Therapeutics in Gynaecology

1. Therapeutics in Gynaecology Shivali Talsania, March 2004

2. Introduction • Hormonal control of the menstrual cycle • Menstrual disorders & therapeutic management • Hormone Replacement Therapy (HRT) • Contraception & Abortifacient • Genital tract infections & treatment • Genito-urinary disturbances & therapeutic management

3. Hormonal Control of the Menstrual Cycle

4. Menstruation: Day 1-4 Shedding of the endometrial lining (hormonal support from CL withdrawn). • Follicular Phase: Day 5-13/14 Gonadotrophin release from the ant. pituitary particularly FSH induces growth of several follicles. Maturing follicles secrete oestradiol inducing a -ve feedback on the hypothalamic-pituitary axis. Reduced FSH/LH induces growth of one follicle. Maturing follicle then secretes prolonged, elevated oestradiol inducing +ve feedback culminating in an LH surge and ovulation (~day 14). • Luteal Phase: Day 14-28 Follicle forms a corpus luteum that secretes progesterone & oestradiol. This supports the lining of the womb for a fertilised egg.

5. Menstrual Disorders • Menorrhagia • Dysmenorrhoea • Anovulatory disorders: Amenorrhoea & Oligomenorrhea • Pre-menstrual syndrome (PMS) • Post-menopausal bleeding (PMB)

6. Menorrhagia –Principles of Rx Look for an underlying cause e.g. pelvic pathology –fibroids or endometriosis (these can present as dysmenorrhoea) or e.g. medical conditions –hypo/hyper thyroidism. If no obvious abnormality is found (dysfunctional uterine bleeding) treat the symptoms i.e. reduce blood loss +/- regulate cycle.

7. Reducing Menstrual Loss • Anti-fibrinolyticse.g. Tranexamic acid - Blood loss by 50% -Contraindicated in thrombo-embolic disease. S/E: N & V, diarrhoea, thrombo-embolic events (rare). • NSAIDs e.g. Mefanamic Acid - Blood loss by 25% in most women. -Inhibits COX & therefore  Pg. Production. -Caution in active peptic ulcer disease (COX 1 inhibition exacerbates disease). S/E: Drowsiness, diarrhoea & thrombocytopenia

8. Reducing Menstrual Loss –Short term solutions! • GnRH agonists -Induces temporary amenorrhoea: overstimulation of the pituitary leads to down-regulation of GnRH receptors   FSH/LH &  oestradiol. -Caution: Bone demineralisation limits Rx to 6-months. Advise re: contraception. -S/E: Menopausal-like symptoms e.g. hot flushes, vaginal dryness &  bone density. This can be reversed w. HRT.

9. Reducing Menstrual Loss –Short term solutions! • Danazol –Synthetic compound both anti-oestrogenic & weakly androgenic -Low doses  bl. loss but higher cause amenorrhoea. -Contraindications: thrombo-embolic disease, androgen dependent tumours. -S/E: Acne, wt gain + hot flushes (menopausal). Non-hormonal contraception advised since it virilises female fetuses. • Gestrinone –Pituitary inhibitor effect (FSH/LH) & androgenic -S/E:As with Danazol.

10. Progesterone Intrauterine System • Indications: menorrhagia, dysmenorrhoea & contraception (99% effective). • 3-months: 86%  bl. loss 12-months: 97%  bl. loss • Contains levonorgestrel • MoA: -Alters Cx mucus -Atrophy of endomet. -May also suppress ovulation in 1/3 users

11. Progesterone Intrauterine System • Partial or complete expulsion is possible. • Irregular bleeding esp. first 3-months. • Change every 5-years. • Ectopic rates very low in IUS users. • May help reduce no. of hysterectomies. • Evidence supports use as progesterone component of HRT.

12. Drugs that regulate cycle & reduce menstrual loss • Combined Hormonal Pill (COCP) -20-50g Oestrogen + Progestogen (1st/2nd/3rd generation) -Available as mono/bi-/tri-phasic preps. • Progestogen-Only Methods: -Progesterone only pills (POP) -Progesterone only injectables -Progesterone only implants -Progesterone intrauterine system

13. COCP • MoA: -Oestrogen -ve secretion of FSH &  ovulation. -Progestogen  -ve LH plus changes Cx mucus to interfere w. sperm transport. -Tubal motility altered. -Atrophy of endometrium. -Uterine receptivity altered.

14. COCP • Taken for 21-days followed by 7-day break, hormonal support withdrawn  bleed. • Pills should be taken within 12-hrs. If more than this (esp. first or last pill of cycle) ovulation may occur and so pills must be continued for 7-days with extra precautions e.g. condoms.

