PRIMARY AND SECONDARY AMENORRHEA
Amenorrhea
● is defined as the absence of menstrual bleeding
and may be primary (never occurring) or
secondary (cessation sometime after initiation).
1. Primary amenorrhea
● is defined as the absence of menses in a
woman who has never menstruated by the
age of 15 years
● includes girls who have not menstruated
within 5 years of breast development, if
occurring by age 10.
● Breast development (thelarche) should
occur by age 13 or otherwise requires
evaluation as well.
● incidence of primary amenorrhea is less
than 0.1%.
2. Secondary amenorrhea
● is defined as the absence of menses for an
arbitrary period, usually longer than 6 to
12 months.
● incidence of secondary amenorrhea of
more than 6 months’ duration in a survey
of a general population of Swedish women
of reproductive age was found to be 0.7%
but has been cited to be as high as 3%
World Health Organization (WHO) classification:
1. WHO type I
● refers to women with low estrogen levels
and low follicle-stimulating hormone (FSH)
and normal prolactin (PRL) levels without
central nervous system (CNS) lesions
2. WHO Type II
● refers to a normal estrogen status with
normal FSH and PRL levels;
3. WHO type III
● refers to low estrogen levels and a high
FSH level, denoting ovarian failure.
PHYSIOLOGY LEADING UP TO MENARCHE
●
●
first sign of puberty is usually the appearance of
breast budding, followed within a few months by
the appearance of pubic hair
mean interval between breast budding and
menarche is 2.3 years
●
●
●
Leptin
●
●
●
●
body composition is more important than total body
weight in determining the time of onset of puberty
and menstruation
Individuals who are moderately obese, between
20% and 30% more than the ideal body weight,
have an earlier onset of menarche than women who
are not obese.
Malnutrition, such as occurs with anorexia nervosa
or starvation, is known to delay the onset of puberty
is the adipocyte hormone
One of the major links between body composition
and the hypothalamic-pituitary-ovarian (HPO) axis,
and thus menstrual cyclicity
produced by adipocytes and correlates well with
body weight
also
important
for
feedback
involving
gonadotropin-releasing hormone (GnRH) and
luteinizing hormone (LH) pulsatility
Ghrelin
● a gastric peptide, interacts with leptin in this regard
particularly when menstrual function is perturbed
-
-
-
ballet dancers, swimmers, and runners have
menarche delayed to approximately age 15 if they
began exercising strenuously before menarche
athletic activities requiring lower body weight and
where success is more subjective (ballet,
gymnastics) compared with swimming.
It was also determined that stress per se is not the
cause of the delayed menarche in these
exercising girls, because girls of the same age with
stressful musical careers did not have a delayed
onset of menarche
●
●
●
●
●
●
1.
2.
3.
4.
5.
6.
metabolic features of amenorrheic athletes, who are
considered to be in a state of negative energy
balance, are fairly characteristic.
These include elevated serum FSH and insulinlike
growth factor-binding protein 1 (IGFBP-1) and
lowered insulin-like growth factor (IGF) levels.
Emotional stress can lead to inhibition of the
GnRH axis.
The mechanism involves an increased secretion of
corticotropin
releasing
hormone
(CRH),
releasing adrenocorticotropic hormone (ACTH),
opioid peptides such as beta-endorphin, and
cortisol.
CRH itself is known to inhibit GnRH.
Before puberty, circulating levels of LH and FSH are
low, with an FSH/LH ratio greater than 1
CNS-hypothalamic axis is extremely sensitive to the
negative feedback effects of low levels of circulating
estrogen.
As the critical weight or body composition is
approached, the CNS-hypothalamic axis becomes
less sensitive to the negative effect of estrogen and
GnRH is secreted in greater amounts, causing an
increase in LH and, to a lesser extent, FSH levels.
This release from the prepubertal “brake” on GnRH
secretion is depicted in Fig. 36.4, which also
illustrates the integral role of neuropeptides such as
kisspeptin
The initial endocrinologic change associated with
the onset of puberty is the occurrence of episodic
pulses of LH during sleep
These pulses are absent before the onset of
puberty. After menarche, the episodic secretions of
LH occur during sleep and while awake.
The last endocrinologic event of puberty is
activation of the positive gonadotropin response to
increasing levels of estradiol (E2), which results in
the midcycle gonadotropic surge and ovulation
PRIMARY AMENORRHEA
Causes
Breasts Absent and Uterus Present
● breast development is a biomarker of ovarian
estrogen production
○ no breast development and a uterus
present = no estrogen production
Gonadal Failure (Hypergonadotropic Hypogonadism)
● Failure of gonadal development - most common
cause of primary amenorrhea
● Gonadal failure
○ most
commonly
caused
by
a
chromosomal disorder or deletion of all
or part of an X chromosome,
○ chromosomal genetic defect and, rarely,
defective
CYP-17
leading
to
17a-hydroxylase deficiency
● Not inherited
● Pure gonadal dysgenesis
○ 46,XX
○ gonadal development is absent
○ + gene disorder - inherited, can occur in
siblings
● cardiovascular or renal anomalies
● shorter stature
○ Turner syndrome - deletion of the entire X
chromosome
○ Deletion of the short arm (p) of the X
chromosome
○
●
●
●
●
●
●
-
-
Deletions of only the long arm (q) usually
do not affect height
Gonadal streak
○ In place of the ovary a band of fibrous
tissue
When ovarian follicles are absent, synthesis of
ovarian steroids and inhibin does not occur.
Breast development does not occur because of the
low circulating E2 levels.
Because the negative hypothalamic-pituitary action
of estrogen and inhibin is not present,
gonadotropin levels are markedly elevated, with
FSH levels being higher than LH.
Estrogen is not necessary for müllerian duct
development or wolffian duct regression, so the
internal and external genitalia are phenotypically
female.
An occasional individual with mosaicism, an
abnormal X chromosome, pure gonadal dysgenesis
(46,XX), or even Turner syndrome (45,X) may have
a few follicles that develop under endogenous
gonadotropin stimulation early in puberty and may
synthesize enough estrogen to induce breast
development and a few episodes of uterine
bleeding, resulting early in premature ovarian
failure, usually before age 25. Rarely, ovulation and
pregnancy can occur.
primary amenorrhea and plasma FSH levels
higher than 40 mIU/mL - no functioning ovarian
follicles in the gonadal tissue.
diagnosis of gonadal failure
primary amenorrhea + FSH levels are
consistently elevated, without requiring
ovarian tissue evaluation.
45,X and Related Abnormalities
● Turner syndrome (45,X)
○ 1 per 2000 to 3000 live births but is much
more common in abortuses.
○ primary amenorrhea
○ absent breast development,
○ other somatic abnormalities
■ short stature (< 60 inches in
height
■ webbing of the neck
■ short fourth metacarpal
■ cubitus valgus.
○ Cardiac abnormality, renal abnormalities,
and hypothyroidism are also more
prevalent.
● chromosomal mosaics
○ X/XX - most common
■ with primary amenorrhea
■ normal female external genitalia
○ X/XXX and X/XX/XXX
■ primary amenorrhea
■ generally taller
■ fewer anatomic abnormalities
than individuals with a 45,X
karyotype
○
●
some of them may have a few gonadal
follicles and ~ 20% have sufficient
estrogen production to menstruate
○ ovulation may occur
Noonan syndrome
○ Isolated phenotypic features of Turner
syndrome (without gonadal failure) in
males
Structurally Abnormal X Chromosome
● 46,XX karyotype but part of one X chromosome is
structurally abnormal
● Deletion of long arm (Xq)
○ Normal height
○ No somatic abnormalities
● Deletion of short arm (Xp)
○ Individual is short
● isochromosome of the long arm of X chromosome
● Other X chromosome abnormalities
○ Ring X
○ Minute
fragmentation
of
the
X
chromosome
Pure Gonadal Dysgenesis (46,XX and 46,XY With
Gonadal Streaks)
● may have a familial/genetic association (siblings)
● normal stature and phenotype
● absence of secondary sexual characteristics
● primary amenorrhea
● Some have a few ovarian follicles, develop breasts,
and may even menstruate spontaneously for a few
years
a.
46,XY gonadal dysgenesis
abnormal testis in utero
incomplete forms with some degree of
testicular tissue
“pure” form as a dysgenetic streak, Swyer syndrome.
If a Y chromosome is present or is found
as part of a mosaic karyotype, with or
without
any
clinical
signs
of
androgenization, gonadectomy should be
performed
17a-Hydroxylase Deficiency with 46,XX Karyotype
● Rare
● primary amenorrhea without breast development
● normal female internal genitalia
● can also occur in genetic males 46,XY
● hypernatremia and hypokalemia
●
●
●
●
●
●
Decreased cortisol, elevated ACTH
Elevated mineralocorticoids
○ because 17a-hydroxylase is not necessary
for the conversion of progester- one to
deoxycortisol or corticosterone.
excessive sodium retention and potassium
excretion,
leading
to
hypertension
and
hypokalemia
Elevated serum progesterone (not converted to
cortisol
cystic ovaries and viable oocytes.
Tx:
sex steroid replacement and cortisol
administration
Genetic Disorders with Hyperandrogenism
● Hyperandrogenism ~ 10% of women with gonadal
dysgenesis.
● Most have Y chromosome or a fragment of it.
● Some may only have DNA fragment that contains
SRY gene without full Y chromosome
● Those with hypergonadotropic hypogo- nadism and
a female phenotype who have any clinical manifestation of hyperandrogenism, such as hirsutism,
should have a gonadectomy, even if a Y
chromosome is not present, because gonadal
neoplasms are common.
CNS-Hypothalamic-Pituitary Disorders
● low estrogen levels are caused by an abnormal or
absent signal to the ovary resulting in very low
circulating gonadotropin levels.
● cause of low gonadotropin production may be
morphologic or endocrinologic
a.
CNS lesions
anatomic lesion of hypothalamus/pituitary gonadotropin.
Can be congenital or acquired
Pituitary adenoma → elevated PRL levels
Chromophobe
adenomas
and
craniopharyngiomas → PRL not elevated
, rarely cause of primary amenorrhea with
low gonadotropin levels
Primary amenirrha +
gonadotropin +/prolactin - CT scanning or MRI of the
hypothalamic pituitary region to r/o cns
lesion
⬇️
⬆️
b.
⬇️
Inadequate GnRH Release (Hypogonadotropic
Hypogonadism)
gonadotropin w/o lesion
Thought to be primary pituitary
failure
hypothalamic defect with insufficient
GnRH
synthesis
or
a
CNS
neurotransmitter defect, resulting in
inadequate GnRH synthesis
abnormal kisspeptin
anosmia - specific defect of the KAL gene
(Xp 22-3)
⬇️
-
Females with Kallmann syndrome and
related forms of gonadotropic deficiency
normal height
growth of long bones (greater
wingspan-to-height ratio)
Men
hypogonadism
wingspan-to-height ratio
altered spatial orientation abilities.
Have tendency to be familial/ inherited
Majority are sporadic
Responds to GnRH administration
⬆️
-
⬆️
c.
Isolated Gonadotropin Deficiency (Pituitary
Disease)
do not respond to GnRH
thalassemia major (with iron deposits in
the pituitary) or retinitis pigmentosa.
prepubertal hypothyroidism, kernicterus, or
mumps encephalitis.
d.
Estrogen resistance
mutation in estrogen receptor alpha (ER
∝) does not allow estrogen signaling or a
biologic response to estrogen action.
endogenous estrogen
gonadotropins (to try to provoke an
estrogen response)
ovaries are cystic
Exogenous estrogen does not normally
induce changes
⬆️
⬆️
BREAST
ABSENT
DEVELOPMENT
PRESENT
AND
UTERUS
Androgen resistance
X-linked recessive or sexlinked AD disorder
“testicular feminization”
androgen receptor synthesis or action does not occur
absence of an X-chromosome gene responsible for
cytoplasmic or nuclear testosterone receptor function
XY karyotype w/ normally functioning male gonads that
produce normal male levels of testosterone and
dihydrotestosterone
Lack of receptors in target organs
lack of male
differentiation of the external and internal genitalia
External genitalia remains feminine
Wolffian duct development
Usually due to testosterone stimulation
but fails to take place
women with this disorder have
no female or male internal genitalia,
normal female external genitalia
short or absent vagina
Pubic hair and axillary hair are absent or scanty as a
lack of androgenic receptors
breast development is normal or enhanced
testosterone is responsible for inhibiting breast
proliferation.
➡️
⬅️
-
-
Thus with androgen resistance, the absence of
androgen action allows even low levels of estrogen to
cause unabated breast stimulation
Estrogen - normal male range
LH is slightly elevated.
