Primary amenorrhea

Definition Failure to initiate spontaneous menses by the age of 16 or evidence of pubertal onset by age of 14. It is a rare condition seen in less than 0.1% of the general population.

Introduction Puberty is a period of transition between childhood life and adult womanhood life during which sexual maturation occurs The hypothalamus is initiator of these pubertal changes in the following order adrenarche, gonadarche and menarche.

Hypothalamus Hypothalamus Pituitary Stalk Pituitary gland Oxytocin ADH PVN Oxytocin ADH SON Hypothalamus Pituitary Stalk Pituitary gland GnRH Satiety center VMN Chiasma

U-shaped LH curve Exercise Anorexia Post-partum High opioid Reversal High opioid High melatonin Low leptin Pre-pubertal still Neonate Child Adult This curve is present even in agonadic child The drop of opioid and melatonin, or rise of leptin allows the release of GnRH

Two independent events of puberty Adrenarche Gonadarche Stimulus CASH GnRH Timing Precedes growth spurt Follows growth spurt Mediator DHEA E2 Manifestation Pubic hair Axillary hair Growth spurt Menarche Disease Not in Addison’s Not in Turner’s

Tanner staging of puberty Stage Age Breasts Pubic hair E2 Pg/ml I 7 Nipple Nil < 10 II 10 Breast bud Sparse labial 10-20 III 11 Smooth contour Dark curled hair 20-40 IV 13 Secondary mound Adult type hair 40-60 V 14 Mature breast Adult distribution > 60 NB: Menarche coincides with stage IV

Second growth spurt It is earlier in females It is higher in males It is related to GH, IGF-1 Gonadal steroids Initiates it Terminates it Increments inches/years 1 2 3 4 Girls Boys 0 2 4 6 8 10 12 14 16 18 20 Age in years

Leveling of amenorrhea For proper menses to occur there should be a nice integration between the hypothalamus, pituitary, ovary and responsive uterus as well as a patent effluent genital tract. We have four levels; Level 1 (Uterus and outflow tract), Level II (Ovary), Level III (Pituitary), Level IV (Hypothalamus)

Categorization Based on presence or absence of 2ry sexual characteristics: No 2ry sexual characteristics Breast development, but no pubic and axillary hair Normal 2ry sexual characteristics Incompletely developed 2ry sexual characteristics

Primary amenorrhea

Cholesterol LDL-c Acetate 3HSD DOC 5P 4P Aldosterone 3HSD 17 OH5P P450SCC 21OHase 11OHase 17OHase 3HSD 17OHase DOC Corticosterone 5P 4P Aldosterone Desmolase 3HSD 21OHase 17 OH5P 17OH4P 11 desoxy cortisol or compound S Desmolase 11OHase 17HSD 11HSD 3HSD DHEA AD Cortisol P450arom E1 Te P450arom Cortisone E2

1ry amenorrhea with no 2ry sexual charachteristics central FSH low Hypogonadotropic hypogonadism: Kallmann’s syndrome: 1ry amenorrhea (lack GnRH)+ Anosmia Craniopharyngioma: either by damaging the hypothalamus or interferes with the transport o hormones If GnRH stimulation test +ve>>> hypothalamus Imaging needed for tumors

Craniopharyngioma Rathke’s pouch tumor GH (Dwarf, obese) Gn (Delayed puberty) ADH (DI) ICT Stalk section Optic chiasm Cystic spaces Squamous epithelium Calcification Enamel-like

1ry amenorrhea with no 2ry sexual charachteristics gonadal FSH high Hypergonadotropic hypogonadism: Unresponsive end organs Differential diagnosis: Turner’s syndrome Swyer’s syndrome Pure gonadal agenesis (46XX & 46XY) Mixed gonadal dysgenesis Abnormal X chromosome

Turner syndrome Turner’s stigmata Sexual infantilism Short stature Webbed neck Spaced nipples Cubitus valgus Shield chest Pigmented nevi Coarctation of aorta Renal anomaly Streak gonads Turner’s Karyotype XO XO/XX XXp- XXr

