UnderstandingAbnormal Uterine

Bleeding (AUB)

What to do with troublesome Ms Menses?

DR. THIAGU CHIDAMBARAMOBSTETRICIAN & GYNAECOLOGISTSARAWAK GENERAL HOSPITAL

Contents

• Abnormal uterine bleeding:– Definition & classification

• Abnormal uterine bleeding – Ovulatory disfunction:– Definition– Prevalence– Symptoms– Consequences and burden

• Normal menstrual physiology

• The hypothalamic-pituitary-ovarian axis (HPO axis)

• AUB-O and the menstrual cycle

• Forms of AUB-O • Diagnosis of AUB-O • Treatment of AUB-O

What isabnormal uterine bleeding (AUB)?

• Abnormal uterine bleeding can occur when a woman experiences a change in menstrual loss, or the degree of loss or vaginal bleeding pattern differs from that experienced by the age-matched general female population1

• AUB is not restricted to menstrual bleeding that is abnormally heavy, but includes bleeding that is abnormal in TIMING2

1. National Institute for Health and Clinical Excellence 2007. Heavy menstrual bleeding [CG24] London: National Institute for Health and Clinical Excellence.2. Munro MG, et al. Int J Gynecol Obstet 2011; 113: 3-13.

FIGO classification system for AUB

Basic classification system1

1. Munro MG, et al. Int J Gynecol Obstet 2011; 113: 3-13.

The basic system comprises:1

Four categories that are defined by visually objective structural criteria(PALM: polyp; adenomyosis; leiomyoma; and malignancy and hyperplasia) Four categories that are unrelated to structural anomalies(COEI: coagulopathy; ovulatory dysfunction; endometrial; iatrogenic) One category reserved for entities that are not yet classified (N) The leiomyoma category (L) is subdivided into patients with at least 1 submucosal myoma and those with myomas that do not impact the endometrial cavity

Polyp

Adenomyosis

Leiomyoma

Malignancy & hyperplasia

Submucosal

Other

Ovulatory dysfunction

Endometrial

Iatrogenic

Not yet classified

CoagulopathyStructural Functional

Birth 10 20 30 40 50 60

Likely causes of AUB vary by patient age

Adapted from Pelea-Nagtalon S. Vignette approach in addressing menstrual disorders.

Oestrogenwithdrawal

Anovulation

Central, intermediate, gonadal

Functional Blood dyscrasia, hypothyrodism, luteal dysfunction

Iatrogenic Anticoagulation, contraception (hormonal intrauterine), haemodialysis

Pregnancy Abortion, ectopic, placental polyp, retained products, trophoblastic disease

Uterine Infection, structural (fibroids, hyperplasia, neoplasia, polyps)

Foreign bodyInfectionSarcoma botryoidesOvarian tumourTrauma

Blood dyscrasia Hypothalamic immaturity Inadequate luteal function Psychogenic (including anorexia and bulimia)

Carcinoma (cervical, uterine) Climacteric Polyps

Atrophic vaginitis Carcinoma (uterine, ovarian) Oestrogen replacement

What isdysfunctional uterine bleeding (DUB)?

• Abnormal uterine bleeding in premenopausal women not caused by pelvic pathology, systemic disease or pregnancy1

• Abnormal vaginal bleeding that occurs during a menstrual cycle that produced no egg (ovulation did not take place). The occurrence of irregular or excessive uterine bleeding in an absence of pregnancy, infection, trauma, new growth or hormone treatment2

1. Muneyyirci-Delale O, et al. Int J Womens Health 2010; 2: 297-302. 2. National Institute for Health and Clinical Excellence 2007. Heavy menstrual bleeding [CG24] London: National Institute for Health and Clinical Excellence.

Prevalence of DUB

• DUB accounts for around 20% of gynecology office visits1

– Heavy menstrual bleeding accounts for 5% of visits to GPs• Between 9 and 30% of reproductive-aged women have

menstrual irregularities requiring medical evaluation3 • Approximately 35–55% of women in late reproductive

age sufferfrom DUB4

1. Muneyyirci-Delale O, et al. Int J Womens Health 2010; 2: 297-302. 2. Santer M, et al. J Clin Epidemiol 2005; 58: 1206-1212. 3. Dangal G. Internet J Gyne Obs 2005; 4(1). 4. Tatarchuk TF, et al. Women’s Health 2009; N6 (42).

So now with the new classification :

DUB = AUB-O (abnormal uterine bleeding – ovulatory dysfunction)

What are the symptomsof AUB-O?

• Patients may present with symptoms that include:1 – Fatigue – Pelvic pain and cramps – Disordered menstrual bleeding

• Old Terminology of menstrual patterns associated with DUB: – Excessive flow (menorrhagia) – Irregular cycles (metrorrhagia) – Cycle length <21 days (polymenorrhoea) – Excessive flow AND irregular cycles (menometrorrhagia)

1. Frick KD, et al. Women’s Health Issues 2009; 19: 70-78.

Consequences and burdenof DUB

• Luteal insufficiency, anovulation and repetitive episodes of heavy menstrual bleeding can result in more serious consequences: – Iron deficiency anaemia1 – Miscarriage2 – Endometrial hyperplasia and endometrial carcinoma3

• Affects women’s health both medically and socially1

1. Pitkin J. Brit Med J 2007; 334(7603): 1110-1111. 2. Daya S. Maturitas 2009; 65(S1); S29-S34. 3. Takreem A, et al. J Ayub Med Coll Abbottabad 2009; 21(2): 60-63.