Testes that are intraabdominal or that occur in the
inguinal canal have an increased risk of developing a
malignancy (gonadoblastoma or dysgerminoma) →
must be removed after age 18
Congenital Absence of the Uterus
Uterine Agenesis
Uterovaginal Agenesis,
Mayer-Rokitansky -Küster-Hauser Syndrome
Hox genes are important for uterine development,
and mu- tations (e.g., in HOXA13)
No pattern of inheritance
2nd most common cause of primary
amenorrhea
Complete Uterine Agenesis
normal ovaries
regular cyclic ovulation
normal endocrine function
normal breast and pubic and axillary hair
development
shortened or absent vagina
Absent uterus
On occasion one or both rudimentary horns may
have some functioning endometrium.
obstructed outflow, cyclic pelvic pain
may be encountered.
Majority are caused by an isolated developmental
defect
Vs. androgen resistance: normal pubic hair
normal endocrinologically; able to have children
(surrogate or gestational carrier)
ABSENT BREAST AND UTERINE DEVELOPMENT
● Rare
● male karyotype
●
gonadotropin
● testosterone: normal or below-normal female range
⬆️
●
Differential diagnosis:
1. 17a-hydroxylase deficiency
Present testes
Female external genitalia
2. 17,20-desmolase deficiency
3. agonadism
Aka vanishing testes syndrome
no gonads present
SECONDARY
SEX CHARACTERISTICS (BREATS)
PRESENT AND FEMALE INTERNAL GENITALIA
(UTERUS) PRESENT
second largest category of individuals with primary
amenorrhea
25% + hyperprolactinemia and prolactinomas
PCOS
PRIMARY
AMENORRHEA
WITH
ABSENT
ENDOMETRIUM
● Rare
● Normal Endocrine function, uterus, ovaries, and
fallopian tubes
● absent endometrium
Differential Diagnosis and Management
● If breasts are absent but a uterus is present, the
diagnostic evaluation should differentiate between
CNS-hypothalamic-pituitary disorders and failure of
normal gonadal development.
○ similar phenotypes because of low E2
levels
○
single serum FSH assay can differentiate
between these two
● hypergonadotropic hypogonadism (FSH . 40
mIU/mL)
○ peripheral WBCl karyotype to check
presence of Y chromosome
○ If present, streak gonads should be
excised
○ If absent, it is unnecessary to remove the
gonads unless there are signs of
hyperandrogenism
● elevated FSH level and an XX karyotype - measure
electrolyte and serum progesterone levels to rule
out 17a-hydroxylase deficiency
● Women with ovarian failure or hypergonadotropic
hypogonadism who wish to become pregnant may
undergo egg donation
● Turner syndrome - cardiac evaluation is mandatory
before pregnancy because of potential risks such as
aortic dissection
● rare individuals without breast development and no
internal genitalia should be referred to an endocrine
center for the extensive evaluation necessary to
establish the diagnosis
SECONDARY AMENORRHEA
Causes
● amenorrhea w/o galactorrhea, hyperprolactinemia,
or
hirsutism
disorders
in
the
CNS
(hypothalamic-pituitary axis), ovary, or uterus.
●
uterine cause of secondary amenorrhea - normal
endocrine function
Uterine Factor
● Intrauterine adhesions (IUAs) or synechiae
● Asherman syndrome
○ can obliterate the endometrial cavity and
produce secondary amenorrhea
Pregnancy complication, prior instrumentation, or,
rarely, endometrial tuberculosis
most common cause: endometrial curettage
associated with pregnancy (evacuation of a live
or dead fetus)
diagnostic dilation and curettage (D&C) in a
nonpregnant woman
severe endometritis or fibrosis after a
myomectomy, metroplasty, or cesarean delivery
Confirmation of dx - hysterosalpingogram
■
●
●
●
CNS and Hypothalamic Causes
● CNS Structural Abnormalities
○ interfering with GnRH release
○ Hypothalamic
lesions:
craniopharyngiomas,
granulomatous
disease (tuberculosis, sarcoidosis), and
sequelae of encephalitis.
gonadotropins and
○
E2
○ withdrawal uterine bleeding will not occur
after progesterone administration
● Drugs
○ Phenothiazine
derivatives,
certain
antihypertensive agents - amenorrhea
without hyperprolactinemia
○ Oral contraceptive steroids
■ acting on the hypothalamus to
suppress GnRH
■ directly on the pituitary to
suppress FSH and LH
■ inhibit ovulation
○ postpill amenorrhea syndrome
■ hypothalamic
pituitary
suppression persists for several
months after oral contraceptives
are discontinued
⬇️
⬇️
oral
contraception–induced
suppression should not last
longer than 6 months
Stress and Exercise
○ Stressful situations, including a sudden
change in a normal routine, can produce
amenorrhea
○ amenorrheic athletes ran more miles
weekly
○ Both stress and exercise can increase
brainderived factors that can inhibit GnRH
release ( CRH, opioid peptides etc.)
Weight Loss
○ malnourished reproductive capacity
○ associated with amenorrhea in women
■ moderately underweight: 15% to
25% less than ideal body weight
■ severely underweight: > 25% of
ideal body weight
○ excessive dietary restrictions, malnutrition
○ anorexia nervosa
○ women with amenorrhea associated with
simple weight loss have direct and indirect
evidence of hypothalamic dysfunction
○ failure of normal GnRH release, with the
lack of a pituitary response under extreme
conditions.
○ Hypoleptinemia, alterations in ghrelin,
and GH and thyroid dysfunction
Polycystic Ovary Syndrome
○ prolonged periods of amenorrhea
○ irregularity or oligomenorrhea - more
common
○ need not be overweight or obese, or have
symptoms and signs of hyperandrogenism
○ elevated serum LH
■ normal in obese
■ Not a diagnostic criterion
○ diagnosis of PCOS may be confirmed by
visualizing
polycystic
ovaries
on
ultrasound
○ Rotterdam criteria for the diagnosis of
PCOS, women may be diagnosed as
having PCOS with only the menstrual
disturbance (in this case amenorrhea) and
polycystic ovaries seen with ultrasound.
mens disturbance,
UTZ
■
⬆️
➕
●
⬇️
➖
Functional Hypothalamic Amenorrhea
○ no anatomic abnormalities
○ not on drugs
○ no history of excessive exercise, stress, or
large changes in body
○ alteration of hypothalamic GnRH
release
○ No cyclic alterations in LH pulsatility
■ no pulses
■ Or persistent pulsatility
○ stress-induced hypothalamic amenorrhea
■ hypnotherapy and cognitive
behavior therapy - restore
ovarian activity
○
○
○
severity of the hypothalamic suppression
can be assessed by a sensitive assay for
E2
■ <
30pg/mL
significant
hypoestrogenism
■ <20 pg/mL - after menopause
If endogenous E2 has been sufficient to
allow the endometrium to proliferate, then
progestogen administration will result in
withdrawal bleeding
■ determined by visualizing the
endometrial
stripe
by
ultrasound
■ < 4 mm = hypoestrogenism
polycystic ovaries on UTZ
25% FHA =
➕
Pituitary Causes (Hypoestrogenic Amenorrhea)
● Neoplasms
○ most pituitary tumors secrete PRL
○ Chromophobe
adenomas
most
common
non–PRL-secreting
pituitary
tumors
○ Basophilic
(ACTH-secreting)
and
acidophilic (GH-secreting) adenomas
may not secrete PRL
○ symptoms of acromegaly or Cushing
disease
○
● Nonneoplastic Lesions
○ Pituitary cells - become damaged or
necrotic as a result of anoxia, thrombosis,
or hemorrhage
○ Sheehan syndrome - pituitary cell
destruction caused by hypotensive
episode during pregnancy
○ Simmonds disease - unrelated to
pregnancy
○ pituitary damage
ACTH and TSH
■
LH and FSH.
■
○
○
●
●
●
●
●
●
●
Occurs before age 40
ovaries cease to produce sufficient
estrogen to stimulate endometrial growth
several years before the age of physiologic
menopause
○ two types of ovarian pathologic findings
■ generalized sclerosis similar to
the findings of a normal
postmenopausal ovary
■ 30%,
numerous
primordial
follicles with no progression
past the early antrum stage are
seen, which looks identical to a
normal ovary
gonadotropin-resistant ovary syndrome
○ a gonadotropin receptor defect
○ primary amenorrhea
○ but usually sufficient estrogen is produced
so that they menstruate for several months
or even years
autoimmune process with autoimmune diseases
○ Hypoparathyroidism
○ Hashimoto thyroiditis
○ Addison disease.
It is recommended that immunologic screening
be performed in young women with POI.
CBC, comprehensive metabolic panel, TSH and
antithyroid antibody levels
adrenal antibodies (against 21-hydroxylase) and
cortisol levels
ACTH stimulation test
general screen for adrenal function by obtaining
levels of dehydroepiandrosterone sulfate (DHEAS)
Diagnostic Evaluation and Management
⬇️
⬇️
➡️⬇️
Ovarian Causes (Hypergonadotropic Hypogonadism)
estrogen secretion by
● Damaged
follicles
no endometrial growth
ovaries
● follicles are damaged due to
○ infection
○ interference with blood supply
○ depletion of follicles caused by bilateral
cystectomies
● amenorrheic after
○ medical treatment of bilateral tubo-ovarian
abscess
○ bilateral cystectomy
○ benign ovarian neoplasms
○ hysterectomy
■ during which the vascular supply
to the ovaries is compromise
(AKA cystic degeneration of the
ovaries)
● premature ovarian failure (POF) or premature
ovarian insufficiency (POI)
○ premature menopause
➡️
●
●
instrumentation
of
the
endometrial cavity,
particularly temporally related to pregnancy, should
alert to the possibility of IUA
History and PE:
○
●
●
●
●
●
●
●
medications currently being used or if oral
contraceptives
have
been
recently
discontinued
○ questions regarding diet, weight loss,
stress, and strenuous exercise are
pertinent
○ history of hot flushes, decreasing breast
size, or vaginal dryness
CBC, urinalysis, and serum chemistries should be
carried out to rule out systemic disease
sensitive TSH assay, serum E2, FSH, and PRL
should be measured
Insulin tolerance test
To rule out mosaicism or a dysgenetic gonad,
including the possibility of a Y cell line, a karyotype
should be obtained in women with POF who are
aged 25 years or younger.
Women with anovulation, including those with
PCOS, who desire conception
○ may be treated with clomiphene citrate or
letrozole, which are effective for inducing
ovulation.
○ Clomiphene is not successful if the
estrogen levels are low
woman with more severe hypothalamic-pituitary
suppression (low estrogen levels) desires fertility,
○ ovulation can be induced with exogenous
gonadotropins or pulsatile GnRH.
Young women with POI and those with a chronic
hypoestrogenic state are also vulnerable to
accelerated atherosclerosis and diabetes and have
been found to have increased all-cause mortality.
PRECOCIOUS PUBERTY
● sequence of the physiologic events of puberty
○ Begins with breast development
○ subsequent appearance of pubic and
axillary hair
○ followed by the period of maximal growth
velocity
○ finally, menarche
● Menarche
○ may occur before the appearance of
axillary or pubic hair in 10% of normal
females
● growth velocity
○ before breast development the is → 6
cm/year
○ Peak height velocity, around age 12 →
velocity is around 8 cm/year
○ by the completion of puberty, around age
14, the velocity is down to 1 cm/year,
explained by closure of the epiphyses
● Precocious puberty
○ defined as the appearance of any signs of
secondary sexual maturation at an early
age
○ girls with breast development or pubic hair
should be evaluated when these signs
occur before age 7 in white girls and age 6
in black girls
○
○
○
○
●
carry out a complete evaluation of
precocious puberty at age 8 years
associated with a wide range of disorders
US incidence: 1 in 10,000 young girls
two primary concerns
■ social stigma associated with the
child being physically different
from her peers
■ diminished ultimate height caused
by the premature closure of
epiphyseal growth centers
Puberty
○ time of accelerated growth, skeletal
maturation, and resulting epiphyseal
closure.
Types of Disorders
● Precocious puberty is subdivided into GnRH
dependent (complete, true) and GnRH independent
(incomplete, pseudo), and these causes have been
subcategorized as feminizing (previously termed
isosexual)
or
virilizing
(previously
termed
heterosexual) Disorders.
● The pathophysiology of precocious puberty is
divided into two distinct categories: a normal
physiologic process involving GnRH secretion with
an integrated hypothalamic-pituitary axis, which
occurs at an abnormal time, or an abnormal
physiologic process independent of an integrated
HPO axis.
● GnRH-dependent precocious puberty involves
premature maturation of the HPO axis and includes
normal menses, ovulation, and the possibility of
pregnancy. GnRH-independent precocious puberty
involves premature female sexual maturation, which
may lead to estrogen-induced uterine stimulation
and bleeding without any normal ovarian follicular
activity.
