PRIMARY AMENORRHEA

By: Zaineb Talib Nimaa Zahra Ali Hasoon Zina Safaa aldien

DIAGNOSIS

Primary amenorrhea can be diagnosed if a patient has normal secondary sexual characteristics but no menarche by 16 years of age. If a patient has no secondary sexual characteristics and no menarche, primary amenorrhea can be diagnosed as early as 14 years of age. Secondary amenorrhea is the absence of menses for three months in women with previously normal menstruation and for nine months in women with previous oligomenorrhea. Secondary amenorrhea is more common than primary amenorrhea.

PUBERITY
Pubertal changes typically occur over a three-year period. The normal menstrual cycle involves a complex interaction between the hypothalamicpituitary- ovarian axis and the outflow tract. Any disruption in this interaction can cause amenorrhea.

thelarche

estrogen

Pubarche/adrenarche

androgen

menarche

GnRH FSH & LH Estrogen & Progesteron Normal outflow tract

CLASSIFICATION
1. According to the cause:
Physiological Pathological 2. According to the onset: Primary amenorrhea. Secondary amenorrhea. 3. According to Hidden or apparant : False amenorrhea ( Crypto menorrhea ). True amenorrhea. 4. According to plan for workup: Physiological. Anatomical . Endocrinological.

CAUSES OF PRIMARY AMENORRHOEA

Chromosomal Hypothalamic (no GnRH) or hypogonadatrophic (no LH or FSH). Causes : Idiopathic, following radiotherapy, following surgery, craniopharyngomas in childhood, Anorexia, Excessive exercise (ballet dancers). Congenital anatomical .

Amenorrhea is only a manifestation of the problem

CHROMOSOMAL ABNORMALITIES
Sex chromosome abnormalities mainly arise from non-disjunction. At the division of the primary oocyte the two chromosomes fail to separate so that a primary oocyte is produced which may have two X chromosomes or none. Fertilization by a spermatozoon which may carry X or Y can therefore result in abnormal patterns, XXX, XXY or XO. YO combination is lethal. Mosaics or individuals of mixed chromosomal patterns may also occur.

ENDOCRINOLOGICAL
Four Sub phenotypes (Breast & uterus ) 1. Absent breast + presence of uterus 2. Presence breast + absence uterus 3. Absence breast + absence uterus 4 . Presence breast + presence uterus (normal)

1.ONLY UTERUS PRESENT WITH NO BREASTS

FSH Serum level : -Low / normal Hypogonadotrophic hypogonadim (hypothalamic- pituitray) - High Hypergonadotropic Hypogonadism (gonadal dysgenesis)

A . CNS-hypothalamic pituitary disorders: Low FSH (hypogonadotropic) 1. CNS lesions 2. Inadequate GnRH Kallmanns 3. Isolated gonadotrophin insufficiency 4. Weight loss/ anorexia 5. Excessive exercise 6. Hyperprolactinoma 7. Hydrocephalus

B. Gonadal failure: High FSH (hypergonadotropic) 1. 45X (Turners Syndrome) 2. 46X; abnormal X (Deletion Disorders) 3. Mosaicism (X/XX, X/XX/XXX) 4. Ovarian Failure 5. Galactossemia 6. Enzymatic failure 17 alpha-hydroxylase deficiency (46XX), CAH

TURNER SYNDROME

Commonest form of gonadal dysgenesis. Incidence 3/10 000 life births Present with primary amenorrhea. The ovaries have undergone atresia during intra-uterine life and consist of stroma with no production of estrogen and no oogenesis. The vagina and uterus are present. C/F: poor growth , short stature, delayed/absent pubertal development,dysmorphic features, skeletal abnormalities (wide carrying angle) , webbed neck, peripheral lymphoedema Associated anomalies are coarctation of the aorta & congenital malformation of the kidneys. Tests: s. FSH (>25 IU/L), s. Estradiol (undetectable), karyotype 45 X, pelvic US ( small uterus, streaks of gonads)

Rx: 1. Acute all patients at diagnosis surveillance and preventative care a) with poor growth : growth hormone until 12 to 14 years of age + oxandrolone (steroid that decrease LH production suppress testosterone production) c) with pubertal delay/arrest (age >12 years)

low-dose oestrogen cyclic progesterone

d) with congenital cardiac anomalies

cardiovascular assessment and evaluation for surgery
2. Ongoing all patients: after establishment of cyclical bleeding

a) b)
c)

ovarian HRT breast implants monitoring + education on reproductive issues

CAH
Group of inherited enzyme deficiencies (AR) that impair normal corticosteroid synthesis by the adrenal cortex. There is overproduction of corticotrophic horm hyperplasia of adrenal cortex which leads to increase in androgen production. The most common enzyme deficiency is 21hydroxylase deficiency (90%) classified as either classical (simple virilising or salt-wasting types) or non-classical. Rare variants: 17-a-hydroxylase deficiency, 11-bhydroxylase deficiency, and 3-beta hydroxysteroid dehydrogenase deficiency

Key Factors in CAH: genetic predisposition ambiguous genitalia failure to thrive vomiting hypotension weight loss Hyperpigmentation
Other features: poor feeding irregular menses infertility male-pattern baldness (females) short stature precocious puberty polycystic ovaries (US) hirsutism severe cystic acne

Tests: serum FSH & LH: normal serum oestradiol: normal to elevated serum 17-hydroxyprogesterone (17-OHP): elevated fasting levels. If >6 nanomol/L in follicular phase distinguishes it from polycystic ovary syndrome serum dehydroepiandrosterone sulphate (DHEAS): elevated total serum testosterone : elevated serum progesterone: a low level confirms follicular phase and helps rule out false elevation of 17-hydroxyprogesterone (17-OHP) pelvic ultrasound: variable endometrial stripe Rx: Glucocorticoid replacement (can be given antenataly to mother of potentially affected fetus)

2.ONLY BREAST WITH NO UTERUS

Karyotype: 46- XX Mullerian Agenesis Normal breasts & sexual hair 46- XY Andogen InsensitivityNormal breasts & absent sexual hair

MULLARIAN AGENESIS
Karyotype is 46XX Causes by heterozygous mutation to the gene responsible for the formation of the Paramesonephric duct absent or deformed mullarian duct. Phenotype is female (normal puberty) with presence of ovaries but absence of uterus+ fallopian tubes+ variable portion vagina. Rx: vaginoplasty to enhance sexuale intercourse.

