Subfertility and reproductive medicine
Polycystic ovarian syndrome (PCOS): overview [link]
Polycystic ovarian syndrome (PCOS): management [link]
Hirsutism and virilization: overview [link]
Hirsutism and virilization: clinical appearance and investigations [link]
Hirsutism: first-line treatment [link]
Hirsutism: second-line treatment [link]
Endometriosis: overview [link]
Endometriosis: diagnosis [link]
Endometriosis: treatment [link]
Gonadotrophin releasing hormone (GnRH) in health and disease [link]
Gonadotrophin releasing hormone (GnRH) agonists and antagonists [link]
Female subfertility: overview [link]
Female subfertility: diagnosis [link]
Female subfertility: management [link]
Male subfertility [link]
Assisted reproduction: IVF and ICSI [link]
Assisted reproduction: other techniques [link]
Ovarian hyperstimulation syndrome (OHSS) [link]
Sexual dysfunction: overview [link]
Sexual dysfunction: classification of disorders [link]
Sexual dysfunction: treatment [link]
Sexual dysfunction: male disorders [link]
Polycystic ovarian syndrome (PCOS): overview
Background
• PCOS is the most common endocrine disorder in women.
• It is responsible for 80% of all cases of anovulatory subfertility.
• Estimated prevalence is 6–10% of women of childbearing age.
• The USS evidence of polycystic ovaries (PCO) is common (20–30% women).
Rotterdam criteria for diagnosing PCOS
Requires the presence of 2 out of the following 3 variables:
• 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 >10 mL.
Aetiology
The pathogenesis of PCOS is not fully known. Given its heterogeneity, it is likely to be multifactorial. There is hypersecretion of LH (increased frequency and amplitude of LH pulses) in ∼60% of PCOS patients (LH stimulates androgen secretion from ovarian thecal cells). An elevated LH:FSH ratio is often seen but this is not needed for the 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 kg/m2 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 sulfate (DHEAS)
• androstenedione
• sex hormone binding globulin (SHBG).
• Exclude other causes of secondary amenorrhoea.
• Pelvic USS.
Long-term health consequences of PCOS
• 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 (
p. [link]).• Long periods of secondary amenorrhoea, with resultant unopposed oestrogen, is a risk factor for endometrial hyperplasia and, if untreated, endometrial carcinoma.
Polycystic ovarian syndrome (PCOS): management
The options should focus on the main concern of the woman.
Lifestyle modification
This is the cornerstone to managing PCOS in an overweight women. Even a modest weight loss (5%) can improve symptoms. Weight loss through diet (dietitian; information leaflets) and exercise should be encouraged, and patients should feel supported.
Controlling symptoms of hyperandrogenism
• Cosmetic (depilatory cream/electrolysis/shaving/plucking).
• Anti-androgens such as eflornithine (Vaniqua®) facial cream, finasteride, or spironolactone:
• can be used to help with acne and hirsutism
• can take 6–9 months to improve hair growth
• avoid pregnancy (feminizes a male fetus).
• COCP:
• reduces serum androgen levels by increasing SHBG levels
• co-cyprindiol (dianette®) combines ethinylestradiol and cyproterone acetate
providing a regular monthly withdrawal bleed and beneficial anti-androgenic effects.
Subfertility (see Ovulation induction, p. [link])
• 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.
Women with PCOS who undergo IVF are at increased risk of ovarian hyperstimulation syndrome (see OHSS, p. [link])
Insulin sensitizers
• Metformin has been most widely used (not licensed for this in the UK):
• may help regulate menstrual cycles and achieve ovulation
• is no better than lifestyle modification
• does not significantly improve hirsutism, acne, weight loss despite lowering androgen levels and improving insulin sensitivity.
Data on the benefit of metformin in PCOS are conflicting and this may be as a result of variations in study populations, degree of obesity and differing definitions of the syndrome.
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). Luteinizing hormone (LH) stimulates ovarian theca cells and adrenocorticotrophic hormone (ACTH) the adrenal glands to synthesize androgen.
Hirsutism
• Hirsutism is the presence of excessive facial and body hair in women.
• It is caused by an increase of systemic or local androgen resulting in a male hair growth pattern.
• The 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 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 congenital adrenal hyperplasia (CAH).
Causes of hirsutism
• Ovary:
• polycystic ovarian syndrome 95%
• androgen-secreting tumours<1%
• luteoma<1%.
