Steroid Hormones,Congenital Adrenal hyperplasia and Testicular Feminaization

1
Steroid Hormones,Congenital Adrenal hyperplasia
and Testicular Feminaization
2
Objectives

• Overview of Steroids
• The Role of Cholesterol
• Adrenal Steroids
• Steroids from the Testis
• Ovarian Steroids
• Congenital Adrenal Hyperplas
• Testicular Feminization

3
Steroid hormones

• All steroid hormones are derived from cholesterol
  and differ only in the ring structure and side
  chains attached to it.
• All steroid hormones are lipid soluble and thus
  are freely permeable to membranes so are not
  stored in cells

4
Steroid Hormones

• produced in the adrenal cortex, testis, ovary,
  and some peripheral tissues (adipose tissue, the
  brain)
• All steroid hormones share a typical (but not
  identical) ring structure.

5

• Steroid hormones have to be carried in the blood
  complexed to specific binding globulins.
• Corticosteroid binding globulin carries cortisol
• Sex steroid binding globulin carries testosterone
  and estradiol
• In some cases a steroid is secreted by one cell
  and is converted to the active steroid by the
  target cell

6
Types of steroid hormones

• Glucocorticoids cortisol is the major
  representative in most mammals
• Mineralocorticoids aldosterone being most
  prominent
• Androgens such as testosterone
• Estrogens, including estradiol and estrone
• Progestogens (also known a progestins) such as
  progesterone

7
Functions of Steroid Hormones

• Steroid hormones play important roles in
• - carbohydrate regulation (glucocorticoids)
• - mineral balance (mineralocorticoids)
• - reproductive functions (gonadal steroids)
• Steroids also play roles in inflammatory
  responses, stress responses, bone metabolism,
  cardiovascular fitness, behavior, cognition, and
  mood.

8
Organization of the Adrenal Gland
There is an adrenal cortex and adrenal medulla

• The adrenal glands comprise 3 separate hormone
  systems
• The zona glomerulosa
• secretes aldosterone
• The zona fasciculata reticularis
• secrete cortisol the adrenal androgens
• The adrenal medulla
• secretes adrenaline

9
Steroid hormone synthesis
A series of enzymatic steps in the mitochondria
and ER of steroidogenic tissues convert
cholesterol into all of the other steroid
hormones and intermediates. An important
control point this process is the transport of
free cholesterol from the cytoplasm into
mitochondria. This step is carried out by the
Steroidogenic Acute Regulatory Protein (StAR) im
10
Source of Cholesterol for Steroid Synthesis
LH
Extracellularlipoprotein
Cholesterolpool
acetate
ATP
cAMP
cholesterol
PKA
Pregnenolone
3bHSD
Progesterone
P450c17
Androstenedione
17bHSD
TESTOSTERONE
11
Adrenal Steroidogenesis

• The first enzymatic step is the conversion of
  cholesterol to pregnenolone, which occurs in the
  mitochondria.
• This reaction is carried out by the enzyme,
  cytochrome P450 side-chain cleavage (P450scc
  also called desmolase, or CYP11A1).
• This is a rate limiting, nonreversible step in
  the initiation of steroid biosynthesis.
• This step occurs in adrenal, ovary, and testis.

12
Steroid Hormone Synthesis
Cholesterol
Pregnenolone (C21)
3-ß-Hydroxysteroid dehydrogenase
Progesterone (C21)
21-a-Hydroxylase
17-a-Hydroxylase
17-a-Hydroxyprogesterone (C21)
11-Deoxycorticosterone (C21)
Androstenedione (C19)
11-Deoxycortisol (C21)
Testosterone (C19)
11- ß -Hydroxylase
Peripheral tissues
Corticosterone
Estradiol (C18)
Cortisol (C21)
Aldosterone (C21)
13
(No Transcript)
14
Adrenal Steroidogenesis

• What determines which pathway is taken?
• Each step of the pathway is regulated by a
  specific enzyme.
• Different zones of the adrenal cortex have
  different relative activities of enzymes,
  resulting in different chemical reactions taking
  place.
• These enzymes are located in the smooth ER.

15
Regulation of ACTH and Cortisol Secretion

• 1. Negative feedback control
• ACTH release from the anterior pituitary is
  stimulated by hypothalamic secretion of
  corticotrophin releasing hormone (CRH).
• CRH ? ? ACTH ? ? ?Cortisol
• ?Cortisol or synthetic steroid suppress CRH
  ACTH secretion

Hypothalamus
Pituitary
Adrenal
16

Pathway of Testosterone Production in the Testis

• The production of androgens from cholesterol is
  identical to that in the adrenal, except that it
  continues from androstenedione to testosterone.

17b-hydroxysteroid oxidoreductase
androstenedione
testosterone
17
Production of Steroids in the Testis

• The main steroid produced in the male is
  testosterone, from the testis. .
• In the male, there is peripheral conversion of
  testosterone to dihydrotestosterone (in androgen
  target tissues, like muscle) by 5a-reductase,
• or to
• and estradiol (mostly in adipose tissue) (E2) by
  cytochrome P450 aromatase.

18
Control of testicular function by the
gonadotrophins
Hypothalamus
GnRH

-
-
Anterior Pituitary
FSH
LH


Testis
Testosterone
Inhibin
AR
Peripheral tissue
Spermatogenesis
19
Ovarian Steroidogenesis

• The ovary produces estrogens (primarily
  estradiol), progesterone, and androgens.
• Ovarian steroids are secreted primarily from
  ovarian follicles and corpora lutea.

