THE FEMALE REPRODUCTIVE SYSTEM

PHYSIOLOGY OF MENSTRUATION
M. DJAUHARI WIDJAJAKUSUMAH
DEPARTEMEN FISIOLOGI
FAKULTAS KEDOKTERAN UNIVERSITAS INDONESIA
 THE FEMALE REPRODUCTIVE
SYSTEM

PHYSIOLOGY OF MENSTRUATION
 2007

Testis Determining Factor

2007

Figure 46-2 Development of the human male reproductive organs and tract. Note the dependence on SRY, a gene
on the Y chromosome that expresses the testis-determing factor, and on hormone products of the gonad
(testosterone , dihydrotestosterone, and anti-Müllerian hormone [AMH]).
Figure 46-3 Development of the human female reproductive organs and tract. Note the independence from
hormonal products of the gonad. Nonetheless, a gene on the X chromosome, AHC, helps determine development
of an ovary and the Wnt gene stimulates Müllerian duct development in the absence of AMH. In the absence of
any gonads, the female format results. AMH, Anti-Müllerian hormone.
 Ganong’s Review
of Med Physiol,
23e 2010

Diagrammatic summary of normal sex determination, differentiation, and evelopment

in humans. MIS, müllerian inhibiting substance; T, testosterone; DHT, dihydrotestosterone.
 Development of the Gonads

 Primitive gonad --> indifferent gonad (cortex and medulla)

 Genetic males (7th week):

 the medulla of indifferent gonad --> testis
 Leydig and Sertoli cells appear
 Testosterone and MIS secreted
 cortex regresses

 Genetic females
 the cortex of indifferent gonad --> ovary
 embryonic ovary does not secrete hormones
 medulla regresses
FIGURE 13–2 Schematic drawing showing the formation of the uterus and vagina. A. At 9 weeks.
Note the disappearance of the uterine septum. B. At the end of the third month. Note the tissue of
the sinovaginal bulbs. C. Newborn. The upper portion of the vagina and the fornices are formed by
vacuolization of the paramesonephric tissue and the lower portion by vacuolization of the
sinovaginal bulbs. (Reproduced with permission from Langman J, Sadler TW. Langman’s Medical
Embryology. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2000.)
Greenspan‘s Basic & Clinical Endocrinology 10e, 2018
 Hymen

 Hymen: a thin membrane that surrounds the opening to the vagina. Hymens
can come in different shapes. The most common hymen in young girls is
shaped like a half moon. This shape allows menstrual blood to flow out of
a girl’s vagina.
Types of Hymens

Imperforate hymen: An imperforate hymen

can be diagnosed at birth. More often, the
diagnosis is made during the teen years. An
imperforate hymen is a thin membrane that
completely covers the opening to the
vagina. Menstrual blood cannot flow out of
the vagina. This usually causes the blood to
back up into the vagina which often develops
into an abdominal mass and abdominal
and/or back pain. Some teens may also have
pain with bowel movements and difficulty
passing urine.
The treatment for an imperforate hymen is
minor surgery to remove the extra hymenal
tissue and create a normal sized vaginal
opening so that menstrual blood can flow out
of the vagina.
Types of Hymens

Microperforate hymen: A microperforate

hymen is a thin membrane that almost
completely covers the opening to a young
women’s vagina. Menstrual blood is usually
able to flow out of the vagina but the
opening is very small. A teen with a
microperforate hymen usually will not be
able to insert a tampon into her vagina
and may not realize that she has a very
tiny opening. If she is able to place a
tampon into her vagina, she may not be
able to remove it when it becomes filled
with blood. The treatment is minor
surgery to remove the extra hymenal
tissue making a normal sized opening
for menstrual blood to flow out.
Types of Hymens

