Download Endocrine System

Endocrine System
By Dr. Pi-Hsueh Li
May 1, 2013
Female(女性) and Male(男性) Gonads(性腺)
Female reproductive endocrinology
Introduction to female reproductive cycle
- Human female reproductive cycle: cyclic, hormonal, and morphologic changes which occur
in the central nervous system (中樞神經系統), anterior pituitary (腦下腺前葉), ovary(卵巢)
and uterus(子宮)
- Menstrual cycle (月經週期): cyclic changes of the ovary and the uterine endometrium(內膜)
resulting in a monthly menstruation period (When fertilization and pregnancy do not occur).
- Only primates(靈長類) menstruate.
- Hormones involved are gonadotropin-releasing hormone (GnRH; 性釋素) –
hypothalamus(下視丘), luteinizing hormone (LH; 黃體促素) and follicle-stimulating
hormone (FSH; 濾泡刺激素) - anterior pituitary, estrogen(雌激素) and progesterone(黃體
素) – ovary(卵巢).
- Production of these hormones are cyclic and regulated by both positive and negative
feedback
- Cycle length: 21-35 days, average 28 days
Phases of the reproductive cycle a woman will pass over her lifetime: oogenesis(卵子生成),
premenarcheal( 初經前的) period, menarche(初經), and menopause(停經)
Oogenesis
- Begins in the fetal ovary when the primordial germ cells proliferate to become oogonia.
- Is completed before birth.
- Approximately 2x106 oocytes in the ovary at birth.
- Only 300,000 oocytes by puberty, each surrounded by a single layer of flattened
follicular cells embedded in a cellular stroma(間質).
- No new ova are formed after birth.
Premenarcheal period
- No ovulation(排卵), no menstruation.
- Reduction of oocytes by atresia(枯萎死亡).
- Oocytes are reduced from 2x106 to about 300,000.
Menarche
- The first menstrual period at puberty and will continue for approximately 40 years.
Menopause
The ovary gradually becomes unresponsive to gonadotropins (luteinizing hormone
and follicle-stimulating hormone) with advancing age, and its function declines, so
that, menstrual cycles disappear.
Most of the primordial follicles have been ovulated or have undergone atresia. (Not
enough estrogen produced to stimulate the luteinizing hormone surge, ovulation does
not occur).
Primary female reproductive organ: ovary
- Non-endocrine function: development of a mature ovum
- Endocrine function: production of two main steroid hormones - estrogens (two major ones:
estradiol and estrone) and progesterone (secreted by the granulosa 顆粒 cells and following
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ovulation by the corpus luteum 黃體); production of three peptide hormones: relaxin 鬆弛
素 (by the corpus luteum), inhibin(抑制素) (by the granulosa cells) and activin(刺激素).
Estrogen biosynthesis - two-cell theory
- The naturally occurring estrogens are 17ß-estradiol, estrone, and estriol. They are C18
steroids. They are secreted by the granulosa cells of the ovarian follicles, the corpus luteum,
and the placenta. The biosynthetic pathway involves their formation from androgens. They
are also formed by aromatization of androstenedione in the circulation. Aromatase(芳香酶)
is the enzyme that catalyzes the conversion of androstenedione to estrone and the
conversion of testosterone to estradiol.
Physiological effects of estrogens
- Female secondary sex characteristics:
- The body changes that develop in girls at puberty - in addition to enlargement of breasts,
uterus, and vagina(陰道) - are due in part to estrogens, which are the "feminizing
hormones," and in part simply to the absence of testicular androgens.
- Body configuration
- Women have narrow shoulders and broad hips, thighs that converge(內聚), and arms
that diverge(外散) (wide carrying angle).
- Female distribution of fat in the breasts and buttocks(臀部).
- Hair distribution
- Has less body hair and more scalp hair
- Pubic(陰部的) hair generally has a characteristic flat-topped pattern.
- Influences softness of the skin.
- Larynx(喉) retains its prepubertal proportions and the voice stays high-pitched.
- Regulate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) output
- Estrogens decrease FSH secretion.
- Under some circumstances, estrogens inhibit LH secretion (negative feedback).
- In other circumstances, estrogens increase LH secretion (positive feedback).
Physiological effects of progesterone
- In most cases (at least in the female reproductive tract) it acts on estrogen-primed tissues.
