Hormones are involved in the control of all of these processes by a complex interaction
between different controlling structures known as the The Hypothalamus – Pituitary –
Gonadal Axis.
In both male and female the major controlling structures are located in the brain (the
hypothalamus), the pituitary gland, (particularly the anterior pituitary), and the gonads.
In the pregnant female important control is also exerted by the placenta. Each structure
interacts with the others primarily by secretion of hormones.
The Pituitary Gland
The anterior pituitary gland is not nervous tissues. It arises embryologically from
Rathke’s Pouch. It has a number of cell types secreting different hormones, most of
which are involved in, or affected by reproduction.
Many pituitary hormones are trophic hormones, which act on other endocrine tissues to
promote the secretion of further hormones.
Hypothalamus and Pituitary
Each secretory cell type in the anterior pituitary is controlled by releasing hormones,
produced by nerve cells in the hypothalamus, which pass to the anterior pituitary in the
Hypophyseal portal system
.
The main reproductive anterior pituitary hormones, the gonadotrophins, FSH ( follicle
stimulating hormone) and LH( luteinising hormone) are produced by one cell type – the
gonadotrophs, and controlled by one releasing hormone – Gonadotrophin Releasing
Hormone (GnRH).
Several groups of hypothalamic neurones secrete GnRH under the influence both of
other structures in the brain (and hence the environment via sensory input) and
circulating hormones. All secrete GnRH in a pulsatile fashion – a burst of secretion
about once an hour. Gonadotrophs in the anterior pituitary secrete gonadotrophins in
response to these pulses of GnRH. In the absence of GnRH no LH or FSH is secreted.
FSH and LH act primarily on the gonads to influence the production of gametes and to
promote the secretion of gonadal steroids – oestradiol and progesterone in the female
and testosterone in the male. In the absence of LH and FSH no gonadal steroids are
secreted.
Control of the hypothalamus – pituitary – gonadal axis occurs at all levels
The Hypothalamus
Gonadal steroids influence GnRH-secreting neurones. They are also affected by their
connection to other parts of the brain influenced by factors such as body weight and
changes in the environment.
In the male:
In the female:
Testosterone inhibits
secretion of GnRH
Oestrogen at moderate concentration inhibits
secretion of
GnRH
Progesterone
enhances
the inhibitory effect of
oestrogen
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Moderate oestrogen reduces the amount of GnRH secreted per pulse, progesterone the
frequency of pulses
Oestrogen at high
LH ‘surge’
concentration promotes the release of GnRH producing an
Progesterone prevents high levels of oestrogen producing a GnRH surge thus blocking
the LH surge
The Anterior Pituitary
Gonadotrophs:
 Secrete both FSH and LH in response to pulsatile
secretion of GnRH by the
hypothalamus
 The amount of FSH and LH secreted in response to each pulse is affected by:
- Oestrogen at moderate concentration which reduces it
- Oestrogen at high concentration which promotes it
 The amount of FSH secreted in response to GnRH is reduced by inhibin
,a
protein hormone produced by developing follicles in the ovary and seminiferous tubules
in the testis.

The Gonads
In the testis LH stimulates the secretion of testosterone by Leydig
Cells. Men
secrete 4-10 mg each day. The amount of testosterone secreted at a given LH level is
relatively constant.
In the Ovary
 During the early phase of follicular development:
- theca interna cells bind LH and are stimulated to produce androgens(principally
androstenedione)
Granulosa
cells bind FSH and are stimulated to produce
enzymes which convert these androgens to oestrogens
- As the follicle grows more oestrogens are produced for a given gonadotrophic
stimulation
 In the pre-ovulatory phase
- LH receptors develop in outer layers of granulosa cells
- The oestrogen concentration is now high and triggers a ‘surge’ of LH which will
stimulate ovulation
 After ovulation
- LH stimulates the corpus luteum
to secrete progesterone and
oestrogen
- As the corpus luteum grows more steroids ( oestrogen and progesterone) are
produced at a given LH concentration
In the female therefore, the events of the ovarian cycle influence the response to
gonadotrophins. This variation produces a so-called ‘ovarian’ or ‘pelvic’ ‘clock’, which is
important in controlling the reproductive cycle of the female.
+
Pregnenolone
DHEA
Basement Membrane
LH
Capillary
Cholesterol
Cholesterol
+
LH
Pregnenolone
Progesterone
Androstenedione
+
Androstenedione
Testosterone
Thecal Cell
Testosterone
FSH
+
Oestradiol Oestrone
Granulosa Cell
The Testis
 LH acts upon Leydig cells to promote the secretion of testosterone. The effects of
LH are enhanced by prolactin and inhibin
 FSH maintains Sertoli cells and makes them responsive to testosterone
 Testosterone acts on Sertoli cells to promote
spermatogenesis
.
 Testosterone acts elsewhere in the body to maintain the male reproductive system
So long as LH and FSH are appropriate both spermatogenesis and testosterone
secretion (and hence the rest of the reproductive system) will be maintained.
Operation of the Whole System in the Male
The male must produce sperm constantly, and be ever ready to deliver them to the
female. This requires constant, appropriate levels of FSH, LH and testosterone.
