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Reproductive Hormones 
PRO. M.C. BANSAL 
M.B.B.S , M.S. , M.I.C.O.G, F.I.C.O.G. 
Founder Principal& Controller; 
Jhalawar ...
Location of 
Endocrine Glands 
In BoDy 
Testes 
in Males
Hormones 
1.Hypothalamus-----GnRH. 
2. Pituitary –Anterior--- Growth Hormones , FSH ,LH 
,Prolactine, ACTH , TSH, Melanin....
Steroid Hormones 
• All steroid hormones are of basically similar structure 
with relatively minor chemical differences le...
structural formula of steroids 27 ,21 ,19 and 18 C arbon compounds
STEROIDOGENEIS 
• Cholesterol is the basic building block in steroidogenesis. 
• All steroid-producing organs except the p...
The Two Cell System
Two Cell 
System Of 
Ovarian Sex 
Steroid 
Production
Digramatic ----------Grannulosa cells 
From Theca cells
Blood Transport of Steroids: -- 99% by( SHBG)In 
bond Form 
• While circulating in the blood, a majority (70%) of the 
pr...
Hormone
Excretion of Steroids: 
• Active steroids and metabolites are excreted as sulfo 
and glucuro conjugates. 
• Conjugation of...
excretion 
of 
steroids 
in 
conjugate 
form 
Either as 
Glucosidu 
-ronate / 
Sulphate
Cellular Mechanism of Action: 
• Hormones circulate in extremely low concentrations and, in 
order to respond with specifi...
Receptors 
The many different types of receptors can be organized into the 
following basic categories: 
Intracellular Rec...
Ion Gate Channels 
• These cell surface receptors are composed of multiple units, 
that after binding, open ion channels. ...
Mechanism of Action for Steroid Hormones: 
• The specificity of the reaction of tissues to sex steroid 
hormones is due to...
• The steroid hormone receptors primarily affect 
gene transcription, but also regulate post 
transcriptional events and n...
Digramatic Illustration of Structure of receptors.l
H= Hormone , R= Receptor 
HOW 
the 
steroid 
Hormone 
enters 
Target 
cells
Intra cellular hormone receptor activity
Role of Growth Factor in Hormone synthesis
Transcription Activity
Estrogen
Primary site of Estrogen and progesterone production
estrogen 
synthesis 
in ovary
Inter relation ship of E1 , E2 & E3 ( Estrogens) 
E3 E2 
E1
E1– ESTRIOL 
E2—ESRADIOL 
E3--ESTRONE
Estrogen Metabolism(Production) 
• Androgens are the common precursors of estrogens. 
• 17a-Hydroxysteroid dehydrogenase a...
Adrenal Cortex ---- Major source of Androstendione– the precurssore for E3 synthesis 
• The conversion of steroids in peri...
Pharmacological Action Of Estrogen 
1) Sex organs: The estrogens bring about pubertal growth spurt-- 
development of secon...
Pharmacological Action of Estrogen--- 
2) Secondary sex characters: 
• Estrogens induces( at puberty) growth of breasts, p...
Pharmacological Action of Estrogen-------- 
• Estrogens decrease plasma LDL cholesterol while HDL and 
triglyceride levels...
Estrogen effect Estrogen& 
Progesterone 
E & P 
withdrawl
Ovarian aging and anovulation , decreased No . Of follicle ----decreased Estrogen 
Production Hence FSH level rises abrupt...
Preparation And Doses of Estrogen -------Table1 
Oral Preparations Doses 
Ethy-inyl estradiole (Lynerol ) 0.01 ,o.03 . 0.0...
Estrogen Preparations ------ ---Table2 
Intravenous— 
Conjugated equine estrogen ( 
Premarin) 
25mg 6 hourly . 
vaginal Pr...
Clinical Uses Of Estrogens-------- 
In combined Oral Contraceptives (OCS) Ethinyl estradiole / Mestranol . 
Post Menopausa...
Side Effects of Estrogen Therapy 
• Nausea and Vomiting. 
• Breast Tenderness.---Increases incidence of ER +Ve carcinoma o...
Selective Estrogen Receptor Modulators(SERMS) 
• There are 2 types of estrogen receptors— 
1. ER a 
2 . ER b 
Drugs which ...
Currently Available SERMS 
Drug Usual Dose Indication Estrogenic effect on Anti estrogenic 
effect on 
Contra Indication 
...
Anti Estrogens 
• Unlike SERMS ( having estrogenic / anti 
estrogenic effect on different tissue ) These 
drugs have only ...
1.Clomiphene Citrate 
• Clomiphine inhibits Negative feedback inhibition of GnRh 
done by indigenous estrogen --- it resul...
1.Clomiphene---Suppress -Ve feed mechanism of 
Estrogen by blocking Receptors 
2.GnRh secretion By 
3.FSH secretion & 
4. ...
1. Clomiphene citrate ----- 
Clinical Use 
Anovulation , PCOD ,Un explained Infertility . Stimulation of 
spermatogenesis...
Estrogen Synthesis Inhibitors---are Aromatase Inhibitors(AIs) 
• Pharmacology conversion of Androgens in to estrogen requ...
Preparations And doses Of Aeromatase 
Inhibitors 
Preparations Doses 
Letrazole 2.5 mg daily 
Anastrazole 1 mg daily . 
Ex...
Mechanism Of action of Leterazole--- 
Ovulation 
• Normally Grannulosa cells produce estrogen –Androgens 
are converted in...
Progestrogens
Production of progesterone: 
• Progesterone , like all other steroid hormones, is synthesized from 
pregnenolone , which i...
Progesterone Metabolism: 
• Like E, peripheral conversion of steroids to progesterone is 
not seen in the non pregnant fem...
Metabolism of progesterone
• In the pre ovulatory phase in adult females, in all pre 
pubertal females, and in the normal male, the blood levels of 
...
Digramatic Illustration of Progesterone hormone
Pharmacological Action Of Progesterone 
• Uterus: The main function of progesterone is preparation of the uterus 
for nida...
• Vagina: Progesterone induces pregnancy like changes in the 
vaginal mucosa-leukocyte infiltration of cornified epitheliu...
Thermogenic Effect Of Progesterone at 
the time of Ovulation
Classification Of Progestins 
• Progesterone—Micronized , 17 Alpha Hydroxy 
progesterone caporate . 
• C 11 – steroid ---M...
Preparations and Dosages 
Preparations Doses Route of administration 
Micronised Progesterone 100-200mg Oral/ vaginal 
!7 ...
Clinical Uses Of Progesterone 
• Diagnostic ---Progesterone Challenge test  
1omg progesterone / day for 10 days If bring...
Clinical Use of progesterone--Therapeutic 
•WithT hEsetrraopgeenutics--- Combined OC pills . Postmenopausal Hormone 
thera...
Side effects of Progesterone Therapy 
• Nausea , Vomiting . 
