1. Menstruel Cycle and Menstruel Cycle Abnormalities Rukset Attar, MD, PhD Department of Obstetrics and Gynecology

2. MENSTRUEL CYCLE Menstruation is the cyclic, orderly sloughing of the uterine lining, in response to the interactions of hormones produced by the hypothalamus, pituitary, and ovaries. Menstruation is the cyclic, orderly sloughing of the uterine lining, in response to the interactions of hormones produced by the hypothalamus, pituitary, and ovaries. The menstrual cycle may be divided into two phases: The menstrual cycle may be divided into two phases: the follicular or proliferative phase, and the follicular or proliferative phase, and the luteal or secretory phase the luteal or secretory phase

3. MENSTRUEL CYCLE Menstrual cycles that occur at intervals less than 21 days are called polymenorrheic, Menstrual cycles that occur at intervals less than 21 days are called polymenorrheic, and menstrual cycles, which are prolonged more than 35 days, are called oligomenorrheic. and menstrual cycles, which are prolonged more than 35 days, are called oligomenorrheic. The menstrual cycle is typically most irregular around the extremes of reproductive life, menarche and menopause, due to anovulation and inadequate follicular development. The menstrual cycle is typically most irregular around the extremes of reproductive life, menarche and menopause, due to anovulation and inadequate follicular development. The luteal phase is relatively constant with a duration of 14 days. The luteal phase is relatively constant with a duration of 14 days. The variability of cycle length is usually derived from varying lengths of the follicular phase of the cycle, ranging from 10 to 16 days. The variability of cycle length is usually derived from varying lengths of the follicular phase of the cycle, ranging from 10 to 16 days.

4. The Follicular Phase Between cycle days 5 and 7 and only one follicle is selected from the cohort of recruited follicles to ovulate and the remaining follicles will undergo atresia Between cycle days 5 and 7 and only one follicle is selected from the cohort of recruited follicles to ovulate and the remaining follicles will undergo atresia By cycle day 8, one follicle exerts its dominance by promoting its own growth and suppressing the maturation of the other ovarian follicles By cycle day 8, one follicle exerts its dominance by promoting its own growth and suppressing the maturation of the other ovarian follicles Serum estrogen levels rise in parallel to the growth of follicle size as well as to the increasing number of granulosa cells Serum estrogen levels rise in parallel to the growth of follicle size as well as to the increasing number of granulosa cells

5. For the positive feedback effect of LH release to occur, estradiol levels must be greater than 200 pg/ml for approximately 50 hours in duration For the positive feedback effect of LH release to occur, estradiol levels must be greater than 200 pg/ml for approximately 50 hours in duration

6. Ovulation Ovulation occurs approximately 10-12 hours after the LH peak. Ovulation occurs approximately 10-12 hours after the LH peak. The LH surge is initiated by a dramatic rise of estradiol produced by the preovulatory follicle The LH surge is initiated by a dramatic rise of estradiol produced by the preovulatory follicle To produce the critical concentration of estradiol needed to initiate the positive feedback, the dominant follicle is almost always >15mm in diameter on ultrasound To produce the critical concentration of estradiol needed to initiate the positive feedback, the dominant follicle is almost always >15mm in diameter on ultrasound The LH surge stimulates The LH surge stimulates luteinization of the granulosa cells luteinization of the granulosa cells synthesis of progesterone responsible for the midcycle FSH surge synthesis of progesterone responsible for the midcycle FSH surge resumption of meiosis and the completion of reduction division in the oocyte with the release of the first polar body resumption of meiosis and the completion of reduction division in the oocyte with the release of the first polar body

