PRIMARY INFERTILITY

Zarul Naim Mohd Tamizi

A 25 year old woman attends the gynaecology clinic with her partner. They have been trying to conceive for 15 months without success.

DEFINITION OF INFERTILITY• The involuntary failure to conceive within 12 months of

commencing unprotected intercourse

• Primary Infertility – inability to get pregnant after one year of continuous sexual relations, in the absence of contraceptive use.-70%

• Secondary Infertility – inability to get pregnant for one year after last delivery or abortion, in the absence of contraceptive use.-30%

AETIOLOGY

• Can be due to female factors or male factors• 20 – 40% of couples will have multiple causes• Causes: Male Factors : 20 – 25% Female Factors: - Anovulation 15 – 20% - Tubal 15 – 40% - Endometriosis 5 – 10% Unexplained: 20 – 30%

CAUSES OF MALE INFERTILITY

• 1) Hypothalamic/Pituitary disease (Hypogonadotrophic Hypogonadism)– 1-2%

• 2) Testicular disease – 30-40% • 3) Disorders of sperm transport – 10-20% • 4) Unexplained – 40-50%

1. HYPOGONADOTROPHIC HYPOGONADISM

• Deficiency of Gonadotrophin releasing Hormone (GnRH) or Gonadotrophins (FSH and LH).

• FSH: stimulates spermatogenesis• LH: enhance testosterone synthesis• May be congenital or acquired

- Kallmanns syndrome

i)Pituitary disease:- Pituitary adenoma- Surgery/radiotherapyii) Negative feedback due to excess androgen or excess estrogen. (eg estrogen producing tumour)

2. TESTICULAR DISEASE• Klinefelter's syndrome- 46XXY• Cryptorchidism: failure of testicular descent• Varicocele• Infections: Mumps orchitis• Radiation• Drugs: Alkylating drugs, antiandrogen• Smoking: more likely to have low sperm count• Hyperthermia: prolonged high testicular temperature leads

to impaired spermatogenesis• Anti-sperm antibodies: identified in men who have had

vasectomy and attempted reversal

3. DISORDERS OF SPERM TRANSPORT

• Genital Tract Obstruction:- Post vasectomy- Congenital absence of the vas deferens – may be associated with

cystic fibrosis

- Infection: Gonorrhoea, Chlamydia, TB

• Defective Ejaculation:- Erectile dysfunction (secondary to neurological disease,

Psychosexual, Drugs)- Retrograde ejaculation- Ejaculatory failure

CAUSES OF FEMALE INFERTILITY

1) Ovulatory disorders – 25% 2) Endometriosis - 15% 3) Tubal factor4) Cervical factor- mucus secretion, previous surgery

(conization, cautery) 5) Sexual dysfunction- dyspareunia, vaginismus

1. OVULATORY DISORDER• PRIMARY OVARIAN FAILURE- Premature ovarian failure- Turner's syndrome- Iatrogenic: surgery/chemotherapy

• SECONDARY OVARIAN DISORDERS- Hypothalamus: weight loss, exercise, Kallman's syndrome- Pituitary: Hyperprolactinaemia, hypopituitarism (tumour,

trauma, surgery)- Thyroid: Hyper/hypothyroid- Ovary: PCOS

2. ENDOMETRIOSIS

• Mechanisms of Impaired Fertility:• I) Anatomic distortion from pelvic adhesions.• II) Damage to ovarian tissue by endometrioma formation

and removal.• III) Production of cytokines which impair the normal

processes of ovulation, fertilization, and implantation.

3. TUBAL FACTOR

• Infection: - PID - Pelvic TB• Surgery:- Abdominal or Pelvic surgery leading to adhesion formation- Tubal ligation• Congenital Anomalies

UNEXPLAINED INFERTILITY

• Possible causes: - Luteal-phase deficiency: Abnormalities of corpus luteum

resulting in reduced progesterone levels

- Failure of rupture of the Graafian follicle- Mild endometriosis- Occult infection- Immunological causes- Psychological causes

Q1) What further history would you obtain to evaluate the possible cause for the infertility?