Turner syndrome Cystic hygroma Fetal hydrops Cystic hygroma

1ry amenorrhea with breast development and lack of pubic & axillary hairs +ve gonadal secretion, no manifestations of androgen secretion Reflects the absence of androgen receptors “complete androgen insensitivity syndrome” (testicular feminization) Genotype : 46XY male intra-abdominal testes Phenotype :female normal contour, no uterus, vaginal dimple….. Due to mullerian-inhibiting substance Gonadectomy,,,, high malignancy rate Raise as female and create new vagina Psychological counseling Islamic view regarding inheritance

Morris syndrome (XY female) Male karyotype Female phenotype Male level of testosterone Complete Receptor failure 5 alpha-reductase defect

1ry amenorrhea with normal 2ry sexual charachteristics Normal gonadal secretion Vast majority 46XX, amenorrhea due to anatomical abnormalities In case of absent vagina and/or uterus: Creation of new vagina is the answer (dilators, vaginoplasty) With yterine/vaginal abnormalities always think of renal abnormalities With no uterus Mullerian agenesis (Mayer-Rokitansky) XY female (Morris’) With a uterus Gynaetresia Imperforate hymen T.S vaginal septum Hypoplasia uteri Genital TB Systemic illness Constitutional delay

1ry amenorrhea with incomplete 2ry sexual charachteristics

Comparison Mullerian agenesis XY female Karyotype XX XY Heredity -ve XLR Sexual hair Female distribution Hairless Te Female range Male range Anomaly Yes Rare Tumor No 5%

Primary amenorrhea with sexual infantilism Obese Frohlich’s syndrome Laurance-Moon-Biedl syndrome Hand-Schuller-Christian disease Prader-Willi syndrome Craniopharyngioma Suprasellar-germinoma Thin Exercise related High B-End High catechol estrogen Anorexia nervosa Weight loss Systemic illness Tuberculosis SCD Thalassemia

Primary amenorrhea with sexual infantilism Tall Pure gonadal agenesis Swyer’s syndrome Kallmann’s syndrome 17 OHase deficiency 17-20 desmolase deficiency Short Pituitary dwarf Sexual Asexual (Laron) Turner’s syndrome Hypothyroidism Constitutional delay of puberty

Comparison Item Pure gonadal agenesis Kallmann’s syndrome Karyotype XX or XY (Swyer’s) XX FSH High Low Gonad Streaks Ovary Humegon No response Good Association Gonadoblastoma Anosmia

Weight loss amenorrhea Simple Anorexia nervosa Age Any Young Psychic No Yes Weight loss Added features 20% of IBW More Dehydration Hormones Normal  GH, rT3, Carotene, DA  PRL, LH, T3, E2, ADH GnRH therapy Useful Not Complication Possible As the fault extends to the pituitary in anorexia, GnRH pulse therapy is not effective in restoring menstruation.

Comparison Turner’s syndrome Noonan’s syndrome Karyotype 45/XO 46/XXp- Gonad Streak Ovary Stigmata Yes Heart CoA PS IQ Normal Low Can Turner cases got pregnancy? Yes

Primary amenorrhea Ch FSH LH E2 Te PRL PWT Turner’s XO   = -ve AIS XY Kallmann XX

Evaluation of primary amenorrhea History Personal history Family history Past history Physical examination Secondary sex characteristics Virile manifestations Weight, height, span Sonographic assessment Laparoscopy Gonadal biopsy

Investigation Buccal smear Karyotying Endocrine evaluation FSH/LH, PRL/TSH Estrogen (PWT, C.I, E2 assay) Androgen (Te, DHEAS)

Management of primary amenorrhea The aim of treatment is to attain maximum physiologic function of which an individual can attain. No treatment until the diagnosis is solid. The majority will be able to achieve satisfactory sexual life but the prospect of fertility may be poor. HRT may be needed for life.