Special pathophysiology of
endocrine system
March 20, 2018
Nuclear and non nuclear actions
of glucocorticoids
Hormonal activity
 At the molecular level there is little difference in the
way how cellular activity is regulated between
classical neurotransmitters that act across synaptic
clefts, intercellular factors acting across gap
junctions, classic endocrine and paracrine activity
and a variety of other chemical messengers involved
in cell regulation - such as cytokines, growth factors
and interleukins;
 Progress in basic cell biology has revealed the
biochemical similarities in the messengers, receptors
and intracellular post-receptor mechanisms
underlying all these aspects of cell function.
Hypothalamic releasing hormones and the pituitary trophic hormones.
Primary aldosteronism (PA),
 characterized by autonomous aldosterone
overproduction by the adrenal glands, affects
6% of the general hypertensive population
and can be either sporadic or familial.
 Aldosterone-producing adenoma (APA) and
bilateral adrenal hyperplasia (BAH) are the
two most frequent subtypes of sporadic PA
and 4 forms of familial hyperaldosteronism
(FH-I to FH-IV) have been identified.
Primary aldosteronism (PA),
 Germline mutations in KCNJ5 and CACNA1H
cause FH-III and FH-IV, respectively, while
germline mutations in CACNA1D cause the
rare PASNA syndrome, featuring primary
aldosteronism seizures and neurological
abnormalities.
Primary aldosteronism (PA),
 Somatic mutations in four genes (KCNJ5,
ATP1A1, ATP2B3 and CACNA1D), differently
implicated in intracellular ion homeostasis,
have been identified in nearly 60% of the
sporadic APAs.
Addison’s disease
 is a primary adrenocortical insufficiency
with a deficiency in corticosteroids and
mineralocorticoids. The most common
cause for a primary adrenocortical
insufficiency in Western populations is
an autoimmune process (80 %). Further
causes are cancer metastases, especially
bronchial carcinoma, malignant
melanoma or renal cell carcinoma.
Addison disease
 is an acquired primary adrenal
insufficiency, which is a rare but
potentially life-threatening endocrine
disorder that results from bilateral
adrenal cortex destruction leading to
decreased production of
adrenocortical hormones including
cortisol, aldosterone, and/or adrenal.
Addison’s disease
 In developing countries, kidney tuberculosis
is still the most common cause of primary
adrenocortical insufficiencies.
Addison’s disease
 The symptoms manifest in a rather diffuse
clinical pattern with unspecific general
symptoms like fatigue, myalgia, nausea,
and weight loss.
Addison’s disease
 In case of inadequate substitution of
adrenocortical hormones, there is a risk of
an Addisonian crisis.
 Triggers of Addisonian crises are stress
situations with an increased demand for
cortisol, e.g. infections or severe physical
stress. The therapy of an Addisonian crisis
is substitution with high-dose
hydrocortisone. Long-term therapy consists
of hydrocortisone und fludrocortisone.
Addison disease
 insidious course of action usually presents
with glucocorticoid deficiency followed by
mineralocorticoid; however, it can present
acutely, especially with inter-current
illness, with adrenal crisis.
 The most common cause of primary
adrenal insufficiency is autoimmune
adrenalitis (Addison disease) which is
associated with increased levels of 21hydroxylase
antibodies.
Embryology of reproduction
 Up to 8 weeks of gestation the sexes share a
common development, with a primitive genital
tract including the Wolffian and Müllerian ducts.
There are additionally a primitive perineum and
primitive gonads.
 In the presence of a Y chromosome the
potential testis develops while the ovary
regresses.
 In the absence of a Y chromosome, the
potential ovary develops and related ducts form
a uterus and the upper vagina.
Embryology
Production of Müllerian inhibitory factor from the
early 'testis' produces atrophy of the Müllerian
duct, while, under the influence of testosterone
and dihydrotestosterone, the Wolffian duct
differentiates into an epididymis, vas deferens,
seminal vesicles and prostate. Androgens
induce transformation of the perineum to
include a penis, penile urethra and scrotum
containing the testes, which descend in
response to androgenic stimulation. At birth,
testicular volume is 0.5-1 mL.
Male and female hypothalamic-pituitary-gonadal axes. Note the close parallels.