• Ideally, the couple should be seen together.FEMALE• Age: 25yo• Previous pregnancies?• Duration of infertility: 15 months• Coital frequency/difficulty with coitus?• Infertility Hx: - Hypothalamus: stress, weight loss, exercise

- Pituitary: headache, bitemporal hemianopia, galactorrhoea- Thyroid: neck swelling, weight gain/loss, appetite etc.- Ovary: hirsutism, diabetes (PCOS); radio/chemotherapy, mumps

(Premature ovarian failure)

• Menstrual Hx: - age of menarche, cycle length, regularity, menorrhagia, IMB,

PCB• Pelvic Pain Hx:- dysmenorrhagia, dysparuenia• Gynae Hx: - cervical smear, previous contraceptive use- Previous STI, PID- Previous gynae surgery• Past Obstetric:- history of ectopic pregnancy

• Past Medical & Surgical Hx: - thyroid disease? Pituitary disease?- abdominal/pelvic surgery?• Medication?• Social Hx: - smoking, alcohol, recreational drug use

MALE• Age• Previous evidence of fertility• Previous STI• History of mumps, testicular maldescent, varicocele,

torsion• Medical disease: DM, cystic fibrosis• Previous surgery: vasectomy,prostate surgery, bladder

neck surgery • Occupational exposure to chemicals, radiation• Smoking, alcohol• Drug use

FEMALE EXAMINATION• General: BMI, vital signs • Evidence of underlying • endocrine disturbance: hirsutism, acne Acanthosis nigricans Goitre Galactorrhoea, visual field defects

• Abdomen: Masses or tenderness

• Pelvis: Assess normality of external genitalia/ state of hymen Assess vagina and cervix Record size, position, mobility of uterus

• Cervical excitation• Assess adnexae for masses/tenderness• Perform cervical smear if necessary• Chlamydia screening

MALE EXAMINATION

• General: BMI• Hair distribution• Evidence of gynaecomastia or hypoandrogenism

• Genitalia: Palpate testes for size, position, volume, consistency• Palpate epididymes for nodularity/tenderness• Check presence of vas or scrotal swelling• Check for presence of varicocoele• Examine penis for structural abnormality

Q2) What initial investigations would you perform?

• The aim of initial investigations is to assess the quality of semen, detect ovulation and exclude pelvic pathology in the woman.

1. Semen analysis• Sample produced by masturbation or after intercourse into a non-

lubricated condom after a period of abstinence of between 3-5 days. • NORMAL VALUES (WHO):

• If abnormal, should be repeated after 3 months.

• volume: 2.0 ml• liquefaction time: within 60 minutes• pH: 7.2• sperm concentration: 20 million per ml• total sperm number: 40 million per ejaculate• motility: 50% (grades a and b) or 25% or more

with progressive motility (grade a) within 60 minutes of ejaculation

• vitality : 75% or more live• white blood cells: fewer than 1 million per ml • normal morphology: 30% or 15% (based on

strict morphological criteria)

2. Assessment of ovulation 1) Pain at ovulation- Mittelschmertz-20% women experienced2) Changes in texture of cervical mucus- thickens3) Measure basal body temperature• - ovulation is marked by a transient fall in temperature followed by a rise in

luteal phase.4) Measuring the mid luteal phase serum progesterone level• - Which increases after ovulation, also indirectly confirms ovulation. • - Test should be done between Day 21-23 • - Value of >30nmol/l confirms ovulation5) Urine LH kit• - picks up mid cycle surge of LH. Positive means that ovulation will occur

within 34-36hrs time. 6) Endometrial biopsy• - to detect secretory endometrium. Progesterone causes endometrial tissue

to change from proliferative to secretory.• - biopsy done 2-3 days before the onset of menses.

3. Hormonal analysis (female)

• LH:FSH ratio- ratio of 2:1 or greater is suggestive of PCOS• TSH, Prolactin- indicated if woman has oligo/amenorrhoea• Testosterone, - if woman has significant hirsutism

4. Evaluation of tubal patency and pelvic factors

• Tubal patency can be assessed by 3 methods: 1) Hysterosalpingography (HSG)2) Laparoscopy and dye 3) Hysterosalpingo-contrast sonography (HyCoSy)

• INDICATION: 1) Infertility patients presented with chronic pelvic pain,

dysmenorrhoea, dyspareunia suggestive pelvic pathology.2) Infertility couple who have normal hormonal profile and semen

analysis.3) Infertility patients who have failed to conceive despite of

responding well to ovulation induction agents for at least 3 cycles.

4) Preliminary investigation before patient undergoes superovulation and IUI.

a) HSG

• Done on day 7-10 menses.• Recommended in primary infertile

woman (<25yo) with duration of infertility less than 3 years.

• Done by injecting water-soluble contrast media through the cervical os.

