REPRODUCTIVE REPRODUCTIVE ENDOCRINOLOGYENDOCRINOLOGY

MALE ANDROGENSMALE ANDROGENS Substances which cause secondary sex characteristics Substances which cause secondary sex characteristics

in Malein Male Natural Androgens:Natural Androgens:

From Testes:From Testes:• Testosterone Testosterone • Dihydrotestosterone (more active) by 5 Dihydrotestosterone (more active) by 5 αα-reductase-reductase

From Adrenal cortex: (weak androgens)From Adrenal cortex: (weak androgens)• DehydroepiandrosteroneDehydroepiandrosterone• AndrostenedioneAndrostenedione

Androsterone – metabolite of testosteroneAndrosterone – metabolite of testosterone

TestosteroneTestosterone

Produced from cholesterol Produced from cholesterol primarily by Leydig cells in primarily by Leydig cells in testestestes

Secreted at adult levels during Secreted at adult levels during 1st trimester1st trimester11, during neonatal , during neonatal lifelife22, continually after puberty, continually after puberty33

Bound in plasma to albumin & sex Bound in plasma to albumin & sex hormone binding globulin (SHBG)hormone binding globulin (SHBG)

Can be converted to the more potent, 5α-Can be converted to the more potent, 5α-dihydrotestosterone (DHT), which is dihydrotestosterone (DHT), which is responsible for many of the responses to responsible for many of the responses to testosterone in the urogenital tract (e.g. testosterone in the urogenital tract (e.g. prostate gland hyperplasia)prostate gland hyperplasia)

Binds to and activates a single androgen Binds to and activates a single androgen receptor (AR) receptor (AR)

Androgen receptors are present in many Androgen receptors are present in many tissues including reproductive tissue, tissues including reproductive tissue, skeletal muscle, brain, kidney etc.skeletal muscle, brain, kidney etc.

Testosterone 17-alkyl substitution Methyltestosterone

Fluoxymesterone

• All androgens contain a Testosterone structures• Testosterone has 19-carbons and in general its a steroidal structure

Cholesterol

Pregnenolone

Progesterone

Corticosterone

11-Desoxy-corticosterone

18-Hydroxy- corticosterone

ALDOSTERONE

17-α- Hydroxy pregnenolone

11- Desoxy- cortisol

17- Hydroxy progesterone

21,β hydroxylase

CORTISOL

11,β hydroxylase

Dehydro-epi androsterone

Andro-stenedione

Oestrone

Oestriol

TESTOSTERONE OESTRADIOL

ACTH

Regulation of SecretionRegulation of Secretion

• LH – Testosterone secretion• FSH – Spermatogenesis• High testosterone – inhibits LH• Estrogen – feedback inhibition• Inhibin – FSH inhibition

• Plasma level of Testosterone:0.3 to 1 mcg/dl (male)20 to 60 ng/dl (female)

Biological Effects - TestosteroneBiological Effects - Testosterone

Androgenic Effects:Androgenic Effects: In the foetus, testosterone promotes development of male In the foetus, testosterone promotes development of male

reproductive tract – internal genitalia, vas deferens, epididymis and reproductive tract – internal genitalia, vas deferens, epididymis and external genitalia (sex differentiation)external genitalia (sex differentiation)

During puberty, testosterone promotes development of :During puberty, testosterone promotes development of : primary sexual characteristics (e.g. enlargement of external genitalia.primary sexual characteristics (e.g. enlargement of external genitalia. secondary sexual characteristics (e.g. male body shape, facial/pubic secondary sexual characteristics (e.g. male body shape, facial/pubic

hair, deeper pitch of voice)hair, deeper pitch of voice)

Adulthood: Baldness, Benign prostatic hyperplasia, Prostatic Adulthood: Baldness, Benign prostatic hyperplasia, Prostatic cancercancer

Testes:Testes: Promotion of spermatogenesis and maturation of spermPromotion of spermatogenesis and maturation of sperm Moderately high dose causes testicular atrophy by inhibiting Moderately high dose causes testicular atrophy by inhibiting

