The Diagnosis and Treatment of Infertility Ashim Kumar, M.D. Reproductive Endocrinology and Infertility Clinical Assistant Professor, UCLA School of Medicine Fertility & Surgical Associates of California, Encino & Thousand Oaks, CA

Infertility 1 in 8 couples affected Definition: Failure to conceive after 1 year of regular, unprotected intercourse Earlier evaluation is recommended if: Women >35 years old Irregular menses History of Pelvic Inflammatory Disease Endometriosis Men with risk factors (e.g. testicular surgery, abnormal semen analysis)

Female Genital Tract

The Menstrual Cycle Follicular Phase Luteal Phase

Fertilization & Implantation

Causes of Infertility ? Unusual Tubal & Pelvic Male Ovulatory Speroff and Fritz –Clinical Gynecologic Endocrinology and Infertility 2005

Critical Factors Affecting Fertility Oocytes Sperm Uterus Fallopian Tubes

Critical Factors Affecting Fertility Oocytes – FSH / Estradiol Ovarian Reserve Age – Quality FSH – Quantity Ovulatory Dysfunction Midluteal Progesterone – Ovulation TSH & Prolactin Sperm Uterus Fallopian Tubes

Evaluation of Ovulation Basal BodyTemperature – Poor Sensitivity Urinary LH kits start 2-3 days before surge is expected ovulation is 24-48 hrs later Midluteal Progesterone > 3 ng/ml shows evidence of ovulation > 10 ng/ml shows evidence of “good” ovulation 1 wk before menses is best

Oocyte Attrition 20 weeks in utero – 6 to 7 million Birth – 1 million Menarche – 300,000 to 400,000 37yr – 25,000 Menopause – 1,000

Ovarian Reserve is the number and quality of eggs in the ovaries

Quantification of Ovarian Reserve Age FSH Inhibin B, AMH Basal antral follicle count Ovarian volume Clomid challenge test FSH stimulation test Serum U/S Response to Stimulation

Age and Female Fertility Peak fertility age 20-24 Decreases some until age 30-32 Declines rapidly after 435

Pregnancy rates, Live births rates and Singleton birth rates for ART-Fresh embryos CDC Data, 2003

Age and Miscarriage Risk <30 yr- 7-15 % 30-34 yr- 8-21% 35-39 yr- 17-28% ≥40 yr- 34-52%

Risk of Chromosomal Abnormality in Newborns by Maternal Age Maternal Fetal Medicine: Practice and Principles. Creasey and Resnick 1994

Meiotic Nondisjunction

Preimplantation Genetic Diagnosis

Preimplantation Genetic Diagnosis

Preimplantation Genetic Diagnosis

Critical Factors Affecting Fertility Oocytes Sperm – Semen Analysis Volume Concentration Motility Morphology Uterus Fallopian Tubes

Microscopic evaluation Semen Analysis The gross examination Microscopic evaluation Appearance (opaque) Volume (2-6 mL) Viscosity (liquefaction,  1 hr) pH value (7-8) Count ( 20 million/mL) Motility (>50%) Morphology ( 30 % normal) (World Health Organization Criteria) Other Tests • Sperm Chromatin Structure Assay / TUNEL • Sperm DNA Decondensation • Sperm Penetration Tests • Postcoital Test

Semen Analysis Should be ordered in any couple who presents for infertility Repeat if abnormal Ideally there should be more than 10 million Normal Motile Sperm 5-20 million – insemination indicated <1 million – ICSI indicated

Sperm Attrition

Additional Male Evaluation FSH, LH Testosterone Prolactin, TSH Karyotype Y Chromosome Microdeletion Urology referral – evaluation for varicocele (ultrasound) Freeze viable sperm if undergoing a diagnostic biopsy

Critical Factors Affecting Fertility Oocytes Sperm Uterus – HSG or SHG Fibroids Polyps Synechiae Fallopian Tubes

Uterine Evaluation Ultrasound Sonohysterogram (saline ultrasound) Hysterosalpingogram MRI Hysteroscopy

Ultrasound Evaluates uterus, adnexa and occasionally the fallopian tubes May be helpful in diagnosing uterine abnormalities

Sonohystogram (SHG) Concurrent saline distention of the uterine cavity and vaginal ultrasonography

Hysterosalpingogram (HSG)

Hysteroscopy Allows direct evaluation the uterine cavity Concurrently diagnose and treat

Critical Factors Affecting Fertility Oocytes Sperm Uterus Fallopian Tubes – HSG Patent vs. Occluded Proximal vs. Distal Occlusion Potential therapeutic effect

Hysterosalpingogram (HSG)

MRI In Lieu of Surgery In Preparation for Surgery Non-surgically evaluate the uterus to differentiate between various forms of congenital anomalies In Preparation for Surgery To map fibroids prior to surgery Help diagnose adenomyosis

Laparoscopy Allows direct visualization of the pelvic anatomy. Can evaluate endometriosis, adhesions, uterine abnormalities or ovarian masses Chromotubation use of a dilute solution of blue dye instilled through the cervix can demonstrate tubal patency or distal tubal occlusive disease. Surgically correct the disease process

Laparoscopy

Laparoscopy Peritubal Adhesions Lysis of Adhesions and Chromotubation

Laparoscopy Resection of Hydrosalpinx

Treatment - Oocytes Controlled Ovarian Hyperstimulation Long Protocol Antagonist Microdose Flare Ovulation Induction Clomid hMG or FSH Clomid + FSH

Treatment - Sperm Intrauterine Insemination (IUI) – place the washed sperm at the top of the uterus near the opening of the fallopian tubes Intracytoplasmic Sperm Injection (ICSI) – directly inject each sperm into each egg

Treatment - Uterus Hormonal – estrogen supplementation to increase endometrial thickness Surgical – remove polyps, fibroids, scar tissue, septum, etc.

Treatment – Fallopian Tubes Surgical – correct tubal disease, endometriosis, scar tissue OI & IUI – if unilateral tubal obstruction IVF – for bilateral tubal disease

Unexplained Infertility Normal Semen analysis, evidence of ovulation, normal uterus, tubes are open Surgery-Laparoscopy-to exclude endometriosis/adhesions Consider the addition of hysteroscopy Stepwise empiric treatment of OI & IUI and IVF

When to Use Assisted Reproductive Technology (ART) Neither fallopian tube is patent Severe endometriosis Severe male factor infertility Unexplained infertility After medical treatment has failed For genetic indications-PGD

Intracytoplasmic Sperm Injection (ICSI)

Embryo Development In Vitro First Division Second Division Zygote 8-cell stage Hatching Blastocyst Morula Blastocysts

Embryo transfer Embryos are inserted into the uterus Embryo

Preimplantation Genetic Diagnosis a procedure that allows embryos to be tested for genetic disorders before they enter the uterus and before pregnancy has begun Thornhill et al, JMD 2002

Donor Oocytes 10% of ivf cycles Indications

Live Births Rates from Own vs. Donor Eggs CDC Data, 2003

2nd Opinion