FOGSI FOCUS 2021

AMENORRHOEA

EDITORS :

DR. ALPESH GANDHI DR. ANITA SINGH PRESIDENT FOGSI VICE PRESIDENT FOGSI

CO-EDITOR DR. TRIPTI SINHA

FEDERATION OF OBSTETRIC & GYNAECOLOGICAL SOCIETIES OF INDIA The FOGSI Team 2020

Dr. Alpesh Gandhi Dr. S Shantha Kumari Dr. Nandita Palshetkar Dr. Jaydeep Tank President President Elect Immediate Past President Secretary General

Dr. Anita Singh Dr. Atul Ganatra Dr. Ramani Devi Dr. Archana Baser Dr. Ragini Agrawal Vice President Vice President Thirunavukkarasu Vice President Vice President Vice President

Dr. Madhuri Patel Dr. Suvarna Khadilkar Dr. Parikshit Tank Dr. Sunil Shah Dy. Secretary General Treasurer Jt. Treasurer Joint Secretary MESSAGE

Dr. S. Shantha Kumari President Elect

Dear FOGSIANS

It is indeed a formidable and challenging task to don the mantle of the President of FOGSI and step into the shoes of the stalwarts and doyens who have brought laurels to FOGSI during their tenure as President. But my confidence is boosted and gets a fillip since I will be supported by my new team of office bearers each of whom have righully earned their place in our organisaon.

I would like to congratulate Dr Anita Singh Vice President FOGSI East Zone and her team of contributors to FOGSI Focus dedicated to the common and oen perplexing clinical problem of amenorrhea. This issue covers the topic of amenorrhea from various perspecves to give a holisc view off this distressing enty. Its management oen oversteps the confines of a gynecologist's domain to ask for soluons from endocrinologists and imaging specialists in the quest to ascertain the diagnosis and decide upon a sasfactory management protocol for the paent ideally individualized for every paent.

Seasoned old me consultants and fresh- in- the -field budding gynaecologists will fall back on it with relief when hard pressed for me coupled with the urgency to manage girls and women with amenorrhea in their daily clinical pracce.

Happy reading and reflecng on past experiences of our own encounters with amenorrhea. foreword

Dear FOGSIANS, 12th June, 2021

It gives me immense pleasure to write this foreword for the FOGSI FOCUS on 'Amenorrhea' which is being edited by our dear and hardworking Dr. Anita Singh, Vice President FOGSI, 2020 .The enre team of Vice Presidents and chairpersons working with Dr. Alpesh Gandhi as President FOGSI, 2020 has done very commendable work, for FOGSI socially, academically and for the fraternity. The prevalence of amenorrhea is approximately 3,000 to 4,000 per 100,000 individuals worldwide. Amenorrhea can be a very perplexing problem if not aended to in an appropriate manner. The treatment for amenorrhea depends on the underlying cause. So taking a detailed history, counselling and reassurance of the girl and her parents is a very essenal part of the management . If primary or secondary amenorrhea is caused by lifestyle factors, destressing, change of weight and physical acvity may help . But if there are constuonal factors, congenital factors, endocrinological issues, it needs a muldisciplinary approach and one must do this at the appropriate me and systemac manner. This FOGSI FOCUS covers all aspects of amenorrhea starng from diagnosis to treatment . Understanding basic examinaon and screening tests would enable gynecologists to diagnose and treat women. Hearty Congratulaons to Dr. Anita Singh and her team of authors who have contributed to this FOGSI FOCUS. We are sure this will be a ready reckoner for clinicians and facilitate in their diagnosis and management of Amenorrhea.

Prof. Dr. Suchitra N. Pandit Consultant - Dept.of OBGYN ,Surya group of Hospitals ,Mumbai President Organisaon Gestosis ( 2016 ll date ) President ISOPARB (2018-20) Chair AICC RCOG ( 2017-20) President FOGSI & ICOG ( 2014-15) preface

In connuaon with its well-established tradion, FOGSI Focus connues its publicaon journey devoted to clinical problems encountered by gynecologists and obstetricians in their paent encounters. Amenorrhea is one such front-line problem with far-reaching and over-arching implicaons on a woman's health.

In this issue we have compiled inputs of eminent, seasoned clinicians who provide clinical insights into the problems of amenorrhea from various perspecves. The chapters are listed on the basis of their eology. Each chapter elaborates on the eo-pathogenesis followed by the clinical presentaon and management opons available, and which need to be discussed during paent counseling.

This crisp but comprehensive capsule of informaon between the covers of this issue of FOGSI Focus will come in handy and useful to consultants and post-graduate students alike as they confront a girl or woman who is worried about the absence or cessaon of her menstrual periods.

We are grateful to our President Dr Alpesh Gandhi who entrusted this academic task to us and extend our sincere thanks to the contributors in this issue who found me from their busy schedule to send in their write-ups.

Dr. Alpesh Gandhi Dr. Anita Singh Dr Trip Sinha List of Contributors

Dr. Anita Singh Dr. Kusum Lata MS,DGO, DNB MD, DNB Vice President, FOGSI (EZ), 2020 Assistant Professor, AIIMS Ex- Professor, Obs/ Gynae New Delhi Patna Medical College, Patna

Dr Aswath Kumar Dr Mandakini Pradhan MD, DGO, FICOG Prof and Head Professor OBG Department of Maternal and Jubilee Mission Medical College Reproducve Health Thrissur Sanjay Gandhi Post Graduate Vice President FOGSI 2019 Instute of Medical Sciences, Naonal Coordinator FOGSI Lucknow

Dr Megha Jayaprakash Dr. Alka Kriplani MS, DGO, MRCOG MD, FRCOG, FAMS, FICOG, FICMCH, Associate Professor OBG FIMSA, FCLS Govt Medical College Thrissur Director, Department of Minimal Invasive and ART Paras Hospitals, Gurgaon

Dr Prak Tambe Dr. Duru Shah Chairperson, AMOGS Endocrinology MD, FRCOG, FICOG, FICS, FCPS, Commiee (2020-22) FICMCH, DGO, DFP Governing Council member, ICOG Director, Gynecworld, the Center for (2021-22) Women's Health and Ferlity, Chairperson, FOGSI Endocrinology Mumbai Commiee (2017-19) Consultant Gynecologist & Managing Council member, MOGS Obstetrician, Ferlity Expert and ISAR

Dr Firdousara Siddiqui Dr Suvarna Khadilkar Resident, Department of Obstetrics Prof & HOD, Department of Obs and and Gynecology, Bombay Hospital, Gyne, and Consultant Gyne- Mumbai Endocrinologist, Bombay Hospital Instute of Medical Sciences, Mumbai Editor Emeritus JOGI Treasurer FOGSI List of Contributors

Dr. Sabahat Rasool Dr Trip Sinha MD, MRCOG, DNB, FMAS Ass Prof. Obs. Gyn Obstetrician, Gynecologist and Sri Krishna Medical College, Ferlity Consultant. Muzaffarpur, Bihar Lecturer, Government L D Hospital, Srinagar

Dr. Vandana Bhaa Dr. Sonia Malik MBBS, MD DGO, MD, FICOG, FIAMS Sr. Consultant Director & HOD, Southend Ferlity & Southend Ferlity & IVF IVF, 2,Palam Marg, 2,Palam Marg, Vasant Vihar, New Delhi Vasant Vihar, New Delhi

Dr. Sunil Shah Ferlity Expert (Germany) Joint secretary FOGSI, Hon. Secretary Ahmedabad. Past VP., AOGS Contents

1. Amenorrhea: An Overview ...... Dr. Anita Singh, Dr. Trip Sinha

2. Hypothalamic and Pituitary amenorrhea ...... Dr. Suvarna Khadilkar, Dr Firdousara Siddiqui

3. Amenorrhea: Endocrine Issues...... Dr. Prak Tambe

4. Hyperprolacnemia ...... Dr. Alka Kriplani, Dr. Kusum Lata

5. Amenorrhea in Polycysc Ovarian Syndrome ...... Dr. Duru Shah, Dr. Sabahat Rasool

6. Developmental anomalies causing amenorrhea ...... Dr. Ashwath Kumar, Dr. Megha Jayaprakash

7. Amenorrhea and Gonadal Dysgenesis ...... Dr. Mandakini Pradhan

8. Premature Ovarian Insufficiency ...... Dr. Sonia Malik, Dr. Vandana Bhaa

9. Asherman's Syndrome ...... Dr. Sunil Shah 1 Dr Anita Singh Amenorrhea: An Overview Dr Trip Sinha

Menstruaon is of great significance and concern to orifice, it is only the end-stage of a complex chain of any woman and her healthcare-provider. The events starng at the higher centers in the cessaon of menstruaon is of even greater concern hypothalamus linked to the events at successively to both and naturally sparks the queson: why did lower levels in the pituitary and ovary with some menstruaon stop? What are the implicaons of its confounding controls by other endocrine glands cessaon in the short and long term? The answers notably the thyroid and adrenals. It is, therefore, not would be contextual and need to be individualized. difficult to understand why invesgang a case of amenorrhea involves methods and assays which look Physiological Basis of Menstruaon into the normalcy or otherwise of the enre HPO In order to understand the eo-pathogenesis of –axis as well as the reproducve oulow tract. amenorrhea it is imperave to look into the Figures 1 and 2 are simplified schemac and pictorial physiological basis of menstruaon. Although the representaons of the events leading to outward manifestaon of menstruaon is the menstruaon and the controls at various levels. oulow of menstrual blood through the vaginal

Ovaries

Figure 1: Simplified schemac representaon of the events leading to menstruaon and controls at various levels

Figure 2: The hypothalamic-pituitary ovarian axis integrated to the reproducve oulow tract The menstrual cycle is divided into the following Health implicaons depend to a large extent on the cyclical and sequenal phases: menstruaon, early eology of amenorrhea. Hence, the need to establish and late follicular/proliferave phase, ovulaon, the cause of amenorrhea over-rides all other early and late luteal/secretory phase followed by its concerns while planning its management. The HPO repeon at regular or irregular cycle lengths which axis must be normal anatomically and funcon may vary in women and oen in the same woman at synchronously at various levels in order that neuro- different periods in her reproducve age span. The transmiers and hormones exert a normal end- different phases of each menstrual cycle have their organ effect on the endometrium ensuring its cyclical own hormonal milieu and endometrial histology. shedding off at the me of menstruaon.

The levels of progesterone, estradiol and inhibin-A This opening chapter of FOGSI Focus dedicated to the from a waning corpus luteum dip pre-menstrually problem of amenorrhea gives a brief capsular triggering a posive feedback on the anterior overview of the subject and sequenally clarifies pituitary to release more follicle-smulang basic concepts related to amenorrhea so that the hormone (FSH) to recruit ovarian graffian follicles subsequent chapters are seen in their proper with its oocytes for the next cycle. Gonadotropin perspecve. Amenorrhea is discussed under the –releasing hormone(GnRH) of hypothalamus is following headings: released into the intra-cranial portal circulaon in Ÿ Definion the vicinity of the pituitary gland in a pulsale Ÿ Classificaon/types of amenorrhea manner to iniate the follicular phase. The estradiol Ÿ Epidemiology and inhibin-B from the developing graffian follicles Ÿ Causes of amenorrhea and their classificaon provide negave feedback to pituitary FSH secreon Ÿ Implicaons of amenorrhea: short term and long so that it wanes by mid-follicular phase. Pituitary term luteinizing hormone(LH) follows a reverse profile in Ÿ Management issues including paent counseling follicular phase, decreasing inially with rising estradiol of early follicular phase but later rising Definion : drascally late in follicular phase(biphasic response). As a simple definion, amenorrhea is the absence or Just before ovulaon, FSH-induced LH receptors are cessaon of menstruaon. An adolescent girl or produced on granulose cells which subsequently woman in the reproducve age group who has never with LH smulaon modulate progesterone had spontaneous menstruaon has primary secreon. Aer adequate estrogen the pituitary LH amenorrhea while a woman who was previously surge is triggered leading to ovulaon 24-36 hours menstruang cyclically/acyclically but has currently later. In the subsequent early luteal phase ll mid- ceased to do so has secondary amenorrhea. The luteal days the estrogen decreases and again rises as terms primary and secondary are further elaborated a secreon from the corpus lureum. Inhibin –A is also upon in the next secon on classificaon /types of secreted concomitantly by the corpus luteum amenorrhea. smulaon. Dramac progesterone rise in this period of the menstrual cycle is a surrogate marker From a care-givers point of view, paents fulfilling for previous ovulaon occurrence. Progesterone, the following criteria merit evaluaon for evaluaon. estrogen and inhibin –A act in tandem on the central 1. No menses by the age of 14 in the absence of hypothalamic-pituitary axis in the luteal phase and growth/development of secondary sexual effecvely suppress gonadotropin secreon and new characteriscs follicular growth. As the corpus luteum withers and 2. No menses by the age of 16 regardless of the dies these hormones decline thus preparing for the presence of normal growth/development of subsequent cycles in an orderly sequence. A more secondary sexual characteriscs elaborate descripon of the menstrual physiology is 3. In previously menstruang women , no beyond the scope of this introductory chapter on menstruaon for an interval of me equivalent to a amenorrhea. (1) total of at least three previous cycles or no menses over a 6 month period(2) Classificaon/types of amenorrhea: be classified as primary and secondary amenorrhea. It helps in classifying the eology of amenorrhea from different perspecves: its me of onset, the A} Primary: a girl who has achieved the age of 14 level at which the eological factor operates and the years but has not menstruated nor shown visible presence and absence of secondary sexual signs of development of secondary sexual characteriscs. This clarity through classificaon characters, or a girl who has reached 15-16 years of helps the clinician to guide his workup for that age with developed secondary sexual characters but parcular paent. Management gets simplified if the not menstruated spontaneously are classified as above eological causes are inially categorized as having primary amenorrhea and merit invesgaon physiological or pathological on the basis of the and appropriate management. paent's history. The pathological group is further categorized into primary and secondary B} Secondary: a woman previously having amenorrhea. This then helps to target more menstruaon has failed to menstruate for the last definively the level at which any defect operates. few months equivalent to her previous three menstrual cycles at least or for the past six months is Depending on the me of its onset, amenorrhea may considered to have secondary amenorrhea.

Primary Amenorrhea Secondary Amenorrhea Constituitional delay(14) % Chronic anovulation(39%) Gonadal failure/ dysgenesis (43%) Hypothyroidism Imperforate hymen Hyperprolactinemia Congenital absence of uterus and vagina Extreme weight change (anorexia/bulimia) Hypothalamic failure( Kallman’s syndrome) Cushing’s syndrome Androgen insensitivity Adrenal tumors (Testicular Feminisation syndrome) Androgen producing ovarian tumors Premature ovarian insufficiency/ failure Pituitary infarction(Sheehan’s syndrome) Surgical extirpation of uterus &/or ovaries Radiotherapy Chemotherapy

Table 1 Summarises the causes of primary and secondary amenorrhea.

Based on its eology, amenorrhea is classified as Causes of amenorrhea and their classificaon follows: There is an exhausve list of pathological causes of amenorrhea. The causes have been logically A} Physiological: amenorrhea in pre-pubertal age classified in the WHO classificaon and by others group, following physiological natural menopause, working in the field of reproducve endocrinology . during pregnancy and lactaon. Physiological amenorrhea does not need any intervenon apart In the WHO classificaon of amenorrhea originally from observaon and documentaon of future there were only three groups; the fourth group was menstrual cycles and/or vaginal bleeding episodes. added subsequently.(3) B} Pathological: amenorrhea arising from any other Group 1 Hypo-gonadotropic hypo-gonadism cause apart from the above should induce the care (27.8%), giver to logically invesgate its cause on the basis of Group 2 Normo-gonadotropic anovulaon (23.7%) and anatomical and physiological basis of Group 3 Hyper-gonadotropic hypo-gonadism menstruaon and its likely aberraons in the index (48.5%) case. These causes may be congenital or acquired. Group 4 Hyper-prolacnemic anovulaon Level of lesion Type of lesions Hypothalamic Craniopharyngioma, Germinoma, Tubercular granuloma, sarcoid granuloma, dermoid cyst , Kallman syndrome Pituitary Craniopharyngioma, Germinoma , Tubercular granuloma, sarcoid granuloma, dermoid cyst, Non-functioning adenomas Hormone - secreting adenomas( prolactinoma, Cushing disease, acromegaly Infarction Lymphocytic hypophysitis Surgical/radiotherapy -induced ablations Sheehan syndrome Diabetic vasculitis Ovary Gonadal dysgenesis, FSH/LH hormone receptordefect, environmental & therapeutic ovarian toxins, galactosemia, Sex chromosome mosaicism, partial deletion of X chromosome, 17 -α hydroxylase deficiency in XX/XY individual ,ovo-testicular di sorder, Uterus Mayer -Rokitstansky - Kuster -Hauser syndrome, absent endometrium, Asherman syndrome(2*curettage, electro -excision, severe acute PID, tuberculosis, schistosomiasis Vagina Imperforate hymen, transverse vaginal septum Miscellaneous Androgen insensitivity Table 2: Eological causes of amenorrhea operang at different levels of the HPO axis and reproducve oulow tract

Aer clinical examinaon, each paent can be absence or presence of secondary sexual categorized into one of two groups on the basis of characteriscs (Table 3). Secondary Sexual Characteristics Secondary Sexual Characteristics Absent present Physiological delay Mullerian agenesis (imperforate hymen, transverse vaginal septum, Mayer-Rokitstansky- Kuster-Hauser syndrome) Gonadal dysgenesis Androgen insensitivity FSH/LH receptor defect Ovo-testicular disorder Sex chromosome mosaicism Absent endometrium Partial deletion of X chromosome Asherman’s syndrome Kallman’s syndrome Severe intra- uterine infections(tuberculosis,PID, schistosomiasis CNS Tumors Hypothalamic/pituitary dysfunction Enzyme deficiencies in XY individuals(5α– reductase, 17,20-lyase,17 α- reductase) Galactosemia Congenital lipoid adrenal hyperplasia Environmental & therapeutic ovarian toxins Table 3: Causes of amenorrhea with and without development of secondary sex characteriscs Emerging iatrogenic causes of amenorrhea include the importance of a rigorous medical and medicaon radiotherapy and chemotherapy for malignancies history. as well exrpave surgery on uterus and ovaries. An Table 4 is a comprehensive list of eological causes expanding list of medicaons frequently prescribed compiled by the the American Society of to women needs to be kept in mind thus emphasizing Reproducve Medicine.(4) I. Anatomic defects (outflow tract) III. Hypothalamic causes A. Mullerian agenesis (M -R-K-H syndrome) A. Dysfunctional B. Complete androgen resistance (testicular 1. Stress feminization) 2. Exercise C. Intrauterine synechiae (Asherman 3. Nutrition -related a. Weight loss, diet, malnutrition b. Eating disorders syndrome) (anorexia nervosa, bulimia) D. Imperforate hymen 4. Pseudocyesis E. Transverse vaginal septum B. Other disorders F. Cervical agenesis —isolated 1. Isolated gonadotropin deficiency G. Cervical stenosis —iatrogenic a. Kallmann syndrome H. Vaginal agenesis —isolated b. Idiopathic hypogonadotropic hypogonadism I. Endometrial hypoplasia or aplasia — 2. Infection congenital a. Tuberculosis b. Syphilis c. Encephalitis/meningitis d. Sarcoidosis 3. Chronic debilitating disease 4. Tumors a. Craniopharyngioma b. Germinoma c. Hamartoma d. Langerhans cell histiocytosis e. Teratoma f. Endodermal sinus tumor g. Metastatic carcinoma

II. Primary hypogonadism IV. Pituitary causes A. Gonadal dysgenesis a. Tumors 1. Prolact inomas 1. Abnormal karyotype 2. Other hormone -secreting pituitary tumor (ACTH, a. Turner syndrome 45,X thyrotropin -stimulating hormone, growth hormone, b. Mosaicism gonadotropin) 2. Normal karyotype b. Mutations of FSH receptor a. Pure gonadal dysgenesis i. 46,XX ii. c. Mutations of LH receptor 46,XY (Swyer syndrome) d. Fragile X syndrome B. Gonadal agenesis C. Enzymatic deficiency B. Space-occupying lesions 1. Empty sella 2. Arterial aneurysm 1. 17a-Hydroxylase deficiency C. Necrosis 1. Sheehan syndrome 2. Panhypopituitarism 2. 17,20-Lyase deficiency D. Inflammatory/infiltrative 3. Aromatase deficiency 1. Sarcoidosis D. Premature ovarian failure 2. Hemochromatosis 1. Idiopathic 3. Lymphocytic hypophysitis 2. Injury a. Chemotherapy b. E. Gonadotropin mutations (FSH) Radiation c. Mumps oophoritis 3. Resistant ovary a. Idiopathic E. Ovarian tumors 1. Granulosa -theca cell tumors 2. Brenner tumors 3. Cystic teratomas 4. Mucinous/serous cystadenomas 5. Krukenberg tumors 6. Metastatic carcinoma V. Other endocrine gland disorders VI. Multifactorial & other causes A. Adrenal disease 1. Polycystic ovary syndrome 1. Adult-onset adrenal hyperplasia 2. Autoimmune disease 2. Cushing syndrome 3. Galactosemia B. Thyroid disease 1. Hypothyroidism 2. Hyperthyroidism Table 4: Classificaon of amenorrhea (not including disorders of congenital sexual ambiguity)-adapted from the American Society of Reproducve Medicine Management issues including paent counseling group to be pregnant unless proved otherwise. No consensus has been reached regarding the point at which oligomenorrhea becomes amenorrhea. Management oen involves inputs from other Some authors suggest the absence of menses for 6 m e d i c a l d i s c i p l i n e s n o t a b l y i n t e r n i s t , months constutes amenorrhea, but the basis for endocrinologist, neuro-surgeon and psychiatrist. this recommendaon is unclear. For a post- However, most cases can be managed by menarchal girl or a reproducve-aged woman to gynecologists and even primary healthcare experience a menstrual cycle interval of more than physicians provided their management plan is 90 days is stascally unusual. Praccally speaking, derived from a clear concept of the HPO axis and the this should be an indicaon for a thorough evaluaon reproducve oulow tract anatomy. to seek the cause. Certain clinical points need to be kept in mind while Important clinical consideraons in management of invesgang a case of amenorrhea. First, though the amenorrhea involve the following issues:- disncon between primary and secondary 1) To manage acvely or merely to keep under amenorrhea is important from the purpose of observaon currently classificaon somemes the cause may overlap both 2) Management modalies for acve intervenon primary and secondary amenorrhea (Figure 3). 3) How long to connue the intervenon Secondly, a girl showing obvious clinical sgmata of certain disorders like Turner's syndrome or vaginal Amenorrhea warrants invesgaons if it occurs in agenesis may be evaluated earlier even before the periods of life when physiological amenorrhea does normal age of menarche and puberty and the not occur. It is prudent clinical pracce to consider all parents counseled regarding her management and cases of amenorrhea in women of reproducve age prognosis holiscally.

