Infertility—A Clinical Infertility—A Clinical Dilemma……Dilemma……

Dr.Kundan V.Ingale.MBBS, DGO, DNB(Mumbai)

Obstetrician & Gynecologist

Consultant in Assisted Reproduction & Genetics

LOKMANYA HOSPITAL, CHINCHWAD

LOKMANYA HOSPITAL, PRADHIKARAN

Introduction

Traditionally, infertility is defined as the inability to

conceive for one year.

Worldwide, 10 to 14% of couples in the

reproductive age group (20-40) face difficulty in

conceiving

90% of infertility is treatable with advances in

medicines and clinical procedures

Line of treatment includes medical and surgical

intervention, Assisted Reproduction Techniques

(ART) or a combination of these modalities.

Infertility is an extraordinarily common medical problem.

INCIDENCEINCIDENCE

• Female Factor: - 40-45%

• Male Factor: -25-40%

• Both: - 10%

• Unexplained: - 10%.

Causes of Infertility

Female

Anovulation (accounts for 25% of infertility)

Tubal factors (accounts for 25% - 40%of infertility)

Uterine & cervical factor (accounts for 10% of infertility)

Immunological cases, age and other factors (accounts for

25% of infertility)

Tubal factor is a common cause of infertility in our country.

HSG – Septate uterus

HSG – Bicornuate uterus

Causes of Infertility

Male

Low sperm count

Low motility

Poor sperm morphology

Other factors such as stress

varicocoele

chromosomal abnormality

Both female and male factors contribute to infertility.

Infertility

Rise in infertility : -

- increased women employment

- Late marriages

- Preferring weekend sex

- highly stressful job

- Onset of childbearing at later age.

Male InfertilityMale Infertility

Volume: 2-5ml pH: 7.2-7.8 Liquefaction time: within 40 mins. Sperm Count: -20-120 million/ml (WHO

Criteria) Sperm motility: >50% after ½ hour. Sperm Morphology: >50% normal.

Abnormal Semen Abnormal Semen Parameters.Parameters.

Oligospermia: - sperm count <20 million/mlMild: -10-20 million/ml

Moderate: -5-10million/mlSevere: -<5 million/ml.

Azoospermia: - Absence of single sperm in ejaculate.

Asthenospermia: -Sperm motility <50%Teratospermia: - <4% normal sperms

associated with poor fertility prognosis.

POLYCYSTIC OVARIAN POLYCYSTIC OVARIAN SYNDROMESYNDROME

Heterogeneous complex condition – Hyperandrogenemia and chronic anovulation.

Associated with Hirsuitism , Hyperinsulinemia & insulin resistance.

Commonest cause of anovulation.

50% patient of PCOS need assistance in reproduction.

Epidemiolgy of PCOS.Epidemiolgy of PCOS.

Affect 5-10%of all reproductive age group women.

50% women attending infertility cilinics.

50% women with recurrent miscarriages.

PCO – LEADING CAUSE OF INFERTILITY.

Chronic anovulation

High LH/Inadequate LH surge

LOW FSH

Inability of H-P axis to respond to adequate & timely feedback signals

Intrinsic follicular weakness / Impaired follicular-Gonadotropin interaction.

Persistently Elevated Estrogen

Failed local ovarian autocrine / paracrine factor

Abnormal Estrogen Clearance / Metabolism

Increased Estrogen secretion

Gonadal

(Ovary& Adrenal)

Extragonadal

(Adipose tissue)

INSULIN RESISTANCE & INSULIN RESISTANCE & HYPERINSULINEMIAHYPERINSULINEMIA

Causes: - Peripheral target tissue resistance.

Decreased insulin receptor number

Decreased insulin binding

Post-receptor failure Decreased hepatic clearance. Increased pancreatic sensitivity.

INSULIN RESISTANCE – OBESE & NON-OBESE WOMEN.

PCO – THE SIGNPCO – THE SIGNPartial suppressed FSH

New Follicular growth

Follicular atresia

Repeated follicular atresia & anovulation

Thickened stroma

PCO

Hyperplastic theca cells

Luteinized due to LH

PCO : Sign , not a disease.

PCOS- DIAGNOSISPCOS- DIAGNOSIS

MAJOR Chronic anovulation

Hyperandrogenemia

Clinical signs of Hyperandrogenemia.

