Fertility Flashcards
Blood test to check if ovulation is occuring?
Serum progesterone 7 days before the end of the menstrual cycle
How if premature ovarian insufficiency diagnosed?
Symptoms of menopause (vaginal dryness, hot flushes, secondary ammrnhorea) plus two elevated FSH test 4-6 weeks apart (>30IU/l)
What drug is typically used first line for infertility in PCOS
clomifene
Ovarian hyperstimulation syndrome (OHSS) is a potential side effect of what?
Ovulation induction in IVF
It is associated with the use of human chorionic gonadotropin (hCG) to mature the follicles during the final steps of ovarian stimulation.
OHSS is provoked by the “trigger injection” of hCG 36 hours before oocyte collection.
How does ovarian hyper stimulation syndrome present?
OHSS often presents with gastrointestinal symptoms such as nausea, vomiting, abdominal pain, bloating, and diarrhoea.
-Abdominal pain and bloating
-Nausea and vomiting
-Diarrhoea
-Hypotension
-Hypovolaemia
-Ascites
-Pleural effusions - SOB
-Renal failure - oliguria, Peripheral odema
-Peritonitis from rupturing follicles releasing blood
-Prothrombotic state (risk of DVT and PE) - SOB
Severity/potential complications of OHSS?
OHSS severity can range from mild to life-threatening, and can result in complications such as thromboembolism, dehydration, pulmonary oedema, and acute kidney injury (AKI).
Life-threatening OHSS tends to have a more delayed onset than milder cases.
For example, if the patient was injected with gonadotropin-releasing hormone (GnRH) agonist in the past week (i.e. as opposed to a fortnight ago), implying that her symptoms are going to be less severe.
Investigation and referral for infertility should be initiated when?
Investigation and referral for infertility should be initiated after the couple has been trying to conceive without success for 12 months. This can be reduced to 6 months if the woman is older than 35, as her ovarian stores are likely to be already reduced and time is more precious.
Causes of infertility
Sperm problems (30%)
Ovulation problems (25%)
Tubal problems (15%)
Uterine problems (10%)
Unexplained (20%)
40% of infertile couples have a mix of male and female causes.
General lifestyle advise for couples trying to get pregnant
The woman should be taking 400mcg folic acid daily
Aim for a healthy BMI
Avoid smoking and drinking excessive alcohol
Reduce stress as this may negatively affect libido and the relationship
Aim for intercourse every 2 – 3 days
Avoid timing intercourse
Timed intercourse to coincide with ovulation is not necessary or recommended as it can lead to increased stress and pressure in the relationship.
Initial infertility investigations
Body mass index (BMI) (low could indicate anovulation, high could indicate PCOS)
Chlamydia screening
Semen analysis
Female hormonal testing (LH+FSH, thyroid, progesterone, Anti-Mullerian hormone, prolactin)
Rubella immunity in the mother
Female hormone testing when investigating infertility
Serum LH and FSH on day 2 to 5 of the cycle
Serum progesterone on day 21 of the cycle (or 7 days before the end of the cycle if not a 28-day cycle).
Anti-Mullerian hormone
Thyroid function tests when symptoms are suggestive
Prolactin (hyperprolactinaemia is a cause of anovulation) when symptoms of galactorrhea or amenorrhoea
When should serum FSH and LH be measured when investigating infertility
Days 2-5
Infertility investigations: high FSH
High FSH suggests poor ovarian reserve (the number of follicles that the woman has left in her ovaries). The pituitary gland is producing extra FSH in an attempt to stimulate follicular development.
Infertility investigations: high LH
High LH may suggest polycystic ovarian syndrome (PCOS).
Infertility investigations: progesterone result
A rise in progesterone on day 21 indicates that ovulation has occurred, and the corpus luteum has formed and started secreting progesterone.
Infertility investigations: Anti-Mullerian hormone result
Anti-Mullerian hormone can be measured at any time during the cycle and is the most accurate marker of ovarian reserve. It is released by the granulosa cells in the follicles and falls as the eggs are depleted. A high level indicates a good ovarian reserve.
Which hormone is the most accurate marker of ovarian reserve?
Anti-Mullerian hormone
Secondary care infertility investigations
Ultrasound pelvis to look for polycystic ovaries or any structural abnormalities in the uterus
Hysterosalpingogram to look at the patency of the Fallopian tubes
Laparoscopy and dye test to look at the patency of the fallopian tubes, adhesions and endometriosis
What is a hysterosalpingogram and what does it involve?