Figure 3: Discrete and overlapping causes of primary and secondary amenorrhea

A well taken history may reveal the correct eology History- taking commences with quesons related to of amenorrhea in up to 85% cases. The inial menstrual-type pains and/or menstrual molimina in consultaon should be devoted to a systemac a girl who does not report menarche. In such girls the elaborate history-taking followed by a complete me since when breast development commenced methodical physical examinaon of not only the should be enquired into. Women who cease to have gynecological organs per se but all systems in general periods aer a previously menstruang should be since amenorrhea may be merely one of the asked to elaborate on their previous menstrual worrying manifestaons of a disease which details especially whether lengthening cycles or secondarily involves the gynecological system of the progressively reduced flow had culminated finally in woman. the amenorrhea. In a young girl it is important to clarify whether she only had menstrual-type bleeds following hormone intake prescribed elsewhere. visual defects should guide invesgaons towards Such a history categorises her as a case of primary the central nervous system; similarly the renal amenorrhea rather than secondary amenorrhea system disorders by causing elevated prolacn levels who responded as a posive hormone challenge and inflammatory bowel disease should also not be withdrawal bleed and gives a pointer to likely overlooked. Progressive hirsusm and /or virilisaon eologies of the amenorrhea. as reported by the paent should be looked into and may be manifestaon of classical late-onset Obstetric history with regard to severe postpartum congenital adrenal hyperplasia, androgen- hemorrhage oen requiring blood transfusion producing ovarian or adrenal tumor. Changes in hair suggests Sheehan's syndrome leading to hypo- distribuon (excessive altered hair growth paern or pituitarism and hypo-gonadotropic amenorrhea; thinning or loss of scalp hair or brows should lead the manual removal of placenta or severe puerperal clinician to invesgate along the line of thyroid sepsis may lead to amenorrhea by causing uterine dysfuncon or polycysc ovarian disease. synechiae (Asherman's syndrome). A host of frequently prescribed medicaons to Personal history with respect to appete, diet and modern day women can cause hyper-prolacnemia caloric intake and exaggerated weight loss/gain may or other central HPO axis dysfuncon by altering indicate hypothalamic dysfuncon (anorexia neuro-transmier secreon and contribute to nervosa or bulimic disorder) as do excessive mental amenorrhea. Examples include androgens, oral and physical stress and radical life-style changes contracepve pills, medroxy- progesterone acetate, including exercise paern. Symptoms related to progestogen intra-uterine systems, GnRH agonists hypo-estrogenism (hot flushes, mood changes, uro- and drugs causing hyper-prolacnemia( genital discomfort) should be enquired into in p h e n o t h i a z i n e s , r e s e r p i n e d e r i v a v e s , relevant contextual sengs. amphetamines, benzodiazepines, an-depressants, dopamine antagonists, opiates).Table shows Central nervous system complaints (headache, commonly prescribed medicaons which can cause seizures, recurrent otherwise unexplained voming, amenorrhea (Table 5)

Group of drug Names of drugs Steroid hormones Oral contraceptive pills, estrogens, progestogens (medroxy - progesterone acetate, progestogen intra -uterine systems), anabo lic steroids, GnRH agonists, androgens Anti -psychotic drugs Resperidone Anti -depressant drugs Benzodiazepines Anti -hypertensive Reserpine derivatives drugs Anti -allergics ? cetrizine Cytotoxic agents Alkylating agents (Busulphan, Cis -platinum Chlora mbucil, Cyclophosphamide, Nitrogen mustardS), Melphalan, , , Procarbazine, , Adriamycin, Anti -epileptics Phenobarbitones,phenytoin,carbamazepine,valproic acid Addiction drugs Cocaine, opiods, amphetamines Miscellaneous Dopamine agonists, cimetidine Table 5: Medicaons likely to cause cessaon of menstruaon Though amenorrhea ulmately manifests as an levels of circulang androgens and the presence and abnormality of the reproducve oulow tract, clues recepvity of androgen receptors for sexual hair as to its cause are oen/generally found in other growth. The dimensions of the clitoris, status of the systems like the central nervous system, endocrine hymen, presence of any transverse septum vaginal system and skin. At the commencement of the and vaginal canalizaon/atresia need to be examinaon, the paent's habitus, body mass index systemacally documented as indicated by the and the waist: hip index need to be documented. An paent's history. If needed a vaginoscopy with a obese or asthenic built especially when associated slender vaginoscope may be done to reveal the with extreme rapid changes. Notable findings in the presence or absence of a cervix. In a sexually acve skin include its dryness or moistness (thyroid woman a complete vaginal speculum examinaon dysfuncon), type and distribuon of hair (hirsusm, followed by an internal bimanual vaginal alopecia), acanthosis nigrans, purple stria. Lid lag, examinaon is to be recorded in a proper format. For exophthalmus and loss of lateral third of brow hair those not sexually acve per rectal assessment of the are pointers to thyroid disorders as also fullness in uterus and adnexa is carried out. the thyroid region of neck, exaggerated reflexes, full bounding peripheral pulse and fine hand tremors. On the basis of a logical history and a well-conducted systemac physical examinaon the subsequent Breast development scored on the basis of Tanner's workup of the paent can be more directed. In classificaon should be documented as surrogate paents who do not demonstrate any obvious markers for estrogen exposure whether natural or eology the workup should be in a stepwise manner exogenous as also advanced breast growth in addressing all levels of the HPO axis and the relaon to expected development for biological age, reproducve oulow tract. regression in size of previously well-developed breasts, breast striae and the presence and The further workup requires blood assays by characteriscs of any nipple discharge. Purple striae different modalies and laboratory techniques for on abdominal skin, buocks and thighs should be hormones related to the HPO axis. Imaging taken note of. A supra-pubic lump could be a techniques like high-resoluon state of art hematometra explaining primary amenorrhea or an ultrasound, computerized tomography and magnec ovarian tumor causing secondary amenorrhea. resonance imaging look into the normalcy or otherwise of the reproducve oulow tract, ovaries Paern of sexual hair growth in the infra-umbilical and intra-cranial hypothalamic and pituitary lesions. area, the shape of the pubic hair line whether in male Oen karyotyping and laparoscopy are indicated in escutcheon paern or not and vulval hair growth order to reach the diagnosis of the cause of amenorrhea.

Investigation modality Test performed Biochemistry Laboratory FSH, LH, estradiol, progesterone, prolactin,auto -immune an tibodies Microbiology laboratory PCR for mycobacterium uberculosis Genetic laboratory Chromosomal karyotyping, gene studies, FMR -1, Anti - CYP21 Imaging facility Ultra sound of ovaries and reproductive outflow tract (Antral follicle count -POI, PCOS dis tribution of multiple peripheral small sized cysts) CT scan of hypothalamus and pituitary MRI of hypothalamus and pituitary Endoscopy Hysteroscopy Laparoscopy Table 5: Invesgaons in evaluang amenorrhea Tables 6 and 7 indicate the levels of hormones and findings useful in clinching the eology responsible other relevant clinical findings and invesgaon for causing amenorrhea.

Table 6: Clinical findings and invesgaons in different causes of primary amenorrhea

Table 7: Clinical findings and invesgaons in different causes of primary amenorrhea

The following two flowcharts depict the sequence to of primary and secondary amenorrhea. be followed while examining and invesgang cases Treatment depends on the underlying cause children or contracepve intenons of amenorrhea. delineated by the abovemenoned workup protocol. Figure 4 is a simplified decision making tree It also takes into consideraon the need for regular summarizing the clinician's approach to a case of periods, future reproducve concerns like desire for amenorrhea.

Ascertain by Hx whether primary or secondary !! Check for hormone -induced withdrawal bleed

Urine pre gnancy test positive manage !! all cases appropriately

Negative

Primary Amenorrhea Secondary Amenorrhea

2*sexual characters + ve 2*sexual characters -ve - Progesterone Challenge Test / E.T.* -Hormone assays -CNS imaging Reproductive Outflow External Stigma of Tract evaluation Chromosomal disorders FSH, LH, TSH, Prolactin (Clinical exam . & eg Turners, AIS Ultrasound) ↑FSH ↑TSH ↑Prolactin HPO axis evaluation ↑ a) Hormonal assays Treat as appropriate b) Chromosomal studies Premature ovarian c) Auto -immune a.b.tests failure Treatment options usually surgical ↑FSH PCOS

*Counsel parents re. prognosis HRTs *Special ART for successful Ovum donation Treat as per pregnancy possible guidelines *E.T. endometrial thickness Figure 4: Simplified decision-making tree for evaluang and treang a case of amenorrhea

This opening chapter of FOGSI focus dedicated to the References very important and o-encountered gynecological 1.Olive D L & Palter S F. Reproducve physiology. In Berek enigma of amenorrhea with all its aendant issues &Novak's Gynecology. Fourteenth Ed.2007. Wolters and concerns orients the reader to the approach Kluwer/Lippinco Williams & Wilkins. Chapter 7. p 173. which needs to be taken by the caregivers at primary 2.Speroff's Clinical Gynecologic Endocrinology and and referral levels when a girl or woman aends for Inferlity;9th Edion/South Asian Edion.2011. Wolters consultaon with this presenng complaint. The Kluwer.Vol.1.Chapter 10. Amenorrhea:p.343 3. Insler V, Melmed H, Mashiah S, Monselise M, Lunenfeld subsequent chapters individually dilate upon the B, Rabau E. Funconal classificaon of paents selected most important causes which confront the fo r go n a d o t ro p i c t h e ra p y. O b stet Gy n e co l . gynecologist. I am confident that readers will find the 1968;32(5):620-6. contained material most useful for themselves in 4. The Pracce Commiee of the American Society for their clinical pracce and confidently and raonally Reproducve Medicine. Current evaluaon of manage paents in their individual pracce setups. amenorrhea. Ferlity and Sterility Vol. 90, Suppl 3, N o v e m b e r 2 0 0 8 . S 2 1 9 - 225.doi:10.1016/j.fertnstert.2008.08.038 2 Hypothalamic and Pitutary Dr Suvarna Khadilkar Amenorrhea Dr Firdousara Siddiqui

Introducon Amenorrhea is a common clinical presentaon which needs a thorough work up to pi point the diagnosis. Intact hypothalamo-pituitary ovarian axis (HPO) is essenal for normal menstruaon. Any dysfuncon in the HPO axis or other endocrine glands can lead to amenorrhea. It is also necessary that the reproducve tract is developed fully and normally for normal menstruaon.

Paent fulfilling any of the following criteria should be evaluated for amenorrhea- Ÿ No menses by age 14 in the absence of growth or development- of secondary sexual characteriscs. Ÿ No menses by age 16 regardless of the presence of normal growth and development of secondary Sexual characteriscs. Ÿ In women who have menstruated previously, no menses for an interval of me equivalent to a total of at least three previous cycles or no menses over a 6-month period [1].

This chapter will focus on amenorrhea caused by dysfuncon or disorders of hypothalamus and pituitary. Pathophysiological consideraons: Condions that oen precede anovulaon include Hypothalamic dysfuncon is one of the most common marked weight loss, physical exercise, physical and causes of Secondary amenorrhea. Secondary mental stress, oral contracepve use. Amenorrhea is amenorrhea, occurs in approximately 3–5 % of adult usually a result of hypogonadotrophic women. According to the American Society of hypogonadism, marked by low or normal LH, FSH, Reproducve Medicine (ASRM), Funconal and estradiol levels. Normal prolacn, and low lepn Hypothalamic Amenorrhea (FHA) accounts for 20–35 are also seen in this type of amenorrhea. LH and FSH % of secondary amenorrhea cases and 3 % of primary however do show response to GnRH smulaon. amenorrhea [ 2]. The incidence is higher in athlete women. 50 % of women who exercise regularly The cyclic nature of the hormonal changes is at halt, experience subtle menstrual disorders and so is the pulsale secreon of GnRH. Persistent slow approximately 30 % of women have amenorrhea frequency of GnRH secreon is inadequate to according to study by DeSouza et al [3]. The female maintain the level of LH synthesis and secreon athlete triad first described in 1997 is complex of required for an ovulatory LH surge, hence leads to distorted eang, amenorrhea and osteoporosis [ 4]. anovulaon. Extreme physical, nutrional or emoonal stress leads to funconal suppression of Hypothalamic amenorrhea is diagnosed only aer reproducon as a psychobiologic response of life ruling out pituitary and ovarian abnormalies. events. Stress elevates corcotropin-releasing hormone Clinicians should also obtain a thorough family (CRH), which inhibits GnRH secreon and history with aenon to eang and reproducve reproducve funcon in animal studies. Some disorders. women with hypothalamic amenorrhea have elevated plasma corsol levels and blunted Invesgaons responses to CRH, which suggests stress-induced Complete blood count, esmaon of electrolytes, abnormalies in CRH secreon. In women where glucose, bicarbonates blood urea nitrogen, amenorrhea is associated with strenuous exercise, creanine is recommended. Liver funcon tests, ESR, data suggest a negave energy balance is a C-reacve protein, and basic endocrine work up is precipitang factor, and plasma lepn levels are also recommended. Basic endocrine work up reduced. Hypolepnemia appears to be an includes serum thyroid-smulang hormone, free important factor in athletes and women at low body thyroxine (T4), luteinizing hormone, follicle- weight. Administraon of recombinant human lepn smulang hormone, estradiol, and an-Mullerian for 3 months may increase GnRH pulsality. hormone. Androgen levels are advised only when clinical hyperandrogenism is present. Disorders of Hypothalamus and Pituitary Leading to Amenorrhea: A baseline bone mineral density (BMD) Ÿ CNS disorders measurement by dual-energy X-ray absorpometry -Chronic hypothalamic anovulaon (DXA) should be obtained with 6 or more months of - Stress amenorrhea. - Increased exercise levels - Anorexia nervosa Pelvic ultrasound in all paents to ensure normalcy, -Pseudocyesis and MRI pelvis only when indicated is advised. -Funconal amenorrhea -Isolated GnRH deficiency Diagnosc tests: – Head trauma Most commonly performed progesterone challenge – Space-occupying lesions, infecons test with 10 mg medroxyprogesterone for 5 days is Ÿ Pituitary disorders useful to differenate between ovarian cause and – Hyperprolacnemia hypothalamic cause. If withdrawal period is - Prolacnoma achieved, then it denotes presence of endogenous - Medicaons estrogen and ensures oulow tract funcon and - PCOS patency. There will be no withdrawal period if there is - Renal failure no endogenous estrogen present like in – Hypoprolacnemia hypothalamo-pituitary causes. – Pituitary stalk resecon – Sheehan's syndrome Following tests are used only when the diagnosis cannot be made with roune clinical examinaon Diagnosis and Management : and invesgaons. Detailed personal history with a focus on following 1. GnRH smulaon test: this is of use to differenate points: between hypothalamic and pituitary causes of Dietary habits, history of eang disorders, exercise hypogonadism.100 μg GnRH is given intravenously. and athlec training; atudes such as perfeconism LH and FSH response is measured with samples at 0, and desire for social approval; highly ambious 20 and 60 minutes In pituitary disease, response is personality, high expectaons for self and others, too either absent or blunted. In hypothalamic disease, many weight fluctuaons, irregular sleep paerns, normal response is seen. stressors, mood fluctuaons, menstrual paern; 2. Clomiphene smulaon test may be useful to fractures, and substance abuse. disnguish organic causes of gonadotropin deficiency (pituitary or hypothalamic pathology) from funconal disorders and idiopathic delayed suscepbility is idenfied on loci for Anorexia puberty. In healthy adults, clomiphene blocks nervosa on chromosome 1 and for bulimia nervosa estrogen feedback mechanisms in the hypo- on Chromosome 10. thalamus, thus leading to a rise in GnRH ( g o n a d o t ro p i n - re l e a s i n g h o r m o n e ) a n d Two types of Anorexia nervosa have been defined consequently circulang LH and FSH. Aer 7 days of restricng and binge/purging. The diagnosc Criteria clomiphene smulaon, if LH levels increase more for bulimia nervosa are disnct from those for than 120% and FSH increases more than 40 %, the anorexia nervosa primarily in that they do not response is considered normal. A normal response include low body weight or amenorrhea. e s s e n a l l y r u l e s o u t o rga n i c c a u s e s o f hypogonadotropic hypogonadism and in delayed The weight loss due to any reason will result in puberty, it is an indicaon that sexual maturity will reducon in total percentage of fat in the body. 22% ensue. of body fat is the crical body fat percentage 3. In hypothalamic-pituitary pathology there is no necessary for sustaining menstruaon. If this response. Not useful in girls with early puberty.To percentage drops below 22% then the amenorrhoa differenate between funconal and organic cause or the menstrual dysfuncon results. Anorexa of amenorrhea, some form of imaging of the brain nervosa paents exhibit hypercorsolism due to (CT or MRI) to rule out a tumor may be useful increased corcotropohin releasing hormone especially when a history of severe or persistent [CRH}and ACTH. CRH directly inhibits GnRh secreon headaches; persistent voming, unexplained change through increased endogenous opioids hence leads in vision, thirst, or urinaon, lateralizing neurologic to speroff's compartment IV amenorrhoea. Brain signs, and any indicaon of pituitary hormone senses the blood levels of lepn If weight loss is due deficiency or excess. to excessive physical exercise, it is found that the athletes have 3 fold lower levels of lepn .therefore Treatment : even athletes have amenorrhoea. General principles : • For acute and morbid paents inpaent therapy is Somemes those suffering with anorexia or bulimia required do not appear underweight. Some may be of average • Correcng the energy imbalance is important weight or slightly overweight. Variaons can be • If nutrional, psychological, and modified exercise anywhere from extremely underweight to extremely intervenon (Cognive behavior therapy CBT) are overweight. The appearance of a person suffering not effecve, oral contracepve pills for with an eang disorder does not dictate the amount maintenance of menstrual cycles and Bone mineral of physical danger they are in, nor does it determine density are required. the severity of emoonal conflict they are enduring. • Bisphosphonates, denosumab, testosterone, and lepn are not recommended [5] Prevenon and idenficaon of early or paral • If CBT is not effecve, treatment with pulsale disorder to prevent full blown syndrome is gonadotropin-releasing hormone (GnRH) as a first important. line, followed by gonadatropin therapy and inducon of ovulaon, is used for treatment of Diagnosis is usually clinical but GnRH levels close to inferlity. zero in presence of high levels of corsol differenate this disorder from pituitary insufficiency. Weight loss Eang disorders : due to other endocrine or other diseases may be Cultural influences, other psychological, biologic, misdiagnosed and vice versa. genec and social factors likely contribute to development of eang disorders. Peripubertal girls Complicaons: and young women having first degree relaves with Paent with anorexia nervosa are at risk for many an eang or affecve disorder or alcoholism are at complicaons related to nutrional and electrolyte increased risk of developing eang disorder. The imbalances Amenorrhea Anovulaon Neuropathies Myopathies Life-threatening cardiac arrhythmias, Eang disorders are relavely rare in India but may Gastris, Esophagis, Weakness from chronic be picked up more oen if acvely looked for. Acve anemia. search may help early diagnosis, as well as effecve The most common cause of death in anorexia treatment and will reduce high mortality associated nervosa is suicide. with it. Change of lifestyle, psychological counseling of not only the peripubertal girls but also of their Treatment: disturbed family is important. Management requires a team approach in which different professionals work together. Individual and Stress or exercise induced amenorrhea: family psychotherapy are effecve in paents with Women who are involved in strenuous recreaonal anorexia nervosa and cognive-behavioral therapy is exercise or other forms of demanding physical effecve in bulimia nervosa. acvity such as dancing have a high prevalence of menstrual irregularity and amenorrhea.[3] The Care of paents with anorexia nervosa includes potenal adverse effect of intense exercise and low stabilizaon for any life-threatening condions (eg, body weight on menstrual funcon is synergisc. shock, cardiac arrhythmias). In addion, protecon of the paent may be necessary if risk of suicide is Exercising amenorrheic women do not exhibit a present. Treatment may include rehydraon, normal diurnal lepn rhythm; treatment with correcon of electrolyte abnormalies (eg, exogenous recombinant human lepn can restore hypokalemia), and instuon of appropriate gonadotropin pulsatality, follicular development and disposion for connuing medical and psychiatric ovulatory funcon in exercising amenorrheic treatment. Consultaon with psychiatry and women.[4] adolescent medicine specialists in order to opmize inpaent care and facilitate outpaent follow-up Congenital GnRH deficiency (normosmic) is seen in care should be done. rare individuals, congenital specific mutaon that prevents normal GnRH neuronal migraon during For nutrional therapy, forced feedings with total embryogenesis or to mutaon in the pituitary GnRH parenteral nutrion or tube feedings provide receptor. nutrients, stabilize nutrient deficiency syndromes, and alter mood when the paent becomes Kallmann Syndrome is Congenital GnRH deficiency nutrionally replenished. Preliminary treatments associated with anosmia or hyposmia the disorder is with opiate antagonists have shown promising known as Kallmann Syndrome, classical X linked results. Monitoring of nutrional status (eg, serum disorder, caused by genec mutaon in the KAL gene. protein and albumin, electrolytes, serum glucose) is Kallmann syndrome can be inherited in autosomal important. As nutrional status improves, outpaent dominant or recessive fashion. treatment can be offered. Daily caloric intake 2600 cal /day is advised. Ongoing psychiatric care is GnRH Receptor Mutaons- There are more than 20 necessary, as the relapse rate is high. inacvang mutaons in the GnRH receptor gene (GNRHR). Some results in interference with normal Prognosis: Signal transducon, some effecvely prevent GnRH • The general prognosis is related to the severity of binding, both results in resistance to GnRH t h e u n d e r l y i n g p e r s o n a l i t y a n d f a m i l y smulaon. psychopathology. • The prognosis for paents with a bulimic Disorder of Anterior Pituitary component is worse than for those without bulimia. Variety of disorder involving anterior pituitary may Death for paents with bulimia is 5-40%. cause amenorrhea ,most common by far is benign A small percentage of paents become symptom Adenomas, Other include craniopharyngioma, free, 30% remain chronically ill, and the rest are meningiomas, gliomas, metastac tumors and vulnerable to the return of symptoms during chondromas. stressful mes . Pituitary adenomas are classified by cell type and size Conclusion: and may be funconal (hormone secreng) or Hypothalamic and pituitary Amenorrhea is an nonfunconal. Tumors less than 10mm in size are underesmated clinical problem. It is related to called microadenomas and those 10mm or larger are profound impairment of reproducve funcons called macroadenomas. Pituitary adenomas may be including anovulaon and inferlity. Women's health incidentally diagnosed while evaluang for in this disorder is disturbed in several aspects neurological Symptoms or workup of menstrual including their skeletal system, cardiovascular irregularies The most common neurological system and mental problems. Paents manifest a symptoms associated with pituitary tumors, decrease of bone mass density, which is related to an macroadenomas is visual impairment, classically increase of fracture risk. Therefore, osteopenia and Bitemporal hemianopsia, other symptoms include osteoporosis are the main long-term complicaons decreased visual acuity, diplopia, headache, CSF of Hypothalamic Amenorrhea. Cardiovascular rhinorrhea, pituitary apoplexy. complicaons include endothelial dysfuncon and abnormal changes in the lipid profile. Hypothalamic Pituitary adenomas (Prolacnoma) are treated with Amenorrhea paents present significantly higher Dopamine agonist bromocripne, Drug of choice and depression and anxiety and also sexual problems recommended dose is 1.25mg at bedme daily for compared to healthy subjects. the first week and then gradually increased. Other promising drug is cabergoline given in dose of Amenorrhea paents should be carefully diagnosed 0.25mg once or twice weekly ll tumors shrink, and properly managed to prevent both short- and transsphenoidal resecon of tumor is done if medical parcularly long-term medical consequences. therapy fails.

Sheehan Syndrome Necrosis of the pituitary following postpartum REFERENCES: hemorrhage may lead to Sheehan syndrome. 1. Hugh S Taylor, Lumina pal, Emre Seli, Speroff''s Syndrome may develop slowly over 8–10 years' me. Clinical Gynecologic Endocrinology and Inferlity, The hormones like GH, FSH and LH, TSH and ACTH are 9th Edion; Wolters kluwer; 2019: (342-395) reduced. Inially failed lactaon can be the 2. Pracce Commiee of American Society for presenng symptom. Secondary amenorrhea and Reproducve Medicine (2006) Current evaluaon of loss of secondary sexual characteriscs are seen in Amenorrhea.Ferl Steril 86:S148 most cases. Replacement of deficient hormones is 3. De Souza MJ et al (2009) High prevalance of subtle necessary in majority of cases to maintain quality of and severe menstrual disturbances in exercising life. women: confirmaon using daily hormone measures.Hum Reprod 25:491-503 Inappropriate secreon of prolacn (including drugs, 4.Os CL et al (1997) American college of Sports other diseases, e.g. hypothyroidism, prolacnoma) medicine posion stand. The Female athlele triad. will affect secreon of LH and FSH. Med Sci Sports Exerc 29:1-9 5. GORDON, Catherine M., et al. Funconal GnRH smulaon test differenates between hypothalamic amenorrhea: an endocrine society hypothalamic and pituitary cause of hypogonadism. clinical pracce guideline. The Journal of Clinical Clomiphene smulaon test disnguishes organic Endocrinology & Metabolism, 2017, 102.5: 1413- cause of gonadotropin deficiency from funconal 1439. hps://doi.org/10.1210/jc.2017-00131 disorder and idiopathic delayed puberty. 6. Dr Suvarna Khadilkar's Endocrinology in Obstetrics Clomiphene blocks estrogen feedback mechanism in and Gynaecology, 1st Edion; FOGSI , Jaypee hypothalamus, normal response rules out publicaon;2015: (155-167) hypogonadotropic hypogonadism and delayed puberty, no response is seen in hypothalamus- pituitary pathology, diagnosis of funconal disorder is made by CT or MRI imaging.[6] 3 Amenorrhoea: Endocrine Issues Dr Prak Tambe

Background hyperandrogenism and polycysc ovary syndrome The recognion that rhythmic producon of have all been dealt with in publicaons since over 50 oestrogen and progestogen by the ovary is central to years ago.1 the cycle of follicular ripening, ovulaon, corpus luteum formaon, degeneraon and menses has Aeology been part of medical science since centuries and is The commonly encountered causes of amenorrhoea affirmed in medical texts. The pathological issues can be categorised as oulow tract abnormalies, surrounding amenorrhoea including congenital and primary ovarian insufficiency, hypothalamic and acquired disease of the ovary, faulty ovarian pituitary disorders, neuroendocrine issues and development, genec issues and sex reversal, sequelae of many chronic disease.

