Amenorrhea is defined as the absence of menstruation. It can be primary, occurring before age 16, or secondary, occurring after menstruation has started. Possible causes of amenorrhea include issues with the hypothalamus, pituitary gland, ovaries, or uterus. Hypothalamic amenorrhea can be caused by stress, eating disorders, excessive exercise, or certain drugs. Evaluation of amenorrhea involves assessing sexual development, hormone levels, imaging tests, and response to medication challenges to determine the underlying cause. Treatment depends on the specific cause but may include hormone replacement, surgery, or lifestyle changes.

1. Amenorrhea Zhanghuiying Department Of Obstetrics & Gynecology Tianjin Medical University General Hospital

2. Definition ★ Amenorrhea is the absence of menstruation. Primary Amenorrhea Absence of menses by age 16 with normal secondary sexual characteristics. Absence of menses by age 14 without secondary sexual development. Secondary Amenorrhea Absence of menses for 6 months in a previously menstruating female or 3 normal intervals in a woman with oligomenorrhea.

3. Events of Puberty Thelarche (breast development) Requires estrogen Pubarche/adrenarche (pubic hair development) Requires androgens Menarche （ the first menses) Requires: GnRH from the hypothalamus FSH and LH from the pituitary Estrogen and progesterone from the ovaries Normal outflow tract

4. Possible results of amenorrhea Cannot conceive Lead to osteoporosis and genital atrophy Increased endometrial hyperplasia which can increase the possibility of endometrial carcinoma from unopposed estrogen secretion Without secondary sexual characteristics may give rise to major social and psychosexual problems.

5. Classification of amenorrhea hypothalamic amenorrhea pituitary amenorrhea ovarian amenorrhea uterine amenorrhea

6. Etiology - hypothalamic amenorrhea Psychological stress Anorexia nervosa, weight loss Increased exercise levels Kallmann syndrome -congenital absence of GnRH drug-induced amenorrhea: anti-psychotics, reserpine, Contracepti ve Space-occupying lesion of CNS

7. Weight-related amenorrhoea Anorexia Nervosa A body mass index (BMI) <17 kg/m ²  menstrual irregularity and amenorrhea Hypothalamic suppression Mean age onset 13-14 yrs (range 10-21 yrs) Low estradiol  risk of osteoporosis

8. Exercise-associated amenorrhoea Common in women who participate in sports (e.g. competitive athletes, ballet dancers) Eating disorders have a higher prevalence in female athletes than non-athletes Hypothalamic disorder caused by abnormal gonadotrophin-releasing hormone pulsatility, resulting in impaired gonadotrophin levels, particularly LH, and subsequently low estrogen levels

9. Contraception related amenorrhea Post-pill amenorrhea is not an entity Depot medroxyprogesterone acetate Up to 80 % of women will have amenorrhea after 1 year of use. It is reversible (estrogen deficiency) A minority of women taking the progestogen-only pill may have reversible long term amenorrhoea due to complete suppression of ovulation

10. Etiology - pituitary amenorrhea tumor Empty sella syndrome Sheehan syndrome

11. Sheehan ’s syndrome Pituitary inability to secrete gonadotropins Pituitary necrosis following massive obstetric hemorrhage is most common cause in women Diagnosis : History and  E2,FSH,LH + other pituitary deficiencies （ TSH Thyroid Stimulating Hormone and ACTH adrenocorticotropic hormone ） Treatment : Replacement of deficient hormones

12. Etiology - ovarian amenorrhea ◆ Gonadal dysgenesis Chromosomally incompetent - Classic turner ’s syndrome (45XO) - Turner variants (45XO/46XX),(46X- abnormal X) - Mixed gonadal dysgenesis (45XO/46XY) Chromosomally competent - 46XX (Pure gonadal dysgenesis ) - 46XY (Swyer’s syndrome) ◆ resistant ovary syndrome ◆ Premature ovarian failure ◆ Polycystic ovary syndrome

13. Typical features of Turner’s Syndrome Sexual infantilism and short stature High FSH and LH levels. • Bilateral streaked gonads. • Karyotype - 80 % 45, X0 - 20% mosaic forms (46XX/45X0)