Septate hymen: A septate hymen is

when the thin hymenal membrane has
a band of extra tissue in the middle
that causes two small vaginal openings
instead of one. Teens with a septate
hymen may have trouble getting a
tampon in or trouble getting a tampon
out. The treatment for a septate hymen
is minor surgery to remove the extra
band of tissue and create a normal
sized vaginal opening.
FIGURE 15–2 Stages of female pubic hair development, according to Marshall
and Tanner. (Photographs from Van Wieringen JC, et al.
Growth Diagrams 1965 Netherlands: Second National Survey on 0 -24 Year
Olds. Institute for Preventive Medicine NO Leiden, Wolters-Noordhoff
Publishing; 1971; with permission.)
Stage P1: Preadolescent; the vellus over the area is no further developed than
that over the anterior abdominal wall (ie, no pubic hair).
Stage P2: Sparse growth of long, slightly pigmented, downy hair, straight or only
slightly curled, appearing chiefly along the labia. This stage is difficult to see on
photographs and is subtle.
Stage P3: Hair is considerably darker, coarser, and curlier. The hair spreads
sparsely over the superior junction of the labia majora.
Stage P4: Hair is now adult in type, but the area covered by it is still considerably
smaller than in most adults. There is no spread to the medial surface of the
thighs.
Stage P5: Hair is adult in quantity and type, distributed as an inverse triangle of
the classic feminine pattern. Spread is to the medial surface of the thighs but not
up the linea alba or elsewhere above the base of the inverse triangle.

Greenspan Endocrinplogy 9e, 2011

Guyton Textbook of Medical Physiology 13e
The fertilization process takes place in the female genital
tract.

Legend
Fig. 5 - The female genital tract

1. Ovary
2. Infundibulum
3. Fimbriae
4. Fallopian or uterine tube
5. Ampullary part of the tube
6. Uterine musculature
7. Uterine mucosa
8. Cervix
9. Portio
10. Vagina
11. Ligamentum ovarii proprium
12. Suspensory ligament of the ovary
13. Ovary cut open (follicles in various stages)
 The Menstrual Cycle

 Regular cyclic changes of the reproductive system of women

 Regarded as periodic preparation for fertilization and pregnancy

 Periodic vaginal bleeding that occurs with the shedding of the uterine
mucosa (menstruation)

 Length of the cycle is variable; average figure is 28 days

 Ovarian cycle and uterine cycle

 Menstrual Cycle

 The menstrual cycle of the ovary includes a follicular phase and a luteal
phase.

 The follicular phase is characterized by growth of the dominant follicle and

ovulation.

 It typically lasts 10 to 14 days. It is, however, this phase that is variable in

duration and most often accounts for the variability in menstrual cycle
length in ovulatory women.

 The luteal phase starts after ovulation and is the period when the ovary
secretes hormones that are essential to accommodate conceptus
implantation.

 This phase is relatively constant and averages 14 days (range, 12-15 days)
in duration.
Greenspan ‗s Basic & Clinical Endocrinology
10e, 2018
Sherwood Human
Physiology From
Cells to Systems
9e, 2016
Sherwood Human
Physiology From
Cells to Systems
9e, 2016
Langman Clinical Embriology 13e, 2015
1. Tertiary follicle 6. Stratum granulosum
2. Ovary cortex (granulosa cells)
3. Medulla of the ovary 7. Antrum folliculi with follicle fluid
4. Theca with capillary network of 8. Peritoneal cavity
the graafian follicle
5. Oocyte within the cumulus
oophorus
 Figure 20-12 Oogenesis

Sherwood Human Physiology,

From Cells To Systems, 9e 2016
 Ovarian Cycle
Follicle Development - Follicular Phase

 Primordial follicles are the fundamental reproductive units that

comprise the pool of oocytes that remain arrested in prophase 1 until
just prior to ovulation.

 Morphologically, they are composed of a primary oocyte that is

surrounded by a single layer of squamous granulosa cells and a
basement membrane.

 They have no blood supply.

