Endocrine topic reviewAmenorrhea

Kanokorn phitakwanich

Menstruation

Pathophysiology

• Hypothalamus generates pulses of gonadotropin-releasing hormone (GnRH).

• GnRH stimulates the pituitary to produce gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH)

• Gonadotropins stimulate the ovaries to produce estrogen (mainly estradiol), androgens (mainly testosterone), and progesterone. These hormones do the following:

The merk manual prefesional edition

• FSH stimulates tissues around the developing oocytes to convert testosterone to estradiol.

• Estrogen stimulates the endometrium, causing it to proliferate.

• LH, when it surges during the menstrual cycle, promotes maturation of the dominant oocyte, release of the oocyte, and formation of the corpus luteum, which produces progesterone.

• Progesterone changes the endometrium into a secretory structure and prepares it for egg implantation (endometrial decidualization)

The merk manual prefesional edition

If pregnancy does not occur

•Estrogen and progesterone production decreases

•Endometrium breaks down and is sloughed during menses.

•Menstruation occurs 14 days after ovulation in typical cycles.

The merk manual prefesional edition

Menstuation cyc

Amenorrhea

Definition

• Absence of menstruation periods

• Primary• Age 16 or 2 yr after the onset of puberty• About age 14 in girls , no puberty • never occurred in the absence of hormonal treatment

• Secondary• menstrual periods are absent for 3–6 months.

Harrison’s Principles of Internal Medicine,18e,

Primary Amenorrhea

The absence of menses

• 16 yr • presence of normal growth and secondary sexual

characteristics

•14yr • absence of secondary sexual characteristics• presence of breast development and cyclic pelvic pain

• Within 2 years of breast development

Harrison’s Principles of Internal Medicine,18e,p385

Secondary Amenorrhea or Oligomenorrhea

• Anovulation and irregular cycles

• 2 years after menarche ,

1–2 years before the final menstrual period.

• Menstrual cycle length is ∼28 days

( normally ranging between 25 and 35 days.)

• Cycle-to-cycle variability in an individual woman who is ovulating consistently is generally +/− 2 days.

Harrison’s Principles of Internal Medicine,18e,p38

• Pregnancy is the most common

• However, many women occasionally miss a single period.

• Three or more months of secondary amenorrhea should prompt an evaluation,

• as should a history of intermenstrual intervals >35 or <21 days or bleeding that persists for >7 days.

• Harrison’s Principles of Internal Medicine,18e,p384

Cause of Amenorrh

• Anatomical outflow tract obstruction

• Primary hypogonad

• Pituitary cause

• Hypothalamus cause

• Endocrine gland disoder

• History

• Cyclic pelvic pain

• Height

• Pubertal development :

eugonadal vs hypogonadal

(breast, pubic hair, axillary hair � Tanner)

• Galactorrhea, and drug association

• Hypothalamic and pituitary disorder : - Mass effect - Hormone axis : Hypo/hyperfunction

• Genernal health problem / Functional hypothalamic disorder

• Family history : delay or absent puberty

• Physical exammination

• V/S : BP , +/- postural hypotension

• Height, growth chart

• Pubertal development : (breast, pubic hair, axillary hair �Tanner)

• PV

• Galactorrhea

• Sign of androgen excess

• Hypothalamic and pituitary disorder : - Mass effect - Hormone axis : (hyper/hypo function)

Stage 1 : prepubertal

Stage 2 : breast bud

Stage 3 : further enlarge of breast

& areolar ,no seperation

Stage 4: areolar & papilla form

second mound

Stage 5 : mature, only projection of

papilla

Tanner staging

Stage1 : villus hair

Stage 2 : Sparse growth of slightly

pigmented hair along labia

Stage 3 : Coarser, curled and

pigmented ; spreads

across pubes

Stage 4 : Adult-type hair but

no spread to medial thigh

Stage 5 : Adult-type hair with spread to medial

thigh but not up linea alba

Tanner staging

Hirsutism score = 9 sites (0-4=36) : ≥ 8

Clitoromegaly

• length (normal <10mm)

• transverse (normal<7mm)

Clitoral index

• sagittal x transverse

• at base>35mm2 (>95%CI)

History and Physical Examination

American Society For reproductive medicin

American Society For reproductive medicin

Harrison’s Principles of Internal Medicin

Primary amenorrhea

American Family Physician Web site at www.aafp.org/a

Secondary Amenorrhea

American Family Physician Web www.aafp.org/afp

Investigation

• UPT,B-hCG

• FSH, LH ,Prolactin,TSH

• Estrogen ,testosterone

• Ultrasound of uterus

• Karyotype analysis

• Progesterone challenge test

• MRI Pituitary

Disorders of Uterus or Outflow Tract

Differentiation of internal genitalia

NEJM. 2004

Disorders of the Uterus or Outflow Tract

• Abnormalities of the uterus and outflow tract typically present as primary amenorrhea.