20
The Puzzle of Estrogen Production in the Ovary

• In the ovary, estradiol is formed from the
  conversion of testosterone into estradiol by the
  enzyme cytochrome P450 aromatase. This occurs in
  granulosa cells.
• However, granulosa cells do not have the enzyme
  17a-hydroxylase/lyase, and thus cannot convert
  progesterone into androgens.
• Where do the androgens required for estrogen
  production in granulosa cells come from?

21
The Two-Cell Theory of Estrogen Production in the
Ovary

• Numerous studies have now shown that the
  androgens required for aromatization come from
  the neighboring theca cells

22
Mechanism of Steroid Hormone Action
23
Steroid Hormones Molecular Action
24
Receptors which work with the same mechanism

• Steroid hormones
• Thyroid hormones
• Retinoic acid
• 1,25-dihydroxycholecalciferol
• All are members of asuperfamily of
  structurally related gene regulators that
  function in a similar way

25
Congenital Adrenal Hyperplasia (CAH)

• It is the result of an inherited enzyme defect in
  steroid biosynthesis
• The adrenals
• Cannot secrete cortisol ? absent negative
  feedback to the pituitary) ? ACTH continues to
  drive steroid biosynthesis ? adrenal hyperplasia
  and accumulation of cortisol precursors
  (depending on which enzyme is lacking)
• Cannot secrete aldosterone ? electrolyte
  disturbances
• Hyponatraemia
• Hyperkalaemia
• The condition might be fatal unless diagnosed
  early

26
21 ?-Hydroxylase Deficiency
17?-hydroxy-progesterone
Progesterone
Androstenedione
X
21 ?-hydroxylase
In peripheral tissues
11-deoxycorticosterone
Testosterone
Precocious sexual development in ?
Virilisation of ?
27
21 ?-Hydroxylase Deficiency
Congenital Adrenal Hyperplasia (CAH),

• Autosomal recessive condition
• Impairs synthesis of cortisol aldosterone
• Accounts for 95 of all cases of CAH
• ? cortisol?? ACTH secretion ? Adrenal gland
  hyperplasia
• Some of the accumulated precursors are diverted
  to the biosynthesis of sex hormones ?signs of
  androgen excess
• In severe cases, mineralocorticoid deficiency is
  evident ? salt H2O loss ? hypovolaemia shock
  ? neonatal adrenal crisis
• Late presentation (adult life) is possible in
  less severe cases

28

• Diagnosis of the most common type (21-hydroxylase
  deficiency) is be finding ? plasma
  17-hydroxyprogesterone as early as 4 days after
  birth.
• ? stimulation of adrenal androgen production ?
  virilization in baby girls, precocious puberty
  in boys.
• Partial enzyme defect ? late onset form ?
  menstrual irregularity hirsutism in young
  females.

29
Diagnosis

• Serum sample taken at least 2 days after birth
  (earlier samples may contain maternally derived
  17-hydroxyprogesterone
• Classic 21-hydroxylase deficiency is
  characterized by markedly elevated serum levels
  of 17-hydroxyprogesterone
• Late-onset 21-hydroxylase deficiency may require
  corticotropin stimulation test
• inject a 0.125-mg or 0.25-mg bolus of
  corticotropin
• measure base-line and stimulated levels of
  17-hydroxyprogesterone. High level after
  stimulation is diagnostic ( 2x upper reference
  range)

30
Genetics of 21 ?-Hydroxylase Deficiency

• Mutations in the CYP21 gene
• DNA testing and detection of mutations can be
  helpful for prenatal diagnosis and confirmation
  of diagnosis

31
(No Transcript)
32
11 ? -Hydroxylase Deficiency
leads to high concentrations of
11-deoxycortisol Leads to high levels of
11-deoxy-corticosterone with mineralocorticoid
effect (salt and water retention) Suppresses
renin/angiotensin system low renin
hypertension Musculanization in females (FPH)
and early virilization in males
33
Disorders of Male Sexual Differentiation

• They are rare group of disorders
• The defect may be in
• Testosterone production (impaired testosterone
  production)
• Androgen receptors (inactive androgen receptors
  ? target tissues cannot respond to stimulation by
  circulating testosterone e.g., Testicular
  feminization syndrome)

34
Testicular Feminization Syndrome

• 46,XY karyotype
• X-linked recessive disorder
• Androgen receptor resistance high
  testosterone blood level
• In peripheral tissue, testosterone will be
  converted by aromatase into estradiol
  feminization
• Patients have normal testes produce normal
  amounts of müllerian-inhibiting factor (MIF),
  therefore, affected individuals do not have
  fallopian tubes, a uterus, or a proximal (upper)
  vagina.

35
Clinical Picture

• Complete androgen insensitivity syndrome (CAIS)
  female external genitalia with normal labia,
  clitoris, and vaginal introitus (MPH)
• Partial androgen insensitivity syndrome (PAIS)
  mildly virilized female external genitalia
  (clitorimegaly without other external anomalies)
  to mildly undervirilized male external genitalia
  (hypospadias and/or diminished penile size)

36
Take Home MessageSteroid Hormones
Characteristics

• Are made from cholesterol, are lipophilic can
  enter target cell
• Are immediately released from cell after
  synthesis
• Interact with cytoplasmic or nuclear receptors
• Activate DNA for protein synthesis
• Are slower acting and have longer half-life than
  peptide hormones
• Examples cortisol, estrogen testosterone