Polycystic Ovarian Syndrome & Amenorrhea.

Valmiki K. Seecheran |Year V MBBS.UWI Cave Hill.

Obstetrics & Gynecology Senior Clerkship.July 2014.

Objectives.

• To discuss the prevalence & pathogenesis of PCOS.• To discuss the clinical presentation of PCOS.• To discuss the various types of work-up for PCOS.• To discuss the management for PCOS.

To begin…

What is PCOS?

• The name Polycystic Ovarian Syndrome refers to the enlarged ovaries that contain many very small cysts.

Background.

• Hyperandrogenic anovulation or Stein-Leventhal syndrome.

• Earliest publication w.r.t PCOS was in 1721, Italy.

• Stein-Leventhal 1935 – American gynecologists.• Amenorrhea.• Infertility.• Hirsutism.• Enlarged polycystic ovaries.

Introduction.

• One of the most common endocrine disorders among females.• Strong evidence – genetic disease.• 5-10% of reproductive age experience PCOS.• Leading cause of female subfertility.

• Anovulation, excess androgenic hormones and insulin resistance.- amenorrhea, irregular menstruation, infertility, acne, hirsutism, obesity & Type II DM.

Definition.

• NIH 1990 (All of the following)• Oligoovulation – irregular ovulation.• Androgen excess.• Exclusion of other disorders than can result in menstrual irregularity and

hyperandrogenism.

• Rotterdam 2003 (2/3 criteria)• Oligoovulation/ anovulation.• Androgen excess.• Polycystic ovaries.• Other entities that would cause these symptoms.

Definition.

• Androgen Excess PCOS Society 2006 (All of the following)• Excess androgen activity.• Oligoovulation/anovulation and/or polycystic ovaries.• Exclusion of other entities that would cause excess androgen activity.

Pathogenesis.

• UNKNOWN.• Speculated theories.

• Genetic linkage.• Daughters of women with PCOS are at an increased risk.

• Hormonal imbalance.• High insulin levels.• High androgen levels.• High luteinizing hormone.• Low estrogen/progesterone.

Signs & Symptoms.

• Pre-puberty.• Increased levels of adrenal androgen.• Increased insulin levels.• Ovarian hyperandrogenism.

• Adolescent and Adulthood• Anovulation.• Hyperandrogenism.• Polycystic ovaries.• Obesity.

• Late adulthood.• Diabetes.• Hypertension.• Cardiovascular disease.

Signs & Symptoms.

• Hair loss from head or thinning of hair.

Signs & Symptoms.

• Acne, oily skin and/or dandruff.

Signs & Symptoms.

• Acanthosis nigricans.

Signs & Symptoms.

• Skin tags.

Signs & Symptoms.

• Hirsutism –Excess hair on face/ chin.

Case.• A 23 year old G0P0 female presents to the office with complaints of

irregular cycles since menarche. Upon further questioning, she has also noticed an increase in facial hair and acne for many years. She denies any history of medical problems and has a strong family medical history of diabetes. On examination, she is noted to have a normal blood pressure, pulse, respiratory rate and temperature. She is obese with a body mass index of 34. She is noted to have some hirsutism and acanthosis nigricans – neck and inner thighs. Her pelvic examination is limited by her obesity but normal. She does not desire pregnancy at this time. Her pregnancy test is negative.

Patient history.

• Demographics.• Name – Jane Doe.• Age – 23 years old.

• Presenting complaint.• Irregular cycles since menarche.

• History of presenting complaint.• Increase in facial hair.• Increase in acne. • G0P0.

• Past medical history.• Nil significant.

• Family history.• +ve family history of diabetes.

Patient history.

• Vitals.• HR – 80 bpm.• RR – 16 bpm.• BP – 120/80 mmHg.• Temperature – 37.5 Celsius.

• Body mass index – 34.• Examination.• Pelvic examination limited by her obesity but normal.• Hirsutism +ve.• Acanthosis nigricans +ve – neck & inner thighs.