MINOR Insulin resistance Perimenarchal onset of

hisuitism and obesity Elevated LH and FSH

ratio Intermittent

anovulation assoc with Hyperandrogenemia

Tubal FactorTubal Factor

Fallopian tube blockage:

Sites : Cornual end, interstitial, isthmus, ampulla, fimbrial end.

FALLOPIAN TUBE FALLOPIAN TUBE BLOCKAGEBLOCKAGE

Tubo-Cornual region: -Tubal spasmSalphingitis

Isthmica nodosa(SIN)Endometriosis

Polyps Isthmus: -

Occlusion-Prior sterilization,tubal pregnancy, SIN, T.B. Endometriosis.

Ampulla: -

Intraluminal adhesions, Tubal pregnancy

Infundibulum: -

Hydrosalphinx, phimosis of distal tubal ostium sec to PID.

Intraperitoneal spread: -

Adhesions.

DIAGNOSIS

Patency of tube– Laparoscopic

chromotubation– Hysterosalphingo

graphy– Falloposcopy– Methylene blue test– Gas hydrotubation– Sonosalphingography– Direct cannulation

Functioning of tubal mucosa– Microsphere

migration– Descending tests

Starch & Gold.

MANAGEMENT OF TUBAL MANAGEMENT OF TUBAL BLOCKBLOCK

Proximal tubal disease: -Tubal cannulation

IVF Mid tubal disease: - Tubal reconstruction

Microsurgery/IVF Fimbrial / distal tubal disease: - Fimbrioplasty Peritubal disease: -Adhesiolysis/IVF T-O mass / multiple tubal block: -IVF/ICSI

Assisted Reproductive Assisted Reproductive TechniquesTechniques

•Intrauterine insemination (IUI)•In Vitro Fertilization (IVF)•Intracytoplasmic sperm Injection (ICSI)•Laser Assisted hatching (LAH)•Pre-implantation genetic diagnosis.(PGD)•In vitro Maturation•Donor oocyte programme.

IUI : Stimulation protocolsIUI : Stimulation protocols Natural cycle Stimulated cycle

CCCC+HMG

CC+HMG/FSH+hCG

FSH/HMG+hCGGnRHa + FSH/HMG + hCG

Follicle monitoring Timing of IUI

Success rate is high if more then one egg is produced.

Clomiphene Citrate Clomiphene Citrate Occupies the Estrogen receptor

Concentration of Estrogen receptor is reduced

No Negative feedback HPO axis is blind to Estrogen

GnRH secretion activated

FSH & LH pulse frequency increased

Maturation of follicles

Results with Clomiphene Results with Clomiphene CitrateCitrate

70% Ovulation rate40% Pregnancy rate5% have multiple pregnancy60% conceive during first three cycles.

If there is no pregnancy in 6 cycles, alternative therapy to be chosen.

IUI with Gonadotropin IUI with Gonadotropin treatmenttreatment

Gonadotropins : contain naturally occurring pituitary hormones (FSH & LH)

Daily injections: creates higher than normal levels of FSH, simulating the ovaries to produce multiple follicles and multiple eggs.

Transvaginal sonography: to check the growing follicles.

Subcutaneous self injection into the thigh or abdomen.

Gonadotropins : IndicationsGonadotropins : Indications

Indications:

-Failure to respond to antiestrogen therapy At least 3 cycles of C.C. and no ovulation Dose: 0-200mg/day for 7 days. At least 6 Ovulatory cycles and not conceived.

-Side effects to antiestrogen therapy irrespective of ovulation

-Two or more miscarriage after C. therapy.

Step Up protocolsStep Up protocols

Ovulation in PCO pts remains a challenge

OHSS, multiple pregnancy & LUF’s are a problem.

Allows right amount of FSH to connect the hormonal imbalance within the PCOS ovary.

Fewer follicles per cycle Safer successful ovulation induction OHSS reduced.

Step Down ProtocolsStep Down Protocols

Principle Principle :

Activating pre-Ovulatory follicles and limiting the number of growing follicles by hormonal therapy.

AdvantagesAdvantages:

Reduced risk of OHSS & multiple pregnancy.

DisadvantagesDisadvantages:

Needs tight monitoring.

Increased cancellation cycles.

Metformin in PCO patientsMetformin in PCO patients

In cases diagnosed to have insulin resistance.

1500mg/day till pregnancy achieved.

Given for at least 2 mths prior to ovulation induction programme.

INTRAUTERINE INSEMINATIONINTRAUTERINE INSEMINATION(IUI)(IUI)

What is IUI?What is IUI?

