* NEUROENDOCRINOLOGY OF

FEMALE REPRODUCTIVE SYSTEM

WITH APPLIED ASPECT (PART- II)

PRESENTED BY- DR. NAMRATA PATEL

(JR-3)
DEPARTMENT OF PRASUTI TANTRA AND STREE ROGA
 *OVARY
* The ovary is essential for periodic release of
oocytes and production of the
steroid hormones, estradiol and progesterone.
* These activities are integrated into the cyclic repetitive process of follicular
maturation, ovulation, and formation and regression of the corpus luteum.
* The ovary fulfills two major objectives: generation of a fertilizable ovum and
preparation of the endometrium for implantation through the sequential
secretion of estradiol and progesterone.
The ovarian central medullary region consisting of stroma , and a hilum. It
contains nerves, blood vessels, and hilus cells, which have the potential to
become active in steroidogenesis. This cells are similar to the testosterone
secreting leydig cells of the testes.
 Ovarion steroidogenesis
* The ovaries secrete pregnenolone , progesterone, 17α hydroxyprogesterone,
dehydroepiandrosterone (DHEA), androstenedione, testosterone, estrone, and
estradiol.
* Estrone and estradiol are produced by preovulatory follicles.
* Progesterone and 17α hydroxyprogesterone are the major products of corpus
luteum.
* The biologically active ovarian steroids are estradiol and progesterone.
* LDL cholesterol is an important source of cholesterol used for steroidogenesis.
* The ovarian granulosa, theca, and corpus luteum cells possess five distinct proteins
with specific enzyme activities for steroid hormone formation.
* These enzymes are responsible for the conversion of cholesterol to the estradiol
and progesterone.
 * STEROIDOGENIC PATHWAY
CHOLESTEROL
StAR
PROGESTERONE
MITOCHONDRION

17 alpha hydroxylase

PREGNENOLONE
17 alpha hydroxylase
17-HYDROXYPREGNENOLONE 17 –HYDROXYPROGESTERONE
desmolase desmolase
DEHYDROEPIANDROSTERONE ANDROSTENEDIONE TESTOSTERONE
(aromatase)

ESTRONE ESTRADIOL
 * TWO CELL, TWO GONADOTROPIN
CONCEPT OF STEROIDOGENESIS
IN FOLLICULAR PHASE-

under the influence of LH

androgens (androstenedione and testosterone ) are

produced in theca cells.

these androgen diffuse into granulosa cells

Aromatized under the influence of FSH

Estradiol & estrone

 * TWO CELLS, ONE GONADOTROPIN
CONCEPT OF STEROIDOGENESIS
AFTER OVULATION-
Under the influence of LH

progesterone synthesized in luteinized granulosa cells

(precursor LDL)

IN LUTEAL PHASE-
androstenedione produced by theca luteal cell

diffuse into granulosa luteal cells

converted into estradiol by LH

All steroid hormones are derived from cholesterol. C27 cholesterol is
converted to the carbon steroid hormones 18,19 and 21 that are secreted by
the ovary.
C21 Steroids –
progesterone, pregnenolone, and 17- hydroxyprogesterone.
Pregnenolone is a precursor of all steroid hormones.

Physiological action of progesterone –

• Cell differentiation and induction of secretory activity in the endometrium of the
estrogen primed uterus.
• Essential for implantation of the fertilized ovum and maintenance of pregnancy.
• It also induces decidualization of the endometrium.
• Increase the viscosity of cervical mucus.
• Promotes lateral (alveolar) development of the breast glands.
 * Cont……………
UTERUS- myohyperplasia and diminishes myometrium contractility.
Increase the tone of circular muscle fibers at the isthmus.

VAGINA – hindered maturation of vaginal epithelium

FALLOPIAN TUBES – stimulates epithelial cells to secrete clear mucus.

which helps in migration of the ovum.

GENERAL ACTION – thermogenic action

enhanced deposition of fat in the tissues
relaxes smooth muscles and ligaments
promotes secretion of sebum by the skin
causes fluid retention
* SECRETION – theca granulosa cells of CL. also from the theca granulosa cells
of the follicle & ovarian stroma.

