Professional Documents
Culture Documents
Hormones
Hormones
Hormones
List the different types of gonadotropin hormones and their respective functions.
List the different glands/tissues that produce gonadotropin hormones.
Describe the endocrine regulation of testicular and ovarian function by GnRH, FSH,
LH, and inhibin.
List the different types of steroid hormones and their respective functions.
Identify the structure of steroid hormones.
Explain the five stages of synthesis of steroid hormones.
Describe the regulation of steroid hormones.
Describe the cellular mechanisms of action of steroid hormones.
subunit of hCG and both stimulate the same receptor, however, the hCG subunit
contains an additional 24 amino acids, and both hormones differ in the composition of
their sugar moieties. The different composition of these oligosaccharides affects
bioactivity and speed of degradation. The biologic half-life of LH is 20 minutes, shorter
than that of FSH (3-4 hours) or hCG (24 hours).
Main functions of LH:
- promoting androgen synthesis in the ovarian thecal cells and in the interstitial
cells of the testes
- induces ovulation by stimulating the cascade of proteolytic enzymes leading
the rupture of the mature Graafian follicle
- maintains the corpus luteum during the menstrual cycle
LH synthesis and secretion by the pituitary is controlled by several factors:
- GnRH
- ovarian estrogens and progesterone
SECRETION OF LH AND FSH
The regulation of FSH and LH embodies pulsatile, periodic, diurnal, cyclic, and stageof-life elements. Regulation is also different in women and men.
The secretions of both LH and FS are stimulated primarily by a single hypothalamic
hormone, gonadotropin-releasing hormone. The cells of origin of GnRH are
predominantly in the arcuate nucleus and the preoptic area of the hypothalamus.
Most projections of the GnRH neurons terminate in the median eminence. The GnRH
released from these terminals is picked up by the capillaries of the portal vessels and
transported to the anterior pituitary.
GnRH is a decapeptide that is initially synthesized as a large precursor prohormone that
also yields other products. The preproGnRH consists of a 23-amino acid signal peptide, a
10-amino acid GnRH, and a 56-amino acid GnRH-associated peptide (GAP). The GnRH
is flanked by pairs of basic amino acids that designate enzymatic cleavage sites.
Other protein
products of
the gonads
influence
FSH secretion
FSH secretion also exhibits a pulsatile pattern that is generally synchronized with the
pattern of LH secretion but is of lesser magnitude (see above right).
The secretion of LH and FSH is regulated by testosterone and estradiol; the basic
regulatory mechanism is classic negative feedback.
Other protein products of the gonads influence FSH secretion. Separate gonadal protein
products selectively suppress (inhibin and follistatin) or stimulate (activin) FSH release.
These protein products may be expressed locally in the pituitary gland and exert their
effects by paracrine and autocrine actions.
Binding of GnRH to membrane receptors increases intracellular Ca++ levels and
phosphorylation of proteins, which together lead to increased LH release. The rise in
intracellular Ca++ occurs via two mechanisms (see below): stimulation of release of Ca++
from intracellular storage sites and increased Ca++ influx from the extracellular fluid.
FSH acts on ovarian granulosa cells and testicular Sertoli cells by binding to a PM
receptor. The FSH receptor shares partial homology with the LH receptor. The increase
in cAMP concentration that follows FSH-receptor binding increases the transcription of
the aromatase gene and markedly stimulates estrogen synthesis. FSH also stimulates
synthesis of inhibin and numerous other protein products of Sertoli and granulosa cells.
Another important effect of FSH is to increase the number of LH receptors in granulosa
cells, thereby amplifying their sensitivity to LH.
In addition to their actions on steroidogenesis, LH and FSH produce diverse metabolic
effects on their target gonadal cells. Glucose oxidation and lactic acid production are
increased, effects that may lead to local vasodilation. The long-term tropic effects of the
two hormones entail stimulation of amino acid transport, RNA synthesis, and general
protein synthesis.
AGE-RELATED CHANGES IN GONADOTROPIN SECRETION
The hypothalamic-pituitary-gonadal axis is unique in that it changes throughout the
human life span. Although the patterns of change in females and males differ, there are
certain common aspects.
Note transient peaks during gestation and early infancy and low levels thereafter in
childhood. Women subsequently develop monthly cyclic bursts, with LH exceeding
FSH; men do not. Both genders show increased gonadotropin production after age 50
years, with FSH exceeding LH.
