AMENORRHEA

Wang Yu Xia, Ph.D., Prof.

Department of Obstetrics and
Gynecology, the first Clinical
College of JiNan University

1
DEFINITION
♦ primary amenorrhea: the absence of
menses by age 16
♦ Secondary amenorrhea: the absence of
menses for 6 months in a woman in
whom normal menstruation has been
established or for the equivalent of 3
cycles in a woman with oligomenorrhea
♦ Oligomenorrhea: menses occurring at an
interval exceeding 35 days

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INCIDENCE
♦ About 97.5% of females begin normal
menstruation by age 16 in the U.S. The
incidence of primary amenorrhea is 2.5%
♦ The incidence of secondary amenorrhea
is quite variable from, 3% in the general
population to 100% under conditions of
extreme physical or emotional stress (eg,
prisoners awaiting execution)

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Amenorrhea is important:
♦ Do not ovulate, so can’t conceive
♦ No estrogen production, so may lead to
osteoporosis and genital atrophy
♦ With some estrogen production may increase
the possibility of endometrial carcinoma from
unopposed estrogen secretion
♦ primary amenorrhea in a girl who has not
already developed secondary sexual
characteristics may give rise to major social
and psychosexual problems

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♦ Hypothalamic Defects
♦ Pituitary Defects
♦ Ovarian Failure
♦ Ovarian Dysfunction

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Hypothalamic Defects
♦ Under normal physiologic circumstances, the
arcuate nucleus releases pulses of gonadotropin
– releasing hormone (GnRH) into the pituitary
portal system approximately every hour

7
♦ Discharge of GnRH releases luteinizing
hormone (LH) and follicle-stimulating
hormone (FSH) from the pituitary; LH and
FSH in turn stimulate ovarian follicular growth
and ovulation

8
♦ Anovulation and amenorrhea will occur
as a result of interference with GnRH
transport, GnRH pulse discharge, or
congenital absence of GnRH (Kallmann’s
syndrome). Any of these situations will
lead to hypogonadotropic hypogonadism

9
 A. DEFECTS OF GnRH
TRANSPORT

♦ Interference with the transport of GnRH:

 pituitary stalk compression or
destruction of the arcuate nucleus
 Pituitary stalk section from trauma,
germinoma, glioma, midline teratomas,
tuberculosis, and irradiation

10
B. DEFECTS OF GnRH
PULSE PRODUCTION
♦ reduction GnRH pulse frequency:
 The metabolic consequence of any
significant reduction
 Little or no LH or FSH result in no
ovarian follicles develop, virtually no
estradiol is secreted

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♦ biochemical status in normal prepubertal
girls with constitutional delayed puberty,
such as in severe stress, extreme weight
loss, or prolonged vigorous athletic
exertion, and in hyperprolactinemia. It
may also be an idiopathic phenomenon

12
♦ Less severe reductions in GnRH pulse:
 result in diminished LH and FSH
secretion with some follicular stimulation
 The stimulation is insufficient to result in
full follicular development and ovulation,
but estradiol is secreted
 may occur with stress,
hyperprolactinemia, vigorous athletic
activity, or in the early stages of eating
disorders. It may also be idiopathic

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C. KALLMANN’ SYNDROME

♦ congenital absence of GnRH:

 do not release LH or FSH from the
pituitary. Ovulation does not occur

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Pituitary Defects

♦ Pituitary causes of amenorrhea are rare;

most are secondary to hypothalamic
dysfunction

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A. CONGENITAL PITUITARY
DYSFUNCTION

♦ Congenital absence:
 Absence of entire pituitary is a rare and
lethal condition. Isolated defects of LH or
FSH production do occur (rarely),
resulting in anovulation and amenorrhea

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B. ACQUIRED PITUITARY
DYSFUNCTION
♦ Sheehan’s syndrome:
 characterized by postpartum
amenorrhea, results from postpartum
pituitary necrosis because of severe
hemorrhage and hypotension
 Surgical ablation and irradiation of the
pituitary as management of pituitary
tumors also cause amenorrhea
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♦ Iron deposition:
 result in destruction of the cells that
produce LH and FSH. This occurs only
in patients with markedly elevated serum
iron levels (ie, hemosiderosis)
 usually because of extensive red cell
destruction (ie,Thalassemia)