• Adrenal gland:
• congenital adrenal hyperplasia<1%
• Cushing's syndrome<1%
• androgen-secreting tumours<1%
• acromegaly 1%
• External causes:
• iatrogenic hirsutism<1%
• drugs with androgenic effects (anabolic steroids, danazol, testosterone)<1%
Reasons for increased androgen levels
• Reduced SHBG levels:
• hyperinsulinemia
• liver disease
• androgens
• hyperprolactinemia
• hypothyroidism.
• Increased production:
• tumours
• enzyme defects (including CAH)
• Cushing's syndrome
• hyperinsulinemia
• increased LH levels stimulate theca cells.
• External androgen sources:
• androgens
• progestogens with androgenic potential
• Increased 5-A reductase sensitivity:
• 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 in 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 hyperinsulinemia
• skin grey-brown, velvety appearance mainly in the neck, axillae, vulva, and groin.
Ferriman-Gallwey Score to grade hirsutism
• 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 pre-treated women. It is therefore usually reserved for clinical studies.
Investigations for hirsutism
• Testosterone:
• measure of ovarian and adrenal activity.
• DHEAS:
• measure of adrenal activity.
• OGTT:
• in women with indication of hyperinsulinemia/insulin resistance.
• 17-OHP:
• to rule out CAH, if indicated.
► TVUSS to visualize polycystic ovaries is not necessary to diagnose PCOS in a woman with hirsutism and oligo-/amenorrhoea.
► 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 weigh reduction in women with PCOS.
• COCP:
• treatment of choice in women not trying to conceive
• progestational component: (LH suppression; 5α-reductase inhibition)
• oestrogenic component: (SHBG ↑)
• ethinylestradiol + cyproterone acetate (co-cyprindion Dianette ®) licensed in UK for facial hirsutism (not for contraception!)
• Medroxyprogesterone acetate:
• if COCP is contraindicated
• LH suppression (less than OCP)
• SHBG ↓ (counter productive)
• testosterone clearance↑(induction of liver enzymes)
• overall, similar results to COCP.
► Discontinue treatment after 1–2 years to observe if ovulatory cycles occur. Suppression of testosterone will last for 6–12 month after discontinuation in anovulatory patients.
Cosmetic approaches
• Hair removal will only be permanent if the dermal papilla is destroyed.
• Non-permanent approaches such as shaving or waxing do not worsen hirsutism.
Hirsutism: second-line treatment
• Spironolactone (50–200 mg daily, ↓ to 25–50 mg qds after few weeks):
• aldosterone antagonist (diuretic)
• inhibits ovarian/adrenal androgens
• competes for androgen receptor in skin
• inhibits 5α-reductase in skin
• slow onset (at least 6 months)
• hyperkalaemia possible (watch renal function)
• add contraceptive as may cause feminization of male fetus.
• Cyproterone acetate (2 mg plus 35 micrograms ethinyl estradiol in co-cyprindiol (Dianette®)):
• progestational agent with antiandrogenic potency
• inhibits LH secretion and binds competitively to androgen receptor
• best after 3 months of treatment
• side effects: fatigue, oedema, weight gain, loss of libido, mastalgia.
• Finasteride (5 mg daily):
• inhibits 5α-reductase (type II>type I; type ↑ in skin, therefore limited potency for hirsutism and alopecia)
• few side effects
• best after 6 months
• teratogenic: contraception needed.
• Flutamide (250 mg daily):
• non-steroidal antiandrogen
• best after 6 months, 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 8 weeks, 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 (400 mg 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.
Endometriosis: overview
Endometriosis is the presence of endometrial-like tissue outside the uterine cavity. It is oestrogen dependent, therefore mostly effects 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).
Incidence of endometriosis
General female population | 10–12% (estimated) |
Infertility investigation | 20–30% |
Sterilization | 6% |
Chronic pelvic pain investigation | 15% |
Dysmenorrhea | 40–60% |
Typical presentation of endometriosis (often combination)
• 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 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 12 years.
► In 2–50% of cases there are no symptoms!
Location of endometriosis
Appearance of endometriosis
• Peritoneal endometriotic lesions:
• appear as minuscule (powder burn) to 1–2 cm lesions (red, bluish, brown, black, white; vesicular, cystic, petechial)
• Ovarian endometriotic cysts:
• endometriomas can be >10 cm in size
• usually filled with brownish fluid (‘chocolate cysts’; old blood and tissue)
• often associated with local fibrosis.