• Mastalgia . 
• Sodium & water Retention. 
• Worsening of Hy...
Antiprogestins 
• Antiprogestins act by binding to progsterone receptors and block 
the progesterone effect on Target cell...
Clinical Use of Mifepristone 
• Medical termination of early (<49 days / 7 weeks from 
LMP) Pregnancy. It is given in 6oom...
Selective Progesterone Receptor 
Modulators (SPRMs) 
• SPRMs act on progesterone receptors , the 
have stimulating effect ...
Androgens
Cerebral 
Cortex – 
Hypothalmo- 
Pituitary 
Testicular Axis 
in male --- 
Androgen 
Production 
+Ve effect on Male 
body( ...
Male Reproductive System _____Androgen production
Androgen Metabolism IN Females: 
Ovary ---The major androgen products of the ovary are 
dehydroepiandrosterone (DHA) and a...
• About one-half of the daily production of DHA and 
androstenedione comes from the adrenal gland; the other 
half of andr...
• The 5β-derivatives are not androgenic, and this is not an 
important pathway; however, the 5α-derivative (a very activ...
Metabolism of 
Testosterone
Diagramatic Illustration Of structure of Androgen Receptor
androgen receptor- 
--Cellular 
machenism
Pharmacological actions of androgens In Women: 
In women, androgens play a key role in the 
hormonal cascade that kick-sta...
Preparations of Androgens 
1.Testosterone Esters – 
- testosterone enanthate 
- testosterone Cypionate. 
- testosterone un...
Clinical Use of Danzol 
Oral 
Endometriosis------600—800mg/day 
Fibrocystic Disease of Breast--100 –200mgdaily. 
Menorrha...
Gestinone 
Effects 
This is a19-Noortestosterone derivatives with 
androgenic,antiestrogenic ,antiprogestrogenic , and an...
Anti Androgens 
• They are used when androgen levels are high and / or their effect on body are 
undesired . 
• In women t...
Androgen Receptor Inhibitors 
Cyproterone Spironolectone Flutamide 
Chemical Nature Synthetic 
Progesterone 
Aldosterone 
...
5 alpha Reductase inhibitors 
• Finestride 
It is a specific inhibitor of 5 reeducates enzyme which 
converts Testosteron...
Neuro endocrinology in female 
steroid Hormones production and 
regulation
Neuro transmitters 
• The most important neurotransmitters in reproductive neuro 
endocrinology are the three MONO AMINES-...
Hypothalmo—pituityary Axis
Neuro – Vascular relation in Hypopthalmus and pituitary
Hypotyhalmo 
- Pituitary- 
Ovarian Axis - 
--Regulation 
of Sex steroid 
Production 
By Ovary In 
Females 
GnRH 
releasing...
Neuro-Endocrinological regulation of Sex Steroid Production From Gonads
Gonadotrophin Releasing Hormone 
• Gonadotrophin releasing hormone is deca peptide, release 
in a pulsatile fashion by the...
GnRH Analogues preparations 
Preparation Doses Route of 
administration 
Bucklin 300ug IN / Sc IN, SC 
Naferelin 400ug IN ...
Diagnostic use of GnRH Analogues 
• Stimulation of hypothalmus with GnRh analogues 
( gonadorelin ) results in3-4 fold ris...
Clinical Indication Of GnRH Analogues 
• Pulsatile administration  Hypothalamic amenorrhea, 
Infertility , Down regulatio...
GnRH Antagonists 
• GnRh antagonist act Blocking GnRh receptors 
on pituitary , faster in action, no initial GnRH 
flare u...
Gonadotrophins --- FSH and LH 
• FSH stimulates follicular growth, and production 
of estrogen by grannulosa cells in ovar...
Preparations of GnRH (FSH & LH ) And doses 
Hormone Source Brand Name Dose route of 
Administration 
Menotropin ( 
equal a...
Clinical uses of FSH and LH preparations 
• DiagnostichCG stimulation is used to stimulate 
testosterone production from ...
Prolactin
Prolactin 
• Prolactin is produced by Lactotrophes of ( 
Insulin like Growth factor) pituitary gland and 
has single chain...
Clinical Use Of Prolactin Inhibitors 
• Hyperprolatinaemia. 
• Prolactinoma . 
• Suppression of Lactation. 
• Mastalgia. 
...
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Reproductive Hormones

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Reproductive Hormones

  1. 1. Reproductive Hormones PRO. M.C. BANSAL M.B.B.S , M.S. , M.I.C.O.G, F.I.C.O.G. Founder Principal& Controller; Jhalawar Medical College and Hospital , Jhalawar. Ex. Principal & Controller; Mahatma Gandhi Medical college And Hospital, Sitapura, Jaipur.
  2. 2. Location of Endocrine Glands In BoDy Testes in Males
  3. 3. Hormones 1.Hypothalamus-----GnRH. 2. Pituitary –Anterior--- Growth Hormones , FSH ,LH ,Prolactine, ACTH , TSH, Melanin. ---Posterior Pituitatry---ADH , Oxytocin, Inhibin. 3.Adrenals---Mineralocorticoids, Glucocortecoids , androgens and precursors of female sex Hormones. 4.Thyroid----T3 and T4. 5. Par thyroid—Paratharmone , calcitonin 6.Beta Langer Hans cells(Pancrease)---Insulin. Alpha cell---Glucagon. 7. Ovary--- Estrogen , progesterone. 8. Testes---- Testosterone.
  4. 4. Steroid Hormones • All steroid hormones are of basically similar structure with relatively minor chemical differences leading to striking alterations in biochemical activity. • The basic structure is the perhydrocyclopenta - nephenanthrene molecule. • The sex steroids are divided into 3 main groups according to the number of carbon atoms they possess. (A)The 21-carbon series includes the corticoids and the progestins, and the basic structure is the pregnane nucleus. (B)The 19-carbon series includes all the androgens and is based on the androstane nucleus. (C) The estrogens are 18-carbon steroids based on the estrane nucleus.
  5. 5. structural formula of steroids 27 ,21 ,19 and 18 C arbon compounds
  6. 6. STEROIDOGENEIS • Cholesterol is the basic building block in steroidogenesis. • All steroid-producing organs except the placenta can synthesize cholesterol from acetate. • Progestins, androgens, and estrogens, therefore, can be synthesized in situ in the various ovarian tissue compartments from the 2- carbon acetate molecule via cholesterol as the common steroid precursor. • During steroidogenesis, the number of carbon atoms in cholesterol or any other steroid molecule can be reduced but never increased. The following reactions can take place: 1) Cleavage of a side chain (desmolase reaction). 2) Conversion of hydroxyl groups into ketones . 3) Conversion of ketones into hydroxyl groups (dehydrogenase reactions). 4) Addition of OH group (hydroxylation reaction). 5) Creation of double bonds (removal of hydrogen). 6) Addition of hydrogen to reduce double bonds (saturation).
