Subfertility

Question 1

Definition of infertility

Answer 1

Infertility is the failure to conceive after having regular unprotected sexual intercourse (every 2-3 days) for one or two years (approximately 50% of women who do not conceive in the first year are likely to do so in the second year.)

Question 2

What proportion of couple will concieve naturally within 1 year and after 2 years of intercourse. What are the chances after 3 years

Answer 2

• 84% of couples in the general population will conceive naturally within 1 year with regular unprotected intercourse, rising to 92% after 2 years and 93% after 3 years
• For couples who have been trying to conceive for more than 3 years, the chance of a spontaneous pregnancy in the next year is 25% or less

Question 3

How can infertility be calssified

Answer 3

• Primary in couples who have never conceived
• Secondary in couples who have previously conceived

Question 4

How is subfertility defined

Answer 4

Generally describes any form of reduced fertility that results delayed conception

Question 5

What is the incidence of subfertility

Answer 5

• 1 in 7 couples have difficulty conceiving and female fertility declines with age- most important factor affecting fertility (affect of paternal age is unclear)
• Female fertility falls sharply at the age of 36

Question 6

What is the process (timeline) of natural conception

Answer 6

• Eggs are fertilisable for about 12-24 hours after ovulation
• Sperm can survive within the female reproductive tract for up to 72 hours
• Ovulation usually occurs 14 days before menstruation
• The fertile window will be different depending on the usual length of the cycle

ALL WOMEN who intend to concieve should commence folic acid (400mcg/day)

Question 7

What are some lifestye factors which confer risk of infertility

Answer 7

smoking, extremes of BMI, excess exercise and stress

Question 8

What are the main causes of infertility

Answer 8

Ovulatory disorders (25% of couples), tubal damage (20% of couples), male infertility (30% of couples) and uterine and peritoneal disorders (10% of couples). Gamete or embryo defects, uterine or endometrial factors, and pelvic conditions such as endometriosis may also have significance.
* Thee is no identifiable cause of infertility in 25% of couples

Question 9

What are some male causes of infertility

Answer 9

• There many be no underlying cause (44% of cases), however semen analysis might reveal decreased number of spermatozoa (oligozoospermia), decreased sperm motility (asthenozoospermia), abnormal sperm on morphological examination (teratozoospermia)
• Identifiable causes include primary spermatogenic disorders- genetic disorders, obstructive azoospermia, varicocele, hypogonadism, vasectomy, stress, lifestyle factors

Can also be divided into pre-testicular, testicular and post-testicular factors of male infertility

Question 10

What are some cuases of primary spermatogenic failure (any spermatogenic abnormality caused by a condition other than hypothalamic disease)

Answer 10

• Congenital- Anorchia (absence of testes), testicular dysgenesis/ cryptorchidism (undescended testes), genetic abnormalities (karyotype, Y-chromosome deletion), Obstructive azoospermia (absence of both spermatozoa and spermatogenic cells in semen and post-ejaculate urine due to bilateral obstruction of the seminal ducts- can be congenital or acquired)
• Acquired- Trauma, testicular torsion, mumps orchitis, exogenous factors (medication cytotoxic or anabolic drugs, irradiation, heat), systemic disease, testicular tumour, varicocele, ejaculation disorders or erectile dysfunciton

Question 11

What are some genetic causes of male infertility

Answer 11

Klinefelter’s syndrome with karyotype 47 XXY, Kallmann syndrome, small testes, cystic fibrosis, androgen insensitivity syndrome

Question 12

What is the management of male factor infertility

Answer 12

• Lifestyle modification (particularly where there is teratozoospermia)- stop smoking, reduce alcohol intake and lose weight
• Men with hypogonadotropic hypogonadism should be offered gonadotrophin drugs since they are effective in improving fertility
• Men with idiopathic semen abnormalities should not be offered anti-oestrogens, gonadotrophins, androgens, bromocriptine or kinin-enhancing drugs because they have not been shown to be effective. Effect of corticosteroids has also been shown to be unclear.
• Men with obstructive azoospermia should be offer surgical correction of epididymal blockage
• Men should not be offered surgery for varicoceles as part of fertility treatment (does not improve pregnancy rates)
• Intrauterine insemination or intracytoplasmic sperm injection (direct injection of sperm into the cytoplasm of an egg)

