Transcript Amenorrhea with Secondary Sexual Characteristics and

Obstetrics & Gynecology Hospital of Fudan University
AMENORRHEA
Wang Ling
menstrual cycle physiology
hypothalamus secrete GnRH in a pulsatile fashion
GnRH stimulates pituitary secrete FSH and LH
which promotes ovarian follicular development and ovulation
ovarian follicle secretes E2
after ovulation, the follicle is converted to corpus luteum
and P is secreted in addition to E2
A complex hormonal interaction for normal menstruation
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menstrual cycle physiology
●If pregnancy not occur, E2 and P secretion decrease and withdrawal bleeding begins
●If any of the components (hypothalamus, pituitary, ovary, uterus, and outflow tract) are nonfunctional,
bleeding cannot occur
Obstetrics & Gynecology Hospital of Fudan University
Contents
1
definition and Classification of amenorrhea
2
etiology of amenorrhea
3
Diagnosis of amenorrhea
4
The management of amenorrhea
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Definition of Amenorrhea
• Primary amenorrhea
Girls experienced menarche at increasingly younger ages during the past
century
the absence of menses at age 13 years when there is no visible development of
secondary sexual characteristics
or age 15 years in the presence of normal secondary sexual characteristics
• Secondary amenorrhea
absence of menstruation for three normal menstrual cycles or 6 months
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Categories
• hypothalamic amenorrhea
• pituitary amenorrhea
• ovarian amenorrhea
• uterine amenorrhea
• anatomic abnormalities of the reproductive tract
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classes of amenorrhea (WHO)
• Group I : no evidence of endogenous estrogen production
normal or low FSH
normal prolactin
no lesion in the hypothalamic-pituitary region
• Group II : evidence of estrogen production
normal prolactin and FSH
• Group III : elevated FSH indicating gonadal insufficiency or failure
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Etiology of Amenorrhea
•
whether secondary sexual characteristics are present
•
absence of secondary sexual characteristics indicates: never exposed to
estrogen
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Amenorrhea without Secondary Sexual
Characteristics
•
breast development is the first sign of estrogen exposure in puberty,
patients without secondary sexual characteristics typically have primary,
not secondary, amenorrhea
•
categorize the causes of amenorrhea in the absence of breast
development on the basis of gonadotropin status
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Hypergonadotropic Hypogonadism Associated with
Absence of Secondary Sexual Characteristics
•
Gonadal dysgenesis: abnormal development of the gonads
•
is associated with high levels of LH and FSH because the gonad fails to produce
the steroids and inhibin that would feed back to pituitary gland to suppress LH
and FSH
•
•
Karyotypic abnormalities are common with primary amenorrhea
approximately 30% primary amenorrhea had an associated karyotypic
abnormality
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Turner syndrome
In addition to gonadal failure
short stature
webbed neck
shield chest
cubitus valgus
low hair line
high arched palate
multiple pigmented nevi
short fourth metacarpals
•
Turner syndrome (45,X) represent the most common form of hypergonadotropic
hypogonadism with primary amenorrhea.
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Other disorders associated with primary
amenorrhea include:
abnormal X chromosomes
mosaicism
pure gonadal dysgenesis (46,XX and 46,XY with gonadal streaks)
Rare enzyme deficiencies that prevent normal estrogen production
Rare gonadotropin receptor inactivating mutations
Individuals with these conditions have gonadal failure and cannot synthesize
ovarian steroids.