● The majority of girls with precocious puberty (70%)
develop a GnRH-dependent process.
● A definitive diagnosis is established more often for
pseudoprecocious puberty, which is usually related
to an ovarian or adrenal disorder.
● If the secondary sex characteristics are discordant
with the genetic and phenotypic gender, the
condition is termed heterosexual or virilizing
precocious puberty.
● This is premature virilization in a female child and
includes development of masculine secondary
sexual characteristics.
● The androgens that cause heterosexual (virilizing)
precocious puberty usually come from the adrenal
gland.
Premature Thelarche
● Premature thelarche is defined as isolated unilateral
or bilateral breast development as the only sign of
secondary sexual maturation.
● It is not accompanied by other associated evidence
of pubertal development, such as axillary or pubic
hair or changes in vaginal epithelium.
● Estrogen levels are normal (prepubertal) together
with estrogen levels in pubertal girls, those with
precocious puberty and adults
● Breast hyperplasia is a normal physiologic
phenomenon in the neonatal period and may persist
until the child is up to 6 months of age.
●
Premature thelarche usually occurs in two waves:
within the first 2 years, and between ages 6 and 8.
●
●
Premature Pubarche or Adrenarche
● Premature pubarche is early isolated development
of pubic hair without other signs of secondary
sexual maturation.
● Premature
adrenarche
is
isolated
early
development of axillary hair.
● Neither of these conditions is progressive, and the
girls do not have clitoral hypertrophy; however, it is
important to differentiate premature pubarche from
the virilization produced by congenital adrenal
hyperplasia.
● Similar to premature thelarche, the child should
have periodic follow-up visits to confirm that the
condition is not progressive.
● Many cases of premature adrenarche evolve into
PCOS.
● Measurements
of
testosterone
and
17-hydroxyprogesterone should also be carried out
to rule out other conditions.
Central Precocious Puberty (GnRH Dependent)
Idiopathic
● Idiopathic
development
is
responsible for
approximately
80%
of
the
cases
of
GnRH-dependent precocious puberty.
● Some of these children are simply at the earliest
limits of the normal distribution of the biologic curve.
● A high incidence of abnormal EEGs in children with
idiopathic precocious puberty has raised the
question of potential CNS disease.
● These girls have no genital abnormality except for
early development.
● Occasionally, follicular cysts of the ovary may form
secondary to increased pituitary gonadotropin
levels.
● In these cases the cysts are the result, not the
cause, of precocious puberty.
● LH responses suggesting GnRH dependency are
more than 5 mIU/mL.
CNS Lesions
● A wide range of inflammatory, degenerative,
neoplastic, or congenital defects that involve the
CNS may produce GnRH-dependent precocious
puberty.
● This occurs in up to 20% of cases and warrants a
careful evaluation by imaging.
● Usually, symptoms of a neurologic disease,
especially headaches and visual disturbances,
precede the manifestations of precocious puberty.
Primary Hypothyroidism
● Hypothyroidism is usually associated with delayed
pubertal development; however, in rare cases,
untreated
hypothyroidism
results
in
GnRH-dependent precocious puberty.
● The hypothyroidism associated with precocious
puberty is caused by primary thyroid insufficiency,
usually Hashimoto thyroiditis, and not by a
deficiency in pituitary TSH.
● The pathophysiology of this syndrome is a result of
the diminished negative feedback of thyroxine,
resulting in an increased production of TSH, which
may be accompanied by an increase in production
of gonadotropins.
Interestingly, hypothyroidism is the only cause of
precocious puberty in which the bone age is
retarded.
This syndrome is usually observed in girls between
the ages of 6 and 8 years.
Peripheral (GnRH-Independent) Precocious Puberty
● The most common cause of pseudo- or feminizing
precocious puberty is an estrogen-secreting ovarian
cyst or large functioning follicle.
● Granulosa cell tumors are the most common type of
solid ovarian tumor resulting in precocious puberty.
● Adrenocortical neoplasms may produce isosexual
(feminizing) or heterosexual (virilizing) precocious
puberty.
● The relationship between congenital adrenal
hyperplasia and puberty depends on the time of
initial diagnosis and therapy.
● In this category, apart from adrenal imaging,
measurements of steroids to rule out the various
forms of adrenal hyperplasia caused by enzymatic
deficiencies (e.g., 21- or 11b-hydroxylase or 3 b-ol
dehydrogenase) should be carried out.
● McCune-Albright syndrome (MAS) is a rare
condition caused by a mutation in the G3 protein
leading to activation of adenylate cyclase.
● Iatrogenic or factitious precocious puberty results
when a young girl has used hormone cream or
ingested adult medications such as oral estrogen or
birth control pills.
Diagnostic Evaluation
● The diagnostic workup of a young child with
precocious puberty begins with a meticulous history
and physical examination.
● The primary emphasis should be to rule out
life-threatening neoplasms of the ovary, adrenal
gland, or CNS.
● The secondary emphasis is to delineate the speed
of the maturation process because this is crucial in
making decisions concerning therapy.
● The height of the girl and exact stage of pubertal
development, including Tanner stage, should be
recorded.
● Acceleration of growth is one of the earliest clinical
features of precocious puberty.
● Thus bone age should be determined by hand-wrist
films and compared with standards for a patient’s
age.
● Diseases of the CNS are suggested by symptoms
such as headaches, seizures, trauma to the head,
and encephalitis.
● Hypothalamic hamartomas can be categorized
based on the tumor topology on MRI.
● Serum levels of LH, PRL, TSH, E2, testosterone,
DHEAS,
HCG,
androstenedione,
17-hydroxyprogesterone, triiodothyronine (T3), and
thyroxine (T4) may be of value in establishing the
differential diagnosis.
● A GnRH agonist stimulation test is diagnostic in
differentiating incomplete from true precocious
puberty as described previously, but it does not
specifically identify children with CNS lesions.
Treatment
● The treatment of precocious puberty depends on
the cause, extent, and progression of precocious
signs and whether the cause may be removed
operatively.
● The goals of therapy are to reduce gonadotropin
secretion and reduce or counteract the peripheral
actions of the sex steroids, decrease the growth
rate to normal, and slow skeletal maturation to allow
development of maximal adult height.
● The present drug of choice for GnRH-dependent
precocious puberty is one of the potent GnRH
agonists, which have been studied extensively.
● Although 3-month regimens are available, therapy
usually begins with a once-per-month preparation at
a dose of 0.3 mg/kg of leuprolide or its equivalent.
● Leuprolide acetate can be administered at doses of
7.5 mg, 11.25 mg, and 15 mg; the larger dose can
be used if there is evidence for pubertal progression
despite treatment.
● Treatment usually continues until around age 11.
● McCune-Albright syndrome is caused by an
activating mutation of a G protein that is coupled
with gonadotropin receptors, resulting in the ovaries
being stimulated autonomously.
● Girls may be treated with aromatase inhibitors
(anastrozole, letrozole), which prevent the
conversion to biologically active estrogens.
● Unfortunately this treatment has had limited
success, as has the use of tamoxifen.
● The child with precocious puberty and her family
need intensive counseling.
● The child will have the psychosocial and behavioral
maturation of children of her chronologic age, not
the age reflected by her physical appearance.
● She may be exposed to ridicule by her peers and to
sexual exploitation.
● Thus the child needs extensive sex education and
help in anticipating and confronting various social
experiences.
CHAPTER 37
HYPERPROLACTINEMIA:
Evaluation and Management
Prolactin is a polypeptide hormone containing 198
amino acids and with a molecular weight of 22 kDa.
● It circulates in 2 different molecular sizes:
○ Monomeric form- small (MW of 22 kDa)
■ Biologically active; approx. 80%
of the hormone is secreted in this
form.
○ Polymeric form - big (MW of 50 kDa)
■ Big PRL is presumed to be a
dimer
○ Larger polymeric form - big big (MW of
>100 kDa)
■ Big-big PRL may present an
aggregation
of
monomeric
molecules.
■ Also
contain
added
sugar
moieties
(glycosylation)
–
decreases biologic activity.
● PRL is synthesized and stored in the pituitary gland
in chromophobe cells called lactotrophs.
○ Encoded by its gene (10kb) on
chromosome 6
○ Main function: to stimulate the growth of
mammary glands tissue and to produce
and secrete milk into the alveoli; thus it has
mammogenic and lactogenic functions.
○ TRH or thyroid-releasing is the principal
stimulating factor.
○ Dopamine (Prolactin inhibiting factor or
PIF) is the major inhibiting factor.
○ Estrogen also improves PRL secretion by
enhancing the effects of TRH and
inhibiting the effects of dopamine
○ A potential direct effect may also be
mediated by galanin.
○ D2 is the principal receptor with which
dopamine interacts
■ Also the target for various
dopamine agonists used in the
treatment of hyperprolactinemia.
○ Normal measurable amounts in adult
women: serum PRL of approx. 8 ng/ml
○ Specific receptors: present in the plasma
membrane of mammary cells and in many
other tissues.
Physiology
● PRL synthesis and release from the lactotrophs are
controlled
by
central
nervous
system
neurotransmitters – which act on the pituitary via
the hypothalamus.
● Inhibition is the major mechanism because
pituitary stalk section results in increased PRL
secretion.
● There are specific dopamine receptors on the
lactotrophs, and dopamine inhibits PRL synthesis
and release in pituitary cell cultures.
●
●
●
●
●
●
●
●
Serotonin and thyrotropin-releasing factors
stimulate PRL release of prolactin.
TRF stimulates PRL release only minimally unless
infused
Serotonin
○ is a PRF or is responsible for secretion of
PRL
○ It also controls the rise of PRL levels
during sleep.
PRL is secreted episodically and serum levels
fluctuate throughout the day and throughout the
menstrual cycle, with peak levels occurring at
midcycle.
Although changes in PRL levels are not as marked
as the pulsatile episodes of luteinizing hormone
(LH), estrogen stimulates PRL production and
release.
○ At puberty: Estrogen increases PRL levels
increase in girls
○ After menopause: there is a slight decline
in PRL
During pregnancy:
○ As estrogen levels increase, there is a
concomitant hypertrophy and hyperplasia
of the lactotrophs.
○ The maternal increase in PRL levels
occurs
soon
after
implantation,
concomitant with the increase in circulating
estrogen.
○ Circulating levels of PRL steadily increase
throughout
pregnancy,
reaching
approximately 200 ng/mL in the third
trimester
■ the rise is directly related to the
increase in circulating levels of
estrogen
■ however, there is a wide range of
values of PRL in pregnancy, and
values as high as 400 ng/mL
can
be
found in normal
pregnancy
○ Lactation does not occur during
pregnancy despite elevated PRL levels
because estrogen inhibits the action of
PRL on the breast by blocking the PRL’s
interactions with its receptor.
○ 1 or 2 days after delivery of the
placenta:
■ estrogen and PRL levels decline
rapidly and lactation is initiated
○ 2 to 3 weeks: PRL levels reach basal
levels in non nursing women
○ Basal levels of circulating PRL decline to
the nonpregnant range:
■ Approximately 6 months after
parturition in nursing women,
■ after each act of suckling – PRL
levels increase markedly and
stimulate milk production for the
next feeding
PRL levels also increase by:
○ Nipple and breast stimulation
○
○
Trauma to the chest wall
Other physiologic stimuli such as
exercise, sleep and stress
○ After ingestion of the midday meal
● PRL fluctuate throughout the day
○ Maximal levels occur during the night while
asleep
○ Smaller increase occurring in the early
afternoon
● Normal PRL levels in nonpregnant women is
usually 20-25 ng/ml
○ Greater than 20-25 ng/ml is a condition
called hyperprolactinemia.
● Stress is the most common cause of slightly
elevated PRL levels
● Hyperprolactinemia can produce disorders of
gonadotropin sex steroid function, resulting in
menstrual cycle derangement such as:
○ oligomenorrhea and amenorrhea
○ anovulation
○ inappropriate lactation or galactorrhea
● The mechanism whereby elevated PRL levels
interfere with gonadotropin release appears to be
related
to
abnormal
gonadotropin-releasing
hormone (GnRH) release.
● Women with hyperprolactinemia have abnormalities
in the frequency and amplitude of LH pulsations,
with a normal or increased gonadotropin response
after GnRH infusion.
● Abnormality of GnRH cyclicity thus inhibits
gonadotropin release but not its synthesis.
○ The reason for this abnormal secretion of
GnRH is an inhibitory effect of dopamine
and opioid peptides at the level of the
hypothalamus.
○ In addition, elevated PRL levels have been
shown to interfere with the positive
estrogen effect on midcycle LH release.