PROLACTIN
Prolactin is a polypeptide hormone synthesized and secreted by lactotrophs (aka
mammotrophs, a type of acidophil) in the anterior pituitary. Lactotrophs account for 1520% of the cell population in the anterior pituitary. However, the percentage increases
dramatically in response to elevated estrogen levels, particularly during pregnancy.
Prolactin is the major hormone responsible for
lactogenesis (milk production) and also participates, along
with estrogen, in breast development. In nonpregnant,
nonlactating females and in males, blood levels of prolactin
are low. However, during pregnancy and lactation, blood
levels of prolactin increase, consistent with the hormones
role in breast development and lactogenesis. Chemically,
prolactin is related to growth hormone, having 198 amino
acids in a single-chain polypeptide with 3 internal disulfide
bridges. Molecular weight is 23,000. Its gene and structure
are homologous to those of hGH, but the molecule has a
major midportion loop.
Synthesis of prolactin proceeds as a prohormone. The N-terminal signal peptide is
cleaved, and transient N-glycosylation takes place before the compound arrives at the
Golgi apparatus. There, the hormone molecules that are subsequently destined to be
stored in granules and released by acute stimuli (or secreted by pregnancy) are
deglycosylated. However, some of the N-glycosylated molecules escape complete
processing, and they are secreted constitutively. These molecules form a major part of
the circulating prolactin in nonpregnant women, and they have lower biological activity.
Prolactin is also synthesized in the brain including the hypothalamus, and in specialized
cells of the uterus, placenta, and breast, and in lymphocytes. In these areas it has
paracrine and autocrine functions.
There is a circadian pattern of prolactin secretion, which rises at night. The first peak
appears 60 to 90 minutes after the onset of slow-wave sleep, and subsequent peaks occur
later, after cycles of REM sleep. Stresses, including anesthesia, surgery, insulin-induced
hypoglycemia, fear, and mental tension, all cause prolactin increase. The purpose of
sleep- or stress-induced prolactin release is unknown.
Normal basal plasma concentrations of prolactin are about 10 ng/ml, and they are
similar in women and men. The half-life of the hormone is 20 minutes, and the daily
production is around 350 g. The kidney is a likely organ of prolactin degradation,
because patients with renal failure often have high plasma prolactin levels.
Inhibitory Factors
Dopamine
Bromocriptine (dopamine
agonist)
Somatostatin
Prolactin (negative feedback)
Prolactin inhibits its own secretion by increasing the synthesis and secretion of dopamine
from the hypothalamus. This action constitutes negative feedback because stimulation of
dopamine secretion causes inhibition of prolactin secretion. Pregnancy and breastfeeding (suckling) are the most important stimuli for prolactin secretion.
In women. Prolactin release is affected by a large variety of stimuli provided by the
environment and the internal milieu, the most important being suckling, increased levels
of ovarian steroid hormones, primarily estrogen, and stress. The release of prolactin in
response to suckling is a classical neuroendocrine reflex. This surge in prolactin release
in response to a sucking stimulus is mediated by a decrease in the amount of dopamine
released by the hypothalamus, relieving the lactotroph from tonic inhibition. Estrogen
stimulates growth of the lactotrophs during pregnancy as well as prolactin gene
expression and release.
conception during breastfeeding. [In males with high prolactin levels (e.g., due to
a prolactinoma), there is a parallel inhibitory effect on GnRH secretion and
spermatogenesis, resulting in infertility.]
Clinical correlation: The pathophysiology of prolactin can involve either a deficiency of prolactin, which
results in the inability to lactate, or an excess of prolactin, which causes galactorrhea (excessive milk
production) and decreased libido. Prolactin excess also causes failure to ovulate and amenorrhea because it
inhibits GnRH secretion.
Dopamine!is!behind!a!lot!of!the!
desire!we!associate!with!eating!
and!sexual!intercourse.!!
Similarly,!all!addictive!drugs!
trigger!dopamine!(the!craving!
neurochemical)!to!stimulate!
the!pleasure/reward!center.!!So!
do!gambling,!shopping,!
overeating!and!other,!
seemingly!unrelated,!activities.!!
Go!shopping:!dopamine.!!
Smoke!a!cigarette:!dopamine.!!
Computer!games:!dopamine.!!
Heroin:!dopamine.!!Orgasm:!
dopamine.!!They!all!work!
somewhat!differently!on!the!
brain,!but!all!raise!your!
dopamine.!
OXYTOCIN
Oxytocin (OTC) is the other hormone released by the posterior pituitary. The primary
role of OTC is to eject milk from the lactating mammary gland and to facilitate uterine
contractions during labor.
