Dr. Mohammed Abdalla

1. Dr. Mohammed Abdalla

2. AMENORRHEA Amenorrhea is the absence or abnormal cessation of menstruation.

3. Primary amenorrhea is defined either as absence of menses by age 14 years with the absence of growth or development of secondary sexual characteristics . OR as absence of menses by age 16 years with normal development of secondary sexual characteristics.

4. Secondary amenorrhea is defined as the cessation of menstruation for at least 6 months or for at least 3 of the previous 3 cycle intervals.

5. PHYSIOLOGY Circulating estradiol stimulates growth of the endometrium. Progesterone, produced by the corpus luteum formed after ovulation, transforms proliferating endometrium into secretory endometrium. If pregnancy does not occur, this secretory endometrium breaks down and sheds as a menstrual blood.

6. the age of the first menses varies by geographic location, as demonstrated by a World Health Organization study comparing 11 countries, which reported a median age of menarche of 13-16 years across centers. PHYSIOLOGY

7. The number of primordial follicles in the human ovary peaks during the fifth gestational month at approximately 7 million. After this initial pool is in place, no additional primordial follicles are formed. In some cases, loss of menstrual regularity is an early sign of declining fertility and impending premature ovarian failure PHYSIOLOGY

8. by age 20 years, women have established regular and persistent patterns of menstrual cycle length with little variation . on an individual basis Relatively stable and predictable menstrual cycle length continues until age 40 years. PHYSIOLOGY

9. In the first year after menarche, the fifth percentile for menstrual cycle length is 23 days and the 95th percentile is 90 days. By the fourth year after menarche, the 95th percentile for cycle length has declined from 90 days to approximately 50 days. by 7 years after menarche, cycles are more stable; the fifth percentile in cycle length is 27 days, and the 95th percentile is 38 days. PHYSIOLOGY

10. How common is it? Secondary amenorrhoea (prevalence about 3%) primary amenorrhoea (prevalence about 0.3%) Between 10 and 20% of women complaining of infertility have amenorrhoea [Franks, 1987]. Up to 50% of competitive runners (training 80 miles per week) and up to 44% of ballet dancers have amenorrhoea [Balen, 1999a].

11. Etiology of PRIMARY amenorrhoea

12. Secondary sexual characteristics present Pregnancy Constitutional delay Genito-urinary malformation, e.g. imperforate hymen, transverse vaginal septum, absent vagina with or without a functioning uterus Androgen insensitivity: XY female or testicular feminization Resistant ovary syndrome

13. Secondary sexual characteristics absent  Hypothalamic dysfunction, e.g. chronic illness, anorexia, weight loss, 'stress' Gonadotrophin deficiency, e.g. Kallman's syndrome Hydrocephalus Tumours of the hypothalamus or pituitary Hypopituitarism Hyperprolactinaemia Gonadal failure, e.g. ovarian dysgenesis/agenesis, premature ovarian failure Hypothyroidism

14. Ambiguous external genitalia  Congenital adrenal hyperplasia Androgen-secreting tumour 5-Alpha-reductase deficiency

15. Turner's syndrome Turner's syndrome is caused by either a complete absence or a partial abnormality of one of the two X chromosomes. About 50% have mosaic forms such as 45X/46XX or 45X/46XY. Features :( short stature, web neck, lymphoedema, shield chest with widely spaced nipples, scoliosis, wide carrying angle, coarctation of the aorta, and streak ovaries.)

16. Constitutional delay In this condition there is no anatomical abnormality and endocrine investigations show normal results. It is caused by immature Pulsatile release of gonadotrophin-releasing hormone; maturation eventually occurs spontaneously.

17. Androgen insensitivity syndrome (AIS) formerly known as testicular feminization, 46XY failure of normal masculinization of the external genitalia in chromosomally male individuals. This failure of virilization can be either complete (CAIS) or partial (PAIS), depending on the amount of residual receptor function. affected individuals have normal testes with normal production of testosterone and normal conversion to dihydrotestosterone (DHT), which differentiates this condition from 5-alpha reductase deficiency.

