GONADAL HORMONES AND INHIBITORS

ESMARLIZA K. TACUD-LUZON,MD, FPOGS, FPSECP, FPSV

SEX STEROIDS
Primarily used therapeutically for replacement therapy and for contraception

Sex steroids:
ESTROGENS ANTI-ESTROGENS
Diethylstilbestrol Clomiphene
Estradiol Tamoxifen
Estril Raloxifene
Estrone Toremifene
Ethinyl estradiol
Mestranol
Quinestrol

Sex steroids:
PROGESTINS ANTI-PROGESTINS
Progesterone Mifepristone
Hydroxyprogesterone
Medroxyprogesteron
e
Megestrol
Norethindrone
Norgestrel

Sex steroids:
ANDROGENS ANTI-ANDROGENS
Androgenic Steroids
Testosterone ( several Finasteride ( 5-
preparations ) reductase inhibitor )
Danazol Cyproterone acetate
Fluoxymesterone Flutamide ( receptor
Methyltestosterone antagonist )
testolactone
ESTROGEN:
THERAPEUTIC USE:
Hormone replacement therapy in postmenopausal women
contraception

Major estrogens:
* estradiol
* estrone
* estriol
Formed from either androstenedione or testosterone as immediate precursors

OVARIES: principal source of circulating estrogen in pre-menopausal women.

* The major secretory product is ESTRADIOL, synthesized by granulosa cells from androgenic
precursors provided by theca cells.

PHYSIOLOGICAL AND PHARMACOLOGICAL ACTIONS OF ESTROGEN:

Developmental actions
- secondary sexual characteristics
- growth and dev’t of vagina, uterus, and fallopian
tubes
- promote breasts ductal growth, stromal dev’t and
accretion of fat
- molding body contour, shaping skeleton, pubertal
growth spurt, epiphyseal fusion
- growth of axillary and pubic hair, pigmentation of
genital region
Control of menstrual cycle

Effects on the reproductive tract

- stimulate proliferation and differentiation in the
fallopian tubes
-  tubal muscular contractility
-  amount and water content of cervical
mucus
- favors rhythmic contractions of uterine
myometrium

Metabolic effects
- (+) effect on bone mass, blocks resorption,
small  in bone formation
- maintain (+) calcium balance
-  level of hydroxylase which convert vit.D to active
 form in the kidneys
- slight  in serum triglycerides, HDL
-  total serum cholesterol, LDL
- alter bile composition-  saturation of bile with
cholesterol --- gallstone formation

Effects on blood coagulation

- enhance coagulability of the blood
-  circulating levels of factor II, VII, IX, and X
-  antithrombin III

Other effects
- induce synthesis of progesterone receptors
- stimulates central components of the stress system, including production of CRH
- promote a sense of well being
- facilitate the loss of intravascular fluid into the extracellular space, producing
edema
- modulate sympathetic nervous system control of smooth muscle function

MECHANISM OF ACTION OF ESTROGEN:

act primarily by regulating gene expression:
Lipophilic hormone - diffuse passively - binds to receptor - Estrogen response elements
- or  transcription of hormone-regulated genes

ABSORPTION, FATE & ELIMINATION:

-Available for oral, parenteral, transdermal, or topical administration.
-Undergoes extensive first pass hepatic metabolism and undergo enterohepatic recirculation.
-Absorbs rapidly and completely from GIT.
-Extensively bound to plasma proteins.
-T1/2 of ethihyl estradiol: 13-27 hours
-Excreted in the bile

UNTOWARD RESPONSES:
Postmenopausal uterine bleeding
Carcinogenic actions
Metabolic and cardiovascular effects
Others:
- nausea and vomiting
- breast fullness and tenderness and edema
- severe migraine
- reactivate/exacerbate endometriosis
- gallbladder disease
- hypertension
THERAPEUTIC USES:
Primary hypogonadism
Hormonal Contraception
Postmenopausal hormone replacement
Others: intractable dysmenorrhea; treatment of hirsutism and menorrhea due to excessive
secretion of androgens by the ovary

Contraindications:
Estrogen-dependent neoplasm
Undiagnosed genital bleeding
Liver disease
History of thromboembolic disorders
Heavy smokers (absolute contraindication)

Preparation and Dosages

Oral (1st pass effect) : used as oral contraceptives and HRT
Transdermal: HRT

PROGESTINS:
* Secreted by the ovary mainly from the corpus luteum during the second half of the menstrual
cycle

PHYSIOLOGICAL AND PHARMACOLOGICAL ACTIONS:

Neuroendocrine actions
-  the frequency of the hypothalamic pulse generator and  the amplitude of LH pulses
released from the pituitary.