Both arginine vasopressin (or ADH) and OTC are synthesized in the cell bodies of
hypothalamic neurons. ADH originates largely in the supraoptic nucleus, and OTC
originates largely in the paraventricular nucleus. However, each hormone is also
synthesized in the alternate site.
OTC is a peptide of nine amino acids (a nonapeptide). The sequence is cysteine tyrosine - isoleucine - glutamine - asparagine - cysteine - proline - leucine - glycine. The
cysteine residues form a sulfur bridge. OTC has a molecular mass of 1007. OTC has a
half-life of typically about three minutes in the blood.
The unique effect of OTC is to cause contraction of the myoepithelial cells of the alveoli
of the mammary glands, in response to cries of the infant and the stimulus of suckling the
nipple. As a result, milk is forced from the alveoli into the ducts, from where it is
evacuated by the infant. The response is very rapid and milk flows within 1 minute.
OTC also has a powerful action on smooth muscle in the uterus. Formation of Ca++calmodulin complexes leads to activation of myosin light chain and to contraction of
smooth muscle cells. Rhythmic contractions of the myometrium are stimulated by very
small doses of OTC, which act by lowering slightly the threshold for membrane
depolarization. Larger doses lower the threshold still further, prevent repolarization and
spiking discharges, and induce a sustained tetanic contraction. Neither maternal plasma
OTC levels nor fetal OTC availability bears a consistent relationship to the progress of
labor during childbirth. Therefore, despite the ability to stimulate rhythmic uterine
contractions, secreted OTC seems to be more a contributing factor than an essential
hormone of human parturition. However, after delivery, it may play an important role in
the sustained contractions that help to maintain hemostasis after the placenta is
evacuated.
Clinical Correlation: Induction of Labor by Synthetic Oxytocin. Although a physiological role for
oxytocin in humans in induction or progression of labor is not well established, it stimulates strong uterine
contractions when used at high doses as a drug. Thus, synthetic oxytocin (sold as medication under the
trade names Pitocin and Syntocinon) is often used in clinical situations in which artificial induction or
stimulation of the progression of labor is medically required. As is generally the case for peptide drugs, it
is not effective orally due to cleavage in the gastrointestinal tract, and it is administered by intravenous
infusion.
In men. OTC and its receptor are found in the testis, epididymis, and prostate and thus
may assist in the movement of sperm, in ejaculation, and in the addition of seminal fluid
to the sperm. OTC plasma levels rise during male sexual activity, and they peak at
ejaculation. [OTC levels also rise during female sexual activity. The hormone and its
receptor are found in the ovary, and OTC assists in ovulation and in the termination of
the corpus luteum.] Recent studies have begun to investigate OTCs role in various
behaviors, including orgasm, social recognition, pair bonding, anxiety, trust, love, and
maternal behaviors.
20,22-desmolase (mitochondria)
3-ol-dehydrogenase
4,5
and -isomerase
17-hydroxylase
Estradiol!and!
progesterone!are!the!
major!secretory!
products!of!the!ovary.!
17-hydroxylase
3-ol-dehydrogenase
4,5
and -isomerase
17,20-desmolase
17,20-desmolase
3-ol-dehydrogenase
4,5
and -isomerase
aromatase
DHEA
17 -OH-steroid dehydrogenase
17 -OH-steroid dehydrogenase
3-ol-dehydrogenase
4,5
and -isomerase
17 -OH-steroid dehydrogenase
aromatase
5 -reductase
Testosterone!is!the!
major!secretory!
product!of!the!testis.!
3-reductase
DIT
TESTOSTERONE
Testosterone is synthesized and secreted by the Leydig cells of the testes.
The steroidogenic pathways in the testes are similar to those for the adrenal cortex, with
two important differences:
- The testes lack the enzymes 21-hydroxylase and 11-hydroxylase, and
therefore cannot synthesize glucocorticoids or mineralocorticoids.
- The testes have an additional enzyme, 17-hydroxysteroid dehydrogenase,
which converts androstenedione to testosterone. Thus, the androgenic endproduct of the testes is testosterone rather than DHEA and androstenedione (the
end-products of the adrenal cortex).
LH stimulates testosterone biosynthesis by
increasing mobilization and transport of cholesterol
into the steroidogenic pathway, an action that takes
place in minutes; as well as by stimulating gene
expression and activity of the steroidogenic enzymes,
a slower process that requires several hours.
Steroidogenic acute regulatory protein (also found in
the adrenal cortex) has a key role in the transfer of
cholesterol from the outer to the inner
mitochondrial membrane, the first step in steroid
hormone biosynthesis, for the conversion of
cholesterol to pregnenolone.