○ It has also been shown that elevated levels
of PRL directly inhibit basal and
gonadotropin stimulated ovarian secretion
of estradiol and progesterone
● Should measure prolactin levels in all women with
galactorrhea, oligomenorrhea and amenorrhea not
explained by another reason such as ovarian
failure.
Special cases in the Measurement of Prolactin: Hook
Effect and Macroprolactin
● Hook Effect:
○ Because of possible aggregation of
molecular forms of PRL when levels are
high, if a tumor (adenoma) is suspected
and values of PRL are only mildly
elevated, the test should be repeated in a
diluted sample.
○ Explained by high endogenous levels of
PRL binding up all the assay antibodies,
leaving an inadequate quantity for the
assay.
○ Dilute the sample before assay when PRL
levels are unexpectedly low.
●
Opposite occurrence when PRL is found to be
elevated in a woman who is normal clinically.
○ This is due to clumping of glycosylated
PRL with immunoglobulin
○ Can be corrected by gel electrophoresis or
by adding polyethylene glycol to the serum
GALACTORRHEA
● Is defined as the nonpuerperal secretion of watery
or milky fluid from the breast that contains neither
pus nor blood
● The fluid may appear spontaneously or after
palpation
○ Palpate the breast , moving from the
periphery toward the nipple in an attempt
to express any secretion.
● Diagnosis: can be confirmed by observing multiple
fat droplets in the fluid under low power
magnification
●
Incidence of galactorrhea in women with
hyperprolactinemia is ranging from 30% to 80%
CAUSES OF HYPERPROLACTINEMIA
Pathologic causes:
● Prolactinoma
● Acromegaly
● Cushing disease
● Hypothalamic disease
● Various pharmacologic agents
● Hypothyroidism
● Chronic renal disease
● Any chronic type of breast nerve stimulation such
as may occur with:
○ thoracic operation
○ herpes zoster infection
○ Chest trauma
● One of the most common causes of galactorrhea
and hyperprolactinemia is the ingestion of
pharmacologic agents particularly:
○ Tranquilizers
■ Phenothiazines and diazepam
can produce hyperprolactinemia
by depleting the hypothalamic
circulation of dopamine or by
blocking its binding sites —
decreasing dopamine action.
○ Narcotics
○ Antihypertensive agents
■ reserpine
depletes
catecholamines
■
●
●
●
●
●
●
●
methyldopa blocks the conversion
of
tyrosine
to
dihydroxyphenylalanine (dopa)
Tricyclic antidepressants block dopamine uptake
Drugs that block the hypothalamic dopamine
receptor include:
○ Propranolol
○ Haloperidol
○ Phentolamine
○ Cyproheptadine
Ingestion of oral contraceptive steroids can also
mildly increase the levels of PRL, with a greater
incidence of hyperprolactinemia occurring with
older, higher-estrogen formulations.
Galactorrhea does not usually occur during oral
contraceptive ingestion because the exogenous
estrogen blocks the binding of PRL to its receptors
Primary hypothyroidism can also produce
hyperprolactinemia and galactorrhea
○ Reason: because of decreased negative
feedback
of
thyroxine
on
the
hypothalamic-pituitary axis
○ The resulting increase in TRH stimulates
PRL secretion and TSH secretion from the
pituitary
○ Approx. 3% to 5% of individuals with
hyperprolactinemia have hypothyroidism.
○ TSH is the most sensitive indicator of
hypothyroidism and should be measured in
all individuals with hyperprolactinemia.
Hyperprolactinemia can occur in those with
abnormal renal disease resulting from decreased
metabolic clearance and increased production rate.
Mild hyperprolactinemia (30 to 40 ng/mL) may
occur in women with polycystic ovary syndrome
(PCOS).
○ occurs in up to 30% of women and may be
related to the chronic state of unopposed
estrogen stimulation
.
CENTRAL NERVOUS SYSTEM DISORDERS
Hypothalamic Causes
● Diseases of the hypothalamus that produce
alterations in the normal portal circulation of
dopamine can result in hyperprolactinemia.
● These include:
○
○
Craniopharyngioma - most common
infiltration of the hypothalamus by
sarcoidosis, histiocytosis, leukemia, or
carcinoma
● These tumors arise from remnants of Rathke’s
pouch along the pituitary stalk.
● Grossly they can be cystic, solid, or mixed, and
calcification is usually visible on a radiograph.
● They are most often diagnosed during the second
and third decades of life and usually result in
impairment of secretion of several pituitary
hormones
Pituitary Causes
● Various types of pituitary tumors, lactotroph
hyperplasia, and the empty sella syndrome can be
associated with hyperprolactinemia.
● As many as 80% of all pituitary adenomas secrete
PRL.
● The most common pituitary tumor associated with
hyperprolactinemia is the prolactinoma, arbitrarily
defined as a:
○ microadenoma if its diameter is less than 1
cm
○ macroadenoma if it is larger
● Hyperprolactinemia has been reported to occur in
approximately:
○ 25% of those with acromegaly and 10%
of those with Cushing disease,
indicating that these pituitary adenomas,
which mainly secrete growth hormone
(GH) and adrenocorticotropic hormone
(ACTH), often also secrete PRL.
● Hyperplasia of lactotroph occurs in approx. 8% of
pituitary glands examined at autopsy
● Individuals with hyperplasia of the lactotrophs
cannot be distinguished from those having a
microadenoma by any clinical, laboratory, or
radiologic method.
● The diagnosis can be made only at the time of
surgical exploration of the pituitary gland.
● Functional hyperprolactinemia is the term used
for the clinical diagnosis of cases of elevated PRL
levels without imaging evidence of an adenoma.
● Primary empty sella syndrome
○ Another cause of hyperprolactinemia
○ a clinical situation in which an intrasellar
extension of the subarachnoid space
results in compression of the pituitary
gland and an enlarged sella turcica.
○ It results from a congenital or acquired (by
radiation or surgery) defect in the sella
diaphragm that allows the subarachnoid
membrane to herniate into the sella turcica
○ It is usually associated with normal
pituitary
function,
except
for
hyperprolactinemia, although some with
primary empty sella syndrome have a
coexistent prolactinoma
○ Serum PRL levels is < 10 ng/ml
○ Some women with this syndrome have
normal PRL levels, with or without
galactorrhea.
PROLACTINEMIA
● PRL was found in approximately 50% of the glands,
indicating that more than 10% of those in the
general
population
have
an
undiagnosed
prolactinoma.
● Overall, approximately 50% of women with
hyperprolactinemia have a prolactinoma.
● The incidence is higher when the PRL levels
exceed 100 ng/mL, and almost all individuals with
PRL levels greater than 200 ng/mL have a
prolactinoma.
● There is an approximate positive correlation
between the size of the adenoma and the PRL
level.
● Significant elevations in PRL affect menstrual
function and may lead to hypoestrogenism
DIAGNOSTIC TEST
Imaging Studies
● Recommended diagnostic techniques:
○ Computed tomography (CT) scan with
intravenous contrast
■ Beneficial for bony structural
abnormalities
○ Magnetic resonance imaging (MRI) with
gadolinium enhancement
■ Provides better soft tissue
definition, without radiation
■ Provides 1-mm resolution and
thus should be able to detect all
microadenomas
■ It is the recommended imaging
study to obtain
Recommended Evaluation
● PRL levels be measured in all women with:
○ Galactorrhea
○ Oligomenorrhea
○ Amenorrhea who do not have an elevated
FSH level
● PRL is also often measured in the workup of
infertility
● If the PRL level is elevated, a TSH assay should be
performed to rule out the presence of primary
hypothyroidism
● If the TSH level is elevated, T3 and T4 should be
measured to rule out the rare possibility of a
TSH-secreting pituitary adenoma
●
●
●
●
If the TSH level is elevated and hypothyroidism is
present, appropriate thyroid replacement should
begin and the PRL level will usually return to normal
If the TSH level is normal and the woman has a
normal PRL level with galactorrhea, no further tests
are necessary if she has regular menses
If PRL levels are persistently elevated (typically .40
ng/mL) and the TSH level is normal, an MRI
(preferably) or CT scan should be obtained to
detect a microadenoma or macroadenoma
○ Macroadenomas are uncommon and
rarely present with a PRL level less than
100 ng/mL
○ If the PRL level is more than 100 ng/mL or
the woman complains of headaches or
visual changes, the likelihood of a tumor
extending beyond the sella turcica is
increased
○ Microadenomas are a common cause of
hyperprolactinemia and remain stable in
most cases
Routine visual field testing and measurements of
ACTH, GH,and thyroid function are not necessary
unless warranted clinically
TREATMENT
Expectant treatment
● Women
with
radiologic
evidence
of
a
microadenoma or functional hyperprolactinemia
who do not wish to conceive may be followed
without treatment by measuring PRL levels once
annually
● If estrogen is deficient, low estrogen levels in
combination with hyperprolactinemia have been
shown to be associated with the early onset of
osteoporosis
○ Thus exogenous estrogen should be
administered.
● Hormonal therapy, as is used for postmenopausal
women, or oral contraceptives may be used
● Those with hyperprolactinemia, with or without
microadenomas, who have adequate estrogen
levels and who do not wish to conceive should be
treated with periodic progestogen withdrawal
○ Medroxyprogesterone acetate, 5 to 10
mg/day for 10 days each month or
○ With combination oral contraceptives to
prevent endometrial hyperplasia
●
●
●
●
●
Directlystimulates dopamine-2 receptors and, as a
dopamine receptor agonist, it inhibits PRL secretion
in vitro and in vivo
After ingestion, bromocriptine is rapidly absorbed,
with blood levels reaching a peak 1 to 3 hours later
Serum PRL levels remain depressed for
approximately 14 hours after ingestion of a single
dose, after which time the drug is not detectable in
the circulation
○ Therefore the drug is usually given at least
twice daily, with initial therapy being
started at half of the 2.5-mg tablet to
minimize side effects
The most common side effects are orthostatic
hypotension, with an incidence of 15%, which can
produce fainting and dizziness as well as nausea
and vomiting
○ To minimize these symptoms, the initial
dose should be taken in bed and with food
at night
Less common adverse symptoms include
headache, nasal congestion, fatigue, constipation,
and diarrhea
CABERGOLINE
● Cabergoline is a long-acting dopamine receptor
agonist is currently preferred over bromocriptine for
primary therapy because of greater efficacy and
fewer side effects
● This agent directly inhibits pituitary lactotrophs,
thereby decreasing PRL secretion
○ It is given orally in doses of 0.25 to 1 mg
twice weekly
○ The initial dose is half a 0.5-mg tablet
twice a week
○ Peak plasma levels occur in 2 to 3 hours,
and the drug has a half-life of 65 hours.
● The effectiveness of cabergoline was greater than
that of bromocriptine
● A potential concern with cabergoline is the
development of cardiac valvular lesions;
however, this has only been observed with large
doses, as used for Parkinson disease, and has not
been reported with lower doses
Medical treatment of prolactinomas
● The
initial
treatment
for
women
with
macroadenomas, as well as for those women with
hyperprolactinemia who are anovulatory and wish to
conceive, should be the administration of a
dopamine receptor agonist. Cabergoline and
bromocriptine have been used successfully
BROMOCRIPTINE
● Semisynthetic ergot alkaloid, developed in 1967 to
inhibit PRL secretion
Operative Approaches for Prolactinoma
●
●
Transsphenoidal
microsurgical
resection
of
prolactinoma has been widely used for therapy
Numerous reports of large series of individuals
treated by this technique have been published
●
●
Radiation Therapy for Macroadenomas
● External radiation with cobalt, proton beam, or
heavy particle therapy and brachytherapy with
yttrium-90 rods implanted in the pituitary have all
been used to treat macroadenomas but are not the
primary mode of treatment
● The current method of choice is probably the
gamma knife and linear accelerator
○ Results have been inconsistent, and
damage to normal pituitary tissue may
occur, leading to abnormal anterior
pituitary function and diabetes insipidus
○ Damage to the optic nerves may also
occur, which led to the more precise
technique of the gamma knife
● Radiation therapy should be used only as
adjunctive management after incomplete operative
removal of large tumors
Pregnancy and Treatment of Prolactinomas
● Many women with hyperprolactinemia, with or
without adenomas, wish to become pregnant
● A small percentage of these women conceive
spontaneously, but most require treatment to induce
ovulation
● With microprolactinomas, less than 1% had
changes in visual fields, radiologic evidence of
tumor enlargement, or neurologic signs
● 2.7% of women with a microadenoma became
symptomatic, and 22.9% of women with a
macroadenoma were symptomatic
● Women with a microadenoma do not require
treatment during pregnancy, whereas women with
macroadenoma only require treatment if they
become symptomatic
● Testing of visual fields every 3 months should be
carried out in all women with a macroadenoma
● Routine measurements of PRL during pregnancy
have been controversial because of the wide range
of values in pregnancy; however, it has been
suggested that if PRL exceeds 400 ng/mL, this level
should prompt visual field testing in women with an
adenoma
● Although cabergoline is the dopamine agonist of
choice for hyperprolactinemia, bromocriptine is
used in pregnancy because there is a greater
experience with bromocriptine, whereas there is no
evidence of an adverse effect with cabergoline
*** Women with Hyperprolactinoma who do not wish to
conceive
● For women who do not wish to conceive and for
whom galactorrhea is not a problem, no therapy is
necessary unless estrogen levels are low
● Thus to prevent osteoporosis in this clinical
situation,
estrogen-progestogen
hormone
●
replacement or oral contraceptives should be given,
regardless of whether an adenoma is present
Long-term evaluation of all women with
hyperprolactinemia should be carried out
Unless a macroadenoma is present, measurement
of PRL levels once a year is advisable
Repeat imaging studies are unnecessary unless
symptoms of headaches or visual disturbances
occur or PRL levels increase substantially
CHAPTER 38: Androgen
Excess in Women
●
●
●
●
●
●
●
●
●
●
Androgen excess in women
○ elevated androgen levels in blood
○ skin manifestations (acne, hirsutism, and
scalp hair loss or alopecia)
○ but many women exhibit only skin
manifestations
without
demonstrable
findings in blood→ due to lack of sensitivity
of current clinical laboratory assays
Merely having elevated androgens in blood
(hyperandrogenemia), per se, should not be the
target of any treatment.
