Fertility and Subfertility Flashcards
Define subfertility.
Failure to conceive after one year of regular unprotected sex
How do we categorise subfertility?
Primary: no previous pregnancies
Secondary: Previous pregnancy
What are the causes of subfertility?
15% Idiopathic
Female (50%): tubal disease, anovulatory (PCOS etc.), endometriosis, uterine factors (asherman’s)
Male (35%): chromosomal abnormality, endocrine causes, drugs, irradiation, infection (mumps/STI)
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.
How common is subfertility?
10-15% of couples of reproductive age.
What are the RFs of subfertility?
smoking, alcohol, weed, excess exercise, extremes of body weight, female age, PID, ruptured appendix
What are the conditions for pregnancy?
- Egg must be produced
- Adequate sperm must be released
- Sperm must reach the egg
- The egg must implant
Describe the physiology of ovulation.
Low oestrogen → positive feedback at hypothalamus → GnRH release pulses
FSH and LH produced in response
Leads to growth and initiates maturation of several follicles of the ovary, each of which contains an immature oocyte
Follicles produce oestradiol → negative feedback on hypothalamus → low FSH/LH
Dominant follicle has sufficient gonadotrophin receptors to survive
o Produces inhibin b → suppresses FSH
High Oestadiol output → threshold potential reached → LH surge
Rupture of follicle at 2cm diameter
Egg collected by fallopian tube fimbriae
Follicle → Corpus Luteum → progesterone production → secretory endometrium
No implantationinvolution of CL→fall of progesterone
Menstruation at 14 days after ovulation
How do we detect of ovulation?
Hx
o Vast majority of women with regular cycles are ovulatory
o Vaginal spotting, increase VD or pelvic pain (‘mittelschmertz’) around time of ovulation
Ex
o Cervical mucus preovulation = acellular, will ‘fern’ when on a dry slide and form ‘spinbarkeit’ = elastic-like strings up to 15cm
o Body temperature drops 0.2c preovulation and rises 0.5c in the luteal phase
o Pattern can be seen on a temperature chart
Ix
Only proof of ovulation = conception
Elevated serum progesterone in mid-luteal phase indicates ovulation
o Low progesterone shows lack of ovulation if taken 7 days before subsequent menstruation (day 21 of 28)
o For women with irregular cycles, repeat progesterone may be required until menstruation starts
Ultrasound scans
o Monitor follicular growth
o Demonstrate fall in size and haemorrhagic nature of CL after ovulation
OTC urine predictor kits will indicate if LH surge has taken place
Define PCOS.
Polycystic ovarian syndrome (PCOS) is a common condition causing metabolic and reproductive problems in women. There are characteristic features of multiple ovarian cysts, infertility, oligomenorrhea, hyperandrogenism and insulin resistance.
How do we diagnose PCOS?
The Rotterdam criteria are used for making a diagnosis of polycystic ovarian syndrome. A diagnosis requires at least two of the three key features:
- Oligoovulation or anovulation, presenting with irregular or absent menstrual periods - (>12 follicles in one ovary or ovarian volume >10ml)
- Hyperandrogenism, characterised by hirsutism and acne
- Polycystic ovaries on ultrasound (or ovarian volume of more than 10cm3)
Diagnosis of exclusions: exclude late onset CAH, Cushing’s, ovarian and adrenal neoplasms, hyperprolactinaemia, hypothyroidism
Describe the presentations of PCOS?
- Oligomenorrhoea or amenorrhoea
- Infertility
- Obesity (in about 70% of patients with PCOS)
- Hirsutism
- Acne
- Hair loss in a male pattern
Presentation: 15-35 y.o. HAIR-AN – Hirsutism, hyper androgenism, infertility (also oligomenorrhoea, amenorrhoea), insulin resistance, acanthosis nigricans
Describe the aetiology of PCOS? What are the RFs?
- Aetiology: FHx, LH and hyperinsulinemia cause increased ovarian androgen production
- RF: FHx, obesity, insulin resistance, HT, AI thyroid disease
What are the complications and other features of PCOS?
In addition to the presenting features, women may also experience:
- Insulin resistance and diabetes
- Acanthosis nigricans
- Cardiovascular disease
- Hypercholesterolaemia
- Endometrial hyperplasia and cancer
- Obstructive sleep apnoea
- Depression and anxiety
- Sexual problems
Acanthosis nigricans describes thickened, rough skin, typically found in the axilla and on the elbows. It has a velvety texture. It occurs with insulin resistance.
