ENDOCRINOLOGY OF

THE REPRODUCTIVE SYSTEM,

PUBERTY AND MENOPAUSE

M. Djauhari Widjajakusumah
The Hypothalamic-Pituitary Unit

GnRH Neurons in The Hypothalamus

 Arcuate Nucleus
 Important region for gonadotropin control in primate
 The driver of the reproductive system
 Generates and releases pulses of GnRH into the portal venous system

 Median Eminence
 GnRH granules are transported by axonal flow to the median eminence
area; the most prominent projections are from arcuate neurons.
 GnRH is released into capillaries  Long Portal Veins  pituitary stalk 
adenohypophysis (anterior pituitary)
 Direct brain - anterior pituitary vascular connection  rapid transport of
undiluted minute amounts of GnRH
The GnRH Pulse Generator

 Arcuate nucleus
 The foremost ventral portion of the medial basal hypothalamus
 The most essential neural center controlling gonadotropin secretion
 Lessions of the arcuate nucleus  abolished basal release of LH
and FSH
 Increase in arcuate nucleus electrical activity precedes
LH discharge

 Subject to modifying influences from extra- and intra-hypothalamic loci

Griffin, J.E., Ojeda, S.R.: Textbook of Endocrine Physiology 3rd ed 1996.

The GnRH Pulse

 GnRH is released in pulsating fashion, concomitantly stimulates LH and FSH

secretion

 Synchronized pulse of GnRH release and pulse of LH release:

 Intermittent (fluctuated) LH release, ultradian (less than 1 day) rhythm
 Oscillate with a period of about 1 hr; 2 hrly between peaks
 Synchronized pulse of GnRH release and pulse of FSH release:
 Lower amplitude of FSH pulse than that of LH:
 smaller amounts of FSH released in response to GnRH pulse
 longer FSH half-life  individual pulses masking effects on the
subsequent ones
 estradiol suppress FSH release at the pituitary level  more evident in
the early follicular phase, postmenopausal period, ovariectomized
individuals (low estradiol conditions)
Gonadotropin-Releasing System

 Adenohypophysis gonadotroph cells

 Cells secrete only LH, or only FSH, or both
 Pulsatile secretion of gonadotropins
 Particularly LH
 Episodes 70-100 mnts
 Interpulse intervals 1 hr (circhoral rhythm)
 Less frequent during the luteal phase (progesterone effect?)
 Sleep-related rhythm (diurnal rhythm)
 increased LH release during sleep

 fundamental feature at the onset of puberty

 A function of hypothalamic LHRH

Griffin, J.E., Ojeda, S.R.: Textbook of Endocrine Physiology 3rd ed 1996.

ADOLESCENCE AND PUBERTY

Adolescence

 The period of growth and maturation of the reproductive system

that culminates at puberty
 The final maturation of of the reproductive system activated by
pituitary gonadotropins
 Secretory and morphological activities of the gonads reach the
adult stage, and the menarche occurs
Adolescence and Puberty

 Puberty

• Refers to the process of physical changes by which a child's body

becomes an adult body capable of reproduction

• The period when the endocrine and gametogenic functions of the gonads
have first developed to the point where reproduction is possible

• Thelarche: development of breasts

• Pubarche: development of axillary and pubic hair

• Menarche: the first menstrual period

 Generally anovulatory
 Regular ovulation about a year later
Control of The Onset of Puberty

 The precise mechanism is still not well understood

 Requires interactions between the brain, the pituitary gland, and the
gonads and their target organs

 Children’s gonads can be stimulated by gonadotropins

 Children’s pituitary contain gonadotropins, but are not secreted
 Children’s hypothalami contain GnRH
 During the period from birth to puberty, a still unknown neural
mechanism is preventing the normal pulsatile release of GnRH
CONTROL OF THE ONSET OF PUBERTY

 THE NEURAL INPUT

 The neuroendocrine GnRH system is fully mature at birth  ‘adult
level’ of gonadotropin secretion
 Pulsatile GnRH activity declines in late infancy until the prepubertal
/adolescence phase (hypothalamic quiescence)
 The initial step that leads to puberty is an restored increase in the
pulsatile release of GnRH  gonadotropins release  puberty
 Proper release of GnRH may require synchronous activity of
specific neuronal system
CONTROL OF THE ONSET OF PUBERTY

 THE METABOLIC INPUT

 Good nutrition advances the onset of puberty, starvation delays it

 Link between nutrition and the activity of GnRH pulse generator
 The hypothesis: a threshold of body weight (percent of body fat) is
critical for allowing initiation of the maturity process
 Probably metabolic cues are relayed to the brain and provide
signals that activate the GnRH pulse generator
Reinitiation of Pulsatile Gonadotropin Secretion in Pubertal
Children
 The first sign of the initiation of sexual maturation
 Low gonadotropin secretion during day-time, increased during the
night
 In the later stages of puberty
 Nocturnal increase of gonadotropin levels replaced gradually by

episodic increase around the clock

 The possible relation between melatonin and the onset of puberty
 Melatonin is argued to inhibit the onset of puberty in humans; its
effects vary markedly from species to species (inhibition 
facilitation)
Puberty as a hormonal process

