This document discusses amenorrhea, including its causes, evaluation, and management. It begins by defining amenorrhea and classifying it as primary or secondary. The causes of amenorrhea are then categorized based on the site of disturbance - the outflow tract, ovary, anterior pituitary, or hypothalamus. For each site, the document lists specific disorders that could cause amenorrhea and discusses the evaluation and management. Hypothalamic and pituitary causes of secondary amenorrhea are emphasized, outlining treatments like lifestyle modifications and hormone therapy.
4. PRIMARY AMENORRHEA
• No menarche till the age of 15 years
OR
• 3 yrs post thelarche no menses
regardless of sec.sexual characters OR
• No pubertal development by the age
of 13 years.
When a girl
fails to attain
menses even
once in her life
considering
following age
criterias
5. Points to Ponder
In most young girls first sign of puberty is growth spurt ( acceleration of growth), followed by
breast budding (thelarche), appearance of pubic hair (pubarche) followed by attainment of
menses (menarche)
Having affirmed the traditional definition, it is important to point out that strict adherence to
these criterias can result in improper management of individual patients.
For example, there is no point to defer evaluation of a patient presenting with typical
phenotype of turner’s syndrome, or, a 13 year old girl presenting with no/ blind vagina should
not be advised to return after 2 years.
6. SECONDARY AMENORRHEA
• Cessation of menses in previously menstruating women for a period
of 3 months in case of regular cycles or
• a period equivalent to 3 cycles in women having irregular menses.
8. Breast Pubic Hair
Prepube
rtal
(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
Tanner Staging
9. Puberty—The Mechanism
• Initiated by release of pulsatile GnRH (hypothalamus)
• Specifically see increased pulsatile patterns of FSH & LH (these start during
sleep and eventually go throughout the day)
• With pulses of GnRH, peaks of estradiol result and eventually menarche
appears
• By late puberty, the mature HPO axis is intact and ovulation occurs
10. Hypothalamus secretes pulsatile GnRH which reaches
pituitary via portal vessels of pituitary stalk
Anterior pituitary secretes FSH &LH
FSH & LH acts on ovaries to produce ovarian
sex steroids
Estrogen and progesterone act on the uterine
endometrium to cause menses in presence of intact
outflow tract.
Ovarian sex steroids also provides feedback signal to
anterior pituitary and hypothalamus to control their
secretions
Environmental factors like stress, excessive weight
gain or loss, excessive exercise or certain drugs can
affect menses through the hypothalamus and CNS.
12. ETIOLOGY
CAUSES OF AMENORRHEA HAVE BEEN SEGGREGATED
INTO FOLLOWING COMPARTMENTS ACCORDING TO
THE SITE OR LEVEL OF DISTURBANCE OR DISORDER
Compartment I:
Disorders of the outflow or uterine target
organ.
Compartment II:
Disorders of the ovary.
Compartment III:
Disorders of the anterior pituitary
Compartment IV:
Disorders of central nervous system
(hypothalamic) factors
13. Disorders of genital outflow tract OR Anatomic/ end organ
defect
Primary amenorrhea
Congenital developmental anomalies
• Imperforate hymen
• Transverse vaginal septum
• Cervical Agenesis
• Vaginal Agenesis
• Mullerian Agenesis (MRKH)
• Androgen Insensitivity Syndrome
(Testicular Feminization)
Complete or incomplete
• Endometrial hypoplasia or aplasia
Secondary amenorrhea
Associated with normal anatomy
acquired conditions
• Cervical stenosis
• Intrauterine adhesions ( Asherman
syndrome)
• Endometrial Damage from surgical
trauma or infection
14. Disorders of the ovary
PRIMARY AMENORRHEA
• Gonadal Dysgenesis/ Agenesis
Abnormal karyotype:
45 XO, Mosaic Turner
46 XY (AIS), Sweyer syndrome (gonadal
dysgenesis)
Normal karyotype :
pure gonadal Agenesis (46 XX)
• Enzymatic Deficiency
17-α Hydroxylase deficiency
17,20-Lyase deficiency
Aromatase deficiency
SECONDARY AMENORRHEA
Premature Ovarian Insufficiency
Numerical and structural chromosomal
abnormalities
• X mosaicism(45X,46XX,47XXX cell line)
• Y (46XY,47XXY,47XYY) cell line
• X translocations, deletions
• Deletion of genes involved in germ cell function
• Fragile X (FMR1) pre-mutation
• Autoimmune disorders
• Radiation therapy
• Chemotherapy
• Galactosemia /infections
• Functional ovarian failure
• SAVAGE SYNDROME Resistant ovary
15. DISORDERS OF ANTERIOR PITUITARY
Presents mostly secondary amenorrhoea. Rarely primary amenorrhea
• SOL/TUMORS -PROLACTINOMAS
• other Hormone Secreting Pituitary Tumors (ACTH, TRH , GH, Gn)
• Hyperprolactinemia ( idiopathic or drug induced)
• Sheehan syndrome or panhypopituitarism
• FSH/LH Receptor mutation
• Empty Sella Syndrome, arterial aneurysm
• Infiltrative Pituitary lesions- Sarcoidosis, Haemochromatosis, Lymphocytic
Hypophysitis
• Surgical or Radiological ablation
23. Evaluation of amenorrhea
HISTORY
• Patient History
• Pubertal development, age at when breast development started.
• premenstrual symptoms, dysmenorrhea/ cyclic abdominal pain
• chronic illness- CKD, Inflammatory bowel disease.
• exposure to radiation, current medications, surgery, trauma
• Secondary amenorrhea- H/O previous menstrual cycle, especially
whether lengthening cycles or progressively reduced flow had
culminated finally in the amenorrhea.
• exercise, weight loss, illicit drug use
• Family History: history of pubertal delay (constitutional), infertility,
Premature menopause
• Review of Systems: anosmia, galactorrhea, headaches, visual changes,
hirsutism or acne, s/sx of thyroid disease, vasomotor symptoms
24. Obstetric history
• with regard to severe PPH, often requiring blood transfusion
suggests Sheehan's syndrome leading to hypopituitarism and
hypo-gonadotropic amenorrhea
• MRP or severe puerperal sepsis(Endometritis), H/O previous
D&C may lead to amenorrhea by causing uterine synechiae
(Asherman's syndrome).
• Personal history with respect to appetite, diet and caloric
intake and exaggerated weight loss/gain may indicate
hypothalamic dysfunction (anorexia nervosa or bulimic
disorder)
• excessive mental and physical stress and radical life-style
changes including exercise pattern.
• Symptoms related to hypo-estrogenism (hot flushes, mood
changes, urogenital discomfort) should be enquired into in
relevant contextual settings.(POF)
25. • CNS- h/o visual s & sx, headaches, recurrent unexplained vomiting.
• Progressive hirsutism and /or virilisation as reported by the patient should
be looked into and may be manifestation of classical late-onset CAH,
androgen producing ovarian or adrenal tumour.
• Changes in hair distribution (excessive, altered hair growth pattern or
thinning or loss of scalp hair or brows) should lead the clinician to
investigate along the line of thyroid dysfunction or PCOS.
• frequently prescribed medications to can cause hyperprolactenemia or
other central HPO axis dysfunction by altering neurotransmitter secretion
and contribute to amenorrhea.
