amenorrhea

obs gyn amenorrhea

1. Amenorrhoea Causes, Evaluation & Management Dr. Priyanka Maru

2. AMENORRHEA

3. CLASSIFICATION OF AMENORRHEA PHYSIOLOGICAL PATHOLOGICAL

4. PRIMARY AMENORRHEA

5. Points to Ponder In most young girls first sign of puberty is growth spurt ( acceleration of growth), followed by breast budding (thelarche), appearance of pubic hair (pubarche) followed by attainment of menses (menarche) Having affirmed the traditional definition, it is important to point out that strict adherence to these criterias can result in improper management of individual patients. For example, there is no point to defer evaluation of a patient presenting with typical phenotype of turner’s syndrome, or, a 13 year old girl presenting with no/ blind vagina should not be advised to return after 2 years.

6. SECONDARY AMENORRHEA Cessation of menses in previously menstruating women for a period of 3 months in case of regular cycles or a period equivalent to 3 cycles in women having irregular menses.

7. Puberty—The Mechanism

8. Breast Pubic Hair Prepubertal (Stage 1) Elevation of the papilla only No pubic hair Stage 2 Elevation of the breast and papilla as a small mound, areola diameter enlarged Sparse, long, pigmented hair chiefly along labia majora Stage 3 Further enlargement without separation of the breast and areola Dark, coarse, curled hair sparsely spread over mons Stage 4 Secondary mound of areola and papilla above the breast Adult-type hair, abundant but limited to mons Stage 5 Recession of areola to contour of breast Adult-type spread in quantity and distribution Tanner Staging

9. Puberty—The Mechanism Initiated by release of pulsatile GnRH (hypothalamus) Specifically see increased pulsatile patterns of FSH & LH (these start during sleep and eventually go throughout the day) With pulses of GnRH, peaks of estradiol result and eventually menarche appears By late puberty, the mature HPO axis is intact and ovulation occurs

10. Physiology of menstruation

11. ETIOLOGY CAUSES OF AMENORRHEA HAVE BEEN SEGGREGATED INTO FOLLOWING COMPARTMENTS ACCORDING TO THE SITE OR LEVEL OF DISTURBANCE OR DISORDER Compartment I: Disorders of the outflow or uterine target organ. Compartment II: Disorders of the ovary. Compartment III: Disorders of the anterior pituitary Compartment IV: Disorders of central nervous system (hypothalamic) factors

12. Disorders of genital outflow tract OR Anatomic/ end organ defect Primary amenorrhea Congenital developmental anomalies Imperforate hymen Transverse vaginal septum Cervical Agenesis Vaginal Agenesis Mullerian Agenesis (MRKH) Androgen Insensitivity Syndrome (Testicular Feminization) Complete or incomplete Endometrial hypoplasia or aplasia Secondary amenorrhea Associated with normal anatomy acquired conditions Cervical stenosis Intrauterine adhesions ( Asherman syndrome) Endometrial Damage from surgical trauma or infection

13. Disorders of the ovary PRIMARY AMENORRHEA Gonadal Dysgenesis/ Agenesis Abnormal karyotype : 45 XO, Mosaic Turner 46 XY (AIS), Sweyer syndrome (gonadal dysgenesis) Normal karyotype : pure gonadal Agenesis (46 XX) Enzymatic Deficiency 17- Hydroxylase deficiency 17,20-Lyase deficiency Aromatase deficiency   SECONDARY AMENORRHEA Premature Ovarian Insufficiency Numerical and structural chromosomal abnormalities X mosaicism(45X,46XX,47XXX cell line) Y (46XY,47XXY,47XYY) cell line X translocations, deletions Deletion of genes involved in germ cell function • Fragile X (FMR1) pre-mutation • Autoimmune disorders • Radiation therapy • Chemotherapy Galactosemia /infections • Functional ovarian failure • SAVAGE SYNDROME Resistant ovary

14. DISORDERS OF ANTERIOR PITUITARY Presents mostly secondary amenorrhoea. Rarely primary amenorrhea SOL/TUMORS -PROLACTINOMAS other Hormone Secreting Pituitary Tumors (ACTH, TRH , GH, Gn ) Hyperprolactinemia ( idiopathic or drug induced) Sheehan syndrome or panhypopituitarism FSH/LH Receptor mutation Empty Sella Syndrome, arterial aneurysm Infiltrative Pituitary lesions- Sarcoidosis, Haemochromatosis, Lymphocytic Hypophysitis Surgical or Radiological ablation

15. Hypothalamic causes Functional hypogonadotropic hypogonadism Stress, Exercise, Nutrition-related. -Weight loss, diet, malnutrition. Eating disorders (anorexia nervosa, bulimia), Pseudocyesis Isolated gonadotropin deficiency – Kallman Syndrome, Idiopathic Hypogonadotropic Hypogonadism Infections -Tuberculosis, Syphilis ,Encephalitis/meningitis &Sarcoidosis Chronic debilitating diseases Tumours – craniopharyngioma, hamartoma, Germinoma, Langerhans cell histiocytosis , Teratoma, Endodermal sinus tumour, Metastatic carcinoma

16. Adrenal disease Adult-onset adrenal hyperplasia Cushing syndrome Thyroid disease Hypothyroidism Hyperthyroidism Ovarian tumors 1. Granulosa-theca cell tumors 2. Brenner tumors 3. Cystic teratomas 4. Mucinous/serous cystadenomas 5. Krukenberg tumors

17. Source- FOGSI focus 2021

18. Source- FOGSI focus 2021

19. Source- FOGSI focus 2021

20. Patient History Pubertal development, age at when breast development started. premenstrual symptoms, dysmenorrhea/ cyclic abdominal pain chronic illness- CKD, Inflammatory bowel disease. exposure to radiation, current medications, surgery, trauma Secondary amenorrhea- H/O previous menstrual cycle, especially whether lengthening cycles or progressively reduced flow had culminated finally in the amenorrhea. exercise, weight loss, illicit drug use Family History : history of pubertal delay (constitutional), infertility, Premature menopause Review of Systems : anosmia, galactorrhea, headaches, visual changes, hirsutism or acne, s/ sx of thyroid disease, vasomotor symptoms

21. Obstetric history with regard to severe PPH, often requiring blood transfusion suggests Sheehan's syndrome leading to hypopituitarism and hypo-gonadotropic amenorrhea MRP or severe puerperal sepsis(Endometritis), H/O previous D&C may lead to amenorrhea by causing uterine synechiae ( Asherman's syndrome). Personal history with respect to appetite, diet and caloric intake and exaggerated weight loss/gain may indicate hypothalamic dysfunction (anorexia nervosa or bulimic disorder) excessive mental and physical stress and radical life-style changes including exercise pattern. Symptoms related to hypo- estrogenism (hot flushes, mood changes, urogenital discomfort) should be enquired into in relevant contextual settings .(POF)

22. CNS - h/o visual s & sx , headaches, recurrent unexplained vomiting. Progressive hirsutism and /or virilisation as reported by the patient should be looked into and may be manifestation of classical late-onset CAH, androgen producing ovarian or adrenal tumour. Changes in hair distribution (excessive, altered hair growth pattern or thinning or loss of scalp hair or brows) should lead the clinician to investigate along the line of thyroid dysfunction or PCOS. frequently prescribed medications to can cause hyperprolactenemia or other central HPO axis dysfunction by altering neurotransmitter secretion and contribute to amenorrhea. Examples include androgens, OCPs, MPA, progestogen intra-uterine systems, GnRH agonists and drugs causing hyperprolactinemia (phenothiazines, reserpine derivatives, amphetamines, benzodiazepines, antidepressants, dopamine antagonists, opiates).