Reproductive tract
-  estrogen-driven endometrial proliferation, secretory endometrium
- scant, viscid endocervical glands secretion
- maintenance of pregnancy, prevent threatened pregnancy
- suppress menstruation and uterine contractility
- inhibits tubal proliferation and differentiation and  tubal muscular contractility

Mammary gland
- proliferation of acini

CNS Effects
-  in body temperature
-  ventilatory responses of respiratory center to CO2---  arterial and alveolar PCO2
in the luteal phase and during pregnancy
- depressant and hypnotic actions in the CNS.

Metabolic effects
 -  basal insulin levels
-  glucose intolerance
- stimulates lipoprotein lipase activity and enhance fat deposition
-  HDL levels
-  effects of aldosterone in the renal tubules

MECHANISM OF ACTION OF PROGESTINS:

- act primarily by regulating gene expression:
Lipophilic hormone - diffuse passively - binds to receptor - progesterone response
elements - or  transcription of hormone-regulated genes

ABSORPTION, FATE AND EXCRETION:

- does not have appreciable activity by oral route due to extensive first-pass hepatic
metabolism
- available in oil solution for IM administration
- bound by albumin and corticosteroid binding globulin
- eliminated via the urine
- t ½ of progesterone: 5 mins

PROGESTINS:
T ½ of norethindrone - 7 hrs
T ½ of norgestrel - 16 hrs
T ½ of gestodene - 12 hrs
T ½ of MPA – 24 hrs

Clinical uses
-HRT
-Contraception
-Long term ovarian suppression (dysmenorrhea, endometriosis and bleeding disorders)
-Delay premature labor
-Test of estrogen secretion

Adverse effects:
Increase BP
Reduce HDL level (more androgenic progestins)
May increase risk of Cancer
OTHER OVARIAN HORMONES
Androgens
- testosterone * (<200 mcg /24 hours)
- androstenedione
- dehydroepiandrosterone
- other hormones: inhibin and activin
relaxin

OTHER OVARIAN HORMONES: Inhibin

Αβ dimer : inhibits FSH
No direct effect on ovarian steroidogenesis

OTHER OVARIAN HORMONES: Activin

ββ dimer (increases FSH secretion)
Modulates the response to LH and FSH

OTHER OVARIAN HORMONES: Relaxin

Related to that of growth-promoting peptides
Similar to insulin
Found in ovary, placenta, uterus and blood
Synthesized in the luteinized granulosa cells of the corpus luteum
Increase glycogen synthesis and water uptake by the myometrium
Decrease uterine contractility

OTHER OVARIAN HORMONES

CRH
Follistatin
Prostaglandins

HORMONAL CONTRACEPTION
TYPES:
1. Combined estrogen and progestins
2. Continuous progestin therapy without concomitant administration of estrogen

COMBINATION AGENTS FORMS

-Monophasic
-Biphasic
-Triphasic

HORMONAL CONTRACEPTION (COC)

-Selective inhibition of pituitary function that inhibits ovulation
-Changes in cervical mucus, uterine endometrium, and motility and secretion in the tubes
-Depress ovarian function in chronic use
HORMONAL CONTRACEPTION (COC): Adverse Effects
Mild (nausea, mastalgia, breakthrough bleeding, edema, HA)
Moderate (breakthrough bleeding, weight gain, increase skin pigmentation,acne,
hirsutism,ureteral dilatation, bacteriuria vaginal infections, amenorrhea)
Severe (thromembolism, MI, CVA,GI disorders like cholestatic jaundice, depression,cancer risk,
alopecia, eruthema multiforme, erythema nodosum, other skin disorders)

HORMONAL CONTRACEPTION (COC):Contraindications

Thrombophlebitis
Thromboembolic phenomena
Cardiovascular and cerebrovascular disorders
Known or suspected estrogen dependent neoplasm
Fibroids
Adolescents
Rifampin

PROGESTIN ALONE CONTRACEPTION

Oral
Implant

For patients in whom estrogen administration is undesirable

150 mg depot of DMPA injection every 3 months

POSTCOITAL CONTRACEPTIVES
“morning after pill”