• Normal pubertal development and a blind vagina

DDx includes obstruction by

Transverse vaginal septum or imperforate hymen

Müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrom

• mutations in the WNT4 gene

Androgen insensitivity syndrome (AIS),

• whX-linked recessive disorder

• accou~10% of all cases of primary amenorrhea

• AIS have a 46, XY karyotype, but lack of androgen receptor responsivene

• severe underandrogenization and female external genitalia.

• Absence of pubic and axillary hair

Secondary amenorrhea or hypomenorrhea

•partial or complete obliteration of the uterine cavity by adhesions that prevent normal growth and shedding of the endometrium

• Curettage performed for pregnancy complications accounts for >90% of cases

•genital tuberculosis is an important cause in endemic regions

Disorders of Uterus or Outflow Tract: Treatment

• Outflow tract requires surgical correction.

• The risk of endometriosis is increased with this condition, perhaps because of retrograde menstrual flow

Müllerian agenesis

•require surgical intervention ,vaginal dilatation (some patients)

•Because ovarian function is normal, assisted reproductive techniques can be used with a surrogate carrier.

Androgen resistance syndrome

•Requires gonadectomy

: risk of gonadoblastoma in the dysgenetic gonads.

•Estrogen replacement is indicated after gonadectomy

•vaginal dilatation may be required to allow sexual intercourse

Disorders of Ovulation

Disorders of Ovulation

• The differential diagnosis is based on the results of initial tests

• pregnancy test

• gonadotropins,

• assessment of hyperandrogenism .

Hypogonadotropic Hypogonadism

Hypothalamic GnRH secretion or pituitary responsiveness to GnR

Low estrogen levels , normal or low levels of LH and FSH .

Present with primary or secondary amenorrhea.

• Association with features suggestive of hypothalamic or pituitary dysfunction

• short stature

• diabetes insipidus

• Galactorrhea

• headache.

• anatomic, genetic, or functional abnormalities

• relatively uncommon, tumors and infiltrative diseases

• following cranial irradiation

• postpartum period: pituitary necrosis (Sheehan syndrome)

• Lymphocytic hypophysitis

• hyperprolactinemia, either from neuroanatomic lesions or medications,

Isolated hypogonadotropic hypogonadism (IHH)

•more common in men than women

•associated with anosmia

•primary amenorrhea.

•A number of genetic causes of IHH have been identified

Functional hypothalamic amenorrhea (HA)

•caused by a mismatch between energy expenditure and energy intake.

•Leptin secretion may play a key role in transducing the signals from the periphery to the hypothalamus in HA.

• HPA axis may also play a role.

•The diagnosis of HA can generally be made on the basis of a careful history, physical examination, and the demonstration of low levels of gonadotropins and normal prolactin levels.

•Eating disorders and chronic disease must be specifically excluded. An atypical history, headache, signs of other hypothalamic dysfunction, or hyperprolactinemia

•CT or MRI to exclude a neuroanatomic cause

Hypergonadotropic hypogonadism

• Ovarian failure is considered premature when it occurs in women younger than age 40.

• As with natural menopause, premature ovarian failure (POF)may wax and wane, and serial measurements may be necessary to establish the diagnosis.

• Once the diagnosis of POF has been established, further evaluation is indicated because of other health problems that may be associated with POF.

• loss of negative-feedback restraint on the hypothalamus and pituitary resulting in increased FSH and LH levels.

• FSH is a better marker of ovarian failure as its levels are lessvariable than LH.

Premature ovarian failure (POF)

• Association chromosome abnormal• Turner syndrome • autoimmune polyglandular failure syndromes• radio and chemotherapy• galactosemia• premutation carriers of the fragile X syndrome

(increased risk of severe mental retardation in male children with FMR1 mutations.)

Chromosomally incompetent ovarian failure

Chromosomally competent ovarian failure

X chromosome deprivation

45,X (classic Turner syndrome)

45,X/46,XX

45,X/46,X,i(Xq)

46,X,i(Xq)

Mixed gonadal dysgenesis

45,X/46,XY

46,XX

Autosomal recessive

Autoimmune

Environmental (e.g., viral)

Neoplastic therapy (e.g., chemotherapy & radiation)

17-hydroxylase deficiency

Ovarian infiltration (TB, mucopolysaccharidosis)

Gonadotropin resistance (Savage or Jones’ syndrome)

galactosemia

46, XY gonadal dysgenesis

Hypergonadotropic hypogonadism

Rarely in other disorders, such as

mutations in the FSH or LH receptors.

Aromatase deficiency and 17 -hydroxylase deficiencyelevated gonadotropins with hyperandrogenism and hypertension)

Gonadotropin-secreting tumorshigh, rather than low, estrogen levels and cause ovarian hyperstimulation or dysfunctional bleeding

Amenorrhea Caused by Ovulatory Disorders: Treatment

• chronically low levels of estrogen

• Development of secondary sexual characteristics

• requires gradual titration of estradiol replacement with eventual addition of a progestin.

• Symptoms of hypoestrogenism

• treated with hormone replacement therapy or oral contraceptive pills.

• Fertility require

• treatment with pulsatile GnRH or exogenous FSH and LH, oocyte donation