ANDROGEN INSENSITIVITY
Karyotype XY There is lack of androgen receptors (deletion on chromosome). phenotypic female, normal breast development sparse pubic hair, blind vaginal pouch, palpable inguinal mass (testes), long arms, large hands and feet; incomplete syndrome may present with a range of ambiguous external genitalia (produce androgen after puberty). Tests: - total serum testosterone:normal male rang - pelvic ultrasound: absent uterus; abdominal or inguinal testes

3. NO BREAST & NO UTERUS (RARE)

- 17 a hydroxylase deficiency : 46XY male pseudohermaphrodite with vaginal dimple with no internal female genitalia and presence of intraabd testis. 46XX sexual infantilism + hypertension Agonadism

ANATOMICAL CAUSES
Outflow tract obstruction - cryptomenorrhoeahidden loss caused by obstruction to normal menstrual flow. Causes include transverse vaginal septum and imperforate hymen. This is most often caused by a septum across the vagina just above the hymen at the embryological junction of the Mullerian ducts and the urogenital sinus in the lower third of the vagina. A complete septum leads to cryptomenorrhoea (vagina filled with blood) and haematocolpos (uterus filled with blood). The lower part of the vagina may be a solid cord; haematocolpos and haematometra may form above this. On inspection of the vulva a bluish bulge is seen just inside the hymen. There may be cyclical attacks of abdominal pain and a mass may be palpable per abdomen (haematocolpos) Mx: Under anaesthesia, incise the septum and express the haematocolpos by suprapubic pressure.

GENERAL APPROACH TO AMENNORHEA

History Patient history

Exercise, weight loss, current or previous chronic illness (Hypothalamic amenorrhea) Menarche and menstrual history (Primary versus secondary amenorrhea) Previous central nervous system chemotherapy or radiation (Hypothalamic amenorrhea) Previous pelvic radiation (Premature ovarian failure) Psychosocial stressors; nutritional and exercise history (Anorexia or bulimia nervosa) Sexual activity (Pregnancy)

Family history

Genetic defects (Multiple causes of primary amenorrhea) Pubic hair pattern (Androgen insensitivity syndrome) Infertility( Multiple) Menarche and menstrual history (mother and sisters) (Constitutional delay of growth and puberty) Pubertal history (e.g., growth delay) ( Constitutional delay of growth and puberty)

Physical examination Anthropomorphic measurements; growth chart (Constitutional delay of growth and puberty) BMI (Polycystic ovary syndrome) Dysmorphic features (e.g., webbed neck, short stature, widely spaced nipples) (Turner) Rudimentary or absent uterus; pubic hair (Mllerian agenesis) Striae, buffalo hump, significant central obesity, easy bruising, hypertension, or proximal muscle weakness (Cushings disease) Tanner staging (Primary versus secondary amenorrhea) Thyroid examination (Thyroid disease) Transverse vaginal septum; imperforate hymen Outflow tract obstruction Undescended testes; external genital appearance; pubic hair (Androgen insensitivity syndrome) Virilization; clitoral hypertrophy (CAH, Androgen-secreting tumor)

Review of systems Anosmia (Kallmann syndrome) Cyclic abdominal pain; breast changes (Outflow tract obstruction or mllerian agenesis) Galactorrhea; headache and visual disturbances (Pituitary tumor) Hirsutism or acne (CAH, POS) Vasomotor symptoms (Premature ovarian failure)

Investigations
Initial hormone tests: Pregnancy test, Prolactin, TFT, LH & FSH, Testosterone Progesterone withdrawal test: medroxyprog 10mg for 5d bleeding means chronic anuvolation (PCOS)

Step 1

step2

No bleeding on progesterone withdrawal test estradiol 2mg for 21 d followed by medroxy prog for 5d bleeding means problem in hypothalamus-pituitary-ovarian axis. If no bleeding outflow tract obstruction.

step3

Measure FSH & LH :- FSH> 30 IU/L + LH >40 IU/L ON >2 OCCASIONS 6 wks apart = OVARIAN FAILURE FSH &LH < 5 IU/L HYPOTHALAMUS (anorexia, systemic illness).

Treatment: depends on cause e.g

COMPLICATIONS OF AMENORRHEA
Cannot conceive Lead to osteoporosis and genital atrophy Increased endometrial hyperplasia which can increase the possibility of endometrial carcinoma from unopposed estrogen secretion Without secondary sexual characteristics may give rise to major social and psychosexual problems.

URGENT CONSIDERTIONS

Patients with secondary sexual development should be assessed for pregnancy. Patients diagnosed with gonadal dysgenesis and androgen insensitivity syndrome are at risk for gonadal tumours such as dysgerminoma or gonadoblastoma and should undergo counselling regarding removal. Patients with hyperprolactinaemia or those diagnosed with hypogonadotrophic hypogonadism and neurological symptoms should undergo neuroimaging to rule out an intracranial neoplasm. Patients with symptoms of rapid virilisation should undergo prompt work-up to rule out adrenal or ovarian tumours.