WOMEN GYNACOLOGY-PART-VI-PROGESTINS

PROGESTINS-THE HORMONES OF PREGNANCY

Progestins are a group of steroidal female sex hormones mostly synthetic.The only naturally occuring progestin is the Progesterone which is the base for these synthetic progestins.Unlike estrogens this progesterone is  secreted during the gestational periods only that means the period from which a fully developed ovum detached from the overy and waiting for a sperm to fertilize it and upto the end of either the menstural cycle if no fertilization happen or upto the end of the pregnancy period if fertilization happened.The hormone progesterone is secreted from the yellow gland Corpus Luteum the gland which is temporarily formed at the gap from which the matured ovum detached from the ovary.

Progesterone the hormone of the pregnancy is controlling both the anterior pituitary-ovary axis and as well as the hypothalamus- anterior pituitary axis during the gestational period by a feed back mechanism to protect the fetus by preventing further maturing of the ovarian follicles.At the domination of progesterone at the set plasma limit during the gestational period there are no further secretions of FSH but, increases the LH pulsative sectretions from the anterior pituitary.The GRH secretions from the hypothalamus also decreased similar to FSH by progesterone While estradiol the main estrogen is controlling only the hypothalamus- anterior pituitary- axis and thus prevent the secretions of FSH and not of LH from the anterior pituitary by feed backchanism for all the times if its plasma level is raised to certain limits.

Once the ovum is fertilized the implantation takes place in one week.A hormone called human chorionic gonadotropin (HCG) is secreted from the a special layer within the uterus known as  trophoblast to keep the carpus luteum to be sustained and functional for some time upto the trophoblast itself becomes a fully developed placenta..This hormone is largely excreted by the kidneys mostly in the morning hours.Detection of this hormone in the urine by a specialised home kit test can confirm Pregnancy.

After several weeks of implantation placenta begins to develop.As a fully developed placenta can sufficiently produce progesteron and estrogen with collaberation of fetal adrenal glands and thereafter the corpus luteum begins to fade as its function is not further required and the secretion of CGH too will fade to be secreted further.

The amount of secretions of progesterone is varying as a few milligram per day at the beginning of follicular phase of the cycle followed by increasing upto 10 to 20 milligram during the luteal phase and further increases to several hundred milligrams during the later parts of the pregnancy period.

In the luteal phase progesterone act on the endometrium produced by the estrogens and decrease its further proliferation by estrogen,and develop a secondary endometrium as a luxury cusion for the convenience of the fertilized egg.

In case if there is no fertilization happened the secretions of progesterone and its domination decreased and the corpus luteum begins to fade at the end of the cycle and the domination of estrogen cause shedding of the secondary endometrium as a waste and excreted as menses at the end of the cycle.

At normal pregnancy period progesterone also act on the cervix and make it into thick and secretions to be more viscid inorder to prevent further entry of sperms through.This mechanism is more beneficiary for the use of synthetic progesterone like Norgestrel as a best oral contraceptives used alone or in combinations with estrogens.This we will discuss later in detail by the following posts.

Progeserone also modify the estrogen controlled matured vaginal epithelium in order to make it convenient and more elastic for delivering the baby 

Progeserone is very important in maintaining pregnancy.During pregnancy it protect the fetus by preventing contractions of the uterus and further mensturation.

During the pregnancy period progesterone along with estrogen acting on the mammary glands and proliferate it for milk production.But at the beginning of the lactating period the actions and secretions of progesterone and estrogen becomes nill.

WOMEN GYNACOLOGY-PART-IV-ESTROGEN OVER ACTIVITY-TREATMENTS

ANTIESTROGEN DRUGS

When secretions of estrogens are above the normal by the over activities of the ovaries the condition is known as hypergonadism of women.This condition may be natural or induced by careless administration of estrogens.In natural or provided hypergonadism the cause may be due to the active overstimulation of the ovaries by pituitary FSH and LH or passively by the hypothalamus stimulation of anterior pituitary by its hormone Gonadoropins releasing Hormones.
Either the conditions the over activities of estrogens cause so many problems in women.

Symptoms

1.Over secretions of estrogen will stop further secretions of FSH and LH by feed back mechanism which inturn block the development and maturity of the follicles leads to infertility.

