Oxford Handbook of Obstetrics and Gynaecology (3 edn)
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Polycystic ovarian syndrome: overview
Background
PCOS is the most common endocrine disorder in women.
Responsible for 80% of all cases of anovulatory subfertility.
Estimated prevalence is 6–10% of women of childbearing age.
USS evidence of polycystic ovaries is seen in 20–30% of women.
Requires the presence of two out of the following three variables and exclusion of other disorders:
Irregular or absent ovulations (cycle >42 days).
Clinical or biochemical signs of hyperandrogenism:
acne
hirsutism
alopecia.
Polycystic ovaries on pelvic USS: ≥12 antral follicles on one ovary.
Ovarian volume >10mL.
Aetiology
The pathogenesis of PCOS is not fully known. There is hypersecretion of LH in ~60% of PCOS patients (LH stimulates androgen secretion from ovarian thecal cells). Elevated LH:FSH ratio is often seen, but is not needed for diagnosis. The following factors have been implicated:
Genetic (familial clustering).
Insulin resistance with compensatory hyperinsulinaemia (defect on insulin receptor).
Hyperandrogenism (elevated ovarian androgen secretion).
Obesity:
BMI >30 in 35–60% of women with PCOS
central obesity
worsens insulin resistance.
Investigations
Basal (day 2–5): LH, FSH, TFTs, prolactin, and testosterone.
If hyperandrogenisim:
dehydroepiandrosterone sulphate (DHEAS)
androstenedione
SHBG.
Exclude other causes of 2° amenorrhoea.
Pelvic USS.
Examination
BMI.
Signs of endocrinopathy, hirsutism, acne, alopecia, acanthosis nigricans.
Obesity, insulin resistance, and metabolic abnormalities including dyslipidaemia are all risk factors for ischaemic heart disease, though long-term studies in PCOS are not proven.
Type II diabetes is a known risk of obesity and insulin resistance, and pregnant women with PCOS are at increased risk of gestational diabetes (
Gestational diabetes, p. 240).
Women diagnosed with PCOS should be asked (or their partners asked) about snoring and daytime fatigue/somnolence, informed of the possible risk of sleep apnoea, and offered investigation and treatment when necessary.
Long periods of 2° amenorrhoea, with resultant unopposed oestrogen, are a risk factor for endometrial hyperplasia and, if untreated, endometrial carcinoma.
Polycystic ovarian syndrome: management
The options should focus on the main concern of the woman.
Lifestyle modification
This is the cornerstone to managing PCOS in overweight women. Even a modest weight loss (5%) can improve symptoms. Moreover, weight loss through exercise and diet has been proven effective in restoring ovulatory cycles and achieving pregnancy. Weight loss through diet and exercise should be encouraged, and patients should feel supported.
Improving menstrual regularity
Weight loss.
COCP.
Metformin.
Controlling symptoms of hyperandrogenism
Cosmetic (depilatory cream, electrolysis, shaving, plucking).
Antiandrogens such as eflornithine facial cream, finasteride, or spironolactone:
can be used to help with acne and hirsutism
can take 6–9mths to improve hair growth
avoid pregnancy (feminizes a male fetus).
COCP:
reduces serum androgen levels by increasing SHBG levels
co-cyprindiol combines ethinylestradiol and cyproterone acetate, providing a regular monthly withdrawal bleed and beneficial antiandrogenic effects.
Subfertility
Weight loss alone may achieve spontaneous ovulation.
Ovulation induction with antioestrogens or gonadotrophins.
Laparoscopic ovarian diathermy.
IVF if ovulation cannot be achieved or does not succeed in pregnancy.
See Female subfertility: management, Ovulation induction, p. 596.
Women with PCOS who undergo IVF are at increased risk of ovarian hyperstimulation syndrome (see Ovarian hyperstimulation syndrome, p. 604).
Insulin sensitizers
Metformin has been most widely used (not licensed for this in the UK):
Metformin combined with ovulation induction with clomifene citrate ↑ ovulation and pregnancy rates, but may not significantly improve live birth rate.
Does not significantly improve hirsutism, acne, or weight loss, despite lowering androgen levels and improving insulin sensitivity.
Psychological issues
PCOS can be difficult to manage and patients may require additional motivation. Symptoms can be distressing and result in low self-esteem. It is therefore important to manage patients sensitively, and to adopt a holistic approach, incorporating all members of the multidisciplinary team.
Hirsutism and virilization: overview
Background
Vellus hair (prepubertal, unpigmented, downy hair) is irreversibly transformed into terminal hair (pigmented, coarse) through either increased free androgen or increased sensitivity of 5-α reductase (conversion of testosterone to the more potent dihydrotestosterone) in the skin. In women testosterone originates either directly from the ovaries (25%) and adrenal glands (25%) or from peripheral conversion of androstenedione or dihydroepiandrostenedione (-sulphate), which are produced in the ovaries and adrenal glands (50%). Testosterone is bound to SHBG (80%) and albumin (19%). In women, only 1% is free (active). LH stimulates ovarian theca cells and ACTH the adrenal glands to synthesize androgen.
Hirsutism
Hirsutism: presence of excessive facial and body hair in women.
Caused by ↑ of systemic or local androgen, resulting in a male hair growth pattern.
Incidence of hirsutism is estimated to be around 10% in developed countries.
Most commonly found in patients with PCOS, together with acne, alopecia, and acanthosis nigricans.
Even mild forms of hirsutism are often felt unacceptable by the patient and may cause mental trauma.
Should also not be confused with hypertrichosis, which is a very rare, androgen-independent disorder:
hypertrichosis can involve vellus, lanugo, and terminal hair occupying the entire body surface including the face (‘werewolf appearance’)
congenital forms have been described (usually more severe)
can be caused by drugs (phenytoin, ciclosporin, glucocorticoids), hypothyroidism, and anorexia nervosa.
Virilization
Can be distinguished from hirsutism by the presence of:
clitoromegaly
balding
deepening of the voice
male body habitus.
Is relatively rare and usually secondary to androgen-producing tumours or CAH.
Polycystic ovarian syndrome 95%.
Androgen-secreting tumours <1%.
Luteoma <1%.
CAH <1%.
Cushing’s syndrome <1%.
Androgen-secreting tumours <1%.