• Examples include androgens, OCPs, MPA, progestogen intra-uterine
systems, GnRH agonists and drugs causing hyperprolactinemia
(phenothiazines, reserpine derivatives, amphetamines, benzodiazepines,
antidepressants, dopamine antagonists, opiates).
28. Primary Amenorrhea: Physical Exam
• Evaluation of pubertal development (height, weight, BMI & arm span) and
growth chart
• Breast development (Tanner staging)
• Axillary hair present or absent
• Evaluation for features of Turner’s syndrome
Webbed neck, low hair line, shield chest, widely spaced nipples
• Examine skin for hirsutism- acne, striae, increased pigmentation
• Pelvic examination- pubic hair development, clitoral size, hymenal opening,
depth of vagina, presence of cervix and uterus
29.
30. Secondary Amenorrhea: Physical Exam
• General physical examination
• Evaluation of Height, Weight, and BMI, waist : hip ratio, arm span
• Examine skin for hirsutism, acne, purple striae (cushing’s), acanthosis
nigricans, dryness or moist skin (thyroid dysfunction)
• Lid lag, exophthalmos and loss of lateral third of brow hair are pointers to
thyroid disorders as also fullness in the thyroid region of neck, exaggerated
reflexes, full bounding peripheral pulse and fine hand tremors.
• Breast exam--look for Galactorrhoea
• Pelvic Exam- Size of uterus, any pelvic mass
Vaginal dryness
36. FLOW CHART FOR INVESTIGATING A CASE OF PRIMARY AMENORRHEA
37.
38.
39.
40.
41.
42. 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 gonadotropins
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.
43. • Karyotyping should also be considered in patients of short stature to
evaluate for Turner syndrome. Patients with this syndrome require
screening for cardiac and renal defects, neurocognitive and behavior
disorders, hypothyroidism, and hearing loss,
• Diagnostic Imaging
Pelvic ultrasonography or magnetic resonance imaging (MRI) can
identify abnormal reproductive anatomy or detect an androgen-
secreting tumor.
• MRI of the brain can identify pituitary and other tumors
• Dual energy x-ray absorptiometry can establish baseline fracture risk in
patients with concerns for primary ovarian insufficiency or functional
hypothalamic amenorrhea
44. Management of amenorrhea ( Acc. to Cause or Site Of lesion)
Hypothalamus and Pituitary Amenorrhea
• Hypothalamic dysfunction is one of the MC causes of Secondary amenorrhea.
• Secondary amenorrhea, occurs in approximately 3–5 % of adult women.
• According to the ASRM, Functional Hypothalamic Amenorrhea (FHA) accounts for
20–35 % of secondary amenorrhea cases and 3 % of primary amenorrhea .
• Hypothalamic amenorrhea is diagnosed only after ruling out pituitary and ovarian
abnormalities.
• Conditions that often precede anovulation include marked weight loss, physical
exercise, physical and mental stress, oral contraceptive use.
• Amenorrhea is usually a result of hypogonadotropic hypogonadism, marked by low
or normal LH, FSH, and oestradiol levels.
• Normal prolactin, and low leptin are also seen in this type of amenorrhea.
• LH and FSH however do show response to GnRH stimulation.
46. • Diagnosis and Management
Detailed personal history with a focus on following points:
• Dietary habits, history of eating disorders, exercise and athletic training;
too many weight fluctuations, irregular sleep patterns, stressors, mood
fluctuations, menstrual pattern; fractures, and substance abuse.
• Obtain a thorough family history with attention to eating and
reproductive disorders.
• CBC, electrolytes, glucose, bicarbonates, BUN, creatinine, LFT, ESR, CRP.
• Endocrine work up includes TFT, LH,FSH,E2,AMH.
• Androgen profile advised if clinical hyperandrogenism is present.
• BMD measurement by dual-energy X-ray absorptiometry (DEXA) should
be obtained with 6 or more months of amenorrhea.
• Pelvic ultrasound in all to ensure normalcy, and MRI pelvis only when
indicated is advised.
47. Diagnostic tests: MC performed progesterone challenge test (PCT)
• with 10 mg medroxyprogesterone for 5 days is useful to differentiate between
ovarian cause and hypothalamic cause. If withdrawal period is achieved, then it
denotes presence of endogenous estrogen and ensures outflow tract function
and patency.
• There will be no withdrawal period if there is no endogenous estrogen present
like in hypothalamo pituitary causes.
• Following tests are used only when the diagnosis cannot be made with routine
clinical examination and investigations.
1. GnRH stimulation test: this is of use to differentiate between hypothalamic
and pituitary causes of hypogonadism.100 μg GnRH is given intravenously. LH and
FSH response is measured with samples at 0, 20 and 60 minutes In pituitary
disease, response is either absent or blunted. In hypothalamic disease, normal
response is seen.
48. • Clomiphene stimulation test may be useful to distinguish organic
causes of gonadotropin deficiency (pituitary or hypothalamic
pathology) from functional disorders and idiopathic delayed puberty.
• In healthy adults, clomiphene blocks oestrogen feedback mechanisms
in the hypothalamus, thus leading to a rise in GnRH and hence LH and
FSH.
• After 7 days of clomiphene stimulation, if LH levels increase more than
120% and FSH increases more than 40 %, the response is considered
normal. A normal response essentially rules out organic causes of
hypogonadotropic hypogonadism and in delayed puberty, it is an
indication that sexual maturity will ensue.
• In hypothalamic-pituitary pathology there is no response.
49. • To differentiate between functional and organic cause of amenorrhea,
some form of imaging of the brain (CT or MRI) to rule out a tumour may
be useful especially when a history of severe or persistent headaches;
persistent vomiting, unexplained change in vision, thirst, or urination,
lateralizing neurologic signs, and any indication of pituitary hormone
deficiency or excess.
• Correcting the energy imbalance.
• Nutritional, psychological, and modified exercise intervention (Cognitive
behaviour therapy CBT). OCPs for maintenance of MC and BMD are
required.
• If CBT is not effective, treatment with pulsatile GnRH as a first line, f/b
gonadotropin therapy and induction of ovulation, is used for treatment of
infertility.
50. Stress or exercise induced amenorrhea
• Involving in strenuous exercise or other forms of demanding physical
activity have a high prevalence of menstrual irregularity and
amenorrhea.
• The potential adverse effect of intense exercise and low body weight
on menstrual function is synergistic.
• Exercising amenorrheic women do not exhibit a normal diurnal leptin
rhythm
• Treatment with exogenous recombinant human leptin can restore
gonadotropin pulsatality, follicular development and ovulatory
function in exercising amenorrheic women.
51. Congenital GnRH deficiency
• Is seen in rarely, congenital specific mutation that prevents normal GnRH
neuronal migration during embryogenesis or to mutation in the pituitary
GnRH receptor.
• Kallmann Syndrome is Congenital GnRH deficiency associated with
anosmia or hyposmia, classical X linked disorder, caused by genetic
mutation in the KAL gene. Kallmann syndrome can be inherited in
autosomal dominant or recessive fashion.
• Idiopathic isolated GnRH deficiency is a similar condition but anosmia is
not a feature.