2.Breast tenderness and cancer

3.Endomerial tenderness and cancer

4.Androgenic defeciency

5.Deep Venous Thrombosis(DVT)

6.Pulmonary Embolism (PE)

7.Changes in lipid and carbohydrate metabolism can cause or enhance hypertriglyceridemia and Diabetes Mellitus

8.Hypertension

9.Gall bladder disease

10.GI distress

11.Migrain

12.Mood disturbances 

Over activities of estrogens are 90% by misuse of estrogen intake mostly by contraceptives or other estrogen therapies like post 

menopausal hormone replacement therapies.

Estrogens are highly carcinogenic and can cause cancers in kidney bone and male sex organs.

Intake of estrogen like Diethyl Stibestreol(DE S) by a pregnant women during the first trmester can cause viginal and cervical cancer.This is is because the fetus cannot metabolize the DES and send it back to mother through the placenta which leads to the accumulation of the drug on her parts.Hence esrogens should be discouraged to take during pregnancy.

Administration of estrogens to post menopausal women as a hormonal replacement therapy may cause endometrial cancer in uterus.But the carcinoma can be cured by discontinuation of the therapy for several years.Hence estrogens should be administered to these patients in low dosages and in cyclic manners.

Although estrogens are having some favourable effects .on lipid metabolism such as lowering LDL,and elevating HDL but they may increase triglyceride levels

On gallbladder estrogens will increase cholesterol level dangerously to cause gallstones and other defects.

Fortunately in modern technics dose deviced for the hormon replacement therapy for post menopausal women are highly safe and in these dosages the incidences of hypertension,heart disease,stroke and thrombosis like DVT and PE are minimised.

Nausea and vomiting can be minimised by taking estrogens with food just before sleep. 

Treatments By Antiestrogens

1.Tamoxifen (Nolvadex)

It is a nonsteroidal anti estrogenic drug that competitively inhibit estrogens by binding to its receptors.

It is used for the treatment of breast cancers in postmenopausal women who receives hormonal replacement therapy.

Side Effects are hotflashes,nausea and vomiting

2.Chlomiphene (Clomid)

Its main action is by partially stimulating the estrogen receptors and thereby preventing the normal estrogenic feed back inhibition of anterior pituitary.There are sufficient secretions of FSH and LH by the pituitary which subsquently stimulates ovulation.

Its main use is to treat infertility.

Side effects are hot flashes,ovarian hyperplasia,Multiple simultaneous births,sight defects.

WOMEN GYNACOLOGY-PART III- FEMALE HYPOGONADISM-TREATMENTS

FEMALE OVARY DEFECTS-INFERTILITY-TREAMENTS-I

Female hypogonadism is a major cause for infertility.This can be a birth defect and it may be a major defect for a female baby.It will be a cause not only for female infertility but also for many physiological defects when the child grows.

In several conditions from the birth,or somewhere in a growing age by genetics or by an accident,the female parts mainly ovaries do not develop and puberty the age at which the child begins to feel as she is a woman does not occur 

Turner's syndrom is a condition in which the overies not formed properly and there is a dysgenesis of ovary the growth of the child stops to make the child to appear like a dwarf.
Estrogens such as estradiol orally or by injections in apporopriate preparations are used to treat the ovarian dysfunctions and to bring the puberty.
Androgens and growth hormone should be used in an appropriate manner to treat the dwarfism.
The symptoms of puberty replicates,the genital structures grow into normal,and the body assumes the normal feminine contour.
Hypopituitarism,the deficiency of anterior pituitary also cause ovarian dysfunction in the child hood.
Thyroid and adrenal cortex deficiencies,may also be a cause for ovarian underdevelopment.The treatment regimen should be the replacement therapies of the appropriate hormones of deficiency.
But in all the cases estrogens should be included to treat the sexual under development.
Administration of growth hormone will bring back the normal adult stature.
Estrogen along with androgen given at normal puberty age can induce a shorter growth.
Dysfunctional uterine bleeding and dysmenorrhea has been treated in earliar days by estrogens alone or in combinations with progesterone as in oral contraceptives.
Girls suffering from unwanted pimples and acne has been treated with oral contraceptives which contains estrogen combination with progesterone.The androgens produced by the ovaries,which causes the acne would be suppressed by estrogens.Also the same treatment can be used to treat hirsutism a condition in which unwanted hair growth like mustache and beard in women.
Estrogen now clinically Used
1.Estradiol(Estrace)
2.Conjugated estrogens (Premarin)
3.Ethinyl estradiol (Estinyl)
4.Quinestrol
Clinical Uses
1.Hypogonadism,under activities of ovaries
2.As Oralcontraceptives
3.Hormon replacement therapy. 
Route of administration Transdermally,intramuscularly and orally
Side effects
1.Post menopausal bleedings
2.Endomerial hyperplasia
3.Breast cancer
4.Cholestasis
5.Prolonged use may cause High Blood Pressure,Thromboembolism,liver cancer.
Estrogens should not be used in the following events:-
1.Breast cancer
2.Pregnancy
3.Liver disease
4.History of thrombophlebities. 

