The Female Reproductive System: Paul F. Terranova, PH.D

C H A P T E R
The Female
38 Reproductive System
Paul F. Terranova, Ph.D.
CHAPTER OUTLINE
■ AN OVERVIEW OF THE FEMALE REPRODUCTIVE ■ FORMATION OF THE CORPUS LUTEUM FROM THE
SYSTEM POSTOVULATORY FOLLICLE
■ THE HYPOTHALAMIC-PITUITARY AXIS ■ THE MENSTRUAL CYCLE
■ THE FEMALE REPRODUCTIVE ORGANS ■ ESTROGEN, PROGESTIN, AND ANDROGEN:
■ FOLLICULOGENESIS, STEROIDOGENESIS, ATRESIA, TRANSPORT AND METABOLISM
AND MEIOSIS ■ PUBERTY
■ FOLLICLE SELECTION AND OVULATION ■ MENOPAUSE
■ INFERTILITY
KEY CONCEPTS
1. Pulses of hypothalamic GnRH regulate the secretion of LH 7. The formation of a functional corpus luteum requires the
and FSH, which enhance follicular development, steroido- presence of an LH surge, adequate numbers of LH recep-
genesis, ovulation, and formation of the corpus luteum. tors, sufficient granulosa cells, and significant proges-
2. LH and FSH, in coordination with ovarian theca and granu- terone secretion.
losa cells, regulate the secretion of follicular estradiol. 8. The uterine cycle is regulated by estradiol and proges-
3. Ovulation occurs as the result of a positive feedback of fol- terone, such that estradiol induces proliferation of the uter-
licular estradiol on the hypothalamic-pituitary axis that in- ine endometrium, whereas progesterone induces differen-
duces LH and FSH surges. tiation of the uterine endometrium and the secretion of
4. Follicular development occurs in distinct steps: primordial, distinct products.
primary, secondary, tertiary, and graafian follicle stages. 9. During puberty, the hypothalamus begins to secrete in-
5. Follicular rupture (ovulation) requires the coordination of creasing quantities of GnRH, which increases LH and FSH
appropriately timed LH and FSH surges that induce in- secretion, enhances ovarian function, and leads to the first
flammatory reactions in the graafian follicle, leading to ovulation.
dissolution at midcycle of the follicular wall by several 10. Menopause ensues from the loss of numerous oocytes in
ovarian enzymes. the ovary and the subsequent failure of follicular develop-
6. Follicular atresia results from the withdrawal of go- ment and estradiol secretion. LH and FSH levels rise from
nadotropin support. the lack of negative feedback by estradiol.
he fertility of the mature human female is cyclic. The tive-feedback effects on the hypothalamus and on pituitary
T release from the ovary of a mature female germ cell or
ovum occurs at a distinct phase of the menstrual cycle. The
gonadotrophs, generating the cyclic pattern of LH and
FSH release characteristic of the female reproductive sys-
secretion of ovarian steroid hormones, estradiol and prog- tem. Since the hormonal events during the menstrual cycle
esterone, and the subsequent release of an ovum during the are delicately synchronized, the menstrual cycle can be
menstrual cycle are controlled by cyclic changes in LH and readily affected by stress and by environmental, psycho-
FSH from the pituitary gland, and estradiol and proges- logical, and social factors.
terone from the ovaries. The cyclic changes in steroid hor- The female cycle is characterized by monthly bleeding,
mone secretion cause significant changes in the structure resulting from the withdrawal of ovarian steroid hormone
and function of the uterus in preparing it for the reception support of the uterus, which causes shedding of the super-
of a fertilized ovum. At different stages of the menstrual cy- ficial layers of the uterine lining at the end of each cycle.
cle, progesterone and estradiol exert negative- and posi- The first menstrual cycle occurs during puberty. Menstrual
667
668 PART X REPRODUCTIVE PHYSIOLOGY
cycles are interrupted during pregnancy and lactation and lation. Both LH and FSH regulate follicular steroidogenesis
cease at menopause. Menstruation signifies a failure to con- and androgen and estradiol secretion, and LH regulates the
ceive and results from regression of the corpus luteum and secretion of progesterone from the corpus luteum. Ovarian
subsequent withdrawal of luteal steroid support of the su- steroids inhibit the secretion of LH and FSH with one ex-
perficial endometrial layer of the uterus. ception: Just prior to ovulation (at midcycle), estradiol has
a positive-feedback effect on the hypothalamic-pituitary
axis and induces significant increases in the secretion of
AN OVERVIEW OF THE FEMALE GnRH, LH, and FSH. The ovary also produces three
REPRODUCTIVE SYSTEM polypeptide hormones. Inhibin suppresses the secretion of
FSH. Activin (an inhibin-binding protein) increases the se-
An overview of the interactions of hormonal factors in fe- cretion of FSH, and follistatin (an activin-binding protein)
male reproduction is shown in Figure 38.1. The female reduces the secretion of FSH.
hormonal system consists of the brain, pituitary, ovaries, Shortly after fertilization, the embryo begins to develop
and reproductive tract (oviduct, uterus, cervix, and vagina). placenta cells, which attach to the uterine lining and unite
In the brain, the hypothalamus produces gonadotropin-re- with the maternal placental cells. The placenta produces
leasing hormone (GnRH), which controls the secretion of several pituitary-like and ovarian steroid-like hormones.
luteinizing hormone (LH) and follicle-stimulating hor- These hormones support placental and fetal development
mone (FSH). throughout pregnancy and have a role in parturition. The
The mature ovary has two major functions: the matura- mammary glands are also under the control of pituitary
tion of germ cells and steroidogenesis. Each germ cell is ul- hormones and ovarian steroids, and provide the baby with
timately enclosed within a follicle, a major source of steroid immunological protection and nutritional support through
hormones during the menstrual cycle. At ovulation, the lactation. Lactation is hormonally controlled by prolactin
ovum or egg is released and the ruptured follicle is trans- (PRL) from the anterior pituitary, which regulates milk
formed into a corpus luteum, which secretes progesterone production, and oxytocin from the posterior pituitary,
as its main product. FSH is primarily involved in stimulat- which induces milk ejection from the breasts.
ing the growth of ovarian follicles, while LH induces ovu-
THE HYPOTHALAMIC-PITUITARY AXIS