Question 13

Describe the normal physiology of ovulation

Answer 13

• Low oestrogen-> positive feedback on the hypothalamus and results in GnRH pulsatility
• This leads to release of FSH and LH
• FSH causes growth and maturation of several follicles in the ovary, each of which contains an immature oocyte
• Follicles produce oestradiol which has a negative feedback effect on the hypothalamus and causes suppression of FSH and LH
• The dominant follicle has sufficient gonadotrophin receptors to survive, it produces inhibin B which further suppresses FSH
• High oestradiol output eventually causes an LH surge, once a threshold potential has been reached
• Casues rupture of the follicle. The egg is collected by fallopian tube fimbrae and the follicle becomes a corpus luteum-> progesterone production-> secretory endometrium.

Question 14

How can anovulation be classified (THREE classifications)

Answer 14

1. Group 1 ovulation disorders (hypogonadotropic hypogonadism) are caused by hypothalamic pituitary failure. This includes conditions such as hypothalamic amenorrhoea (commonly due to low body weight or excessive exercise), Sheehan’s, Kallmann’s syndrome. Accounts for around 10% of women with anovulation. Women typically present with amenorrhea, characterised by low gonadotrophins and oestrogen deficiency.
2. Group II ovulation disorders are defined as dysfunctions of the hypothalamic-pituitary ovarian axis. This includes PCOS and hyperprolactinaemic amenorrhoea (85% of women with ovulation disorders have a group II anovulation disorder)
3. Group III ovulation disorders are caused by ovarian failure and are characterised by high gonadotrophins and hypogonadism and a low oestrogen level. 4-5% of women with ovulation disorders have a group III disorder.

Question 15

Management of group 1 anovulation disorders

Answer 15

Advise women with group I disorders that they can improve their chances of regular ovulation, conception and uncomplicate pregnancy by:
* Increasing their body weight if they have a BMI of less than 19
* Moderating their exercise levels if they undertake high levels of exercise

Offer women with group 1 ovulation disorders pulsatile administration of GnRH or gonadotrophins with LH activity to induce ovulation

Question 16

Management of group 2 anovulation disorders

Answer 16

Advise women with group 2 disorders who have a BMI of 30 or over to lose weight (this alone might restore fertility).

Offer one of the following treatments: clomiphene or metformin (when insulin insensitivity and obesity associated) or a combination of the above
* Clomiphene citrate is a selective oestrogen receptor modulator- stops negative feedback of oestrogen on the hypothalamus, increasing GnRH pulsatility
* Before starting clomiphene, give woman a progesterone fisrst to induce a withdrawal bleed so that you are at the start of the cycle
* Usually continued for 6 cycles
* For women taking clomiphene citrate, offer USS monitoring during at least the first cycle of treatment to ensure that they are taking doses that minimises the risk of multiple pregnancy and do not continue for longer 6 months
* Side effects of metformin include nausea, vomiting, GI disturbance

In women with PCOS who are resistant to clomiphene treatment can alternatively consider:
* Combination therapy (metformin + clomiphene)
* Letrozole (aromatase inhibitor with anti-oestrogen effects)
* GnRH OR GnRH agonist (not both concomitantly since risk of ovarian hyperstiulation)
* Ovarian drilling

Hyperprolactinaemic amenorrhoea- offer treatment with dopamine agonists such as cabergoline

Question 17

What are some medications that can affect fertility

Answer 17

NSAIDs (inhibit ovulation), COX inhibitors, spironolactone (cause infertility and menstrual irregularities), chemotherapy, neuroleptics, contraceptives (especially PROVERA depot), recreational drug use

Question 18

What are some tubal, uterine and cervical risk factors for infertility

Answer 18

STIs or PID, previous sterilisation, endometriosis (tubal distortion and limitation of fimbrial motility due to pelvic adhesions), cervical mucus defect, submucosal fibroids (may distort the uterine cavity and impair implantation), previous cervical or pelvic surgery