18. 5-alpha-reductase deficiency (5-ARD) inability to convert testosterone to the more physiologically active dihydrotestosterone (DHT). Because DHT is required for the normal masculinization of the external genitalia in utero, genetic males with 5-ARD are born with ambiguous genitalia (ie, male pseudohermaphroditism). The described clinical abnormalities range from infertility with normal male genital anatomy to underdeveloped male with hypospadias to predominantly female external genitalia, most often with mild clitoromegaly.

19. Measuring the clitoris is an effective method for determining the degree of androgen effect. The clitoral index can be determined by measuring the glans of clitoris in the anteroposterior and transverse diameter. A clitoral index greater than 35 mm2 is evidence of increased androgen effect. A clitoral index greater than 100 mm2 is evidence of virilization. 5-alpha-reductase deficiency (5-ARD)

20. Imperforate hymen Imperforate hymen represents the most common and most distal form of vaginal outflow obstruction. Clinical presentations range from an incidental finding on physical examination of an asymptomatic patient to discovery on an evaluation for primary amenorrhea or abdominal or back pain. The differential diagnosis of uterovaginal obstruction includes disorders of vaginal development, such as transverse vaginal septum or complete vaginal agenesis, Duplication anomalies of the uterovaginal tract often involve one tract that is decompressed and one that is obstructed.

22. Etiology of secondary amenorrhoea

23. No features of androgen excess present  Physiological, e.g. pregnancy, lactation, menopause Iatrogenic, e.g. depot medroxyprogesterone acetate contraceptive injection, radiotherapy, chemotherapy Systemic disease, e.g. chronic illness, hypo- or hyperthyroidism Uterine causes, e.g. cervical stenosis, Asherman's syndrome (intra-uterine adhesions) Ovarian causes, e.g. premature ovarian failure, resistant ovary syndrome Hypothalamic causes, e.g. weight loss, exercise, psychological distress, chronic illness, idiopathic Pituitary causes, e.g. hyperprolactinaemia, hypopituitarism, Sheehan's syndrome Causes of hypothalamic/pituitary damage, e.g. tumours, cranial irradiation, head injuries, sarcoidosis, tuberculosis

24. Features of androgen excess present  Polycystic ovary syndrome Cushing's syndrome Late-onset congenital adrenal hyperplasia Adrenal or ovarian androgen-producing tumour

25. Polycystic ovary syndrome This condition is characterized by hirsutism, acne, alopecia, infertility, obesity, and menstrual abnormalities (amenorrhoea in 19% of cases). Ultrasound examination of the ovaries typically shows multiple, small peripheral cysts. up to a third of women in the general population have polycystic ovaries on ultrasound examination [DTB, 2001]. Endocrine abnormalities include increased serum concentrations of testosterone, prolactin, luteinizing hormone (LH) (with normal follicle-stimulating hormone [FSH] levels), and insulin resistance with compensatory hyperinsulinaemia.

26. Menopause/ovarian failure occurring before the age of 40 years is considered premature. Auto-immune disease is the most common cause; auto-antibodies to ovarian cells, gonadotrophin receptors, and oocytes have been reported in 80% of cases. Before puberty or in adolescents, ovarian failure is usually due to a chromosomal abnormality, e.g. Turner mosaic, or previous radiotherapy, or chemotherapy Premature ovarian failure

27. Ovarian failure (premature menopause)

28. autoimmune related dysfunction The most common association is with thyroid disease, but the parathyroids and adrenals can also be affected. Several studies have shown laboratory evidence of immune problems in about 15-40% of women with premature ovarian failure. In general, ovarian biopsy is not indicated in patients with premature ovarian failure since no clinically useful information will be obtained.

29. Hyperprolactinaemia A prolactinoma is the commonest cause of hyperprolactinaemia (60% of cases). Other causes include non-functioning pituitary adenoma (disrupting the inhibitory influence of dopamine on prolactin secretion); dopaminergic antagonist drugs (e.g. phenothiazines, haloperidol, clozapine, metoclopramide, domperidone, methyldopa, cimetidine); primary hypothyroidism (thyrotrophin-releasing hormone stimulates the secretion of prolactin), or it may be idiopathic. Prolactin acts directly on the hypothalamus to reduce the amplitude and frequency of pulses of gonadotrophin-releasing hormone.