The green lines indicate negative feedback
Hypothalamic-pituitary-testicular axis
 Pulses of GnRH (LHRH) are released from the hypothalamus
and stimulate LH and FSH release from the pituitary.
 LH stimulates testosterone production from Leydig cells of
the testis.
 Testosterone acts systemically to produce male secondary
sexual characteristics, anabolism and the maintenance of
libido. It also acts locally within the testis to aid
spermatogenesis. Testosterone circulates largely bound to
sex hormone-binding globulin (SHBG). Testosterone feeds
back on the hypothalamus/pituitary to inhibit GnRH
secretion.
 FSH stimulates the Sertoli cells in the seminiferous tubules
to produce mature sperm and the inhibins A and B.
 Inhibin causes feedback on the pituitary to decrease FSH
secretion.
 The secondary sexual characteristics of the male for which
testosterone is necessary are the growth of pubic, axillary
and facial hair, enlargement of the external genitalia,
deepening of the voice, sebum secretion, muscle growth and
frontal balding.
The female
 In the adult female, higher brain
centres impose a menstrual cycle
of 28 days upon the activity of
hypothalamic GnRH.
 Pulses of GnRH, at about 2-hour
intervals, stimulate release of
pituitary LH and FSH.
 LH stimulates ovarian androgen
production by the ovarian theca
cells.
The female
 FSH stimulates follicular development and
aromatase activity (an enzyme required
to convert ovarian androgens to
oestrogens) in the ovarian granulosa
cells. FSH also stimulates release of
inhibin from ovarian stromal cells which
inhibits FSH release.
 Although many follicles are 'recruited' for
development in early folliculogenesis, by
day 8-10 a 'leading' (or 'dominant')
follicle is selected for development into a
mature Graafian follicle.
The female
 Oestrogens show a double feedback action
on the pituitary, initially inhibiting
gonadotrophin secretion (negative
feedback), but later high-level exposure
results in increased GnRH secretion and
increased LH sensitivity to GnRH (positive
feedback), which leads to the mid-cycle LH
surge inducing ovulation from the leading
follicle.
 The follicle then differentiates into a corpus
luteum, which secretes both progesterone
and estradiol during the second half of the
cycle (luteal phase).
The female
 Oestrogen initially and then progesterone cause
uterine endometrial proliferation in preparation
for possible implantation; if implantation does
not occur, the corpus luteum regresses and
progesterone secretion and inhibin levels fall so
that the endometrium is shed (menstruation)
allowing increased GnRH and FSH secretion.
 If implantation and pregnancy follow, human
chorionic gonadotrophin (HCG) production from
the corpus luteum maintains corpus luteum
function until 10-12 weeks of gestation, by
which time the placenta will be making
sufficient oestrogen and progesterone to
support itself.
The female
 Oestrogens also induce secondary sexual
characteristics, especially development of
the breast and nipples, vaginal and vulval
growth and pubic hair development.
 They also induce growth and maturation of
the uterus and Fallopian tubes.
 They circulate largely bound to sex
hormone-binding globulin (SHBG).
Hormonal and follicular changes during the normal menstrual cycle.
The control of prolactin secretion.
Physiology of prolactin
secretion
 Prolactin is under tonic dopamine inhibition
(=PIH-prolactin inhibitory hormon), while
other factors known to increase prolactin
secretion (e.g. TRH) are probably of less
importance.
 Function:
 Stimulation of milk secretion
 Reduction of gonadal activity. It decreases
GnRH pulsatility at the hypothalamic level
and, to a lesser extent, blocks the action of
LH on the ovary or testis, producing
hypogonadism. These actions may be
clinically relevant.
Puberty
The mechanisms initiating puberty
are poorly understood but are
thought to result from withdrawal of
central inhibition of GnRH release.
LH and FSH are both low in the
prepubertal child. In early puberty,
FSH begins to rise first, initially in
nocturnal pulses; this is followed by
a rise in LH with a subsequent
increase in testosterone/oestrogen
levels.
Puberty
 In boys, pubertal changes begin at between
10 and 14 years and are complete at
between 15 and 17 years.
 The genitalia develop, testes enlarge and
the area of pubic hair increases.