Gonadotrophin secretionGonadotrophin secretion

Testosterone – anabolic effectsTestosterone – anabolic effects

Pubertal spurt of growth at puberty – both boy and girlPubertal spurt of growth at puberty – both boy and girl Bone growth – thickness and lengthBone growth – thickness and length Oestrogen from testosterone – fuse of bones and Oestrogen from testosterone – fuse of bones and

mineralizationmineralization Muscle building – if aided by exerciseMuscle building – if aided by exercise Positive nitrogen, minerals and water balance – increase Positive nitrogen, minerals and water balance – increase

in weightin weight Increase in appetiteIncrease in appetite Acceleration of erythropoiesisAcceleration of erythropoiesis

Androgens – Targets of ActionAndrogens – Targets of Action

Mechanism of ActionMechanism of ActionAndrogen receptor:Androgen receptor: Both, testosterone and DH testosterone – act via Androgen Both, testosterone and DH testosterone – act via Androgen

receptors (AR) – nuclear receptor super familyreceptors (AR) – nuclear receptor super family 5 5 αα-reductase 1 and 2 -reductase 1 and 2 Ligand binding and DNA binding domainsLigand binding and DNA binding domains Mutations in AR: Incomplete sexual developmentMutations in AR: Incomplete sexual development

Estrogen Receptor:• Teststerone converts to estrogen by CYP19• Deficiency of CYP19 and estrogen receptor – failure to fuse long bones, osteoporosis etc.

T DHT DHT- R

T- R

R

R

T- R

Nucleus

90%

10%

5- α reductase

cytoplasm

Therapeutic Uses of AndrogensTherapeutic Uses of Androgens Androgen replacement therapy (ART)Androgen replacement therapy (ART) ART uses derivatives of testosterone, rather than synthetic ART uses derivatives of testosterone, rather than synthetic

Androgens, because they are safe, effective and easy to monitorAndrogens, because they are safe, effective and easy to monitor

1.1. Androgen deficiency:Androgen deficiency: clinical diagnosis confirmed by hormone assaysclinical diagnosis confirmed by hormone assays is usually caused by is usually caused by

• underlying testicular disorders (high LH, but low testosterone levels)underlying testicular disorders (high LH, but low testosterone levels)• hypothalamic-pituitary disorders (low LH and low testosterone hypothalamic-pituitary disorders (low LH and low testosterone

levels)levels)

Goal: Mimic the normal testosterone concentration as closely as possible Goal: Mimic the normal testosterone concentration as closely as possible (serum concentration monitoring)(serum concentration monitoring)

If untreated, does not shorten life expectancy, but is associated with If untreated, does not shorten life expectancy, but is associated with significant morbidity (ambiguous genitalia, delayed puberty & infertility)significant morbidity (ambiguous genitalia, delayed puberty & infertility)

Treated by androgen replacement therapy (ART), usually for the remainder Treated by androgen replacement therapy (ART), usually for the remainder of life. The aim is to restore tissue androgen exposure by using the natural of life. The aim is to restore tissue androgen exposure by using the natural androgen testosteroneandrogen testosterone

Uses – contd.Uses – contd.

2.2. HypopituitarismHypopituitarism Monitoring at anticipated time of pubertyMonitoring at anticipated time of puberty

2.2. AIDS related muscle wastingAIDS related muscle wasting3.3. Hereditary angioneurotic edema (methyltestosterone)Hereditary angioneurotic edema (methyltestosterone)4.4. AgingAgingMisuse:Misuse: involves prescription with no acceptable medical involves prescription with no acceptable medical

indicationindication Examples of misuse include:Examples of misuse include:

male infertilitymale infertility male sexual dysfunction or impotencemale sexual dysfunction or impotence ““male menopause” (andropause)male menopause” (andropause)

no convincing evidence that androgen therapy is either no convincing evidence that androgen therapy is either effective treatment or safe for older men unless there effective treatment or safe for older men unless there is frank androgen deficiencyis frank androgen deficiency

Androgens – Adverse EffectsAndrogens – Adverse Effects Virilization: Virilization:

may occur in women receiving relatively high doses may occur in women receiving relatively high doses for prolonged periods, such as for estrogen-for prolonged periods, such as for estrogen-dependent mammary carcinomadependent mammary carcinoma

Cholestatic JaundiceCholestatic Jaundice may be produced by steroids possessing a 17-alpha may be produced by steroids possessing a 17-alpha

methyl group – oral Vs parenteralmethyl group – oral Vs parenteral Priapism (sustained erection)Priapism (sustained erection) OligospermiaOligospermia Edema--via promotion of salt and water retention. Edema--via promotion of salt and water retention. Precocious puberty and short staturePrecocious puberty and short stature AcneAcne Hepatic carcinoma - oralHepatic carcinoma - oral Gynaecomastia – children and liver diseaseGynaecomastia – children and liver disease

