Primary amenorrhea is usually caused by genetic or anatomical abnormalities. The most common cause is gonadal dysgenesis, occurring in 43% of primary amenorrhea cases. Other common causes include Müllerian agenesis (15%), physiological delay of puberty (14%), polycystic ovary syndrome (7%), and isolated gonadotropin releasing hormone deficiency (5%). Secondary amenorrhea can be caused by decreased ovarian function (hypogonadism) due to low gonadotropin stimulation (hypogonadotropic hypogonadism) or primary ovarian failure (hypergonadotropic hypogonadism). Functional hypothalamic amenorrhea is a common cause of acquired secondary

1. Amenorrhea
• Normal menses require adequate ovarian production of steroid hormones
• The endometrium must be able to respond normally to hormonal stimulation,
and the cervix, vagina, and introitus must be present and patent.
Definition
• Amenorrhea has classically been defined as primary (no prior menses) or
secondary (cessation of menses).
• Primary amenorrhea is defined as 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.

2. Prevalence
• Pathologic amenorrhea
o3 to 4 % in reproductive-aged populations
• Physiologic amenorrhea
oPrior to puberty
oPregnancy and lactation
oMenopause
oContinuous COCs administration

3. Definition
• Primary amenorrhea is defined as the absence of menses at age 15
years in the presence of normal growth and secondary sexual
characteristics. ( up to date 2018)
• Secondary amenorrhea is absence of menses for more than three
months in girls or women who previously had regular menstrual
cycles or six months in girls or women who had irregular menses.

4. Secondary amenorrhea for 3 months or oligomenorrhea involving fewer than nine cycles a year is also
investigated (American Society For Reproductive Medicine, 2008).
Evaluation is considered for an adolescent:
(1) who has not menstruated by age 15 or within 3 years of thelarche or
(2) has not menstruated by age 14 and shows signs of hirsutism, excessive exercise, or eating disorder
(ACOG-2017)

5. CLASSIFICATION SYSTEM
• Decreased ovarian function (hypogonadism) may result either from a
lack of stimulation by the gonadotropins (hypogonadotropic
hypogonadism) or from primary failure of the ovary
(hypergonadotropic hypogonadism)

7. ANATOMIC DISORDERS
Inherited Disorder
• It is frequent in adolescents, and pelvic anatomy is abnormal
in approximately 15 percent of women with primary amenorrhea

8. Primary amenorrhea is usually the result of a genetic or anatomical abnormality.

9. A. Gonadal dysgenesis- 43 percent
B. Müllerian agenesis -15 percent
C. Physiological delay of puberty (constitutional or illness -14 percent)
D. Polycystic ovary syndrome (PCOS) – 7 percent
E. Isolated GnRH deficiency – 5 percent (extremely rare)
F. Transverse vaginal septum – 3 percent
G. Weight loss/anorexia nervosa – 2 percent
H. Hypopituitarism – 2 percent
*What is the most common etiology for primary amenorrhea?
*In a large case series of primary amenorrhea, up to date 2018

12. Lower Outflow Tract Obstruction
• Amenorrhea is associated with imperforate hymen (1 in 2000
women), a complete transverse vaginal septum (1 in 70,000
women), or isolated vaginal atresia
• Thus , the amount of uterine bleeding is normal, but
its normal path or egress is obstructed or absent
• Moreover, in women with out flow blockage, an increase in
retrograde menstruation may lead to endometriosis development
 Patients with out flow obstruction have a 46,XX karyotype, female secondary sexual characteristics,
and normal ovarian function

13. Müllerian Defects
• Patients have a 46,XX karyotype and normal ovarian function.

14. Anatomic defects that may lead to amenorrhea.
the müllerian ducts give rise
to the upper vagina, cervix, uterine
corpus, and fallopian tubes.
In complete müllerian agenesis, of
ten called
Mayer-Rokitansky-Kuster-Hauser
syndrome, patients fail to
develop any müllerian structures, and
examination reveals only a vaginal
dimple

15. Importantly, complete müllerian agenesis may be confused with complete androgen insensitivity syndrome.

16. Acquired Disorders
Cervical Stenosis
 Stenosis most commonly involves the internal os
• Causes may be:
 D and C
 Conization
 LEEP
 Infection
 Neoplasia
 Radiation