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♦ Pituitary microadenomas and macroadenomas:
 due to elevated prolactin levels, but the
mechanism(s) underlying this cause of
amenorrhea are unclear (amenorrhea-
galactorrhea syndrome)
 Hypothyroidism
may also lead to
elevated prolactin
levels and thereby
lead to amenorrhea

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Ovarian Failure
♦ Primary ovarian failure: characterized
by elevated gonadotropins and low
estradiol (hypergonadotropic
hypogonadism)
♦ Secondary ovarian failure: almost always
due to hypothalamic dysfunction and is
characterized by normal or low
gonadotropins and low estradiol
(hypogonadotropic hypogonadism)

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A. STEROID ENZYME
DEFECTS
♦ Genetic defects in enzymes 1–4
females have normal internal female
genitalia and 46,XX karyotype. However,
they cannot produce estradiol and thus
they fail to menstruate or have breast
development

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B. OVARIAN RESISTANCE
(SAVAGE’S) SYNDROME
♦ Patients with this syndrome have
elevated LH and FSH levels, and the
ovaries contain primordial germ cells. A
defect in the cell receptor mechanism is
the presumed cause

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C. OVARIAN DYSGENESIS

♦ If the primitive oogonia do not migrate to

the genital ridge, the ovaries fail to
develop. Streak gonads, which do not
secrete hormones, develop instead, and
the result is primary amenorrhea (pure
gonadal dysgenesis; Swyer’s syndrome)

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♦ In patients with
Turner’s syndrome (45,XO)
or mosaicism (45,XO/XX),
the oogonia migrate normally
to the ovary but undergo rapid
atresia, so that by puberty no oogonia remain.
These patients usually have primary
amenorrhea, but some—particularly those with
the mosaic abnormality—may menstruate
briefly, and a few have conceived

24
D. PREMATURE OVARIAN
FAILURE
♦ Menopause occurs when the ovaries fail
secondary to depletion of ova. If this
occurs before age 40, it is considered
premature. It is marked by amenorrhea,
increased gonadotropin levels and
estrogen deficiency

25
Ovarian Dysfunction
♦ PCOS : the series of hyperandrogenemia,
hirsutism, anovulation, obesity, and
insulin resistance

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♦ the exact mechanism is unknown, a high
level of basal insulin plays a key role in
its pathogenesis
♦ Abnormally elevated baseline insulin
leads to increased androgens via
decreased sex-hormone binding globulin

29
♦ insulin may have a direct effect on the
ovary via a second messenger part that
results in increased androgen production.
♦ Elevated insulin levels may explain the
abnormal LH pulsation and abnormal
follicle development
♦ Elevated LH:FSH ratio

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♦ Though the exact pathophysiology of
PCOS remains unclear, restoration of
ovulation can be achieved with oral
hypoglycemic agents such as metformin
and troglitazone as well as clomiphene
citrate

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TREATMENT

1. Management of Patients Desiring

Pregnancy — Ovulation Induction
2. Management of Patients Not Desiring
Pregnancy

32
1. Management of Patients Desiring
Pregnancy— Ovulation Induction
♦ Ovulation Induction in Patients With
Amenorrhea-Galactorrhea With
Pituitary Macroadenoma
 Bromocriptine: main medical therapy

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 surgical therapy: lesion is large and
causing symptoms such as visual changes
or headaches
 About half of surgically treated patients
will menstruate normally after this
procedure

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♦ Ovulation Induction in Patients With
Amenorrhea-Galactorrhea Without
Macroadenoma (Including Patients With
Microadenomas)
 bromocriptine: response to therapy
 The usual dose is 2.5 mg orally twice
daily, but it is generally titrated until
serum prolactin is normal—often
possible with as little as 1.25 mg daily

35
 Once pregnancy has been achieved
bromocriptine may be discontinued
 macroadenomas may need to continue
therapy throughout pregnancy to avoid
further growth of the lesion

36
♦ Ovulation Induction in Patients With
Hypothyroidism
 frequently respond to thyroid
replacement therapy

37
♦ Ovulation Induction in Patients With
Primary Ovarian Failure
 can be made to ovulate only under very
rare circumstances
 Seldom Patients autoimmune oophoritis
can be successfully treated with
corticosteroids.