• GnRH Receptor Mutations- There are more than 20 inactivating mutations
in the GnRH receptor gene (GNRHR). Some results in interference with
normal Signal transduction, some effectively prevent GnRH binding, both
results in resistance to GnRH stimulation.
52. Disorder of Anterior Pituitary
• MC by far is benign Adenomas, Other include craniopharyngioma, meningiomas,
gliomas, metastatic tumours and chondromas.
• Pituitary adenomas may be functional (hormone secreting) or non functional.
• Tumours less than 10mm-- Microadenomas
• 10mm or larger-- Macroadenomas.
• Incidentally diagnosed while evaluating for neurological Symptoms or workup of
menstrual irregularities.
• The MC neurological symptoms a/w macroadenomas is visual impairment,
classically Bitemporal hemianopsia, other include decreased visual acuity, diplopia,
headache, CSF rhinorrhoea, pituitary apoplexy.
• Treated with Dopamine agonist bromocriptine recommended dose is 1.25mg at
bedtime daily for the first week and then gradually increased.
• Cabergoline given in dose of 0.25mg once or twice weekly till tumour shrinks.
• Trans sphenoidal resection of tumour is done if medical therapy fails
53. • During pregnancy, the pituitary gland enlarges due to estrogen
stimulation of lactotroph cells. This enlarging tissue may compress
the superior hypophyseal artery, making vulnerable to changes in
blood supply.
• Acute infarction and ischemic necrosis of the pituitary gland
resulting from postpartum hemorrhage and hypovolemic
hypotension
• PRESENTATION:
• Failed lactation after delivery (classical presenting symptom).
• others: lethargy, anorexia, weight loss, secondary amenorrhea,
loss of sexual hair and fatigue.
• Deficiencies in GH, prolactin, and gonadotropins are most
common. Others include ACTH and TSH deficiencies.
• MX---Replacement of deficient hormones is necessary in majority
of cases to maintain quality of life.
Sheehan’s Syndrome
54. • Hypothalamic and pituitary Amenorrhea is an underestimated clinical
problem.
• It is related to profound impairment of reproductive functions including
anovulation and infertility.
• There may be skeletal system, cardiovascular system and mental problems.
• Decrease of BMD, which is related to an increase of fracture risk.
• Osteopenia and Osteoporosis are the main long-term complications of
Hypothalamic Amenorrhea.
• Cardiovascular complications include endothelial dysfunction and
abnormal changes in the lipid profile.
• Significantly higher depression and anxiety and also sexual problems.
• Amenorrhea patients should be carefully diagnosed and properly managed
to prevent both short- and particularly long-term medical consequences.
55. Asherman’s syndrome
• An acquired condition that refers to the existence of scar tissue in the endometrial
cavity . This scar tissue makes the walls of the uterus adhere and reduces the size of
the uterine cavity. It is also known as intrauterine synechiae or intrauterine
adhesions (IUA).
• Vigorous curettage of gravid or non-gravid uterus accounts for 90 % cases. It can be
due to a single D & C or multiple similar procedures. This causes damage to basal
endometrium layer leading to IUA. Chances of adhesions are more likely even after
post partum or post abortal D&C done two to four weeks after delivery or abortion.
• Myomectomy also increases the risk of IUA. Scar tissue after Caesarean section or
from sutures used to stop haemorrhages is an important cause of IUA. It was seen in
19-27% of women receiving compression sutures to control PPH.
• Acute and chronic infections of the reproductive organs causing endometritis like
mycobacterium tuberculosis, chlamydia and schistosomiasis.Following septic
abortion.
• Radiation treatment for carcinoma cervix
57. Classification of Asherman’s Syndrome
Toaff and Ballas classified IUA on the basis of appearance of endometrial cavity in HSG in 1978.
March's classification by hysteroscopy was also introduced in 1978.
58. Types according to site
• Depending on the site and severity of the adhesions, AS is divided
into the following types:-
● Intrauterine fibrosis without visible adhesions or obliteraon of cavity
(Unstuck Asherman's or endometrial sclerosis)
● Cervical canal atresia or atretic amenorrhoea
● Uterine cavity adhesions
▪Central adhesion without obliteration of cavity
▪Partial obliteration and constriction of the cavity
▪Complete obliteration of whole cavity
●Uterine cavity combined with cervical canal adhesion
59. Clinical Presentation :
●Hypomenorrhea: scanty flow or secondary Amenorrhea usually
following dilatation and curettage
● Severe cramping pain during menstruation Inferlity and recurrent
implantation failure (RIF) due to insufficient vascularity
● Recurrent pregnancy losses (RPL)
● Placenta previa and placenta accreta
● Intra-uterine growth retardation
• Scanty or no withdrawal bleed with exogenous hormones
60. Diagnosis
• Hysterosalpingography. This has a sensitivity of 75 to 81% with a
specificity of 80%. The extent and location of synechie can be easily
seen in HSG . The radiographic image depends on the site and severity
of disease. IUA typically shows multiple, irregular linear filling defect
.When there is extensive symmetrical obliteration of uterine cavity the
uterus may appear small and in severe cases cavity is not visualised at
all.
61. • 2 D and 3 D USG with Colour doppler: a very thin irregular echogenic
endometrium with very little or no colour flow in the base is usually
seen . Different sizes of endometrial cavity may be seen at different
level.
• Saline infusion sonography (SIS ) / Sonohysterography : SIS uses saline
solution that flows into the uterus to make imaging clearer. It is a safe
and accurate method of endometrial cavity evaluation.
• MRI: This can be of use when adhesions involve the endocervical
canal.
• Investigations- to detect tuberculosis, chlamydia or schistosomiasis.
• Hysteroscopy. The best way to diagnose and manage Asherman's
syndrome is hysteroscopy. IUA can be easily diagnosed and treated in
the same sitting. The European Society for Hysteroscopy classification
of intrauterine adhesions grades AS as follows:-
64. Treatment
• Operative hysteroscopy: sharp dissection by scissors
As a rule adhesions are removed from the lower part of the uterus
to upper part. Flimsy and central adhesions are dealt first f/b lateral
and dense adhesions
• Thermal/ laser or electro dissection
• Use of a sharp needle (Touhy needle) - do not cause thermal damage
to the residual endometrium and has lesser chance of perforating the
uterus during surgery. It is done under fluoroscopic guidance under
GA and image intensifier control .
65. STEPS TO PREVENT REFORMATION
• After adhesiolysis the one or more of the following measures may be taken
to prevent reformation of intra-uterine adhesions:-
a. Mechanical separation of anterior wall and posterior wall by an
intrauterine contraceptive device followed by hormonal therapy for
regeneration of the endometrium:
Intra uterine device
Foley's catheter ( paediatric size)
uterine balloons
Supplementation with 4-6mg of estradiol for 30 days along with MPA 10mg
in the last 10 days of estradiol supplementation is given.
b. Anti-Tuberculous therapy: If hysteroscopic finding suggest endometrial
Koch's infection then ATT is given in full dose and regime.
66. c. Treatment of PID for chlamydia with Doxycycline is started
d. Hyaluronic acid: In the past decades hyaluronic acid was used to
prevent intraperitoneal and intrauterine adhesions formation.
Newer interventions to restore normal endometrium include the
following :
a. Pharmacological interventions: Estradiol valerate, Sildenafil and
Nitric oxide.
