Transcript Anovulation- the most frequent cause of female infertility

Anovulation- the most frequent
cause of female infertility.
It can be connected with:
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Irregular menstruation
Oligomenorrhea
Amenorrhea
Regular menstruations can also occur
Anovulation- the reasons:
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Hyperprolactinemia
Hypothalamic- pituitary dysfunction
Ovarian failure
PCO
Diagnostic methods:
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PRL/MCP, FSH, LH, E2 serum concentrations
between 3 - 6 day of cycle.
P test and ultrasound ovarian assessment.
Hyperprolactinemia:
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PRL > 20 ng/ml, MCP > 300%
Causes: stress, hypothalamic failure, PCO, psychotropic
drugs (e.g. trnquilizers), rare - adenoma
When PRL>27.8 ng/ml determine TRH - hypothyreosis?
Syndroms: Oligomenorrhea or amenorrhea, infertilityanovulation, deficient activity of the corpus luteum,
galactorrhea in 33%.
Treatment: Bromocriptine
Hypothalamic- Pituitary
dysfunction
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P test - negative, FSH, LH <5 mj/ml or normal,
E2<40 pg/ml
Causes: the most frequent congenital hypothalamicpituitary insufficiency, stress, excessive exercise,
weight loss, malnutrition.
Management:
– Elimination risk factors
– GnRH
– hMH, FSH
Ovarian failure
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FSH >20mj/ml
Possible in each age:
In younger women (age 30) frequently genetic
causes- karyotype evaluation.
 In woman at reproductive age it can be transient or
permanent.
 Causes: idiopathic, autoimmunological- thyroid
inflammation, myasthenia, thrombocytopenia,
rheuamtoid disease, adrenal failure, vitiligo,
hemolytic anemia. past surgeries, chemio- or
radiotherapy, inflammations, 17- hydroxylase
hypoactivity, hormonal ovarian resistance.
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Ovarian failure- treatment
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E/P, in women at the beginning of ovarian
failure ovulation can be restored in about
20% of women.
hMG treatment is ineffectiveness and
autoimmunologic process can intensify
Variety of syndroms in PCO
according to Balen et al.
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Obesity 38 - 50%
Dysmenorrhea
Infertility in 75%
Hyperandrogenism in 48%
Without syndroms 20%
Hormonal diagnostics:
 T, A
 LH
 LH:FSH
 Insulin level in fasting state
 PRL
 SHBG
Body weight reduction
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Decreasing the E1 and LH concentrations
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Decreasing the P 450C activity and free
Testosterone concentration
Metformin
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Decrease the insulin level and restore
correct steroidogenesis
(take place the proper cytochrome P 450 C 17 alfa
phosphorylation)
INFERTILITY
DIAGNOSIS
Hysterosalpingography (HSG)
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Hysterosalpingogram- x-ray imaging of the
uterus and fallopian tubes after instillation
of a contrast liquid
Routine infertility evaluation (basic test)
Assess morphology of endocervical canal,
uterine cavity, tubes.
Rule out tubal occlusion, synechiae, uterine
anomalies.
Contraindications to HSG:
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active PID with abdominal
tenderness or palpable mass
recent uterine/tubal surgery
active uterine bleeding
pregnancy (schedule exam before
ovulation to avoid early pregnancy)
Normal hysterosalpingogram.
A smooth triangular uterine cavity and spill from the
ends of both tubes.
HSG showing a normal uterus and blocked tubes
No "spill" of dye is seen at the ends of the tubes
Hysterosalpingogram showing a uterus with a myoma
that is pushing in to the cavity.
A hysterosalpingogram indicate intrauterine adhesions
(synechia)
Tubal Recannulization and Selective
Salpingography
Selective hysterosapingography, or proximal tubal
cannulization may open the tubes avoiding surgery.
LAPAROSCOPY
The camera and instruments are inserted into the abdomen or
chest through small skin cuts allowing the surgeon to explore the
whole cavity without the need of making large standard
openings dividing skin and muscle.
After the cut is made in the umbilical area a special ( Veress)
needle is inserted to start insufflation. A pressure regulator CO2
insufflator is connected to the needle. The pressure obtained
should not be beyond 15 mmHg.