1. The brain's hypothalamus begins to release pulses of GnRH. True

puberty is often termed "central puberty" because it begins as a
process of the central nervous system
2. Cells in the anterior pituitary respond by secreting LH and FSH into the
circulation
3. The ovaries or testes respond to the rising amounts of LH and FSH by
growing and beginning to produce estradiol and testosteron
4. Rising levels of estradiol and testosterone produce the body changes
of female and male puberty
 PRECOCIOUS PUBERTY

 Pubertal changes before the age of 8 years

 Isosexual precocious puberty: sexual development is consistent
with genetic sex
 Heterosexual precocious puberty: sexual development is
inconsistent with genetic sex ( virilism)
 True precocious puberty
 Pseudoprecocious puberty
PRECOCIOUS PUBERTY

 TRUE PRECOCIOUS PUBERTY

 The gonads are the source of the sex hormones
 Premature activation of the hypothalamic-pituitary unit
 Secondary sex characteristics with gametogenesis
 PSEUDOPRECOCIOUS PUBERTY
 Primary ovarian / testes (gonadal) abnormality independent of pituitary
stimulation
 Leydig cell tumors of testis
 Granulosa cell tumors of ovary
 Adrenal (extragonadal)
 Androgen-secreting tumors (in males)
 Estrogen-secreting tumors (in females)
 DELAYED PUBERTY

 Lack of physical manifestation of puberty beyond the norm of pubertal

age (17 in females, 20 in males)

 Organic causes
 CNS disorders: delay in activation of the hypothalamic pulse
generator
 Gonadotropin deficiency
 Gonadal failure (dysgenesis)
 Environmental factors
 Nutrtion
 Weight
 Stress
 Exercise
MENOPAUSE

• Menopause is the time in a woman's life when the function of the

ovaries ceases.

• Menopause is defined as absence of menstrual periods for 12

months.

• The menopausal transition starts with varying menstrual cycle length

and ends with the final menstrual period.

• Perimenopause means "around the time of menopause.“

• Postmenopause is the entire period of time that comes after the last
menstrual period.
MENOPAUSE

• Between the ages of 45 - 55 year

• may occur as earlier as the 30s or 40s or may not occur until a
woman reaches her 60s.

• Unresponsiveness of human ovaries to gonadotropin with advancing

age

• Declining function of the ovaries --> sexual cycles disappear

(menopause)

• Declining number of primordial follicle

• No appreciable quantities of ovarian progesterone and estradiol

• Atrophic uterus and vagina

• Increased FSH and LH

THE PERIMENOPAUSAL AND MENSTRUAL CYCLICITY

PERIMENOPAUSE
Follicle pool
inhibin FSH Acceleration of Follicular
Maturation

Shorter Cycle
Follicle Pool

Estradiol Delayed (+) feedback Longer Cycle

MENOPAUSE
Follicle Pool

Estradiol LH FSH Cycle Arrest

 MENOPAUSE
 Common Symptoms

 Hot flashes / hot flushes (75%): warmth sensation spreading from

trunk to face
 prevented by estrogen treatment

 unknown cause

 coincide with surges of LH secretion (bursts at intervals of 30’ -

60’)
 LH is not responsible for the symptom

 Night sweats
 Various psychic symptoms
MENOPAUSE
Hot flashes & night sweats
 A feeling of warmth that spreads over the body and is often most
pronounced in the head and chest.
 Usually last from 30 seconds to several minutes
 Sometimes associated with flushing and is sometimes followed by
perspiration.
 Are likely due to a combination of hormonal and biochemical fluctuations
brought on by declining estrogen levels.
 May begin before the menstrual irregularities characteristic of menopause
begin.
 About 80% of women will be finished having hot flashes after five years
(in about 10% of women, hot flashes can last as long as 10 years)
 Tend to decrease in frequency over time.
 Sometimes hot flashes are accompanied by night sweats, resulting in
unrefreshing sleep and daytime tiredness
MENOPAUSE

Vaginal symptoms
 A result of the lining tissues of the vagina becoming thinner, dryer, and
less elastic as estrogen levels fall.

 Symptoms may include vaginal dryness, itching, or irritation and/or pain

with sexual intercourse (dyspareunia).

 The vaginal changes also lead to an increased risk of vaginal infections.

MENOPAUSE

Urinary symptoms
 The lining of the urethra undergoes changes similar to the tissues of the
vagina, becomes dryer, thinner, and less elastic with declining estrogen
levels.