B. Stem cells transplantation-- intra-uterine infusion of autologous stem
cells.
C. Fresh platelet rich plasma (PRP): Intra- uterine infusion of freshly
prepared PRP along with estradiol valerate 12 mg. This can be repeated
after 72 hours.
Post-operative assessment Diagnostic hysteroscopy and repeat surgery
if required is done mostly after three months of the initial procedure.
67. CERVICAL STENOSIS
CAUSES:
• conization, LEEP
• Dilatation and curettage
• Neoplasia, Radiation
• Congenital
•spotting after menses—>most common complaint,
however amenorrhea is rare
•DIAGNOSIS: Inability to pass dilator through the os
•The treatment for cervical stenosis is careful dilation,
ideally performed under ultrasound guidance.
•Temporary placement of a urinary or specialized balloon
catheter for an interval of approximately 2 weeks provides
ongoing drainage of the uterine cavity and may help to
prevent recurrence.
68. Developmental anomalies causing amenorrhea
• After the 5th week of IUL, two Mullerian ducts grow
towards each other in the midline. Fusion of the
lateral portions of these ducts start to occur in a
caudocranial direction from 7-8 wks of IUL and is
completed by 12 weeks of IUL with formation of a
uterovaginal canal. Fusion results in the formation of
a midline septum which gets resorbed from below
upwards and resorption is completed by 20 weeks of
IUL. Concavity of the fundus of the uterus changes
to dome shaped. The fallopian tubes, uterus, cervix
and upper part of vagina including the fornices are
of Mullerian origin.
• A solid vaginal cord from the lower end of the fused
uterovaginal canal elongates and vertically fuses
with the sino vaginal bulbs from the(endodermal)
urogenital sinus by 8 weeks IUL. This results in a
vaginal plate formation. Most of the vagina is
formed by the canalization of the vaginal plate
between 20-26 weeks IUL.
69. Mullerian anomalies
can be defects in any
one or more of the
following:
1) Synthesis
2) Fusion
3) Resorption
70. Mullerian Agenesis
Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome
• Complete absence of uterus, cervix and the upper 2/3 of the vagina
• Incidence 1/5000 (1/4000-1/10,000 female newborns)
• Normal XX Karyotype
• Normal ovarian function
• Otherwise normal pubertal development
• Mullerian agenesis is the second most common cause(10-15%) for Primary
amenorrhoea
• Most cases are sporadic but a few familial have been seen.
• An association with errors in fetal or maternal galactose metabolism
(galactose-1- phosphate Uridyl transferase GALT gene mutations ) resulting
in increased intrauterine galactose exposure and mullerian anomaly has
been noted.
Deligeoroglou et. Al 2010 & ASRM Practice Committee. Amenorrhea. Fertil Steril 2008.
71. Genes involved
• Mutations in AMH Gene Or AMH Receptor gene
• Association with WNT gene/ GALT gene mutation
• There are also isolated reports of HOX ,WNT4 and HNF1B gene
mutations but exact causative factor is still unknown.
72. Classification
• Type A (typical) (64%)- isolated symmetrical uterovaginal aplasia /
hypoplasia
• Type B(atypical)( 24%)- asymmetrical UV aplasia/hypoplasia with
malformations of tubes, ovaries +/- renal system
Associated Conditions:
• concurrent urinary tract anomalies
• Ex: Ectopic kidney, renal agenesis, horseshoe kidney
• associated skeletal anomalies
• Ex: spinal anomalies, absent digits, webbed fingers, toes
• Type C (MURCS) (12%)-Mullerian duct aplasia, renal dysplasia,
cervicothoracic somite anomalies(heart and skeletal)-may be
familial(WNT4 gene mutations)
73. Presentation
• Pubertal age girl of normal stature with well developed secondary
sexual characteristics presenting with primary amenorrhea.
• Cyclic pain is usually absent in Mullerian agenesis unless functioning
endometrium is present.
• On examination there will be a vaginal dimple or 1-2 cm blind ending
vaginal pouch with otherwise normal external female genitalia. This is
the part of the vagina that develops from the urogenital sinus.
The diagnosis of MRKH can be arrived at with history and
examination but karyotyping is justified to rule out Complete
Androgen Insensitivity Syndrome (46,XY) which can present in a
similar fashion. Male sex hormones in MRKH are in the normal
female range. Absence of uterus with presence of ovaries can be
made out with an ultrasound scan but MRI is more accurate to
delineate finer details as well as pick up urological anomalies.
75. Management
• Empathetic counselling.
• Management is essentially aimed at achieving a fair length of vagina
for coital function.
• If there is the rare functioning endometrium, then laproscopic
removal of the uterine remnant should be done.
• She should be assured that vaginoplasty gives good results when
done by trained specialists.
• She and her partner can have their genetic offspring by IVF with their
own gametes and surrogate uterus.
• There is also the option of uterine transplantation that has evolved
tremendously over the past decade.
77. Dilators
• Frank (active)
• Dilate at a 15 degree angle daily after warm bath for 20 minutes.
• Progressively work up to larger dilators
• Success defined as non-painful intercourse or vaginal length of 7cm
• Studies demonstrate up to an 88% success rate at 19 months of use.
78. Ingram (passive)
• The patient is instructed to sit on a dilator fixed to a specially
designed bicycle seat every day for at least 2 hours. The diameter of
the dilator is increased on an average every month.
• Patient may be allowed to have coitus after the use of the largest
dilator for 1 or 2 months. Otherwise continued dilation is required .If
dilatation is unsuccessful or unacceptable, operative vaginoplasty is
indicated.
79. Surgical
• Abbe-Wharton-McIndoe operation - gold standard technique for
vaginoplasty.
• The principles to be followed are
(a) dissection of an adequate space between the rectum and the bladder
(b) Inlay split-thickness skin grafting and
(c) cardinal principle of continuous dilatation during the contractile phase of
healing.
After inserting an indwelling urethral catheter and a finger in the rectum, a
transverse incision is made on the mucosa of the vaginal vestibule and
dissection of the space between the bladder and rectum carefully until the
under surface of the peritoneum is reached. This creates the neovaginal
surface.
80.
81. The Counseller - Flor modification of the McIndoe technique uses a
sterilised foam rubber mould shaped for the vaginal cavity from a foam
rubber block and covered with a condom.
• Success rates in recent times is 80-100 %.
• Buccal mucosa is being increasingly used as it has tissue similarities
compared to native vagina with excellent healing and no visible scar.
• There are also exciting reports of the use of autologous in vitro grown
vaginal tissue.
82. Vecchietti procedure
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
intraperitoneally.
Traction device used to pull mold up 1-1.5 cm per day for 7- 10
days.
Thereafter standard dilator usage
83. • Williams vulvo vaginoplasty A horse-shoe incision is made in the
vulva and skin is mobilized to form the perineal pouch /neovagina.
• Colovaginoplasty/ Ruge procedure It involves formation of a
neovagina using sigmoid colon grafts.
• Davydov procedure This technique uses peritoneum to line the
neovagina.