  7. 7. The Two Cell System
  8. 8. Two Cell System Of Ovarian Sex Steroid Production
  9. 9. Digramatic ----------Grannulosa cells From Theca cells
  10. 10. Blood Transport of Steroids: -- 99% by( SHBG)In bond Form • While circulating in the blood, a majority (70%) of the principal sex steroids, estradiol and testosterone, is bound to a protein carrier, known as sex hormone-binding globulin (SHBG) produced in the liver. • Another 30% is loosely bound to albumin, leaving only about 1% unbound and free ; THE ACTIVE FORM . • A very small percentage also binds to corticosteroid-binding globulin. • Hyperthyroidism, pregnancy, and exogenous estrogen administration / endogenous production of estrogen --all increase SHBG levels. • Corticoids, androgens, progestins, growth hormone, insulin, and Insulin like Growth factor 1 (IGF-1) decrease SHBG.
  11. 11. Hormone
  12. 12. Excretion of Steroids: • Active steroids and metabolites are excreted as sulfo and glucuro conjugates. • Conjugation of a steroid converts a hydrophoboic compound into a hydrophilic one and generally reduces or eliminates the activity of a steroid. • Estrogen conjugates can have biologic activity, and it is known that sulfated conjugates are actively secreted and may serve as precursors, present in the circulation in relatively high concentrations because of binding to serum proteins. • Ordinarily, however, conjugation by liver and intestinal mucosa is a step in deactivation preliminary to, and essential for, excretion into urine and bile.
  13. 13. excretion of steroids in conjugate form Either as Glucosidu -ronate / Sulphate
  14. 14. Cellular Mechanism of Action: • Hormones circulate in extremely low concentrations and, in order to respond with specific and effective actions, target cells require the presence of special mechanisms. • There are two major types of hormone action at target tissues. • One mediates the action of tropic hormones (peptide and glycoprotein hormones) with receptors at the cell membrane level. • In contrast, the smaller steroid hormones enter cells readily, and the basic mechanism of action involves specific receptor molecules within the cells. • It is the affinity, specificity, and activity of the receptors present on cell membrane of target cell, together with the large concentration of receptors inside the cell itself, that allow a small amount of hormone to produce a biologic response.
  15. 15. Receptors The many different types of receptors can be organized into the following basic categories: Intracellular Receptors • Receptors in the nucleus of target cell lead to transcription activation. • Examples include the receptors for estrogen and thyroid hormones. G Protein Receptors • These receptors are composed of a single polypeptide chain that spans the cell membrane. • Binding to a specific hormone leads to interaction with G proteins that, in turn, activate second messengers. • Examples include receptors for tropic hormones, prostaglandins, light, and odors. • The second messengers include the adenylate cyclase enzyme, the phospholipase system, and calcium ion changes.
  16. 16. Ion Gate Channels • These cell surface receptors are composed of multiple units, that after binding, open ion channels. • The influx of ions changes the electrical activity of the cells. • The best example of this type is the acetylcholine receptor. Receptors with Intrinsic Enzyme Activity • These transmembrane receptors have an intracellular component with tyrosine or serine kinase activity. • Binding leads to receptor autophosphorylation and activity. Examples include the receptors for insulin and growth factors (tyrosine kinase) and the receptors for activin and inhibin (serine kinase). Other Receptors • Receptors that do not fit the above categories include the receptors for LDL, prolactin, growth hormone, and some of the growth factors.
  17. 17. Mechanism of Action for Steroid Hormones: • The specificity of the reaction of tissues to sex steroid hormones is due to the presence of intracellular receptor proteins. • Different types of tissues, such as liver, kidney, and uterus, respond in a similar manner. • The mechanism includes: (1) steroid hormone diffusion across the cell membrane (2) steroid hormone binding to receptor protein (3) interaction of a hormone-receptor complex with nuclear DNA (4) synthesis of messenger RNA (mRNA) (5) transport of the mRNA to the ribosomes (6) protein synthesis in the cytoplasm that results in specific cellular activity.
  18. 18. • The steroid hormone receptors primarily affect gene transcription, but also regulate post transcriptional events and non genomic events. Steroid receptors regulate gene transcription through multiple mechanisms, not all of which require direct interactions with DNA.
  19. 19. Digramatic Illustration of Structure of receptors.l
  20. 20. H= Hormone , R= Receptor HOW the steroid Hormone enters Target cells
  21. 21. Intra cellular hormone receptor activity
  22. 22. Role of Growth Factor in Hormone synthesis
  23. 23. Transcription Activity
  24. 24. Estrogen
  25. 25. Primary site of Estrogen and progesterone production
  26. 26. estrogen synthesis in ovary
  27. 27. Inter relation ship of E1 , E2 & E3 ( Estrogens) E3 E2 E1
  28. 28. E1– ESTRIOL E2—ESRADIOL E3--ESTRONE
  29. 29. Estrogen Metabolism(Production) • Androgens are the common precursors of estrogens. • 17a-Hydroxysteroid dehydrogenase activity converts androstenedione to testosterone, which is not a major secretory product of the normal ovary. • It is rapidly demethylated at the C-19 position and aromatized to estradiol, the major estrogen secreted by the human ovary. • Estradiol is also produced to a major degree from androstenedione via estrone. • Estrone itself is also secreted in significant amount by ovaries. • Thus estradiol and estron are only two varieties of E Hormones secreted by ovary. • Estriol is produced by the peripheral metabolite of estrone and estradiol and not a secretory product of the ovary. • The formation of estriol is an example of typical general metabolic detoxification and conversion of biologically active material to less active forms. • This mechanism of peripheral production of estriol ( aromatization in fatty tissue) is the only source of estrogen in menopausal women.
  30. 30. Adrenal Cortex ---- Major source of Androstendione– the precurssore for E3 synthesis • The conversion of steroids in peripheral tissues is not always a form of inactivation. • Free androgens produced by ovarian stroma/ adrenals are peripherally converted in to free estrogens, for example, in skin and adipose cells. • The location of the adipose cells influences their activity , women with central obesity (the abdominal area) produce more peripheral conversion of androgens into estriol (E3). • Enough estriol(E3) may be derived from adipose tissue sufficient to produce bleeding in the postmenopausal woman. • In female the adrenal gland remains the major source of circulating androgens particularly as Androstenedione. • In male, almost all of the circulating estrogens (though minimal) is derived from peripheral conversion of androgens but it is not sufficient to cause feminization.