• Deep infiltrating endometriosis:
• rectovaginal nodules can frequently result in fibrosis of the surrounding tissue and often have a solid appearance.
Women's Health Specialist Library. www.library.nhs.uk/womenshealth/
The investigation and management of endometriosis. RCOG Guideline 24 www.rcog.org.uk
Endometriosis: diagnosis
History
• Menstrual cycle.
• Nature of the pain:
• site
• relationship to cycle (mid cyle/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
• possibly for endometriosis of urinary bladder or rectum.
• Laparoscopy with biopsy for histological verification
• especially important for deep infiltrating lesions
• positive is confirmative, negative does not rule it out
• endometriomas >3 cm should to be resected to rule out malignancy (rare).
• Laparoscopy should not be performed within 3 months of hormonal treatment (leads to underdiagnosis).
• Indications for laparoscopy:
• NSAID-resistant lower abdominal pain/dysmenorrhea
• 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, 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.
Grading of endometriosis
The current system (Revised American Society of Reproductive Medicine classification, rASRM 1996) classifies the extent of endometriosis on a point system, taking into account:
• Location:
• peritoneal
• ovarian
• pouch of Douglas.
• Size
• <1 cm
• 1–3 cm
• >3 cm
• Depth of infiltration:
• superficial
• deep.
• Adhesions
• 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:
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This value of system 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 12–24 months after stopping.
► It is acceptable to treat women empirically with progestagens or COCP without a laparascopic diagnosis. It is unclear whether it is preferable to take the COCP conventionally or over 3 months continuously (tri-cycling). 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 17.1.
Table 17.1 Medical treatment for pain from endometriosis
Drug | Applications/duration | Effect | Side effects |
|---|---|---|---|
COCP | 21 days with 7 day break or tricyclic 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 Acine Irregular bleeding Depression |
Gonadotropin realising ormone (GnRh) analogues | SC/IM injection or nasal spray 3–6 months (if longer only with ‘add-back’ HRT) | Ovarian suppression | Loss of bone density (reversible) Hot flushes Vaginal dryness Headaches Depression |
Levonorgestrel-releasing IUD | Intrauterine Long term (change every 5 years if age <40) | Endometrial suppression; sometimes ovarian suppression | Irregular bleeding Spontaneous expulsion |
Danazol | Oral 6months (longest experience) | Ovarian suspression | Acne Hirsutism Irrevesible voice changes |
Aromatase inhibitors | Oral Probably 6months (not licensed) | Local oestrogen suspension in endometrial lesions | Ovarian cyst Loss of bone density (reversible) |
Surgical treatment
• No RCTs have compared medical vs surgical treatment.
• There are no data supporting preoperative hormonal treatment.
• Postoperative 6 months treatment with GnRH analogues is effective in delaying recurrence at 12 and 24 months (not the case with COCP).
• Coagulation, excision, or ablation are the 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 benefit in hormonal treatment (?–ve effect as delays ovulation).
• NSAIDs have been shown to inhibit ovulation when taken at mid cycle (probably through suppression of necessary PG production).
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 (≥3 cm) 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 (GnRH) 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 2–4 minutes.
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 luteinizing hormone (LH) and low-frequency pulses of follicle stimulating hormone (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 Chapter 14, p. [link]).
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.
Gonadotrophin releasing hormone (GnRH) agonists and antagonists
The short half-life of natural GnRH restricts its pharmacological use to i.v. 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 (Zoladex)
• leuprorelin acetate (Prostap)
• nafarelin (Synarel).
• Administration:
• subcutaneous 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 estradiol levels are suppressed by approximately 21 days
• remain at similar levels to postmenopausal women with continued dosing.
• Indications and adverse effects are shown in text boxes, p. [link].
• Adequate barrier contraception should be used during treatment as there is a theoretical risk of teratogenicity and miscarriage.
Bone mineral density (BMD)
• Up to 6% BMD may be lost after the first 6 months treatment.
• If treatment is to be continued for longer than 3–6 months, the use of ‘addback’ HRT is recommended:
• combined GnRH agonist and HRT addback has been shown to be safe for a period of up to 2 years
• small ongoing studies suggest that longer term use will also be safe.