WOMEN GYNECOLOGY-PART-V--FEMALE SEX PROBLEMS-TREATMENTS

DELAYING AND INDUCING THE LABOUR AND ABORTION

THE UTERUS OR WOMB

The above picture shows the entire female genitalia with arrow marks to indicate the parts.
The arrow marked A is the Uterus or Womb which serves as the carrier bag to protect the fetus for the entire duration of pregnancy normally of 266 to 300 days.Inside the uterus the endometrium the inner linings of the uterus become a cushion bed which has been nicely developed for luxurious stay of the fetus indicated by an arrow marked E in the above picture.This endometrium is developed and protected by an hormone from the corpus luteum of the ovary known as Progesterone the hormone of Pregnancy as it along with corpus luteum would be ceased either at the end of the pregnancy period or at the end of the menstural cycle if no fertilization resulted
The Uterine muscles are composed of pace makers similar to heart muscles wih a power of auto electrical contractive stimulus.The pace makers would automatically trigger the stimuli normally at the beginning and slowly increasein intensity and become strong at the completion of the normal pregnancy period of 266 to 300 days.The stimuli produce waves of contraction.The waves would easily be conducted through out the uterine muscles by the low contraction resisting cell gaps with rhythm.These cell junctions would be increased in number and maintained by the progesterone and estrogens as the pregnancy period grows into later trimesters.
Oxitocin a hormone from the posterior pituitary will be released throughout the pregnancy period.The hormone is a powerful contractor of uterine muscle will act on it to give a final strong stimuli to induce the labour for delivering the baby.
Eventhough the secretion of oxitocin is constant from the pituitary all the times and throughout the pregnancy period but the responsiveness of the uterine muscle to oxitocin is gradual.Slow at the beginning of the pregnancy period and peak at the last trimester.
Any pathalogical condition which disturb this system would result in abortion.
Abortions can be manually induced or prevented by treatments at various situations.
Drugs That Induce Abortions
1.Oxitocin (Exoginous)
2.Prostaglandins (PGE-2,PGF-2a,15-methyl PGF-2a
3.Ergot Alkaloids (Ergonovine)
Drugs That Delay Uterine Motility
1,. Magnesium sulphate;
2.b-2adrenergic agonists 
3.Ca-2 blockers
4.Prostaglandin synthetase inhibitors..
Induction of Labour
In situation such as Diabetes Mellitus,Hypertension,Isoimmunization,Intrauterine growth defects,and placental defects the continuation of pregnancy may become risky to the mother or baby more than the delivery.
Before the pharmacological induction is carried out various things should be considered such as the fetal maturity,the fetal position,fetal distress,placental abnormalities,and previous uterine surgery.
The drug of choice for inducing labour is Oxitocin.A dilute solution of oxitocin can be infused intra venously as a slow infusion to induce a safe labour as 10 milliunits per ml.The procedure should be with gradual increase of the dosage by starting with 1 milliunit/ml and gradually increase for every 30 minutes and maintain at 4 milli unit /ml.for atleast 1 hr before bring it to the optimum dosage of 10 milliunit/ml