Environment
Age Drugs The hypothalamic-pituitary axis has an important role in
regulating the menstrual cycle. GnRH, a decapeptide pro-
duced in the hypothalamus and released in a pulsatile man-
Brain
⫹Ⲑ⫺
ner, controls the secretion of LH and FSH through a portal
Centers vascular system (see Chapter 32). Blockade of the portal
system reduces the secretion of LH and FSH and leads to
ovarian atrophy and a reduction in ovarian hormone secre-
Hypothalamus ⫺
tion. The secretion of GnRH by the hypothalamus is regu-
lated by neurons from other brain regions. Neurotransmit-
ters, such as epinephrine and norepinephrine, stimulate the
GnRH Dopamine secretion of GnRH, whereas dopamine and serotonin in-
hibit secretion of GnRH. In addition, ovarian steroids and
peptides and hypothalamic neuropeptides can regulate the
Anterior pituitary ⫺ secretion of GnRH. GnRH stimulates the pituitary go-
nadotrophs to secrete LH and FSH. GnRH binds to high-
affinity receptors on the gonadotrophs and stimulates the
FSH/LH ⫹ ⫺ PRL
secretion of LH and FSH through a phosphoinositide-pro-
Inhibin ⫺ ,
tein kinase C-mediated pathway (see Chapter 1).
activin ⫹ , ⫹
A graph of LH release throughout the female life span is
Ovary
follistatin ⫺ shown in Figure 38.2. During the neonatal period, LH is re-
leased at low and steady rates without pulsatility; this pe-
riod coincides with lack of development of mature ovarian
Estradiol,
progesterone,
follicles and very low to no ovarian estradiol secretion. Pul-
androgen satile release begins with the onset of puberty and for sev-
⫹ ⫹ eral years is expressed only during sleep; this period coin-
cides with increased but asynchronous follicular
Reproductive Secondary sex development and with increased secretion of ovarian estra-
tract characteristics diol. Upon the establishment of regular functional men-
Regulation of the reproductive tract in the strual cycles associated with regular ovulation, LH pulsatil-
FIGURE 38.1
female. The main reproductive hormones are ity prevails throughout the 24-hour period, changing in a
shown in boxes. Positive and negative regulations are depicted by monthly cyclic manner. In postmenopausal women whose
plus and minus signs. ovaries lack sustained follicular development and exhibit
CHAPTER 38 The Female Reproductive System 669
Plasma LH conc. Day Night Day Night Day Night Day Night Day Night
FIGURE 38.2
Relative levels of
LH release in hu-
man females throughout life. (Modi-
Neonatal Pubertal Tonic Midcycle Postmenopausal fied from Yen SSC, et al. In: Ferin M, et
al., eds. Biorhythms and Human Repro-
Reproductive duction. New York: Wiley, 1974.)
low ovarian estradiol secretion, mean circulating LH levels tures change in a cyclic manner under the influence of the
are high and pulses occur at a high frequency. reproductive hormones.
The ovaries are in the pelvic portion of the abdominal cav-
ity on both sides of the uterus and are anchored by ligaments
THE FEMALE REPRODUCTIVE ORGANS (Fig. 38.3). An adult ovary weighs 8 to 12 g and consists of an
outer cortex and an inner medulla, without a sharp demarca-
The female reproductive tract has two major components: tion. The cortex is surrounded by a fibrous tissue, the tunica
the ovaries, which produce the mature ovum and secrete albuginea, covered by a single layer of surface epithelium
progestins, androgens, and estrogens; and the ductal sys- continuous with the mesothelium covering the other organs
tem, which transports ovum, is the place of the union of the in the abdominal cavity. The cortex contains oocytes en-
sperm and egg, and maintains the developing conceptus closed in follicles of various sizes, corpora lutea, corpora al-
until delivery. The morphology and function of these struc- bicantia, and stromal cells. The medulla contains connective
Isthmus
Fundus
Ampulla
Corpus Broad ligament
Uterus
Oviduct
Myometrium Fimbria
Endometrium
Ovary
Infundibulum
Primordial follicle
Cervix
Primary follicle
Vagina
Ovarian ligament Atretic follicle
Ovarian vessels Early antrum formation
Corpus albicans
Mature corpus luteum Ovary Graafian follicle
Early corpus luteum
Stroma Germinal epithelium
Ovulation
FIGURE 38.3 The female reproductive organs. (Modified from Patton BM. Human Embryology. New
York: McGraw-Hill, 1976.)
and interstitial tissues. Blood vessels, lymphatics, and nerves cation (keratinization) of the vaginal epithelium, whereas
enter the medulla of the ovary through the hilus. progesterone opposes those actions and induces the influx
On the side that ovulates, the oviduct (fallopian tube) of polymorphonuclear leukocytes into the vaginal fluids.
receives the ovum immediately after ovulation. The Estradiol also activates vaginal glands that produce lubri-
oviducts are the site of fertilization and provide an envi- cating fluid during coitus.
ronment for development of the early embryo. The
oviducts are 10 to 15 cm long and composed of sequential
regions called the infundibulum, ampulla, and isthmus. FOLLICULOGENESIS, STEROIDOGENESIS,
The infundibulum is adjacent to the ovary and opens to the ATRESIA, AND MEIOSIS
peritoneal cavity. It is trumpet-shaped with finger-like pro-
jections called fimbria along its outer border that grasp the Most follicles in the ovary will undergo atresia. However,
ovum at the time of follicular rupture. Its thin walls are cov- some will develop into mature follicles, produce steroids,
ered with densely ciliated projections, which facilitate and ovulate. As follicles mature, oocytes will also mature by
ovum uptake and movement through this region. The am- entering meiosis, which produces the proper number of
pulla is the site of fertilization. It has a thin musculature and chromosomes in preparation for fertilization.
well-developed mucosal surface. The isthmus is located at
the uterotubal junction and has a narrow lumen surrounded The Primordial Follicle Contains an
by smooth muscle. It has sphincter-like properties and can Oocyte Arrested in Meiosis
serve as a barrier to the passage of germ cells. The oviducts
transport the germ cells in two directions: sperm ascend to- Female germ cells develop in the embryonic yolk sac and
ward the ampulla and the zygote descends toward the migrate to the genital ridge where they participate in the
uterus. This requires coordination between smooth muscle development of the ovary (Table 38.1). Without germ
contraction, ciliary movement, and fluid secretion, all of cells, the ovary does not develop. The germs cells, called
which are under hormonal and neuronal control. oogonia, actively divide by mitosis. Oogonia undergo mi-
The uterus is situated between the urinary bladder and tosis only during the prenatal period. By birth, the ovaries
rectum. On each upper side, an oviduct opens into the uter- contain a finite number of oocytes, estimated to be about 1
ine lumen, and on the lower side, the uterus connects to the million. Most of them will die by a process called atresia. By
vagina. The uterus is composed of two types of tissue. The puberty, only 200,000 oocytes remain; by age 30, only
outer part is the myometrium, composed of multiple layers 26,000 remain; and by the time of menopause, the ovaries
of smooth muscle. The inner part, lining the lumen of the are essentially devoid of oocytes.
uterus, is the endometrium, which contains a deep stromal When oogonia cease the process of mitosis, they are called
layer next to the myometrium and a superficial epithelial oocytes. At that time they enter the meiotic cycle (or meio-
layer. The stroma is permeated by spiral arteries and con- sis, to prepare for the production of a haploid ovum), become
tains much connective tissue. The epithelial layer is inter- arrested in prophase of the first meiotic division, and remain
rupted by uterine glands, which also penetrate the stromal arrested in that phase until they either die or grow into ma-
layer and are lined by columnar secretory cells. The uterus ture oocytes at the time of ovulation. The primordial follicle
provides an environment for the developing fetus, and (Fig. 38.4) is 20 ␮m in diameter and contains an oocyte,
eventually, the myometrium will generate rhythmic con- which may or may not be surrounded by a single layer of flat-
tractions that assist in expelling the fetus at delivery. tened (squamous) pregranulosa cells. When pregranulosa
The cervix (neck) is a narrow muscular canal that con- cells surround the oocyte, a basement membrane develops,
nects the vagina and the body (corpus) of the uterus. It separating the granulosa from the ovarian stroma.
must dilate in response to hormones to allow the expulsion
of the fetus. The cervix has numerous glands with a colum-
A Graafian Follicle Is the Final Stage of
nar epithelium that produces mucus under the control of
Follicle Development
estradiol. As more and more estradiol is produced during
the follicular phase of the cycle, the cervical mucus changes Folliculogenesis (also called follicular development) is the
from a scanty viscous material to a profuse watery and process by which follicles develop and mature (see Fig.
highly elastic substance called spinnbarkeit. The viscosity 38.3). Follicles are in one of the following physiological
of the spinnbarkeit can be tested by touching it with a piece states: resting, growing, degenerating, or ready to ovulate.
of paper and lifting vertically. The mucus can form a thread During each menstrual cycle, the ovaries produce a group
up to 6 cm under the influence of elevated estradiol. If a of growing follicles of which most will fail to grow to ma-
drop of the cervical mucus is placed on a slide and allowed turity and will undergo follicular atresia (death) at some
to dry, it will form a typical ferning pattern when under the stage of development. However, one dominant follicle
influence of estradiol. generally emerges from the cohort of developing follicles
The vagina is well innervated, and has a rich blood sup- and it will ovulate, releasing a mature haploid ovum.
ply. It is lined by several layers of epithelium that change Primordial follicles are generally considered the non-
histologically during the menstrual cycle. When estradiol growing resting pool of follicles, which gets progressively
levels are low, as during the prepubertal or post- depleted throughout life; by the time of menopause, the
menopausal periods, the vaginal epithelium is thin and the ovaries are essentially devoid of all follicles. Primordial fol-
secretions are scanty, resulting in a dry and infection-sus- licles are located in the ovarian cortex (peripheral regions
ceptible area. Estradiol induces proliferation and cornifi- of the ovary) beneath the tunica albuginea.
TABLE 38.1 Different Stages in the Development of an Ovum and Follicle
Stage Process Ovum Follicle

Fetal life Migration Primordial germ cells
Mitosis Oogonia Primordial follicle
First meiotic division begins Primary oocyte Primary follicle
Birth Arrest in prophase
Growth of oocyte and follicle
Puberty Follicular maturation Secondary follicle
Cycle Antral follicle
Ovulation Resumption of meiosis Secondary oocyte Graafian follicle

Emission of first polar body
Arrest in metaphase
Corpus luteum
Fertilization Second meiotic division complete Zygote
Emission of second polar body
Implantation Mitotic divisions Embryo
Blastocyst
Parturition Body Patterning Fetus Corpus albicans
Progression from primordial to the next stage of follicu- acquire receptors for FSH and start producing small
lar development, the primary stage, occurs at a relatively amounts of estrogen. The theca externa remains fibroblastic
constant rate throughout fetal, juvenile, prepubertal, and and provides structural support to the developing follicle.
adult life. Once primary follicles leave the resting pool, Development beyond the primary follicle is go-
they are committed to further development or atresia. Most nadotropin-dependent, begins at puberty, and continues in
become atretic, and typically only one fully developed fol- a cyclic manner throughout the reproductive years. As the
licle will ovulate. The conversion from primordial to pri- follicle continues to grow, theca layers expand, and fluid-
mary follicles is believed to be independent of pituitary go- filled spaces or antra begin to develop around the granulosa
nadotropins. The exact signal that recruits a follicle from a cells. This early antral stage of follicle development is re-
resting to a growing pool is unknown; it could be pro- ferred to as the tertiary follicular stage (see Fig. 38.4). The
grammed by the cell genome or influenced by local ovarian critical hormone responsible for progression from the pre-
growth regulators. antral to the antral stage is FSH. Mitosis of the granulosa
The first sign that a primordial follicle is entering the cells is stimulated by FSH. As the number of granulosa cells
growth phase is a morphological change of the flattened increases, the production of estrogens, the binding capac-
pregranulosa cells into cuboidal granulosa cells. The ity for FSH, the size of the follicle, and the volume of the
cuboidal granulosa cells proliferate to form a single contin- follicular fluid all increase significantly.
uous layer of cells surrounding the oocyte, which has en- As the antra increase in size, a single, large, coalesced
larged from 20 ␮m in the primordial stage to 140 ␮m in di- antrum develops, pushing the oocyte to the periphery of
ameter. At this stage, a glassy membrane, the zona the follicle and forming a large 2- to 2.5-cm-diameter
pellucida, surrounds the oocyte and serves as means of at- graafian follicle (preovulatory follicle; see Fig. 38.4). Three
tachment through which the granulosa cells communicate distinct granulosa cell compartments are evident in the
with the oocyte. This is the primary follicular stage of de- graafian follicle. Granulosa cells surrounding the oocyte are
velopment, consisting of one layer of cuboidal granulosa cumulus granulosa cells (collectively called cumulus
cells and a basement membrane. oophorus). Those cells lining the antral cavity are called
The follicle continues to grow, mainly through prolifer- antral granulosa cells and those attached to the basement
ation of its granulosa cells, so that several layers of granu- membrane are called mural granulosa cells. Mural and
losa cells exist in the secondary follicular stage of develop- antral granulosa cells are more steroidogenically active
ment (see Fig. 38.4). As the secondary follicle grows deeper than cumulus cells.
into the cortex, stromal cells, near the basement membrane, In addition to bloodborne hormones, antral follicles have
begin to differentiate into cell layers called theca interna a unique microenvironment in which the follicular fluid con-
and theca externa, and a blood supply with lymphatics and tains different concentrations of pituitary hormones,
nerves forms within the thecal component. The granulosa steroids, peptides, and growth factors. Some are present in
layer remains avascular. the follicular fluid at a concentration 100 to 1,000 times
The theca interna cells become flattened, epithelioid, higher than in the circulation. Table 38.2 lists some parame-
and steroidogenic. The granulosa cells of secondary follicles ters of human follicles at successive stages of development in
Primordial Basement membrane