  31. 31. Pharmacological Action Of Estrogen 1) Sex organs: The estrogens bring about pubertal growth spurt-- development of secondary sex characters and changes in the female including--- development of breast , growth of uterus, fallopian tubes and vagina. Suppresses FSH and LH secretion , stimulates LH surge, • Vaginal epithelium gets thickened, stratified and cornified, intracellular Glycogen deposition---lacto bacilli produce lactic acid--- Vaginal Ph -- acidic. • They are responsible for the proliferation of endometrium in the pre ovulatory phase and it is only in concert with estrogens that progesterone brings about secretory changes. • Estrogens increase rhythmic contractions - the fallopian tubes and uterus, • Induces watery alkaline secretion from the cervix favorable to sperm penetration. • They also sensitize-- the uterus to oxytocin and PGs. • Deficiency of estrogen is responsible for atrophic changes in the female reproductive tract that occur after menopause
  32. 32. Pharmacological Action of Estrogen--- 2) Secondary sex characters: • Estrogens induces( at puberty) growth of breasts, proliferation of ducts and stroma and fat deposition in breast. • Growth of pubic and axillary hair., though the sex hair growth is initiated by androgens( derived from Adrenals) to start with. • Feminine contours and behavior. 3) Metabolic effects: • Estrogens are anabolic, similar to but weaker than testosterone. • Effect on carbohydrate , protein and lipid metabolism---Increases fasting blood sugar level , increase serum hormone binding protein , Increase in HDL and decrease in LDL • Estrogen is important in maintaining bone mass primarily by retarding bone reabsorption. , its declined level in menopause is responsible for menopausal osteoporosis. • It promotes positive calcium balance, partly by inducing renal hydroxylase enzyme which generates active form of Vit D, • Pharmacological doses of estrogens can result in mild salt and water retention--- edema may develop. • BP may rise after prolonged use. • it is cardio protective in normal physiological dose. • Increase in coagulation factors and Fibrinolysis.
  33. 33. Pharmacological Action of Estrogen-------- • Estrogens decrease plasma LDL cholesterol while HDL and triglyceride levels are raised. • The raised HDL : LDL ratio is probably responsible for rarity of atherosclerosis in premenopausal women. • However, blood coagulability is increased due to induction of synthesis of clotting factors (factors II, VII, IX and X). • Fibrinolytic activity in plasma also tends to increase. • Estrogen increase Lithogenecity of bile by increasing cholesterol secretion and reducing bile secretion. • Estrogen increases Plasma levels of sex hormone binding globulin (SHBG), thyroxine binding globulin (TBG) and cortisol binding globulin (CBG) -----but without any change in active form of hormonal status
  34. 34. Estrogen effect Estrogen& Progesterone E & P withdrawl
  35. 35. Ovarian aging and anovulation , decreased No . Of follicle ----decreased Estrogen Production Hence FSH level rises abruptly in menopausal and andropause age
  36. 36. Preparation And Doses of Estrogen -------Table1 Oral Preparations Doses Ethy-inyl estradiole (Lynerol ) 0.01 ,o.03 . 0.05 , 0.1 mg daily Conjugated equine estrogen (premarine , conjugase ) 0.3 .0.625 .1.25 mg daily. Estrified Estrogen( Estratab ) 0.3 . 0.625 mg daily. Micronised Estrogen (Estrace) 1-2 mg daily. Trans dermal--- Estradiol Patches (E straderm) Estradiol Gel ( (Estrogel) 0.025, 0.05 mg twice a day 1.25 mg daily Intramuscular preparations – Estradiol Velerate(Delestrogen ) Estradiol cypionate (depo-estrogen) 10,20mg once in 4 weeks 1.5-2mg once in 4 weeks.
  37. 37. Estrogen Preparations ------ ---Table2 Intravenous— Conjugated equine estrogen ( Premarin) 25mg 6 hourly . vaginal Preparations--- 1. Estradiol Creams(Estrace ) 2.Conjugate estrogen Creams(Premarin) 3. Estradiole vaginal ring (Estring) 4.Estradiole vaginal (Vagifem ) 0.01% daily . 0.025 . -2mg / day 1ring once in 3 months. 1 tablet daily . EstradioleImplant 25 ,50, 100mg once in 3 months.
  38. 38. Clinical Uses Of Estrogens-------- In combined Oral Contraceptives (OCS) Ethinyl estradiole / Mestranol . Post Menopausal Hormone Therapy. Conjugated Estrogen ,implant , patch . For Development Of secondary Sex Characters – Turners Syndrome. Hypogonadotrophic – hypogonadism. Partial Androgen insensitivity Ethenyl estradiole 0.1mg / day continuously for 3-6 months than maintenance therapy—0.01 mg / day cyclically for 21 days . FUB— Ethanol Estradiole / Iv conjugate 25mg 6hrly till bleeding controlled followed by ocs /ocs only Vulvovaginitis in Children Vaginal Cream Post menopausal vaginal atrophy / cystitis Vaginal cream, gel . Ring . Tablet
  39. 39. Side Effects of Estrogen Therapy • Nausea and Vomiting. • Breast Tenderness.---Increases incidence of ER +Ve carcinoma of breast in female with heredo familial predisposition. • Migraine. • Thrombo embolism . • Endometrial carcinoma –with prolonged unopposed use. • Gallbladder disease. • Stroke . • DVT. • Hepatic Adenoma. • Intra Hepatic Choleastesis.---Jaundice. • Water and electrolyte pretension. • Worsens Hypertension.
  40. 40. Selective Estrogen Receptor Modulators(SERMS) • There are 2 types of estrogen receptors— 1. ER a 2 . ER b Drugs which bind to or modify a particular type of receptor have abroad spectrum of action --- estrogenic / antiestrogen on different tissues. SERMS--- are non steroidal drugs – have estrogenic action on bone, brain , liver But antiestrogenic action on breast and endometrium .
  41. 41. Currently Available SERMS Drug Usual Dose Indication Estrogenic effect on Anti estrogenic effect on Contra Indication Temoxifen 10-20 mg / day Breast cancer ,Gynaecomastia , Hot flushes. Liver, endometrium – increased risk of Ca .Endo. bone(inhibits osteoclasts –prevent osteoporosis, brain Breast .---Prevent recurrence of ca breast .Decrease ca by 50 %in contra lateral breast, % yrs therapy increases disease free survival women with uterus –need follow up by TVs and End Sampling. And not to give when high risk factor for Ca,. Endo. +Ve Reloxifene. 60 mg / day Postmenopausal osteoporosis, Breast Cancer BONE– post menopausal osteoporosis prevented Breast-ER+ve cases of Ca breast are benefitted- Ormeloxifene— (centochrome , Saheli,Seviesta) Azoxifene 30-60mg , 60 mg tab--2 tabs state – 1 tab bi weekly for DUB. 20mg DUB , Contraception( 30mg twice a week for 3 months then once a week ) Breast cancer It cause asynchrony between ovulation andendomatrum --- preventing conception. Present
  42. 42. Anti Estrogens • Unlike SERMS ( having estrogenic / anti estrogenic effect on different tissue ) These drugs have only anti estrogenic effect on all the tissue where ever estroge4n receptors are present. • Two main drugs belong to this category --- 1. Clomiphene Citrate. 2. Fulvestrant .