7. Ovulation Prostaglandins and proteolytic enzymes such as collagenase and plasmin, are increased in response to LH and progesterone. Prostaglandins and proteolytic enzymes such as collagenase and plasmin, are increased in response to LH and progesterone. Although the precise mechanism is not known, proteolytic enzymes and prostaglandins are activated and digest collagen in the follicular wall, leading to an explosive release of the oocyte-cumulus complex Although the precise mechanism is not known, proteolytic enzymes and prostaglandins are activated and digest collagen in the follicular wall, leading to an explosive release of the oocyte-cumulus complex Prostaglandins may also stimulate ovum release by stimulation of smooth muscle within the ovary. Prostaglandins may also stimulate ovum release by stimulation of smooth muscle within the ovary. The point of the dominant follicle closest to the ovarian surface where this digestion occurs is called the stigma The point of the dominant follicle closest to the ovarian surface where this digestion occurs is called the stigma

8. Luteal Phase After ovulation, the granulosa cells continue to enlarge, become vacuolated in appearance, and begin to accumulate a yellow pigment called lutein. After ovulation, the granulosa cells continue to enlarge, become vacuolated in appearance, and begin to accumulate a yellow pigment called lutein. The luteinized granulosa cells combine with the newly formed theca-lutein cells and surrounding stroma to become what is known as the corpus luteum. The luteinized granulosa cells combine with the newly formed theca-lutein cells and surrounding stroma to become what is known as the corpus luteum. The corpus luteum is a transient endocrine organ that predominately secretes progesterone and its primary function is to prepare the estrogen primed endometrium for implantation of the fertilized ovum. The corpus luteum is a transient endocrine organ that predominately secretes progesterone and its primary function is to prepare the estrogen primed endometrium for implantation of the fertilized ovum. The basal lamina dissolves and capillaries invade into the granulosa layer of cells in response to secretion of angiogenic factors by the granulosa and thecal cells The basal lamina dissolves and capillaries invade into the granulosa layer of cells in response to secretion of angiogenic factors by the granulosa and thecal cells

9. Abnormalities of The Menstrual Cycle Major abnormalities of menstruation during the reproductive years : Major abnormalities of menstruation during the reproductive years : amenorrhea and amenorrhea and abnormal uterine bleeding abnormal uterine bleeding pregnancy pregnancy

10. Amenorrhea Amenorrhea may be defined as Amenorrhea may be defined as the absence of menstruation for 3 or more months in women with past menses (i.e., secondary amenorrhea) or the absence of menstruation for 3 or more months in women with past menses (i.e., secondary amenorrhea) or No menses by age 14 in the absence of growth or development of secondary sexual characteristics or No menses by age 14 in the absence of growth or development of secondary sexual characteristics or No menses by age 16 regardless of the presence of normal growth and development of secondary sexual characteristics ( primary amenorrhea) No menses by age 16 regardless of the presence of normal growth and development of secondary sexual characteristics ( primary amenorrhea)

11. The basic requirements for normal menstrual function thus include four anatomically and functionally distinct structural components The basic requirements for normal menstrual function thus include four anatomically and functionally distinct structural components the genital outflow tract including the uterus, the genital outflow tract including the uterus, the ovary, the ovary, the pituitary, and the pituitary, and the hypothalamus—thus providing a natural and useful hierarchy for organizing the diagnostic evaluation of amenorrhea. the hypothalamus—thus providing a natural and useful hierarchy for organizing the diagnostic evaluation of amenorrhea.

12. Amenorrhea can result from congenital or acquired disease or dysfunction at any level in the system and can involve more than one mechanism eg PCOS involves a number of interrelated pathophysiologic mechanisms operating at the ovarian, pituitary and hypothalamic level Amenorrhea can result from congenital or acquired disease or dysfunction at any level in the system and can involve more than one mechanism eg PCOS involves a number of interrelated pathophysiologic mechanisms operating at the ovarian, pituitary and hypothalamic level

13. Accordingly, the many causes of amenorrhea can be categorized according to the site or level of the disorder or disturbance: Accordingly, the many causes of amenorrhea can be categorized according to the site or level of the disorder or disturbance: Disorders of the genital outflow tract and uterus Disorders of the genital outflow tract and uterus Disorders of the ovary Disorders of the ovary Disorders of the anterior pituitary Disorders of the anterior pituitary Disorders of the hypothalamus or central nervous system Disorders of the hypothalamus or central nervous system

