Download An overview of the endocrine regulation of both male and - ivf

An overview of the endocrine regulation of both male and female
reproduction is given. The first part of the presentation contains
information about the male reproductive endocrine system, the second
part focuses on the hormonal regulation
p
g
of the female reproductive
p
system.
1
The Y chromosome contains the genes directing the differentiation
towards the male reproductive system. Whereas the small arm of the Y‐
chromosome contains SRY gene, the long arm contains the genes
necessaryy for spermatogenesis.
p
g
SRY directs the development
p
of the male
internal genital system.
The external reproductive characteristics of the male are entirely
modelled by androgens, testosterone in particular.
2
The development of the female internal genital system is regulated by
default. However, in the presence of the Anti‐Muellerian Hormone
(AMH), produced and exreted by the Sertoli cells of the testes into the
fetal blood circulation, the Muellerian Duct will regress.
g
3
The testis consists of two major compartments; the testicular tubules,
which contain the Sertoli cells together with all spermatogenic cells, and
the interstitium, which contains capillaries and Leydig cells. The Sertoli
cells secrete both AMH and Inhibin B, whereas the Leydig
y g cells secrete
Testosterone. The Sertoli cells contain the FSH receptor, whereas the
Leydig cells the LH‐receptor.
4
The Leydig Cells are capable of Steroidogenesis from cholesterin to
testosterone. For that purpose they contains a number of steroidogenic
enzymes. Steroidogenesis in the Leydig cells is regulated by LH.
5
Steroidogenesis in the Leydig cells starts during fetal development. The
amnoitic fluid surrounding male fetuses contains higher levels of
testosterone than that surrounding female fetuses. The fetal production
of testosterone is crucial for testicular descent. Duringg embryogenesis
y g
testes arise in the abdomen, but they must migrate through the inguinal
canal to the scrotum. In addition to AMH, testosterone is crucial for this
migration, which may take place in the last weeks of gestation.
If testicular descent does not take placein time, cryptorchidism may be
the consequence.
6
In addition, to testicular descent fetal production of testosterone is
crucial for priming of the hypothalamus towards a male pattern of
gonadotropin release during early infancy. Early infancy of the male is
characterized byy a significant
g
secretion of LH in the p
pituitary,
y which is
involved in stimulation the production of testosterone in the testes.
In the female neonatal infant, however, FSH secretion predominates
thereby stimulating the ovary, sometimes leading to the development of
ovarian cysts.
7
The endocrine function of the Sertoli cells can be stimulated by
administration of recombinant FSH. This is exemplified by the rapid rise
of inhibin B and AMH serum levels.
In the male AMH is important during fetal development until puberty.
Theraafter, AMH levels decline being low during adulthood. In contrast,
testerone levels are high during fetal development and during early
infancy, then decline until puberty. From puberty on, testerone levels
remain high during the entire adulthood.
8
Fetal testerone is crucial for testicular descent, but also for the formation
of the external genital system. Insufficient action of testerone leads to
cryptorchidism and hypospadias. Both pathological entities may have
various degrees
g
of severity.
y
9
Another marker of insufficient testosterone activity during fetal
development is given by the anogenital distance. Anogenital distance
may be reduced through chronic low testosterone levels during fetal
development,
p
or, converselyy , through
g exposure
p
to compounds
p
with
estrogenic activity, such as phthalates.
10
The activity of both the Sertoli and the Leydig cells are regulated by a
negative feedback system. Testosterone exerts a negative control over
the LH secretion by the anterior part of the pituitary. Inhibin B exerts a
negativ
g
control over the FSH secretion in the anterior p
part of the p
pituitaryy
as well. Negative feedback control ensures adequate supply with
gonadotropins of the target organs .
11
In addition to testosterone, estrogens, estradiol in particular, may also
exert a powerful negative control over the secretion of both FSH and LH
in the pituitary. Wheras the testis is not able to produce significant
amounts of estrogens,
g
estrogens
g
mayy be p
produced in other organs,
g
most
notably in the adipocytes.
