Human Life Cycle 1 - The ovaries, the ovarian cycle and manipulating fertility
Anil Chopra
1. Identify the hormones that are important in the maintenance of the different stages
of the ovarian cycle. Identify the site of production of these hormones, from the
hypothalamus to the ovary.
2. State the stages of follicular development relative to the stages of germ cell (i.e.
oocyte) development.
3. Elucidate the development of a follicle from the primordial follicular stage
through to the mature follicle.
4. Explain the events which occur at ovulation, relating them to the hormones
which are important in bringing about these events.
5. Describe the development of the corpus luteum.
6. Distinguish between the corpus luteum of pregnancy and the corpus luteum of
menstruation, indicating the hormones which are important for their maintenance.
7. Define the normal ranges of hormones related to ovarian function.
8. Elucidate the hormonal methods of stimulating the ovary and indicate the site of
action of each of these hormones.
9. Describe the ultrasound and biochemical definitions of polycystic ovary syndrome
and the methods of ovulation induction which would be appropriate in this
condition.
10. Describe the methods of ovulation induction in estrogen deficient women.
11. Describe the complications of ovulation induction treatment.
12. Define the menopause, the symptoms of estrogen deficiency and the possible long
term risks associated with estrogen deficiency.
13. Outline the methods of Hormone Replacement Therapy and the clinical
indications for additional progesterone therapy.
14. Outline how to monitor the effectiveness of Hormone Replacement Therapy and
the necessary screening as part of ongoing treatment.
15. Outline the adverse effects of Hormone Replacement Therapy in both sequential
and continuous combined treatments.
Two main functions of the ovaries:
- production of a mature gametes (ova) by oogenesis
- production of steroid hormones (steroidogenesis)
The Menstrual Cycle and Fertilisation
OVARIAN CYCLE
ENDOMETRIAL CYCLE
FOLLICULAR PHASE
OESTROGEN
(17-OESTRADIOL)
OVULATION
PROLIFERATIVE PHASE
LUTEAL PHASE
PROGESTERONE
and
17-OESTRADIOL
SECRETORY PHASE
The menstrual cycle is a 28 day cycle that consists of 2 main phases, the follicular and
secretory phase. Changes occur due to hormone levels and affect 2 main organs, the
ovaries and the endometrium.
Endometrial cycle:
1. Menstrual phase – first day of menstruation  beginning of cycle, lasts 4-5 days
2. Proliferative phase – post-menstruation build up of endometrium, ~ 9 days.
Growth of follicles controlled by oestrogen of follicles. 2-3 fold increase in
endometrial thickness, phase of repair and proliferation – epithelium repairs, gland
increase number and length, spiral arteries lengthen.
Link with ovarian cycle: follicular phase – growth of follicle, when follicle has
developed, the ovum is released  ovulation (~ day 14)
Hormonal control: pituitary – FSH and LH, ovary 3. Secretory phase - ~13 days
Progesterone (and oestrogen)
Formation of corpus luteum, glandular epithelium, thickening endometrium, spiral
arteries.
The Ovarian Cycle:
1. Follicular phase
 At the beginning of the menstrual cycle, ovarian follicles begin to grow and
develop
 Initially, each follicle consists of an outer layer of thecal cells and an inner layer
of granulosa cells which surround the ovum.
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In the maturation process, the ovum increases in size and both groups of cells
proliferate under hormonal influence.
The thecal cells form two distinct layers: an outer fibrous capsule (the theca
externa) and an inner glandular and vascular layer (the theca interna).
The development and growth of follicles depends on the synthesis of specific
hormone receptors and adequate levels of the relevant hormones; the
adenohypophysial gonadotrophins luteinising hormone (LH) and folliclestimulating hormone (FSH).
Thecal cells  LH receptors
granulosa cells  FSH and oestrogen receptors.
The follicles which have reached this stage of development with the necessary
receptors when the gonadotrophins are present in the right quantities  ripen. All
other follicles will regress and be absorbed into the stroma  atresia
binding of LH to its thecal cell receptors stimulates these cells to synthesise
androgens.
