Amenorrhea

S
 Introduction

S Menstrual irregular is normal within first 2-3 years after

menarche.

S Prolonged amenorrhea is not normal related to significant

morbidity

S Estrogen deficiency or estrogen replete

S Amenorrhea may result from different conditions

S A systemic evaluation: a detailed history, physical

examination, hormone levels to identify underlying causes
 Normal menstrual cycle

Menarche

S 16-17 years in mid-1800s

S 12 years in 1900s

S Better nutrition and socioeconomic living conditions

Physiology of normal menstrual
cycle
Physiology of menstrual cycle
Tanner scale
 Amenorrhea

Primary amenorrhea Secondary amenorrhea

Etiology
 Primary amenorrhea

No period by age 14 in the absence of growth or

development of secondary sexual characteris<cs.

No period by age 16 regardless of the presence of normal
growth and development with the appearance of
secondary sexual characteris<cs.
 Primary amenorrhea

S Absence of menarche by age 16 yrs

S Causes: Reindollar et al . Am. J Obstet Gynecol 1981

S Chromosomal abnormalities (45%)
S Physiological delay (20%)
S Mullerian agenesis (15%)
S Imperforate hymen or vaginal septum (5%)
S Hypothalamic GRH deficiency (5%)
S Anorexia nervosa (2%)
S Hypopituitarism (2%)
S Prolactinoma, hypothyroidism,
craniopharyngioma, adrenal disease (<1%)
 Hypothalamic causes

S Eating disorders

S Exercise-induced amenorrhea

S Medication-induced amenorrhea

S Chronic illnesses

S Stress-induced amenorrhea

S Kallmann syndrome
 Eating disorders

Anorexia nervosa

S Prevalence: 0.3-0.5%, highest incidence in 15-19 years

S Disturbance of neurotransmitter of GnRH release

S LH, FSH, and estradiol are low

S Pulsatile LH reverts to prepubertal pattterns and uterine shrink

sixe

S Contributing factors: LBW, excessive exercise, stress-induced

activation of hypothalamic-pituitary-adrenal axis, and caloric
restriction with negative energy balance
Bulimia nervosa

S Prevalence: 5%

S Normal weight and regular menses

S Irregular menses due to repeated episodes of dietary

restriction

S Eating disorder not otherwise specified (EDNOS): if criteria

do not meet either anorexia nervosa or bulimia nervosa
Exercise-induced amenorrhea

S Female athlete triad syndrome: Irregular menses, disorder eating,

and osteoporosis/osteopenia

S Prevalence: 12-79% of athletes, 23.5% of menstrual irregularity

S Suppression of GnRH

S Lean sports

S Strength sports: elevated androgen, LH, LH/FSH ratio impaired

follicular development anovulation and amenorrhea
Medication-induced amenorrhea

S 50% of patient with antipsychotic, 12% of amenorrhea

S Pituitary dopamine D2 receptor blockade 5-10-fold

prolactin levels

S Prolactin inhibits HPO axis suppressing GnRH

S Blocking positive feedback of estradiol

S Dopamine antagonists e.g. methyldopa cause

hyperprolactinemia and amenorrhea
 Stress-induced amenorrhea

S Physical and psychological stresses interrupt homeostasis

and redirect energy e.g. reproduction to CNS and
cardiovascular systems.

S HP-adrenal axis increases CRH secretion

S HPO axis: CRH inhibit GnRH

S Glucocorticoids inhibit pituitary LH, ovarian estradiol and

progesterone - amenorrhea (similar to menopause)
 Chronic illnesses

S Lead to pubertal delay and menstrual cessation

S Affect nutritional, behavior, and hormonal aspects.