Acromegaly 1%.
Iatrogenic hirsutism <1%.
Drugs with androgenic effects (anabolic steroids, danazol, testosterone) <1%.
Hyperinsulinaemia.
Liver disease.
Androgens.
Hyperprolactinaemia.
Hypothyroidism.
Tumours.
Enzyme defects (including CAH).
Cushing’s syndrome.
Hyperinsulinaemia.
Increased LH levels stimulate theca cells.
Androgens.
Progestagens with androgenic potential.
Insulin growth factor-1 in patients with insulin resistance or hyperinsulinaemia.
Hirsutism and virilization: clinical appearance and investigations
Women mostly present with coarse and pigmented (terminal) hair on the face (upper lip, chin), chest, abdomen, back, and thighs. Ethnic differences in the severity of hair growth are common. Fair-skinned white women show less hair growth, while Mediterranean women have the greatest amount of terminal hair. Genetic differences in the activity of 5-α reductase seem to correlate with the severity of disease. Hirsutism is often accompanied by seborrhoea, acne, and male pattern alopecia.
History
Age:
children with non-classical CAH
pregnant women with luteoma.
Rate of onset of symptoms: rapid onset of severe symptoms may indicate an androgen-producing tumour.
Menstrual cycle: oligo- or amenorrhoea.
Genetic factors:
PCOS
enzyme deficiencies
type II diabetes.
Drugs:
COCPs with androgen effects
drug abuse (body builders).
General health and other symptoms:
Cushing’s
acromegaly
liver disease.
Physical examination
Exclude hypertrichosis.
Signs of virilization should prompt a search for an androgen-producing tumour.
BP:
↑ with Cushing’s and acromegaly
↓ in hypothyroidism and CAH.
Look for acanthosis nigricans:
marker of insulin resistance and hyperinsulinaemia
skin grey-brown, velvety appearance mainly in the neck, axillae, vulva, and groin.
Nine locations are evaluated and each receives a score between 0 (no growth) and 4 (complete hair cover):
Upper lip.
Chin.
Chest.
Upper abdomen.
Lower abdomen.
Upper back.
Lower back.
Upper arms.
Thighs.
A score >8 is considered androgen excess.
This score is subjective, difficult to compare between different ethnic groups, and has a reduced validity in pretreated women. It is therefore usually reserved for clinical studies.
Testosterone: measure of ovarian and adrenal activity.
DHEAS: measure of adrenal activity.
OGTT: in women with indication of hyperinsulinaemia/insulin resistance.
17-OHP: to rule out CAH, if indicated.
▶ TVS/USS to visualize polycystic ovaries is not necessary to diagnose PCOS in a woman with hirsutism and oligo-/amenorrhoea. However, TVS/USS should always be done, first, to exclude any ovarian tumours and, second, to help in confirming the diagnosis.
▶ Investigations to rule out rare causes of hirsutism such as Cushing’s syndrome and acromegaly should be undertaken if clinically indicated.
Hirsutism: first-line treatment
Treatment is aimed at the underlying cause (especially important for the non-ovarian causes such as Cushing’s or CAH).
Lifestyle changes aiming at weight reduction in women with PCOS.
COCP:
treatment of choice in women not trying to conceive
progestational component—LH suppression; 5-α reductase inhibition)
oestrogenic component—SHBG ↑
COCP with ethinylestrodid + drospirenone
ethinylestradiol + cyproterone acetate (co-cyprindiol) licensed in the UK for facial hirsutism (not for contraception!).
Medroxyprogesterone acetate:
if COCP is contraindicated
LH suppression (less than COCP)
SHBG ↓ (counterproductive)
testosterone clearance ↑ (induction of liver enzymes)
overall, similar results to COCP.
▶ Discontinue treatment after 1–2yrs to observe if ovulatory cycles occur. Suppression of testosterone will last for 6–12mths after discontinuation in anovulatory patients.
Cosmetic approaches
Hair removal will only be permanent if dermal papilla is destroyed.
Non-permanent approaches, such as shaving and waxing, do not worsen hirsutism.
Permanent measures
Laser
694–1064nm.
Uses melanin in hair bulb as chromophore.
Heat causes papillar destruction.
Works best on fair-skinned women with dark hair.
Dark-skinned patients at higher risk of dermal damage (scarring and discomfort as more energy is needed).
Electrolysis
Fine probe inserted into skin.
Short-wave radio frequency causes heat, thereby destroying dermal papilla.
Only permanent measure approved by the Food and Drug Administration (FDA).
Non-permanent measures
Local chemical depilatories (not for face).
Bleaching.
Waxing.
Tweezing.
Mechanical epilators.
Hirsutism: second-line treatment
Spironolactone (50–200mg daily, ↓ to 25–50mg qds after a few weeks):
aldosterone antagonist (diuretic)
inhibits ovarian/adrenal androgens
competes for androgen receptor in skin
inhibits 5-α reductase in skin
slow onset (at least 6mths)
hyperkalaemia possible (watch renal function)
add contraceptive as may cause feminization of male fetus.
Cyproterone acetate (2mg plus 35 micrograms ethinylestradiol in co-cyprindiol):
progestational agent with antiandrogenic potency
inhibits LH secretion and binds competitively to androgen receptor
best after 3mths of treatment
side effects—fatigue, oedema, weight gain, libido loss, mastalgia.
Finasteride (5mg daily):
inhibits 5-α reductase (type II >type I; type I in skin, therefore limited potency for hirsutism and alopecia)
few side effects
best after 6mths
teratogenic—contraception needed.
Flutamide (250mg daily):
non-steroidal antiandrogen
best after 6mths, also for treatment of alopecia
hepatotoxicity (monitor liver enzymes regularly)
add contraceptive as may cause feminization of male fetus.
Eflornithine hydrochloride (cream topically bd):
inhibits ornithine decarboxylase, responsible for hair growth
reduces speed of hair growth and hair becomes less coarse
works within 8wks, but quick recurrence after cessation
may worsen acne (obstructing pilosebaceous glands)
recommended for postmenopausal hair growth on upper lip.
GnRH agonists (depot prescriptions):
suppress gonadotrophins, thereby suppressing ovarian androgens
should be combined with add-back HRT
expensive and equally effective as other approaches.