17. Intrauterine Adhesions
Asherman syndrome
In a series of 1856 women with
Asherman syndrome, 88 percent
followed postabortal or postpartum
uterine curettage
Destruction of the basal endometrium
Causes may be:
• vigorous curettage
• Miscarriage complicated by infection
• Metroplasty, myomectomy, or
cesarean delivery, or infection related
to an intrauterine device
• tuberculous endometritis
• Diagnosis can be made with either
HSG or SIS
• Definitive diagnosis requires
hysteroscopy
• HSG is used to concomitantly asses
tubal patency
• Intrauterine adhesions
characteristically appear as irregular,
angulated filling defects within the
cavity
• Rx-hysteroscopic lysis of adhesions

18. HYPERGONADOTROPIC HYPOGONADISM
• It implies primary dysfunction within the ovary rather than
hypothalamic or pituitary dysfunction
• It can also be termed premature ovarian failure (POF)

19. Premature ovarian failure
• POF is defined as loss of oocytes and the surrounding support cells
prior to age 40 years.
• The diagnosis is determined by two serum FSH levels that measure
greater than a threshold range of 30 to 40 mIU/mL and are obtained
at least 1 month apart.

20. POF
• Incidence: 1/1000 in age <30 yrs and 1/100 in age <40 yrs

21. Heritable Disorders
Gonadal Dysgenesis
 In general, approximately 90 percent of individuals with gonadal dysgenesis
from a loss of X genetic material never menstruate
 the most frequent cause of POF
 oocytes undergo accelerated atresia
 The karyotype can be normal or abnormal
 Normal…46 xx or 46 xy
 Abnormal… 45 x-Turner syndrome and chromosomal mosaics

22. Specific Genetic Defects
Single gene mutations
fragile X mental retardation
CYP17 mutations
• Affected patients have sexual infantilism and
primary amenorrhea due to absent estrogen secretion.
• Sexual infantilism describes patients with a lack of breast development,
absent pubic and axillary hair, and a small uterus.
FSH or LH hormone gene mutations
galactosemia is a rare cause of POF.

23. Acquired Abnormalities
• Infection(e.g. mumps oophoritis), environmental exposures(cigarette
smoking, heavy metals, solvents,
pesticides, and industrial chemicals)
, autoimmune disease, or medical treatments.
• Autoimmune disorders account for an estimated 40 percent
of POF cases
• Iatrogenic ovarian failure is relatively common.
• Surgery related to ovary , chemotherapy ,radiotherapy
• POF 20 to Chemotherapy or radiotherapy depends on dose,pt’s age ,drug
choice(e.g. Alkylating agents)

24. HYPOGONADOTROPIC HYPOGONADISM
• It implies that the primary abnormality lies in the hypothalamic-
pituitary axis.
• Poor gonadotropin stimulation of the ovaries leads to
impaired follicular development

25. Hypothalamic Disorders
Inherited Hypothalamic Abnormalities
• Idiopathic hypogonadotropic hypogonadism (IHH)
• Kallmann syndrome- hyposmia or anosmia
• Anosmin-1 is critical for normal migration of both GnRH and olfactory
neurons
• KS is also associated with midline facial
anomalies such as cleft palate, unilateral renal agenesis, cerebellar ataxia,
epilepsy, neurosensory hearing loss, and synkinesis
• Kallmann syndrome can be distinguished from IHH by olfactory testing

27. Acquired Hypothalamic Dysfunction
• Acquired hypothalamic abnormalities are much more frequent
than inherited deficiencies.
• Also called “hypothalamic amenorrhea’’
• encompasses three main categories: eating disorders, excessive
exercise, and stress.

28. Eating Disorders.
• Both anorexia nervosa and bulimia can lead to amenorrhea.
• Hypothalamic dysfunction is severe in anorexia and may affect
other hypothalamic-pituitary axes

29. Exercise induced Amenorrhea
• Significant loss of fat 20 to ballet, gymnastics, and long-distance
running
• Puberty may be delayed in girls who begin training before menarche

30. Female athlete triad
It consists of:
• Menstrual dysfunction
• Low energy availability and
• Low bone mineral density

31. Stress induced Amenorrhea.
• Frequently associated with leaving for college, test taking, or wedding
planning

32. Functional Hypothalamic Amenorrhea pathophysiology
It must be emphasized that
each cause of functional
hypothalamic amenorrhea
may act via one or all of
these pathways.
Opioids alter GnRH pulsatility
Primarily produced in adipose
tissue, leptin provides an
important link between energy
balance and reproduction
Patients with anorexia nervosa
have been found to have low
circulating leptin levels
Leptin has
been termed a
“satiety actor”