Most patients with these conditions have primary
amenorrhea and lack secondary sexual
characteristics
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Other Causes of Primary Ovarian Failure without
Secondary Sexual Characteristics
• Severe damage to the ovaries before the onset of puberty
• Ovarian dysfunction can occur in association with irradiation
of the ovaries, chemotherapy, or combinations of radiation
and other chemotherapeutic agents
• Other causes of premature ovarian failure (also known as
primary ovarian insufficiency) are more commonly
associated with amenorrhea after the development of
secondary sexual characteristics
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Hypogonadotropic Hypogonadism Associated with the
Absence of Secondary Sex Characteristics
•
hypothalamus fails to secrete adequate GnRH or pituitary disorder
associated with inadequate production or release of pituitary
gonadotropins
•
Physiologic Delay
•
Kallmann Syndrome
•
Other Causes of Gonadotropin-Releasing Hormone Deficiency
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Amenorrhea Associated with a Lack of Secondary
Sexual Characteristics
•
Abnormal pelvic examination
5α-reductase deficiency, 17, 20-lyase deficiency, or 17α-hydroxylase deficiency in XY
individual
Congenital lipoid adrenal hyperplasia
Luteinizing hormone receptor defect
•
Hypergonadotropic hypogonadism
Gonadal dysgenesis
Follicle-stimulating hormone receptor defect
Partial deletion of X chromosome
Sex chromosome mosaicism
Environmental and therapeutic ovarian toxins
17α-hydroxylase deficiency in XX individual
Galactosemia
Congenital lipoid adrenal hyperplasia in XX individual
Hypogonadotropic hypogonadism
Physiologic delay
Kallmann syndrome
Central nervous system tumors
Hypothalamic/pituitary dysfunction
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Evaluation of Amenorrhea Associated with the Absence
of Secondary Sexual Characteristics
•
careful history and physical examination
•
serum FSH and LH levels to differentiate hypergonadotropic and
hypogonadotropic of hypogonadism
•
Turner syndrome: coarctation of the aorta (up to 30%) and thyroid dysfunction,
echocardiography and thyroid function studies
•
karyotype abnormal and contains the Y chromosome, as in gonadal dysgenesis,
the gonads should removed to prevent tumors
•
karyotype is normal, FSH is elevated, consider 17α-hydroxylase deficiency
because it may be a life-threatening disease
•
FSH level low, diagnosis of hypogonadotropic hypogonadism. Central nervous
system lesions should be ruled out by imaging using CT or MRI, especially if
galactorrhea, headaches, or visual field defects
•
Physiologic delay is a diagnosis of exclusion that is difficult to distinguish from
insufficient GnRH secretion
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Obstetrics & Gynecology Hospital of Fudan University
Treatment of Amenorrhea Associated with the Absence
of Secondary Sexual Characteristics
• Individuals with primary amenorrhea associated with gonadal
failure and hypergonadotropic hypogonadism need cyclic
estrogen and progestogen therapy to initiate, mature, and
maintain secondary sexual characteristics
• Prevention of osteoporosis is an additional benefit of estrogen
therapy
• If possible, therapeutic measures are aimed at correcting the
primary cause of amenorrhea
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Amenorrhea with Secondary Sexual Characteristics
and Abnormalities of Pelvic Anatomy
1. Müllerian anomalies
2. Androgen insensitivity
3. True hermaphrodism
4. Absent endometrium
5. Asherman syndrome
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Amenorrhea with Secondary Sexual Characteristics
and Abnormalities of Pelvic Anatomy
•
Outflow and Müllerian Anomalies
1. blockage of the outflow tract,
outflow tract is missing
or no functioning uterus.
2. for menses occur, endometrium must be
functional and must be patency of the cervix and
vagina
3. Most müllerian abnormalities have normal
ovarian function, thus will have normal secondary
sexual characteristic development
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Absence of Functioning Endometrium
• Amenorrhea may occur if there is no
functioning endometrium
• Asherman syndrome
• more common with secondary
amenorrhea or hypomenorrhea
• occur in patients with risk factors for
endometrial or cervical scarring
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Androgen Insensitivity
• Phenotypic females with complete
congenital androgen insensitivity develop
secondary sexual characteristics but do not
have menses
• Genotypically, male (XY) but have a
defect prevents normal androgen receptor
function, leading to the development of the
female phenotype
• Serum testosterone in normal male range
• vagina may be absent or short
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Evaluation Amenorrhea, Normal Secondary Sexual Characteristics,
Suspected Anatomic Abnormalities
• Most congenital abnormalities can be diagnosed by physical
examination:
•
An imperforate hymen is diagnosed by the presence of a bulging membrane