S Similar pathways to hypothalamic amenorrhea (eating

disorders, stress, and medications)

S E.g. renal and liver diseases, immunodeficiency, diabetes,

and inflammatory bowel disease
 Kallmann syndrome

S Hypogonadotropic hypogonadism and anosmia

S Genetic mutation: KAL gene at Xp22.3

S Incidence: 1:10,000 in males and 1:50,000 in females

S Defects of olfactory and GnRH neurons (olfactory placode)

S Sexual development failure and primary amenorrhea

 Pituitary causes

S Hyperprolactinemia

S Prolactimona

S Cranipharyngioma

S Isolated gonadotropin deficiency

 Hyperprolactinemia

S 10-40% of hyperprolactinemia are amenorrhea

S Normal GnRH gonadotropin suppression low levels of

estradiol

S Multiple causes: physiological states (pregnancy and lactation),

certain medications, endocrinopathies (primary hypothyroidism
and PCOS), systemic diseases ( SLE, rheumatoid arthritis), and
chronic renal failure.

S Pituitary gland tumor

 Prolactinoma

S Anterior pituitary gland tumors

S Microadenomas (<10 mm) and macroadenoma (>10 mm)

S 50-60% of women with hyperprolactinemia

S Elevated prolactin on GnRH pulsatility decrease in

pituitary LH & FSH estradiol-deficit states
 Isolated gonadotropin
deficiency

S Defined by complete or partial absence of GnRH-induced

gonadotropin secretion, normal anatomy of HP, normal
baseline of HP axis, normal sense of smell

S If problems of olfactory function are present referred to

Kallmann syndrome

S 20% of genetic disorders GnRHR (GnRHR54 gene)

mutation and its ligand, kisspeptin
 Craniopharyngioma

S Epithelial tumors from craniopharyngeal duct in sellar or parasellar

region

S 2-5% of intracranial neoplasms 5-15% of intracranial tumors in

children

S Uncertain pathogenesis

S Symptoms: endocrine, visual, behavior, and cognitive

S Hormonal disruption

S 30-80% of LH/FSH deficiency menstrual dysfunction

 Thyroid causes

S Hypothyroidism

S Hyperthyroidism
 Hypothyroidism

S Incidence: 0-40%

S Females > males ; often in adolescence

S 20-70% of menstrual disturbance in hypothyroidism are detected

earlier

S Hypermenorrhea or oligomenorrhea (common) and amenorrhea

S TSH-releasing hormone prolactin >> - hyperprolactinemia

 Hyperthyroidism

S 20-60% 0f menstrual irregularities 20% of amenorrhea

S Mechanism of amenorrhea is not clear combination of

hormonal disorders, nutritional deficiency, and emotional stress

S Hyperthyroid SHBG >> - estrogen >>

S Androgens (testosterone and androstenedione) >> - estrogen/

estriol/estrone >>

S LH >>

S Amenorrhea
 Adrenal causes

S Congenital adrenal hyperplasia (CAH)

S Cushing syndrome
 CAH

S Autosomal recessive of steroidogenesis

S 90% of 21-hydroxylase deficiency

S Conversion P to deoxycorticosterone and 17-OH P to 11-

deoxycortisol lead to mineralocorticoids and glucocorticoids

S Androgen pathway: CRH >> - ACTH >> - androgen >>

 CAH

Clinical features:

S Classic forms: slat wasting or ambiguous genitalia in

infancy, 1 in 16,000 births

S Non-classic (0.2% in population): premature pubarche in

childhood, hirsutism and amenorrhea in adults

S Adequate treatment reverses HP axis suppression

 Cushing syndrome

S High circulating cortisol level

S Due to iatrogenic exogenous cortisone

S Others: hypersecretion of corticotropin by anterior pituitary

gland microadenoma (Cushing disease), adrenal tumors,
and lung cancer

S Direct suppression of HPO axis

S Oligomenorrhea and amenorrhea

 Ovarian causes

S Polycystic ovarian syndrome (PCOS)