Normal menstrualphysiology1

Oestrogen levels increase gradually during the follicular phase and fall just before ovulation. Levels are maintained during the luteal phase and fall before menstruation

Progesterone levels increase during the luteal phase and fall sharply just before menstruation

1. Chrousos G, et al. Ann Intern Med 1998; 129: 229-240.

Normal menstrual function and the hypothalamic-pituitary-ovarian axis

Menstrual cycle events are controlled by hormones secreted by three key organs known as the hypothalamic-pituitary-ovarian axis (HPO axis):1 • The hypothalamus in the brain secretes GnRH • The pituitary gland just below the

hypothalamus secretes: – FSH necessary for the development of the

immature ovum (the primordial follicle inthe ovary)

– LH which triggers ovulation • The ovary secretes the steroid hormones

oestrogen and progesterone

1. Dangal G. Internet J Gyne Obs 2005; 4(1).

Ovaries

ProgesteroneOestrogen

Secretory(Luteal)Phase

Proliferative(Follicular)

Phase

Hypothalamus

Anterior PituitaryGnRH

FSH/LH

FSH, follicle stimulating hormone; GnRH, gonadotrophic releasing hormone;LH, luteinising hormone

Normal menstrual function and the hypothalamic-pituitary-ovarian axis1

The interplay of hormones in the HPO axis is regulated by afeedback mechanism: • The secretion of FSH and LH from the pituitary gland is

under the control of GnRH from the hypothalamus • The hypothalamus in turn is controlled by the levels of the

ovarian steroid hormones oestrogen and progesterone in the blood by means of a feedback mechanism

• The hypothalamus may also be affected by external factors e.g. stress

1. Dangal G. Internet J Gyne Obs 2005; 4(1).

DUB and themenstrual cycle

• DUB can occur at any time between menarche and menopause in ovulatory or anovulatory cycles1

• Pathophysiology of DUB: – Anovulatory: hypothalamic-pituitary-

ovarian axis – Ovulatory: endometrial molecular

mechanisms

1. Chen BH, Giudice LC. West J Med. 1998; 169(5): 280-4.

Anovulatory DUB• Deviations from the normal cycle due to disruptions in the balance of the HPO axis

– When ovulation does not occur, the effects of oestrogen are unopposed, leading to continuous proliferation of the endometrium1

– Proliferation without periodic shedding causes the endometrium to outgrowits blood supply

– This leads to irregular shedding of the endometrium1 • Bleeding episodes are irregular, prolonged or excessive • Far more frequent than ovulatory DUB1 • Common in pubertal and perimenopausal periods2

1. Brenner PF. Am J Obstet Gynaecol 1996. 175(3 Pt 2): 766-9. 2. Pitkin J. Brit Med J 2007; 334(7603): 1110-1111.

Ovulatory DUB

• Defects in the control mechanisms of menstruation1

– Ovulatory DUB is secondary to defects in local endometrial hemostasis

– Bleeding occurs cyclically• Far less frequent than

anovulatory DUB2 1. Pitkin J. Brit Med J 2007; 334(7603): 1110-11112. Brenner PF. Am J Obstet Gynaecol 1996. 175(3 Pt 2): 766-9.

Forms of DUB: acute, chronicand intermenstrual bleeding

1. National Institute for Health and Clinical Excellence 2007. Heavy menstrual bleeding [CG24] London: National Institute for Health and Clinical Excellence. 2. Munro MG, et al. Int J Gynaecol Obstet 2011; 113: 3-13.

Heavy menstrual bleeding Intermenstrual bleeding

Acute

Chronic

An episode of heavy bleeding that, in the opinion of the clinician, is of sufficient quantity to require immediate interventionto prevent further blood loss2

Excessive menstrual blood loss which interferes witha woman’s physical, social, emotional and/or materialquality of life1

Bleeding that occurs between clearly defined cyclic andpredictable menses2

Bleeding from the uterine corpus that is abnormal in volume, regularity, and/or timing, and has been present for themajority of the past 6 months2

Diagnosis of DUB:a ‘diagnosis of exclusion’1

1. Pitkin J. Brit Med J 2007; 334(7603): 1110-1111. 2. Qi Y. Chin J Obstet Gynecol 2009; 44(3). [Translated from Chinese]. 3. National Institute for Health and Clinical Excellence 2007. Heavy menstrual bleeding [CG24] London: National Institute for Health and Clinical Excellence.

Diagnosis requires

Thorough medical history2,3 Auxiliary examinations2,3Physical examination2,3

Diagnosis of DUB:a ‘diagnosis of exclusion’1

1. Pitkin J. Brit Med J 2007; 334(7603): 1110-1111. 2. Qi Y. Chin J Obstet Gynecol 2009; 44(3). [Translated from Chinese]. 3. National Institute for Health and Clinical Excellence 2007. Heavy menstrual bleeding [CG24] London: National Institute for Health and Clinical Excellence.

