Disorders of the ovaries

Anatomy of the ovaries

 Histology of the ovaries
• Germinal epithelium
• Tunica albuginea
• Cortex:
¾ Follicular structures in all stages of development
¾ Hilar cells (interstitial cells)
¾ Stroma (connective tissue elements)
• Medulla:
¾ Stroma (connective tissue elements)
 Hormones of the ovary
• Estrogens
• Progesterone
• Androgens
• Hormone precursors
• Other:
¾ Inhibin
¾ Activins
¾ Relaxin
¾ Locally active agents (prostaglandins, follistatin)
 P450scc
Cholesterol Pregnenolone

3βHSD/ISOM P450c17

Progesterone 17α-Hydroxypregnenolone

P450c17 P450c17

17α-Hydroxyprogesterone 17KR
DHEA Androstenediol
P450c17 3βHSD/ISOM 3βHSD/ISOM
17KR
Androstenedione Testosterone
ARO ARO
16OH 17KR
16α -Hydroxyestrone Estrone 17β-Estradiol

Estriol

Biosynthesis of estrogens and progesterone

 Places of estrogen formation
• Theca interna cells
• Granulosa cells
• Corpus luteum
• Placenta
• Blood (aromatization of androstenedione)
• Liver
• Adipose cells, skin
• Adrenal glands
 Biological activity of estrogens
• Development of ovarian
follicles
• Stimulation of oviduct
motor activity
• Enlargement of uterus
blood flow
• Enlargement of uterus
muscle mass, contractility
and sensitivity to oxytocin
• Hypertrophy of uterus
mucosa
• Activation of vaginal
mucosa
• Libido
• Hyperlasia of breast ducts
during puberty
• Nipple pigmentation
• Female adipose tissue
composition
• Water and sodium
preservation
• Anti-acne properties
• Diminution of plasma
cholesterol
• Anti-artheriosclerotic
properties
• Bone protection
 Biological activity of estrogens
• Pro-thrombotic properties • Stimulation of
(in high doses): activation angiotensinogen, TBG
of prothrombin production
production, stimulation of
platelet adhesion, • Anabolic properties
diminution of AT-III • Hyperglycemic properties
activity
• Positive and negative
feedback control on
gonadotropin release
• Stimulation of estrogen
and progesterone receptors
expression
Places of progesterone production
• Corpus luteum
• Placenta
• Granulosa cells
• Adrenal cortex
Biological activity of progesterone
• Luteomimetic activity
• Typical changes in uterus
and vagina
• Anti-estrogen properties in
uterus muscle, elevation of
beta adrenergic receptors
number
• Contraction of uterine
cervix
• Stimulation of beast
glandular development
• Lactation supporting
• Anti-androgenic activities
• Feedback control of
gonadotropin release
• Activation of
termogenesis
• Activation of basal
metabolism
• Anti-aldosterone
properties
 Hormone transport
• Estradiol
¾SHBG
¾Albumin (less affinity)
¾Free
• Progesterone
¾CBG
¾Albumin (weakly)
¾Free
Hormone binding to the transport
proteins in women
Hormone Free SHBG CBG Albumin

Estradiol 1 70 0,1 30

Estrone 3,6 16,3 0,1 80,1

Progesterone 2,4 0,6 17,7 79,3

Testosterone 1,4 66 2,3 30,4

Dihydro- 0,5 78,4 0,1 21

testosterone
Androstene- 7,5 6,6 1,4 84,5
dione
Cortisol 3,8 0,2 89,7 6,3
 Metabolism of estrogens
• Rapid conversion of estradiol to estrone by 17β-hydroxysteroid
dehydrogenase in the liver, reentering of some estrone into the
circulation
• Conjugation of estrone with sulfuric acid
• Conversion of estrone to 16α-hydroxyestrone (then to estriol) or
to 2- or 4-hydroxyestrone (catechol estrogen, with biological
activity)
• Conversion of catechol estrogens to the 2-metoxy and 4-metoxy
compounds by catechol-O-methyltransferase (COMT)
• Formation of 2- or 4-hydroxyestradiol and conversion of them by
COMT
• Conversion of estriol to estriol 3-sulfate-16glucuronide
 Estradiol Estrone

2-Hydroxyestradiol 2-Hydroxyestrone
16α-hydroxyestrone
4-Hydroxyestradiol 4-Hydroxyestrone

