Infertility – Basic Science & NICE Guidelines

Question 1

Infertility

Answer 1

-Failure to achieve pregnancy after two years of frequent unprotected intercourse

-Six months for 2ry infertility and women above 36 year old

-Affects 1:6 couples (15%)

Question 2

Infertility

Answer 2

• 84% of couples achieve pregnancy after one year
• 92% achieve pregnancy after 2 years
• 94% achieve pregnancy after 3 years

*that’s why its okay for a young person to try for 2 years before offering treatment.

*Women are born with a specific amount of follicles or eggs and there is a consistent depletion of the eggs as women age and in fact, the decline from the number of eggs starts when a woman was a fetus in the uterus.

*The vast majority of eggs are wasted before puberty.

Question 3

New NICE Guideline for Infertility definition:

Answer 3

a) . The period of time people have been trying to conceive without success after which formal investigation is justified and possible treatment implemented.
b) “If a woman has not conceived after a year, offer further clinical assessment and investigation, along with her partner”
c) “If a woman is using AI (Artificial Insemination) has not conceived after 6 cycles of treatment, offer further clinical assessment and investigation. When AI is using partner sperm, the referral should include her partner”

In artificial insemination, a doctor inserts sperm directly into a woman’s cervix, fallopian tubes, or uterus.

Question 4

New NICE Guideline

Answer 4

Refer early for specialist consultation:

1. Women aged >36 years
2. There is a known cause of infertility or history of predisposing factors
3. Investigations show there is no chance of pregnancy with expectant management

Question 5

Causes of Infertility

Answer 5

•Female Factor 30%

•Male Factor 30%

•Combined 10%

•Unexplained 25% (inability to find a medical reason).

•Other causes 5%

EXTRA NOTES;

*low ovarian reserve is not yet recognised as a cause of infertility but it is recognised as a reason to offer treatment.

*Women who have endometriosis tend to have lower fertility potential than women wo do not have endometriosis.

Question 6

Female Factors Causing Infertility

Answer 6

•Ovulation disorder: PCO (80%), PCOS, POF (premature ovarian failure/aging), Hypopituitarism (no FHS/LH), RadioChemo Treatment.

*we don’t know why women have PCOS but it is related to high Androgen levels, low insulin sensitivity that can mess up ovulation and behaviour of ovaries. these women tend to have multiple follicles. these women do not recruit follicles and ovulate like normal women.

•Tubal blockage: PID (pelvic inflammatory disease) PID is commonly caused by Chlamydia, endometriosis, previous ectopic pregnancy and the tube is removed and the other tube might not be healthy.

•Age-related: Limited Ovarian Reserve

•Uterine problems: Synechiae (adhesion inside the uterine cavity/ this is very rare), polyp (extra pieces of endometrium sitting in the endometrial cavity), fibroid.

Question 7

BASIC INFERTILITY WORK UP

Answer 7

•HISTORY AND EXAMINATION OF BOTH PARTNERS

• FSH/LH AND OESTRADIOL, PROLACTIN, TFT ON (DAY 2 OR 3)

• MID LUTEAL PROGESTERONE (regular cycles) (can sometimes be called day 21 blood test) this is not accurate. Progesterone levels peak 7 days before starting your next period. this is why its called day 21 blood test) but how about women who have a 35-day cycle. so her progesterone levels will need to be checked at day 28 and not 21. that’s why its better to call it MID LUTEAL PROGESTERONE.
• CHLAMYDIA SWAB & Rubella
• HSG (hysterosalpingogram) -(to test the fallopian tubes)
• PELVIC ULTRASOUND

*Fibroid is a benign overgrowth of the myometrium (wall of the uterus).

Question 8

Female Ovulatory Cycle

Answer 8

• The ovulation cycle begins by an increase in FSH levels, it stimulates the ovarian follicles to mature and this helps make estrogen.
• Estrogen has a negative feedback effect on the pitutary, making FSH go down.
• When the follicle is ready to release the egg inside, estrogen levels reach its peak. This then have a positive feedback effect on the pituitary leading to LH surge.
• The follicle then ruptures, to release the egg.
• After ovulation, progesterone starts to go up to make the endometrium ready for implantation. if she does not get pregnant, the corpus luteum can only survive for 18 days, there will be shedding/breakdown of the endometrium.

