female. Radiological examination and CT scan An intravenous urogram is carried out in all cases of uterine or vaginal malformation, as there are often associated abnormalities of the ureters and kidneys in these cases. A lateral X-ray tomogram or a computed tomography (CT) scan of the sella turcica may show it to be expanded by a pituitary tumour; this examination should be made in all cases in which there is a raised prolactin level, or clinical reason to suspect such a tumour. Ultrasound An ultrasound scan of the pelvis is useful for determining the size of ovaries, the presence of follicles and their size. The importance of this non-invasive investigation is increased when following ovarian problems longitudinally for the usefulness of treatments can be measured by observations on follicular development. Laparoscopy Laparoscopy and biopsy of the gonads is not indicated if the diagnosis can be made by less invasive methods. If the diagnosis is certain after clinical examination, perhaps with the addition of chromosomal or hormonal studies, little purpose is served by proving, in Turner's syndrome for example, that the ovaries are mere streaks. However, laparoscopy is useful in cases which there is doubt about the nature of the gonads, or if it is uncertain whether there are any primordial oocytes in the ovary, when ovarian biopsy is performed. Laparoscopy is also occasionally useful in cases of vaginal atresia to determine whether the uterus is present, although an ultrasound scan will usually give the answer. In cases of testicular feminization, laparotomy is usually required to remove the testes after the secondary sexual characteristics have been established, to prevent the danger of dysgerminoma arising. Ovarian dysgenesis and absence of the uterus cannot be altered, but in some girls morale can be improved by intermittent oestrogen therapy. This will cause breast enlargement and monthly withdrawal bleeding if the uterus is present. A low dose combined oral contraceptive pill can be used. After an interval of 7 days the cycle is repeated. For delayed puberty in girls whose ovaries are shown to contain oocytes, ovulation may be induced with human gonadotrophin. GnRH and synthetic analogues are a better alternative, admin-stered intravenously or subcutaneously in pulses by a portable pump. SECONDARY AMENORRHOEA A patient who has previously menstruated must have a patent lower genital tract, an endometrium which has responded to ovarian hormones and ovaries which have responded to gonadotrophins. In every case pregnancy must be excluded, even if the patient thinks it to be unlikely. This done, a systematic management is: Previous menstrual history Enquiry about the patient's previous menstrual history is made. If she has had irregular cycles for many years there is little point in investigating or treating a minor abnormality unless infertility is her problem. Change in the patient's environment Enquiry should be made about any recent change in her social and emotional environment, any stress that she has undergone, or any attempt at severe dieting. General medical examination After a history of recent or long-standing illness is sought, a general examination is made (including observation of the body build, weight and hair distribution) to exclude any general illness. The breasts and pelvic organs are examined. Any appropriate investigations, such as triiodo-thyronine binding capacity and free thyroxine indices for suspected disorder of the thyroid, are performed. Serum prolactin, FSH, LH, oestradiol, testosterone, SHBG are measured. If pregnancy is not desired, and if the patient has no evidence of any underlying disease which has caused the amenorrhoea, at this point the doctor must decide whether there is any useful purpose in further investigation. In some cases the further steps will be as follows: Hormone assays Generally, LH levels correspond with those for FSH, although the latter may be a more sensitive index of pituitary function and show earlier change. By assessment of the tests relating to the various levels of the hypothalamic-pituitary-ovarian axis, the patient's problems can be placed at the appropriate level. With hypothalamic or pituitary failure the levels of both gonadotrophins and ovarian hormones will be low; with failure of ovarian response, because of lack of negative feedback the gonadotrophin levels may be raised. Reversal of the FSH/LH ratio with a raised LH level (to 1:3) with a raised serum testosterone may indicate a polycystic ovary syndrome. Ultrasound scan This identifies ovarian follicles and, if done serially, can be used to guide dosage of ovarian stimulants. Radiographic tomography or CT scan Visualization of the pituitary fossa may be required. If amenorrhoea is judged to be caused by stress or an emotional problem, spontaneous recovery is to be expected if the problem can be removed or alleviated by the passage of time. If it is caused by some underlying disease or nutritional deficiency this must be treated or removed. If no cause is obvious and the patient wants periods and contraception, the combined OC pill may be given. If she wishes to conceive, induction of ovulation can be produced by clomid, gonadotrophins or pulsatile GnRH. A polycystic ovary syndrome may be treated by laser drilling or wedge resection of the ovaries. Those found to have high levels of prolactin (above 1000 mIU/L) must have the assay repeated, as temporary rises may occur from stress. Hypo-thyroidism or the effect of drugs such as phe-nothiazines must also be excluded. If radiological examination or CT scan of the sella turcica does not reveal a pituitary adenoma then microadeno-mata are assumed to be present and the prolactin level can be reduced with the dopamine agonist, bromocriptine. The dose has to be varied according to the prolactin level and this treatment should be employed only in units that have the facilities for hormone assays. The dose is increased very cautiously, starting at 2.5 mg daily. In summary, provided the uterus is present, primary amenorrhoea can be treated with hormones to induce menstruation. With secondary amenorrhoea, the ability to induce menstruation will depend on the state of the endometrium and the hypothalamic-pituitary-ovary axis. The latter can be influenced by drug therapy. Conception in both cases can only occur if there is ovarian tissue with primary ovarian follicles. Prepubertal Bleeding without Secondary Signs of Puberty Puberty in the female is the process of biologic change and physical development after which sexual reproduction becomes possible. This is a time of accelerated linear skeletal growth and development of secondary sexual characteristics, such as breast development and the appearance of axillary and pubic hair. The usual sequence of the physiologic events of puberty begins with breast development, the subsequent appearance of pubic and axillary hair, followed by the period of maximal growth velocity, and lastly, menarche. Menarche may occur before the appearance of axillary or pubic hair in 10% of normal females. Normal puberty occurs over a wide range of ages (see Chapters 4 and 38 [Reproductive Endocrinology and Primary and Secondary Amenorrhea and Precocious Puberty]). Precocious puberty is arbitrarily defined as the appearance of any