2-Metoxyestradiol 2-Metoxyestrone
Estriol
4-Metoxyestradiol 4-Metoxyestrone

Metabolism of estrogens
 Metabolism of progesterone
• Rapid clearance from the circulation (T1/2 - 5
minutes)
• Conversion to 20α-hydroxyprogesterone (1/5 the
activity of progesterone)
• Conversion to pregnanediol and conjunction with
glucuronic acid in the liver. (Pregnanediol
glucuronide excretion with urine indicates the
production rate of progesterone)
Mechanism of action
 Relaxin
• Polypeptide extracted from ovary
• Places of formation: ovary (luteinized granulosa
cells), placenta, uterus
• Plays role in the time of parturition (cause
relaxation of the pelvic ligaments and softening of
the uterine cervix
• Increases glycogen synthesis and water uptake by
myometrium and decreases its contractility
 Other ovarian hormones and
regulatory substances
• Inhibin: decreases FSH secretion
• Activin: increases FSH secretion
• Follistatin: binding protein for inhibin and
activin, delays maturation of the ovocyte in
the developing preovulatory follicle.
 The menstrual cycle
• Median length: 28 days (25-35 days)
• Follicular (proliferative) phase: the interval
from the onset of menses to ovulation,
variable in duration
• Luteal (secretory) phase: the interval from
ovulation to the onset of menstrual
bleeding, relatively constant and averages
14 +/- 2 days
FSH profile during the menstrual
cycle
• Increase in LH and FSH level few days prior to
menses
• More rapid increase of FSH than those of LH with
maximum level during the half phase of the
follicular phase
• Gradual diminution during the second half
• Brief peak at midcycle
• Continuous diminution until the lowest
concentration during second half of luteal phase
 LH profile during the menstrual
cycle
• Gradual increase during the follicular phase,
pulses occur every hour
• Large peak at midcycle lasting 1-3 days
(midcycle LH surge)
• Gradual diminution to lowest concentration
in the late luteal phase, pulses occur every
4-8 hours
PRL profile during the menstrual
cycle
• No consistent cyclic changes in individual
PRL profiles during the normal menstrual
cycle
• Slight elevation of PRL in the preovulatory
and luteal phases
 Estradiol profile during the
menstrual cycle
• Low level of estradiol during first half of follicular
phase
• Rapid increase about week prior to the midcycle
gonadotropin surge, with peak on the day
preceding (or on the day of) the LH surge
• Rapid diminution after LH surge
• Secondary increase with a peak in the midportion
of the luteal phase
• Diminution to the end of luteal phase
 Estrone profile during the
menstrual cycle
• Plasma patterns of estrone during the menstrual
cycle are similar to those of estradiol, but with less
changes in concentrations
• Ratio estrone/estradiol varies throughout the cycle
• The highest ratio at the time of menses (lowest
estradiol production)
• The lowest ratio in the preovulatory period
 Progesterone profile during the
menstrual cycle
• Low concentration during follicular phase
• Small increase at the time of LH surge,
followed by the rise over the next 4-5 days
• Plateau during the midportion of the luteal
phase
• Rapid diminution until the first day of
menses
 Androgens profile during the
menstrual cycle
• Testosterone: 50-70% arises primarily from the
peripheral conversion of androstenedione, plasma level
constant during follicular and luteal phase, slight
elevation during preovulatory phase
• Androstenedione: arises primarily from direct secretion
from ovaries and adrenal glans (only 10% is formed by
peripheral conversion).
• Adrenal secretion of androstenedione not vary during
menstrual cycle (diurnal variations are present)
• Ovarian secretion of androstenedione resembles that of
estradiol
 Ovarian cycle
Primordial follicle
Primary follicle
Secondary (preantral) follicle
Tertiary (antral) follicle
Preovulatory (graafian) follicle
Ovulation
Corpus hemorrhagicum
Corpus luteum
Corpus albicans
 Primordial follicle
• Primordial follicle constitute an inactive or resting pool
9 Small oocyte arrested in the diplotene stage of meiotic prophase
9 Ring of granulosa cells, poorly differentiated
9 Based membrane surrounding the granulosa cells, separating them from
ovarian stroma
• During late fetal life and throughout the prepubertal years a small
percentage of this follicles are continually resuming growth. At
early stage of development and prior to antrum formation,
growth is arrested and the follicles undergo atresia (about 400000
follicles remain at puberty)
• The earliest morphologic change indicating that the primordial
follicle has left the pool of resting follicles is increase in size of
the oocyte
 Formation of primary follicle
• Enlargement of oocyte
• Formation of zona pellucida, membrane
surrounding the oocyte
• Assuming the cuboidal shape by the
granulosa cells
 Formation of secondary
(preantral) follicle
• Rapid proliferation of granulosa cells and
formation of multilayered covering out the oocyte
• Formation of small patches of fluid between the
granulosa cells
• Blood vessels do not penetrate basement
membrane (granulosa layer remains unvascular
until after ovulation has occurred)
• Formation of the thecal layer outside the basement
membrane (cells indistinguishable from
mesenchymal fibroblasts)
 Formation of tertiary (antral)
follicle
• Production and accumulation of fluid within
the granulosa cell layer
• Formation of follicular cavity (antrum)
• Oocyte and a portion of surrounding
granulosa cells (cumulus cells) are
displaced to one site of the follicular cavity
 Formation of preovulatory
(graafian) follicle
• Rapid accumulation of follicular fluid
• The growth of granulosa cells
• Enlargement of the follicle to the diameter
of 2-2,5 cm
• ovulation
 Formation of corpus
hemorrhagicum and luteum
• Antrum fills with blood and lymph fluid
• The wall of follicle collapses and became convoluted
and vessels from the thecal layer invade the granulosa
layer
• Luteinization of granulosa cells, formation of corpus
luteum which lasts about 14 days if pregnancy does
not occur
• Replacement by fibrous tissue and formation of corpus
albicans
• Unknown mechanism of luteolysis (prostaglandins ?)
 Control of ovarian function
• Unknown factors that stimulate primordial
follicles (not pituitary gonadotrpins)
• Development of beyond the preantral or
early antral stage depends upon the
interaction of pituitary gonadotropins,
ovarian steroids and local factors within
follicle
 Control of ovarian function
• Gonadotropin releasing hormone (GnRH, LHRH,
LHRF)
¾ Decapeptide
¾ Synthesized by neurosecretory cells within the
hypothalamus, secreted from median eminence to portal
bloodstream
¾ Essential for LH and FSH synthesis and release
¾ Pulastile secretion, pulses every 1-3 hours
¾ Continuous infusion of GnRH after several hours
inhibits gonadotropin release (down regulation)
 Control of ovarian function
• FSH
¾Receptors located only in the granulosa cells
¾Activation of P450 aromatase and conversion
of androgen precursors to estrogens
• LH
¾Receptors located in theca, interstitial and luteal
cells
 Control of ovarian function
• Estradiol:
¾Induction of proliferation of granulosa cells in
small follicles (even in the absence of FSH
estradiol per se stimulates follicular growth to
the preantral stage)
¾Induction of the formation of LH receptors in
granulosa cells (in concert with FSH)
 Control of ovarian function
• Androgenes
¾Precursors of estrogen synthesis in granulosa
cells
¾High concentration of testosterone or
dihydrotestosterone or increased ratios of
androgen to estrogen have been found in
follicles undergoing atresia and suggests an
inhibitory action of androgens on follicular
development
 Artery Theca cell Granulosa Follicular
FSH cell fluid
Cholesterol
LH
Pregnenolone
Vein
Androstene- Androstene- Androstene- Androstene-
dione dione dione dione

