Sub-fertility Causes &Management Dr. Yousef Gadmour Professor, Al-fateh university Senior consultant, Al-Jalla Hospital Tripoli , Libya

Definitions: Sub fertility- Involuntary failure to conceive within 12 months of commencing unprotected sexual intercourse. Primary infertility - No previous pregnancy. Secondary infertility- previous pregnancy. (whatever the outcome)

Causes (and approximate incidence) 1. Idiopathic - 25 per cent 2. Sperm defects or functional disorder - 25 per cent 3. Ovulation failure - 20 per cent 4. Tubal damage - 15 per cent 5. Endometriosis - 5 per cent 6. Coital failure - 5 per cent 7. Cervical mucus defect - 3 per cent 8. Obstruction of sperm ducts - 2 per cent

Principles of management: Deal with the sub fertile couple together. No one is at fault or to blame. Give good explanations of causes , prognosis and outline of treatment of sub fertility. Carry out investigations and treatments consistency in proper sequence.

History - General Frequency and timing of intercourse Both couples should be present. Age. Previous pregnancies by each partner. Length of time without pregnancy. Sexual history : Frequency and timing of intercourse Use of lubricants Impotence, anorgasmia, dysparunia Contraceptive history

History - Male Infections; gonorrhea , tuberculosis. Radiation, toxic exposures ,drugs. Mumps orchitis. Testicular injury/surgery. occupation (Excessive heat exposure). Smoking. Diabetes mellitus.

History - Female Detailed menstrual history ; Irregular menses, amenorrhea. Hirsutism. Galactorrhoea. Previous pregnancies and mode of deliveries. Ectopic pregnancy history. PID.

History - Female Appendicitis. IUCD use. Endometriosis. Stress. Weight changes. Excessive exercise. Cervical and uterine surgery.

Physical Examination - Male Weight & Height (BMI). Size of testicles (orchidometry). Testicular descent. Varicocele. Outflow abnormalities (hypospadias, etc). General look- Klinefelter syndrome (47XXY). Kallmann syndrome (hypothalamic hypogonadism) (delayed puberty ,normal stature, no smell ). Weight & Height (BMI). Size of testicles (orchidometry). Testicular descent. Varicocele. Outflow abnormalities (hypospadias, etc). General look- Klinefelter syndrome (47XXY).

Physical Examination - Female Weight & Height (BMI) Hirsutism Thyroid examination Abdominal examination Speculum examination - HVS, endocervical swap Vaginal examination- Uterosacral nodularity, Uterine mobility USS-(Vaginal)

General laboratory investigations: Female FBS(GTT). TFT. chlamydial antibody titer. Rubella antibody titer (If negative, immunize and advise not to try for pregnancy for 3 months). HIV,HBV,HCV.

General laboratory investigations: Female Day 2 FSH, LH. Serum prolactin (fasting). Day 21 serum progesterone.

General laboratory investigations: Male HIV,HBV,HCV. FBS (GTT). TFT. Serum Testosterone, FSH, PRL levels.

Routine investigation in the female Assessment of Ovulation Basal body temperature Mid luteal serum progesterone Endometrial biopsy Ultrasound monitoring of ovulation

BBT Cheap and easy, but… Inconsistent results. Provides evidence after the fact. May delay timely diagnosis and treatment; 98% of women will ovulate within 3 days of the nadir. Biphasic profiles can also be seen with LUF syndrome.

Luteal Phase Progesterone Pulsatile release, thus single level may not be useful unless elevated. Performed 7 days after presumptive ovulation ( day 21 ). If done properly , level >15 ng/ml consistent with ovulation.

Endometrial Biopsy Invasive, but the only reliable way to diagnose luteal phase defect (LPD). Performed around 2 days before expected menstruation (= day 28 by definition). Lag of >2 days is consistent with LPD. Must be done in two different cycles to confirm diagnosis of LPD. Controversy exists over the relevance of luteal phase defect as a cause of infertility and the accuracy of the endometrial biopsy in assessing the delay.

Postcoital test (PK tests) Scheduled around 1-2d before ovulation (increased estrogen effect) 48hours of male abstinence before test No lubricants Evaluate 8-12h after coitus (overnight is ok!) Remove mucus from cervix (forceps, syringe)

Postcoital test (PK test) PK (normal values in yellow) Quantity (very subjective) Quality (spinnbarkeit) (>8 cm) Clarity (clear) Ferning (branched) Viscosity (thin) WBC’s (~0) progressively motile sperm/hpf (5-10/hpf)

Problems with the PK test Subjective. Timing varies; may need to be repeated. In some studies, “infertile” couples with an abnormal PK conceived successfully during that same cycle.

