1. Infertility UNC School of Medicine Obstetrics and Gynecology Clerkship Case Based Seminar Series

2. Objectives for Infertility  Define infertility  Describe the causes of male and female infertility  Describe the evaluation and initial management of an infertile couple  List the psychosocial issues associated with infertility

3.  Failure of a couple to conceive after 1 year of regular intercourse without use of contraception  Primary infertility – No prior pregnancies  Secondary infertility – Prior pregnancy Definition

4.  Infertility affects 10-15% of reproductive-age couples in the U.S.  Approx. 85% of couples achieve pregnancy within 1 year  Conception rate (fecundability)  25% conceive within 1 mo.  60% conceive within 6 mo.’s  75% conceive within 9 mo.’s  90% conceive within 18 mo.’s Prevalence

5. Successful conception requires a specific series of events: 1.Ovulation of competent oocyte 2.Production of competent sperm 3.Juxtaposition of sperm and oocyte in a patent reproductive tract 4.Fertilization 5.Generation of a viable embryo 6.Transport of the embryo to the uterine cavity 7.Implantation of the embryo into the endometrium Etiology

6.  Major causes of of infertility:  Female factor – 60%  Ovulatory dysfunction  Abnormalities of female reproductive tract  Peritoneal factors  Reproductive aging  Male factor – 20%  Abnormal semen quality  Abnormalities of male reproductive tract  Idiopathic – 15% Infertility in ~ 20-40% of couples has multiple causes Etiology

7.  Female  Duration of infertility and prior evaluation or therapy  Menstrual cycle (length and characteristics)  Symptoms associated with ovulation (e.g. breast tenderness, bloating, mood changes)  Full OBHx and GynHx  Prior pregnancies, surgeries, or STD’s  Sexual history (frequency of intercourse)  Chronic medical illness  Family history (infertility, birth defects, genetic disorders)  Social history (smoking, EtOH, drugs) Infertility: History

8.  Male  Prior children  Genital tract infections  Genital surgery or trauma  Chronic medical illness  Medications (e.g. Furantoins, CCB)  EtOH, drugs, or smoking  Sexual history (frequency of intercourse) Infertility: History

9.  Female  Height, weight, BMI  Pelvic exam  Masses  Tenderness (Adnexa, Cul-de-sac)  Structural abnormalities (Vagina, Cervix, or Uterus)  Male (Urologist referral)  Evidence of androgen deficiency  Structural defects (e.g. varicocele, hernia) Infertility: Physical Exam

10. Male factor: Evaluation Initial evaluationFurther evaluation Male FactorSemen analysis Urologic evaluation FSH, LH, and testosterone level Genetic evaluation Epididymal sperm aspiration (PESA, MESA) Testicular biopsy

11. ElementReference value Ejaculate volume1.5-5.0 mL pH> 7.2 Sperm concentration> 20 million/mL Motility> 50% Morphology> 30% normal forms Male factor: Evaluation  Semen analysis  Following 2-4 day period of abstinence  Repeated x1 for accuracy

12. Male factor: Evaluation  Urologic evaluation  Physical Exam  Varicocele  Congenital absence of vas deferens (CAVD)  Transrectal ultrasound  Vasography, Seminal vesiculography  Epididymal sperm aspiration (PESA or MESA)

13. Male factor: Evaluation  Endocrine evaluation  Indication: Oligospermia (< 10million/mL) or sexual dysfunction (decreased libido, impotence)  FSH, LH, testosterone  Genetic evaluation  Indication: Azoospermia (no sperm)  CFTR mutation  Karyotype (Klinefelter’s, Y chromosome deletion)  Testicular biopsy  Indication: Nonobstructive azoospermia  Palpable vasa  Normal testis volume  Normal FSH/LH

14. Female factor: Evaluation FactorInitial evaluationFurther evaluation OvulationHistory and physical exam Basal body temp charting Ovulation predictor kit Mid-luteal phase progesterone level Endocrine testing Endometrial biopsy Reproductive tract (uterus or fallopian tubes) Hysterosalpingogram (HSG) Ultrasound Saline-infusion sonography Hysteroscopy Laparoscopy PeritonealLaparoscopy Reproductive agingFSH, estradiol, or AMH

15. Female factor: Menstrual Cycle

16.  Ovulation  Initial evaluation :  Basal body temp – rise for > 10 days indicates ovulation  Ovulation predictor kit – detects LH surge in urine  Further evaluation:  Mid-luteal phase progesterone level - level > 3 ng/mL provides qualitative evidence of recent ovulation  Endocrine testing (TSH, prolactin, FSH, LH, Estradiol, DHEA-S)  Endometrial biopsy  Not routinely performed Female factor: Evaluation