84. Imperforate Hymen
• Most common obstructive lesion of
the female genital tract
• 1/1000 female births
• Classic appearance of bulging, blue-
domed, translucent membrane
• Can present with hematocolpos or
urinary retention
• Differs from vaginal septum in that an
imperforate hymen bulges with
valsalva
• Treatment: Surgical Resection
• Hymenectomy versus
hymenotomy
85. • TREATMENT- HYMENOTOMY
• Definitive surgery - as delay leads to development of severe
endometriosis & infertility
• OBJECTIVE-to open the hymenal membrane to leave a normal patent
vaginal orifice Simple cruciate incision in the hymen to the base of the
hymeneal ring & excise its central portion for drainage of sequestered
menstrual fluid
87. Transverse Vaginal Septum
• Failure of canalization of distal third of the vagina
• Most common in upper and middle third of vagina
• Diagnosis
• Usually present after puberty with amenorrhea and pelvic pain
• Normal vaginal orifice, shortened vagina and no visible cervix
• Palpable hematocolpos, hematometra
• Does not bulge with valsalva maneuver
• MRI helps with diagnosis
TREATMENT
Surgical excision with primary anastomosis / graft application for atretic
segments.
88. Androgen Insensitivity
• Male pseudo hermaphroditism /
Testicular Feminisation
• Male karyotype (46,XY) /
phenotypically female;
normal at birth
• Inactivating mutation in the
gene encoding the intracellular
androgen receptor (Xq )
89. Androgen Insensitivity
• Incidence 1/60,000
• although 9% of causes of primary amenorrhea
• Genetics: X-linked recessive
• Phenotype: Female;
• Genotype: XY
• Female external genitalia –underdeveloped with
small vaginal dimple
• Absent uterus and cervix.
• Cryptorchidic gonads
• Absent axillary and pubic hair
• Breast development
• Cause:
Mutations in the androgen receptor
90. Androgen Insensitivity
• Physical Examination:
• Slim and taller than average female/ enuchoid appearance
• Large breasts with juvenile nipples
• Absent pubic/axillary hair, no acne or other signs of androgen action
• May have inguinal hernia
• Underdeveloped labia minora, blind vaginal pouch and absence of midline
structures
• Laboratory: Testosterone in the normal to high male range, elevated serum LH
levels
• Karyotype: confirms diagnosis XY
92. TREATMENT
• Creation of a functional vagina
• Gonadectomy- laparoscopically/inguinal incisions
In Complete AIS, gonadectomy – delayed
Smooth pubertal development
Gonadal tumours occur rarely before puberty
• In Incomplete AIS, Partial AIS prompt gonadectomy
prevents unwanted virilisation
could be with ambiguous genitalia
• Hormonal Therapy-long term estrogen treatment
• Appropriate psychological counselling for both patient and parents
5-10%; overall incidence of gonadal
tumours
93. Androgen Insensitivity: Removal of Gonads
• Location of testicular gonads is variable
• Intrabdominal cavity/ Labio scrotal folds/Inguinal region
• Recommend removal after complete pubertal development
• Enhance bone maturation and puberty
• Recommend at age 16-18
• Once testes removed, treat with hormone replacement
therapy,
Gonadectomy followed by neovagina creation
Female identity reinforced rather than questioned
94.
95. • Incomplete or defective formation of the gonads,
resulting from a disturbance in germ cell migration or organization
Cause of primary amenorrhea (30-40%)
Turner syndrome - MC cause of gonadal dysgenesis
GONADAL DYSGENESIS
96. • 45 X Karyotype
• Assortment of structural X chromosome abnormalities such as
deletions, ring and iso –chromosomes
• Mosaicism
• Incidence-1 in 2,000-5,000 live born phenotypic females
J Clin Endocrinol Metab 2007
Classically 45 XO or mosaic
99% of pregnancies affected end in spontaneous abortions
Turner’s Syndrome
97. Turner’s Syndrome
• Cause:
• Absence of ovarian determinant gene
result in premature loss of germ cells
• Fetuses with Turner’s have the same amount of germ cells at
midgestation as do 46, XX
• As gestation continues, accelerated loss of germ cells occurs
• Many XO individuals lose all germ cells prior to birth;
• less than 15% have enough germ cells to start pubertal process by
adolescence
15% begin but do not complete pubertal development
5% complete puberty and begin menstruation
98. • Short stature (loss of one copy of
SHOX gene on X chromosome)
• Absence of sexual development
• Webbed neck
• Low set ears and posterior hairline
• Widely-spaced nipples (“shield
chest”)
• Short fourth metacarpals
• Increased carrying angle at the
elbow (“cubitus valgus”)
Turner’s Syndrome
99. Turner’s Syndrome
• 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)
Turner’s Syndrome
100. DIAGNOSIS
• Karyotype
- include examination of at least 30 cells, to detect significant mosaicism
5% women with Turner syndrome have a karyotype containing all or
part of a Y chromosome
Evaluation
• CBC, LFT, KFT, Blood Sugar, Lipid Profile (every 2yrs)
• TSH & FT4 (every 1-2 yr)
• Anti Endomysial antibody ( for coeliac disease at time of diagnosis)
• Renal USG (normal-once, abnormal 3-5yrs)
• Audiometry (teen, every 10 yrs)
• ECHO (once btw 12-15 yrs, normal -every 5yrs,abnormal-more often)
• MRI aorta- Periconceptional
• FISH analysis
FISH analysis is most clearly
indicated for those exhibiting any
evidence of virilization or having a
chromosomal fragment of
uncertain origin
101. Clinical management
• Those with coarctation of aorta should undergo surgery for its correction.
Growth hormone therapy should begin as soon as height falls below the 5th
percentile. (2-8 yrs) - 0.375 mg/kg weekly dose in 7 divided doses upto 7 yrs
Delayed diagnosis (9-12yrs) - GH + anabolic steroid Oxandrolone 0.05 mg/kg/d.
help to maximize growth for older girls.
Estrogen therapy decreases height velocity and gain in height. Therefore generally
not recommended before age 13 or14 yrs
102. TREATMENT
• Estrogen treatment should begin at a low dose(0.25-0.5mg micronized estradiol
or its equivalent) and increase gradually at 3-6 months interval until reaching the
final dose( 2 mg micronized estradiol)goal is to complete sexual maturation over a
period of 2-3 yrs .Continue till menopausal age
• Cyclic progesterone ( medroxy progesterone acetate 5mg daily for 12-14 days of
each month) should begin after the first episode of menstrual bleeding or after
12-24 months of treatment
• OCP s good for long term use
103. Fertility
• All TS counselled about ability to conceive decreasing with age.
• Spontaneous pregnancies in 4.8-7.6 % but miscarriage rate in such is
30.8-45.1%
• Young mosaic should be counselled about fertility preservation
• For most OD is only way to achieve viable pregnancy.
• Intensive cardiac screening before pregnancy
• High risk of obstetrical complications like preeclampsia & c-section
104. PERIODIC MEDICAL EVALUATUION IN TURNER SYNDROME
No. test Follow up , if normal If abnormal
1 2D ECHO 5 yearly More frequently depending on abnormality
2 USG KUB Once in lifetime
every 3-5 years, More frequently depending on
abnormality
3 T4, TSH 1-2 yearly More frequently depending on abnormality
4 FBS,lipid profile,LFT,KFT 2 yearly More frequently depending on abnormality
5 Audiometry 10 yearly More frequently depending on abnormality
6 Anti endomysial ab Once in lifetime( for celiac disease)
105. Gonadal Dysgenesis XY -SWYER SYNDROME
Swyer syndrome is a condition in which people with one X chromosome and one Y
chromosome (normally present in males) have a female appearance.