During the entire procedure trained persons must be engaged and uterine activities should be carefully watched.
It contractions are forceful and violent wih increased frequencies or alarm signals raised for a tired muscle cells the infusion of oxitocin must be immediately stopped.
Fetal discomfort can be easily estimated with its cardiac beats.
If there is a tetany like uterine contraction it should be relaxed by the use of a b-2 adrenergic agonist such as terbutalin.
To avoid undesirable side effects the terbutalin should be given as slow subcutaneous injection.
When the progression of labour becomes normal the rate of infusion of oxitocin should be minimised or stopped as per the need.The infusion should be maintained at the lowest possible rate inorder to maintain an adequate progression of labour.
When employed in term oxitocin induce labour in majority of cases.
Amniotomy the artificial ruputing of fetal membranes along with oxitocin can also be used to induce labour.These procedures should be done with experienced obstetricians to avoid fetal distress.
Augmentation of the Labour.
If augmentation of the labour proceeded normally in that case infusion of oxitocin is not necessry and should not be used.
In normal labour the force of normal contraction of the uterus should not be disturbed by drug induced augmentation as this will make incoordinaed force full contraction of the uterus against partially dilated cervix and may causes uterine rupture,severe laceration of the mother,trauma of the fetus,and a tetany like contraction may compromise the pacental exchange and a disconnection of oxigen supply to the fetus.
In case of dysfunctional labour the labour can be augmented by an experienced obstetrician by the oxitocin successfully.Bu an unjustified and careless use of oxitocin may itself induce dysfunctional labour.
Therapeutic Abortion
If pregnancy is dangerous to the mother aborting the baby is prescribed to save the mother by the doctors.
Suction curettage is the method usually employed by the doctors to induce abortion.
Mifepristone a 19-norsteroid a progesterone antagonist is usually employed in this method.Mifepristone when  administered along with prostaglandin can induce 99%abortion at early pregnancy.Also in early pregnancy a combination of mifepristone along with methotrexate, and misoprostol can induce 96% abortion .
Beyond the first week of he second trimester there are so many options are available to induce abortion.Intra amniotic injection of a hypertonic sodium chloride (20%) are used with many failures and this produces follows several potential hazards of hypertonicity.
Vaginal suppositories of PGE-2 (Dinoprostone and Prosten E-2) has been inserted into the vigina with the intervals of 3 to 5 hours has been tried successfully.
In circumstances such as if still the uterine cantent are not eliminated completely but uterus is ruptured the intramuscular injection of 0.25 mg of carboprost tromethamine,a 15-methyle PGE-2a Hemabate) has been proved effective.Subsquent doses of 0.5 mg can be given with 2 hrs intervals.Nausea and vomiting are the side effects of these prostaglandins.
Intra vajinal suppostories of misoprostol also can be tried for every 12 hours.
After abortion whether its auto or induced abortion the bleeding should be controlled similar to normal labour procedures by ergonovine and oxitocin.

