AMENORRHEA

1. Obstetrics & Gynecology Hospital of Fudan University AMENORRHEA Wang Ling

2. menstrual cycle physiology hypothalamus secrete GnRH in a pulsatile fashion GnRH stimulates pituitary secrete FSH and LH which promotes ovarian follicular development and ovulation ovarian follicle secretes E2 after ovulation, the follicle is converted to corpus luteum and P is secreted in addition to E2 A complex hormonal interaction for normal menstruation Obstetrics & Gynecology Hospital of Fudan University

3. menstrual cycle physiology ●If pregnancy not occur, E2 and P secretion decrease and withdrawal bleeding begins ●If any of the components (hypothalamus, pituitary, ovary, uterus, and outflow tract) are nonfunctional, bleeding cannot occur Obstetrics & Gynecology Hospital of Fudan University

4. Contents 1 definition and Classification of amenorrhea 2 etiology of amenorrhea Diagnosis of amenorrhea 3 The management of amenorrhea 4 Obstetrics & Gynecology Hospital of Fudan University

5. Definition of Amenorrhea • Primary amenorrhea Girls experienced menarche at increasingly younger ages during the past century the absence of menses at age 13 years when there is no visible development of secondary sexual characteristics or age 15 years in the presence of normal secondary sexual characteristics • Secondary amenorrhea absenceof menstruation for three normal menstrual cycles or 6 months Obstetrics & Gynecology Hospital of Fudan University

6. Categories • hypothalamic amenorrhea • pituitary amenorrhea • ovarian amenorrhea • uterine amenorrhea • anatomic abnormalities of the reproductive tract Obstetrics & Gynecology Hospital of Fudan University

7. classes of amenorrhea (WHO) • Group I : no evidence of endogenous estrogen production normal or low FSH normal prolactin no lesion in the hypothalamic-pituitary region • Group II : evidence of estrogen production normal prolactin and FSH • Group III : elevated FSH indicating gonadal insufficiency or failure Obstetrics & Gynecology Hospital of Fudan University

8. Etiology of Amenorrhea • whethersecondary sexual characteristics are present • absence of secondary sexual characteristics indicates: never exposed to estrogen Obstetrics & Gynecology Hospital of Fudan University

9. Amenorrhea without Secondary Sexual Characteristics • breast development is the first sign of estrogen exposure in puberty, patients without secondary sexual characteristics typically have primary, not secondary, amenorrhea • categorize the causes of amenorrhea in the absence of breast development on the basis of gonadotropin status Obstetrics & Gynecology Hospital of Fudan University

10. Hypergonadotropic Hypogonadism Associated with Absence of Secondary Sexual Characteristics • Gonadal dysgenesis: abnormal development of the gonads • is associated with high levels of LH and FSH because the gonad fails to produce the steroids and inhibin that would feed back to pituitary gland to suppress LH and FSH • Karyotypic abnormalities are common with primary amenorrhea • approximately 30% primary amenorrhea had an associated karyotypic abnormality Obstetrics & Gynecology Hospital of Fudan University

11. Turner syndrome In addition to gonadal failure short stature webbed neck shield chest cubitus valgus low hair line high arched palate multiple pigmented nevi short fourth metacarpals • Turner syndrome (45,X) represent the most common form of hypergonadotropic hypogonadism with primary amenorrhea. Obstetrics & Gynecology Hospital of Fudan University

12. Other disorders associated with primary amenorrhea include: abnormal X chromosomes mosaicism pure gonadal dysgenesis (46,XX and 46,XY with gonadal streaks) Rare enzyme deficiencies that prevent normal estrogen production Rare gonadotropin receptor inactivating mutations Individuals with these conditions have gonadal failure and cannot synthesize ovarian steroids. Most patients with these conditions have primary amenorrhea and lack secondary sexual characteristics Obstetrics & Gynecology Hospital of Fudan University

13. Other Causes of Primary Ovarian Failure without Secondary Sexual Characteristics • Severe damage to the ovaries before the onset of puberty • Ovarian dysfunction can occur in association with irradiation of the ovaries, chemotherapy, or combinations of radiation and other chemotherapeutic agents • Other causes of premature ovarian failure (also known as primary ovarian insufficiency) are more commonly associated with amenorrhea after the development of secondary sexual characteristics Obstetrics & Gynecology Hospital of Fudan University

14. Hypogonadotropic Hypogonadism Associated with the Absence of Secondary Sex Characteristics • hypothalamus fails to secrete adequate GnRH or pituitary disorder associated with inadequate production or release of pituitary gonadotropins • Physiologic Delay • Kallmann Syndrome • Other Causes of Gonadotropin-Releasing Hormone Deficiency Obstetrics & Gynecology Hospital of Fudan University