signs of secondary sexual maturation at an early specific age more than 2.5 standard deviations below the mean. Precocious puberty is covered in detail in Chapter 38 . A common clinical problem that is sometimes mistaken for precocious puberty is prepubertal bleeding in children without any other signs of puberty such as breast development Table -- Differential Diagnosis of Prepubertal Bleeding Without Any Breast Development Foreign object Genital trauma Genital abuse Lichen sclerosus Infectious vaginitis (especially from Shigella) Urethral prolapse Breakdown Friable of genital labial warts or adhesions vulvar Vaginal lesions tumor Rare presentation of McCune–Albright syndrome (typically have breast development) Isolated menarche (controversial) Vaginal Bleeding The normal sequence of puberty is that thelarche precedes menarche. In children with prepubertal bleeding without breast budding there is almost never an endocrinologic cause, with the exception being a very rare presentation of McCune–Albright syndrome. The differential diagnosis of vaginal bleeding without pu-bertal development includes foreign body, vulvar excoriation, lichen sclerosus, shigella vaginitis, separation of labial adhesions, trauma (abuse and accidental), urethral prolapse, and friable genital warts. Rare causes include malignant tumors (sarcoma botryoides and endodermal sinus tumors of the vagina) and an unusual presentation of McCune–Albright syndrome. Lists of the differential diagnosis of prepubertal bleeding often also include accidental estrogen exposure (for example from ingestion of a mother's birth control pills). However, in reality such exposure would rarely provide enough endometrial stimulation to produce a withdrawal bleed without breast budding. Neonates may develop a white mucoid vaginal discharge or a small amount of vaginal spotting. Both conditions are secondary to exposure during pregnancy to the high levels of estrogen and are self-limited. In a 20-year review of vaginal bleeding, 52 cases were identified in girls 10 years and younger from the Chelsea Hospital for Women in London. Genital tumors, precocious puberty, vulvar lesions, and urethral prolapse were the four leading causes in this series. This report was from a referral center and therefore may not truly represent the cases seen in the practitioner's office. The absence of sexual abuse in this study likely reflects referral patterns. However, it should be remembered that although the differential diagnosis of prepubertal bleeding includes sexual abuse, the vast majority of sexually abused children do not have prepubertal bleeding. In some settings, such as emergency departments, it is more likely that the cause of prepubertal bleeding is sexual abuse than in tertiary referral practice where the cause of the bleeding is often unclear to the referring physician. ABNORMALLY INCREASED AND IRREGULAR UTERINE BLEEDING (DURING MENSTRUAL LIFE) Excessive menstrual bleeding is called menorrhapa. Strictly, this term should be used only to describe heavy menstrual loss with a normal cycle, but it is often used more loosely. Straightforward descriptions such as excessive or prolonged bleeding, or frequent cycles, are preferable. For clarity, the period should be described as a fraction with the numerator referring to the number of days of bleeding and the denominator, the length of cycle e.g. 4-7/22-31. It is important to realize that abnormalities of menstruation are only symptoms and do not describe pathological entities. Before treatment is given the cause must be determined and any endocrine treatment without previous investigation is to be condemned. Excessive or irregular vaginal bleeding may be caused by the following: LOCAL LESIONS Causing regular excessive periods: uterine fibroids adenomyosis pelvic endometriosis salpingo-oophoritis intrauterine contraceptive device Causing irregular bleeding; urethral caruncle polyps—cervical, endometrial and fibroid carcinoma of the cervix carcinoma of the uterine body oestrogen-secreting ovarian tumour, granulosa or theca cell tumour. The diagnosis and treatment of all these conditions have been described in previous chapters. In this chapter the conditions in which these local lesions have been excluded will be considered. GENERAL DISEASES In some cases of myxoedema menorrhagia occurs; this will respond to treatment with thyroxine. In advanced cases there is usually amenorrhoea. It is probable that the thyroid deficiency affects the pituitary gland. Blood diseases are very rare causes of menorrhagia. However, it may occur in acute leukaemia, thrombocytopenic purpura and hereditary capillary fragility (von Willebrand's disease), but in all these diseases the diagnosis is evident on other grounds. Anaemia is almost invariably the effect and not the cause of menorrhagia. Change of country with climatic change and stress can cause menorrhagia. EMOTIONAL CAUSES Women suffering from a psychosomatic disturbance may temporarily develop heavy or frequent periods which resolve when the cause has subsided, just as other individuals may present with peptic ulcers, for example. The menstrual irregularity in these cases is due to disturbance of pituitary function, which arises in turn from hypothalamic response to activity of higher centres. Some, but not all, cases of dysfunctional bleeding which are described in the next section have an emotional cause, and this possibility must always be considered. DYSFUNCTIONAL UTERINE BLEEDING The term dysfunctional uterine bleeding refers to those cases in which the bleeding is not due to some diagnosed local disorder, such as new growth or pelvic infection, or to some complication of pregnancy. It may occur at any age between the menarche and the menopause. Heavy or irregular bleeding without abnormal physical signs on ordinary examination will always suggest this diagnosis, but this must never be taken for granted because curettage may reveal that there is a local cause for the bleeding after all. An endometrial polyp may be discovered, unsuspected retained products of conception, or even early malignant disease of the endometrium or cervix may be found. CAUSES Dysfunctional bleeding may be caused by alters-1 tion in the output, or balance, of gonadotrophic or ovarian hormones, and probably also of endomet- j rial prostaglandins. Under the influence of prostaglandins, bleeding from the endometrium is controlled by vasocon-striction, myometrial contraction and local aggregation of platelets with deposition of fibrin around them. The endometrium and myometrium are able to synthesize prostaglandins from arachi-donic acid by the action of the enzyme cyclo-oxygenase. The endometrium manufactures: PGF^oi, which causes myometrial contraction and vasoconstriction PGE2, which causes myometrial contraction but is a vasodilator Prostacyclin (PGLi), which causes myometrial relaxation and vasodilatation and also inhibits platelet activity. It is believed that PGF^ normally plays the chief part in preventing excessive menstrual bleeding. In theory abnormal bleeding may occur if there is a decrease in production of PGFza, or an increase in production of PGEa or of prostacyclin. In support of this suggestion, a relative decrease in PGF^n against PGEa has been reported in the endometrium in some cases of menorrhagia. Drugs