 These primordial follicles develop between the sixth and ninth

months of gestation and harbor the complete supply of ovarian
follicles.
Greenspan ‗s Basic & Clinical
Endocrinology 10e, 2018
 Initiation of Follicular Growth

 The initiation of follicular growth begins with the transition of the dormant
primordial follicle into the growth phase.

 The exact mechanisms controlling the initial recruitment of the primordial

follicle are under investigation. It is suggested that the resting follicular pool
is probably under tonic inhibitory control.

 The initial recruitment process induces growth in some primordial follicles;

other neighboring follicles remain quiescent for many months or years.

 It is thought that the recruitment of these follicles is a continuous process

that begins once the germ pool is created and ends with follicular
exhaustion.

 This complex process is gonadotropin-independent.

Greenspan ‗s Basic & Clinical
Endocrinology 10e, 2018
 Initiation of Follicular Growth

 Several studies have suggested that an intraovarian signaling network,

involving members of the TGF superfamily, is responsible for primordial
follicle recruitment.
 It is also known that recruitment and growth of the follicle absolutely
requires cell-to-cell contact with neighboring granulosa cells and the
oocyte.
 These cells transfer various factors, nutrients, and waste to and from the
oocyte through gap junctions derived from connexins.
 One theory proposes that the oocyte actively influences its own fate by
secreting various factors.
 These include two particular growth factors related to TGF-β, which are
produced by the oocyte early in follicular development, growth
differentiation factor (GDF)-9 and bone morphogenic protein (BMP)-15.

Greenspan ‗s Basic & Clinical

Endocrinology 10e, 2018
 Ovarian Cycle
Follicle Development - Follicular Phase

Primordial follicle

 formed during fetal life (3rd - 7th month)

 contains a primary oocyte surrounded by a single layer of
granulosa cells
 more than 2000.000 in each ovary at birth

Primary follicle

 consists of a primary oocyte surounded by multiple layers of

granulosa cells and a layer of theca cells
 developed from several primordial follicles each month starting at
puberty (10-14 yrs)
 Ovarian Cycle
Follicle Development - Follicular Phase

Secondary follicle

 Developed from primary follicles at the beginning of each cycle in

response to the rising levels of FSH

 Granulosa cells continue to proliferate, secrete a fluid, forming a

fluid-filled cavity: antrum
 Ovarian Cycle
Follicle Development - Follicular Phase

Vesicular / Graafian / Mature follicle

 only one secondary follicle (dominant follicle) completely matures

 Graafian follicle; other secondary follicles disintegrate / atresia
(atretic follicles)

 Graafian follicle ruptures  ovulation (at about the 14th day of the
cycle)  secondary oocyte ejected into the open end of Fallopian
tube
 Follicular Atresia

•In mammals, 99.9% of all the follicles (oocytes) die by atresia. Only +
400 reach ovulatory stage

•A fundamental property of atresia is the activation of apoptosis in the

oocyte and granulosa cells. Apoptosis is a complex process involving
ligand signaling pathways that are coupled to cell death.

•The importance of FSH in preventing apoptosis has led to the concept

that FSH is a follicle survival factor

•The physiological mechanisms governing atresia remain poorly

understood.
Pathways of steroid biosynthesis. The pathways for synthesis of progesterone and
mineralocorticoids (aldosterone), glucocorticoids (cortisol), androgens (testosterone and
dihydrotestosterone), and estrogens (estradiol) are arranged left to right. The enzymatic activities
catalyzing each bioconversion are written in the boxes. For those activities mediated by specific
cytochrome P450, the systematic name of the enzyme ("CYP" followed by a number) is listed in
parentheses. CYPB2 and CYP17 have multiple activities. The planar structures of cholesterol,
aldosterone, cortisol, dihydrotestosterone, and estradiol are placed near the corresponding labels.
 FIGURE 13–5 Kisspeptin is a key regulator
of the hypothalamic-pituitary-gonadal
(HPG) axis. KiSS-1 neurons in the
anteroventral periventricular nucleus
(AVPV) and arcuate nucleus (Arc) within
the hypothalamus express kisspeptin,
which has an important role in triggering
the release of gonadotropin releasing
hormone (GnRH). The cognate receptor
for kisspeptin is GPR54. GnRH stimulates
expression and release of gonadotropins
(follicle stimulating hormone [FSH],
luteinizing hormone [LH]), which
stimulate follicular growth and steroid
production in the ovaries. These steroids
feedback (positive and negative) to
further regulate the HPG axis and
synchronize the ovarian cycle.
(Reproduced with permission from
Roseweir AK and Millar RP. The role of
Greenspan ‗s kisspeptin in the control of gonadotrophin
Basic & Clinical secretion. Hum Reprod Update. 2009
Endocrinology Mar-Apr;15(2): 203-212.)
10e, 2018
 Control of Follicular Function

