Prognostic factors and patient selection for ART
- optimal age 23-40
- ovarian reserve
- past reproductive hx and previous fertility rx
Measures of ovarian reserve
- early follicle phase FSH - levels correlate well with response to ovarian stimulation (even though inter-cycle variability is high)
- antral follicle count (AFC) using USS is also an effective predictor of ovarian stimulation
- AMH - produced by the granulosa cells present in preantral and antral follicles (can be measured any time in the cycle with low inter-cycle variability
AFC and relationship to ovarian reserve
- total AFC 4 or less = predictor for low response to gonadotropin stim
- greater than 16 for a high response
AMH and relationship to ovarian reserve
- AMH 5.4 pmol/l or less for low response to gonadotropin stim
- 25 pmol/l or greater for high response
FSH and relationship to ovarian reserve
> 8.9 predicts a low response to gonadotropin stim
Assessment and screening before undergoing fertility rx
- information about treatment and its risks
- written consent for use and storage of gametes and embryos
- booking bloods incl rubella status, screening for hep B, C and HIV
- offer STI screening
- PMH and optimise any medical condition that may affect the chance of success or pose a risk in pregnancy to the mother or fetus
- cx screening UTD
General health and dietary advice for couples trying to conceive or undergoing fertility rx
- alcohol: women should avoid and men <3 units/day as excessive intake is detrimental to sperm quality
- smoking: negative effect of nicotine on ovarian, uterine and placenta function. There is also an association with reduced sperm quality
- BMI: men and women with BMI >29 are likely to have reduced fertility (in NZ have to have BMI <32 to be eligible for publically funded IVF as this optimizes response to fertility rx)
- folic acid supplementation: before conception and for up to 12w to reduce risk fetal NTD
- caffeine: current evidence does not suggest an association between caffeine and fertility issues
A 27-year-old fit and healthy woman suffers from secondary amenorrhea (one period every 6 months). What is the single most useful hormone measurement you would ask for?
Random FSH
FSH can help differentiate between hypogonadotrophic hypogonadism (at the level of the hypothalamus/pituitary), ovarian dysfunction (PCOS) or ovarian failure (primary ovarian insufficiency). Waiting for a period to perform a Day 3 FSH is impractical in her case, since she only has one period every 6 months. LH is not as useful as FSH for investigating the level of dysfunction. Estradiol cannot differentiate between hypothalamic/pituitary causes and ovarian failure (in both cases, estrogen is low). Estradiol levels may also fluctuate substantially. Thyroid imbalance is a rather uncommon cause of menstrual disturbance. In most cases, the woman has overt symptoms or signs of thyroid imbalance.
A 25 years old woman is coming to see you in clinic with secondary amenorrhea of 12 months. Her weight progressively increased from 65kg (BMI 23) to 85kg (BMI 31).
What is the most likely cause of her amenorrhoea?
Significant weight gain can disrupt the hormonal balance and lead to menstrual irregularities, including amenorrhea. Research shows that a weight loss of approximately 5-10% of the initial body weight is often sufficient to restore normal menstruation in cases where amenorrhea is linked to weight gain. This is because excessive adipose tissue can interfere with the hypothalamic-pituitary-ovarian axis, leading to menstrual disturbances
A 25-year-old woman presents with acne, hirsutism, and irregular menstrual cycles. Initial blood tests show elevated total and free testosterone levels.
What would be the most appropriate next investigation?
Measure serum DHEA and DHEA-s
In cases of clinical hyperandrogenism with elevated total and free testosterone levels, it is important to assess adrenal androgens to help determine whether the source of excess androgens is adrenal or ovarian. This can aid in diagnosing conditions such as congenital adrenal hyperplasia or androgen-secreting tumors.
A 25-year-old woman presents with irregular menstrual cycles, weight gain, and increased facial hair. Laboratory investigations reveal elevated insulin levels and a diagnosis of insulin resistance. Further testing shows elevated androgen levels and decreased levels of sex hormone-binding globulin (SHBG).
What is the most likely mechanism by which insulin resistance contributes to the development of PCOS symptoms?
Decreased hepatic production of SHBG. In women with PCOS, insulin resistance leads to hyperinsulinemia, which decreases hepatic production of SHBG. This reduction in SHBG increases free circulating androgens, contributing to symptoms such as hirsutism, acne, and menstrual irregularities. Additionally, insulin resistance amplifies ovarian androgen production, further exacerbating hyperandrogenism and disrupting normal ovulatory cycles.
A 26-year-old woman with polycystic ovary syndrome presents with irregular menstrual cycles, hirsutism, and acne. She is not interested in becoming pregnant at this time.
What is the most appropriate initial management for her symptoms?
COCP =first-line to regulate menstrual cycles, reduce androgen levels, and improve symptoms of hirsutism and acne. Provides both cycle control and anti-androgenic effects, making it an effective management option for PCOS symptoms. Other options, like metformin and spironolactone, may be added if symptoms persist
Hormone levels in PCOS vs adrenal pathology
If testosterone levels are not elevated, it is likely PCOS (70% of PCOS women have normal serum testosterone levels). If testosterone levels are significantly elevated (more than twice the upper normal limit), consider adrenal pathology (tumours, Cushing, adrenal hyperplasia). Elevated LH levels (with normal FSH levels) are common in PCOS, but can occur with any condition that manifests with hyper-androgenaemia.