Last resort treatment
Ketoconazole (400mg daily):
antifungal agent
reduces androgen levels by inducing hepatic cytochrome p450 metabolic pathways
hepatotoxicity (monitor liver enzymes regularly)
loss of scalp hair
abdominal pain.
Most of the drugs mentioned are not licensed for this indication. Cyproterone acetate/ethinylestradiol, and eflornithine are the exceptions.
About 17% of patients are menopausal, mainly with facial hirsutism.
Eflornithine cream.
Spironolactone.
Cyproterone acetate with HRT (not ethinylestradiol).
Estradiol + drospirenone HRT.
Endometriosis: overview
Endometriosis is the presence of endometrial-like tissue outside the uterine cavity. It is oestrogen dependent, and therefore mostly affects women during their reproductive years. If the ectopic endometrial tissue is within the myometrium itself it is called adenomyosis.
Aetiology
The exact aetiology remains unknown, various theories exist, but none accounts for all aspects of endometriosis.
Retrograde menstruation with adherence, invasion, and growth of the tissue (Sampson): most popular theory; however, >90% show menstrual blood in pelvis at time of menstruation.
Metaplasia of mesothelial cells (Meyer).
Systemic and lymphatic spread (Halban).
Impaired immunity (Dmowski).
Embryological theory
General female population: 10–12% (estimated).
Infertility investigation: 20–50%.
Sterilization: 6%.
Chronic pelvic pain investigation: 20–50%.
Dysmenorrhea: 40–60%.
Infertility.
Pain (often chronic pelvic pain):
cyclic or constant (ectopic endometrial tissue undergoes same cycle, causing repeated inflammation, which may result in the formation of adhesions)
severe dysmenorrhoea (can be due to adenomyosis)
dyspareunia (deep; indicates possible involvement of uterosacral ligaments)
dysuria (involvement of bladder or peritoneum or invasion into bladder)
dyschezia and cyclic pararectal bleeding (for rectovaginal nodules with invasion of rectal mucosa)
chronic fatigue.
Pain symptoms are often non-specific, resulting in the delay of the diagnosis by up to 12yrs.
▶ In 2–50% of cases there are no symptoms!
Pelvis (most common):
ovaries
pouch of Douglas
broad ligaments
uterosacral ligaments
bladder
Lungs.
Brain.
Muscle.
Eye.
▶ Endometriosis has been described in girls prior to menarche, and in men.
Peritoneal endometriotic lesions: appear as minuscule (powder burn) to 1–2cm lesions (red, bluish, brown, black, white; vesicular, cystic, petechial).
Ovarian endometriotic cysts:
endometriomas can be >10cm in size
usually filled with brownish fluid (‘chocolate cysts’; old blood and tissue)
often associated with local fibrosis and adhesions.
Deep infiltrating endometriosis: rectovaginal nodules can frequently result in fibrosis of surrounding tissue. Often have solid appearance.
Further reading
RCOG. (2006). Endometriosis, investigation and management. Green-top guideline 24. Available at: 
http://www.rcog.org.uk/womens-health/clinical-guidance/investigation-and-management-endometriosis-green-top-24
Women’s Health Specialist Library. www.womenshealthresearch.org/
Endometriosis: diagnosis
History
Menstrual cycle.
Nature of the pain:
site
relationship to cycle (mid cycle/dysmenorrhoea)
deep dypareunia.
Haematuria or rectal bleeding during menstruation.
Examination
Bimanual pelvic examination for:
adnexal masses (endometriomas) or tenderness
nodules/tenderness in the posterior vaginal fornix or uterosacral ligaments
fixed retroverted uterus
rectovaginal nodules.
Speculum examination of vagina and cervix (rarely, lesions may be visible).
Investigations
Transvaginal USS:
Endometriomas
Embryological theory
Laparoscopy with biopsy for histological verification:
especially important for deep infiltrating lesions
positive is confirmative, negative does not rule it out
endometriomas >3cm should to be resected to rule out malignancy (rare).
Laparoscopy should not be performed within 3mths of hormonal treatment (leads to underdiagnosis).
Indications for laparoscopy:
NSAID-resistant lower abdominal pain/dysmenorrhoea
pain resulting in days off work/school or hospitalization
pain and infertility investigation.
It is good practice to document the extent of disease (photos or DVD).
MRI, intravenous urography (IVU), or barium enema (to assess extent of rectovaginal, bladder, ureteric, or bowel involvement).
Serum CA125 is sometimes elevated with severe endometriosis, but there is no evidence that it is a useful screening test for this condition.
The current system (Revised American Society of Reproductive Medicine classification, rASRM 1996) classifies the extent of endometriosis on a point system, taking into account:
Peritoneal.
Ovarian.
Pouch of Douglas.
<1cm.
1–3cm.
>3cm.
Superficial.
Deep.
Filmy or dense.
Extent of enclosure (<1/3; 1/3–2/3, >2/3).
Colour and form.
The points are added up and the stage of endometriosis is graded accordingly:
Stage I: Minimal endometriosis (1–5 points).
Stage II: Mild endometriosis (6–15 points).
Stage III: Moderate endometriosis (16–40 points).
Stage IV: Severe endometriosis (>40 points).
This system of values is highly controversial because of its subjectivity. The severity of disease has not been shown to have any correlation with the severity of pain. It may be of value in infertility prognosis and management.
Endometriosis: treatment
The approach should be determined by:
Reason for treatment (pain or fertility).
Side effect profile.
Cost-effectiveness of each drug.
▶ All drugs are equally effective in relieving pain and are associated with up to 50% recurrence after approximately 12–24mths after stopping.
▶ It is acceptable to treat women empirically with progestagens or COCP without a laparascopic diagnosis. Combined hormonal contraceptives, ideally administered continuously, should be considered as first-line agents. NSAIDs are effective and may be used with hormonal drugs.
▶ Severe cases of endometriosis should be referred to a centre with expertise in advanced laparoscopic surgery.
Treatments for pain
Medical treatment
See Table 18.1.
