1. AMENORRHEA Obstetrics & Gynecology Hospital of Fudan University
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 2 3 4 definition and Classification of amenorrhea
etiology of amenorrhea 3
Diagnosis of amenorrhea 4
The management of amenorrhea
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
absence of 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
whether secondary 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 examination    5α-reductase deficiency, 17, 20-lyase deficiency, or 17α-hydroxylase deficiency in XY individual    Congenital lipoid adrenal hyperplasia    Luteinizing hormone receptor defect
Hypergonadotropic hypogonadism   Gonadal 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 individual Hypogonadotropic hypogonadism    Physiologic 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. 2. Androgen insensitivity 3. True hermaphrodism 4. Absent endometrium
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
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. D Trial of estrogen/progesterone to stimulate bleeding
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
The answer is B.
In this patient with primary amenorrhea, breast development, and a blind vaginal pouch, the most appropriate next step is a karyotype to differentiate between müllerian agenesis and complete androgen insensitivity.
A testosterone level can also be used to differentiate between the two; however, this was not listed as an option.
Absence of pubic and axillary hair is seen with complete androgen insensitivity, and can also be used to differentiate from müllerian agenesis, but confirmation with testosterone or karyotype is necessary.
It is key to differentiate müllerian agenesis from complete androgen insensitivity as it is imperative to remove the Y-containing gonad in the latter due to the risk of a germ cell malignancy in this tissue.
Obstetrics & Gynecology Hospital of Fudan University

39. A Premature ovarian insufficiency B Polycystic ovary syndrome
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
The answer is B
This woman fits the criteria for PCOS with her amenorrhea and clinical (acne) and biochemical hyperandrogenism (testosterone is elevated).
Premature ovarian insufficiency would be suggested by elevated FSH, not LH.
Her LH is elevated, but this elevated LH to FSH ratio is often seen with PCOS.
Her laboratory test is not consistent with hypothyroidism, a prolactinoma or hypothalamic amenorrhea.
Obstetrics & Gynecology Hospital of Fudan University

40. A Polycystic ovary syndrome B Müllerian agenesis
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
The answer is C
The most likely explanation for this patient’s amenorrhea is functional hypothalamic amenorrhea given her reported exercise routine and height and weight.
PCOS is another possible explanation, but is less likely given; lacks any signs of androgen excess.
A prolactinoma would also be on the differential, but she does not report galactorrhea.
Müllerian agenesis is ruled out as this is a case of secondary amenorrhea; she had menstrual cycles in the past.
Obstetrics & Gynecology Hospital of Fudan University

41. B Polycystic ovary syndrome C Functional hypothalamic amenorrhea
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
The answer is D
This patient presents with a classic story for Sheehan’s syndrome, or infarction of the pituitary caused by profound postpartum hemorrhage.
Her inability to breastfeed is a classic presentation of this disorder. Her symptoms of fatigue and constipation in addition to amenorrhea suggest panhypopituitarism not just functional hypothalamic amenorrhea, and laboratory test confirms this suspicion with profoundly low thyroid and prolactin levels in addition to suppressed gonadotropins.
Asherman’s syndrome could be an explanation for her amenorrhea given her surgical procedure; however,it would not explain her low FSH or other symptomatology.
Obstetrics & Gynecology Hospital of Fudan University

42. E Trial of oral contraceptive pills
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
The answer is C.
This patient presents with premature ovarian insufficiency since her laboratory testing reveals an elevated FSH with a low estradiol.
A karyotype is the next step in any woman who presents with premature ovarian insufficiency under the age of 30. Given her short stature and secondary amenorrhea, she most likely has a mosaic Turner’s syndrome (45X/46XX). When requesting a karyotype, it is important for the laboratory to know you are looking for a mosaic pattern as more metaphase spreads need to be counted.
If the karyotype was normal, then testing for autoimmune ovarian insufficiency would be indicated.
Pelvic ultrasound would not be the first test.
Total testosterone would not be indicated unless there were signs of hyperandrogenism.
A pituitary MRI would be indicated with low gonadotropins associated with low estradiol (hypogonadotropic amenorrhea).
A trial of oral contraceptive pills would just tell you she has a uterus and patent outflow tract but would not help diagnose the cause of her amenorrhea. However, combined oral contraceptive pills can be used as treatment for premature ovarian insufficiency.
Obstetrics & Gynecology Hospital of Fudan University

43. END
Obstetrics & Gynecology Hospital of Fudan University