Amenorrhea Dr. Maysa’ Khadra A/Professor in Reproductive Endocrinology and Infertility Dept of Obstetrics and Gynaecology University of Jordan; Jordan University Hospital

Amenorrhea definition Primary: No period by age 14 in the absence of growth or development of secondary sexual characteristics. or No period by age 16 regardless of the presence of normal growth and development with the appearance of secondary sexual characteristics.

Amenorrhea definition Secondary: In a woman who is menstruating , it is the absence of periods for a length of time equivalent to a total of at least three previous cycle intervals or six months of amenorrhea Oligomenorrhea is defined as an interval of more than 35 days between periods

differential diagnosis of amenorrhoea Disorders of outflow Disorders of the ovary Disorder of the anterior pituitary Disorders of the central nervous system

Disorders of outflow Asherman’s syndrome Mullerian Anomlies Cervical stenosis Imperforate hymen Transverse vaginal septum Mullerian agenesis Vaginal and uterine aplasia- Rokitansky Kuster Hauser syndrome Androgen insensitivity

Cyclical abdominal pain urinary retention 37-60% back pain Constipation distended bluish membrane at the introitus

46XY karyotype, X-linked recessive mutations in AR, the gene for the human Androgen Receptor, located at Xq11-12 Undervirilization and/or infertility in XY persons undescended testis in abdomen or inguinal canals No uterus or vagina-AMH no prostate or internal male gentalia No pubic or axillary hair normal breast development 25% chance of developing benign testicular tumors and a 4-9% chance of malignancy.

Disorders of the ovary Streak ovaries Turner’s syndrome xo or mosaicism XY Gonadal dysgenesis Resistant ovary syndrome Premature ovarian failure Polycystic ovarian syndrome hormone secreting ovarian tumors

Genetic mosaicism (46XX/45XO) is most often implicated, nondisjunction (45XO) and partial monosomy (46XX ) XO : primary amenorrhea Mosaic: premature ovarian failure, streak gonads and infertility Horse shoe kidneys-HTN Hypothyroidism- Hashimoto’s risk of gonadoblastoma (45 XO/46 XY)

Gonadal dysgenesis It is characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo. This loss leads to extremely hypoplastic and disfunctioning gonads mainly composed of fibrous tissue, hence the name streak gonads. absence of both Mullerian inhibiting factor and testosterone regression of the Wolffian ducts due to absence of testosterone The absence of Mullerian inhibiting factor will allow the Mullerian ducts to differentiate into the oviducts and uterus individual will be genotypically male (i.e., XY), yet will possess female-like internal and external reproductive characteristics

Gonadal dysgenesis pure gonadal dysgenesis, 46, XX Swyer syndrome: pure gonadal dysgenesis, 46, XY type of hypogonadism in which no functional gonads are present to induce puberty in an externally female person whose karyotype is then found to be XY. The gonads are found to be partially non-functional streaks Mutation of the SRY gene: When such a gene is defective, the indifferent gonads fail to differentiate into testes in an XY (genetically male) fetus absence of breasts ( streak gonads), and the presence of a uterus and pubic hair (adrenals) High risk of malignancy esp. gonadoblastoma, gonads should be removed as cancer may develop in infancy

Disorders of the anterior pituitary Non- functional adenomas Prolactin secreting adenomas Empty sella syndrome or compression of pituitary stalk Sheehan’s syndrome Galactosemia: Fewer oogonia result as a direct result of the toxic effect of galactose metabolites on germ cell migration to the genital the genital ridge

Disorders of the central nervous system Hypothalamic amenorrhea weight loss, anorexia, bulimia Excessive exercise-induced amenorrhea (decreased body fat and elevated endorphins and CRH) Inherited genetic defects- Kallman’s syndrome

Primary amenorrhea- causes Chromosomal abnormalities (45%) Physiological delay (20%) Mullerian agenesis (15%) imperforate hymen or vaginal septum (5%) Hypothalamic GRH deficiency (5%) anorexia nervosa (2%) Hypopituitarism (2%) Prolactinoma, hypothyroidism, craniopharyngima, adrenal disease ( < 1%)

Primary amenorrhea- 2 questions approach Has puberty occurred ? “No”, then “normal stature or short? “yes”, then Feminizing or Virilizing

Has puberty occurred ? NO Normal to tall GnRH Deficiency Pure FSH deficiency FSH low Pure gonadal dysgenesis FSH high

Has puberty occurred ? NO Short= something else is going on Hypopituitarism Turner’s Hypothyroidism FSH slightly high, TSH high

Has puberty occurred ? Yes Virilizing 46 xx 46 xy Virlizing female intersex Congenital adrenal hyperplasia Virlizing male intersex Partial androgen insensitivity syndrome Leydig cell hypoplasia

Has puberty occurred ? Yes Feminizing 46,xx 46,xy Idiopathic delay Mullerian agenesis Serum testosterone Complete androgen insensitivity syndrome Serum testosterone

Presentation with primary amenorrhea : feminizing Uterovaginal agenesis low transverse vaginal septum Complete androgen insensitivity All the entities of secondary amenorrhea: Pregnancy Central Ovarian failure Uterine Ovarian or adrenal tumor metabolic

Diagnostic evaluation When to investigate? No menarche by 15.5-16 years Investigate earlier if : Galactorrhea Short stature Dysmorphic features Virilisation Abnormal pubertal development Out of keeping with family history of menarche Symptoms or signs of hypothalamic-pituitary disease Parent/adolescent concerned

Investigations Thorough history and physical exam Estrogen FSH/LH level High-ovarian failure(turner’s,chemo, autoimmune) Low or normal-hypothal-pit axis, constitutional Thyroid function tests Karyotype Bone age Prolactin Testosterone, DHEAS, 17-oh Prog, androstenedione Pelvic US, imaging “routine bloods” looking for chronic illness