which block the action of cyclo-oxygenase, such as mefe-namic acid, are sometimes effective in checking menorrhagia. In some cases of dysfunctional bleeding the cycles are ovulatory but in others, perhaps the majority, ovulation is not occurring. Ovulatory cycles In ovulatory cycles excessive bleeding may be caused by corpus luteum insufficiency, with decreased secretion of oestrogen and progesterone in the second half of the cycle. The luteal phase is abnormally short, but at the same time the en-dometrium shows irregular ripening, with patchy response to the hormones and consequent prolongation of menstrual bleeding. On the other hand, the corpus luteum persists longer than is normal, sometimes with the formulation of a luteal cyst. The luteal phase of the cycle is then prolonged, but there is eventual irregular shedding of the endometrium, with prolonged and heavy bleeding. Anovular cycles In women with dysfunctional bleeding with anovular cycles the oestrogen secretion rises to high levels, and then the output of FSH is reduced by feedback, so that the oestrogen level falls and endometrial shedding takes place. In many women with anovular cycles the loss is not excessive, and unless they are complaining of infertility nothing abnormal may be noticed. But in a few cases the endometrial shedding is irregular and incomplete, and is associated with excessive blood loss. Cystic glandular hyperplasia In cystic glandular hyperplasia, oestrogen production rises to high levels, but there is no feedback inhibition of the pituitary gland, so FSH secretion and high oestrogen levels continue, perhaps for 6-8 weeks. There is amenorrhoea during this time but the prolonged action of the abnormally high level of oestrogen, in the absence of progesterone, causes endometrial hyperplasia. On macroscopical examination the endometrium is very thick, and in places almost polypoid. Microscopical examination shows hypertrophy of the columnar epithelium of the endometrial glands, and many of the glands show cystic dilatation so that the tissue has many large, round holes. There are areas of necrosis in the stroma, with small haemorrhages and leucocytic infiltration. The myometrium may also show some hyperplasia. After a time the oestrogen level begins to fluctuate and when it falls excessive endometrial bleeding ensues. Bleeding may also occur because parts of the grossly hypertrophied endometrium have outgrown their blood supply. Bleeding tends to be heavy, prolonged and irregular. In cases of dysfunctional bleeding successive episodes may vary in pattern. It is clear that an emotional upset, presumably acting through the hypothalamus, can sometimes precipitate an episode of dysfunctional bleeding, but in most cases no such trigger is evident. It has been suggested that in dysfunctional bleeding of puberty the output of gonadotrophins is erratic, whereas near the menopause the ovary may be failing to respond. It is worth repeating that in about half of the cases of dysfunctional uterine bleeding no histological abnormality of the endometrium is found on curettage, and in some of these cases the cause of the bleeding remains obscure. Hormone assays are equally unhelpful. Cases can be grouped roughly by the ages of the patients into those occurring at puberty, during the childbearing period and near the menopause. Although this classification has little basis in pathology it is useful when considering management. ABNORMAL BLEEDING AROUND PUBERTY Menorrhagia for a few periods after the menarche is not uncommon. This cyclical bleeding is anovular in type. Less commonly there may be severe and continuous bleeding with a diminishing haemoglobin level—such cases are similar to those described as cystic glandular hyperplasia, and show endometrial hyperplasia from the effect of oestrogen in the absence of progesterone. Nearly all cases recover spontaneously in a few months. An ultrasound examination should be made to exclude an ovarian tumour, but there is no indication for curettage unless the medical history strongly suggests the possibility of tuberculosis. In a few cases with heavy bleeding norethisterone 5 mg three times daily is given by mouth, gradually reducing the dose over the succeeding 10 days. Iron is prescribed if the girl is anaemic. ABNORMAL BLEEDING IN THE CHILDBEARING YEARS Abnormal bleeding without obvious local cause is not uncommon in women of this age group. The bleeding may be cyclical or irregular. The uterus may be slightly and symmetrically enlarged, particularly in parous women. It is not uncommon for abnormal bleeding of endocrine origin to undergo spontaneous remission; in young women without abnormal physical signs it is worth waiting for a short time to see if normal menstruation returns. When abnormal bleeding persists the following options may be tried: Under 40 years of age, one can use the combined oral contraceptive pill for non-smoking and non-obese women. Otherwise non-steroidal anti-inflammatory drugs (NSAID) which inhibit pros-taglandin synthesis in the endometrium will relieve both menorrhagia and sysmenorrhoea (e.g. mefe-namic acid 500 mg tds given during ther period). Alternatively, anti-fibrinolysins will reduce bleeding by inhibiting plasminogen activity that may cause nausea and vomiting in a third of cases (tranexamic acid is given at a dose of 1.5gtds during the period). In a woman over 40 years of age, heavy bleeding of recent onset should be managed by hyseroscopy and diagnostic D & C, to exclude endometrial pathology such as endomet-rial hyperplasia. If nothing sinister is found at D & C, other measures include danazol which competitively binds sex hormones to their receptors and inhibits their production by direct enzymatic action. It is given orally as a dose of 200-800 mg daily in divided doses. It sometimes causes unpleasant masculinizing side effects. GnRH analogues may be used to inhibit gona-dotrophin secretion but they are expensive and cause menopausal side effects and osteoporosis. If these measures fail, endometrial resection or ablation can be considered. About one third of patients will have amenorrhoea, one third will be improved and one third will be unchanged. Finally, hysterectomy may be offered when menorrhagia cannot be controlled by any of these methods and there are still some 7 years before the menopause is expected. The ovaries are not removed unless involved by pathology or over the age of 50. Between the ages of 45 and 50 the case for their removal is more controversial and needs to be discussed on an individual case with each patient. INTERMENSTRUAL BLEEDING Slight bleeding may occur at mid-cycle at the time of ovulation—it only lasts for a few hours. Breakthrough bleeding may occur with oral contraception. Irregular bleeding between the periods may be associated with a local lesion in the genital tract. A urethral caruncle occasionally bleeds. Intercourse may cause bleeding from carcinoma of the cervix, from an adenomatous (mucous) polyp of the cervix, or from a vascular cervical erosion, especially during pregnancy or if the patient is taking the oral contraceptive pill. Endometrial adenomatous polypi may cause intermenstrual bleeding, and sometimes carcinoma of the body of the uterus may occur coincidentally before the menopause. It must be strongly emphasized