• They are typically raised as females, have a female gender identity, have typical
female external genitalia, and have a normal uterus and Fallopian tubes.
• However in place of functional gonads (ovaries or testes), they have
undeveloped, residual gonadal tissue called streak gonads. Streak gonads often
become cancerous, so they are usually surgically removed as early as possible.
• Swyer syndrome may be caused by mutations in any of several genes. The
inheritance pattern depends on the responsible gene.
106. Gonadal Dysgenesis: 46 XY Swyer Syndrome
• Cause: Associated with deletion in sex determining region (SRY gene) On Y
chromosome
• Streak gonads present; No testes formation
• Anti-Mullerian hormone and testosterone are not produced hence
• 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 they are at increased risk (25%) for germ cell
tumors: most common Gonadoblastoma ,Dysgerminoma
• Estrogen therapy & progestin therapy .
• Pregnancy can be achieved with IVF using donor oocytes.
108. Complete AIS
• tall women with XY chromosomes
• Absent sexual hair
• Breast development present
• Could have family history
• Undescended testes, no scrotum or penis
• No uterus only blind vagina but normal external
genitalia
• Testosterones adequate, FSH & LH mildly elevated
• Late gonadectomy, only HRT with estrogen,
Neovagina
• Donor oocyte with surrogacy required for fertility
issue
Swyer
• Taller women with XY chromosomes.
• Lower bone density, no pubertal development
• Breast development absent
• No family history
• Streak gonads
• Normal female genitalia, normal uterus and
fallopian tubes
• No testosterone or AMH, very high FSH and LH
• Require HRT after Gonadectomy estrogen Plus
Progesterone
• Pregnancy by Donor eggs possible
109. 46 XX GONADAL DYSGENESIS
• XX gonadal dysgenesis is a type of female hypogonadism in which no
functional ovaries are present to induce puberty in an otherwise
normal girl whose karyotype is found to be 46,XX.
• With nonfunctional streak ovaries she is low in estrogen levels
(hypoestrogenic) and has high levels of FSH and LH.
• Estrogen and progesterone therapy is usually then commenced
110. RESISTANT OVARY SYNDROME
previously known as Savage syndrome, is a cause of ovarian
failure that can lead to secondary amenorrhea.
• Resistant ovaries result from a functional disturbance of the
gonadotropin receptors in the ovarian follicles. It may be a cause of
primary or secondary amenorrhea and is resistant to exogenous
gonadotropin stimulation.
• Diagnosis of this condition requires that the patient has a normal
46,XX karyotype, normal secondary sexual characteristics, elevated
plasma follicle-stimulating hormone and luteinizing hormone – in
the menopausal range – and that normal, multiple follicles are seen
on ovarian biopsy.
• Spontaneous reversal of the receptor resistance may occur.
111. Primary Ovarian Insufficiency
• Primary ovarian insufficiency affects approximately one in 100
females and is defined by follicle dysfunction or depletion, with
cessation of menses before 40 yrs.
• It is diagnosed in patients <40 years with 2 S. FSH levels in the
menopausal range (>30 IU) obtained at least one month apart.
• Clinically Vasomotor symptoms and vaginal dryness are common.
• 5–10% of women with POI experience spontaneous conception and
delivery.
112. Diagnostic criteria for POI
Diagnostic criteria for POI
• Younger than 40 years of age
• Oligo/amenorrhoea lasting 4 months
• Two FSH levels ≥ 30 iu/ml one month apart
113. ETIOLOGY
• X mosaicism , 50% - abnormal karyotype , gonadal dysgenesis
chromosomal: pre mutation of FMR 1 GENE
• Age, types of medication, and number of doses
• alkylating agents or procarbazine
• Pelvic irradiation (especially doses more than 10 Gy)
Chemo radiation
Environmental factors- smoking, alcohol, poor nutrition, exposure
to solvents, pesticides.
Endocrinopathies: hypothyroidism, hypoadrenalism
Autoimmune: anti adrenal, anti TPO/ thyroglobulin, ovarian
antibodies
Infectious/infiltrative- herpes zoster, CMV , mumps oophoritis
Rare genetic: mutation of gene encoding
receptor/enzyme/regulator
114. POF
• Most cases are idiopathic
• A karyotype is abnormal in approximately one-third of patients with primary
amenorrhea, and it should be offered to all patients with a diagnosis of primary
ovarian insufficiency to identify Turner syndrome (or variants), (mostly present
<30 yrs age)
• Patients diagnosed with primary ovarian insufficiency should be offered testing
for FMR1 gene premutation, which confers the risk of fragile X syndrome in
children.
• Testing for thyroid and adrenal antibodies and annual or biennial screening for
hypothyroidism.
115. ETIOPATHOGENESIS
• It could be spontaneous or induced and includes chromosomal,
genetic, autoimmune, metabolic, infectious, environmental or
idiopathic causes.
• The two main pathogenic mechanisms causing POI are - follicle
depletion and follicle dysfunction.
• Galactosemia:
—Autosomal recessive disorder.
—Deficiency of enzyme of galactose 1- phosphate uridyl transferase
—Affected women have fewer primordial follicles due to toxicity of
galactose metabolites.
116. Etiopatho. Of POI
• POI occurs through two main mechanisms:
(i) inadequate formation of the follicular pool in utero; and
(ii) abnormally extensive or fast depletion of the follicular pool via atresia
during post-natal (neonatal, childhood and adult) life.
• POI should not be equated with menopause. The main difference lies in
the fact that with POI, ovarian function can still be present albeit
unpredictable and/or intermittent.
• Moreover, it is believed that roughly 50% of women with POI retain
intermittent ovarian function for many years, may exhibit spontaneous
follicular development, and commence menstruation (Rebar and Connolly,
1990).
• This is strongly supported by the fact that 5%–10% of women with POI can
conceive (van Kasteren and Schoemaker, 1999) and deliver a child (Rebar
et al., 1982; Nelson et al., 2005) without any medical intervention, even
years after diagnosis was established. Similarly, Hipp et al. (2016) reported
117. PRESENTATION
• The most common presenting symptom – amenorrhea– PRIMARY OR
SECONDARY.
• Hot flushes or vaginal symptoms like dryness or dyspareunia, abnormal bleeding
patterns
• Family history of early menopause
• Investigations:
- basal FSH and basal estradiol levels
- Anti mullerian hormone testing
119. Fragile X syndrome
• Fragile X syndrome (FXS), also called Martin-Bell syndrome, is a non-Mendelian
trinucleotide repeat disorder. FXS is the most prevalent inherited cause of mild to
severe intellectual disability and the most common monogenic cause of autism
spectrum disorder (ASD). It accounts for about one-half of cases of X-linked
mental retardation and is the most common cause of mental impairment after
trisomy 21.