Drug | Applications/ duration | Effect | Side effects |
COCP | Continuous >> cyclic Long term | Ovarian suppression | Headaches Nausea DV Stroke |
Medroxy- progesterone acetate or other progestagens | Orally or IM/SC injection (depot) Long term | Ovarian suppression | Weight gain Bloating Acne Irregular bleeding Depression |
GnRH analogues | 2nd line therapy SC/IM injection or nasal spray Short or long term Should never be used without add-back HRT | Ovarian suppression | Loss of bone density (reversible) Hot flushes Vaginal dryness Headaches Depression |
Levonorgestrel- releasing IUD | Intrauterine Long term (change every 5yrs if age <40) | Endometrial suppression; sometimes ovarian suppression | Irregular bleeding Spontaneous expulsion |
Danazol | Oral 6mths (longest experience) | Ovarian suppression | Acne Hirsutism Irreversible voice changes |
Aromatase inhibitors | Oral Probably 6mths (still experimental and not licensed) | Local oestrogen suppression in endometrial lesions | Ovarian cysts Loss of bone density (reversible) |
Drug | Applications/ duration | Effect | Side effects |
COCP | Continuous >> cyclic Long term | Ovarian suppression | Headaches Nausea DV Stroke |
Medroxy- progesterone acetate or other progestagens | Orally or IM/SC injection (depot) Long term | Ovarian suppression | Weight gain Bloating Acne Irregular bleeding Depression |
GnRH analogues | 2nd line therapy SC/IM injection or nasal spray Short or long term Should never be used without add-back HRT | Ovarian suppression | Loss of bone density (reversible) Hot flushes Vaginal dryness Headaches Depression |
Levonorgestrel- releasing IUD | Intrauterine Long term (change every 5yrs if age <40) | Endometrial suppression; sometimes ovarian suppression | Irregular bleeding Spontaneous expulsion |
Danazol | Oral 6mths (longest experience) | Ovarian suppression | Acne Hirsutism Irreversible voice changes |
Aromatase inhibitors | Oral Probably 6mths (still experimental and not licensed) | Local oestrogen suppression in endometrial lesions | Ovarian cysts Loss of bone density (reversible) |
Surgical treatment
No RCTs have compared medical with surgical treatment.
Surgical management indicated once medical treatment has failed in most of the minimal to moderate endometriosis.
There are no data supporting preoperative hormonal treatment.
Postoperative 6mths treatment with GnRH analogues is effective in delaying recurrence at 12 and 24mths (not the case with COCP).
Coagulation, excision, or ablation are recommended surgical techniques and should be done by laparoscopy.
As a last resort hysterectomy may be considered in patients with severe, treatment refractory dysmenorrhoea: if performed, bilateral oophorectomy should be considered with add-back HRT.
Treatments for subfertility
Medical treatment
No medical treatment can improve fertility in endometriosis patients.
Surgical treatment
Spontaneous pregnancy rate after surgical removal of endometriotic lesions is probably ↑ in minimal/mild endometriosis.
Unclear efficacy for moderate/severe disease as no RCTs exist.
Endometriomas (≥3cm) should be removed: best by cystectomy rather than drainage to ↓ recurrence rates.
▶ Fertility-sparing surgery should be the goal, to increase chance of spontaneous conception. However, in moderate to severe disease, IVF may be the treatment of choice.
Gonadotrophin-releasing hormone in health and disease
Biochemistry
GnRH is a decapeptide synthesized in the hypothalamus.
Released in a pulsatile manner in both males and females.
Acts on G-protein coupled receptors in the anterior pituitary.
Has a short half-life (t1/2) of 2–4min.
Physiological functions
The frequency and amplitude of the GnRH pulses are more important than absolute hormonal levels. During the fetal and neonatal periods GnRH is involved in normal development. The amplitude of pulsatile release is then decreased during childhood until puberty. It is not known what factor(s) trigger the increased frequency and amplitude of secretion seen during puberty, but this results in the release of gonadotrophins (high-frequency pulses of LH and low-frequency pulses of FSH) from the anterior pituitary gland and subsequently sex steroids from the ovary. A complex system of positive and negative feedback loops between GnRH, LH, FSH, progesterone, and oestrogen regulate the normal menstrual cycle (see Physiology of the menstrual cycle, p. 502).
Congenital GnRH deficiency
Congenital hypothalamic hypogonadism is usually only diagnosed in females when a delay in puberty is noted, as female infants are phenotypically normal.
When associated with an absence of the sense of smell (anosmia) it is known as Kallman’s syndrome.
It can be difficult to distinguish hypothalamic hypogonadism from delayed puberty; however, in the former, pubic hair is present as adrenarche occurs normally and children are usually of normal height for their age.
Acquired GnRH deficiency
Acquired GnRH deficiency can be due to:
Damage to the hypothalamus by:
trauma
tumour.
Disruption of the hypothalamic–pituitary axis can occur 2° to:
intense physical training
anorexia nervosa.
GnRH as a treatment
Pulsatile intravenous infusions of GnRH can be used to induce puberty and ovulation with a congenital deficiency.
If deficiency is acquired, it is more usual to use oestrogen and progesterone on a long-term basis, or LH/FSH to induce ovulation.
Gonadotrophin-releasing hormone agonists and antagonists
The short half-life of natural GnRH restricts its pharmacological use to IV pulsatile use. However, longer-acting GnRH analogues (agonists) or receptor antagonists can be used to induce a temporary, reversible menopausal state as a treatment for a number of conditions.
GnRH analogues
A number of different GnRH analogues exist, including:
goserelin acetate
leuprorelin acetate
nafarelin
Administration:
SC injection (daily, monthly, or 3-monthly)
intranasally
intravaginally.
They produce a prolonged activation of the GnRH receptor, resulting in an initial ↑ in FSH and LH secretion: this may cause a worsening of symptoms (‘initial flare’).
Continued activation of the receptor leads to ↓ LH/FSH secretion:
serum oestradiol levels are suppressed by approximately 21 days
remain at similar levels to postmenopausal women with continued dosing.
Adequate barrier contraception should be used during treatment as there is a theoretical risk of teratogenicity and miscarriage.
Pre-surgery:
endometrial thinning prior to ablation/resection
fibroid shrinkage prior to myomectomy/hysterectomy.
Endometriosis.
Adenomyosis.
Assisted reproduction: pituitary down-regulation prior to superovulation.
Diagnostic tool in chronic pelvic pain (see Chronic pelvic pain, p. 568).
Breast cancer.
Prostate cancer.
