INFERTILITY

Emad Darwish MD
Professor of Obstetrics & Gynecology Alexandria Faculty of Medicine

Role of male partner in conception: Spermatogenesis: production of a sufficient amount of normal motile sperm capable of fertilizing the ovum. Production of normal seminal fluid for sperm transportation and nutrition. Deposition of semen in the vagina near the cervix: Patent duct system (epididymis , vas deferens & ejaculatory ducts) Prober coitus. Prober ejaculation.

 Role of female partner in conception: Ovarian factor: Normal ovulation & functioning corpus luteum. Tubal factor: Oocyte pick up & transportation. Sperm transportation. Site for fertilization and zygote transportation to the uterine cavity. Uterine factor: Normal cavity & endometrium for implantation & fetal growth. Cervical factor: Patent cervix & adequate cervical mucus. Vaginal factor: proper coitus, semen deposition & transportation.

Conception:
Regular unprotected coitus (without contraception) results in pregnancy in: 25 % within one month. 60 % within 6 months. 80 % within one year. 90 % within 18 months.

Fecundability: It is the ability to have pregnancy within a single menstrual cycle (20-25 %). Fecundity: It is the ability to have live birth baby within a single menstrual cycle. Infertility: Failure of conception after one year of regular unprotected coitus.

N.B.: Some define infertile after 18 months of regular unprotected coitus, (as 90 % of women get pregnant within this period).
Sterility: Complete inability to achieve conception.

Physiological infertility: Before menarche. After menopause. Fertility is reduced during lactation.

Types of infertility:
Primary infertility: No history of previous pregnancy. Secondary infertility: History of previous pregnancy regardless of the mode of termination. Relative infertility: History of conception with inability to achieve a live birth baby. N.B.: Unexplained infertility: is failure to achieve pregnancy without any obvious cause (fertility workup is usually normal).

Etiology of infertility:
Male factor 30%

Female factor Combined factors Unexplained

40% 10-20 %
Infertility

10-20%
Male factor Female factor Combined factors Unexplained

Male factor of infertility

Etiology of male infertility: 1- Defective spermatogenesis: It includes: Azoospermia: no spermatozoa in the semen. Aspermia: complete absence of semen. Hypospermia: decreased semen volume (<2 ml on at least two semen analyses). Oligospermia: decreased sperm number (< 15 million/ml). Asthenospermia: decreased sperm motility. Teratospermia: increased abnormal sperm morphology.

Causes of defective spermatogenesis:

a) Primary testicular disorder: (Due to testicular defect with intact hypothalamic - pituitary axis).
Chromosomal disorders: Klinefelter syndrome (XXY). Undescended testicles. Infection: Orchitis (after mumps infection in adult life). Testicular atrophy: after accidental ligation of the testicular artery during operation. Chemicals & drugs (cemetidine- spironolactone - heavy metals insecticides beta blockers-ethanol- nitrofurane excessive smoking & narcotics). Immunological disorders: antisperm-antibodies may develop after orchitis or testicular trauma suppression of spermatogenesis. Malnutrition. Chronic illness (malignancy- tuberculosis & renal failure). Aging is associated with reduced spermatogenesis. Idiopathic. Irradiation.

2- Defective seminal plasma: Chronic infection of accessory reproductive glands (prostatitis or seminal vesiculitis) Pyospermia or leucocytospermia (Excessive pus in semen) hostile to sperm impaired sperm function & motility. 3- Duct obstruction: Bilateral obstruction of the epididymis, vas deferens or ejaculatory ducts (may be congenital, inflammatory or accidentally ligated) obstructive azoospermia. 4- Coital defects: Frequency: due to stress, travel or marital problems). Impotence: psychologic or organic (due to diabetic neuropathy, secondary to drugs as -blockers or cimetidine). 5- Defective ejaculation: Premature ejaculation or hypospadias sperm deposition extra vaginal. Retrograde ejaculation: (due to prostatectomy, diabetic neuropathy or drugs)

Evaluation of the male factor of infertility:

A. History: - Age & occupation: exposure to heat, chemicals or irradiation. - Habit: smoking, alcohol or drugs. - Pubertal development & undescended testis. - Orchitis or genital infection. - Genital tract surgeries. - Detailed coital history (potency, frequency). B. Physical examination: - General examination: - Nutritional status (over & under weight) - Systemic disorders (thyroid enlargement) - Secondary sex characters, hair distribution & gynecomastia. - Local examination: - Penile: anomalies as hypospadias - Testes: number, size, consistency & varicocele. - Rectal examination: to detect prostatic enlargement.

