AOGD Bulletin January 2020

Evaluation of AmenorrheaSruthi Bhaskaran1, Abha Sharma21Associate Professor, 2Senior Specialist & Medical Superintendent (MCH), Department of Obstetrics & Gynecolgy UCMS/GTB Hospital,New DelhiWhen approached logically and systematically,the diagnostic evaluation of amenorrhea truly isstraightforward, involving thorough history takingand a finite number of laboratory tests and proceduresalready familiar to almost all clinicians.The purpose of this chapter is to provide a systematicstrategy for the evaluation of amenorrhea that willyield an accurate diagnosis.Definition of Amenorrhea1 No menses by age 13 in the absence of growth ordevelopment of secondary sexual characteristics No menses by age 15 regardless of the presenceof normal growth and development of secondarysexual characteristics In women who have menstruated previously, nomenses for an interval of time equivalent to a totalof at least three previous cycles or no menses over a3-month period.It is important to point out that unduly strict adherenceto these criteria with a disregard to the overall clinicalpicture can result in a delay in identifying seriousunderlying health conditions. For example, thereis no reason to defer the evaluation of a young girlwho presents with the classical phenotype of Turnersyndrome. Similarly, a 14-year-old girl who has novagina should not be advised to return in 2 yearsbefore initiating evaluation and offering intervention.All patients deserve a considerate evaluation at initialpresentation.2 Finally, the possibility of pregnancy asa reason for amenorrhea must always be considered.Traditionally, amenorrhea has been categorized asprimary or secondary.Primary amenorrhea describes patients who havenever menstruated, andSecondary amenorrhea describes those who havemenstruated previously but now do not.With a few exceptions, the causes of primary amenorrheaare similar to the causes of secondary amenorrhea (Fig. 1)The basic requirements for normal menstrual functionincludes four anatomically and functionally distinctstructural components—(1) the genital outflow tractincluding the uterus, cervix, and vagina; (2) the ovary;(3) the pituitary; and (4) the hypothalamus —thusproviding a natural and useful hierarchy for organizingthe diagnostic evaluation of amenorrhea. Causes ofamenorrhea can be categorized according to the site orlevel of the disorder or disturbance2Secondary AmenorrheaPrimary AmenorrheaCentral nervous systemPhysiological delay Kallmansyndrome GnRH receptor mutationCNS hypothalamus tumors1. Pituitary tumorsa) Prolactinomasb) Other hormone-secretingpituitary tumor (ACTH,thyrotropin-stimulatinghormone, growth hormone,gonadotropin)2. Inactivating mutation in β subunitof LH / FSHVol.19, No.9; January, 2020HypothalamusAnterior PituitaryMidbrain lesions- Encephalitis, Meningitis,tumors & fractures of base of skull1. Anorexia nervosa2. Sudden loss of weight3. Exercise amenorrhea4. Nutritional & emotional stress5. Peudocyesis6. Hypothalamic tumors7. Chronic diseases1. Pituitary tumors2. Pituitary failure (Sheehan’s syndrome)3. Empty sella syndrome4. Infiltrative pituitary lesions -Sarcoidosis,Hemochromatosis, Lymphocytic hypophysitis5. Surgical or radiological ablationSurgical or radiological ablation7

a) Gonadal dysgenesis-abnormalkaryotype-Turner syndrome 45x/mosaicism, normal karyotype- puregonadal dysgenesis- 46xx, 46xyb) Gonadal agenesisc) Enzyme deficiency-17αHydroxylase deficiency, 17,20-Lyase deficiency, Aromatasedeficiencyd) POI- Idiopathic, Chemotherapy,Radiation, Mumps oophoritis,resistant ovaryOvary1. Premature ovarian failure- Numerical &structural abnormalitya) X-chromosome mosaicism (45X, 46XX,47XXX cell line)b) Y-chromosome mosaicism (46XY, 47XXY,47XYY cell line)c) X-chromosome translocation deletions &structural abnormalitiesd) Deletion of genes involved in germ cellfunctione) Fragile X premutation f) Autoimmuneg) Radiation h) Chemotherapyi) Galactosemia j) Infection-mumps, HIV2. Polycystic ovarian syndromeMullerian agenesis Androgeninsensitivity syndrome TBendometritis Endometrialhypoplasia/aplasia (congenital)UterusAshermans syndrome (secondary to prioruterine surgery / curettage), Infections (PID,Tuberculosis, SchistosomiasisImperforate