Question 19

What surgical options exist for treating tubal/uterine causes of infertility

Answer 19

• Tubal microsurgery and laparoscopic tubal surgery- for mild tubal disease
• Tubal catheterisation or cannulation- May be used in women with proximal tubal obstruction- selective salpingography plus tubal catheterisation or hysteroscopic tubal cannulation
• Women with amenorrhoea who are found to have intrauterine adhesions should be offered hysteroscopic adhesiolysis
• After identification of fibroids can offer myomectomy- hysteroscopy, laparocopy, laparotomy or fibroid embolisation
• IVF

Question 20

In whom is intrauterine insemination a viable treatment option

Answer 20

Mild endometriosis, mild male factor infertility, couples who do not have intercourse, single women, same sex couples using donor sperm, unexplained infertility

Question 21

Describe the process of intrauterine insemination

Answer 21

• A catheter is passed through the cervix so is in the lower part of the uterine cavity. Sperm is then injected into the uterine body to allow them to pass into the fallopian tube (sperm selected are motile and morphologically normal- then concentrated)
• Sperm are usually injected 24 hours before ovulation occurs
• May be preceded by mild stimulation with SC injections of FSH (stimulates ovaries to produce 2-3 mature follicles)
• Triggering ovulation and timing the insemination may be achieved by a SC hCG injection

Question 22

Investigations for male factor infertility

Answer 22

Semen analysis:
* Reference ranges: Semen volume (1.5ml or more), pH (7.2 or more), Sperm concentration (15 million spermatozoa per ml or more), total (39 million spermatozoa per ejaculate or more), total motility (40%) viability (58% live), morphology (4% or more normal morphology)
* If the results of the first semen analysis is abnormal a repeat confirmatory test should be offered (should be repeated after 3 months to allow cycle of spermatozoa)
* Factors affecting semen analysis: hot baths tight underwear, smoking, alcohol, raised BMI, caffeine
* Men should abstain from ejaculation for at least 3 days and at most 7 days prior to semen analysis testing, avoid hot baths, tight underwear etc.

Vasography and testicular biopsy if indicated

Question 23

Investigations for female infertility

Answer 23

Initial investigations in women, often performed in primary care:
* BMI (low could indicate anovulation, high may subfertility, PCOS), chlamydia screening , rubella immunity in the mother
* Hormone testing: Serum LH and FSH on day 2 to 5 of the cycle
* High LH may suggest PCOS
* Serum progesterone on day 21 of the cycle (or 7 days before the end of the cycle if not on a 28-day cycle) if they have irregular cycles
* A rise in progesterone on day 21 indicates that ovulation has occurred and that the corpus luteum has formed
* AMH
* TFTs where symptoms are suggestive
* Prolactin (if hyperprolactinaemic anovulation is suspected)- galactorrhoea or amenorrhoea

Ovarian reserve testing:
* A woman’s age should be used as an initial predictor of chances of success in natural conception or IVF
* One of the following then can be used to predict the likely response to GnRH stimulation in IVF: Total antral follicle count- Greater than 16 indicates high reserve, less than 4 indicates low reserve and likelihood of IVF success, AMH- can be measured at any time in the menstrual cycle (greater than 25 indicates high reserve, less than 5.5 indicates low reserve)-> Produced by granulosa cells and does not change in response to gonadotrophins, so it is the most successful biomarker of ovarian reserve
* FSH- greater than 8.9 IU/l for a low reserve, and less than 4 IU/l for a high reserve

Pelvic USS- to look for PCOS or structural abnormalities of the uterus
* Also allows for assessment of antral follicle count

Hysterosalpingogram- to look at the patency of fallopian tubes
* Usually only performed when there are risk factors for tubal damage (previou
* A type of scan used to assess the shape of the uterus and patency of the fallopian tubes- also of therapeutic benefit since tubal cannulation under x-ray guidance can be performed during the procedure to open up the tubes
* A small tube is inserted into the cervix, a contrast medium is injected through the tube and fills the uterine cavity and fallopian tubes. X-ray images are then taken (shows abnormalities + obstruction
* There is a risk of infection, so prophylactic antibiotics are given and screening for chlamydia and gonorrhoea are completed before the procedures ectopic, endometriosis PID)