Outflow tract abnormalities Hypothalamic or pituitary disorders (continued) Other endocrine gland disorders Acquired Constituional delay of puberty Adrenal insufficiency Cervical stenosis Empty sella syndrome Androgen-secreting tumor (e.g., ovarian Intrauterine adhesions Functional (overall energy deficit or stress) or adrenal) Congenital Eating disorder Cushing syndrome 5α-reductase deficiency Stress Diabetes mellitus, uncontrolled Androgen insensitivity syndrome Vigorous exercise Late-onset congenital adrenal hyperplasia Imperforate hymen Weight loss Polycystic overy syndrome (multifactorial) Műllerian agenesis Gonadotropin deficiency (e.g., Kallmann syndrome) Thyroid disease Transverse vaginal septum Hyperprolactinemia Amenorrhea attributed to chronic disease Primary ovarian insufficiency Adenoma (prolactinoma) Celiac disease Acquired Chronic kidney disease Inflammatory bowel disease Autoimmune Medications or illicit drugs (e.g., antipsychotics, Other chronic disease Chemotherapy or radiation opiates) Physiologic or induced Congenital Physiologic (pregnancy, stress, exercie) Breastfeeding Gonadal dysgenesis (other than Infarction (e.g., Sheehan syndrome) Contraception Turner syndrome) Infiltrative disease (e.g., sarcoidosis) Exogenous androgens Turner syndrome or variant Infectio (e.g., meningitis, tuberculosis) Menopause Hypothalamic or pituitary disorders Medications or illicit drugs (e.g., cocaine) Pregnancy Autoimmune disease Trauma or surgery Brain radiation Tumor (primary or metastatic)

Table 1 Spectrum of disorders presenng with amenorrhoea2

Clinical findings The physical examinaon should idenfy A detailed history and thorough clinical evaluaon is anthropometric and pubertal development trends. a must though with the advent of new diagnosc All paents should be offered a pregnancy test and methodologies in our armamentarium, this is assessment of serum follicle-smulang hormone, somemes ignored. The history should include luteinising hormone, prolacn, and thyroid- menstrual onset and paerns, breast and pubic hair smulang hormone levels. Addional tesng, development, eang and exercise habits, presence including karyotyping, serum androgen evaluaon of psychosocial stressors, body weight changes, a n d p e l v i c o r b ra i n i m a g i n g s h o u l d b e medicaon use, galactorrhoea and any chronic individualised.[2,3,4] illness. Addional quesons may target neurologic, vasomotor, hyperandrogenic or thyroid-related symptoms. Findings Asociations

History Chemotherapy or radiation Impairment of specific organ or structure, (e.g., brain, pituitary, ovary) Family history of early or delayed menarche Constitutional delay of puberty Galactorrhea Pituitary tumor Hirsutism, acne Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing Illicit or prescription drug use syndrome Loss of smell (anosmia) Multiple associations, consider effect on prolactin Menarche and menstrual history Kallman syndrome (GnRH deficiency) Sexual activity Primary vs. secondary amenorrhea Significant headaches or vision changes Pregnancy Temperature intolerance, palpitations, diarrhea, Central nervous system tumor, empty sella syndrome constipation, tremor, depression, skin changes Thyroid disease Vasomotor symptoms (e.g., hot flashes or night sweats) Primary overian insufficiency, natural menopause Weight loss, excessive exercise, poor nutrition, Functional hypothalamic amenorrhea psychosocial distress, diets

Physical examination Abnormal thyroid examination Thyroid disorder Acanthosis nigricans or skin tags Hyperinsulinemia (PCOS) Anthropomorphic measurements; growth charts Multiple associations; Turner syndrome, constitutional delay of puberty Body mass undex High: PCOS Low: Functional hypothalamic amenorrhea Bradycardia Functional hypothalamic amenorrhea (e.g., anorexia nervosa) Breast development (normal progression) Presence of circulating estrogen* Dysmorphic features (e.g., webbed neck, short Turner syndrome stature, low hairline) Male pattern baldness, increased facial hair, acne Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH, Cushing Pelvic examination syndrome Absence or abnormalities of cervix or uterus Clitoromegaly Rare congenital causes including Müllerian agenesis or androgen Presence of transverse septum or imperforate insensitivity syndrome hymen Androgen-secreting tumor; CAH; 5α- reductase deficiency Reddened or thin vaginal mucosa Outflow tract obstruction Sexual maturity rating abnormal Decreased endogenous estrogen Striae, buffalo hump, central obesity, hypertension Turner syndrome, constitutional delay of puberty, rare causes Cushing syndrome

Table 2 Pathognomonic findings on clinical examinaon2

Invesgaons missed, the socioeconomic status of the paent These should be tailored to the differenal diagnosis should be taken into consideraon so that we do not aer history and clinical examinaon. While a baery over-burden the paent. of tests is oen ordered to ensure that no diagnosis is

Findings Associations

Laboratory testing (refer to local reference values) 17-hydroxyprogesterone level High: late-onset CAH (collected at 8 a.m.)

Anti-Müllerian hormone High: Functional hypothalamic amenor- rhea, PCOS Low: Primary ovarian insfciency

Complete blood count and Abnormal: chronic disease (e.g., elevated metabolic panel liver enzymes in functional hypothalamic amenorrhea) Findings Asociations

Estradiol Low: Poor endogenous estrogen production (suggestive of poor current ovarian function)

Follicle-stimulating hormone High: Primary ovarian inssufciency; and luteinizing hormone Turne syndrome Low: Functional hypothalamic amenorrhea Normal: PCOS; intrauterine adhesions; multiple others

Free and total testosterone; High: Hyperandrogenism, PCOS, ovarian dehydroepiandrosterone sulfate or adrenal tumor, CAH, Cushing syndrome

Karyotype Abnormal: Turner syndrome, rare chro- mosomal disorders

Pregnancy test Positive: Pregnancy, ectopic pregnancy

Prolactin High: Pituitary adenoma, medications, hypothyroidism, other neoplasm

Thyroid-stimulating hormone High: Hypothyroidism Low: Hyperthyroidism

Radiographic testing Dual energy x-ray absorptiometry Evaluation of fracture risk

MRI of the adrenal glands Androgen-secreting adrenal tumor

MRI of the brain (including sella)* Tumor (e.g., microadenoma)

Pelvic organ ultrasonography or Morphology of pelvic organs, polycystic magnetic resonance imaging ovarian morphology, androgen-secreting ovarian tumor

Table 3 A Snapshot of invesgaons in amenorrhoea2

While ordering a multude of invesgaons is quite is equally important. A muldisciplinary team easy and commonplace in modern pracce, having approach is also important to ensure that the the appropriate clinical knowledge to interpret them diagnosis is not missed.

LH (IU LH/ FSH (IU 17-OHP AMH DHEA-S Estradiol per L) FSH per L) Prolactin Testosterone TSH

Congenital adrenal High Normal High Low < 15 > 1 < 10 Normal High Normal hyperplasia normal

Functional hypotha- Normal High Normal Low < 10ϯ ~ 1 < 10ϯ Low Low normal Low lamic amenorrhea normal normal Hyperprolactinemia Normal Normal Normal or Low < 10 > 10 < 10 High Normal High slightly high normal Menopause Normal Low Normal Low < 15 < 1 >15 Normal Low normal Normal

Polycystic ovary Normal Normal High Low < 15 > 1 < 10 High High or high Normal syndrome of high normal normal normal

Primary ovarian Normal Low Normal Low < 15 < 1 > 15 Normal Low normal Normal insufficiency

Table 4 Interpreng hormonal invesgaons in amenorrhoea2 Primary ovarian insufficiency most common causes of secondary amenorrhea and Primary ovarian insufficiency affects approximately accounts for the reproducve dysfuncon seen in one in 100 women and is defined by follicle under-nutrion, excessive exercise, severe dysfuncon or depleon and two serum FSH levels in emoonal stress and chronic disease. From an the menopausal range obtained at least one month evoluonary standpoint, it is adapve for an animal apart. Vasomotor symptoms and vaginal dryness are to allocate energy resources for its own survival common. Most cases are idiopathic; however, rather than reproducon in the face of nutrional or irradiaon, chemotherapy, infecons, tumors, physical stress. Therefore, FHA is a physiological autoimmune processes, and chromosomal response to environmental and physical stressors.[7] irregularies can also cause primary ovarian insufficiency. A karyotype is abnormal in During periods of physical, nutrional, or extreme approximately one-third of paents and it should be emoonal stress, the hypothalamo-pituitary-adrenal offered to all paents with this diagnosis to idenfy (HPA) axis is acvated and inhibits the HPO axis at Turner syndrome or its variants.[5] mulple levels. At the level of the hypothalamus, CRH suppresses GnRH secreon. At the level of the Hormone replacement therapy (HRT) may reduce pituitary, ACTH has been shown to have negave associated vasomotor symptoms, bone mineral reproducve effects. Women with FHA also have density loss and cardiovascular risk and should be higher 24-hour mean plasma corsol levels which connued unl the age of natural menopause. A suppresses reproducve funcon at the common post-pubertal regimen of HRT is 100 mcg of hypothalamic, pituitary and uterine levels. daily transdermal estradiol or 0.625 mg of daily oral conjugated estrogens, adding 200 mg of micronised Women with Cushing's disease and women on long- oral progesterone daily for 12 days each month. term supra-physiological prednisolone therapy have Transdermal estrogen may be associated with lower a reduced LH response to GnRH, thus suggesng that venous thromboembolism risk than oral glucocorcoids also suppress the responsiveness of formulaons. It is also recommendedto add 1,200 pituitary gonadotrophs to hypothalamic input. mg of calcium daily and 1,000 IU of vitamin D daily Glucocorcoids also inhibit the effects of estradiol on withregular weight-bearing exercises to maintain the uterus. Thus, a cross-talk between the HPA and bone mineral density in accordance with guidelines HPO axes promotes the development of amenorrhea for postmenopausal women. as a funconal adaptaon to stress.[8]

Funconal hypothalamic amenorrhoea (FHA) FHA, or stress-induced anovulaon, is one of the

Fig 1 Neuroendocrine regulaon mechanisms FHA is a diagnosis of exclusion and evaluaon Any sellar mass or lesion can cause amenorrhea via typically reveals low or low-normal serum-luteinizing hyperprolacnemia due to stalk disrupon and/or hormone and follicle-smulang hormone levels and compression of the pituitary gonadotrophs, low serum estradiol. Low levels of lepn, low insulin parcularlywhen the lesion is ≥ 1 cm. In the case of levels, high FGF-21 and low kisspepn levels are all funconing adenomas, hormonal effects may also seen in FHA. Bone mineral density tesng should be play a role inthe development of amenorrhoea. considered aer six months of amenorrhea, severe nutrional deficit, or history of stress fracture. Primary hypothyroidism TRH secreted by the hypothalamus, smulates Treatment should correct the underlying cause to release of TSH by the pituitary and also restore ovulatory funcon through behaviour smulatesprolacn release. Women with primary change, nutrional repleon, stress reducon, and hypothyroidism have a heightened prolacn weight gain. A muldisciplinary team including a response toTRH, resulng in greater prolacn clinician, nutrionist or registered diecian and secreon in response to TRH smulaon leading to therapist may be opmal. Paents with severe h y p e r p r o l a c n e m i a a n d r e s u l t a n t bradycardia, hypotension, orthostasis, or electrolyte amenorrhoea.Primary hypothyroidism may also lead abnormalies may require inpaent treatment.9 to significant enlargement of the pituitary gland due to thyrotrophand lactotroph hyperplasia, but Hyperprolacnaemia treatmentof hypothyroidism should result in Elevated serum prolacn may induce amenorrhea by regression ohe hyperplasiaand normalisaon of inhibing gonadotrophs.Pregnancy and lactaon are the prolacn levels.12,13 the important differenal diagnoses which need to be excluded. Hyperprolacnaemic women have Cushing's disease reduced LH-pulsefrequency and reduced LH Amenorrhea is a common finding in women with responsiveness to estrogen with GnRH suppression. ACTH-secreng adenomas (Cushing's disease). Common causes include medicaon use Cushing's disease is associated with amenorrhoea, (anpsychocs), pregnancy and pituitary adenomas. higher mean serum corsol levels and lower Most paents with elevated serum prolacn and estradiol and SHBG levels. Amenorrhea in Cushing's those refractory to medical treatment will require disease is more likely mediated bysuppression of MRI of the pituitary.Symptomac prolacnomas may GnRH by corsol rather than hyperandrogenaemia.14 be treated with dopamine agonists or resecon. Acromegaly Lactotroph adenomas Amenorrhea and inferlity are also common findings Prolacn-secreng adenomas (lactotroph i n w o m e n w i t h G H - s e c r e n g adenomas) are the most common subtype of adenomas(acromegaly). Amenorrhoea is associated secretory pituitaryadenoma. These tumours are withhigher GH levels and lower LH and estradiol usually benign and prolacn levels typically correlate levels. As with any sellar mass, compression of with tumour size.Individuals with large adenomas pituitarygonadotrophs, or hyperprolacnemiadue to can have prolacn levels on the order of 10 ng/mL, secreon of prolacn by the tumour or yet with poorlydifferenated or cysc lesions, stalkdisruponmay result in the development of prolacn levels will be lower than expected based on amenorrhoea. Another potenal cause may size.10,11 beincreased androgen bioavailability due to decreased SHBG levels.15 Stalk disrupon and sellar masses Dopamine is produced by neurons in the arcuate Rare condions nucleus of the hypothalamus and tonically Thyrotroph adenomas, chest wall injury, chronic suppressespituitary prolacn producon. Any renal failure, metastac infiltraon, hypophysis, disrupon of the stalk connecng the hypothalamus granulomatous disease like sarcoidosis, to the pituitary canprevent the flow of dopamine into haemochromatosis, Langerhans cell hisocytosis, the pituitary gland and result in hyperprolacnemia traumac brain injuries, radiaon etc. all represent and amenorrhoea. rarer issues disrupng the HPA axis. Sheehan's syndrome Unlike most paents with IHH, individuals with GnRH During pregnancy, the pituitary gland enlarges due to receptormutaons typically do not respond to estrogen smulaon of lactotroph cells. This convenonal doses of pulsale GnRH administraon, enlarging ssue may compress the superior althoughsuccessful concepon with high-dose hypophyseal artery, making the and vulnerable to pulsale GnRH has been reported. The underlying changes in blood supply. Women with significant mutaons may confersuscepbility to the postpartum haemorrhage may develop ischaemic development of FHA.18,19,20 necrosis of the pituitary gland, resulng in hypopituitarism. Congenital adrenal hyperplasia (CAH) CAH is a family of inherited disorders characterised Sheehan's syndrome is now less commonly seen in by defects in corsol producon, resulngin developed countries due to improvements in PPH increased ACTH producon due to reduced negave management; however, recent reports suggest f e e d b a c k a n d c o n s e q u e n t a d r e n a l that its incidence in the developed world may be glandproliferaon. Although there are rare forms of greater than previously thought. A retrospective CAH that result in inferlity, including 11β- study from France demonstrated a mean delay of 9 hydroxylasedeficiency, 17α-hydroxylase deficiency years before diagnosis, suggesting that the and 3β-hydroxysteroid dehydrogenase deficiency, diagnosis is often overlooked in developed CAHmost commonly arises from autosomal 16, 17 countries. recessive mutaons in the gene that encodes 21- hydroxylase - (21-OH), CYP21A2, which result in Idiopathic hypothalamic amenorrhoea shunng of steroid precursors toward androgen IHH is a heterogeneous group of disorders where biosynthesis. there is delayed or absent pubertal development—typically due to GnRH deiciency There isconsiderable variability in disease or a GnRH receptor mutation— coupled with phenotype, depending on the severity of the normal anatomical indings on mutaon. Classical 21-OHdeficiency is typically hypothalamic/pituitary imaging. diagnosed at birth and can present with severe salt wasng and/or prenatalvirilisaon of external The typical presentation is primary amenorrhoea. female genitalia, whereas non-classical CAH The associated phenotypic indings include ( N C 2 1 O H D ) p r e s e n t s w i t h s i g n s o f anosmia (Kallman's syndrome). Genetic hyperandrogenism including hirsusm, acne, mutations that impair neuronal migration frontalbalding, and menstrual irregularies. commonly result in concurrent hypogonadism and anosmia due to the shared embryonic The oligomenorrhea in women with 21-OH development of GnRH and olfactoryneurons. deficiency is likely due to elevated androgen These include mutations in the KAL1 gene, the and/orprogesterone levels. Paents with classic 21- FGF-1 receptor, FGF-8, the gene encoding OH deficiency with irregular menstrual cycles have semaphorin-3A, the CHD7 gene and the genes elevatedprogesterone and androstenedione levels encoding prokineticin-2 and prokineticin that are associated with reduced LH-pulse amplitude receptor-2. andfrequency. The exact mechanism by which androgens act to induce oligomenorrhea is Genetic defects in GnRH secretion and function unknown, but hyperandrogenaemia may be a have also been identiied in cases of IHH with contribung factor in CAH. Elevated levels of normosmia. Kisspeptin is a potent regulator of progesterone, a substrate of21-OH, also likely GnRH secretion and mutations in KISS1 and contribute to menstrual irregularity. KISS1R, the genes encoding kisspeptin and its receptor, cause hypogonadism. Mutations of the Although classical CAH is relavely rare, NC21OHD is gene encoding leptin, its receptor and mutations o n e o f t h e m o s t c o m m o n a u t o s o m a l in the pro hormone convertase 1 gene, GnRH recessivediseases known, occurring in 1 in 100 receptor mutations have all been associated with individuals in a mixed ethnic populaon and at a both hypogonadotropic hypogonadism and severe obesity. much higherfrequency (1 in 27) in the Ashkenazi smulated 17- hydroxyprogesterone levels thatare Jews. It isimportant to disnguish NC21OHD from intermediate between normal subjects and those o t h e r ca u s e s o f hy p e ra n d ro ge n i s m a n d with classical 21-OH deficiency.21,22,23 oligomenorrhea, such aspolycysc ovary syndrome. Management pathways and algorithms The most definive hormonally based diagnosc test We present two simplified pathways for invesgang for NC21OHD is ACTHsmulaon test measuring and treang primary and secondary amenorrhoea, serum concentraons of 17-hydroxyprogesterone with parcular aenon to the endocrine issues (17-OHP), a substrate of 21-OH, aerACTH surrounding this condion. administraon. Paents with NC21OHD have

Fig 2 Evaluaon of primary amenorrhoea2

Fig3Evaluation of secondary amenorrhoea2 Conclusions 10. Delgrange E, Trouillas J, Maiter D, Donckier J, In conclusion, physiological, pathological and Tourniaire J. Sex-related difference in the growth iatrogenic causes contribung to disrupon of the ofprolacnomas: a clinical and proliferaon marker study. HPA and HPO axes constute a majority of cases of J Clin Endocrinol Metab. 1997;82:2102–2107. a m e n o r r h o e a a n d i nfe r l i t y. F u n c o n a l 11. Molitch ME. Diagnosis and treatment of pituitary hypothalamic amenorrhoea, a physiological adenomas: a review. JAMA. 2017; 317(5): 516-524. response to physical, emoonal or nutrional stress 12. Shahshahani MN, Wong ET. Primary hypothyroidism, is the most common cause of neuroendocrine amenorrhea, and galactorrhea. Arch Intern amenorrhoea and idenfyingthis enty is essenal in Med.1978;138:1411–1412. order to diagnose and treat the underlying disorder. 13. Onishi T, Miyai K, Aono T, Shioji T, Yamamoto T. Primary Given the consequences of noreang amenorrhea, hypothyroidism and galactorrhea. Am JMed. viz., loss of bone mass and ferlity issues, prompt 1977;63:373–378. diagnosis and instuon of treatment is crical. 14. Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD, et al. Menstrual abnormalies in women withCushing's disease are correlated with hypercorsolemia rather than raised References circulang androgen levels. JClin Endocrinol 1. Jeffcoate TN. Amenorrhoea. Br Med J. 1965 Aug Metab.1998;83:3083–3088. 14;2(5458):383-8. doi: 10.1136/bmj.2.5458.383. PMID: 15. Kaltsas GA, Mukherjee JJ, Jenkins PJ, et al. Menstrual 20722181; PMCID: PMC1845417. irregularity in women with acromegaly. J ClinEndocrinol 2. Klein DA, Paradise SL, Reeder RM. Amenorrhea: A Metab. 1999;84:2731–2735. Systemac Approach to Diagnosis and Management. Am 16. Kristjansdor HL, Bodvarsdor SP, Sigurjonsdor Fam Physician. 2019 Jul 1;100(1):39-48. PMID: 31259490. HA. Sheehan's syndrome in modern mes: anaonwide 3. ACOG Commiee opinion no. 651: menstruaon in girls retrospecve study in Iceland. Eur J Endocrinol. and adolescents: using the menstrual cycle as a vital sign. 2011;164:349–354. Obstet Gynecol. 2015;126(6):e143–e146. 17. Ramiandrasoa C, Casne F, Raingeard I, et al. 4. Pracce Commiee of American Society for Delayed diagnosis of Sheehan's syndrome in adeveloped Reproducve Medicine. Current evaluaon of country: a retrospecve cohort study. Eur J Endocrinol. amenorrhea. FerlSteril. 2008;90(5 suppl):S219–S225. 2013;169:431–438. 5. Geckinli BB, Toksoy G, Sayar C, et al. Prevalence of X- 18. Young J, Metay C, Bouligand J, et al. SEMA3A deleon aneuploidies, X-structural abnormalies and 46,XY sex in a family with Kallmann syndrome validatesthe role of reversal in Turkish women with primary amenorrhea or semaphorin 3A in human puberty and olfactory system p r e m a t u r e o v a r i a n i n s u ffi c i e n c y . E u r J development. Hum Reprod.2012;27:1460–1465. ObstetGynecolReprod Biol. 2014; 182: 211-215. [PubMed: 22416012] 6. Burgos N, Cintron D, Latortue-Albino P, et al. 19. Bergman JE, de Ronde W, Jongmans MC, et al. The Estrogen-based hormone therapy in women with r e s u l t s o f C H D 7 a n a l y s i s i n c l i n i c a l l y primary ovarian insuficiency: a systematic review. wellcharacterizedpaents with Kallmann syndrome. J Clin Endocrine. 2017; 58(3): 413-425. Endocrinol Metab. 2012;97:E858–E862. 7. Fourman LT, Fazeli PK. Neuroendocrine causes of 20. Dodé C, Teixeira L, Levilliers J, et al. Kallmann amenorrhea--an update. J Clin Endocrinol Metab. 2015 syndrome: mutaons in the genes encodingprokinecin- Mar;100(3):812-24. doi: 10.1210/jc.2014-3344. 2 and prokinecin receptor-2. PLoS Genet. 2006;2:e175. 8. Biller BM, Federoff HJ, Koenig JI, Klibanski A. 21. New MI. Extensive clinical experience: nonclassical Abnormal cortisol secretion and responses 21-hydroxylase deficiency. J Clin EndocrinolMetab. tocorticotropin-releasing hormone in women with 2006;91:4205–4214. hypothalamic amenorrhea. J Clin Endocrinol 22. Bachelot A, Chakhtoura Z, Plu-Bureau G, et al. Metab.1990;70:311–317. Influence of hormonal control on LH pulsality 9. De Souza MJ, Nattiv A, Joy E, et al.; Expert Panel. 2014 andsecreon in women with classical congenital adrenal female athlete triad coalition consensus statement on hyperplasia. Eur J Endocrinol. 2012;167:499–505. treatment and return to play of the female athlete triad: 23. Levin JH, Carmina E, Lobo RA. Is the inappropriate 1st international conference held in San Francisco, gonadotropin secreon of paents with polycyscovary California, May 2012 and 2nd international conference syndrome similar to that of paents with adult-onset held in Indianapolis, Indiana, May 2013. Br J Sports c o n g e n i t a l a d r e n a l h y p e r p l a s i a ? Med. 2014; 48(4): 289. FerlSteril.1991;56:635–640. 4 Hyperprolacnemia : Dr. Alka Kriplani Management Update Dr. Kusum Lata