Hymen Transversevaginal septum Vaginal agenesiscervical agenesisOutflow tractCervical stenosis following surgical procedureslike LEEP, Cone biopsyOther endocrine gland disordersA.Adrenal disease1. Adult-onset adrenal hyperplasia2. Cushing syndromeB. Thyroid disease1. Hypothyroidism2. HyperthyroidismPrimary Amenorrhea Disorders of sexualdevelopment Gonadal dysgenesis Mullerian agenesis Androgen insensitivitysyndrome Physiologic delay GnRH deficiency Transverse vaginal septum Imperforate hymenSecondary Amenorrhea Pregnancy Functional hypothalamic Hypothalamic/pituitarytumors Chronic illness Hyperprolactinemia Empty sella syndrome Thyroid disease PCOS/NCCAH/CAH POI Cushing Infiltrating pituitarylessions Sheehan syndrome Asherman Cervical stenosisFig 1: Overlap of causes between primary and secondary Amenorrhea1Evaluation of AmenorrheaPrimary amenorrhea1,2Step 1- HISTORY1. H/o completion of other stages of puberty- growthspurt, development of axillary and pubic hair,8breast development.- ovarian or pituitary failure orchromosomal anomaly2. Family h/o delayed or absent puberty- familialdisorder3. What is her height relative to family membersshort stature may indicate TURNER SYNDROMEAOGD Bulletin

OR HYPOTHALAMIC-PITUTARY DISEASE.4. H/o Neonatal or childhood health problemsNeonatal crisis may suggest CAH5. Symptoms of virilization- Acne, hirsutism,deepening of voice etc.- PCOS/ androgen secretingovarian or adrenal tumor.6. H/o stress, change in weight, diet or exercise habitsor illness- Hypothalamic amenorrhea7. H/o any drug intake that might cause amenorrhea phenothiazines, reserpine derivatives, ineantagonists, opiates can cause hypothalamo-pitutarydysfunction.8. H/o any drug intake like hormones leading todevelopment of breast9. H/o Galactorrhea (h/o drugs like metoclopramide,antipsychotics)10.Symptoms of other hypothalamo-pitutary diseaseincluding headches, visual field defects, fatigue, orpolyuria and polydipsia?2. if uterus absent- karyotype, serum testosterone,FSH, LH- (46 XX, normal female testosteronelevels e, normal FSH- Mullerian agenesis/ 46 XY,normal male testosterone levels, normal FSHAndrogen insensitivity syndrome (AIS)/ 46XY/46XX, normal female testosterone, high FSHGonadal dysgenesis) - Y chromosome materialincreases the risk of Gonadoblastoma in dysgeneticgonads- gonadectomy recommended in AIS afterpuberty and immediately on diagnosis in Swyersyndrome.3. If uterus present and outlet obstruction ruled outHCG (rule out pregnancy/ S.TSH/S.prolactin/ FSHSecondary amenorrhea1,2Step 1:- Rule out pregnancy- UPT/hCGStep 2: HistoryApart from the points in history as in a case of primaryamenorrhea following should be noted1. Age at menarche. Menses preceding amenorrhea –regularity/ amount11.Cyclical pelvic or lower abdominal pain or urinarycomplaints- Cryptomenorrhea2. H/o preceding dilatation curettage or other uterinesurgery12.H/o exposure to tuberculosis, radiation orchemotherapy in childhood3. H/o obstetrical events-lactation, massive PPH(Sheehans syndrome), dilatation and curettageStep 2 : Physical examination1. Height, weight, BMI and arm span (normal armspan for adults is within 5 cm of height)2. Breast development- Tanner stage, axillary hairpresent/absent3. Abdominal examination - inguinal area- lump-s/otestis, enlarged uterus- hematometra4. Genital examination- Pubic hair- Tanner staging,clitoral size, hymen, depth of vagina and presenceof cervix, uterus and ovaries (mainly by pelvicultrasound) by gentle one finger examination orrectal examination.5. Hirsutism, acne, striae, increased pigmentation6. Classic physical features of Turner syndrome- lowhair line, web neck, shield chest and widely spacednipples, blood pressure both arms- coarctation ofAortaStep 3: Basic laboratory testing- depends on findingsof physical examination whether Mullerian structuresare present or absent1. pelvic ultrasound - presence of uterus, cervix andovariesVol.19, No.9; January, 20204. H/o chronic illness such as diabetes, renalfailure (which is often associated with elevatedprolactin levels, primarily reflective of alteredrenal clearance), or inflammatory bowel disease,previous head trauma, tuberculosis.5. H/o time and duration of any treatment withoral