• 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.
Indications for GnRH analogue treatment
• 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 Chapter 16,
p. [link]).• Breast cancer.
• Prostate cancer.
Adverse effects of GnRH agonists/antagonists
• Hot flushes.
• Mood swings.
• Vaginal dryness.
• Abnormal vaginal bleeding.
• Decreased libido.
• Breast swelling/tenderness.
• ↑ LDL ↓ HDL.
• Insomnia.
• Headaches.
• Loss of bone mineral density.
• Alterations in eyesight.
• Initial flare (agonists only).
• Bruising at injection site.
Female subfertility: overview
• Subfertility is very common, with 1 in 6 couples seeking specialist help.
• ˜84% will achieve a pregnancy in 1 year of regular unprotected sexual intercourse (UPSI):
• this ↑ to 92% after 2 years.
• Referral for specialist advice should be considered after at least 1 year of trying, though in certain situations prompt investigations and referral may be recommended:
• female age>35 years
• known fertility problems
• anovulatory cycles
• severe endometriosis
• previous PID
• malignancy.
• Couples should be treated on an individual basis, as 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 which may or may not be diagnosed.
Causes of subfertility
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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 not ideal. Also ask if a cervical smear is needed and about breast examinations.
• Age.
• Duration of subfertility and coital frequency.
• Menstrual cycle regularity and LMP (?pregnant).
• Pelvic pain (dysmenorrhoea; dysparuenia).
• Cervical smear history.
• Previous pregnancies.
• History of ectopic pregnancy.
• Previous tubal or pelvic surgery.
• Previous or current STIs.
• Previous pelvic inflammatory disease (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 PCOS); 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>30 nmol/L)
• semen analysis (see Male subfertility, p. 00[link]).
• 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.
Assessment of tubal patency
• Hysterosalpingogram (HSG):
• easily done
• good sensitivity and specificity
• can be uncomfortable
• may have false-positive results (suggesting tubal blockage due to spasm).
• Laparoscopy and dye test:
• day-case procedure which 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.
• Hysterocontrast-salpingography (HyCoSy):
• 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.
• Anti-oestrogens (e.g. clomifene 50 mg 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 over-response).
• Gonadotrophins or pulsatile GnRH:
• used for low oestrogen/normal FSH or clomifene-resistant PCOS
• injections
• expensive
• multiple pregnancy risk
• ultrasound monitoring (abandon cycle if over-response)
• more easily titrated.
• Laparoscopic ovarian diathermy:
• aims to restore ovulation in patients with PCOS
• Effect lasts 12–18 months if successful
• Insulin sensitizers (metformin 500 mg 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).
Psychological issues
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.
Male subfertility
Accounts for 20–25% cases of subfertile couples. Investigation should start in primary care after 1 year, 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)
• Volume >2mL.
• Concentration >20 × 106/mL.
• Motility >50% forward.
Azoospermia: No sperm in ejaculate.
Oligozoospermia: Reduced number of sperm in ejaculate.
Investigations
• FSH: elevated in testicular failure.
• Karyotype: exclude 47XXY.
• Cystic fibrosis screen: 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 (intrautertine insemination)
• ICSI (intracytoplasmic sperm injection).
• Donor sperm.
• Adoption.
Pathogenesis of male subfertility
• Semen abnormality (85%):
• idiopathic oligoasthenoteratozoospermia (OATS)
• testis cancer
• drugs (includiing alcohol, nicotine)
• genetic
• varicocele.
• Azoospermia (5%):
• pretesticular: anabolic steroid abuse; idiopathic hypogonadotrophic hypogonadism (HH); Kalmann's, pituitary adenoma
• non-obstructive: cryptorchidism, orchitis, 47XXY, chemo-radiotherapy
• obstructive: congenital bilateral absence of the vas deferens (CBAVD), vasectomy, Chlamydia, gonorrhoea).
• Immunological (5%):
• antisperm antibodies
• idiopathic
• infection
• unilateral testicular obstruction.
• Coital dysfunction (5%):
• mechanical cause with normal sperm function
• ejaculation normal (hypospadias, phimosis, disability)
• retrograde ejaculation (diabetes, bladder neck surgery, phenothiazines)
• failure in ejaculation (MS, spinal cord/pelvic injury).
