1. Dr. Afaf Ibrahim AlNoury Associate professor of OBS & GYN King Abdul Aziz University Amenorrhea

2. Welcome ….

3. Amenorrhea

4. Few problem in gynecologic endocrinology are as challenging or taxing to the clinician as amenorrhea.

5. Definition of amenorrhea Any patient fulfilling the following criteria should be evaluated as having the clinical problem of amenorrhea: Any patient fulfilling the following criteria should be evaluated as having the clinical problem of amenorrhea: 1. No period by age 16 regardless of the presence of normal growth and development with the appearance secondary sexual characteristics. 2. No period by age 14 in the absence of growth or development of secondary sexual characteristics. 3. In a woman who has been menstruating, the absence of periods for a length of time equivalent to a total of at least 3 of the previous cycle intervals or 6 months of amenorrhea.

6. It is useful to employ a diagnostic evaluation that segregates causes of amenorrhea into the following compartments: It is useful to employ a diagnostic evaluation that segregates causes of amenorrhea into the following compartments: Compartment I: Compartment I: Disorders of the outflow or uterine target organ. Compartment II: Compartment II: Disorders of the ovary. Compartment III: Compartment III: Disorders of the anterior pituitary. Compartment IV: Compartment IV: Disorders of central nervous system (hypothalamic) factors.

7. Central nervous system Hypothalamus Anterior Pituitary Ovary Uterus environment menses Compartment IV Compartment III Compartment II Compartment I progesterone Estrogen LH FSH Gn RH

8. Evaluation of amenorrhea A careful history and physical examination should seek the following: A careful history and physical examination should seek the following: evidence for psychological dysfunction or emotional stress, family history of apparent genetic anomalies, signs of a physical problem with a focus on nutritional status, abnormal growth and development, the presence of a normal reproductive tract, and evidence for CNS disease. A patient with amenorrhea is then exposed to a combined therapeutic and laboratory dissection according to the depicted flow diagrams. evidence for psychological dysfunction or emotional stress, family history of apparent genetic anomalies, signs of a physical problem with a focus on nutritional status, abnormal growth and development, the presence of a normal reproductive tract, and evidence for CNS disease. A patient with amenorrhea is then exposed to a combined therapeutic and laboratory dissection according to the depicted flow diagrams. The initial step in the workup of the amenorrheic patient after excluding pregnancy begins with a measurement of thyroid-stimulating hormone (TSH), aprolactin level, and a pregestational challenge. The initial step in the workup of the amenorrheic patient after excluding pregnancy begins with a measurement of thyroid-stimulating hormone (TSH), aprolactin level, and a pregestational challenge. Step 1

9. Amenorrhea TSH Prolactin Presentational challenge + withdrawal bleed Normal prolactin Normal TSH An ovulation hypothyroidism Elevated TSH

10. There are two rare situations associated with a negative withdrawal response, despite the presence of adequate levels of endogenous estrogen. In both situations, the endometrium is decidualized and, therefore, it will not be shed following the withdrawal of exogenous progestin. There are two rare situations associated with a negative withdrawal response, despite the presence of adequate levels of endogenous estrogen. In both situations, the endometrium is decidualized and, therefore, it will not be shed following the withdrawal of exogenous progestin. Polycystic ovaries. Polycystic ovaries. Specific adrenal enzme deficiency. Specific adrenal enzme deficiency. All anovulatory patients require therapeutic management. All anovulatory patients require therapeutic management. Minimal therapy of anovulatory women requires the monthly administration of a progestational agent. Minimal therapy of anovulatory women requires the monthly administration of a progestational agent. If, at any time, an anovulatory patient fails to have withdrawal bleeding on a monthly progestin program, this is a sign (providing the patient is not pregnant ) that she has moved to the negative withdrawal bleed category. If, at any time, an anovulatory patient fails to have withdrawal bleeding on a monthly progestin program, this is a sign (providing the patient is not pregnant ) that she has moved to the negative withdrawal bleed category.