23. Primary Amenorrhea: Physical Exam Evaluation of pubertal development ( height, weight, BMI & arm span) and growth chart Breast development (Tanner staging) Axillary hair present or absent Evaluation for features of Turner’s syndrome Webbed neck, low hair line, shield chest, widely spaced nipples Examine skin for hirsutism - acne, striae, increased pigmentation Pelvic examination- pubic hair development, clitoral size, hymenal opening, depth of vagina, presence of cervix and uterus

24. Secondary Amenorrhea: Physical Exam General physical examination Evaluation of Height, Weight, and BMI, waist : hip ratio, arm span Examine skin for hirsutism, acne, purple striae ( cushing’s ), acanthosis nigricans, dryness or moist skin (thyroid dysfunction) Lid lag, exophthalmos and loss of lateral third of brow hair are pointers to thyroid disorders as also fullness in the thyroid region of neck, exaggerated reflexes, full bounding peripheral pulse and fine hand tremors. Breast exam--look for Galactorrhoea Pelvic Exam- Size of uterus, any pelvic mass Vaginal dryness

25. The need for chromosome evaluation All patients under the age of 30 who have been assigned the diagnosis of ovarian failure on the basis of elevated gonadotropins must have a karyotype determination. The presence of mosaicism with a Y chromosome requires excision of the gonadal areas because the presence of any testicular component within the gonad carries with it a significant chance of malignant tumor formation.

26. Karyotyping With absent uterus, ovaries or sec. sex characters, hyperandrogenism, POI , short stature,≤ 30 years of age Women with XY chromosomes –most commonly -AIS(Androgen Insensitivity Syndrome)-4.1 per 100000 live birth -Gonadal dysgenesis( Swyer Syndrome)-1.5 per 100000 live births

27. Karyotyping should also be considered in patients of short stature to evaluate for Turner syndrome. Patients with this syndrome require screening for cardiac and renal defects, neurocognitive and behavior disorders, hypothyroidism, and hearing loss, Diagnostic Imaging Pelvic ultrasonography or magnetic resonance imaging (MRI) can identify abnormal reproductive anatomy or detect an androgen- secreting tumor .  MRI of the brain can identify pituitary and other tumors  Dual energy x-ray absorptiometry can establish baseline fracture risk in patients with concerns for primary ovarian insufficiency or functional hypothalamic amenorrhea 

28. Hypothalamus and Pituitary Amenorrhea Hypothalamic dysfunction is one of the MC causes of Secondary amenorrhea. Secondary amenorrhea, occurs in approximately 3–5 % of adult women. According to the ASRM, Functional Hypothalamic Amenorrhea (FHA) accounts for 20–35 % of secondary amenorrhea cases and 3 % of primary amenorrhea . Hypothalamic amenorrhea is diagnosed only after ruling out pituitary and ovarian abnormalities. Conditions that often precede anovulation include marked weight loss, physical exercise, physical and mental stress, oral contraceptive use. Amenorrhea is usually a result of hypogonadotropic hypogonadism, marked by low or normal LH, FSH, and oestradiol levels. Normal prolactin, and low leptin are also seen in this type of amenorrhea. LH and FSH however do show response to GnRH stimulation .

29. Disorders of Hypothalamus and Pituitary Leading to Amenorrhea: Chronic hypothalamic anovulation Stress Increased exercise levels Anorexia nervosa, bulimia nervosa, Pseudocyesis Functional amenorrhea--- isolated GnRH deficiency, Kallman syndrome, – Head trauma – Space-occupying lesions, infections Pituitary disorders – Hyperprolactinemia - Prolactinoma - Medications - PCOS - Renal failure Hypo prolactinemia – Pituitary stalk resection, Sheehan's syndrome

30. Diagnosis and Management Detailed personal history with a focus on following points: Dietary habits, history of eating disorders , exercise and athletic training; too many weight fluctuations , irregular sleep patterns, stressors , mood fluctuations, menstrual pattern; fractures, and substance abuse. Obtain a thorough family history with attention to eating and reproductive disorders. CBC, electrolytes, glucose, bicarbonates, BUN, creatinine, LFT, ESR, CRP. Endocrine work up includes TFT, LH,FSH,E2,AMH. Androgen profile advised if clinical hyperandrogenism is present. BMD measurement by dual-energy X-ray absorptiometry (DEXA) should be obtained with 6 or more months of amenorrhea. Pelvic ultrasound in all to ensure normalcy, and MRI pelvis only when indicated is advised.

31. Diagnostic tests: MC performed progesterone challenge test (PCT) with 10 mg medroxyprogesterone for 5 days is useful to differentiate between ovarian cause and hypothalamic cause. If withdrawal period is achieved, then it denotes presence of endogenous estrogen and ensures outflow tract function and patency. There will be no withdrawal period if there is no endogenous estrogen present like in hypothalamo pituitary causes. Following tests are used only when the diagnosis cannot be made with routine clinical examination and investigations. 1. GnRH stimulation test: this is of use to differentiate between hypothalamic and pituitary causes of hypogonadism.100 μ g GnRH is given intravenously. LH and FSH response is measured with samples at 0, 20 and 60 minutes In pituitary disease, response is either absent or blunted. In hypothalamic disease, normal response is seen.

32. Clomiphene stimulation test may be useful to distinguish organic causes of gonadotropin deficiency (pituitary or hypothalamic pathology) from functional disorders and idiopathic delayed puberty. In healthy adults, clomiphene blocks oestrogen feedback mechanisms in the hypothalamus, thus leading to a rise in GnRH and hence LH and FSH. After 7 days of clomiphene stimulation, if LH levels increase more than 120% and FSH increases more than 40 %, the response is considered normal. A normal response essentially rules out organic causes of hypogonadotropic hypogonadism and in delayed puberty, it is an indication that sexual maturity will ensue. In hypothalamic-pituitary pathology there is no response.

33. To differentiate between functional and organic cause of amenorrhea, some form of imaging of the brain (CT or MRI) to rule out a tumour may be useful especially when a history of severe or persistent headaches; persistent vomiting, unexplained change in vision, thirst, or urination, lateralizing neurologic signs, and any indication of pituitary hormone deficiency or excess. Correcting the energy imbalance. Nutritional, psychological, and modified exercise intervention (Cognitive behaviour therapy CBT). OCPs for maintenance of MC and BMD are required. • If CBT is not effective, treatment with pulsatile GnRH as a first line, f/b gonadotropin therapy and induction of ovulation, is used for treatment of infertility.