After satisfactory insuflation the needle is removed
and a 10 mm trocar is inserted through the
previous umbilical wound.
Laparoscopic view of a normal pelvis.
Uterus in midline. Tubes and ovaries (white structures)
also visible.
Contraindications to
laparoscopy:
Circulatory and respiratory
insufficiency
 Hypovolemic shock
 Ileus
 Peritonitis
 Abdominal or diaphragmic hernia
 Tumors in abdominal cavity
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Pelvic laparoscopy is also not
recommended for patients with:
– severe obesity
– existing severe pelvic adhesions from
previous surgeries
Pelvic Laparoscopy: Risks
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Risks for any anesthesia are:
• reactions to medications
• problems breathing
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Risks for any surgery are:
• bleeding
• infection
• damage to adjacent organs
HYSTEROSCOPY
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Assess the endocervical canal, uterine cavity
and uterine openings of the oviducts.
Enables to make the intrauterine operations.
Hysteroscopic view of a uterine septum.
A septum can cause recurrent miscarriage.
A large polyp at the top of the uterine cavity
Contraindications to
hysteroscopy:
Infections of reproductive organs
 Massive bleeding from uterus
 Pregnacy
 Cervical cancer
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Hysteroscopy. Risks.
Uterine perforation
 Bleeding
 Infection
 Pulmonary embolism (rare)
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Polycystic ovarian syndrome (PCOS) occur in 510% of reproductive-aged women
PCOS  ovulatory dysfunction or absent
ovulation  infertility
 infrequent or irregular menstrual
cycles
absence of ovulation  no progesterone
production in the second half of the menstrual
cycle  the risk for an abnormal buildup of the
lining of the uterus (endometrial hyperplasia) or
cancer.
Another feature to PCOS is clinical or
laboratory hyperandrogenism  increased
circulating amounts of or increased
responsiveness to "male" hormones like
testosterone or DHEAS
Symptoms: oily skin or acne and excess hair
on the face, between the breasts, or on the
lower abdomen.
Changes in the ovaries in
ultrasound
Ultrasound findings: poly (many), cystic
(small collections of fluid).
The eggs in the ovaries do not develop
to maturity  many small "follicles"
(small fluid-filled sacs containing
immature eggs) seen on ultrasound.
The ovaries of women PCOS are often
enlarged as well.
Another common feature of PCOS is
increased body weight and trouble in
losing weight.
Mechanism: insulin resistance (the cells
of women with PCOS do not respond
as well to their bodies' own insulin) 
women with PCOS are at higher risk
for developing diabetes during
pregnancy or later in life.
Treatment Strategies
The aim: to help regulate menstrual cyclicity and
prevent endometrial hyperplasia.
Oral contraceptives (birth control pillsBCPs). BCPs also help reduce acne and facial hair
in most patients with PCOS.
In women who do not require oral contraception,
progesterone given for 10-12 days every 30- 60
days will induce a reliable menses.
For women with PCOS who desire pregnancy,
ovulation induction (COH) is often necessary.
