Detailed primary amenorrhea presentation during postgraduation days

1. PRIMARY AMENORRHEA
Presented by,
UNIT-IIIA
IPGME&R and SSKM Hospital,
Kolkata.

2. PHYSIOLOGY OF MENSTRUATION
FSH LH
Estrogen Progesterone
Menstruation
ENVIRONMENT
HYPOTHALAMUS
ANT. PITUITARY
OVARY
UTERUS

3. DEFINITION-
• Amenorrhea is the absence of
menstruation.
• Primary Amenorrhea-
– Absence of menses by age of
15 regardless of secondary
sexual characteristics.
OR
– Absence of menses by age of
13 without development of
secondary sexual
characteristics
Novak’s 15th edition….

4. • Thelarche (breast development)
– Requires estrogen
• Pubarche (pubic hair development)
– Requires androgens
• Menarche(the first mense)
Requires:
– GnRH from the hypothalamus
– FSH and LH from the pituitary
– Estrogen and progesterone from the ovaries
– Normal outflow tract
Generally takes 4.5 yrs.
Differs cuturally between ethnic groups
Events of Puberty

5. CLASSIFICATION OF AMENORRHEA
AMENORRHEA
PHYSIOLOGICAL PATHOLOGICAL
 Pre-puberty
 Pregnancy
related
 Menopause
 Primary
 ANATOMIC ABNORMALITY
 HYPERGONADOTROPHIC HYPOGONADISM
 HYPOGONADOTROPHIC HYPOGONADISM
 ASYNCHRONOUS PUBERTAL DEVLOPMENT
 Secondary

6. PRIMARY AMENORRHOEA
A. Anatomic abnormalities of the genital outflow tract
1. Müllerian dysgenesis (Mayer -Rokitansky–Küster–Hauser
syndrome)
2. Distal genital tract obstruction
a. Imperforate hymen
b. Transverse vaginal septum
c. cervical atresia
d. vaginal atresia
B. Hypergonadotropic (follicle–stimulating hormone >40
mIU/mL) hypogonadism (gonadal “failure”)
1. Gonadal dysgenesis with stigmata of Turner syndrome
2. Pure gonadal dysgenesis
a. 46,XX
b. 46,XY
3. Early gonadal “failure” with apparent normal ovarian development

7. • C. Hypogonadotropic (luteinizing hormone and follicle–
stimulating hormone <10 mIU/mL) hypogonadism
• 1. Constitutional delay
• 2. Isolated gonadotropin deficiency
• a. Associated with midline defects (Kallmann )
• b. Independent of associated disorders
• c. Prader–Labhart–Willi syndrome
• d. Laurence–Moon–Bardet–Biedl syndrome
• e. Many other rare syndromes (Frohlich syndrome)
• 3. Associated with multiple hormone deficiencies
• 4. Neoplasms of the hypothalamic–pituitary area
• a. Craniopharyngiomas
• b. Pituitary adenomas
• c.Others

8. • Infiltrative processes (Langerhans cell–type histiocytosis)
• After irradiation of the central nervous system
• Severe chronic illnesses with malnutrition
• Anorexia nervosa and related disorders
• Severe hypothalamic amenorrhea (rare)
• Antidopaminergic and gonadotropin–releasing hormone–inhibiting
drugs(especially psychotropic agents, opiates).
• Primary hypothyroidism
• Cushing syndrome
• Use of chemotherapeutic (especially alkylating) agents.
C. Hypogonadotropic (luteinizing hormone and follicle–
stimulating hormone <10 mIU/mL) hypogonadism…. (contd)

9. D. Asynchronous pubertal development-
• Complete androgen insensitivity syndrome
(testicular feminisation synd.)
• Incomplete androgen insensitivity syndrome

10. PRIMARY AMENORRHEA
. Ovarian failure 36%
. Hypogonadotrophic Hypogonadism 34%
. PCOS 17%
. Congenital lesions (other than dysgenesis) 4%
. Hypopituitarism 3%
. Hyperprolactinaemia 3%
. Weight related 3%
Current Evaluation of Amenorrhea. Fertility and Sterility 2008 80(3): S219-
S225

11. OBJECTIVES OF EVALUATION:
1.) Understand the causes of primary
amenorrhea .
2.) How to elicit a pertinent history and perform
a focused physical exam to evaluate primary
amenorrhea.
3.) Understand how to perform and interpret
selected diagnostic tests and imaging to
evaluate primary amenorrhea .