33. Pseudocyesis
• Pseudocyesis is considered in any woman with amenorrhea and
pregnancy symptoms.
• A common link in these patients is a history of severe grief ,
such as recent miscarriage, infant death, or longstanding infertility

34. Anatomic Destruction
• Any process that destroys the hypothalamus can impair GnRH secretion
and lead to hypogonadotropic hypogonadism and amenorrhea
• craniopharyngiomas, germinomas, endodermal sinus tumors,
eosinophilic granuloma (Hand-Schuller-Christian syndrome),
gliomas, and metastatic lesions
• The most common of these
tumors, craniopharyngiomas, are located in the suprasellar region and
frequently present with headaches and visual changes.
• Alternatively, impaired GnRH secretion may follow
trauma, radiation, infections such as tuberculosis, or infiltrative
diseases such as sarcoidosis

35. Anterior pituitary Gland Disorders
Inherited Abnormalities
• Different types of mutation
Acquired Pituitary Dysfunction
 Most pituitary dysfunction is acquired after menarche and
there fore presents with normal pubertal development followed
by secondary amenorrhea.

36. Acquired Pituitary Dysfunction….
• Pituitary adenomas are the most frequent cause of acquired
pituitary dysfunction
• Significantly elevated serum prolactin levels (> 100 ng/
mL) are almost always due to a pituitary mass
• Pituitary tumors also may indirectly alter gonadotrope function by a
mass effect
• pituitary function may also be diminished by inflammation, infiltrative
disease, metastatic lesions,surgery, or radiation treatment
• pituitary apoplexy-Spontaneous hemorrhage into a pituitary
adenoma

37. Acquired pituitary dysfunction….
• Sheehan syndrome refers to panhypopituitarism.
• It classically follows massive postpartum hemorrhage and associated
hypotension.
• The abrupt, severe hypotension leads to pituitary ischemia and
necrosis

38. Eugonadotropic amenorrhea
oPolycystic ovarian syndrome
oNonclassic congenital adrenal hyperplasia
oOvarian tumor
oHyperprolactinemia and thyroid disorders

39. polycystic Ovarian Syndrome
• the most common cause of chronic anovulation with estrogen
present

40. Nonclassic congenital adrenal hyperplasia
• Also termed adult-onset CAH or late-onset CAH
• It is due to a mutation in the CYP21A2 gene, which encodes the 21-
hydroxylase enzyme
• Patients are unable to convert progesterone to cortisol and aldosterone, thus
increasing the production of androgens
• Result in anovulation and amenorrhea
• Mimics the presentation of PCOS with hyperandrogenism and irregular
menstrual cycles

41. Hyperprolactinemia and Thyroid Disorders
• TRH prompts pituitary gland thyrotropes to produce TSH.
• In addition, TRH also binds to pituitary lactotropes, increasing
prolactin secretion.
• This tight link between thyroid function and prolactin levels
justifies measurement of a TSH with prolactin levels when
initiating evaluation for galactorrhea or amenorrhea.

42. ….
• Classically, hypothyroidism is stated to cause anovulation
and subsequent heavy menstrual bleeding
• Hyperthyroidism is implicated in amenorrhea
• Nevertheless,
these patterns are not strictly observed

43. EVALUATION
• History
• Detailed menstrual hx
• Uterine or ovarian surgery
• Hx of postoperative infection
• Review of symptoms(new-onset headaches or visual changes)
• Bilateral milky breast discharge may reflect hyperprolactinemia
• heat or cold intolerance, weight
changes, and sleep or bowel motility abnormalities..thyroid disease

44. History..
• Hirsutism and acne are often seen with PCOS or with nonclassic CAH
• Cyclic pelvic pain would suggest a reproductive tract outlet
obstruction
• Hot flushes and vaginal dryness point to hypergonadotropic
hypogonadism, that is, POF
• Family history include premature cessation of menses or a history of
autoimmune disease, including thyroid disease, which would suggest an
increased risk or POF

45. History…
• A history of irregular menses, infertility, or signs
of excess androgen production is often noted with PCOS.
• Sudden neonatal death may have occurred in family members
carrying mutations in the CYP21A2 gene responsible for CAH
• Drug and evironmetal toxin exposure( smoking,antipsychotics …)
• antipsychotics increase prolactin levels.