34. Involving in strenuous exercise or other forms of demanding physical activity have a high prevalence of menstrual irregularity and amenorrhea. The potential adverse effect of intense exercise and low body weight on menstrual function is synergistic. Exercising amenorrheic women do not exhibit a normal diurnal leptin rhythm Treatment with exogenous recombinant human leptin can restore gonadotropin pulsatality , follicular development and ovulatory function in exercising amenorrheic women.

35. Is seen in rarely, congenital specific mutation that prevents normal GnRH neuronal migration during embryogenesis or to mutation in the pituitary GnRH receptor. Kallmann Syndrome is Congenital GnRH deficiency associated with anosmia or hyposmia, classical X linked disorder, caused by genetic mutation in the KAL gene. Kallmann syndrome can be inherited in autosomal dominant or recessive fashion. Idiopathic isolated GnRH deficiency is a similar condition but anosmia is not a feature. GnRH Receptor Mutations- There are more than 20 inactivating mutations in the GnRH receptor gene (GNRHR). Some results in interference with normal Signal transduction, some effectively prevent GnRH binding, both results in resistance to GnRH stimulation.

36. MC by far is benign Adenomas, Other include craniopharyngioma, meningiomas, gliomas, metastatic tumours and chondromas. Pituitary adenomas may be functional (hormone secreting) or non functional. Tumours less than 10mm- - Microadenomas 10mm or larger- - Macroadenomas. Incidentally diagnosed while evaluating for neurological Symptoms or workup of menstrual irregularities. The MC neurological symptoms a/w macroadenomas is visual impairment, classically Bitemporal hemianopsia, other include decreased visual acuity, diplopia, headache, CSF rhinorrhoea, pituitary apoplexy. Treated with Dopamine agonist bromocriptine recommended dose is 1.25mg at bedtime daily for the first week and then gradually increased. Cabergoline given in dose of 0.25mg once or twice weekly till tumour shrinks. Trans sphenoidal resection of tumour is done if medical therapy fails

37. During pregnancy, the pituitary gland enlarges due to estrogen stimulation of lactotroph cells. This enlarging tissue may compress the superior hypophyseal artery, making vulnerable to changes in blood supply. Acute infarction and ischemic necrosis of the pituitary gland resulting from postpartum hemorrhage and hypovolemic hypotension PRESENTATION : Failed lactation after delivery (classical presenting symptom). others: lethargy, anorexia, weight loss, secondary amenorrhea, loss of sexual hair and fatigue. Deficiencies in GH, prolactin, and gonadotropins are most common. Others include ACTH and TSH deficiencies. MX- --Replacement of deficient hormones is necessary in majority of cases to maintain quality of life.

38. Hypothalamic and pituitary Amenorrhea is an underestimated clinical problem. It is related to profound impairment of reproductive functions including anovulation and infertility. There may be skeletal system, cardiovascular system and mental problems. Decrease of BMD, which is related to an increase of fracture risk. Osteopenia and Osteoporosis are the main long-term complications of Hypothalamic Amenorrhea. Cardiovascular complications include endothelial dysfunction and abnormal changes in the lipid profile. Significantly higher depression and anxiety and also sexual problems. Amenorrhea patients should be carefully diagnosed and properly managed to prevent both short- and particularly long-term medical consequences.

39. An acquired condition that refers to the existence of scar tissue in the endometrial cavity . This scar tissue makes the walls of the uterus adhere and reduces the size of the uterine cavity. It is also known as intrauterine synechiae or intrauterine adhesions (IUA). Vigorous curettage of gravid or non-gravid uterus accounts for 90 % cases. It can be due to a single D & C or multiple similar procedures. This causes damage to basal endometrium layer leading to IUA. Chances of adhesions are more likely even after post partum or post abortal D&C done two to four weeks after delivery or abortion. Myomectomy also increases the risk of IUA. Scar tissue after Caesarean section or from sutures used to stop haemorrhages is an important cause of IUA. It was seen in 19-27% of women receiving compression sutures to control PPH. Acute and chronic infections of the reproductive organs causing endometritis like mycobacterium tuberculosis, chlamydia and schistosomiasis.Following septic abortion. Radiation treatment for carcinoma cervix

40. Toaff and Ballas classified IUA on the basis of appearance of endometrial cavity in HSG in 1978. March's classification by hysteroscopy was also introduced in 1978.

41. Depending on the site and severity of the adhesions, AS is divided into the following types:- ● Intrauterine fibrosis without visible adhesions or obliteraon of cavity (Unstuck Asherman's or endometrial sclerosis) ● Cervical canal atresia or atretic amenorrhoea ● Uterine cavity adhesions ▪Central adhesion without obliteration of cavity ▪Partial obliteration and constriction of the cavity ▪Complete obliteration of whole cavity ●Uterine cavity combined with cervical canal adhesion

42. ●Hypomenorrhea: scanty flow or secondary Amenorrhea usually following dilatation and curettage ● Severe cramping pain during menstruation Inferlity and recurrent implantation failure (RIF) due to insufficient vascularity ● Recurrent pregnancy losses (RPL) ● Placenta previa and placenta accreta ● Intra-uterine growth retardation Scanty or no withdrawal bleed with exogenous hormones

43. Hysterosalpingography. This has a sensitivity of 75 to 81% with a specificity of 80%. The extent and location of synechie can be easily seen in HSG . The radiographic image depends on the site and severity of disease. IUA typically shows multiple, irregular linear filling defect .When there is extensive symmetrical obliteration of uterine cavity the uterus may appear small and in severe cases cavity is not visualised at all.

44. 2 D and 3 D USG with Colour doppler : a very thin irregular echogenic endometrium with very little or no colour flow in the base is usually seen . Different sizes of endometrial cavity may be seen at different level. Saline infusion sonography (SIS ) / Sonohysterography : SIS uses saline solution that flows into the uterus to make imaging clearer. It is a safe and accurate method of endometrial cavity evaluation. MRI : This can be of use when adhesions involve the endocervical canal. Investigations- to detect tuberculosis, chlamydia or schistosomiasis. Hysteroscopy . The best way to diagnose and manage Asherman's syndrome is hysteroscopy. IUA can be easily diagnosed and treated in the same sitting. The European Society for Hysteroscopy classification of intrauterine adhesions grades AS as follows:-

45. Hysteroscopic view of intrauterine synechiae Recurrence rate is high- 20-60%

46. Operative hysteroscopy : sharp dissection by scissors As a rule adhesions are removed from the lower part of the uterus to upper part. Flimsy and central adhesions are dealt first f/b lateral and dense adhesions Thermal/ laser or electro dissection Use of a sharp needle (Touhy needle) - do not cause thermal damage to the residual endometrium and has lesser chance of perforating the uterus during surgery. It is done under fluoroscopic guidance under GA and image intensifier control .