12. CAREFUL MEDICAL HISTORY
PHYSICAL EXAMINATION
Height, weight, BMI, Skin, Acne, Hirsutism
Breast: Indicator of estrogen production
or exposure to exogenous
estrogen
Abdominal Examination
External Genitalia and pubic hair,axillary hair
PV ex./ PS ex./PR ex
INVESTIGATIONS
APPROACH TO A CASE OF PRIMARY
AMENORRHOEA

13. INVESTIGATIONS-
– HORMONAL PROFILE
(beta-HCG,FSH,LH,TSH,PROLACTIN, sex hormones)
– USG/MRI
– Karyotyping
– Laparoscopy
– Mlscellaneous

14. EVALUATION
• Normal sec. sexual character development
• Absence of sec. sexual character development
• Asynchronous development of secondary
sexual characteristics
• Heterosexual development of secondary
sexual characteristics.

15. Tanner Staging:
Developed by James Tanner and originally published in 1968
as an objective way to assess pubertal development
Prepuberta
l
(Stage 1)
Elevation of the
papilla only
No pubic hair
Stage 2 Elevation of the breast
and papilla as a small
mound, areola
diameter enlarged
Sparse, long, pigmented
hair chiefly along labia
majora
Stage 3 Further enlargement
without separation of
the breast and areola
Dark, coarse, curled hair
sparsely spread over
mons
Stage 4 Secondary mound of
areola and papilla
above the breast
Adult-type hair,
abundant but limited to
mons
Stage 5 Recession of areola to
contour of breast
Adult-type spread in
quantity and
distribution

16. STEPWISE APPROACH
IN A CASE OF
AMENORRHEA

17. Blind or Absent Vagina
Symptoms of obstructed
menses
Asymtomatic
Imperforate
Hymen
Tr. Vaginal
Septum
Normal Pubic hair
Very Scant / Absent pubic
hair
Mullerian Agenesis
Androgen
Insensitivity
Syndrome
I) NORMAL SEC. SEXUAL CHARACTER

18. Ultrasonography
Karyotyping
Outflow tract Normal anatomy
46 XX 46XY obstruction
FSH, LH,TSH
Absent uterus XY female Prolactin
and vagina
(MRKH)
Normal /low ↑LH/FSH ↑FSH,LH ↑prolactin
hypothalamus PCO Ovarian Hyperprolactinemia
Uterus absent Uterus present

19. Normal FSH, PRL, TSH
Normal estrogen Low estrogen
idiopathic, pco CT/ MRI
Ov. Neoplasm
Obesity, Cushing synd. Normal abnormal
Cong. adrenal hyperplasia
Chr. Diseases pituitary/ hypothal
pulmonary, liver tumor, infection
renal infarction

20. 2) ABSENT SEC. SEXUAL CHARACTER
Height
Normal Short
FSH,LH FSH,LH
Low high low high
Hypogonado Karyotyping karyotyping
trophic intracranial
lesion
hypo POF (XX) XY agenesis XO or
Gonadism ROS (XX) XY enzymatic mosaic turner

21. 3) ASYNCHRONOUS DEVELOPMENT
• Complete androgen insensitivity syndrome
• Incomplete Androgen insensitivity syndrome

22. 4) Heterosexual development
• Cong. Adrenal hyperplasia
• Androgen secreting tumor
• 5 reductase deficiency
• Partial androgen receptor deficiency
• True hermaphrodite
• Absent mullerian inhibitor

23. SPECIFIC CAUSES

24. IMPERFORATE HYMEN
• Represents junction of sinovaginal bulbs with urogenital
sinus; formed from endoderm of urogenital sinus epithelium
• May be discovered at birth because of presence of
suprapubic mass "mucocolpos or hydrocolpos"
• More commonly however it remains undetected until puberty
(hematocolpos).
• Patient presents with c/o cyclic perineal,pelvic or abd
pressure or pain resulting from accumulation of obstructed
menstrual blood or urinary retention
• Genital ex.reveals no obvious vaginal orifice and a thin often
bulging, blue perineal membrane.