A hysterosalpingogram is a type of scan used to assess the shape of the uterus and the patency of the fallopian tubes. Not only does it help with diagnosis, but it also has therapeutic benefit. It seems to increase the rate of conception without any other intervention. Tubal cannulation under xray 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. Xray images are taken, and the contrast shows up on the xray giving an outline of the uterus and tubes. If the dye does not fill one of the tubes, this will be seen on an xray and suggests a tubal obstruction.
What is a key risk of performing a hysterosalpingogram and how can it be minimised?
There is a risk of infection with the procedure, and often antibiotics are given prophylactically for patients with dilated tubes or a history of pelvic infection.
Screening for chlamydia and gonorrhoea should be done before the procedure.
What is the laparoscopy and dye test used to investigate infertility in secondary care
The patient is admitted for laparoscopy.
During the procedure, dye is injected into the uterus and should be seen entering the fallopian tubes and spilling out at the ends of the tubes.
This will not be seen when there is tubal obstruction.
During laparoscopy, the surgeon can also assess for endometriosis or pelvic adhesions and treat these.
What can be used to treat infertility caused by anovulation?
Weight loss for overweight patients with PCOS can restore ovulation
Clomifene may be used to stimulate ovulation
Letrozole may be used instead of clomifene to stimulate ovulation (aromatase inhibitor with anti-oestrogen effects)
Gonadotropins may be used to stimulate ovulation in women resistant to clomifene
Ovarian drilling may be used in polycystic ovarian syndrome
Metformin may be used when there is insulin insensitivity and obesity (usually associated with PCOS)
What is clomifene, and how and when does it work to treat infertility secondary to anovulation?
Clomifene is an anti-oestrogen (a selective oestrogen receptor modulator).
It is given on days 2 to 6 of the menstrual cycle.
It stops the negative feedback of oestrogen on the hypothalamus, resulting in a greater release of GnRH and subsequently FSH and LH.
What is ovarian drilling and how can it manage infertility secondary to anovulation?
Ovarian drilling involves laparoscopic surgery.
The surgeon punctures multiple holes in the ovaries using diathermy or laser therapy.
This can improve the woman’s hormonal profile and result in regular ovulation and fertility.
How can infertility due to tubal factors be managed?
Tubal cannulation during a hysterosalpingogram
Laparoscopy to remove adhesions or endometriosis
In vitro fertilisation (IVF)
How can infertility due to uterine factors be managed?
Surgery may be used to correct polyps, adhesions or structural abnormalities affecting fertility.
How can infertility due to sperm issues be managed?
Surgical sperm retrieval is used when there is a blockage somewhere along the vas deferens preventing sperm from reaching the ejaculated semen. A needle and syringe is used to collect sperm directly from the epididymis through the scrotum.
Surgical correction of an obstruction in the vas deferens may restore male fertility.
Intra-uterine insemination involves collecting and separating out high-quality sperm, then injecting them directly into the uterus to give them the best chance of success. It is unclear whether this is any better than normal intercourse.
Intracytoplasmic sperm injection (ICSI) involves injecting sperm directly into the cytoplasm of an egg. These fertilised eggs become embryos, and are injected into the uterus of the woman. This is useful when there are significant motility issues, a very low sperm count and other issues with the sperm.
Donor insemination with sperm from a donor is another option for male factor infertility.
What is semen analysis used for?
Semen analysis is used to examine the quantity and quality of semen and sperm. It assesses for male factor infertility.
Instructions for men providing a sperm sample
Abstain from ejaculation for at least 3 days and at most 7 days
Avoid hot baths, sauna and tight underwear during the lead up to providing a sample
Attempt to catch the full sample
Deliver the sample to the lab within 1 hour of ejaculation
Keep the sample warm (e.g. in underwear) before delivery
Lifestyle factors that may decrease quality and quantity of semen
Hot baths
Tight underwear
Smoking
Alcohol
Raised BMI
Caffeine
Why and when might repeat semen samples be indicated?
A repeat sample is indicated after 3 months in borderline results or earlier (2 – 4 weeks) with very abnormal results.
What is measured in a semen analysis
Volume
pH
Concentration
Motility
Total number of sperm
Vitality of sperm
Percentage of sperm
Normal semen volume
More than 1.5ml
Normal semen pH
Over 7.2
Normal sperm concentration
more than 15 million per ml
Normal total number of sperm
more than 39 million per sample
Normal sperm motility
more than 40% of sperm are mobile
Normal sperm vitality
more than 58% of sperm are active
Normal sperm percentage
More than 4%
What is polyspermia
Polyspermia (or polyzoospermia) refers to a high number of sperm in the semen sample (more than 250 million per ml).