46. Physical Examination
• General appearance
• Eating disorder…low BMI+tooth enamel
erosion
• Signs of Turner syndrome are evaluated, including short stature,
webbed neck, shield-shaped chest
• cleft palate…. developmental defect of the anterior pituitary gland.
• Hypertension…. mutation in the CYP17 gene and shunting of the
steroidogenic pathway toward aldosterone
• Visual field defects…. pituitary gland or CNS tumor

47. p/e…
• Skin is inspected for acanthosis nigricans, hirsutism, or acne, which may indicate
PCOS or other hyperandrogenism causes
• Supraclavicular fat, abdominal striae, and hypertension may be noted in those
with Cushing syndrome.
• Hypothyroidism can present with an abnormally enlarged thyroid gland, delayed
reflexes, and bradycardia.
• Sparse or absent axillary or pubic hair may reflect either lack
of adrenarche or androgen insensitivity syndrome
• Markedly elevated levels of androgens can produce
signs of virilization, most noticeably clitoromegaly, voice deepening and male
pattern balding
• Evidence of estrogen production includes a pink, moist vagina and cervical mucus

48. Testing
• The differential diagnosis of amenorrhea is extensive
• Testing may be modified by patient history and physical
examination
• All reproductive-aged women with amenorrhea are assumed
pregnant until proven otherwise.
• Thus, a urinary or serum β-hCG level is almost always obtained

49. the progesterone challenge test
• One regimen is medroxyprogesterone acetate(Provera) given as a 10-mg
daily oral dose for 10 days
• Withdrawal bleeding …. woman is assumed to produce estrogen and
to have a developed endometrium and patent out flow tract
• No withdrawal bleeding …. estrogen progesterone test
• If a woman again fails to bleed several days after
completing the 21 hormone-containing pills, then an anatomic
abnormality is diagnosed
• Is there chance of incorrect test?

50. …
• Specifically, up to 20 percent of women in whom estrogen is present
will fail to bleed following progesterone withdrawal
• Conversely, menses may be observed after progesterone
administration in up to 40 percent of women with hypothalamic
amenorrhea due to stress, weight loss, or exercise and in up
to 50 percent of women with POF

51. Serum Hormone Levels
• For any woman found to have a normal pelvic examination
1. Serum β-hCG
2. TSH
3. FSH
4. Prolactin

54. TREATMENT
• Treatment of amenorrhea depends on its etiology and
patient goals such as a desire to treat hirsutism or seek pregnancy.
• Anatomic abnormalities often require surgical correction
• Hypothyroidism …. levothyroxine is 1.6 µg/kg/day…recheck after 6-
8weeks
• Hyperprolactinemia…. dopamine agonist, such as bromocriptine or
cabergoline

55. Estrogen Replacement
• This therapy is instituted in essentially every patient with
hypogonadism to avoid osteoporosis
• C/I…estrogen-sensitive tumor
• Women with a uterus also require continuous or intermittent
progesterone administration to protect against endometrial
hyperplasia or cancer
• Frequently, it is easiest to prescribe COCs.
• For most individuals, continuation until approximately
age 50, the usual age of menopause, seems reasonable

56. polycystic Ovarian Syndrome
• cyclic or chronic
progesterone
• Metiformin …DM
• nonclassic CAH..steroids

57. Infertility
• POF is not reversible, and affected individuals can be offered in vitro
fertilization using a donor oocyte to conceive
• Women with PCOS will frequently ovulate
following treatment with the selective estrogen-receptor modulator
clomiphene citrate, or with an aromatase inhibitor such
as letrozole.
• Clomiphene citrate is believed to act by transient inhibition of
estrogen feedback at the hypothalamus and pituitary gland

58. Patient education
• Patients are adequately counseled regarding their diagnosis,
its long-term implications, and treatment options.
• All women with an intact endometrium must understand the risks of
unopposed estrogen action, whether the estrogen is exogenous,
such as through hormone therapy, or endogenous, such as
in PCOS.
• For hypoestrogenic women, clinicians explain the importance of estrogen
replacement to protect against bone
loss.
• Last, even if not raised by the patient, the potential or lack of potential for
future child-bearing is discussed