Reproductive function is controlled by steroids from the gonads. These are produced by specific cells in the ovary and testis which respond to pituitary gonadotrophins - luteinisinghormone (LH) and follicle stimulating hormone (FSH). As with many other hormones, sex steroids inhibit secretion of their trophic hormones (negative feedback). Under a specific set of circumstances oestrogen may stimulate secretion olgonadotrophins (positive feedback).

Protein hormones exert their effect on target cells by combining with cell surface receptors. Steroid receptors are located predominantly in the nucleus. The receptor is made up of one steroid binding unit and two non-binding subunits. The binding unit has one binding site for steroid and one for DNA; attachment of the latter to regulatory regions of nuclear DNA controls transcription of RNA and hence protein synthesis. Receptor molecules which are not attached to steroid cannot bind with DNA because the DNA binding site is capped with a specific protein known as heat-shock-protein 90 (HSP 90). The combination of steroid with receptor causesa conformational change, after which it can displace the HSP 90. All the nuclear steroid receptors are members of a single family of proteins. The receptors for thyroid hormone and retinoic acid are part of the same family. The binding units of these receptors are structurally related to some oncogenes. The biological activity is maintained only for as long as the receptor is occupied by the hormone. Thus steroids such as oestrogen, whose receptors have long half-lives, are present in lower concentrations than others, such as progesterone and cortisol, whose receptors have short half-lives.

Larger protein hormones, such as the trophic hormones, cannot enter the cell. They combine with a specific surface receptor which activates adenyl cyclase in the cell membrane. This catalyses production of a second messenger, cyclic adenosine 3' 5'-monophosphate (cyclic AMP), from ATP. Excessive build-up of this substance is prevented by another enzyme, phosphodiesterase. Cyclic AMP activates protein kinases which cause phosphorylation, and thereby activation of specific enzymes. A second and very similar system involves formation of inositoltriphosphate.

Protein hormones are synthesised on ribosomes and stored by the Golgi apparatus in separate vesicles within the same cell. They are released into the circulation by fusion of these vesicles with the cell membrane, a process involving entry of calcium into the cell and contraction of myofibrils. Connections with neighboring cells, through gap junctions, synchronise this process. Excess vesicles are phagocytosed by lysosomes. Most protein hormones are modified after they have been formed on the ribosomes. For example ACTH and insulin are cleaved from larger molecules, and human chorionic gonadotrophin (hCG), LH, FSH and thyroid-stimulating hormone (TSH) gain a carbohydrate moiety before they are secreted.

All steroid hormones (and thyronines) are carried in blood largely bound to proteins. It is only the ‘free` fraction that is able to move into cells and exert a biological effect. If there is an increase in binding proteins the free fraction is diminished; a compensatory increase in trophic hormone then occurs and restores the total amount of free hormone.

The median eminence of the hypothalamus is connected to the pituitary gland by the pituitary stalk. The hypothalamus stretches from the,optic chiasm in front to the mamillary bodies behind. The hypothalamus receives its arterial supply from the circle of Willis, and the supra-optic nucleus has the richest blood supply of any area in the brain. Capillaries draining the median eminence enter the portal system, which passes into the anterior pituitary.Many nuclear groups - hypothalamic centres - exist in the hypothalamus.The paraventricular and supra-optic centres synthesise posterior pituitary hormones and the ventromedial nuclei control satiety.

The anterior pituitary forms 'from

Rathke’s pouch, an upward

evagination of the ectodenn of the

pharyngeal roof. From the upper

pan cells proliferate to form the

pars tuberalis, which partly

encircles the pituitary stalk; the

posterior part forms the pars

intermedia, which is prominent in the

fetus but becomes atrophic at birth.

The pituitary lies in a depression in

the sphenoid, the sella turcica. The

sella turcica is covered by a layer of

dura mater (the diaphragma sellae)

through which the pituitary stalk

passes.

The pituitary ‘is supplied with blood

by the portal system originating in

the hypothalamus and by a direct

arterial supply.

Ovaries with developing oocytes are present in the female fetus from an early stage of development. By the end of the second trimester in utero, the number of oocytes has reached a maximum and they arrest at the first prophase step in meiotic division. No new oocytes are formed during the female lifetime.With the onset of menarche, the primordial follicles containing oocytes will activate and grow in a cyclical fashion, causing ovulation and subsequent menstruation in the event of non-fertilization. In the course of a normal menstrual cycle, the ovary will go through three phases:I Follicular phase2 Ovulation3 Luteal phase.

The initial stages of follicular development are independent of hormone stimulation. However, follicular development will fail at the preantralstage and follicular atresia will ensue if pituitary hormones LH and FSH are absent. FSH levels rise in the lirst days of the menstrual cycle, when oestrogen, progesterone and inhibin levels are low. This stimulates a cohort of small antralfollicles on the ovaries to grow. Within the follicles, there are two cell types which are involved in the processing of steroids, including oestrogen and progesterone. These are the theca and the granulosa cells, which respond to LH and FSH stimulation, respectively. LH stimulates production of androgens from cholesterol within theca cells. These androgens are converted into oestrogens by the process of aromatization in granulosa cells, under the influence of FSH. The roles of FSH and LH in follicular development are demonstrated by studies on women undergoing ovulation induction in whom endogenous gonadotrophin production has been suppressed. If pure FSH alone is used for ovulation induction, an ovulatory follicle can be produced, but oestrogen production is markedly reduced. Both FSH and LH are required to generate a normal cycle with adequate amounts of oestrogen.