What is normospermia
Normospermia (or normozoospermia) refers to normal characteristics of the sperm in the semen sample
What is oligospermia
Oligospermia (or oligozoospermia) is a reduced number of sperm in the semen sample. It is classified as:
Mild oligospermia (10 to 15 million / ml)
Moderate oligospermia (5 to 10 million / ml)
Severe oligospermia (less than 5 million / ml)
What is cryptozoospermia
Cryptozoospermia refers to very few sperm in the semen sample (less than 1 million / ml).
What is azoospermia
Azoospermia is the absence of sperm in the semen
Pre testicular causes of male infertility
Testosterone is necessary for sperm creation. The hypothalamo-pituitary-gonadal axis controls testosterone. Hypogonadotrophic hypogonadism (low LH and FSH resulting in low testosterone), can be due to:
Pathology of the pituitary gland or hypothalamus
Suppression due to stress, chronic conditions or hyperprolactinaemia
Kallman syndrome
Testicular causes of male infertility
Testicular damage from:
Mumps
Undescended testes
Trauma
Radiotherapy
Chemotherapy
Cancer
Genetic or congenital disorders that result in defective or absent sperm production, such as:
Klinefelter syndrome
Y chromosome deletions
Sertoli cell-only syndrome
Anorchia (absent testes)
Post testicular causes of male infertility
Obstruction preventing sperm being ejaculated can be caused by:
Damage to the testicle or vas deferens from trauma, surgery or cancer
Ejaculatory duct obstruction
Retrograde ejaculation
Scarring from epididymitis, for example, caused by chlamydia
Absence of the vas deferens (may be associated with cystic fibrosis)
Young’s syndrome (obstructive azoospermia, bronchiectasis and rhinosinusitis
Investigations following abnormal semen analysis
The initial steps for investigating abnormal semen analysis include a history, examination, repeat sample and ultrasound of the testes.
Patients with abnormal semen results are referred to a urologist for further investigations. Further investigations that may be considered include:
Hormonal analysis with LH, FSH and testosterone levels
Genetic testing
Further imaging, such as transrectal ultrasound or MRI
Vasography, which involves injecting contrast into the vas deferens and performing xray to assess for obstruction
Testicular biopsy
Potential management of male infertility
Surgical sperm retrieval where there is obstruction
Surgical correction of an obstruction in the vas deferens
Intra-uterine insemination involves separating high-quality sperm, then injecting them into the uterus
Intracytoplasmic sperm injection (ICSI) involves injecting sperm directly into the cytoplasm of an egg
Donor insemination involves sperm from a donor
Limitations of IVF
In vitro fertilisation involves fertilising an egg with sperm in a lab, then injecting the resulting embryo into the uterus. There are many steps along the way, and it is a complicated and expensive process. As a result, funding criteria are very strict and vary between areas. Couples are limited to a set number of cycles funded by the NHS.
Each attempt has a roughly 25 – 30% success rate at producing a live birth.
What is IUI
Intrauterine insemination (IUI) is different from IVF. It is a more straightforward process, and involves injecting sperm into the uterus, avoiding intercourse.
Why might IUI be used to attempt to conceive
IUI is used in cases such as donor sperm for same-sex couples, HIV (avoiding unprotected sex) and practical issues with vaginal sex.
How does a cycle of IVF work
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. Embryos that are not used immediately may be frozen to be used at a later date.
Frozen embryos can potentially be used years later, even after a successful pregnancy.
What are the steps involved in IVF
Suppressing the natural menstrual cycle
Ovarian stimulation
Oocyte collection
Insemination / intracytoplasmic sperm injection (ICSI)
Embryo culture
Embryo transfer
What are the protocols for suppression of the natural menstrual cycle used in IVF
There are two protocols for the suppression of the natural menstrual cycle, preventing ovulation and ensuring the ovaries respond correctly to the gonadotropins (i.e. FSH).
Suppression of the natural cycle involves either the use of GnRH agonists or GnRH antagonists.
The choice between the GnRH agonist and GnRH antagonist protocol depends on individual factors.
How does the GnRH agonist protocol of suppressing the natural menstrual cycle during IVF work and what does it involve?
An injection of a GnRH agonist (e.g. goserelin) is given in the luteal phase of the menstrual cycle, around 7 days before the expected onset of the menstrual period (usually day 21 of the cycle).
This initially stimulates the pituitary gland to secrete a large amount of FSH and LH.
However, after this initial surge in FSH and LH, there is negative feedback to the hypothalamus, and the natural production of GnRH is suppressed.
This causes suppression of the menstrual cycle.
How does the GnRH antagonist protocol of suppressing the natural menstrual cycle during IVF work and what does it involve?
Daily subcutaneous injections of a GnRH antagonist (e.g. cetrorelix) are given, starting from day 5 – 6 of ovarian stimulation.
This suppresses the body releasing LH and causing ovulation to occur.