FSH binds to the granulosa cells which have a powerful aromatising enzyme
(CYP450 aromatase) capable of converting thecal cell androgens to oestrogens.
Oestradiol released from the granulosa cells  acts directly on these cells 
further proliferation and growth  local positive feedback loop at the cellular
level.
Insulin-like growth factor, IGF-I, is another hormone which is produced by the
growing follicles and it probably plays an important role in growth and
development processes.
As the plasma oestradiol levels rises during the mid-follicular phase, a selective
negative feedback by the oestradiol in the FSH production occurs. This effect,
together with inhibin, (produced by the FSH-stimulated granulosa cells), results in
a decrease in the plasma concentration of FSH
In the maintained basal presence of FSH, together with the increasing quantities of
oestrogen, the outer layers of granulosa cells of the remaining (Graafian) follicle
now synthesise receptors specific for LH. This Graafian follicle is now capable of
further maturation under the influence of its own oestrogens alone, and has no
need for further FSH. It enters the final maturation process which consists of the
terminal growth of the follicle and the release of its ovum into the peritoneum by a
process called ovulation. The stimulus for this event is a sudden surge in LH
which is accompanied by a smaller surge in FSH (due to rise in oestrogen levels).
Just prior to ovulation, the granulosa cells begin to synthesise progestogens
(mainly 17α-hydroxyprogesterone at this stage) instead of converting androgens to
oestrogens. These cells also gave reduced capacity to respond to oestrogens and
FSH during this short, pre-ovulatory phase.
2. Luteal phase:
 Following ovulation rise in progesterone production by the outer granulosa cells
 small increase in the basal body temperature (of the order of 0.3-0.6°C). This is
a useful clinical indicator that ovulation has taken place.
 LH surge causes conversion of the follicular remnants to a corpus luteum
 Some thecal cells become incorporated with the corpus luteum, composed
principally of hyperthyroid granulosa cells.
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These cells contain high concentrations of lipids and are rich in mitochondria, and
their transformation to luteal cells is associated with an increasing production of
progesterone as well as oestradiol.
If pregnancy occurs, the corpus luteum persists and continues to secrete steroids
until the foetoplacental unit can assume this function usually by the twelfth week.
If pregnancy does not occur the high plasma concentration of progesterone exerts
a powerful negative feedback on the hypothalamo-hypophysial axis, in addition to
any negative feedback by oestradiol and other luteal factors such as inhibin.
Consequently LH (and FSH) support is withdrawn, the corpus luteum degenerates
(luteolysis), and ovarian steroid production decreases.
The luteolytic process in humans may also be influenced by the oestrogens
produced by the luteal cells themselves. Other luteolytic factors produced by the
corpus luteum itself, such as oxytocin, may also be involved in luteolysis.
There are a number of changes in the hormonal levels in the blood, the largest of all
being the LH surge around day 14, which in turn induces a rise in oestradiol and
causes ovulation.
ADRENALS AND GONADS
ADRENALS ONLY
ALDOSTERONE
CHOLESTEROL
PREGNENOLONE
PROGESTERONE
17-OH PROGESTERONE
CORTICOSTERONE
DEOXYCORTICOSTERONE
11-DEOXYCORTISOL
ANDROSTENEDIONE
CORTISOL
TESTOSTERONE
DIHYDROTESTOSTERONE
OESTRONE
17- OESTRADIOL
MAINLY GONADS NORMALLY
The thecal cells of the ovaries
produce androgens (along with the
adrenal medulla), and the corpus
luteum is responsible for the
production of 17β-oestradiol and
progesterone.
Menstrual cycles continue
throughout the woman’s life unless
fertilisation of the ovum occurs.
Hormonal changes in pregnancy
In the first 5-6 weeks of pregnancy,
the maternal ovaries produce the
main gonadal steroids.
The rising levels of oestrogens and
progesterone cause a fall in LH and
FSH levels. Slowly, the developing
foetoplacental unit begins to form
more and more hormones namely human Chorionic Gonadotrophin. This maintains
the corpus luteum throughout pregnancy (normally it is broken down).