contraceptive pills, progestins (e.g., depotmedroxyprogesterone acetate [MPA], progestinimplants, or intrauterine system), GnRH agonistsor drugs that can affect central neurotransmittersecretion and thereby disrupt hypothalamopituitarysignals that are critical to normal menstrualfunction (phenothiazines, reserpine derivatives,amphetamines, benzodiazepines, antidepressants,dopamine antagonists, opiates)6. Family history- autoimmune disorders, spontaneousPOI or intellectual disabilityStep 3: Physical examination1. Height, weight, BMI2. Skin- soft, warm, moist with rapid pulse, finetremor, hyperreflexia- hyperthyroidism. Coarse,dry skin, slow pulse, diminished reflexes, thinningof hair- hypothyroidism9

3. Hirsutism, acne, striae, acanthosis nigricans4. Parotid gland swelling and/or erosion of teethenamel- eating disorder (bulimia nervosa)5. Breast- galactorrhea, atrophyStep 4: Basic laboratory testsApart from Urine pregnancy test or HCG to ruleout pregnancy minimal laboratory testing shouldinclude serum prolactin, TSH and FSH. If clinicalevidence of hyperandrogenism- - serum totaltestosterone, 17-hydroxyprogesterone (if high risk)to rule out non classic 21-hydroxylase deficiency anddehydroepiandrosterone sulfate (DHEA-S) to look foradrenal source of androgens. Serum total testosterone 200 ng/dl, DHEA-S 380μg/dl- evaluate forandrogen secreting adrenal or ovarian tumors byimaging studies. Serum total testosterone 80 150ng/dl- PCOS.Evaluation of Primary Amenorrhea-Algorithm1Secondary sexual characteristicsAbsentPresent (UPT-VE)Physical examination/USGSymptoms ofoutflow obstructionKaryotype- 46 XY5α reductase def, 17 αhydroxylase 17-20 lyase def,Congenital lipoid adrenalhyperplasia, LH receptordefect, Gonadal regressionUterus presentFSH, LH levelHigh 20 IU per L10yesEvaluate as for20 adism- Kallmann syndrome- Physiological delay- Disorders of low estrogenstatus before pubertyKaryotype- Y Line- Turners (XO)- Pure gonadaldysgenesis- Swyers(XY), XX- Premature ovarianinsufficiency (XX)NoKaryotypingTransverseVaginal septumLow ( 5 IU/ L) or NormalHypergonadotropichypogonadismAbnormalUterus absent withblind / absent vaginaUterus Absent uterusNormal46XYBreast normalsexual hair -absentAIS46 XXBreast, sexualhair normalMullerian agenesis,MRKH syndrome- FSH receptor defect- Environment toxins- Congenital lipoid adrenalhyperplasia in XX- 17α hydroxy. def. in XXAOGD Bulletin

Evaluation of Secondary Amenorrhea1Secondary amenorrhea and UPT -VES. TSH, S.ProlactinBoth normalNormal Prolactin,abnormal TSH levelNormal TSH, abnormalprolactin emiaClinical assessment ofestrogen status*Withdrawl bleed ve onPCT** Estrogen normalWithdrawl bleed -ve on PCT Low estrogenEstrogen Progesterone challenge****FSH normalChronicanovulationPCOSIiopathic- Feedback disordersHpothalamicdysfunction- Obesity- Cushing syndrome- Androgen secretingadrenal tumor- Congenital rogensecretingWithdrawl bleed veWithdrawl bleed -veS. FSH/LHEnd organ defect- uterinesynechie/Asherman syndrome***FSH 20-40 IU/LLH 40 IU/LFSH 5 ncy- 45 XOFMR 1 mutationChromosomal RadiationChemotherapy infectionsAutoimmune- Galactosemia Idiopathic-FSH normalHypogonadotropichypogonadism- Hypothalamicdysfunction-Anorexia- Exercise induced- Stress- Malnutrition- PseudocyesisAbnormalneurologicalexaminatonCT/MRI, EEG- Chronic diseasesPulmonary/renal/ diabetes- Addison disease- Pitutary- Hypothalamic lesionstumors infectioninfarction- Pitutary failure- Sheehan- Diabetic vasculitis* h/o vaginal dryness or hot flashes, serum estradiol level 40 pg/mL (inter assay discrepancies often exist and serum estrogen levels can vary greatlyon a day-today basis), Vaginal ultrasound demonstrating a thin endometrium (other reasons for non functional endometrium ruled out), progestogenchallenge test-little utility in routine performance (False positives and false negatives are common).1,4,5** PCT- progesterone challenge test- tab medroxyprogesterone acetate 5-10 mg for 7-10 days.*** FSH levels should be repeated after 1 month for confirmation of POI.