Ovulation_Induction_Flashcards
What is the cause of infertility in approximately one-quarter of couples?
Ovulation disorders are the cause of infertility in approximately one-quarter of couples.
Why is ovulation induction often required for couples with ovulation disorders?
Ovulation may occur sometimes, but natural spontaneous conception is usually unlikely.
What does normal ovulation require?
Normal ovulation requires the close functioning of positive and negative feedback loops between the hypothalamus, pituitary gland, and ovaries.
What happens during the early follicular phase of the menstrual cycle?
An increase in gonadotropin-releasing hormone (GnRH) pulse frequency increases the release of follicle-stimulating hormone (FSH) and luteinising hormone (LH), allowing for stimulation and development of multiple ovarian follicles.
What happens during the mid-follicular phase of the menstrual cycle?
FSH gradually stimulates estradiol production, which produces a negative feedback loop on the hypothalamus and pituitary gland to suppress FSH and LH concentrations.
What happens during the luteal phase of the menstrual cycle?
There is a switch from negative to positive feedback of estradiol, resulting in a surge of LH secretion, leading to follicular rupture and ovulation.
What are the three main categories of anovulation?
Class 1 (hypogonadotropic hypogonadal anovulation) - notably hypothalamic amenorrhoea, Class 2 (normogonadotropic normoestrogenic anovulation) - polycystic ovary syndrome, Class 3 (hypergonadotropic hypoestrogenic anovulation) - premature ovarian insufficiency.
What is the goal of ovulation induction?
To induce mono-follicular development and subsequent ovulation, leading to a singleton pregnancy, which tends to be far lower risk and preferable.
What is the first-line treatment for patients with polycystic ovarian syndrome?
Exercise and weight loss, as ovulation can spontaneously return with even a modest 5% weight loss.
What is the first-line medical therapy for patients with PCOS?
Letrozole, due to the reduced risk of adverse effects on endometrial and cervical mucus compared to clomiphene citrate.
What is the mechanism of action of letrozole?
Letrozole is an aromatase inhibitor, reducing the negative feedback caused by estrogens to the pituitary gland, increasing the amount of FSH production and promoting follicular development.
What are the side effects of letrozole?
Fatigue (20%), dizziness (10%).
What is the mechanism of action of clomiphene citrate?
Clomiphene is a selective estrogen receptor modulator (SERM) that acts primarily at the hypothalamus, blocking the negative feedback effect of estrogens, leading to increased GnRH pulse frequency and FSH and LH production, stimulating ovarian follicular development.
What are the side effects of clomiphene citrate?
Hot flushes (30%), abdominal distention and pain (5%), nausea and vomiting (2%).
For which class of ovulatory dysfunction is gonadotropin therapy mostly used?
Class 1 ovulatory dysfunction, notably women with hypogonadotropic hypogonadism.
What is ovarian hyperstimulation syndrome (OHSS)?
A potential life-threatening side effect of ovulation induction, characterized by ovarian enlargement with multiple cystic spaces and increased capillary permeability, leading to fluid shift and potential complications like hypovolaemic shock, acute renal failure, and thromboembolism.
What are the management options for ovarian hyperstimulation syndrome (OHSS)?
Fluid and electrolyte replacement, anti-coagulation therapy, abdominal ascitic paracentesis, pregnancy termination to prevent further hormonal imbalances.
summarise
Ovulation induction
Ovulation disorders are the cause of infertility in approximately one-quarter of couples who have difficulty conceiving naturally, and whilst ovulation may occur sometimes, natural spontaneous conception is usually unlikely. Therefore, for these couples, ovulation induction is often required and will typically depend on the cause of anovulation in the first place.
Normal ovulation requires the close functioning of a number of positive and negative feedback loops between the hypothalamus, pituitary gland and ovaries.
The early follicular phase requires an increase in gonadotropin-releasing hormone (GnRH) pulse frequency which increases the release of follicle-stimulating hormone (FSH) and luteinising hormone (LH), to allow for stimulation and development of multiple ovarian follicles, and usually only one of which will become the dominant ovulatory follicle in that menstrual cycle.
In the mid-follicular phase, FSH gradually stimulates estradiol production, following which estradiol itself produces a negative feedback loop on the hypothalamus and pituitary gland to suppress FSH and LH concentrations.
In the luteal phase, there is a unique switch from negative to positive feedback of estradiol, resulting in a surge of LH secretion and this leads to subsequent follicular rupture and ovulation.
It is the unique balance of hormones and their feedback loops which leads to normal ovulation with each menstrual cycle, however with each class of ovulatory dysfunction, there is an alteration in this fine balance which may lead to irregular or complete anovulation.