15. Amenorrhea Associated with a Lack of Secondary Sexual Characteristics • Abnormal pelvic examination5α-reductase deficiency, 17, 20-lyase deficiency, or 17α-hydroxylase deficiency in XY individual   Congenital lipoid adrenal hyperplasia   Luteinizing hormone receptor defect • Hypergonadotropic hypogonadismGonadal dysgenesis   Follicle-stimulating hormone receptor defect   Partial deletion of X chromosome   Sex chromosome mosaicism   Environmental and therapeutic ovarian toxins   17α-hydroxylase deficiency in XX individual   Galactosemia   Congenital lipoid adrenal hyperplasia in XX individualHypogonadotropic hypogonadismPhysiologic delay   Kallmann syndrome   Central nervous system tumors   Hypothalamic/pituitary dysfunction Obstetrics & Gynecology Hospital of Fudan University

16. Evaluation of Amenorrhea Associated with the Absence of Secondary Sexual Characteristics • careful history and physical examination • serum FSH and LH levels to differentiate hypergonadotropic and hypogonadotropic of hypogonadism • Turner syndrome: coarctation of the aorta (up to 30%) and thyroid dysfunction, echocardiography and thyroid function studies • karyotype abnormal and contains the Y chromosome, as in gonadal dysgenesis, the gonads should removed to prevent tumors • karyotype is normal, FSH is elevated, consider 17α-hydroxylase deficiency because it may be a life-threatening disease • FSH level low, diagnosis of hypogonadotropic hypogonadism. Central nervous system lesions should be ruled out by imaging using CT or MRI, especially if galactorrhea, headaches, or visual field defects • Physiologic delay is a diagnosis of exclusion that is difficult to distinguish from insufficient GnRH secretion Obstetrics & Gynecology Hospital of Fudan University

17. Obstetrics & Gynecology Hospital of Fudan University

18. Treatment of Amenorrhea Associated with the Absence of Secondary Sexual Characteristics • Individuals with primary amenorrhea associated with gonadal failure and hypergonadotropic hypogonadism need cyclic estrogen and progestogen therapy to initiate, mature, and maintain secondary sexual characteristics • Prevention of osteoporosis is an additional benefit of estrogen therapy • If possible, therapeutic measures are aimed at correcting the primary cause of amenorrhea Obstetrics & Gynecology Hospital of Fudan University

19. Amenorrhea with Secondary Sexual Characteristics and Abnormalities of Pelvic Anatomy • Müllerian anomalies • 2. Androgen insensitivity • 3. True hermaphrodism • 4. Absent endometrium • 5. Asherman syndrome Obstetrics & Gynecology Hospital of Fudan University

20. Amenorrhea with Secondary Sexual Characteristics and Abnormalities of Pelvic Anatomy • Outflow and Müllerian Anomalies 1. blockage of the outflow tract, outflow tract is missing or no functioning uterus. 2. for menses occur, endometrium must be functional and must be patency of the cervix and vagina 3. Most müllerian abnormalities have normal ovarian function, thus will have normal secondary sexual characteristic development Obstetrics & Gynecology Hospital of Fudan University

21. Absence of Functioning Endometrium • Amenorrhea may occur if there is no functioning endometrium • Asherman syndrome • more common with secondary amenorrhea or hypomenorrhea • occur in patients with risk factors for endometrial or cervical scarring Obstetrics & Gynecology Hospital of Fudan University

22. Androgen Insensitivity • Phenotypic females with complete congenital androgen insensitivity develop secondary sexual characteristics but do not have menses • Genotypically, male (XY) but have a defect prevents normal androgen receptor function, leading to the development of the female phenotype • Serum testosterone in normal male range • vagina may be absent or short Obstetrics & Gynecology Hospital of Fudan University

23. Evaluation Amenorrhea, Normal Secondary Sexual Characteristics, Suspected Anatomic Abnormalities • Most congenital abnormalities can be diagnosed by physical examination: • An imperforate hymen is diagnosed by the presence of a bulging membrane that distends during Valsalva maneuver, Ultrasonography or MRI • differentiate a transverse septum or complete absence of the cervix and uterus from a blind vaginal pouch in a male pseudohermaphrodite. Androgen insensitivity is likely when pubic and axillary hair is absent • An absent endometrium is an outflow tract abnormality that cannot be diagnosed by physical examination with primary amenorrhea • Asherman syndrome cannot be diagnosed by physical examination. It is diagnosed by performing hysterosalpingography, saline infusion sonography (also known as saline hysterogram), or hysteroscopy Obstetrics & Gynecology Hospital of Fudan University

