The hormones include estrogen and progesterone produced from the ovaries, and testosterone synthesized
from the testes. Gonadal steroid receptors form a part of "superfamily"which acts as ligand-activated transcription
factors. Gonadal steroids works through classic and non-classic receptors at both sites i.e. the membrane
or in the cytosol. They regulate functions like neuronal excitability, cell death and influences transcriptional activity.
Estrogen
Earlier estrogen produced by ovaries were considered as a 'woman's hormone', but later on their role in
males was also studied. In mammals, these hormones are synthesized by gonads and adrenal glands,
and released in the circulation.
In females, estrogen hormone is present in three different physiological forms namely estrone (E1), estradiol
(E2, or 17B-estradiol), and estriol (E3). Estrogens are released in a cyclical manner, in larger amounts during
the time of ovaries synthesis to maintain ovulation and reproductive capacity. Estrogen action is not confined
only to reproduction but, it also has profound effect on learing, memory, neurodegenerative as well as
neurodevelopmental processes.
Different forms of estrogens are required at different stages that play their respective roles. E2, the most potent
form is present during the premenopausal period in a woman's life. E1 comes into picture after menopause and
is synthesized in adipose tissue from adrenal dehydroepiandrosterone. E3 is the least potent of all estrogens
and is generated from El via 16a-hydroxylation: plays a larger role during pregnancy when it is produced in
large quantities by the placenta.
Synthesis
E2 is an 18 carbon steroid with an aromatic A-ring and is most potent form of circulating estrogen. This
estradiol-17B is predominant in non-pregnant females while estrone and estriol are present in lower amounts.
Aromatase is an enzyme that catalyzes conversion of (C-19) precursors to estrogens and is found in number of
human tissues and cells, including ovarian granulosa cells, the placental syncytiotrophoblast, adipose and skin
fibroblasts, bone, and the brain.
cholesterol is the source for synthesis of all steroid hormones where pregnenolone, acts as a precursor. Pregnenolone,
result from enzymatic cleavage of a 6-carbon side-chain of the 27- carbon cholesterol molecule at mitochondrial
level and the reaction is catalyzed by cytochrome P450 side chain cleavage enzyme (P450cc CYP11A1).
Many sites are known for the synthesis of these hormones
Ovarian granulosa cells secrete progesterone and estradiol (E2), whereas, ovarian luteal cells secrete
progesterone and its metabolite 20 a-hydroxyprogesterone. Corpus luteum and placenta also produce
progesterone. Testicular leydig cells are the site of testosterone production and neuro-steroids i.e.
steroids synthesized by brain de novo from cholesterol.
Testosterone
Popularly known as 'male hormone', it is essential for development of secondary sexual characteristics and
also has stimulatory effects on bones, muscles, erythropoietin, libido, penile erection, mood and cognition
centres in the brain.
Testosterone plays an important role in all stages of life from the intrauterine life to the advanced age.
Starting from the early development, the fetus which has the Y chromosome is destined to become a male
and carries testicular determining gene. This gene leads the transformation of undifferentiated gonad into
testes, which further produces testosterone and Mullerian Inhibiting Factor (MIF). MIF induces degeneration
of the Mullerian system which is the internal ductal apparatus of female. While testosterone is responsible
for growth and development of Wolffian system which comprises of epididymus, vas deferens, seminal
vesicle and prostate gland.
In puberty, hypothalamus triggers the secretion of gonadotropin releasing hormone (GnRH) which results in
release of two important hormones namely, luteinizing hormone (LH) and follicle stimulating hormone (FSH).
This stimulates production of testicular testosterone and leads to development of secondary sex characteristic
such as growth spurt, increased libido, increased erectile function, acne, increased body hair, increased muscle
mass, deepening of the voice and spermatogenesis. Testosterone shows positive effects on bones by getting
converted to estradiol with the help of aromatase enzyme, thereby inhibiting osteoclastic activity and subsequent
bone resorption. It also stimulates osteoblastic activity on converting to dihydrotestosterone (DHT).
In males, the Leydig cells present in testes consists of receptors Testosterone Estrogen for LH, and synthesizes
testosterone after LH stimulation. While in females, in the ovary, steroidogenic cells of the follicle are primarily
under control of pituitary LH and FSH, which act by
Progesterone
Progesterone also called as 'The Pregnancy Hormone', plays an important role in menstrual cycle, prepares uterus
for pregnancy and mammary glands for lactation. Progesterone is secreted in smaller amounts from ovaries and
adrenal cortex during first half of menstrual cycle while larger amounts are produced by corpus luteum in the latter half.
in pregnancy, progesterone is largely produced by the corpus luteum until about 10 weeks of gestation. Maternal
levels of 17-a-hydroxyprogesterone rises in early pregnancy and embarks the activity of corpus luteum. Studies
have shown that progesterone plays a more crucial role in successful implantation than estrogen.