Laparoscopy and dye test- to look at the patency of fallopian tubes, adhesions and endometriosis
* Same idea, but during laparoscopy

People undergoing IVF treatment should be offered testing for HIV, hepatitis B and hepatitis C

Question 24

What intial advice should be given for infertility

Answer 24

• People who are concerned about their fertility should be informed that over 80% of couples in the genera population will conceive within 1 year if:
• The woman is aged under 40 years and they do not use contraception and have regular sexual intercourse (of those wo done not half will do so within the second year)
• Over 50% of women aged under 40 years will conceive within 6 cycles of intrauterine insemination (IUI) (half of those remaining will do some with a further 6 cycles)
• Women who are trying to become pregnant should drink no more than 1 to 2 units of alcohol once or twice per week (3 to 4 units per day for men)
• Women who smoke should be informed that this is likely to reduce their fertility (same for men)
• Women with a BMI > 30 should be informed that they are likely to take longer to conceive and that losing weight will increase their chances of conception
• Women who have a BMI < 19 and who have irregular menstruation or are not menstruating should be advised that increasing body weight will improve their chance of conception
• Men should avoid wearing tight underwear
• Dietary supplementation with folic acid before conception and up to 12 weeks’ gestation reduces the risk of having a baby with neural tube defects (should take 0.4mg per day)

Question 25

What is IVF, what are some indications for IVF

Answer 25

Involves fertilising an egg with a sperm in a lab, then injecting the resulting embryo into the uterus. Each attempt has a 25-30% chance of success of producing a liver birth

A cycle of IVF involves a single episode of ovarian stimulation and collection of oocytes (eggs).

A single cycle may produce several embryos. Each of these embryos can be transferred separately in multiple attempts at pregnancy, all during one “cycle” of IVF. Eggs can be frozen.

Indications for IVF: Almost all causes of subfertility (tubal disease, endometriosis, failed ovulation induction, failed IUI, unexplained subfertility)

Question 26

What are the criteria for referral for IVF

Answer 26

• In women aged under 40 years who have not conceived after 2 years of regular unprotected intercourse or 12 cycles of artificial insemination (where 6 or more are by intrauterine insemination), offer 3 full cycles of IVF, with or without ICSI (NHS OR privately funded)
• In women aged 40 to 42 years who have not conceived after 2 years of regular unprotected intercourse or 12 cycles of artificial insemination (where 6 or more are by intrauterine insemination), offer 1 full cycle of IVF, with or without ICSI, provided: they have never previously had IVF treatment, have no evidence of low ovarian reserve