Anabolic Steroids – Therapeutic Anabolic Steroids – Therapeutic usesuses

1.1. Catabolic states: Acute illness, severe Catabolic states: Acute illness, severe trauma, major surgerytrauma, major surgery

2.2. Renal insufficiency – frequency of Renal insufficiency – frequency of dialysisdialysis

3.3. Osteoporosis – elderly malesOsteoporosis – elderly males

4.4. Suboptimal growth in boysSuboptimal growth in boys

5.5. AnaemiaAnaemia

6.6. Perfomance enhancementPerfomance enhancement

Oestrogens

OestrogensOestrogens

IntroductionIntroduction

Most estrogen in the female is produced in Most estrogen in the female is produced in the ovaries by the the ovaries by the theca interna theca interna and the and the granulosagranulosa cells of the follicles. cells of the follicles.

CH3OH

H

H

H

HO

ESTRADIOL

CH3

H

H

H

HO

O

ESTRONE

CH3OH

H

H

H

HO

OH

ESTRIOL

Oxidized in liver

hydr

oxyla

tion

Natural Oestrogens

1.

2.

3.

Regulation of SecretionRegulation of Secretion

Daily secretion: 10 to Daily secretion: 10 to 100 mcg per day100 mcg per day

During pregnancy – During pregnancy – large quantity by large quantity by placenta – upto 30 placenta – upto 30 mg per daymg per day

Post menopausal: 2 – Post menopausal: 2 – 10 mcg per day only10 mcg per day only

Actions of OestrogensActions of Oestrogens

On sexual organs (primary and secondary sexual characteristics)On sexual organs (primary and secondary sexual characteristics) Brings about pubertal changes in vagina, fallopian tube and uterus – Brings about pubertal changes in vagina, fallopian tube and uterus –

growthgrowth

Vagina: cornification of epithelial cells with thickening and stratification Vagina: cornification of epithelial cells with thickening and stratification of epitheliumof epithelium

Ovaries : stimulate follicular growth; small doses cause an increase in Ovaries : stimulate follicular growth; small doses cause an increase in weight of ovary; large doses cause atrophyweight of ovary; large doses cause atrophy

Cervix: Rhythmic contractions of uterus and fallopian tube - increase of Cervix: Rhythmic contractions of uterus and fallopian tube - increase of cervical mucous and alkaline watery secretion with a lowered viscosity cervical mucous and alkaline watery secretion with a lowered viscosity (favoring sperm access)(favoring sperm access)

Secondary Sex CharactersSecondary Sex Characters Metabolic effects: AnabolicMetabolic effects: Anabolic

Oestrogens PhysiologyOestrogens Physiology

Other Pharmacological ActionsOther Pharmacological Actions

Bone:Bone: Important for maintaining bone mass – increased Important for maintaining bone mass – increased expression of bone mass proteins (osteocalcin, alkaline expression of bone mass proteins (osteocalcin, alkaline phosphatase)phosphatase) Generation of vit.D3 – induction of renal hydroxylase Generation of vit.D3 – induction of renal hydroxylase

enzymeenzyme Oedema Oedema – salt and water retention– salt and water retention Increased LDL and decreased HDL levelIncreased LDL and decreased HDL level Increased coagulability: II, VII, IX and XIncreased coagulability: II, VII, IX and X Lithogenicity of BileLithogenicity of Bile Increased SHBG, TBG and CBGIncreased SHBG, TBG and CBG

Mechanism of ActionMechanism of Action

2 ERs are – 2 ERs are – ERERαα and ERß and ERß ERERαα - uterus, vagina, breast and blood vessels - uterus, vagina, breast and blood vessels ERß – Prostate and OvariesERß – Prostate and Ovaries Work via a steroid hormone mechanism.Work via a steroid hormone mechanism. Entering the target cells and binding to specific cytosolic Entering the target cells and binding to specific cytosolic

receptors receptors The steroid-receptor complex is then translocated to the The steroid-receptor complex is then translocated to the

nucleusnucleus Where it alters gene expressionWhere it alters gene expression Coactivator proteins and corepressor proteinsCoactivator proteins and corepressor proteins