Pregnenolone is a key intermediate for all classes
of steroid hormones. After formation in the
mitochondria, it is transported to the SER, where the
remainder of the biosynthetic reactions takes place.
Pregnenolone can be converted to testosterone via
the delta 5 or delta 4 pathways. These refer to the
stage at which the double bond in ring B (position
5,6) is switched to ring A (position 3,4). The delta 5 intermediates include 17hydroxypregnenolone, DHEA, and androstenediol, while the delta 4 intermediates are
progesterone, 17-hydroxyprogesterone, and androstenedione. The delta 5 pathway is
the major route for testosterone production in the testis, whereas the delta 4 pathway
predominates in the ovary.
- Note that up until this last enzymatic reaction, the enzymatic steps involved in
testosterone synthesis are similar to those involved in androstenedione synthesis
by the adrenal glands. It is the activity of 17-hydroxysteroid dehydrogenase and
the enzymatic conversion of androstenediol to testosterone that are specific to
the testes.
Although estrogens are only minor products of testicular steroidogenesis, they are
present as a normal circulating constituent in men. Androgens are converted to estrogens
by the action of the enzyme complex P450arom. The products of aromatization of
testosterone and androstenedione are estradiol and estrone, respectively. In men, there is
some aromatase activity in both Leydig and Sertoli cells, but aromatization mainly takes
place in peripheral tissues. Aromatization is a complex reaction involving removal of the
methyl group in position 19 and rearrangement of ring A into an unsaturated ring.
The action of LH on the Leydig cell is mediated through specific membrane receptors
of high affinity and low capacity. A single Leydig cell possesses about 15,000 LH
receptors. Occupancy of less than 5% of these is sufficient to elicit maximal
steroidogenic response.
cAMP, produced in response to LH, activates protein kinase A. Although by itself quite
stable, cAMP is cleaved and inactivated by phosphodiesterase. LH stimulates
steroidogenesis by acting at two principal sites. One is phosphorylation of cholesterol
esterase, which releases cholesterol from its intracellular stores and transports it to the
mitochondria. The other is activation of the rate-limiting enzyme, mitochondrial
cytochrome P450scc, which yields pregnenolone from cholesterol.
Testosterone is not stored in the Leydig cells but diffuses into the blood immediately
after being synthesized. An adult man produces 6-7 mg/day of testosterone. This amount
slowly declines after age 50 to 4 mg/day by age 70-80. Hence, men do not undergo a
sudden cessation of sex steroid production upon aging, as women do during their
postmenopausal period.
Testosterone circulates bound to plasma proteins, with only 2-3% present as the free
hormone. About 30-40% is bound to albumin and the remainder to sex steroid-binding
globulin (SSBG), a 94 kd glycoprotein produced by the liver. SSBG binds both estradiol
and testosterone, with a higher binding affinity for testosterone. Because only free
(unbound) testosterone is biologically active, SSBG essentially functions as a reservoir
for the circulating hormone. The synthesis of SSBG is stimulated by estrogens ands
inhibited by androgens.
Clinical Correlation: 5-Reductase inhibitors such as finasteride (marketed as Proscar, Propecia, etc.)
block the conversion of testosterone to DHT and, therefore, block the production of active androgens in
some target tissues. Because the growth of the prostate gland and male pattern baldness depend on DHT
rather than testosterone, 5-reductase inhibitors can be used in low doses as a treatment for benign
prostatic hypertrophy and hair loss in males, and as treatment for prostatic cancer in high doses.
Mediated by Dihydrotestosterone
Differentiation of penis, scrotum, and
prostate
Male hair pattern
Male pattern baldness
Sebaceous gland activity
Growth of prostate
SEXUAL DIFFERENTIATION
The process of sexual differentiation (i.e., the pattern of development of the gonads,
genital ducts, and external genitalia) produces the most fundamental and obvious
differences between the genders. However, during the first 5 weeks of gestation, the
gonads of males and females are indistinguishable and their genital tracts are unformed.
Between this stage of the indifferent gonad and that of the mature individual of either
gender, the process of sexual differentiation takes place.
SRY gene is the sex determining region of
the Y chromosome. SRY encodes the testisdetermining factor (TDF). SRY (TDF)
appears to initiate differentiation of the gonad
into a testis.
Anti-Mllerian hormone
causes the Mllerian ducts
to atrophy.
Ovarian sex steroids and neural monoamines (norepinephrine, epinephrine) may exert
stimulatory (+) or inhibitory (-) (or both) effects on the secretion of GnRH or pituitary
gonadotropins (or both). Note that dopamine inhibits prolactin release, but has no effect
on LH or FSH.