25. Treatment-
-Relief of symptoms
-Definitive surgery as soon as possible-
a simple cruciate incision in the hymen
and to allow drainage of altered menstrual fluid or
a sterile puncture of the distended membrane and enlarged to
allow insetion of a 16F Foley’s cathter which is placed for 2 weeks.

26. TRANSVERSE VAGINAL SEPTUM
• Failure of vertical fusion ( complete
cavitation of the vaginal plate between
the sinovaginal bulbs and uterovaginal
canal).
• More common in the upper portion,
that is, at the junction between the
sinovaginal plate and the caudal end of
the fused müllerian ducts.
• The septum may be obstructive, with
accumulation of mucus or menstrual
blood, or may be non-obstructive,
allowing for egress of mucus and
blood.

27. Clinical Manifestations
• Obstructive transverse vaginal
septum:-
• -- usually present during
adolescence with cyclic lower
abdominal pain, amenorrhea, and
gradual development of a central
pelvic mass.
• Nonobstructive or incomplete
transverse vaginal septum
• -- complain of abnormal menstrual
flow, pain with intercourse, difficulty
in placing or removing tampons, or
obstructed labor

28. Diagnosis:
 On physical ex-normal vaginal orifice,shortened vagina of varying
length,no visible cervix and a palpable hematocolpos in the
proximal vaginal segment or a pelvic mass from hematometra and
hematosalpinges.
 Valsalva maneuver distinguishes it from imperforate hymen-in
case of imperforate hymen there is distention at the introitus.
 Pelvic ultrasonography-reveal extent and level.
 Abdominal/pelvic MRI defines clearly the length of the atritic
segment and septal thickness.
 Avoid diagnosis by inserting a needle which may convert a
hematocolpos into a pyocolpos.

29. Treatment :
1.Surgical repair is dependent upon septal thickness.
2.Skin grafts may occasionally be necessary to cover a
defect left by excision of very thick septa.
3.Smaller septa may be approached by excision with an
end-to-end anastomosis of the upper to the lower vagina

30. CERVICAL ATRESIA/AGENESIS
 Cervical agenesis is absence of a cervix,
Milder forms of the condition, in which the
cervix is present but deformed and
nonfunctional - cervical atresia or cervical
dysgenesis.
 Congenital cervical atresia is a rare classIIB
(AFS) Müllerian anomaly
 Complication: hematometra,hematosalpinx,
endometriosis,endometrioma
 Ultrasound and MRI - most helpful in
preoperative evaluation of Müllerian
anomalies.
 Intravenous pyelogram because of known
incidence of urinary tract anomalies

31. • TREATMENT
• first line : combined oral contraceptive
pill, medroxyprogesterone acetate or a gonadotropin-
releasing hormone analogue to suppress menstruation
 Surgical methods of management
involve neovaginoplasty or recanalization of the cervix.
 Attempts to create an endometrial-vaginal fistula
- short-term restoration of the menses ,conception is highly
unlikely because the cervical mucus is absent
 Surgical efforts to preserve fertility is usually difficult
Hysterectomy- definitive therapeutic method

32. Mayer Rokitansky Kuster Hauser syndrome(MRKH)
• Mayer –congenital absence of vagina as one of the
abnormalities
• Rokitanski and Kuster –vagina absent, small
bipartite uterus, normal ovaries and associated
anomalies
• Hauser-emphasised spectrum of associated
anomalies
• 15% of 1ry amenorrhea (2nd only to gonadal
dysgenesis)
• CAUSE: Mutations in Antimullerian Hormone or
Antimullerian Hormone receptor
• Association with Wnt gene, GALT gene
• Normal breasts, sexual hair and external female
genitalia
• Normal female range testosterone level
• Karyotype 46-XX.