Direct placement of processed highly motile, concentrated sperm, washed free of seminal plasma and other debris, into the uterus as close to the ovulated oocytes as possible.

Reduces distance of travel

Artificial insemination.

IUIIUI

The Goal is to place as many active, well-formed sperms as close to the ovulated eggs as possible, thereby

increasing their chances of meeting.

Indications for IUIIndications for IUI

Female factor:Anatomic defects

Cervical factors

Ovulatory dysfunction

Unexplained infertility

Minimal endometriosis

Antisperm antibodies in cervix

Psychological & Psychogenic sexual dysfunction

Male Factor:Anatomic defects of the penisSexual or ejaculatory dysfunctionRetrograde ejaculationImpotencyImmunological increased viscosityOligoasthenoteratozoospermiaAzoospermia

Steps involved in COH & IUISteps involved in COH & IUI

Monitoring of a natural or stimulated cycle:

so that the time of ovulation is apparent

Preparation of Sperm wash:

From either male partner or donor

Procedure of Insemination:

Sperm sample is then inserted into woman’s uterus via a catheter through the cervix.

IUI : ComplicationsIUI : Complications

Uterine cramping -5%Spotting -1%G I upset -0.5%Infection -0.2%OHSS -1%Multiple gestation Ectopic gestation

Artificial Insemination

Efficacy of superovulation & Efficacy of superovulation & IUI IUI

Treatment No.of pregnancies Pregnancy rate/couple

Intracervical insemination

23 10

Intrauterine insemination

42 18

Super ovulation & Intracervical insemination

44 19

Super ovulation & intrauterine insemination

77 33

IUI ResultsIUI Results751 cycles in 322 couples

Treatment Fecundity/Cycle

COH 6.3%

IUI 3.4%

COH + IUI 19.6%

Chaffkin L.M.;Nulsen,J.C.,1991

IUI FailuresIUI Failures

Poor respondersHyperstimulationLUFEndometrial problemsInsatisfactory semen preparations

INTRACYTOPLASMIC SPERM INTRACYTOPLASMIC SPERM INJECTIONINJECTION

(ICSI)(ICSI)

ICSI Procedure

ICSI involves injection of single sperm into the egg

Success Rates

If 4 good quality embryos are produced following ICSI and the age of the woman is < 37 years, the pregnancy rates are 45%

The hallmark to success is good quality embryos

Intra Cytoplasmic Sperm Injection (ICSI)

The advent of ICSI has revolutionised male factor fertility.

Revolutionary treatment for patients with severe

male factor infertility

Fertilisation rate of mature eggs injected with

immobilised sperm reached levels comparable to

those obtained in conventional IVF

Also used to treat couples experiencing failure or

low fertilisation rates under conventional IVF

conditions

Phases of IVF Cycle

One cycle is spread over a period of 25-30 days.

Pituitary suppression (Down regulation)

Done with Day 21 Lupride inj followed by

stimulation with HMG or r-FSH.

Ovarian stimulation

Fixed regimen - Step up and Step Down

Egg retrieval

34-36 hours after ovarian trigger

Phases of IVF Cycle

One cycle is spread over a period of 25-30 days.

Fertilisation by ICSI

Embryo transfer

Luteal phase and pregnancy

Donor ProgrammeDonor Programme

Donor sperms : -– azoospermia

Donor oocyte : - – Premature ovarian failure– Advanced maternal age with poor ovarian

reserve

Donor embryo : - – Severe male as well as female factor.

78bp

250bp

100bp

50bp

1 2 3 4 5 6 7 8 9

250bp

50bp

861bp

242bp

285bp

Preimplantation genetic Diagnosis (PGD)

The Micromanipulator

Cleavage stage Embryo Biopsy

Polar Body Biopsy

FISH -Trisomy 18, X, Y

FISH - Polyploidy

PCR - Cystic Fibrosis F 508 Mutation

PCR - Thalassemia

PGD - Earliest form of prenatal diagnosis.

Cryopreservation

For future fertilisation attempts

Laparoscopy

Looking inside the abdominal cavity

Hysteroscopy

Looking inside the uterus

Myths about infertilityMyths about infertility

Timing of intercourse Frequency of intercourse Certain coital positions improve chances of

conception Orgasm, libido, stress & tension IUI improves chances of conception Drugs to improve sperm count Cold baths, loose pants Unexplained infertility

Assisted Reproduction mimics human reproduction

Getting close to nature

“The greatest motivational act one person can do for

another is to listen.”

Roy Moody