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Endocrine topic review
Amenorrhea
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.
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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)
Tanner staging
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
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/
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 less
variable 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.)
Hypergonadotropic hypogonadism
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)
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
Mixed gonadal dysgenesis
45,X/46,XY
Rarely in other disorders, such as
mutations in the FSH or LH receptors.
Aromatase deficiency and 17 -hydroxylase deficiency
elevated gonadotropins with hyperandrogenism and hypertension)
Gonadotropin-secreting tumors
high, 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