C. Investigations of the male factor of infertility: i. Semen analysis: Done by direct visualization under microscope or by computer (CASA: computer assisted semen analysis). Semen is obtained after 2-5 days of abstinence period by masturbation or coitus interruptus into a clean container.

Semen Analysis
Volume Normal: 2-6 ml > 6 ml may be due to chronic prostatitis or seminal vesiculitis. <2 ml may be due to obstruction or retrograde ejaculation (hypospermia) > 20 million/ml (new WHO strict criteria: < 15 million/ml) 7.2-8 (alkaline) Completed within 30 minutes. > 50 % motile > 30 % is considered normal according to the WHO criteria. not exceed 10 %.

Sperm count: Reaction (pH): Liquefaction: Motility: morphology: Agglutination:

Cellular elements:

< 5 x106/ml rounded cells of which < 1x106/ml are WBCs.

. Testicular biopsy: To differentiate between obstructive & nonobstructive azoospermia. Should be done where facilities for sperm freezing is available.

Treatment of male infertility:

A. Non-specific measures: - Correction of unfavorable conditions (stress, excessive smoking, alcohol ). - Weight reduction. - Preserve testicular low temperature by avoiding tight clothes, cold showers. - Treatment of systemic & endocrinal disorders as hypothyroidism & diabetes. - Vitamins & minerals supplements.

B. Medical treatment:

Hormonal therapy: Estrogen like compounds: clomiphene citrate & tamoxifen have been used in treatment of oligospermia. Gonadotropins: FSH & hCG may be used in treatment of hypogonadotrophic hypogonadism Androgens: Testosterone or synthetic androgen may be used in cases of oligospermia & asthenospermia. Bromocriptine: In case of hyperprolactinemia.
Antibiotics: In cases of chronic infection of prostate & seminal vesicles. Steroid therapy: In cases of immunological infertility associated with the presence of antisperm antibodies.

C. Treatment of erectile & ejaculatory disorders: - Psychotherapy & Sildenafil (Viagra). - adrenergic agonists: in retrograde ejaculation to increase the tone of urethral sphincter. - ART: as IUI. D. Surgical treatment: - Varicocelectomy. - Short-circuit operations: in cases of obstructive azoospermia. All these modalities are less important after ART

E. Assisted reproductive techniques (ART) : 1- Artificial insemination (intrauterine insemination IUI): in cases of poor semen quality (oligospermia, asthenospermia, teratospermia & leucocytospermia) or in cases of erectile or ejaculatory disorders. Technique: Prepared semen is injected into the uterine cavity at the time of ovulation (determined by transvaginal US). Controlled ovarian stimulation may be done to improve pregnancy rate.

IUI

ICSI

2- In-vitro fertilization - embryo transfer (IVF-ET) & Intracytoplasmic sperm injection (ICSI): Done in cases of severe oligospermia (sperm count < 10 million /ml) or azoospermia.
N.B.: IMSI: using a high power magnification to select morphologically normal sperms for ICSI

Other methods of assisted reproductive techniques (rarely done): a) Gamete intrafallopian transfer (GIFT): The ovum & the sperm are placed into a patent fallopian tube via laparoscopy. b) Zygote intrafallopian transfer (ZIFT): A zygote is placed into a patent fallopian tube via laparoscope. c) Subzonal insemination (SUZI): A small hole is made in the zona pellucida by micromanipulation (zonal drilling) then a sperm is introduced in the perivitelline space under the zona.

Ovarian factor of infertility

Incidence: 30-40 % of female infertility. Causes: Ovulatory failure (i.e. anovulation). Luteal phase defect (LPD).