Abstract inhibitory, prevenng prolacn release and is Hyperprolacnemia is the most common endocrine mediated by the neurotransmier dopamine. disorder of the hypothalamic-pituitary axis. It The smulatory signal is mediated by the presents as an ovulatory disorder and is oen hypothalamic hormone thyrotropin-releasing associated with secondary amenorrhea or hormone. The balance between the two signals oligomenorrhea, galactorrhea and osteopenia. determines the amount of prolacn released When hyperprolacnemia is confirmed, a cause for from the anterior pituitary gland and the the disorder needs to be sought. This involves a amount cleared by the kidneys influences the careful history and examinaon, followed by concentraon of prolacn in the blood. (1,2) laboratory tests and diagnosc imaging of the sella turcica. Dopamine agonists are the treatment of Epidemiology choice for the majority of paents. Cabergoline has The occurrence of clinically apparent been shown to be more effecve and beer hyperprolacnemiadepends on the study tolerated than bromocripne. Transsphenoidal populaon and occurs in less than 1% of the surgery is usually reserved for paents who are general populaon (3).The rate is higher among intolerant or resistant to dopamine agonists or when paents with specific symptoms that may be hyperprolacnemia is caused by non-prolacn- aributable to hyperprolacnemia. Its secreng tumors compressing the pituitary stalk. incidence is esmated at 9% among women with amenorrhea, 25% among women with Introducon galactorrhea and as high as 70% among women Prolacn is a pituitary-derived hormone that plays a with amenorrhea and galactorrhea.(3) 17 % pivotal role in a variety of reproducve funcons. It PCOS paents present with hyperprolacnemia. negavely modulates the secreon of pituitary Of these paents, approximately 30% have hormones responsible for gonadal funcon including prolacn-secreng tumors.The prevalence is luteinizing hormone(LH)and follicle-smulang a b o u t 5 % a m o n g m e n w h o p r e s e n t hormone(FSH).Hyperprolacnemia is a condion of withimpotence or inferlity.(4) elevated prolacn levels in blood which could be physiological, pathological, pharmacological or ETIOLOGY idiopathic in origin. Management depends on the The diagnosis of hyperprolacnemia should be cause and on the effects it has on the paent.In this suspected in female paents presenng with review we summarize advances in our understanding oligomenorrhea, amenorrhea, galactorrhea, or of the clinical significance of hyperprolacnemia and inferlity. Hyperprolacnemia can be its management. physiological or pathological. Some of the common causes are listed in Figure 1(5) Regulaon of Prolacn secreon Prolacnomas account for 25-30% of Prolacn is a 198-amino acid protein (23-kd) funconing pituitary tumors and are the most produced in the lactotroph cells of the anterior f r e q u e n t c a u s e o f c h r o n i c pituitary gland. Its primary funcon is to enhance hyperprolacnemia.[6] Prolacnomas are breast development during pregnancy and to induce divided into two groups: (i) Microadenomas lactaon. Prolacn is under dual regulaon by (smaller than 10 mm) which are more common hypothalamic hormones delivered through the i n p r e m e n o p a u s a l w o m e n a n d ( i i ) hypothalamic–pituitary portal circulaon. Under Macroadenomas (10 mm or larger) which are most condions the predominant signal is more common in men and postmenopausal women. Clinical presentaon variaons do occur.[12] Serum prolacn levels are Clinical presentaon in women is more obvious and higher in the aernoon than 2in the morning, and occurs earlier than in men. They typically present hence should preferably be measured in the with oligomenorrhea, amenorrhea, galactorrhea, or morning. inferlity(7-9). Galactorrhea is less common in postmenopausal women due to lack of estrogen.[3] According to the Endocrine Society Guidelines for Physiological Pathological diagnosis and treatment of hyperprolacnemia(13), a single measurement of serum prolacn is Coitus Hypothalamic -pituitary stalk damage Exercise Granulomas recommended to establish the diagnosis of Lactation Infiltrations/Irradiation hyperprolacnemia; a level above the upper limit of Pregnancy Trauma: pituitary stalk section, suprasellar Sleep surgery normal confirms the diagnosis as long as the serum Stress Tumors: cranio -pharyngioma hypothalamic me tastases, meningioma, sample was obtained without excessive suprasellar pituitary mass extension venipuncture stress(14). Pituitary Prolactinoma Acromegaly Pialls in Lab diagnosis Macroadenoma (compressive) Macroprolactinemia Macroprolacnemia: The big prolacn or Surgery * Macroprolacn is a less bio-acve form consisng of Trauma Pharmacological Systemic disorders dimers, trimers, or polymers of prolacn or prolacn- immunoglobulin immune complexes and it should be Anesthetics Hypothyroidism Anticonvulsant Polycystic ovarian disease suspected when a paent's clinical history and/or Antidepressants Chest - neuroge nic chest wall trauma, surgery, radiological data are incompable with the PRL Antihistamines (H2) Chronic renal failure Antihypertensives Cirrhosis value.(15,16) It is detected by polyethylene glycol Dopamine receptor blockers Epileptic seizures precipitaon method although gel filtraon Estrogens: oral contraceptives; Neuroleptics/antipsychotics chromatography remains the gold standard.(17) Opiates and opiate antagonists

Figure 1: Causes of hyperprolacnemia(5) Hook Effect: When there is a discrepancy between a very large pituitary tumour and a mildly elevated Prolonged hypoestrogenism secondary to prolacn level, serial diluon of serum samples to hyperprolacnemia causes osteopenia. Bone loss eliminate an artefact that can occur with some occurs secondary to hyperprolacnemia- mediated immune-radiometric assays due to saturaon of the sex steroid aenuaon. Spinal bone density is capture anbodies is recommended.(18) decreased by approximately 25% in women with hyperprolacnemia (10) and isnot necessarily Other Laboratory Studies restored with normalizaon of prolacn levels. Serum TSH,blood urea nitrogen and creanine should be done as hypothyroidism and renal failure The paents can also present with neurological are the two common causes of increased PRL. symptoms caused by mass effects of the pituitary tumor. Symptoms include headaches and visual loss Pregnancy should always be excluded unless the such as bitemporal hemianopia , hypopituitarism, paent is postmenopausal or has had a seizures, and cerebrospinal fluid rhinorrhea (11). hysterectomy. In addion, hyperprolacnemia is a normal finding in the postpartum period. DIAGNOSTIC EVALUATION The evaluaon is aimed at excluding physiologic, Role of Imaging pharmacological and other secondary causes of Any paent who has hyperprolacnemia without an hyperprolacnemia. A detailed drug history should idenfied cause requires imaging of the be obtained because many medicaons cause hypothalamic-pituitary area. A mildly elevated hyperprolacnemia* with prolacn levels of less serum prolacn level may be due to a non- than 100 ng/ml. funconing pituitary adenoma or cranio- Normal serum prolacn levels vary between 5 and 25 pharyngioma compressing the pituitary stalk, ng/ml in females although physiological and diurnal although prolacn levels that are very high (>250 restored in 70-90% of the women within 6-8 weeks. ng/mL) are almost always associated with a Ovulatory cycles return in 50-75% of women (24) but prolacnoma.[19] Magnec resonance imaging treatment is required for at least one year (MRI) with gadolinium enhancement provides the depending on the response of the woman. As soon best visualizaon of the sellar area. as pregnancy is confirmed, dopamine agonists should be immediately stopped. MANAGEMENT The treatment of hyperprolacnaemia depends on Medical Therapy the underlying causes, natural course of the disease Dopamine agonists have become the treatment of and the aim of treatment. The goals of treatment for choice for the majority of paents with are hyperprolacnemia namely bromocripne and ● Normalizaon of prolacn level cabergoline. Bromocripne was the first dopamine ● Restoraon of gonadal funcon and ferlity agonist to be introduced into clinical pracce. It is a ● Avoidance of the adverse effects of chronic semisynthec ergot derivave of ergoline, a D2 hyperprolacnemia like osteoporosis. receptor agonist with antagonist properes at D1 receptors. Its half-life is relavely short and has to A n a d d i o n a l g o a l o f t r e a t m e n t i n be taken 2 or 3 mes daily.[25]It is effecve in macroprolacnoma paents is tumour shrinkage normalizing serum prolacn levels and restoring with relief of mass symptoms. Current therapeuc gonadal funcon in 80 to 90% of paents with opons include medical therapy, surgery and varying degrees of tumor size reducon..[26] The radiotherapy. most common adverse effects are nausea, voming and headache(up to 60% of paents). Postural Management of Drug induced Hyperprolacnemia hypotension is common especially when iniang Although hyperprolacnemia commonly occurs with therapy and can result in dizziness (25%). Other side psychotropic medicaon use, only a minority of effects include a Raynaud-type syndrome of painless paents - typically those with hypogonadism need to digital vasospasm, drowsiness, fague, leg cramps, be considered for treatment. Aer a work-up to rule insomnia, blurred vision, and paresthesia.[27] out alternave causes of hyperprolacnemia, and bone density measurement, gonadal steroid Side effects can usually be minimized by introducing replacement should be considered to preserve the drug at a very low dosage (0.625 or 1.25 mg/d), skeletal health and maintain compliance with a taking the tablets with food and by very gradual dose successful psychiatric medicaon regimen.The escalaon. Therapeuc dosages are generally in the treang psychiatrist should be consulted for any range of 2.5 to 15 mg/d in hyperprolacnemic change in psychotropic regimen. paents, but 5 to 17%[28]of paents are found to be resistant, requiring dose up to 30 mg/d. 26] Another Whether to treat a paent who has anpsychoc alternave to oral treatment is vaginal usage of the drug-3induced hyperprolacnemia with a dopamine same drug which is well tolerated. Vaginal absorpon agonist remains controversial. Some studies suggest is nearly complete and first-pass metabolism via liver that dopamine agonist therapy will normalize is avoided allowing lower therapeuc dosing.[29] It prolacn levels in only up to 75% of such paents but i s a l s o a v a i l a b l e i n a l o n g a c n g fo r m may lead to exacerbaon of the underlying (depot-bromocripne) for intramuscular injecon psychosis.(20-23) and a slow release oral form.[30,31]

Management of Idiopathic Hyperprolacnemia Cabergoline is an ergoline derivave with high In about 40% of moderate hyperprolacnemia, the affinity and selecvity for the D2 receptor. It has an cause of PRL hypersecreon cannot be determined. extremely long plasma half-life of about 65 hours In such cases, it is classified as idiopathic allowing once- or twice-weekly administraon. It has hyperprolacnemia. Medicaon treatment with been shown to achieve normal serum prolacn levels dopamine agonists is effecve and cyclic menses are in 85 to 86% and restoraon of normal gonadal funcon in 90 to %.[32,33] Cabergoline and bromocripne have been compared should stop dopamine agonist aer confirmaon of in a mulcenter collaborave study involving 459 pregnancy. Roune prolacn monitoring should not women with hyperprolacnemic amenorrhea..[34] be done. Stable normoprolacnemia was achieved in 186 of the 223 (83%) women in the cabergoline group Management of Prolacnoma compared with 138 of 236 (59%) women in the Cabergoline is considered to have higher efficacy in bromocripne group (P <0.001).Resumpon of normalizing prolacn levels and pituitary tumor ovulatory cycles or pregnancy occurred in 72 and shrinkage. In a placebo-controlled study, cabergoline 52% respecvely (P <0.001). treatment (0.125–1.0 mg twice weekly) for 12–24 months in paents harboring prolacn-secreng Cabergoline is more effecve and causes fewer microadenomas resulted in normalizaon of adverse effects than bromocripne. However, it is prolacn levels in 95% of paents. Cabergoline much more expensive and is oen used in paents restored menses in 82% of women with who cannot tolerate the adverse effects of amenorrhea.(37). I-n a retrospecve study of 455 bromocripne or in those who do not respond to paents, cabergoline normalized prolacn levels in bromocripne. 92% of paents with idiopathic hyperprolacnemia or a microprolacnoma and in 77% of 181 paents Therapy should be connued for approximately 12- with macroadenomas.(38) In pregnant women with 24 months (depending on the degree of symptoms or prolacnoma bromocripne is the treatment of tumor size) and then withdrawn if prolacn levels choice due to its larger published data as no have returned to the normal range. Aer withdrawal, congenital malformaon has been reported ll now, approximately one sixth of paents maintain normal and its shorter half life as compared to cabergoline. prolacn levels. Response to therapy should be monitored by checking fasng serum prolacn levels When to disconnue therapy and checking tumor size with MRI. Most women Four recent studies (39–42) suggest that in a subset (approximately 90%) regain cyclic menstruaon and of paents, dopamine agonist withdrawal may be achieve resoluon of galactorrhea. safely undertaken aer two years in paents who have achieved normoprolacnemia and significant Management of Hyperprolacnemia- related tumor volume reducon. The risk of recurrence aer Inferlity withdrawal ranges from 26 to 69%. All studies have Inconstant ovulaon and chronic anovulaon are shown that recurrence is predicted by prolacn condions observed in hyperprolacnemic paents levels at diagnosis and by the tumor size. as well as the occurrence of frequent luteal phase defects. In order to induce ferlity it is important to For paents who aer two years of therapy have maintain the effecve PRL lowering dose for 10–12 achieved normal prolacn levels and no visible months since it takes me to normalise ovulatory tumor remnant and for whom dopamine agonists cycles and half of the pregnancies occur aer the first have been tapered or disconnued, follow-up six months of therapy. If ovulaon does not occur includes: 1) measurement of serum prolacn levels despite the normalized PRL to increase the success every 3 months for the first year and then annually rate a cyclical treatment with clomiphene citrate can thereaer; and 2) MRI if prolacn increases above be added.(35) In paents with idiopathic normal levels.In women with micro-prolacnomas, it hyperprolacnemia aer treatment with may be possible -to disconnue dopaminergic bromocripne, in 80% women PRL levels are therapy when menopause occurs. normalized, and in the absence of other causes of inferlity, pregnancy occurs in 60-80%. (36) Surgery General indicaons for pituitary surgery include Management of Pregnancy in women with paent drug intolerance, tumors resistant to medical hyperprolacnemia- unrelated to Prolacnoma therapy, persistent visual-field defects in spite of Dopamine agonists are the treatment of choice and medical treatment, and paents with large cysc or women who are not harbouring any prolacnoma hemorrhagic tumors. Trans-nasal/trans-sphenoidal microsurgical excision of prolacnoma is the 6. Webster J, Scanlon MF. Prolacnomas. In: Sheaves R, procedure of choice. Hyperprolacnemia recurred Jenkins PJ, Wass JA, editors. Clinical Endocrine Oncology. within 5 years aer surgery in about 50% of paents Oxford: Blackwell Science; 1997. p. 189-94. with microprolacnomas who were inially thought 7.Gillam MP, Molitch ME, Lombardi G, Colao A. Advances to be cured.(43) Re-evaluaon of long-term results in the treatment of prolacnomas. E ndocr Rev 2006; indicates a success rate of about 75% for surgical 27:485–534 removal of micro-prolacnoma. However, the results 8. Klibanski A. Clinical pracce. Prolacnomas. N E ngl J Med 2010; 362:1219–1226 of surgery for macro-prolacnoma are poor with a 9. Schlechte JA. Clinical pracce. Prolacnoma. N E ngl J long-term success rate of only 26%.(44) Med 2003; 349:2035–2041 10. Schlechte J, el-Khoury G, Kathol M, WalknerL . Radiotherapy should be reserved for resistant or Forearm and vertebral bone mineral in treated and malignant prolacnomas. Normalizaon of hyper- untreated hyperprolacnemic amenorrhea. J Clin E prolacnemia occurs in approximately one third of ndocrinolMetab 1987; 64:1021–1026 paents treated with radiaon. Radiaon therapy is 11.P. Biller BM. Hyperprolacnemia. Int J FerlWomens a s s o c i a t e d w i t h s i d e e ff e c t s i n c l u d i n g Med 1999;44:74-77 hypopituitarism and, rarely, cranial nerve damage or 12.R. Melmed S, Jameson JL. Disorders of the anterior second tumor formaon (45). pituitary and hypothalamus. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL,Longo DL, Jameson JL, editors. Harrison's Principles of Internal Medicine, 16th ed. New Conclusion: York: McGraw Hill; 2008. p. 2076-97. Once diagnosis of hyperprolacnemia is confirmed 13 ShlomoMelmed, Felipe F. Casanueva, Andrew R. the underlying cause of the disorder needs to be Hoffman, David L. Kleinberg, Victor M. Montori, Janet A. determined and common causes like hypothyroidism Schlechte, John A. H. Wass, Diagnosis and Treatment of and drug intake should be ruled out. Medical therapy Hyperprolacnemia: An Endocrine Society Clinical is the mainstay of treatment in most of the women Pracce Guideline, The Journal of Clinical Endocrinology with surgery being reserved for paents who are & Metabolism, Volume 96, Issue 2, 1 February 2011, unresponsive to medical therapy. Cabergoline, which Pages 273–288, hps://doi.org/10.1210/jc.2010-1692 has a long half-life allowing once or twice weekly 1 4 . M a n c i n i T, C a s a n u e v a F F, G i u s n a A . dosing, and a beer tolerability profile, has become H y p e r p r o l a c n e m i a a n d p r o l a c n o m a s . E the dopamine agonist of choice. The management of ndocrinolMetabClin N orth .Am 2008; 37:67–99, viii 15. Chahal J, Schlechte J. Hyperprolacnemia. Pituitary pituitary adenomas requires a muldisciplinary 2008 11: 141–146 approach. 16. Glezer A, Soares CR, Vieira JG, Giannella-Neto D, Ribela M T , G o ffi n V , B r o n s t e i n M D . H u m a n References: macroprolacndisplays low biological acvity via its 1. Asa SL, Ezzat S. The pathogenesis of pituitary tumours. homologous receptor in anew sensive bioassay. J Clin E Nat Rev Cancer 2002; 2:836-49. ndocrinolMetab 2006; 91:1048–1055 2. Vallee-Kasic S, Morange-Ramos I, Selim A, Gunz G, 17.Gibney J, Smith TP, McKenna TJ .The impact on clinical Morange S, Enjalbert A, et al. Macroprolacnemia pracce of roune screening for macroprolacn. J r e v i s i t e d : a s t u d y o n 1 0 6 p a e n t s . J ClinEndocrinolMetab 2005; 90:3927–3932 ClinEndocrinolMetab2002;87:581-8 18. Petakov, M.S., et al., Pituitary adenomas secreng 3. Biller BM, Luciano A, Crosignani PG, Molitch M, Olive D, large amounts of prolacn may give false low values in et al. Guidelines for the diagnosis and treatment of immunoradiometric assays. The hook effect. J Endocrinol hyperprolacnemia.J Reprod Med 1999;44(Suppl Invest., 1998. 21(3): p. 184-8. 12):1075-84. 19.Biller BM, Luciano A, Crosignani PG, et al. Guidelines 4.Josimovich JB, Lavenhar MA, Devanesan MM, Sesta HJ, for the diagnosis and treatment of hyperprolacnemia. J Wilchins SA, Smith AC. Heterogeneous distribuon of Reprod Med 1999;44(suppl 12):1075-1084 serum prolacn values in apparently healthy young 20.Cavallaro R, CocchiFetal.Cabergoline treatment of women, and the effects of oral contracepve medicaon. risperidone-induced hyperprolacnemia:a pilot study. J FerlSteril1987;47:785-91. Clin Psychiatry 2004; 65:187–190 5. Melmed S, Kleinberg D,KronenbergHM, MelmedS 2 1 . C o h e n LG , B i e d e r m a n J . Tr e a t m e n t o f ,Polonsky KS, L arsen PR, eds. Williams textbook of risperidoneinduced hyperprolacnemia with a dopamine endocrinology. 11th ed. Philadelphia: S aunders Elsevier agonist in children. J Child AdolescPsychopharmacol 2008; 185–26 2001; 11:435–440 22.Smith S. Neurolepc-associated hyperprolacnemia. 36. Webster J, Piscitelli G, Polli A, Ferrari CI, Ismail I, Can it be treated with bromocripne? J Reprod Med 1992; Scanlon MF. A comparison of cabergoline and 37: 737–740 bromocripne in the treatment of hyperprolacnemic 23. Tollin SR. Use of the dopamine agonists bromocripne amenorrhea. Cabergoline Comparave Study Group. N and cabergoline in the management of risperidone- Engl J Med 1994;331:904-909 induced hyperprolacnemia in paents with psychoc 37.Webster J, Piscitelli G, Polli A, D'Alberton A, False L, disorders. J EndocrinolInvest 2000;23:765–770. Ferrari C, Fiore P, Giordano G, L'Hermite M, Ciccarelli E. 24. Webster J, Piscitelli G, Polli A, Ferrari CI, Ismail I, Dosedependent suppression of serum prolacn Scanlon MF. A comparison of cabergoline and bycabergoline in hyperprolacnaemia: a placebo bromocripne in the treatment of hyperprolacnemic controlled,double blind, mulcentre study. E uropean amenorrhea. Cabergoline Comparave Study Group. N Mulcentre Cabergoline D ose-finding S tudy Group. Clin Engl J Med 1994;331:904-909 E ndocrinol (Oxf) 1992; 37:534–541 25.Webster J. A comparave review of the tolerability 38. Verhelst J, Abs R, Maiter D, van den Bruel A et profiles of dopamine agonists in the treatment of al.Cabergoline in the treatment of hyperprolacnemia: a hyperprolacnaemia and inhibion of lactaon. Drug Saf study in 455 paents. J Clin E ndocrinolMetab 1999; 1996;14:228-238 84:2518–2522 26.Molitch ME. Disorders of prolacn secreon. 39. Biswas M, Smith J, Jadon D, McEwan P, Rees DA, EndocrinolMetabClin North Am 2001;30:585-610 Evans LM, Scanlon MF, Davies JS.Long-term 27.Webster J. A comparave review of the tolerability remissionfollowing withdrawal of dopamine agonist profiles of dopamine agonists in the treatment of therapy in subjectswith microprolacnomas. hyperprolacnaemia and inhibion of lactaon. Drug Saf ClinEndocrinol (Oxf) 2005; 63:26–31 1996;14:228-238 40. Colao A, Di Sarno A, Cappabianca P, Di Somma C, 28. A7.Morange I, Barlier A, Pellegrini I, Brue T, Enjalbert Pivonello R, Lombardi G. Withdrawal of long- A, Jaquet P. Prolacnomas resistant to bromocripne: termcabergoline therapy for tumoral and nontumoral long-term efficacy of quinagolide and outcome of hyperprolacnemia.N Engl J Med 2003; 349:2023–2033 pregnancy. Eur J Endocrinol 1996;135:413-420 41. D e k k e r s O M e t a l . R e c u r r e n c e o f 29. Vance ML, Evans WS, Thorner MO. Drugs five years hyperprolacnemia aerwithdrawal of dopamine later. Bromocripne. Ann Intern Med 1984;100:78-91 agonists: systemac review andmeta-analysis. J 30. Merola B, Colao A, Caruso E, Sarnacchiaro F, Brigan F, ClinEndocrinolMetab2010;95:43–51 Lancranjan I,et al. Oral and injectable long-lasng 42. Kharlip J, Salvatori R, Yenokyan G, Wand bromocripne preparaons inhyperprolacnemia: GS.Recurrence of hyperprolacnemia aer withdrawal of Comparison of their prolacn lowering acvity, long-term cabergoline therapy. J ClinEndocrinolMetab tolerability and safety. GynecolEndocrinol1991;5:267-76. 2009; 94:2428–2436 31. Brue T, Lancranjan I et al.A long-acng repeatable 43.Serri O, Rasio E, Beauregard H, Hardy J, Somma M. form of bromocripne as long-term treatment of Recurrence of hyperprolacnemia aer selecve prolacn-secreng macroadenomas: A mulcenter study. transsphenoidaladenomectomy in women with FerlSteril1992;57:74-80 prolacnoma. N Engl J Med 1983;309:280-3. 32. Webster J, Piscitelli G, Polli A, et al. The efficacy and 44. Serri O, Hardy J, Massoud F. Relapse of tolerability of long-term cabergoline therapy in hyperprolacnemia revisited. N Engl J Med hyperprolacnaemic disorders: an open, uncontrolled, 1993;329:1357. mulcentre study. European Mulcentre Cabergoline 45.Brada M, Jankowska P. Radiotherapy for Study Group. ClinEndocrinol 1993;39:323-329 pituitaryadenomas. EndocrinolMetabClin North Am 33.Verhelst J, Abs R, Maiter D, et al. Cabergoline in the 2008; 37:263–275. treatment of hyperprolacnemia: a study in 455 paents. J ClinEndocrinolMetab 1999;84:2518-2522 34.Crosignani PG. Management of hyperprolacnemic inferlity. Middle East Ferlity Society Journal 2012; 17: 63–69 35. Diamant YZ, Yarkoni S, Evron S. Combined clomiphene bomocripn treatment in anovulatory, oligomenorrheic and hyperprolacnemic women resistant to separate clomiphene or bromocripne regimens. Inferlity 1980;3:11–6.