• Fragile X syndrome has traditionally been considered an X-linked
dominant condition with variable expressivity and possibly
reduced penetrance.However, due to genetic anticipation and X-inactivation in
females, the inheritance of Fragile X syndrome does not follow the usual pattern
of X-linked dominant inheritance, and some scholars have suggested
discontinuing labelling X-linked disorders as dominant or recessive.[47] Females
with full FMR1 mutations may have a milder phenotype than males due to
variability in X-inactivation
120. FRAGILE X SYNDROME
• Genetic disorder which occurs as a result of a mutation of the Fragile X messenger
Ribonucleoprotein X (FMR1) gene on the X chromosome, most commonly an increase in the
number of CGG trinucleotide repeats in the 5' untranslated region of FMR1.
• Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females.
• In unaffected individuals, the FMR1 gene contains 5–44 repeats of the sequence CGG, most
commonly 29 or 30 repeats. Between 45 and 54 repeats is considered a "grey zone", with a
premutation allele generally considered to be between 55 and 200 repeats in length.
• Although the onset of menstruation appears normal among premutation carriers, approximately
1% experience their final menses before 18 years.
• If personal or family history of ovarian failure or an elevated FSH levels before age 40 years
without a known cause, fragile X premutation carrier testing should be offered.
121. • Individuals with fragile X syndrome have a full mutation of
the FMR1 allele, with over 200 CGG repeats. These individuals with a
repeat expansion greater than 200, there is methylation of the CGG
repeat expansion and FMR1 promoter, leading to the silencing of
the FMR1 gene and a lack of its product.
• This methylation of FMR1 in chromosome band Xq27.3 is believed to
result in constriction of the X chromosome which appears 'fragile'
under the microscope at that point, a phenomenon that gave the
syndrome its name.
• A subset of people with intellectual disability and symptoms
resembling fragile X syndrome are found to have point mutations
in FMR1. This subset lacked the CGG repeat expansion
in FMR1 traditionally associated with fragile x syndrome
122. Clinical features
• Long face with long palpebral fissures as well as a broad philtrum
• Prominent forehead and protruding ears with soft cartilage
• High-arched palate and dental crowding
• Hyperextensible finger joints and thumbs
• Hypotonia
• Biting, hand flapping, poor eye contact, language disorders from cluttered
speech to complete lack of speech depending on phenotype severity
• Mild to profound intellectual disability.
• The behavioural phenotype includes ADHD, speech and language
delay, anxiety and autism spectrum disorders.
• POF in females
124. Diagnosis and management
• The fragile X abnormality is now directly determined by
analysis of the number of CGG repeats using polymerase chain
reaction (PCR) and methylation status using Southern
blot analysis.
• There is no cure for the underlying defects of FXS. Management
of FXS may include speech therapy, behavioral
therapy, occupational therapy, special education, or
individualised educational plans.
125. Diagnosis and Initial Evaluation of Primary
Ovarian Insufficiency
• Menstrual irregularity for at least 3 consecutive months
• FSH - greater than 30–40 mIU/mL and estradiol levels - less than 50 pg/mL (two
random tests at least 1 month apart)
• Prolactin and TFT, anti TPO antibodies
• Pelvic ultrasonography
• If diagnosis is confirmed:
• Karyotype
FMR1 premutation, Turner mosaic
• Adrenal antibodies
— 21-hydroxylase (CYP21)
129. Hyperprolactenemia
• M/C endocrine disorder of the hypothalamic-pituitary axis.
• Presents as an ovulatory disorder
• Often associated with secondary amenorrhea or oligomenorrhea,
galactorrhoea and osteopenia.
• Prolactin plays a pivotal role in a variety of reproductive functions.
• Prolactin is a 198-amino acid protein (23-kDa) produced in the
lactotroph cells of the anterior pituitary gland.
• Prolactin is under dual regulation by hypothalamic hormones
delivered through the hypothalamic–pituitary portal circulation.
• Inhibitory signal is mediated by the neurotransmitter dopamine.
• The stimulatory signal is mediated by the hypothalamic hormone
thyrotropin-releasing hormone.
130. Etiology
• Hyperprolactinemia can be physiological or pathological.
• Prolactinomas account for 25-30%
They typically present with oligomenorrhea,
amenorrhea, galactorrhea, or infertility.
Prolonged hypoestrogenism secondary to
hyperprolactinemia causes osteopenia.
131. Medication induced hyperprolactinemia
• Psychotropic medications.
Neuroleptics act by blocking dopamine receptors. Serotonin
uptake inhibitors may increase prolactin levels by increasing
serotonergic inhibition of dopaminergic neurons.
• Other medications.
Gastrointestinal motility agents and antihypertensives have also
been associated with hyperprolactinemia. Serum prolactin levels
increase 6-fold after oral or iv metoclopramide and domperidone
also stimulates prolactin release. Methyldopa, an α-adrenergic
agonist, and verapamil, a calcium-channel blocker, both increase
prolactin levels, likely by decreasing dopamine synthesis.
132.
133. • A single measurement above the upper limit of normal confirms the diagnosis
given the sample was obtained without excessive veni puncture stress.
• When in doubt , sampling repeated on a different day at 15-20 mins intervals to
account for possible prolactin pulsatility.
• PITFALLS IN DIAGNOSIS:
-Macroprolactin-
less bio-active form, dimer/polymer, detected by polyethylene glycol precipitation
method although gel filtration chromatography remains the gold standard.
-Hook effect- serial dilution of serum samples to eliminate an artefact that
can occur with some immune-radiometric assays
Serum TSH, blood urea nitrogen and creatinine.
134. Role of MRI
• A mildly elevated serum prolactin level may be due to a non
functioning pituitary adenoma or craniopharyngioma compressing
the pituitary stalk.
• Prolactin levels that are very high (>250 ng/mL) are almost always
associated with a prolactinoma.
• Magnetic resonance imaging (MRI) with gadolinium enhancement
provides the best visualization of the sellar area.
135. MANAGEMENT
• The goals of treatment for are
● Normalization of prolactin level
● Restoration of gonadal function and fertility
● Avoidance of the adverse effects of chronic hyperprolactinemia like
osteoporosis.
• An additional goal of treatment in macroprolactinoma patients is
tumour shrinkage with relief of mass symptoms.
• Current therapeutic options include medical therapy, surgery and
radiotherapy
136. Drug induced hyper prolactinemia
• Gastric motility drugs should be stopped and some other medication
with no CNS side effects can be started after the treating physician
consultation.
• Continuation of other medications depend upon risk : benefit ratio.
• Whether to treat a patient who has anti psychoctic drug-induced
hyperprolactinemia with a dopamine agonist remains controversial.
Some studies suggest that dopamine agonist therapy will normalize
prolactin levels in only up to 75% of such patients but may lead to
exacerbation of the underlying psychosis.
• The treating psychiatrist should be consulted for any change in
psychotropic regimen.
137. TREATMENT
• Depends on cause.
• Dopamine agonist-
1. Bromocriptine
- Dose: 1.25mg daily,increase by 1.25 mg weekly
-Therapeutic dose range:2.5-15 mg /day in divided doses
2.Cabergoline
-selective dopamine type 2 agonist
- fewer side effects, greater potency, longer duration of action
-Side effects: with long term use—> valvular heart disease
- Dose : 0.25-0.5 mg once/twice weekly upto 3 mg.
continued for approximately 12- 24 months (depending on the degree of
symptoms or tumour size) and then withdrawn if prolactin levels have returned
to the normal range)
Response to therapy should be monitored by checking fasng serum prolacn levels
and checking tumor size with MRI.
