FERTILITY & ART

DR SUNDARNARAYANAN M.D, FICS

DIP LAP (GER), DIP MIS (FRA),
DIP ART (ISR), DIP US (CRA)
 INFERTILITY
 Primary infertility: The inability to
conceive after 1 year of unprotected
intercourse for a woman younger than 35,
or after 6 months of unprotected
intercourse for a woman 35 or older (Speroff
& Fritz, 2005).

 Secondary infertility: The inability of a

woman to conceive who previously was
able to do so (Speroff & Fritz, 2005).
 FERTILITY FACTS

 80% of couples will conceive within 1 year of

unprotected intercourse

 86% will conceive within 2 years.

 Infertility is more common in older women.

However, increased age reduces the efficacy
of any form of treatment.
? DECLINING FERTILITY
 INFERTILITY IN INDIA
 National census reports of the past three
decades showed that infertility has risen by 50
percent in the country.

 A whopping 46% of Indians, between the ages

of 31 and 40, require medical intervention to
conceive.

 Male infertility is almost as high as female

infertility.
INFERTILITY- CAUSES
 FERTILITY AMOUNG INDIAN
WOMEN
 13 percent of ever-married women aged 15-49
years were childless in 1981 (rural 13.4 percent
and urban 11.3 percent) .

 which increased to 16 percent in 2001 (rural

15.6 percent and urban 16.1 percent).

 Over half of married women aged 15-19 years

were childless in 1981, which increased to 70
percent in 2001.
 FEMALE FERTILITY
 OVARIAN AGE
 Delayed marriage

 Declining libido

 Deferred childbirth
 Ovary - Female Age
 Women are born with their lifetime egg
supply
 4 million at 20 weeks gestation
 400,000 at birth
 100,000 eggs left at time of puberty
 Fertility initially declines at age 27
 Significant decline at age 35-39
 Rare pregnancies after age 40
AGE SPECIFIC FERTILITY
AGE SPECIFIC FERTILITY
RATE

Age Women Births ASFR

15-19 100,000 20,000 0.200
20-24 120,000 40,000 0.333
25-29 90,000 50,000 0.556
30-34 100,000 20,000 0.200
35-39 80,000 8,000 0.100
40-45 95,000 1,000 0.011
 Infertility increases with aging

15 20 25 30 • Less ovulation
• Chromosomal
Infertility per cent

defects
• More LPD
• Less uterine
receptivity
10
5

25-29 30-34 35-39 40-44 years

Why does fertility decline with increasing
maternal age?
 Decline in the number of eggs
 Every month there is loss of a group of
eggs
 Decline in the quality of eggs
 As the egg ages, errors in the dividing
embryo increase
 These errors may result in aneuploidy
(an incorrect number of chromosomes)
Genetically abnormal oocytes in infertile
women

100
90
80
Abnormal ( %)

70
60
50
40
30
20
10
0
<30 35 40 42 45
Age (years)
 Associated Factors
 PCOS
 Premature ovarian failure
 Endometriosis
 PID
 Fibroids
 Previous abdominal surgery (adhesions)
 Cervical/uterine abnormalities
 Cervical/uterine surgery
 PCOS -Anovulatory causes
 Hormone imbalance
 Obesity
 Anorexia
 Significant stress
 Patients display:
 Irregular menstrual cycles
 Skipped cycles
 Minimal or absent premenstrual symptoms
 Premature ovarian failure
 Menopause prior to age 40
 Decreased Estrogen
 Increased FSH
 Decreased AFC & AMH
 Causes
 Autoimmune
 Genetic
 Idiopathic
 1-2% pregnancy rate
 MALE FACTORS
  Irregular sperm production & Hampered
sperm delivery
 Mental and emotional stress
 Erectile dysfunction or early ejaculation
 Obesity
 Sexually Transmitted Diseases , mumps
 Diet imbalance
 Addiction to smoking or alcoholism
 Sedentary existence
 One in every five healthy young men between the age
from 18 to 25 suffer from abnormal sperm count.
 INFERTILITY EVALUATION
 Discovering which cause of infertility affects a
particular couple is the basis of fertility care.

 Causes are shared almost equally by men and

women.