MUST MEASURE OVARIAN RESERVE BEFOREHAND

Question 27

Descrie the process of IVF

Answer 27

• Suppressing the natural menstrual cycle - Involves GnRH agonist (goserelin)- given during the luteal phase (usually day 21) to suppress GnRH. Can also give GnRH antagonist daily SC injections (Cetrorelix) starting from day 5 - 6 of ovarian stimulation.
• This prevents ovulation and ensures that ovaries respond correctly to gonadotrophins
• Ovarian stimulation - involves using medications to promote the development of multiple follicles in the ovaries. This starts at the beginning of the menstrual cycle (usually day 2), with subcutaneous injections of follicle-stimulating hormone (FSH) over 10 to 14 days. FSH stimulates the development of follicles, and this is closely monitored with regular TVUSS
• When enough follicles have developed to an adequate size (usually around 18 millimetres), the FSH is stopped, and an injection of human chorionic gonadotropin (hCG) is given. This injection of HCG is given 36 hours before collection of the eggs. The hCG works similarly to LH does naturally, and stimulates the final maturation of the follicles, ready for collection. This is referred to as a “trigger injection”.
• Oocyte collection- eggs are collected from the ovaries under the guidance of TVUSS. A needle is inserted through the vaginal wall into each ovary to aspirate the fluid from each follicle. This fluid contains the mature oocytes from the follicles. The procedure is usually performed under sedation (not a general anaesthetic). The fluid from the follicles is examined under the microscope for oocytes.
• Insemination / intracytoplasmic sperm injection (ICSI)- The sperm and egg are mixed in a culture medium. Thousands of sperm need to be combined with each oocyte to produce enough enzymes (e.g. hyaluronic acid) for one sperm to penetrate the corona radiata and zona pellucida and fertilise the egg.
• Embryo culture- Dishes containing the fertilised eggs are left in an incubator and observed over 2 – 5 days to see which will develop and grow. They are monitored until they reach the blastocyst stage of development (around day 5).
• Embryo transfer- After 2 – 5 days, the highest quality embryos are selected for transfer. A catheter is inserted under ultrasound guidance through the cervix into the uterus. A single embryo is injected through the catheter into the uterus, and the catheter is removed. Generally, only a single embryo is transferred. Two embryos may be transferred in older women (i.e. over 35 years). Any remaining embryos can be frozen for future attempts at transfer.

Question 28

How is pregnancy confirmed in IVF. How is pregnancy promoted

Answer 28

• A pregnancy test is performed around day 16 after egg collection. When this is positive, implantation has occurred. Even after a positive test, there is still the possibility of miscarriage or ectopic pregnancy.
• Progesterone is used from the time of oocyte collection until 8 – 10 weeks gestation, usually in the form of vaginal suppositories. This is to mimic the progesterone that would be released by the corpus luteum during a typical pregnancy. From 8 – 10 weeks the placenta takes over production of progesterone, and the suppositories are stopped.
• An ultrasound scan is performed early in the pregnancy (around 7 weeks)

Question 29

Definition of ovarian hyperstimulation syndrome

Answer 29

Complication of ovarian stimulation during IVF infertility treatment. It is associated with the use of hCG to mature the follicles during the final steps of ovarian stimulation.

Question 30

Pathophysiology of ovarian hyperstimulation syndrome

Answer 30

• The primary mechanism for OHSS is an increase in (VEGF) released by the granulosa cells of the follicles. VEGF increases vascular permeability, causing fluid to leak from capillaries. Fluid moves from the intravascular space to the extravascular space. This results in oedema, ascites and hypovolaemia.
• The use of gonadotrophins (LH and FSH) during ovarian stimulation results in the development of multiple follicles. OHSS is provoked by the “trigger injection” of hCG 36 hours before oocyte collection. HCG stimulates the release of VEGF from the follicles. The features of the condition begin to develop after the hCG injection.
• There is also activation of the renin-angiotensin system. A notable finding in patients with OHSS is a raised renin level. The renin level correlates with the severity of the condition.

Question 31

Risk factors for ovarian hyperstimulation syndrome

Answer 31

Younger age, lower BMI, raised AMH, higher antral follicle count, PCOS, raised oestrogen levels during ovarian stimulation

Question 32

Presentation of ovarian hyperstimulation syndrome

Answer 32

• Early OHSS presents within 7 days of the hCG injection. Late OHSS presents from 10 days onwards
• Abdominal pain and bloating, nausea and vomiting, diarrhoea, hypotension, ascites, RF, pleural effusions, DVT, PE
• Mild: abdominal pain and bloating
• Moderate: nausea and vomiting with ascites seen on USS
• Severe: ascites, low urine output (oliguria), low serum albumin, raised Hct
• Critical: severe ascites, no urine output, VTE and ARDS

Question 33

How can OHS be prevented, how can it be managed

Answer 33

• Prevention: in women at higher risk GnRH antagonist protocols or lower doses of GnRH should be used. Additionally lower doses of hCG should be used.
• Management is supportive with treatment of complications (LMWH, ascitic fluid removal, IV colloids, TOP to prevent further hormone imbalance)

Question 34

Complications of OHS

Answer 34

Hypovolaemic shock, acute RF, VTE