A 19-year-old woman with secondary amenorrhea, hirsutism and substantially elevated testosterone levels. The most appropriate diagnosis is
The substantially elevated testosterone levels suggest an adrenal cause. Young women (<30 years) with this presentation need to be investigated for late-onset adrenal hyperplasia. The 17-OH-progesterone test is the simplest screening test for this condition.
Risk factors for OHSS pre-trigger
- PCOS,
- high AFC/AMH,
- high E2/many follicles.
- (Also: young age, low BMI, hCG use, fresh transfer)
An IVF cycle
- FSH given to levels much higher than in a natural menstrual cycle to stimulate multiple antral follicles to develop
- Oestrogen levels therefore also much higher than in natural cycle
- Trigger injection (LH equivalent) will then trigger the eggs to mature
- Egg collection needs to happen within 36h after trigger (as otherwise ovulation will occur)
- IVF vs ICSI -> 5-day incubation -> blastocyst
- At blastocyst stage, if genetic testing is required, can be via biopsy of the trophectoderm, and embryo can be frozen while awaiting results
- At the blastocyst stage can then undergo either embryo transfer, or freezing (embryos do not deteriorate with freezing)
- After transfer, UPT after 10 days
Risks of undergoing ovarian stimulation?
- OHSS
- Elevated serum oestrogen levels
- VTE
- Ovarian torsion
Risks of undergoing egg collection?
- Bleeding
- Infection
- Anaesthetic risks
- Damage to surrounding structures (bladder, bowel, blood vessels)
- Inability to safely access ovaries
Reducing the risk of OHSS
Step 1: Use an appropriate dose of FSH to stimulate the ovaries (low ovarian reserve = can safely use high dose FSH stimulation. High ovarian reserve - requires decreased dose)
Step 2: Use an appropriate trigger medication
- Used to mimic the LH surge that occurs in the normal menstruation -> induces oocyte maturation and ovulation.
- LH not used because of short half life
- 2 options: hCG trigger or GnRH agonist trigger
- hCG has long half-life (stays in the bloodstream for approx 10 days) & the dual presence of hyperstimulated ovaries and hCG can result in OHSS
- GnRH agonist: (REMEMBER: FSH and LH release from the anterior pituitary requires pulsatile release of GnRH from the hypothalamus) if GnRH antagonist is used to suppress ovulation during an IVF cycle, then GnRH agonist can be used as a trigger -> GnRH agonist has an initial flare effect: anterior pit releases LH and FSH, then there is a suppressive effect. Flare effect can be used to trigger oocyte maturation. And since the flare effect is short-lived, and LH has a short half-life, OHSS is avoided.
**Can’t use GnRH agonist trigger if GnRH agonist being used to suppress ovulation.
** Small risk of “trigger failure” in this regimen (e.g. if there is functional hypogonadotropic hypogonadism) - no oocyte maturation -> failed egg collection
Bleeding risk with egg collection (pathological basis and mitigation of risk)
- Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are angiogenic and both are present in follicular fluid
=> stimulated ovaries are very vascular
Mitigation of bleeding risk:
- Haem review prior to commencement of IVF cycle
- Thrombocytopenia -> platelet infusion immediately prior to egg collection
- Haemophilia (less common and milder in females) -> clotting factor replacement
- vWD -> consider desmopressin (DDAVP), clotting factor replacement, clot stabilizing meds, e.g. tXA
- In all situations, avoid meds/supplements that are known to increase bleeding risk, e.g. aspirin, fish oil
- If patient has high VTE risk, start clexane at time of FSH injections, then cease at time of trigger (always administered 36h prior to egg collection). Recommence 12-24h after egg collection.
Mitigating infection risk in egg collection in immunosuppressed patients
- MDT - involvement of patient’s specialist team essential
- Granulocyte colony-stimulating factor (G-CSF) to stimulate neutrophil production an option in some cases when conducting egg/embryo freezing for fertility preservation in women w haematological malignancy
- IV antibiotic administration at time of egg collection (low threshold for administration, always used in pts w endometriosis due to increased risk of infection)
- Option of 24h admission for IVABs after egg collection in v high risk patients
sometimes risk of infection is too great and it is not possible to safely conduct an egg collection
What about IVF when there is concern for elevated serum oestrogen levels? e.g. oestrogen receptor positive breast cancer
- Use of aromatase inhibitor (e.g. letrozole 5mg daily) during an IVF cycle substantially reduces peak oestrogen levels without impairing outcome
PIGD
- Carrier screening can be performed at any time, but preferable to screen before a couple conceives so they have time to understand and consider their reproductive options, such as preimplantation genetic diagnosis
- In Aus, genetic carrier screening for CF, spinal muscular atrophy, and fragile X is covered by medicare for women
- Expanded carrier screening usually costs approx $600-1000
- Pre-implantation genetic testing is available where one member of couple has an autosomal dominant or X-linked conditions, or where both members of couple are carriers of an autosomal recessive condition (bx embryo after its been growing for 5 days)
