An absent or short vagina is uncommon but can be corrected by plastic surgery. The membrane at the mouth of the vagina where the M llerian and urogenital systems fuse (the hymen) ma y be imperforate. There is apparent primary amenorrhoea, with a history of monthly abdomina l pain and swell- ing, and the membrane bulging under the pressure of dammed up menstrual b lood (haematocolpos). It is relieved by a cruciate incision in the membrane. NB: in some co mmunities, female \200\230circumcision \200\231 (p247) is still practiced, and this is ano ther cause of haematocolpos. \200\207Renal system abnormalities often coexist with genital ones, so IVU and ultra- sound should be performed. Ovary Thin, rudimentary \200\230streak \200\231 ovaries are found in Turner \200\231s syndrome (p655). Ovaries are absent in test icular feminization syndrome, but primitive testes are present (p134). Remnants of developm ental tissue (eg the Wolffi an system) may result in cysts around the ovary and in the broa d ligament. y g o o c e a n y G l Uterine retroversion About 20% of women normally have a retroverted retro \202 exed uterus which is fully mobile. It is diffi cult to palpate bimanually unless you can push it into anteversion by pressure on the cervix. It causes no problems except (rarely) if it fails to lift out of the pelvis at 12 weeks of pregnancy, presenting with discomfort and retention of urine, eg at 14 weeks; catheterization and lying prone may relieve it. In \202 ammation in the pelvis (due to infection or endometriosis) can cause adhesions whi ch tether the uterus in a retroverted position. The patient may present with dysmenorrhoea, dyspareunia, or subfertility \200\224problems which can only be relieved by treatment of t he underlying disease. 247 Female genital cutting/mutilation/circumcision Circumcision is a misnomer, as it implies a parallel with male circumcision, which is incorrect. Another term is female genital cutting /mutilation (aff ected women prefer the term genital cutting). 140 million women are believ ed to be aff ected (2 million/year). The female \200\230operation \200\231 is carried out later (at 5 \200\2237yrs) and may be much more damaging and extensive, eg as practiced in S omalia. In the UK most aff ected women come from Somalia, Kenya, Eritrea, Ethiopia and the Yemen. It is common in Mali, Guinea and Egypt. Procedures include clitoridectomy infundi bulation (removal of the clitoris, labia minora and labia majora, with oversewing or apposi tion by thorns). Even the milder Sunna entails removal of part of the clitoris, and more ma y be removed than intended. At betrothal, an attendant cuts the scar tissue to allow interc ourse. Long-term problems include very slow urination, urinary tract infections, haematocol pos, dyspareunia or non-consummation, obstructed labor, in- creased susceptibility to HIV a nd other blood-borne diseases as well as emo- tional trauma. Social expectations are changi ng in countries that practice \200\230cutting \200\231 but parents believe the social harm of not cutting is greater than the physical, psychological and legal risk of \200\230cutt ing \200\231.10 De \201 bulation may be performed before marriage; ideally electively at 2 0 weeks \200\231 gestation, or in the 1st stage of labor. If not corrected antenatally de- liver in a unit with emergency obstetric care, having planned labor after ex- pert advice. If vaginal examination is poorly tolerated, or anterior episiotomy anticipated, off er epid ural. Only extreme anatomical distortion making de- \201 bulation impossible is an indica tion for cesarean section (but note that NICE guidelines 2011 allow for more patient choice ).11 Repair post-delivery should appose raw edges and control bleeding but must not result in a vaginal open- ing making intercourse diffi cult or impossible.12 In 2003 \200\2235 fem al genital cut- ting aff ected 1.4% of UK maternities and was implicated in 4 maternal deat hs.9 Labial cosmetic surgery is becoming more common in affl uent countries and is comparab le with more minor types of cutting, thereby posing ethical con- cerns.13 y g o o c e a n y G l Normal menstruation Puberty is the development of adult sexual characteristics. The sequenc e: breast buds \200\203growth of pubic hair \200\203axillary hair \200\203menses begin (men arche) from 10yrs onwards (mean 13yrs and falling \200\224earlier if low birth weight; Af rican; short & overweight in childhood; urban environment; various fascinat- ing pheromone- related family events mediating anti-inbreeding strategies).1 14 Investigate if no periods by 15yrs 15 (p250) or no signs of puberty by 14. A growth spurt (p184) is the 1st change i n puberty and is usually completed 2yrs after menarche when the epiphyses fuse. The menstru al cycle ( \201 g 1). The cycle is controlled by the \200\230hypothalamic \200\223pi- tui tary \200\223ovarian (HPO) axis \200\231. Pulsatile production of gonadotrophin-releasing h ormones by the hypothalamus stimulates the pituitary to produce the gon- adotrophins: folli cle-stimulating hormone (FSH) and luteinizing hormone (LH). These stimulate the ovary to pr oduce estrogen and progesterone. The ovar- ian hormones modulate the production of gonadotr ophins by feeding back on the hypothalamus and pituitary. 