o The early stages of pre-antral follicular growth and oocyte

maturation precede the follicular phase and do not require
gonadotropic stimulation.

o Hormonal support is required, for further follicular development and

antrum formation, and for estrogen secretion.

o FSH induces antrum formation.

o Both FSH and estrogen stimulate proliferation of the granulosa cells.

Sherwood Human Physiology,

From Cells To Systems, 9e
2016
 Control of Follicular Function

o LH and FSH are required for synthesis and secretion of estrogen by

the follicle.

o Thecal cells produce androgens but have limited capacity to convert

them into estrogens.

o Granulosa cells contain the enzyme aromatase, they can convert

androgens into estrogens, but they cannot produce androgens in
the first place.

Sherwood Human Physiology,

From Cells To Systems, 9e
2016
 Control of Follicular Function

o Part of the estrogen produced by the growing follicle is secreted into the
blood and is responsible for the steadily increasing plasma estrogen levels
during the follicular phase.

o The remainder of the estrogen remains within the follicle, contributing to

the antral fluid and stimulating further granulosa cell proliferation

 The rising, moderate levels of estrogen characterizing the follicular phase act
directly on the hypothalamus to inhibit the ARC nucleus kiss1 neurons, thus
indirectly inhibiting GnRH secretion and thereby suppressing GnRH-
prompted release of FSH and LH from the anterior pituitary.

 Estrogen selectively inhibits FSH secretion by the gonadotropes.

Sherwood Human Physiology, From Cells To Systems, 9e

2016
Sherwood Human
Physiology, From Cells
To Systems, 9e 2016
 Control of Follicular Function

 Estrogen selectively inhibits FSH secretion by the gonadotropes.

 This differential secretion of FSH and LH by the gonadotropes

induced by estrogen is in part responsible for the declining plasma
FSH level, unlike the rising plasma LH concentration, during the
follicular phase as the estrogen level rises

 Another contributing factor to the fall in FSH during the follicular

phase is secretion of inhibin by the follicular cells.

 Inhibin preferentially inhibits FSH secretion by acting at the anterior

pituitary, just as it does in the male

 The decline in FSH secretion brings about atresia of all but the single
dominant, most mature of the developing follicles.
Sherwood Human Physiology, From Cells To Systems, 9e
2016
Control of Ovulation

 Ovulation and subsequent luteinization of the ruptured follicle are

triggered by an abrupt, massive increase in LH secretion.

 This LH surge brings about four major changes in the follicle:

1. It halts estrogen synthesis by the follicular cells

2. It reinitiates meiosis in the mature follicle‘s oocyte by blocking
release of oocyte maturation inhibitor (OMI) produced by the
granulosa cells. This substance is responsible for arresting
meiosis in the primary oocytes once they are wrapped within
granulosa cells in the fetal ovary.

Sherwood Human Physiology, From

Cells To Systems, 9e 2016
Control of Ovulation

3. It triggers production of local prostaglandins, which induce

ovulation by promoting vascular changes that cause rapid
follicular swelling while inducing enzymatic digestion of the
follicular wall. Together, these actions lead to rupture of the
weakened wall that covers the bulging follicle

4. It causes differentiation of follicular cells into luteal cells.

Because the LH surge triggers both ovulation and
luteinization, formation of the corpus luteum automatically
follows ovulation.