38
 Otherwise, almost all patients with
primary ovarian failure fall into the
category of idiopathic premature ovarian
failure and cannot be made to ovulate
 IVF with donor oocytes is the only way
they can have children

39
♦ Ovulation Induction in Patients With
Hypoestrogenic Hypothalamic
Amenorrhea (Progestin-Challenge
Negative)
 clomiphene: with low estrogen levels, the
pituitary does not release high quantities
of LH and FSH. Therefore, clomiphene
citrate is not likely to stimulate
gonadotropin release

40
♦ but many reproductive endocrinologists
treat such patients successfully with a
single course of clomiphene citrate, 150
or 250mg daily for 5 days, on the chance
that ovulation will occur

41
 Human menopausal gonadotropin (hMG):
usually first line therapy. Patients
showing some ovarian stimulation by
clomiphene can be treated with a
combination of clomiphene and hMG—
the advantage being a reduction in the
amount of hMG required and thus a
substantial cost savings
 monitored with serial ultrasound and
estradiol determinations to avoid
hyperstimulation

42
♦ Hyperstimulation is the stimulation of too
many follicles, with associated ovarian
enlargement and ascites, ovarian
hyperstimulation syndrome (OHSS)

43
♦ Ovulation Induction in Patients Who
Bleed in Response to Progestin
Challenge(Progestin-Challenge Positive)
 clomiphene: all these patients respond to
it
 The starting dose is 50 mg orally daily for
5 days. This can be increased to a
maximum of 250 mg orally daily in 50-
mg increments until ovulation is induced.
Ovulation occurs 5–10 days after the last
dose

44
 Patients with elevated androgens who do
not respond to clomiphene citrate may
respond to combined treatment with oral
hypoglycemic agents and clomiphene
 hMG: not effective above

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 Surgical wedge resection: in PCOS
 Unfortunately, wedge resection may
cause postoperative pelvic adhesions,
resulting in mechanical infertility

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 The placement of multiple holes in the
ovary with either cautery or the CO2
laser appears to give similar results to
wedge resection. Adhesions have also
been noted with this technique

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♦ 2. Management of Patients Not Desiring
Pregnancy
 Oral contraceptives: good replacement
therapy for most women
 Combinations of estrogens and
medroxyprogesterone: conjugated
estrogen, days 6 through 25 of the cycle;
medroxyprogesterone, days 16 through
25

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 medroxyprogesterone acetate, 10mg
orally daily for 10–13 days every month
or every other month: respond to the
progestin challenge, to induce withdrawal
bleeding and to prevent the development
of endometrial hyperplasia and
carcinoma

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 Thinking and answer:
1. Please introduce diagnosis and
assistant diagnostic methods of
amenorrhea including checking of
ovarian and hypothalamic and
pituitary function.
2. How many causes of amenorrhea?
3. Please list therapeutic principles of
amenorrhea.

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PERIMENOPAUSE &
PERIMENOPAUSE SYNDROME
Definition:
♦ Perimenopause: the time when a
woman’s body begins its transition into
menopause which signals the ending of
her reproductive years. From 2 to 8 years
between ages 39-50. Function of the
ovaries declines and the body’s estrogen
levels drop
♦ Perimenopause syndrome: a group of
symptoms occuring before, during, and
after menopause. Including physical and
emotional changes
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Etiology & Pathogenesis

A. MENOPAUSE
There are two types of menopause,
classified according to cause.
♦ 1. Physiologic menopause
♦ 2. Artificial menopause

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1. Physiologic menopause
Mechanism
♦ First, oocytes responsive to
gonadotropins disappear from the ovary
♦ second, the few remaining oocytes do not
respond to gonadotropins
♦ Marriage, childbearing, height, weight,
and prolonged use of oral contraceptives
do not appear to influence the age of
menopause. Smoking, however, is
associated with early menopause
♦ Spontaneous cessation of menses before
age 40 is called premature menopause or
premature ovarian failure
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2. Artificial menopause
♦ The permanent cessation of ovarian
function brought about by surgical
removal of the ovaries or by
radiation therapy is called an
artificial menopause

