Transcript Female sex hormones

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Gonads:According to both sexes, the gonads are two:
Ovaries (female) secrete:
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Progesterone
Oestrogen: It is the end product that can control
secretion of hypothalamus and pituitary.
Testes (male): imp for the production of
testosterone
Secretion of these glands is controlled by
hypothalamic-pituitary gonadal axis (HPG axis).
• Female sex hormones:
• Levels of LH and FSH (therefore oestrogen and
progesterone) are different according to the period
of menstrual cycle phase:
• A typical cycle consists of 28 days; Follicular phase,
(day 1 until day 14). Ovulatory phase (48 hrs after
day 14) and Luteal phase: The remaining time until
the end of the cycle.
• At the first day (time of bleeding), there is low levels
of oestrogen and progesterone. This low level of
oestrogen results in loss of negative feedback
mechanism with gradual increase in LH and FSH.
• FSH will act on several ovarian follicles (about 5 to
6), but it results in development of a single follicle
(Graafian follicle), which becomes mature and
prepares the ovum.
• LH at the same time stimulates secretion of
oestrogen from developing follicles. This
oestrogen increases to a peak level at 12 hrs
before the day 14. This peak of oestrogen
undergoes positive feedback stimulation of LH
secretion and results in peak increase in LH
level. This is called LH-surge which is critical
for ovulation.
• After ovulation, the empty follicle is called
corpus luteum or yellow body, which releases
progesterone and oestrogen.
• Progesterone prepares the uterus for
implantation of fertilized ovum if present. This
is the luteal phase. If there is no implantation,
the endometrium shedding occurs and the
cycle takes place again.
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Disorders of the gonads:
Primary ovarian failure: due to defect in
ovaries -------→ low oestrogen levels -------→
high levels of LH and FSH (caused by loss of
negative feedback mechanism) e.g.
menopause
Secondary ovarian failure: due to diseases
in hypothalamus (no GnRH) or pituitary
result in-------→ low levels of LH and FSH ------→ low levels of oestrogen e.g.
panhypopituitarism.
Both of these conditions can result in
amenorrhoea and infertility.
Male sex hormones:
• LH stimulates Leydig's cells of testes to secrete
testosterone. This hormone is responsible for male
secondary sex characteristics, and gives male
characters in general.
• It inhibits gonadotropin secretion by negative
feedback inhibition, similar to that of ovarian hormones
in females.
• If there is testicular failure due to any cause it is called
primary endocrine disease, where there is low level of
testosterone, resulting in loss of negative feedback
mechanism, with stimulation of LH secretion, so the
level of LH will be very high in blood.
• But if there is hypothalamic or pituitary diseases, level
of LH and FSH are low, so level of testosterone is also
within low limits this is secondary testicular failure
(secondary endocrine disease).
FSH stimulates spermatogenesis and its level
is not controlled by testosterone, but by
another factor called inhibin, which is
secreted from Sertoli's cells (in testes) or
from mature sperm.
Therefore if there is low FSH this will result in
oligospermia or azoospermia and infertility
in males The indicators of defect in
spermatogenesis are high levels of FSH
(in blood), with very low level of inhibin
(glycoprotein secreted by seminiferous
tubules).
• Types Sex Hormones:
• Androgens: These are a group of
19C steroids, required for
differentiation of male genital tract and
development of secondary male sex
characteristics. They also influence
muscle bulk, bone mass and sexual
performance in males.
• In females, androgens act as
precursors of oestrogen (18C
steroids) and they are important in low
levels for normal libido in female.
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There are several types of androgens:
Testosterone (most important androgen in
blood):
• In male it is secreted from Sertoli cells, whilst in
females 50% testosterone is derived from
peripheral conversion of androstenedione, 25 %
originate from ovaries and 25% from the adrenal
glands.
Structurally, testosterone is a 19C steroid and has
unsaturated bond between C 4- and C 5- and a
ketone group at C 17. Testosterone is converted
to a more potent steroid called
dihydrotestosterone (DHT) by the enzyme 5reductase, which presents in prostate, genital
skin and seminal vesicles.
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Androstenedione: produced from testosterone
in peripheral tissues, it may also be produced by
adrenal or ovaries, or peripheral conversion of
plasma dehydroepiandrosterone (DHEA).
Both are weak androgens they act more as prehormones for testosterone.
Biosynthesis occurs in testis and adrenals by two
pathways:
Pregnenolone is transformed to 17hydroxypregnenolone and then to DHEA, later
on to androstenedione and testosterone.
Pregnenolone to progesterone, then to
androstenedione. This pathway is more active.
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Metabolism
In blood, testosterone is bound to plasma
protein, sex hormone-binding globulin (SHBG).
In women, only 1% while in males 3% of total
testosterone is free, which is the biologically
active form.
The main metabolites of androstenedione and
testosterone are produced by reduction of ketone
group at carbon 3- and also carbon 7- positions.
Most of these androgens are converted irreversibly to 17keto- steroids which conjugate with sulphuric acid and
glucoronic acid, excreted as water-soluble substances in
urine.
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Several methods have been used to detect androgens in
serum and urine, the main one is radioimmunoassay
(RIA) and enzyme-linked fluoroimmunoassay (ELFIA).