that distends during Valsalva maneuver, Ultrasonography or MRI
•
differentiate a transverse septum or complete absence of the cervix and uterus
from a blind vaginal pouch in a male pseudohermaphrodite. Androgen
insensitivity is likely when pubic and axillary hair is absent
•
An absent endometrium is an outflow tract abnormality that cannot be
diagnosed by physical examination with primary amenorrhea
•
Asherman syndrome cannot be diagnosed by physical examination. It is
diagnosed by performing hysterosalpingography, saline infusion sonography
(also known as saline hysterogram), or hysteroscopy
Obstetrics & Gynecology Hospital of Fudan University
Obstetrics & Gynecology Hospital of Fudan University
Treatment with Amenorrhea, Normal Secondary Sexual
Characteristics, and Abnormalities of Pelvic Anatomy
•
imperforate hymen, making a cruciate incision to open the vaginal orifice
•
transverse septum, surgical removal is required
•
Hypoplasia or absence of the cervix in the presence of a functioning uterus is
more difficult to treat than other outflow obstructions
•
vagina is absent or short, progressive dilation to making it functional
•
complete androgen insensitivity, the testes be removed after pubertal
development is complete to prevent malignant degeneration
•
Adhesions in the cervix and uterus (Asherman syndrome) be removed using
hysteroscopic resection with scissors or electrocautery
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Amenorrhea with Secondary Sexual Characteristics
and Normal Pelvic Anatomy
• the most common causes are pregnancy
• polycystic ovarian syndrome
• Hyperprolactinemia
• primary ovarian insufficiency (also known as premature ovarian
failure)
• hypothalamic dysfunction
• Pregnancy must be considered in all women of reproductive age
with amenorrhea
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Polycystic Ovarian Syndrome
•
associated with hyperandrogenism, ovulatory dysfunction, and polycystic ovaries
•
exclude patients with significantly elevated prolactin, significant thyroid dysfunction,
adult-onset congenital adrenal hyperplasia, and androgen-secreting neoplasms
from being classified as PCOS
•
Rotterdam 2003 criteria required two of three of the following for PCOS diagnosis:
hyperandrogenism, oligomenorrhea or amenorrhea, polycystic ovaries by
ultrasound
•
Even though PCOS usually causes irregular bleeding rather than amenorrhea, it
remains one of the most common causes of amenorrhea
•
In patients who are hirsute and amenorrheic and appear to have PCOS,
androgen-secreting adrenal tumors and congenital adrenal hyperplasia should be
considered
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Hyperprolactinemia
• is a common cause of anovulation in women
• Elevation of prolactin produces abnormal GnRH secretion, which
can lead to menstrual disturbances
• other central nervous system (CNS) lesions that disrupt the normal
transport of dopamine down the pituitary stalk, and by medications
that interfere with normal dopamine
• If elevated TSH and elevated prolactin levels are found together, the
hypothyroidism should be treated before hyperprolactinemia is
treated
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Primary Ovarian Insufficiency (Premature Ovarian
Failure)
• presence of amenorrhea for 4 months or more, two serum FSH
levels in the menopausal range for who is less than 40 years of age
• decreased follicular endowment or accelerated follicular atresia
• If the ovary does not develop or stops its hormone production before
puberty, the patient will not develop secondary sexual characteristics
without exogenous hormone therapy. If ovarian insufficiency begins
later in life, the woman will have normal secondary sexual
characteristics
• a heterogenous disorder with many potential causes
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Pituitary and Hypothalamic Lesions
• Tumors of the hypothalamus or pituitary, prevent appropriate
hormonal secretion
• Pituitary Lesions; Sheehan syndrome, postpartum necrosis of
pituitary resulting from a hypotensive episode
•
If hypopituitarism occurs before puberty, menses and secondary
sexual characteristics will not develop
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Altered Hypothalamic Gonadotropin-Releasing
Hormone Secretion
• Abnormal secretion of GnRH accounts for one-third of
amenorrhea
• When decrease in GnRH pulsatility is severe, amenorrhea
results
• Decreased leptin levels are associated with hypothalamic
amenorrhea, regardless of whether it is caused by exercise, eating
disorders, or idiopathic factors
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Eating Disorders
• Anorexia nervosa is an eating disorder that affects 5% to 10%
of adolescent women
• refusal to maintain body weight above 15% below normal, an
intense fear of becoming fat, altered perception of one's body
image and amenorrhea
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Weight Loss and Dieting, etc
Weight loss
can cause amenorrhea even if weight does not decrease below normal