30. Weight-related amenorrhoea A regular menstrual cycle is unlikely to occur if the body mass index (BMI) is less than 19 (normal range 20-25). Weight loss may be due to illness, exercise, or eating disorders, among which anorexia nervosa lies at the extreme end of the spectrum.

31. Post-pill' amenorrhoea This is defined as absence of menstruation for 6 months following cessation of the combined oral contraceptive pill. It probably results from A transient inhibition of gonadotrophin-releasing hormone .

32. Progestogen-associated amenorrhoea Depot medroxyprogesterone acetate inhibits the secretion of gonadotrophins and thus suppresses ovulation. After 1 year of use, 80% of women have amenorrhoea or very scanty, infrequent vaginal bleeding. There is partial oestrogen deficiency in women who use depot medroxyprogesterone acetate. The progestogen-only pill leads to reversible long-term amenorrhoea in a minority of women, due to complete suppression of ovulation. The levonorgestrel-releasing intra-uterine device commonly results in amenorrhoea after a few months. This is thought to be mainly a local effect, but suppression of ovulation can occur in some women (in some cycles).

33. ASSESSMENT of primary amenorrhea

39. Secondary Amenorrhea

40. History A good history can reveal the etiologic diagnosis in up to 85% of cases of amenorrhea.

41. If the history and physical exam are suggestive of a certain etiology : for the sake of efficiency and cost-effectiveness, the workup can sometimes be more directed according to history. ( in 85% of cases)

42. In patients that will not demonstrate any obvious etiology for their amenorrhea on history and physical exam. These patients can be worked up in a logical manner using a stepwise approach.

43. How do I assess my patient with secondary amenorrhoea? Risk of pregnancy Associated symptoms, e.g. galactorrhoea, hirsutism, hot flushes, dry vagina, symptoms of thyroid disease Recent change in body weight Recent emotional upsets Level of exercise Previous menstrual and obstetric history Previous surgery, e.g. endometrial curettage, oophorectomy Previous abdominal, pelvic, or cranial radiotherapy Family history, e.g. of early menopause Drug history, e.g. progestogens, combined oral contraceptive, chemotherapy

44. Height and weight: calculate body mass index if appropriate. Signs of excess androgens, e.g. hirsutism, acne Signs of virilization, e.g. deep voice, clitoromegaly in addition to hirsutism, and acne Signs of thyroid disease . Acanthosis nigricans: this hyperpigmented thickening of the skin folds of the axilla and neck is a sign of profound insulin resistance. It is associated with polycystic ovary syndrome (PCOS) and obesity. Breast examination for galactorrhoea. Fundoscopy and assessment of visual fields if there is suspicion of pituitary tumour. Pelvic examination . How do I assess my patient with secondary amenorrhoea?

47. Complications and prognosis Osteoporosis: women with amenorrhoea associated with oestrogen deficiency are at significant risk of developing osteoporosis. This increased risk persists even if normal menses are resumed. Oestrogen deficiency is of particular concern in younger women as a desirable peak bone mass may not be attained Cardiovascular disease Young women with amenorrhoea associated with oestrogen deficiency may be at increased risk of cardiovascular disease Women with polycystic ovary syndrome have an increased risk of developing cardiovascular disease, hypertension, and type 2 diabetes [Hopkinson et al, 1998].

48. Endometrial hyperplasia: women with amenorrhoea but no associated oestrogen deficiency are at increased risk of endometrial hyperplasia and endometrial carcinoma . Infertility: women with amenorrhoea generally do not ovulate. Psychological distress: amenorrhoea often causes considerable anxiety, Many women have concerns about loss of fertility, loss of femininity, or worry about an unwanted pregnancy. The diagnosis of Turner's syndrome, testicular feminization, or developmental anomaly can be traumatic for both girls and their parents .

49. Thank you