14. Evaluation of Amenorrhea a careful medical history and physical examination a careful medical history and physical examination In those with primary or secondary amenorrhea having a patent vagina and visible cervix, the likelihood of a genital outflow tract abnormality is very small. In those with primary or secondary amenorrhea having a patent vagina and visible cervix, the likelihood of a genital outflow tract abnormality is very small. The only possibilities that need be considered are cervical stenosis and intrauterine adhesions (Asherman syndrome) or other endometrial damage that may result from surgical trauma or infection. The only possibilities that need be considered are cervical stenosis and intrauterine adhesions (Asherman syndrome) or other endometrial damage that may result from surgical trauma or infection. In those with primary amenorrhea In those with primary amenorrhea Imperforate Hymen Imperforate Hymen Transverse Vaginal Septum Transverse Vaginal Septum Müllerian Agenesis Müllerian Agenesis Androgen Insensitivity Syndrome Androgen Insensitivity Syndrome

15. In women with normal genital tract anatomy and no relevant history to suggest the possibility of cervical stenosis or Asherman syndrome, disorders of the genital outflow tract and uterus can be excluded and further stepwise evaluation is required to determine the cause of amenorrhea. In women with normal genital tract anatomy and no relevant history to suggest the possibility of cervical stenosis or Asherman syndrome, disorders of the genital outflow tract and uterus can be excluded and further stepwise evaluation is required to determine the cause of amenorrhea. Attention now may be focused on the next level of the reproductive system, the ovary. Attention now may be focused on the next level of the reproductive system, the ovary.

16. Abnormalities of ovarian function are the most common overall cause of amenorrhea and include a wide variety of disorders ranging from simple chronic anovulation, as in women with PCOS, obesity, thyroid disorders and hyperprolactinemia, to complete ovarian failure relating to chromosomal abnormalities or other genetic disorders such as Fragile X (FMR1) premutations and galactosemia, autoimmune disease, radiation or chemotherapy. Abnormalities of ovarian function are the most common overall cause of amenorrhea and include a wide variety of disorders ranging from simple chronic anovulation, as in women with PCOS, obesity, thyroid disorders and hyperprolactinemia, to complete ovarian failure relating to chromosomal abnormalities or other genetic disorders such as Fragile X (FMR1) premutations and galactosemia, autoimmune disease, radiation or chemotherapy.

17. Serum Estradiol Concentration-40 pg/mL clearly suggests the presence of functional ovarian follicles but also is common during a premature or normal perimenopause and occurs sporadically in women with hypothalamic amenorrhea. Serum Estradiol Concentration-40 pg/mL clearly suggests the presence of functional ovarian follicles but also is common during a premature or normal perimenopause and occurs sporadically in women with hypothalamic amenorrhea. estrogenic” cervical mucus estrogenic” cervical mucus progestin challenge test progestin challenge test endometrial thickness,- 6 mm endometrial thickness,- 6 mm A high serum FSH concentration is a reliable indication of ovarian follicular depletion or failure A high serum FSH concentration is a reliable indication of ovarian follicular depletion or failure

18. Hypogonadotropic state: Prepubertal, Hypothalamic or pituitary dysfunction Hypogonadotropic state: Prepubertal, Hypothalamic or pituitary dysfunction Serum FSH<5 IU/L Serum LH<5 IU/L Serum FSH<5 IU/L Serum LH<5 IU/L Hypergonadotropic state: Postmenopausal, Castrate, or Ovarian failure Hypergonadotropic state: Postmenopausal, Castrate, or Ovarian failure Serum FSH >20 IU/L Serum LH >40 IU/L Serum FSH >20 IU/L Serum LH >40 IU/L Normal Normal Serum FSH 5–20 IU/L Serum LH 5–20 IU/L Serum FSH 5–20 IU/L Serum LH 5–20 IU/L

19. When evaluation reveals clear evidence of normal ovarian estrogen production and the serum FSH level also is normal, the diagnosis of chronic anovulation is established. When evaluation reveals clear evidence of normal ovarian estrogen production and the serum FSH level also is normal, the diagnosis of chronic anovulation is established. thyroid disorders thyroid disorders prolactin disorders prolactin disorders PCOS, PCOS, obesity, obesity, stress or exercise, and stress or exercise, and reproductive aging. reproductive aging.