248 \200 Day 1 of the cycle is the \201 rst day of menstruation. Cycle lengths vary greatly (eg 20 \200\22345 days in adolescence); only 12% are 28 days. Cycles soon after me- narche and be fore the menopause are most likely to be irregular and ano- vulatory. In the \201 rst 4 d ays of the cycle, FSH levels are high, stimulating the development of a primary follicle in the ovary. The follicle produces estrogen, which stimulates the development of a glandular \200\230proliferative \200\231 endometrium and of cervical mucus which is receptive to sp erm. The mucus becomes clear and stringy (like raw egg white) and if allowed to dry on a sl ide produces \200\230ferning patterns \200\231 due to its high salt content. Estrogen also controls FSH and LH output by positive and negative feedback. y g o o c e a n y G l 14 days before the onset of menstruation (on the 16th day of the cycle of a 30-day cycle) t he estrogen level becomes high enough to stimulate a surge of LH. This stimulates ovulation . Having released the ovum, the primary follicle then forms a corpus luteum and starts to p roduce progesterone. Under this in \202 uence, the endometrial lining is prepared for impl antation: glands become convoluted ( \200\230secretory phase \200\231). The cervical mucus becomes viscid and hostile to sperm and no longer ferns. If the ovum is not fertilized the corpus luteum breaks down, so hormone levels fall. This causes the spiral arteries in the u ter- ine endothelial lining to constrict and the lining sloughs \200\224hence menstruation. Menstruation is the loss of blood and uterine epithelial slough; it lasts 2 \200\2237 days and is usually heaviest at the beginning. Normal loss is 20 \200\22380mL (median 28mL). Cl imacteric The ovaries fail to develop follicles. Without hormonal feedback from the ovary, gonadotrophin levels rise. Periods cease (menopause), usually at 50 years of age (p256). P ostponing menstruation (eg on holiday) Try norethisterone 5mg/8h PO from 3 days before the period is due until bleeding is acceptable, or take 2 packets of combined contraceptive Pil ls without a break. 1 The socioendocrinology of family life: Presence in the household of the biological father delays sexual maturation \200\224as does having a sister at home (esp. an elder sister). B rothers have no in \202 uence, but half- or step-brothers at home are associated with an e arlier menarche. In addition, stressful life events such as immigration for adoption is ass ociated with early menarche (risk of precocious puberty \200\200 \211\21020, p184). 249 y g o o c e a n y G l Fig 1. The menstrual cycle. De \201 ning menstrual abnormalities Primary amenorrhoea (see p251) This is failure to sta rt menstruating. It needs investigation in a 15-year-old, or in a 14-year-old who has no br east de- velopment. For normal menstruation to occur she must be structurally normal with a functioning control mechanism (hypothalamic \200\223pituitary \200\223ovarian axis). Secon dary amenorrhoea (see p251) This is when periods stop for >6 months, other than due to preg nancy. Hypothalamic \200\223pituitary \200\223ovarian axis disorders are common, ovarian an d endometrial causes are rare. Ovarian insuf \201 ciency/failure This may be secondary to chemotherapy, radiotherapy or surgery. Many genetic disorders can cause ovarian follicle dy sfunction or depletion-especially those aff ecting X chromosomes. 16 One X chromosome is ne eded for ovarian diff erentiation, but 2 are needed by oo- cytes. In Turner \200\231s syndr ome (XO), oocyte apoptosis starts as 12 weeks and numbers deplete in the 1st 10yrs of life, mosaics 45XO/46XX may menstruate for several years after menarche. Oligomenorrhoea This is infrequent periods. It is common at the extremes of reproductive life when regular ovulati on often does not occur. Menstrual cycles in adolescents are typically <45 days, even in th e 1st year. 17 A common cause throughout the reproductive years is polycystic ovary syndrom e (p252). Menorrhagia (p253) This is excessive blood loss. Dysmenorrhoea This is painful pe riods ( nausea or vomiting). 