- The principal target organs of progesterone are the uterus, the breasts, and the brain.
- Uterus. Progesterone is responsible for the progestational changes in the endometrium
and causes a reduction of contractions and reduced smooth muscle tone.
- Mammary gland. Progesterone stimulates the final morphological development of
tubules and secretory alveoli.
- Regulate gonadotropin (LH and FSH) output. The feedback effects of progesterone are
exerted at both the hypothalamic and the pituitary level. Large doses inhibit LH
secretion and potentiate the inhibitory effect of estrogens. Progesterone injections can
prevent ovulation in humans.
Menstrual cycle (月經週期)
- The menstrual cycle is a complex of cyclic changes that include changes in the ovaries,
uterine endometrium, cervix, vagina, and mammary gland.
Ovarian Cycle (卵巢週期)
Follicular growth phase: formation of the Graafian follicle (成熟卵泡)
- Under endocrine stimulation 6-12 primary follicles develop by increasing in the size of
the oocyte and in the number of layers of granulosa cells surrounding each oocyte and
theca cells adjacent to the follicle.
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Only one follicle develops into a mature follicle. The others by some unknown process
become atretic and disappear with time. Stromal cells become arranged around the
follicle to form the well-vascularized theca.
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Antrum(濾泡腔) formation (a large cavity forms around ovum)
- Continued proliferation of granulosa cells and the incorporation of surrounding
interstitial cells into the theca are accompanied by the accumulation of fluid in
spaces within the granulosa cells. As the follicle enlarges, a single large vesicle or
antrum is formed. The oocyte is supported in the antrum by a stalk of granulosa
cells, the cumulus oophorus.
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The fully developed mature follicle is known as a Graafian follicle.
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By day 14, ovulates (liberating the oocyte).
- If the ovum is fertilized, development starts and usually reaches the blastocyst stage
before it enters the uterus to become implanted in the uterine endometrium.
- If the ovum is not fertilized it dies.
Luteal phase: formation of the corpus luteum
- The cells of the ruptured Graafian follicle proliferate, enlarge and fill the collapsed
antrum of the follicle. This new structure becomes a solid, round mass of steroidogenic
cells, called the corpus luteum which is initially red in color but then becomes
yellowish.
- Ruptured follicle is filled with blood.
- The granulosa and theca cells rapidly increase in number and the blood is absorbed.
- Vascular elements from the theca penetrate the granulosa cells.
- The granulosa cells begin to accumulate large quantities of cholesterol.
- This luteiniziation process leads to the formation of corpus luteum.
- Corpus luteum produces estrogens and progesterone.
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If fertilization and implantation do not occur:
- The corpus luteum begins to involute.
- The luteal cells cease their synthetic activity and disappear, and the whole structure,
replaced with scar tissue, becomes the corpus albicans.
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If implantation occurs, the corpus luteum increases in size and remains active during the
early weeks of pregnancy until its function of steroidogenesis is taken over by the
placenta; thus the corpus luteum maintains the uterine endometrium in early pregnancy.
Uterine Cycle (子宮週期)
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During the proliferative phase (增生期), under the influence of estrogens the uterine
endometrium grows thicker and the glandular structure elongates into tubes with spiral
arteries distributed throughout the endometrium.
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During the secretory phase (分泌期; e.g. after ovulation), the endometrial glands become
coiled and tortuous under the influence of estrogen and progesterone, and they begin to
secrete a clear fluid.
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Menstruation occurs when the corpus luteum stops secreting estrogen and progesterone.
Bleeding from the spiral arteries and sloughing of the endometrium persists for 3-5 days,
followed by a new growth of the endometrium.
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Changes in blood levels of FSH, LH, estrogens, and progesterone during a normal
menstrual cycle
Follicular Phase
- Gonadotropin (LH and FSH) levels begin to rise in early follicular phase.
- During second half of follicular phase, estrogens, androgens, and 17-OH-progesterone
begin to rise.
- Estradiol peaks on day before LH surge (ovulatory phase).
Ovulation
- FSH and LH peaks bring about ovulation.
- Up until ovulation progesterone levels have remained low.
Luteal Phase
- Corpus luteum forms from granulosa cells of the follicle.