14. Turner’s syndrome ( Classic 45-XO) Mosaic (46-XX / 45-XO)

15. Ovarian dysgenesis streak gonad

16. Premature ovarian failure Manopause occurs before 40 years old. Serum estradiol < 50 pg/ml and FSH > 40 IU/ml on repeated occasions

17. Etiology uterine amenorrhea Absence of uterus Asherman syndrome anatomic abnormalities of the reproductive tract Imperforate Hymen

18. Asherman’s syndrome History of pregnancy associated D&C Rarely after CS , myomectomy T.B endometritis, Diagnosis : HSG or hysterescopy Treatment : lysis of adhesions; D&C or hysterescopy + estrogen therapy Hysterosalpingography Uterine synechiae

19. Imperforate Hymen

20. Mayer-Rokitansky-Kuster-Hauser Syndrome (utero-vaginal agenesis) 15% of primary amenorrhea Normal secondary development & external female genitalia Normal female range testosterone level Absent uterus and upper vagina & normal ovaries Karyotype 46-XX 15 ~ 30% renal, skeletal and middle ear anomalies

21. Androgen Insensitivity Normal breasts but no sexual hair Normal looking female external genitalia Absent uterus and upper vagina Karyotype 46, XY Male range testosterone level Treatment : gonadectomy after puberty + HRT

22. congenital adrenal hyperplasia Autosomal recessive trait Most common form is due to 21-hydroxylase deficiency Mild forms Closely resemble PCO S Severe forms show Signs of severe androgen excess High 17-OH-progesterone blood level abn ormal looking female external genitalia Presence of uterus and upper vagina Treatment : cortisol replacement and Corrective surgery

23. Other causes of Secondary Amenorrhea Pituitary disorders Hyperprolactinemia Prolactinoma Medications Renal failure Hypoprolactinemia Pituitary resection Sheehan’s syndrome Thyroid disorders Hyper- or hypothyroidism

24. Diagnosis of Amenorrhea

25. Diagnosis History Physical examination Physical examination begins with vital signs, including height and weight, and with sexual maturity ratings Laboratory evaluation

26. Evaluation of Primary Amenorrhea Physical exam to determine presence of uterus FSH Karyotype

27. Primary Amenorrhea Is there normal development of secondary sexual characteristics? NO Think hypogonadism or hypogonadotropism

28. Amenorrhea with Immature Secondary Characteristics FSH Serum level Low / normal High Hypogonadotropic hypogonadism Gonadal dysgenesis

29. Hypogonadism (gonadal failure) Gonadal dysgenesis Chromosomally abnormal - Classic T urner ’s syndrome (45XO) - Turner variants (45XO/46XX),(46X-abnormal X) - Mixed gonadal dysgenesis (45XO/46XY ) Chromosomally normal - 46XX (Pure gonadal dysgenesis ) - 46XY (Swyer’s syndrome ) Irradiation Chemotherapy galactosemia Note: gonadotropins (FSH/LSH) will be high, similar to menopause

30. Hypogonadotropism Hypothalamic dysfunction Kallmann’s syndrome Anorexia nervosa Space-occupying lesion of CNS Pituitary damage (surgery/radiation) Constitutional delay

31. Primary Amenorrhea Is there normal development of secondary sexual characteristics? YES Think Pregnancy Mullerian anomaly Androgen insensitivity

32. Mullerian Anomalies Mullerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome) Imperforate hymen Transverse vaginal septum

33. Evaluation of Secondary Amenorrhea History Nutrition/exercise habits, weight change Sexual/contraceptive practice History of uterine/cervical surgery Physical exam Height/weight Hirsutism Galactorrhea Estrogen status of tissues Laboratory hCG  PRL & TSH  progesterone challenge  FSH  if high  karyotype

34. Negative Pregnancy.test TSH ,PROLACTIN, Progesterone challenge test withdrawal bleeding without withdrawal bleeding hypoestrogenic compromised outflow tract +ve.est/progest challenge test -ve.est/progest challenge test FSH>30-40 Normal FSH HSG OR hysteroscopy Asherman’s FSH low . repeat Repeat+serum estrogen level PreOvFailure hypothalamic-pituitary failure anovulation Procedures of Diagnosis Secondary Amenorrhea

35. Treatment -- Selfstudy treatment varies depending upon the causes of the amenorrhea.