Hot flushes.
Mood swings.
Vaginal dryness.
Abnormal vaginal bleeding.
Decreased libido.
Breast swelling/tenderness.
↑ low density lipoprotein (LDL), ↓ high density lipoprotein (HDL).
Insomnia.
Headaches.
Loss of bone mineral density.
Alterations in eyesight.
Initial flare (agonists only).
Bruising at injection site.
Bone mineral density (BMD)
Up to 6% BMD may be lost after the first 6mths treatment.
If treatment is to be continued for longer than 3mths, the use of ‘addback’ HRT is recommended: combined GnRH agonist and HRT add-back has been shown to be safe for a period of up to 5–10yrs.
Resumption of menstruation and return of fertility occur soon after stopping treatment.
GnRH antagonists
GnRH antagonists, such as cetrorelix, bind to receptors without activation and therefore do not cause an initial worsening of symptoms. They are currently licensed for assisted conception protocols and are used experimentally in endometriosis treatments. However, their effect on BMD and other side effects are similar to agonists.
Female subfertility: overview
Very common, with 1 in 6 couples seeking specialist help.
~84% will achieve a pregnancy in 1yr of regular UPSI: this ↑ to 92% after 2yrs.
Referral for specialist advice should be considered after at least 1yr of trying, though in certain situations prompt investigations and referral may be recommended:
female age >35yrs
known fertility problems
anovulatory cycles
severe endometriosis
previous PID
malignancy.
Treat couples on an individual basis. There is not necessarily a right answer as to when investigations and treatment should start.
The management of subfertility aims to correct any specific problem that may or may not be diagnosed.
Ovulation disorder: 21%.
Tubal factor: 15–20%.
Male factor: 25%.
Unexplained: 28%.
Endometriosis: 6–8%.
Premature ovarian failure.
Genetic: Turner’s syndrome (45XO; hypergonadotrophic hypogonadism).
Autoimmune.
Iatrogenic:
surgery
chemotherapy.
PCOS.
Excessive weight loss or exercise.
Hypopituitarism:
tumour
trauma
surgery.
Kallman’s syndrome (anosmia; hypogonadotrophic hypogonadism).
Hyperprolactinaemia.
Female subfertility: diagnosis
History
It is vitally important to take a relevant and careful history in a sensitive manner, however embarrassing this may be for you. Couples are often seen together and sometimes it can be difficult to ask about sensitive issues; if necessary, each partner can be seen alone, though this is not ideal. Also ask if a cervical smear is needed and about breast examinations.
Age.
Duration of subfertility.
Menstrual cycle regularity and LMP (pregnancy test?).
Pelvic pain (dysmenorrhoea; dyspareunia).
Cervical smear history.
Previous pregnancies.
History of ectopic pregnancy.
Previous tubal or pelvic surgery.
Previous or current STIs.
Previous PID.
Coital frequency.
Any relevant medical or surgical history.
Drug history (any prescription drugs that may be contraindicated in pregnancy and ask about recreational drug use).
Smoking.
Number of units alcohol/week.
Folic acid.
Clinical examination
General examination
BMI
Signs of endocrine disorder: hyperandrogenism (acne, hair growth, alopecia), acanthosis nigricans (see Polycystic ovarian syndrome: overview, p. 570); thyroid disease (hypo- and hyperthyroidism); visual field defects (? prolactinoma).
Pelvic examination
Exclude obvious pelvic pathology (adnexal masses, uterine fibroids, endometriosis (painful, fixed uterus), vaginismus).
Cervical smear.
Chlamydia screening.
Investigations
Primary care
Chlamydia screening.
Baseline (day 2–5) hormone profile including FSH (high in POF; low in hypopituitarism), LH, TSH, prolactin, testosterone.
Rubella status.
Mid-luteal progesterone level (to confirm ovulation >30nmol/L).
Semen analysis (see Male subfertility, p. 598).
Secondary care
This assessment should ideally take place within a specialist clinic with appropriately trained multidisciplinary staff. The history should be confirmed with the couple and any missing details checked.
Easily done.
Good sensitivity and specificity.
Can be uncomfortable.
May have false +ve results (suggesting tubal blockage due to spasm).
Day-case procedure that can be combined with a hysteroscopy to assess the uterine cavity if necessary.
‘Gold standard’.
Pelvic pathology (endometriosis, peritubular adhesions) can be diagnosed and treated.
Requires general anaesthetic.
Carries surgical risks.
Ultrasound with galactose-containing contrast medium.
Similar sensitivity to HSG.
No radiation exposure.
Female subfertility: management
Management depends on duration and possible cause of subfertility. Couples should be informed of their options and given relevant evidence-based advice so they can make an informed choice.
Lifestyle modification
Healthy diet.
Stop smoking/recreational drugs.
Reduce alcohol consumption.
Regular exercise.
Folic acid.
Avoid timed intercourse (every 2–3 days).
Avoid ovulation induction kits/basal temperature measurements (no evidence of success, and stressful).
Ovulation induction
PCOS is the most common cause of secondary amenorrhoea and is responsible for 75–80% of anovulatory subfertility. Correction of the specific problem such as hyperprolactinaemia or excessive weight may be enough.
Weight loss/gain as appropriate.
Antioestrogens (e.g. clomifene 50mg days 2–6):
↑ endogenous FSH levels via negative feedback to pituitary
8–10% multiple pregnancy
side effects (hot flushes, mood labiality)
clomifene limited to 12 cycles maximum (? possible link to ovarian cancer)
needs ultrasound monitoring (abandon cycle if overresponse).
Gonadotrophins or pulsatile GnRH:
used for low oestrogen/normal FSH or clomifene-resistant PCOS
injections
expensive
multiple pregnancy risk
ultrasound monitoring (abandon cycle if overresponse)
more easily titrated.
Laparoscopic ovarian diathermy:
aims to restore ovulation in patients with PCOS
effect lasts 12–18mths if successful.
Insulin sensitizers (metformin 500mg tds):
used in women with PCOS
may achieve spontaneous ovulation
can be combined with clomifene to increase efficacy
recent conflicting data
not licensed
weight loss is more effective.
Surgery:
preferably laparoscopic
treat endometriosis (laser/diathermy/excision)
tubal surgery (microsurgery/adhesiolysis).