that in every case of intermenstrual bleeding at any age the diagnosis must be established before treatment is given, otherwise an occasional carcinoma may be missed, with fatal results. Diagnostic curettage must be performed in all cases in which a local cause is not found on ordinary examination with a speculum, and in all cases where local treatment is followed by persistence of the intermenstrual bleeding. DYSMENORRHOEA AND PREMENSTRUAL TENSION Although menstruation is often painless, many women suffer from discomfort or pain in association with periods at some time during their reproductive life. It has been customary to classify cases of dysmenorrhoea into two main groups: • primary or spasmodic dysmenorrhoea • secondary or congestive dysmenorrhoea. These terms are unsatisfactory because they have been used in two senses; to indicate the time of origin of the complaint (at puberty or later) and, alternatively, to express an opinion about the cause of the pain and whetherjtji secondary to evident pelvic disease. It may be more useful to classify the cases into: • those due to evident pelvic disease • those without evident pelvic disease. DYSMENORRHOEA CAUSED BY PELVIC DISEASE The type of pain experienced is very variable. It may precede the onset of a period for about a week. The pain is often a dull ache felt equally on both sides of the lower abdomen and back, sometimes extending down the thighs. Apart from the discovery of abnormal physical signs of endometriosis or pelvic inflammatory disease on examination, two features suggest that there may be underlying pelvic disease. First, the symptoms may appear after some years of painless menstruation, and secondly, there may be other symptoms of pelvic disease such as menorrhagia, dyspareunia or infertility. An acute colicky pain may occur if a fibro-myomatous polyp is being extruded through the cervix, and in some women an intrauterine contraceptive device will cause colicky dysmenorrhoea. Dysmenorrhoea caused by pelvic disease is best treated according to the cause. DYSMENORRHOEA WITHOUT EVIDENT PELVIC DISEASE This is the commoner type of dysmenorrhoea and it usually occurs in girls or young women. It is difficult to state its frequency, as most women have occasionally experienced some degree of pain. Severe pain only occurs in a minority, but there is no doubt that it can be incapacitating and often leads to absence from work. The pain is spasmodic or colicky in nature, usually starting on the first day of the period. It may last for several hours or continue throughout the first and second day. Not infrequently the menstrual flow is scanty at first, and the pain often becomes easier when the flow is properly established. The acute colicky pain may be followed by a dull ache. Nausea and vomiting, and occasionally diarrhoea may occur, and sometimes headache and fainting. Most women present for advice between 16 and 25 years old. They may say that they have had pain ever since their periods started, but closer questioning will usually show that the periods were painless at first, and only became painful after a few months or even years, sometimes becoming progressively worse. Examination usually reveals no general local abnormality. The patient is physically healthy, although she may be somewhat tense. A vaginal examination, or if the hymen is intact a rectal examination, must always be made to exclude unexpected pelvic pathology. In nearly every case the genital tract is normal. THE CAUSE OF THE PAIN IN WOMEN WITHOUT EVIDENT PELVIC DISEASE The pain is usually due to the spasm of the uterine muscle, which is sufficiently intense to cause ischaemia. The cause of the muscle spasm is not certain, and several factors have been discussed. Cervical obstruction Although organic stricture of the cervix can cause menstrual pain this is exceedingly rare, and there is no evidence of obstruction in the ordinary cases. Dilatation of the cervix is still sometimes practised but seldom effects a permanent cure. Dysmenorrhoea occurs only when ovulation has occurred; anovular cycles are painless, as is seen in women using oral contraception. It is probable that necrosis of the endometrium is caused by prostaglandins, especially PGFzo,, and this also causes spasm of the myometrium. The endometrial content of PGF2n increases under the influence of progesterone in the second half of the cycle. Administration of prostaglandins to normal women can produce many of the symptoms associated with dysmenorrhoea, and prostaglandin inhibitors will relieve these symptoms. Psychological factors Although spasmodic dysmenorrhoea is often described as psychosomatic, because of the lack of any recognizable pelvic pathology, it is wrong to state that all these patients are neurotic. Upbringing can have some effect; a girl may have come to expect that menstruation must be painful, while adolescence may bring fears of sex or child-bearing. However, the majority of patients areentirely free from any fear or phobia. It is true that they may have an increased sensitivity to painful stimuli, but this may sometimes be the effect of recurrent pain rather than the cause. Nerve pathways Division of the sympathetic superior hypogastric plexus (wrongly called the presacral nerve) may abolish pain during menstruation by interrupting the sensory pathway. Treatment Attention should be paid to the woman's general health, and it is advisable to enquire about her family and social life so as to discover, and if possible to correct, any cause of emotional stress. It will help to tell her, after examination, that she is normal and to explain that menstruation is a healthy normal function. During an attack of severe pain many patients take a hot bath and then relax in bed with a hot water bottle. Analgesic drugs such as aspirin, codeine or dihydrocodeine should be prescribed. Antispasmodic drugs such as atropine are usually ineffective, although many proprietary preparations containing such drugs are sold. Drugs which inhibit the production of prostaglandins in the endometrium may diminish myometrial contractions and therefore relieve dysmenorrhoea. These drugs, which are given orally 3 times daily during the period, include mefenamic acid (Ponstan) 500 mg, flufenamic acid 200 mg and indomethacin 50 mg. The most effective medical treatment is to suppress ovulation with the combined oral contraceptive pill containing 20 to 30 micrograms of oestrogen. The fact that this is a contraceptive should be mentioned. Alternatively, an oral progestogen such as dydrogesterone (Duphaston) is often used in doses of 10 mg daily by mouth from days 5 to 25 of each cycle. Obviously, hormonal treatment is unsuitable for a patient who wishes to become pregnant. In patients aged over 30 whose symptoms are unrelieved by other measures laparoscopy should always be considered, as small endometriomatous lesions may otherwise be missed. Presacral sympathectomy is usually reserved for patients who have not obtained relief by other methods; the operation is seldom performed now. The superior hypogastric plexus conveys afferent fibres from the uterus. It lies immediately behind the parietal peritoneum in front of the fifth lumbar vertebra and between the diverging iliac arteries. After opening the abdomen the posterior parietal peritoneum