follicle Oocyte
Granulosa cells
Primary Basement membrane

follicle Granulosa cells
Fully grown oocyte
Zona pellucida
Secondary Basement membrane

follicle Granulosa cells
Zona pellucida
Fully grown oocyte
Presumptive theca
Theca externa
Basement membrane
Fully grown oocyte
Early tertiary
Multiple layers of
follicle
granulosa cells
Zona pellucida
Antrum
Theca interna
Graafian
follicle
Theca interna
Cumulus oophorus
Zona pellucida
Antrum (follicular fluid) FIGURE 38.4
The developing follicle,
Corona radiata from primordial through
graafian. (Modified from Erickson GF. In:
Basement membrane Sciarra JJ, Speroff L, eds. Reproductive En-
Granulosa cells docrinology, Infertility, and Genetics. New
Theca externa York: Harper & Row, 1981.)
the follicular phase. There is a 5-fold increase in follicular di- The follicular fluid contains other substances, including
ameter and a 25-fold rise in the number of granulosa cells. As inhibin, activin, GnRH-like peptide, growth factors, opioid
the follicle matures, the intrafollicular concentration of FSH peptides, oxytocin, and plasminogen activator. Inhibin and
does not change much, whereas that of LH increases and activin inhibit and stimulate, respectively, the release of
that of PRL declines. Of the steroids, the concentrations of FSH from the anterior pituitary. Inhibin is secreted by
estradiol and progesterone increase 20-fold, while androgen granulosa cells. In addition to its effect on FSH secretion,
levels remain unchanged. inhibin also has a local effect on ovarian cells.
TABLE 38.2 Different Parameters of Follicles During the First Half of the Menstrual Cycle
Granulosa
Cycle Diameter Volume Cells FSH
(day) (mm) (mL) (⫻106) ng/mL LH PRL A E2 P4
1 4 0.05 2 2.5 — 60 800 100 —
4 7 0.15 5 2.5 — 40 800 500 100
7 12 0.50 15 3.6 2.8 20 800 1,000 300
12 20 0.50 50 3.6 2.8 5 800 2,000 2,000
FSH, follicle-stimulating hormone; LH, luteinizing hormone; PRL, prolactin; A, androstenedione; E2, estradiol; P4, progesterone. (Modi-
fied from Erickson GF. An analysis of follicle development and ovum maturation. Semin Reprod Endocrinol 1986;4:233–254.)
Granulosa and Theca Cells Both Participate is subsequently converted to androstenedione by 3␤-hy-
in Steroidogenesis droxysteroid dehydrogenase. The androgens contain 19
carbons. Testosterone and androstenedione diffuse from
The main physiologically active steroid produced by the the thecal compartment, cross the basement membrane,
follicle is estradiol, a steroid with 18 carbons. Steroidoge- and enter the granulosa cells.
nesis, the process of steroid hormone production, depends In the granulosa cell, under the influence of FSH, with
on the availability of cholesterol, which originates from cAMP as a second messenger, testosterone and androstene-
several sources and serves as the main precursor for all of dione are then converted to estradiol and estrone, respec-
steroidogenesis. Ovarian cholesterol can come from plasma tively, by the enzyme aromatase, which aromatizes the A
lipoproteins, de novo synthesis in ovarian cells, and choles- ring of the steroid and removes one carbon (see Fig. 38.5;
terol esters within lipid droplets in ovarian cells. For ovar- see Fig. 37.9). Estrogens typically have 18 carbons. Estrone
ian steroidogenesis, the primary source of cholesterol is can then be converted to estradiol by 17␤-hydroxysteroid
low-density lipoprotein (LDL). dehydrogenase in granulosa cells.
The conversion of cholesterol to pregnenolone by cho- In summary, estradiol secretion by the follicle requires
lesterol side-chain cleavage enzyme is a rate-limiting step cooperation between granulosa and theca cells and coordi-
regulated by LH using the second messenger cAMP nation between FSH and LH. An understanding of this
(Fig. 38.5). LH binds to specific membrane receptors on two-cell, two-gonadotropin hypothesis requires recogni-
theca cells, activates adenylyl cyclase through a G protein, tion that the actions of FSH are restricted to granulosa cells
and increases the production of cAMP. cAMP increases because all other ovarian cell types lack FSH receptors. LH
LDL receptor mRNA, the uptake of LDL cholesterol, and actions, on the other hand, are exerted on theca, granulosa,
cholesterol ester synthesis. cAMP also increases the trans- and stromal (interstitial) cells and the corpus luteum. The
port of cholesterol from the outer to the inner mitochondr- expression of LH receptors is time-dependent because
ial membrane, the site of pregnenolone synthesis, using a theca cells acquire LH receptors at a relatively early stage,
unique protein called steroidogenic acute regulatory pro- whereas LH receptors on granulosa cells are induced by
tein (StAR). Pregnenolone, a 21-carbon steroid of the FSH in the later stages of the maturing follicle.
progestin family, diffuses out of the mitochondria and en- The biosynthetic enzymes are differentially expressed
ters the ER, the site of subsequent steroidogenesis. in the two cells. Aromatase is expressed only in granulosa
Two steroidogenic pathways may be used for subse- cells, and its activation and induction are regulated by
quent steroidogenesis (see Fig. 37.9). In theca cells, the FSH. Granulosa cells are deficient in 17␣-hydroxylase
delta 5 pathway is predominant; in granulosa cells and the and cannot proceed beyond the C-21 progestins to gen-
corpus luteum, the delta 4 pathway is predominant. Preg- erate C-19 androgenic compounds (see Fig. 38.5). Conse-
nenolone gets converted to either progesterone by 3␤-hy- quently, estrogen production by granulosa cells depends
droxysteroid dehydrogenase in the delta 4 pathway or to on an adequate supply of exogenous aromatizable andro-
17␣-hydroxypregnenolone by 17␣-hydroxylase in the gens, provided by theca cells. Under LH regulation, theca
delta 5 pathway. In the delta 4 pathway, progesterone gets cells produce androgenic substrates, primarily an-
converted to 17␣-hydroxyprogesterone (by 17␣-hydroxy- drostenedione and testosterone, which reach the granu-
lase), which is subsequently converted to androstenedione losa cells by diffusion. The androgens are then converted
and testosterone by 17,20-lyase and 17␤-hydroxysteroid to estrogens by aromatization.
dehydrogenase (17-ketosteroid reductase), respectively. In In follicles, theca and granulosa cells are exposed to dif-
the delta 5 pathway, 17␣-hydroxypregnenolone gets con- ferent microenvironments. Vascularization is restricted to
verted to dehydroepiandrosterone (by 17,20-lyase), which the theca layer because blood vessels do not penetrate the
Theca cell Granulosa cell
Cholesterol
Basement membrane
Capillary
Cholesterol
Receptor
cAMP
⫹ The two-
Receptor
LH FIGURE 38.5
LH cAMP ⫹ ATP cell, two-
Pregnenolone
ATP Pregnenolone gonadotropin hypothesis.
The follicular theca cells, un-
Progesterone der control of LH, produce
17OH pregnenolone androgens that diffuse to the
follicular granulosa cells,
Androstenedione where they are converted to
Dehydroepiandrosterone cAMP estrogens via an FSH-sup-
Testosterone ⫹ ported aromatization reac-
Receptor
tion. The dashed line indi-

