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Optional Course, Year VI- General Medicine

Clinical Embryology & Assisted Human


Reproduction

Female Infertility
Course 2

Asist. Univ. Dr. Raluca Tulin


Endocrinology/ Embryology Specialist
Profile: Anatomy
Embryology Departament, UMF Carol Davila;

Infertility
15% of couples
Pregnancy absence after a year of unprotected
sexual intercourse (6 months if f>35 years old)
Primary (no previous pregnancies)
Secondary (the couple already had a pregnancy/child)

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Ovogeneza si varsta

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Ovogenese
Long period (L3 IU 12-14 50 years)
in which the oocyte can be found in the
prophase of the reduction meiosis
(suspended prophase) this can lead to
chromosomal anomalies in elderly
mothers
High possibility of Down Syndrome when
it comes to mothers >35 years old
What is the age of your oocytes?????
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Ovulation
Releasing the secondary oocyte from
the ovary under LH action
Signs:
Cervical mucus volume increase,
white egg-like, alkaline, elastic
Ovulation tests
Mittelschmerz
Basal body temperature (+0.4-0.8 C)
AFTER ovulation
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Ovarian cycle is NOT Uterine cycle

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Ovarian cycle
Follicular phase
Ovulation
Lutheal phase

Body temperature
Gonadotropin
hormons (LH, FSH)
HH. Sexual (E2,
Progesteron)
Uterine cycle

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Menstruatin
Proliferative
Secretory

The boring hormonal life!!!


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Couple Infertility

In Africa, In the Sub-Saharan area -20-60% of couples are infertile

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Does age matter?


Age Class

births/1,000

15-19

41.6

20-24

102.6

25-29

115.6

30-34

95.1

35-39

43.8

40-44

8.7

45-54

0.5

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The Success of IVF

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Younger than 35:


Age 35-37:
Age 38-40:
Age 41-42:
Age 43:
Greater than 43:

42% Live birth


35.1% Live birth
25% Live birth
14.5% Live birth
5.9% Live birth
2.9% Live birth

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Causes of Female Infertility

Tubal
Ovulatory
Cervical
Others (Obesity BMI>30 or <19; smoking,
alcohol, recreational drugs)

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Investigating Female Infertility


Ovulation documenting

Measuring body temperature (high for more than 10


days)
Progesterone day 21 (>10 ng/ml )
FSH in day 3; if >15 mIU/mL ( low ovarian reserve or
early menopause)

Tubal factors

Hysterosalpingography for tubal permeability


Laparoscopy for peritoneal factor evaluation
Hysteroscopy

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Paraclinically History
AGE
History (menarche, MC, sexual history: sexual intercourse
frequency, pelvic pain, endometriosis (BIRTHS); drugs;
surgery; genetic illnesses; vaccinations;
Associated pathologies (thyroid, hirsutism, acne, breast
discharge- galactorrhoea);
Paraclinically:
AMH, PRL, TSH, FT4, FSH, LH, E2, Testosterone bio available,
Ab anti rubella, Ab anti toxoplasma
Chlamydia, Mycoplasma (Pelvi Inflamatory Disease major
cause of tube infertility and cervicitis)
Ab anti sperm cells (interferes with fertilization)
Hepatitis B, C , HIV, syphilis
Endometrial biopsy (premenstrual phase)
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High risk infertility groups

Over 35 years old


Early menopause in family medical history
Only one ovary
OPCS
Endometriosis
Neoplasia history (chemotherapy,
radiotherapy)
Insufficient response to ovarian stimulation
Uterine anomalies
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Uterine tubes are aprox10-12 cm long and have 1-4 mm


diameter.
Subdivided in 4 segments: interstitial, isthmus, ampulla,
infundibulum
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Hysterosalpingography
Radiological procedure ( involving X -rays ) used for visualization
of the uterine cavity and fallopian tubes . The most commonly
indicated suspicion of blocked tubes. Also visualizes the size
and shape of the uterus ( uterine cavity ) in infertility problems.
To check the success of the tubal ligation procedure
Contraindication:
Pregnancy and pelvic infections (advised to take prophylactic antibiotic
before any other procedure)

Optimum time before ovulation (day 1-4 of MC)


Through a transvaginal, trans cervical cannula (usually with a
minimum local anesthesia) a contrast dye is inserted and then
the radiological clich is developed.
The following will become visible: the uterus, fallopian tubes
(the contrast dye reaches the peritoneal cavity and is absorbed)
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Laparoscopy
Allows diagnostic and treatment
through a 1cm incision (with
pneumoperitoneum) at the umbilical
level

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Ring sterilization
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Hysteroscopy
Hysteroscope is transcervical introduced
Indications
Uterine bleeding (myomas, endometrial
polyps, endometrial atrophy)
Infertility (intrauterine synechiae,
submucosal fibroids)
Uterine malformations

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Uterine polyp

Double Uterus

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Intrauterine Synechiae
Ashermans syndrome

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Endometrial Ca.