just below the aortic bifurcation is incised to expose the plexus, a segment of which is then removed. PREMENSTRUAL TENSION The premenstrual tension syndrome is a separate entity from painful periods. It mostly occurs in women over 30 years of age. It is characterized by premenstrual discomfort in the lower abdomen and back, and in the breasts. It is often described as a bloated feeling of distension or pelvic engorge-ment, which precedes the period by a week or 10 days. Sometimes the onset of the menstrual flow brings relief. It is accompanied by varying degrees of irritability, depression and other emotional disturbances, and not infrequently by headache. Some women may notice a deterioration in their concentration, and it is said that there is a relationship between violent and antisocial behaviour and this conditipn. Examination performance may be affected at this time. Patients may show a gain of weight of 1 kg or more in the latter part of the menstrual cycle due to salt and water retention. The retention of fluid is partly due to ovarian steroids, but there is also an increased output of antidiuretic hormone from the posterior pituitary gland. It may also be caused by a relative lack of progesterone. Emotional stress often contributes to the symptoms, and the social relationships of the patient must be reviewed. A pelvic examination to exclude unexpected pelvic pathology is also essential. Treatment The exploration of emotional and work-related stress often allows the woman to reveal her problems and to compensate accordingly. Reassurance and simple psychotherapy will help, but it also may be necessary to treat the symptoms with various drugs. Some women obtain relief with diuretics such as chlorothiazide 500 mg three times daily in the premenstrual week. Progestogens help some women taken ether orally (norethisterone 5 mg bd or dydrogesterone lOmgbd from day 15-25) or rectally (cyclogest 200 mg supositories) for the same period of time. Oestrogens have been used to suppress ovulation on the basis that cyclical ovarian activity is necessary for the symptoms of premenstrual tension. They can be given as oestradiol implants (25-100 mg) which last for three to six months. A disadvantage is the prolonged action of the implants and a more flexible approach is to use transdermal oestradiol patches in a strength that can vary from 50-200 /Ag every 3 days. Both of these have to have concomitant cyclical norethisterone (5 mg daily for the last 12 days of the cycle) to prevent endometrial hyperplasia. Combined oral contraceptive pills may also be of benefit because they suppress ovulation. Evening primrose oil (gamma linolenic acid) has been widely used: it may have some benefit. Prostaglan-din synthetase inhibitors may improve fatigue, headaches, general aches and pains and general mood symptoms. The dose is mefenamic acid 250 mg three times a day starting 12 days before the anticipated onset of menstruation and increasing to 500 mg three times daily during menstruation. Danazol which suppresses gonadotrophin secretion and abolishes cyclical ovarian function may be of help. The dose varies between 200— 400 mg a day but unwanted androgenic effects such as weight gain, hirsutism and acne have been a problem particularly with the higher dosage. Gonadotrophin-releasing hormone analogues (GnRH) have been used for premenstrual tension but, because of their unwanted menopausal side effects and long-term risk of osteoporosis, they are not warranted. Some respond to a mild tranquillizer (e.g. diazepam 2.5 mg bd) or an antidepressant (e.g. amytriptyline 50 mg a day). Bromocriptine (2.5—5.0 a day) may be tried if mastalgia is a problem. V. Self-assessment tasks: 1. What classifications of abnormalities of menstrual cycle do you know? 2. What is bleeding of juvenile period? 3. Clinical picture of certain forms of abnormalities of menstrual cycle. 4. Methods of non-hormonal hemostasis by bleedings. 5. When can hormonal hemostasis be prescribed? 6. What are the indications for surgical treatment of bleedings? 7. What is primary amenorrhea? 8. What is secondary amenorrhea? 9. Make up a plan of examination of a patient with primary amenorrhea. 10. Make up a plan of examination of a patient with secondary amenorrhea. ENDOMETRITIS During reproductive life endometritis is uncommon, except after delivery or abortion. The cavity of the uterus is protected against bacterial invasion by the acid barrier of the vagina and the cervical mucus, and in addition the shedding of the en-dometrium at each menstrual period prevents organisms from gaining a foothold for long. However, after delivery or abortion lochial discharge forms an excellent culture medium and organisms may enter the tissues at the site from which the placenta has separated. Endometritis may follow operations such as curettage, or the insertion of an intrauterine device. When an intrauterine device is in place the subjacent endometrium shows infiltration with polymorphonuclear leucocytes. This may merely be a response to the foreign body, but in a few cases actinomyces-like organisms have been noticed in smears or cultured from the uterus. Gonococcal infection may spread upwards from the cervix to the endometrium and tubes, while tuberculosis endometritis often follows tuberculous salpingitis. With advanced carcinoma of the endometrium or of the cervix, especially if the cervical canal is obstructed, infection occurs. After the menopause there may be ascending infection which causes what was formerly called senile endometritis, now called atrophic endometritis. PELVIC INFLAMMATORY DISEASE Pelvic inflammatory disease (PID) is a clinical syndrome attributed to the ascending spread of micro-organisms (unrelated to pregnancy or surgery) from the vagina and cervix to the endometrium, fallopian tubes and or contiguous structures. The clinical syndrome usually begins with an acute episode which can be followed either by complete resolution or gradual subsidence into a more chronic process which may also exhibit further acute or subacute resurgences. At the other extreme, however, it may be a clinically benign condition which goes unrecognized and is only diagnosed when the damage has been done and the woman is under investigation for infertility or has an ectopic pregnancy. It is suggested that only a minority of women whose infertility is due to tubal damage give a history of previous overt disease. Diagnosis of pelvic inflammatory disease Even experienced gynaecologists have difficulty in correctly diagnosing PID; the symptoms are often unreliable. Hare (1986) produced an algorithm for pelvic inflammatory disease. He advised that unless three or more of his listed symptoms were present, in addition to abdominal pain and dyspareunia, the diagnosis must remain uncertain. He felt that signs were more usual than symptoms, but at least three signs should be elicited. Obviously if doubt remains laparoscopy should be performed—both for the immediate safety of the patient, in making the correct diagnosis, and for planning treatment. ACUTE SALPINGITIS Pathology In acute salpingitis both tubes are congested, red and oedematous and there is usually a seropurulent exudate. The plicae of the tubal mucosa are swollen, and the epithelium covering them is shed in places. It is possible for this type