*Part of the assessment of ovarian reserve is to check FSH level because this is the main driver of the ovaries and if FSH level is high, it means that the woman has low ovarian reserve because that means that the driver is working harder than neccesary. As in the ovaries are not responding well.

*The ovulation prediction sold in pharmacies will test for LH / Estrogen surge.

Question 9

Ultrasound Evaluation
Antral Follicle Count

Answer 9

Part of the assessment of ovarian reserve is to count the number of follicles which are all potential eggs. the Higher the Antral Follicle Count, the better the ovarian reserve and we count the follicles by doing a vaginal scan measuring the small follicles.

• Part fo the assessment of ovarian reserve is to test a hormone called AMH (Anti-Müllerian hormone). This hormone comes directly from the follicles and it gives the best value of the reserve.
• The higher the Antral Follicle Count, the higher the AMH, the better the ovarian reserve. unlike FAH where the Higher the FSH, the lower the ovarian reserve.

Question 10

AMH

Answer 10

• Produced by the Granulosa cells (inside the Antra follicles)
• High production in pre-antral and small antral stages
• Levels of AMH constant through monthly periods but declines with age.
• Increasing age means a decreased follicle pool
• Increasing age means a decreasing AMH level
• Higher AMH levels predict a good response
• Lower AMH levels predict a poor response

*The advantage of testing AMH is that FHS has to be timed between day 2 and 3 or day 2-5 of a menstrual period. AMH does not fluctuate and does not have to be timed in relation to the menstrual cycle, you can test AMH for any woman at any time.

Question 11

The most useful investigations for women with infetrtility

Answer 11

-Ovarian Reserve Assessment

-Day 2-3 FSH, LH, oestradiol, AMH

-Pelvic Ultrasound & antral follicle count

Question 12

Effect of female age on fertility potential

Answer 12

As a woman becomess more mature the number of follicles reduces.

Question 13

BASIC INFERTILITY WORK UP

TEST OF TUBAL PATENCY - HSG

Answer 13

Testing the fallopian tube, we can do hysterosalpingogram ( an x-ray procedure WITH A DYE)

Question 14

HyCoSy (Ultrasound & Dye) test

Hysterosalpingo Contrast Sonography

Answer 14

-This is an alternative for HSG.

Question 15

BASIC INFERTILITY WORK UP

TEST OF TUBAL PATENCY – LAPAROSCOPY & DYE

Answer 15

This is the Gold standard test in comparison to the ultrasound and xray.

Question 16

BASIC INFERTILITY WORK UP

SEMEN ANALYSIS

Answer 16

Normal SEMEN ANALYSIS; the volume should be 1.5-6mls. 4% should be normal looking.

Sperm Count > 15 x 106 / ml

Risk of motlity of the sperm should be 33 %

total motility should be about 40%

Abnormal forms < 96%

Question 17

Semen analysis

Answer 17

You can see the normal-looking sperm vs the abnormal-looking sperms. Men have to ejaculate lots and lots of sperm because vast majority of sperm are abnormal.

-In IVF, we get rid of all the abnormal-looking sperm to use the best and most normal looking sperm to fertilise the eggs.

Question 18

Recent NICE Guidelines reccomendation

Answer 18

• AMH (Anti-Mullarian Hormone) & not FSH to check ovarian reserve because AMH has a better predictive value of the ovarian reserve.
• No fund for IUI (Intrauterine Insemmination)
• No lower age for women when you offer fertility treatment (but for some regions in the UK 18 is the minimum age).
• Upper age for women to get fertility help is 42 years
• Treat single women
• Treat same-sex couples

Question 19

New NICE Guideline

Answer 19

For Unexplained infertility:

1. Do not offer Intrauterine insemination (IUI) as sometimes it has the same effect as natural intercourse.
2. Do not offer oral ovulation stimulation of voluation (i.e FSH injection).
3. Offer IVF for women who have not conceived after 2 years and this is unexplained infertility.