  43. 43. 1.Clomiphene Citrate • Clomiphine inhibits Negative feedback inhibition of GnRh done by indigenous estrogen --- it results in increased secretion of GnRH ---FSH secretion, LH surge and induces ovulation . • It is prescribed in dose of 50 – 150 mg / day since 2nd day to 6th day after LMP., the period of time when Estrogen is rising and a crop of Follicles are in race of development and selection of dominant follicle occurs in ovary. • Clomiphene binds to estrogen receptors on hypothalamus and blocks -ve feed effect of the estrogen on hypothalamus thus Pulsatile GnRH secretion ensures the resultant rise in FSH secretion From Pituitary ---- stimulates ovarian multiple follicles to develop ,Estrogen produce from these follicles with its +be feed mechanism brings about ovulation ( multiple)
  44. 44. 1.Clomiphene---Suppress -Ve feed mechanism of Estrogen by blocking Receptors 2.GnRh secretion By 3.FSH secretion & 4. LH Surge By Anterior Pituitary Ovary Estrogen. hypothalamous Ovary 5.Multiple follicle run in race of Maturation and 1 or more follicles become dominant follicle to ovulate
  45. 45. 1. Clomiphene citrate ----- Clinical Use Anovulation , PCOD ,Un explained Infertility . Stimulation of spermatogenesis in males having Azoo / Hypospermia due to hypogonadotrohin –hypogonadism. Doses Started in low dose (50mg /day )on day 2for 5 days --- can be increased gradually up to 150-200 mg / day –Maximum for 6cycles For induction of ovulation. In male 25mg/ day for 25 days a month up to 6 months for treatment of Azoo/ hypospermia. Side effects Hot flushes , blurring of vision and scotoma , abdominal discomfort , Nausea & vomiting , multiple ovulation --- multiple pregnancy , Luteal phase defect , Anti estrogenic effect on cervical mucous and endometrial changes ,Ovarian cysts and cancer (> 1year of use ) and ovarian hyper stimulation syndrome. 2. Fulvestrant---is similar to tomexiphen but having only anti estrogenic effect on all tissue , it is used in women with breast cancer (ER+ve) . It is administered as IM depo Preparation
  46. 46. Estrogen Synthesis Inhibitors---are Aromatase Inhibitors(AIs) • Pharmacology conversion of Androgens in to estrogen require Aromatase enzymes. • This enzyme is predominantly present in grannulosa cells and peripheral adipose tissue , liver breast and placenta. • By inhibiting the action of this –aromatase enzyme biosynthesis of estrogen can be blocked in vitro as well as in vivo . Types Of AIs—The are of two types— 1. Type I : Steroidal Agents ( Formestane and Exemastane ). They bind with aromatase and their binding is irreversible causing permanent blockage of aromatization –no more estrogen synthesis. 2.Type II : Non steroidal agents(Anastrazole and Latrozole ) The binding with aromatase is reversible hence short acting blocking effect on estrogen production occurs. Clinical Use postmenopausal breast cancer—second lime therapy in recurrent cases, 1st line as adjuvant ,Preoperative ( neo adjuvant ).Ovulation Induction , endometriosis, Fibroid s. Endometrial stromal sarcoma, peripheral precaucious puberty , congenital adrenal hyperplasia ,short stature girls--- prevents fusion of epiphysi of long bones , Gynaecomastia.
  47. 47. Preparations And doses Of Aeromatase Inhibitors Preparations Doses Letrazole 2.5 mg daily Anastrazole 1 mg daily . Exemestane ( steroidal agent – permanent inhibitor ) 25 mg daily Side Effects of AIs Arthralgia and arthritis Dyslipidaema. Vaginal Dryness. Coronary heart disease . Osteoporsis. osteonecrosis of Jaw. Note --- Letrazole is not recommended for induction of ovulation in India as it is an anti cancer drug . Its use for induction of ovulation is also not approved by drug controlling authorities of USA and British Pharmacopeia.
  48. 48. Mechanism Of action of Leterazole--- Ovulation • Normally Grannulosa cells produce estrogen –Androgens are converted in Estrogen by the action of Aromatase Enzyme. • Laterozole temporarily inhibits aromatase enzyme  No estrogen production no more – ve feed action of estrogen on Hypothalamous-->Pulsatile secretion of GnRH occurs GnRH Stimulates anterior Pituitary FSH secretion FSH acts on Grannulosa cell--- development of FSH receptors and Initiates race of development of multiple follicle to win as dominant follicle . • By now the inhibitory effect on aromatase enzyme( Leterozole) wears off-Estrogen production by Grannulosa cells re start– Rising estrogen level  It further stimulate anterior pituitary  FSH is produce and LH surge occurs causing –Ovulation of dominant Follicle.
  49. 49. Progestrogens
  50. 50. Production of progesterone: • Progesterone , like all other steroid hormones, is synthesized from pregnenolone , which in turn is derive from cholesterol. • Cholesterol undergoes double oxidation to produce 20,22- dihydroxycholesterol . • This vicinal diol is then further oxidized with loss of the side chain starting at position C-22 to produce pregnenolone . • This reaction is catalyzed by cytochrome P450scc. • The conversion of pregnenolone to progesterone takes place in two steps. First, the 3-hydroxyl group is oxidized to a keto group and second, the double bond is moved to C-4, from C-5 through a keto/enol tautomerization reaction. • This reaction is catalyzed by 3beta-hydroxysteroid dehydrogenase/delta(5)-delta(4)isomerase. • Progesterone in turn is the precursor of the mineralocorticoids, aldosterone, and after conversion to 17- hydroxyprogesterone of cortisol and androstenedione. • Androstenedione can be converted totestosterone, estrone and estradiol.
  51. 51. Progesterone Metabolism: • Like E, peripheral conversion of steroids to progesterone is not seen in the non pregnant female; rather, the progesterone production rate is a combination of secretion from the adrenals and the ovaries. • Including the small contribution from the adrenal, the production rate of progesterone in the pre ovulatory phase is less than 1 mg/day. • During the luteal phase, production increases to 20 to 30 mg/day. • The metabolic fate of progesterone, as expressed by its many excretion products, is more complex than estrogen. • About 10 to 20% of progesterone is excreted as pregnanediol.
  52. 52. Metabolism of progesterone
  53. 53. • In the pre ovulatory phase in adult females, in all pre pubertal females, and in the normal male, the blood levels of progesterone are at the lower limits of immunoassay sensitivity: less than 1 ng/mL. • After ovulation, i.e., during the luteal phase blood level of progesterone ranges from 3 to 15 ng/mL. • In congenital adrenal hyperplasia, progesterone blood levels can be as high as 50 times above normal. • Pregnanetriol is the chief urinary metabolite of 17 alpha hydroxyprogesterone and has clinical significance in the adrenogenital syndrome, in which an enzyme defect results in accumulation of 17 alphahydroxy-progesterone and increased excretion of pregnanetriol.