Delayed Labour

Drugs are used to delay the labour by inhibiting uterine contractions in the following situations:-

1.To prevent premature labour.

2.To carry out other therapeutic measures

Drugs that are used in this procedure are called as Tocolytic agents:-

1.Magnesium sulphate

2.b-2 adrenergic agonists

3.Calcium channel blockers

4.Prostaglandin synthetase inhibitors.

Some patients may well respond to bedrest to prevent early contractions of the uterus.If not only tocolytics should be tried.

The delayed labour should be equally weighed between its advantages and risks.In general the use of tocolytic agents are reserved for those pregnancies where the gestational age is greater than 20 weeks and less than 36 weeks.A child born within this range of pregnancy period is considered as premature.

Before starting the drug therapy a consideration must be made with a minimal dilating requirement of cervix is less than 4 cm.and cervical effacement(the thinning of the cervix) is less than 80%.

Contraindications to tocolytics 1.Rupture of uterine,cervical or amniotic membranes 

2.Eclampsia,a condition in which convulsions occur in a pregnant woman with high blood pressure

3.Preeclampsia,a condition of eclampsia with organ damage such as kidney in high blood pressure.

4.Chorioamnionitis Infections of the fetal membranes the chorion and amnion.

5.Premature detachment of placenta

6.Fetal distress.

b-2 Adrenergic Agonists

1.Ritodrine (FDA approved to delay labour)

2.Terbutaline 

Ritodrine hydrochloride(Utopar)  is available for oral and i.v. injections

Ritordine HCl is slowly infused at the rate of 0.1 mg/min and if tolerated the rate is further increased by 0.5/min for 10 min and further increased to a maximum of .035 mg/min until labour is controlled.Once attained the controll the infusion is continued usually for 12 hrs at the rate attained.

Oral adminisration should be stared before 30 min of the termination of the infusion by 10 mg per every 2 hours for the first 24 hrs.followed by 10 to 20 mg per every 4 to 6 hrs.The total daily dose should not exceed 120 mg.

Terbutalin (Bricanyl) should be given orally 2.5 to 5 mg every 6 hrs and intra venously at 10 to 80 mic.gm/min and subcutaneosly at 0.1 to 0.4 mic gm /min for 1 to 4 hours.

WOMEN GYNACOLOGY-PART-II-FEMALE SEX HORMONES

FEMALE SEX HORMONES

Steroids are the chemical compounds in which the structural formula is composed of peculiar four membered rings namely A,B,C,and D resumbles that of a compound known as cyclo pentano perhydro phenantherene 

In our body all the male and female sex hormones are produced from cholesterol which is a steroid and hence all of them have the steroid structure in their molecules.Among these steroids body can convert one from other as per the need very easily by simple sructural modification.The female sex hormones are all seroids with an aromated phenolic A ring.Hence aromatization of a male sex hormone (Androstenedione) at the A ring will result in the conversion to female sex hormone (Estradiol,the main estrogen in our body) by our body out side ovary.

Our body is secreting in the ovary three female sex hormones namely Estradiol,Estrone,and Estriol.Out of these estradiol comprises the major part.

Esradiol is the main estrogen secreted by our body in the ovary in equillibrium with estrone.Both estradiol and estrone are finally convered to estriol before excretion.

For oral ingetion as estradiol is 100% deactivated by liver on first pass,to prevent this there are esterified semisynthetic estradiols are available for oral contraceptive use.They are Ethinyl estradiol,Mestranol
For intra muscular injections semisynthetic esters like estradiol cypionate and estradiol valerate are highly active as these esters are slowly released from the muscles to give prolonged contraceptive actions
There are nonsteroidal estrogens are available such as diethyl stilbestrol,dienestrol,chlorotrianisene.These non steroidal hormones are nowadays less atractive in use.
Pharmacological actions of Female sex hormones
The specificity of estrogen actions are at the estrogen receptors on estrogen sensitive organ tissues such as vagina,uterus,mammary glands,anterior pituitary and hypothalamus.Estrogen receptors are all nuclear receptors and hence when estrogen bind to the receptor it become a complex with it and enter into the cell and attach with the DNA of the nucleous and exhibit its actions like anabolism or catabolism or enzyme synthesis.One best example is estrogen act on bone receptors and inhibit bone resorption and stimulate new bone formation.It act on kidneys and increase the production of an enzyme,hydroxylase which convert vitamin D to D-3.
On lipid metabolism estrogens slightly increase triglyceride and HDL levels but decrease LDL and total cholesterol.
Uses
1.As contraceptives (combined with progesterone)
2.Treatment of menopausal syndromes such as:-
a.Vasomotor disorders.
b.Urogenital atrophy
c.Psychological disorders 
3.Acne
4.Osteoporosis both senile and postmenopausal
5.Prostate cancer
Toxicity
1.GI distress like nausea,vomiting anorexia and diarrhea.
2.Cardiovascular effects like high blood pressure,thrombo embolism,stroke amd heart attack.
3.Fluid retension
4.Hypertriglyceridemia
5.Endomerial (Uterine) Cancer on prolonged use only
6.Liver cancer on prolonged use only
 

WOMEN GYNACOLOGY-PART-I

FEMALE OVARY SYSTEM

INTRODUCTORY

Basically the female sexual system differs from male sexual system by the separation of the genital pathways from the urinary path ways where as in males both are united at the outlet level to form a combined urino-genital system.Here we will see the entire pharmaco-gynaecology of women comprehensively in parts by parts.