 Thus, the midcycle burst in LH secretion is a dramatic point in the

cycle; it terminates the follicular phase and initiates the luteal phase

Sherwood Human Physiology, From

Cells To Systems, 9e 2016
Sherwood Human
Physiology, From
Cells To Systems, 9e
2016
Langman Clinical Embriology 13e, 2015
 Control of Ovulation

The LH surge brings about four major changes in the follicle:

1. It halts estrogen synthesis by the follicular cells.

2. It reinitiates meiosis in the mature follicle‘s oocyte by blocking

release of oocyte maturation inhibitor produced by the
granulosa cells, which is responsible for arresting meiosis in the
primary oocytes once they are wrapped within granulosa cells
in the fetal ovary.

Sherwood Human Physiology, From Cells To

Systems, 9e 2016
 Control of Ovulation

The LH surge brings about four major changes in the follicle:

3. It triggers production of local prostaglandins, which induce

ovulation by promoting vascular changes that cause rapid
follicular swelling while inducing enzymatic digestion of the
follicular wall. Together, these actions lead to rupture of the
weakened wall that covers the bulging follicle

4. It causes differentiation of follicular cells into luteal cells. Because

the LH surge triggers both ovulation and luteinization, formation
of the corpus luteum automatically follows ovulation; LH surge
terminates the follicular phase and initiates the luteal phase.

Sherwood Human Physiology, From Cells To

Systems, 9e 2016
 Figure 81–5
Postulated mechanism of
ovulation.
Guyton & Hall Textbook Of Physiology
11th ed
The FSH peak, facilitated by the
increased estrogen levels in the
follicle, stimulates the
production of an adequate
number of LH receptors on the
granulosa cells for luteinization.
[Greenspan’s Basic & Clinical
Endocrinology 9e, 2011]
Basal body temperature and
plasma hormone concentrations
during the normal human
menstrual cycle. Values are
aligned with respect to the day
of the midcycle LH peak. FSH,
follicle-stimulating hormone; LH,
luteinizing hormone; M, menses.
 LH Receptors on Granulosa Cells

 Increased estrogen levels in the follicle facilitate FSH induction of LH

receptors on the granulosa cells, allowing the follicle to respond to the
ovulatory surge of LH levels.
 Without estrogen, LH receptors do not develop on the granulosa cells.
 The FSH peak stimulates the production of an adequate number of LH
receptors on the granulosa cells for luteinization.

Greenspan’s Basic &

Clinical Endocrinology
9e, 2011
 Control of Ovarian steroids synthesis
LH FSH
Theca cells Granulosa cells

Cholesterol Cholesterol

Pregnenolone Pregnenolone

Progesterone Progesterone

Androstenedione Androstenedione

Testosterone Testosterone

Estradiol

Preovulatory follicle Estrone

 Greenspan ‗s
Basic & Clinical
Preovulatory Endocrinology
follicle 9e, 2011

Greenspan ‗s Basic & Clinical Endocrinology 9e, 2011

 Greenspan ‗s
Corpus Basic & Clinical
Luteum Endocrinology
9e, 2011
 Greenspan ‗s Basic &
Clinical
Two-cell hypothesis - Figure 13–7 Endocrinology 9e,
2011

 A. The preovulatory follicle produces estradiol through a paracrine interaction

between theca and granulosa cells. The theca cells provide the substrate,
androstenedione, to the granulosa cell for estradiol production. The granulosa
cells express the enzymes necessary for transformation of androstenedione to
estradiol (P450 aromatase, 17β hydroxysteroid dehydrogenase-1).