Loss of 10% body mass in 1 year is associated with amenorrhea
Exercise
decrease in the frequency of GnRH pulses
Stress
Obesity
Other Hormonal Factors
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Evaluation with Amenorrhea in the Presence of
Normal Pelvic Anatomy and Normal Secondary
Sexual Characteristics
•
pregnancy test (hCG) in a reproductive-age
Clinical assessment of estrogen status
Serum TSH
Serum prolactin
Serum FSH level
Vaginal ultrasound for assessment of antral follicle count in the ovaries can
be considered
Imaging of the pituitary and hypothalamic assessment if prolactin is
elevated or if hypothalamic amenorrhea is suspected
Obstetrics & Gynecology Hospital of Fudan University
Obstetrics & Gynecology Hospital of Fudan University
Treatment for Amenorrhea in the Presence of Normal Pelvic
Anatomy and Normal Secondary Sexual Characteristics
pregnant may be counseled regarding the options for continued care
thyroid abnormalities are detected, thyroid hormone, radioactive iodine,
or antithyroid drugs administered as appropriate
hyperprolactinemia, treatment may include discontinuation of
contributing medications, treatment with dopamine agonists such as
bromocriptine or cabergoline, and, rarely, surgery for particularly large
pituitary tumors
POI, hormone replacement to diminish symptoms and to prevent
osteoporosis
Gonadectomy is required when a Y cell line is present
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Study Questions
Obstetrics & Gynecology Hospital of Fudan University
A 15-year-old girl, she has never had a period. She seemed to grow and develop
breasts at the same time as the other girls in school, but that she has not yet started
to menstruate. She is active in sports at her school and plays the piano. an
examination reveals Tanner IV breast and pelvic examination reveals a blind vaginal
pouch. Ultrasound confirms absence of a uterus. An FSH level is normal at 5.8
mIU/mL. The next step in the evaluation is:
A
B
C
D
E
MRI of the pituitary
Karyotype
Visual field testing
Trial of estrogen/progesterone to stimulate bleeding
Creation of a neovagina using graduated dilators
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A 24-year-old female with the complaint of missed menstrual cycles. She states her
period has never been regular, and that in the past it was common for her to skip a
month or two between cycles. Now, however, she has not had a period in the past 7
months. She denies sexual activity, reports no medical problems, and her only
prescribed medication is a face wash for acne. On review of systems she reports a
weight gain of 7kg over the past year. Her laboratory test reveals an FSH level of 8.7
mIU/mL, LH of 22.2 mIU/mL, estradiol of 45 pg/mL, TSH of 2.2 mIU/mL, prolactin of
12 ng/mL, and total testosterone of 98 ng/dL. The most likely diagnosis is:
A
B
C
D
E
Premature ovarian insufficiency
Polycystic ovary syndrome
Prolactinoma
Functional hypothalamic amenorrhea
Hypothyroidism
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A 27-year-old woman complaining of not getting her period. She came off of the birth
control pill 9 months ago to attempt pregnancy and has not had a period since.
Multiple home pregnancy tests have been negative. She states she underwent
menarche at the age of 12 years, and that she did not always get a period every
month during high school but was told this was normal because she was an athlete.
She continues to be very athletic, running 5 to 6 times per week and also bikes. She
has no hirsutism or acne. The most likely reason for her amenorrhea is:
A
B
C
D
E
Polycystic ovary syndrome
Müllerian agenesis
Functional hypothalamic amenorrhea
Prolactinoma
Swyer syndrome
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A 32-year-old woman returns to your care 5 months after the birth of her child. She had
a postpartum hemorrhage following vaginal delivery of her son, requiring emergency
surgery and multiple blood transfusions. She complains of fatigue, constipation, and
states that her periods have not returned despite the fact that she has not been able to
breastfeed. Her laboratory test reveals an FSH level of 1.2 mIU/mL, TSH of 0.3 IU/mL,
and prolactin of 1 ng/mL. The most likely etiology of her secondary amenorrhea is:
A Asherman’s syndrome
B Polycystic ovary syndrome
C Functional hypothalamic amenorrhea
D Sheehan’s syndrome
E Kallman’s syndrome
Obstetrics & Gynecology Hospital of Fudan University
A 26-year-old female is referred to your office by her primary care doctor. She reports
regular menses in the past, but has not had a period for 2 years. She did not bleed after a
course of progesterone prescribed by her doctor. On examination she is 58 inches tall, has
normal secondary sexual characteristics. Laboratory test reveals an FSH level of 82
mIU/mL and estradiol of 26 pg/mL. What is the next step in her evaluation?
A
B
C
D
E
Pelvic ultrasound
Total testosterone
Karyotype
Pituitary MRI
Trial of oral contraceptive pills
Obstetrics & Gynecology Hospital of Fudan University
END
Obstetrics & Gynecology Hospital of Fudan University