Assisted reproduction (IUI, IVF, oocyte donation).
Subfertility and its management can be very distressing. Some treatments have side effects and are not guaranteed to be successful. The stress of this and disappointment of failed treatment needs to be addressed. Couples should be offered counselling before and after treatment, along with information regarding patient support groups.
Further reading
Male subfertility
Accounts for 20–25% of cases of subfertile couples. Investigation should start in primary care after 1yr, or earlier if history of genital surgery, cancer treatment, or previous subfertility. Trend of declining sperm concentration is not affecting global fecundity but there is increasing ‘testicular dysgenesis syndrome’ with an increase in cryptorchidism, testicular cancer, and hypospadias. Normal male fertility is dependent on normal spermatogenesis, erectile function, and ejaculation.
Normal semen analysis (WHO criteria 2009)
Volume >1.5mL.
Concentration >15 × 106/mL.
Progressive motility >32%.
Total motility >40%.
Azoospermia
No sperm in ejaculate.
Oligozoospermia
Reduced number of sperm in ejaculate.
Investigations
FSH: elevated in testicular failure.
Karyotype: exclude 47XXY.
Cystic fibrosis screen: congenital bilateral absence of the vas deferens (CBAVD).
Management
Treat any underlying medical conditions.
Address lifestyle issues (↓ alcohol, stop smoking).
Review medications:
antispermatogenic (alcohol, anabolic steroids, sulfasalazine)
antiandrogenic (cimetidine, spironolactone)
erectile/ejaculatory dysfunction (α or β blockers, antidepressants, diuretics, metoclopramide).
Medical treatments:
gonadotrophins in hypogonadotrophic hypogonadism
sympathomimetics (e.g. imipramine) in retrograde ejaculation.
Surgical:
relieve obstruction
vasectomy reversal.
Surgical treatment of varicocele does not improve pregnancy rate and is therefore not indicated.
Sperm retrieval:
from postorgasmic urine in retrograde ejaculation
surgical sperm retrieval from testis with 50% chance of obtaining sperm (greater if FSH is normal).
Assisted reproduction:
IUI
IVF-ICSI (in vitro fertilization and intracytoplasmic sperm injection).
Donor sperm.
Adoption.
Idiopathic oligoasthenoteratozoospermia (OATS).
Testis cancer.
Drugs (including alcohol, nicotine).
Genetic.
Varicocele.
Pretesticular: anabolic steroid abuse; idiopathic hypogonadotrophic hypogonadism (HH); Kalmann’s, pituitary adenoma.
Non-obstructive: cryptorchidism, orchitis, 47XXY, chemoradiotherapy.
Obstructive: CBAVD, vasectomy, Chlamydia, gonorrhoea.
Antisperm antibodies.
Idiopathic.
Infection.
Unilateral testicular obstruction.
Mechanical cause with normal sperm function.
Ejaculation normal (hypospadias, phimosis, disability).
Retrograde ejaculation (diabetes, bladder neck surgery, phenothiazines).
Failure in ejaculation (multiple sclerosis (MS), spinal cord/pelvic injury).
Assisted reproduction: in vitro fertilization and intracytoplasmic sperm injection
Assisted reproductive technologies (ART) refer to all fertility treatments in which sperm and oocytes are handled with the aim of achieving pregnancy. It includes IVF, ICSI, preimplantation genetic diagnosis (PGD), PGS, egg donation, and surrogacy.
In vitro fertilization
Indications may include:
Tubal disease.
Male factor subfertility.
Endometriosis.
Anovulation.
↓ Fecundity observed with ↑ maternal age.
Unexplained infertility for more than 2yrs.
Success is dependent on many factors including:
Duration of subfertility:↓ success with ↑ duration.
Age:
pregnancy rates are highest between 25 and 35 with a steep decline thereafter
elevated basal FSH levels may indicate a poor response to ovarian stimulation.
Previous pregnancy: higher chance of successful IVF outcome.
Previous failed IVF cycles: ↓ success.
Presence of hydrosalpinx or intramural fibroid: ↓ success.
Smoking and ↑ BMI: ↓ success.
Intracytoplasmic sperm injection
A single sperm is injected into the ooplasm of the oocyte in ICSI.
Used for men with severely abnormal semen parameters.
May also be tried when failed fertilization has occurred in IVF cycles.
Higher fertilization rates are obtained if the selected sperm exhibit some motility, but otherwise there are no strict selection criteria.
Has greatly ↑ the success of IVF with severe male factor subfertility.
Sperm may be retrieved from ejaculate or surgically from epididymis or testes.
Men with severe oligozoospermia should have karyotype and cystic fibrosis screening prior to ICSI.
There are concerns regarding transmission of genetic mutations when using ICSI. Sperms containing oxidatively induced DNA damage are capable of fertilizing oocytes. There is an ↑ incidence of Y chromosome deletions on subfertile men and this may be further propagated by transmission to the offspring born by ICSI, resulting in infertility.
▶ In preparation, the HFEA consents and ‘Welfare of the Child’ issues must be considered.
Down-regulation of the ovaries using GnRH analogues from day 21 (luteal phase) of the previous cycle: alternatively in antagonist cycles (‘short protocol’) GnRH antagonists are co-administered with gonadotrophins during ovarian stimulation.
Ovarian stimulation with recombinant FSH or human menopausal gonadotrophins: response is monitored by transvaginal USS.
Follicular maturation by administration of hCG, when significant mature-size follicles are seen on USS.
Transvaginal oocyte retrieval by needle-guided aspiration (36h later).
Sperm sample collected (or thawed if frozen), prepared, and cultured with oocytes overnight.
Fertilization checks of embryos.
Embryo transfer by a fine catheter through cervix on day 2–3 (cleavage stage) or day 5 (blastocyst stage):
a maximum of 2 embryos are transferred in women under 40 and there is current debate on the move to single embryo transfer given increased neonatal morbidity/mortality and ensuing costs of multiple pregnancy
blastocyst transfers increase the success rates of IVF.
Surplus embryos may be cryopreserved for future frozen embryo replacement cycles.
Luteal support given in form of progestagens.
Pregnancy test 2wks later.
Assisted reproduction: other techniques
Preimplantation genetic diagnosis
Aims to reduce the recurrence of genetic risk in couples known to carry a heritable genetic condition.