 B. In the corpus luteum, granulosa-lutein cells gain vascularity, LH receptors, and

the enzymes necessary for progesterone synthesis. The theca-lutein cells remain
the source of androstenedione for estradiol production in granulosa-lutein cells.
Gonadotropins, steroidogenic factor-1 (SF-1), and steroidogenic acute regulatory
protein (StAR) play crucial roles in steroidogenesis with the ovary (ATP, adenosine
triphosphate; cAMP, cyclic adenosine monophosphate; FSH-R, follicle- stimulating
hormone receptor; LH-R, luteinizing hormone receptor; P450 arom, P450
aromatase; 17β- HSD-I, 17-β hydroxysteroid dehydrogenase-I). (Redrawn with
permission from Larsen et al, eds. The physiology and pathology of the female
reproductive axis. In: Williams Textbook of Endocrinology . Saunders; 2003; 604.)
Control of the Corpus Luteum

 LH ―maintains‖ the corpus luteum—that is, after triggering development of

the CL, LH (and FSH – Greenspan) stimulates ongoing steroid hormone
secretion by CL.

 Under the influence of LH (and FSH – Greenspan), the CL secretes both

progesterone and estrogen, with progesterone being its most abundant
hormonal product

 The plasma progesterone level increases for the first time during the luteal
phase.

 No progesterone is secreted during the follicular phase (except for a small

amount a few hours before ovulation).

 The follicular phase is dominated by estrogen and the luteal phase by

Sherwood Human
progesterone Physiology, From
Cells To Systems, 9e
2016
Sherwood Human Physiology, From Cells To Systems, 9e 2016
Control of the Corpus Luteum

 A transitory drop in the level of circulating estrogen occurs at midcycle as

the estrogen-secreting follicle meets its demise at ovulation.

 The estrogen level climbs again during the luteal phase because of the CL‘s
activity, although it does not reach the same peak as during the follicular
phase.

 Progesterone keeps the modestly high estrogen level during the luteal
phase from triggering another LH surge.

 Progesterone, which dominates the luteal phase, powerfully inhibits LH

secretion as well as FSH secretion by acting at both the hypothalamic ARC
nucleus and the anterior pituitary

 Inhibition of FSH and LH prevents new follicular maturation and ovulation

during the luteal phase.
Sherwood Human Physiology, From Cells To
Systems, 9e 2016
Control of the Corpus Luteum

 Following ovulation and in response to LH, the granulosa cells (membrana)

and thecal interstitial cells that remain in the ovulated follicle differentiate
into granulosa lutein and theca lutein cells, respectively, to form the corpus
luteum.

 LH induces the granulosa lutein cells to produce vascular endothelial

growth factor (VEGF), which plays an important role in developing the
corpus luteum vascularization.

 This neovascularization penetrates the basement membrane and provides

the granulosa lutein cells with LDL for progesterone biosynthesis.

Greenspan’s Basic &

Clinical Endocrinology
9e, 2011
Control of the Corpus Luteum

 After ovulation, the luteal cells upregulate their LH receptors by an

unknown mechanism.

 This is critical in that it allows basal levels of LH to maintain the

corpus luteum.

 Rescue of the corpus luteum with hCG from the developing

conceptus works through the LH receptor, which is vital for
embryonic life.

Greenspan’s Basic &

Clinical Endocrinology
9e, 2011
Estrogen induces the
synthesis of
progesterone
receptors in the
endometrium
 Menstruation Process
Corpus luteum regresses

Endometrium hormonal support withdrawn

Endometrial thinning & spiral Endometrium necrotic foci

arteries coiling Prostaglandin release

vasospasm

Necrosis of spiral arteries Endometrium necrotic foci

walls coalesce

Spotty hemorrhages Menstrual flow

INFLUENCES OF ESTROGEN AND PROGESTERONE ON THE UTERUS

o Estrogen

 stimulates growth of myometrium and endometrium

 stimulates proliferation of epithelial cells, glands, and blood
vessels in the endometrium, increasing this lining to a thickness of
3 to 5 mm (proliferative phase, lasts from the end of menstruation
to ovulation)
 peak estrogen levels trigger the LH surge responsible for
ovulation
 induces the synthesis of progesterone receptors in the
endometrium  progesterone can exert an effect on the
endometrium only after it has been ―primed‖ by estrogen.