 Peak height velocity is reached between
ages 12 and 17 years during stage 4 of
testicular development.
 Full spermatogenesis occurs comparatively
late.
The age of development of features of puberty. Stages and testicular size show
mean ages, and all vary considerably between individuals. The same is true of
height spurt, shown here in relation to other data. Numbers 2 to 5 indicate stages
of development
Puberty
 In girls, events start a year earlier.
 Breast bud enlargement begins at ages 9-13
years and continues to 12-18 years.
 Pubic hair growth commences at ages 9-14
years and is completed at 12-16 years.
 Menarche occurs relatively late (age 11-15
years)
 Peak height velocity is reached earlier (at
age 10-13 years)
 Growth is completed much earlier than in
boys.
Precocious puberty
 Development of secondary sexual
characteristics, or menarche in girls, at or
before the age of 9 years is premature. All
cases require specialist assessment by a
paediatric endocrinologist.
 Idiopathic (true) precocity is most common
in girls and very rare in boys. This is a
diagnosis of exclusion. With no apparent
cause for premature breast or pubic hair
development, and an early growth spurt, it
may be normal and may run in families.
The following are other forms of precocity:
 Cerebral precocity. Many causes of hypothalamic
disease, especially tumours, may present in this way. In
boys this must be rigorously excluded.
 McCune-Albright syndrome. This is usually in girls, with
precocity, polyostotic fibrous dysplasia and skin
pigmentation (café-au-lait).
 Premature thelarche. This is early breast development
alone, usually transient, at age 2-4 years. It may
regress or persist until puberty. There is no evidence of
follicular development.
 Premature adrenarche. This is early development of
pubic hair without significant other changes, usually
after age 5 years and more commonly in girls.
Delayed puberty
 Over 95% of children show signs of pubertal
development by age 14 years. In its absence,
investigation should begin by age 15 years.
Causes of hypogonadism (see below) are
clearly relevant but most cases represent
constitutional delay.
 In constitutional delay, pubertal development,
bone age and stature are in parallel. A family
history may confirm that other family
members experienced the same delayed
development, which is common in boys but
very rare in girls.
Delayed puberty
 In boys, a testicular volume > 5 mL indicates the
onset of puberty. A rising serum testosterone is
an earlier clue.
 In girls, the breast bud is the first sign.
Ultrasound allows accurate assessment of ovarian
and uterine development. Basal LH/FSH levels
may identify the site of a defect, and GnRH
(LHRH) tests can indicate the stage of early
puberty. If any progression into puberty is
evident clinically, investigations are not required.
When delay is great and problems are serious
(e.g. severe teasing at school), low-dose shortterm
sex hormone therapy is used. Specialist
assessment is advisable.
The menopause
 The menopause, or cessation of periods, naturally
occurs about the age of 45-55 years. During the late
forties, FSH initially, and then LH concentrations begin
to rise, probably as follicle supply diminishes.
Oestrogen levels fall and the cycle becomes disrupted.
Most women notice irregular scanty periods coming on
over a variable period, though in some sudden
amenorrhoea or menorrhagia occur.
 Eventually the menopausal pattern of low estradiol
levels with grossly elevated LH and FSH levels (usually
> 50 and > 25 U/L, respectively) is established.
 Menopause may also occur surgically, with
radiotherapy to the ovaries and with ovarian disease
(e.g. premature menopause).
Premature menopause
 The most common cause of
premature menopause in women
(before age 40) is ovarian failure,
which may be autoimmune or of
unknown aetiology.
 HRT should be given, as the risk of
osteoporosis and premature
ischaemic heart disease far outweigh
the risks (?).
The ageing male
 In the male there is no sudden 'change of life'. However,
there is a progressive loss in sexual function with
reduction in morning erections and frequency of
intercourse.
 The age of onset varies widely, but overall testicular
volume diminishes and sex hormone-binding globulin
(SHBG) and gonadotrophin levels gradually rise.
 If premature hypogonadism is present for any reason,
replacement testosterone therapy should be given to
prevent osteoporosis.
 Lowering of androgens forms part of the therapy of
prostate hypertrophy and prostate cancer. Finasteride, an
inhibitor of 5α-reductase, is used in benign prostatic
hypertrophy. It prevents the conversion of testosterone to
dihydrotestosterone, which causes prostatic hypertrophy.