Androstenedione ⫹ ATP FSH cates that granulosa cells
cAMP
cannot convert progesterone
Estradiol Estrone to androstenedione because
Testosterone of the lack of the enzyme
17␣-hydroxylase.
basement membrane. Theca cells, therefore, have better ac- hypertrophy and may remain in the ovary for extended pe-
cess to circulating cholesterol, which enters the cells via riods of time.
LDL receptors. Granulosa cells, on the other hand, prima-
rily produce cholesterol from acetate, a less efficient
process than uptake. In addition, granulosa cells are bathed Meiosis Resumes During the Periovulatory Period
in follicular fluid and exposed to autocrine, paracrine, and All healthy oocytes in the ovary remain arrested in prophase
juxtacrine control by locally produced peptides and growth of the first meiosis. When a graafian follicle is subjected to a
factors. “Juxtacrine” describes the interaction of a mem- surge of gonadotropins (LH and/or FSH), the oocyte within
brane-bound growth factor on one cell with its membrane- undergoes the final stages of meiosis, resulting in the pro-
bound receptor on an adjacent cell. duction of a mature gamete. This maturation is accomplished
FSH acts on granulosa cells by a cAMP-dependent by two successive cell divisions in which the number of chro-
mechanism and produces a broad range of activities, in- mosomes is reduced, producing haploid gametes. At fertil-
cluding increased mitosis and cell proliferation, the stimu- ization, the diploid state is restored.
lation of progesterone synthesis, the induction of aro- Primary oocytes arrested in meiotic prophase 1 (of the
matase, and increased inhibin synthesis. As the follicle first meiosis) have duplicated their centrioles and DNA
matures, the number of receptors for both gonadotropins (4n DNA) so that each chromosome has two identical
increases. FSH stimulates the formation of its own recep- chromatids. Crossing over and chromatid exchange occur
tors and induces the appearance of LH receptors. The com- during this phase, producing genetic diversity. The re-
bined activity of the two gonadotropins greatly amplifies sumption of meiosis, ending the first meiotic prophase
estrogen production. and beginning of meiotic metaphase 1, is characterized by
Androgens are produced by theca and stromal cells. disappearance of the nuclear membrane, condensation of
They serve as precursors for estrogen synthesis and also the chromosomes, nuclear dissolution (germinal vesicle
have a distinct local action. At low concentrations, andro- breakdown), and alignment of the chromosomes on the
gens enhance aromatase activity, promoting estrogen pro- equator of the spindle. At meiotic anaphase 1, the homol-
duction. At high concentrations, androgens are converted ogous chromosomes move in opposite directions under
by 5␣-reductase to a more potent androgen, such as dihy- the influence of the retracting meiotic spindle at the cel-
drotestosterone (DHT). When follicles are overwhelmed lular periphery. At meiotic telophase 1, an unequal divi-
by androgens, the intrafollicular androgenic environment sion of the cell cytoplasm yields a large secondary oocyte
antagonizes granulosa cell proliferation and leads to apop- (2n DNA) and a small, nonfunctional cell, the first polar
tosis of the granulosa cells and subsequent follicular atresia. body (2n DNA). Each cell contains half the original 4n
number of chromosomes (only one member of each ho-
Follicular Atresia Probably Results From a mologous pair is present, but each chromosome consists
Lack of Gonadotropin Support of two unique chromatids).
The secondary oocyte is formed several hours after the
Follicular atresia, the degeneration of follicles in the ovary, initiation of the LH surge but before ovulation. It rapidly
is characterized by the destruction of the oocyte and gran- begins the second meiotic division and proceeds through a
ulosa cells. Atresia is a continuous process and can occur at short prophase to become arrested in metaphase. At this
any stage of follicular development. During a woman’s life- stage, the secondary oocyte is expelled from the graafian
time approximately 400 to 500 follicles will ovulate; those follicle. The second arrest period is relatively short. In re-
are the only follicles that escape atresia, and they represent sponse to penetration by a spermatozoon during fertiliza-
a small percentage of the 1 to 2 million follicles present at tion, meiosis 2 resumes and is rapidly completed. A second
birth. The cause of follicular atresia is likely due to lack of unequal cell division soon follows, producing a small sec-
gonadotropin support of the growing follicle. For example, ond polar body (1n DNA) and a large fertilized egg, the
at the beginning of the menstrual cycle, several follicles are zygote (2n DNA, 1n from the mother and 1n from the fa-
selected for growth but only one follicle, the dominant fol- ther). The first and second polar bodies either degenerate
licle, will go on to ovulate. Because the dominant follicle or divide, yielding small nonfunctional cells. If fertilization
has a preferential blood supply, it gets the most FSH (and does not occur, the secondary oocyte begins to degenerate
LH). Other reasons for the lack of gonadotropin support of within 24 to 48 hours.
nondominant follicles could be a lack of FSH and LH re-
ceptors or the inability of granulosa cells to transduce the
gonadotropin signals. FOLLICLE SELECTION AND OVULATION
During atresia, granulosa cell nuclei become pyknotic
(referring to an apoptotic process characterized by DNA The number of ovulating eggs is species-specific and is in-
laddering), and/or the oocyte undergoes pseudomatura- fluenced by genetic, nutritional, and environmental factors.
tion, characteristic of meiosis. During the early stages of In humans, normally only one follicle will ovulate, but mul-
oocyte death, the nuclear membrane disintegrates, the tiple ovulations in a single cycle (superovulation) can be
chromatin condenses, and the chromosomes form a induced by the timed administration of gonadotropins or
metaphase plate with a spindle; the term pseudomaturation is antiestrogens. The mechanism by which one follicle is se-
appropriate because these oocytes are not capable of suc- lected from a cohort of growing follicles is poorly under-
cessful fertilization. During atresia of follicles containing stood. It occurs during the first few days of the cycle, im-
theca cells, the theca layer may undergo hyperplasia and mediately after the onset of menstruation. Once selected,
the follicle begins to grow and differentiate at an exponen- is also an increased production of follicular fluid, disaggrega-
tial rate and becomes the dominant follicle. tion of granulosa cells, and detachment of the oocyte-cumu-
In parallel with the growth of the dominant follicle, the lus complex from the follicular wall, moving it to the central
rest of the preantral follicles undergo atresia. Two main fac- portion of the follicle. The basement membrane separating
tors contribute to atresia in the nonselected follicles. One is theca cells from granulosa cells begins to disintegrate, gran-
the suppression of plasma FSH in response to increased estra- ulosa cells begin to undergo luteinization, and blood vessels
diol secretion by the dominant follicle. The decline in FSH begin to penetrate the granulosa cell compartment.
support decreases aromatase activity and estradiol produc- Just prior to follicular rupture, the follicular wall thins by
tion and interrupts granulosa cell proliferation in those non- cellular deterioration and bulges at a specific site called the
dominant follicles. The dominant follicle is protected from a stigma, the point on the follicle that actually ruptures. As
fall in circulating FSH levels because it has a healthy blood ovulation approaches, the follicle enlarges and protrudes
supply, FSH accumulated in the follicular fluid, and an in- from the surface of the ovary at the stigma. In response to the
creased density of FSH receptors on its granulosa cells. An- LH surge, plasminogen activator is produced by theca and
other factor in selection is the accumulation of atretogenic granulosa cells of the dominant follicle and converts plas-
androgens, such as DHT, in the nonselected follicles. The minogen to plasmin. Plasmin is a proteolytic enzyme that
increase in DHT changes the intrafollicular ratio of estrogen acts directly on the follicular wall and stimulates the produc-
to androgen and antagonizes the actions of FSH. tion of collagenase, an enzyme that digests the connective
As the dominant follicle grows, vascularization of the tissue matrix. The thinning and increased distensibility of the
theca layer increases. On day 9 or 10 of the cycle, the vascu- wall facilitates the rupture of the follicle. The extrusion of the
larity of the dominant follicle is twice that of the other antral oocyte-cumulus complex is aided by smooth muscle con-
follicles, permitting a more efficient delivery of cholesterol traction. At the time of rupture, the oocyte-cumulus complex
to theca cells and better exposure to circulating go- and follicular fluid are ejected from the follicle.
nadotropins. At this time, the main source of circulating The LH surge triggers the resumption of the first meiosis.
estradiol is the dominant follicle. Since estradiol is the pri- Up to this point, the primary oocyte has been protected by
mary regulator of LH and FSH secretion by positive and neg- unknown factors within the follicle from premature cell divi-
ative feedback, the dominant follicle ultimately determines sion. The LH surge also causes transient changes in plasma
its own fate. estradiol and a prolonged increase in plasma progesterone
The midcycle LH surge occurs as a result of rising levels concentrations. Within a couple of hours after the initiation
of circulating estradiol, and it causes multiple changes in the of the LH surge, the production of progesterone, androgens,
dominant follicle, which occur within a relatively short time. and estrogens begins to increase. Progesterone, acting
These include the resumption of meiosis in the oocyte (as al- through the progesterone receptor on granulosa cells, pro-
ready discussed); granulosa cell differentiation and transfor- motes ovulation by releasing mediators that increase the dis-
mation into luteal cells; the activation of proteolytic en- tensibility of the follicular wall and enhance the activity of
zymes that degrade the follicle wall and surrounding tissues; proteolytic enzymes. As LH levels reach their peak, plasma
increased production of prostaglandins, histamine, and other estradiol levels plunge because of down-regulation by LH of
local factors that cause localized hyperemia; and an increase FSH receptors on granulosa cells and the inhibition of gran-
in progesterone secretion. Within 30 to 36 hours after the ulosa cell aromatase. Eventually, LH receptors on luteinizing
onset of the LH surge, this coordinated series of biochemical granulosa cells escape the down-regulation, and proges-
and morphological events culminates in follicular rupture terone production increases.
and ovulation. The midcycle FSH surge is not essential for
ovulation because an injection of either LH or human chori-
onic gonadotropin (hCG) before the endogenous go- FORMATION OF THE CORPUS LUTEUM FROM
nadotropin surge can induce normal ovulation. However, THE POSTOVULATORY FOLLICLE
only follicles that have been adequately primed with FSH
will ovulate because they contain sufficient numbers of LH In response to the LH and FSH surges and after ovulation,
receptors for ovulation and subsequent luteinization. the wall of the graafian follicle collapses and becomes con-
Four ovarian proteins are essential for ovulation: the prog- voluted, blood vessels course through the luteinizing gran-
esterone receptor, the cyclooxygenase enzyme (which con- ulosa and theca cell layers, and the antral cavity fills with
verts arachidonic acid to prostaglandins), cyclin D2 (a cell blood. The granulosa cells begin to cease their proliferation
cycle regulator), and a transcription factor called C/EBP␤ and begin to undergo hypertrophy and produce proges-
(CCAAT/enhancer binding protein). The mechanisms by terone as their main secretory product. The ruptured follicle
which these proteins interact to regulate follicular rupture are develops a rich blood supply and forms a solid structure
largely unknown. However, mice with specific disruption of called the corpus luteum (yellow body). The mature corpus
genes for any of these proteins fail to ovulate, and these pro- luteum develops as the result of numerous biochemical and
teins are likely to have a functional role in human ovulation. morphological changes, collectively referred to as luteiniza-
The earliest responses of the ovary to the midcycle LH tion. The granulosa cells and theca cells in the corpus lu-
surge are the release of vasodilatory substances, such as his- teum are called granulosa-lutein cells and theca-lutein
tamine, bradykinin, and prostaglandins, which mediate in- cells, respectively.
creased ovarian and follicular blood flow. The highly vascu- Continued stimulation by LH is needed to ensure mor-
larized dominant follicle becomes hyperemic and edematous phological integrity (healthy luteal cells) and functionality
and swells to a size of at least 20 to 25 mm in diameter. There (progesterone secretion). If pregnancy does not occur, the
corpus luteum regresses, a process called luteolysis or luteal LH; therefore, LH is referred to as a luteotropic hormone.
regression. Luteolysis occurs as a result of apoptosis and Lack of LH can lead to luteal insufficiency (see Clinical Fo-
necrosis of the luteal cells. After degeneration, the cus Box 38.1).
luteinized cells are replaced by fibrous tissue, creating a Regression of the corpus luteum at the end of the cycle is
nonfunctional structure, the corpus albicans. Therefore, the not understood. Luteal regression is thought to be induced
corpus luteum is a transient endocrine structure formed from by locally produced luteolytic agents that inhibit LH action.
the postovulatory follicle. It serves as the main source of cir- Several ovarian hormones, such as estrogen, oxytocin,
culating steroids during the luteal (postovulatory) phase of prostaglandins, and GnRH, have been proposed, but their
the cycle and is essential for maintaining pregnancy during role as luteolysins is controversial. The corpus luteum is res-
the first trimester (see Case Study) as well as maintaining cued from degeneration in the late luteal phase by the action
menstrual cycles of normal length. of human chorionic gonadotropin (hCG), an LH-like hor-
The process of luteinization begins before ovulation. Af- mone that is produced by the embryonic trophoblast during
ter acquiring a high concentration of LH receptors, granu- the implantation phase (see Chapter 39). This hormone
losa cells respond to the LH surge by undergoing morpho- binds the LH receptor and increases cAMP and proges-
logical and biochemical transformation. This change terone secretion.
involves cell enlargement (hypertrophy) and the develop-
ment of smooth ER and lipid inclusions, typical of steroid-
secreting cells. Unlike the nonvascular granulosa cells in the THE MENSTRUAL CYCLE
follicle, luteal cells have a rich blood supply. Invasion by
capillaries starts immediately after the LH surge and is facil- Under normal conditions, ovulation occurs at timed inter-
itated by the dissolution of the basement membrane be- vals. Sexual intercourse may occur at any time during the cy-
tween theca and granulosa cells. Peak vascularization is cle, but fertilization occurs only during the postovulatory