The pilosebaceous unit (PSU) is composed of a
sebaceous component and pilary component from
which the hair shaft arises.
○ Abnormalities
of
the
sebaceous
component → acne
○ abnormalities of the pilary unit →
excessive growth (hirsutism) or excessive
shedding (alopecia)
2 types of hair:
○ vellus hair- soft, fine, and unpigmented
○ terminal hair-coarse, thick, pigmented, and
undergoes cyclic changes
Androgen is necessary to produce development of
terminal hair
○ duration of the anagen phase is directly
related to the levels of circulating androgen
and determines the length of hair, which
varies in different parts of the body
○ For facial hair it is approximately 4 months
Activity level of the enzyme 5-alpha-reductase
(5a-reductase) most directly influences the degree
of androgenic effect on hair growth.
With elevated levels of circulating androgen or
increased activity of 5a-reductase, terminal hair
appears where normally only vellus hair is present.
With these alterations, the length of the anagen
phase is prolonged and the hair becomes thicker.
Hirsutism:
○ In the milder forms, hair is found only on
the upper lip and chin
○ with increasing severity it appears on the
cheeks, chest (intermammary), abdomen
(superior to the umbilicus), inner aspects
of the thighs, lower back, and intergluteal
areas.
The severity of the hirsutism can be roughly
quantified by a modified scoring system of Ferriman
and Gallwey
○ A score greater than 7 or 8 → only
pertains to the Caucasian or African
American population
○ Greater than 3→ In Asian women
●
●
●
●
●
●
●
●
●
●
Hypertrichosis→ Increased hair growth only on the
extremities or in isolated areas
Virilization is a relatively uncommon clinical finding
and its presence is usually associated with
markedly elevated levels of circulating testosterone
(2 ng/mL).
○ Signs of virilization usually occur over a
relatively short period
○ These signs are caused by the
masculinizing
and
defeminizing
(antiestrogenic) actions of testosterone
and include:
■ temporal balding
■ clitoral hypertrophy
■ decreased breast size
■ dryness of the vagina
■ increased muscle mass
Women with virilization are almost always
amenorrheic.
Suspect androgen-secreting neoplasms → who
develops signs of virilization, particularly if the onset
is rapid
PHYSIOLOGY OF ANDROGENS IN WOMEN
● Androgen production: from glandular tissues,
(ovaries and adrenals) and from non glandular
(peripheral) tissues
● Major androgen produced by the ovaries is
testosterone and that of the adrenal glands is
dehydroepiandrosterone sulfate (DHEAS).
○ Measurement of the amount of these two
steroids in the circulation provides clinically
relevant
information
regarding
the
presence and source of increased
androgen production.
● Conversion
of
androstenedione
and
dehydroepiandrosterone (DHEA) to testosterone
occurs in peripheral tissues
●
●
●
●
●
The ovaries secrete only approximately 0.1 mg of
testosterone/ day, mainly from the thecal and
stroma cells. Other androgens secreted by the
ovary are androstenedione (1 to 2 mg/day) and
DHEA (,1 mg/day)
The adrenal glands, in addition to secreting large
quantities of DHEAS (6 to 24 mg/day), secrete
approximately the same daily amount of
androstenedione (1 mg/day) as the ovaries and less
than 1 mg of DHEA/day.
The normal adrenal gland secretes little
testosterone
Androstenedione and DHEA do not have strong
androgenic activity but are peripherally converted at
a slow rate to the biologically active androgen,
testosterone.
Approximately two-thirds (0.22 mg) of the daily
testosterone produced in a woman originates from
the ovaries
○ Thus increased circulating levels of
testosterone usually indicate abnormal
ovarian androgen production.
For practical purposes, circulatory levels of DHEAS
reflect an adrenal source of production, and in
women more than 95% is adrenal derived
○ Although DHEAS serves as a good marker
of adrenal hyperandrogenism, several
guidelines for the evaluation of androgen
excess in women omit this measurement,
because DHEAS itself is a “weak”
androgen and may not contribute much to
the overall androgenicity.
○ Nevertheless it is our perspective that the
measurement of DHEAS gives a more
complete picture of androgen production.
Occasionally, in women who have increased
production of ovarian DHEA ,such as some with
polycystic ovary syndrome (PCOS), the elevated
levels of DHEAS might have an ovarian component
because DHEA may be converted to DHEAS in the
circulation.
Another specific marker of adrenal androgen
production, used for research purposes, is
11bhydroxyandrostenedione, because the adrenal
primarily has the ability to 11-hydroxylate
androstenedione, whereas the ovary has a limited
ability to do so.
Most testosterone in the circulation (85%) is tightly
bound to sex hormone–binding globulin (SHBG)
and is believed to be biologically inactive.
An additional 10% to 15% is loosely bound to
albumin, with only approximately 1% to 2% not
bound to any protein (free testosterone)
○ Serum testosterone can be measured as
the total amount, the amount that is
believed to be biologically active (unbound,
or non-SHBG bound), and as the free
form.
To exert a biologic effect, testosterone is
metabolized peripherally in target tissues to the
more potent androgen 5adihydrotestosterone (DHT)
by the enzyme 5a-reductase
●
●
●
●
●
●
After further 3-keto reduction, DHT is converted to
another
metabolite,
5a-androstane-3a,17b-diol
(3a-diol).
3a-Diol is conjugated to the sulfate or glucuronide.
The
glucuronide,
5a-androstane-3a,17b-diol
glucuronide (3a-diol-G), is a stable, irreversible
product of intracellular 5a-reductase activity and
reflects this activity in blood
Even with normal circulatory levels of androgen,
increased 5a-reductase activity in the PSU results
in increased androgenic activity, producing
hirsutism
Measurements of 5a-reductase activity in skin
biopsies have found that the level of activity
correlated well with the degree of hirsutism present
3a-diol-G levels can be directly measured in serum
○ the most accurate indicator of the
degree
of
peripheral
androgen
metabolism in women, as long as the
level of glandular production (testosterone)
is appreciated.
●
●
If testosterone and DHEAS are normal but there is
significant hirsutism, then measuring 3a-diol-G may
not be necessary and one may merely assume a
peripheral source of androgen excess
CAUSES OF ANDROGEN EXCESS
● administration of androgenic medication.
○ Testosterone
○ 19-norprogestogen
○ Danazol
● abnormal gonadal development
○ external sexual ambiguity or primary
amenorrhea
○ androgen excess
○ Y chromosome
● during pregnancy - increased ovarian testosterone
production.
○ luteoma of pregnancy→ unilateral or
bilateral solid ovarian enlargement
○ hyperreactio luteinalis→ bilateral cystic
ovarian enlargement
○ After pregnancy is completed, the
excessive ovarian androgenic production
resolves
spontaneously
and
the
androgenic signs regress
“Idiopathic” hirsutism and PCOS are the most
common disorders, together making up more than
90% of cases.
○ PCOS is the most common disorder
Idiopathic Hirsutism (Peripheral Disorder of Androgen
Metabolism)
-
-
-
-
Idiopathic hirsutism is diagnosed when there are
signs of hirsut-ism and regular menstrual cycles in
conjunction with normal circulating levels of
androgens (both testosterone and DHEAS).
Because this type of disorder is often present in
certain families and ethnicities, it has also been
called familial, or constitutional, hirsutism.
Because neither ovarian nor adrenal androgen production is increased, the cause of the androgen
excess has been called idiopathic hirsutism
the cause of hirsutism is largely the result of
increased 5􏰀- reductase activity
TX: Antiandrogens that block peripheral
testosterone action or interfere with 5-RA
Polycystic Ovary Syndrome
most common disorder diagnosed in women
presenting with symptoms and signs of androgen
excess.
women who are anovulatory and have irregular
periods as well as hyperandrogenism, as
determined by signs such as hirsutism or elevated
blood levels of androgens, testosterone, or
DHEAS.
most important feature of PCOS is that it is a
hyperandrogenic disorder
Functional or Idiopathic Hyperandrogenism
- Eu- ropean clinicians; it is considered to occur in up to 15%
of women presenting with hirsutism
Stromal Hyperthecosis
Stromal hyperthecosis is an uncommon benign ovarian
disor- der in which the ovaries are typically bilaterally
enlarged to ap- proximately 5 to 7 cm in diameter.
Like PCOS, this disorder has a gradual onset and is
initially as- sociated with anovulation or amenorrhea
and hirsutism; however, unlike PCOS, with
increasing age the ovaries se- crete steadily
increasing amounts of testosterone.
Androgen-Producing Tumors
Tumors are rare, occurring less than 1% of the time in
women presenting with hyperandrogenism, but they
represent the most important reason for evaluating women
with androgen excess.
Ovarian Neoplasms
Androgen-producing
ovarian
tumors usually
produce rapidly progressive signs of virilization.
the tumor is almost always (􏰉85% of the time)
palpable during bimanual examination
markedly elevated levels of testosterone (more than
2.5 times the upper limits of the normal range), with
normal levels of DHEAS, usually facilitate the
diagnosis.
Adrenal Tumors
Almost all the androgen-producing adrenal tumors
are adenomas or carcinomas that generate large
amounts of the C19 steroids normally produced by
the
adrenal
gland—DHEAS,
DHEA,
and
androstenedione.
computed tomography (CT) scan or magnetic
resonance imaging (MRI) of the adrenal to confirm
the diagnosis
Late or Adult-Onset 21-Hydroxylase Deficiency
Congenital adrenal hyperplasia (CAH) is an inherited disorder caused by an enzymatic defect (usually
21-hydroxylase [21-OHase] or, less often, 11-hydroxylase),
resulting in de- creased cortisol biosynthesis. As a
consequence, adrenocortico- tropic hormone (ACTH)
secretion increases and adrenal cortisol precursors produced
proximal to the enzymatic block accumu- late.
The
steroids
involved
are
mainly
to
17-hydroxyprogesterone and androstenedione, and
androstenedione in turn is converted to
testosterone, which produces signs of androgen
excess
Both classic CAH and LOCAH are transmitted in an
autosomal recessive manner at the CYP21A2 locus
in proximity to the HLA-B locus
Molecular genotyping is primarily used for prenatal
testing when there is a known severe mutation to
determine the risk of having a severely affected
child.
Corticosteroid treatment is normally reserved for patients wishing to conceive to restore ovulatory
function
Cushing Syndrome
Excessive adrenal production of glucocorticoids
caused by in- creased ACTH secretion (Cushing
-
-
disease) or adrenal tumors produces the signs and
symptoms of Cushing syndrome.
Cushing syndrome can be easily excluded by
performing
an
overnight
dexamethasone
suppression test
Late-night salivary cortisol is now consid- ered to be
the most accurate method and is the primary
method of choice.
THE DIAGNOSTIC APPROACH FOR WOMEN WITH
ANDROGEN EXCESS
Women with androgen excess present with acne, hirsutism,
or alo- pecia, and some women have more than one of these
three complaints
Measurements of total testosterone, free (unbound)
testoster- one, or the free androgen index have all
been advocated to assist in the diagnosis of
androgen excess.
the laboratory workup should include an accurate
measure of testosterone (unbound testosterone or
the free androgen index [testosterone/SHBG is
optional]), DHEAS, and 17-hydroxypro- gesterone
when LOCAH is suspected
● Masculinizing ovarian or adrenal tumors are
associated with rapidly progressive signs of
hirsutism and virilization.