24. Obstetrics & Gynecology Hospital of Fudan University

25. Treatment with Amenorrhea, Normal Secondary Sexual Characteristics, and Abnormalities of Pelvic Anatomy • imperforate hymen, making a cruciate incision to open the vaginal orifice • transverse septum, surgical removal is required • Hypoplasia or absence of the cervix in the presence of a functioning uterus is more difficult to treat than other outflow obstructions • vagina is absent or short, progressive dilation to making it functional • complete androgen insensitivity, the testes be removed after pubertal development is complete to prevent malignant degeneration • Adhesions in the cervix and uterus (Asherman syndrome) be removed using hysteroscopic resection with scissors or electrocautery Obstetrics & Gynecology Hospital of Fudan University

26. Amenorrhea with Secondary Sexual Characteristics and Normal Pelvic Anatomy • the most common causes are pregnancy • polycystic ovarian syndrome • Hyperprolactinemia • primary ovarian insufficiency (also known as premature ovarian failure) • hypothalamic dysfunction • Pregnancy must be considered in all women of reproductive age with amenorrhea Obstetrics & Gynecology Hospital of Fudan University

27. Polycystic Ovarian Syndrome • associated with hyperandrogenism, ovulatory dysfunction, and polycystic ovaries • exclude patients with significantly elevated prolactin, significant thyroid dysfunction, adult-onset congenital adrenal hyperplasia, and androgen-secreting neoplasms from being classified as PCOS • Rotterdam 2003 criteria required two of three of the following for PCOS diagnosis: hyperandrogenism, oligomenorrhea or amenorrhea, polycystic ovaries by ultrasound • Even though PCOS usually causes irregular bleeding rather than amenorrhea, it remains one of the most common causes of amenorrhea • In patients who are hirsute and amenorrheic and appear to have PCOS, androgen-secreting adrenal tumors and congenital adrenal hyperplasia should be considered Obstetrics & Gynecology Hospital of Fudan University

28. Hyperprolactinemia • is a common cause of anovulation in women • Elevation of prolactin produces abnormal GnRH secretion, which can lead to menstrual disturbances • other central nervous system (CNS) lesions that disrupt the normal transport of dopamine down the pituitary stalk, and by medications that interfere with normal dopamine • If elevated TSH and elevated prolactin levels are found together, the hypothyroidism should be treated before hyperprolactinemia is treated Obstetrics & Gynecology Hospital of Fudan University

29. Primary Ovarian Insufficiency (Premature Ovarian Failure) • presence of amenorrhea for 4 months or more, two serum FSH levels in the menopausal range for who is less than 40 years of age • decreased follicular endowment or accelerated follicular atresia • If the ovary does not develop or stops its hormone production before puberty, the patient will not develop secondary sexual characteristics without exogenous hormone therapy. If ovarian insufficiency begins later in life, the woman will have normal secondary sexual characteristics • a heterogenous disorder with many potential causes Obstetrics & Gynecology Hospital of Fudan University

30. Pituitary and Hypothalamic Lesions • Tumors of the hypothalamus or pituitary, prevent appropriate hormonal secretion • Pituitary Lesions; Sheehan syndrome, postpartum necrosis of pituitary resulting from a hypotensive episode •  If hypopituitarism occurs before puberty, menses and secondary sexual characteristics will not develop Obstetrics & Gynecology Hospital of Fudan University

31. Altered Hypothalamic Gonadotropin-Releasing Hormone Secretion • Abnormal secretion of GnRH accounts for one-third of amenorrhea • When decrease in GnRH pulsatility is severe, amenorrhea results • Decreased leptin levels are associated with hypothalamic amenorrhea, regardless of whether it is caused by exercise, eating disorders, or idiopathic factors Obstetrics & Gynecology Hospital of Fudan University

32. Eating Disorders • Anorexia nervosa is an eating disorder that affects 5% to 10% of adolescent women • refusal to maintain body weight above 15% below normal, an intense fear of becoming fat, altered perception of one's body image and amenorrhea Obstetrics & Gynecology Hospital of Fudan University

33. Weight Loss and Dieting, etc • Weight loss • can cause amenorrhea even if weight does not decrease below normal • Loss of 10% body mass in 1 year is associated with amenorrhea • Exercise • decrease in the frequency of GnRH pulses • Stress • Obesity • Other Hormonal Factors Obstetrics & Gynecology Hospital of Fudan University