**** E P challenge- Tab Conjugated equine estrogen 0.625 mg once a day x 21 days tab medroxyprogesterone acetate 10 mg once a day for the last10 daysReferences1. Baker V, Beal S. Berek and Novak Sixteenth edition. Ch 34.Amenorrhea. pg 2036.2. Taylor H, Pal L, Seli E. Speroff’s clinical gynecologicendocrinology and infertility. Ninth Edition. Chapter 10.Amenorrhea3. Current evaluation of amenorrhea. The Practice Committee ofthe American Society for Reproductive MedicineFertility andSterility Vol. 86, Suppl 4, November 2006.Vol.19, No.9; January, 20204. Rarick LD, Shangold MM, Ahmed SW. Cervical mucusand serum estradiol as predictors of response to progestinchallenge. Fertil Steril 1990;54:353–5.5. Nakamura S, Douchi T, Oki T, Ijuin H, Yamamoto S, NagataY. Relationship between sonographic endometrial thicknessand progestininduced withdrawal bleeding. Obstet Gynecol1996;87:722–5.11

Adolescent Polycystic Ovary Syndrome - Still anEnigma!Megha Mittal1, Pratima Mittal21Senior Resident, 2Professor, VMMC & Safdarjung Hospital, New DelhiPolycystic Ovary Syndrome (PCOS) is a heterogenoussyndrome of unknown aetiology and is a leadingcause of anovulatory endocrinopathy. PCOS of latehas taken an epidemic form with a prevalence of 8%- 13% in women of reproductive age1,2. The diagnosisand management of adolescent PCOS is different inadolescent from that of adults. To address the queriesand gaps this article summaries the diagnosis andmanagement in adolescent PCOS after reviewing therecent guidelines.Adult v/s Adolescent PCOS – Diagnostic ChallengesThese can be considered two different entities becausetargeted areas and outcomes of priority in these twophases of life are different.The Rotterdam criteria used in diagnosis of adultPCOS requires at least 2 of 3 features3.1. oligo-anovulation2. Clinical/Biochemical evidence of hyperandrogenism3. Polycystic ovaries on ultrasound.However diagnosis of adolescents PCOS has strongerfocus on clinical features like irregular menses, acne,hirsuitism and alopecia. Adolescent PCOS is difficultto diagnose as 85% of menstrual cycle are anovulatoryduring early post menarchal years. Even after 3 years;50%of cycles are anovulatory. Acne is commonin adolescent irrespective of PCOS and hirsuitismassociated with PCOS develops later. Polycysticovaries are often a normal finding in adolescencebecause of multifollicular development.The ESHRE/ASRM sponsored 3rd PCOS consensusgroup (Amsterdam 2010) concluded that the diagnosticcriteria for adolescent PCOS should be different fromthat in adults with focus on treatment of individualmanifestations and surveillance of high risk groupsuch as those with hirsuitism, irregular cycles andobesity [level B] 5ESHRE/ASRM 2018 set up evidence based guidelinesfor diagnosis and treatment of PCOS6. They proposedthat the diagnosis of PCOS in adolescence should havestronger focus on clinical features; limited indicationsof ultrasonography; and simpler tests for biochemicalhyperandrogenism.For diagnosis of PCOS they opined that6:A) Menstrual cycles should be considered abnormalin adolescents if :12 First year post menarchal any one cycle 90 daysis abnormal. 1 to 3 years post menarche 21 or 45d. More than 3 year post menarche to perimenopause 21 to 35 or 8cycles/year. Primary amennorhoea by age 15 to 3 years postthelarche.NOTE:- Adolescents who don’t meet the diagnosticcriteria and are at “increased risk” (obesity hirsuitism,H/o diabetes and PCOS in family) should be reassessedafter 8 years post menarche7.B) Biochemical/Clinical hyperandrogenism Clincal hyperandrogenismShould be reported in the presence of acne,alopecia and hirsuitism. Reported unwantedexcess hair growth /alopecia should be consideredimportant regardless of severity. Assess hirsutismusing modified Ferriman Gallwey score (mFG)with a level 8 indicating hirsutism. The Ludwigvisual score is used for assessing the degree anddistribution of alopecia Biochemical hyperandrogenismShould be assessed by calculated free androgenindex (FAI) using values of total testosteroneand SHBG. Direct levels of free testosteroneshould not be measured in view of poorsensitivity and unreliable accuracy. DHEAS andAndrostenedione can be considered if total/freetestosterone is not elevated.C) Polycystic appearing ovaries on USGUSG should not be used for diagnosis of PCOSwith gynaecological age 8years i.e. less than 8years post menarche because of multi folliculardevelopment at this stage6. However it should bedone to rule out other pathologies. In most adolescents TAS is done because theyare sexually inactive; herein the diagnosis ofPolycstic Ovary Morphology (PCOM) is bestfocused on ovarian volume with a threshold of 10ml. Transvaginal USG approach is preferred indiagnosing PCOS, if sexually active. TVS (frequency bandwidth 8 MHz) on eitherovary follicle number 20 and/or an ovarianAOGD Bulletin