Ovarian Function, Hyperstimulation and Management
Anovulation: the absence of ovulation due to abnormal endocrinology. It is a
common cause of infertility, normally easily treated.
Presentation
• Amenorrhoea (>6 months) – no period in the last 16 months
• Oligomenorrhoea (cycle >42 days) – irregular periods
• Irregular menses (e.g. cycles varying between 2 and 6 weeks in duration)
Causes of Amenorrhoea
 Primary ovarian failure
 Hypothalamic/pituitary
o Hyperprolactinaemia
o Weight loss/exercise related
o Idiopathic (isolated GnRH deficiency)
 Polycystic ovary syndrome
 Genital tract disorder
 Pregnancy
Causes of Oligomenorrhoea
 Polycystic ovary syndrome
 Perimenopausal
 Recovered weight loss
 Uncertain cause
Polycystic Ovary Syndrome
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Commonest cause of anovulation (~80% cases of anovulatory infertility)
Characterised by androgen excess clinical (hirsutism/acne/frontal hair loss) and/or
biochemical (raised testosterone)
Mechanism of anovulation uncertain: arrested antral follicular development
Anovulatory menses or oestrogen-replete amenorrhoea (have enough oestrogen)
Clinical and/or biochemical evidence of androgen excess
Polycystic ovaries
Polycystic Ovaries on Ultrasound scan
normal
normal
PCO
PCO
more follicles, more stroma
Endocrine Diseases Associated with PCOS
• Hypothalamic-pituitary disease
• prolactinoma
• acromegaly
• Cushing’s
• non-functioning tumours
• Sheehan’s syndrome
• Adrenal disease
• CAH, - enzyme block of cortisol production
• virilising tumours (androgen secreting tumours)
• Addison’s disease
• Thyroid disease
• Hypothyroidism
• hyperthyroidism
Investigations for Anovulation
 FSH, LH (3-11 u/l)
 Prolactin (50 - 500 mu/l)
 Assessment of oestrogen status (if amenorrhoea)
o Serum oestradiol (100-1200 pmol/l)
o early follicular phase E2 (100-400 pmol/l)
o Endometrial thickness
o Progestogen withdrawal test (medroxyprogesterone 5mg/day for 5 days).
o TSH (0.5-5.0 mu/l)
o Pelvic ultrasonography
o Testosterone (0.5-3.0 nmol/l)#
o Progesterone (>20 nmol/l)
3 Different Outcome Groups
• High FSH, low E2 = primary
ovarian failure
• Normal/low FSH, low E2 =
hypothalamic/pituitary
disorder
– Measure prolactin
• Ultrasound scan with normal
FSH, normal E2 (± high LH)
= PCOS
normal
PCOS
probably related to
abnormal endocrine
environment
• leading to relative
deficiency of FSH
Treatment
Treat the underlying cause e.g. if they are not ovulating due to
weight loss, then treat the weight loss. If Cushing’s syndrome,
treat pituitary adenoma.
Induction of Ovulation
• Antioestrogens (clomiphene) (PCOS)
• Gonadotrophins (hypothalamic/pituitary causes;
PCOS)
• Pulsatile GnRH (hypothalamic amenorrhoea)
• Dopamine agonists (hyperprolactinaemia)
Superovulation: to override the physiology and stimulate the
development of many follicles e.g. for IVF treatment.
GnRH treatment is generally effective in treatment of
anovulation and PCOS.
The first choice of treatment is Clomiphene. This is a selective oestrogen receptor
modulation SERM which works by blockade of the oestrogen receptors in the
hypothalamus and thus increasing the release of GnRH.
If the treatment with Clomiphene fails to work then administer human menopausal
Gonadotrophin HMG. The Gonadotrophins LH and FSH were purified from urine
and injected. Now they are available as recombinant hormones.
The outcome of the treatment is affected by any pre-treatment, any other initial causes
of anovulation, and BMI (BMI of over 25 can increase the threshold of FSH and
reduce pregnancy rate). Weight loss dramatically increases rate of ovulation.