Categories of ovulatory disorders
Before understanding the process of ovulation induction, it is paramount to understand the main causes of ovulatory dysfunction first
There are three main categories of anovulation:
Class 1 (hypogonadotropic hypogonadal anovulation) - notably hypothalamic amenorrhoea (5-10% of women)
Class 2 (normogonadotropic normoestrogenic anovulation) - polycystic ovary syndrome (80% of cases)
Class 3 (hypergonadotropic hypoestrogenic anovulation) - premature ovarian insufficiency (5-10% of cases). In this class, any attempts at ovulation induction are typically unsuccessful and therefore usually require in-vitro fertilisation (IVF) with donor oocytes to conceive
Goals of ovulation induction
It is ideal to start with the least invasive and simplest management option first, and work the way up to more complicated and intensive treatment
For most women, it is the goal to induce mono-follicular development and subsequent ovulation as opposed to multi-follicular development, and this is to ultimately lead to a singleton pregnancy, which tends to be far lower risk and therefore preferable
Forms of ovulation induction
Exercise and weight loss
Typically this is the first-line treatment for patients with polycystic ovarian syndrome, as ovulation can spontaneously return with even a modest 5% weight loss
Therefore, particularly for overweight or obese women with polycystic ovarian syndrome, this should be trialled solely first, and then artificial ovulation induction be considered
Letrozole
According to UptoDate, this is now considered the first-line medical therapy for patients with PCOS, due to the reduced risk of adverse effects on endometrial and cervical mucous compared to clomiphene citrate
Mechanism of action: letrozole is an aromatase inhibitor, reducing the negative feedback caused by estrogens to the pituitary gland, therefore increasing the amount of follicle-stimulating hormone (FSH) production and promoting follicular development
The rate of mono-follicular development is much higher with letrozole use compared to clomiphene, which is a key goal in ovulation induction
Side effects: fatigue (20%), dizziness (10%)
Clomiphene citrate
While most women with PCOS will respond to clomiphene treatment and ovulate (80% of women), the rates of live birth are higher with letrozole therapy, hence why it has become a first-line treatment instead
Mechanism of action: clomiphene is a selective estrogen receptor modulator (also known as SERMs), which acts primarily at the hypothalamus, blocking the negative feedback effect of estrogens. This subsequently leads to an increase in gonadotropin-releasing hormone (GnRH) pulse frequency and therefore FSH and LH production, stimulating ovarian follicular development
Side effects: hot flushes (30%), abdominal distention and pain (5%), nausea and vomiting (2%)
Gonadotropin therapy
This tends to be the treatment used mostly for women with class 1 ovulatory dysfunction, notably women with hypogonadotropic hypogonadism
For women with PCOS, this tends to be only considered after attempt with other treatments has been unsuccessful, usually after weight loss, letrozole and clomiphene trial
This is because the risk of multi-follicular development and subsequent multiple pregnancy is much higher, as well as increased risk of ovarian hyperstimulation syndrome
Mechanism of action: pulsatile GnRH therapy involves administration of GnRH via an intravenous (or less frequently, subcutaneous) infusion pump, leading to endogenous production of FSH and LH and subsequent follicular development
Ovarian hyperstimulation syndrome
Ovarian hyperstimulation syndrome (OHSS) is one of the potential side effects of ovulation induction, and unfortunately can be life-threatening if not identified and managed promptly
In OHSS, ovarian enlargement with multiple cystic spaces form, and an increase in the permeability of capillaries leads to a fluid shift from the intravascular to the extra-vascular space, which has the potential to result in multiple life-threatening complications including:
Hypovolaemic shock
Acute renal failure
Venous or arterial thromboembolism
This is a rare side effect which varies in severity, with the risk of severe OHSS occurring in less than 1% of all women undergoing ovarian induction
Depending on the severity, the management includes:
Fluid and electrolyte replacement
Anti-coagulation therapy
Abdominal ascitic paracentesis
Pregnancy termination to prevent further hormonal imbalances
A 34-year-old woman attends clinic feeling generally unwell. Her abdomen has become uncomfortable and distended over the last 2 days, and she is suffering from loose stools. She also feels dyspnoeic on exertion. On examination all observations are within normal range and there is generalised abdominal tenderness with no guarding. The patient is undergoing fertility treatment and the previous week was injected with gonadorelin analogue.
Given the above history, which of the following is the most likely diagnosis?
Appendicitis
Ectopic pregnancy
Ovarian cyst rupture
Ovarian hyperstimulation syndrome (OHSS)
Ovarian torsion
Ovarian hyperstimulation syndrome (OHSS)
Ovarian hyperstimulation syndrome is a potential side-effect of ovulation induction
Ovarian hyperstimulation syndrome (OHSS) is a potential side effect of ovulation induction. As with the above patient, OHSS often presents with gastrointestinal symptoms such as nausea, vomiting, abdominal pain, bloating, and diarrhoea. Other features of OHSS include shortness of breath, fever, oliguria, and peripheral oedema.
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. In the above scenario, 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.
OHSS buzz words
feeling generally unwell
abdomen has become uncomfortable and distended
loose stools
dyspnoeic on exertion
generalised abdominal tenderness with no guarding.
patient is undergoing fertility treatment - injected with gonadorelin analogue.