● Serum testosterone levels higher than 2 ng/mL,
with normal DHEAS levels, indicate the probable
presence of an ovarian tumor.
● The diagnosis can be confirmed by bimanual pelvic
examination and ultrasonography, CT, or MRI.
● Women with a rapid progression of virilization and
DHEAS levels greater than 8 mg/mL most likely
have an androgen-producing adrenal adenoma;
CT or MRI can confirm the diagnosis.
● Values suggestive of an androgen-secreting tumor
are lower in a postmenopausal woman; values of
testosterone greater than 0.9 ng/mL (90 ng/dL) and
DHEAS levels greater than 4 ug/mL are significant.
● The diagnosis of ovarian stromal hyperthecosis
should be suspected for women with these signs
and testosterone levels greater than 1.5 ng/mL.
● The diagnosis of LOHD is established by
measurement of 17-hydroxyprogesterone, either by
testing of an early morning serum sample or after
ACTH stimulation.
TREATMENT OF ANDROGEN EXCESS
● The most successful disorder to treat is acne
followed by hirsutism and finally alopecia.
Specific Disorders
Ovarian and Adrenal Tumors
● Tumors are best identified by high-grade imaging
techniques.
● Suppression and stimulation tests have not been
beneficial because many tumors are LH responsive
and androgens are suppressed somewhat with OCs
and gonadotropin-releasing hormone (GnRH)
agonists.
● Almost all Sertoli-Leydig cell tumors are unilateral.
●
●
●
●
●
●
●
If the woman has not completed her family and
these tumors are well differentiated and confined to
one ovary, the tumors may be treated by unilateral
salpingo-oophorectomy.
hilus cell tumors
○ occur after menopause
○ treated
by
bilateral
salpingo-oophorectomy
and
total
abdominal hysterectomy.
Adrenal adenomas and carcinomas should also
be treated by operative removal.
Adrenal carcinomas often have metastasized to
the liver by the time the androgenic signs have
developed. Despite chemotherapy, the prognosis is
poor after metastases have occurred.
Stromal hyperthecosis is also best treated by
bilateral salpingo-oophorectomy in older women.
After removal of the ovaries of women with stromal
hyperthecosis or any of the androgen-producing
tumors, the acne and oiliness of the skin disappear, breast size increases, and clitoral size
decreases.
The excess central hair becomes finer and grows
less rapidly but does not disappear.
Electrolysis or laser treatment can remove the body
hair more effectively once the source of PSU
stimulation has been removed.
Late-Onset 21-Hydroxylase Deficiency (Congenital
Adrenal Hyperplasia)
● The androgen excess and menstrual irregularity can
be treated as in women with PCOS, usually with an
OC
● if women wish to conceive, it is preferable to use
glucocorticoids such as hydrocortisone (15 to 20
mg), prednisone (5 to 7.5 mg), or dexamethasone
(0.5 to 0.75 mg) in divided doses.
● Doses as low as 2.5 mg of prednisone or 0.25 mg
dexamethasone may be used initially.
● The
aim
of
treatment
is to suppress
androstenedione and bring 17-hydroxyprogesterone
and progesterone levels into the normal range.
Ovulation usually resumes rapidly.
Polycystic Ovary Syndrome
● lifestyle measures and weight loss will assist in the
treatment of hyperandrogenism in PCOS
Treatment of Skin Manifestations of Androgen
Excess: Hirsutism
● Although ovarian or adrenal androgen excess
increases
the
likelihood
of
complaints,
enhancement of these effects because of increased
5a-RA largely explains the abnormalities.
● Thus a successful strategy usually requires an
antiandrogen added to suppression therapy, usually
with an OC.
● Although it is reasonable to begin with monotherapy
(OC), particularly if the disorder is relatively mild, in
women with more significant complaints and
findings, an antiandrogen can be used initially
●
●
It is important to use antiandrogens in conjunction
with an OC because of the concerns of exposure
during pregnancy.
In women who have “idiopathic” hirsutism and very
mild and localized complaints, it is also reasonable
not to use medical therapy and to use hair removal
alone, as described later.
Oral Contraceptives
● usually prescribed orally, but the effect would be
similar with transdermal or vaginal preparations
● suppress ovarian androgens by inhibiting LH
stimulation of the ovary.
● decrease adrenal androgens (DHEAS) by about
30% and inhibit 5a-RA.
● The potency of ethinyl estradiol in OCs increases
SHBG, which results in lower free or unbound
testosterone.
● it would seem logical to use a less androgenic
progestogen
(norgestimate,
desogestrel,
drospirenone) than more androgenic ones
(levonorgestrel)
● The increased risk with the less androgenic OCs is
relatively small, and the absolute risk of thrombosis
in young women is also rare and less than that of
normal pregnancy. It is important, however, to use
lower-dose estrogen products (20 mg).
● obesity is an additional risk for thrombosis, and thus
lifestyle management is important, particularly in
women with PCOS.
Antiandrogens
● Peripheral androgen blockade with antiandrogens is
dose related.
● Receptor blockade with spironolactone and
flutamide and a specific 5a-2 inhibitor, finasteride,
are the agents most commonly used.
● Cyproterone acetate (2 mg), which is a
progestogen, is most often used in combination with
ethinyl estradiol as an OC
● Drospirenone in the doses used in contraceptives
(3 mg) does not have appreciable antiandrogenic
activity and is estimated to have an equivalent
effect of 10 mg of spironolactone.
● Spironolactone
○ treatment of choice for women with
idiopathic hirsutism, as well as many with
PCOS
○ an androgen receptor blocker
○ decreases ovarian testosterone production
and inhibits 5a-RA.
○ 200 mg/day of spironolactone is more
effective than 100 mg/day
○ With the higher dose of spironolactone,
liver function test results and plasma
electrolyte levels are usually unchanged,
and side effects occur infrequently, except
for irregular uterine bleeding.
○ The latter can be controlled with
concomitant use of OCs.
○ Electrolytes and blood pressure should be
monitored for the first few weeks of
●
●
●
therapy to ensure that hypotension and
hyperkalemia do not occur.
Flutamide
○ pure androgen blocker that has shown
efficacy in the treatment of hirsutism.
○ There is a dose-response relationship (250
to 750 mg/day), and even lower doses
have some efficacy;
○ the major concern is hepatic toxicity
Finasteride
○ a 5a-reductase inhibitor (5 mg/day)
○ an effective treatment for hirsutism
○ 5 mg has similar efficacy as 100 mg of
spironolactone
○ specific 5a-2 inhibitor (there are two
isoenzymes for 5a reductase: 1 and 2)
○ hirsutism is likely a combination of both
types 1 and 2
○ second-line treatment when there are side
effects
or
problems
with
using
spironolactone.
Dutasteride
○ an inhibitor of enzyme types 1 and 2
○ clinically available for use in men.
Other Agents for Treatment
● GnRH agonist with estrogen or an OC add-back
○ For severe cases
○ expensive and cannot be used for
long-term therapy.
○ It has been used in women with high levels
of circulating androgens.
● Ketoconazole
○ blocks adrenal and gonadal steroidogenesis
by
inhibiting
cytochrome
P450–dependent enzyme path- ways,
○ 200 mg, twice daily - to treat
hyperandrogenism associated with PCOS
and idiopathic hirsutism.
○ decreases hair growth and acne
○ but major side effects and complications
(including hepatitis) occur in most women
so treated.
● Glucocorticoids
○ treatment of androgen excess
○ Because of its potential for serious side
effects,
glucocorticoids
are
not
recommended for treating androgen
excess but may be considered as an
adjunct to ovulation induction in some
women.
● Insulin sensitizers
○ have been proposed as agents to treat
androgen excess and have been used in
women with PCOS.
● Eflornithine cream 13.9%
○ topical treatment for facial hirsutism.
○ inhibitor of ornithine decarboxylase, which
is an enzyme necessary for the growth and
development of the hair follicle.
Follow-up for Treatment of Hirsutism
●
●
Because of the length of the hair growth cycle,
responses to treatment should not be expected to
occur within the first 3 months of therapy, and it
usually takes about 6 months to see a response.
Remaining excess hair can be removed by
electrolysis or laser techniques. Treatment should
be continued for 3 years and then stopped to
determine whether hirsutism recurs. If so, therapy
can be reinitiated.
Hair Removal Techniques
● can be used as a primary treatment for mild isolated
hirsutism or should be initiated after adequate
suppressive therapy to remove unwanted hair once
the growth rate has been inhibited by therapy.
● Electrolysis uses electrical energy through a wire
electrode. Destruction of hair follicles results in its
permanent removal.
● Photoepilation uses lasers that apply heat to
pigmented hair follicles.
● Four types of lasers: Nd:YAG, diode, alexandrite,
and ruby, and a meta-analysis suggested
superiority of the diode laser.
● Long wavelength, long pulse duration lasers such
as the Nd:YAG or diode are recommended for
pigmented darker hair.
● For women with light or blond hair, electrolysis is
recommended.
Acne Vulgaris
● Acne vulgaris is a manifestation of androgen
excess, although it need not be, and particularly in
adolescents it merely reflects the physiologic
responses of the PSU to the changing hormonal
status and alterations in the bacteriologic flora.
● androgens stimulate sebum production, and
high doses of estrogen can inhibit it.
● Among hyperandrogenic disorders, acne vulgaris is
the disorder that is most successfully treated.
● Among women who present with acne, 52% can be
found to have androgen excess, with increases in
unbound testosterone being the most frequently
encountered
● An enhancement of 5a- reductase, mostly type 1,
is a large part of the androgen abnormalities in acne
● Treatment is usually with combination OCs, which is
at least as effective as chronic antibiotic therapy.
● Among OCs, less androgenic progestogens have
been preferred.
● The estrogen component of the contraceptive pill
inhibits sebum production, although it usually does
not require increasing ethynyl estradiol greater
than the 35-mg dose.
● Although most antiandrogenic agents are effective
(Fig. 38.12), OCs and pure antiandrogens are
superior to finasteride.
● If OCs alone are not completely successful, as with
hirsutism, the addition of antiandrogens are
beneficial.
Alopecia: Female Pattern Hair Loss
● Previously called androgenic alopecia
●
●
●
●
●
●
●
●
●
This may or may not be associated with androgen
excess.
Hair loss is usually on the frontal scalp and vertex,
with relative sparing of the occipital scalp.
Androgen excess, perhaps estrogen abnormalities,
and genetics play into the cause.
With androgen excess, exaggerated 5a-RA has
been implicated in women with alopecia
Antiandrogen therapy is the mainstay of
treatment.
In women, spironolactone and flutamide (to be
used with caution) have efficacy; however,
finasteride, which is used widely in men, may not
be effective in women
Minoxidil is also used to stimulate hair growth.
combination of minoxidil with an antiandrogen is the
most effective treatment for FPHL
genetic manipulations and stem cell therapy may
prove to be beneficial.
POLYCYSTIC
SYNDROME
●
●
●
●
●
●
●
●
●
●
●
Phenotype C
○ Hyperandrogenism and polycystic ovaries
in ovulatory women
Phenotype D
○ irregular cycles and polycystic ovaries in
the
absence
of
documented
hyperandrogenism
Androgen Excess and Polycystic Ovary Syndrome
(AEPCOS) Society definition:
○ hyperandrogenism as a key feature
○ recognizes that women with PCOS can
have polycystic ovaries on US or
menstrual irregularity (anovulation)
OVARIAN
most
common
endocrine
disorder
in
reproductive-age women
first described in 1935 by Stein and Leventhal as a
syndrome consisting of amenorrhea, hirsutism, and
obesity in association with enlarged polycystic
ovaries
NIH definition: diagnosis does not require findings
on ultrasound (US) of characteristic polycystic
ovaries
Classic features:
○ signs of elevated androgens
■ hirsutism, oligomenorrhea or
amenorrhea
○ present in as many as 15% to 20% of
reproductive-age women
diagnosis is usually made after the exclusion of
other causes of irregular cycles and elevated
androgens
Rotterdam Criteria (ESHRE/ASRM):
○ Menstrual irregularity
○ symptoms of findings of hyperandrogenism
○ polycystic ovaries on US
○ 2 out of three = PCOS
Phenotype A
○ classic phenotype
○ includes all 3 criteria with US findings of
polycystic ovaries
Phenotype B
○ denotes women with the NIH definition
when there are no US findings
●
●
Diagnosis of PCOS is made on a clinical basis
laboratory measurements can be supportive but are
not necessary
OVARIAN MORPHOLOGY
● US findings of polycystic ovaries:
○ classic definition required 12 or more
peripherally oriented cystic structures (2-9
mm) in one sonographic plane, and
typically the finding in one ovary is
sufficient
○ the total follicle count in each ovary
that is most diagnostic
○ Ovarian volume: 10 mL or more is
diagnostic
○ Follicle number per ovary (FNPO) should
be 19-20 or 22
○ Anti-mullerian hormone (AMH) >4.7
ng/mL - surrogate marker of FNPO for the
diagnosis of PCO; not diagnostic as US;
levels vary
● Polycystic-appearing ovaries (PAO), polycystic
ovarian morphology (PCOM) or simply PCO
○ 10-25% of the normal reproductive-age
population (no S/Sx of PCOS) may have
polycystic ovaries found on US.