  54. 54. Digramatic Illustration of Progesterone hormone
  55. 55. Pharmacological Action Of Progesterone • Uterus: The main function of progesterone is preparation of the uterus for nidation and maintenance of pregnancy due to prevention of endometrial shedding, decreased uterine motility and inhibition of immunological rejection of Fetus from pregnant Uterus (Immunomodulation) • Progesterone brings about secretory changes in the estrogen primed endometrium: hyperemia and tortuocity of glands . • Continued action of progesterone (as when pregnancv occurs) brings about decidual changes in endometrium- --stromal hyperplasia and it becomes spongy ,hypervascular , the glands atrophy afterwards. • It also decreases sensitivity of myometrium to oxytocin and PGs • Cervix: Progesterone converts the watery cervical secretion induced by estrogens to viscid, scantv and cellular infiltration which is hostile to sperm penetration. Fern and straechability in thread( spin Barket) properties disappear.
  56. 56. • Vagina: Progesterone induces pregnancy like changes in the vaginal mucosa-leukocyte infiltration of cornified epithelium (KI index decreases e,g More % of navicular cells). • Breast: Progesterone causes proliferation of acini in the mammary glands • Body temperature: It causes a slight (0.5,'C) rise in body temperature by resetting the hypothalamic thermostat and increasing heat production. • Respiration: Progestins in relatively higher doses stimulate respiration, as occurs during Pregnancy. • Metabolism: Prolonged use of oral contraceptives impairs glucose tolerance in some women. This has been ascribed to the progestational component. • Progestins, especially those with androgenic activity (19- nortestosterone derivatives) tend to raise LDL and lower HDL levels.
  57. 57. Thermogenic Effect Of Progesterone at the time of Ovulation
  58. 58. Classification Of Progestins • Progesterone—Micronized , 17 Alpha Hydroxy progesterone caporate . • C 11 – steroid ---Medroxy progesterone acetate , Magestrol acetate. • Pregnanes –(17 acetoxyprogesterone deravatives ) Lynestrenol. • Estranes –(19 –Nor testosterone derivatives )— Norethsterone, norethinedrol ,Norethydrone, ethynedilol diacetate. • Gonanes– Norgestrel ,Levonorgestrel . • Newer Progestins---Desogestrel ,Gestodene ,Norgestimate . • Spironolactone Derivatives---Drospirenone . • Other Progestins ---Dienogest ,Nomegestrol ,Nestorone , trimegestone.
  59. 59. Preparations and Dosages Preparations Doses Route of administration Micronised Progesterone 100-200mg Oral/ vaginal !7 – alpha Hydroxy –prog.Caporate 250-500mg weekly IM MPA 2.5-5 mg 150 mg Oral IM Depot Megestrol Acetate 10mg oral Norethysterone 5mg oral Norgestrel 5mg oral Lvonorgestrel Desogestrel Gestodene Drospirenone Norplant I & II Implanon Vaginal Ring Progestasert Lenorgestrel (Mirena) 5mg 10 mg 75 ug (withEE2) 3mg (with EE2 ) 36mg,70mg Etonogestrel 67mg releases 20ug/day Progesterone—38mg 52 mg oral oral Oral oral Sub dermal Sub dermal Transvaginal IUCD IUCD
  60. 60. Clinical Uses Of Progesterone • Diagnostic ---Progesterone Challenge test  1omg progesterone / day for 10 days If brings about with drawl bleeding in a women with secondary amenorrhea– indicate sufficient amount of Estrogen is present , endometrial is able to respond to hormones ,when No with drawl bleeding occurs– Either there is no sufficient estrogen production or the endometrial is not primed (no proliferative changes could develop) as it is damaged by local disease like Tuberculosis or Asher Man’s syndrome.
  61. 61. Clinical Use of progesterone--Therapeutic •WithT hEsetrraopgeenutics--- Combined OC pills . Postmenopausal Hormone therapy Progestin-only Contraceptives Minipill, Norgestrel . Desogestrel .MPA –depot , Implants, IUCD--Mirena Emergency Contraception Levonorgestrel DUB Duphaston , Promolut-N , Diavary , Regosterone. Recurrent Abortions Duphaston , 17 –alpha Hydroxyprogesterone acetate, micronised progesterone. Secondary Amenorrhoea with normal / increased Estrogen Norethisterone Lutial phase Defect in ART cycles Micronised Progesterone Preterm Labour Endometriosis Endometrial Hyperplasisa Advanced endometrial Cancer Postponement of menses Micronized Progesterone Norethisterone, MPA. MPA , Megetrol acetate. MPA , Megestrol Acetate. Nor ethisterone.
  62. 62. Side effects of Progesterone Therapy • Nausea , Vomiting . • Mastalgia . • Sodium & water Retention. • Worsening of Hypertension. • Depression. • Dyslipidaemia . • Thromboembolism . • Brest cancer –prolog use. • osteoporosis – Prolong use. • 19 nor testosterone Der55ivatives – can cause hirsutism--- Virilisation of fetus if given to pregnant women.
  63. 63. Antiprogestins • Antiprogestins act by binding to progsterone receptors and block the progesterone effect on Target cell. • Mifepristone--- Derivative of norethisterone. • When given in Luteal phase ---cause luteolysis—resulting in menstruation as with drawl bleeding . • In early Pregnancy –lutolytic effect  decreased Progesterone levels , decidual breakdown and embryonic demise—Endogenous production of PGs start myometrial contractions --- Abortion . • If given in(2oomg oral) late proliferative Phase( 11- 14 Day ) , it causes Suppression of LH surge --- No Ovulation. • These drugs also have anti androgenic and anti gluco corticoid action also and cause rise in ACTH level . • These drugs are metabolized in liver. Preparations – 1. Mifepristone 2 . Onapristone 3 .Epostone.
  64. 64. Clinical Use of Mifepristone • Medical termination of early (<49 days / 7 weeks from LMP) Pregnancy. It is given in 6oomg orally initially, Adding Mesoprostol 400 ug (oral / vaginal ) after 24-36 hrs gives > 95 % success. Products are expelled within 5 days . • Post coital pill 1o mg if taken immediate after intercourse in pre ovulatory phase. • Also useful in--- cervical ripening , Endometriosis, break through bleeding IN MPA dept therapy , Leomyoma, breast cancer (PR +VE ),Ovarian cancer , cushing’s syndrome and premenstrual psychotic depression etc. • Side Effects Nausea, vomiting , Uterine Cramps , adrenal insufficiency and cardiac Failure.
  65. 65. Selective Progesterone Receptor Modulators (SPRMs) • SPRMs act on progesterone receptors , the have stimulating effect (progestogenic ) as well as Anti progestogenic effect on different tissue Having different type of PRs. • Only drug yet developed is ASOPRISINIL. • It is under trial in cases of endometriosis, fibroids and breast cancer.