50% of British women complain of moderate pain, 12% of sever e disabling pain. Primary dysmenorrhoea is pain without organ pathology \200\224often start ing with anovulatory cycles after the menarche. It is crampy with ache in the back or groin , worse during the \201 rst day or two. Excess prostaglandins cause painful uterine contr actions, producing ischaemic pain. \201\227: NSAIDs inhibit pros- taglandins, eg mefenamic acid 500mg/8h PO during menstruation so reduce contractions and hence pain. No particular preparation seems superior. 18 Par- acetamol is a good alternative to NSAIDs. In pain with ovulatory cycles, ovula- tion suppression with the combined Pill can help (thus dysmenorrho ea may be used as a covert request for contraception). Smooth muscle antispasmod- ics (eg a lverine 60 \200\223120mg/8h PO) or hyoscine butylbromide (20mg/6h PO) give unreliable resul ts. Cervical dilatation at birth may relieve it but surgical dilata- tion may render the ce rvix incompetent and is no longer used as therapy. Secondary dysmenorrhoea: Associated path ology: adenomyosis (p288), endometriosis, chronic sepsis (eg chlamydial infection), \201 broids \200\224and so it appears later in life. It is more constant through the period, and may be as- sociated with deep dyspareunia. Treatment of the cause is the best plan. IUCDs increase dysmenorrhoea, except the Mirena which usually reduces it. Intermenstrual bleedi ng This may follow a midcycle fall in estrogen pro- duction. Other causes: Cervical polyps; ectropion; carcinoma; cervicitis/vagi- nitis; hormonal contraception (spotting); IUCD; chl amydia; pregnancy-related. Postcoital bleeding Causes: Cervical trauma; polyps; cervical, e ndometrial and vaginal carcinoma; cervicitis and vaginitis of any cause. Screen for chla- m ydia and treat if positive. Refer all with persistent bleeding. Risk of cervical carcinoma in those with post-coital bleeding is 1 : 2400 aged 45 \200\22354; 1 : 44,000 aged 20 \200 \22324. 19 Postmenopausal bleeding This is bleeding occurring >1yr after the last period. I t must be considered due to endometrial carcinoma until proved otherwise (p278). Other caus es: Vaginitis (often atrophic); foreign bodies, eg pessaries; carcinoma of cervix or vulva; endometrial or cervical polyps; oes- trogen withdrawal (hormone replacement therapy or ova rian tumor). She may confuse urethral, vaginal, and rectal bleeding. 250 \200 y g o o c e a n y G l 251 Onset of menstruation: menarche & amenorrhoea \200\207Always ask yourself \200\230Could s he be pregnant? \200\231 See pregnancy tests (p6). Primary amenorrhoea (see also p250). Thi s may cause great anxiety. In most patients puberty is just late (often familial), and reas surance is all that is needed. In some, the cause is structural or genetic, so check: \200 Has she got normal external secondary sexual characteristics? If so, are the \200 internal genitalia normal (p246)? Causes can be the same as for secondary amenorrhoea: consider tests be- low. If she is not developing normally, examination and karyotyping may reveal Turner \200\231s syndrome (p655) or testicular feminization (p134). The aim of treat- ment is to help the pa tient to look normal, to function sexually, and, if pos- sible, to enable her to reproduce if she wishes. y g o o c e a n y G l Causes of secondary amenorrhoea \200 Hypothalamic \200\223pituitary \200\223ovarian cause s are common (34% of cases) as con- trol of the menstrual cycle is easily upset, eg by stre ss (emotions, exams), \200\200exercise, weight loss. Up to 44% of competitive athletes hav e amenorrhoea. \200 Hyperprolactinaemia (14%). (30% have galactorrhoea.) Other hormonal i m- balances (hypo- or hyperthyroidism). Severe systemic disease, eg renal fail- ure. Pituit ary tumors and necrosis (Sheehan \200\231s syndrome) are rare. Ovarian causes: polycystic ovary syndrome (p252) is common (28%); tu- mours; ovarian insuff i ciency/failure (premature menopause: the cause in 12%, it aff ects 1% 20 of women under 40 see p250). \200 Uterine causes: pregnancy-related, Asherman \200\231s syndrome (uterin e adhesions after a D&C: consider also TB, p274). \200\230Post-Pill amenorrhoea \200\231 i s generally oligomenorrhoea/secondary amenorrhoea masked by regular withdrawal bleeds so, i f need be, investigate as below. Tests \200 \200 HCG (eg urinary) to exclude pregnancy. \200 Serum free androgen index ( \200\200 in polycystic ovary syndrome). \200 FSH/LH (l ow if hypothalamic pituitary cause but may be normal if weight loss or excessive exercise t he cause: raised eg FSH>20IU/L if premature menopause, in which case, if age <30 and concer ns for future fertility, refer for karyotyping 21). \200 Prolactin ( \200\200by stress, h ypothyroidism, prolactinomas and drugs, eg phenothiazines, domperidone, metoclopramide). If level >1000IU/L do MRI scan (p294). 