Question 20

New NICE Guideline

Answer 20

-Offer 3 full IVF cycles to women under 40 year

-Offer one full cycle to women aged 40-42 years provided:

1. Never had IVF before
2. No evidence of low ovarian reserve
3. Discuss implications of IVF & pregnancy at this age. (there is a higher risk of chromosomal abnormality and miscarriage as well). such as down syndrome.

Question 21

New NICE Guideline

Answer 21

-Clomid & FSH injections:

1. No association with cancer
2. No association with cancer in children born after using either of the 2 methods.
3. Long term health outcomes in women & children are still awaited. Clomid has been used for at least 50 years.

Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Us

Question 22

Couples having IVF:

Answer 22

1. Chance of Live Birth falls with rising female age
2. IVF is more effective in women who achieved pregnancy before
3. Absolute risks of long term adverse outcomes in children born as a result of IVF are low

Question 23

Kent Surrey Sussex Funding Criteria for IVF

Answer 23

• Female age less than 40 year
• AMH level at 5 or above
• BMI 19-29.9
• No existing children including adopted children
• Both non-smoker

Question 24

KSS Funding Criteria

Answer 24

• Ovulation induction is offered when indicated
• No IUI except for heterosexual couples who cannot achieve intercourse
• No fund for treatment involving the use of donor eggs or sperm or surrogacy
• 2 fresh IVF & 2 frozen treatment cycles are available on the NHS

Question 25

Metformin v Placebo for women with PCOS

Answer 25

•RCT 143 anovulatory PCOS, mean BMI 38 kgm-2

-Metformin is suggested to women with PCOS. it improves insulin sensitivity. metformin has side effects like nausea/dairhoea.

• Significant increase in number of cycles, and fall in BMI and waist circumference in both groups
• No difference in ovulation rate between the groups Improvements seen in those who lost weight in each group

Question 26

Clomiphene with Metformin or Placebo

Answer 26

• Two very large RCTs have failed to show any benefit from Metformin.
• Clomiphene alone results in highest live birth rate. No benefit combining with Metformin

Question 27

CC and/or metformin alone or in combination

Answer 27

Question 28

CC and/or metformin alone or in combination

Answer 28

-CC superior to metformin and combination confers no advantage in achieving live birth

Question 29

Metformin for women with PCOS

Answer 29

• Increased oocyte glucose and pyruvate consumption and reduced lactate production in oocytes from PCOs
• Associated with abnormal oocyte karyotypes
• Metformin therapy improves metabolism in eggs
• Increased live birth and lower OHSS with IVF

Question 30

In-Vitro Fertilisation (IVF)

Answer 30

• Invented mainly for Tubal damage.
• replace what happens in the fallopian tube
• The fertilised egg will stay inside the fallopian tube for 5 days, reaching the endometrial cavity at the blastocyst stage to implant on the endometrium to make the woman pregnant.

Question 31

IVF or ICSI – standard long protocol

Answer 31

• In IVF we are stimulating the ovaries to release a number of eggs and generate a number of embryos, we chose the best quality embryo to put back which is more likely not to mis carry.
• if the remaining embryos are good enough, they can be frozen.
• we give daily FSH injection to stimulate the ovaries.
• Buserelin is a synthetic form of a hormone which occurs naturally in your body. It is used as part of some types of fertility treatment. It works by acting on the pituitary gland in your brain to stop the production of natural hormones that control the release of eggs from your ovaries.

Question 32

Ovarian Stimulation post injection

Answer 32

-Remember that eggs develop inside the follicles.

Question 33

Egg Collection

Answer 33

Question 34

IVF

Answer 34

Question 35

ICSI (Intra-cytoplasmic sperm injection)

Answer 35

Question 36

Surgical Sperm Retrieval

Answer 36

-For men who can’t have sperm in their ejaculate

Question 37

Embryo development

Answer 37

Answer 38

Question 39

Treatment Outcome

Answer 39

•Overall pregnancy rate (PR) is 53.5%

•Overall Live Birth rate (LB) is 47.8%

•Pregnancy for women < 35 year is 60%

•LB rate for women < 35 year is 56.6%