 Often the cause is mixed involves multiple

causes, with some belonging to the man and
some to the woman
 Overview of Evaluation
 Female
 Ovary
 Tube
 Corpus
 Cervix
 Peritoneum
 hormonal
 Male
 Sperm count and function
 Ejaculate characteristics, immunology
 Anatomic anomalies
 Hormonal imbalance
 History-General
 Both couples should be present & Preferably
they should be alone.
 Age
 Medical & surgical history
 Previous pregnancies by each partner
 Length of time without pregnancy
 Sexual history
 Frequency and timing of intercourse
 Impotence, anorgasmia, dyspareunia
 Contraceptive history
 History-Male
 History of pelvic infection
 Radiation, toxic exposures (including drugs)
 H/O Mumps
 Testicular surgery/injury
 Excessive heat exposure (spermicidal)
 Life style including smoking & alcohol abuse
 Sexual dysfunction
 History-Female
 Irregular menses, amenorrhea, detailed
menstrual history
 Previous conceptions including abortions &
ectopics.
 Previous treatment history.
 Abdominal and uterine surgeries
 Family H/O infertility, DM
 Stress & exercise
 Weight changes
 Physical Exam-Male
 Size of testicles
 Testicular descent
 Varicocele
 Outflow abnormalities (hypospadias, etc)
 Physical Exam-Female
 General exam including thyroid
 Secondary sexual characters
 galactorrhea
 Abdomino-pelvic mass & tenderness
 Uterine position & mobility
 Uterosacral nodularity
 Cervical abnormalities
 Pelvic masses
 Ovarian Function
 Document ovulation:
 Follicular study
 Luteal phase progesterone
 D3 FSH, LH, E2 to asses ovarian function
 TSH & PRL if needed.
 Testosterone and DHESO4 in PCOS
 AFC & AMH to asses ovarian reserve
before proceeding to ART
 Ovarian Function
 Three main types of dysfunction

 Hypogonadotropic, hypoestrogenic (central)

 Normogonadotrophic, normoestrogenic (e.g.

PCOS)

 Hypergonadotropic, hypoestrogenic (POF)

 Tubal Function
 Evaluate tubal patency whenever there is a
history of PID, endometriosis or other
adhesiogenic condition

 Patency confirmation is mandatory before

proceeding to ART like IUI

 Tests
 HSG / HyCoSy
 Laparoscopy
 Hysterosalpingography (HSG)
 Radiologic procedure requiring contrast

 Performed optimally in early proliferative

phase (to avoid existing pregnancy)

 If previous history of PID, give prophylactic

antibiotics or consider laparoscopy

 Increase chances of pregnancy.

 Hysterosalpingography (HSG)

 Can be
uncomfortable
 Sedation if
required

Can detect intrauterine and

tubal disorders (anatomic not
physiological) but not always
definitive
 Laparoscopy
 Required in any surgically
correctable pelvic pathology and
unexplained infertility
 Can offer diagnosis and treatment
in one sitting
 Uses :
 Induction of ovulation (pcos)
 Diagnosis and excision of
endometriosis
 Adhesiolysis
 Management of adnexal masses
 Myomectomy
 Tubal reconstructive surgery
 HYSTEROSCOPY
 Infertility workup is
incomplete without
hysteroscopy.
 Uses
 Detect uterine anaomolies
 Tubal cannulation
 Septal resection
 Adhesiolysis
 Myomectomy
 meteroplasty
 Uterine Corpus
 Mullerian defects
(congenital)
 Absent uterus
 Bicornuate/sept
ate
 Uterine muscle
tumor
 25-30% of women
 Benign (>95%)
 Cervical Function
 Infection
 Culture test and antibiotics.
 Stenosis
 dilatation
 Immunologic Factors
 Sperm-mucus interaction
 anti sperm antibodies
 Peritoneal Factors
 Endometriosis
 main factor for infertility
 Diagnosis & best treatment by laparoscopy
 Can be familial can occur in adolescents
 Etiology unknown but likely multiple ones
 Medical options remain suboptimal
 Other causes
 PID
 Post surgical adhesions
 Female Infertility - Hormones
 Endocrine abnormality (hormones)
 Thyroid
 Prolactin
 Polycystic ovary syndrome (PCOS)
 Estrogen, insulin
 Hypothalamic hypogonadism
 Stress
 Exercise (athlete)
Other Causes of Female Infertility

 Chromosome abnormalities
 Turner’s syndrome (XO)
 Androgen Insensitivity (XY)
 Male pseudohermaphrodite
 Female phenotype
 Blind vaginal canal
 Inguinal hernia (50%)
Sperm Are Also Required!!
 Male Factors-Semen Analysis
 Sample collected after 3-days abstinence

 Sample should be produced manually, no

lubricants
 Rapid delivery of sample to the lab.
 Two semen analysis 3-months apart
 Do not say azoo without centrifugation
 Semen analysis
WHO criteria
 Volume; 2-4 ml
 Count; > 20 million/ml
 Motility; > 50%
progressive
 Morphology; > 15%
normal (strict criteria)
 Pus cells; < 1 million/ml
 Grading of sperm motility
Macleod scale
 D - immotile
 Living immotile (Asthenospermia)
 Dead immotile (Necrosprmia)