5 Dr. Duru Shah Amenorrhea in Polycysc Ovary Syndrome (PCOS) Dr. Sabahat Rasool

PCOS is the most common gynecologic endocrine estrogen secreon. Estrogen and inhibin A levels disorder represented by a cluster of signs and steadily increase and lead to increase in Luteinizing symptoms. It is the most common cause of Hormone (LH) pulse frequency. FSH levels gradually anovulaon, which may lead to oligomenorrhea, decline but remain adequate enough to support the amenorrhea , and abnormal uterine bleeding. dominant follicular growth. The rest of the follicles Chronic anovulaon increases the risks of undergo apoptosis. During the later part of follicular endometrial hyperplasia and cancer due to growth, estrogen and FSH lead to increased LH unopposed estrogen dominance. receptors in the dominant follicle. Aer exceeding the threshold concentraon, estradiol induces the The diagnosc criteria are many, yet controversial. mid-cycle LH surge, which completes follicular The most commonly followed Roerdam Criteria maturaon, ovulaon and formaon of corpus established in 2003 conclude that the disorder is luteum. Serum estradiol levels fall precipitously post- diagnosed if two of the following three criteria are ovulaon and the corpus luteum starts secreng present [1]: progesterone. Under the effect of progesterone, the 1. Oligoanovulaon endometrium transforms from proliferave to 2. Clinical or biochemical signs of hyperandrogenism secretory morphology. If there is no pregnancy, 3 . P o l y c y s c a p p e a r i n g o v a r y ( i e s ) o n corpus luteum regresses and the hormonal support ultrasonography with a volume of ≥ 10 ml, and /or to endometrium is withdrawn, which eventually more than 12 follicles of sizes between 2 and 9 mm leads to menses. Any defect at any level of this normal physiology of female can cause anovulaon / Pathogenesis of Oligo/amenorrhea amenorrhea [2]. The absence of menses in a girl / women of reproducve age is related to the disturbance of PCOS and Gonadotropin Secreon normal hormonal and physiological mechanisms. Women with PCOS have an increased serum LH concentraon, low-normal FSH levels, and Normal Ovulaon Cycle consequent increased LH to FSH raos [3-5]. LH pulse The normal physiological mechanism of ovulaon frequency contributes to increased LH levels [6]. LH requires perfect coordinaon between the pulse frequency in PCOS is relavely constant at one hypothalamus, pituitary, ovary and the uterus at all pulse per hour and lacks the normal cyclic variaon. levels. Towards the end of a menstrual cycle, the This hourly LH pulse frequency is within the range of corpus luteum regresses and ovarian hormones frequencies observed in the late follicular phase of estradiol, progesterone and inhibin-A plummet to normal women. Increased LH frequency may be an basal levels. This sudden crash of hormones intrinsic defect in hypothalamic funcon. An increase withdraws the negave feedback on the in GnRH pulse frequency, the negave feedback hypothalamus and the pituitary. Pulse frequency of effects of chronically elevated estrone levels from gonadotropin-releasing hormone (GnRH) secreon peripheral conversion of androstenedione to estrone increases and smulates the pituitary secreon of and normal to mildly increased inhibin B levels all follicle-smulang hormone (FSH). FSH acts on contribute to low FSH levels [7,8]. Excessive LH ovaries to recruit a fresh cohort of follicles. Serum secreon leads to disordered folliculogenesis and Inhibin B and estrogen levels rise starng from early anovulaon, leading to oligo/amenorrhea [9,10]. follicular phase. During the mid-follicular phase, FSH- smulated aromatase acvity in the granulosa cells Normal ovulaon causes normal menses that is helps in the connued follicular development and cyclical at 21-35 days' interval. Intermenstrual intervals of lesser than 21 and more than 35 days are 2. Nawaz G, Rogol AD. Amenorrhea. [Updated 2020 indicave of ovulatory dysfuncon[11]. Menstrual Nov 18]. In: StatPearls [Internet]. Treasure Island dysfuncon in the form of oligo/amenorrhea is (FL): StatPearls Publishing; 2020 Jan-. Available from: observed in 60-85% of women with PCOS, and as hps://www.ncbi.nlm.nih.gov/books/NBK482168/ polymenorrhea in less than 2% [12,13]. Anovulaon 3. Taylor AE, McCourt B, Marn KA et al. in PCOS results in amenorrhea and oligomenorrhea determinants of abnormal gonadotropin secreon in [14] clinically-defined women with polycysc ovary syndrome. J Clin Endocrinol Metab 1997;82:2248 Management 4. Rebar R, Judd HL, Yen SS, Rakoff J, Vandenberg G, C h r o n i c a n o v u l a o n i n P C O S l e a d s t o Naolin F. characterizaon of the inappropriate oligomenorrhea (with less than eight menstrual gonadotropin secreon in polycysc ovary cycles annually) which may be the presenng syndrome. 1976;57:1320 symptom in many such women. Some also present 5. Balen AH. Hypersecreon of leunizing hormone with amenorrhea or abnormal uterine bleeding. Due and polycysc ovary syndrome. Hum Reprod to constant, unopposed estrogen exposure, 1993;8:123 endometrial abnormalies in the form of 6.Kazer RR, Kessel B, Yen SS. Circulang leunizing endometrial hyperplasia and even cancer are more hormone pulse frequency in women with polycysc common in such women [15, 16]. Chronic ovary syndrome. J Clin Endocrinol Metab anovulaon, hyperinsulinemia and obesity all 1987;65:233 contribute to developing endometrial cancer in 7.Lockwood GM, Muukrishna S, Groome Np, women with PCOS [17,18]. Endometrial sampling Mathews DR, Ledger WL. Mid-follicular phase pulses must be done for risk assessment for endometrial of inhibin B are absent in polycysc ovary syndrome abnormalies taking into account the age, and are iniated by successful laparoscopic ovarian endometrial thickness, number of cycles per year, diathermy: a possible mechanism regulang degree of obesity and hyperinsulinemia and emergence of dominant follicle. J Clin Endocrinol hyperandrogenic milieu. An endometrial thickness Metab 1988;83:1730 exceeding 12 mm is suggesve of endometrial 8.Laven JSE. Absent biologically relevant associaons hyperplasia and may warrant a sampling [19]. between serum inhibin B concentraons and characteriscs of polycysc ovary syndrome in The most commonly prescribed treatment for normogonadotrophic anovulatory inferlity. Hum menstrual abnormalies in PCOS is the combined Reprod 2001;16:1359 oral contracepve (COC) pill. It provides endometrial 9.Johnstone EB, Rosen MP, Neril R et al. the polycysc protecon through its progesterone and thus stunts ovary post-roerdam: a common, age-dependent endometrial growth from unopposed estrogen and finding in ovulatory women without metabolic cycles regularise with lighter bleeding. Besides, significance. J Clin Endocrinol Metab 2010;95:4965 COCs are effecve for suppressing LH-mediated 10.Chang RJ, Laufer LR, Meldrum DR, et al. steroid ovarian androgenesis, thus correcng the secreon in polycysc ovary disease aer ovarian hyperandrogenic milieu [20-22]. Estrogen is suppression by a long-acng gonadotropin-releasing contraindicated in some women, in them horone agonist. J Clin Endocrinol Metab 1983;56:897 progesterone-alone preparaons can be used either 11.McCartney Ch R, Marshall JC. Polycysc ovary in a connuous or a cyclical form. syndrome. N Engl J Med 2016;375:1398 12.Azziz R, Sanchez LA, Knochenhaeur ES, Moran C, References Lazenby J, Stephens KC, Taylor K, Boots LR. Androgen 1. Roerdam ESHRE/ASRM-Sponsored PCOS excess in women:experience with over 1000 Consensus Workshop Group. Revised 2003 consecuve paents. J Clin Endocrinol Metab consensus on diagnosc criteria and long-term 2004;89:453 health risks related to polycysc ovary syndrome. Ferl Steril 81:19,2004 13.Carmina E, Rosato F, Janni A, Rizzo M, Longo RA. 19.Paraskevaidis E, Kalantaridou SN, Papadimitriou Relave prevalence of of different androgen excess D, et al. Transvaginal uterine ultrasonography disorders in 950 women referred because of clinical compared with endometrial biopsy for the detecon hyperandrogenism. J Clin Endocrinol Metab of endometrial disease in premenopausal women 2006;91:214.Malcolm CE, Cumming DC. Does w i t h u t e r i n e b l e e d i n g . A n c a n c e r R e s anovulaon exist in eumenorrheic women? Obstet 2002;22:182920.Givens JR, Anderson RN, Wiser WI, Gynecol 2003;102:317 Fish SA. Dynamics of suppression and recovery of 15.Farhi DC, Nosanchuk J, Silverberg SG. Endometrial plasma FSH, LH, androstenedione and testosterone adenocarcinoma in women under 25 years of age. in polycysc ovary disease using an oral Obstet Gynecol 1986;68:741 contracepve. J Clin Endocrinol Metab 1974;727:38 16.Gitsh G, Hanzal E, Jensen D, Hacker NF. 21.Dewis P, Petsos P, Newman M, Anderson DC. The Endometrial cancer in premenopausal women 45 treatment of hirsusm with a combinaon of years and younger. Obstet Gynecol 1995;85:504 desogestrel and ethinyl estradiol. Clin Endocrinol 17.Wild S, Pierpoint T, Jacobs H, McKeigue P. Long- (Oxf) 1985;29:22 term consequences of polycysc ovary syndrome : 22.Culberg G, Hamberger L, Mason LA, Mobacken results of 31 year follow upstudy. Hum Ferl H, Samsoie G. effects of a low-dose desogestrel- 2000;3:101 ethinylestradiol combinaon on hirsusm 18.Hardiman P, Pillay OC, Aomo W. Polycysc ovary androgens and sexhormone binding globulin in syndrome and endometrial carcinoma. Lancet women with polycysc ovary syndrome. Acta Obstet 2003;361:1810 Gynecol Scand 1985;195:64 6 Developmental Anomalies Dr Aswath Kumar Causing Amenorrhoea Dr Megha Jayaprakash

Around 7 % of young females present with a Recent studies hold that the vagina develops under reproducve tract anomaly. A clear knowledge of the influence of the müllerian ducts and estrogenic the steps of development of the uterus, cervix and smulaon.A solid vaginal cord from the lower end vagina from the Mullerian (Paramesonephric) ducts of the fused uterovaginal canal elongates and is important to understand the classificaon of vercally fuses with the sinovaginal bulbs from Mullerian anomalies. The steps are summarised in the(endodermal) urogenital sinus by 8 weeks brief below. IUL.This results in a vaginal plate formaon. Most of the vagina is formed by the canalizaon of the vaginal Aer the 5 th week of IUL, two Mullerian ducts grow plate between 20-26 weeks IUL. towards each other in the midline.Fusion of the lateral porons of these ducts start to occur in a Though there are some doubts regarding the extent caudocranial direcon from 7-8 wks of IUL and is of vagina that develops from the Mullerian ducts and completed by 12 weeks of IUL with formaon of a whether the vagina remains open in fetal life,it is uterovaginal canal. Fusion results in the formaon of agreed that the vagina has a dual origin.The hymen is a midline septum which gets resorbed from below the septum at the juncon of the sinovaginal bulbs upwards and resorpon is completed by 20 weeks of and the urogenital sinus proper. IUL..Concavity of the fundus of the uterus changes to domeshaped. The fallopian tubes,uterus,cervix and Hence Mullerian anomalies can be defects in any one upper part of vagina including the fornices are of or more of the following: Mullerian origin. 1) Synthesis 2) Fusion 3) Resorpon

Disorder o f Condition Term inolog y Diagram Structures +- / Synthes is Both M ullerian Agene sis Both Fallopian tubes m ay M ullerian M RKH Syndrom e be + ducts abse nt Low er part of vagin a +

Synthes is O ne side Unicornuate ute rus O ne Fallopian tub e + M ullerian H alf of uterus,cervix and duct absen t upper vagina +

Lateral Both Didelphic uter us 2 tube s fusion M ullerian 2 uter i ducts form 2cervi x but fail to 2upper vagin a fuse

Lateral Both ducts Bicornuate 2 tube s fusion present but unicollis,bicornuate 2 uter i incom plete bicolli s 1 vagin a fusion

Resorptio n Both ducts Septate,Subseptate M idline septum pres ent present and uteru s fuse,but septum fails to resor b

Resorptio n Fundus does Arcuate uter us Flat topped fundus or not becom e concav e dom eshape d

One of the oldest and most familiar classificaon systems for developmental abnormalies of Mullerian ducts is the one by American Ferlity Society (AFS) Buram and Gibbons in 1988(Table 1)

CLASS ANOMALY I Segmental Mullerian Agenesis/hypoplasia A Vaginal B Cervical C Fundal D Tubal E Combined II Unicornuate A Communicating rudimentary horn B Noncommunicating horn C No uterine cavity D No horn III Didelphis IV Bicornuate A Complete B Partial V Septate A Complete B Partial VI Arcuate VII Diethylstilbesterol - related

It has an embryological basis and focuses mainly on 2. Unilateral obstrucon of a cavity of a double lateral fusion defects of the uterus. A more detailed uterus embryological classificaon that incorporates 3. Unilateral vaginal obstrucon associated with vercal fusion defects and unusual configuraons is double uterus the one given below. B. Symmetric-unobstructed 1. Didelphic uterus Modified American Ferlity Society Classificaon of a. Complete longitudinal vaginal septum Uterovaginal Anomalies b. Paral longitudinal vaginal septum c. No longitudinal vaginal septum Class I. Dysgenesis of the Müllerian ducts 2. Septate uterus Class II. Disorders of vercal fusion of the Müllerian a. Complete ducts 1) Complete longitudinal vaginal septum A. Transverse vaginal septum 2) Paral longitudinal vaginal septum 1. Obstructed 3) No longitudinal vaginal septum 2. Unobstructed b. Paral B. Cervical agenesis or dysgenesis 1) Complete longitudinal vaginal septum Class III. Disorders of lateral fusion of the Müllerian 2) Paral longitudinal vaginal septum ducts 3) No longitudinal vaginal septum A. Asymmetric-obstructed disorder of uterus or 3. Bicornuate uterus vagina usually associated with ipsilateral renal a. Complete agenesis 1) Complete longitudinal vaginal septum 1. Unicornuate uterus with a noncommunicang 2) Paral longitudinal vaginal septum rudimentary anlage or horn 3) No longitudinal vaginal septum b. Paral 2) Without endometrial cavity 1) Complete longitudinal vaginal septum b. Without a rudimentary horn 2) Paral longitudinal vaginal septum Class IV. Unusual configuraons of vercal-lateral 3) No longitudinal vaginal septum fusion defects 4. T-shaped uterine cavity (diethylslbestrol related) 5. Unicornuate uterus ESHRE/ESGE CONUTA classificaon that was a. With a rudimentary horn proposed in 2013 by Grimbizis et al allows a more 1) With endometrial cavity precise anatomical descripon of any defect or a) Communicang combinaon of defects in the uterus,cervix and b) Noncommunicang vagina.It also has a place for unclassified 2) Without endometrial cavity malformaons.

UTERINE Anomaly Main class Subclass U0 Normal uterus U1 Dysmorphic uterus a Tshaped b Infantile c others U2 Septate uterus a Partial b Complete U3 Bicorporeal uterus a Partial b Complete c Bicorporeal Septate U4 Hemi uterus a with rudimentary cavity b without rudimentary cavity U5 Aplastic a with rudimentary cavity b without rudimentary cavity U6 Unclassified Malformations

CERVICAL/VAGINAL Anomaly Co-Existent Class C0 Normal Cervix C1 Septate Cervix C2 Double “Normal” cervix C3 Unilateral cervical aplasia C4 Cervical aplasia

V0 Normal vagina V1 Longitudinal non -obstructing vaginal septum V2 Longitudinal obstructing vaginal septum

It is evident that AFS Class I and Classes I and II of amenorrhoea early in reproducve life. Modified AFS classificaon as well as Classes U5 C4 V3 and V4 of ESHRE classificaon are obstrucve This chapter will focus on the Mullerian anomalies anomalies that can present with that present with primary amenorrhoea. IMPERFORATE HYMEN in the vagina(haematocolpos) and in the uterine It comes in Class V3 of ESHRE/ESGE classificaon. cavity(haematometra).At the me of expected menarche,these paents develop cyclical abdominal This occurs when the hymen which is formed by and pelvic pain due to the obstructed blood invaginaon of the posterior wall of the urogenital flow/Cryptomenorrhoea.They may also present with sinus does not undergo spontaneous dissoluon urinary retenon due to the pressure of the during the perinatal period.It is generally a sporadic distended vagina pressing on the urethra . anatomical defect and is usually isolated.But there are case reports of familial occurrence and Classical presentaon is as primary amenorrhoea associaon with Mullerian anomalies. w i t h w e l l d e v e l o p e d s e c o n d a r y s e x u a l characteriscs. Examinaon reveals the vaginal As the HPO axis is intact and the uterine orifice closed by a bulging (oen bluish) thin endometrium is responsive to cyclic ovarian membrane which becomes prominent with a hormones,there is cyclic shedding of the menstrual Valsalva maneuver.(Fig 1A) endometrium. This results in the collecon of blood

Figure 1A Before surgery Fig 1B A er sur g ery Ultr asound scan usually picks up the haematocolpos (Fig 1C) and haematometra if present. Definive treatment is in the form of surgery which This belongs to Class I in AFS classificaon and occurs should not be delayed as there is risk of when the müllerian poron of the vagina fails to endometriosis and permanent inflammatory canalize with the urogenital sinus poron of the scarring.The classical procedure is pung a cruciate vagina. Paents have age appropriate secondary incision on the bulging membrane to let the collected sexual characteriscs and will present with cyclic blood out(Fig 1B) and oversewing the hymenal edges pelvic pain and amenorrhoea at puberty just like aer giving a single dose of prophylacc paents with imperforate hymen. anbiocs.An alternave method is to do a sterile puncture and widen it to about 0.5 cm to insert a A vaginal dimple is present on examinaon, however Foley's catheter for irrigaon of vagina with the bluish hue is not seen.A rectal examinaon may saline.This catheter can be le in place for another 2 be done to determine the level of obstrucon but weeks for complete drainage. MRI of pelvis should be done to determine the distance between the lower end of the LOWER VAGINAL ATRESIA haematocolpos and the perineum.This distance is important in deciding the management. When the distance of the atrec vagina is ≤3 cm from the Fig 2: Courtesy-Prof Presannakumari perineum, a straighorward vaginal pull-through Bhanumathy(Retd) procedure may be performed . When the distance is Dept of OBG Govt Medical College Trivandrum) more than 3 cm, use of a gra becomes necessary to minimize risk of vaginal stricture postoperavely. CERVICAL ATRESIA / DYSGENESIS can be offered, which will protect the ovaries from damage by endometriosis.Such a paent can then opt for IVF and surrogacy. Fig 3: Courtesy-Prof Presannakumari Bhanumathy(Retd) Dept of OBG Govt In case of cervical dysgenesis, various forms are Medical College Trivandrum) noted. a) fragmented parts with no connecon to uterus b) hypoplasc cervix with no endocervical lumen c) cervical body replaced by a fibrous band with or Cervical atresia is relavely rare and is a AFS Class I without endocervical glands (ESHRE C4)anomaly.When present, it is usually seen d) well formed cervical body but a poron of the in associaon with absence or atresia of a poron or lumen is obliterated whole of the vagina .As the small uterine cavity fills Fragmented cervix usually warrants hysterectomy. up quickly,the paent presents soon, usually aer 1 - In cases where some amount of stroma and 2 menstrual cycles with pelvic pain and endocevical glands are present,Cannulizaon amenorrhoea.In the absence of the cervical techniques to create a cervicovaginal anastamosis support,the distended uterus has a tendency to are described.Endocervical graing procedures for undergo torsion and present as acute abdomen. cervical fibrous band are also reported.But morbidity of these procedures is quite high with On examinaon,there is usually a vaginal dimple with low success rates. no bulge.Examinaon under anaesthesia along with Ultrasound scan and MRI will be needed to help in TRANSVERSE VAGINAL SEPTUM preoperave diagnosis which is sll challenging.It is oen difficult to accurately diagnose as the lowermost part of the uterus may be ballooned out to mimic an upper vagina versus a truncated cervix.

Preoperave planning and surgical management opons vary depending on whether the cervix is totally absent or is dysgenec and counseling regarding the opons will depend on the diagnosis. Fig 4: Courtesy-Prof Presannakumari Bhanumathy(Retd) If the cervix is totally absent, it is difficult to construct Dept of OBG Govt Medical College Trivandrum) a neocervix. Creaon of the unique mucus producing It is a modified AFS Class IIA and ESHRE class V3 endocervical mucosa which is important in ferlity, is defect.This is considered a vercal fusion defect as next to impossible.One opon is to bridge the lower the vaginal plate fails to canalize during end of the uterus to the vagina aer excising the embryogenesis.It is considered a maldevelopment atrec porons similar to posrachelectomy and of the urogenital sinus as it fails to fuse with the then opt for IVF. But this procedure has significant mullerian structures.This is much rarer than vaginal m o r b i d i t y i n t h e f o r m o f r e t r o g r a d e or uterovaginal agenesis.Oen quoted incidence menstruaon,endometriosis,sepsis and strictures rate is around 1 in 72,000. requiring reoperaons There are reports of experimental methods to keep the tract patent using In contrast to other Mullerian anomalies,transverse silicone stents and creaon of a neocervical lining vaginal septum is not commonly associated with with intesnal gras but these are based at other anomalies.Imperforate anus and bicornuate anecdotes . uterus may be seen occasionally.The most common site for a transverse vaginal septum is the If the paent is unwilling for this approach, upper vagina(46%),followed by midvagina(40%) Laparoscopic removal of the uterus aer ureteral and lower vagina(14%).The septum tends to be stenng along with vaginoplasty in the same sing thicker as it gets closer to the cervix. Neonates and young infants can somemes present A transverse incision is made through the vault of the with lifethreatening complicaons due to fluid short vagina and the areolar ssue between the retenon.The endocervical and upper vaginal bladder and rectum is carefully dissected to reach secreons in response to maternal oestrogens can the cervix.The edges of the upper and the lower cause hydrocolpos and fluid retenon above the vaginal mucosa are undermined and mobilized to septum.It can produce hydroureteronephrosis, anastomose with interrupted delayed absorbable Inferior venacaval compression, conspaon, sutures. intesnal obstrucon and cardiorespiratory failure due to obstrucon to diaphragmac movements. For high and thick(more than 1 cm) septae, various methods are described.One is to use Z-plasty, Y- But the classical picture is a pubertal girl with age plasty, or cross-plasty technique to reduce the appropriate secondary sexual characteriscs thickness of the septum.If the atrec vaginal presenng with primary amenorrhoea and cyclical segment is too long to bridge, use of gras will abdominal pain.On examinaon, there may be a become necessary. Somemes the thick septum shortened vagina varying in length with the site of appears thinned out in MRI due to pressure of the the septum,no cervix visible and no bulging on haematocolpos.Hence the surgeon should be Valsalva maneuver.A haematocolpos may be prepared to use these methods if the need arises. palpable above the septum on doing a rectal examinaon.If the septum is not idenfied and It is important to maintain patency and avoid excised early on,severe endometriosis can develop strictures by keeping a so foam rubber mould and a fixed mass may be palpable on bimanual pelvic covered in sterile condom inside the vagina for examinaon due to formaon of haematometra and atleast 4-6 weeks.Healing can be evaluated aer 10 haematosalpinges. But somemes there may be a days. In a girl who is not sexually acve,its advised to ny orifice through which the paent menstruates as wear lubricated dilators/silicone mould for many seen in Figure 5 months during the constricve phase of healing to maintain length and patency.