34. Evaluation with Amenorrhea in the Presence of Normal Pelvic Anatomy and Normal Secondary Sexual Characteristics • pregnancy test (hCG) in a reproductive-age • Clinical assessment of estrogen status • Serum TSH • Serum prolactin • Serum FSH level • Vaginal ultrasound for assessment of antral follicle count in the ovaries can be considered • Imaging of the pituitary and hypothalamic assessment if prolactin is elevated or if hypothalamic amenorrhea is suspected Obstetrics & Gynecology Hospital of Fudan University

35. Obstetrics & Gynecology Hospital of Fudan University

36. Treatment for Amenorrhea in the Presence of Normal Pelvic Anatomy and Normal Secondary Sexual Characteristics pregnant may be counseled regarding the options for continued care thyroid abnormalities are detected, thyroid hormone, radioactive iodine, or antithyroid drugs administered as appropriate hyperprolactinemia, treatment may include discontinuation of contributing medications, treatment with dopamine agonists such as bromocriptine or cabergoline, and, rarely, surgery for particularly large pituitary tumors POI, hormone replacement to diminish symptoms and to prevent osteoporosis Gonadectomy is required when a Y cell line is present Obstetrics & Gynecology Hospital of Fudan University

37. Study Questions Obstetrics & Gynecology Hospital of Fudan University

38. A 15-year-old girl, she has never had a period. She seemed to grow and develop breasts at the same time as the other girls in school, but that she has not yet started to menstruate. She is active in sports at her school and plays the piano. an examination reveals Tanner IV breast and pelvic examination reveals a blind vaginal pouch. Ultrasound confirms absence of a uterus. An FSH level is normal at 5.8 mIU/mL. The next step in the evaluation is: A MRI of the pituitary B Karyotype C Visual field testing D Trial of estrogen/progesterone to stimulate bleeding E Creation of a neovagina using graduated dilators Obstetrics & Gynecology Hospital of Fudan University

39. A 24-year-old female with the complaint of missed menstrual cycles. She states her period has never been regular, and that in the past it was common for her to skip a month or two between cycles. Now, however, she has not had a period in the past 7 months. She denies sexual activity, reports no medical problems, and her only prescribed medication is a face wash for acne. On review of systems she reports a weight gain of 7kg over the past year. Her laboratory test reveals an FSH level of 8.7 mIU/mL, LH of 22.2 mIU/mL, estradiol of 45 pg/mL, TSH of 2.2 mIU/mL, prolactin of 12 ng/mL, and total testosterone of 98 ng/dL. The most likely diagnosis is: A Premature ovarian insufficiency B Polycystic ovary syndrome C Prolactinoma D Functional hypothalamic amenorrhea E Hypothyroidism Obstetrics & Gynecology Hospital of Fudan University

40. A 27-year-old woman complaining of not getting her period. She came off of the birth control pill 9 months ago to attempt pregnancy and has not had a period since. Multiple home pregnancy tests have been negative. She states she underwent menarche at the age of 12 years, and that she did not always get a period every month during high school but was told this was normal because she was an athlete. She continues to be very athletic, running 5 to 6 times per week and also bikes. She has no hirsutism or acne. The most likely reason for her amenorrhea is: A Polycystic ovary syndrome B Müllerian agenesis C Functional hypothalamic amenorrhea D Prolactinoma E Swyer syndrome Obstetrics & Gynecology Hospital of Fudan University

41. A 32-year-old woman returns to your care 5 months after the birth of her child. She had a postpartum hemorrhage following vaginal delivery of her son, requiring emergency surgery and multiple blood transfusions. She complains of fatigue, constipation, and states that her periods have not returned despite the fact that she has not been able to breastfeed. Her laboratory test reveals an FSH level of 1.2 mIU/mL, TSH of 0.3 IU/mL, and prolactin of 1 ng/mL. The most likely etiology of her secondary amenorrhea is: A Asherman’s syndrome B Polycystic ovary syndrome C Functional hypothalamic amenorrhea D Sheehan’s syndrome E Kallman’s syndrome Obstetrics & Gynecology Hospital of Fudan University

42. A 26-year-old female is referred to your office by her primary care doctor. She reports regular menses in the past, but has not had a period for 2 years. She did not bleed after a course of progesterone prescribed by her doctor. On examination she is 58 inches tall, has normal secondary sexual characteristics. Laboratory test reveals an FSH level of 82 mIU/mL and estradiol of 26 pg/mL. What is the next step in her evaluation? A Pelvic ultrasound B Total testosterone C Karyotype D Pituitary MRI E Trial of oral contraceptive pills Obstetrics & Gynecology Hospital of Fudan University

43. END Obstetrics & Gynecology Hospital of Fudan University