Testosterone Testosterone Testosterone Testosterone

Estradiol FSH
Estradiol
Estradiol Estradiol

Synthesis and secretion of androgens and estradiol in the preovulatory follicle

 Control of ovarian function
• Local agents:
¾ The concentrations of pituitary gonadotropins and ovarian
steroids within the follicular fluid rather than the serum
concentration correlate most closely with both the mitotic and
synthetic activity of the granulosa cells as well as with the
future viability of the oocyte
¾ FSH and LH levels in antral fluid are highest durind the late
follicular phase
¾ PRL levels are highest in small follicles
¾ Fluid concentrations of steroids are 10000-40000 times grater
than their serum levels
¾ Androgen concentrations do not differ in follicular fluid from
either small or large follicles
¾ Estradiol concentration in antral fluid rises reaching maximal
levels in large follicles
 Control of ovarian function
• Inhibins A and B
¾ Glycoprotein with two subunits, common alpha subunit and
different beta (βA and βB)
¾ Secreted from granulosa cells
¾ Inhibits FSH secretion
• Activin
¾ Composed of two beta subunits
¾ Stimulates FSH secretion
¾ Modulates the response to LH and FSH, enhances FSH
stimulation of progesterone synthesis and aromatase activity
in granulosa cells, suppresses LH-induced progesterone
response, stimulates LH-induced aromatase activity
 Control of ovarian function
• Negative feedback:
¾ Ovarian steroids limit or reduce the secretion of pituitary
gonadotropins (throughout most of the normal menstrual
cycle)
• Positive feedback:
¾ Estradiol and progesterone, under certain conditions, can
induce the release of LH and FSH
¾ High concentrations of estradiol in the latter part of follicular
phase initiate preovulatory surge of LH, that stimulates
increase in progesterone level that further augments LH surge
and coupled with estradiol initiates the midcycle surge of
FSH
¾ Positive feedback develops after 48-72 hours of sustained
estrogen stimulation
 Higher neural centers
Monoamines
Opioids (-) (NE,E,DA)

Hypothalamus
(+,-) (+,-)