Drugs that increase insulin sensitivity in PCOSMetformin  help induce ovulation
 help women to lose weight
In women who cannot tolerate oral
medications or have failed several
different regimens of medication,
surgical induction of ovulation can also
be attempted (laser or electrosurgical
techniques to place small holes in the
ovaries in an effort to normalize the
hormonal environment and allow
ovulation to occur)
ANDROLOGY
Dr hab. Rafał Kurzawa
CLINIC of REPRODUCTION and
GYNECOLOGY
POMERANIAN ACADEMY of MEDICINE
Infertility- epidemiology
Symptomatology of male
infertility
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TYPE
TYPE
TYPE
TYPE
TYPE
I – erection problems (0,3-7%)
II – azoospermia (0,9%-16%)
III – immunological infertility (3,4%-25%)
IV – abnormal seminal quality (23%-48%)
V – idiopathic sperm dysfunction (0-25%)
Diagnosis
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General examination
Semen analysis
Other diagnostic tests:
– USG
– Hormonal diagnostic
– Diagnostic tests for Assisted Reproductive Technology
TYPE I – erection problems (0,3-7%)
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Normal ejaculation
– Hypospermia (semen volume < 2,0 ml) – chronic prostatitis
– Impotence
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Retrograde ejaculation
– Neurogenic– DM, SM
– Anatomical
– Jatrogenic – drugs, operations
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disejaculation
– Functional – anorgazmia
– Neurogenic – spinal injury
– Jatrogenic – drugs, chemiotherapy, radiotherapy, operations
TYPE II – azoospermia (0,9%16%)
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Pre-testicular causes
– Hypothalamic or pituitary disorder – LH, FSH deficiency,
Kallman syndrome, trauma, tumors, inflammation, meningitis
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Testicular causes
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Primary testicular failure
Congenital – 47XXY, del Y, AZF
Acquired- mumps, testicular torsion, castration
Jatrogenic – radiotherapy, chemiotherapy
Post-testicular causes
– Congenital – CBAVD, CF
– Acquired – inflammations (gonorrhea)
– Jatrogenic – vasectomy, hernia operation
Diagnostic tests for Assisted
Reproductive Technology- ICSI
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FSH
– If < 12IU – sperm biopsy is
effective in 80-90%
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Blocked ejaculatory duct
(Micro-Epidydymal Sperm
Aspiration –MESE)
Other
(Testicular Sperm
Extirpation- TESE,
Testicular Sperm AspirationTESA)
TYPE III – immunological
infertility (3,4%-25%)
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antisperm antibodies – the
immune system may
produce antibodies that
attack and weaken or
disable sperm
– Auto-immunological
diseases
– Concequences of
testicular trauma
TYPE IV – abnormal sperm quality
(23%-48%)
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Congenital
– Undescended testicles
Sexually transmitted disease
(gonorrhoea) or testicular
infection (mumps)
Vascular
– Testicular torsion
– Varicocoeles
Diseases:
– Thyroid faiure; Addison
disease, hepar diseases; DM,
auto-immunological
diseases;
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Environmental factors
– Drugs (sulfasalazine, T,
chemiotherapy)
– Temperature
– Other factors (X-rays, lead,
cigarette smoke, alcohol;
marijuana, frequently
wearing tight-fitting pants
and underwear)
Immunological
– Testitis
Genetic
– del Y, aberrations (count
and structure of
chromosomes)
Idiopathic [46%]
Morphologic images
Treatment
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Risk factor elimination
Give up smoking
Testicular temperatue decrease
Regular sexual intercourses (2-3 per week)
Antioxydants
– Vitamin E, C, Zinc
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Tetracicline
– Chlamydia Trachomatis infection
Treatment (pharmacotherapy)
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Risk factor elimination
Hormonal treatment
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Testosterone
hCG
FSH
C.C, tamoxyphen
Varicose veins in the spermatic
cord
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Physical examination
–I
– II
– III
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Valsalva test examination ( or during cough)
large veins during palpation
visible varicouse veins
Other diagnostic test
– Semen analysis (SA)
– USG
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Treatment
– Operation
– ART.: IUI, IVF, ICSI
Diagnostic and therapeutic algorithm
(male)
Sperm analysis
IUI
O, A, T, OA, OT, TA, OAT
Treatment:
operation, CC,
hMG (FSH)
grave O, A, T, OA, OT, TA, OAT
azoospermia
Testicular cells?