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B. PREMENOPAUSAL STATE
♦ During the menopausal transition,
Concentrations of follicle-stimulating
hormone (FSH) are strikingly elevated
during the early follicular phase and fall
as estradiol increases during follicular
maturation
♦ The mechanism responsible for this early
rise of FSH is probably related to inhibin.
Inhibin is a polypeptide hormone that is
synthesized and secreted by granulosa
cells. It causes negative feedback on FSH
released by the pituitary. As the oocyte
number decreases, inhibin levels fall,
resulting in a rise in FSH levels
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♦ Occasionally, estradiol levels will shortly
rise to concentrations 2 or 3 times higher
than is normally seen, probably reflecting
the recruitment of more than 1 follicle for
ovulation. Then during postmenopause
estradiol levels will decrease distinctly
♦ After corpus luteum formation, often
with limited secretion of progesterone

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C. CHANGES IN HORMONE
METABOLISM ASSOCIATED WITH
THE MENOPAUSE
♦ 1. Androgens
♦ 2. Estrogens
♦ 3. Progesterone
♦ 4. Gonadotropins

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1. Androgens
♦ In postmenopausal women, there is a
reduction of circulating
androstenedione to approximately
50% of the concentration found in
young women

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2. Estrogens
♦ After a woman has passed the
menopause, there is good clinical
evidence of reduced endogenous
estrogen production in most subjects

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3. Progesterone
♦ Since postmenopausal ovaries do not
contain functional follicles, ovulation
does not occur and progesterone
levels remain low

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4. Gonadotropins
♦ With the menopause, both LH and
FSH levels rise substantially, with
FSH usually higher than LH

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Clinical Findings

A. SYMPTOMS AND SIGNS

1. Reduced endogenous estrogens
a. Reproductive tract
Alteration of menstrual function is the
first clinical symptom, and then:
(1) Abrupt cessation of menstruation is
fairly rare, because the decline of
ovarian function usually proceeds
slowly
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(2) The most common pattern is a
gradual decrease in both amount
and duration of menstrual flow,
tapering to spotting, and eventually
to cessation
(3) A minority of patients have more
frequent or heavier vaginal bleeding

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♦ Vagina: The vaginal rugae progressively
flatten. Minimal trauma with douching
or coitus may result in slight vaginal
bleeding. local bacterial invasion is likely
to initiate vaginal pruritus, leukorrhea,
and a hyperemic appearance
♦ Cervix: It usually decreases in size, and
there is a reduction of secretion of
cervical mucus
♦ Uterus: Atrophy of it is also seen, with
shrinkage of both the endometrium and
myometrium
♦ oviducts and ovaries: also decrease in size
postmenopausally
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b. Urinary tract
♦ Estrogen plays an important role in
maintaining the epithelium of the bladder
and urethra. Marked estrogen deficiency
may produce atrophic changes in these
organs similar to those that occur in the
vaginal epithelium
♦ eg, urinary urgency, incontinence, loss of
urethral tone, tenderness, and
occasionally hematuria, etc.
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c. Hot flushes
♦ episodic disturbance consisting of sudden
flushing and perspiration. The duration
of the whole episode varies from
momentary to as long as 10 minutes; the
average length is 4 minutes. The
frequency varies from 1–2 an hour to 1–2
a week

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♦ It has been observed in about 75% of
women who go through the physiologic
menopause or have a bilateral
ovariectomy. 82% experience the
disturbance for more than 1 year and 25–
50% complain of the symptom for more
than 5 years

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d. Osteoporosis
♦ Although gradual bone loss occurs in all
humans with aging, this loss is
accelerated in women after cessation of
ovarian function. Osteoporotic bones are
more susceptible to fractures
♦ estrogens have direct effects on bone,
since estrogen receptors exist in
osteoblasts, osteoclasts, macrophages,
and T cells. Estrogen also seems to
enhance bone formation by a direct local
action on osteoblasts
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e. Cardiovascular system
♦ Before the age of menopause, very few
women die of a heart attack. After the
menopause, a woman’s risk increases
progressively until age 70
♦ estrogen could protect against coronary
artery disease