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Syckle cell Anemia


Hemolytic Anemia

AR (needs 2 alleles)
High HbS %
Under hypoxia, it creates
chains of hemoglobin and
they polymerize and
creates bridges that
deform the hematite
T- transplant
medular/hidroxyurea
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Tay Sach
AR Death of nervous
system
Absence of
Hexosamindase A (Hex-A)
accumulation of fat
acids in nervous cell
Hearing loss, blindness,
lowering muscle tone,
dementia, paralysis,
convulsions, red sports on
retina,
IT CANNOT BE TREATED,
IT CANNOT BE SLOWED
DOWN
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Children are born normal, and


develop normal in the first 6 months
Most of them die by the age of 4-5
years old
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Cystic fibrosis
AR, Affects 1/2500 nb (Caucasians) and
1/10.000 (Asians); Life expectancy 30/40
years (1960- they lived approx. 6 months)
Lung, pancreas, reproductive organs
loading with thick mucus low in chlorine
CFTR mutation (cystic fibrosis
transmembrane conductance
regulator) gene

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DAY 21 (middle of luteum


stage)
Progesterone >10 ng/ml
suggests ovulation

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SOPC

usully LH/FSH
>3

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>12 follicles/ovary with 2-9mm diameter


Ovarian volume>10 ml
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Testosterone
Free (2-3%)(BD)
Poorly connected to albumin (BD)
Strongly connected to SHBG

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Endometriosis
Presence of functional endometrial tissue
outside the uterine cavity (ANYWHERElungs, intestines, peritoneal cavity, brain)
6-10% of women
Aneuploidies cells 11, 16, 17
Asymptomatic infertility, chronic pelvic
pain, dysmenorrhea (especially following a
pain-free period)

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CA-125 useful in monitoring treatment response,


correlates with the severity of the illness. Developed
in ovarian cancer or other pelvic neoplasia
GOLD STANDARD- abdominal laparoscopy
(endometrioses cysts)

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Any suspicious lesion needs


histologic confirmation

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Treatment is aimed at lowering estrogen


(stimulates endometriosis tissue)
Microdoses of contraceptive (30-35 microg
ethinyl estradiol), continuous, long term (612 months) pseudo-pregnancy/
amenorrhea
Progestogens (decidualization and
endometriosis tissue atrophy)
Medroxyprogesterone acetate every 3 months
150mg
Dydrigesterone 20-30mg/day continuous or day
5-25
Lynestrenol 10mg/day
Levonodesterl DIU (12 months)
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Progesterone antagonists (antiprogesterone


effect)
Mifepristone (RU -486 ) strong antiprogestronic and in
high doses antiglucocorticoid ; 25-100 mg / day

Danazol (derived 17-etiniltestosteron)


200mg*3/day until it reaches amenorrhea
inhibits GnRH production of gonadotropins and
decreases the frequency of pulsations FSH and
LH and steroidogenesis and inhibit production of
estrogen and progestin
Create an environment of hypercortizolemia ,
hyperandrogenic , hypoestrogenic unfavorable
endometriosis . Inhibits ovulation .
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Aromates inhibitors (anastrozol 1mg/day)


SERM
Raloxifene

Agonists GnRH (T1/2 3-8 ore, compared


to -3.5 minute endogenous hormone)suppresses gonadotropins secretions
(i.m, s.c, intranasal)
LEUPROLIDE, BUSERELINE, NAFARELINE,
DESLORELINE, GOSERELINE, TRIPTORELINE
Induce a reversible pseudomenopause through
down regulation of the pituitary glad. Maxim 6
months. Induces status hypoestrogenic.

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? Why dont women get


their period during
pregnancy?

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Androsperms are more resistant to


alkaline environment!!!
What is the time period for high
chances of getting a baby boy?

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???????????
Patient 27 years, without significant
PPA
Regular MC 35 Days
Maximum fertile period?
How do we document ovulation?
(post?)

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?????????
Patient 35 years - high body
temperature for mostly 20 days
Dg??? posible

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Take home messages


1. .

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2. .

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3.

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4. .

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Questions..zzzz??

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The sexualisation of the body


Definition: complex morpho-functional and
behavioural events that determine sexual
dimorphism and make procreation possible
Stages:
A.
- genetical sex (chromosomally);
B.
- gonadic sex;
C.
- internal genital sex;
D.
- external genital sex;
E.
- neuro- behavioural sex

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The sexualisation of the body


A. Genetic sex: 23x - 46xx
23x or 23 y
- 46xy
B. Gonadic sex end of month 2 v.i.u
1. Undifferentiated gonad stage
2. Differentiated gonad stage, unisexual
Testicular histologic month 3 v.i.u
Ovary - histologic month 6 v.i.u.