47. After adhesiolysis the one or more of the following measures may be taken to prevent reformation of intra-uterine adhesions:- a. Mechanical separation of anterior wall and posterior wall by an intrauterine contraceptive device followed by hormonal therapy for regeneration of the endometrium: Intra uterine device Foley's catheter ( paediatric size) uterine balloons Supplementation with 4-6mg of estradiol for 30 days along with MPA 10mg in the last 10 days of estradiol supplementation is given. b. Anti-Tuberculous therapy : If hysteroscopic finding suggest endometrial Koch's infection then ATT is given in full dose and regime.

48. c. Treatment of PID for chlamydia with Doxycycline is started d. Hyaluronic acid: In the past decades hyaluronic acid was used to prevent intraperitoneal and intrauterine adhesions formation. Newer interventions to restore normal endometrium include the following : a. Pharmacological interventions: Estradiol valerate, Sildenafil and Nitric oxide. B. Stem cells transplantation- - intra-uterine infusion of autologous stem cells. C. Fresh platelet rich plasma (PRP): Intra- uterine infusion of freshly prepared PRP along with estradiol valerate 12 mg. This can be repeated after 72 hours. Post-operative assessment Diagnostic hysteroscopy and repeat surgery if required is done mostly after three months of the initial procedure.

49. CAUSES: conization, LEEP Dilatation and curettage Neoplasia, Radiation Congenital spotting after menses—>most common complaint, however amenorrhea is rare DIAGNOSIS : Inability to pass dilator through the os The treatment for cervical stenosis is careful dilation, ideally performed under ultrasound guidance. Temporary placement of a urinary or specialized balloon catheter for an interval of approximately 2 weeks provides ongoing drainage of the uterine cavity and may help to prevent recurrence.

50. After the 5th week of IUL, two Mullerian ducts grow towards each other in the midline. Fusion of the lateral portions of these ducts start to occur in a caudocranial direction from 7-8 wks of IUL and is completed by 12 weeks of IUL with formation of a uterovaginal canal. Fusion results in the formation of a midline septum which gets resorbed from below upwards and resorption is completed by 20 weeks of IUL. Concavity of the fundus of the uterus changes to dome shaped. The fallopian tubes, uterus, cervix and upper part of vagina including the fornices are of Mullerian origin. A solid vaginal cord from the lower end of the fused uterovaginal canal elongates and vertically fuses with the sino vaginal bulbs from the(endodermal) urogenital sinus by 8 weeks IUL. This results in a vaginal plate formation. Most of the vagina is formed by the canalization of the vaginal plate between 20-26 weeks IUL.

51. Mullerian anomalies can be defects in any one or more of the following: 1) Synthesis 2) Fusion 3) Resorption

52. Mullerian Agenesis Mayer-Rokitansky- Kuster -Hauser (MRKH) syndrome Complete absence of uterus, cervix and the upper 2/3 of the vagina Incidence 1/5000 (1/4000-1/10,000 female newborns) Normal XX Karyotype Normal ovarian function Otherwise normal pubertal development Mullerian agenesis is the second most common cause(10-15%) for Primary amenorrhoea Most cases are sporadic but a few familial have been seen. An association with errors in fetal or maternal galactose metabolism (galactose-1- phosphate Uridyl transferase GALT gene mutations ) resulting in increased intrauterine galactose exposure and mullerian anomaly has been noted. Deligeoroglou et. Al 2010 & ASRM Practice Committee. Amenorrhea. Fertil Steril 2008.

53. Genes involved Mutations in AMH Gene Or AMH Receptor gene Association with WNT gene/ GALT gene mutation There are also isolated reports of HOX ,WNT4 and HNF1B gene mutations but exact causative factor is still unknown.

54. Type A (typical) (64%)- isolated symmetrical uterovaginal aplasia / hypoplasia Type B(atypical )( 24%)- asymmetrical UV aplasia/hypoplasia with malformations of tubes, ovaries +/- renal system Associated Conditions: concurrent urinary tract anomalies Ex: Ectopic kidney, renal agenesis, horseshoe kidney associated skeletal anomalies Ex: spinal anomalies, absent digits, webbed fingers, toes Type C (MURCS) (12%)-Mullerian duct aplasia, renal dysplasia, cervicothoracic somite anomalies(heart and skeletal)-may be familial(WNT4 gene mutations)

55. Pubertal age girl of normal stature with well developed secondary sexual characteristics presenting with primary amenorrhea. Cyclic pain is usually absent in Mullerian agenesis unless functioning endometrium is present. On examination there will be a vaginal dimple or 1-2 cm blind ending vaginal pouch with otherwise normal external female genitalia. This is the part of the vagina that develops from the urogenital sinus. The diagnosis of MRKH can be arrived at with history and examination but karyotyping is justified to rule out Complete Androgen Insensitivity Syndrome (46,XY) which can present in a similar fashion. Male sex hormones in MRKH are in the normal female range. Absence of uterus with presence of ovaries can be made out with an ultrasound scan but MRI is more accurate to delineate finer details as well as pick up urological anomalies.

56. Diagnosis Left: MRI showing absence of uterus and vagina Karyotype : definitive

57. Empathetic counselling. Management is essentially aimed at achieving a fair length of vagina for coital function. If there is the rare functioning endometrium, then laproscopic removal of the uterine remnant should be done. She should be assured that vaginoplasty gives good results when done by trained specialists. She and her partner can have their genetic offspring by IVF with their own gametes and surrogate uterus. There is also the option of uterine transplantation that has evolved tremendously over the past decade.

58. 1) Nonsurgical – Frank's dilators(active) Ingrams method(passive) 2) Surgical – Abbe-Wharton -McIndoe vaginoplasty – Williams vulvovaginoplasty – Colo vaginoplasty/ Ruge procedure – Davydov vaginoplasty – Makinoda's 2 step operation -- Vecchietti operation

59. Dilators Frank (active) Dilate at a 15 degree angle daily after warm bath for 20 minutes. Progressively work up to larger dilators Success defined as non-painful intercourse or vaginal length of 7cm Studies demonstrate up to an 88% success rate at 19 months of use.

60. The patient is instructed to sit on a dilator fixed to a specially designed bicycle seat every day for at least 2 hours. The diameter of the dilator is increased on an average every month. Patient may be allowed to have coitus after the use of the largest dilator for 1 or 2 months. Otherwise continued dilation is required .If dilatation is unsuccessful or unacceptable, operative vaginoplasty is indicated.

61. Abbe-Wharton-McIndoe operation - gold standard technique for vaginoplasty. The principles to be followed are (a) dissection of an adequate space between the rectum and the bladder (b) Inlay split-thickness skin grafting and (c) cardinal principle of continuous dilatation during the contractile phase of healing. After inserting an indwelling urethral catheter and a finger in the rectum, a transverse incision is made on the mucosa of the vaginal vestibule and dissection of the space between the bladder and rectum carefully until the under surface of the peritoneum is reached. This creates the neovaginal surface.

62. The Counseller - Flor modification of the McIndoe technique uses a sterilised foam rubber mould shaped for the vaginal cavity from a foam rubber block and covered with a condom. Success rates in recent times is 80-100 %. Buccal mucosa is being increasingly used as it has tissue similarities compared to native vagina with excellent healing and no visible scar. There are also exciting reports of the use of autologous in vitro grown vaginal tissue.