Diagnosis requires

Thorough medical history2,3 Auxiliary examinations2,3Physical examination2,3

Including:• Patient’s age• Menstrual history• Marital history & fertility• History of endocrine diseases or

coagulation disorders• History of recent medication

Look for positive signs of:• Anaemia• Hypothyroidism• Hyperthyroidism• Polycystic ovary syndrome (PCOS)• Haemorrhagic disorders

Gynaecologic examination to rule out:• Vaginal, cervical or uterine diseases

• Complete blood count (rule outanaemia/thrombocytopenia)• Coagulation function tests• Pregnancy tests• Pelvic ultrasound (rule out uterine

lesions)• Measurement of basal body

temperature (confirm ovulation &rule out luteal insufficiency)• Determination of hormone levels

Medical treatments: key points• Non-hormonal therapies are considered first line treatments1

• The aim of treatment is to1) prevent excessive menstrual bleeding and2) regulate menstrual bleeding2

• Factors to consider when choosing a treatment:1

– Degree of bleeding (acute or chronic)– Age-related factors– Need for contraception– Adverse effect profile

1. Pinkerton JV. Menopause 2011; 18: 453-461. 2. Hickey M, et al. Progestogens with or without oestrogen for irregular uterine bleeding associated with anovulation. Cochrane Database of Systematic Reviews 2012, Issue 10. Art.No.: CD001895. DOI: 10.1002/14651858.CD001895.pub3. 3. Qi Y. Chin J Obstet Gynecol 2009; 44(3). [Translated from Chinese].

Treatment goals for managing thesymptoms of DUB

Excessive flow

Symptoms of menstrual bleeding

Normalisation ofmenstrual bleeding amount

Management of symptoms

Irregular cycles Improvement in regularity andduration of menstrual cycle

Cycle length <21 days Normalisation ofmenstrual cycle length

+Improvement in endometrial

characteristics

Hormonal treatments for DUB1

• Progestogens:(e.g. progesterone, dydrogesterone, medroxyprogesterone acetate [MPA])– Suitable for patients with a haemoglobin level of greater than 80g/L and stable vital signs

• Compound short-acting oral contraceptives:(e.g. desogestrel-ethinyl estradiol, gestodene-ethinyl estradiol, compound cyproterone acetate)– Indicated for long and severe anovulatory bleeding

• Synthetic progestogens:(e.g. levonorgestrel, norethisterone)– Can cause thinning of the uterine lining, thus reducing severity of bleed

1. Qi Y. Chin J Obstet Gynecol 2009; 44(3). [Translated from Chinese].

Clinical Guidelinessupport the prescription of progestogens

• “Progestogen therapy administered for 21 days of the menstrual cycle results in a significant reduction in menstrual blood loss, although they have been found to be ineffective unless taken at high doses”1

Ministry of Health, Malaysia 1. Ministry of Health, Malaysia 2004. Management of Menorrhagia [MOH/P/PAK/95.04]. Putrajaya: Ministry of Health. 2. Qi Y. Chin J Obstet Gynecol 2009; 44(3). [Translated from Chinese].

Cycle regulation with naturalprogesterone and synthetic progestins1

Properties Dydrogesterone Progesterone

Testosterone &19 nortestosterone

derivativesProgesterone

derivatives

Blocking of ovulation –* + + +Oestrogenic – ± + –Androgenic – – + +Masculinisation of foetus – – + +Relaxation of uterine tissue + + – ±Adrenal atrophy – – + +Thermogenicity – + + +Blood clotting – – + +Blood lipids – – + –+ effect; – no effect; ± equivocal; * at normal dosage “natural”

Progesterone

Lynestrenol 5 mgNorethisteron 5 mgMedrogeston 5 mg

MPA 10 mg

Levonorgestrel

1. Schindler AE, et al. Maturitas 2009; 46(S1): 7-16.

Improvement inendometrial characteristics

Progestogen actions on the endometrium • Stops oestrogen-induced growth of the

endometrium • Stabilises endometrial vasculature and

blocks unrestricted vessel growth1 • Initiates the clotting cascade1 • Haemostatic and anti-fibrinolytic action

(PAI-1 pathway)1 • Inhibits matrix metallo-proteinase

activity1

1. Lockwood CJ. Menopause 2011; 18(4): 408–411.

Process for prescription:patient-specific considerations

• Diagnosis and choice of treatment depends on many patient-specific considerations, e.g:– What age is the patient?

(causes of AUB/DUB vary with age)– Is the patient trying to conceive? Or do they require

contraception? (certain treatments block ovulation)– Does the patient have any underlying medical conditions?

(e.g. haematologic or coagulation disorders)– Is the patient a smoker? (smokers have an increased risk of

venous thrombosis with low-dose oral contraceptives)1

1. Kemmeren JM, et al. Brit Med J 2001; 323(7305):131.