approach to a patient with amenorrhea and management of PCOS

1. Approach to a patient with amenorrhea and management of PCOD
ADRIJA HAJRA, 2nd YEAR MD STUDENT, DEPARTMENT OF INTERNAL MEDICINE, SSKM & IPGMER, KOLKATA

3. Physiology of normal menstrual cycle:

6. Amenorrhea:
Primary
Secondary
Absence of menses at age 15 years in the presence of normal growth and secondary sexual characteristics
Or
At the age 13 years with absence of secondary sexual characteristics
Absence of menses for more than three months in girls or women who previously had
regular menstrual cycles or six months in girls or women who had irregular menses

7. Causes of amenorrhea:
1) Outflow tract obstruction:
Congenital:
Imperforate hymen
Müllerian agenesis
Transverse vaginal septum
Acquired:
Asherman syndrome (intrauterine synechiae)
Cervical stenosis
2) Primary ovarian insufficiency:
Congenital
Gonadal dysgenesis (other than Turner syndrome)
Turner syndrome or variant
Acquired
Autoimmune destruction
Chemotherapy or radiation

8. Pituitary:
Autoimmune disease
Cocaine
Cushing syndrome
Empty sella syndrome
Hyperprolactinemia
Infiltrative disease (e.g., sarcoidosis)
Medications
Antidepressants
Antihistamines
Antihypertensive
Antipsychotics
Opiates
Sheehan syndrome
Surgery
Radiation
Genetic: SOX2, LHX3, PROP1

9. Hypothalamic
Eating disorder
Gonadotropin deficiency (e.g., Kallmann syndrome)
Infection (e.g., meningitis, tuberculosis, syphilis)
Malabsorption
Rapid weight loss (any cause)
Stress
Traumatic brain injury
Tumor
Other endocrine gland disorders:
Adrenal disease
Adult-onset adrenal hyperplasia
Androgen-secreting tumor
Chronic disease
Constitutional delay of puberty
Cushing syndrome
Ovarian tumors (androgen producing)
Polycystic ovary syndrome (multifactorial)
Thyroid disease

10. Physiologic:
Breastfeeding
Contraception
Exogenous androgens
Menopause
Pregnancy

11. Approach to a female with amenorrhea:

14. Primary amenorrhea:

15. Breasts Absent and Uterus Present
Serum FSH
Low or Normal
High
Hypogonadotropic
Hypogonadism
Hypergonadotropic
Hypogonadism
CT scan, Prolactin
Blood Pressure
Normal
High
Non-prolactin
Secreting tumor
of the CNS
Inadequate
GnRH
Pituitary
Adenoma
Normal
High
Karyotype
45 X
46 X, abn X
Mosaic
Pure gondal
Dysgenesis
w/ 26 XX or
46 XY
17 alpha
Hydroxylase
Deficiency
(Congenital
Adrenal
Hyperplasia)

16. Breasts Present and Uterus Absent
Karyotyping
Testosterone
46XX
Normal
46XY
High
Congenital Absence of the
Uterus
Androgen Insensitivity
(Testicular Feminization)

17. Breasts Absent and Uterus Absent
Karyotype (XY)
Laparoscopy
testes
present
testes
absent
Enzyme Deficiency:
17, 20 desmolase
17 - Hydroxylase
(with XY karyotype)
Agonadism

18. Breasts Present and Uterus Present
Prolactin
Normal High
Hypothalamic causes
Pituitary causes
Ovarian causes
Uterine causes
Outflow tract disorders
Pituitary Lesion
(Prolactinoma)

19. CNS; HP
Disorder
History and physical examination completed for a
patient with primary amenorrhea
Secondary sexual characteristics present
No Yes
Measure FSH and LH levels
Uterus absent
or abnormal
Uterus present
or normal
Karyotype analysis Outflow obstruction
FSH and LH < 5 IU/ L
Hypergonadotropic
hypogonadism
Karyotype analysis 46, XY 46, XX
Yes
Perform ultrasonography of uterus
FSH > 20 IU/ L and
LH > 40 IU/ L
Hypogonadotropic
hypogonadism
Gonadal
Failure
Androgen Sensitivity
Syndrome
Mullerian
agenesis
Imperforate
hymen or
transverse
vaginal septum
No
Evaluate for secondary
amenorrhoea

20. Evaluation of Secondary Amenorrhea
Medroxyprogesterone acetate
(5-10 mg BID for 5 days)
Uterine Bleeding No Uterine Bleeding

21. Uterine bleeding: positive response
LH
High
(>25mIU/ml)
Normal or
Low
Testosterone (Ovarian)
DHEAS (Adrenal)
Ultrasound
Hypothalamic
Dysfunction
(drug, stress or
exercise, weight
loss)
Polycystic Ovarian
Syndrome
Prolactin
Normal High
Induce bleeding monthly with progestins,
oral contraceptives;
Dexamethasone Spironolactone
Hyperthyroidism
TSH
Induce uterine bleeding
monthly with DMPA 10
mg/day for 12 days
Work-up for
hyperprolactinemia
Evaluation of Secondary Amenorrhea
(It bleeding occurs)

22. If bleeding does not occur: No uterine bleeding: negative
response
FSH
Premature
Ovarian
Failure
Hypothalamic
Pituitary
Disorder
High (>30 mIU/ml)
Normal or Low
TSH (hypothyroidism)
Prolactin
(hyperprolactinemia)
CT scan of CNS
If < 25 years old; karyotype
If < 35 years old; antinuclear
antibodies, 24 hr urine cortisol
test
Negative
Estrogen
Progesterone test
Asherman’s
Syndrome
HSG
Hysteroscopy