 C - sluggish non-linear
 B - sluggish linear
 A- rapid linear (progressive)
 Male Factors
 Repeat Semen analysis

 Serum TSH, FSH, LH,PRL levels

 RBS and semen C/S

 Scrotal doppler study

 Testicular biopsy in azoospermia

 Male Factor (oligo/azoo)
 Hypogonadotrophic
 hMG,GnRH
 CC, hCG results poor
 Testicular (common)
 Anti oxidants
 ? Testosterone,hMG, hCG
 Obstructive
 Sugery (poor results)
 ICSI (TESE, MESA)
 Male Factor
 Idiopathic oligospermia
 No effective treatment
 ?IVF
 donor insemination
 Varicocoele
 Ligation? (no definitive data )
 Retrograde ejaculation
 Ephedrine, imipramine
 AIH with recovered sperm
 Sperm
 How many are needed for fertilization?
 Natural conception
 20,000,000
 Intra-uterine insemination
 1,000,000
 In-vitro fertilization (IVF)
 10,000
 Intra-cytoplasmic sperm injection (ICSI)
 1 per ovum
 Unexplained Infertility
 5-10% of couples
 Review previous tests for validity
 Empiric treatment:
 Ovulation induction
 IUI
 Consider IVF and its variants
 Adoption
 Infertility Treatments
 Improve Timing of Intercourse
 Intrauterine insemination (IUI)
 Clomiphene citrate (Clomid) + IUI
 FSH + IUI
 In Vitro Fertilization (IVF) / ICSI
 “Standard” IVF
 Egg donation + IVF
 Egg Freezing + IVF
 Ovarian stimulation

 Un-stimulated cycles
 CC-stimulated cycles
 HMG-stimulated cycles
 GnRHa-HMG stimulated cycles
 Ovulation Induction
 Clomiphene citrate

 70% induction rate,

 20%cumulative pregnancy rate after 6 cycles
 Patients should typically be normoestrogenic
 Induce menses and start on day
 Multifetal rates 5-10%
 Gonadotropin induction
 IUI, FSH or FSH + IUI
 Patients with unexplained infertility

Treatment Cycles Pregnancy Pregnancy per

cycle
IUI 30 1 2.7%
FSH 49 3 6.1%
FSH+IUI 34 9 26.4%

Serhall et al, Fertil Steril 1988;49:602

Intrauterine Insemination (IUI)

Goal is to Maximize the Chance of Fertilization

• Increase Number of Eggs
• Position motile concentrated Sperm Closer to Eggs
ASSISTED RERODUCTIVE
TECHNOLOGIES
 ART
 It is the art of getting the gametes together or gamete
manipulation.
 This in vitro imitation of natural reproduction resulted in
the first test tube baby Louise Brown (Edward and
Steptoe 1978).
 The art is ever expanding and the scope now covers
infertility ,PGD, gene therapy and cloning.
 ART and embryo cryopreservation are real advances in
the medical history
 Historical Perspective
 1978 Louise Joy Brown, first IVF baby
 1981 Elizabeth Carr, first IVF baby in USA
 1983 First birth after egg donation
 1985 First birth from cryopreserved embryo
 1985 Transvaginal ultrasound for follicle
monitoring
 1990 First report of births after PGD
 1990 First report of egg donation to older mothers
 1992 First human birth after ICSI
 Indication for ART

 Male factor
 Tubal factor
 PCOS not responding to IUI
 Reduced ovarian reserve
 Advanced age
 Unexplained infertility
 ART TECHNIQUES
 Micro manipulation
 IVF
 ICSI

 Preimplantation
manipulation
 Assisted embryo
hatching
 Blastomere biopsy
 Gene therapy and
cloning
 Baseline assessment
Sonographic evaluation Endocrine evaluation
 Ovaries  E2
 Size
 Position
 P4
 Cysts  FSH
 AFC  LH
 AMH
 Uterus
 Size
 Pathology Male factor
 Endometrial thickness Semen analysis
 TET
Semen c/s
 GnRHa-HMG protocol
Short down regulation
E2 400 pg/ml/large follicle

Day-8 evaluation hCG

Shot PR/cycle 18%

HMG ampoules 36 hr 48 hr
Lupron 1 mg sc every day OPU ET
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 days of the cycle
Monitoring EOD

18 mm
CYCLE MONOTORING
 Triggering ovulation
 hCG 10,000 IU IM shot
 Follicles
 Leading follicle 18-20
mm
 Endometrium
 Thickness > 7 mm OPU
 Trilaminar halo
34-36 hr after shot
appearance
ET
 E2
 400
pg/ml/follicle > 18 After 48/72 hr later
mm
Egg Retrieval
In Vitro Fertilization (IVF)
ICSI
Fertilization

 2 Pronuclei (2PN)

 1 day after egg

retrieval
 Day 3 Embryo

Pre-Implantation Genetic Testing Stage

DAY 5 BLASTOCYST
Assisted Hatching
Embryo Transfer
Embryo Transfer
How Many Embryos are Transferred?