reached 7 to 8 days after ovulation. period. Once pregnancy occurs, ovulation ceases, and after
Differentiated theca and stroma cells, as well as granulosa parturition, lactation also inhibits ovulation. The first men-
cells, are incorporated into the corpus luteum, and all three strual cycle occurs in adolescence, usually around age 12.
classes of steroids—androgens, estrogens, and progestins— The initial period of bleeding is called the menarche. The
are synthesized. Although some progesterone is secreted first few cycles are usually irregular and anovulatory, as the
before ovulation, peak progesterone production is reached 6 result of delayed maturation of the positive feedback by
to 8 days after the LH surge. The life span of the corpus lu- estradiol on a hypothalamus that fails to secrete significant
teum is limited. Unless pregnancy occurs, it degenerates GnRH. During puberty, LH secretion occurs more during
within about 13 days after ovulation. During the menstrual periods of sleep than during periods of being awake, result-
cycle, the function of the corpus luteum is maintained by ing in a diurnal cycle.
CLINICAL FOCUS BOX 38.1
Luteal Insufficiency ceptors mediate the action of LH, which stimulates prog-
Occasionally, the corpus luteum will not produce sufficient esterone secretion. An insufficient number of LH receptors
progesterone to maintain pregnancy during its very early could be due to insufficient priming of the developing fol-
stages. Initial signs of early spontaneous pregnancy termi- licle with FSH. It is well known that FSH increases the num-
nation include pelvic cramping and the detection of blood, ber of LH receptors in the follicle. Third, the LH surge could
similar to indications of menstruation. If the corpus luteum have been inadequate in inducing full luteinization of the
is truly deficient, then fertilization may occur around the ide- corpus luteum, yet there was sufficient LH to induce ovu-
alized day 14 (ovulation), pregnancy will terminate during lation. It has been estimated that only 10% of the LH surge
the deficient luteal phase, and menses will start on sched- is required for ovulation, but the amount required for full
ule. Without measuring levels of hCG, the pregnancy detec- luteinization and adequate progesterone secretion to
tion hormone, the woman would not know that she is preg- maintain pregnancy is not known.
nant because of the continuation of regular menstrual If progesterone values are low in consecutive cycles at
cycles. Luteal insufficiency is a common cause of infertil- the midluteal phase and do not match endometrial biop-
ity. Women are advised to see their physician if pregnancy sies, exogenous progesterone may be administered in
does not result after 6 months of unprotected intercourse. order to prevent early pregnancy termination during a
Analysis of the regulation of progesterone secretion by fertile cycle. Other options include the induction of follic-
the corpus luteum provides insights into this clinical prob- ular development and ovulation with clomiphene and
lem. There are several reasons for luteal insufficiency. hCG. This treatment would likely produce a large,
First, the number of luteinized granulosa cells in the corpus healthy, estrogen-secreting graafian follicle with suffi-
luteum may be insufficient because of the ovulation of a cient LH receptors for luteinization. The exogenous hCG
small follicle or the premature ovulation of a follicle that is given to supplement the endogenous LH surge and to
was not fully developed. Second, the number of LH recep- ensure full stimulation of the graafian follicle, ovulation,
tors on the luteinized granulosa cells in the graafian follicle adequate progesterone, and luteinization of the develop-
and developing corpus luteum may be insufficient. LH re- ing corpus luteum.
LH peak
50 50
40 40
(mIU/mL)
(mIU/mL)
30 30
FSH
20 20
10 10
LH
0 0
20
17-Hydroxyprogesterone
Progesterone (ng/mL)
10 300
Estradiol (pg/mL)
(ng/mL)
200 17-OH P
1
P 1
E2β
100
0
Follicle diameter
Corpus luteum
diameter (mm)
20 20
Luteal
(mm)
regression
10 10
Day: 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Menses Ovulation
Phase: Menstrual Follicular Ovulatory Luteal
Day of menstrual cycle
FIGURE 38.6 Hormonal and ovarian events during the menstrual cycle. P, progesterone; E2␤, estra-
diol; 17-OH P, 17-hydroxyprogesterone.
The average menstrual cycle length in adult women is 28 ception and lactation and is subjected to modulation by
days, with a range of 25 to 35 days. The interval from ovu- physiological, psychological, and social factors.
lation to the onset of menstruation is relatively constant, av-
eraging 14 days in most women and is dictated by the fixed
life span of the corpus luteum. In contrast, the interval from The Menstrual Cycle Requires Synchrony
the onset of menses to ovulation (the follicular phase) is Among the Ovary, Brain, and Pituitary
more variable and accounts for differences in cycle lengths
among ovulating women. The menstrual cycle requires several coordinated elements:
The menstrual cycle is divided into four phases hypothalamic control of pituitary function, ovarian follicu-
(Fig. 38.6). The menstrual phase, also called menses or lar and luteal changes, and positive and negative feedback
menstruation, is the bleeding phase and lasts about 5 days. of ovarian hormones at the hypothalamic-pituitary axis.
The ovarian follicular phase lasts about 10 to 16 days; folli- We have discussed separately the mechanisms that regulate
cle development occurs, estradiol secretion increases, and the synthesis and release of the reproductive hormones;
the uterine endometrium undergoes proliferation in re- now we put them together in terms of sequence and inter-
sponse to rising estrogen levels. The ovulatory phase lasts action. For this purpose, we use a hypothetical cycle of 28
24 to 48 hours, and the luteal phase lasts 14 days. In the days (see Fig. 38.6), divided into four phases as follows:
luteal phase, progesterone is produced, and the en- menstrual (days 0 to 5), follicular (days 0 to 13), ovulatory
dometrium secretes numerous proteins in preparation for (days 13 to 14), and luteal (days 14 to 28).
implantation of an embryo. During menstruation, estrogen, progesterone, and in-
The cycles become irregular as menopause approaches hibin levels are very low as a result of the luteal regression
around age 50, and cycles cease thereafter. During the re- that has just occurred and the low estrogen synthesis by im-
productive years, menstrual cycling is interrupted by con- mature follicles. The plasma FSH levels are high while LH
levels are low in response to the removal of negative feed- occurs before the LH surge. This rise is important for aug-
back by estrogen, progesterone, and inhibin. A few days menting the LH surge and, together with estradiol, pro-
later, however, LH levels slowly begin to rise. FSH acts on motes a concomitant surge in FSH. There are indications
a cohort of follicles recruited 20 to 25 days earlier from a that the midcycle FSH surge is important for inducing
resting pool of smaller follicles. The follicles on days 3 to 5 enough LH receptors on granulosa cells for luteinization,
average 4 to 6 mm in diameter, and they are stimulated by stimulating plasminogen activator for follicular rupture,
FSH to grow into the preantral stages. In response to FSH, and activating a cohort of follicles destined to develop in
the granulosa cells proliferate, aromatase activity increases, the next cycle.
and plasma estradiol levels rise slightly between days 3 and The LH surge reduces the concentration of 17␣-hy-
7. The designated dominant follicle is selected between droxylase and subsequently decreases androstenedione
days 5 and 7, and increases in size and steroidogenic activ- production by the dominant follicle. Estradiol levels de-
ity. Between days 8 and 10, plasma estradiol levels rise cline, 17-hydroxyprogesterone increases, and progesterone
sharply, reaching peak levels above 200 pg/mL on day 12, levels plateau. The prolonged exposure to high LH levels
the day before the LH surge. during the surge down-regulates the ovarian LH receptors,
During the early follicular phase, LH pulsatility is of low accounting for the immediate postovulatory suppression of
amplitude and high frequency (about every hour). Coin- estradiol. As the corpus luteum matures, it increases prog-
ciding pulses of GnRH are released about every hour. As esterone production and reinitiates estradiol secretion.
estradiol levels rise, the pulse frequency in GnRH further Both reach high plasma concentrations on days 20 to 23,
increases, without a change in amplitude. The mean plasma about 1 week after ovulation.
LH level increases and further supports follicular steroido- During the luteal phase, circulating FSH levels are sup-
genesis, especially since FSH has increased the number of pressed by the elevated steroids. The LH pulse frequency is
LH receptors on growing follicles. During the midfollicular reduced during the early luteal phase, but the amplitude is
to late follicular phase, rising estradiol and inhibin from the higher than that during the follicular phase. LH is impor-
dominant follicle suppress FSH release. The decline in tant at this time for maintaining the function of the corpus
FSH, together with an accumulation of nonaromatizable luteum and sustaining steroid production. In the late luteal
androgens, induces atresia in the nonselected follicles. The phase, both LH pulse frequency and amplitude are reduced
dominant follicle is saved by virtue of its high density of by a progesterone-dependent, opioid-mediated suppres-
FSH receptors, the accumulation of FSH in its follicular sion of the GnRH pulse generator.
fluid (see Table 38.2), and the acquisition of LH receptors After the demise of the corpus luteum on days 24 to 26,
by the granulosa cells. estradiol and progesterone levels plunge, causing the
The midcycle surge of LH is rather short (24 to 36 withdrawal of support of the uterine endometrium, culmi-
hours) and is an example of positive feedback. For the LH nating within 2 to 3 days in menstruation. The reduction
surge to occur, estradiol must be maintained at a critical in ovarian steroids acts centrally to remove feedback inhi-
concentration (about 200 pg/mL) for a sufficient duration bition. The FSH level begins to rise and a new cycle is ini-
(36 to 48 hours) prior to the surge. Any reduction of the tiated.
estradiol rise or a rise that is too small or too short elimi-
nates or reduces the LH surge. In addition, in the presence
of elevated progesterone, high concentrations of estradiol Estradiol and Progesterone Influence Cyclic
do not induce an LH surge. Paradoxically, although it ex-
Changes in the Reproductive Tract
erts negative feedback on LH release most of the time, pos-
itive feedback by estradiol is required to generate the mid- The female reproductive tract undergoes cyclic alterations
cycle surge. in response to the changing levels of ovarian steroids. The
Estrogen exerts its effects directly on the anterior pitu- most notable changes occur in the function and histology
itary, with GnRH playing a permissive, albeit mandatory, of the oviduct and uterine endometrium, the composition
role. This concept is derived from experiments in monkeys of cervical mucus, and the cytology of the vagina
whose medial basal hypothalamus, including the GnRH- (Fig. 38.7). At the time of ovulation, there is also a small but
producing neurons, was destroyed by lesioning, resulting in detectable rise in basal body temperature, caused by prog-
a marked decrease in plasma LH levels. The administration esterone. All of the above parameters are clinically useful
of exogenous GnRH at a fixed frequency restored LH re- for diagnosing menstrual dysfunction and infertility.
lease. When estradiol was given at an optimal concentration The oviduct is a muscular tube lined internally with a cil-
for an appropriate time, an LH surge was generated, in spite iated, secretory, columnar epithelium with a deeper stromal
of maintaining steady and unchanging pulses of GnRH. tissue. Fertilization occurs in the oviduct, after which the
The mechanism that transforms estradiol from a nega- zygote enters the uterus; therefore, the oviduct is involved
tive to a positive regulator of LH release is unknown. One in transport of the gametes and provides a site for fertiliza-
factor involves an increase in the number of GnRH reception and early embryonic development. Estrogens maintain
tors on the gonadotrophs, increasing pituitary responsive- the ciliated nature of the epithelium, and ovariectomy
ness to GnRH. Another factor is the conversion of a stor- causes a loss of the cilia. Estrogens also increase the motil-
age pool of LH (perhaps within a subpopulation of ity of the oviducts. Exogenous estrogen given around the
gonadotrophs) to a readily releasable pool. Estrogen may time of fertilization can cause premature expulsion of the
also increase GnRH release, serving as a fine-tuning or fail- fertilized egg, whereas extremely high doses of estrogen
safe mechanism. A small but distinct rise in progesterone can cause “tube locking,” the entrapment of the fertilized
egg and an ectopic pregnancy. Progesterone opposes these receptors. Under the combined action of progesterone and
actions of estrogen. estrogen, the endometrial glands become coiled, store
The endometrium (also called uterine mucosa) is com- glycogen, and secrete large amounts of carbohydrate-rich
posed of a superficial layer of epithelial cells and an under- mucus. The stroma increases in vascularity and becomes
lying stromal layer. The epithelial layer contains glands edematous, and the spiral arteries become tortuous (see
that penetrate the stromal layer. The glands are lined by a Fig. 38.7). Peak secretory activity, edema formation, and
secretory columnar epithelium. overall thickness of the endometrium are reached on days 6
The endometrial cycle consists of four phases. The pro- to 8 after ovulation in preparation for implantation of the
liferative phase coincides with the midfollicular to late fol- blastocyst. Progesterone antagonizes the effect of estrogen
licular phase of the menstrual cycle. Under the influence of on the myometrium and reduces spontaneous myometrial
the rising plasma estradiol concentration, the stromal and contractions.
epithelial layers of the uterine endometrium undergo hy- The ischemic phase, generally not depicted graphically,
perplasia and hypertrophy and increase in size and thick- occurs immediately before the menses and is initiated by
ness. The endometrial glands elongate and are lined with the declining levels of progesterone and estradiol caused by
columnar epithelium. The endometrium becomes vascular- regression of the corpus luteum. Necrotic changes and
ized, and more spiral arteries, a rich blood supply to this re- abundant apoptosis occur in the secretory epithelium as it
gion, develop. Estradiol also induces the formation of collapses. The arteries constrict, reducing the blood supply
progesterone receptors and increases myometrial excitabil- to the superficial endometrium. Leukocytes and
ity and contractility. macrophages invade the stroma and begin to phagocytose
The secretory phase begins on the day of ovulation and the ischemic tissue. Leukocytes persist in large numbers
coincides with the early to midluteal phase of the menstrual throughout menstruation, providing resistance against in-
cycle. The endometrium contains numerous progesterone fection to the denuded endometrial surface.
Ovulation
Proliferative phase Secretory phase