OVARIAN STEROIDS
The ovarian steroid hormones,
progesterone and 17-estradiol, are
synthesized by the ovarian follicles
through the combined functions of
the granulosa cells and the theca
cells. Virtually all steps in the
biosynthetic pathway are the same as
those for the adrenal cortex and the
testes. Recall that the adrenal cortex
produces all intermediates up to the
level of androstenedione, but
because it lacks the enzyme 17hydroxysteroid dehydrogenase, it
does not produce testosterone.
Recall also that the testes, having
17-hydroxysteroid dehydrogenase,
produce testosterone as their major
hormonal product. In the ovaries, all
steps in the biosynthetic pathway are
present, including aromatase, which
converts testosterone to 17-estradiol, the major ovarian estrogen.
ESTROGEN STEROIDS
Estrogens are a group of steroid compounds, named for their importance in the estrus
cycle, functioning as the primary female sex hormones.
Estrogens are of three types: estrone (E1), estradiol (E2) and estriol (E3). At equal
concentrations, E2 has a stronger biological effect than E1, which is more powerful than
E3 (i.e., E2 > E1 > E3).
Natural estrogen compounds can contain any combination of these 3 types of estrogen;
the most common formulation is 10% estrone, 10% estradiol, and 80% estriol. Estriol is
thought to have a protective effect: estriol inhibits estrone and estradiol binding to the
estrogen receptor.
While estrogens are present in both men and women, they are usually present at
significantly higher levels in women of reproductive age. Estrogen functions include:
- promote the development of female secondary sex characteristics
enlargement of the breasts
body shape = narrow shoulders and broad hips
distribution of fat breasts and buttocks
no change in larynx
less body hair and more scalp hair
growth of pubic and axillary hair
-
E1 (Estrone) Synthesis
In women of reproductive age, E1 is mainly produced from the enzymatic conversion of
androstenedione, which is secreted under the influence of LH by the thecal cells. The
aromatase activity depends on FSH. In menopausal women and in men, E1 and its
sulphate represent the main circulating estrogens. The biological function of E1 is
speculative, but it could be related to the regulatory effect that the conversion of E1 into
E2 has on the degree of estrogenization.
E3 (Estriol) Synthesis
In women of reproductive age, the very low concentrations of E3 are produced by
hepatic hydroxylation of E1 and E2. During pregnancy, E3 is produced in large
quantities from the fetal-placental unit. As 17-hydroxylase is lacking in the placenta and
3-hydroxydehydrogenase is absent in the fetus, the E3 production is dependent on a
fetal-placental collaboration. The E3 concentrations strongly increase during pregnancy,
indicating the fetal-placental cooperation. For this reason, the level of E3 has been used
to assess high-risk pregnancies. While the biological role of E3 is unknown, it is
considered the major estrogen of pregnancy. E3 has weak estrogenic properties in most
maternal organs, but increases uteroplacental blood flow.
The placenta lacks enzymes needed to produce estrogens but has very high aromatase
activity to convert androgens to estrogens. The fetal adrenal glands supply the placenta
with weak androgens for conversion to estrogens. These glands produce
dehydroepiandrosterone sulphate (DHEA-S), most of which is converted to 16hydroxy-DHEA-S by the fetal liver. E3 is produced by the placenta from fetal 16-OHDHEA-S.
The fetus does not produce progesterone or estrogens, thereby avoiding exposure to
high concentrations of these steroids. Although the fetus produces large amounts of weak
adrenal androgens, masculinization of the female fetus does not occur because the
placenta acts as a large sink for fetal androgens.
Clinical Correlation: Selective Estrogen Receptor Modulators. The importance of understanding the
estrogen receptor (ER) has been greatly heightened by the discovery of selective estrogen receptor
modulators (SERMs), such as Raloxifene and Tamoxifen.
These pharmaceutically produced
nonsteroidal ER ligands have varied ER profiles. Tamoxifen antagonizes the action of estrogens on the
breast, but mimics the action of estrogens on the uterine endometrium. It is an excellent chemotherapeutic
agent for breast cancer, but it can also rarely produce endometrial cancer of the uterus. Raloxifene has
beneficial agonist effects on bone and serum lipids, but not on breast or endometrium. It is therefore a safe
treatment for osteoporosis, but its antagonist effects on the brain produce, as a side effect, the hot flashes
associated with estrogen deficiency.