UTEROVAGINAL AGENESIS (MAYER-ROKITANSKY- KÜSTER-HAUSER SYNDROME) It belongs to Class Ie in AFS/ASRM classificaon and Class U5 C4 V4 in ESHRE/ESGO classificaon.

Mullerian agenesis is the second most common cause(10-15%) for Primary amenorrhoea and occurs one in 5000 newborn girls.It is characterized by vaginal agenesis with varying degrees of uterine Fig 5: Courtesy-Prof Presannakumari Bhanumathy(Retd) agenesis. Dept of OBG Govt Medical College Trivandrum) Most cases are sporadic but a few familial aggregates U l t r a s o u n d p e l v i s c a n r e v e a l have been idenfied. An associaon with errors in h a e m a t o c o l p o s , h a e m a t o m e t r a a n d fetal or maternal galactose metabolism( galactose-1- haematosalpinges.but an MRI is essenal to phosphate Uridyltransferase GALT gene mutaons ) delineate the level and thickness of the septum resulng in increased intrauterine galactose (atrec poron of the vagina) and for preoperave exposure and mullerian anomaly has been planning. Excision of transverse vaginal septum noted.There are also isolated reports of HOX ,WNT4 should be done by trained specialists. and HNF1B gene mutaons but exact causave factor is sll unknown. Though MRKH syndrome is characterized by absent (46,XY) which can present in a similar fashion. Male or rudimentary uterus with vaginal agenesis, 7—10 sex hormones in MRKH are in the normal female % of them can have funconing endometrium. The range. Absence of uterus with presence of ovaries ovaries are enrely normal in the great majority of can be made out with an ultrasound scan but MRI is these paents as the karyoptype is normal female more accurate to delineate finer details as well as 46,XX. pick up urological anomalies. MRI in Fig 7 shows uterine agenesis in a paent with MRKH syndrome Due to the close embryological associaon between Mullerian(paramesonephric) and Wolffian (mesonephric) ducts, 15-40% of MRKH syndrome has urological anomalies like unilateral renal agenesis, ectopic and horse shoe kidney as well as duplex collecng system.

Classificaon of MRKH Syndrome Type A(typical)(64%)-isolated symmetrical uterovaginal aplasia / hypoplasia T y p e B ( at y p i ca l ) ( 2 4 % ) - a sy m m et r i ca l U V aplasia/hypoplasia with malformaons of tubes, ovaries +/- renal system Type C (MURCS) (12%)-Mullerian duct aplasia,renal Fig 7 dysplasia,cervicothoracic somite anomalies(heart Empathec counseling of the paent and family and skeletal)-may be familial(WNT4 gene mutaons) regarding the condion and the treatment opons is of paramount importance. Management is Typical presentaon is a pubertal age girl of normal essenally aimed at achieving a fair length of vagina stature with well developed secondary sexual for coital funcon. If there is the rare funconing characterisics presenng with primary endometrium,then laparaoscopic removal of the amenorrhoea. Unlike transverse blockage of the uterine remnant should be done. mullerian system as in imperforate hymen and transverse vaginal septum, cyclic pain is usually She should be assured that vaginoplasty gives good absent in Mullerian agenesis unless funconing results when done by trained specialists.She and her endometrium is present. On examinaon there will partner can have their genec offspring by IVF with be a vaginal dimple or 1-2 cm blind ending vaginal their own gametes and surrogate uterus.There is also pouch with otherwise normal external female the opon of uterine transplantaon that has genitalia.(Fig 6).This is the part of the vagina that evolved tremendously over the past decade. develops from the urogenital sinus. Methods to create a neovagina may be classified into 1) Nonsurgical --Frank's dilators(acve) -- Ingrams method(passive) 2) Surgical – Abbe-Wharton-McIndoe vaginoplasty – Williams vulvovaginoplasty – Colovaginoplasty/Ruge procedure – Davydov vaginoplasty – Makinoda's 2 step operaon – Vecchie operaon Fig 6 Frank's dilaon Acve non surgical method of creang an arficial The diagnosis of MRKH can be arrived at with history vagina using dilators made of different polymers. and examinaon but karyotyping is jusfied to rule This was described in 1938 and ACOG sll out Complete Androgen Insensivity Syndrome recommends this as the first line management to be Ingram Technique The Counseller-Flor modificaon of the McIndoe This is a passive method of dilaon where the paent technique uses a sterilised foam rubber mold shaped is instructed to sit on a dilator fied to a specially for the vaginal cavity from a foam rubber block and designed bicycle seat every day for atleast 2 hours, covered with a condom ( Fig 10) The diameter of the dilator is increased on an average every month. Paent may be allowed to have coitus aer the use of the largest dilator for 1 or 2 months. Otherwise connued dilaon is required .If dilataon is unsuccessful or unacceptable, operave vaginoplasty is indicated

Abbe-Wharton-McIndoe operaon Most experts recommend this as the gold standard technique for vaginoplasty. The principles to be Fig 10 followed are The skin gra is then placed over the form and its (a)dissecon of an adequate space between the undersurface exteriorized and sewn over the form rectum and the bladder (b)Inlay split-thickness skin with interrupted vercal maress sutures.(Fig 11) graing and © cardinal principle of connuous dilataon during the contracle phase of healing

Aer inserng an indwelling urethral catheter and a finger in the rectum, a transverse incision is made on the mucosa of the vaginal vesbule(Fig 8) and dissecon of the space between the bladder and rectum carefully unl the undersurface of the peritoneum is reached. This creates the neovaginal Fig 11 space. The edges of the gra are sutured to the skin edge with a b s o r b a b l e sutures.

Fig 12 Fig 8 Aer 10 days, the form is removed and the neovagina A split-skin gra that is uniformly thick and i s i r r i g a t e d a n d adequately long and wide is taken.(Fig 9) checked. (Fig 13)

She is instructed to remove and clean the form daily and wear it connuously for 6 weeks. She can switch to wearing the mould at bedme later.

Fig 9 Success rates in recent mes is 80-100 %.Apart from bladder and rectum is carried to the peritoneal bleeding, infecon, constricon due to granulaon cavity. Aer peritoneal perforaon, the uterine ssue and gra failure,there is a 4 % postoperave structures, when present, is pulled down and fistula rate and enterocoele formaon. sutured to the newly created vaginal space. This also requires the long term use of postoperave moulds. Buccal mucosa is being increasingly used as it has ssue similaries compared to nave vagina with Vecchie operaon excellent healing and no visible scar.There are also The operave phase involves posioning an acrylic excing reports of the use of autologous in vitro shaped olive at the perineum and the tracon grown vaginal ssue. sutures extraperitoneally. The tracon device, which provides constant tracon on the perineal olive, is Williams vulvovaginoplasty posioned on the abdomen. During the A horse-shoe incision is made in the vulva and skin is postoperave invaginaon phase, the neovagina is mobilized to form the perineal pouch /neovagina.It created by applying constant tracon to the olive. is technically simple with lesser complicaons and The process reportedly occurs at a rate of 1.0 to 1.5 postoperave pain.There is no need for dilataon cm per day, developing a 10- to 12-cm vagina in 7 to 9 and it can be done in paents who do not intend to days. have intercourse in the near future.It is not applicable for paents with poorly developed labia Laparoscopic modificaon of Vecchie operaon is and it creates an unusually angled vagina. It is now popular. considered the operaon of choice for paents needing a reoperaon due to failure of primary surgery and also it is useful in paents with pelvic References kidney. 1. Berek JS,Berek DL .Berek and Novak's Gynecology.16th Ed.Wolters Kluwer;2020. Colovaginoplasty/ Ruge procedure 2. Handa Victoria L, Van Le Linda. Te Linde's Operave It involves formaon of a neovagina using sigmoid Gynecology, 12th Ed. Lippinco Williams & Wilkins colon gras.Advantage is ample vaginal length(12 ;2020 cm) without vaginal dilataon and can be chosen 3.Jones HW,Rock JA. Te Linde's Operave where there is no other opon of gra..Disadvantage Gynecology. 11th Ed. Philadelphia: Wolters Kluwer, is the need for laparotomy,mucus discharge from the United States; 2015. neovagina.Ota and colleagues have reported a series 4.McIndoe A.The treatment of congenital absence done laparoscopically. and obliterave condions of the vagina.Br J Plast Surg 1950;2:254. Davydov procedure 5.Pra JH,Smith GR.Vaginal reconstrucon with a This technique uses peritoneum to line the sigmoid loop.Am J Obstet Gynecol 1966;96:31. neovagina.It involves dissecon to create the 6.Sadler TW. Langman's Medical Embryology.14th neovaginal space, freeing up peritoneum from the Ed.Lippinco Williams & Wilkins(Wolters pelvis,and sewing the apex closed from the Kluwer);2018 abdominal side.This is done by a combinaon of 7.Subhadra devi V. Inderbir Singh's Human vaginal and laparoscopic approaches.It requires Embryology.11th Ed.Jaypee Brothers Medical postoperave long term use of dilators. Publishers;2018. 8.Taylor HS,Pal L,Seli E. Speroff's Clinical gynecologic Makinoda's two step technique Endocrinology and inferlity.9th Ed.Wolters It is a nongraing method of vaginal creaon.The Kluwer;2020. inial step is noninvasive dilataon using a vaginal mold. In the second step ,the apex of the dilated vaginal space is incised and dissecon between the 7 Amenorrhoea and Gonadal Dr. Mandakini Pradhan dysgenesis

Definion: Empty sella syndrome Amenorrhoea refers to the absence of menstrual Autoimmune, Cushings syndrome periods. It is subcategorised into primary and Infiltrave disease (e.s. Sarcoidosis) secondary causes. Cocaine

Primary – failure to commence menses (absence of Medicaons: like Andepressants, Anhistamines, menarche) in girls aged 16+, in the presence of Anpsychoc, Opioids secondary sexual characteriscs such as pubic hair Gonadotropin deficiency (e.g., Kallmann syndrome) growth and breast development, or girls aged 14+, in Traumac brain injury the absence of secondary sexual characteriscs. Eang disorder including celiac disease Infecon (e.g., meningis, tuberculosis, syphilis) Secondary – cessaon of periods for more than six PCOS months aer the menarche (aer excluding Endocrine disorder including thyroid dysfuncon pregnancy). Gonadal dysgenesis and amenorrhoea: Causes of amenorrhoea: Gonadal dysgenesis is the name given to any of a Oulow tract abnormality: multude of condions that can cause impaired Congenital: development of the gonads, i.e., the testes or Mullerian agenesis ovaries. The most notable of these condions is Imperforated hymen, Transverse vaginal septum Turner syndrome, a disorder affecng 1 in every 2500 Complete androgen resistance live female births. Acquired: Asherman syndrome (intrauterine synechiae) Understanding the genecs behind gonadal Cervical stenosis dysgenesis allows clinicians to beer predict the disorder's phenotypic presentaon, in turn, Primary ovarian insufficiency improving both screening methods for associated Congenital medical problems and the ongoing care of those Turner syndrome or variant medical problems. 46,XY gonadal dysgenesis Receptor abnormalies and enzyme deficiency Gonadal dysgenesis is a genec condion due to Complete androgen insensivity syndrome errors in cell division and or alteraons in genec 5-alpha reductase deficiency material, leading to complete or paral loss of 17- alpha hydroxylase deficiency gonadal development. The development of gonadal P450 oxidoreductase deficiency dysgenesis begins early either at ferlizaon or Estrogen resistance shortly aer in the early stages of the embryo and Acquired fetus. Autoimmune destrucon Chemotherapy or radiaon The causes of gonadal dysgenesis and amenorrhoea Pituitary could be pure gonadal dysgenesis (46, XY female), Hyperprolacnemia Complete Gonadal Dysgenesis (46, XX) or Sweyer syndrome and Turner syndrome. Pure Gonadal Dysgenesis the ssues are unable to respond due to the absence Pure gonadal dysgenesis is the term given to of androgen receptors. Affected individuals have phenotypically female individuals with streak gonads normal female gender, are within the stature range who are of normal stature and have none of the of males, and develop breasts at puberty. However, physical sgmata associated with Turner's they fail to menstruate, and pubic and axillary hair is syndrome. Such individuals have either a 46,XX or scant. This is oen the first indicaon of the 46,XY karyotype. The 46,XX defect may be inherited condion. Somemes, paents present with an as an autosomal recessive, with 10% having associated nerve deafness. The 46,XY defect may be inguinal hernia in childhood, and this leads to the inherited as an X-linked recessive, with clitorimegaly discovery of testes in the inguinal canals; however, occurring in 10 to 15% and gonadal tumors the testes usually remain within the pelvis and are (gonadoblastoma) developing in 25% if the gonads only idenfied by laparotomy. This reveals a short, are not removed blind-ending vagina, the absence of uterus and fallopian tubes, and the failure of development of 46,XY Gonadal Dysgenesis Wolffian structures. As there is a risk that tescular Paents with pure gonadal dysgenesis are born as tumors (dysgerminoma) may develop, the testes are phenotypic females. Amniocentesis with a 46,XY removed and the paent maintained for life on a karyotype that does not produce the expected small daily dose of estrogen. The disorder is inherited phenotype on fetal ultrasonography now allows as an X-linked recessive trait and the carrier state in earlier diagnosis than was previously possible. Dorsal pedal edema and some Turner characteriscs may be normal females may somemes be recognized by the the only obvious somac manifestaons of the patchy distribuon of sex hair. Half the XY offspring of defect. Müllerian structures are present, but gonads a carrier are at risk of being affected. Incomplete are not palpable due to failure of gonadal forms of androgen insensivity are also recognized, differenaon. Testosterone and MIS are due to mutaons of the androgen receptor locus undetectable, indicang dysgenesis of the gonad. disnct from the complete form. Paral masculinizaon occurs leading to sexual ambiguity at Pure gonadal dysgenesis in XY females also occurs in birth and virilizaon at puberty. individuals with SOX9 mutaons (campomelic dysplasia), with WT mutaons (Denys–Drash 2. 5-α-Reductase deficiency (pseudovaginal syndrome), with duplicaons of the Xp21 region (DSS perineoscrotal hypospadias). Deficiency of 5-α- gene), and with deleons of the short arm of chromosome 9 (including the DMRT1 gene) and the reductase leads to failure of conversion of long arm of chromosome 10. The gene locus involved testosterone to dihydrotestosterone. XY infants with in the last condion has not yet been idenfied. In all severe enzyme deficiency have a small hypospadic these genec aberraons, addional clinical features phallus, a blind vaginal pouch, and absent Müllerian of varying severity are associated, usually leading to derivaves. Over 50% are raised as XY females. At substanal handicap. Invesgaon of XY females for puberty, the paents virilize, do not develop breasts, the underlying genec defect has been largely and undergo a gender identy change to male responsible for our present understanding of the gender. genec pathway in mammalian sex differenaon. As the underlying defect has been idenfied in only a 3. Several other rare disorders of steroid biosynthesis proporon of XY females, other loci important in sex may lead to sex reversal in XY females: differenaon remain to be discovered. (a) tescular unresponsiveness to gonadotrophin; (b) congenital lipoid adrenal hyperplasia; Apart from pure gonadal dysgenesis, several other (c) 3-β-hydroxysteroid dehydrogenase deficiency; disorders are associated with sex reversal in XY (d) 17-hydroxylase deficiency; and females are as follows: (e) 17 β-hydroxysteroid oxidoreductase deficiency. 1. Androgen insensivity (tescular feminizaon). This condion is the result of mutaons of the X- Deficiency of each of these enzymes can be linked androgen receptor gene. The developing tess associated with female external genitalia, absence of secretes normal amounts of testosterone but Müllerian derivaves, and a blind vaginal pouch. 46, XX Gonadal Dysgenesis mutaons in the WT1 gene have been seen in some Paents with pure gonadal dysgenesis and 46,XX cases. karyotype have a normal stature, sexual infanlism, and bilateral streak gonads. A marked heterogeneity, Turner syndrome: both genecally and clinically, has been noted in the Mulple genotypes have been discovered among expression of the disease, even in the same kindred. Turner syndrome paents. The typical 45X type and The molecular basis of the condion is sll not well mosaic types, such as 45X/46XX, 45X/46XX/47XXX, understood. The frequency of consanguinity in 45X/46XY, are considered paral gonadal dysgenesis. affected families points to an autosomal gene A d d i o n a l l y , s o m e m o s a i c s c o n t a i n necessary for normal ovarian development and isochromosomes, ring chromosomes, and Xq funcon. Alternavely, the condion may result from deleons. Studies have found that as suspected, an X-linked gene mutaon or deleon in sporadic mosaic forms of the disease tend to have decreased cases. Adult height is lower in 46,XX than in 46,XY symptoms and phenotypic presentaon due to some gonadal dysgenesis, which suggests the existence of cell lines having normal genec informaon. a Y-specific growth gene that promotes height independently of gonadal steroids. The main clinical The development of Turner syndrome stems from features are the lack of sgmata of Turner syndrome. meioc and mitoc errors that lead to a lack of a Presenng signs at the age of puberty include lack of second X chromosome. The exact mechanisms that breast development, primary amenorrhea, and make Turner syndrome so much more common than elevated gonadotropins. these other chromosomal disorders are unclear. Sll, the belief is that non-disjuncon and chromosomal Pure 46, XX gonadal dysgenesis is typically caused by loss during the first few rounds of mitosis in the alteraons to genec informaon needed for ovarian embryo is the cause. Non-disjuncon during mitosis development, present at the proximal Xp, and distal in the early stages of the fetus can also result in the Xq regions of the X chromosome. These alteraons formaon of two separate lines of somac cells include gene translocaons, deleons, and 45X/46XX or 45X/46XY. The development of two cell mutaons. As discussed above, during meiosis I, lines of differing genec makeup is called mosaicism homologous chromosomes can undergo crossing and results in cells across the body having different over, and during this period, translocaons and sets of genec material, which can also result in deleons can occur. The mutaons causing 46, XX different phenotypic presentaons in other parts of gonadal dysgenesis, can be sporadic or familial. the body. Mutaons in genes coding for the FSH receptor of the ovaries have implicaons in familial and sporadic Molecular mechanism: cases. Analysis of pedigrees of families with girls with Turner Syndrome results in at least part of the cells of 46, XX gonadal dysgenesis have found an autosomal the body lacking a secondary X chromosome. recessive paern, although all the possible genes However, normal female cells undergo X inacvaon, and mutaons involved remain undiscovered. A large where there is the ulizaon of the genes of only one number of 46, XX gonadal dysgenesis cases have links of the X chromosomes. The inacvated X with the autosomal recessive condion congenital chromosome is turned into heterochroman that is adrenal hyperplasia. Congenital adrenal hyperplasia inacve. This process gets completed by genes in the is most oen caused by a 21-hydroxylase enzyme X inacvaon centre near the long arm of the X deficiency, which leads to a build-up of the precursor chromosome Xq. It would be logical to assume that for the enzyme 17-hydroxyprogesterone, which is Turner syndrome should have no complicaons converted to testosterone, causing virilizaon. In because, aer X inacvaon, a normal cell has the addion to the genec causes of 46 XX gonadal same amount of genec material as a Turner dysgenesis, the disorder can also stem from syndrome cell, but this is not the case. The reason for autoimmune disease, infecon, and infarct. this is that about 25% of the genes on the inacvated X chromosome avoid inacvaon. Loci on the X and Y Complete 46, XY gonadal dysgenesis is due to the chromosome have been mapped that reveal there deleon of the SRY gene in 10-15% of cases and due are pseudoautosomal regions near the end of the Xp to a mutaon in SRY or DDH genes in another 10-15% and Yp arms that maintain their nucleode sequence of cases. True agonadism or a complete lack of throughout meioc recombinaon and the genes in gonads is yet another type of gonadal dysgenesis. these areas escape X inacvaon. These areas are The exact mechanisms involved are unclear, but referred to as PAR1 and PAR2. Mulple genes have now been implicated as genes have been implicated; however, the exact candidates to be involved in Turner syndrome. intricacies of what causes this type of gonadal SHOX/PHOG is one of the first genes in the Xp. Yp dysgenesis is unclear. pseudoautosomal region implicated and is believed to be involved in linear growth. Researchers found a Inacvang mutaons in the FSHR gene coding for German family with a point mutaon in SHOX/PHOG the follicle-smulang hormone receptor is linked to to all have short stature, further implicang this gene 46, XX dysgenesis, mainly in the Finnish populaon. in the short stature of Turner syndrome. Although Mutaon in this receptor leads to blocks in follicular development that cause the follicles to remain in the there is evidence there implicang SHOX and short primary or antral stage. The depleon of the follicles stature, the extent of its contribuon to this feature is also seen with this mutaon. of Turner syndrome has not been established. It appears that SHOX may not be the only factor Addionally, studies have tried to find other genes involved in short stature, and itself may have an that might have specific links to 46, XX gonadal effect on other genes that lead to short stature. dysgenesis, and the gene BMP15 appears to be a possible candidate. However, a definite link to Another gene linked to Turner syndrome is gonadal dysgenesis remains unaffirmed. BMP15 is a RPS4X/RPS4Y; although the data remains gene that codes for proteins apart from the inconclusive regarding this gene, it is thought to transforming growth factor-beta family made by possibly be a factor in lymphedema and lymphac oocytes. A rare amino acid substuon at p.A180T in abnormalies noted in Turner syndrome. This gene BMP15 was present in a small number of paents resides in the Yp region of the Y chromosome and has with ovarian failure in several studies; addional an X-linked homolog that escapes X inacvaon. studies have found that this amino acid substuon may be a rare polymorphism. Another gene linked to Turner syndrome is ZFX/ZFY; it is not thought to be the sole cause of Turner The cases linked to congenital adrenal hyperplasia syndrome but part of the gonadal dysgenesis due to 21-hydroxylase deficiency have direct links to symptoms. Mice studies have revealed that ZFX over 100 different mutaons in the CYP21A2 gene knockout mice had reduced germ cell numbers and [9]. Regarding premature ovarian failure, a large heterozygous female mice showed a reducon in number of genes, including FMR1, AIRE, FOXL2, and oocytes in comparison to their wild type POLG, all share links to disnct syndromes that counterparts but a reducon that was less than what include ovarian failure among their symptoms. was present in the knockout mice. This paern of However, there have been no specific links made reducon in germ cell/oocyte number is similar to between these genes and 46XX gonadal dysgenesis. what appears in 45, X Turner syndrome paents versus their mosaic counterparts. 46, XY Pure Gonadal Dysgenesis

Addionally, recent studies ulizing embryonic stem The SRY gene on the Y chromosome essenally is a cells with Turner syndrome have shown addional switch that turns on the processes of tescular genes that might have involvement, including development. The other main gene involved in male pseudoautosomal genes ASMTL and PPP2R3B, which reproducve development is SOX9, which is involved were found to have decreased expression in Turner in the acon of Mullerian inhibing substance. The syndrome cells, and CSF2RA, which the Turner cells Mullerian inhibing substance is involved in showed reduced upregulaon. These genes are inhibing the development of female internal involved in processes affecng DNA methylaon, the genitalia and allows for the male development to cell cycle, and placentaon. Lastly, there has been take place. Addionally, MAP3K1 is also a common speculaon that an X-linked gene DAX1 that gene linked to 46, XY gonadal dysgenesis, and has suppresses tescular differenaon may cause the been reported to be involved in 13 to 18% of paents. gonadal dysgenesis seen in 45X/45 XY mosaics. MAP3K1 expression downregulates SOX9, which then causes signaling to mirror what occurs in 46, XX Pure Gonadal Dysgenesis ovarian development leading to abnormal tescular 46, XX complete gonadal dysgenesis is inherited in an development. The downregulaon of the tescular autosomal recessive paern, and several loci and development pathway leads to impaired gonadal development. Clinical presentaon: Estrogen replacement therapy (ERT). ERT can help Fetal presentaon: cysc hygroma, fetal hydrops, start the secondary sexual development that heart defect, horse shoe kidney normally begins at puberty (around age 12). This includes breast development and the development Newborn: webbed neck, short neck, manifestaon of wider hips. ERT also provides protecon against due to cardiac defect, skin edema especially edema bone loss. in dorsum of feet Combinaon of estrogen and progesterone to be At puberty: primary amenorrhoea, short stature, started aer 6-12 months of ERT i.e. aer secondary webbed neck, widely spaced nipples, cardiac sexual character is well developed. It is also to be problems such as a bicuspid aorc valve or started in girls who haven't started menstruang by coarctaon of the aorta, horseshoe kidney and age 15. sensorineural hearing loss, mulple nevei. Most girls with Turner syndrome tend to have a normal Regular health checks and access to a wide variety of intelligence level but may have issues with verbal and specialists are important to care for the various social skills. health problems that can result from Turner syndrome. These include ear infecons, high blood Tesng: pressure, and thyroid problems. Chromosomal analysis or karyotype is the test whereby Turner syndrome can be confirmed in Human growth hormone. If given in early childhood, clinically suspected cases. hormone injecons can oen increase adult height A karyotype involves sending whole blood in a by a few inches. sodium heparin tube to the lab for tesng, which may The mean adult height in paents with Turner take up to two week, but a rushed result ulizing syndrome is 4 , 8 in (140 cm); but with growth fluorescence in situ hybridizaon(FISH) can idenfy hormone and estrogen therapy, the average height monosomy X in under 24 hours. increases to 5 (150 cm). Growth hormone therapy is typically disconnued aer the paent reaches a Treatment: bone age of 14 years; sex hormone therapy is Although there is no cure for Turner syndrome, some generally connued throughout life. treatments can help minimize its symptoms. These include:

Guidelines for management of Turner syndrome

Investigation Findings Treatment

At diagnosis Blood pressure If high, Renal Antihypertensive measurement evaluation

Karyotype (Chromosomal Presence of Y Laproscopic analysis) chromosome gonadectomy to prevent gonadoblastoma

USG abdomen Renal malformation

Cardiac evaluation and Congenital heart ECHO defect

TSH Thyroiditis (hypo- Replacementt herapy or hyperthyroid ) as per the diagnosi s

Hearing evaluation Sensory neural Hearing aid if needed hearing defec t

At diagnosis if older than Strabismus; Ophthalmologic one year hyperopia evaluation

Lymphedema Support stockings; decongestive physiotherapy

Yearly Height, weight and BP Short stature, measurement Obesity and hypertension

Ear evaluation Otitis media

TSH and Blood sugar Hypothyroidism, As per report (fasting and postprandia l) diabetes and and lipid profile (fasting ) hyperlipidemia

Liver enzymes If elevated for Ultrasonography to more than 6 evaluate for hepatic months steatosis; hepatology consult

Psychologica levaluation Self-esteem; Psychoeducational learning issues evaluation (school based); suppor t

After 4 yrs of Tissue transglutaminase Celiac disease age (every 2- immunoglobulin A 4 yrly) measurement

From 7 years Malocclusion and other Orthodontic and older tooth anomalies evaluation

From 10 Osteopenia; osteoporosis Elemental years of age and bone mineral densit y calcium (1,200 to to adulthood 1,500 mg per day); vitamin D supplementation; appropriate estrogen therapy; Conclusion: Amenorrhoea may be due to gonadal dysgenesis. 4. Van PL, Bakalov VK, Bondy CA. Monosomy for Though Turner syndrome is the most common cause, the X-chromosome is associated with an other causes like complete gonadal dysgenesis and atherogenic lipid profile. J Clin Endocrinol pure gonadal dysgenesis may contribute to it. Metab. 2006;91:2867–70.5. Bondy CA, for Supporve treatment with estrogen therapy, growth the Turner Syndrome Consensus Study hormone and cyclical progesterone and oestrogen is Group. Care of girls and women with Turner possible. Future reproducve outcome depends syndrome: a guideline of the Turner upon the cause. Syndrome Study Group. J Clin Endocrinol KEY RECOMMENDATION FOR PRACTICE Metab. 2007;92:10–25. · Cardiovascular evaluaons should be 6. Suon EJ, McInerney-Leo A, Bondy CA, performed at diagnosis to rule out Gollust SE, King D, Biesecker B. Turner congenital heart defects. syndrome: four challenges across the · Ongoing estrogen therapy should be lifespan. Am J Med Genet A. 2005;139:57–66. iniated in the preteen years. 7. Hanton L, Axelrod L, Bakalov V, Bondy CA. The · Calcium and vitamin D supplementaon importance of estrogen replacement in should be iniated at 10 years of age. young women with Turner syndrome. J · If any Y chromosome material is shown on Womens Health. 2003;12:971–7. the karyotype, prophylacc laparoscopic 8. Quigley CA, Crowe BJ, Anglin DG, Chipman JJ. gonadectomy is required. Growth hormone and low dose estrogen in · Short stature should be treated with human Turner syndrome: results of a United States growth hormone unl the paent reaches a mul-center trial to near-final height. J Clin bone age of 14 years. Endocrinol Metab. 2002;87:2033–41 9. Stephure DK, for the Canadian Growth Bibliography: Hormone Advisory Commiee. Impact of 1. Gardner RJ, Sutherland GR. Chromosome growth hormone supplementaon on adult Abnormalies and Genec Counseling. 3rd height in Turner syndrome: results of the ed. New York, N.Y.: Oxford University Press, Canadian randomized controlled trial. J Clin 2004:199–200. Endocrinol Metab. 2005;90:3360–6. 2. Rao E, Weiss B, Fukami M, Rump A, Niesler B, 10. THOMAS MORGAN, MD, Washington Mertz A, et al. Pseudoautosomal deleons University School of Medicine, St. Louis, encompassing a novel homeobox gene cause Missouri, Am Fam Physician. 2007 Aug growth failure in idiopathic short stature and 1;76(3):405-417. T u r n e r s y n d r o m e . N a t G e n e t . 1997;16:54–63. 3. Mazzan L, Cacciari E, for the Italian Study Group for Turner Syndrome (ISGTS). Congenital heart disease in paents with T u r n e r s y n d r o m e . J P e d i a t r . 1998;133:688–92. 8 PREMATURE OVARIAN Dr. Sonia Malik INSUFFICIENCY Dr. Vandana Bhaa

INTRODUCTION Hence, it is a state of hypergonadotropic The human ovary funcons both as a reproducve hypogonadism idenfied by menstrual disturbance and endocrine gland and both these funcons are with raised gonadotropins and low estradiol levels. complementary to each other. Ovarian insufficiency This clinical syndrome is characterized by means that the ovary fails to perform its funcons. unpredictable fluctuaons in ovarian acvity in 50 % Natural mean age of menopause is around 50 years of women and 5-10% may sll conceive and when it occurs before the age of 40 it is spontaneously and deliver a child.[1] considered as premature and is known as premature ovarian failure.[1] Primary Ovarian Insufficiency was Loss of ovarian reserve in POI can be confused with first addressed by Fuller Albright in 1942.[2] low ovarian reserve, although these are two separate Subsequently, several different terms have been enes represenng different paents with different used with variaons. In 2011, Cooper and colleagues management needs. Although they lie on the same [3] aer an updated search of PUBMED regarding spectrum, women with POI face challenges much different terminologies being used to define this wider than ferlity alone . condion since 1949, recommended the term “insufficiency” instead of “failure.” Further, since Diagnosc criteria for POI the term “primary” highlighted that the primary Ÿ Younger than 40 years of age defect of the syndrome lay in the ovaries and Ÿ Oligo/ammennorrhea lasng 4 months secondary ovarian insufficiency indicated a central Ÿ Two FSH levels ≥ 30 iu/ml one month apart defect in the pituitary, the term “primary ovarian insufficiency” was agreed upon. To differenate it from natural menopause an age limit was defined as ETIOLOGY these women have different needs and management The eopathogenesis of POI is manifold. It could be opons. The ESHRE special interest group in spontaneous or induced and includes chromosomal, Reproducve Endocrinology summoned a workshop genec, autoimmune, metabolic, infecous, at Utrecht in 2013 and finally decided the environmental or idiopathic causes. (Table 1) terminology “Premature Ovarian Insufficiency“ to The two main pathogenic mechanisms causing POI avoid confusion as the terms “primary “ and are - follicle depleon and follicle dysfuncon. “secondary” were used to classify amennorrhea in relaon to menarche. Mechanism for POI

Thus premature ovarian insufficiency is the most widely used term for loss of normal ovarian Ovarian Follicle Depletion Ovarian follicle dysfunction hormonal and reproducve funcon in women before the age of 40 because of premature depleon of oocytes .

DEFINITION Low initial follicle number Accelerated follicular loss The condion is said to be present when a woman who is less than 40 years of age experiences amenorrhea of 4 months or more with two follicle s m u l a n g h o r m o n e l e v e l s ≥ 30 iu/ml obtained at least one month apart.[4,5] Premature Activation Premature Death In the fetus, germ cells proliferate to form about 7 Adrenal autoimmunity, clinical or subclinical million oocytes by about 20 weeks of intrauterine accounts for 2-10% of POF. [12] The laer may also life. This number falls rapidly unl birth to about be a part of autoimmune polyglandular syndromes 300,000 to 400,000 . These form the follicular pool (APS) when accompanied by other autoimmune and co relates with the ovarian reserve The laer can endocrinopathies. The associaon of POF and be exhausted prematurely because of inherently low addison's disease is explained by sharing of inial numbers or an increased rate of follicular autoangens between ovary and adrenal glands and atresia. Low inial numbers can be due to histological examinaon of ovarian biopsies in these disturbance in any process involving germ cell cases reveal lymphocyc and plasma cell infiltraon formaon, migraon or mitosis and meiosis of of the ovary specially around hormone producing oogonia. In mild cases the inial follicle number cells of the developing follicles. though low, may sll be sufficient to support pubertal development , start of menarche, and in few cases Other endocrine autoimmune disorders associated even ferlity but ovarian funcon will deteriorate with POF are hypothyroidism(13.8%), insulin early in reproducve life. Two funconing X dependent diabetes mellitus (1.7%),[13] chromosomes are necessary for normal ovarian hypophysis and non endocrine autoimmune funcon. 10-12% of females diagnosed with POI have condions like systemic lupus erythematosus, chromosomal abnormalites of which 94% are linked autoimmune hemolyc anemia, viligo, rheumatoid to X chromosome 6 in form of monosomy arthris, crohns disease. Parietal cell anbodies in /aneuploidy, mosaicism,rearrangements, pernicious anemia and acetylcholine esterase translocaons, X isochromosome and ring anbodies seen in myasthenia gravis can block FSH chromosome. In the presence of only one X /LH receptors though the data is not very supporve. chromosome as in Turners syndrome, ovarian follicular pool is depleted by puberty and the paent Mutaons in FSH and LH receptors located on presents with primary amenorrhoea but mosaic chromosome arm 2p can also result in follicular genotypes such as 45XO/46XX present with dysfuncon and hence POF and these paents may secondary amenorrhoea as the rate of atresia is present with primary amennorrhoea. relavely slower. Associaon between fragile X Iatrogenic POF can be caused by radiotherapy, premutaon carrier status and premature ovarian chemotherapy or surgical procedures as failure is well established with a prevalence of 0.8% in hysterectomy and oophorectomy used for malignant women with sporadic POI and up to 13 % in women or benign diseases. The risk of developing POI aer with a posive family history.7, 8, 9 However the radiotherapy is dependent on dose and age . mechanism by which FMR-1 premutaon causes POF Similarly, the gonadotoxic effect of chemotherapy is is not well understood. Molecular invesgaons largely drug and dose dependent and is related to have revealed number of potenal genes like FMR1, age. Any pelvic surgery affecng the vascular supply FRAXE/FMR2, BMP15 for POF on X chromosome to the ovary or causing inflammaon in that area can though none of them has been accepted as a genec lead to detrimental effects later on. marker . Infecons such as viruses like herpes zoster , POF may also be the result of toxic assemblage as in cytomegalovirus, can lead to ovarian failure as galactosemia where there is direct toxicity from indicated by anecdotal case reports but only mumps increased metabolites, aberrant glycolysaon of oophoris has been considered to be a cause of POI glycoproteins and acvaon of apoptosis of oocytes. in 3-7 % cases.[14] Bacteria like Mycobacterium [10] tuberculosis are now known to be established cause of POI.[15] Autoimmune mechanisms are involved in the pathogenesis of POF and the prevalence is rated to Environmental toxins like cigaree smoking, alcohol, be around 30-40%.[11] Autoimmune oophoris poor nutrion and exposure to endocrine disruptors accounts for less than 5 % of women presenng with like heavy metals, solvents, pescides, industrial spontaneous POI/POF. chemicals are implicated in influencing POI but further studies are needed to validate this. [16,17] Thus several causes for POI have been described but thorough invesgaons. the causave factor remains elusive even aer

Table 1 : Eology of Premature Ovarian Insufficiency

Genetic (10– 12%) X – chromosome ( 94%—) Turner ; Fragile X Autoimmune Addison’s disease, Thyroid; Coeli ac

Environmenta l Smoking,Alcohol,Nutrition,Bispheno l A Iatrogenic Radiotherapy, Chemotherapy, Excision of B/L endometrioma,s B/L Oophorectom y Infectious Mumps ( 3– 7 %) Metabolic Classic Galactosaemia, 17 OHde ficiency Idiopathic

CLINICAL PESENTATION -- Prior pelvic surgeries, irradiaon or chemotherapy Clinical presentaon of POI is variable and may --Uterine cause like asherman syndrome depend on the eology. Some women may not --Symptoms of adrenal insufficiency, hypothyroidism experience any symptoms while in others the or other autoimmune disorders symptoms may disappear transiently because of --Family history of POI, male mental retardaon fluctuang ovarian funcon. Irregularity in suggesve of Fragile X syndrome, autoimmune menstrual paern is the main presenng feature. disorders Paents with Turner's syndrome or premutaon carriers of Fragile X syndrome may present with Paents with early stage ovarian insufficiency may primary amenorrhea while older age group may not have any posive physical findings. A physical present with secondary amenorrhea and symptoms examinaon should include of estrogen deficiency. Hot flushes, night sweats are -- height common but mood variaons , vaginal dryness and -- weight dyspareunia may also be very disturbing for the -- body mass index paent. Some women may present with inferlity as -- any evidence of galactorrhoea the only complaint. -- any physical sgmata suggesve of genec syndrome like short stature , webbed neck , low set EVALUATION ears in Turner's syndrome Diagnosis is based on presence of menstrual -- signs of autoimmune disorders like viligo, disturbance and biochemical confirmaon in increased pigmentaon of gums as in Addison's women < 40 years of age in the form of disease oligo/amenorrhea of more than 4 months and an -- thyroid enlargement as in Grave's disease elevated FSH level of > 30 IU/L on two occasions more -- changes in pigmentaon such as premature grey than 4 weeks apart. hair as in autoimmune hypothyroidism -- presence of hirsusm, acne, stria, acanthosis Women with low AMH and regular cycles aending nigrans and viligo . ferlity clinics should not be diagnosed as POI . There is no evidence to include ultrasound, laproscopy with Invesgaons or without ovarian biopsy for diagnosc purpose. Baseline tests include urine for human chorionic gonadotropin levels to rule out pregnancy. Standard History and physical examinaon blood chemistry include thyroid profile, prolacn Elicitaon of detailed history is important to exclude levels, fasng glucose, electrolytes and renal – the other common causes of amenorrhea like funcon tests. Other relevant tests can be offered pregnancy, hypothalamic amenorrhea (due to depending on the clinical presentaon of the paent. excessive exercise, stress or weight loss), Follow up tests can be done depending on the inial hyperprolacnemia (as suggested by headaches and test results. In case of increased inial FSH level, the galactorrhoea) and polycysc ovarian syndrome . same should be repeated aer 4 weeks to confirm the diagnosis. Serum AMH decline with age in healthy women but low AMH is more prevalent in developing fragile X associated tremor/ataxia POI paents. However, low AMH is also seen in syndrome( FXTAS) , a late onset neurological problem women with poor ovarian reserve having regular involving progressive cerebellar gait ataxia and cycles . This should not be taken as an indicator of POI intenon tremors in male carriers. This is important but may be done to assess ovarian reserve. from a counselling point of view. Ultrasound should be done for every paent to assess ovarian size, volume, antral follicle count and Roune screening of autosomal gene mutaons is endometrial thickness but again this modality is for not recommended unless there is an evidence evaluaon and plan of treatment and not for suggesng a specific mutaon ( e.g. BPES). diagnosis of POI. 20% paents with primary amenorrhea and 50 % with secondary amenorrhea Although presently there is no specific treatment for will respond to progesterone challenge test [18] to paents with autoimmune POI , their idenficaon is evaluate estrogen status but the clinical implicaon important to rule out other co exisng autoimmune remains doubul. diseases as Addisons disease. Therefore screening for adrenocorcal anbodies ( ACA) and more Second line invesgaons ( Table 2) specifically 21 hydroxylase (21 OH) autoanbodies, 10-12% of women diagnosed to have POI have thyroid peroxidase anbodies, an thyroglobulin chromosomal abnormalies and the incidence is anbodies and ovarian anbodies is indicated.If any higher in females with primary amenorrhea ( 21%) as paent is posive for these anbodies , she should be compared to those with secondary amenorrhoea referred to an endocrinologist and if paent is (11%).[19,20] negave during inial screening, retesng is not indicated unless specific symptoms develop later in Therefore chromosomal analysis should be life. performed in all women with non iatrogenic POI. Karyotyping is the gold standard though newer Bone density by dual energy x-ray absorpometry technologies like microarray based comparave (DEXA) scan should be considered in women with POI genomic hybridisaon do exist. as 50% of them are at risk of developing osteopenia.4

Presence of fragile X premutaon can have a bearing Since there is no established cause – effect on the paent and her family and hence is indicated relaonship between viral infecons , environmental in all paents of POI. The paents daughters may be toxins and POI, roune tesng for these is not carriers and there is a risk of developing POI in recommended. grandchildren. Also there is an increased risk of