Many couples are fertile, but IVF allows embryo biopsy, single cell diagnosis, and the transfer of unaffected embryos to the woman.
Biopsies are usually done at cleavage stage, and PCR or FISH used for genetic diagnosis.
Intrauterine insemination
Couples who may benefit include those with:
mild male factor subfertility
unexplained subfertility
coital difficulties
same sex couple.
Sperm is prepared and placed into the uterus to aid conception.
The lower threshold for sperm concentration suitability for IUI has been suggested as a total motile count of >10M/mL.
NICE recommend up to 6 cycles of IUI, but most studies have reported optimal outcome within the first 4 cycles.
There is no consensus on the role of simultaneous ovarian stimulation, but this should be considered in endometriosis and unexplained infertility when outcome is less favourable.
If >3 follicles develop the treatment cycle should be cancelled as there is a high rate of multiple pregnancies (>25%).
Egg donation
May offer a chance of pregnancy for women previously considered to be irreversibly sterile.
This includes women with:
ovarian failure (gonadal dysgenesis, premature, cancer patients 2° to surgery and chemoradiotherapy or menopausal)
older women (>45yrs)
those with repeated IVF failure.
Donor insemination
Indicated in men:
with azoospermia and failed surgical sperm recovery
at high risk of transmitting genetic disorders (e.g. Huntington’s disease)
at high risk of transmitting infections (HIV).
Also used for women with no male partner.
The success of ICSI has ↓ demand for donor insemination.
Insemination is usually intrauterine: with/without ovarian stimulation and 36–40h after hCG administration.
Success rates vary from 4% (aged 40–44) to 12% (<34yrs) per cycle.
There are strict criteria for gamete donation, which is regulated by the HFEA.
Ideally, donors should have no severe medical, psychiatric, or genetic disorders.
Donors must be counselled.
Donors must undergo a full infection screen.
Donors may be known or anonymous to the recipient.
Egg donors should ideally be <35yrs old.
Each donor can only be used in up to 10 families within the UK.
In April 2005 donor anonymity was lifted, meaning that when children born from the use of donor gametes reach the age of 18, they can contact the HFEA for identifying information on the donor.
▶ The supply of donor gametes in the UK is limited. The HFEA may authorize the procurement of gametes from abroad if the supplying clinic fulfils the same quality of standards as the UK.
The couple who want the child provide both sets of gametes.
Following IVF the embryos are transferred to the surrogate.
This accounts for <0.1% of the total IVF cycles in the UK.
Indications include women who have congenital absence of the uterus (Rotikansky’s syndrome), following hysterectomy, or with severe medical conditions incompatible with pregnancy.
The surrogate is inseminated by the sperm of the male partner of the couple wanting the child.
Counselling and legal advice is necessary for all parties involved in the surrogacy.
Ovarian hyperstimulation syndrome
Ovarian hyperstimulation syndrome (OHSS) is a complication of ovulation induction or superovulation. Incidence is 0.5–10% and in 1/200 cases it is severe, requiring hospitalization. VEGF is central to underlying pathophysiology.
It is characterized by:
ovarian enlargement
shifting of fluid from the intravascular to the extravascular space.
Fluid accumulates in the peritoneal and pleural spaces.
There is intravascular fluid depletion, leading to:
haemoconcentration
hypercoaguability.
Risk factors include:
polycystic ovaries
younger women with low BMI
previous OHSS.
Prevention
Management is focused on prediction and active prevention. This may involve low-dose gonadotrophins, cycle cancellation, ‘coasting’ during stimulation, or elective embryo cryopreservation for replacement in a further frozen–thawed cycle.
In vitro maturation may be used in women with polycystic ovaries, with high antral follicle counts collecting immature eggs, thus avoiding ovarian stimulation and the risk of OHSS.
Treatment
The treatment is supportive, with the aims of:
Symptomatic relief.
Prevention of haemoconcentration and thromboembolism.
Maintenance of cardiorespiratory function.
Treatment should consist of:
Daily assessment of:
hydration status (FBC, U&E, LFTs, and albumin)
chest and respiratory function (pleural effusions)
ascites (girth measurement and weight)
legs (for evidence of thrombosis).
Strict fluid balance with careful maintenance of intravascular volume.
Thromboprophylaxis:
compression stockings
consider heparin.
Paracentesis for symptomatic relief (+/– IV replacement albumin).
Analgesia and antiemetics.
Sexual dysfunction: overview
Sexual health is a state of physical, emotional, mental, and social well-being in relation to sexuality, not merely the absence of disease or dysfunction. Sexual health necessitates the possibility of having pleasurable and safe sexual experiences, free of coercion, discrimination, and violence. Sexual rights must therefore be respected, protected, and fulfilled.
The prevalence of female sexual dysfunction (FSD) is highly definition-dependent (whether dissatisfaction and disinterest constitute FSD is debated).
Rates are up to 43% in women aged 18–59 compared with 31% in men. Increasing age is inversely proportional to sexual activity. 1/3 of all women over 60 may be sexually active (55% if married). Up to 50% of men will have some degree of erectile dysfunction, which rises to 67% by 70.
Menopause is associated with deterioration of sexual function, with one study suggesting an increase in FSD from 42–88% (45–55yr olds).
Dyspareunia is common and may be present in up to 1/3 of women.
Normal sexual function
Masters and Johnson proposed four components of the sexual response: arousal/excitement, plateau, orgasm, and resolution (based on biological, predominantly male, responses). More recently, intimacy-based models include features of satisfaction, pleasure, and relationship context. Overall the ‘normal’ for female sexuality is not well characterized and currently FSD is under construction.
Diagnosis
See the woman as she chooses to present herself, with or without a partner, and explore ‘why now?’ Many present when not in relationships, concerned about their sexual responses.
Presentation may be overt or covert—it is often useful to give the patient time to explore this and always think of the possibility of somatization of problems.
Are you sexually active/do you have a partner?
Do you have any difficulties?
Are they a problem for you?
Do you have pain associated with intercourse?
Examination
‘The moment of truth’ is a frequent occasion for disclosure of sexual problems manifesting as difficulties with examination, exposure, humiliation, or fantasies of disease or disgust.
Be led by the patient.