of inflammation to subside without leaving any gross changes, but in most cases damage is done to the ciliated epithelium of the tube, causing infertility or a delay in the transport of the fertilized ovum and therefore an ectopic pregnancy. The infected tube frequently becomes occluded. The lumen of the interstitial part is so fine that the slightest inflammatory reaction blocks it. The fimbriae adhere at the other end of the tube and are drawn into the tube, and the abdominal ostium is sealed. Once the ends are closed, inflammatory exudate collects and distends the tube. When the collection of fluid is more or less clear it is called a hydrosalpinx, when it is purulent, a pyosalpinx. Because the ampullary end of the tube distends more easily than the isthmus the tube becomes retort-shaped If the infecting organisms are virulent they can pass deep into the wall of the tube, which becomes thickened, and as the covering peritoneum becomes involved in the inflammation peritoneal adhesions occur. The ovaries are also affected by the inflammation. They become enlarged by oedema and adhere to the fallopian tubes by filmy adhesions. If the infection is severe the ovary develops small abscesses, or may form part of the wall of an abscess cavity with the tube and adjacent structures. A distended tube may communicate with a cyst of the ovary, forming a tubo-ovarian abscess. In some cases the inflammation does not result in the collection of pus within the lumen of the tube. Inflammatory changes within the muscle wall produce areas of variable thickening and fibrosis, often with kinking. This condition is called interstitial salpingitis, and is often found as a residual lesion in patients whose symptoms have resolved. Symptoms and signs The patient feels ill and complains of lower abdominal pain, which is worse on movement. Vomiting may occur at the onset and the bowels are constipated. The pulse rate is increased and the temperature is raised, often above 39.5°C. The tongue is dry but not usually furred. Because there is pelvic hyperaemia there may be a mucous discharge from the uterus which may be purulent if there is cervicitis or infection by Trichomonas vaginalis. Because there is oophoritis the menstrual cycle is often upset. In many cases in which the infection is of low virulence all symptoms disappear in a few days, and the true nature of the illness is never discovered. Examination shows tenderness and rebound tenderness over the pelvis and both iliac fossae. If peritonitis is present there may be rigidity and abdominal distension over the lower abdomen. Pelvic examination causes pain, especially on movement of the uterus. In many cases the tenderness in the fornices is such that no other physical signs can be made out. In less acute cases a sense of fullness is noticed in the lateral fornices on bi-manual examination. The converse is perhaps more useful; if bimanual pressure to the side of the uterus is not painful, the patient is certainly not suffering from acute salpingitis. If there is a peritubal abscess, the encysted serous peritonitis around it forms a mass, which may become palpable above the symphysis pubis. It is irregular in outline and partly resonant on percussion because of adhering coils of intestine. In order to relax the abdominal muscles over this tender mass the patient often lies in bed with both knees flexed. Abscess formation, inside or outside the tube, is accompanied by deterioration of the patient's condition. She looks and feels ill, and complains of increasing pain. Her appetite deteriorates and she sleeps badly. Temperature and pulse rate increase and rigors may occur; there is increasing leuco-cytosis. The pelvic mass increases in size, and if left alone the abscess usually points and drains into the rectum; this event is often preceded by mucous diarrhoea. With modern antibiotic treatment the formation of a large pelvic mass is seen less often than it used to be, and, left alone, it tends to absorb after one or two weeks. The tender fallopian tubes may then be felt as oblong, tender, fixed masses behind the uterus. The patient may be left with blocked tubes and more or less dense pelvic adhesions. Diagnosis At its onset acute salpingitis must be distinguished from acute appendicitis. If the appendix is pelvic, the signs may be similar. The history will often be helpful, for in salpingitis there will generally be history and signs of recent abortion or delivery or of gonococcal infection. In appendicitis the pain usually starts near the umbilicus and later becomes localized to the right iliac fossa; in salpingitis the pain starts in the lower abdomen and is bilateral. The temperature with salpingitis is usually higher, often reaching 39.5°C, whereas in appendicitis it seldom exceeds 38.5°C;the pulse rate, however, is not as high in salpingitis as in appendicitis. Vomiting may occur with either condition but is more constant with appendicitis. A furred tongue suggests appendicitis. In cases of salpingitis, vaginal examination shows tenderness in both lateral fornices; in appendicitis the signs will be more marked on the right side. If a pyosalpinx has formed, the history will usually make the nature of the swelling obvious. However, if the patient is first seen at this stage, the swelling will have to be differentiated from an ectopic gestation with a tubal mole or from a small ovarian cyst. Treatment Bed rest, adequate fluid intake and analgesics are the basic necessities in the treatment of acute salpingitis, but the selection of suitable antibiotics, in adequate dosage, is also essential. Should an intrauterine contraceptive device be in place it should be removed after antibiotic cover is achieved. Bacterial swabs are taken from the cervix and urethra and should be tested for Chlamydia and, although gonococcal salpingitis is now less common in the UK, this must also be excluded. However, treatment should be carried out without waiting for a bacteriological report, so as to avoid permanent damage to the tubes. There is no ideal antibiotic regime for the treatment of salpingitis. Treatment should begin with a single (antigonococcal) dose of spectinomycin (2 g intramuscularly) or cefuroxime (1.5 g intramuscu-larly), followed by a tetracycline (e.g. oxytetracy-cline 500 mg four times daily by mouth, or doxy-cycline 100 mg twice daily by mouth), plus oral metronidazole 400 mg daily for 14 days. Initial parenteral therapy (tetracycline hydrochloride 500 mg 12 hourly intravenously plus metronidazole 500 mg intravenously or per rectum) may be required in severe cases. Pregnant patients, or those who are intolerant of tetracyclines, should be given erythromycin stearate 500 mg four times daily by mouth, plus metronidazole as above for 14 days. However, this latter regimen will not be effective against Mycoplasma hominis, and is unreliable for N. gonorrhoeae. Recurrent PID is not uncommon and the risk of infertility or ectopic pregnancy increases with further episodes of infection. It is therefore important to trace the patient's contacts, and her partners should be referred to a genitourinary medicine clinic for investigation and treatment. Surgical treatment of acute salpingitis is seldom called for and if laparotomy (performed when the diagnosis is doubtful and appendicitis may be a