Further questions.

• Complete menstrual history – pattern, cycle, bleeding, 1st menarche.• Hirsutism? Acne? Alopecia? Infertility?• Dietary patterns?• Uncontrolled/ controlled symptoms? – Duration? Onset? Severity?• Family history? – Diabetes? CVD? PCOS?• Lifestyle factors? – Exercise? Smoking? Alcohol?• Medication – phenytoin, glucocorticoids – transient hirsutism.

Work-up.

• Blood investigations.• ↑ LH. • ↔FSH. • ↓ E2 (estradiol). • ↑ Testosterone. • ↑ Prolactin.• ↑ estrogen – which ultimately results in increased risk of endometrial

hyperplasia / endometrial cancer. • TFTs – for hyperthyroidism: ↓TSH ↑T4

• Glucose & Lipid profiling.• Endometrial biopsy.

Work-up.

• Ultrasound examination• Show >5 follicles per ovary.• ‘String of pearls’ appearance.

Treatment goals.

1. Reduce circulating androgen levels.2. Protect the endometrium from unopposed estrogen and reduce risk

of endometrial cancer.3. Encourage weight loss + healthy lifestyle changes.4. Induce ovulation when pregnancy is desired.5. Monitor for development of diabetes & CVD.

Management

• Oral contraceptive pill – ethinyl estradiol.• 1st line treatment.• Reduce LH & FSH by decreasing GnRH.• Decrease ovarian androgen production.• All types reduce levels of free testosterone by approximately 50%.• Regulate dysfunctional bleeding.• Limits unopposed estrogen.

Management

• Metformin• Anti-diabetic agent – Insulin sensitizer.• Clinical trials have shown that metformin effectively reduce androgen levels

and improve insulin sensitivity and facilitate weight loss.• Can be used as an adjunct in ovulation.

Management.• If trying to conceive,• The American College of Obstetricians and Gynecologists (ACOG)recommend

clomiphene citrate as first-line therapy to stimulate ovulation when fertility is desired.• Selective modulator of the oestradiol receptor.• Metformin as an adjunct.• Increases risk of multiple pregnancy and ovarian cancer.• Spironolactone, finasteride – antiandrogenic but teratogenic.

Management.

• 2nd line treatment• Ovarian drilling is recommended as second line if clomiphene is not working.

Helps to reduce steroid production. • A laser fibre or electrosurgical needle punctures the ovary 4 to 10 times. This

treatment results in a dramatic lowering of male hormones within.• Studies have shown that up to 80 percent of patients will benefit from such

treatment.

Management.

• Diet + Activity.• Comprehensive program of diet and exercise to reduce risk of developing

diabetes mellitus. • Moderate physical activity.• Reduce alcohol/ smoking.• Reduce hyperinsulinemia & hyperandrogenism – even with 5% weight loss.

Long term Monitoring

• Patients need regular check ups for early detection and management of any untoward sequelae.• Patient education.• Increased risk of CVD, Diabetes.• Lifestyle modifications.

• Women with PCOS are at increased risk of obstetrical complications.• Gestational diabetes.• Preeclampsia.• Cesarean delivery.• Pre/Post-term delivery.

Long term Monitoring.

• The American Association of Clinical Endocrinologists and the American College of Endocrinology recommend screening for diabetes by age 30 years in all patients with PCOS, including obese and non-obese women.• Patients with PCOS are also at an increased risk for endometrial

hyperplasia and carcinoma.• The Royal College of Obstetricians and Gynecologists (RCOG) recommends

induction of withdrawal bleeding with progestogens a minimum of every 3-4 months.

• No known association with breast or ovarian cancer has been found; thus, no additional surveillance is needed.

Objectives.

• To discuss the prevalence & pathogenesis of amenorrhea.• To discuss the clinical presentation of amenorrhea.• To discuss the various types of work-up for amenorrhea.• To discuss the management for amenorrhea.