If neither of these treatments works then one can perform a Laporoscopic ovarian
diathermy. This is a surgical procedure where multiple diathermy points are
introduced (holes) to each ovary. The trauma to the cortex of the ovary makes the
ovaries more responsive to endogenous gonadotrophin secretion. The risks include the
induction of multiple pregnancies and ovarian hyperstimulation (Symptoms include
abdominal pain, bloating with nausea and constipation, and if sever requires intensive
care).
Menopause and Hormone Replacement Therapy
In the last 100 years the average life expectancy has risen by around 30 years, which
means that women are living longer past the age of menopause. The menopause
normally occurs between the ages of 45-55 preceded by a “perimenopause” – a period
of oligomenorrhoea. Often women are infertile before they get to the menopause.
Females are born with a life-time’s
supply of oocytes.
Only one oocyte per month matures
into the ovum. The rest undergo a
process of atresia. These germ cells
are not replenished and hence the
number and quality of oocytes
declines with age along with
frequency of intercourse.
Ageing
 LH remains stable throughout
life
 The FSH levels increase in the early follicular phase from the ages of 35-40
onward. This is possibly due to the:
o Decreased inhibin B secretion from antral follicles
o Increased FSH may explain increase in dizygotic twins
 Cycle lengths get shorter with age due to shorter follicular phase
 Decreased number of antral follicles with ageing.
 Variable cycles (reduced availability of small antral follicles for selection?).
Peri-Menopause
This is often a time of infertility and
oligomenorrhoea. As ovarian reserve
of follicles declines, oestradiol levels
fall and FSH increases. The high
levels of FSH may “hyperstimulate”
the next “crop” of follicles (Multiple antral
follicles and/or follicular cysts may develop)
Oestradiol levels may transiently become
supraphysiological and FSH is suppressed and
as a result, cause abnormal menstrual cycles.
Post-Menopause
• Androgen production decreases but still
produced by adrenal and, in small
amounts, by ovary
• Low levels of oestrogen in circulation
produced mainly by peripheral conversion
of androgen
• Gonadotrophins remain high
Diagnosis of Menopause
In order to diagnose menopause, patient must have not had a menstrual cycle in 12
months, a rise in LH and FSH levels to over 20u/l, and a fall in oestradiol levels.
The lack of oestrogen has a number of effects:
Vasomotor
• Hot flushes/sweating
• Palpitations
• Headaches
Genitourinary tract
• Vaginal dryness and dyspareunia
• Urge incontinence, dysuria, urinary frequency
Neurological/ Psychological
• Forgetfulness, lack of concentration,
• depression, irritability, anxiety
• loss of libido
• tiredness, insomnia
Skeletal
• Bone loss leading to osteopoenia/osteoporosis
Cardiovascular
• Increased risk of CHD and stroke?
• Risk of cardiovascular events lower in premenopausal female population
compared to male population
• Post menopause rates of cardiovascular disease increase and eventually equal
those in the male population
Hormone Replacement Therapy
Hormone replacement therapy aims to treat the symptoms of oestrogen deficiency and
prevent osteoporosis and cardiovascular risk. Treatment is started as soon as the onset
of menopausal symptoms.
There are 3 main types of HRT:
- Oestrogen alone
- Combined oestrogen and progestogen
- SERM – selective oestrogen receptor modulator
The side effects are predominantly oestrogenic and include breast enlargement,
nausea, vomiting, mood changes, migraine and headache. Its long term side effects
include:
• Small but significant increase in risk of breast cancer, but the risk is related to
duration of HRT use, not age at which treatment is started.
Foetal Growth Rates
Human growth differs in rate and occurs up until around the age of 18 in boys and 16
in girls. Growth is fastest at birth and gradually declines with a pronounced increase
during the adolescent growth spurt.
The foetus grows in a distinctive way, with the different organs
growing at different speeds.
There are a number of different environmental
factors that affect foetal growth including the maternal age, weight, nutrition, and
drug use (smoking, alcohol). It can also be affected by foetal genotype, gender and
hormones.