possibility) shows that the tubes are acutely inflamed, they should not be removed if there is any hope of restoration of function. Bacterial swabs should be taken from any pus and from the lumen of the tubes before closing the abdomen. Surgery may be contemplated in the very rare cases of deterioration in spite of active medical forms of treatment. When there is definite evidence of a pelvic abscess, this must be drained. Where the patient suffers from repeated recurrent attacks of acute salpingitis the tubes become irretrievably blocked and their removal during a quiescent phase is advised. CHRONIC SALPINGITIS An abscess often does not form after an attack of acute salpingitis, yet the disease obviously fails to resolve completely. A patient with chronic salpingitis may be ambulant and even follow her regular employment. However, she does not feel well and many ordinary daily tasks become a burden. The menstrual loss is often heavy and is preceded by congestive dysmenorrhoea with pain which precedes, and lasts throughout, each period. The inflammation of the ovaries may upset the menstrual cycle and produce irregular bleeding. In addition to menstrual pain there is often continuing dull pain or aching in the lower abdomen or back. There is dyspareunia and there may be an excessive cervical discharge. On pelvic examination there is tenderness and residual thickening of one or both tubes, or a fixed tender mass in the rectouterine pouch of Douglas due to bilateral pyosalpinges. Ovarian endometriomatous cysts may cause pelvic pain and menorrhagia, and the physical signs closely resemble those of chronic salpingitis with bilateral tubal swellings. The absence of a history of infection after abortion or delivery, gonorrhoea, any suggestion of tuberculosis and the absence of pyrexia, help in reaching the correct diagnosis. Treatment Only prolonged antibiotic therapy and convalescence have any prospect of resolving this condition. It may be necessary to continue treatment for 3-6 months, changing between the various broad spectrum antibiotics. Often these measures fail and surgical treatment is indicated. While healthy tissue should obviously be conserved, the patient should not be left with infected tissues which will need further surgical treatment. This means that both tubes may have to be removed, and in such cases, especially if there is menorrhagia and discharge, total hysterectomy is often wise. An effort should be made to find and conserve any healthy ovarian tissue. Tuberculous infection of the genital tract is becoming uncommon in the UK; it is seen more often in developing countries. The infection is a chronic one, and is almost invariably secondary to a tuberculous infection in the lung, although by the time the genital infection becomes manifest the primary lesion may be quiescent or healed. Although it is theoretically possible for a patient to be infected directly from a male with tuberculous epididymitis, this event is almost unknown. The fallopian tube is the most common site of initial infection in the pelvic organs. Diagnosis Since, in nearly every case of active tuberculous salpingitis, the endometrium is involved, histolo-gical examination of curettings will show the presence of tubercles. Part of the material removed by currettage is sent for bacterial culture or guinea-pig Fig. 5.6 Bilateral tuberculous pyosalpinges. The walls of both tubes are thickened and they contain caseous material. Tubercles are seen on the peritoneal surface inoculation. In every case a radiological examination of the chest must be made. Treatment It is recommended that extrapulmonary tuberculosis should be treated in the same way as pulmonary tuberculosis. Several drugs are given in combination to prevent the emergence of resistant strains. Use of an intensive four-drug regimen (for example, rifampicin, isoniazid, ethambutol and pyrazinamide) for 8 weeks allows the total treatment to be reduced to 6 months. Infections of the Upper Genital Tract Pelvic inflammatory disease (PID) is an infection of the upper genital tract. The disease process may include the endometrium, fallopian tubes, ovaries, myometrium, parametrium, and pelvic peritoneum. o Pathophysiology and Microbiology. PID is caused by the spread of infection via the cervix. Although PID is associated with sexually transmitted infections of the lower tract, its process is polymicrobial. N. gonorrhoeae or C. trachomatis are implicated in many cases, but numerous micro-organisms may be involved. A positive endocervical culture result for a particular pathogen does not necessarily correlate with positive intra-abdominal culture findings. o Prevention. Emphasis must be placed on aggressive treatment of lower genital tract infection and early aggressive treatment of upper genital tract infection. This helps reduce the incidence of long-term sequelae. Treatment of sexual partners and education is important in reducing the rate of recurrent infections. Table 24.10 Centers for Disease Control and Prevention Treatment Recommendations for Neisseria Gonorrhoeae Durat Medication Recommended Dosage ion Use pregnancy in Cefixime 400 mg 1 dose — 125 mg 1 dose Recommended 500 mg 1 dose Contraindicated 400 mg 1 dose Contraindicated 250 mg 1 dose Contraindicated PO Ceftriaxone IM Ciprofloxacin PO Ofloxacin PO Levofloxacin PO PLUS treatment for Chlamydia if not ruled out Azithromycin 1 g PO 1 dose Recommended Doxycycline 100 mg 7 days Contraindicated 500 mg 7days Recommended PO bid Erythromycin base PO qid From Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2006. MMWR 2006;55(No. RR-11), with permission. o P.299 o o Risk factors include a previous history of PID, multiple sex partners, defined as more than two partners in 30 days, and infection by a sexually transmitted organism. Use of an IUD can increase the risk of PID by up to six times but only within the first 3 weeks after placement. Thereafter, the risk is relatively low (10). Use of nonbarrier contraception is also a developing risk factor. o Signs and Symptoms. The most common presenting symptom is abdominopelvic pain. Other complaints are variable, including vaginal discharge or bleeding, fever and chills, nausea, and dysuria. o Diagnosis of PID is difficult because the presenting signs and symptoms vary widely. Because of the sequelae of PID, especially infertility, ectopic pregnancy, and chronic pelvic pain, health care providers should maintain a low threshold for diagnosis PID (4). Minimal Criteria. Empiric treatment should be initiated in young women at risk for STDs if they are experiencing pelvic or lower abdominal pain, if no other cause can be identified, and if one or more of the following are present on pelvic examination: Cervical motion tenderness Uterine tenderness Adnexal tenderness Additional Criteria for Diagnosis Oral temperature >101В°F (>38.3В°C) Abnormal cervical or vaginal mucopurulent discharge Presence of white blood cells on saline microscopy of vaginal secretions Elevated erythrocyte sedimentation rate Elevated C-reactive protein Laboratory documentation of cervical infection with N. gonorrhoeae or C. trachomatis Specific Criteria for PID Endometrial biopsy with histopathologic evidence of endometritis Transvaginal sonography or magnetic resonance imaging techniques showing thickened, fluid-filled