23. Polycystic ovarian syndrome

24. ARCHARD & THIERS : Diabetes of bearded women

26. Diagnostic criteria for PCOS:
NIH statement:
To include all of the following:
1. Hyperandrogenism and /or hyperandrogenemia
2. Oligo-ovulation
3. Exclusion of related disorders 21-hydroxylase deficient non-classical adrenal hyperplasia
Thyroid dysfunction
Hyperprolactinemia
Neoplastic androgen secretion
Drug induced androgen excess Cushing syndrome
Syndrome of severe insulin resistance

27. ESHRE/ASRM Statement(Rotterdam 2003):
To include two of the following, in addition to exclusion of related disorders:
1. Oligo-ovulation or anovulation (amenorrhea, irregular uterine bleeding)
2. Clinical and/or biochemical signs of Hyperandrogenism (e.g. hirsutism, elevated serum total or free testosterone)
3. Polycystic ovaries (USG)
AES Suggested criteria for the diagnosis of PCOS (2006):
To include all of the following:
1. Hyperandrogenism: hirsutism and/or hyperandrogenemia
2. Ovarian dysfunction: Oligo- anovulation and/or polycystic ovaries
3. Exclusion of other androgen excess or related disorders

28. Pathophysiology of PCOS:
Gonadotropin production in PCOS
Accelerated GnRH-LH pulsatile activity
Central opoid tone appears to be suppressed
The frequency not amplitude may increase in obese women
Low LH does not rule out diagnosis of PCOS, high LH/FSH ratio suggests anovulation

29. Steroid production in PCOS:

30. Role of insulin in PCOS:
Animal studies have shown that in the obese state,
insulin receptor signaling in GnRH neurons increases
GnRH pulsatile secretion and consequent LH secretion,
contributing to reproductive dysfunction
 Insulin enhances the transcription of the LH-beta gene
FSH and Insulin or IGFs cannot synergize in the presence
of insulin resistance
Insulin resistance ----- Hyperinsulinemia--------
Hyperthecosis
Elevated insulin concentrations have been associated
with lower levels of SHBG

31. Insulin appears to augment expression of:
StAR
CYP11A1
17-α-hydroxylase/17,20-lyase (CYP17A1)
3-β-hydroxysteroid dehydrogenase (3-β-HSD)
and aromatase (CYP19A1) expression
contributing to an excess in the production of progesterone,
17-α-hydroxyprogesterone, and testosterone in polycystic
ovaries in comparison to healthy ovaries

32. Role of obesity:

33. Some other factors:
Genetic factors
Dietary Patterns and Hyperandrogenemia
Leptin in PCOS
Polycystic Ovary Syndrome in Non obese Women
Chronic Inflammation

35. Laboratory findings in case of PCOS:
Testosterone-
Dehydroepiandrosterone sulfate level-
LH:FSH- 3:1
Insulin level-
Ovarian biopsy and endometrial biopsy

36. Management of PCOS:
Goals:
• Amelioration of hyperandrogenic symptoms
• Management of underlying metabolic abnormalities and reduction of risk factors for type 2 diabetes
and cardiovascular disease
• Prevention of endometrial hyperplasia and carcinoma, which may occur as a result of chronic anovulation
• Contraception for those not pursuing pregnancy, as women with oligomenorrhea ovulate
intermittently and unwanted pregnancy may occur
• Ovulation induction for those pursuing pregnancy
Lifestyle changes
Oral contraceptives and risk assessment

37. WOMEN NOT PURSUING PREGNANCY:
1) Menstrual dysfunction:
combined estrogen-progestin contraceptives : first-line therapy for menstrual dysfunction and endometrial protection.

38. Antiandrogens
Finasteride and Cyproterone acetate
Gonadotropin-releasing hormone (GnRH) agonists: to suppress ovarian androgen production
Mechanical means such as shaving, waxing, depilatories, electrolysis, or laser treatment.
2) Androgen excess:
Estrogen-progestin contraceptive : first-line pharmacologic therapy
For women with hirsutism and contraindications to OCs, spironolactone alone can be used
To start with an OC containing 20 mcg of ethinyl estradiol combined with a progestin with minimal
androgenicity (such as norgestimate)
Higher doses of ethinyl estradiol (30 to 35 mcg) are needed in some women for optimal suppression of
ovarian androgens and management of hyperandrogenic symptoms.

39. 3) Metabolic abnormalities:
Weight reduction ( reduction of BMI )
Diets
Bariatric surgery
Insulin resistance/type 2 diabetes
Metabolic effects of OCs in PCOS
Dyslipidemia: Statins
Obstructive sleep apnea
Nonalcoholic steatohepatitis
Depression/anxiety

40. WOMEN PURSUING PREGNANCY
Ovulation induction:
Weight loss
Clomiphene citrate
Letrozole
Metformin
Gonadotropin therapy
Thiazolidinedione
In vitro fertilization

42. Special situations:
1) PCOS & Type I diabetes
2) PCOS & gestational diabetes mellitus
3) Treatment of PCOS in adolescents

43. Conclusion:
 Metabolic defects play important role in pathogenesis of PCOS
 Screening and prevention of type 2 diabetes in young adolescent girls are important
 Oral contraceptive pills improve PCOS symptoms and Metformin helps improve the insulin resistance
 Consideration of dietary and lifestyle interventions are important in PCOS patients
 Physicians should always consider the reproductive consequences in a particular patient