Hypogonadism
 Cryptorchidism By the age of 5 years both
testes should be in the scrotum. After that age
the germinal epithelium is increasingly at risk,
and lack of descent by puberty is associated with
subfertility. Surgical exploration and orchidopexy
are usually undertaken but a short trial of HCG
occasionally induces descent: an HCG test with a
testosterone response 72 hours later excludes
anorchia. Intra-abdominal testes have an
increased risk of developing malignancy; if
presentation is after puberty, orchidectomy is
advised.
Hypogonadism
 Klinefelter's syndrome Klinefelter's syndrome
(seminiferous tubule dysgenesis), a chromosomal
disorder (47XXY) affecting 1 in 1000 males, involves
both loss of Leydig cells and seminiferous tubular
dysgenesis. Patients usually present with
 poor sexual development
 small or undescended testes
 gynaecomastia
 or infertility.
 They are occasionally mentally retarded.
 Confirmation is by chromosomal analysis. Treatment is
androgen replacement therapy unless testosterone
levels are normal. No treatment is possible for the
abnormal seminiferous tubules and infertility.
Hypogonadism
 Kallmann's syndrome This is due to isolated GnRH
deficiency. It is often associated with decreased or
absent sense of smell (anosmia), and sometimes with
other bony (cleft-palate), renal and cerebral
abnormalities (e.g. colour blindness). It is often familial
and is usually X-linked; one sex-linked form is due to an
abnormality of a cell adhesion molecule. Fertility is
possible.
 Oligospermia or azoospermia These may be
secondary to androgen deficiency and can be corrected
by androgen replacement. More often they result from
primary testicular diseases, in which case they are rarely
treatable. Azoospermia with normal testicular size and
low FSH levels suggests a vas deferens block, which is
sometimes reversible by surgical intervention.
Gynaecomastia
Gynaecomastia is development of
breast tissue in the male.
Pubertal gynaecomastia occurs in
perhaps 50% of normal boys, often
asymmetrically. It usually resolves
spontaneously within 6-18 months,
but after this duration may require
surgical removal, as fibrous tissue will
have been laid down. The cause is
thought to be relative oestrogen
excess.
Gynaecomastia
 In the older male, gynaecomastia
requires a full assessment to exclude
potentially serious underlying disease,
such as bronchial carcinoma and
testicular tumours (e.g. Leydig cell
tumour).
 Drug effects are common (especially
digoxin and spironolactone), and once
these and significant liver disease are
excluded most cases have no definable
cause. Surgical removal is occasionally
necessary.
Range of serum prolactin seen in common causes of hyperprolactinaemia.
Hypogonadism in female
 Impaired ovarian function, whether primary
or secondary, will lead both to oestrogen
deficiency and abnormalities of the
menstrual cycle. The latter is very sensitive
to disruption, cycles becoming anovulatory
and irregular before disappearing
altogether. Symptoms will depend on the
age at which the failure develops.
Amenorrhoea : Absence of periods or
markedly irregular infrequent periods
(oligomenorrhoea) are the commonest
presentation of female gonadal disease.
Hypogonadism in female
 Polycystic ovary syndrome Polycystic ovary syndrome
is the most common cause of oligomenorrhoea and
amenorrhoea in clinical practice and should always be
considered in the context of menstrual dysfunction.
 Weight-related amenorrhoea A minimum bodyweight
is necessary for regular menstruation. While anorexia
nervosa is the extreme form, this condition is common
and may be seen at weights within the 'normal' range.
The biochemistry is indistinguishable from gonadotrophin
deficiency and some patients have additional mild
endocrine disease (e.g. polycystic ovarian disease).
Restoration of bodyweight is usually effective in restoring
menstruation, but in the many cases where this cannot
be achieved then oestrogen replacement must be
considered. Similar problems occur with intensive
physical training in athletes and dancers.
Hypogonadism in female
 Hypothalamic amenorrhoea Amenorrhoea
with low oestrogen and gonadotrophins in the
absence of organic pituitary disease, weight
loss or excessive exercise is described as
hypothalamic amenorrhoea. This may be
related to 'stress', to previous weight loss or
stopping the contraceptive pill, but some
patients appear to have defective cycling
mechanisms without apparent explanation.