- Estrogen and progesterone rise.
- Rise in progesterone level during luteal phase is followed by increase in basal body
temperature.
- Gonadotropins and gonadal steroids decline preceding onset of menses in late luteal phase.
Contraceptive(避孕的) steroids(類固醇) interfere with fertility(生育力)
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Contraceptive pill (避孕藥; a combination of synthetic estrogens and progesterone) suppresses
LH levels. Without the LH surge, ovulation does not occur leaving no ovum to be fertilized.
- Orally administered steroids by suppressing ovulation.
Contragestation(墮胎) by the progesterone antagonist (anti-progesterone): RU486
- RU486 (a new medical tool for fertility control) Is an anti-progesterone steroid acting at the
receptor level.
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Structure
- With a 17-longer side chain to increase affinity.
- An 11ß-phenyl group which plays the determining role in conferring antagonist activity.
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RU486 binds to the progesterone receptor and therefore excludes progesterone from
exerting its action. The action of RU486 is particularly significant in the endometrium
where it prevents initiation and progression of pregnancy in the first weeks (contragestive
effects) The blockage of the progesterone activity causes detachment of the embryo,
leading to a drop in human chorionic gonadotropin (hCG; 人類絨毛膜性腺激素) and to
luteolysis(黃體退化). Prostaglandins(前列腺素) are produced, thus increasing contractility
of the uterus muscles.
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RU486 has been introduced to the market in France in 1987 and is being tested in 15
countries of both the developed and the developing world.
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RU486, active as soon as progesterone is involved, is a "contragestive" agent, efficient in
"contragestation".
Mammary gland (乳腺)
- The breast and mammary glands provide optimal nourishment for infants. Although
lactation (the period during which milk is produced and secreted) occurs just after birth,
the development of breast tissue and preparation for this act occurs during puberty.
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This growth and development is mediated by female gonadal steroid hormones as part of
secondary sex characteristics.
In direct preparation for lactation, the breast develops more fully via high levels of
estrogens, progesterone, and prolactin(泌乳素).
Besides beginning milk production and sustaining it, which is primarily mediated by
prolactin, milk must be “let down” and ejected to allow for suckling, a process mediated
by the posterior pituitary hormone oxytocin(催產素) production.
Prolactin (PRL)
- Is also known as lactogenic hormone.
- PRL is synthesized by acidophils called lactotrophs in the anterior pituitary gland. In
females, lactotrophs hypertrophy, and prolactin secretion increases during pregnancy.
Control of secretion
- PRL secretion is under a constant tonic inhibition by dopamine from the paraventriculaar
and arcuate nuclei of the hypothalamus.
- Dopamine agonists (bromocriptine) block PRL secretion.
- Bromocriptine administration during the postpartum(產後) period reduces PRL
secretion to nonlactating levels and terminates lactation. Bromocriptine is used to
directly inhibit PRL from anterior pituitary.
Physiological actions of prolactin
- Plays an important role in the development of mammary gland and in milk synthesis.
- Differentiation of lobuloalveolar system during pregnancy requires PRL, estrogens, and
progesterone.
- PRL stimulates galactosyltransferase activity, leading to the synthesis of lactose.
- In women, high concentrations of PRL are associated with suppressed LH secretion and
anovulation.
- Account for an absence of menses during postpartum lactation.
Oxytocin (催產素)
- Oxytocin is a small peptide hormone produced by magnocellular neurons of the
paraventricular and supraoptic nuclei of the hypothalamus and secreted from the posterior
pituitary.
Physiological actions of oxytocin
- Causes uterine smooth muscle (myometrium) contractions during labor
- The sensitivity of the myometrium to exogenous oxytocin during pregnancy increases as
pregnancy advances.
- Oxytocin plays a role in labor and has been shown to be a useful therapeutic agent in the
induction of labor.
- Causes contraction of myoepithelial cells of the mammary gland, which squeezes the milk
out of the alveoli into the ducts and hence out of the nipple (milk ejection).
Control of oxytocin secretion
- Oxytocin release occurs in response to two types of stimuli: suckling stimulus from teats;
distention of the cervix and vagina during parturition.
Male reproductive endocrinology
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The male gonads are the testes.