The endocrine influences in ` menstruation are clear. However, the paracrine

mediators less so, Prostaglandin F2 alpha, endothelin-1 and platelet activating factor (PAP)

are vasoconstrictors which are produced within the endometrium and are thought likely to

be involved in vessel constriction, both initiating and controlling menstruation. They may be

balanced by the effect of vasodilator agents, such as prostaglandin EZ, prostacyclin

(PGI) and nitric oxide (NO), which are also produced by the endometrium. Recent

research has shown that progesterone withdrawal increases endometrial prostaglandin

(PG) synthesis and decreases PG metabolism. The COX-2 enzyme and chemokines are

involved in PG synthesis and this is likely to be the target of non-steroidal anti-

inflammatory agents used for the treatment of heavy and painful periods. Endometrial repair

involves both glandular and stromal regeneration and angiogenesis to reconstitute the

endometrial vasculature. VEGF and fibroblast growth factor (FGF) are found within the

endometrium and both are powerful angiogenic agents. Epidermal growth factor (EGF)

appears to be responsible for mediation of oestrogen-induced glandular and stromal

regeneration. Other growth factors, such as transforming growth factors (TGFS) and IGFS,

and the interleukins may also be important. Greater understanding of mediators of

menstruation is important in the search for medications to control heavy and painful periods.

Mefenamic acid is a PG synthetase inhibitor which is widely used as a treatment for heavy

menstrual bleeding. It is believed to act by increasing the ratio of the vasoconstrictor

PGF2ot to the vasodilator PGE2. Mefenamic acid reduces menstrual loss by a mean value

of 20-25 per cent in women with very heavy bleeding, and further more effective agents are

still being sought.

The three major naturally occurring estrogens in women are estrone (E1), estradiol (E2), and estriol (E3). Estradiol is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity. During menopause, estrone is the predominant circulating estrogen and during pregnancy estriol is the predominant circulating estrogen in terms of serum levels. Though estriol is the most plentiful of the three estrogens it is also the weakest, whereas estradiol is the strongest with a potency of approximately 80 times that of estriol.

The three major naturally occurring estrogens in women are estrone (E1), estradiol (E2), and estriol (E3). Estradiol is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity. During menopause, estrone is the predominant circulating estrogen and during pregnancy estriol is the predominant circulating estrogen in terms of serum levels. Though estriol is the most plentiful of the three estrogens it is also the weakest, whereas estradiol is the strongest with a potency of approximately 80 times that of estriol.

estrone

estron

e

estradiol

Structural Promote formation of

female secondary sex characteristics

Accelerate metabolism Increase fat stores Stimulate endometrial g

rowth Increase uterine growth Increase vaginal

lubrication Thicken the vaginal wall Maintenance of vessel

and skin Reduce bone

resorption, increase bone formation

Protein synthesis Increase hepatic

production of binding proteins

Coagulation

Increase circulating level

of factors 2, 7, 9, 10, plasminogen

Decrease antithrombin III

Increase platelet adhesiveness

Lipid

Increase HDL, triglyceride

Decrease LDL, fat deposition

Fluid balance

Salt (sodium) and water retention

Increase cortisol, SHBG

Gastrointestinal tract

Reduce bowel motility

Increase cholesterol in bile

Melanin

Increase pheomelanin,

reduce eumelanin

Cancer

Support hormone-sensitive breast

cancers (see section below)

Lung function

Promotes lung function by

supporting alveoli (in rodents but

probably in humans).

Uterus lining

Estrogen together with progesterone promotes

and maintains the uterus lining in preparation

for implantation of fertilized egg and

maintenance of uterus function during

gestation period, also

upregulates oxytocin receptor in myometrium

Ovulation

Surge in estrogen level induces the release

of luteinizing hormone, which then triggers

ovulation by releasing the egg from

the Graafian follicle in the ovary.

Sexual receptivity in estrus

Promotes sexual receptivity,[15] and

induces lordosis behavior.[16] In non-human

mammals, it also induces estrus (in heat) prior

to ovulation, which also induces lordosis

behavior. Female non-human mammals are

not sexually receptive without the estrogen

surge, i.e., they have no mating desire when

not inestrus.

Lordosis behavior

Regulates the stereotypical sexual receptivity

behavior; this lordosis behavior is estrogen-

dependent, which is regulated by

the ventromedial nucleus of thehypothalamus.

Progesterone is the most important progestogen in thebody, the result of its action as a potent agonist ofthe nuclear progesterone receptor (nPR).

.

Progesterone is sometimes called the "hormone of pregnancy", and it has many roles relating to the

development of the fetus:

Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the

same time progesterone affects the vaginal epithelium and cervical mucus, making it thick and impenetrable

to sperm. If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation.

Normal menstrual bleeding is progesterone-withdrawal bleeding. If ovulation does not occur and the corpus

luteum does not develop, levels of progesterone may be low, leading to anovulatory dysfunctional uterine

bleeding.

During implantation and gestation, progesterone appears to decrease the maternal immune response to

allow for the acceptance of the pregnancy.

Progesterone decreases contractility of the uterine smooth muscle.In addition progesterone

inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk

production.It belongs to an important group of endogenous steroids called neurosteroids. It can be synthesized

within the central nervous system

Progesterone increases core temperature (thermogenic function) during ovulation.

Progesterone reduces spasm and relaxes smooth muscle. Bronchi are widened and mucus regulated.

(PRs are widely present in submucosal tissue.)

Progesterone acts as an antiinflammatory agent and regulates the immune response.

Progesterone reduces gall-bladder activity.

Progesterone normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and

use of fat stores for energy.

Progesterone appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of

estrogen.

Progesterone plays an important role in the signaling of insulin release and pancreatic function, and may

affect the susceptibility to diabetes or gestational diabetes

The use of progesterone and its analogues have many medical applications, both to address acute

situations and to address the long-term decline of natural progesterone levels. Because of the poor bioavailability

of progesterone when taken orally, many synthetic progestins have been designed with improved oral

bioavailability and have been used long before progesterone formulations became available.