Definition

• Primary amenorrhea.• Failure of menarche to occur when expected in relation to the onset of pubertal

development.• No menarche by age 16 years with signs of pubertal development.• No onset of pubertal development by age 14 years.

• Secondary amenorrhea.• Absence of menstruation for 3 or more months in a previously menstruating

women of reproductive age.

Events of Puberty

• Thelarche – breast development.• Requires estrogen.

• Pubarche/adrenarche – pubic hair development.• Requires androgens.

• Menarche – the first menses.• GnRH from the hypothalamus.• FSH and LH from the pituitary.• Estrogen and progesterone from the ovaries.• Normal outflow tract.

Classification.

• Hypothalamic Amenorrhea.• Pituitary Amenorrhea.• Ovarian Amenorrhea.• Uterine Amenorrhea.• Other.

Etiology – Hypothalamic.

Primary.• Congenital GnRH deficiency.• Weight loss.• Organic disease.• Constitutional.

Secondary.• Weight loss – Anorexia nervosa.• Exercise.• Organic disease.• Emotional stress.• Pseudocyesis.

Anorexia Nervosa.

• BMI < 17 kg/m2 -> menstrual irregularity and amenorrhea.• Hypothalamic suppression.• Mean age onset ( 13-14 years)• Low estradiol -> risk of osteoporosis.

Exercise-associated amenorrhea.

• Common in athletic women/ ballet dancers.• Eating disorders have a higher prevalence in

female athletes than non-athletes.• Hypothalamic disorder caused by abnormal

GnRH pulsatility – results in impaired gonadotrophin levels, particularly LH and subsequently low estrogen levels.

Contraception related amenorrhea.

• Post pill amenorrhea is not an entity.• Depot medroxyprogesterone acetate – Up to

80% of women will have amenorrhea after 1 year of use – reversible.• A minority of women taking the progesterone-

only pill may have reversible long term amenorrhoea due to complete suppression of ovulation.

Etiology – Pituitary.

Primary.• Hyperprolactinaemia.• Pituitary failure.

Secondary.• Hyperprolactinaemia.• Sheehan’s syndrome.• Organic disease.

Hyperprolactinaemia.

Increased prolactin

Suppresion of GnRH

Supression of FSH, LH

Impaired follicular development

Hyperprolactinaemia – Causes.

Drug Induced

PhenothiazinesTricyclic

AntidepressantsMethyldopa

ResperineMorphineCimetidine

Prolactinoma

Micro-adenoma

Macro-adenoma

Primary hypothyroidism Idiopathic

Sheehan’s syndrome.

• Pituitary inability to secrete gonadotropins.• Pituitary necrosis following massive obstetric hemorrhage is most

common cause in women.• Diagnosis.• History and E2, FSH, LH + other pituitary deficiencies ( Decreased TSH and

ACTH)

• Treatment.• Replacement of deficient hormones.

Etiology – Ovarian.

Primary.• Gonadal dysgenesis• Chromosomally incompetent.

• Turner’s syndrome (45X0)• Chromosomally competent

• Pure gonadal dysgenesis (46XX)

• Ovarian agenesis• Chemotherapy and

radiotherapy.

Secondary.• PCOS.• Resistant ovary.• Hormone producing tumours.• Chemo/radiotherapy.• Gonadal dysgensis.

Etiology – Uterine.

Primary.• Utero-vaginal agenesis.

Secondary.• Asherman’s syndrome.

Mayer-Rokitansky-Kuster-Hauser SyndromeUtero-vaginal agenesis• 15% of primary amenorrhea.• Normal secondary development & external female genitalia.• Normal female range testosterone level• Absent uterus and upper vagina & normal ovaries.• Karyotype 46XX.• 15-30% - Renal, skeletal and middle ear anomalies.

Imperforate Hymen.