Clinical Correlation: Hormone Replacement Therapy. Despite the proposed cardioprotective effects of
estrogen, the leading causes of death are similar in men and women: (1) cardiovascular disease, (2) cancer,
and (3) stroke. The Womans Health Initiative studied the effects of hormone replacement therapy
(combined use of estrogen and progesterone known as HRT) on postmenopausal women. The results
showed that, compared to women in the placebo group, women on HRT have higher rates of breast cancer,
coronary heart disease, stroke, and pulmonary embolism. The only benefits noted were reduced rates of hip
fracture and colon cancer. These findings from the Womans Health Initiative have contributed to the
controversy surrounding the use of combined estrogen and progestin.
PROGESTERONE STEROIDS
Two sex hormones play a role in the control of the menstrual cycle: estradiol and
progesterone. While estrogen peaks twice, during follicular growth and during the luteal
phase, progesterone remains virtually absent prior to ovulation, but becomes critical in
the luteal phase and during pregnancy. Many tests for ovulation check for the presence
of progesterone. These sex hormones come under the influence of the pituitary gland,
and both FSH and LH play necessary roles.
FSH stimulates immature follicles in the ovaries to grow. LH triggers ovulation. The
GnRH from the hypothalamus controls the pituitary, yet both the pituitary and
hypothalamus receive feedback from the follicle. After ovulation, the corpus luteum
which develops from the burst follicle and remains in the ovarysecretes both estradiol
and progesterone. Only if pregnancy occurs do hormones appear in order to suspend the
menstrual cycle, while production of estradiol and progesterone continues. Abnormal
hormonal regulation leads to disturbance in the menstrual cycle.
Functions of progesterone
Converts the endometrium to its secretory stage to prepare the uterus for implantation.
At the same time progesterone affects the vaginal epithelium and cervical mucus. If
pregnancy does not occur, progesterone levels will decrease, leading to menstruation.
Normal menstrual bleeding is progesterone withdrawal bleeding.
During implantation and gestation, progesterone appears to decrease the maternal
immune response to allow for the acceptance of the pregnancy.
Progesterone decreases contractility of the uterine smooth muscle by increasing the
RMP and preventing electrical coupling between myometrial cells. In addition,
progesterone decreases uptake of extracellular Ca++ required for contraction of
myometrial cells by down-regulating the expression of genes that encode subunits of
voltage-dependent calcium channels. Progesterone also prevents uterine contractions by
blocking the ability of estradiol to induce membrane expression of -adrenergic receptors
(-adrenergic activation causes contractions).
The fetus metabolizes placental progesterone in the production of adrenal
mineralocorticoids and glucosteroids.
A drop in progesterone levels is possibly one step that facilitates the onset of labor. In
addition, progesterone inhibits lactation during pregnancy. The fall in progesterone
levels following delivery is one of the triggers for milk production.
Progesterone is thermogenic, raising the core temperature. It reduces spasm and
relaxes smooth muscle. Bronchi are widened and mucus regulated. Progesterone
receptors are widely present in submucosal tissue. Progesterone acts as an antiinflammatory agent and regulates the immune response.
Progesterone synthesis
Progesterone, like all other steroid hormones, is
synthesized from pregnenolone, a derivative of cholesterol.
This conversion takes place in two steps. The 3-hydroxyl
group is converted to a keto group and the double bond is
moved to C-4 from C-5.
Progesterone is the precursor of aldosterone, and after conversion to 17hydroxyprogesterone to cortisol and androstenedione. Androstenedione can be converted
to testosterone, estrone, and estradiol. Progesterone is important for aldosterone
synthesis, as 17-hydroxyprogesterone is for cortisol, and androstenedione for sex
steroids.
The early peak of hCG rescues the corpus luteum, which is responsible for the early rise
in progesterone secretion. The placenta assumes production of progesterone by about
gestation week 9. Estriol secretion begins later because maturation of the fetal adrenal
glands, which supplies androgen precursors top the placenta, is necessary for estriol
production.
Placental Progesterone
The placenta is the main source of progesterone during pregnancy. From the luteal
phase to term, maternal progesterone levels rise six- to eight-fold. Although progesterone
originates almost entirely from the corpus luteum before 6 weeks gestation, its
production shifts to the placenta after the 7th week. Beyond 12 weeks, the placenta is
definitively the major source of progesterone.
While the placenta produces large amounts of progesterone, it has limited capacity to
synthesize cholesterol de novo. Maternal cholesterol in the form of low-density
lipoprotein (LDL) cholesterol is the principal source of precursor for the biosynthesis of
progesterone during pregnancy.