20. Chronic Anovulation With inappropriate steroid feedback With inappropriate steroid feedback Functional androgen excess (PCOS) Functional androgen excess (PCOS) Adrenal Hypoplasia Adrenal Hypoplasia Neoplasms producing androgens or estrogens Neoplasms producing androgens or estrogens Neoplasms producing hCG (including trophoblastic disease) Neoplasms producing hCG (including trophoblastic disease) Liver and renal disease Liver and renal disease Obesity Obesity Other endocrine disorders Other endocrine disorders Thyroid dysfunction Thyroid dysfunction Adrenal hyperfunction Adrenal hyperfunction

21. Chronic Anovulation Hypothalamic Hypothalamic Psychogenic, including pseudocyesis Psychogenic, including pseudocyesis Exercise-associated Exercise-associated Eating disorders, nutritional Eating disorders, nutritional 2° to systemic illness 2° to systemic illness Hypothalamic neoplasms Hypothalamic neoplasms Pituitary Pituitary Isolated gonadotropin deficiency (including Kallmann syndrome) Isolated gonadotropin deficiency (including Kallmann syndrome) Hypopituitarism Hypopituitarism Pituitary neoplasms, including microadenomas Pituitary neoplasms, including microadenomas

22. When evaluation reveals clear evidence of low ovarian estrogen production and the serum FSH level is consistently high, the diagnosis of ovarian failure is established. When evaluation reveals clear evidence of low ovarian estrogen production and the serum FSH level is consistently high, the diagnosis of ovarian failure is established. Ovarian Failure Ovarian Failure

23. Premature Ovarian Failure Cytogenetic Alterations of the X Chromosome Cytogenetic Alterations of the X Chromosome Mutations of Specific Genes Mutations of Specific Genes Enzymatic Defects Enzymatic Defects Steroidogenic enzyme defects Steroidogenic enzyme defects 17α-Hydroxylase or 17,20-lyase deficiency 17α-Hydroxylase or 17,20-lyase deficiency 20,22-Desmolase deficiency 20,22-Desmolase deficiency Aromatase deficiency Aromatase deficiency Galactosemia Galactosemia Defects in Gonadotropin Secretion or Action Defects in Gonadotropin Secretion or Action Receptor and post-receptor defects Receptor and post-receptor defects Secretion of biologically inactive gonadotropin Secretion of biologically inactive gonadotropin α- or β-Subunit defects α- or β-Subunit defects

24. Premature Ovarian Failure Immune Dysfunction Immune Dysfunction Association with other autoimmune disorders (15-20% of cases, 4% with steroidogenic cell autoimmunity) Association with other autoimmune disorders (15-20% of cases, 4% with steroidogenic cell autoimmunity) Isolated Isolated In association with congenital thymic aplasia In association with congenital thymic aplasia Physical Insults Physical Insults Chemotherapeutic (especially alkylating) agents Chemotherapeutic (especially alkylating) agents Ionizing radiation Ionizing radiation Viral agents Viral agents Surgical extirpation Surgical extirpation Gonadotropin-Secreting Pituitary Tumors (Extremely Rare) Gonadotropin-Secreting Pituitary Tumors (Extremely Rare) Idiopathic Idiopathic

25. all patients under age 30 with a diagnosis of ovarian failure, a karyotype should be obtained to exclude chromosomal translocations, deletions, and mosaicism all patients under age 30 with a diagnosis of ovarian failure, a karyotype should be obtained to exclude chromosomal translocations, deletions, and mosaicism A karyotype also identifies those having a Y chromosome in whom gonadectomy is indicated due to the risk for malignant transformation (20–30%). A karyotype also identifies those having a Y chromosome in whom gonadectomy is indicated due to the risk for malignant transformation (20–30%). FMR1- fragile X FMR1- fragile X the presence of anti-adrenal antibodies strongly implies autoimmune oophoritis as the cause of POF and identifi es women who should be carefully evaluated and followed to exclude adrenal insuffi ciency- Anti-CYP21 the presence of anti-adrenal antibodies strongly implies autoimmune oophoritis as the cause of POF and identifi es women who should be carefully evaluated and followed to exclude adrenal insuffi ciency- Anti-CYP21