 Ovaries are major female reproductive parts situated at either side of the trunk embedded in the pelvic cavities of the female as tiny glands.These glands composed of tiny follicles known as Graafian Follicles.They are the main secreters of the female sex hormones known as estrogens.
The estrogens are mainly responsible for all changes at the age of puberty of the females and account for the secondary sexual characters of the females.
The direct action of estrogens causes the healthy development of the ovaries,fallopian tubes,uterus vajina and breast.
Also estrogens causes the shiny and soft female skin and structrure by evenly distributing the fat of the body.
Neuroendocrine Regulations of Mensuration
The hypothalamus which is situated at just below the thalamus in the brain secretes a hormone known as Gonadotropin Releasing Hormone (GnRH) in a pulsative manner.Then the GnRH act pulsatively on the anterior pituitary and stimulate it to release pulsatively the Gonadotropic Hormones or Gonadotropins which are the two hormones similar to male,the LH(the leutinizing hormone) and the FSH (the follicle stimulaing hormone).These two hormones act in a pulsative manner on the ovaries and causes the maturation of the follicle into ovum,and the secretions of the ovarian hormones estrogens and progesterone.
Progesterone exert a feed back mechanism on hypothalamus and pituitary whereas estrogen is having a feed back mechanism on pituitary only.
The full development of the follicle into ovum takes a theorital period of 11 to 14 days which is the mid cycle of the menses.At this this point the matured ovum detach itself from the ovary and enter into the fallopian tube and wait their for fertilization by a single spermatozoa.The ovum's life time is only 24 hrs whereas the sperm's life time is 72 hrs.The empty space occuppied by the detached ovum develops into a yellow gland known as Corpus Luteum which begins to secrete more progesterone and estrogen by the action of LH which  by feed back mechanism stop the stimulation of the overy further by the hypothalamus pituitary axeses until the cycle ends with fertilization or empty completion.If the ovum get successfully fertilized the progesterone and the corpus luteum will function throughout the entire period of pregnancy to protect the fetus.If not during the next half the cycle the corpus luteum begins to caese.The progesterone prepare the endometrium of the uterus like a cushion convenient for the reception of the fertilized ovum into it for stay.If no fertilization at the end of the period the entire things whould be shed off as menses.Then the next cycle would be resut.In the entire process the secretions of the steroids from the hypothalamus and pituitary axes must be pulsative with a regular intervals otherwice a continue secretion may cause continue stimulation of the ovaries which will result in painfull amenorrhea.

MALE HYPER GONADISM-TREATMENTS

ANTI ANDROGENIC TREATMENTS

Anti androgenic treatments are options prescribed for the treatments when androgens are over dosed and the male sex organs are over powered to precipitate so many unwanted serious and non serious side effects.

If androgens are administered carelessly without a doctor's supervision the following side effects are observed.

1.Over musculinization

2.Over virilization

3.Hirutism in women

4.Depression of menses,acne and clitoral enlargement

5.Rarely hepatic adenomas and carcinomas

6.Cholestatic jaundice

7.Prostatic hyperplasia. 

Anti Androgens

1.Gonadotropin Releasing alalogues:- Leuprolide or Gonadorelin

This drug is available as subcutaneous daily dose injection and should be prescribed by a doctor and given by him in his office.This drug resembles structurally similar to the hypothalamus gonadotropin releasing hormone and imitating it and thereby suppressing the release of gonadotropic hormone and thereby inhibiting the gonads.At the inistial state it may incease the levels of LH and FSH the two gonadotropins,but on continuation of the treatment it will suppress their levels 

Mostly used in Prostate enlargement

2.Receptor Inhibitors:- Cyproterone  Bicalutamide and Fluamide

It is a non steroidal synthetic androgen receptor blocker mostly used for treating Prostate Cancer.

Also can be used to treat hyper androgenic actiivity and hirutism in women.

 Bicalutamide is a newer medicine and because of its more convenience and lesser side effects it mostly replaces Flutamide.

3.Steroid synthesis Inhibitors:- Ketaconazle,and Spinolactone(Aldactone)

4.5-a-Reductase Inhibitors:-Dutostride and Finastride

These drugs can be taken orally according to doctor's advise.They inhibit the conversion of the less active testosterone into the more active dihydrosterone by inhibiting the enzyme 5-a-Reductase.