 Related to age and embryo quality

 <35 = 2
 35-37 = 2-3
 38-40 = 3-4
 >40 = up to 5

 For patients with 2 or more failed IVF cycles, or a

poor prognosis, can add more based on clinical
judgement
What Happens to the Other Embryos?

 Freeze Embryos
 Donate For Research/Stem Cells
 Embryo Adoption
 Discard
 Post transfer care
 Luteal supplementation
 Serum beta HCG after 15
days
 TVS after 1-2 weeks
 Embry reduction if needed
 IVF Success Rates

 Female age
< 30 – 40 %
 30-35 – 35%
 35-37 – 30%
 38-40 – 20%
 >40 – 10%
 IVF success rate
in relation to indication

Indication Success of IVF

Endometriosis 32%
Unexplained 31%
infertility
Cervical factor 28%
Male factor 15%
Immunologic factor 10%
 IVF Statistics

 65 % singletons

 30 % twins

 < 5% triplets or more

 Special ART Procedures

 Egg donation
 Surrogacy
 Preimplantation genetic diagnosis (PGD)
 Embryo/ oocyte Freezing
Egg Donation
 Egg donation
 IVF for two
 Known/anonymous
donor
 <35 years old
 Donor
 Standard controlled
ovarian
hyperstimulation
 Egg retrieval

 Recipient
 Embryo transfer
Who are candidates to be an egg donor ?

 21-35 years old (older if a friend or relative)

 FSH <10
 Negative donor
 Good health and genetic history
 Preferably prior egg donation experience
 How many eggs were produced?
 Did pregnancy result?
Who are candidates for egg reception ?
 Premature ovarian failure
 Ovarian insufficiency (e.g. FSH>15 )
 Physiologic menopause
 Maternal age over 43
 History of poor egg/embryo quality or
multiple IVF failures
 How old is too old?

Danger to mother
Decreased life expectancy of
parents
Quality of parenting
Is 55 a “physiological limit”?
Pregnancy in the Sixth Decade of Life: Obstetric
Complications

 Pre-eclampsia
 35%
 Background Incidence 3-10%

 Gestational Diabetes
 20%
 Background Incidence 5%
 Pregnancy in the 6th decade of life:
Conclusion

 There does not appear to be any definitive

medical reason for excluding these women
from attempting pregnancy on the basis of
age alone
 Gestational Surrogacy:
Indications

 Absent uterus- congenital or iatrogenic

 Abnormal uterus
 Medical contraindication to pregnancy
 Recurrent pregnancy wastage
 Repeated IVF failures with good embryos
Preimplantation Genetic Diagnosis (PGD)

 Can test embryos for

genetic abnormalities
prior to implantation
 Has been successfully
used in diagnosing and
preventing inherited
genetic diseases
 Uses single cell
(blastomere) at 8-cell
stage
 PGD – Clinical Indications

 Single gene defects

 Balanced
translocations
 Advanced maternal
age (aneuploidy)
 Repetitive IVF failure
 Recurrent pregnancy
loss
 Embryo selection
 Embryo/Oocyte Cryopreservation

• Slow-freeze Technique
• Vitrification (Rapid
Freeze) Technique
 Clinical Applications of Egg Freezing

 Oocyte cryopreservation could be a clinical

tool for:
 Women at risk of losing ovarian function
 Women desiring fertility preservation
(e.g. delayed maternity)
 Eliminating ethical concerns of embryo
cryopreservation
 Solving the dilemma of abandoned frozen
embryos in the IVF laboratory
 Future considerations
 Oocyte cryopreservation
 “Pausing the biological clock”
 Cytoplasmic transfer
 Donation of enucleated oocytes
 Reproduction without gametes
 Use of nuclear material from somatic
cells
 Donated or synthetic cytoplasm
 Reconstituted oocytes
 Summary
 Infertility is a common problem & Society
places huge pressure on early conception

 Evaluation must be thorough preferably by a

RE and treatment to be individualized

 Advanced treatment is available, including

ART but age is an important factor in
deciding outcome and timely treatment is
advisable.
Thank you