15. Relative contraindications: Risk of arterial disease e.g. BP, FH, DM, smoking, age (>35-yrs), obesity and migraine. Absolute contraindications: IHD Arterial thrombosis Venous thrombosis Stroke Hyperlipidaemia Focal migraine Liver disease Pregnancy Oestrogen-dependent tumours COCP

16. Major Advantages: If used correctly, almost 100% effective in terms of contraception (Failure rate w. ‘perfect’ use 0.1% but in reality ~3%).  incidence of benign breast lumps, functional ovarian cysts, endometriosis & PID (??). Protection from ovarian & endometrial ca. (WHO). Related to  no. of ovulations &  ruptures of the ovarian capsule. Major Disadvantages: Venous affect ~thrombo-embolic events (adverse effect on clotting related to dose of oestrogen). Arterial affect ~MI, CVA. Small  risk of breast ca. soon after exposure (risk normalises 10-yrs post exposure). Impaired liver function. Minor S/E’s incl. wt gain, N&V, breast enlargement. COCP

17. The Future • Combined oestrogen-progestogen I.V. (more reliable). • Transdermal patches • Soft silastic or vinyl rings (as shown) developed to act locally through vaginal mucosa (worn for three wks & removed for 7-days).

18. POP • MoA (less effective than COCP –May be affected by age & body wt. PI = 1.17 using Levonorgestrel POP): -Suppresses ovulation in only 15-40% of cycles -Alters Cx mucus to  sperm penetration (reaches its peak within 2-3 hrs then decreases slowly ~impt. of taking POPs regularly at same time). -Induces endometrial changes. -May affect tubal motility,  risk of ectopic pregnancy (injection reliably inhibits ovulation by suppressing LH+/- FSH protective).

19. Advantages: Can be used by those w. contraindications to COCP Does not incr. risk of venous thrombosis, CVD or cerebral thrombosis (WHO) Disadvantages: Irregular bleeding Headache Acne Breast pain Nausea Dysmenorrhoea POP

20. Dysmenorrhoea Associated w. Pg. in the endometrium & contraction + ischaemia of the uterine muscle • Treat underlying cause e.g. fibroids or endometriosis, if present otherwise treat symptomatically. • NSAIDs • Ovulation suppression e.g. COCP • Glyceryl trinitrate patches

21. Anovulatory disorders: Amenorrhoea & Oligomenorrhoea 1°: No menses by age of 16 (+/- secondary sexual characteristics) • Constitutional delay • Genetic e.g. Turner’s • Autoimmune • Irradiation or chemotherapy • Imperforate hymen/transverse vaginal septum

22. 2: Absence of menses for 6-months or more (disorders listed can cause primary failure) • Disorders of gonadotrophin regulation: -Kallmann’s syndrome -Hyperprolactinaemia • Functional: -Hypothalamic hypogonadism • Gonadotrophin deficiency: -Pituitary tumour/ surgery/irradiation • Systemic disease: -Hyper/hypo thyroidism • Ovarian dysfunction: -PCOS

23. Management of Anovulation Treating infertility e.g. ovarian failure in PCOS • Clomiphen citrate ~Anti-oestrogenic. Occupies oestrogen receptor in hypo. inducing Gn release  FSH/LH. -Caution: cysts in PCOS may enlarge, ovarian hyperstimulation, uterine fibroids, ectopics &  multiple births.

24. Management of Anovulation Treating infertility e.g. ovarian failure in PCOS • Pituitary Gn’s (+/- LH) -Indicated in non-responders to Clomiphen, hypothalamic hypogonadism & hypopituitarism -Caution in hyperprolactinaemia, tumours of hypo. or pit. & ovarian cysts (not PCOS) -S/E: As with Clomiphen

25. Management of Anovulation Treatment of excess hormones • Hyper-androgenism e.g. PCOS, CAH. Rx w. anti-androgens. • Hyperprolactinaemia –use dopamine receptor agonist to restore -ve feedback &  prolactin e.g. Bromocriptine/ Cabergoline. -Caution: contraceptive advice since OCP may  prolactin conc. -S/E: N&V, postural hypotension & drowsiness.

26. Management of Anovulation Treatment of hormone deficiency • Oestrogen –Replacement via HRT • Progesterone –Replacement with cyclical progestogens or COCP.

27. Pre-Menstrual Syndrome Defined as “…psychological, behavioural & physical symptoms starting in the luteal phase & ending during menstruation”. • Progesterone thought to be responsible. • If mild –many experience relief w. COCP. • If severe –SSRI’s, high-dose oestrogen (risk of endometrial ca.) or GnRH agonists (6-month limit).