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Normal range in male adult is (3-10) ng/mL, while in
females it is (0.3- 0.7) ng/mL.
The highest level of testosterone in males occurs in the
morning and decreases to 25% in evening. Slow and
progressive decline occurs after 5th decade of life. In
females, highest level is during puberty or 1 to 2 days at
mid cycle.
Clinical disorders: there are two types of disorders
that affect androgen level, depending on the
tissue affected; these are primary or secondary
endocrine diseases.
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Progesterone: during menstrual cycle, progesterone in
conjugation with oestrogen regulates function of sex
characteristics. It is important for preparing uterus for
implantation and maintenance in pregnancy. In nonpregnant women, progesterone is secreted from corpus
luteum whilst during pregnancy it is secreted from
placenta. Minor sources also occur in adrenal cortex and
testes in male.
Structurally, progesterone is a 21C steroid contains keto
group at carbon 3-, double bond between carbon 4- and
carbon 5-. Both of these structural characters are
essential for progesterone activity.
Synthetic compounds called 19-nortestosterone that is
widely used as an oral contraceptive, which is more
potent than progesterone itself.
• Metabolism: the production of progesterone in
ovaries occurs the same as for steroidogenesis
in adrenal cortex, in which acetate converts to
cholesterol, then enters through the pathway of
pregnenolone.
• In ovarian tissue the precursor is LDL
cholesterol, from which the secretion of
progesterone is under the control of LH.
• In blood, progesterone is bound to CBG (it
doesn't have a specific binding protein). The free
level is 10-20% of total, which remains constant
throughout the normal menstrual cycle.
• Its peak level occurs at luteal phase, reaching
30mg/day (in non-pregnant women). At third
trimester (last 3 months of pregnancy), the level
reaches 300mg/d.
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Inactivation of this hormone occurs
through two procedures:
Reduction of pregnenidiol (conjugated
form with glucoronic acid) then excreted
out as water-soluble substance in urine.
This urine pregnenidiol is used as index of
endogenous production of progesterone.
Conjugated with sulphuric acid and
excreted outside the body.
Clinical significance:
during follicular phase of cycle, serum level is 1ng/mL, but after
ovulation, production of PRG from corpus luteum increases to
a maximum of (10-20) ng/mL in the fourth to seventh day of
luteal phase.
This level remains elevated for four to six days, and then decreases
suddenly to baseline level at about 24hr before bleeding.
Since the increase or decrease in PRG level is related to corpus
luteum (and so ovulation), we can use PRG as indicator of
ovulation. If the level of PRG at luteal phase is similar to that of
follicular phase, or the summation of three consequent
measures at the last seven days of cycle, is less than 15ng/mL,
this indicates that the cycle is un-ovulatory cycle, which could
be the cause of infertility.
• Oestrogen: responsible for
• development and maintenance sex hormones and
secondary sex characteristics of females.
• Regulation of menstrual cycle, and maintenance of
pregnancy,
• Shared with PRL and PRG in breast development for
lactation but it Inhibits milk secretion, as it inhibit
prolactin action on lactating glands (so it can be used
clinically for this purpose).
• Most estrogens are produced in corpus luteum and
(during pregnancy) from placenta.
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Oestradiol (E2) is the most potent estrogen.
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Structurally, estrogen consists of an 18C and has
the following features:
1. Presence of aromatic (phenol) ring A
2. Presence of hydroxyl group at C-17 (C-16 in
case of oestriol).
• Phenolic hydroxyl group at C-3 gives the
compound its acidic properties.
• The phenol ring A and oxygen at carbon 17are essential for biological activity. Any
substituents at other positions will diminish
the feminizing activity of this hormone.
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Biosynthesis:
the three classes are produced by ovarian tissue which
has active aromatase system that converts androgens to
oestrogens.
In menopausal women (ovarian failure), the main source
of oestrogen is from peripheral adrenal conversion of
androstenedione to oestrone¹. The major site for
conversion is adipose tissue, explaining high levels of
oestrone in post-menopausal women and also the uterine
bleeding that occurs in such women.
In blood, oestradiol² is strongly bound to SHBG and
loosely to albumin, while only 2-3% is free (active).In
contrast, oestrone is almost always bound to albumin.
During pregnancy the major source of oestrogen is the
placenta, which secretes large quantities in milligrams;
the main oestrogen produced is oestriol³ (during
pregnancy).
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Metabolism: oestradiol forms reversible
redox system with oestrone, which is
metabolised through two pathways; 2hydroxylation pathway, with production of
catecholestrogen and 16-hydroxylase
pathway with formation of oestriol.
Some pathological conditions, such as in
hyperthyroidism, the 2-hydroxylation
pathway is increased. During liver disease
or hypothyroidism the reverse occurs.
Oestrogen is inactivated in liver and
excreted in urine (like all other steroids).
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Clinical significance: oestradiol is almost
always secreted from ovaries, therefore is
essential for evaluation of ovarian function.
Oestriol is of limited diagnostic use, but we
use it in diagnosis of post-menopausal
bleeding and menstrual dysfunction.
Oestriol is only used during pregnancy to
evaluate the foeto-placental dysfunction.