33. TWO TYPES:
type A (Symmetric rudiment uteri ,normal FT)
type B (Asymmetric rudiment ut. and absent / hypoplastic FT)
ASSOCIATED ANOMALIES:
•Urologic anomalies(15-40%) -u/l renal agenesis,horse-shoe
kidney,duplication of the collecting system
•Skeletal malformation-vertebra, ribs ,pelvis.(10-15%).-
hemivertebra,Klippel-Feil syndrome
•Cardiac anomalies
DIAGNOSIS-
•medical h/o, physical ex, karyotype,
• renal usg , spinal x-ray. MRI,
• laparoscopy

37. TREATMENT
Surgery is indicated
 with symptoms of Hematometra, endometriosis or a hernia
into the inguinal canal
 Primary goal: creation of a functional vagina by progressive
dilatation (non-surgical) or surgical creation of neovagina.
• Vaginal Reconstruction :
Vaginoplasty : Mac Indoes Vaginoplasty ,Williams
vulvovaginoplasty , Vecchietti procedure
 Fertility – by surrogacy
 Psychological support

38. Dilators (Frank and Ingram) :
•Dilate at a 15 degree angle by applying pressure
daily for 20 minutes.
•Progressively work up to larger dilators
•Success defined as non-painful intercourse or vaginal length of
7cm
•Other techniques of applying pressure-leaning forward on a
bicycle seat.
Treatment contd..

39. McIndoe Neovagina
•Use a skin graft or artificial skin placed over a mold forming a tube with
one closed end
•Incision made in the vaginal dimple and cavity dissected to level of
peritoneum.
•Labia majora are sewn together.
•Bed rest for 7 days and then mold removed.

40. Vecchietti Vaginoplasty :
•Creation of neovagina by invagination
•Small acrylic mold placed in the vaginal dimple.
•Abdominal incision made—traction stitches placed on the abdominal
peritoneum and attached to the mold.
Traction device used to pull mold up 1-1.5 cm per day. Takes approximately
7-9 days.
Williams Vaginoplasty
Use labia majora in order to create vagina
•Disadvantage—produce shorter vaginal cavity
Sigmoid Vaginoplasty
•Pulldown of sigmoid colon to introitus followed by end to end
reanastomosis.
•Advantages: good vaginal length
•Disadvantages: report of foul smelling discharge and odor

41. LAPAROSCOPIC VECCHIETTI OPERATION
• An acrylic olive is positioned within vaginal
dimple and connected to threads passed
through rectovesical space, into
peritoneal cavity under laparoscopic
control and through to the abdominal
wall, where they are attached to a traction
device
• Steady increasing traction is applied to the
threads, and neovagina is stretched by
approximately 1 cm per day.
• traction device and olive are removed
after 7–10 days.
• not recommended where there is scarring
from previous reconstructive surgery.

42.  Incomplete or defective formation of gonads-disturbance in
germ cell migration d/t strutural or numerical sex
chromosome abn.or mutation.
 It is among the most common causes of amenorrhea(30-40%).
 Commonest is TURNER SYNDROME
• Chromosomally incompetent
- Classic Turner’s syndrome (45XO)
- Turner variants (45XO/46XX),(46X-abnormal X)
- Mixed gonadal dygenesis (45XO/46XY)
• Chromosomally competent
- 46XX
- 46XY (Swyer’s syndrome)
Gonadal dysgenesis

43. Secondary sexual character absent with short stature
• TURNER’S SYNDROME:
• Normal ovarian development until 20 wks of
intrauterine life – then atresia
• 45XO karyotype
• Cause: Absence of ovarian determinant genes result
in premature loss of germ cells
• Normal female phenotype at birth
• Normal internal genitalia with streak ovaries
• Short stature, webbed neck, shield chest, cubitus
valgus, short metacarpals, low hair line, high arched
palate.