  66. 66. Androgens
  67. 67. Cerebral Cortex – Hypothalmo- Pituitary Testicular Axis in male --- Androgen Production +Ve effect on Male body( Sexual aswell as Asexual systems
  68. 68. Male Reproductive System _____Androgen production
  69. 69. Androgen Metabolism IN Females: Ovary ---The major androgen products of the ovary are dehydroepiandrosterone (DHA) and androstenedione (and only a very little testosterone), which are secreted mainly by stromal tissue derived from theca cells. With excessive accumulation of stromal tissue or in the presence of an androgen-producing tumor, testosterone becomes a significant secretory product of ovary. The normal accumulation of stromal tissue at midcycle results in a rise in circulating levels of androstenedione and testosterone at the time of ovulation. Adrenals ---Under normal circumstances, adrenal gland production of the sex steroids is less significant than gonadal production of androgens , estrogens and progesterone. .
  70. 70. • About one-half of the daily production of DHA and androstenedione comes from the adrenal gland; the other half of androstenedione is secreted by the ovary. • but 50%of DHA is from theAdrenals;20% from ovary and rest comes from peripheral tissues. • The production rate of testosterone in the normal female is 0.2-0.3 mg/day, and approximately 50% arises from peripheral conversion of androstenedione (and a small amount from DHA) to testosterone, whereas 25% is secreted by the ovary and 25% by the adrenal. • Reduction of the unsaturation (an irreversible pathway) in testosterone is very significant, producing derivatives very different in their special configuration and activity.
  71. 71. • The 5β-derivatives are not androgenic, and this is not an important pathway; however, the 5α-derivative (a very active pathway) is extremely potent. Indeed, dihydrotestosterone (DHT), the 5α-derivative, is the principal androgenic hormone in a variety of target tissues and is formed within the target tissue itself. • In men, the majority of circulating DHT is derived from testosterone that enters a target cell and is converted by means of 5α-reductase to DHT. • In women, because the production rate of androstenedione is greater than testosterone, blood DHT is primarily derived from androstenedione and partly from dehydroepiandrosterone. • Thus, in women, the skin production of DHT may be predominantly influenced by androstenedione.
  72. 72. Metabolism of Testosterone
  73. 73. Diagramatic Illustration Of structure of Androgen Receptor
  74. 74. androgen receptor- --Cellular machenism
  75. 75. Pharmacological actions of androgens In Women: In women, androgens play a key role in the hormonal cascade that kick-starts puberty, stimulating hair growth in the pubic and underarm areas. Additionally, these hormones are believed to regulate the function of many organs, including the reproductive tract, bone, kidneys, liver and muscle. In adult women, androgens are necessary for estrogen synthesis and have been shown to play a key role in the prevention of bone loss, as well as arousal of sexual desire and satisfaction. They also regulate body function before, during and after menopause.
  76. 76. Preparations of Androgens 1.Testosterone Esters – - testosterone enanthate - testosterone Cypionate. - testosterone undecanoate. 2. 17 alpha –Alkylated androgens - Methyl Testosterone - Oxandrolone - Fluoxy mestenone - Danazole 3. 19 N0r Derivatives - Gestinone.
  77. 77. Clinical Use of Danzol Oral Endometriosis------600—800mg/day Fibrocystic Disease of Breast--100 –200mgdaily. Menorrhagia –200mg /day. Mastalgia--- 50—100mg/day . Immune thrombocytic Pupura 200mg/day. Angoeodema------200mg/day . Emergency Contrceptive—200mg stat post coital. Vaginal  Endometriosis—1500mg
  78. 78. Gestinone Effects This is a19-Noortestosterone derivatives with androgenic,antiestrogenic ,antiprogestrogenic , and anti gonadotrphic action. • It suppresses LH surge and basal LH secretion from pituitary and increases free testosterone level . • It has been used in treatment of Endometriosis and has been found to be effective as GnRH analogues. • The recommended dose is 2.5 mg twice a week. • About 80% of women become amenorrhoeic. Side effects  Its effects are similar to Danezol ,but less severe. Nausea, Muscle cramps , weight gain , Acne, oily skin , Facial hair growth etc.
  79. 79. Anti Androgens • They are used when androgen levels are high and / or their effect on body are undesired . • In women their principal use is in Hirsutism . • Varieties 1, One who decrease androgen production . 2, One those inhibit the action of androgens on target cell by blocking their receptors. Anti androgens A. Inhibitors of androgen secretions—GnRH analogues, anti fungal like Imidazole and Ketaconazole. B. Inhibitors of Androgenic action on target cells— (a) inhibitors of testosterone action ---Cyproterone Acetate ,Spironolactone, Flutamide , Bicalutamide ,Nilutamide and Cimetidine . ( b ) 5 alpha Reductase enzyme inhibitors ---Finasteride and Dutasteride.
  80. 80. Androgen Receptor Inhibitors Cyproterone Spironolectone Flutamide Chemical Nature Synthetic Progesterone Aldosterone antagonist Substituted anilide Mechanism of action plasma T,A-dione, SHBG ,anti glco corticoid Suppression of T biosynthesis, Inhibition of5 alpha redutase. anti androgen , week inhibitor of T biosynthesis. Indiocations Hirsutism , Acne Hirsutism hirsutism Doses 100mg / day for 5- 15 D with EE2 30ug /day for 5-26 d of cycle 50-200mg/ day 250 mg 2-3 time / day Side effects Nausea , wt gain , headache, fatigue, irregular menses , Teratogenic Irregular menses, Mastalgia, urticaria,hair loss ,Hyperkalaemia, Feminization of fetus,Teratogenic Dry skin, Blue green discolouration of urine .Hepatotoxicity , Teratogen
  81. 81. 5 alpha Reductase inhibitors • Finestride It is a specific inhibitor of 5 reeducates enzyme which converts Testosterone into the more potent androgen , Dihydrotestosterone. Used in 1.Rx of benign hyperplasia of Prostate. 2. Hirsutism along withjcombined Ocs. 3. also useful in females with male type baldness. Indications—Hirsutism and male type of baldness in females. Side effects --- Hypersensitivity ,Teratogenicity . Dose– 5-10mg/day
  82. 82. Neuro endocrinology in female steroid Hormones production and regulation
  83. 83. Neuro transmitters • The most important neurotransmitters in reproductive neuro endocrinology are the three MONO AMINES--- Dopamines, Norepinephrine and Serotinins. • Dopamoine containing fibers that regulate pituitary function arise chiefly in hythalmic—arcuate nucleus ; these fibers project to median eminence where Dopamine enters the portal vessels of hypothalmo –hypophysial system . • Dopamine present in small amount in portal system is sufficient to inhibit the release of Prolactin (PRL). • Dopamine is most potent and important PRL inhibiting Factor (PIF). • Pulsatle and phasic Inhibtion of prolactin release in pulsatle manner is principally responsible for pulsatile secretion of GnRH --- in turn secretion of Gonadotrophins (FSH and LH ) in phasic stages of normal menstrual cycle. • Endogenous prolactin releasing substances like TSH ,Vasopressin , Vasoactive Intestinal peptides (VIP) , opoids and acetyline. • There are 5 types of dopamine receptors groped in D1 & D2 sp[ecific ligends. Anterior Pituitary primarily express D2 type of specific ligends. • Opoids tone in brain plays acentral role in menstrual cyclicity by suppressing GnRh release.