A. Ovulatory failure (anovulation): Causes: i. Hypothalamic disorders: By altered GnRH or dopamine release (prolactin inhibiting factor). Stress, psychological & environmental upsets desire or fear of pregnancy. Body weight changes: obesity or underweight anorexia nervosa Drugs: Hormonal contraceptives (post pill amenorrhea). Antidepressants & Phenothiazine derivatives. Hypothalamic syndromes: as Kallmanns, Frhlich, Chiari-Frommel, Laurence-Moon-Biedl syndromes, all are associated with hypothalamic dysfunction ovarian dysfunction & anovulation.

 ii. Pituitary disorders: Prolactinoma (micro or macroadenoma): hyperprolactinemia ovarian dysfunction & anovulation. Sheehan's syndrome & panhypopituitarism. iii. Other endocrinal disorders: may be associated with ovarian dysfunction & anovulation such as: Thyroid dysfunction: hypothyroidism or hyperthyroidism. Adrenal dysfunction: Cushing's syndrome & adrenogenital syndrome. Uncontrolled DM. iv. Ovarian dysfunction: Ovarian dysgenesis. Ovarian resistant syndrome. Premature ovarian failure. Polycystic ovarian syndrome. iv. Chronic debilitating diseases.

B. Luteal phase defect: In which the luteal phase may be: Too short (< 8 days ) or Inadequate progesterone release by corpus luteum. Both cause lead to implantation failure of fertilized ovum or early pregnancy loss.

N.B.: Luteinized unruptured follicle (LUF) syndrome: Characterized by normal biological & biochemical manifestations of ovulation with no release of ovum. LUF syndrome is usually due to inadequate folliculogenesis.

Evaluation of the ovarian factor:

History: Menstrual history (as regular cycle exclude ovulatory cause). History of post partum hemorrhage (Sheehans syndrome). History of psychological, stress & weight changes (weight loss or obesity). History of chronic & endocrine dysfunction. History of drug or hormonal contraceptive intake. Physical examination: General examination: for secondary sex characters (exclude Turner's stigma, hirsutism & galactorrhea) & thyroid enlargement. Local examination: To exclude abnormal development of the genital system, adnexal cysts or tumors.

 Diagnosis of ovulation: Symptoms suggestive of ovulation :

Regular menstruation. Mid-cyclic pain (Mittle Schmerz), mid-cyclic spotting & mid-cyclic excessive mucoid vaginal discharge. Basal body temperature chart: as Progesterone is a thermogenic hormone causes body temperature by 0.3 - 0.5 C.

Temperature is recorded daily in the early morning & blotted on chart, Biphasic curve of basal body temperature is characteristic of ovulation.

Hormonal assay: Serum progesterone: measured in mid-luteal phase (usually day 21 of 28 days cycle). The most important. Serum progesterone 10 ng/ml or more indicates ovulation. LH: Detection of LH. Urinary pregnanediol (metabolite of progesterone excreted in urine after ovulation. Premenstrual endometrial biopsy: Progesterone secreted by the corpus luteum secretory endometrium. So endometrial biopsy taken 2 days before the expected menstruation (in case of regular cycles) or on the first day of menstruation (in case of irregular cycles) shows secretory endometrium in cases of ovulatory cycles.

Vaginal cytology: E2 secreted by the growing follicles changes in the exfoliated vaginal cells cells are separate, large, polyhedral with eosinophilic cytoplasm and pyknotic nuclei & have no folded edges. Vaginal smear is clean (i.e. no leucocytes are present). Progesterone moderate sized oval cells with basophilic cytoplasm and vesicular nuclei & folded edges. The cells tend to aggregate in clumps. Vaginal smear is dirty (i.e. contains leucocytes).

Cervical mucus changes: The pre-ovulatory cervical mucus (estrogenic) is: Clear, acellular, copious & less viscous Can be stretched between two points into threads (positive Spinnbarkeit test) Shows arborization or palm-leaf appearance on drying (positive Ferning test). The post-ovulatory cervical mucus (Progesterone) is Cellular, Scanty & viscid Negative both Spinnbarkeit & Ferning tests.

 Ultrasound monitoring : Transvaginal ultrasound is used to monitor follicular growth until the dominant follicle reaches 18-25 mm in diameter (mature follicle). Ovulation is characterized by a sudden reduction in the size of the follicle appearance of fluid in Douglas Pouch.