GnRH (-)
(-)
(+,-)
Pituitary
(-) (+,-)
(+)
Estradiol Inhibin Activin FSH LH Progesterone
Ovary
Follicles Stroma Corpus
luteum
(-)
Testosterone
The major hypothalamic-pituitary-ovary interactions
 Histology of the endometrium
• The basal layer: it is in direct contact with the
myometrium, undergoes little change throughout
the menstrual cycle, and is not sloughed during
menses
• The functional layer: arises from the basal layer
and eventually surrounds the entire lumen of the
uterine cavity. The functional layer can be
subdivided further into two components:
¾ compact layer: a thin superficial layer
¾ spongiosa layer: deeper layer of which most of the
secretory or fully developed endometrium is composed
The blood supply of the endometrium
• The spiral arteries: arise within the myometrium from
branches of the uterine artery, pass through the basal
endometrial layer, and extend into the functional zone
• The straight artery, proximal portion of the spiral
artery, distributes blood to tissues of the basal layer and
is not influenced by changes in estrogen and
progesterone secretion
• The spiral arteries, undergo cyclic regeneration and
degeneration during each menstrual cycle in response to
hormonal changes
 Endometrial cycle

• Proliferative phase
• Secretory phase
• Menstrual phase
 Proliferative phase
• When menstrual flow ceases, a thin layer of basal endometrial
tissue remains. This tissue, consisting of the remnants of glands
and stroma, grows rapidly. Epithelial cells from the glands
proliferate and cover the raw stromal surfaces with a layer of
simple columnar epithelium.
• In the early proliferative phase, most of the glands are straight,
short, and narrow. The glandular epithelium exhibits increasing
mitotic activity.
• Throughout the proliferative phase, there is continued and rapid
growth of both the epithelial and stromal components of the
endometrium.
• By the late proliferative phase of the menstrual cycle, the
surface of the endometrium is somewhat undulant. The glands are
becoming tortuous and are lined by tall columnar cells with basal
nuclei. Pseudostratification of nuclei is prominent. The stroma at
this time is moderately dense, with many mitotic figures.
 Secretory phase
• During the secretory phase, histologic changes occur very
rapidly. During the first half of this phase, the appearance of the
glandular epithelium is most useful in precise dating of the
endometrium, whereas in the second half, accurate dating
depends largely on the characteristics of the stroma.
• On the 16th day of the cycle (second postovulatory day),
subnuclear, glycogen-rich vacuoles become prominent in
the glandular epithelium. The vacuoles push the epithelial cell
nuclei into a central position within the cells.
• By the 19th day (fifth postovulatory day), few vacuoles remain
within the cells.
• Acidophilic intraluminal.glandular secretory material is most
apparent on day 21.
• Stromal edema, which is variable during the proliferative phase,
also becomes prominent at this time and peaks on day 22.
 Secretory phase
• By day 24, pseudodecidual or predecidual changes begin to appear
within the stroma. These changes are initially most apparent near
the spiral arteries and eventually encompass large areas of the
stroma. Lymphocytic infiltradon of the stroma increases markedly
in conjunction with the appearance of pseudodecidual changes,
and by day 26, PMN invasion also is apparent.
• If the blastocyst implants successfully, serum concentrations of
hCG and, secondarily, progesterone begin to increase 7-10 days
after ovulation (ie, days 21-24 of the menstrual cycle). The rising
levels of progesterone produce a type of endometrial change
known as decidualization. The decidua of pregnancy consists
primarily of plump, eosinophilic stromal cells that have a
pavement-like appearance.
 Secretory phase
• In the early stages of pregnancy, the cells of the
glandular epithelium become distended with clear
cytoplasm and possibly with enlarged and
hyperchromatic nuclei, a feature called the Arias-
Stella phenomenon.
• With advancing pregnancy, the endometrial
glands gradually atrophy.
 Menstrual phase
• In the absence of pregnancy, changes in the
endometrium secondary to declining hormone
production by the corpus luteum can be observed by
day 24.
• The functional layer of the stroma begins to shrink, and
the endometrial glands become more tortuous and saw-
toothed in appearance.
• Intermittent constriction of the spiral arteries leads to
stasis within the capillaries of the functional layer,
tissue ischemia and extravasation of blood into the
stroma with formation of small hematomas. Eventually,
desquamation and sloughing of the entire functional
layer of the endometrium occurs.
 Cervical mucus
• Cervical mucus is a complex secretion produced by the glands
of the endocervix. It is composed of 92-98% water and
approximately 1% inorganic salts of which NaCl is the main
constituent. The mucus also contains free simple sugars,
polysaccharides, protein and glycoproteins. Its pH is usually
alkaline and ranges from 6.5 to 9.
• Estrogen stimulates the production of copious amounts (up to
700 mg/d) of clear, watery mucus through which sperm can
penetrate most readily.