63. Creation of neovagina by invagination Small acrylic mold placed in the vaginal dimple. Abdominal incision made—traction stitches placed on the abdominal peritoneum and attached to the mold intraperitoneally. Traction device used to pull mold up 1-1.5 cm per day for 7- 10 days. Thereafter standard dilator usage

64. Williams vulvo vaginoplasty A horse-shoe incision is made in the vulva and skin is mobilized to form the perineal pouch /neovagina. Colovaginoplasty / Ruge procedure It involves formation of a neovagina using sigmoid colon grafts. Davydov procedure This technique uses peritoneum to line the neovagina.

65. Imperforate Hymen Most common obstructive lesion of the female genital tract 1/1000 female births Classic appearance of bulging, blue-domed, translucent membrane Can present with hematocolpos or urinary retention Differs from vaginal septum in that an imperforate hymen bulges with valsalva Treatment: Surgical Resection Hymenectomy versus hymenotomy

66. TREATMENT- HYMENOTOMY Definitive surgery - as delay leads to development of severe endometriosis & infertility OBJECTIVE-to open the hymenal membrane to leave a normal patent vaginal orifice Simple cruciate incision in the hymen to the base of the hymeneal ring & excise its central portion for drainage of sequestered menstrual fluid

67. Vaginal Septum

68. Transverse Vaginal Septum Failure of canalization of distal third of the vagina Most common in upper and middle third of vagina Diagnosis Usually present after puberty with amenorrhea and pelvic pain Normal vaginal orifice, shortened vagina and no visible cervix Palpable hematocolpos, hematometra Does not bulge with valsalva maneuver MRI helps with diagnosis TREATMENT Surgical excision with primary anastomosis / graft application for atretic segments.

69. Androgen Insensitivity Male pseudo hermaphroditism / Testicular Feminisation • Male karyotype (46,XY) / phenotypically female; normal at birth • Inactivating mutation in the gene encoding the intracellular androgen receptor ( Xq )

70. Androgen Insensitivity Incidence 1/60,000 although 9% of causes of primary amenorrhea Genetics: X-linked recessive Phenotype: Female; Genotype: XY Female external genitalia –underdeveloped with small vaginal dimple Absent uterus and cervix. Cryptorchidic gonads Absent axillary and pubic hair Breast development Cause: Mutations in the androgen receptor

71. Androgen Insensitivity Physical Examination: Slim and taller than average female/ enuchoid appearance Large breasts with juvenile nipples Absent pubic/axillary hair, no acne or other signs of androgen action May have inguinal hernia Underdeveloped labia minora, blind vaginal pouch and absence of midline structures Laboratory: Testosterone in the normal to high male range, elevated serum LH levels Karyotype: confirms diagnosis XY

72. ANDROGEN INSENSITIVITY SYNDROME Androgen insensitivity syndrome is characterized by the resistance of peripheral tissues to testosterone in patients with 46,XY chromosomal patterns.

73. TREATMENT Creation of a functional vagina Gonadectomy- laparoscopically/inguinal incisions In Complete AIS , gonadectomy – delayed Smooth pubertal development Gonadal tumours occur rarely before puberty In Incomplete AIS , Partial AIS prompt gonadectomy prevents unwanted virilisation could be with ambiguous genitalia Hormonal Therapy-long term estrogen treatment Appropriate psychological counselling for both patient and parents 5-10%; overall incidence of gonadal tumours

74. Androgen Insensitivity: Removal of Gonads Location of testicular gonads is variable Intrabdominal cavity/ Labio scrotal folds/Inguinal region Recommend removal after complete pubertal development Enhance bone maturation and puberty Recommend at age 16-18 Once testes removed, treat with hormone replacement therapy, Gonadectomy followed by neovagina creation Female identity reinforced rather than questioned

75. • Incomplete or defective formation of the gonads, resulting from a disturbance in germ cell migration or organization Cause of primary amenorrhea (30-40%) Turner syndrome - MC cause of gonadal dysgenesis GONADAL DYSGENESIS

76. 45 X Karyotype Assortment of structural X chromosome abnormalities such as deletions, ring and iso –chromosomes Mosaicism Incidence-1 in 2,000-5,000 live born phenotypic females J Clin Endocrinol Metab 2007 Classically 45 XO or mosaic 99% of pregnancies affected end in spontaneous abortions Turner’s Syndrome

77. Turner’s Syndrome Cause: Absence of ovarian determinant gene result in premature loss of germ cells Fetuses with Turner’s have the same amount of germ cells at midgestation as do 46, XX As gestation continues, accelerated loss of germ cells occurs Many XO individuals lose all germ cells prior to birth; less than 15% have enough germ cells to start pubertal process by adolescence 15% begin but do not complete pubertal development 5% complete puberty and begin menstruation

78. Short stature (loss of one copy of SHOX gene on X chromosome) • Absence of sexual development • Webbed neck • Low set ears and posterior hairline • Widely-spaced nipples (“shield chest”) • Short fourth metacarpals • Increased carrying angle at the elbow (“cubitus valgus”) Turner’s Syndrome

79. Turner’s Syndrome Associated Abnormalities Cardiac Anomalies Coartation of aorta in 30% of patients, also bicuspid aortic valve, mitral valve prolapse Recommend echocardiography be performed every 3-5 years Renal Anomalies Horseshoe Kidney Need retroperitoneal ultrasound once diagnosed Hypothyroidism 10% of patients with Turner’s Syndrome Recommend yearly screening of T4/TSH and antibodies Deafness (audiometry) Turner’s Syndrome

80. DIAGNOSIS Karyotype - include examination of at least 30 cells, to detect significant mosaicism 5% women with Turner syndrome have a karyotype containing all or part of a Y chromosome Evaluation • CBC, LFT, KFT, Blood Sugar, Lipid Profile (every 2yrs) TSH & FT4 (every 1-2 yr ) Anti Endomysial antibody ( for coeliac disease at time of diagnosis) Renal USG (normal-once, abnormal 3-5yrs) Audiometry (teen, every 10 yrs ) • ECHO (once btw 12-15 yrs , normal -every 5yrs,abnormal-more often) • MRI aorta- Periconceptional FISH analysis FISH analysis is most clearly indicated for those exhibiting any evidence of virilization or having a chromosomal fragment of uncertain origin

81. Clinical management Those with coarctation of aorta should undergo surgery for its correction. Growth hormone therapy should begin as soon as height falls below the 5 th percentile. (2-8 yrs ) - 0.375 mg/kg weekly dose in 7 divided doses upto 7 yrs Delayed diagnosis (9-12yrs) - GH + anabolic steroid Oxandrolone 0.05 mg/kg/d. help to maximize growth for older girls. Estrogen therapy decreases height velocity and gain in height. Therefore generally not recommended before age 13 or14 yrs

82. TREATMENT Estrogen treatment should begin at a low dose(0.25-0.5mg micronized estradiol or its equivalent) and increase gradually at 3-6 months interval until reaching the final dose( 2 mg micronized estradiol)goal is to complete sexual maturation over a period of 2-3 yrs .Continue till menopausal age Cyclic progesterone ( medroxy progesterone acetate 5mg daily for 12-14 days of each month) should begin after the first episode of menstrual bleeding or after 12-24 months of treatment OCP s good for long term use