 Can lead to an increased risk of urinary tract infection , feeling the need to
urinate more frequently, or leakage of urine (urinary incontinence).

 The incontinence can result from a strong, sudden urge to urinate or may
occur during straining when coughing, laughing, or lifting heavy objects.
MENOPAUSE

Emotional and cognitive symptoms

 Women in perimenopause often report a variety of cognitive (thinking)
and/or emotional symptoms:
 fatigue, memory problems, irritability, rapid changes in mood

 Difficult to determine which behavioral symptoms are due directly to the

hormonal changes of menopause
 Night sweats that can also contribute to feelings of tiredness and fatigue,
which can have an effect on mood and cognitive performance
 Many women may be experiencing other life changes during the time of
perimenopause or after menopause, such as stressful life events, that
may also cause emotional symptoms.
MENOPAUSE

Osteoporosis
 Osteoporosis is the deterioration of the quantity and quality of bone that
causes an increased risk of fracture.
 The density of the bone (bone mineral density) normally begins to
decrease in women during the fourth decade of life.
 Normal decline in bone density is accelerated during the menopausal
transition.
 Age and the hormonal changes due to the menopause transition act
together to cause osteoporosis.
 The process leading to osteoporosis can operate silently for decades.
Women may not be aware of their osteoporosis until suffering a painful
fracture.
MENOPAUSE

Cardiovascular disease
 Prior to menopause, women have a decreased risk of heart disease and
stroke when compared with men. Around the time of menopause,
women’s risk of cardiovascular disease increases.
 Coronary heart disease rates in postmenopausal women are two to three
times higher than in women of the same age who have not reached
menopause.
 The increased risk for cardiovascular disease may be related to declining
estrogen levels, but postmenopausal women are not advised to take
hormone therapy simply as a preventive measure to decrease their risk of
heart attack or stroke.
MENOPAUSE

Hormone therapy
 Estrogen and progesterone therapy
 Oral contraceptive pills
 Plant estrogens (phytoestrogens, isoflavones)
 Local (vaginal) hormone treatments

Antidepressant medications

Lifestyle factors in controlling the symptoms and

complications of menopause
 MENOPAUSE

Hormone therapy
Estrogen and progesterone therapy

 Hormone replacement therapy (HRT), consists of estrogens or a

combination of estrogens and progesterone (progestin).
 The most effective way to control the symptoms of menopause
related to declining estrogen levels such as hot flashes and
vaginal dryness.
 Combination of estrogens and progesterone increases risk for
stroke and breast cancer
 Estrogen therapy alone is associated with an increased risk for
stroke, and endometrial cancer, but not for breast cancer.
 Must take into account the inherent risks and benefits of the
treatment along with each woman's own medical history.
 It is currently recommended that hormone therapy should be
used at the smallest effective dose for the shortest possible time.
MENOPAUSE

Hormone therapy
Oral contraceptive pills
 Another form of hormone therapy often prescribed for women in
perimenopause to treat irregular vaginal bleeding.
 Prior to treatment, other causes of erratic vaginal bleeding must be
excluded.
 Women in the menopausal transition tend to have considerable
breakthrough bleeding when given estrogen therapy.
 Oral contraceptives are often given to women in menopause transition
to regulate menstrual periods, relieve hot flashes, as well as to provide
contraception.
MENOPAUSE

Hormone therapy

Plant estrogens (phytoestrogens, isoflavones)

 Chemical compounds found in soy and other plants that are
phytoestrogens, or plant-derived estrogens.
 Have a chemical structure that is similar to the estrogens
naturally produced by the body
 Effectiveness as an estrogen has been estimated to be much
lower than true estrogens, has been estimated to be only
1/1000 to 1/100,000 of that of estradiol.
 May help relieve hot flashes and other symptoms of
menopause.
 Further research is needed to fully characterize the safety and
potential risks of phytoestrogens.
MENOPAUSE

Hormone therapy
Local (vaginal) hormone treatments

 Vaginal hormonal treatments for the symptoms of vaginal estrogen

deficiency.
 Include the vaginal estrogen ring, vaginal estrogen cream, or vaginal
estrogen tablets.
 Local and oral estrogen treatments are sometimes combined.
MENOPAUSE

Antidepressant medications

 Effective in controlling the symptoms of hot flashes in up to 60% of

women.
 May be associated with side effects, including decreased libido or sexual
dysfunction.
MENOPAUSE

Lifestyle factors in controlling the symptoms and

complications of menopause

 Many of the symptoms of menopause and the medical complications that

may develop in postmenopausal women can be lessened or even
avoided by taking steps to lead a healthy lifestyle.
 Regular exercise can help protect against cardiovascular disease as well
as osteoporosis, and exercise also has known mental health benefits.
 Proper nutrition and smoking cessation will also reduce your risk of
cardiovascular disease.
Thank you