 Laparoscopy & transvaginal endoscopy (fertiloscope): The hole for release of mature follicle (stigma of ovulation) can be seen by laparoscopy. Corpus luteum (yellow) can be seen by laparoscopy or fertiloscope in ovulatory cycles. N.B.: laparoscopy is not a routine for diagnosis of ovulation, but diagnosis of ovulation is done during laparoscopy for investigation or management of a case of infertility.

Fertiloscope

IV. Diagnosis of luteal phase defect: By: Serial serum progesterone assessment. Endometrial biopsy: Endometrium is out of phase (i.e. the histological dating is behind the cycle dating by more than 2 days).

The most important : 1- Mid luteal serum progesterone 2- U/S follicular scanning 3- BBT chart

Treatment of defective ovarian factor:

A. Treatment of ovulation failure (anovulation): I. Medical induction of ovulation: a) Estrogen-like compounds: - Act on the hypothalamic-pituitary axis. - Compete with E2 for the estrogen receptors escape of the hypothalamus & anterior pituitary gland from the estrogen negative feed-back mechanism GnRH pituitary FSH & LH ovarian stimulation & ovulation.

Clomiphene citrate: It is non-steroidal drug, has both estrogenic & antiestrogenic effects. Tamoxifen: Side effects of estrogen-like compounds: Ovarian hyperstimulation. rate of multiple pregnancy. Hot flushes & visual disturbances.

b) Gonadotropin therapy (FSH): Preparations of FSH:

Administered (IM injections) is done by different induction protocols according to the condition & follicular response monitored by the TV ultrasound. When the stimulated follicles reach 18 mm bt TVUS hCG (5000 IU) is given to trigger ovulation. Careful monitoring during gonadotropin therapy is important to ensure successful outcome & avoid ovarian hyperstimulation syndrome (OHSS) by:
Serial serum E2. TV Ultrasound monitoring of follicles size & number.

Human menopausal gonadotropin hMG. Purified FSH. Recombinant FSH (manufactured by genetic engineering).

Side effects & complications: Ovarian hyperstimulation Characterized by: Abdominal distension. Nausea. Vomiting. Diarrhea. Ovarian enlargement. In severe cases: ascites, pleural effusion, hypovolemia & thromboembolic disorders due to hemoconcentration. Multiple pregnancies.

GnRH therapy: Agonist and Antagonist Is indicated in hypothalamic dysfunction (Given in pulses of 10-20 g at 90 minutes intervals (IM or subcutaneously) by a pump). But used mainly to down regulate the pituitary prior to ovulation induction with HMGto ensure maturation of all follicles at the same time and to prevent premature LH surge. Or: given to suppress ovulation in cases of endometriosis as a treatment. Dopamine agonist therapy: Bromocriptine (2.5-5 mg/day) or Lisuride (0.2-0.4 mg/day) in cases of hyperprolactinemia.

II. Surgical induction of ovulation: Laparoscopic wedge resection: obsolete operation done in cases of PCOs, but seriously affects ovarian reserve. Laparoscopic ovarian drilling: (by electrocautery) in cases of polycystic ovarian disease (its use should be limited to PCO resistant cases to medical Rx). Other surgical procedures: Surgical excision of prolactinoma in case of hyperprolactinemia. Surgical excision of adrenal tumors.

Ovarian Drilling

B. Treatment of luteal phase defect: - Induction of ovulation followed by progesterone (IM, oral or vaginal) given during the luteal phase.

Vaginal factor of infertility

The vagina may be unable to receive the semen or its secretion or discharge is hostile to the sperm. Etiology of defective vaginal factor: Congenital vaginal anomalies: Vaginal aplasia, atresia or hypoplasia Vaginal septum: transverse or longitudinal Acquired vaginal stenosis: post operative or post infection Vaginismus: aparuria or failure of intercourse

 Evaluation of the vaginal factor: History & vaginal examination: to know the cause. Treatment: Surgical correction of vaginal congenital anomalies, surgical excision of vaginal tumors. Psychotherapy for cases of vaginismus.