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Female sex
At birth 1-2 mil primary foliculles (contain primary
oocytes);
Puberty: 400.000 primary foliculles;
Adult 400 develop into mature follicules (contain
secondary oocytes)
Ovogenesis oocytes I oocytes II needs both X
chromosomes in the absence of one follicular atresia
(Turner syndrome- associated with foliculle-genesis)

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Intersexuality
Sexualisation disorder characterized by a
mismatch of sexual characters belonging
to some females , like males
TRUE hermaphroditism
MALE/FEMALE
PSEUDOHERMAPHRODITISM

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TRUE hermaphroditism
The simultaneous presence in the same gonads
or different GONADS, testicular and ovarian
tissue ( ovary , testis, ovotestis )
Variable karyotype: 46,XX or mosaicism or 46,XY
Differentiation OGI, OGE variable
OGE masculine, feminine, ambigue
OGI feminine/proper gonad of the same side
The sexualization of puberty - usually female
type

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TRUE hermaphroditism
Hormonal values are variable
Karyotype - variable
DG +: OGE ambiguous , highlighting
the gonads of both types;
Treatment:
- Extraction of gonads(d.o after
puberty)
- OGE correction
Hormone replacement therapy
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FEMALE
PSEUDOHERMAPHRODITISM
LOOKS like male, but XX

The presence of female gonad ( ovary ) as one gonad ,


genital tract and male secondary sexual characters are
ambiguous ( intersex )
PHM is more common than PHM, as is often given
adrenogenital Congenital Syndrome ( CAH -Congenital
Adrenal hyperplasia ) which is quite frequent (about 1 /
5000nn )
Causes :
adrenogenital congenital syndrome which deficits enzyme
( 21 -hydroxylase deficiency or deficiency of 11 hydroxylase )
- deficient cortisol with excess androgen production
Pregnant women exposure to androgens
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Congenital Adrenal
Hyperplasia
Deficit 21-hidroxilaza (CYP21Achromosomal
6p21.3; REN cortex SR) deficit of cortisol and
aldosteron with secretion increase of DHEA,
androstendion and testosterone
OTHER ENZYMES:

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11-betahidroxilaza
(8q21)
OR
3-betahidroxisteroid
dehYdrogenase
(1p13)
or
Aromatase

In v.i.u ovaries and OGI ( uterus , fallopian tubes and


vagina higher ) develop normally thought the lack of
inhibited AMH (produced by testicular Sertoli cell) .
The nervous system is affected in the womb by
increased levels of androgens Severe sexual
identity .
AMH- absent with Testosterone- very high; salt loss;
Caritip, implicated genes
Treatment: Glucoccorticoids and mineralocorticoids
entire life (inhibits ACTH and androgenes production
BUT substitutes the deficit) ; Adrenalectomy (+/-) +
even plastic recovery of feminine OGE ???????????

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Prader Scale evaluation Female


Pseudohermaphroditismul

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MALE
PSEUDOHERMAFRODITISM
looks like woman, but XY
The presence of male gonad ( testicle ) as one gonad
, genital tract and female secondary sexual
characteristics are ambiguous ( intersex )
Intersexuality is clinically varied:
predominantly male look = micropenis with hypospadias
Completely ambiguous look = fused labia, partially clitoris,
but with micropenis, urinary meatus based phallus
Predominantly female look = vulva with enlarged clitoris
Phenotype may be normal girl

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Causes of PHM
PSM apears through :
gonad embryo destruction before masculinity ( before
seven . 6-12 v.i.u)
defective biosynthesis of testosterone(deficit 17hydroxylase/17,20-lyase or 17--Hydroxysteroid
dehydrogenase)

defect formation of dihydrotestosterone(deficit 5


reductase)
defective receptor for androgen action ( shape in which
the androgen receptor is completely nonfunctional =
feminizing testicle )
Action faulty hormone antimllerian ( man with uterus and
fallopian still present in the form of an inguinal hernia)
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Androgen Insensivity Syndrome


(Resistance to androgens)

The lack of androgen receptors(Xq11Xq12 gene)


F variable phenotypes
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MALE
PSEUDOHERMAPHRODITISM
Feminizing testicle syndrome ( Morris ) - fully resistant
to androgen ( receptor defects ) ;
Karyotype 46, XY

Female phenotype - "hairless woman"


OGE type female ; girls with inguinal hernias
Vagina finger glove ;
Without a uterus ; Wolff and abdominal testicle were
derived
Large plasma testosterone values for female for normal
male ;
Serum estrogene - concentrations similar to women
Treatment: testicle removal , substitution treatment .
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Joan of Arc

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Queen Elizabeth I

Mrs Wallis Simpson

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Since 2004, (Athens) The International Olympic


Committee has introduced mandatory testing of sex in
female competitions

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