TESE, MESA
ICSI
Sperm analysisrecommendation by WHO
– General male infertility diagnostic test- SA
– sterility
– sample should be delivered to laboratory in 60
min. after ejaculation
– abstinence min. 48 hours max. 7 days
– the next semen analysis between 7 days and 3
months
Seminal quality, cytology and
sperm quantitation
– liquefaction
– viscosity
– volume
– color
– pH
– smell
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Sperm count
Sperm motion analysis
WBC count (pyospermia)
Spermatozoa count
Antisperm antibodies
Sperm morphology
Microbiology
Semen analysis
– Microscope
– Makler counting chamber
– Immunobead test (IgG, IgA or IgM)
– CASA
(computer-assisted sperm analysis)
Sperm motion analysis
1- immotile
2- weak movement with no forward progression
3- forward progression
4- rapid forward progression; vigorous tail
movement
Seminal quality- ranges
– Liquefaction < 60 minutes
– Volume > 2 ml
– Color- gray to white opalescent fluid
– pH 7,2 – 8,0
IMMUNOBEAD TEST
Microscopic polyacrylamide spheres, ranging in
size from 2 to 10 um, coated with anti-human
immunoglobins against human IgG, IgA or
IgM
Normal sperm range
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Motility
>50% 3 or 2 ; or >25% 3
Sperm count
>20·106/ml
WBC count
<106/ml
Spermatogonia
<5·106/ml
Autoagglutinating <10%
Immunebead test <10%
Sperm morphology >30% normal forms (WHO);
5-14% strict criteria (Kruger)
Definitions of „abnormal” counts
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Normozoospermia
Oligozoospermia < 20·106/ml
Astenozoospermia <50% 3 or 2 ; or <25% 3
Teratozoospermia <30%
Azoospermia no sperm
Assisted Reproductive
Techniques
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IUI
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(intrauterine insemination)
AIH
(artificial insemination by
husband)
AID
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IVF
(in vitro fertilization)
ZIFT
(zygote intrafallopian transfer)
PROST
(pronuclear stage intrafallopian
transfer)
(artificial insemination by
donor)
IVF-ET
GIFT
ICSI
(gamet intrafallopian
transfer)
(in vitro fertilization and embryo
transfer)
(intracytoplasmic sperm
injection)
Indications to IUI
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Cervical factor
Chronic anovulation (COH-PCOS)
Male factor
Immunologic disorders
Endometriosis
Idiopatic infertility
IUI
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CONCLUSION:
unjustified more than 4
correct IUI
Proceeding
- Ovulation stimulation
- Sperm preparation (>1-4·106/ml)
- Artificial insemination
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Efficacy (depended on indications and stimulation
protocol)
– 10 – 30% pregnancies per cycle
– 40 – 60% accumulated no improvement after 4
cycles
Sperm preparation (IUI, IVF)
gradient
1
2
semen
40%
Silica
semen
80%
Silica
3
Sperm liquefaction
Prepare the „gradient”
Stratification on gradient
Centrifugation
Again centrifugation in EBSS
ART
Ovulation stimulation for IUI
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Clomiphene citrate
– 50 – 250 mg p.o., day 5-9
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Clomiphene citrate + hMG (FSH)
– 50 – 250 mg p.o., day 5-9
– 75 IU from day 9
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hMG (FSH)
– 75 – 150 IU from day (3) 5
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Aim
– growth 1-3 follicles to 18mm. When E2 250–300
pg/ml/follicle 10.000IU hCG is administered to cause
ovulation
Basic indications to IVF
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Partial or complete tubal obliteration
Chronic anovulation (COH-PCOS)
Male factor
Immunologic disorders
Endometriosis
Idiopatic infertility
Indications to ICSI
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Indications to ICSI with sperm from ejaculate
O, A, T, OAT
<1-4·106/ml after preparation
<5%
normal forms
failure of classic IVF (no fertilization)
Indications to MESA
azoospermia (obstruction of ejaculatory ductsobstructive azoospermia)
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Indications to TESE
azoospermia (patency of ejaculatory ductsnonobstructive azoospermia)
IVF-ET (classic)
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Ovulation stimulation
Sperm preparation
Collecting the oocytes (under ultrasound control)
Oocytes maturity assessment
Oocytes insemination
Fertilization assessment (16-24h)
Embryo culture to 4 (48h) - 8 (72h)
blastomers stage or to blastocyst stage (120h)
Embryo transfer (ET)
Embryo cryopreservation
ICSI
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Ovulation stimulation
Sperm preparation
Collecting the oocytes (under ultrasound control)
Oocytes maturity assessment
Intracytoplasmic sperm injection
Fertilization assessment (16-24h)
Embryo culture to 4 (48h) - 8 (72h) blastomers stage
or to blastocyst stage (120h)
Embryo transfer (ET)
Embryo cryopreservation
Ovulation stimulation for IVF
(COH – controlled ovarian hyperstimulation)
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Short protocoł
aGnRH from day 1
hMG (FSH) 150–300IU from day 3
Long protocoł
aGnRH from day 20 previous cycle
hMG (FSH) 150–300 IU from day 3
Aim
growth some follicles. When dominant follicle is
>18mm and 2 other at least 16 mm and E2
>1000pg/ml but <5000pg/ml (OHSS risk), 10.000IU
hCG is administered to cause oocytes maturity)
IVF - ICSI (skuteczność)
IVF
ICSI
ICSI
MESA
ICSI
TESE
Fertilizations
50%
65%
60%
55%
Cells
divisions
90%
95%
Pregnancies
per cycle
15-25%
25-35%
35-45%
25-35%
Effectiveness of 1 mikrosurgery is equal with
cumulative efficacy of 5 IVF trials
IVF - ICSI (effectiveness)
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Implantation percentage when 1
embryo is transferred in stage 4 – 8
blastomers is 12,5 – 17,5%
About 60% of embryos goes to stage of
4 blastomers (and far?)