• An x-ray is performed to see if there is spill into peritoneal cavity. This indicates that both fallopian tubes are patent.

b) Laparoscopy and dye

• Is a gold standard.• INDICATIONS: 1) if HSG is abnormal2) patient symptomatic (dysmenorrhoea, dyspareunia)3) secondary infertility with evidence of ovulation.4) Prior to superovulation and IUI.• Provide direct view of the pelvic organs.• Methylene blue dye is inserted through a cannula in the cervix to

demonstrate tubal patency. • Invasive test, requires hospital admission, done under GA.

c) HyCoSy

• Involves a standard pelvic US scan at which galactose-containing US contrast medium is inserted into uterine cavity.

• Outline any abnormalities such as submucosal fibroids, endometrial polyps before passing down the fallopian tubes to confirm tubal patency.

• Other methods of testing for tubal patency:

1) Salpingoscopy- A salpingoscope can be passed down

an operating laparoscope and inserted into the ampullary portion of the fallopian tube.

2) Falloposcopy- A falloposcope (diameter <1mm) is

inserted into fallopian tube from uterian cavity.

- expensive and mainly use for research.

Q3) If no obvious abnormality is found to account for the couple's delay in becoming pregnant, what management would

you advise?

• No specific treatment would be indicated until they had been trying to conceive for at least 2-3 years, because of the relatively high spontaneous pregnancy rate during this time. Advice the patient to have sexual intercourse during “ fertile period”.

• If the couple fail to conceive, the reason could be due to 'unexplained' infertility. The options for management are:

1) to do nothing further, in the hope of spontaneous pregnancy-2-3%

2) proceed to ovarian stimulation with gonadotrophins (with or without IUI)-10-20%

3) Assisted conception (IVF or GIFT)-15-20%

Ovarian Induction• 1st line:Clomiphene citrate- is a selective estrogen

receptor modulator (SERM) that increases production of gonadotropins by inhibiting negative feedback on the hypothalamus.

-Start 50 mg daily/bd for 5 days form D2-6-Monitor by follicular tracking of D21 serum progesterone-Increase by 50mg to maximum 200mg daily-Duration of tx not more than 6 cycles with clomid-Consider other method of ovarian induction after fail to

conceive after 6 cycles-SE: Visual disturbance, N+V, allergies, Hypoestrogen

Ovarian Induction• 2nd line: FSH-Start with 75 IU daily from D2-Increase dosage by 75 IU if poor follicular

growth-Stimulation by IM HCG 5000-10000 IU once

follicle reaches 18-20mm -Coitus/ IUI 36 hours after HCG injection

Ovarian Induction• Others:a. Ovarian drilling: PCOS patient that resistant to

clomiphene - Laser fiber or electrosurgical needle punctures

the ovary 4 to 10 times->results in a dramatic lowering of androgen within days.

- As effective as Gonadotrophin but not associated with multiple pregnancy

b. Metformin: - In combination with clomiphene: PCOS patient

that resistant to clomiphene and who have BMI >25

Selection for IUI

• Female age<40 years old• Minimum 2 years infertility• Confirmed patent tube (HSG/

laparoscopy)• Ovulating• Fail to conceive on Clomiphene

after 3 successful ovulatory cylcle• Unexplained infertility• Cervical factor infertility

Method of IUI• Fresh specimen should be available

for preparation at least 2 hours prior to IUI

• Dorsal position and sterile technique• Speculum examination• 0.2-0.6 ml washed sperm injected

into uterine cavity via uterine catheter attached to 1 cc syringe

• Allow patient to rest for 15 minutes• Unsuccessful 3 UI is an indication for

IVF, GIF, ICSI

IVF• AKA Invitro Fertilization• Method: -Eggs collected under LA by aspiriting

follicle under US control. -Then, eggs mixed with wash sperm and

transferred to growth medium.-Can transfer up to 3 embryo, but 2 are

preferable due to less obstetric complication

-Other embryo can be frozen for future transfer

• Criteria: Fallopian tube need not to be patent

GIFT

• AKA Gamette Intra Fallopian Transfer

• Method: Eggs are collected laparoscopically, mixed with sperm and transferred back to fallopian tube

• Criteria: Need at least one functioning tube

THANK YOU

ICSI

• AKA Intracytoplasmic Sperm Injection

• Method: Injection of one sperm into ooplasm using very fine needle.

• Useful in:-very low sperm count-weak sperm