83. Fertility All TS counselled about ability to conceive decreasing with age. Spontaneous pregnancies in 4.8-7.6 % but miscarriage rate in such is 30.8-45.1% Young mosaic should be counselled about fertility preservation For most OD is only way to achieve viable pregnancy. Intensive cardiac screening before pregnancy High risk of obstetrical complications like preeclampsia & c-section

84. No. test Follow up , if normal If abnormal 1 2D ECHO 5 yearly More frequently depending on abnormality 2 USG KUB Once in lifetime every 3-5 years, More frequently depending on abnormality 3 T4, TSH 1-2 yearly More frequently depending on abnormality 4 FBS,lipid profile,LFT,KFT 2 yearly More frequently depending on abnormality 5 Audiometry 10 yearly More frequently depending on abnormality 6 Anti endomysial ab Once in lifetime( for celiac disease)

85. Gonadal Dysgenesis XY - SWYER SYNDROME Swyer syndrome is a condition in which people with one X chromosome and one Y chromosome (normally present in males) have a female appearance. • They are typically raised as females, have a female gender identity, have typical female external genitalia, and have a normal uterus and Fallopian tubes. • However in place of functional gonads (ovaries or testes), they have undeveloped, residual gonadal tissue called streak gonads. Streak gonads often become cancerous, so they are usually surgically removed as early as possible. • Swyer syndrome may be caused by mutations in any of several genes. The inheritance pattern depends on the responsible gene.

86. Gonadal Dysgenesis: 46 XY Swyer Syndrome Cause: Associated with deletion in sex determining region (SRY gene) On Y chromosome Streak gonads present; No testes formation Anti-Mullerian hormone and testosterone are not produced hence Normal uterus and fallopian tubes, female external genitalia Estrogen also not produced from streak gonads therefore breast development does not occur Elevated FSH/LH Streak Gonads need removal as they are at increased risk (25%) for germ cell tumors: most common Gonadoblastoma ,Dysgerminoma Estrogen therapy & progestin therapy . Pregnancy can be achieved with IVF using donor oocytes .

87. Swyer Syndrome Dysgerminoma in an adolescent patient with Swyer Syndrome

88. Complete AIS tall women with XY chromosomes Absent sexual hair Breast development present Could have family history Undescended testes, no scrotum or penis No uterus only blind vagina but normal external genitalia Testosterones adequate, FSH & LH mildly elevated Late gonadectomy, only HRT with estrogen , Neovagina Donor oocyte with surrogacy required for fertility issue Swyer Taller women with XY chromosomes. Lower bone density, no pubertal development Breast development absent No family history Streak gonads Normal female genitalia, normal uterus and fallopian tubes No testosterone or AMH, very high FSH and LH Require HRT after Gonadectomy estrogen Plus Progesterone Pregnancy by Donor eggs possible

89. 46 XX GONADAL DYSGENESIS XX gonadal dysgenesis is a type of female hypogonadism in which no functional ovaries are present to induce puberty in an otherwise normal girl whose karyotype is found to be 46,XX. • With nonfunctional streak ovaries she is low in estrogen levels (hypoestrogenic) and has high levels of FSH and LH. • Estrogen and progesterone therapy is usually then commenced

90. RESISTANT OVARY SYNDROME previously known as Savage syndrome , is a cause of ovarian failure that can lead to secondary amenorrhea . • Resistant ovaries result from a functional disturbance of the gonadotropin receptors in the ovarian follicles . It may be a cause of primary or secondary amenorrhea and is resistant to exogenous gonadotropin stimulation. • Diagnosis of this condition requires that the patient has a normal 46,XX karyotype, normal secondary sexual characteristics , elevated plasma follicle-stimulating hormone and luteinizing hormone – in the menopausal range – and that normal, multiple follicles are seen on ovarian biopsy . • Spontaneous reversal of the receptor resistance may occur.

91. Primary Ovarian Insufficiency Primary ovarian insufficiency affects approximately one in 100 females and is defined by follicle dysfunction or depletion, with cessation of menses before 40 yrs. It is diagnosed in patients <40 years with 2 S. FSH levels in the menopausal range (>30 IU) obtained at least one month apart.  Clinically Vasomotor symptoms and vaginal dryness are common. 5–10% of women with POI experience spontaneous conception and delivery.

92. Diagnostic criteria for POI Younger than 40 years of age Oligo/amenorrhoea lasting 4 months Two FSH levels ≥ 30 iu /ml one month apart

93. ETIOLOGY

94. POF Most cases are idiopathic  A karyotype is abnormal in approximately one-third of patients with primary amenorrhea , and it should be offered to all patients with a diagnosis of primary ovarian insufficiency to identify Turner syndrome (or variants), (mostly present <30 yrs age) Patients diagnosed with primary ovarian insufficiency should be offered testing for   FMR1  gene premutation , which confers the risk of fragile X syndrome in children.  Testing for thyroid and adrenal antibodies and annual or biennial screening for hypothyroidism .

95. It could be spontaneous or induced and includes chromosomal, genetic, autoimmune, metabolic, infectious, environmental or idiopathic causes. The two main pathogenic mechanisms causing POI are - follicle depletion and follicle dysfunction. Galactosemia : —Autosomal recessive disorder. —Deficiency of enzyme of galactose 1- phosphate uridyl transferase —Affected women have fewer primordial follicles due to toxicity of galactose metabolites.

96.  POI occurs through two main mechanisms: inadequate formation of the follicular pool  in utero ; and abnormally extensive or fast depletion of the follicular pool via atresia during post-natal (neonatal, childhood and adult) life. POI should not be equated with menopause. The main difference lies in the fact that with POI, ovarian function can still be present albeit unpredictable and/or intermittent. Moreover, it is believed that roughly 50% of women with POI retain intermittent ovarian function for many years, may exhibit spontaneous follicular development, and commence menstruation ( Rebar and Connolly, 1990 ). This is strongly supported by the fact that 5%–10% of women with POI can conceive ( van Kasteren and Schoemaker, 1999 ) and deliver a child ( Rebar et al., 1982 ;  Nelson et al., 2005 ) without any medical intervention, even years after diagnosis was established. Similarly,  Hipp et al. (2016)  reported that 12.6% of women diagnosed with FXPOI conceived spontaneously after diagnosis. The time to conception after diagnosis ranging up to 12 years ( Hipp et al., 2016 ).