tubes with or without free pelvic fluid or tubo-ovarian complex o Laparoscopic abnormalities consistent with PID Treatment for PID should have as its goals the prevention of tubal damage that leads to infertility and ectopic pregnancy and prevention of chronic infection. Many patients can be successfully treated as outpatients, and early ambulatory P.300 treatment should be the initial therapeutic approach. Antibiotic choice should target the major etiologic organisms (N. gonorrhoeae and C. trachomatis) but should also address the polymicrobial nature of the disease (Tables 24.11 and 24.12). Criteria for Hospitalization Surgical emergencies (e.g., appendicitis) should not be excluded. The patient is pregnant. The patient does not respond clinically to oral antimicrobial therapy. The patient is unable to follow or tolerate an outpatient oral regimen. The patient has severe illness, nausea and vomiting, or high fever. The patient has a tubo-ovarian abscess. o Sequelae. Approximately 25% of PID patients experience long-term sequelae. Infertility due to tubal occlusion affects anywhere from 6% to 60% of women following an episode of PID, depending on severity, whereas the risk of ectopic pregnancy is approximately 6 to 10 times normal. Chronic pelvic pain and dyspareunia have also been reported. Fitz-HughCurtis syndrome is the development of fibrous perihepatic adhesions resulting from the inflammatory process of PID. This can cause acute right upper quadrant pain and tenderness. Table 24.11 Centers for Disease Control and Prevention Recommendations for Inpatient Management of Pelvic Inflammatory Disease Regimen Cefotetan A 2 g IV every 12 hours 2 g IV every 6 hours or Cefoxitin PLUS Doxycycline * 100 mg orally or IV every 12 hours Treatment with doxycycline (100 mg PO BID) should continue to complete 14 days. If TOA, add clindamycin or metronidazole for more effective anaerobic coverage. Regimen B Clindamycin 900 mg IV every 8 hours PLUS Gentamicin loading dose IV or IM (2 mg/kg) w/maintenance dose (1.5 mg/kg) q 8 * hours. Single daily dosing may be substituted. Treatment with doxycycline 100 mg PO BID or clindamycin 450 mg PO QID should continue to complete a total of 14 days. If TOA, use clindamycin rather than doxycycline for more effective anaerobic Alternative Ofloxacin coverage. Regimens 400 mg IV every 12 hours or Levofloxacin WITH 500 mg or IV once daily WITHOUT Metronidazole 500 mg IV every 8 hours 6 hours 12 hours or Ampicillin/sulbactam 3 g IV every PLUS Doxycycline 100 mg PO or IV every Parenteral therapy can be discontinued 24 hours after patient improves clinically. From Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2006. MMWR 2006;55(No. RR-11), with permission. Table 24.12 Centers for Disease Control and Prevention Recommended Treatment Schedules for Outpatient Treatment of Pelvic Inflammatory Disease Regimen Ofloxacin A 400 mg PO twice a PO daily Г— day 14 days or Levofloxacin 500 mg WITH Г— 14 or Metronidazole 500 mg PO days WITHOUT twice a day < 14 Regimen days B Ceftriaxone 250 mg IM single dose or Cefoxitin 2 g IM in a single dose and Probenecid, 1 g PO administered concurrently in a single dose or Other parenteral third-generation cephalosporin (e.g., ceftizoxime, cefotaxime) PLUS Doxycycline 100 mg PO WITH twice a day Г— or Metronidazole Alternative 500 mg PO 14 days WITHOUT twice a day Г— 14 days Regimen Amoxicillin/clavulanic acid + doxycycline (GI symptoms might limit compliance) From Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2006. MMWR 2006;55(No. RR-11), with permission. Endometritis (Nonpuerperal) o Pathophysiology. Endometritis is caused by the ascension of pathogens from the cervix to the endometrium. Pathogens include C. trachomatis, N. gonorrhoeae, Streptococcus agalactiae, cytomegalovirus, HSV, and Mycoplasma hominis. Organisms that produce bacterial vaginosis may also produce histologic endometritis, even in women without symptoms. Endometritis is also an important component of PID and may be an intermediate stage in the spread of infection to the fallopian tubes. o Signs and Symptoms Chronic Endometritis. Many women are asymptomatic. The classic symptom of chronic endometritis is intermenstrual vaginal bleeding. Postcoital bleeding, menorrhagia, and a dull, constant lower abdominal pain are other complaints. o Acute Endometritis. Uterine tenderness is common. Diagnosis. The diagnosis of chronic endometritis is established by endometrial biopsy and culture. The classic histologic findings of chronic endometritis are an inflammatory reaction of monocytes and plasma cells in the endometrial stroma (five plasma cells per highpower field). A diffuse pattern of inflammatory infiltrates of lymphocytes and plasma cells throughout the endometrial stroma or even stromal necrosis is associated with severe cases of endometritis. o Treatment. The treatment of choice for chronic endometritis is doxycycline, 100 mg PO bid for 10 days. Broader coverage of anaerobic organisms may also be considered, especially in the presence of bacterial vaginosis. When endometritis is associated with acute PID, treatment should focus on the major etiologic organisms, including N. gonorrhoeae and C. trachomatis, and should also include broader polymicrobial coverage. V. Self-assessment tasks: 1. Classification of inflammatory gynaecological diseases in girls and juvenile. 2. Clinical picture, diagnostics of inflammatory diseases of internal genitals in girls and juvenile. 3. Methods of diagnostics of clamidiosis. 4. Prescribe the treatment of clamidiosis in accordance to age. 5. What is ureaplasmatic vulvovaginitis? Clinical picture, diagnostics of treatment. 6. What is gardnerelosis? Methods of its diagnostics in girls and juvenile and its treatment. 7. Bacterial vaginosis. Methods of its diagnostics and treatment in juvenile. VI. Literature. 1. American Academy of Pediatrics Committee on Quality Improvement, Subcommittee on Urinary Tract Infection. Practice Parameter: The diagnosis, treatment and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 1999;103;4:843–852. 2. Sanfilippo JS. Pediatric and Adolescent Gynecology, 2nd Ed. Philadelphia: WB Saunders, 2001:227–231. 3. Reiter EO, Lee PA. Adolescent endocrinology: delayed puberty. Adolesc Med 2002;13 (1):101–118. 4. Larsen PR. Williams Textbook of Endocrinology, 10th Ed. Elsevier, 2003:1171–1202. 5. Stenchever MA. Comprehensive Gynecology, 4th Ed. Mosby, 2001:280–288. 6. Kaplowitz PB. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implication for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics 1999;104 (4 Pt 1):936–941. 7. Antoniazzi F, Zamboni G. Central precocious puberty: current treatment options. Paediatr Drugs 2004;6 (4):211–231. 8. Speroff L, Glass RH, Kase NG. Clinical Gynecologic Endocrinology and Infertility, 5th Ed. Baltimore: Williams & Wilkins, 1994:380–382. 9. Eugster EA, Rubin SD, Reiter EO, et al. Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr 2003;143 (1):60–66. 10. Speroff L, Glass RH, Kase NG. Clinical Gynecologic Endocrinology and Infertility, 5th Ed. Baltimore: Williams & Wilkins, 1994:340–342. 11. Sanfilippo JS. Pediatric and Adolescent Gynecology, 2nd Ed. Philadelphia: WB Saunders, 2001:277–287. 12. Sanfilippo JS. Pediatric and Adolescent Gynecology, 2nd Ed. Philadelphia: WB Saunders, 2001:605–608.