Williams Textbook of Endocrinology, 11th ed 2008

 Influences of Estrogen and Progesterone on the Uterus

o Progesterone

 converts the estrogen-primed endometrium into a hospitable and

nutritious lining suitable for implantation of a fertilized ovum.
 accumulation of electrolytes and water  endometrial
connective tissue becomes loose and edematous  facilitates
implantation of the fertilized ovum.
 prepares the endometrium to sustain an early-developing embryo
 induces the endometrial glands to secrete and store large
quantities of glycogen
 causes tremendous growth of the endometrial blood vessels.
 reduces the contractility of the uterus to provide a quiet
environment for implantation and embryonic growth.
Williams Textbook of Endocrinology, 11th ed 2008
Figure 16-3 Effect of pulsatile or continuous administration of gonadotropin-releasing hormone (GnRH) to
ovariectomized monkeys rendered them GnRH-deficient by placement of a lesion in the hypothalamus.
Release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) was restored by hourly GnRH
infusion, inhibited during a continuous infusion, and again restored after reinstitution of pulsatile GnRH
administration.

Williams Textbook of Endocrinology, 11th ed 2008

 Gonadotropin-releasing Hormone

o The variations in GnRH pulse frequency are achieved, at least in

part, by gonadal steroid feedback.

 Estradiol increases GnRH pulse frequency

 Elevated progesterone levels decrease GnRH pulse frequency

and thereby lead to the preferential biosynthesis and secretion
of FSH that is observed in the late luteal phase.

Williams Textbook of Endocrinology, 11th ed 2008

 Gonadotropin-releasing Hormone

o Estrogen signaling to GnRH neurons appears to be critical for both

suppressing FSH and LH and also coordinating the preovulatory
surge release of LH.

o GnRH neurons are directly regulated by estradiol primarily through

estrogen receptor-β, and indirectly through estradiol-sensitive
afferent neurons.

o Direct treatment of GnRH neurons with estradiol generally represses

GnRH gene expression but, in vivo, this repression is transiently
overcome by indirect estradiol-dependent signals relayed by afferent
neurons.

o Thus, estradiol can inhibit or stimulate GnRH secretion and

coordinate both follicular maturation and the preovulatory surge
release of LH.[16]
Williams Textbook of Endocrinology, 11 ed 2008
th
 Gonadotropin-releasing Hormone

o GnRH pulsatility is also modulated by the action of locally released neurotransmitters.

 Norepinephrine stimulates GnRH release, whereas dopamine exerts an inhibitory

effect
 β-Endorphin and other opioids may also serve to suppress the hypothalamic
release of GnRH. (effect of physical exercise on menstrual cycle)
 The gonadal steroids modify endogenous opioid activity, and the negative
feedback of steroids on gonadotropins appears to be mediated, at least in part, by
endogenous opioids.
 Thus, it was proposed that sex steroids enhance the activity of endogenous
opioids that in turn exert an inhibitory effect on GnRH secretion.
 The negative effect of opioids on GnRH secretion is also clinically explicable
because the reduced GnRH secretion associated with hypothalamic amenorrhea
may be mediated by an increase in endogenous opioid inhibitory tone.

Williams Textbook of Endocrinology, 11th ed 2008

 Gonadotropin-releasing Hormone

o Kisspeptins, encoded by the Kiss1 gene, and their receptor, GPR54,

play key roles in the regulation of GnRH secretion

o Mutations or targeted knockout of GPR54 produce isolated

hypogonadotropic hypogonadism in humans and mice, indicating
that signaling through this receptor is essential for sexual
development and function.

o Kisspeptins stimulate GnRH and gonadotropin secretion in

prepubertal and adult animals.

o Kisspeptin- and GPR54-expressing neurons are targets for the

negative and positive feedback actions of sex steroids.