Pregnancies percentage per cycle
(patients < 40)
– Less than 7 oocytes
– More than 7 oocytes
- 13%
- 29%
Cryopreservation
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Freezing and storage
– Embryos
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Stage 2 pronucleus
Stage 2-4 blastomers
Stage blastocyst
– Oocytes and ovarian tissue
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Benefits
– Low cost, no OHSS, possibility of more „aggresive”
ovulation stimulation in first cycle
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Effectiveness
- 10 – 20% pregnancies per cycle
Preparation to cryo-ET
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Natural cycle (indication is growth the
ovarian follicle)
alternatively supplement therapy with
estrogens and progestagens
Controlled cycle aGnRH with supplement
estrogens and progestagens therapy
Complications and
potential risk of ART
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Complications
– OHSS
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Rare cardio- pulmonary failure, renal failure, DIC ...
– Multiple pregnancy (5 – 40% !)
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Prematurity and preterm labours (to 98%), PIH (25%),
bleeding (35%), anemia (15%), isthmocervical
insufficiency (15%)
Strategies:
Transfer of 1-2 embryos; multiembryo transfer and consecutive
embrioreduction or leaving this problem for obstetricians and
neonatologists
Complications and
potential risk of ART
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Potential risk
– Ovarian cancer
 Increased risk of serous carcinomas, low malignancy (high
grade)
 More frequent after Clomiphene citrate
 No confirmation in large randomised clinical trials !!!
– Theoretical risk of hormonosensitive neoplasm (breast,
endometrium)
– Genetic defects transfer
 Male infertility (AZF, delY...)
 Besides no risk of malformations was confirmed (but too short
observations) – 2,2–2,7%
IVM & IVC
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IVM
(in vitro maturation)
– OHSS prevention
– In vitro culture of ovarian follicles from antral to developed follicle–
IVF – IVC – ET
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Multiple pregnancy prevention- IVC
culture)
(in vitro
– In vitro culture of embryos to blastocyst stage (the best one for
implantation) – 40-60% of pregnancies (blastocyst –sequential
media) when compare to 12,5 – 17,5% (embryo in the stage of 24-8 blastomers)
– Culture the embryos to this stage make some problems. About 3560% of embryos in vitro goes to blastocyst stage.
– IVC gives the possibility of reliable evaluation the embryos quality.
Preimplantation diagnostic
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Indications
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Age > 35 (?)
Previous child with chromosome abnormalities
Carrier of genetic defects
– Aneploidies (e.g. Down syndrome)
– Monogenic disorders (np. fibrocystic disease)
– X-linked inheritance (hemophilia) (important child sex)
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Sampling
– Blastomers biopsy
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Methods
– PCR (polymerase chain reaction)
– FISH (fluorescent in-situ hybridization)
Conditions to start ART
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IUI
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– Woman
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Vaginal
bacteriological
examination
– Man
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3-7 days of sexual
abstinence
IVF
– Woman
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Vaginal bacteriological examination
hormonal profile
Cervical canal explore with a probe
(?)
Hysteroscopy (?)
– Man
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3-7 days of sexual abstinence
Sperm bacteriological examination
prophylactic antibiotic therapy (?)