Days 0 4 8 12 16 20 24 28 32
Progesterone
Plasma level
Estradiol
99
Degrees (F)
Basal body temperature

98
97
100
Vaginal
cornification and
50 pyknotic index
0
3⫹
Cervical mucus
2⫹ ferning
1⫹
0
Glycogen vacuoles
4 Gland
Endometrium Cyclic changes in the uterus,
3
mm
FIGURE 38.7
cervix, vagina, and body tempera-
2 Artery ture in relationship to estradiol, progesterone, and
1 ovulation during the menstrual cycle. (Modified
from Odell WD. The reproductive system in women.
0
Menses Menses
In: Degroot LJ, et al, eds. Endocrinology. Vol 3. New
York: Grune & Stratton, 1979.)
Desquamation and sloughing of the entire functional The most important progestin is progesterone. It is se-
layer of the endometrium occurs during the menstrual creted in significant amounts during the luteal phase of the
phase (menses). The mechanism leading to necrosis is only menstrual cycle. During pregnancy, the corpus luteum se-
partly understood. The reduction in steroids destabilizes cretes progesterone throughout the first trimester, and the
lysosomal membranes in endometrial cells, resulting in the placenta continues progesterone production until parturi-
liberation of proteolytic enzymes and increased production tion. Small amounts of 17-hydroxyprogesterone are se-
of vasoconstrictor prostaglandins (e.g., PGF2␣ ). The creted along with progesterone. Progesterone binds
prostaglandins induce vasospasm of the spiral arteries, and equally to albumin and to a plasma protein called corticos-
the proteolytic enzymes digest the tissue. Eventually, the teroid-binding protein (transcortin). Progesterone is me-
blood vessels rupture and blood is released, together with tabolized in the liver to pregnanediol and, subsequently,
cellular debris. The endometrial tissue is expelled through excreted in the urine as a glucuronide conjugate.
the cervix and vagina, with blood from the ruptured arter- Circulating androgens in the female originate from the
ies. The menstrual flow lasts 4 to 5 days and averages 30 to ovaries and adrenals and from peripheral conversion. An-
50 mL in volume. It does not clot because of the presence drostenedione and dehydroepiandrosterone (DHEA) orig-
of fibrinolysin, but the spiral arteries constrict, resulting in inate from the adrenal cortex (see Chapter 34), and ovarian
a reduction in bleeding. theca and stroma cells. Peripheral conversion from an-
Changes in the properties of the cervical mucus promote drostenedione provides an additional source of testos-
the survival and transport of sperm and, thus, can be im- terone. Testosterone can also be converted in peripheral
portant for normal fertility. The cervical mucus undergoes tissues to dihydrotestosterone (DHT) by 5␣-reductase.
cyclic changes in composition and volume. During the fol- However, the primary biologically active androgen in
licular phase, estrogen increases the quantity, alkalinity, women is testosterone. Androgens bind primarily to SHBG
viscosity, and elasticity of the mucus. The cervical muscles and bind to albumin by about half as much. Androgens are
relax, and the epithelium becomes secretory in response to also metabolized to water-soluble forms by oxidation, sul-
estrogen. By the time of ovulation, elasticity of the mucus fation, or glucuronidation and excreted in the urine.
or spinnbarkeit is greatest. Sperm can readily pass through
the estrogen-dominated mucus. With progesterone rising
either after ovulation, during pregnancy, or with low-dose
progestogen administration during the cycle, the quantity PUBERTY
and elasticity of the mucus decline; it becomes thicker (low During the prepubertal period, the hypothalamic-pituitary-
spinnbarkeit) and does not form a ferning pattern when ovarian axis becomes activated—an event known as go-
dried on a microscope slide. With these conditions, the nadarche—and gonadotropins increase in the circulation
mucus provides better protection against infections and and stimulate ovarian estrogen secretion. The increase in go-
sperm do not easily pass through. nadotropins is a direct result of increased secretion of GnRH.
The vaginal epithelium proliferates under the influence Factors stimulating the secretion of GnRH include gluta-
of estrogen. Basophilic cells predominate early in the fol- mate, norepinephrine, and neuropeptide Y emanating from
licular phase. The columnar epithelium becomes cornified synaptic inputs to GnRH-producing neurons. In addition, a
(keratinized) under the influence of estrogen and reaches decrease in ␥-aminobutyric acid (GABA), an inhibitor of
its peak in the periovulatory period. During the postovula- GnRH secretion, may occur at this time. It is also known that
tory period, progesterone induces the formation of thick the response of the pituitary to GnRH increases at the time
mucus, the epithelium becomes infiltrated with leukocytes, of puberty. Collectively, numerous factors control the rise in
and cornification decreases (see Fig. 38.7). ovarian estradiol secretion that triggers the development of
physical characteristics of sexual maturation.
Estradiol induces the development of secondary sex
ESTROGEN, PROGESTIN, AND ANDROGEN: characteristics, including the breasts and reproductive
TRANSPORT AND METABOLISM tract, and increased fat in the hips. Estrogens also regulate
the growth spurt at puberty, induce closure of the epi-
The principal sex steroids in the female are estrogen, prog- physes, have a positive effect in maintaining bone forma-
estin, and androgen. Three estrogens are present in signif- tion, and can antagonize the degrading actions of
icant quantities—estradiol, estrone, and estriol. Estradiol is parathyroid hormone on bone. Therefore, estrogens have
the most abundant and is 12 and 80 times more potent than a positive effect on bone maintenance, and later in life, ex-
estrone and estriol, respectively. Much of estrone is derived ogenous estrogens oppose the osteoporosis often associ-
from peripheral conversion of either androstenedione or ated with menopause.
estradiol (see Fig 37.9). During pregnancy, large quantities As mentioned earlier, the first menstruation is called
of estriol are produced from dehydroepiandrosterone sul- menarche and occurs around age 12. The first ovulation
fate after 16␣-hydroxylation by the fetoplacental unit (see does not occur until 6 to 9 months after menarche be-
Chapter 39). Most estrogens are bound to either albumin cause the hypothalamic-pituitary axis is not fully respon-
(⬃60%) with a low affinity or to sex hormone-binding sive to the feedback effects of estrogen. During the pu-
globulin (SHBG) (⬃40%) with high affinity. Estrogens are bertal period, the development of breasts, under the
metabolized in the liver through oxidation or conversion to influence of estrogen, is known as thelarche. At this time,
glucuronides or sulfates. The metabolites are then ex- the appearance of axillary and pubic hair occurs, a devel-
creted in the urine. opment known as pubarche, controlled by adrenal an-
drogens. The adrenals begin to produce significant through 1,25-dihydroxyvitamin D3.