These are achieved by
negative
feedback:
 If testosterone levels tend to rise this will inhibit GnRH secretion, so reducing
production of LH and FSH
 Levels are reduced further by testosterone reducing sensitivity of gonadotrophs to
GnRH
 So testosterone levels fall back
 If spermatogenesis proceeds too rapidly inhibin
levels rise
 Inhibin reduces secretion of FSH by acting on gonadotrophs in the pituitary
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4.1
Complete these flow charts showing hormonal feedback control mechanisms.
Add the names of the hormones released and the feedback control mechanisms
to the anterior pituitary and hypothalamus.
In the male:
(-)
Hypothalamus
GnRH
(-)
(FSH only)
(-)
(LH only)
Anterior Pituitary
FSH
LH
Sertoli Cells
Leydig Cells
Testes
Inhibin
Testosterone
(-)
Negative Feedback control
Effects in
Reproductive Tract
and other organs
4.2
In the female the picture is complex as hormone levels, function and control vary
according to the phase of the menstrual cycle. Complete this flow chart for
middle follicular phase; i.e., before ovulation has occurred.
(-)
Hypothalamus
(?)
GnRH
(-)
(FSH only)
(-)
Anterior Pituitary
FSH
LH
Granulosa Cells
Theca Cells
Ovaries
Androgens
Inhibin
Oestrogen
Effects in
Reproductive Tract
and other organs
(-)
Negative Feedback control
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4.3
Complete this flow chart, again for the female, but now as is occurring at
ovulation showing positive feedback.
(+)
Hypothalamus
GnRH
(+)
Anterior Pituitary
(Hormone)
LH surge
Ovaries
Ovulation
(Effect on ovary)
(Hormone)
Oestrogen
(+)
Positive Feedback
4.4
Discriminate between the roles of oestrogen in the early follicular phase and its
role at ovulation.
In the early follicular phase, ( which is dominated by oestrogen) oestrogen at low levels
exerts a negative (inhibitory) feedback on gonadotrophin release.
As the follicle grows and ovulation approaches at mid cycle, the rising levels of
oestrogen have become such that a positive (stimulatory) feedback occurs producing a
surge of LH release.
4.5 At the menopause the ovary contains dwindling number of follicles. What will
happen to:
Oestrogen secretion
o plasma FSH
o the secretion of GnRH from the hypothalamus?
Oestrogen secretion wanes
FSH levels will rise considerably
GnRH levels will rise
Because Feedback from gonadal steroids much reduced
4.6
In pregnancy, once the placenta has developed it begins to secrete oestrogen
and progesterone. The secretion is independent of LH and FSH. What will happen to:
o Plasma levels of FSH
o Plasma levels of LH
o Hypothalamic secretion of GnRH
in a pregnant woman?
FSH levels will fall
LH levels will fall
GnRH levels will fall
Because placental oestrogen & progesterone exert negative feedback inhibition at both
hypothalamus and pituitary
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4.7
The drug clomiphene is an oestrogen antagonist sometimes used in the
treatment of infertility. It is given for 5 days at the start of the menstrual cycle
What will be the effects on:
o GnRH secretion
o Plasma levels of FSH and LH
GnRH secretion will rise as clomiphene antagonises feedback inhibition
LH & FSH secretion will also rise, with a larger increase in LH levels as FSH is
suppressed by inhibin
4.8
What would be the effects on gonadotrophin secretion of a constant moderately
high dose of a progesterone like drug?
Progesterone enhances negative feedback of oestrogen
At moderate / high doses this will reduce LH and FSH secretion
And it will block positive feedback effect of high oestrogen, so no LH surges
So ovulation is suppressed (you’ll see this when we talk about progesterone implants
for contraception)
4.9
Would a constant low dose of a progesterone like drug have the same effect? In
this case which parts of the reproductive system might still be affected?
At lower doses, progesterone does not reliably block the effect of high oestrogen so
does not reliably prevent an LH surge and ovulation will probably still occur
But low dose progestogens will affect cervical mucus, making it acidic and inhibiting
sperm transport ( you’ll see this when we talk about the mini-pill )
4.10 If the anterior pituitary gland is transplanted to another site in the body the
secretion of LH, FSH, TSH, GH and ACTH falls to negligible levels. Why?
Releasing hormones are diluted to ineffective concentrations in the general circulation.
The portal nature of the hypophyseal vessels normally ensures that releasing hormones
reach the pituitary at relatively high concentration
4.11
The transplanted anterior pituitary, however, hypersecretes prolactin. Why?
A major part of control of prolactin secretion is inhibition by dopamine.
This is removed if the anterior pituitary is transplanted and the dopamine is diluted in the
general circulation
4.12
The major hypothalamic hormone inhibiting prolactin secretion is dopamine
(prolactin inhibitory hormone). The actions of dopamine are mimicked by the
drug bromocriptine and antagonised by drugs like haloperidol, metoclopramide
and domperidone. What will happen to prolactin levels if a woman is given
bromocriptine?
They should fall, as it mimics the inhibitory effect of dopamine on lactotrophs
4.13. Prolactin, and particularly hyperprolactinaemia, suppresses fertility by disturbing
the pulsatile release of GnRH. What do you think might happen to the fertility of
a woman given metoclopramide?
Fertility may be reduced, as prolactin levels rise because the inhibitory effects of
dopamine are themselves inhibited since metoclopramide inhibits dopamine
(Steroidal synthesis figures have been adapted from Medical Physiology, 2nd Edition, Rhoades, RA and
Tanner, GA. Lippincott and Wilkins)
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