Cervical factor of infertility

Functions of Cervical mucus: Sperm capacitation: by providing energy supply during transport through the cervical canal. Ferning: cervical mucus at time of ovulation is arranged in lanes to facilitate ascent of sperm, while in the luteal phase it forms a network with narrow meshes impenetrable to sperm. Neutralizes vaginal acidity. Acts as a reservoir for continuous supply of sperm to the fertilization site in the fallopian tubes.

Etiology of cervical infertility: Organic cervical disorders: Stenosis: Congenital or acquired. Tumor or polypi, benign or malignant tumors. Infections: chlamydia & mycoplasma infections. Functional disorders of the cervical mucus: Quantitative: Inadequate cervical mucus secondary to cauterization or to antiestrogenic drugs as clomiphene citrate. Qualitative: hostile mucous due to presence of antisperm antibodies.

Evaluation of the cervical factor: History & examination: cervical stenosis, infection or cervical tumors. Post-coital test PCT(Sims-Huhner Test): N.B.: regarding evidence-based medicine the role of the PCT has been questioned and its use has become controversial. Evaluation of the cervical mucus score: 4 parameters are graded (Each parameter is given a degree from 0-3): - Amount. - Stretchability. - Ferning. - Degree of opening of the external os. -Cervical mucus score < 8 weak estrogenic stimulus. -Cervical mucus score > 8 considered normal. The number & motility of sperm in the cervical mucus (by high power field):

Results of PCT:

Positive post-coital test: > 5 motile sperm/HPF with progressive motility. A positive PCT means that there is: Normal spermatogenesis. Normal coitus. Normal ejaculation & adequate cervical mucus. Non-conclusive PCT: 1-5 motile sperm/ HPF usually indicate oligospermia. Negative post-coital test : Negative PCT if: No sperms in cervical mucus either azoospermia or a coital-ejaculatory defect. Immobile or agglutinated sperms presence of antisperm antibodies in the cervical mucus (i.e. immunological infertility). False negative.

Post Coital Test

IV- Antisperm antibodies test: To detect antisperm antibodies in serum or in cervical mucus. V- Culture & sensitivity test of the cervical mucus: To detect the chlamydia, mycoplasma or other cervical infections.

Treatment of cervical factor:

IUI is the most common treatment modality for cervical factor whatever the cause Treatment of cervical infections: By proper antibiotics after culture & sensitivity. Treatment of insufficient, viscid cervical mucus: Oral doses of ethinyl estradiol 10 g 3 times daily for 3 days from day 11-13 of the cycle may improve the cervical mucus quality.

 Treatment of immunological infertility: Condom used for 6 months then coitus is allowed without condom during the fertile period of the woman. Corticosteroid: results are controversial. Surgical treatment of organic cervical disorders:
Cervical dilatation in cases of congenital or acquired cervical stenosis. Surgical removal of cervical tumors.

Tubal factor of infertility

Functions of fallopian tubes: Pick up & transport of the ovum to the site of fertilization. Capacitation of the sperm & its transport to the site of fertilization. Nourishment & maturation of the oocyte. Transport of the fertilized ovum to the uterine cavity. Incidence: Tubal factor of infertility is responsible for 3040 % of the female infertility.

Etiology: Bilateral tubal obstruction: Congenital tubal aplasia or atresia (rare). Salpingitis: the commonest cause of tubal obstruction, it may be caused by specific organisms (gonococcus- chlamydia or tuberculosis) or by non-specific bacteria following childbirth, abortion or the use of IUDS. Previous surgery on or near the fallopian tubes. Tumors of the uterus (fibromyomata) or broad ligament cysts or tumors. Pelvic adhesions secondary to: Pelvic peritonitis, appendicitis or diverticulitis. Pelvic endometriosis. Pelvic & peri-tubal adhesions may interfere with the pick up of the ovum either mechanically or by biochemical substances (PGs & interleukins) that affect tubal motility. Pelvic adhesions & pelvic endometriosis are referred to as peritoneal factor of infertility.