40% of those with hyperprolactinaemia have a pituitary tumor. \200 TFT (4% of women with amenorrhoea have abnor- mal thyroid function). \200 Testosterone level: levels >5nmol/L may indicate an- drogen secreting tumor or late onset c ongenital adrenal hyperplasia so need more investigation, eg dehydroepiandosterone sulfate level. Treatment is related to cause. Premature ovarian failure cannot be reversed but horm one replacement (p256) is necessary to control symptoms of oestro- gen de \201 ciency and protect against osteoporosis. Pregnancy can be achieved with oocyte donation and in vitro f ertilization techniques. Hypothalamic \200\223pituitary axis malfunction: If mild (eg stres s, moderate weight loss) there is suffi cient activity to stimulate enough ovarian estrogen to produce an endometrium (which will be shed after a progesterone chal- lenge, eg medroxy progesterone acetate 10 mg/24h for 10 days),22 but the timing is disordered so cycles are n ot initiated. If the disorder is more severe the axis shuts down (eg in severe weight loss) . FSH and LH and hence oestro- gen levels are low. Reassurance and advice on diet or stress management, or psychiatric help if appropriate (p348), and time may solve the problem. She should be advised to use contraception as ovulation may occur at any time. If she wants fe rtility restored now, or the reassurance of seeing a period, mild dysfunction will respond to clomifene but a shut-down axis will need stimula- tion by gonadotrophin-releasing hormon e (see p294 for both). Polycystic ovarian syndrome (PCOS) This would be better named polyfollicular ovary syndrome . It comprises hyperandrogenism, oligo-ovulation, and polycystic ovaries on ultrasound in t he absence of other causes of polycystic ovaries, eg as seen with later on- set adrenal hyp erplasia and Cushing \200\231s. The cause is unknown. It is common (5 \200\22320% of premen opausal women). Acne, male pattern baldness and hir- sutism can all be features. Darkened s kin (acanthosis nigricans) on neck and skin \202 exures may re \202 ect hyperinsulinaemi a. LH is raised in 40%, testosterone in 30%. Subfertility may be a problem. The result appe ars to be a vicious circle of ovarian, hypothalamic \200\223 and adrenal dysfunction. 252 \200 Insulin resistance and hyperinsulinaemia are features. There may be diabe- tes (40% have im paired glucose tolerance or diabetes by age 40: all are at risk, but if obese, especially s o). During pregnancy do GTT by 20 weeks. \200\22523 Insulin re- sistance/metabolic syndrom e is likely to be a problem in those with obesity \200\224 eg waist >80cm (p530) 24 + any 2 of: triglycerides >1.7mmol/L; HDL cholesterol <1.1mmol/L; BP >130/85; fasting glucose >5.6 mmol/L. MI, stroke and transient ischaemic attack rate is \200\200 (eg \211\2103). Hypertension may also be a problem. Hormonal cycling is disrupted, ova- ries become enlarge d by unruptured follicles, the endometrium hyperplastic. Ovarian and endometrial cancer ris ks are increased. y g o o c e a n y G l Stein \200\223Leventhal syndrome eponymizes the subset of obese hirsute women with polycystic ovaries. Diagnosis: Exclude thyroid dysfunction, hyperprolactinaemia, conge nital adrenal hyperplasia, androgen secreting tumors, and Cushings syndrome (OHCM p217). \200\22523 If clinically hyperandrogenic and total testosterone >5nmol/L check 17-hydroxypr ogesterone and exclude androgen secreting tumors. US scan shows \211 12 peripheral ovarian follicles, or \200\200 ovarian volume (>10cm3). Management: Advise smoking avoidance. Fin d and treat diabetes, hyperten- sion, dyslipidaemia and sleep apnoea. Encourage weight loss and exercise to increase insulin sensitivity. Metformin improves insulin sensitivity, mens trual disturbance, and ovulatory function (as eff ective as clomiphene). 25 It is recom- me nded by NICE for those of body mass index >25 trying to conceive. Clomifene (best if with metformin) 26 usually induces ovulation (50 \200\22360% conceive in 1st 6 months of treatment; so off er before using other methods; use on specialist advice) . Warn of risk of multiple pregnancy and ovarian cancer (p283). Monitor response by ultraso und in at least 1st cycle. Those not ovulat- ing in response to clomifene are at \200\200 risk of ovarian hyperstimulation (p311) with assisted conception so in vitro maturation (IV M p293) is a good alterna- tive. Ovarian drilling (creating holes in ovaries by diathermy w ith the intent of reducing steroid production) is recommended by NICE \200 27 for those no t re- sponding to clomifene (though it may be useful as primary treatment). 28 RCOG recomme nds for those with BMI <25. 65% conceive. \200\22523 It does not increase risk of multiple pregnancy. Pregnancy rates are similar to those with assisted con- ception. 29 Preterm bir th, pre-eclampsia, gestational diabetes, and large babies complicate pregnancy so treat as high risk. 30 The combined Pill will control bleeding and reduce risk of unopposed oes- trogen on the end ometrium (risk of endometrial carcinoma). Recommend regular withdrawal bleeds, eg 3-monthly , for example induced with dydro- gesterone 10mg/12h PO on days 11 \200\22325 in those in w hom estrogen use is not wanted or is contraindicated. 