26. When estrogen levels are clearly low, a serum FSH level in the low normal range (5–10 I/L) When estrogen levels are clearly low, a serum FSH level in the low normal range (5–10 I/L) When there is no clear explanation for hypogonadotropic hypogonadism (e.g., significant physical, nutritional, or emotional stress) or for hyperprolactinemia (e.g., medications), further evaluation with imaging is indicated to exclude tumors and to help distinguish between pituitary and hypothalamic causes. When there is no clear explanation for hypogonadotropic hypogonadism (e.g., significant physical, nutritional, or emotional stress) or for hyperprolactinemia (e.g., medications), further evaluation with imaging is indicated to exclude tumors and to help distinguish between pituitary and hypothalamic causes. The method of choice is MRI (with gadolinium contrast) because it is more sensitive and accurate than other imaging techniques for detection of abnormalities within and near the sella turcica. The method of choice is MRI (with gadolinium contrast) because it is more sensitive and accurate than other imaging techniques for detection of abnormalities within and near the sella turcica.

27. The routine endocrine evaluation of women with amenorrhea includes the measurement of serum The routine endocrine evaluation of women with amenorrhea includes the measurement of serum TSH, TSH, prolactin, prolactin, FSH FSH E2 E2 Women with pituitary macroadenomas require additional evaluation, including a serum free T4, IGF-1 (GH deficiency), and morning cortisol level (6:00–9:00 A.M.) ( Adrenal insufficiency). Women with pituitary macroadenomas require additional evaluation, including a serum free T4, IGF-1 (GH deficiency), and morning cortisol level (6:00–9:00 A.M.) ( Adrenal insufficiency).

28. Diagnosis History and physical examination History and physical examination Body dimensions and habitus Body dimensions and habitus Distribution and extent of terminal androgen- stimulated body hair Distribution and extent of terminal androgen- stimulated body hair Extent of breast development by Tanner staging and the presence or absence of any breast secretions Extent of breast development by Tanner staging and the presence or absence of any breast secretions External and internal genitalia External and internal genitalia FSH, TSH, and prolactin FSH, TSH, and prolactin progestin challenge progestin challenge total testosterone and dehydroepiandrosterone sulfate total testosterone and dehydroepiandrosterone sulfate

29. Etiology of Abnormal Uterine Bleeding Organic causes Organic causes Associated with disorders of the reproductive tract Associated with disorders of the reproductive tract Pregnancy-related disorders Pregnancy-related disorders Malignancies Malignancies Benign uterine abnormalities (i.e., fibroids, polyps) Benign uterine abnormalities (i.e., fibroids, polyps) Iatrogenic causes (i.e., IUDs, estrogens) Iatrogenic causes (i.e., IUDs, estrogens) Lower genital tract disease Lower genital tract disease Functional ovarian cysts and other benign ovarian neoplasms Functional ovarian cysts and other benign ovarian neoplasms Systemic disease Systemic disease Coagulation disorders (Primary or secondary) Coagulation disorders (Primary or secondary) Thyroid dysfunction Thyroid dysfunction Liver disease Liver disease Dysfunctional (anovulatory) uterine bleeding (DUB) Dysfunctional (anovulatory) uterine bleeding (DUB)

30. Abnormal Uterine Bleeding Menorrhagia (hypermenorrhea) is heavy or prolonged menstrual flow Menorrhagia (hypermenorrhea) is heavy or prolonged menstrual flow submucous myomas, submucous myomas, complications of pregnancy, complications of pregnancy, adenomyosis, adenomyosis, IUDs, IUDs, endometrial hyperplasias, endometrial hyperplasias, malignant tumors, and dysfunctional bleeding are causes of menorrhagia. malignant tumors, and dysfunctional bleeding are causes of menorrhagia.