volume 10ml (Absence of corpora lutea, cystor dominant follicle) If 8MHz frequency for PCOM-an ovarianvolume 10ml on either ovaryInvestigationsInvestigation required for diagnosis and managementof PCOS are tabulated under Table 1Table 1: Investigations for diagnosis and management of PCOSEssential investigationsDesirable investigations Serum TSH & Serum prolaction Serum Androstenedione 17 OH progesterone FSH/LH 2 hr 75 gm OGTT Fasting Insulin levels Lipid profile Vitamin D3 Calculated free Testosterone Free Testosterone Free Androgen Index Ultrasonography (TVS/TAS) torule out other pathologies/fordiagnosisScreening be done for Obstructive Sleep Apnea8 Emotional wellbeing, Eating Disorders and Body Image Issues Assess Qualityof LifeScreening for Metabolic DisordersSince PCOS is associated with metabolic issues inadult life therefore screening for these conditionsand lifestyle modifications are an integral part of themanagement. Adolescent PCOS should be screenedfor the following conditionsA. Insulin resistance and obesity: Height; weight and ideally waist circumferenceshould be measured and BMI calculated OGTT/HbA1c should be measured every one to three years.B. Hypertension: -All women should have Bloodpressure measured annually.C. Hyperlipidemia: -All obese and overweight womenshould have fasting lipid profile.D. Obstructive sleep apnea: - Is very commonlyassociated with PCOS and its metabolic dysfunctions.Hence screening for OSA through a simple screeningtool eg. Berlin’s questionnaire is recommended8,9.E. Emotional well-being:-anxiety and depressivesymptoms should be routinely screened in alladolescents.F. Body image issues:- Negative body image issueshould be screened by using questionnaire.G. Eating habits:- SCOFF tool can be used forscreening.H. Quality of life: -modified (PCOS Q) may be usefulclinically to highlight PCOS features.Treatment modalities based on ESHRE 2018Vol.19, No.9; January, 2020guidelines6:Holistic approach for management of PCOS isrequired and pharmacological therapy in PCOS needsto be considered along with health education, lifestylemodifications and other options including cosmetictherapy and counselling. Objectives of managementin adolescent PCOS are treatment of menstrualIrregularity; management of hirsutism, alopeciaand acne i.e individual PCOS manifestations inadolescents should be treated. Another importantgoal is to reduce the far reaching consequences ofinsulin resistance and glucose intolerance as well asdevelopment of metabolic syndrome in these cases byinculcating good life style measures.A. Lifestyle measures- This is advocated as initialmanagement and as an adjuvant with any othermodality: Diet – Achievable goals such as 5% to 10%weight loss in those with excess weight yieldssignificant clinical improvement Overweight and obese: Advocate an energydeficit of 30% or 500 - 750 kcal/day (1,200 to1,500 kcal/day) Individualized approach for tailoring of dietarychanges: consider food preferences, avoid undulyrestrictive and nutritionally unbalanced diets Reduce carbohydrate to only 40% of totalcalories (130gms/d) 3 main meals / 3 snacks Avoid refined carbohydrates and sugars inprocessed foods Increase fibre content in diet by increasingfruit and vegetables / oat bran / barley Increase of intake of omega 3/6 fatty acids –fish / nut / olive oil Never skip breakfast / meals. Eat breakfastwithin 2 hours of waking up. Exercise – For modest weight-loss, prevention ofweight-regain and greater health benefitsA minimum of 250 min/week of moderateintensit

Dr Indu Chawla Dr Kiran Guleria Dr Manash Biswas Dr Manju Khemani Dr Manju Puri Dr Mala Srivastava Dr Ranjana Sharma Dr Renu Mishra Dr Reva Tripathi Dr Rupali Dewan Dr S N Basu Dr Sangeeta Gupta Dr Shalini Rajaram Dr Suman Lata AOGD Executive Committee 2019-20 Patrons Dr D Takkar Dr K