• Congenital disorder.• Hymen without an opening obstructs the vagina.• Failure to perforate during fetal development – failure of sinovaginal

bulbs to canalize.• Surgical.

Imperforate Hymen.

Haematocolpos & Haematometra

Asherman’s syndrome.

• Fritsch syndrome.• Adhesions/ fibrosis of endometrium associated with dilation and

curettage.• Destruction of stratum basalis of endometrium.• Diagnosis – Hysteroscopy. • Treatment – Uterine sound, operating hysteroscopy, IUCD, Estrogen.

Congenital Adrenal Hyperplasia.

• Autosomal recessive trait.• 21-hydroxylase deficiency.• +ve Family history.• Resembles PCOS.• High 17-OH progesterone blood level.• Presence of uterus and upper vagina.• Treatment:• Cortisol replacement + Corrective surgery.

Androgen Insensitivity.

• Testicular feminizing syndrome.• Normal breasts but no sexual hair.• Normal looking female external genitalia.• Absent uterus and upper vagina.• Karyotype 46, XY.• Male range testosterone level.• Treatment:• Gonadectomy – postpuberty + HRT.

History.

• RULE OUT PREGNANCY.• Menstrual history: age at menarche, LMP, previous menstrual pattern,

diet, medications, stress.• Galactorrhea, radio/chemotherapy, weight loss/gain.• Intense exercise/ dieting.• Estrogen deficiency – hot flushes, night sweats.

Physical.

• Tanner staging – breast development, pubic hair distribution.• Thyroid examination.• Hair distribution – Androgen excess/ insensitivity• External genitalia and vagina – atrophy, clitoromegaly, imperforate

hymen.• Palpation of uterus/ ovaries.

Investigations.

• Progesterone challenge to assess estrogen status.• Medroxyprogesterone acetate 10 mg for 10 days.• Uterine bleed within 2-7 days - +ve test.• Withdrawal bleeding occurs – adequate estrogen.• No bleeding – hypoestrogenism.

• Bloodwork investigations.• Ultrasound.• Karyotype if indicated.

Treatment.• Hypothalamic dysfunction.

• Stop drugs, stress manangement, moderate nutrition & exercise.• Clompihene citrate if pregnancy desired.• OCP to induce menstruation.

• Hyperprolactinemia.• Bromocriptine.• Surgery for macroadenoma

• Hypoestrogenism.• Karyotype.• Removal of gonadal tissue if Y chromosome present.

• PCOS.• Supplemental vitamin D + calcium intake along with moderate weight

bearing exercises to combat bone degeneration.

Conclusion

• Primary amenorrhea.• The overall reproductive prognosis is grim.• Only the patients with idiopathic pubertal delay can be expected to have

normal reproductive capacity.• It is possible for most patients to achieve satisfying sexual function with

appropriate management.

• Secondary amenorrhea.• As all fields of clinical medicine, the treatment of patients should be directed

against the underlying disease state.• Clinical reviews should be held 3-6 months.

Take home points.

To end…

• Primary amenorrhea – absence of menses by age 16.• Secondary amenorrhea – absence of menses for > 6 months.• 3 main mechanisms of pathophysiology of amenorrhea.

• Failure/malfunction of hypothalamic-pituitary-gonadal axis.• Absence of end organs.• Obstruction of outflow tract.

• Hypothalamic, Pituitary, Ovarian & Uterine classifications of amenorrhea.• *Test for Pregnancy.• Progesterone challenge.• Treat underlying disease state/ symptomatic treatment.

To end…

• PCOS is common – 5-10% of women (reproductive age).• Anovulation, hirsutism, infertility, obesity, insulin resistance.• Strong family link.• Treatment• Interrupt self-perpetuating cycle – OCP, weight reduction, clomiphene.• Prevent endometrial hyperplasia from unopposed estrogen using

progesterone.• If pregnancy is desired – medical induction of ovulation.

Thank you.