11. Step 2 Orally active estrogen is administered in quantity and duration certain to stimulate endometrial proliferation and withdrawal bleeding provided that a completely reactive uterus and patent outflow tract exist. Orally active estrogen is administered in quantity and duration certain to stimulate endometrial proliferation and withdrawal bleeding provided that a completely reactive uterus and patent outflow tract exist. If there is no withdrawal flow, the diagnosis of a defect in the compartment I systems (endometrium, outflow tract) can be made with confidence. If there is no withdrawal flow, the diagnosis of a defect in the compartment I systems (endometrium, outflow tract) can be made with confidence. If withdrawal bleeding does occur, one can assume that compartment I system have normal functional abilities if properly stimulated by estrogen. If withdrawal bleeding does occur, one can assume that compartment I system have normal functional abilities if properly stimulated by estrogen.

12. Step 3 Serum LH Serum FSH Clinical state 5-20 IU/L, with the ovulatory midcycle peak about 2 times the base level Normal adult female Less than 5 IU/L Hypogonadotropic state: prepubertal, hypothalamic, or pituitary dysfunction Less than 40 IU/L Greater than 20 IU/L Hypogonadotropic state: prepubertal, hypothalamic, or pituitary dysfunction This step involves an assay of the level of gonadotropins in the patient. This step involves an assay of the level of gonadotropins in the patient. Step 3 is designed to determine whether the lack of estrogen is due to a fault in the follicle (compartment II) or in the CNS-pituitary axis (compartments III and IV). Step 3 is designed to determine whether the lack of estrogen is due to a fault in the follicle (compartment II) or in the CNS-pituitary axis (compartments III and IV).

13. High Gonadotropins High gonadotropins accompanied by ovaries not contain follicles )overian failure) High gonadotropins accompanied by ovaries not contain follicles )overian failure) There are rare situation in which high gonadotropins can be accompanied by ovaries that contain follicles. There are rare situation in which high gonadotropins can be accompanied by ovaries that contain follicles. 1. On rare occasions, tumors can produce gonadotropins. 2. A single gonadotropin deficiency. 3. Due to a gonadotropin-secreting pituitary adenoma. 4. Duing the perimenopausal period 5. In the resistant or insensitive ovary syndrome 6. Secondary amenorrhea caused by premature ovarian failure can be due to autoimmune disease. 7. Calactosemia is a rare inherited autosomal recessive disorder of galactose metabolism due to a deficiency of galactose-1-phosphate uridyl transferase. 8. The final rare clinical situation is that associated with specific enzymatic deficiencies the 17-hydroxylase deficiency (P450c17) is present in both ovaries and the adrenal gland.

14. The need for chromosome evaluation All patients under the age of 30 who have been assigned the diagnosis of ovarian failure on the basis of elevated gondotropins must have a karyotype determination. All patients under the age of 30 who have been assigned the diagnosis of ovarian failure on the basis of elevated gondotropins must have a karyotype determination. The presence of mosaicism with a Y chromosome requires excision of the gonadal areas because the presence of any testicular component within the gonad carries with it a significant chance of malignant tumor formation. The presence of mosaicism with a Y chromosome requires excision of the gonadal areas because the presence of any testicular component within the gonad carries with it a significant chance of malignant tumor formation. Normal conadotropins Why is it that hypoestrogenic (negative progestational withdrawal) patients will frequently have normal circulating levels of FSH and LH as measured by immunoassay. Why is it that hypoestrogenic (negative progestational withdrawal) patients will frequently have normal circulating levels of FSH and LH as measured by immunoassay. The molecules are qualitatively altered and biologically inactive. The molecules are qualitatively altered and biologically inactive. Another very rare possibility is an inherited disorder of gonadotropin synthesis leading to the production of immunologically active but biologically inactive hormones. Another very rare possibility is an inherited disorder of gonadotropin synthesis leading to the production of immunologically active but biologically inactive hormones.

15. Low Gonadotropins If the gonadotrpin assay is abnormally low, or in the normal range, one final localization is required to distinguish between a pituitary (compartment III) or CNS-hypothalamic (compartment IV) cause for the amenorrhea. If the gonadotrpin assay is abnormally low, or in the normal range, one final localization is required to distinguish between a pituitary (compartment III) or CNS-hypothalamic (compartment IV) cause for the amenorrhea. This is achieved by imaging evaluation of the sella turcica for signs of abnormal. This is achieved by imaging evaluation of the sella turcica for signs of abnormal.