44. Associated Abnormalities :
•Cardiac Anomalies
(Coartation of aorta in 30% of patients, also bicuspid aortic
valve, mitral valve prolapse )
Recommend echocardiography be performed every 3-5 years
•Renal Anomalies
Horseshoe Kidney (Need retroperitoneal ultrasound once
diagnosed )
•Hypothyroidism (10% of patients with Turner’s Syndrome )
Recommend yearly screening of T4/TSH and antibodies
•Deafness (audiometry)

48. Treatment : -
• GH therapy 0.375mg/kg weekly for about 7 yrs
starting at as early as 2-8 yrs.
• To promote sexual maturation – exogenous estrogen
such as 0.025 mg/day transdermal estradiol or 0.3-
0.625mg CEE orally daily at about 12-13 yrs of age.
• 5-10 mg MPA added to prevent endometrial
hyperplasia after first experience of bleeding or after
6 months of E therapy.

49. GONADAL DYSGENESIS: 46XX
•Refers to a number of conditions in which abnormal development leads to
streak gonads
•Incidence: <1/10,000 in women less than 30
•Familial inheritance 7-30%
•Premutations in the FMR1 gene (Fragile X Syndrome)
•15% of carriers have POF
•Associated with :
•autoimmune diseases (18-30%) like Hashimoto’s Thyroiditis, Addison’s
disease, hypoparathyroidism, vitiligo
•Acquired: Radiation, chemotherapy, Environmental, Childhood viruses

50. 46 XY Swyer Syndrome
Cause: Associated with mutations in the SRY gene
•Streak gonads present; No testes formation
•Anti-Mullerian hormone and testosterone not produced
•Normal uterus and fallopian tubes, female external genitalia
•Estrogen also not produced from streak gonads therefore
breast development does not occur
•Elevated FSH/LH
•Streak Gonads need removal as increased risk (25%) for
germ cell tumors: most common gonadoblastoma

51. RESISTANT OVARY SYNDROME OR
SAVAGE SYNDROME
• ? Absence or malfunction of FSH receptor in ovarian
follicle
• ↑ gonadotrophin
• Apparently normal ovarian tissue
• Some degree of sec. sexual character
• Rare cause of primary amenorrhea
• May resolve spontaneously
• If hot flushes-Rx with estrogen

52. Secondary sexual character absent with normal height:
KALLMAN SYNDROME (congenital GnRH deficiency; olfacto-
genital syndrome)
• congenital GnRH deficiency with anosmia/hyposmia
• Maldevelopment of hypothalamus - ↓ GnRH, Pituitary normal
Mutation of X chromosome KAL 1 gene encoding anosmin-1 and FGFR-1 gene.
• Males patients: Delayed puberty and hypogonadism
• Female patients: Primary amenorrhea and failure of secondary sexual
development
• Long-term treatment: cyclic estrogen and progestin(to induce sec. sexual
character and to prevent osteoporosis
• Diagnosis of exclusion
• Repetitive GnRH administration restores normal function.
• Fertility may also be restored by the administration of gonadotropins or by
using a portable infusion pump to deliver subcutaneous, pulsatile GnRH

53. Laurence-Moon-Bardet-Biedl Syndrome
• Rare autosomal recessive disorder
• Characterized by mental retardation;
obesity; and hexadactyly, brachydactyly,
or syndactyly
• Central diabetes insipidus may or may not
be associated
• GnRH deficiency occurs in 75% of males
and half of affected females.
• Retinal degeneration begins in early
childhood
• -most patients are blind by age 30

54. PRADER-WILLI
SYNDROME:

55. Frohlich Syndrome (Adiposo Genital Dystrophy)
• Broad spectrum of hypothalamic lesions
• Hyperphagia, obesity, and central
hypogonadism
• Decreased GnRH production results in
attenuated pituitary FSH and LH
synthesis and release
• Deficiencies of leptin, or its receptor,
cause these clinical features