Tubal Function Evaluate tubal patency whenever there is a history of PID, endometriosis or other adhesiogenic condition. Tests: HSG Laparoscopy Falloposcopy (not widely available)

Hysterosalpingography (HSG) Can be uncomfortable. Done at the end of menses. Can detect intrauterine and tubal disorders but not always definitive.

Laparoscopy Invasive; requires OT or office setting. Can offer diagnosis and treatment in one sitting. Not necessary in all patients. Uses (examples): Lysis of adhesions Diagnosis and excision of endometriosis Myomectomy Tubal reconstructive surgery Test of tubal patency by dye test

Falloposcopy Hysteroscopic procedure with cannulation of the Fallopian tubes. Can be useful for diagnosis of intraluminal pathology. Promising technique but not yet widespread.

Assessment of uterine cavity Hysteroscopy It is advisable to assess the uterine cavity pathology as submucous fibroid, polyps, uterine malformation, and others . Outpatient hysteroscopy, hysterosalpingography are equivalent regarding evaluation of uterine cavity pathology

Routine investigation in the male Semen analysis Test after (~3) days abstinence from intercourse. If abnormal parameters, repeat twice, 2 weeks apart Normal values: Volume: 2 to 6 ml Density: 20 to 250 million /ml Motility: > 50 % with forward motion within 2 hours Morphology: > 50 % normal sperm

Other Male Investigation Doppler USS (varicocele). Testicular Biopsy.

Treatment Options

Ovarian Disorders Anovulation Central amenorrhea Clomiphene Citrate (CC) ± hCG Human Menopausal Gonadotropin (hMG) Pure FSH Central amenorrhea CC first, then hMG Pulsatile GnRH

Ovarian Disorders Hyperprolactinaemia: Drugs :Bromocriptin, Carbegoline(Dostinex), Quinagolide (Norprolac) Surgery if macroadenoma Premature ovarian failure : ? high-dose hMG (not very effective) Luteal phase defect: Progesterone suppositories during luteal phase CC ± hCG

Ovulation Induction Clomiphene Citrate Compete with natural oestrogens by blocking receptors in target organs including the pituitary, leading to increased FHS levels. 70% induction rate, ~40% pregnancy rate. Patients should typically be normoestrogenic. Induce menses and start on day 2 for 5 days. With high dosages, antiestrogen effect dominate. Multiple pregnancy rates 5-10%. Monitor effects with USS & D21 progesterone.

hMG LH +FSH (also FSH alone = Metrodin) For patients with hypogonadotrophic hypoestrogenism or normal FSH and E2 levels Close monitoring essential, including estradiol levels & USS 60-80% pregnancy rates overall, lower for PCOS patients 10-15% multiple pregnancy rate

Risks CC Vasomotor symptoms Ovarian enlargement Multiple gestation NO risk of malformations hMG Multiple gestation OHSS (~1%) Can often be managed as outpatient Diuresis Severe cases fatal if untreated in ICU setting

Fallopian Tubes Tuboplasty IVF

Corpus Asherman syndrome Fibroids (rarely need treatment) Hysteroscopic Lysis of adhesions (scissor) Postop. ; IUCD, E2 Fibroids (rarely need treatment) Myomectomy ( hysteroscopic, laparoscopic, open) ??Uterine artery embolization. Uterine anomalies (rarely need treatment) Metroplasty.

Peritoneum (Endometriosis) From a fertility standpoint, excision beats medical management (Laser therapy ). Lysis of adhesions. GnRH-a (Not a cure and has side effects & expensive). Danazol (side effects, cost). Continuous OCP’s ( poor fertility rates ). Chances of pregnancy highest within 6 -12 months after treatment.

Male Factor Hypogonadotrophism Varicocoele Retrograde ejaculation hMG GnRH CC, hCG ( results poor ) Varicocoele Ligation? ( No definitive data yet ) Retrograde ejaculation Ephedrine, imipramine AIH with recovered sperm

Male Factor Idiopathic oligospermia No effective medical treatment IVF (in-vitro fertilization) ICSI ( Intra- cytoplasmic sperm injection ) TESE( Testicular Sperm Extraction ) MESA(Microsurgical Epididymal Sperm Aspiration) ?? donor insemination

Unexplained Infertility 15-20% of couples Consider PRL, laparoscopy, other hormonal tests, cultures, Antisperm Abs. testing, sperm penetration assay if not done. Review previous tests for validity. Empirical treatment: Ovulation induction IUI Consider IVF and its variants Adoption

Summary Sub fertility is a common problem. Sub fertility is a disease of couples. Evaluation must be thorough, but individualized. Treatment is available, including IVF, but can be expensive, invasive, and of limited efficacy in some cases. Consultation with a reproductive endocrinologist is advisable.

Thanks