* METABOLISM – bound to albumin (79%)

corticosteroid binding globulin (17.7%)
It metabolized in liver and excreted as PREGNANEDIOL in the urine.

PROGESTERONE Follicular phase Luteal phase

Daily production 2-3 mg 20-30 mg

Serum value Less than 1ng/ml Less than 5 ng/ml

excretion Less than 1 mg 3-6 mg

 *Synthetic progesterone
* parent compounds – progesterone, testosterone, 17 alpha hydroxy
progesterone, 19-nor- testosterone.
* Natural progesterone is rapidly inactivated by metabolism & not active by
oral, IM route. So, it has to be dissolve in oil & absorption is erratic.
* Crystalline progesterone is poorly absorbed via intestine – dispersion in small
particles – increased surface area & uptake.
* Isomer of progesterone - DYDROGESTERONE
* 17 alpha hydroxy progesterone is not active – it become active when 17-
hydroxyl (acetate or caproate) group is attached to it.
* progestational activity of 17- acetoxy progesterone is enhanced by adding
substituents such as methyl or chloride groups.
* Commonly used synthetic progesterone is-
MEDROXY PROGESTERONE ACETATE
19- norTestosterone
derivatives-
-Androgenioc side
effects
-Altered lipid profile
-Insulin resistance

-least androgenic

-Spironolactone
derivative
-Antiandrogenic
 USES
Diagnostic –
progesterone challenge test
(medroxy-progesterone acetate 10 mg daily for 5 days)

Theraprutic-
contraception- combined & progesterone only preparations.

DUB - It causes secretory changes in the endometrium (anovulatory cycle)

Can also be used for regulation of MC giving by either from day 5 to 25 or day 15 to 25.

ENDOMETRIOSIS –

Endometrial hyperplasia & carcinoma –

As a add-back therapy with GnRH – to prevent osteoporosis

Luteal phase defect-

Dysmenorrhea- (dydrogesterone 5 mg, day5 - day25 )

SIDE EFFECTS
5-50
 * C19 Steroids –
The ovary secrets a variety of C19 steroids, including DHEA, androstenedione,
and testosterone, all of which primarily serve as distant or immediate
precursors for the potent androgen, DHT, or potent estrogen, estradiol.
ANDROGENS-
sources- adrenal (25%), ovaries(25%), adipose tissue(50%)
- produced by all three cells of ovary – stroma, theca and granulosa.
- Under the control of LH.
- principal site of metabolism is liver.
- reduced to androsterone and Excreted in urine as 11 deoxy-17 ketosteroids.
- In adult female - Daily production of androstenedione = 3mg
testosterone = 0.2-0.3 mg
- blood testosterone level is around 20-80 ng/dl
Testosterone 5-alpha reductase di hydro testosterone binds with receptors
 *Therapeutic aspect
* Androgens are not active by oral route, methyl testosterone is used as
sublingual tablets to bypass the enterohepatic circulation.
* Derivatives-
* danazol (isoxazole derivative of 17 alpha- ethinyl testosterone)
* gestrinone (19- nor testosterone derivative)

*USES-
* ENDOMETRIOSIS
* MALE INFERTILITY
* DECREASED LIBIDO IN MENOPAUSAL WOMEN
* MASTALGIA & FIBROCYSTIC DISEASES
 * C18 Steroids –
the naturally occuring estrogens are C18 sterois characterised by the presence
of an aromatic (a ring),
phenolic hydroxyl group at C3, and at C17 – estra di ol
Hydroxyl group at C3, C16, C17 – Es tri ol
a ketone group at C17 – estr one
 * Physiological action of estrogen
SECONDARY SEX CHARACTERS – induce feminine characters.
ACTION ON THE GENITAL ORGANS – develop into maturity and induce cyclic
changes for reproduction.
VULVA & VAGINA –
increase thickening of lining epithelium, cornification of the superficial cells
and deposition of glycogen which converted into lactic acid by Doderlein
bacilli.
UTERUS –
increase vascularity and muscle hyperplasia. Cyclic changes in endometrium –
regeneration and proliferation.
CERVIX-
Hypertrophy of cervix and increase cervical gland secretion. The secretion is
more watery, alkaline with electrolytes and less protein.
FALLOPIAN TUBES-
Increased vascularity and motality.