31. Abnormal Uterine Bleeding Hypomenorrhea (cryptomenorrhea) is unusually light menstrual flow, sometimes only spotting. Hypomenorrhea (cryptomenorrhea) is unusually light menstrual flow, sometimes only spotting. An obstruction such as hymenal or cervical stenosis An obstruction such as hymenal or cervical stenosis Uterine synechiae (Asherman’s syndrome) Uterine synechiae (Asherman’s syndrome) oral contraceptives occasionally oral contraceptives occasionally

32. Abnormal Uterine Bleeding Metrorrhagia (intermenstrual bleeding) is bleeding occurring at any time between menstrual periods. Metrorrhagia (intermenstrual bleeding) is bleeding occurring at any time between menstrual periods. Ovulatory bleeding occurs at midcycle as spotting and can be documented with basal body temperatures. Ovulatory bleeding occurs at midcycle as spotting and can be documented with basal body temperatures. Endometrial polyps and endometrial and cervical carcinomas Endometrial polyps and endometrial and cervical carcinomas Exogenous estrogen administration Exogenous estrogen administration

33. Abnormal Uterine Bleeding Polymenorrhea Polymenorrhea Menometrorrhagia Menometrorrhagia Oligomenorrhea Oligomenorrhea Contact bleeding (postcoital bleeding) Contact bleeding (postcoital bleeding) Cervical cancer Cervical cancer Cervical eversion, Cervical eversion, cervical polyps, cervical polyps, cervical or vaginal infection (eg, due to Trichomonas), or atrophic vaginitis cervical or vaginal infection (eg, due to Trichomonas), or atrophic vaginitis

34. Etiology of Abnormal Uterine Bleeding DUB DUB results from a functional abnormality of the hypothalamic-pituitary-ovarian axis results from a functional abnormality of the hypothalamic-pituitary-ovarian axis the frequency of the various causes of AUB varies with the age of the patient. the frequency of the various causes of AUB varies with the age of the patient. DUB is more common early and late in the reproductive years. DUB is more common early and late in the reproductive years.

35. Causes of DUB Prepuberty Prepuberty Newborn girls sometimes spot for a few days after birth because of placental estrogenic stimulation of the endometrium in utero. Newborn girls sometimes spot for a few days after birth because of placental estrogenic stimulation of the endometrium in utero. Withdrawal of the estrogen at birth leads to sloughing of the endometrium. Withdrawal of the estrogen at birth leads to sloughing of the endometrium. Accidental trauma to the vulva or vagina is the most common cause of bleeding during childhood. Accidental trauma to the vulva or vagina is the most common cause of bleeding during childhood. Vaginitis with spotting, most often because of irritation from a foreign body, also may occur. Vaginitis with spotting, most often because of irritation from a foreign body, also may occur. Prolapse of the urethral meatus and tumors of the genital tract also must be considered in the differential diagnosis. Prolapse of the urethral meatus and tumors of the genital tract also must be considered in the differential diagnosis.

36. Causes of DUB When the bleeding is due to the ingestion of estrogen-containing drugs (typically oral contraceptives) by children, there is rarely significant pubertal development. When the bleeding is due to the ingestion of estrogen-containing drugs (typically oral contraceptives) by children, there is rarely significant pubertal development. Sexual abuse always must be considered in the young girl presenting with abnormal bleeding. Sexual abuse always must be considered in the young girl presenting with abnormal bleeding. Thus, it is clear that most of the prepubertal causes of bleeding are really not uterine in origin. Thus, it is clear that most of the prepubertal causes of bleeding are really not uterine in origin.