S Gonadal dysgenesis

S Premature ovarian failure

 PCOS

S 10-20% of 18-25 years worldwide

S Rotterdam criteria (2003): 2/3 of oligo- of anovulation,

hyperandrogenism, polycystic ovaries by US
S Pathogenesis is unclear

S Combination of defects in insulin resistance, ovarian and/or

adrenal hypersensitivity

S Insulin resistance and hyperinsulinemia obesity

S Insulin >> - SHBG << - testosterone >>

Oligo- or anovulation
Hyperandrogenism
Polycystic ovaries
Polycystic ovaries
 PCOS

Typical hormonal findings:

S Free testosterone >>

S DHEAS >>

S Androstenedione >>

S LH >>

S LH/FSH ratio >>

 PCOS treatment

If overweight - weight loss is critical!!!

S Menstrual irregularity OCP, progestogens, mirena

S Hair growth Hair removal, OCP, anti-androgens

S Acne Topical treatment, OCP

S Psychosexual dysfunction

S Infertility To be discussed
 PCOS treatment

Manage Long term Risks

S Diabetes

S Cardiovascular disease

S Endometrial hyperplasia
 Gonadal dysgenesis

S Abnormal gonadal development

S E << - LH & FSH >>

S Turner syndrome (45,X): 1 in 2,500 births in females

S Swyer syndrome (XY gonadal dysgenesis)

 Turner syndrome

(45,X) (46,XX) (47,XXX)

 Premature ovarian failure

S Premature ovarian insufficiency

S Gonadotropin >> - estrogen <<

S Conditions: autoimmune oophoritis, mumps oophoritis,

chemotherapy, irradiation, galactosemia

S Trisomy 21, fragile X female carriers, sarcoidosis

 Uterine causes

S Androgen insensitivity (Testicular feminization syndrome)

S Uterine adhesions (Asherman syndrome)

S Mullerian agenesis

S Cervical agenesis
 Androgen insensitivity

S Testicular feminization syndrome

S 1/20,000 1/99,000

S X-linked recessive of single gene

S Due to defect of androgen binding in androgen receptor site

S Normal testosterone, XY, female phenotype, normal breast

development, minimal axillary and pubic hair, and a short vagina
S Testes (+)/cryptorchid

S Primary amenorrhea
 Uterine adhesions

S Asherman syndrome

S Intrauterine synechiae/scarring

S Previous infection or post-curettage due to postpartum or

post-abortal endometritis

S Amenorrhea, recurrent abortion, infertility

 Mullerian agenesis

S Mayer-Rokitansky-Kuster-Hauser syndrome

S Absence of vagina, absence or abnormal uterus, normal ovaries

S 1 in 4,000 / 1 in 5,000 females births

S Normal secondary sexual characteristics and ovarian function

S Primary amenorrhea

S Etiology: unknown

S AMH? AMH receptor genetic mutation?

Symmetrical fusion defects
 Cervical agenesis

S Rare

S Isolated with normal uterus

S Amenorrhea, cyclic abdominal pain, distended utreus

S Due to outflow outlet obstruction, hematosalpinx and

endometriosis
 Vaginal causes

S Imperforate hymen

S Transverse vaginal septum

S Vaginal agenesis - isolated

 Imperforate hymen

S 1 in 1,000 women

S Diagnosed in childhood, but often in adolescence with

abdominal pain and primary amenorrhea

S Typical findings: bulging, bluish hymen, hematocolpos,

hematometra

S If large mass may cause acute urinary retention

 Transverse vaginal septum

S 1:80,000 women with complete transverse vaginal septum due to

incomplete fusion of mullerian duct and urogenital sinus

S Location: lower middle upper vagina

S 80-90% in middle/upper vagina with normal appearance

S Perforated septum is often present

S Amenorrhea and hematocolpos

S Urogenital tract and rectum malformations

Transverse vaginal septum
 Vaginal agenesis isolated

S Associated with uterine agenesis

S Rare case vaginal agenesis with normal uterus

 Secondary amenorrhea

S Pregnancy

S Breastfeeding

S OCP

S PCOS

S Menopause

S Exogenous androgens