Assisted reproduction: IVF and ICSI
Assisted reproductive technologies (ART) refer to all fertility treatments in which sperm and oocytes are handled with the aim of achieving pregnancy. It includes in vitro fertilization (IVF), intra-cytoplasmic sperm injection (ICSI), pre-implantation genetic diagnosis (PGD), egg donation, and surrogacy.
In vitro fertilization (IVF)
Indications may include:
• Tubal disease.
• Male factor subfertility.
• Endometriosis.
• Anovulation.
• ↓ fecundity observed with ↑ maternal age.
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 (ICSI)
• 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 the 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 increased 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.
IVF: how it's done
► In preparation, 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 (36 hours 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):
• a maximum of 2 embryos are transferred in women under 40 and current debate on move to single embryo transfer given increased neonatal morbidity/mortality and ensuing costs of multiple pregnancy
• blastocyst transfer may be considered.
• Surplus embryos may be cryopreserved for future frozen embryo replacement cycles.
• Luteal support given in form of progestogens.
• Pregnancy test 2 weeks later.
Assisted reproduction: other techniques
Preimplantation genetic diagnosis (PGD)
• 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 fluorescent in-situ hybridization (FISH) used for genetic diagnosis.
Intrauterine insemination (IUI)
• Couples who may benefit include those with:
• mild male factor subfertility
• minimal/mild endometriosis
• unexplained subfertility
• coital difficulties.
• 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 >10 M/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 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 secondary to surgery and chemo-radiotherapy or menopausal)
• older women (>45 years)
• those with repeated IVF failure.
Donor insemination
• Indicated in men
• with azoospermia and failed surgical sperm recovery
• at high risk of transmitting genetic disorders (eg. 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 DI.
• Insemination is usually intrauterine.
• ± ovarian stimulation and 36–40 h after hCG administration.
• Success rates vary from 4% (aged 40–44) to 12% (<34 years).
Special concerns regarding donation of gametes
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 <35 years 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.
Surrogacy
• IVF surrogacy:
• 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.
• ‘Natural surrogacy’:
• 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 (OHSS)
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. Vascular endothelial growth factor (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 up to 43% in women aged 18–59 compared to 31% in men. Increasing age is inversely proportional to sexually 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.
The menopause is associated with a deterioration of sexual function with one study suggesting an increase in FSD from 42–88% (45–55 year old).
Dyspareunia is common and may be present in up to 1/3 of women.
Normal sexual function
Masters and Johnson proposed 4 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 female sexual dysfunction (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.
Vital questions in a psychosexual history
• 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.
Tips on handling consultations
• Be led by the patient.
• The patient is the expert—help her understand her behaviour.
• Reflect your thoughts and feelings.
• Try to understand 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.
Consider discussing possible fantasies
• Feeling too small.
• Feeling too big.
• Feeling too loose.
• Vagina with teeth.
• Sharp penis.
Institute of Psychosexual Medicine. www.ipm.org.uk
British Association of Sexual & Marital Therapy. www.basrt.org.uk
Vulval Pain Society. www.vulvalpainsociety.org.uk
Mary Clegg—devices. www.maryclegg.com
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.
Sexual pain disorders
Dyspareunia
• 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, ultra sound scan and if necessary laparascopy.
Vaginismus
• 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 secondary 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.
Non-coital sexual pain disorders
• Vulval vestibulitis is the most common pain disorder, but 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, 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 desire disorder (HSDD).
• Testosterone patches are also licensed in the UK.
• Tibolone is licensed for treatment of loss of desire in postmenopausal women.
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.
Vaginal trainers or dilators
May be of use for women with vaginismus and are recommended for those having prolapse procedures and post radiotherapy.
Perineal injections
100 mg hydrocortisone, 10 mL 0.5% bupivicaine, and 1500 units hyaluronidase—may be of value for perineal injuries or for pain trigger points.
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 are:
• Serum glucose.
• Lipids.
• Testosterone (early morning).
• Blood pressure.
• Pulse.
• Weight.
• Genitalia.
• Prostate.
New-onset erectile dysfunction may be a marker for cardiovascular disease.
Treatment options
• Phosphodiesterase inhibitors:
• Sildenafil (Viagra®) and vardenafil ↑ erectile function in 60–70%
• they act in 20–60 minutes and last for up to 8 hours.
• 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.