Progesterone functions to:
- promote endometrial stromal differentiation = decidualization;
- stimulates lobular-alveolar development of the mammary gland in preparation
for milk secretion but suppresses milk protein synthesis before parturition;
- inhibit smooth muscle contractility;
- decrease prostaglandin formation and increases the rate of prostaglandin
inactivation, which helps maintain myometrial quiescence and prevent the
onset of uterine contractions; and
- inhibit immune responses like those involved in graft rejection.
Like progesterone, during the first several weeks of gestation, and throughout the time
of the luteal-placental shift, 17-hydroxyprogesterone concentrations primarily reflect
the steroidogenic status of the corpus luteum. However, unlike progesterone, the ovaries
continue to be a significant source of 17-hydroxyprogesterone throughout pregnancy.
During the third trimester, the placenta also uses fetal D5-sulfoconjugated precursors to
secrete increasing amounts of 17-hydroxyprogesterone, and the placenta is the major
source of this hormone at term.
BIRTH CONTROL
Oral contraceptives contain combinations of estrogen and progesterone or
progesterone alone. The combination preparations exert contraceptive effects primarily
through negative feedback effects on the anterior pituitary. The contraceptive effect of
progesterone alone is based primarily on its effects on cervical mucus and tubal motility.
Oral birth control pills do not contain progesterone but a progestin.
[A progestin is a synthetic progestagen that has progestinic effects similar to progesterone. The
two most frequent uses of progestins are for hormonal contraception (either alone or with an
estrogen), and to prevent endometrial hyperplasia from unopposed estrogen in hormone
replacement therapy. Progestins are also used to treat secondary amenorrhea, dysfunctional
uterine bleeding and endometriosis, and as palliative treatment of endometrial cancer, renal cell
carcinoma, breast cancer, and prostate cancer.]
Mechanism involved
Combination estrogen-progestin: constant
concentrations over a 21-day period followed by
7 days rest
Phasic estrogen-progestin: varying concentrations
throughout the 21-day period and 7 days of
placebo
Progestin only: constant progesterone dose daily
PARTURITION
Just as the maintenance of the pregnant state depends on a unique hormonal milieu, its
termination probably also depends on specific hormonal changes. However, the exact
mechanism by which parturition, or the process of giving birth, is initiated remains
unclear. Progesterone, estrogen, cortisol, relaxin, oxytocin, CRH, prostaglandins,
and catecholamines all influence the initiation and maintenance of labor and the final
uterine evacuation. The most dominant endocrine factor is a decrease in the
progesterone effect and an increase in the estrogen effect, commonly on the same targets.
Because species variations exist, it is difficult to extrapolate the results of animal studies directly to
humans, even if the studies have been performed in subhuman primates.
Myometrial quiescence
Myometrial activation
Myometrial gap junctions
Prostaglandin F2 and E production
Local oxytocin production
Oxytocin receptors
Cervical rigidity
Matrix metalloproteinase
Cervical ripening
Progesterone
+
NA
+
-
Estrogen
+
+
+
+
+
NA
+
The table above illustrates the effects of progesterone and estrogen on factors involved
in parturition. The diagram below illustrates current concepts of the endocrine regulation
of parturition.
Parturition, the
delivery of the fetus,
occurs ~40 weeks
after the onset of the
last menstrual period.
The fetus initiates signals that decrease the ratio of effective progesterone to estrogen in
the myometrium. This increases prostaglandin production, which abolishes uterine
quiescence and stimulates uterine contractions. OTC produced in the decidua and
placenta and a small maternal contributioncombined with markedly increased oxytocin
receptors as a result of the higher estrogen/progesterone ratiomay contribute to labor
but are not essential. However, OTC sustains uterine contractions after expulsion of the
fetus in order to minimize maternal loss of blood. Cortisol from the fetal adrenal,
stimulated by CRH and fetal ACTH, prepares the fetus to adapt to extrauterine life
successfully. Placental CRH is greatly augmented by mutual positive feedback effects
with cortisol and prostaglandins. CRH is also a myometrial stimulant. In addition, a
critical level of CRH may act as a placental alarm that triggers the process.
PARTURITION
The gestation period is approximately 40 weeks, and is measured from the first day of the
last menstrual period. Expulsion of the fetus, its placenta, and other membranes from the
uterus occurs during labor. This process is characterized by thinning and dilation of the
cervix and by strong regular contractions of the uterus. The four phases of uterine
activity during pregnancy and labor are:
Phase 0 is a long phase during which the uterus remains quiescent, under the influence of
progesterone. The peptide relaxin, secreted by the corpus luteum, assists in maintaining
the uterus in a relaxed state.