• Progesterone, even in the presence of high plasma levels of
estrogen, reduces the secretion of mucus.
• Both during the luteal phase of the menstrual cycle and during
pregnancy, the mucus is scant, viscous, and cellular.
• During most of the menstrual cycle, 20-60 mg of mucus
is produced each day.
 Cervical mucus
• Spinnbarkeit is the property that allows
cervical mucus to be stretched or drawn into a
thread.
• Spinnbarkeit can be estimated by stretching a
sample of mucus between 2 glass slides and
measuring the maximum length of the thread
before it breaks.
• At midcycle, spinnbarkeit usually exceeds 10 cm.
 Cervical mucus
• Ferning, or arborization, refers to the characteristic microscopic
pattern cervical mucus forms when dried on a slide.
• Ferning results from the crystallization of inorganic salts around
small and optimal amounts of organic material present in
cervical mucus.
• As serum concentrations of estradiol increase, the composition of
cervical mucus changes, so that dried mucus begins to
demonstrate ferning in the latter part of the follicular phase.
• In the periovulatory interval, when estradiol levels are maximal
and prior to significant progesterone secretion, ferning is most
prominent and the mucus is thin, watery, and contains few cells.
• As serum progesterone concentrations increase following
ovulation, the quality of the mucus changes and ferning
disappears.
 Cervical mucus
• The absence of ferning can reflect either
inadequate stimulation of endocervical glands by
estrogen or inhibition by increased secretion of
progesterone.
• Persistent ferning throughout the menstrual cycle
suggests anovulatory cycles or insufficient
progesterone secretion.
 Vaginal epithelium
• The vaginal mucosa is composed of a stratified
squamous epithelium and does not contain glands. Cells
in the outer layer during the reproductive years are
flattened and may contain keratohyaline granules, but
true cornification does not normally occur
• The epithelial cells of the vagina, like other tissues of
the female reproductive tract, respond to changing
levels of ovarian sex steroids
• Estrogen stimulates the proliferation and maturation of
the epithelial cells, resulting in a thickening of the
vaginal mucosa and increased glycogen content of the
epithelial cells. This glycogen is fermented to lactic acid
by the normal bacterial flora of the vagina, thus
accounting for the mildly acid pH of vaginal fluid
 Vaginal epithelium
• Superficial cells are mature, flat, usually polygonal, squamous
epithelial cells with pyknotic, hyperchromatic nuclei. These cells
develop in response to high levels of unopposed estrogen
stimulation.
• Intermediate cells are relatively mature squamous epithelial cells
with eosinophilic or cyanophilic cytoplasm and a vesicular,
nonpyknotic nucleus. The appearance of the nucleus is the
critical factor in differentiating intermediate cells from
superficial cells.
• Intermediate cells predominate in endocrinologic states in which
progesterone levels are high, such as in pregnancy or in the
midluteal phase of the menstrual cycle
• Basal-parabasal cells are thick, small, oval or round, immature
cells with large vesicular nuclei and cyanophilic cytoplasm.
Parabasal cells usually indicate estrogen deficiency and are the
predominant cell type in the prepubertal and postmenopausal
periods.
 Vaginal epithelium
• (1) the karyopyknotic index (KPI), the ratio of superficial cells to
intermediate cells
• (2) the eosinophilic index (EI), the ratio of mature eosinophilic
cells to mature cyanophilic cells
• (3) the maturation index (MI), the percentage of basal,
intermediate, and superficial cells present, in that order. Since only
MI includes as a factor the presence of all three cell types, it may
provide more information than the other two indices.
• When the vaginal epithelium has been stimulated by estrogen, MI
may range from (0/40/60) at mid cycle, when estradiol
concentrations are highest, to (0/70/30) late in the luteal phase,
when progesterone effects are most prominent. A finding of
parabasal cells with a few intermediate cells and no superficial
cells indicates that the vaginal epithelium has received little or no
estrogen stimulation. The MI in this instance may be (100/0/0) or
(80/20/0).
DISORDERS OF OVARY &
MENSTRUAL FUNCTION
Abnormal ovarian endocrine function is
manifested by:
¾Evidence of inappropriate estrogen secretion
(e.g., precocious puberty)
¾Deficient estrogen secretion (e.g., delayed
puberty)
¾Disturbances or alterations of the menstrual
cycle of mature women
¾Evidence of excessive androgen production
Types of abnormal vaginal bleeding
Definition Causes

Uterine myomas and endometrial polyps,

Hyepermenorrhea Cyclic bleeding in excessive
hyperpasia, adenomyosis, endometritis, von
(menorrhagia) amount
Willenbrad’s disease

Cyclic bleeding in Cervical obstruction, synechia of

Hypomenorrhea
abnormally small amount endometrium, tuberculosis of endometrium

Frequent periods Shortening of follicular phase, luteal

Polymenorrhea
(cycle length of < 21 days) insufficiency, frequent anovulatory bleeding

Infrequent periods
Oligomenorrhea Anovulation, systemic disturbances
(cycle length of > 35 days)