12
The normal target organs of testosterone in the adult male are the
larynx, the bones, the hair follicles in certain skin areas, the muscles and
the prostate. Men with chronic low testosterone levels may suffer of
bone loss leadingg to osteoporosis,
p
anemia , loss of the secondaryy sexual
characteristics.
The action of testosterone on the larynx, leading to deep voice, is
irreversible.
13
The female endocrine system is characterized by its cyclicity. During
reproductive live , the uterine endometrium is shed regularly during
menstruation. The menstruation is the most visible sign of the female
reproductive
p
hormone system.
y
Regularly
g
y occurringg menstruations are a
typicial sign of a healthy endocrine reproduction system in the female.
The very first menstruation during puberty is the menarche, the last
defines menopause.
14
During fetal life, the female gonads are loaded with a stock of oogonia,
later primordial follicles, which are thought to represent the entire
fertility reserve of a lifetime. From birth on, the stock of primordial
follicles is steadilyy reduced. This reduction is most p
pronounced until
puberty. From puberty on primordial follicles may undergo development
until mature follicles, which may undergo ovulation thereby liberating an
oocyte. During the entire reproductive lifetime of a women, only 400
follicles may undergo ovulation.
After menopause, the ovary hardly contains any primordial follicles any
more and none of them is capable of ovulation.
15
The early development of a primordial follicle up to a preovulatory
Graafian follicle lasts approximately three months. Only the last two
weeks of that development is hormonally regulated. Many follicles may
undergo
g development,
p
but duringg follicular development
p
the cohort of
maturing follicles is steadily reduced until only one follicle may undergo
ovulation.
The process of follicular loss is called follicular atresia and on the cellular
level is regulated by apoptosis.
16
The hormonally regulated part of follicular development , ovulation and
luteal phase synchronizes follicular development with the function of
associated organs, important for female fertility, such as the vagina, the
cervix and the endometrium.
17
Whereas both FSH and LH, both secreted in the anterior part of the
pituitary, are crucial for regulating ovarian function and the latter part of
follicular development, including ovulation and the formation of the
luteal body,
y the p
production and secretion of FSH and LH are regulated
g
byy
the gonadotropin‐releasing hormone (GnRH). GnRH is secreted by the
neuronal endings of neurons located in a number of hypothalamic nuclei,
located in the lower part of the brain. GnRH has a very short half life and
is secreted into a capillary network, which is drained into the anterior
part of the pituitary. The cells producing both the FSH and LH contain
receptor s for the GnRH (GnRH receptors).
18
The secretion of GnRH into the portal vein system of the hypothalamo‐
pituitary portal vein system is not constant during the menstrual cycle.
The secretion of GnRH is characterized by pulses. During follicular
development,
p
both the number of p
pulses p
per time interval and their
amplitude steadily rises. These changes are regulated by estrogens.
During the luteal phase the number of pulses per time intervall reduces,
but their amplitutes is augmented.
19
GnRH is a decapeptide.
20
The female has the potential to produce three distinct gonadotropins.
Each gonadotropin is a protein consisting of two chains of amino acids.
All three gonadotropins share the alpha‐chain, whereas the beta‐chains
are distinct. The beta‐chains of LH and HCG are veryy similar, but that of
HCG is longer. LH and HCG bind to the same receptor (the LH receptor),
whereas FSH binds specifically to the FSH receptor, which in the female
is present only in the granulosa cells of the ovarian follicle.
The half life of each gonadotropin is detrmined by the beta‐chain but
also by glycosylic residues on both amino acid chains.
21
Due to the short half life of LH the pulsatility of the secretion of GnRH is
measured by determining the concentration of LH in serum samples
collected at short intervals. Due to the long half life of FSH, the serum
levels of FSH remain constant over time despite
p the p
pulsatile p
pattern of
GnRH stimulation of its secreting cells.
22
The menstrual cycle is characterized by a rapid sequence of changes in
the concentrations of FSH and LH, of eatradiol and progesterone and of
inhibin A and inhibin B. The endocrine environment of the day can only
be jjudges
g byy knowingg the date of the last menstruation.