28. Post-Menopausal Bleeding Vaginal bleeding occurring 12-months after cessation of menstruation • Exclude malignancy (D&C, endometrial Bx, USS assessment of endometrial thickening & Cx smear). -Atrophic vaginitis can be treated w. topical oestrogen. If long-term use, add progestogen to combat hyperplasia. -Administer HRT preparations.

29. Hormone Replacement Therapy • Oral, implant or transdermal therapies • Preparations contain oestrogen +/- progestogen (usually indicated unless woman without uterus). • Aims of therapy: ~to reduce symptoms of oestrogen depletion. ~to prevent disorders arising from oestrogen depletion e.g. osteoporotic fractures. ~to avoid disorders that may be common w. oestrogen therapy e.g. endometrial & breast ca.

30. Advantages: Control of menopausal symptoms. Long-term benefits including  bone density loss,  skin collagen loss,  bladder dysfunction,  libido. Protection against bowel & ovarian ca. May prevent Alzheimer’s. Disadvantages: Irregular bleeding Wt gain Risk of thrombo-embolic events. Small,  risk of stroke w. unopposed oestrogen BUT 0.90-fold lower risk with combined oestr-prog. Endometrial ca. (progestogens lessen effect but exposure during each cycle critical).  risk of breast ca. (1/12): 2.3%  risk/yr of exposure. HRT

31. HRT or Not? • HRT can improve QoL in women w. hypo-oestrogenic symptoms. • Long-term Rx should be offered to those at risk of or established osteoporosis. • Do not offer to women at high risk of CVD. • Long-term Rx assoc. w. increased incidence of breast cancer. • Women should be counselled properly before starting or stopping.

32. Hormonal Contraception • COCP or PO methods (as detailed earlier) • Emergency contraception: ~Hormonal methods: combined pill or progesterone only. ~Emergency IUD (inserted upto 5-days after unprotected intercourse).

33. Hormonal Emergency Contraception • Hormonal methods may delay or inhibit ovulation if given in the first half of cycle while IUDs produce endometrial changes. • POP more effective than COCP (WHO): Both are better at preventing pregnancy when 1st dose taken within 24-hrs of unprotected intercourse. • Pregnancy is the only absolute contraindication • Nausea is the most common S/E (less pronounced when using the progestogen only prep.).

34. Combined ‘morning-after pill’ 50g of ethinylestradiol and 500g norgestrel Two tablets taken within 72-hrs of intercourse with two further tablets 12-hrs later Progestogen-only emergency pill Two tablets of 750g of levonorgestrel taken 12-hrs apart, first dose within 72-hrs of intercourse Available OTC at £20 Hormonal Emergency Contraception

35. Abortifacients: Medical Induction of Abortion • Abortion is illegal unless under specific indications as defined by law (Abortion Act, 1967). • Up to 9-wks: Surgical or Medical –Mifepristone 600mg + Gemeprost 1mg after 48-hrs (complete abortion in 95%). • 9-13 wks: Surgical (vacuum aspiration). • After 12-wks: Surgery less safe  expulsion by vaginal Pg. +/- Oxytocin, 48-hrs after administration of Mifepristone.

36. Abortifacients: Medical Induction of Abortion • Mifepristone (anti-progesterone) is a pre-treatment to facilitate medical abortion. It sensitises the uterus to subsequent administration of prostaglandin. • Gemeprost (or Misoprostol) administered vaginally is the preferred prostaglandin for medical induction of late therapeutic abortion. • Oxytocin induces labour usually w. an amniotomy. Administered by slow i.v. infusion or infusion pump. Be aware of hyperstimulation.

37. Genital Tract Infections & Rx Non-Sexually Transmitted Diseases • Candidiasis (Candida albicans most common) -20% have no symptoms. -Immunosuppression (antibiotics, DM, steroids) is a risk factor. -Rx ~Topical imidazoles (Canesten) /oral Fluconazole • Bacterial Vaginosis (Incl. Gardnerella, Mycoplasma & Uroplasma –overgrowth ofanaerobes) -Commonest cause of vaginal Dx (12% of women) -Rx ~Metronidazole or Clindamycin cream

38. Genital Tract Infections & Rx Sexually Transmitted Diseases • Bacterial infections: Gonorrhoea & Chlamydia. • Viral Infections: HIV, genital warts (HPV) & genital herpes (HSV). • Spirochaetes: Syphilis. • Protozoal: Trichomoniasis. • Crab lice & Scabies

39. Bacterial • Gonorrhoea (25% incr. between 1998-1999) -Infects mucosal surface of the genital tract, glands, Cx, FTs & epididymides. Also possible: anal canal & distal rectum, oropharynx & the eye. • Vertical transmission possible • Non-specific symptoms with a normal Ex. Possible (take proper endocervical swabs). • Salpingitis is a local complication • Rx (uncomplicated anogenital) ~Ciprofloxacin, Ofloxacin or Ampicillin, single dose.