17.  Reproductive tract  Initial evaluation:  Hysterosalpingogram (HSG)  Detect uterine anomalies (septate or bicornuate uterus, uterine adhesions, uterine leiomyoma)  Detect patency of fallopian tubes (occlusion, hydrosalpinx, salpingitis)  Ultrasound – alternative to HSG to evaluate uterus Female factor: Evaluation

18.  Reproductive tract  Further evaluation:  Saline-infusion sonography (SIS)  Hysteroscopy  Laparoscopic chromotubation Female factor: Evaluation

19.  Peritoneal factors  Laparoscopy  Endometriosis  Pelvic/adnexal adhesions Female factor: Evaluation

20.  Reproductive aging  Indications:  > 35 years of age  1 st degree relative with early menopause  Previous ovarian insult (surgery, chemotherapy, radiation)  Smoking  Poor response to ovarian stimulation  Unexplained infertility  Candidate for IVF Female factor: Evaluation

21.  Reproductive aging  Cycle day 3 serum FSH and estradiol  Abnormal (“diminished ovarian reserve”)  FSH > 10 IU/L  Estradiol > 75-80 pg/mL  Clomiphene citrate challenge test  Cycle day 10 serum FSH  Serum antimullerian hormone (AMH) Female factor: Evaluation

22.  Prevalence ~ 15%  Factors that cannot be identified  Sperm transport defects  Inability of sperm to fertilize egg  Implantation defects Idiopathic Infertility

23. Infertility: Management  Male Factor  Avoidance of alcohol  Scheduled intercourse  Ligation of venous plexus for significant varicocele  Intrauterine insemination (IUI) with washed sperm  Intracytoplasmic sperm injection (ICSI) + IVF  Donor sperm insemination

24.  Anovulation  Oral medications:  Clomiphene citrate  Dopamine agonists (Bromocriptine) - hyperprolactinemia  Injectable medications:  Gonadotropins (FSH/hMG, hCG)  Laparoscopic “ovarian drilling ”  Complications: Ovarian hyperstimulation, Multiple pregnancy Infertility: Management

25.  Reproductive tract abnormality  Uterine: Myomectomy, Septoplasty, Adhesiolysis  Tubal: Microsurgical tuboplasty, Neosalpigostomy  Peritoneal: Laparascopic treatment of endometriosis, Adhesiolysis  Idiopathic infertility  Ovarian stimulation + IUI  Clomiphene or gonadotropins (hMG, hCG)  IVF Infertility: Management

26.  Used for:  Severe male factor  Tubal disease  Couples who failed other treatments  Requires  Controlled ovarian hyperstimulation  Retrieval of oocytes  In vitro fertilization and embryo transfer  Procedures  IVF + embryo transfer (IVF-ET)  Intracytoplasmic sperm injection + embryo transfer (ICSI-ET)  Donor egg IVF + embryo transfer Infertility: Management (IVF)

27.  The psychological stress associated with infertility must be recognized and patients should be counseled appropriately. Psychological

28. Bottom Line Concepts  Infertility is defined as one year of unprotected coitus without conception. Infertility may be primary or secondary.  Multiple causes must be considered for infertility diagnosis and treatment.  Male and female reproductive tract anatomy and physiology should be reviewed in order to generate a full differential diagnosis.  Components of an initial infertility workup include a thorough history and physical examination. Laboratory investigations include a semen analysis, documentation of ovulation, and hysterosalpingogram.  Dysfunction of the hypothalamic-pituitary-ovarian (HPO) axis and medical illness, including thyroid disease and pituitary tumors, can cause ovulatory disturbances.  Success rates with IVF depend on the etiology of infertility and the age of the female partner.

29. References and Resources  APGO Medical Student Educational Objectives, 9 th edition, (2009), Educational Topic 48 (p102-103).  Beckman & Ling: Obstetrics and Gynecology, 6th edition, (2010), Charles RB Beckmann, Frank W Ling, Barabara M Barzansky, William NP Herbert, Douglas W Laube, Roger P Smith. Chapter 38 (p337-346).  Hacker & Moore: Hacker and Moore's Essentials of Obstetrics and Gynecology, 5th edition (2009), Neville F Hacker, Joseph C Gambone, Calvin J Hobel. Chapter 34 (p371-378).