More than 6 months since

Amenorrhea Anovulation or outflow tract disorders
last period

Except for ovulatory bleeding or spotting,

Bleeding between normal
Metrorrhagia this symptom usually indicates disease of the
cycles
vagina, cervix or uterus
 AMENORRHEA
• The great majority of disorders of ovarian
function causing amenorrhea occur without known
or identifiable structural changes in the
components of the complex system required for
normal ovulatory cycles. They can result from:
• Abnormalities in function of the central
mechanism that regulates the pulsatile secretion of
GnRH (stress, extreme weight loss, drug)
• Abnormalities in feedback
• Changes in intraovarian regulatory mechanisms.
 Amenorrhea and hipogonadism
Amenorrhea Hipogonadism
• Primary (in the absence of • Primary (due to hormonal
sexual maturation over 16 insufficiency of ovaries)
years of age) • Secondary (due to low
• Secondary (in patients gonadotropin secretion)
with normal secondary sex ¾ Pituitary
characteristics) ¾ Hypothalamic
 Causes of primary amenorrhea
Primary ovarian disorders
¾ Gonadal agenesis
¾ Turner’s syndrome (gonadal dysgenesis)
¾ P450c17 (17α-Hydroxylase) deficiency
Disorders due to central nervous system disease
¾ Hypogonadism and anosmia (failure of development of
the olfactory lobe and deficiency of GnRH)
¾ Prepubertal pituitary and central nervous system tumors
 Causes of secondary amenorrhea
Abnormalities of the outflow tract
¾ Müllerian defects
¾ Asherman’s syndrome (uterine synechia)
Primary gonadal disorders
¾ Premature ovarian failure
¾ Testicular feminization
¾ Resistant ovary syndrome
¾ Functioning ovarian tumors
Disorders of the pituitary
¾ Pituitary tumors
¾ Hyperprolactinemia
¾ Empty sella syndrome
Disorders due to central nervous system abnormalities of regulation of
gonadotropin secretion
¾ Hypothalamic amenorrhea
¾ Amenorrhea in athletes
¾ Anorexia
¾ Post-pill amenorrhea
 Primary gonadal disorders
Elevated gonadotropin concentrations
• Premature ovarian failure. Occurs in women under
the age of 35. In some patients ovarian failure is
associated with ovarian autoantibodies (and to
other glands – Schmidt’s syndrome
• Testicular feminization. This disorder in its classic
form is characterized by primary amenorrhea and
absent uterus, and the absence of pubic
and auxiliary hair. Affected patients are male
pseudohermaphrodites with testes and an XY
karyotype. Patients have normal-appearing female
sexual characteristics which are incongruent with
the genetic sex.
 Primary gonadal disorders
Functioning ovarian tumors
• Germ cell tumors
¾ Germinomas (dygerminoma, seminoma, gonocytoma,
ebryonal carcinoma) – may produce hCG
¾ Teratomas – may contain hormone secreting elements
¾ Gonadoblastomas
• Sex cord-mesenchymal tumors
¾ Granulosa-theca cell tumors – usually secrete estrogens
¾ Sertoli-Leydig cell tumors (arrhenoblastoma,
androblastoma) – usually secrete androgens
• Hilar cell (lipoid cell) tumors – usually secrete
androgens
 Circulating androgens in women
Source of circulating hormone
Relative
Serum level
Hormone androgenic Peripheral
(ng/ml) Adrenal Ovary
activity conversion