Williams Textbook of Endocrinology, 11th ed 2008

 Normal Menstruation

 Menstrual blood
 75% arterial blood, 25% venous blood
 Contains tissue debris, prostaglandins, and fibrinolysin.
Fibrinolysin lyses clots  menstrual blood does not contain clots,
unless the flow is excessive.

 Duration of menstrual flow:

 3-5 days (1-8 days)

 Amount of blood loss:

 slight spotting  80 ml ( > 80 ml is abnormal); average amount 30 ml.
 Uterine Bleeding Disorders

Menorrhea (Gr. men: month, rhoia: flow)

• Normal discharge of the menses

Amenorrhea

• Physiologic amenorrhea
Normal absence of menstruation before the menarche, during
pregnancy, lactation, and after menopause
• Primary amenorrhea
Lack of menarche at least 16 yr of age; failure of menstruation to
occur at puberty.
• Secondary amenorrhea
Cessation of menstruation after it has once been established at
puberty.
 Uterine Bleeding Disorders

Menorrhagia

• Excessive uterine bleeding occurring at the regular intervals of

menstruation, the period of flow being greater than usual duration.

Metrorrhagia

• Uterine bleeding, usually of normal amount, occurring at completely

irregular intervals, the period of flow sometimes being prolonged.

Oligomenorrhea

• Markedly diminished menstrual flow.

• Reduction in the frequency of menstruation so that the interval between
cycles is as long as 39 to 90 days.
 Uterine Bleeding Disorders

 Dysfunctional uterine bleeding

 The terms dysfunctional uterine bleeding and anovulatory bleeding are used
interchangeably and denote inappropriate stimulation of the endometrium
during dysfunctional states of the reproductive system.

 Bleeding manifestations of anovulatory cycles in the absence of uterine

pathology or systemic illness

 Acyclic production of estrogen during anovulatory cycles gives rise to irregular

shedding of the endometrium

 Anovulatory uterine bleeding arising from responses of the endometrium to

inappropriate production of ovarian steroids

 Common examples of anovulatory bleeding include those associated with

exercise-related anovulation, hyperprolactinemia, hypothyroidism

Williams Textbook of Endocrinology 12e ; 2011

 Management of Dysfunctional Uterine Bleeding

 If ovulatory function can be restored, anovulatory bleeding usually gives

way to predictable cyclic periods.

 Exogenous estrogen and progestin are administered for several purposes.

 The indications for hormonal treatment of uterine bleeding include the need
 to stop acute uterine bleeding

 to maintain predictable bleeding episodes

 to prevent endometrial hyperplasia.

 Hormonal treatments are used to stop anovulatory uterine bleeding and to

induce predictable bleeding episodes.

Williams Textbook of Endocrinology 12e ; 2011

 Management of Dysfunctional Uterine Bleeding
[Oral Contraceptive]

 Use of combination oral contraceptives in an acute or chronic fashion is the

most common treatment for irregular uterine bleeding.

 The estrogen component of the pill stabilizes the endometrial tissue and
stops shedding within hours; it decreases ovarian secretion of sex steroids
by suppression of gonadotropins within several days.

 The progestin component of the pill directly affects endometrial tissue to

decrease shedding over days and potentiates ovarian suppression induced
by estrogen.

 The progestin (in the presence of estrogen) induces differentiation of the

endometrial tissue into a stable form called pseudodecidua.

Williams Textbook of Endocrinology 12e ; 2011

 Common Gynecologic Problem

Dysmenorrhea

• Painful menstruation
• Primary dysmenorrhea:
Unknown etiology, associated with psychogenic factors, uterine muscle
spasm due to increased prostaglandin secretion.

• Secondary dysmenorrhea:
Associated with demonstrable causes: uterine hyperplasia, pelvic
inflammatory disease, pelvic tumors, endometriosis.

• Primary and secondary dysmenorrhea may be aggravated by psychic and

emotional factors.
Thank you