Table 2: Summary of diagnosc work up6

TEST POSITIVE NEGATIVE Karyotyping Refer to geneticist, Repeat karyotype in ( to rule out Turners syndrome endocrinologist , epithelial cells in cases of ) cardiologist high suspicion Y chromosome materia l Discuss gonadectomy with the patient Fragile X Refer to geneticist ACA/ 21 OH antibodies1 Refer to endocrinologist Repeat in case of clinical signs and symptoms TPO -Ab1 Follow up with TSH annually 1 POI of unknown cause or if an immune disorder is suspected SEQUELE in women with POI ,the choice of an HRT regimen POI can have the following long term effects : should be based on individual preferences 1. Psychological effect on the quality of life and self considering compliance and the need for esteem. contracepon as the key factors. 2. Early onset Cardiovascular disease and mortality.[21] From the limited data that is available , transdermal 3. Osteoporosis in 8 -14% cases causing increased estrogens may be the preferred route with lower side risk of fractures. [4] effects. It has advantages of rapid onset and 4. Neurocognive decline and Alzheimer's specially terminaon, self administraon, achievement of in surgical menopause. [22] therapeuc levels with lower doses, beer paent 5. Inferlity in majority of cases. compliance and avoidance of first pass metabolism. 6. Pregnancy/Obstetric complicaons. [23] Few studies suggest it to be free of an excess risk of thrombosis.[24] The route of synthec progesns MANAGEMENT can be same as that for post menopausal women. Management of POI essenally depends upon the Higher levels of progesterone can be achieved in the needs of the paent, but the psychological well- uterus with lower doses using vaginal route. being and general health must be addressed in all Moreover vaginal administraon of natural paents. The diagnosis of POI can be emoonally micronized progesterone is more effecve in creang over whelming. It is important to educate and an “in phase” secretory endometrium aer estrogen counsel the paent and allow her enough me to priming as compared to oral progesterone.[25] accept the diagnosis. Paent needs to be given mely informaon and opons to resolve her Levonogestrel intrauterine device (Mirena) avoids problem and a muldisciplinary approach should be the adverse effects of oral progesns [26] and allows taken. An endocrinologist and genecist may be the usage of estrogen only systemic preparaons . involved for their specific needs. Cyclical combined HRT regimen is preferable for most Specific treatment is required for women with POI specially for those aiming at •Premature ageing pregnancy with donor oocytes. This regimen leads •Ferlity to regular proliferaon of endometrium , withdrawl bleed and hence regular monthly cycles. This Premature ageing regimen also establishes a normal endometrial Long term hormonal replacement therapy (HRT) is development which is required in adolescents with needed to relieve symptoms of estrogen deficiency POI with primary amenorrhea. Though some (vasomotor, genitourinary symptoms, sexual connuous combined HRT regimens may be safer in dysfuncon, mood instability issues ) and for primary young women with POI but they are more likely to prevenon of cardiovascular diseases and experience break through bleeding as compared to osteoporosis. Starng the exogenous hormonal women of older age group where there is greater therapy at an early stage is recommended to achieve uterine atrophy. No progesterone supplementaon maximum benefit since longer the duraon of is required for women with POI and an absent uterus. estrogen deficiency, the more severe are the Dose of estrogen is trated according to the sequele. Young women on HRT should connue the vasomotor symptoms which may not be the same therapy ll menopause. There aer the risks and required for bone or cardiovascular protecon. Aim benefits of connuing the hormones should be is to achieve the physiological estradiol levels as in reviewed. The main goal of HRT is to mimic normal women with normal menstrual cycles (50 – 100 physiological endocrinology with regards to pg/ml)[27] and these can be achieved by 100 mcg estrogens. A wide range of HRT formulaons are estradiol given transdermally [28] or 2 to 4 mg per available for oral, transdermal, subcutaneous and day when given orally. [28] Dose of progestogen will vaginal route. In the absence of robust evidence depend on the dose of estrogen and the regimen comparing the different types of hormonal therapy used . Data evaluang the risks of various regimens of HRT resoluon and concepon and if it occurs then the in young women with POI is scarce and conflicng. cause of POI should be considered as it may have Extrapolang the evidence from studies in older implicaons for the future progeny (e.g. FMR1 women may not be appropriate. HRT has not been premutaon). Different treatments in the form of found to increase the incidence of breast cancer in estrogens, gonadotropins and corcosteroids have young women with POI , however progesns should been tried to increase the natural concepon rates be given in combinaon with estrogens to protect without much success. the endometrium in women with intact uterus. There was no increased risk of stroke in women using Ferlity preservaon may be considered in highly HRT for POI.[7] selected cases in females who are at risk for POI because of natural low ovarian reserve (Turners Whether androgen replacement should be done in syndrome ) or as a result of disease or medical young females with POI remains a controversy. It is treatment or in sisters of POI paents . seen that in women who underwent oophorectomy Cryopreservaon of oocytes, embryos have good at a young age became hypoandrogenic as more than success rates and are no longer experimental . In 25 %of androgens in premenopausal females are vitro maturaon (IVM) is a beneficial method for contributed by ovaries.[29] This can have a ferlity preservaon for reproducve age women deleterious effect on general and sexual health of a who have a contraindicaon to ovarian smulaon female. Though there is not much research on the or who are at risk for ovarian hypersmulaon use of testosterone in women with POI , it can be syndrome . used in transdermally ( gel/patch/cream ) or through an implant. A transdermal patch, Intrinsa is being For prepubertal females with cancer or post pubertal used for women who have undergone bilateral paents who cannot delay cancer treatment, oophorectomy with hysterectomy and face cryopreservaon of ovarian ssue prior to therapy decreased libido.[30] hold promising results. Cortex of the ovary containing ovarian follicles is cryopreserved via The general measures including physical acvity, vitrificaon or slow freezing techniques. The same adequate diet, calcium and vitamin D supplements, can be thawed and transplanted to the pelvis lifestyle intervenons like avoidance of smoking and (orthotopic transplantaon) or extrapelvic alcohol abuse are advocated. BMD and DEXA scans subcutaneous ssue such as forearm or abdomen are helpful in idenfying women with osteoporosis (heterotopic transplantaon ) at a later stage. who may be benefied with bisphosphonates. Efficacy of non hormonal modalies is not Orthotopic transplantaon gives an advantage of a documented but may be considered in women with possibility of natural concepon while heterotopic contraindicaons to HRT. transplantaon requires an IVF aer oocyte retrieval from the extra pelvic site. The main concern Ferlity regarding transplantaon is the fear of reseeding the Available opons are : tumour cells. • In Vitro Ferlizaon with Autologous Versus Donor Oocytes or Embryos For women requiring chemotherapy or radiotherapy, • Ferlity preservaon follicular damage can be prevented by gonadal • Adopon shielding, surgical transposion of the ovaries or oophoropexy, ovarian suppression by GnRH It should not be presumed that inferlity in women analogues . with POI is irreparable as ovarian acvity may occur in these women but the likelihood cannot be The success of these prevenve measures will predicted. There is about 5 % chance of spontaneous depend on many factors -- women's age and ming being of utmost importance. The most established opon for paents of POI Arficial Ovary : The concept is to develop an desiring a pregnancy is oocyte donaon or engineered “arficial ovary” consisng of isolated adopon. Endometrial preparaon with estrogen preantral follicles along with ovarian cells in a 3 D priming followed by progesterone therapy for matrix or scaffold . It is an ovarian environment which making the endometrium recepve needs to be allows the follicles to grow.[33] done in these cases before the embryo transfer .Oocytes may be donated altruiscally or from a CONCLUSION known donor (oen a sister) as per the rules and Loss of ovarian acvity before the age of 40 is the guidelines exisng for that country. hallmark of premature ovarian insufficiency. It is characterized by hypoestrogenemia and raised Women at an increased risk of maternal mortality or gonadotropins. Despite a number of recognised in whom pregnancy is medically contraindicated can causes for POI, the cause is not idenfied in a opt for gestaonal carrier. significant number of women. In view of long term health consequences of POI, management should be Ferlity Preservaon Opons iniated at the earliest. Appropriate counselling, Ÿ Oocyte cryopreservaon psychological support and hormone replacement Ÿ Invitro maturaon therapy is the cornerstone of care. Since there is a Ÿ Embryo cryopreservaon small chance of spontaneous concepon, oocyte Ÿ Ovarian ssue cryopreservaon donaon is an established opon for ferlity . Ÿ Ovarian transposion Ferlity preservaon at a correct me appears as an Ÿ Gonadal shielding encouraging modality for those at risk for POI. Ÿ Ovarian suppression by GnRH analogues REFERENCES: 1. Puneet Arora ,David W Polson Review Diagnosis and Future prospects managementv of premature ovarian failure The Obstetrician & Gynaecologist 2011;13:67–72 Preserving oogonial stem cells : Recent research on 10.1576/toag.13.2.67.27648 2. Albright F, Smith P, Fraser R. A syndrome characterized preserving the oogonial stem cells (OSC) in by primary ovarian insufficiency and decreased stature. ancipated cases of POI and then replacing into the Am J Med Sci 1942;204: 625-648 ovary later on may revoluonize the ferlity pracce. 3. Cooper AR, Baker VL, Sterling EW, Ryan ME, Woodruff TK, Nelson LM. The me is now for a new approach to Acvaon of ovarian follicles : In vitro acvaon primary ovarian insuffi. Ferl Steril 2011;95: 1890-1897 protocols of immature primordial follicles from 4 Bachelot A, Rouxel A, Massin N, Dulon J, Courllot C, cryopreserved ovarian ssue of prepubertal girls at Matuchansky C,et al. Phenotyping and genec studies of risk for POI are sll under development . The aim is to 357 consecuve paents presenng with premature increase the number of viable acvated follicles ovarian failure. Eur J Endocrinol 2009;161:179–87. available for in vitro growth procedures.[31] doi:10.1530/EJE-09-0231 5. Nelson LM. Clinical pracce. Primary ovarian i n s u ffi c i e n c y . N E n g l J M e d Feto- protecve agents : Clinical applicaon of 2009;360:606–14.doi:10.1056/NEJMcp0808697 adjuvant therapies like “feto- protecve” agents -- 6. Management of women with premature ovarian sphingosine – 1 – phosphate and granulocyte colony insufficiency smulang factor have been shown to prevent Guideline of the European Society of Human chemotherapy induced ovarian damage and Reproducon and Embryology POI Guideline follicular depleon but at present their Development Group December 2015 fetoprotecve capacity and their potenal 7.Conway GS, Payne NN, Webb J, Murray A, Jacobs PA. interacon with cancer therapy is quesonable.[32] Fragile X premutaon screening in women with premature ovarian failure. Hum Reprod 1998;13: 1184- 1187 8. Wienberger MD, Hagerman RJ, Sherman SL, 21 Gallagher LG, Davis LB, Ray RM, Psaty BM, Gao DL, McConkie-Rosell A, Welt CK, RebarRW, et al. The FMR1 Checkoway H, Thomas DB. Reproducve history and p r e m u t a o n a n d r e p r o d u c o n . F e r l mortality from cardiovascular disease among women S t e r i l 2 0 0 7 ; 8 7 : 4 5 6 – 6 5 . texle workers in Shanghai, China. Int J Epidemiol doi:10.1016/j.fertnstert.2006.09.004 2011;40: 1510-1518 9. Murray A, Schoemaker MJ, Benne CE, Ennis S, 22. Bove R, Secor E, Chibnik LB, et al.: Age at surgical Macpherson JN, Jones M, Morris DH, Orr N, Ashworth A, menopause influences cognive decline and Alzheimer Jacobs PA, Swerdlow AJ. Populaon-based esmates of pathology in older women. Neurology. 2014; 82(3): 222–9 the prevalence of FMR1 expansion mutaons in women 23. Cabanes L, Chalas C, Chrisn-Maitre S, Donadille B, with early menopause and primary ovarian insufficiency. Felten ML, Gaxoe V, Jondeau G, Lansac E, Lansac J, Letur Genet Med 2014;16: 19-24 H, N'Diaye T, Ohl J, Pariente-Khayat A, Roulot D, Thepot F, 10 .Forges T, Monnier-Barbarino P, Leheup B, Jouvet P. Zenaty D. Turner syndrome and pregnancy: clinical Pathophysiology of impaired ovarian funcon in pracce. Recommendaons for the management of galactosaemia. Hum Reprod Update 2006;12:573–84 paents with Turner syndrome before and during doi:10.1093/humupd/dml031. pregnancy. Eur J Obstet Gynecol Reprod Biol 2010;152: 11. Conway GS,Kaltsas G, Patel A,Davies MC,JacobsHS: 18-24 Characterizaon of idiopathic premature ovarian failure . 24. Scarabin PY, Oger E and Plu-Bureau (2003) Differenal Ferl Steril 1996; 65:337-341 associaon of oral and transdermal oestrogen- 12.Bakalov VK,Vanderhoof VH, Bondy CA,and NelsonLM replacement therapy with venous thromboembolism (2002) Adrenal anbodies detect asymptomac auto risk. Lancet 362,428–432 immune adrenal insufficiencyin young women with 25. Fatemi HM, Bourgain C, Donoso P, Blockeel C, spontaneous premature ovarian failure . Hum Reprod Papanikolaou EG, Popovic-Todorovic B, Devroey P. Effect 17,2096-2100 of oral administraon of dydrogestrone versus vaginal 13. Hoek A, Schoemaker J, Drexhage HA. Premature administraon of natural micronized progesterone on the ovarian failure and ovarian autoimmunity. Endocr Rev secretory transformaon of endometrium and luteal 1997;18:107–34. doi:10.1210/er.18.1.107 endocrine profile in paents with premature ovarian 14.Morrison JC, Givens JR, Wiser WL, Fish SA: Mumps failure: a proof of concept. Hum Reprod 2007;22: 1260- oophoris: a cause of premature menopause. Ferl Steril 1263 1975; 26: 655–659 26. Beral V (2003) Breast cancer and hormone- 15.15.P R Jirge , S M Chougule, A Keni, S Kumar, D Modi replacement therapy in the Million Women Study. Lancet Latent genital tuberculosis adversely affects the ovarian 362,419 reserve in inferle women Human Reproducon, 27.MacNaughton J, Banah M, McCloud P, Hee J, Burger H. Volume 33, Issue 7, July 2018, Pages 1262–1269, Age related changes in follicle smulang hormone, hps://doi.org/10.1093/humrep/dey117 luteinizing hormone, oestradiol and immunoreacve 16. Di Prospero F, Luzi S, Iacopini Z: Cigaree smoking inhibin in women of reproducve age. Clin Endocrinol damages women's reproducve life. Reprod Biomed (Oxf) 1992;36: 339-345 Online 2004; 8: 246– 247 28. Popat VB, Vanderhoof VH, Calis KA, Troendle JF, 17. Sharara FI, Seifer DB, Flaws JA: Environmental Nelson LM. Normalizaon of serum luteinizing hormone toxicants and female reproducon. Ferl Steril 1998; 70: levels in women with 46,XX spontaneous primary ovarian 613–622 insufficiency. Ferl Steril 2008. 18.Rebar RW, Connolly HV. Clinical features of young 29. .Janse F, Tanahatoe SJ, Eijkemans MJ, Fauser BC. women with hypergonadotropic amenorrhea. Ferl Steril Testosterone concentraons, using different assays, in 1990;53:804–810 different types of ovarian insufficiency: a systemac 19. Jiao X, Qin C, Li J, Qin Y, Gao X, Zhang B, Zhen X, Feng Y, review and meta-analysis. Hum Reprod Update 2012;18: Simpson JL, Chen ZJ. Cytogenec analysis of 531 Chinese 405 women with premature ovarian failure. Hum Reprod 30. Testosterone patches for female sexual dysfuncon. 2012;27: 2201-2207 Drug Ther Bull 20 . Kalantari H, Madani T, Zari Moradi S, Mansouri Z, 009;47:304.doi:10.1136/dtb.2009.02.0007 Almadani N, Gourabi H, Mohseni Meybodi A. Cytogenec 31. Del Mastro L,Ceppi M, Poggio F, Bighin C, Peccatori F, analysis of 179 Iranian women with premature ovarian Demeestere I,et al. Gonadotropin releasing hormone failure. Gynecol Endocrinol 2013;29: 588-591 analogues for the prevenon of chemotherapy induced l 2011;40: 1510-1518 premature ovarian failure in cancer women : systemac review and meta analysis of randomized trials. Cancer Treat Rev 2014; 40:675-83 32. Francisca Marnez, on behalf of the Internaonal 33. Vanacker J, Dolmans MM, Luyckx V, Donnez J, Amorim Society for Ferlity Preservaon–ESHRE–ASRM Expert CA. First transplantaon of isolated murine follicles in Working Group1 Update on ferlity preservaon from the alginate. Regen Med 2014;9:609–619 Barcelona Internaonal Society for Ferlity Preservaon–ESHRE–ASRM 2015 expert meeng: indicaons, results and future perspecves†‡)) Hum Reprod. 2017 Sep; 32(9): 1802–1811 9 ASHERMAN'S SYNDROME Dr. Sunil Shah Amenorrhea: An Overview

Definion: synechiae or intrauterine adhesions (IUA). Although Asherman's syndrome (AS) is an acquired condion the first case was described and published by that refers to the existence of scar ssue in the Heinrich Fritsch in 1894, its full descripon was endometrial cavity . This scar ssue makes the given much later by Israeli Gynaecologist Joseph walls of the uterus adhere and reduces the size of Asherman in 1948. the uterine cavity. It is also known as intrauterine

Figure 1: Diagramac represenon oif normal uterine cavity and uterus with Asherman's syndrome

Incidence: Ÿ Vigorous cureage of gravid or non-gravid uterus Asherman's syndrome (AS) is an under-reported and accounts for 90 % cases. It can be due to a single D under-diagnosed disease.Its actual incidence is & C or mulple similar procedures. This causes impossible to know as most cases are asymptomac. damage to basal endometrium layer leading to Only symptomac paents report to gynaecologists IUA. Chances of adhesions are more likely en aer and are invesgated. Bharadwaj et al found that 4.6% post partum or post abortal D&C done two to four inferle paents have AS .(1) It is seen in 40%cases of secondary removal of placental residues or repeat weeks aer delivery or -aboron. Myomectomy cureage following incomplete aboron.(2)* Salzani also increases the risk of IUA. et al found the incidence of IUA to vary from 15% - Ÿ Scar ssue aer Caesarean secon or from 40% aer cureage.(3) Some researchers esmate sutures used to stop haemorrhages is an that IUA occurs in nearly 20% women who had important cause of IUA. It was seen in 19-27% of dilaon and cureage (D&C) or intra-uterine procedures aer complicaons in pregnancy and in women receiving compression sutures to control postpartum. It is also more frequently found in PPH. (4) countries with a high incidence of tuberculosis. Ÿ Acute and chronic infecons of the reproducve organs causing endometris like mycobacterium Aeology tuberculosis, chlamydia and schistosomiasis. The following predisposing factors or antecedent event can contribute to the *development of AS:- Ÿ Following sepc aboron Ÿ Radiaon treatment for carcinoma cervix Classificaons - basis of appearance of endometrial cavity in HSG in 1978. March's classificaon by hysteroscopy was also AS is classified on the basis various characteriscs like introduced in 1978. The classificaon of AS site of adhesions, extent of adhesions, vascularity introduced by American Ferlity Society 1988 is as of adhesions and the type of adhesions in the follows (Table 1):- uterine cavity. Toaff and Ballas classified IUA on the

Classification Condition

Cavity involved <1-3 1/3-2/3 >2/3

1 2 3

Types of adhesions Flimsy Flimsy and dense Dense

1 2 3

Menstrual pattern Normal Hypomenorrhoea Amenorrhoea

0 2 4

Prognostic HSG SCORE HYSTEROSCOPY classification SCORE

Stage 1 ( Mild) 1-4

Stage 2 ( moderate) 5-8

Stage 3 ( severe) 9-12

Table 1: Classificaon by American Ferlity Society, 1988

Types: ● Severe cramping pain during menstruaon Depending on the site and severity of the adhesions, Inferlity and recurrent implantaon failure (RIF) AS is divided into the following types:- due to insufficient vascularity ● Intrauterine fibrosis without visible adhesions or ● Recurrent pregnancy losses (RPL) obliteraon of cavity (Unstuck Asherman's or ● Placenta previa and placenta accreta endometrial sclerosis) ● Intra-uterine growth retardaon ● Cervical canal atresia or atrec amenorrhoea ● Uterine cavity adhesions Diagnosis: ▪Central adhesion without obliteraon of cavity The following inial invesgaons help to rule out ▪Paral obliteraon and constricon of the cavity t h e d i ffe r e n t c a u s e s o f a m e n o r r h e a o r ▪Complete obliteraon of whole cavity hypomenorrhea ●Uterine cavity combined with cervical canal 1. Urine pregnancy test adhesion 2. Hormonal assa y s t o rule out PC OD , Menopause either premature or regular Clinical Presentaon : 3. Pin hole cervix: Cervical sound inseron ●Hypomenorrhea:scanty flow or secondary Amenorrhea usually following dilataon and Various imaging studies can detect the intra uterine cureage adhesions, but complete informaon and therapeuc intervenons can be done by hysteroscopy only. 1. Hysterosalpingography. This has a sensivity of 75 2 D and 3 D USG with Colour doppler: a very thin to 81% with a specificity of 80%. (12) The extent and irregular echogenic endometrium with very lile or locaon of synechiea can be easily seen in HSG . The no colour flow in the base is usually seen . Different radiographic image depends on the site and severity sizes of endometrial cavity may be seen at different of disease.(5) IUA typically shows mulple,irregular level. linear filling defect .When there is extensive 3 . S a l i n e i n f u s i o n s o n o g r a p h y ( S I S ) / symmetrical obliteraon of uterine cavity the uterus Sonohysterography : SIS uses saline soluon that may appear small and in severe cases cavity is not flows into the uterus to make imaging clearer. It is a visualised at all. safe and accurate method of endometrial cavity evaluaon.(6)

Figure3: 2D Ultrasound showing Figure 2: Hysterogram of uterus with Asherman's syndrome Asherman's syndrome6666666

4. Hysteroscopy. The best way to diagnose and manage Asherman's syndrome is hysteroscopy. IUA can be easily diagnosed and treated in the same sing. The European Society for Hysteroscopy classificaon of intrauterine adhesions grades AS as follows:-

Grade Description I Flimsy, thin or invisible. Easily ruptured by hysteroscopic sheath alone Cornual areas normal II Singular firm adhesions Connecting separate parts of the uterus Visualization of both ostia possible Cannot be ruptured by sheath alone IIa Occluding adhesions only in the region of the internal os Upper uterine cavity normal III Multiple firm adhesions Connecting separate parts of the uterus Unilateral obliteration of ostial areas of tubes IIIa Extensive scarring uterine cavity wall with amenorrhoea or severe hypomenorrhea IIIb Combination of III and IIIa IV Extensive firm adhesions with agglutination of uterine cavity walls Occlusion of both the ostia Ta ble 2: TheEuropean Society for Hysteroscopy Classification of Intra-uterine adhesions 5. MRI: This can be of use when adheshions involve ● Use of a sharp needle (Touhy needle) or - do not the endocervical canal. cause thermal damage to the residual endometrium 6. Invesgaons to detect tuberculosis, chlamydia or and has lesser chance of perforang the uterus schistosomiasis. during surgery. It is done under fluoroscopic guidance under general anesthesia and image Guidelines for diagnosis of intrauterine adhesions intensifier control . (13) ● Thermal energy or laser source are also efficient 1.Hysteroscopy is the most accurate method for for hysteroscopic adhesiolysis but can lead to diagnosis of IUAs and should be the invesgaon of damage of the residual endometrium. 8,10,11 choice when available. Level B evidence. ● Other hysteroscopic techniques: This technique is 2.If hysteroscopy is not available, HSG and SHG(SIS) usually used in treatment of severe cohesive IUAs are reasonable alternaves. Level B evidence. when roune hysteroscopically directed adhesiolysis 3.Magnec resonance imaging should not be used is not possible . It is effecve in creang cavity in for diagnosis of IUAs outside of clinical research severe IUAs. In this technique, aer dilang cervix studies. Level C evidence. with dilator and using glycine as the distension medium ,several myometrial incisions , 4-mm-deep Management: The management strategy mainly are created with a Collin's knife electrode from the depends upon: fundus to isthmus.14 A simultaneous laparoscopy A. Dilataon and cureage: This is no longer used as may be performed to observe the distal end of the a treatment modality. It can further aggravate the tube in paents with history of pelvic inflammatory adhesions . disease or ectopic pregnancy. Aer the procedures, B. Hysteroscopic resecon of intra-uterine estradiol is given to prevent re formaon of adhesions: The goal of treatment is to make the adhesions. In cases of cervical stenosis, the uterus regain its normal size and shape. The procedure can be done under ultra sound guidance magnified and direct view of intrauterine adhesions to prevent creaon of false passage and uterine allows a safe and immediate treatment. In addion perforaon . to diagnosis, hysteroscopy can also be used to treat ● Hysterotomy: If adhesions are severe and the IUA by cung the adhesions with very small scissors, uterine cavity cannot be entered then laparotomy lasers, or other types of instruments that use hooks followed by hysterotomy may be done. This is rarely or electrodes. The p of the hysteroscope along with done in current pracce. uterine distension usually breaks down the filmy adhesions.7 As a rule adhesions are removed from Aer adhesiolysis the one or more of the following the lower part of the uterus to the upper part8. Flims- measures may be taken to prevent reformaon of y and central adhesions are dealt first followed by intra-uterine adhesions:- lateral and dense adhesions.9 a. Mechanical separaon of anterior wall and posterior wall by an intrauterine contracepve device followed by hormonal therapy for regeneraon of the endomeum:Intra uterine device, Foley's catheter ( pediatric size) or uterine balloons and different types of gels are used.. Supplementaon with 4-6mg of estradiol for 30 days along with medroxyprogesterone acetate 10mg in the last 10 days of estradiol supplementaon is given.6 b. An-Tuberculous therapy: If hysteroscopic finding suggest endometrial Koch's infecon then Figure 4: Hysteroscopic view of ATT is given in full dose and regime. intra-uterine synechiae c. Treatment of PID for chlamydia with Doxycycline 2 . W e s t e n d o r p I C , A n j u m W M , M o l B W, is started6. VonkJ.PrevalenceofAshermans syndrome aer d. Hyaluronic acid: In the past decades hyaluronic secondary removal of placental remnants or repeat acid wa6s used to prevent intraperitoneal and cureage for incomplete aboron .Human Reprod.1998;13(12):3347-3350 intrauterine adhesions formaon. 3. SalazaniA,Yeta DA, GaliaJRE , Bedane AJ, Montearo IMU. Prevalence of uterine synechia aer aboron N e w e r i n t e r v e n o n s t o re st o re n o r m a l evacuaon cureage .Sao paulo Med J 2007,125(5):261- endometrium include the following : 264 4. Rasheeda SM, Amin MM, Abd Ella AHet al : a. Pharmacological intervenons: Estradiol valerate, Reproducve performance aer conservave surgical Sildenafil and Nitric oxide. treatment of PPH. Int J GynaecolObstet 2014; 214(3):248- 52 B. Stem cells transplantaon intra-uterine infusion of 5. Shahzad GH,AhmadF,Vosough A, Zafar I FA.A textbook autologous stem cells: Endometrial cells has intrinsic and atlas of hysterosalpingography.1st edion. capacity to regenerate. Endometrial ssue contains Tehran:Boshra Publicaons;2009 ,pp173-181. 6. de Kroon CD, de Bock GH,Dieden SW ,Jansen FW.Saline progenitor cells, mesenchymal and stromal cells. contrast hysterosonography in abnormal uterine Intra. Preliminary study suggests good outcome but b l e e d i n g : A s y s t e m a c r e v i e w a n d m e t a data to date is insufficient to recommend regular use analysis.BJOG.2003; 110:938-47. of this therapy . 7. Sugimoto O. Diagnosc and therapeuc hysteroscopy for traumac intrauterine adhesions. Am J Obstet C. Fresh platelet rich plasma (PRP): Intra- uterine Gynecol. 1978;11:539–547 infusion of freshly prepared PRP along with estradiol 8.Yu D, Wong YM, Cheong Y, Xia E, Li TC. Asherman valerate 12 mg. This can be repeated aer 72 hours. sy n d ro m e - o n e c e nt u r y l ate r. F 6 3 e r l S te r i l . So far this is being mostly used is research sengs. 2008;11:759–779. doi: 10.1016/j.fertnstert.2008.02.096. 9. Deans R, Abbo J. Review of intrauterine adhesions. J Post-operave assessment Minim Invasive Gynecol. 2010;11:555–569. doi: 10.1016/j.jmig.2010.04.016. Diagnosc hysteroscopy and repeat surgery if 10 Hysteroscopic treatment of severe Asherman's required is done mostly aer three months of the syndrome and subsequent ferlity. inial procedure. Capella-Allouc S, Morsad F, Rongières-Bertrand C, Taylor S, Fernandez H Outcomes Hum Reprod. 1999 May; 14(5):1230-3 It is measured in terms of menstrual blood flow, 11. Review Intrauterine adhesions. An update.Al-Inany pregnancy rates and its outcomes. The more severe HActa ObstetGynecol Scand. 2001 Nov; 80(11):986-93. the disease, the poorer is the outcome aer 1 2 . S o a r e s S R , B a r b o s a d o s R e i s M M , adhesiolysis . In a retrospecve cross-seconal study CamargosAF.Diagnosc accuracy of sonohysterography, of 357 women3, the pregnancy rates aer transvaginal sonography, and hysterosalpingography in adhesiolysis were 61 percent in mild IUA, 53 percent paents with uterine cavity diseases. FerlSteril. 2000 Feb; 73(2):406-11. in moderate IUA, and 25 percent in severe IUA. 15 13. Elevang AAGL. Gynecologic Surgery. AAGL Pracce The mean me to concepon was 9.7± 3.7 months. Report: Pracce Guidelines on Intrauterine Adhesions Miscarriage ,Intrauterine growth restricon, Developed in Collaboraon With the European Society of preterm delivery, abnormal placentaon is more Gynaecological Endoscopy (ESGE). GynecolSurg common in these paents. 2017;14:6. 10.1186/s10397-017-1007-3 14.Protopapas A, Shushan A, MagosA . Myometrial References - scoring: a new technique for the management of severe 1. BaradwanS, Bharadwaj A, AI - Jaroudi D. The associaon Asherman's syndrome.FerlSteril. 1998 May; 69(5):860- between menstruatalcycle paern and hysteroscopic 15. Chen L, Zhang H, Wang Q, et al. Reproducve March classificaon with endometrial thickness among Outcomes in Paents With Intrauterine Adhesions i n f e r l e w o m e n w i t h A s h e r m a n ` s Following Hysteroscopic Adhesiolysis: Experience From syndrome.Medicine.2018,97(27):e11314 the Largest Women's Hospital in China. J Minim Invasive Gynecol 2017; 24:299.