56. Weight-related amenorrhoea:
Anorexia Nervosa
• 1o or 2o Amenorrhea is often first sign (commonest cause of amenorrhea
among teenagers)
• A body mass index (BMI) <17 kg/m² menstrual irregularity and amenorrhea
• Hypothalamic suppression ,hypogonadotropic state.
• Abnormal body image, intense fear of weight gain, often strenuous exercise
• O/E-hypotension, bradycardia ,hypothermia,dry skin and lanugo hairs
• Mean age onset 13-14 yrs (range 10-21 yrs)
• Low estradiol  risk of osteoporosis , osteopenia
• Bulemics less commonly have amenorrhea due to fluctuations in body wt,
but any disordered eating pattern (crash diets) can cause menstrual
irregularity.
• Treatment :  body wt. (Psychiatrist referral)

57. Female Athlete Triad
• Established as a diagnosis in 1992
• Amenorrhea, osteoporosis, and eating
disorder among female athletes
• Most common: gymnastics, ballet, and long-
distance running
• Bone Mineral Density evaluation: Athletes
generally have higher BMD
• A Z-score less than -1.0 requires evaluation

58. Androgen insensitivity syndrome
• It is a form of male pseudohermaphoditism (incidence 1 in
60,000)
• Normal male karyotype (46XY) and testes that produce both
testosterone and AMH.
• Failure of development of testis
• Enzymatic failure of testis to produce androgen(incomplete)
• Absence of androgen receptor or failure of
function(inactivating
Mutation in gene encoding androgen receptor).
Androgen insensitivity syndrome

59. Androgen insensitivity syndrome --- cont..
• Phenotypicaly female
• Normal breast development
• Very Scanty /absent pubic hair
• Normal vulva with short blind vagina
• Uterus and tubes absent, Testes in abdomen/ groin
• Eunuchoid body habitus
• Male range testosterone,Sr. LH also elevated
reflecting androgen insensitivity at hypothalmo-
pituitary level.
• Treatment:
• gonadectomy after puberty + HRT(Malignant
potential of gonad (5-10%)– removal after puberty
(to smoothen pubertal development and as it is
very rare)
• ? Vaginal creation (dilatation VS Vaginoplasty)
 Psychological counselling

60. Heterosexual development
• Congenital adrenal hyperplasia –
21 hydroxylase deficiency (commonest)
17 Hydroxylase deficiency
17,20-desmolase deficiency
• Androgen secreting tumor – Arrhenoblastoma
• 5 -Reductase deficiency
XY, testis, virilization at puberty, no mullerian
structure, non development of breast, normal male internal
genitalia but non development of external genitalia

61. Congenital Adrenal Hyperplasia
• Enzyme defect leading to excessive androgen
production
• Autosomal recessive trait
• Milder form of disease diagnosed later in life (late
onset) and resembles PCOS
• May present with primary amenorrhea but even
more classical: hirsutism, virilization, anovulation
• Abnormal looking female external genitalia
• Presence of uterus and upper vagina.
• Diagnosis: Fasting 17-OHP-
• If >300ng/dL ACTH stim test
• Levels >1000 ng/dL are indicative of late-onset CAH
• TREATMENT: cortisol replacement and Corrective
surgery

62. Constitutional Delay
•Puberty occurs at a time greater than 2.5 standard deviations
from the mean
•Family history of delayed puberty
•Characteristics:
•Significantly shorter
•Bone age lags behind age matched controls
•Often present at early Tanner stage 2
•Low gonadotropin levels
•Diagnosis of exclusion—exclude other reproductive
disorders

63. Summary
• Menstruation is an indication of cyclic ov. activity, in turn
dependent upon an intact HPO axis.
• Pertinent history, Physical exam, USG, base line endocrinal
investigation, and karyotyping will find the etiology in most of
the cases
• To look at primary amenorrhea as an isolated event is
misleading a it is part of whole development of puberty
• More useful to look upon sec. sexual development as the
criteria for investigation in association with primary
amenorrhea
• Absence of sec sexual character indicates – never been
exposed to optimal level of sex hormones

64. Summary
• Sharing of information regarding chromosomal sex
should always be done but after developing
sufficient rapport with the patient and guardian with
proper counseling.
• Successful management is dependent upon correct
diagnosis of the etiology
• HRT is required in hypoestrogenic state for
development of sec. sexual character and also to
maintain BMD.