31, \200\22523 Hirsutism may be treated cosmetically, or with an anti-androgen, eg cy- proterone 2mg/day, as in co-cyprindiol (avoid pregnancy). Spironolactone 25 \200\223200mg/24h/PO is also antia ndrogenic (avoid pregnancy as teratogenic). Finasteride 5mg/24h/PO has also been used for h irsutism; again avoid preg- nancy. Neither spironolactone nor \201 nasteride is licensed for this use. 253 Menorrhagia This is increased menstrual blood loss (de \201 ned as >80mL/cycle); in realit y loss is rarely measured, so management deals with those whose heavy menstrual bleeding in terferes with life. What makes a woman consult may be a change in volume (clots, \202 ood s, etc), or a change in life (eg job change, or depression). Ask about both. Is she hypothy roid (eg constipation; weight \200\200; OHCM p212) or anemic? Examine with these in mind. C auses In girls, pregnancy and dysfunctional uterine bleeding are likely. With increasing ag e, think also of IUCD, \201 broids, endometriosis and adenomyosis, pelvic infection, poly ps. Also hypothyroidism. In perimenopausal women, consider endometrial carcinoma. Ask about general bleeding problems as she may have a blood dyscrasia, eg von Willebrand \200\231s. Do abdominal and pelvic ex- amination \200\224which may reveal polyps, \201 broids, or en dometriosis. Tests FBC; TFT; consider clotting studies; ultrasound or laparoscopy if pelvic pathology suspected; ultrasound + endometrial sampling, or hysteroscopy and directed biops y if irregular bleeding or suspected cancer (eg persistent inter- menstrual bleeding, >45yr s and failed/ineff ective treatment). Dysfunctional uterine bleeding (DUB) This is heavy an d/or irregular bleeding in the absence of recognizable pelvic pathology. It is associated w ith anovula- tory cycles, so is common at the extremes of reproductive life or it may be ov ulatory (eg with inadequate luteal phase). Teenage menorrhagia generally settles without in terference as cycles become ovulatory. If PV is normal and organic pathology is ruled out, this is the diagnosis, by exclusion. Treating menorrhagia \200 32 \200\224Drugs Progester one-containing IUCDs, eg Mire- na should be considered 1st line treatment for those wanti ng contraception. They reduce bleeding (by up to 86% at 3 months, 97% at 1yr), are eff ecti ve in dysfunctional uterine bleeding and reduce \201 broid volume after 6 \200\22318 mont hs \200\231 use. 5-year follow-up gives satisfaction levels similar to hysterectomy (in the 58% still using this method). 33 \200 y g o o c e a n y G l 2nd line recommended drugs are anti \201 brinolytics, antiprostaglandins or the Pill. Anti \201 brinolytics Taken during bleeding these reduce loss (by 49%) \200\224eg tranexamic a cid 1g/6 \200\2238h PO (for up to 4 days). CI: thromboembolic disease \200\224 but this is no more common in those on tranexamic acid. Antiprostaglan- dins, eg mefenamic acid 500mg/8 h PO pc (CI: peptic ulceration) taken during days of bleeding particularly help if there is also dysmenorrhoea. They reduce bleeding by 29%. The combined Pill is eff ective but see c ontraindications (p300). 3rd line recommendation is progestogens IM (p304) or norethisterone 5mg/8h PO days 5 \200\22326 of menstrual cycle (also used to stop heavy bleeding). Rarely gonadotrophin (LHRH) releasing hormones are used (p276). Surgery Endometrial resection (p308) is suitable for women who have com- pleted their famil ies and who have <10wk size uterus and \201 broids <3cm. Abla- tion is now commoner than hysterectomy in the UK for menorrhagia. About 30% become amenorrhoeic and a further 50% hav e reduced \202 ow after any method of ablation. Contraception is still required. If not u sed pregnancy is commoner in those who bleed (3.2% vs 0.3%). 34 Treat as with uterus for HR T (p256). For women wishing to retain fertility who have \201 broids >3cm consider uter- ine artery embolization or myomectomy (p276). Women not wishing to retain fertility, with a uterus >10wk size and \201 broids >3cm may bene \201 t from hysterectomy (p308), vaginal hysterectomy being the preferred route. The premenstrual syndrome (PMS) Most women notice that their mood or physical state may be worse premen- strually. Symptoms may be mild one month and severe the next, eg depending on external events and tend to be worse in the 30s and 40s and improve on the combined Pill. 3% of women regularly have cyclical symptoms so severe that they cause major disruption to their lives: premenstrual syndrome (PMS) or tension (PMT). Causes: See BOX. Symptoms Common est symptom patterns are tension and irritability; de- pression; bloating and breast tender ness; carbohydrate