Phase&1!represents!activation!of!the!uterus!when!close!to!term.!!In!the!weeks!
preceding!parturition,!there!is!weak,!lowKfrequency!myometrial!activity!called!
contractures!(also!known!as!Braxton0Hicks!contractions!or!false!labor).!!In!phase!
1,!there!is!increased!myometrial!expression!of!receptors!for!oxytocin!and!excitatory!
prostaglandins&(PGE2,!PGF2 ).&&The!appearance!of!many!new!gap&junctions!
promotes!coordinated!contraction!of!the!myometrial!smooth!muscle!cells.!!These!
changes!are!associated!with!a!transition(from(contractures(to(true(contractions.!
!
Phase&2!is!the!dramatic!stage!of!labor!when!there!is!stimulation!of!the!uterus,!with!
increasing!oxytocin!and!prostaglandin!levels!inducing!true!uterine&contractions!
and!dilation&of&the&cervix.!!The(products(of(conception(are(delivered(at(parturition,(
ending(phase(2.!
!
In!phase&3,!the!uterus!returns!to!its!normal!size!with!the!assistance!of!sustained!
contractions!of!the!myometrium,!which!also!assists!in!blood!clotting.!
HYPOTHALAMUS-PITUITARY-ADRENAL/GONADAL AXIS
In addition to gonadal differentiation, normal sexual development also requires normal
development of the entire HPA/HPG axis, also referred as the reproductive axis. HPA
and HPG form a functional endocrine axis with hormonal regulation and feedback loops.
In contrast to the testes and adrenals, which produce hormones during fetal life, the
ovaries start to release steroid hormones when they are first stimulated by gonadotropins
at the onset of puberty.
Proteins
Pituitary or
Syncytiotrophoblast
>5000 daltons
Hydrophobic
Membrane
Freely soluble
Steroids
Ovaries or Testes
~300 daltons
Hydrophilic
Intracellular
SHBG
(Sex Hormone Binding Protein)
or Albumin
REVIEW QUESTIONS
1. Which one of the following steroids is synthesized from cholesterol without being
hydroxylated by 17-hydroxylase?
A. Corticosterone
B. Cortisol
C. Testosterone
D. Estradiol
E. Androstenedione
2. Which step in testosterone synthesis is activated by LH?
A. Androstenedione to testosterone
B. Cholesterol to pregnenolone
C. Testosterone to DHT
3. Which steroidogenic enzyme is not present in the gonads?
A. 17-hydroxylase
B. 21-hydroxylase
C. cholesterol desmolase
4. Which hormone maintains the corpus luteum of pregnancy?
A. LH
B. hCG
C. Estradiol
D. Progesterone
5. Which of the following organs are needed to synthesize estrogen during the third
trimester of pregnancy?
A. Corpus luteum
B. Fetal adrenal cortex
C. Fetal liver
D. Maternal adrenal cortex
E. Maternal liver
F. Maternal ovaries
G. Placenta
6. In a genetic male with deficiency of 5-reductase, which of the following masculine
features are present?
D. Days 23-24
E. Days 25-26
28. A blood sample is taken from a 27-year-old woman for hormone analysis. The
sample contains low levels of FSH and LH and high levels of estrogen, progesterone, and
inhibin. Assuming a normal 28-day menstrual cycle, on which day of the womans
menstrual cycle was the blood sample taken?
A. Day 1
B. Day 7
C. Day 14
D. Day 21
E. Day 28
29. Which of the following enzymes or substrates does the fetus provide for the placenta
to produce estrogen?
A. Aromatase
B. DHEA-S
C. 21-Hydroxylase
D. Pregnenolone
E. Progesterone
F. 5-Reductase
G. Testosterone
30. A 23-year-old woman consulted her midwife 1 day after the uncomplicated delivery
of her first child. She was concerned about her lack of milk production and that she was
only producing a thin yellow fluid at the breast. The midwife reassured her that this
was normal and that milk production would begin within 1-2 days. Which hormone(s)
was suppressing her milk production?
A. Estrogen
B. Inhibin
C. Oxytocin
D. Progesterone
E. Prolactin
Answers: 1A, 2B, 3B, 4B, 5BCEG, 6ABDE, 7C, 8A, 9D, 10C, 11E, 12C, 13B, 14BC,
15AB, 16D, 17A, 18C, 19C, 20A, 21D, 22A, 23D, 24A, 25A, 26A, 27C, 28D, 29B,
30AD