  84. 84. Hypothalmo—pituityary Axis
  85. 85. Neuro – Vascular relation in Hypopthalmus and pituitary
  86. 86. Hypotyhalmo - Pituitary- Ovarian Axis - --Regulation of Sex steroid Production By Ovary In Females GnRH releasing Hormone FSH & LH Estrogen & Progester one -Ve And +Ve Feed machanism Regulate the Production Of E & P hormones
  87. 87. Neuro-Endocrinological regulation of Sex Steroid Production From Gonads
  88. 88. Gonadotrophin Releasing Hormone • Gonadotrophin releasing hormone is deca peptide, release in a pulsatile fashion by the hypothalamus. • This pulsatile pattern is crucial for synthesis and secretion of Gonadotrophins ---FSH and LH etc. • Continuation administration of GnRH hormones/Their synthetic analogues. lead to transient increased levels of FSH and LH ( flare up effect )– then it is followed by prolong desensitization of GnRH receptors present on pituitary cells --- resulting prolong inhibition of FSH and LH secretion ( down Regulations ). • This is the basis of use GnRH analogues in clinical practice. • Half life of GnRH is only 2-4 minutes hence GnRh analogues with enhanced potency and duration of action have been synthesized. • They are in activated by gastric juice hence the are given parentally.
  89. 89. GnRH Analogues preparations Preparation Doses Route of administration Bucklin 300ug IN / Sc IN, SC Naferelin 400ug IN daily In ( Intra Nasal ) Goserelin 3.6mg implait 3 monthly 3.6mg monthly Sc implant ( Sub Cutaneous) IM Depot Leuprolide 3.75 mg IM monthly IM ,SC, DEPOT
  90. 90. Diagnostic use of GnRH Analogues • Stimulation of hypothalmus with GnRh analogues ( gonadorelin ) results in3-4 fold rise in FSH and LH levels in a women having Hypothalamic amenorrhea (hypothalamic Failure ). If it is due to pituitary failure --- No such response ( no rise in FSH& LH secretion). • In central precocious puberty , basal FSH and LH levels are in the range of post pubertal range; Groh analogues administration will result in 3-4 fold rise in their serum level indicating that hypothalamus-pituitary ovarian axis is synchronized and active . In peripheral is sexual precocious puberty , FSH & LH levels are low and there is no increase after Groh stimulation.
  91. 91. Clinical Indication Of GnRH Analogues • Pulsatile administration  Hypothalamic amenorrhea, Infertility , Down regulation prior to ovulation Induction , ovulation induction in hypothalamic dysfunction. • Daily or monthly administration Central precocious puberty , endometriosis , Uterine myomas to reduce their size ( preoperatively ), DUB ., Endometrial preparation for TCRE. Hormone responsive breast carcinoma, cryptorchidism and prostatic cancer in males. Side effects Hot Flushes , Vaginal dryness ,insomnia ,dyslipidaemia , osteoporosis. Add Back Therapy  due to side effects ,GnRH therapy is usually limited to 6 months. If treatment is to be given for long duration Add back therapy with combined oral pills / or estrogen alone is given . When estrogen is contra indicated Tibolone may be considered.
  92. 92. GnRH Antagonists • GnRh antagonist act Blocking GnRh receptors on pituitary , faster in action, no initial GnRH flare up and used for rapid down regulationprior to ovulation in ART. • Preparations available Cetrorelix, genirelix and aberalix use d as sub cutaneous injection. Not commomnly used because of their hypersensitivity reaction.
  93. 93. Gonadotrophins --- FSH and LH • FSH stimulates follicular growth, and production of estrogen by grannulosa cells in ovary . • LH surge (+ve Feed mechanism of rising estrogen on pituitary) triggers Ovulation , stimulates Progesterone production , Sustain the life of carpus luteum and supports implantation of fertilized ova in decidual bed . • Commercially available preparations of FSH & LH are used for these functions in ART practice.
  94. 94. Preparations of GnRH (FSH & LH ) And doses Hormone Source Brand Name Dose route of Administration Menotropin ( equal amount of FSH and LH) Extracted from urine of Pregnant women Pergonal Repronex 75 IU IM Urofolicotrophin (u FSH ) Highly purified Form from urine of pregnant women Bravelle FSH-- 75 IU SC Recombinat (rFSH ) These are Expensive and not used as routine Synthesized by DnA recombinant Technology Gonal F Puregon Follistin . 50 IU SC Chorionic Gonadotrophin Pregnyl Profesi Novarel More LH effect extracted from urine of pregnant women 1000-5000IU IM
  95. 95. Clinical uses of FSH and LH preparations • DiagnostichCG stimulation is used to stimulate testosterone production from Leydig cells of testes --- thus detect Leydig cell function . This test is used in children with ambiguous genitalia – hCG response in the form of rise in Testosterone level indicates presence of testes/ testicular component. • Therapeutic Uses FSH and LH (hCG)---infertility for induction of ovulation ,Hypogonadotrophic hypogonadism and cryptorchadism. hCG alone ---Recurrent pregnancy loss and luteal ph support in IVF . Side Effects  Multifetal pregnancy , and ovarian hyper stimulation syndrome (OHSS) in induction of ovulation in ART.
  96. 96. Prolactin
  97. 97. Prolactin • Prolactin is produced by Lactotrophes of ( Insulin like Growth factor) pituitary gland and has single chain of 198 amino acids; it plays a vital and major role in preparation of breasts for lactation and continuous milk secretion . • Drugs used to inhibit Prolactn (PRL) Preparation Doses (mg) Route of Administration Bromoergocryptine 2.5-7.5 Oral/vaginal /day Cabergoline o.25-o.5 Oral twice weekly Quinagolide o.1-0.5 Oral / day Pergolide o.o25-o.5 Oral daily
  98. 98. Clinical Use Of Prolactin Inhibitors • Hyperprolatinaemia. • Prolactinoma . • Suppression of Lactation. • Mastalgia. • Infertility / amenorrhea due to hyper prolactinaemia. • Side effects Nausea,vomiting , headache , postural hypotension , nasal congestion ,CNS effect like—insomnia, hallucinations, psychosis. These drugs should be starte with smalldose and then increase gradually at interval of ½ week. Mild side effects usually subside as time passes.

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