craving and headache; clumsiness; libido \200\201. Almost any symptom ma y feature. Diagnosis Suggest symptom diary. If she has PMS her symptoms are worst before pe riods, are relieved by menstruation, and there is at least one symp- tom-free week afterwar ds. Diaries may also reveal psychiatric disorders (which may be worse premenstrually) or me nstrual disorders. Treatment Simply to acknowledge her problem, listen, and reassure may be all that is needed to help her to cope. Are her partner and children under- standing? Can she rearrange work schedules to reduce stress premenstrually? Some women \201 nd self-hel p groups supportive. Health measures, eg improved diet, reducing smoking and drinking, incr eased exercise and relaxation, often help. Herbal remedies are not scienti \201 cally test ed but some \201 nd them help- ful, eg sage and fennel for irritability. Any drug evokes a big placebo eff ect, improving 90% in some studies. Pyridoxine (vit B6) 10mg/24h PO for t he symp- tomatic period or continuously, may help low mood and headache (DOH says higher, m ore eff ective doses cause neuropathy). For severe cyclical mastalgia consider: 1 Reduce sa turated fats eaten: these increase the affi nity of estrogen-recep- 254 \200 y g o o c e a n y G l tors for estrogen. 2 Bromocriptine 2.5mg/12h PO days 10 \200\22326, even if prolactin normal. 3 Danazol 100 \200\223200mg/12h PO for 7 days before menstruation (see below). Some bene \201 t from sup pression of ovulation with the combined Pill (Yas- min may be especially suitable and see ms to help reduce \202 uid retention 35), 36 estrogen patches or implants, with cyclical progesterone, or danazol 200mg/24h (SE nausea, weight gain, masculinization of the female f etus, so advise barrier contraception). Avoid diuretics unless \202 uid retention is se- vere (when spironolactone 25mg/6h PO days 18 \200\22326 of the cycle is the drug of choice) . SSRIs, eg \202 uoxetine 20mg/day PO help, 37 with 30% experiencing remission (but the li cense for use in PMS in UK has been withdrawn), and can be used just in the luteal phase. 3 8 Venlafaxine has also been shown to be bene \201 cial. Cognitive behavioral therapy has b een shown to be as eff ective at \202 uoxetine, eff ects possibly lasting longer when ass essed at 12 months. Alprazolam (0.25mg/day PO during the luteal phase) also helps, with appar- ently low risk o f dependence. Buspirone has also been used as a anxiolytic, though SSRIs are felt to be mor e eff ective. 39 Agnus castus fruit extract helped symptoms in 50% of women in a placebo-co ntrolled trial. 40 Goserelin (p276) may help severe PMS but symptoms return when ovarian activity recommences and after 6 months \200\231 use bone thinning can be detected. Adding tibolone can ameliora te this eff ect. Goserelin is better used to predict the severely aff ected women who may b ene \201 t from hysterectomy with oo- phorectomy (results in 96% satisfaction rates 41 \200\224these women can then have estrogen replacement). Follow-up: it is not \200\230cheating \200\231 to ensure that her next appointment will no t be in the premenstrual phase \200\224more objectivity may be upcoming. 255 The Rapkin hypothesis and putative pathways in PMS42,43 Some physiological and pharmacologi cal observations. \200 There is no evidence that ovarian events cause premenstrual syndro me: models presupposing progesterone de \201 ciency have not been con \201 rmed (and prog esterone suppositories are no panacea for the condition). Arti \201 cially altering circulating progesterone and estradiol (oestradiol) does not ind uce premenstrual symptoms in previously well women \200\224only in those already prone to P MS. Studies with psychoactive compounds suggest that the key events are oc- curring in the brai n, not the ovary \200\224eg an abnormal CNS response to nor- mal progesterone excursions oc curring in the luteal phase. y g o o c e a n y G Allopregnanolone and pregnenolone (metabolites of progesterone) are psychoactive, interacti ng with \200 -aminobutyric acid A (GABA-A) receptors. \200 Allopregnanolone is anxiolyti c, so lower levels may be associated with l anxiety. Putative conclusion: Neurons or glia in those with PMS preferentially metab- olize progeste rone to pregnenolone (which heightens anxiety) rather than allopregnanolone (which is anxio lytic and up-regulates serotonin receptors, so ameliorating depression). On this view, alpr azolam, by augmenting GABA- A-receptor function, is a substitute for allopregnanolone. The menopause and HRT The climacteric is the time of waning fertility leading up to the las t period (menopause). The menopause enables grandmothering \200\224a unique institution, in humans (and whales). Problems are related to falling estrogen levels. \200 Menstrual irr egularity as cycles become