DIAGNOSIS IN ADOLESCENCE
● Rotterdam criteria should not be used
○ because all the 3 criteria for the diagnosis
are in a state of flux and change during
adolescents, including the evolution and
disappearance of polycystic ovaries
● PCOS should not be diagnosed unless all three
criteria are firmly in place and at a minimum of 3
years postmenarche
● For the ovarian US criterion, because abdominal
US is the mainstay, ovarian volumes of 10 mL or
greater should be the criterion used
MENSTRUAL IRREGULARITY
● includes oligomenorrhea (cycles longer than 35
days) and a menstrual frequency of every few
months and frank amenorrhea (longer than 6
months missed).
● been reported that menstrual irregularity is the
best correlate of insulin resistance in women
with PCOS
ANDROGEN EXCESS (HYPERANDROGENISM)
● cardinal feature of women with PCOS
● may be difficult to diagnose
● production of androgens in excess may emanate
from the ovary, the adrenal gland, or the periphery
● symptoms of androgen excess, particularly of
hirsutism, are sufficient for the inclusion of this
parameter in the diagnosis of PCOS
● blood measurements of testosterone may not
always be accurate and often are normal in women
with symptoms
● androgen excess has been implicated in
contributing to abnormalities in LH secretion, weight
gain and adipose deposition and the metabolic
derangements of PCOS
● 11-oxygenated androgens (derived from the
adrenal) - quantitatively the most abundant
androgens in women with PCOS
● Adipose tissues also secrete androgen - seems
to contribute to lipid abnormalities and insulin
resistance in women with PCOS
CHARACTERISTIC ENDOCRINE FINDINGS
● abnormal gonadotropin secretion caused by
increased gonadotropin-releasing hormone (GnRH)
pulse amplitude or increased pituitary sensitivity to
GnRH
○ result in tonically elevated LH levels in ~⅔
of the women
● After a bolus of GnRH, there is usually an
exaggerated response of LH but not of FSH
● typically the women with PCOS who are more
obese will be found to have normal LH levels
● women with PCOS who are thin often have
elevated levels
● high tonic levels of LH (“inappropriate gonadotropin
secretion)
○ due to elevated androgen & unbound
estradiol
or
hypothalamic/pituitary
●
●
●
●
●
●
●
●
●
●
functional
abnormalities
related
to
neurotransmitters such as dopamine
FSH levels in women with PCOS are normal or low
An elevated LH level or an elevated LH/FSH ratio
is neither specific for nor required for the
diagnosis of PCOS
○ These measurements should not be used
as diagnostic tools
↑ amount of non–SHBG-bound estradiol is caused
by a ↓ in SHBG levels, which is brought about by
the ↑ levels of androgens and obesity, with ↑ insulin
levels present in many of these women
Estrone is also ↑ because of ↑ peripheral (adipose)
conversion of androgen
tonically ↑ levels of biologically active estradiol may
stimulate ↑ GnRH pulsatility and produce tonically↑
LH levels and anovulation
Relative hyperestrogenism
○ lowered SHBG level increases the
biologically active fractions of androgens in
the circulation
○ elevated
levels
of
estrone
and
non–SHBG-bound
estradiol
often
unopposed by progesterone because of
anovulation
○ increases the risk of endometrial
hyperplasia
■ enhanced further in some women
with PCOS who seem to have
progesterone resistance
○ progesterone does not work as well in
downregulating the actions of estrogen on
the endometrium
Androgens from a variety of sources are elevated in
women with PCOS
○ Serum testosterone levels usually 0.55-1.2
ng/mL
○ androstenedione levels usually 3-5 ng/mL
almost all women with PCOS have elevated levels
of circulating androgens, the presence or absence
of hirsutism depends on whether those androgens
are converted peripherally by 5-alpha-reductase to
the more potent androgen dihydrotestosterone
(DHT) reflected by increased circulating levels of
3-alpha-androstanediol glucuronide (3a-diol-G)
Women with PCOS who are not hirsute have
elevated circulatory levels of testosterone,
DHEAS, or both, but not 3a-diol-G
~20-30% of women with PCOS also have mildly
elevated levels of prolactin (20 to 35 ng/mL)
○ related to the ↑ pulsatility of GnRH, as a
result of a relative dopamine deficiency or
tonic stimulation from unopposed estrogen
INSULIN RESISTANCE
● Insulin and insulin-like growth factor 1 (IGF-1)
enhance
ovarian
androgen production by
potentiating the stimulatory action of LH on ovarian
androstenedione and testosterone secretion.
● High levels of insulin bind to the receptor for IGF-1
(significant homology of the IGF-1 receptor with the
insulin receptor)
●
●
●
●
●
●
●
●
●
●
●
Granulosa cells also produce IGF-1 and
IGF-binding proteins (IGFBPs) → result in paracrine
control and enhancement of LH stimulation and
production of androgens by the theca cells in
women with PCOS
IGFBP levels are lower in women with PCOS,
increases bioavailable IGF-1, increases stimulation
of the theca cells in combination with LH to produce
higher levels of androgen production
elevated insulin levels (as well as androgen)
○ stimulate
adipocyte
production
of
adipokines (adipocytokines),
■ interfere with the metabolism and
breakdown of adipose tissue
■ further enhance IR
IR in PCOS
○ primarily characterized by an insulin
resistance in peripheral tissues, manifest
primarily in muscle and adipose and
minimally at the level of ovary or adrenal
reflects these events with the less efficient
serine phosphorylation (rather than
tyrosine phosphorylation)
■ resulting in less efficient insulin
action (metabolic effect)
■ but with no effects on the
production of androgens (intact
mitogenic effect)
■ Androgen enhances this effect,
intensifying interaction
The proximate cause of IR in PCOS is unknown;
○ not caused by insulin receptor defects but
by signaling abnormalities
○ genetic factors contribute to these findings.
Most women with PCOS will be found to have
euglycemia with peripheral IR
In more severe cases
○ evidence
of
beta cell (secretory)
dysfunction, which increases the risk of
type 2 diabetes. .
The negative effects of obesity and PCOS on
insulin resistance are additive.
Although clinicians may assume most women with
PCOS have some degree of IR, particularly those
who are older and who are overweight or obese
○ it is recommended that testing should be
directed at ruling out diabetes and
glucose
intolerance,
rather
than
diagnosing IR
Fasting glucose levels are a poor predictor of
diabetes in PCOS.
A convenient way to assess glucose status is the
measurement of the level of hemoglobin A1C.
○ Values greater than 5.8% suggest
prediabetes
○ Values greater than 6% suggest frank
diabetes
●
●
●
Various techniques have been used to diagnose IR
in women with PCOS
○ it can be argued that women who are
overweight or obese with PCOS have IR,
and it is not necessary to confirm it.
○ methods include fairly complicated but
more accurate measures used only in a
research setting:
■ clamp test
■ intravenous frequent sampling
glucose tolerance test
■ Insulin tolerance test.
Using fasting glucose and insulin measurements
and calculating the quantitative insulin sensitivity
check index (QUICKI) or homeostasis model
assessment of insulin resistance (HOMA-IR)
○ have been useful and correlate well with
the more invasive technique
■ It may not be necessary to
compute these parameters and
clinicians should assume that
women who are overweight or
obese with PCOS are insulin
resistant
■ an oral glucose tolerance test
should be carried out to rule out
impaired glucose tolerance or
diabetes, which cannot be
assumed or discounted.
If fasting blood is obtained to detect IR, HOMA
or QUICKI are the most valuable parameters
ANTIMÜLLERIAN HORMONE IN PCOS
● Müllerian-inhibiting substance (MIS) or AMH
○ a glycoprotein produced by the granulosa
cells of preantral follicles.
● Because of the larger number of preantral follicles
in PCOS, the MIS or AMH level is significantly
elevated in women with PCOS.
● Physiologically, AMH attenuates a sensitivity of
FSH in stimulating granulosa cells
○ levels are higher in clomiphene-resistant
women and in those who are chronically
anovulatory compared with those with
more regular cycles, even as they age
●
AMH levels have also been positively correlated
with LH levels.
● AMH is involved in the pathophysiology of
anovulation in PCOS,
○ some of the hereditary nature of women
with PCOS.
○ higher levels of AMH in amniotic fluid
program the fetus in utero to have higher
LH and androgens and dysregulate the
hypothalamic-pituitary-ovarian
axis,
resulting in the development of PCOS
● Because AMH correlates with the number of
ovarian preantral follicles,
○ AMH may be used as a blood test to
substitute for US findings of a polycystic
ovary.
○ cutoff value of 4.7 ng/mL with values
greater than this being consistent with
PCOS
■ degree of overlap in values of
AMH between PCOS and normal
women precludes its routine use
■ milder phenotypes such as C and
D have lower levels of AMH
PATHOPHYSIOLOGIC CONSIDERATIONS
● genetic predisposition to PCOS
○ several genes are involved
■ are susceptibility genes that
predispose the women affected to
develop PCOS.
● A review by Kosova and Urbanek
○ pointed out the many difficulties in finding
a direct genetic linkage, which are related
to the nature of the disorder, its
heterogeneity, and the large sample size
required to find meaningful associations
○ multiple family studies of sisters, brothers,
and daughters of affected women all
showing some traits associated with
aspects of PCOS.
● Environmental factors are clearly involved
○ in which PCOS is not always concordant
on a genetic basis
● Maternal exposure to androgen (monkey model)
○ to contribute to the development of PCOS
○ Tata and colleagues
■ where
the
pregnancy
environment, related to AMH may
also be implicated.
● Genome-wide association studies in Han Chinese
and European families
○ susceptibility genes with some consistency
○ loci at 2p16.3, 2p21, and 9q 33.3
○ LH/human chorionic gonadotropin (HCG)
receptor
■ a thyroid adenoma locus,
○ DENND1A, potentially affecting function of
the endoplasmic reticulum.
● It has been long established that a vicious cycle
propagates the disorder in PCOS, regardless of
how it begins (Strauss, 2009)
○
●
●
●
●
●
●
●
●
●
●
dopamine
deficiency
in
the
hypothalamus
■ might give rise to the exaggerated
LH responses in PCOS
○ It has been observed that morphologically
identifiable polycystic ovaries are seen in
children
○ adolescent, ovarian morphology has been
shown to be variable and can change from
being polycystic to normal and viceversa.
■ This occurrence predicts puberty
and other normal endocrinologic
events, suggesting a central role
for altered PCOM in the disorder.
Not all women with isolated polycystic ovaries have
PCOS
An ovary is polycystic in up to 20% of girls (Bridges
and colleagues)
○ ovary transitions early in life from normal to
polycystic appearing (PAO).
○ This influence occurs in a specific way by
genetic factors or environmental factors, or
it is induced by other endocrine
disturbances (Lobo, 1996).
PAO
○ normal menses
○ normal androgen levels
○ normal ovulatory function and parity
○ if subjected to various susceptibility factors
(likely genetic) or environmental or other
challenges or insults, with varying degrees
of severity
○ may develop a full-blown syndrome
(PCOS)
○ if full-blown, exhibits the full extent of
hyperandrogenism and anovulation, with
the most extreme form of this menstrual
disturbance being amenorrhea
■ the type A or B phenotype
according to Rotterdam criteria
In this spectrum of disorders, the androgen
disturbances may also be near normal.
Menstrual disturbance may be mild.
requires that normal homeostatic factors may be
able to ward off stressors or insults in some women
who can go through life without PCOS but have
PAO, which does not change morphologically.
a woman’s homeostatic mechanisms may at any
time, early or later in reproductive life, allow
symptoms of PCOS to emerge with varying degrees
of severity.
Two of the major insults:
○ weight gain
○ psychological stress
typical teenager born with PAO may develop PCOS
fairly quickly
PCOS picture may only develop later in life in some
women, even after having children, with weight gain
Consequences of Polycystic Ovary Syndrome
●
●
The importance of diagnosing PCOS is that there
are known long-term consequences of the
diagnosis warranting lifelong surveillance:
○ metabolic and cardiovascular risks
○ risk of certain cancers with aging.