Testosterone 100 0,2-0,7 5-25 5-25 50-70

Dihydro-
250 0,05-0,3 100
testosterone

Androstene-
10-20 0,5-2,5 30-45 45-60 10
dione

DHEA 5 1,3-9,8 80 20

DHEA-S minimal 400-3200 >95 <5

 Causes of increased androgen
production
Ovarian causes
¾ Polycystic ovary syndrome (LH-dependent androgen excess,
hyperandrogenic chronic anovulation)
¾ Hyperthecosis
¾ Androgen-producing ovarian tumors
¾ Virilization of pregnancy (luteoma)
Adrenal causes
¾ Congenital or adult-onset adrenal hyperplasia
¾ Androgen producing adrenal tumors
¾ Cushing’s syndrome
Other
¾ Idiopathic familiar hirsutism
¾ Incomplete testicular feminization
¾ Postmenopausal state
¾ Iatrogenic (androgens, cyclosporine, danazol, diazoxide, minoxidil,
phenytoin)
Polycystic ovary syndrome (PCOS)
• The term functional ovarian hyperandrogenism is a
more appropriate name
• Most common reproductive endocrine disorder: 5-7%
women of reproductive age
• Enlarged ovaries
• White glistening because of thickened capsule
• Many small follicles in various stages of development
and atresia at the surface
• Hyperplastic and luteinized theca cells
• Changes not specific (seen with androgen excess from
any source)
Polycystic ovary syndrome (PCOS)
• Continuous stimulation of the ovary by
disproportionately high levels of LH
• Chronic stimulation leads to increased ovarian
androgen secretion and characteristic morphological
changes in the ovaries
• Increased estrogen production: a result of peripheral
conversion of androgens (mainly androstenedione to
estrone)
• Development of endometrial hyperplasia
(adenocarcinoma) due to hyperestrogenism and low
progesterone
• Insulin resistance
 Etiology of PCOS
• Unknown cause (several causes ?)
• Initiation by excessive adrenal androgen production at
the time of puberty or by stress-induced increase in
adrenal androgen secretion
• Peripheral conversion of androgen to estrogen could
facilitate the secretion of increased amounts of LH,
leading to increased ovarian androgen production and
impaired follicular maturation
• Inhibited aromatase reduces androgen conversion to
estrogen
• The lack of estrogen locally reduces IGF-1, which
normally sensitizes the follicle to FSH
 Etiology of PCOS
• Unclear relationship between insulin resistance and
hyperandrogenism (in some patients lowering insulin
level restores ovulatory cycles and reduces testosterone
level)
• One common defect could explain this relationship
¾ Phosphorylation of a serine residue on the insulin receptor
inhibits signal transmission
¾ Serine phosphorylation of the steroidogenic factor-1 also
alters the activity of the P450c17 gene, so that the lyase
activity is enhanced and the 17-hydroxylase activity is
decreased
¾ Activation of a creatinine kinase-dependent signaling cascade
might account for the coincident manifestations of insulin
resistance and increased androgen production
 Increased LH,
decreased FSH
Increased pituitary Increased ovarian
pulsatile LH release stromal stimulation

Decreased
Adrenal
follicular
androgen
maturation

Increased pituitary Increased ovarian

sensitivity to GnRH androgen production

Increased acyclic estrogen

production (extraglandular
conversion of androgen)
Pathophysiology of PCOS
 Clinical findings in women with
PCOS
• Infertility
• Hirsutism
• Amenorrhea
• Obesity
• Functional bleeding
• Dysmenorrhea
• Virylisation
 Adult-onset congenital adrenal hyperplasia
Cholesterol P-450c17 P-450c17 Sulfokinase
(7) (8) (9)

P-450scc (1)
Pregnenolone 17α-Hydroxy DHEA DHEA
pregnenolone sulfate
3βHSD/ISOM
(2)

Progesterone 17α-Hydroxy Androstenedione

progesterone
P-450c21 (3) (1) Cholesterol 20,22-hydroxylase:20,22-
desmolase activity
11-Deoxy
corticosterone (2) 3-hydroxysteroid dehydrogenase:∆5-
11-Deoxycortisol
oxysteroid isomerase activity
P-450c11 or (3) 21α-hydroxylase activity
P450c11AS (4)
(4) 11β-hydroxylase activity
Corticosterone Cortisol
(5) 18-hydroxylase activity
P450c11AS (5) (6) 18-dehydrogenase
18-Hydroxy
corticosterone (7) 17α-hydroxylase activity
P450c11AS (6) (8) 17,20-liase/desmolase activity

Aldosterone (9) Sulfokinase activity

 Hirsutism
Classification of hair:
• Vellus: fine, soft and non pigmented, found most
over the body and predominate prior to puberty
• Terminal: coarse and pigmented, before puberty
normally found on the scalp and eyebrows. During
puberty androgens cause transformation of vellus
hairs into terminal (in women principally the
axillary and pubic region and lesser extend the
extremities) due to increased 5α-reductase activity
 Hirsutism
The definition of hirsutism:
• The presence of increasing numbers of terminal
hairs on the face, chest, back, lower abdomen, and
inner thighs.
The definition of virilization:
• Somatic changes caused by high androgen levels
(levels normally found only in men) including:
frontal balding, deepening of the voice, breast
atrophy, clitoral enlargement, increased muscle
mass and loss of normal female body contours
 Hirsutism
Causes:
• Increased androgen production
¾Adrenal
¾Ovarian
¾Both
• Reduced serum concentration of SHBG and
elevation of free testosterone
• Idiopathic (end-organ hypersensitivity)
 Conditions affecting SHBG
synthesis
Decreased Increased
• Hypothyroidism • Hyperthyroidism
• Androgen therapy • Pregnancy
• Corticosteroid therapy • Estrogen therapy
• Obesity • Cirrhosis
• Acromegaly
 Development factors of
androgen-dependent hirsutism
Increased ovarian or adrenal androgen secretion
Decreased SHBG synthesis by liver
Reduced serum SHBG
Increased serum level of bioactive testosterone
Increased 5α-reductase activity
in hair follicle
Increased DHT formation