anovulatory, before stopping. \200 Vasomotor disturbance \200 \224sweats, palpitations, and \202 ushes (brief, nasty, and 256 \200 may occur every few minutes for >10yrs, disrupting life and sleep). Atrophy of estrogen-dependent tissues (genitalia, breasts) and skin. Vagi- nal dryness can lead to vaginal and urinary infection, dyspareunia, traumatic bleeding, stress incontinence , and prolapse. Osteoporosis: the menopause accelerates bone loss which predisposes to fracture of femur neck, radius, and vertebrae in later life. Attitudes to the menopause vary widely, and partly depend on irritability, de- pression, \200\230empty nest syndrome \200\231 \200\224all exacerbated by the menopause. M anagement \211 20% of women seek medical help. \200 Is it the menopause? Thyroid and psy chiatric problems may present similarly. 2 FSH levels >30IU/L is suggestive of menopause: u nreliable if on oestrogens. \200 Counseling helps psychosocial and physical symptoms; enl ist family \200\231s support. \200 Menorrhagia may respond to treatment (p253). A D&C is required if irregular y g o o c e a n y G bleeding is abnormal (it may be diffi cult to decide). l Use contraception until >1y amenorrhoea if >50y; 2y if <50y (55 if on hormones). \200 Hot \202 ushes may respond to clonidine 50 \200\22375 g/12h PO, HRT, or tibolone (NB: risk of endometrial cancer increased compared to non-users). Vaginal dryness responds to estrogen (can be used locally). Hormone replacement therapy (HR T) Estrogen is not a panacea for all problems, but may help \202 ushes and atrophic vagin itis. It postpones menopau- sal bone loss but is no longer recommended just for osteoporosi s prevention. no protection against dementia in Trials show no cardiovascular bene \201 ts , the over-65s, and increased stroke and thromboembolism in users. HRT \200\200breast canc er risk (p257), endometrial cancer ( \200\200risk with unopposed estrogen or sequential pro gesterone, possible \200\201risk with continuous combined), and those using for >10yrs hav e double the risk of ovarian cancer of non-users. 44 Women with a uterus should also receive cyclical progestogens to reduce incidence of endome trial carcinoma, \200\224or use tibolone 2.5mg/day PO, a prepa- ration which aims not to ca use bleeds \200\224or continuous combined estrogen/ progestogen combinations, eg Kliofem , estradiol (=oestradiol) 2mg and norethisterone 1mg. For both these, start if >1yr after th e last period, or, if changing from cyclical HRT, wait until after 54yrs of age; bleeding i s common, in the 1st 4 months of use \200\224reassure; if after 8 months, do endometrial bi opsy. Kliofem may be useful if cyclical HRT causes \200\230premenstrual \200\231 symptom s. There may be advantages in using \200\230lipid-friendly \200\231 progestogen, dydrogest erone (no androgenic, mineralocorticoid, or oestrogenic action), eg Femoston 2/10 but see p303 for possible SE (DVT). Raloxifene, a selective estrogen receptor mod- ulator (SERM) p rotects bones while reducing breast 45 and endometrial cancer risk. It is ineff ective for \202 ushes. For thromboembolism, see OPPOSITE. HRT contraindications: \200 Estrogen-dep endent cancer \200 Past pulmonary em- bolus \200 Undiagnosed PV bleeding \200 LFT \200 \200 \200 Pregnancy \200 Breastfeeding \200 Phlebitis. Avoid or monitor closely in Du bin \200\223Johnson/Rotor syndromes (OHCM p712). If past spontaneous DVT/PE: is there throm bophilia (OHCM p368)? Side-effects: Weight \200\200; \200\230premenstrual \200\231 syndrom e; cholestasis; vomiting. Alternative therapies \200\22546 eg black cohosh (can cause hepa totoxicity ) \200\224p515. Annual check-up: Breasts; BP (stop if BP >160/100 pending invest igation and treatment). Weight; any abnormal bleeding? Creams, pessaries, and rings are useful for vaginal symptoms, eg Ovestin , ie estriol 0.1% , 1 applicator-full PV daily for 3 weeks, then twice weekly. They are absorbed but, if used intermittently, progestogens are probably unnecessary. If creams are unacceptable, conside r an estrogen-containing vaginal ring (eg Estring ), replaced every 3 months, for up to 2y rs. Vagifem is an estra- diol (=oestradiol) 25 g or 10 g vaginal tablet used daily for 2 weeks, and then twice weekly, with reassessment every 3 months. Transdermal patches are l ess \200\230medical \200\231 but are expensive and women with a uterus still need progesto gen, eg as tablets or Evorel conti patches. Estradiol (=oestradiol) patches supply 25 \200\223100 g/24h for 3 \200\2234 days. SE: dermatitis. Oestradiol gel 2 measures are appl ied daily to arms, shoulders, or inner thighs. Women with a uterus using gel also require p rogestogens for 12 days per cycle. HRT and cancer The Women \200\231s Health Initiative 48 con \201 rmed \200\200breast cancer risk (and showed excess stroke and heart attack risk, and 2-fold increase in dementia 49 in users): the Million Women Study 50 showed that there is greater risk when combined estrogen/progesterone preparations are used (relative risk=R R 2) compared to estrogen alone (RR 1.3) or tibolone (RR 1.45). Risk in- creases with lengt h of use. Ovarian cancer is increased in current users after 5 years \200\231 use (estrogen component RR 1.2). 