40. Bacterial • Chlamydia (No. of cases , assoc. w. under 25s, multiple sexual partners, no barrier contraception, OCP & termination of pregnancy). • Intracellular organism, causing PID in 10-14% of women. Presents as IMB/PCB w. Cx excitation or symptomless tubal infection. Take proper endocervical swabs. • Can present as septic arthritis (monoarthritis). • Rx ~Doxycycline for 7-days or Azithromycin single dose (useful potential non-compliers).

41. Chlamydia

42. Viral Human Immunodeficiency Virus •  incidence in women. • Risk factors: multiple partners, other STDs, non-barrier contraceptive methods, i.v. drug abuse & high risk male contact. • AIDS defined by opportunistic illnesses or malignancy or CD4 count of <200. • Usually present w. oral and genital candidiasis. • Rx ~Anti-retrovirals early.

43. Viral Genital Warts (HPV) • Importance lies in the fact that virus can affect cervix,  risk of malignancy (CIN). • 200 different types of HPV (low risk vs. high risk types e.g. 16, 18, 33). • Rx ~Podophyllin (contains mutagens). ~Cryotherapy or surgical treatment (curettage, electrosurgery & scissor excision).

44. Viral Genital Herpes (HSV types 1 & 2) • Impt. co-factor for transmission of HIV. • Establish latency in dorsal root ganglion of nerves and can become re-activated e.g. stress, UV-light. • Initially erythematous papules from which characteristic herpetic vesicles erupt. • Take vesicular fluid or swab lesions. • Rx ~Acyclovir or Valacyclovir

45. Spirochaete Syphilis –Treponema pallidium • Occurs in phases: 1˚, 2˚, 3˚. • Superficial lesions in early syphilis are infectious, late syphilis is non-infectious. • During pregnancy, syphilis carries a high risk of congenital infection. • Rx of all phases is with Penicillin.

46. Protozoan Trichomoniasis (T.Vaginalis) • Relatively uncommon in the UK. • Can act as a co-factor for HIV. • Risk factors: non-barrier contraceptive use, smoking & low socio-economic class. • Women usually present w. vaginitis & vulvitis. Dx is green frothy, itchy & malodorous (usually grey & non-itchy). Classic ‘strawberry cervix’ in 2% of cases. • Rx ~Metronidazole, single dose (better compliance & fewer side-effects).

47. Scabies Requires prolonged contact. Itching worse at night. Rash bilaterally symmetrical. May lead to excoriation & eczema. Rx ~combination of oral (Ivermectin) (mites located in the skin rather than on) & topical treatment (Malathion or Permethrine). Crab lice Not only spread sexually found in many coarsely hairy parts. Main symptom is itching. Lice may be visible +/- rust coloured spots on underclothes. Ex may reveal bluish macules. Rx ~Superficial  responds well to topical insecticidal treatment of all coarsely hairy areas e.g. any louse lotion. Parasites

48. Genito-Urinary Disturbances Urinary Incontinence • Detrusor instability is treated with a combination of drug therapy & conservative methods used for managing urge incontinence e.g. pelvic floor exercises & bladder training. • Stress incontinence is generally managed by non-drug methods.

49. Detrusor Instability • Uninhibited detrusor contractions either on stimulation or spontaneously. • 35% of incontinence cases. • Pt c/o of urgency, urge incontinence, frequency & nocturia. • Rx ~Anticholinergics: Oxybutynin (direct relaxant effect on smooth muscle). S/Es limit use. • Flavoxate (less marked S/Es but also less effective). Propiverine & Trospium (newer anticholinergics). ~Role for Tricyclic Antidepressants & synthetic ADH to  urine production.

50. References • Medicine Supplement. Contraception. MPS Company Ltd. Volume 29:9 2001. • Medicine Supplement. Sexually Transmitted Infections. MPS Company Ltd. Volume 29:8 2001. • Medicine Supplement. Hormone Replacement Therapy. MPS Company Ltd. Volume 29:10 2001. • Janice Rymer, Ruth Wilson, Karen Ballard. Clinical review: Making decisions about hormone replacement therapy. BMJ. 2003;326:322-326 ( 8 February).