The patient is the expert—help her understand her behaviour.
Reflect your thoughts and feelings.
Try to understand the relationship between the physical findings, such as prolapse, and the psychological reaction to them.
Be aware of powerful subconscious defences in the patient, especially with lack of libido and desire disorders.
Feeling too small.
Feeling too big.
Feeling too loose.
Vagina with teeth.
Sharp penis.
Further reading
British Association of Sexual & Marital Therapy. www.basrt.org.uk
Institute of Psychosexual Medicine. www.ipm.org.uk
Mary Clegg—devices. www.maryclegg.com
Vulval Pain Society. www.vulvalpainsociety.org/
Sexual dysfunction: classification of disorders
Desire disorder
Persistent or recurrent deficiency (or absence) of sexual fantasies/thoughts and/or desire for or receptivity to sexual activity, which causes personal distress (75% of women and 25% of men attending a psychosexual clinic).
The majority of women who have little or no desire are able to derive pleasure from sexual activity. Presentation itself indicates sufficient interest to be hopeful of cure.
Arousal disorder
Persistent or recurrent inability to attain or maintain sufficient sexual excitement, causing personal distress, which may be expressed as a lack of subjective excitement or genital (lubrication/swelling) or other somatic responses. Understanding the sequence of sexual events and the interplay of physical factors (pain, lubrication, environment) helps to deal with the root cause. Lack of sensation is a common presentation of secondary personal or relationship issues.
Orgasmic disorder
Persistent or recurrent difficulty, delay in, or absence of attaining orgasm following sufficient sexual stimulation and arousal, which causes personal distress.
7–10% of women never achieve orgasm with or without a partner. This may not be a concern. Those who can achieve orgasm with masturbation but not with a partner may need to explore their ability to let go or lose control. Up to 25% of women with lifelong anorgasmia have been sexually abused. Women with acquired orgasmic difficulties should explore hormonal status, concomitant medications, and relationship issues. Up to 5% of women with anorgasmia will have an organic cause.
Sexual dysfunction secondary to a general medical condition
Endocrine disorders, psychiatric disorders, and a number of medications will interfere with the sexual response cycle. Treatment of the condition or alteration of therapies may help, but education and explanation may minimize the impact on sexual relationships.
Dermatological disorders, e.g. psoriasis and lichen sclerosis, infections, such as thrush and recurrent herpes, and atrophic vaginitis are treatable causes of superficial dyspareunia, but may have significant psychological sequelae.
Poor arousal may be the result or cause of sexual pain: lubricants and topical anaesthetic gels may help break the cycle.
Deep dyspareunia may be related to a number of medical conditions (endometriosis, PID, adhesions) determined by examination, USS and if necessary laparascopy.
Difficulty of the woman to allow vaginal entry of a penis, finger, or object despite the wish to do so.
This can involve pelvic floor and/or adductor thigh muscle spasm.
Vaginismus should be regarded as a symptom or sign and not a diagnosis.
It is generally 2° to another cause—physical, psychological, or both.
Fear of pain and anticipation of difficulty evolves into avoidance behaviour.
Check at examination for the presence of anatomical problems, e.g. vaginal septum.
Vulval vestibulitis is the most common pain disorder, but it is frequently difficult to treat.
Treatment of any skin condition, desensitization, and treatment with topical anaesthetics and lubricants is first-line therapy in conjunction with an exploration of the psychosexual issues.
Amitriptyline and gabapentin can be considered short term to interrupt the pain cycle.
Sexual dysfunction: treatment
Lifestyle
Address issues including those affecting body image and general well-being, reduction of stress, and dealing with relationship/marital issues.
Education
Teach people about their bodies and encourage exploration.
Using ‘bibliotherapy’ for those needing ‘permission’ to look at erotic and sexual education material.
Personal lubricants can be useful for those with arousal difficulties and atrophy (recommend oils or special preparations, but be aware of mineral oil damage to condoms).
Hormonal treatments
Oestrogen replacement in menopausal women may improve sexuality as well as symptoms of vaginal atrophy: vaginal oestrogens can be used long term.
Testosterone implants have been used successfully in those who have been oophorectomized and have hypoactive sexual desire disorder (HSDD).
Testosterone patches are also licensed in the UK.
Tibolone is licensed for treatment of loss of desire in postmenopausal women.
Complementary therapies
No good evidence for Yohimbine, gingko, khat, or ginseng.
Behavioural therapy
Most sex therapists will use a combination of psychotherapeutic techniques and behavioural interventions. Sensate focus uses a programme of exercises building up in stages:
Non-genital sensate focus.
Genital sensate focus.
Vaginal containment.
Vaginal containment with movement.
Devices for anorgasmia
Clitoral stimulators.
Vibrators.
Vaginal trainers or dilators
May be of use for women with vaginismus and are recommended for those having prolapse procedures and postradiotherapy.
Perineal injections
100mg hydrocortisone, 10mL 0.5% bupivicaine, and 1500U hyaluronidase—may be of value for perineal injuries or for pain trigger points.
Surgery
Rarely necessary—may be for those with a rigid hymen, significant skin webs at the fourchette postsurgery or childbirth, or septae.
Motivation for treatment (especially in the male partner).
Quality of the non-sexual relationship.
Sexual dysfunction: male disorders
If you have elicited a problem in a sexually active couple the difficulties of both partners should be gently sought.
Male sexual disorders
Erectile dysfunction (ED) most common.
Desire disorders.
Ejaculatory disorders.
Erectile dysfunction
Routine tests recommended
Serum glucose.
Lipids.
Testosterone (early morning).
BP.
Pulse.
Weight.
Genitalia.
Prostate.
New-onset erectile dysfunction may be a marker for cardiovascular disease.
Treatment options
Phosphodiesterase inhibitors:
sildenafil and vardenafil ↑ erectile function in 60–70%
they act in 20–60min and last for up to 8h.
Tadalafil may be useful for premature ejaculation.
Apomorphine:
dopamine agonist
less efficacious (40–50%).
Androgens: for men with hypogonadism.
Intracavernous prostaglandin injections.
Intraurethral prostaglandin pellets.
Vacuum devices.
Penile implants.
▶ It is important to remember the psychosexual aspects of sexual difficulties for both partners, as well as concentrating on pharmacological treatments.