37. Causes of DUB Adolescents Adolescents as many as half of all menstrual cycles are anovulatory when menses begin as many as half of all menstrual cycles are anovulatory when menses begin Typically, anovulatory bleeding occurs at intervals longer than normal menstrual cycles, while bleeding due to organic causes tends to occur more frequently than regular menses. Typically, anovulatory bleeding occurs at intervals longer than normal menstrual cycles, while bleeding due to organic causes tends to occur more frequently than regular menses. In most cases of anovulatory bleeding beginning in adolescence, there is spontaneous resolution. In most cases of anovulatory bleeding beginning in adolescence, there is spontaneous resolution. However, it is important to remember that up to 20% of patients with AUB during the teenage years have a primary coagulation disorder. However, it is important to remember that up to 20% of patients with AUB during the teenage years have a primary coagulation disorder. It is also important to rule out pregnancy-related bleeding during the reproductive years It is also important to rule out pregnancy-related bleeding during the reproductive years

38. Causes of DUB Woman over the age of 40 Woman over the age of 40 Malignancy Malignancy Most causes of such bleeding are benign Most causes of such bleeding are benign Endometrial hyperplasia clearly is a possibility in women who do not ovulate on a regular basis, even at a much earlier age than 40 Endometrial hyperplasia clearly is a possibility in women who do not ovulate on a regular basis, even at a much earlier age than 40 The finding of endometrial hyperplasia after the menopause always should result in a search for a source of estrogen, either from exogenous therapy or from an endogenous (commonly ovarian) neoplasm. The finding of endometrial hyperplasia after the menopause always should result in a search for a source of estrogen, either from exogenous therapy or from an endogenous (commonly ovarian) neoplasm.

39. Diagnosis history history physical examination physical examination The hemodynamic stability of any patient with abnormal bleeding should be assessed. The hemodynamic stability of any patient with abnormal bleeding should be assessed. The pelvic examination will rule out obvious organic causes. The pelvic examination will rule out obvious organic causes. complete blood count to assess hematological status, complete blood count to assess hematological status, a platelet count and a platelet count and other coagulation studies to rule out a coagulation defect, other coagulation studies to rule out a coagulation defect, and thyroid function studies to rule out a thyroid abnormality. and thyroid function studies to rule out a thyroid abnormality.

40. Diagnosis endometrial biopsy endometrial biopsy is indicated in any woman over age 35 with AUB, is indicated in any woman over age 35 with AUB, in any woman with a prolonged history of irregular bleeding, and in any woman with a prolonged history of irregular bleeding, and in most, if not all, women with severe bleeding in most, if not all, women with severe bleeding endometrial thickness endometrial thickness there is almost never any significant pathology when the endometrial thickness is less than 5 mm there is almost never any significant pathology when the endometrial thickness is less than 5 mm sometimes termed saline infusion sonography (SIS), sometimes termed saline infusion sonography (SIS), hysteroscopy hysteroscopy

41. New Classification System for AUB at Reproductive Ages PALM-COEİN Classification PALM-COEİN Classification Polyp Polyp Adenomyosis Adenomyosis Leiomyoma, Leiomyoma, Malignity ve hyperplasia Malignity ve hyperplasia Coagolopathy Coagolopathy Ovulatuary dysfunction, Ovulatuary dysfunction, Endometrial Endometrial Iatrojenik Iatrojenik Nonclassified Nonclassified

42. PALM: PALM: Structurel Causes for AUB at reproductive ages Polyp (AUB-B) Polyp (AUB-B) Adenomyosis (AUB-A) Adenomyosis (AUB-A) Leiomyoma (AUB-L) Leiomyoma (AUB-L) Submucous myoma (AUB-L sm) Submucous myoma (AUB-L sm) Other myomas (AUB-Lo) Other myomas (AUB-Lo) Malignity or hyperplasia (AUB-M) Malignity or hyperplasia (AUB-M)

43. COEİN: COEİN: Nonstructurel Causes Coagulopathy (AUB-C) Coagulopathy (AUB-C) Ovulatuary dysfunction(AUB-O) Ovulatuary dysfunction(AUB-O) Endometrial (AUB-E) Endometrial (AUB-E) Iatrogenik (AUB-I) Iatrogenik (AUB-I) Nonclassified (AUB-N) Nonclassified (AUB-N)