2.6.4 BIOSYNTHESIS OF ESTROGEN
Estrogens, in females, are
produced primarily by the ovaries, and during pregnancy, the placenta
(Nelson and Bulun, 2011). Follicle-stimulating hormone (FSH) stimulates
the ovarian production of estrogens by the granulosa cells of the
ovarian follicles and corpora lutea. Some estrogens are also produced in
smaller amounts by other tissues such as the liver, adrenal glands, and
the breasts. These secondary sources of estrogens are especially
important in postmenopausal women. Fat cells produce estrogen as well
(Marieb, 2013).
In females, synthesis of estrogens starts in theca
internal cells in the ovary, by the synthesis of androstenedione from
cholesterol. Androstenedione is a substance of weak androgenic activity
which serves predominantly as a precursor for more potent androgens such
as testosterone as well as estrogen (Häggström and Richfield, 2014).
This compound crosses the basal membrane into the surrounding granulosa
cells, where it is converted either immediately into estrone, or into
testosterone and then estradiol in an additional step. The conversion of
androstenedione to testosterone is catalysed by 17β-hydroxysteroid
dehydrogenase (17β-HSD), whereas the conversion of androstenedione and
testosterone into estrone and estradiol respectively is catalysed by
aromatase, enzymes which are both expressed in granulosa cells. In
contrast, granulosa cells lack 17α-hydroxylase and 17,20-lyase, whereas
theca cells express these enzymes and 17β-HSD but lack aromatase. Hence,
both granulosa and theca cells are essential for the production of
estrogen in the ovaries.
Estrogen levels vary through the menstrual
cycle, with levels highest near the end of the follicular phase just
before ovulation.
2.7 PROGESTERONE
Progesterone is a steroid
hormone produced in both menand women by the adrenal cortex and gonads,
in the central and peripheral nervous systems (CNS and PNS), and in
women by the placenta during pregnancy (Lo & Lamb,2004; Rhen &
Cidlowski, 2004; Strauss, 2004; Yen, 2004). progesterone is commonly
referred to as a “hormone of pregnancy†because it plays a vital role in
preparing the endometrium for implantation, successful gestation, and
normal development of the fetus (Carmina and Lobo,2014; Mesiano and
Jaffe, 2014). Progesterone is also essential for preventing lactation
during pregnancy. Decreasing levels of progesterone initiates the
withdrawal bleeding that marks the onset of menstruation (Hall, 2004;
Strauss and Williams, 2014).
In women, progesterone levels are
relatively low (2ng/ml) during the follicular phase of the menstrual
cycle. However, progesterone production in the follicular phase is
required for ovulation and is mediated by luteinizing hormone (LH) as
one of its early actions in the ovulatory process. Induction of
progesterone receptors in ovarian granulosa cells occurs within hours of
pulsatile LH release (LH surge) during ovulation (Strauss &
Williams, 2004).
This was demonstrated by studies using progesterone
receptor antagonists and progesterone synthesis inhibitors to prevent
ovulation in rats and monkeys (Micevych et al., 2003). After ovulation
occurs, the ruptured follicle is reorganized into the corpus luteum,
which produces increasing amounts of progesterone during the luteal
phase. Progesterone reaches its maximal levels (5 ng/ml) in the mid
luteal phase of the cycle (Carmina and Lobo, 2004; Strauss, 2004).
2.7.1 BIOSYNTHESIS OF PROGESTERONE
Progesterone
is synthesized from pregnenolone, a derivative of cholesterol
(Schumacher et al., 2007; Strauss, 2004). In progesterone biosynthesis,
cholesterol is converted through the enzymatic action of cytochrome P450
to pregnenolone, which is then converted to progesterone by
3-beta-hydroxysteroiddehydrogenase/_5-4_isomerase in the smooth
endoplasmic reticulum. From this point, progesterone may enter a variety
of biochemical pathways to synthesize various steroid hormones. Two
major enzymes are involved in further metabolism of progesterone: 5
alpha reductase-I/IIand 5 beta reductase, producing 5 alpha
dihydroprogesterone and 5 beta dihydroprogesterone, respectively. This
is the rate-limiting step in the metabolism of progesterone.
The
first pathway, via 3 alpha hydroxysteroid dehydrogenase (HSD)-II/III
enzyme, results in production of 3 alpha 5alpha-tetrahydroprogesterone
(THP; allopregnanolone), the main neuroactive steroid, and 3 alpha 5
beta-THP (isoallopregnanolone). The second pathway produces 3 alpha
5beta-THP (pregnanolone) via 3 alpha HSD and 3 beta 5beta-THP
(isopregnanolone) via 3 beta HSD enzymes (Finn et al., 2016; Niswender,
2012; Pluchino et al., 2016; Schumacher et al., 2007).