Increased conversion of vellus to terminal hair

 Menopause
• Menopause begins with the last episode of
menstrual bleeding induced by the cyclic
endogenous secretion of ovarian hormones.
It normally occurs between ages of 42 and
60 years. It occurs prematurely as a result of
surgical removal, irradiation, or
abnormalities of the ovaries
 Menopause – hormonal changes
• The circulating levels of gonadotropins begin to
increase several years before ovulation ceases.
• Production of estrogen and progesterone decrease for 2
years before and continue to decrease for 2 years after
the menopause.
• Irregular cycles and anovulatory bleeding are not
uncommon.
• The increase in FSH is greater than that of LH and
reflects the lack of feedback inhibition by estrogen and
inhibin. The stoma cells of the ovary respond to
increased LH stimulation by producing more
androstenedione but only tiny amounts of estrogen
 Menopause – hormonal changes
• The average production rate of estradiol falls to
12 µg/24 h (44 nmol/24 h), and the clearance rate is
reduced. Since very little estradiol is found in ovarian
or adrenal veins, most of the circulating estradiol
is derived from estrone, which in itself is produced
by the peripheral conversion of androstenedione.
The average production rate for estrone is 55 µg/24
h (202 nmol/24 h), and there is a 20% reduction in
its clearance.
• Progesterone levels are approximately 30% of
the concentration seen in young women during the
follicular phase. The source of this progesterone is
the adrenal.
 Menopause – hormonal changes
• Reduced androgen levels
• Androstenedione falls to about half of the concentration
found in young women, and most of that apparently
comes from the adrenal, as suggested by its peak
concentrations at 8 AM and nadir concentrations at 3-4
PM. The clearance rate does not change. The average
production rate is about 1,5 mg/24 h (5200 nmol/24 h).
About 20% of it is thought to come from the ovary.
 Menopause – hormonal changes
• Testosterone production rates are approximately 150
µg/24 h (52 nmol/24 h), as compared to about 200 µg
/24 h (693 nmol/24 h) in younger women. This fall is
less than that seen after ovariectomy, indicating that
testosterone is produced by conversion of
androstenedione as well as being secreted by the adrenal
and ovary
• Progressive decline of circulating DHEA levels an its
sulfate ester (DHEAS). The decrease of circulating
levels of beta-endorphin in postmenopausal women can
be reversed by DHEA.
Menopause – clinical manifestations
Early manifestations
• Menstrual changes
• Vasomotor symptoms
• Atrophic changes in the genitourinary system
• Hair and skin changes
• Emotional changes

Later manifestations
• Osteoporosis
• Cardiovascular disease
Menopause – clinical manifestations
Menstrual changes
• Interval of irregular cycles with shortening
of the follicular phase
• Interval of anovulatory bleedings
• Gradual diminution in the amount of
menstrual flow and its duration
 Menopause – clinical manifestations
Vasomotor symptoms
• Hot flushes (75% of women) associated with periodic increases in
core temperature, causing reflex peripheral vasodilatation,
increase in pulse rate and sweating due to declining estrogen
levels
• Synchronous with the pulsatile release of LH
• Most frequently in a warm environment and at night
• The hot flush often starts with a sensation of pressure in the head,
followed by a feeling of warmth in the head and neck and upper
thorax. It may be associated with palpitations and gradually
spreading waves of heat over the entire body. The feeling of
warmth and flushing is quickly followed by sweating. The
sweating and vasodilation lead to heat loss and a decrease in core
temperature of approximately 0.2 °C. These episodes last 10-20
minutes.
Menopause – clinical manifestations
Atrophic changes in the genitourinary system
• The decline in estrogen production results in reduction
in mucus secretion and gradual atrophy of the vaginal
and urethral epithelium. These changes lead to itching,
dyspareunia, and burning.
• Similar changes in the urinary tract may give rise to
atrophic cystitis, with symptoms of urgency,
incontinence, and frequency.
• The cervix decreases in size, and the mucus secretion
diminishes.
• The endometrium and myometrium also undergo
atrophy
Menopause – clinical manifestations
Skin and hair changes:
• Thinning and wrinkling
• Loss of some under-arm and pubic hair and
occasionally replacement of vellus hair on the chin
and upper lip by terminal hairs.
Emotional changes:
• Anxiety, depression, and irritability are
commonly reported
• Sleep disturbances caused by hot flushes
 Menopause – clinical manifestations
Osteoporosis:
• Results from a combination of in creased bone
resorption and decreased bone formation
• In its early stages, it is predominantly a disease of
trabecular bone
• Affected patients show increased calcium loss from
bone
• The problem is enhanced in winter months because of
decreased activity and decreased exposure to sunlight
and by the difficulty of maintaining calcium balance at
normal levels of intake
Menopause – clinical manifestations
• Cardiovascular disease
• Accelerated rise in cholesterol and LDL,
and LDL receptors decline
• Not affected level of HDL (still higher than
in men)
• Not much different levels of VLDL and TG
• Increased risk for cardiovascular disorders