97. PRESENTATION The most common presenting symptom – amenorrhea– PRIMARY OR SECONDARY. Hot flushes or vaginal symptoms like dryness or dyspareunia, abnormal bleeding patterns  Family history of early menopause Investigations: - basal FSH and basal estradiol levels  - Anti mullerian hormone testing 

98. Clinical presentation

99. Fragile X syndrome (FXS), also called Martin-Bell syndrome, is a non-Mendelian trinucleotide repeat disorder . FXS is the most prevalent inherited cause of mild to severe intellectual disability and the most common monogenic cause of autism spectrum disorder (ASD). It accounts for about one-half of cases of X-linked mental retardation and is the most common cause of mental impairment after trisomy 21.  Fragile X syndrome has traditionally been considered an  X-linked dominant  condition with variable expressivity and possibly reduced  penetrance .However , due to  genetic anticipation  and  X-inactivation  in females, the inheritance of Fragile X syndrome does not follow the usual pattern of X-linked dominant inheritance, and some scholars have suggested discontinuing labelling X-linked disorders as dominant or recessive. [47]  Females with full FMR1 mutations may have a milder phenotype than males due to variability in X-inactivation

100.   Genetic disorder which occurs as a result of a mutation of the Fragile X messenger Ribonucleoprotein X ( FMR1 )   gene   on the  X chromosome , most commonly an increase in the number of CGG  trinucleotide repeats  in the  5' untranslated region  of  FMR1 . Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females. In unaffected individuals, the  FMR1  gene contains 5–44 repeats of the sequence CGG , most commonly 29 or 30 repeats. Between 45 and 54 repeats is considered a "grey zone ", with a premutation allele generally considered to be between 55 and 200 repeats in length. Although the onset of menstruation appears normal among premutation carriers, approximately 1% experience their final menses before 18 years. If personal or family history of ovarian failure or an elevated FSH levels before age 40 years without a known cause, fragile X premutation carrier testing should be offered.

101. Individuals with fragile X syndrome have a full mutation of the  FMR1  allele, with over 200 CGG repeats. These individuals with a repeat expansion greater than 200, there is  methylation  of the CGG repeat expansion and  FMR1   promoter , leading to the silencing of the  FMR1  gene and a lack of its product. This methylation of  FMR1  in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears 'fragile' under the microscope at that point, a phenomenon that gave the syndrome its name. A subset of people with intellectual disability and symptoms resembling fragile X syndrome are found to have point mutations in  FMR1.  This subset lacked the CGG repeat expansion in  FMR1  traditionally associated with fragile x syndrome

102. Clinical features Long face with long palpebral fissures as well as a broad philtrum Prominent forehead and protruding ears with soft cartilage High-arched palate and dental crowding Hyperextensible finger joints and thumbs Hypotonia Biting, hand flapping, poor eye contact, language disorders from cluttered speech to complete lack of speech depending on phenotype severity Mild to profound intellectual disability. The behavioural phenotype includes ADHD, speech and language delay, anxiety and autism spectrum disorders. POF in females

103. Fragile X baby

104.  The fragile X abnormality is now directly determined by analysis of the number of CGG repeats using  polymerase chain reaction  (PCR) and methylation status using  Southern blot  analysis. There is no cure for the underlying defects of FXS. Management of FXS may include  speech therapy ,  behavioral therapy ,  occupational therapy ,  special education , or individualised educational plans.

105. Diagnosis and Initial Evaluation of Primary Ovarian Insufficiency Menstrual irregularity for at least 3 consecutive months FSH - greater than 30–40 mIU /mL and estradiol levels - less than 50 pg/mL (two random tests at least 1 month apart) Prolactin and TFT, anti TPO antibodies Pelvic ultrasonography If diagnosis is confirmed: Karyotype FMR1  premutation, Turner mosaic Adrenal antibodies — 21-hydroxylase (CYP21) Nelson LM. Clinical practice. Primary ovarian insufficiency.  N Engl J Med 2009;360:606–14

106. 1. Hormone therapy : micronised estradiol 1-2 mg daily OR conjugated equine estrogen 0.625- 1.25 mg daily OR transdermal patch 0.1mg/24 hrs along with, micronised progesterone 200mg daily OR , medroxyprogesterone acetate 10mg daily for 12-14 days. Fertility : infertility treatment is done by IVF using donor oocytes. 3. Psychological and emotional support

107. Oocyte cryopreservation Invitro maturation Embryo cryopreservation Ovarian tissue cryopreservation Ovarian transposition Gonadal shielding Ovarian suppression by GnRH analogues

108. M/C endocrine disorder of the hypothalamic-pituitary axis. Presents as an ovulatory disorder Often associated with secondary amenorrhea or oligomenorrhea, galactorrhoea and osteopenia. Prolactin plays a pivotal role in a variety of reproductive functions. Prolactin is a 198-amino acid protein (23-kDa) produced in the lactotroph cells of the anterior pituitary gland. Prolactin is under dual regulation by hypothalamic hormones delivered through the hypothalamic–pituitary portal circulation. Inhibitory signal is mediated by the neurotransmitter dopamine. The stimulatory signal is mediated by the hypothalamic hormone thyrotropin-releasing hormone.

109. Hyperprolactinemia can be physiological or pathological. Prolactinomas account for 25-30% They typically present with oligomenorrhea, amenorrhea, galactorrhea , or infertility. Prolonged hypoestrogenism secondary to hyperprolactinemia causes osteopenia.

110. Psychotropic medications. Neuroleptics act by blocking dopamine receptors. S erotonin uptake inhibitors may increase prolactin levels by increasing serotonergic inhibition of dopaminergic neurons. Other medications. Gastrointestinal motility agents and antihypertensives have also been associated with hyperprolactinemia. Serum prolactin levels increase 6-fold after oral or iv metoclopramide and domperidone also stimulates prolactin release. Methyldopa, an α- adrenergic agonist, and verapamil, a calcium-channel blocker, both increase prolactin levels, likely by decreasing dopamine synthesis.

111. A single measurement above the upper limit of normal confirms the diagnosis given the sample was obtained without excessive veni puncture stress. When in doubt , sampling repeated on a different day at 15-20 mins intervals to account for possible prolactin pulsatility . PITFALLS IN DIAGNOSIS : - Macroprolactin - less bio-active form, dimer/polymer, detected by polyethylene glycol precipitation method although gel filtration chromatography remains the gold standard. -Hook effect- serial dilution of serum samples to eliminate an artefact that can occur with some immune-radiometric assays Serum TSH, blood urea nitrogen and creatinine .

112. A mildly elevated serum prolactin level may be due to a non functioning pituitary adenoma or craniopharyngioma compressing the pituitary stalk. Prolactin levels that are very high (>250 ng/mL) are almost always associated with a prolactinoma. Magnetic resonance imaging (MRI) with gadolinium enhancement provides the best visualization of the sellar area.

113. The goals of treatment for are ● Normalization of prolactin level ● Restoration of gonadal function and fertility ● Avoidance of the adverse effects of chronic hyperprolactinemia like osteoporosis. An additional goal of treatment in macroprolactinoma patients is tumour shrinkage with relief of mass symptoms. Current therapeutic options include medical therapy, surgery and radiotherapy

114. Gastric motility drugs should be stopped and some other medication with no CNS side effects can be started after the treating physician consultation. Continuation of other medications depend upon risk : benefit ratio. Whether to treat a patient who has anti psychoctic drug-induced hyperprolactinemia with a dopamine agonist remains controversial. Some studies suggest that dopamine agonist therapy will normalize prolactin levels in only up to 75% of such patients but may lead to exacerbation of the underlying psychosis. The treating psychiatrist should be consulted for any change in psychotropic regimen.