DHEA
Dehydroepiandrosterone (DHEA) is a weak androgen, first isolated and identified by Butenandt, a German
scientist in 1939. It is formed in zona reticularis of the adrenal gland and in the ovaries, and is converted
to estradiol and testosterone. About 85% of DHEA is secreated by adrenal while ovaries contribute around
15%. DHEA-S (sulphate ester of DHEA), synthesized in the adrenal gland and DHEA are common sex steroid
in women. Both act as a precursor for production of estrogen and androgens. Loss of well-being, lowered
libido, and lower sexual function in both premenopausal and postmenopausal women is accounted to
decline in these hormones with respect to ageing.
Hypothalamus pituitary gonadal axis (HPG)
Reproduction, the backbone for survival of species, demands co-ordination with peripheral organ and nervous
system. This is regulated by the hypothalamic-pituitary-gonadal axis, which comprises of hypothalamus, anterior
pituitary gland and gonads that coordinates reproductive behavior with ovulation. Release of gonadotropin-releasing
hormone (GnRH) is the primary signal from the central nervous system. Hypophyseal portal vasculature where,
it ultimately acts upon the gonadotropes of the anterior pituitary to stimulate the release of the gonadotropins,
luteinizing hormone (LH) and follicle stimulating hormone (FSH). In both sexes, circulating LH, stimulates the
secretion of steroid hormones from the gonads,
binding to their respective high affinity receptors that are present on granulosa and theca cell membranes.
FSH actions are restricted to the granulosa cells where FSH receptors work to activate the aromatase enzyme
and allow synthesis of estrogens from aromatizable androgens (testosterone and andro-stenedione). A
negative feedback is exerted on the GnRH and FSH by estradiol that is released by the developed ovarian
follicles. On reaching the peak concentration, estradiol triggers surge release of GnRH which further leads
to release of LH that ultimately induces ovulation.
Role of Gonadal Steroid Hormones in Cardiovascular diseases (CVD)
Estrogens contributes in lowering the incidences of CVD, as compared to same aged men thereby providing
an added advantage to females belonging to reproductive ages. Although, this advantage disappears in
menopausal and post menopausal women due to estrogen deficiency or in some cases due to ovariectomy.
Role of Gonadal Steroid Hormones in Bone Health
Estrogen and testosterone have an affirmative influence on growth, maturation, and maintenance of skeleton
in both males and females. Their effects are carried out through nuclear hormonal receptors, membrane associated
receptors and signaling cascades. Bone mass accumulation initiates from childhood and peak bone mass can
be achieved in the mid-twenties, spine and hip bones, such as the radius, reach a peak at the age of 40 years.
After this as the age progresses, bone mass normally declines. Two kinds of cells osteoclasts (bone resorbing
cells) and osteoblasts (bone forming cells) regulate the balance between bone resorption and bone formation.
In females, menopause is marked by decrease in production of estradiol while an increase in levels of follicle
-stimulating hormone (FSH). Loss of ovarian function forms the primary reason for osteoporosis development.
In menopausal and post menopausal women, estrogen deficiency is the underlying pathogenic factor for bone
loss associated osteoporosis.
Estrogen affects bone by different mechanisms such as
- Reduces bone reabsorption by lowering the sensitivity of bone mass to PTH (parathyroid hormone)
- Inhibits reabsorption of bone by increasing the production of calcitonin
- Accelerates calcium resorption by the intestine
- Reduces the calcium excretion from the kidney, and
- Affect directly the bone via estrogen receptors
Both poles - Excess and Deficiency
In both males and females, the disorder of the hypothalamic-pituitary-gonadal axis is a major cause of sexual
dysfunctions. Hypogonadism i.e. failure of gonadal functioning (testes in men and ovaries in females), menstrual
disorders, hirsutism, and virilization in females are some of the common problems resulting due to disturbed
gonadal functions. Screening for these includes assessment of LH, FSH, estrogen and testosterone.
Few cases of hyperandrogenism (hirsutism, acne, or menstrual dysfunction) are also observed. Most of these
symptoms are secondary to polycystic ovarian syndrome. Small proportion of hyperandrogenism has causes
such as androgen secreting ovarian or adrenal tumors, pituitary tumors, and Cushing's syndrome.