What is the differential diagnosis of hirsutism?
An important feature of polycystic ovarian syndrome is hirsutism. Hirsutism can also be caused by:
- Medications, such as phenytoin, ciclosporin, corticosteroids, testosterone and anabolic steroids
- Ovarian or adrenal tumours that secrete androgens
- Cushing’s syndrome
- Congenital adrenal hyperplasia
What role does insulin resistance have in PCOS?
- Insulin resistance is a crucial part of PCOS. When someone is resistant to insulin, their pancreas has to produce more insulin to get a response from the cells of the body.
- Insulin promotes the release of androgens from the ovaries and adrenal glands. Therefore, higher levels of insulin result in higher levels of androgens (such as testosterone).
- Insulin also suppresses sex hormone-binding globulin (SHBG) production by the liver. SHBG normally binds to androgens and suppresses their function.
- Reduced SHBG further promotes hyperandrogenism in women with PCOS.
The high insulin levels contribute to halting the development of the follicles in the ovaries, leading to anovulation and multiple partially developed follicles (seen as polycystic ovaries on the scan).
Diet, exercise and weight loss help reduce insulin resistance.
What are the investigations for PCOS?
The NICE clinical knowledge summaries recommend the following blood tests to diagnose PCOS and exclude other pathology that may have a similar presentation:
- Testosterone
- Sex hormone-binding globulin
- Luteinizing hormone
- Follicle-stimulating hormone
- Prolactin (may be mildly elevated in PCOS)
- Thyroid-stimulating hormone
Hormonal blood tests typically show:
- Raised luteinising hormone
- Raised LH to FSH ratio (high LH compared with FSH)
- Raised testosterone
- Raised insulin
- Normal or raised oestrogen levels
OGTT
Imaging
- USS pelvis:
- 12 or more follicles in at least one ovary (measuring 2-9mm)
- Increased ovarian volume (>10cm3)
- In women starting cyclical progestogen due to prolonged amenorrhoea/AUB/excess weight, only do TVUSS to assess endometrial thickness after first withdrawal bleed
- The follicles may be arranged around the periphery of the ovary, giving a “string of pearls” appearance.
How do we interpret the results of the OGTT?
- Fasting glucose 6.1-6.9 mol/L - impaired fasting glucose
- 2-hour glucose 7.8-11.1 = IGT
- >11.1 = DM
- If OGTT shows impaired glucose tolerance: Annual OGTT
- If OGTT normal: Annual random fasting glucose
How do we think about managing PCOS?
- General management
- Manage risk of endometrial cancer
- Manage infertility
- Manage hirtuisim
- Manage acne
What is the general management of PCOS?
It is crucial to reduce the risks associated with obesity, type 2 diabetes, hypercholesterolaemia and cardiovascular disease. These risks can be reduced by:
- Weight loss
- Low glycaemic index, calorie-controlled diet
- Exercise
- Smoking cessation
- Antihypertensive medications where required
- Statins where indicated (QRISK >10%)
Patients should be assessed and managed for the associated features and complications, such as:
- Endometrial hyperplasia and cancer
- Infertility
- Hirsutism
- Acne
- Obstructive sleep apnoea
- Depression and anxiety
Weight loss is a significant part of the management of PCOS. Weight loss alone can result in ovulation and restore fertility and regular menstruation, improve insulin resistance, reduce hirsutism and reduce the risks of associated conditions.
Orlistat may be used to help weight loss in women with a BMI above 30. Orlistat is a lipase inhibitor that stops the absorption of fat in the intestines.
What can be given to resolve the oligomenorrhea/amenorrhea?
COCP or Cyclical oral progesterone – if amenorrhoea/dysfunctional uterine bleeding
• This increases sex hormone-binding globulin which helps relieve androgenic symptoms
o Regulates the withdrawal bleed (should take place at least every 3-4months)
How do we manage the risk of endometrial cancer in PCOS?