16. Amenorrhea TSH Prolactin Progestional challenge Galactorrhea TSH Prolactin coned-down view of sella Turcica - withdrawal+ withdrawalElevated TSH Normal prolactin normal TSH Prolactin > 100 or abnormal coned-down view Estrgen and progestin cycle - Withdrawal bleed+Withdrawal bleed FSH, LH assay low High normal Coned-down view of sella turcica Abnormal coned - view End organ problem Hypothalamic amenorrhea hypothyroidism Anovulation MRI Ovarian failure

17. Compartment I: Disorders of the Outflow Tract or Uterus Imperforate hymen Imperforate hymen Obliteration of the vaginal orifice, and lapses in continuity of the vaginal canal. Obliteration of the vaginal orifice, and lapses in continuity of the vaginal canal. The cervix or the entire uterus may be absent. The cervix or the entire uterus may be absent. The uterus be present, but the cavity absent. The uterus be present, but the cavity absent. The endometrium may be congenitally,lacking. The endometrium may be congenitally,lacking. A Sherman's syndrome Mullerian Anomalies Lack of mullerian development (mayer-Rokitansky-kuster syndrome) is the diagnosis for the individual with primay amenorrhea and no apparent vagina. Lack of mullerian development (mayer-Rokitansky-kuster syndrome) is the diagnosis for the individual with primay amenorrhea and no apparent vagina. Mullerian Agenesis

18. Androgen insensitivity (feminization) The male pseudohermaphrodite is a genetic and gonadal male with failure of virilization. The male pseudohermaphrodite is a genetic and gonadal male with failure of virilization. Transmission of this disorder is by means of an x-linked recessive gene that is responsible for the androgen intracellular receptor. Transmission of this disorder is by means of an x-linked recessive gene that is responsible for the androgen intracellular receptor. Differences between mullerian agenesis and Testicular feminization Testicular Feminization Mullerian agenesis 46,xy46,xxKaryotype Maternal x-linked recessive; 25% risk of affected child,25% risk of carrier Not known Heredity Absent to sparse Normal female Sexual hair Normal to slightly elevated male level Normal female Testosterone leve RareFrequent Other anomalies 5%incidence of malignant tumors Normal incidence Conadal neoplasis

19. Clinically, the diagnosis should be considered in: Clinically, the diagnosis should be considered in: 1. A female child with inguinal hernias because the testes are frequently partially descended. 2. A patient with primary amenorrhea and an absent uterus. 3. A patient with absent body hair. This syndrome is marked by a unique combination: This syndrome is marked by a unique combination: 1. Normal female phenotype. 2. Normal make karyotype. 46.XY. 3. Normal or slightly elevated mate blood testosterone levels and a high LH.

20. Compartment II: Disorders of the Ovary Problems in gonadal development can present with either primary or secondary amenorrhea from 30 to 40% of primary amenorrhea cases have gonadal streaks due to abnormal development:gonadal dysgensis. These patients can be grouped according to the following karyotypes: Problems in gonadal development can present with either primary or secondary amenorrhea from 30 to 40% of primary amenorrhea cases have gonadal streaks due to abnormal development:gonadal dysgensis. These patients can be grouped according to the following karyotypes: 50%-45,x 50%-45,x 25%-Mosaics 25%-Mosaics 20%-46,xx 20%-46,xx Turner syndrome Mosaicism XY conadal Dysgenesis Conadal agenesis The resistant Ovary syndrome Premature Ovarian Failure