amounts of androgens (dehydroepiandrosterone and an- Menopausal symptoms are often treated with hormone
drostenedione) 4 to 5 years prior to menarche, and this replacement therapy (HRT), which includes estrogens and
event is called adrenarche. The adrenal androgens are re- progestins. HRT is not an uncommon treatment to improve
sponsible in part for pubarche. Adrenarche is independ- the quality of life. In some patients, treatment with estro-
ent of gonadarche. gen can cause adverse effects, such as vaginal bleeding,
nausea, and headache. Estrogen therapy is contraindicated
in cases of existing reproductive tract carcinomas or hyper-
tension and other cardiovascular disease. The prevailing
MENOPAUSE
opinion is that the benefit of treating postmenopausal
Menopause is the time after which the final menses occurs. women with estrogens for limited periods outweighs any
It is associated with the cessation of ovarian function and risk of developing breast or endometrial carcinomas.
reproductive cycles. Generally, menstrual cycles and bleed-
ing become irregular, and the cycles become shorter from
the lack of follicular development (shortened follicular INFERTILITY
phases). The ovaries atrophy and are characterized by the
presence of few, if any, healthy follicles. One of five women in the United States will be affected by
The decline in ovarian function is associated with a de- infertility. A thorough understanding of female endocrinol-
crease in estrogen secretion and a concomitant increase in ogy, anatomy, and physiology are critical to gaining in-
LH and FSH, which is characteristic of menopausal women sights into solving this major health problem. Infertility can
(Table 38.3). It is used as a diagnostic tool. The elevated be caused by several factors. Environmental factors, disor-
LH stimulates ovarian stroma cells to continue producing ders of the central nervous system, hypothalamic disease,
androstenedione. Estrone, derived almost entirely from the pituitary disorders, and ovarian abnormalities can interfere
peripheral conversion of adrenal and ovarian androstene- with follicular development and/or ovulation. If a normal
dione, becomes the dominant estrogen (see Fig. 37.9). Be- ovulation occurs, structural, pathological, and/or endocrine
cause the ratio of estrogens to androgens decreases, some problems associated with the oviduct and/or uterus can pre-
women exhibit hirsutism, which results from androgen ex- vent fertilization, impede the transport or implantation of
cess. The lack of estrogen causes atrophic changes in the the embryo, and, ultimately, interfere with the establish-
breasts and reproductive tract, accompanied by vaginal ment or maintenance of pregnancy.
dryness, which often causes pain and irritation. Similar
changes in the urinary tract may give rise to urinary distur- Amenorrhea Is Caused by Endocrine Disruption
bances. The epidermal layer of the skin becomes thinner
and less elastic. Menstrual cycle disorders can be divided into two cate-
Hot flashes, as a result of the loss of vasomotor tone, os- gories: amenorrhea, the absence of menstruation, and
teoporosis, and an increased risk of cardiovascular disease are oligomenorrhea, infrequent or irregular menstruation. Pri-
not uncommon. Hot flashes are associated with episodic in- mary amenorrhea is a condition in which menstruation has
creases in upper body and skin temperature, peripheral va- never occurred. An example is Turner’s syndrome, also
sodilation, and sweating. They occur concurrently with LH called gonadal dysgenesis, a congenital abnormality caused
pulses but are not caused by the gonadotropins because they by a nondisjunction of one of the X chromosomes, resulting
are evident in hypophysectomized women. Hot flashes, con- in a 45 X0 chromosomal karyotype. Because the two X chro-
sisting of episodes of sudden warmth and sweating, reflect mosomes are necessary for normal ovarian development,
temporary disturbances in the hypothalamic thermoregula- women with this condition have rudimentary gonads and do
tory centers, which are somehow linked to the GnRH pulse not have a normal puberty. Because of ovarian steroid defi-
generator. ciency (lack of estrogen), secondary sex characteristics re-
Osteoporosis increases the risk of hip fractures and es- main prepubertal, and plasma LH and FSH are elevated.
trogen replacement therapy reduces the risk. Estrogen an- Other abnormalities include short stature, a webbed neck, a
tagonizes the effects of PTH on bone but enhances its ef- coarctation of the aorta, and renal disorders.
fect on kidney, i.e., it stimulates retention of calcium. Another congenital form of primary amenorrhea is hy-
Estrogen also promotes the intestinal absorption of calcium pogonadotropism with anosmia, similar to Kallmann’s syn-
TABLE 38.3 Serum Gonadotropin and Steroid Levels in Premenopausal and Postmenopausal Women
Menstrual Cycle
Hormone Units Follicular Preovulatory Luteal Postmenopausal