Why is suppression of the natural menstrual cycle necessary in IVF
Without suppression of the natural gonadotropins (LH and FSH) using either the GnRH agonist or antagonist protocol, ovulation would occur and the follicles that are developing would be released before it is possible to collect them.
Ovarian stimulation step of IVF
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.
The FSH stimulates the development of follicles, and this is closely monitored with regular transvaginal ultrasound scans.
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”.
Ooctye collection step of IVF
The oocytes (eggs) are collected from the ovaries under the guidance of a transvaginal ultrasound scan. 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.
Oocyte insemination step of Ovf
The male produces a semen sample around the time of oocyte collection. Frozen sperm from earlier samples may be used.
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.
What is ICSI and when does it have a role in IVF
Intracytoplasmic sperm injection (ICSI) is a treatment used mainly for male factor infertility, where there are a reduced number or quality of sperm. It is an addition to the IVF process.
After the eggs are harvested, and a semen sample is produced, the highest quality sperm are isolated and injected directly into the cytoplasm of the egg.
Embryo culture stage of IVF
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 step of IVF
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.
Pregnancy testing following IVF
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.
When the pregnancy test is negative, implantation has failed. At this point, hormonal treatment is stopped. The woman will go on to have a menstrual period. The bleeding may be more substantial than usual given the additional hormones used during ovarian stimulation.
What is used to help maintain pregnancy resulting from IVF and when?
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.
What monitoring and when would a woman who has become pregnant through IVF need in comparison to a woman who had conceived naturally
An ultrasound scan is performed early in the pregnancy (around 7 weeks) to check for a fetal heartbeat, and rule out miscarriage or ectopic pregnancy.
When the ultrasound scan confirms a health pregnancy, the remainder of the pregnancy can proceed with standard care, as with any other pregnancy.
Complications of IVF overall process
Failure
Multiple pregnancy
Ectopic pregnancy
Ovarian hyperstimulation syndrome
Complications of egg collecting procedure
Small risk of:
Pain
Bleeding
Pelvic infection
Damage to the bladder or bowel
When does early vs late ovarian hyper stimulation syndrome occur
Early OHSS presents within 7 days of the hCG injection. Late OHSS presents from 10 days onwards.
Risk factors of ovarian hyperstimulation syndrome
Younger age
Lower BMI
Raised anti-Müllerian hormone
Higher antral follicle count
Polycystic ovarian syndrome
Raised oestrogen levels during ovarian stimulation
Pathophysiology of ovarian hyperstimulation syndrome
The primary mechanism for OHSS is an increase in vascular endothelial growth factor (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.
Prevention of ovarian hyperstimulation syndrome
Women are individually assessed for their risk of developing OHSS.
During stimulation with gonadotrophins, they are monitored with:
Serum oestrogen levels (higher levels indicate a higher risk)
Ultrasound monitor of the follicles (higher number and larger size indicate a higher risk)
In women at higher risk several strategies may be used to reduce the risk:
Use of the GnRH antagonist protocol (rather than the GnRH agonist protocol)
Lower doses of gonadotrophins
Lower dose of the hCG injection
Alternatives to the hCG injection (i.e. a GnRH agonist or LH)
How is the severity of ovarian hyperstimulation syndrome definied
Mild: Abdominal pain and bloating
Moderate: Nausea and vomiting with ascites seen on ultrasound
Severe: Ascites, low urine output (oliguria), low serum albumin, high potassium and raised haematocrit (>45%)
Critical: Tense ascites, no urine output (anuria), thromboembolism and acute respiratory distress syndrome (ARDS)
Management of ovarian hyperstimulation syndrome
Management is supportive with treatment of any complications. This involves:
Oral fluids
Monitoring of urine output
Low molecular weight heparin (to prevent thromboembolism)
Ascitic fluid removal (paracentesis) if required
IV colloids (e.g. human albumin solution)
Patients with mild to moderate OHSS are often managed as an outpatient. Severe cases require admission, and critical cases may require admission to the intensive care unit (ICU).
What can be used to monitor the intravascular volume in ovarian hyperstimulation syndrome
Haematocrit may be monitored to assess the volume of fluid in the intravascular space. Haematocrit is the concentration of red blood cells in the blood. When the haematocrit goes up, this indicates less fluid in the intravascular space, as the blood is becoming more concentrated. Raised haematocrit can indicate dehydration.
Primary vs secondary infertility
Infertility can be primary or secondary. Primary infertility is when a pregnancy has never been achieved by a person, and secondary infertility is when at least one prior pregnancy has been achieved.
Side effects of ovulation induction
Bloating.
Nausea.
Headaches.
Loss of breath.
Hot flashes.
Weight gain.
Tenderness in the pelvic region.
Blurry vision.