115. Depends on cause. Dopamine agonist- 1. Bromocriptine - Dose: 1.25mg daily,increase by 1.25 mg weekly -Therapeutic dose range:2.5-15 mg /day in divided doses 2.Cabergoline -selective dopamine type 2 agonist - fewer side effects, greater potency, longer duration of action -Side effects: with long term use—> valvular heart disease - Dose : 0.25-0.5 mg once/twice weekly upto 3 mg. continued for approximately 12- 24 months (depending on the degree of symptoms or tumour size) and then withdrawn if prolactin levels have returned to the normal range) Response to therapy should be monitored by checking fasng serum prolacn levels and checking tumor size with MRI.

116. Trans-nasal/trans-sphenoidal microsurgical excision of prolactinoma is the procedure of choice. Recurred within 5 years after surgery in about 50% of patients with micro prolactinomas who were initially thought to be cured. Radiotherapy should be reserved for resistant or malignant prolactinomas.

117. Regardless of the size of the adenoma, there is no indication for treatment with dopamine agonists or for imaging during pregnancy in the absence of symptoms; treatment may be safely discontinued when pregnancy is established. Breastfeeding poses no significant risk for tumor growth in women with micro adenomas or macro adenomas that remain asymptomatic during pregnancy, but is contraindicated for those with neurologic symptoms at the time of delivery.

118. The most commonly prescribed treatment for menstrual abnormalities in PCOS is the combined oral contraceptive (COC) pill. It provides endometrial protection through its progesterone and thus stunts endometrial growth from unopposed estrogen and cycles regularise with lighter bleeding. Besides, COCs are effective for suppressing LH-mediated ovarian androgenesis, thus correcting the hyperandrogenic milieu. Estrogen is contraindicated in some women, in them progesterone-alone preparations can be used either in a continuous or a cyclical form.

119. S UBCLINICAL HYPOTHYROIDISM H igh TSH, normal FT4 HYPERTHYROIDISM low TSH, normal FT4, high T3 SECONDARY HYPOTHYROIDISM (pituitary)
low TSH, low FT4

120. Both primary hypothyroidism (elevated TSH) and primary hyperthyroidism (low TSH) may result in chronic anovulation and amenorrhea- primary or secondary amenorrhea. Few women with hypothyroidism will develop a secondary hyperprolactinemia and even Galactorrhoea. The likelihood of hyperprolactinemia increases with the duration of hypothyroidism Mechanism: gradual depletion of hypothalamic dopamine (prolactin-inhibiting factor) constant stimulation of pituitary lactotropes by thyrotropin-releasing hormone (TRH), which may cause pituitary hypertrophy or hyperplasia.

121. congenital adrenal hyperplasia (CAH) CAH is a family of inherited disorders characterized by defects in cortisol production, resulting in increased ACTH production due to reduced negative feedback and consequent adrenal gland proliferation.  Classic 21-OH deficiency is typically diagnosed at birth and can present with severe salt wasting and/or prenatal virilization of external female genitalia. Nonclassic CAH presents postnatally with signs of hyperandrogenism including hirsutism , acne, frontal balding, and menstrual irregularities.

122. Although there are rare forms of CAH that result in inferltiity , including 11 β hydroxylase deficiency, 17 α- hydroxylase deficiency and 3 β- hydroxysteroid dehydrogenase deficiency. CAH most commonly arises from autosomal recessive mutations in the gene that encodes 21- hydroxylase - (21-OH), CYP21A2, which result in shunting of steroid precursors toward androgen biosynthesis.

123. In – utero : Female external genitalia develop until 20 weeks and size of clitoris depends on levels rather than timing of androgen exposure. Internal genitalia are normal female type due to normal ovarian steroidogenesis and absence of AMH. Oligomenorrhea in women with 21-OH deficiency is likely due to elevated androgen and/or progesterone levels that are associated with reduced LH-pulse amplitude and frequency . Elevated levels of progesterone, a substrate of 21-OH, also likely contribute to menstrual irregularity.  Fertility is lower than normal, due to chronic anovulation , abnormalities of genital anatomy, psychological factors, decreased sexual activity. Outcome of pregnancies are normal except for increased incidence of GDM.

124. Diagnosis of CAH High serum concentrations of 17 OHP. NEONATES with salt wasting … > 3500ng/dl. (Normal newborn<100ng/dl) ACTH stimulation test with cosyntropin at 0 th and 60 th min levels > 10,000ng/dl diagnostic. Screening repeated at 1-2weeks of age with careful monitoring and genotyping in the interim. In children morning values > 82ng/dl, confirmed by ACTH stimulation. In Adult women >800ng/dl, stimulated values > 1500ng/dl diagnostic. 21 hydroxylase deficiency differentiated from other forms of CAH by serum concentrations of 11 deoxycortisol and 17 α pregnanalone . In non-classical forms 17 OHP levels only slightly elevated.

125. TREATMENT OF CAH To replace sufficient amounts of deficient hormones along with cortisol to reduce excess ACTH secretion. In neonates – lifesaving In children - normal growth and sexual maturation. In adults - for hirsutism, menstrual abnormalities & infertility. Prenatal treatment of mothers at risk for having an affected child: begin dexamethasone CVS sex determination & genotyping dexamethasone ( upto 1.5 mg in divided doses continued ONL Y IN AFFECTED FEMALE FETUS to prevent virilization. Treatment should begin at 4-5 weeks and not later than 9 weeks. Positive HCG

126. Most common cause: prolonged glucocorticoids (e.g., prednisone) intake. Other: cortisol-secreting adrenal adenomas and carcinomas ectopic production of ACTH corticotrophin-releasing hormone (CRH) by brochial carcinoids

127. Presentation: Progressive central obesity moon face buffalo hump purple striae (abdomen and flanks) hyperpigmentation (caused by excess ACTH), which is most noticeable in areas exposed to light (the face, neck, and back of the hands) amenorrhea hirsutism and acne proximal muscle wasting and weakness osteoporosis glucose intolerance, diabetes

128. Diagnosis: 24-hour urinary free cortisol excretion (twice), the late-night (11:00 P.M.) salivary cortisol level (twice) performing an overnight or low-dose dexamethasone suppression test (All the three screening tests have similar diagnostic accuracy)

129. overnight dexamethasone suppression test: administer 1.0 mg of dexamethasone between 11:00 P.M. and midnight —>> measure the serum cortisol at 8:00 A.M. the following morning —>>value less than 1.8 mg/dL is a normal result. low-dose dexamethasone suppression test: administer 0.5 mg of dexamethasone every 6 hours over 2 days for a total of 8 doses—>> measure serum cortisol 2 or 6 hours after the last dose; as with the overnight test—>>a value less than 1.8 mg/dL is a normal result.

130. Treatment trans sphenoidal surgery (the permanent cure rate is approximately 70%). Bilateral total adrenalectomy —>> lifelong daily glucocorticoid and mineralocorticoid treatment. therapy: Radiotharapy those not cured by surgery. effective in approximately 45% of adult patients.