Women with polycystic ovarian syndrome have several risk factors for endometrial cancer:
- Obesity
- Diabetes
- Insulin resistance
- Amenorrhoea
Options for reducing the risk of endometrial hyperplasia and endometrial cancer are:
- Mirena coil for continuous endometrial protection
-
Inducing a withdrawal bleed at least every 3 – 4 months with either:
- Cyclical progestogens (e.g. medroxyprogesterone acetate 10mg once a day for 14 days)
- Combined oral contraceptive pill
Why are patients with PCOS at higher risk of endometrial cancer?
Under normal circumstances, the corpus luteum releases progesterone after ovulation. Women with PCOS do not ovulate (or ovulate infrequently), and therefore do not produce sufficient progesterone. They continue to produce oestrogen and do not experience regular menstruation. Consequently, the endometrial lining continues to proliferate under the influence of oestrogen, without regular shedding during menstruation. This is similar to giving unopposed oestrogen in women on hormone replacement therapy. It results in endometrial hyperplasia and a significant risk of endometrial cancer.
Women with extended gaps between periods (more than three months) or abnormal bleeding need to be investigated with a pelvic ultrasound to assess the endometrial thickness. Cyclical progestogens should be used to induce a period prior to the ultrasound scan. If the endometrial thickness is more than 10mm, they need to be referred for a biopsy to exclude endometrial hyperplasia or cancer.
How can we among infertility?
Weight loss is the initial step for improving fertility. Losing weight can restore regular ovulation.
A specialist may initiate other options where weight loss fails. These include:
- Clomifene
- Laparoscopic ovarian drilling
- In vitro fertilisation (IVF)
Metformin and letrozole may also help restore ovulation under the guidance of a specialist; however, the evidence to support their use is not clear.
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.
Women that become pregnant require screening for gestational diabetes. Screening involves an oral glucose tolerance test, performed before pregnancy and at 24 – 28 weeks gestation.
How can we manage hirsutism in PCOS?
Weight loss may improve the symptoms of hirsutism. Women are likely to have already explored options for hair removal, such as waxing, shaving and plucking.
Co-cyprindiol (Dianette) is a combined oral contraceptive pill licensed for the treatment of hirsutism and acne.
It has an anti-androgenic effect, works as a contraceptive and will also regulate periods. The downside is a significantly increased risk of venous thromboembolism. For this reason, co-cyprindiol is usually stopped after three months of use.
Topical eflornithine can be used to treat facial hirsutism. It usually takes 6 – 8 weeks to see a significant improvement. The hirsutism will return within two months of stopping eflornithine.
Other options that may be considered by a specialist experienced in treating hirsutism include:
- Electrolysis
- Laser hair removal
- Spironolactone (mineralocorticoid antagonist with anti-androgen effects)
- Finasteride (5α-reductase inhibitor that decreases testosterone production)
- Flutamide (non-steroidal anti-androgen)
- Cyproterone acetate (anti-androgen and progestin)
How do we manage acne in PCOS??
The combined oral contraceptive pill is first-line for acne in PCOS. Co-cyprindiol may be the best option as it has anti-androgen effects; however, there is a significantly increased risk of venous thromboembolism.
Other standard treatments for acne include:
- Topical adapalene (a retinoid)
- Topical antibiotics (e.g. clindamycin 1% with benzoyl peroxide 5%)
- Topical azelaic acid 20%
- Oral tetracycline antibiotics (e.g. lymecycline)
How should we counsel a patient on PCOS?
Summarise the management of PCOS.
How do we split up the causes of anovulation?
- Hypothalamic
- Pituitary
- Ovarian
- Other
What are the hypothalamic causes of anovulation?
Hypothalamic hypogonadism
o Low GnRH → FSH/LH → No ovulation
o Associated with anorexia, diets, athletes and those under stress
Kallmann’s syndrome
o GnRH secreting neurones fail to develop
o GnRH pump induces ovulation
What are the female investigations for subfertility?
Initial investigations, often performed in primary care:
- Body mass index (BMI) (low could indicate anovulation, high could indicate PCOS)
- Chlamydia screening
- Female hormonal testing (see below)
- Rubella immunity in the mother
Female hormone testing involves:
- 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
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.
High LH may suggest polycystic ovarian syndrome (PCOS).
A rise in progesterone on day 21 indicates that ovulation has occurred, and the corpus luteum has formed and started secreting progesterone.
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.
Further investigations, often performed in secondary care:
- 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
Summarise the management of subfertility.
How do we counsel on subfertility’