23
Whereas most of the menstrual cycle the interaction between the ovary
and the hipothalamo‐pituitary unit is guided by negative feedback
inhibition, the LH pead preceding the ovulation is induced by positive
feedback.
24
This slide illustrates the dimensions of the maturing ovarian follicle. The
preovulatory Graafian follicle has a diameter of 20 to 24 mm and is
surrounded by a network of capillaries in the theca internal. Within the
Graafian follicle resides the oocyte,
y which has a diameter of 150 µ
µm.
25
The maturing ovarian follicle consists of two compartments: the inner
part, granulosa, and the out er part, the theca interna. The antrum of the
ovarian follicle contains a fluid, which is characterized by very high
concentrations of sexual steroids, mostlyy estrogens.
g
The inner p
part of the
ovarian follicles does not contain any blood vessels. Separated from the
inner part of the follicle by a basal membrane, resides the theca interna.
Until follcular diameter of approximately 12 mm, the cells of the theca
interna carry the LH receptor, whereas the granulosa cells carry the FSH
receptor only. Both the cells of the theca interna and of the granulosa
contain some of the enzymes needed for steroidogenesis and both cells
types are complimentory. Only the granulosa cells have the enzyme
aromatase, with which estrogens can be synthetized and secreted.
26
During the final stages of preovulatory follicular development the
granulosa cells obtain in addition the the FSH receptor also the LH
receptor. Both are thought to stimulate.n estrogen production and
secretion together
g
leadingg to a rapid
p rise of the estrogen
g concentrations
in the follicular fluid. From there, estrogens, estradiol in particular,
diffuse out off the dominant follicle into the blood circulation, where it
prepares the Fallopian tubes, the uterus and the cervix for fertilization
and pregnancy.
27
During the follicular phase of the menstrual cycle the ovarian follicle is
capable of full steroidogenesis, until the production of estradiol. After
ovulation, in the luteal body, steroidogenesis is blunted, as only sexual
steroids up
p to p
progestagens
g
g
can be synthetized.
y
28
Various estrogens.
29
Estrogens can bind to two different nucleas receptors, the alpha‐ and the
beta‐estrogen receptor.
Not only are both estrogen receptor located in different organs and
tissues, but also the affinity of the various estrogens to either receptor is
different.
Within the ovary the distribution of both estrogen nuclear receptors is
different. Wheras the alpha‐receptor is located predominantly in the
endometrium and in the mammary tissue, the beta‐receptor is more
prevalent in the ovary.
p
y In addition, the abundance of each receptor
p mayy
vary during the menstrual cycle.
32
Outside the genital system, the estrogen receptors are also important, not the least in shaping the female aspect of the body.
33
In addition to the classical nuclear estrogen receptors, which exert their
function in estrogen response elements throughout the genome, non‐
genomic estrogen signalling has been shown to exert rapid signalling as
well. Non‐genomic
g
estrogen
g signalling
g
g is known to occur via membrane‐
bound receptors systems and has been deminstrated to be a target of
endocrine disruptor compounds.
34
In the female in particular the adrenal cortex provides an additional
source of sexual steroids, androgens in particular. Whereas testosterone
is produced predominantly in the ovary, dihydroepiandrosterone (DHEA)
is p
predominantlyy p
produced in the adrenal cortex. Both in men and
women steroidogenesis in the adrenal cortex undergoes significant
changes during progressive life and plays an important role in early
infancy, during puberty and declines with increasing age (adrenopause).
35
The fetal adrenal cortex is particularly important inproviding androgenic
substrates for aromatase in the placenta. The endocrine function of the
fetal adrenal cortex depends on ACTH production in the fetal pituitary.
36
The complex interaction of the fetal adrenal cortex and the placenta is
crucial for providing substrates to the placental aromatase and for the
production of estrogens. The placenta is able to produce progestagens, but not of androgens.
g
37
The adrenal cortex is also important in initiating steroidogenesis during
the early stages of puberty. Ovarian inhibin may also stimulate
steroidogenesis in the adrenal cortex by competing with activins to the
adrenal activin receptors.
p
38