ESTROGEN AND PROGESTERONE INHIBITORS AND ANTAGONISTS:

Tamoxifen and related partial agonist estrogens
( Toremifine, Raloxifene, Clomiphene )
Mifepristone
Danazol
Other inhibitors
- testolactone, anastrozole, letrozole, exemestane, fadrozole, GNRH and its analogs

TAMOXIFEN
- competitive partial partial agonist inhibitor of estradiol at the estrogen receptor
- used in palliative treatment of advanced breast cancer in postmenopausal women
* SIMILAR WITH TOREMIFENE

RALOXIFENE
- partial agonist at some, but not all, estrogen receptors
- SELECTIVE ESTROGEN RECEPTOR MODULATOR

CLOMIPHENE
 - an older partial agonist, a weak estrogen that also acts as a competitive inhibitor of
endogenous estrogens
- used as an OVULATION INDUCING AGENT

MIFEPRISTONE
- 19-norsteroid that binds strongly to the progesterone receptor and inhibits the activity
of progesterone
- (+) luteolytic properties

DANAZOL
- an isoxazole derivative of ethisterone with weak progestational, androgenic, and
glucocorticoid activities
- used to suppress ovarian function vy inhibiting the midcycle surge of LH and FSH

ANDROGENS & ANABOLIC STEROIDS, ANTIANDROGENS:

TESTOSTERONE
* the most important androgen secreted by the testis
- produced by the Leydig cells (95%) and adrenals (5%)

OTHER ANDROGENS:
- dihydrotestosterone
- androstenedione
- dehydroepiandrosterone
- pregnenolone and progesterone and their 17-hydroxylated derivatives

TESTOSTERONE
Converted to dihydrotestosterone by 5 -reductase.

PHYSIOLOGIC EFFECTS:
- growth –promoting properties
- penile and scrotal growth
- male secondary sexual characteristics
- stimulate and maintain male sexual function.
-  lean body mass and stimulated body hair growth and sebum secretion.

TESTOSTERONE
- reduction of hormone binding and other carrier proteins
-  liver synthesis of clotting factors, triglyceride lipase, 1-antitrypsin, haptoglobin, and
sialic acid
- stimulate renal erythropoeitin secretion
-  HDL

TESTOSTERONE
 - rapidly absorbed after oral administration
- largely converted to inactive metabolites

MECHANISM OF ACTION:
- binds to intracellular androgen receptor - growth and differentiation and synthesis
of variety of enzymes and other functional proteins

CLINICAL USES:
Androgen replacement therapy in men
Gynecologic disorders
- reduce breast engorgement postpartum
- for the treatment of endometriosis
- for HRT
- for chemotherapy of breast tumors in premenopausal women
Protein anabolic agents
Anemia ( aplastic anemia )
Osteoporosis
Use as growth stimulators
Improving sports performance
For aging males to  lean body mass and hct and  in bone turnover

ADVERSE EFFECTS:
Masculinizing actions
- hirsutism, acne, amenorrhea, clitoral enlargement, deepening of voice
Endometrial bleeding upon discontinuation
Alter serum lipids,  susceptibility to atherosclerosis

ANDROGEN SUPPRESSION
GnRH analogs
- goserelin
- nafarelin
- buserelin
- leuprolide acetate
* Produce gonadal suppression
ANTIANDROGENS:
Steroid Synthesis Inhibitors
- Ketoconazole
Finasteride ( 5-reductase inhibitor; treat BPH and stimulate hair growth )
Receptor Inhibitors (used to treat excessive hair growth in women and prostate cancer in
men)
- Cyproterone and cyproterone acetate
- Flutamide
- Bicalutamide and nilutamide
- Spironolactone

CHEMICAL CONTRACEPTION IN MALES

Testosterone and testosterone enanthate: 400 mg per month will produce azoospermia
Testosterone enanthate 100 mg IM + Levonorgestrel 500 mg OD produce azoospermia
Cyproterone acetate produce oligospermia

GOSSYPOL
Cottonseed derivative
Destroys elements of seminiferous epithelium
20 mg/day of gossypol or gossypol lactic acid x 2 months followed by maintenance of 60
mg/week
AE: Hypokalemia

THANK YOU VERY MUCH AND HAVE A GOOD DAY.

GOD BLESS.