Oestrogen - KineticsOestrogen - Kinetics

Bound to plasma protein (SHBG)Bound to plasma protein (SHBG) Conjugated with glucoronic acid and Conjugated with glucoronic acid and

excreted in urineexcreted in urine Enterohepatic circulation – deconjugation Enterohepatic circulation – deconjugation

in intestinein intestine

Therapeutic UsesTherapeutic Uses

Hormone Replacement Therapy to Menopause womanHormone Replacement Therapy to Menopause woman Problems of menopause:Problems of menopause:

Vasomotor disturbancesVasomotor disturbances Urogenital atrophyUrogenital atrophy Osteoporosis and fracturesOsteoporosis and fractures Dermatological changesDermatological changes Risk of cardiovascular diseasesRisk of cardiovascular diseases

Dosage: Oestrogen equivalent to 0.625 mg of EE/day in Dosage: Oestrogen equivalent to 0.625 mg of EE/day in cyclical mannercyclical manner

Progestin preparation (medroxy progesterone/norethisterone) is Progestin preparation (medroxy progesterone/norethisterone) is used – 2.5 mg dailyused – 2.5 mg daily

TTS preparations may be preferredTTS preparations may be preferred

Progestins

Actions of ProgesteroneActions of Progesterone

Uterus:Uterus: Responsible for Luteal phase of endometriumResponsible for Luteal phase of endometrium High level (pregnancy and luteal phase) High level (pregnancy and luteal phase)

prevents secretion of gonadotrophinsprevents secretion of gonadotrophins Maintenance of pregnancy – nidation and Maintenance of pregnancy – nidation and

maintenance of pregnancymaintenance of pregnancy Decrease uterine motilityDecrease uterine motility Depression of T-cell function and CMIDepression of T-cell function and CMI

MenstruationMenstruation

Actions – contd.Actions – contd. Cervix:Cervix: viscid and cellular secretion – no sperm penetration viscid and cellular secretion – no sperm penetration

Vagina:Vagina: Pregnancy like changes – leucocyte infiltration and Pregnancy like changes – leucocyte infiltration and cornified epitheliumcornified epithelium

Breast:Breast: Proliferation of acini in mammary glands Proliferation of acini in mammary glands Prepares breast for lactation together with estrogenPrepares breast for lactation together with estrogen

Metabolism:Metabolism: impairment of glucose toleranceimpairment of glucose tolerance Counteraction of benefits of oestrogensCounteraction of benefits of oestrogens

CNS:CNS: Sedation Sedation Respiration:Respiration: Stimulation Stimulation Body temperature:Body temperature: rise in temperature rise in temperature Pituitary:Pituitary: Weak Gn inhibitor, suppresses ovulation if given during Weak Gn inhibitor, suppresses ovulation if given during

follicular phase follicular phase

Progesterone – contd.Progesterone – contd.

MOA: MOA: Receptors are confined to female genital tracts, Receptors are confined to female genital tracts,

breasts and CNSbreasts and CNS PRs are present in nucleus of target cellsPRs are present in nucleus of target cells PR exists in 2 forms – PR-A and PR-B isoforms PR exists in 2 forms – PR-A and PR-B isoforms

(differing activities)(differing activities)

Uses of ProgestinsUses of Progestins

ContraceptiveContraceptive Hormonl replcement therapyHormonl replcement therapy Dysfunctional Uterine Bleeding: anovulatory Dysfunctional Uterine Bleeding: anovulatory

cyclescycles Endometriosis: anovulatory hypoestrogenic state Endometriosis: anovulatory hypoestrogenic state

is created by progesteroneis created by progesterone Premenstrual syndromePremenstrual syndrome Threatened and habitual abortionThreatened and habitual abortion Endometrial carcinomaEndometrial carcinoma

Adverse EffectsAdverse Effects

Breast engorgement, headache, rise in body temp., Breast engorgement, headache, rise in body temp.,

oedema, acne & mood swings oedema, acne & mood swings

Masculinization of external genitalia in the foetusMasculinization of external genitalia in the foetus

Increased incidences of congenital abnormalitiesIncreased incidences of congenital abnormalities

Irregular bleeding or amenorrheaIrregular bleeding or amenorrhea

Lower HDL (19-nortestosterone derivatives)Lower HDL (19-nortestosterone derivatives)

HyperglycaemiaHyperglycaemia