Tubal patency is evaluated using one or more of the following methods: a- Tubal insufflation or Rubin's test (not done, only for historical interest) b- Hysterosalpingography (HSG) c- Laparoscopy.

 b- Hysterosalpingography (HSG): Technique: By injecting a radio-opaque dye through the cervix. Timing: Post-menstrual (last day of menstruation) to ensure open cervix and exclude pregnancy. Criteria of tubal patency: Both tubes are finely delineated. Free peritoneal spill in the second X-ray film Advantages: Outline the uterine cavity detect congenital uterine anomalies, submucous fibromyomata & intrauterine adhesions. Tubal patency: the site of the tubal block can be determined. Other tubal pathology: hydrosalpinx, tuberculous salpingitis. Peritoneal or peri-tubal adhesions. Disadvantages: Ascending Infection. Allergic reactions.

c- Laparoscopy: It is the method of choice in investigating the tubal & peritoneal factors of infertility. Advantages: can reveal : Tubal patency (chromopertubation). Pelvic & peritoneal adhesions. Ovarian & pelvic endometriosis. Pathological lesions of the uterus (congenital anomalies- fibromyomata ) or the ovaries (PCOS. Tumors or rndometriosis) d- Others Culdoscopy (transvaginal laparoscopy). Salpingoscopy. Falloposcopy. Hysteroscopic tubal cannulation.

Treatment of defective tubal or peritoneal factors of infertility

A. Tubal surgery:

B. Laparoscopic: Adhesiolysis: dissection & cutting of pelvic adhesions or peri-tubal adhesions. Fimbrioplasty: in cases of distal tubal block. Tubal anastomosis: in cases of segmental tubal block. C- Hysteroscopic or ultrasound tubal cannulation: In case of corneal tubal block. D. ART: (IVF-ET): Success rate is high (30-40 %). N.B.: it may be necessary to remove a damaged fallopian tube (e.g.: hydrosalpinx) by operative laparoscopy to increase the success rate of IVF-ET.
The line of management of choice in tubal factor of infertility

Tubal surgery is also of limited value in tubal infertility:

Uterine factor of infertility

Etiology: Uterine aplasia, rudimentary or hypoplastic uterus. Uterine anomalies as septate, subseptate, bicornuate uterus.... Refractory or non-responsive endometrium to ovarian steroid hormone. Intrauterine synechia (Asherman's syndrome). Tuberculous endometritis. Uterine fibromyomata. Adenomyosis.

Diagnosis: History. Examination. Investigations: Endometrial biopsy:

Reveals the responsiveness of the endometrium to ovarian hormones & tuberculous endometritis.

 Ultrasound: 2D Transvaginal:
Uterine size, position, congenital anomalies & tumors of the uterus. Uterine index: gives an idea about the degree of development of the uterus. Others

SIS. 3&4D US

 HSG:
To diagnose uterine congenital anomalies, intrauterine adhesions, submucous fibromyomata..

 Hysteroscopy:
For direct visualization of the interior of the uterus, diagnosis and surgical correction of intrauterine adhesions, uterine anomalies & submucous fibromyomata.

Treatment of uterine infertility: i. Medical treatment: Antituberculous therapy for 12-18 months is beneficial for tuberculous endometritis. Estrogen hormonal therapy may be of value in case of uterine hypoplasia. ii. Hysteroscopic surgery: Resection of the uterine septum, intrauterine adhesions or submucous fibromyomata. iii. Myomectomy: Indicated in cases of submucous fibromyomata causing repeated pregnancy loss or fibromyoma compressing the cervical canal or the interstitial part of the fallopian tubes .

Unexplained infertility
Definition: Failure of a couple to conceive with no identifiable cause & the investigations of infertility reveals no abnormalities.

Before considering infertility as an unexplained problem the following criteria should be present: No identifiable cause could be detected by clinical examination of both partners. Normal semen parameters by analysis of two specimens. Normal ovulation & adequate luteinization. Positive post-coital test. Patent & functioning fallopian tubes. Normal uterine factor by HSG, HSK & endometrial biopsy.

 Treatment of unexplained infertility: Unexplained infertility should be managed by assisted reproductive techniques: Controlled ovarian hyperstimulation + IUI: This procedure has to be repeated for 3 trials. IVF-ET. ICSI.

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