Function: (1) Endocrine - secretion of male sex hormone, testosterone(睪固酮); (2) nonendocrine- production of sperm(精子)
Components: (1) Leydig(萊氏) cells: primary hormone producer; have Lluteinizing
hormone receptor (2) Sertoli(賽氏) cells line the basement membrane of the seminiferous
tubules(曲細精小管); produce mullerian-inhibiting substance (anti-mullerian hormone 抗
暮氏管激素), inhibin, seminiferous tubule fluid, and an androgen-binding protein; can
aromatize androgens to estrogens; and play a supporting role for the germ cells.
Chemistry and biosynthesis of testosterone:
- Testosterone, the major secretory product of the testis, is a C19 steroid with an -OH
group in the 17 position. It is synthesized from cholesterol in the Leydig cells and is also
formed from androstenedione secreted by the adrenal cortex. According to current
concepts, the biosynthetic pathways in all endocrine organs that form steroid hormones
are similar, the organs differing from one another only in the enzyme systems they
contain. In the Leydig cells, the 11- and 21-hydroxylases found in the adrenal cortex are
absent, but 17-hydroxylase is present.
- In some target tissues, testosterone is converted to dihydrotestosterone(二氫睪固酮) via
5-reductase(還原酶)
Transport of testosterone:
- Ninety-eight percent of the testosterone in plasma is bound to protein: 65% is bound to
gonadal steroid-binding globulin (GBG) or sex steroid-binding globulin and 33% to
albumin. GBG also binds estradiol. The plasma testosterone level (free and bound) is
approximately 525 ng/dL (18.2 nmol/L) in adult men and 30 ng/dL (1.0 nmol/L) in adult
women. It declines somewhat with age in males.
Physiological effects of testosterone:
- Regulate spermatogenesis - FSH and testosterone are required for the initiation of
spermatogenesis during sexual maturation.
- Responsible for secondary sex characteristics: development and maintenance
- Hair distribution: Development of the male-type hair pattern that includes pubic hair
formation in a diamond-shaped escutcheon(盾), beard growth, and a male scalp(頭)
hair pattern that includes regression of the heir in the temples(太陽穴) and the
expression of male pattern baldness..
- Body configuration: Shoulders broaden. Muscles enlarge (myotropic).
- Voice: Larynx enlarges. Thickening of the vocal cords (聲帶), voice becomes deeper.
- Mental: Produce aggressive warlike behavior. Develop interest in opposite sex.
- Directly inhibits LH secretion, via an action on the anterior pituitary.
Congenital 5-reductase deficiency (male feminizing syndrome 男性女性化): absence of
5-reductase.
- Individuals are born with male internal genitalia including testes, but they have female
external genitalia (外生殖器) and are usually raised as girls. However, when they reach
puberty, LH secretion and circulating testosterone levels are increased. They develop male
body contours(輪廓) and male libido(性慾). They usually change their gender identities
and become boys.
Normal ejaculate(射精) and male fertility:
- A normal ejaculate: the end product of the normally functioning male reproductive system.
Ejaculate volume - 2.5-3.5 ml
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Sperm concentration - 60-100 x 106 sperm/ml
Percent motile sperm - 40-60%
Percent morphology - greater than 60%
pH - 7.2-7.5
There are strong associations between impaired fertility and sperm concentrations.
Below 20 x 106 sperm/ml
Less than 40% motility
Less than 60% normal morphology
Human in vitro fertilization (體外授精) methods can now produce a successful conceptus
with as few as 20,000 sperm.
Male Sterility(不能生育):
- Cryptorchidism(隱睪症) - The testes remaining in the abdominal cavity or inguinal(腹骨
溝的) canal.
No spermatogenesis(精子生成).
Androgen production - normal or reduced.
- Low fertility
Low sperm count - often associated with decreased gonadotropin secretion.
Abnormal sperm: Sperm count is normal, sperm motility is reduced, the capacity for
fertilization is low.
Selective chemical activity of some androgens:
- It is often advantageous to have androgenic compounds which exhibit certain selective
activities of the parent compound.
- Nor-testosterone (no methyl at the 19 position): more myotropic than testosterone
without sex effects; used for geriatric cases and weight lifters.
- Methyl testosterone (methyl at the 17 position): methyl resists degradation by the liver;
several times more potent than testosterone in all respects.
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