51 Endometrial cancer risk is \200\200 with unopposed estrogen use, \200\211 with cyclical progesterone added, and possibly \200\201 with continuous combined added progesterone. 52 Lung cancer mortality (but not incidence) is increased, (so stop, if lung cancer develops). 53 Hence our policy on HRT is: \200 To discuss the risk of breast cancer with each patient considering HRT. \200 To document this discussion in the patien t \200\231s notes. \200 Encourage breast awareness and to report breast change. Formal br east examination by nurses may give false reassurance (advice of the UK \200\231s Chief Med ical Offi cer). Mammographic screening may be less eff ective in current users. 54 It is di ffi cult if aged 40 \200\22350yrs (breast density \200\200). \200 To use for symptomatic treatment (warn symptoms often return on stop- ping therapy however long it has been used f or) at the lowest dose needed to control symptoms, for the shortest time possible. 257 y g o o c e a n y G l To be wary about HRT in those with a family history of breast cancer. \200 To consider st opping HRT before 5 completed years of therapy. HRT is no longer licensed for osteoporosis prevention: consider raloxifene (which \200\201risk of breast cancer; it is related to tam oxifen), 55 or bisphosphonates. HRT and venous thromboembolism (VTE) Overall HRT doubles ri sk (which \200\200 with age). Consider other predisposing factors, such as prolonged immob ility, surgery, obesity, severe varicose veins (others see p16). On starting explain risk a nd advise to seek urgent help if symptoms develop. Stop HRT if VTE de- velops. Before start ing, elicit personal and family history of venous thrombo- embolism (VTE), discuss thrombop hilia screen if history. Thrombophilia \200\200 risk ( \211\2108 if Factor V Leiden or pro thrombin 20210A mutation). If thrombophilic seek expert advice. Transdermal use has less ri sk, and oral HRT is contraindicated if past history of VTE. SERM therapy (OPPOSITE) carries same VTE risk as HRT. NICE \200 56 says stop 4 weeks pre-elective surgery; RCOG \200\225 57 says consider cases individually and use thromboprophylactic measures for surgery. Termination of pregnancy (TOP) \200\207Under British law, no one has to have an abortion, and no one has to do one. Worldwide, >20% of pregnancies are terminated and in the UK \205 \223 of women have had a TOP by age 45. Incidence: >200,000 TOP/yr in Great Britain (GB). L egal (GB) constraints The Abortion Act 1967 (amended 2002) and Human Fertilization and Embr yology Act 1990 allow termination if: A There is risk to mother \200\231s life if pregnancy continues. B Termination is necessary to prevent permanent grave injury to physical/ 258 \200 mental health of the woman. C Continuance risks injury to the physical or mental health of the woman greater than if terminated (and fetus not >24 weeks). D Continuance risks injury to physical/mental health of existing children of the woman greater than if terminated (and fetus not >24 weeks). E There is substantial risk that if the child were born he/she would suff er such physical or mental abnormalities as to be seriously handicapped. At present, two doctors must sign c erti \201 cate HSA1. If <16yrs try to get pa- tient \200\231s consent to involve her paren ts or other adult.1 97% are for ground C; 1% for D. <1% of TOPs are done after 20 weeks, us ually after amniocentesis, or when very young or menopausal mothers have concealed, or not recognized, pregnancy. TOPs after 24 weeks may only be carried out in NHS hospitals. Before TOP \200\207She has to live with the decision for the rest of her life. \200 Identify t hose needing support eg counseling. Not needed if sure of decision. \200 Is she de \201 nitely pregnant (eg reliable urine test)? Give information on and choice of methods. If ult rasound needed (eg dates unsure) ask if she wishes to see images. Off er cytology screening if not up to date. If she chooses TOP: \200 Screen for chlamydia: ( other STIs if rele vant). \200 Give antibiotic prophylaxis to reduce post-op infection rate (10% without) eg metronidazole 1g PR/800mg PO at TOP and azithromycin 1g PO same day. y g o o c e a n y G l Discuss contraception (IUCD or sterilization at operation need plans). \200 If RhD \200 \223ve she needs anti-D (all gestations, whatever method see p9). Bloods for Hb, ABO + RhD group and antibodies; HIV, hepatitis B & C, and hemoglobin opathies, if relevant.