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f. Psychologic changes
♦ Some reports indicated an increased
incidence of minor symptoms such as
irritability, dysphoria, and nervousness
early in the menopausal transition

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♦ Double-blind studies have found
improvements in self-reported
irritability, mild anxiety, and dysphoria
in women treated with estrogen alone or
combined with progestin

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g. Alzheimer’s Disease
♦ Research indicates that estrogen
influences areas of the brain known to be
important for memory

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Treatment

♦ As long as ovarian function is sufficient

to maintain some uterine bleeding, no
treatment is usually required.
Occasionally, women complain of hot
flushes while menstrual function is still
present. Treatment with low dose oral
contraceptive pills, if no
contraindications exist, will relieve these
symptoms and help to regulate menstrual
cycles during the premenopause
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A. COUNSELING
♦ Every woman with climacteric symptoms
deserves an
adequate explanation of
the physiologic event she
is experiencing, in order
to dispel her fears and
minimize symptoms such
as anxiety, depression,
and sleep disturbance

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♦ Reassurance should be emphasized.
Specific reassurance about continued
sexual activity is important

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B. ESTROGEN REPLACEMENT
1. Methods
♦ Estrogen alone: a standard dosage of
estrogen, such as 0.625 mg of conjugated
equine estrogens, should be given daily
♦ Progestogen-estrogen therapy:
(1) administer a progestin such as
medroxyprogesterone acetate at a dosage
of 5–10 mg/d for 12–14 days each month
of the second half. But 80–90% of women
will experience some vaginal bleeding
monthly
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(2) An alternative is to prescribe a
lower dosage, 2.5 mg, continuously.
The combined, continuous
administration of estrogen plus
progestin promotes endometrial
atrophy and results in amenorrhea
in 70–90% of women who use
continuous therapy for more than 1
year

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2. Complications
♦ Side effects of estrogen therapy include
endometrial cancer, breast cancer,
hypertension, thromboembolic disease,
lipid metabolism, etc.

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♦ Other dose-related effects include uterine
bleeding, generalized edema, mastodynia
and breast enlargement, abdominal
bloating, signs and symptoms resembling
those of premenstrual tension, headaches,
and excessive cervical mucus

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3. Contraindications to estrogen
replacement therapy
♦ Undiagnosed vaginal bleeding, acute liver
disease, chronic impaired liver function,
acute vascular thrombosis (with or
without emboli), and endometrial or
breast carcinoma, etc.

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♦ Estrogen therapy may stimulate growth
of malignant cells remaining after
treatment of breast or endometrial
carcinoma and may thus hasten the
recurrence of cancer. Therefore, it is
prudent to avoid estrogen therapy until
arrest is likely

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4. Management guidelines for estrogen
replacement therapy
♦ Current indications for estrogen therapy
are relief of menopausal symptoms
(including hot flushes and vaginal
atrophy) and prevention of osteoporosis.
Risks and benefits must be evaluated for
each patient

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♦ Progestins have been shown to reduce
the occurrence of endometrial cancer.
Epidemiologic studies have shown
significant reduction of the occurrence of
endometrial cancer with estrogen plus
progestin compared with estrogen alone

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Special Treatment Problems
uterine bleeding
♦ If the bleeding is heavy or prolonged, a
biopsy should be performed. If
endometrial hyperplasia is present, the
medications can be discontinued, or a
progestin can be given each day of
estrogen administration

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♦A pretreatment biopsy and yearly
endometrial biopsies are necessary in all
women receiving estrogens alone to
determine the presence of hyperplasia

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♦ Estrogen withdrawal or combined
estrogen-progesterone therapy may be
employed to treat the hyperplasia. It is
presumed, but not established, that the
incidence of endometrial cancer will be
reduced if the programs discussed above
are instituted

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Qestions:
1. What clinical symptoms and signs will be
found during perimenopause?
2. What’s the mechanism of physiologic
menopause
3. How to treat perimenopause syndrom?

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