With aging, concerns for cardiovascular disease
(become more prominent):
○ Hypertension
○ Metabolic syndrome
○ Diabetes
○ Cancer (endometrial and ovarian)
WEIGHT GAIN/OBESITY AND METABOLIC SYNDROME
● Weight gain as women age
○ major predictor of abnormal metabolic
findings
○ emergence of cardiovascular (CV) disease
risks
○ all the symptoms of PCOS are worse
with increasing body weight.
● The prevalence of obesity varies widely in different
countries.
○ It is lowest in countries such as China and
Japan (10%)
○ highest in the United States and some
other Western countries (70%)
● There is increased abdominal and visceral fat in
women with PCOS
○ correlated to IR and metabolic dysfunction
(Lord, 2006).
● lifestyle management has to be a priority for
women with PCOS and must be maintained
lifelong.
● Metabolic syndrome
○ largely driven by obesity
○ leads to diabetes and CV disease (CVD)
○ has a prevalence during the reproductive
years
● The prevalence of metabolic syndrome in the
United States is approximately 60% in young (20 to
39 years) obese women with PCOS (Apridonidze,
2005).
● The diagnosis is made using Adult Treatment
Panel III criteria (three of five of the following:
○ waist circumference .88 cm
○ high-density lipoprotein ,50 mg/dL
○ triglycerides .150 mg/dL
○ blood pressure .130/85 mm Hg
○ fasting blood sugar .110 mg/dL
● prevalence of metabolic syndrome in PCOS is still
increased but is much lower (5% to 9%)
● constellation of risk factors that make up metabolic
syndrome place women with PCOS
○ at increased risk for CVD and diabetes,
○ but there is nothing specific of more
significance regarding metabolic syndrome
in PCOS.
DIABETES
● Type 2 diabetes mellitus is more prevalent (two to
three times higher) in women with PCOS of
reproductive age (Legro, 1999).
○
●
●
●
●
driven by IR, worsened by:
■ overweight status
■ menstrual irregularity
it is extremely important to screen for diabetes
in the overweight population with PCOS
○ best done with an oral glucose tolerance
test
Lack of precision in the screening for diabetes with
hemoglobin A1c measurements
○ precluded the recommendation of using
hemoglobin A1c as a screening tool
○ proven to be useful in the follow-up of
women as they are being treated.
Diet and exercise remain the mainstays of
treatment
Metformin has a significant role to play.
○ In at-risk women
○ glucose intolerance
○ prediabetes
○ often used with doses of 1500 mg/day
○ Doses are often higher in the presence of
diabetes
QUALITY-OF-LIFE ISSUES
It is generally stated that there is poor quality of life among
women with PCOS, most likely related to:
➔ burden of being overweight,
➔ having irregular cycles and decreased fertility,
➔ and having skin concerns (acne and hirsutism)
➔ although not all women have the same number or
degree of these symptoms
●
●
●
●
Depression - factor which may play a major role
in women with PCOS seeking care and being
compliant with diet, lifestyle, and various
treatments - fourfold increase among women with
PCOS
Anxiety disorder is also prevalent, with a two- to
threefold increase
Strong argument has been made for screening
women with PCOS for anxiety and depression
Interventions such as weight loss, are able to
improve quality of life
CARDIOVASCULAR CONCERNS
➔ Women with PCOS have characteristic lipid and
lipoprotein abnormalities
➔
➔
➔
➔
➔
➔
Abnormal lipoprotein particles are also present =
increase CV risk
Women with the milder phenotypes diagnosed
using the Rotterdam criteria have fewer CV risk
factors.
There are no definitive data on whether PCOS
increased CV mortality
Although multiple risk factors are present (IR, lipids,
adipocytokines, inflammatory markers, surrogate
markers of atherosclerosis on imaging) retrospective analyses have shown no increase
in mortality, except among women with diabetes
2018 reassessment - unless a woman with PCOS
has “classic” features of PCOS and has
diabetes and obesity, there is no evidence for
increased CV morbidity and mortality in women
with PCOS
Because of the large constellation of risk factors
and lack of adverse outcome data, it could be
hypothesized that there may be some inherent
protective factors in PCOS
CANCERS IN POLYCYSTIC OVARY SYNDROME
➔ There is an age-specific onset for some of the
consequences of PCOS
➔ Risk for all cancers increases with aging, but
endometrial cancer can begin at a younger age
because of long-term anovulation and unopposed
estrogen stimulation of the endometrium
➔ Breast cancer does not seem to be increased in
women with PCOS, both endometrial and ovarian
cancer are increased
➔ data for these are negatively affected by the
heterogeneity of the patient population and their
retrospective nature and most pertain to women
diagnosed with classic PCOS
➔ It is likely that women with milder phenotypes may
have little or no increased risk
➔ Endometrial cancer is increased at least two- to
threefold, even when controlling for weight (due to
unopposed estrogen, and possible defect in
progesterone signaling in the endometrium among
cancer patients
➔ Data are less strong for ovarian cancer, but the
risk is thought to be about 2.5 times increased level of risk can be brought down to a normal rate
with the use of oral contraceptives (OCs)
➔ Decreased risk of these cancers with the use of
OCs for about 5 years is well known and translates
into a good strategy for normalizing cancer risk in
women with PCOS - because many women
normally would be treated with OCs in any event for
other symptoms
➔ Metformin
◆ used for women with PCOS
◆ has inhibitory effects on various
cancers
◆ data are strongest for endometrial and
breast cancer
➔
➔
➔
three main categories of complaint:
◆ androgen excess and symptoms of
hyperandrogenism;
◆ irregular bleeding (dysfunctional uterine
bleeding) and risks of endometrial disease
as a result of unopposed estrogen
stimulation from anovulation;
◆ fertility concerns and subfertility mostly because of anovulation
Common complaint is weight gain or the inability to
lose weight - related to IR and metabolic concerns
Regardless of complaints, lifestyle management is
an extremely important component of any
treatment regimen
Androgen excess
➔ acne, hirsutism, and alopecia
➔ occurs in the majority of women with PCOS, but not
in all women
➔ symptoms are sufficiently mild
➔ treatment involves the use of an OC, with or without
an antiandrogen
OVARIAN AGING: POLYCYSTIC OVARY SYNDROME
AND MENOPAUSE
➔ With aging, ovaries decrease in size and androgen
levels decrease as women - true for those with
PCOS as well
➔ Some juncture in time, the phenotype of PCOS
may change or disappear
➔ As women with PCOS age, their menstrual
cycles, if irregular when younger, become more
regular and ovulatory - because of a decrease in
the total follicular cohort and subsequently lower
levels of AMH
➔ By the fourth decade nearly half of the women had
evidence of ovulatory function, and in 8% the
diagnosis of PCOS could no longer be made
➔ There may be preserved fertility in women with
PCOS as they age - confirmed in one retrospective
study in an in vitro fertilization (IVF) model, in which
the live birth rate was higher at an older age
compared with women with tubal disease
➔ As women enter menopause (despite lowered
androgen levels) hirsutism may still be prevalent
➔ There is a persistence of the metabolic issues
that existed at an earlier age requiring continued
vigilance in managing and following these women
ISOLATED POLYCYSTIC OVARIES
➔ Women with normal ovulatory function and PAO or
PCOM have a subtle form of ovarian
hyperandrogenism
when
stimulated
with
gonadotropins or HCG
➔ (+) subtle changes in insulin sensitivity and altered
lipoproteins - considered as a risk factor for
developing the consequences of PCOS
TREATMENT OF POLYCYSTIC OVARY SYNDROME
➔ should be directed at the specific complaint
Irregular bleeding
➔ Treatment should be directed at supplying the
missing progesterone in anovulatory women
➔ Potentially can lead to endometrial hyperplasia or
cancer if not treated.
➔ Women who are overweight and older are a
higher-risk group, and endometrial biopsy may
be indicated
➔ Most have menstrual irregularity who have IR and
are more likely to have metabolic dysfunction
➔ Oral contraceptives (OCs)
◆ most logical and effective treatment,
particularly because they reduce the risk of
endometrial cancer
◆ may also be indicated for treatment of
symptoms of androgen excess
➔ Progestogen therapy
◆ can be used for other women;
◆ may be used at 2- to 3-month intervals to
shed the endometrium in chronically
anovulatory women
◆ medroxyprogesterone acetate (5 to 10 mg)
or norethindrone acetate (2.5 to 10 mg)
may be used in this setting
➔ More complicated cases of menometrorrhagia are
treated, as would other patients.
Fertility concerns and subfertility
➔ Treatment is predominantly a result of
anovulation
➔ women with the ovulatory phenotype C may have
subtle ovulatory disturbances
➔ Some women have endometrial defects in
progesterone and insulin signaling
➔ Before treatment with ovulation induction - rule out
other fertility factors, specifically male factors
by obtaining a semen analysis
TREATMENT OF SUBFERTILITY IN POLYCYSTIC OVARY
SYNDROME
Before ovulation induction:
normalize overt abnormalities in glucose tolerance
encourage weight loss for overweight women
➔
Ovulation induction may be accomplished by a
variety of agents, including:
➔
➔
➔
metformin, clomiphene, letrozole, gonadotropins,
and pulsatile GnRH, as well as ovarian diathermy or
drilling
Adjunctive measures include use of:
dexamethasone,
dopamine
agonists,
thiazolidinediones, and various combinations
-today these agents are rarely used
IVF (stimulated or unstimulated) may be indicated in
difficult-to-manage cases or if other in fertility
factors are present
Although metformin had been used as a first-line
treatment for infertility - clomiphene is superior to
metformin for first-line therapy
IVF
●
●
●
●
for women who fail to conceive with ovulation
induction over six cycles
those with other infertility factors
only caveat to IVF treatment in women with
PCOS is the higher-than-normal risk of OHSS
(always in mind: significant dose adjustments in the
treatment regimen, and using antagonist cycles,
possibly metformin (when indicated), and the GnRH
agonist trigger)
frozen embryos transfer has been shown to be
more successful than fresh embryo transfers because of an exaggerated endometrial response
to medications used during IVF
Metformin:
➔ if overweight or with obesity to achieve better
metabolic control before pregnancy
➔ if with more casual approach to their fertility
(metformin takes longer to become effective and
may not induce ovulation in some women)
➔ even if it cannot induce ovulation - continued use
may be beneficial when combined with clomiphene
or gonadotropins
➔ improvement in oocyte quality has been suggested,
but the effect has not been proved
➔ decrease the risk of ovarian hyperstimulation
syndrome (OHSS) in women with PCOS
undergoing IVF
Clomiphene
● Mainstay for ovulation induction
● Most pregnancies occur within the first few cycles
● reasonable to use, with or without metformin, as an
initial approach, after obtaining a semen analysis,
but not for more than three or four ovulatory cycles
before a more comprehensive workup is undertaken
Letrozole
● 2.5 to 5 mg/day, 5 days
● efficacious as an alternative to clomiphene
● suited for women who have side effects with
clomiphene
● randomized head-to head comparison: letrozole
was found to be superior - confirmed in a
Cochrane review
● cost analysis: letrozole to be more cost effective establishing its place as first-line treatment for
women with PCOS
Low-dose gonadotropin therapy
● highly effective as a second-line treatment
● for failure with oral agents
● for patient who may have transitory low estrogen
status
● no evidence that any one gonadotropin preparation
is better than another
Pulsatile GnRH therapy
● rarely used, primarily because its use is
cumbersome and less effective in PCOS compared
with its use for hypothalamic amenorrhea
Ovarian drilling (diathermy)
● a reasonable second-line therapy
● particularly in clomiphene failures and when
gonadotropin therapy has proved difficult
● resulted in similar pregnancy rates (against
standard gonadotropin therapy) but with a lower
rate of multiple pregnancies
● rarely carried out - in part because of cost concerns
METABOLIC AND WEIGHT CONCERNS
➔
➔
➔
Key management strategy = altering lifestyle
variables
Exercise regimens - when coordinated with a group
of similar women, have been shown to be beneficial
This approach should be part of all therapies for
PCOS - acknowledging that some women with
PCOS who are thin or normal weight probably
already have a healthy lifestyle
Metabolic syndrome (MBS)
➔ Driven largely by weight
➔ Usually treated by a combination of diet and
metformin
➔ Six- to 12-month therapy = reduce weight by 5% to
7%, as well as to reduce insulin resistance and
improve metabolic parameters
Bariatric surgery
➔ Used in women with PCOS and obesity
➔ Most of the symptoms of PCOS were found to
disappear after surgery
➔ Carries risks and should not be considered as
first-line therapy.
Antiandrogens (specifically flutamide)
● may also be efficacious for reducing body weight
and visceral fat in women with PCOS
● combination
of
drospirenone
and
17a-ethinylestradiol (EE2) with flutamide and
metformin also has been used successfully in
adolescents - this multidrug regimen has not been
tested in an adult population
Improvement of lifestyle variables (weight reduction and
fitness) - should be the mainstay of all treatments