21. Compartment III : disorders of the Anterior Pituitary Hypogonadism and delayed puberty deserve brain evaluation by MRI. Hypogonadism and delayed puberty deserve brain evaluation by MRI. Compartment IV:Central Nervous System Disorders Hypothalamic Amenorrhea Patients with hypothalamic amenorrhea (hypogonadotropic hypogonadism ) have a deficiency in GnRH pulsatile secretion. Patients with hypothalamic amenorrhea (hypogonadotropic hypogonadism ) have a deficiency in GnRH pulsatile secretion. Hypothalamic problems are usually diagnosed by exclusion of pituitary lesions and are the most common category of hypogonadotropic amenorrhea, a functional suppression of reproduction,often a psychobiologic response to life events. Hypothalamic problems are usually diagnosed by exclusion of pituitary lesions and are the most common category of hypogonadotropic amenorrhea, a functional suppression of reproduction,often a psychobiologic response to life events. The degree of GnRH suppression determines how these patients present clinically. The degree of GnRH suppression determines how these patients present clinically. Mild duppression can be associated with a marginal effect on reproduction, specifically an inadequate luteal phase. Mild duppression can be associated with a marginal effect on reproduction, specifically an inadequate luteal phase. Moderate suppression of Gn RH secretion can yield anovulation with menstrual irregularity, and profound suppression is manifested by hypothalamic amenorrhea. Moderate suppression of Gn RH secretion can yield anovulation with menstrual irregularity, and profound suppression is manifested by hypothalamic amenorrhea.

22. 1. Onset between ages 10 and 30. 2. Weight loss of 25% or weight below normal for age and height. 3. Special attitudes: Denial. Denial. Distorted body image. Distorted body image. Unusual hoarding or handing of food. Unusual hoarding or handing of food. 4. At least one of the following: Lanugo. Lanugo. Bradycardia, Bradycardia, Overactivity, Overactivity, Episodes of overeating (bulimia), Episodes of overeating (bulimia), Vomiting, which may be self disorder Vomiting, which may be self disorder 5. Amenorrhea 6. No known medical illness. 7. No other psychiatric disorder. 8. Other characteristics:  constipation.  Low blood pressure.  Hypercarotenemia.  Diabetes insipidus. Weight loss, anorexia, bulimia Diagnosis of Anorexia Nervosa

23. Exercise and Amenorrhea ↑CRH Stress ↑Endorphins ↓ T 3 ↓ T 4 ↓ TSH ↓ TRH ↓ GnRH ↑ACTH ↑ Corticol ↑ Somatostatin -

24. Inherited Genetic Defects 1- Amenorrhea and Anosmia, kallmann ’ s syndrome. 2- Molecular Explanations for Hypogonadotropic Amenorrhea. 3-Adrenal Hypopasia. 1- Amenorrhea and Anosmia, kallmann ’ s syndrome. 2- Molecular Explanations for Hypogonadotropic Amenorrhea. 3-Adrenal Hypopasia. Postpill Amenorrhea Hormone Therapy: The patient who is hypoestrogenic and who is not a candidate for induction of ovulation deserves hormone therapy. The patient who is hypoestrogenic and who is not a candidate for induction of ovulation deserves hormone therapy. This includes patients appropriately and diagnosed as having gonadal failure, patients with hypothalamic amenorrhea, and postgonadectomy patients. This includes patients appropriately and diagnosed as having gonadal failure, patients with hypothalamic amenorrhea, and postgonadectomy patients. * periodic measurements of bone density are worthwhile to assess adequacy of hormonal treatment and to provide evidence of lifestyle and dieting changes.

25. It is not enough to provide hormone therapy when disturbed mensrual function is secondary to psychobiologic stress responses. appropriate support and counseling are necessary to help patients develop coping mechanisms other than extreme dieting and exercise. It is not enough to provide hormone therapy when disturbed mensrual function is secondary to psychobiologic stress responses. appropriate support and counseling are necessary to help patients develop coping mechanisms other than extreme dieting and exercise. All available skills and resources should be utilized to promote healthy attitudes and healthy behaviors. All available skills and resources should be utilized to promote healthy attitudes and healthy behaviors. The presence of amenorrhea in athletes and recreational exercisers should be regarded as a sign of negative balance, a condition requiring appropriate interventions. The presence of amenorrhea in athletes and recreational exercisers should be regarded as a sign of negative balance, a condition requiring appropriate interventions. Note:

26. Thank you and best regards