LH mIU/mL 2.5–15 15–100 2.5–15 20–100
FSH mIU/mL 2–10 10–30 2–6 20–140
Estradiol pg/mL 70–200 200–500 75–300
Progesterone ng/mL ⱕ0.5 ⱕ1.5 4–20 ⱕ0.5
drome in males (see Chapter 37). Patients do not progress ies reveal that exogenous TRH increases the secretion of
through normal puberty and have low and nonpulsatile LH PRL. The mechanism by which elevated PRL levels sup-
and FSH levels. However, they can have normal stature, press ovulation is not entirely clear. It has been postulated
female karyotype, and anosmia. The disorder is caused by a that PRL may inhibit GnRH release, reduce LH secretion in
failure of olfactory lobe development and GnRH defi- response to GnRH stimulation, and act directly at the level
ciency. Primary amenorrhea can also be caused by a con- of the ovary by inhibiting the action of LH and FSH on fol-
genital malformation of reproductive tract structures origi- licle development.
nating from the müllerian duct, including the absence or Oligomenorrhea can be caused by excessive exercise
obstruction of the uterus, cervix, or upper vagina. and by nutritional, psychological, and social factors.
Secondary amenorrhea is the cessation of menstrua- Anorexia nervosa, a severe behavioral disorder associated
tion for longer than 6 months. Pregnancy, lactation, and with the lack of food intake, is characterized by extreme
menopause are common physiological causes of second- malnutrition and endocrine changes secondary to psycho-
ary amenorrhea. Other causes are premature ovarian fail- logical and nutritional disturbances. About 30% of patients
ure, polycystic ovarian syndrome, hyperprolactinemia, develop amenorrhea that is not alleviated by weight gain.
and hypopituitarism. Strenuous exercise, especially by competitive athletes and
Premature ovarian failure is characterized by amenor- dancers, frequently causes menstrual irregularities. Two
rhea, low estrogen levels, and high gonadotropin (LH and main factors are thought to be responsible: a low level of
FSH) levels before age 40. The symptoms are similar to body fat, and the effect of stress itself through endorphins
those of menopause, including hot flashes and an in- that are known to inhibit the secretion of LH. Other types
creased risk of osteoporosis. The etiology is variable, in- of stress, such as relocation, college examinations, general
cluding chromosomal abnormalities; lesions resulting illness, and job-related pressures, have been known to in-
from irradiation, chemotherapy, or viral infections; and duce some forms of oligomenorrhea.
autoimmune conditions.
Polycystic ovarian syndrome, also called Stein-Leven-
Female Infertility Is Caused by
thal syndrome, is a heterogeneous group of disorders char-
acterized by amenorrhea or anovulatory bleeding, an ele- Endocrine Malfunction and Abnormalities
vated LH/FSH ratio, high androgen levels, hirsutism, and in the Reproductive Tract
obesity. Although the etiology is unknown, the syndrome The diagnosis and treatment of amenorrhea present a chal-
may be initiated by excessive adrenal androgen production, lenging problem. The amenorrhea must first be classified as
during puberty or following stress, that deranges the hypo- primary or secondary, and menopause, pregnancy, and lac-
thalamic-pituitary axis secretion of LH. Androgens are con- tation must be excluded. The next step is to determine
verted peripherally to estrogens and stimulate LH release. whether the disorder originates in one of the following ar-
Excess LH, in turn, increases ovarian stromal and thecal an- eas: the hypothalamus and central nervous system, the an-
drogen production, resulting in impaired follicular matura- terior pituitary, the ovary, and/or the reproductive tract.
tion. The LH-stimulated ovaries are enlarged and contain Several treatments can alleviate infertility problems; for
many small follicles and hyperplastic and luteinized theca example, some success has been achieved in hypothalamic
cells (the site of LH receptors). The elevated plasma an- disease with pulsatile administration of GnRH. When hy-
drogen levels cause hirsutism, increased activity of seba- pogonadotropism is the cause of infertility, sequential ad-
ceous glands, and clitoral hypertrophy, which are signs of ministration of FSH and hCG is a common treatment for
virilization in females. inducing ovulation, although the risk of ovarian hyperstim-
Hyperprolactinemia is also a cause of secondary amen- ulation and multiple ovulations is increased. Hyperpro-
orrhea. Galactorrhea, a persistent milk-like discharge from lactinemia can be treated surgically by removing the pitu-
the nipple in nonlactating individuals, is a frequent symp- itary adenoma containing numerous lactotrophs
tom and is due to the excess prolactin (PRL). The etiology (prolactin-secreting cells). It can also be treated pharmaco-
of hyperprolactinemia is variable. Pituitary prolactinomas logically with bromocriptine, a dopaminergic agonist that
account for about 50% of cases. Other causes are hypo- reduces the size and number of the lactotrophs and PRL se-
thalamic disorders, trauma to the pituitary stalk, and psy- cretion. Treatment with clomiphene, an antiestrogen that
chotropic medications, all of which are associated with a binds to and blocks estrogen receptors, can induce ovula-
reduction in dopamine release, resulting in an increased tion in women with endogenous estrogens in the normal
PRL secretion. Hypothyroidism, chronic renal failure, and range. Clomiphene reduces the negative feedback effects
hepatic cirrhosis are additional causes of hyperprolactine- of estrogen and thus increases endogenous FSH and LH se-
mia. In some forms of hypothyroidism, increased hypo- cretion. When reproductive tract lesions are the cause of
thalamic thyrotropin-releasing hormone (TRH) is thought infertility, corrective surgery or in vitro fertilization is the
to contribute to excess PRL secretion, as experimental stud- treatment of choice.
REVIEW QUESTIONS
DIRECTIONS: Each of the numbered (E) Increased secretion of FSH (A) The oviduct and has entered the
items or incomplete statements in this 5. The theca interna cells of the graafian second meiotic division
section is followed by answers or by follicle are distinguished by (B) The uterus and has completed the
completions of the statement. Select the (A) Their capacity to produce first meiotic division
ONE lettered answer or completion that is androgens from cholesterol (C) Metaphase of mitosis
BEST in each case. (B) The lack of cholesterol side-chain (D) The graafian follicle, which then
cleavage enzyme enters the oviduct
1. Estradiol synthesis in the graafian (C) Aromatization of testosterone to (E) The uterus, extruding the second
follicle involves estradiol polar body and implanting
(A) Activation of LH-stimulated (D) The lack of a blood supply 10.The enzyme, 5␣-reductase is
granulosa production of androgen (E) The production of inhibin responsible for
(B) Stimulation of aromatase in the 6. Disruption of the hypothalamic- (A) Conversion of cholesterol to
granulosa cell by FSH pituitary portal system will lead to pregnenolone and enhancing
(C) Decreased secretion of (A) High circulating levels of PRL, low steroidogenesis
progesterone from the corpus luteum, levels of LH and FSH, and ovarian (B) Conversion of testosterone to
resulting in increased LH atrophy dihydrotestosterone
(D) Inhibition of the LH surge during (B) Enhanced follicular development as (C) Aromatization of testosterone to
the preovulatory period a result of increased circulating levels estradiol
(E) Synergy between FSH and of PRL (D) Increasing the synthesis of LH
progesterone (C) Ovulation, followed by increased (E) Female secondary sex
2. Granulosa cells do not produce circulating levels of progesterone characteristics
estradiol from cholesterol because they (D) A reduction of ovarian inhibin
do not have an active levels, followed by increased SUGGESTED READING
(A) 17␣-Hydroxylase circulating FSH Carr BR, Blackwell RE. Textbook of Re-
(B) Aromatase (E) Excessive androgen production by productive Medicine. Norwalk, CT:
(C) 5␣-Reductase the ovaries Appleton & Lange, 1998.
(D) Sulfatase 7. Inhibin is an ovarian hormone that Griffin JE, Ojeda, SR. Textbook of En-
(E) Steroidogenic acute regulatory (A) Inhibits the secretion of LH and docrine Physiology. 4th Ed. New York:
protein PRL Oxford University Press, 2000.
3. A clinical sign indicating the onset of (B) Is produced by granulosa cells and Johnson MH, Everitt BJ. Essential Repro-
the menopause is inhibits the secretion of FSH duction. Oxford: Blackwell Science,
(A) The onset of menses near age 50 (C) Only has local ovarian effects and 2000.
(B) An increase in plasma FSH levels no effect on the secretion of FSH Kettyle WM, Arky RA. Endocrine Patho-
(C) An excessive presence of corpora (D) Has two forms, A and B, with the physiology. Philadelphia: Lippincott-
lutea same ␤ subunits but distinct ␣ subunits Raven, 1998.
(D) An increased number of cornified (E) Binds activin and increases FSH Van Voorhis BJ. Follicular development.
cells in the vagina secretion In: Knobil E, Neill JD, eds. The En-
(E) Regular menstrual cycles 8. Spinnbarkeit formation is induced by cyclopedia of Reproduction. New
4. Increased progesterone during the (A) Secretory endometrium York: Academic Press,
postovulatory period is associated with (B) Progesterone action on the uterus 1999;376–389.
(A) Proliferation of the uterine (C) Androgen production from the Van Voorhis BJ. Follicular steroidogenesis.
endometrium ovaries In: Knobil E, Neill JD, eds. The Ency-
(B) Enhanced development of graafian (D) Estrogen action on the vaginal clopedia of Reproduction. New York:
follicles secretions Academic Press, 1999;389–395.
(C) Luteal regression (E) Prolactin secretion Yen SSC, Jaffe RB, Barbieri RL. Reproduc-
(D) An increase in basal body 9. Successful fertilization is most likely to tive Endocrinology. 4th Ed. Philadel-
temperature by 0.5 to 1.0⬚C occur when the oocyte is in phia: WB Saunders, 1999.

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C H A P T E R

THE HYPOTHALAMIC-PITUITARY AXIS

Corpus Broad ligament

Ovarian vessels Early antrum formation

Mature corpus luteum Ovary Graafian follicle

Early corpus luteum

Stroma Germinal epithelium

TABLE 38.1 Different Stages in the Development of an Ovum and Follicle

Stage Process Ovum Follicle

Cycle Antral follicle

Ovulation Resumption of meiosis Secondary oocyte Graafian follicle

Primordial Basement membrane

Primary Basement membrane

Secondary Basement membrane

Theca cell Granulosa cell

tion. The dashed line indi-

CLINICAL FOCUS BOX 38.1

Day of menstrual cycle

Proliferative phase Secretory phase

Basal body temperature

drogens. The adrenals begin to produce significant through 1,25-dihydroxyvitamin D3.

Hormone Units Follicular Preovulatory Luteal Postmenopausal

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