BREAST-
Increased proliferation of the ducts and stromal tissues.
Increased vascularity and pigmentation of the areola. accumulation of fat.

BLOOD-
Increase blood coagulability by increasing fibrinogen. Platelets become more
adhesive.

LOCOMOTOR SYSTEM-
Conserves calcium and phosphorus and encourages bone formation (decreases
osteoclastic activity).

GENERAL ACTION-
increase sodium nitrogen and fluid retention of the body.
Lowers blood cholesterol ( HDL & LDL)
enhances coagulibility ( II, VII, IX, X) Decrease antithrombin III
Amount of estrogen production and blood level =

ESTRADIOL FOLLICULAR AT OVULATION LUTEAL PHASE

PHASE
DAILY 50 150-300 100
PRODUCTION
(µg)
SERUM VALUES 50 300-600 150-200
(pg/ml)
DAILY 10-25 35-100 25-75
EXCRETION
(µg)
SITE OF PRODUCTION-
• granulosa cells of the follicles and luteinized granulosa cells of CL.
• small quantity is also produced from the theca cells and ovarian stroma.
• Another important source of estrone is extra-glandular conversion of
androstenedione in peripheral tissues.

METABOLISM-
Bound to albumin -30%
Bound to sex hormone binding globulin (SHBG)- 69%
remaining free- 1%
the estriol is conjugated in liver with glucuronic or sulphuric acid.
Excretion through urine and bile.
ENTEROHEPATIC CIRCULATION OF ESTROGEN- the bile fraction on reaching the
intestine are broken down by microorganisms and then reabsorbed as active
hormones.

Estrone sulfate is serve as a reservoir for estrone and eventually estradiol

formation in a number of tissues.
- Has 2 receptors ER
- ER
Conjugation is chief drawback of therapeutic use of natural oestrogens.
If some foreign substitute is attached to the natural estrogen then it will no longer
fits to the enzyme & metabolized slowly.
SYNTHATIC OESTROGENS

STEROIDAL –
ETHINYL OESTRADIOL

MESTRANOL -
3-methyl ether of
Ethinyl estradiol
Another molecule which breaks up slowly & releasing long term - ACETATE &
BENZOATE

Longer chain fatty acids – CAPROATES & VALERATES

NON STEROIDAL FORMS-
DES (di ethyl stilboestrol) & dienestrol – pharmacologically uterotropic

Horse produces a number of estrogens chemically – EQUILIN & EQUILENIN

which is excreted in conjugated form in urine & can be extracted together with oestrogens
such as oestrone sulphate, K/A CONJUGATED EQUINE OESTROGENS
SIDE EFFECTS
 * PEPTIDES
The ovary produces a large number of peptides. They include numerous
growth factors and cytokines.
inhibin, activin, and follistatin are produced in ovarian granulosa cells
under the control of FSH and LH.
inhibin and activin are also produced by other tissues, including adrenal,
pituitary, and placenta.

INHIBIN – inhibits FSH synthesis & secretion

ACTIVIN – stimulates FSH release and its action in the ovary.

FOLLISTATIN – inhibit activin and suppresses FSH activity

 * LEPTIN
Various metabolic fuels, including glucose and fatty acids, can
regulate the function of the reproductive axis, and blocking
cellular utilization of these fuels can lead to suppression of
gonadotropin secretion and decreased gonadal activity.
Leptin is a peptide and is produced by adipose cells. It
enhances the release of GnRH.

CLINICAL IMPORTANCE-
Leptin administration has been shown to reverse the
suppressive effect of undernuttrition on the reproductive axis,
perticularly kisspeptin neurons.
Role of diet in controlling reproductive
physiology in light of role of leptin and its
relation with HPO axis
Leptin , a product of peripheral adipose tissue , is a positive regulator of the
HPO axis. This adipokine enables a link between body fat and reproduction.
Nutritional, metabolic, stress, and circadian inputs all appear to act through
these peptides to modulate reproductive physiology.

role of agni w.s.r. to liver in regulation

reproductiver physiology
Metabolism of estrogen is also very important because disturbance in it
associated with disturbed folliculogenesis , impaired oviduct function , impair
growth of embryo and placenta, abortion, endometriosis, PCOS etc.