138. Surgery
• Trans-nasal/trans-sphenoidal microsurgical excision of prolactinoma
is the procedure of choice.
• Recurred within 5 years after surgery in about 50% of patients with
micro prolactinomas who were initially thought to be cured.
• Radiotherapy should be reserved for resistant or malignant
prolactinomas.
139. •Regardless of the size of the adenoma, there is no indication for
treatment with dopamine agonists or for imaging during
pregnancy in the absence of symptoms; treatment may be safely
discontinued when pregnancy is established.
•Breastfeeding poses no significant risk for tumor growth in
women with micro adenomas or macro adenomas that remain
asymptomatic during pregnancy, but is contraindicated for those
with neurologic symptoms at the time of delivery.
Management During Pregnancy
140. • The most commonly prescribed treatment for menstrual abnormalities in
PCOS is the combined oral contraceptive (COC) pill. It provides
endometrial protection through its progesterone and thus stunts
endometrial growth from unopposed estrogen and cycles regularise with
lighter bleeding.
• Besides, COCs are effective for suppressing LH-mediated ovarian
androgenesis, thus correcting the hyperandrogenic milieu.
• Estrogen is contraindicated in some women, in them progesterone-alone
preparations can be used either in a continuous or a cyclical form.
AMENORRHEA IN PCOS-- MANAGMENT
142. THYROID DISORDER
• Both primary hypothyroidism(elevated TSH) and primary
hyperthyroidism (low TSH) may result in chronic anovulation and
amenorrhea- primary or secondary amenorrhea.
• Few women with hypothyroidism will develop a secondary
hyperprolactinemia and even Galactorrhoea. The likelihood of
hyperprolactinemia increases with the duration of hypothyroidism
Mechanism:
• gradual depletion of hypothalamic dopamine (prolactin-inhibiting factor)
• constant stimulation of pituitary lactotropes by thyrotropin-releasing hormone
(TRH), which may cause pituitary hypertrophy or hyperplasia.
143. congenital adrenal hyperplasia (CAH)
• CAH is a family of inherited disorders
characterized by defects in cortisol
production, resulting in increased ACTH
production due to reduced negative
feedback and consequent adrenal gland
proliferation.
• Classic 21-OH deficiency is typically
diagnosed at birth and can present with
severe salt wasting and/or prenatal
virilization of external female genitalia.
• Nonclassic CAH presents postnatally with
signs of hyperandrogenism including
hirsutism, acne, frontal balding, and
menstrual irregularities.
144. • Although there are rare forms of CAH that result in inferltiity,
including 11β hydroxylase deficiency, 17α-hydroxylase deficiency and
3β-hydroxysteroid dehydrogenase deficiency.
• CAH most commonly arises from autosomal recessive mutations in
the gene that encodes 21- hydroxylase - (21-OH), CYP21A2, which
result in shunting of steroid precursors toward androgen biosynthesis.
145. • In –utero: Female external genitalia develop until 20 weeks and size of clitoris
depends on levels rather than timing of androgen exposure. Internal genitalia are
normal female type due to normal ovarian steroidogenesis and absence of AMH.
• Oligomenorrhea in women with 21-OH deficiency is likely due to elevated
androgen and/or progesterone levels that are associated with reduced LH-pulse
amplitude and frequency .
• Elevated levels of progesterone, a substrate of 21-OH, also likely contribute to
menstrual irregularity.
• Fertility is lower than normal, due to chronic anovulation, abnormalities of genital
anatomy, psychological factors, decreased sexual activity. Outcome of
pregnancies are normal except for increased incidence of GDM.
146. TREATMENT OF CAH
• To replace sufficient amounts of deficient hormones along with cortisol to reduce excess
ACTH secretion.
• In neonates – lifesaving
• In children - normal growth and sexual maturation.
• In adults - for hirsutism, menstrual abnormalities & infertility.
Prenatal treatment of mothers at risk for having an affected child:
begin dexamethasone CVS sex determination &
genotyping
dexamethasone (upto 1.5 mg in divided doses continued ONL Y IN AFFECTED FEMALE FETUS to prevent
virilization. Treatment should begin at 4-5 weeks and not later than 9 weeks.
Positive HCG
147.
148. CUSHING SYNDROME
•Most common cause: prolonged glucocorticoids
(e.g., prednisone) intake.
•Other:
• cortisol-secreting adrenal adenomas and
carcinomas
• ectopic production of ACTH
• corticotrophin-releasing hormone (CRH) by
brochial carcinoids
149. Presentation:
• Progressive central obesity
• moon face
• buffalo hump
• purple striae (abdomen and flanks)
• hyperpigmentation (caused by excess ACTH), which is most
noticeable in areas exposed to light (the face, neck, and back of
the hands)
• amenorrhea
• hirsutism and acne
• proximal muscle wasting and weakness
• osteoporosis
• glucose intolerance, diabetes
150. Diagnosis:
• 24-hour urinary free cortisol excretion (twice),
the late-night (11:00 P.M.)
• salivary cortisol level (twice)
• performing an overnight or low-dose
dexamethasone suppression test
(All the three screening tests have similar
diagnostic accuracy)
151. •overnight dexamethasone suppression test:
administer 1.0 mg of dexamethasone between 11:00
P.M. and midnight —>> measure the serum cortisol at 8:00
A.M. the following morning —>>value less than 1.8 mg/dL is
a normal result.
•low-dose dexamethasone suppression test:
administer 0.5 mg of dexamethasone every 6 hours over
2 days for a total of 8 doses—>> measure serum cortisol 2 or
6 hours after the last dose; as with the overnight test—>>a
value less than 1.8 mg/dL is a normal result.
152. Treatment
• trans sphenoidal surgery (the permanent cure rate
is approximately 70%).
• Bilateral total adrenalectomy —>> lifelong daily
glucocorticoid and mineralocorticoid treatment.
therapy:
• Radiotharapy
• those not cured by surgery.
• effective in approximately 45% of adult patients.
Hinweis der Redaktion
GnRN remains suppressed during childhood despite low estrogen levels.
At maturation- ativation of gonaostat??
Normal arm span is within 5cm of height
Mullerian Agenesis
Incidence: 1/5000
Presenting Sx: primary amenorrhea age 15-17 (second only to gonadal dysgenesis in cause of primary amenorrhea)
Characteristics: Really appear normal except they have amenorrhea. Usually normal secondary sexual development (breast, pubic hair etc). Several variations as alluded to in classification slide.
Cause: EXACT UNKNOWN?
Kataoka, ML. Togashi K, Yamaoka T, Koyama T, Ueda H, Kobayashi H, Rahman M, Higuchi T, Fujii S. Posterior cul-de-sac obliteration associated with endometriosis: MR Imaging Evaluation. Radiology. March 2005. (234) 815-823
1.) TVS can be complete or incomplete and situated in the upper, middle, lower
2.) Upper and Middle third vaginal septa are most prevalent
1. Mutations in the androgen receptor result in defective androgen action in target tissues
1.) Once germ cells are depleted, the only remaining tissue is connective tissue: hence the streak gonad.