 Hypothyroidism Oligomenorrhoea and
amenorrhoea are frequent findings in severe
hypothyroidism in young women.
Hypogonadism in female
Other Pregnancy must always be
considered as a possible cause. The
possibility of genital tract
abnormalities, such as an
imperforate hymen, should also be
remembered, especially in primary
amenorrhoea. Severe illness, even
in the absence of weight loss, can
lead to amenorrhoea, as can
stopping the contraceptive pill.
Hirsutism and polycystic ovary syndrome
 Hair in the beard, moustache, breast, chest, axilla,
abdominal midline, pubic and thigh areas is sexhormone
dependent.
 Any excess in the latter regions is thus usually a
marker of increased ovarian or adrenal androgen
production.
 Some authorities divide patients with hirsutism into
those with no elevation of serum androgen levels and
no other clinical features (usually labelled 'idiopathic
hirsutism') and those with an identifiable endocrine
imbalance (most commonly polycystic ovary
syndrome (PCOS), or rarely other causes).
Polycystic ovary syndrome (PCOS)
 PCOS, originally known in its severe form as the SteinLeventhal
syndrome, is characterized by multiple small
cysts within the ovary and by excess androgen
production from the ovaries and to a lesser extent from
the adrenals, although whether the basic defect is in the
ovary, adrenal or pituitary remains unknown.
 The precise levels of androgens in blood vary widely
from patient to patient. In addition, oestrogens are
converted to androgens in adipose tissue, which
represents a further source of androgen excess in obese
patients. The response of the hair follicle to circulating
androgens also seems to vary between individuals with
otherwise identical clinical and biochemical features, and
the reason for this variation in end-organ response
remains poorly understood.
Polycystic ovary syndrome (PCOS
 The ovarian 'cysts' represent arrested follicular development.
Studies have shown an association of polycystic ovarian syndrome
with anovulation and insulin resistance, which may also be
associated with hypertension, hyperlipidaemia and increased
cardiovascular disease prevalence.
 Familial or idiopathic hirsutism does occur, but usually involves a
distribution of hair growth which is not typically androgenic.
Similarly, non-androgen-dependent hair growth occurs with drugs
such as phenytoin, diazoxide, minoxidil and ciclosporin. Iatrogenic
hirsutism also occurs after treatment with androgens, or more
weakly androgenic drugs such as progestagens or danazol. Rarer,
and more serious, endocrine causes of hirsutism and virilization
include congenital adrenal hyperplasia, Cushing's syndrome and
virilizing tumours of the ovary and adrenal. All these conditions
should be considered in any patient with hirsutism - as this may
be their only presenting complaint.
Disorders of sexual differentiation
 Disorders of sexual differentiation are rare but
may affect chromosomal, gonadal, endocrine
and phenotypic development. Such cases
always require extensive, multidisciplinary
clinical management. An individual's sex can be
defined in several ways:
 Chromosomal sex. The normal female is 46XX,
the normal male 46XY. The Y chromosome
confers male sex; if it is not present,
development follows female lines.
 Gonadal sex. This is obviously determined
predominantly by chromosomal sex, but
requires normal embryological development.
Biosynthetic pathway of steroid
hormones in vertebrates
 The relevant sex-steroids are in the
squares with the red borders. Both males
and females produce androgens and
estrogens. The difference does no not
reside in their types of sex steroids but in
their titres in the blood. Females convert
more testosterone into estradiol. Hence
the testosterone titre is higher in males,
while the opposite is true for estradiol.
Commun Integr Biol. 2018; 11(1): e1427399
Commun Integr Biol. 2018; 11(1):
e1427399
Disorders of sexual differentiation
 Phenotypic sex. This describes the normal
physical appearance and characteristics of male
and female body shape. This in turn is a
manifestation of gonadal sex and subsequent
sex hormone production.
 Social sex (gender). This is heavily dependent
on phenotypic sex and normally assigned on
appearance of the external genitalia at birth.
 Sexual orientation - heterosexual, homosexual
or bisexual. Some studies suggest that there
may be some element of genetic determination
of homosexuality.
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