M4: Gonadosteroids Flashcards
Gonadal Hormones
FEMALE Sex Hormones:
1. Estrogens: develop and female sexual characteristics
- Progestins: control of ovarian cycle and maintain pregnancy
MALE Sex Hormones:
1. Androgens = develop and male sexual chracterisitics
Types of Estrogens
- Natural (Endogenous):
Drug:estradiol = secreted by ovaries - Semisynthetic
Drug: thinylestradiol → inactive prodrug
- Estradiol valerate - Synthetic
Drug: Mestranol and Stilboestrol
*Pharmacokinetics of Estrogens
Absorption Through:
- GIT
- Skin
- Mucous membranes (e.g., vaginal pessaries)
Transport by Binding to:
- Albumin
- Sex steroid-binding globulin
Half-life: 13 hours
Metabolism and Degradation:
- In the liver
- Synthetic estrogens are less prone to degradation than natural
- Excretion through kidneys in urine
Therapeutic Indications of Estrogens
Contraception in females
Replacement therapy (estrogen deficiency):
- Menopausal symptoms (hormone replacement therapy; HRT)
- Female hypogonadism
Menstrual Disorders: e.g., menorrhagia
Acne
Prostatic cancer – anti-androgen effect
Female HYPOgonadism
Due to impaired ovarian function
Types:
- Pre-pubertal → delayed puberty
- Post-pubertal → secondary amenorrhea and infertility
Treatment of Primary Hypogonadism:
- Begins at 11-13 years of age
- Stimulate development of secondary sex characters and menstruation
- Stimulate optimal growth
Small doses of estrogen on days 1 to 21 of each month (mimic normal cycle)
HYPERestrogenemia
Increased estrogens levels
In males →
- Feminization e.g., gynaecomastia, soft voice, …
- Infertility
In females →
- Endometrial carcinoma (progestins reduce the risk)
- Breast cancer (effect of progestins unknown)
Antiestrogens
- Tamoxifen:
- Potent estrogen receptor blocker in breast tissue
- Used in the treatment of hormonally responsive breast cancer:
Treatment following unilateral excision of breast cancer reduces risk of cancer in the second breast
- Clomiphene:
- Selective estrogen receptor modulator (SERM):
- Inhibits estrogen-mediated negative feedback on hypothalamus → Ovulation Induction: used in the treatment of infertility due to ovulation disturbances
- Letrozole:
Aromatase enzyme Inhibitor → decrease estrogen synthesis
Indications:
- Hormonally responsive breast cancer
Only in post-menopausal women
- Ovulation induction – treatment of infertility (less chance of twins)
- Gynecomastia in men
Androgens
PROGESTINS:
- Types
- Therapeutic Indications
TYPES OF PROGESTINS
1. Natural (endogenous):
Drug = Progesterone: secreted by corpus luteum and placenta
- Synthetic:
1st generation compounds:
Drugs: Medroxyprogesterone, norethindrone, norgestrel
2nd generation compounds:
Drug: Levonorgestrel
3rd generation compounds:
Drugs: Desogestrel, gestodene, norgestimate
- Least androgenic effect
THERAPEUTIC INDICATIONS:
- Contraception in females
- Hormone replacement therapy (HRT)
Endometriosis (functional endometrial tissue outside the uterus)
- Endometrial carcinoma
- Dysmenorrhea (painful menstruation)
- Menstrual disorders
ANTIprogestins
Mifepristone (RU-486):
Mechanism: progesterone receptor blocker
Indication:
- Therapeutic abortion: alone = 70%
- Combined with prostaglandins → PGE 1 or 2: 95%
3 Hormonal Contraception Drugs
- Oral Contraceptives (OCC)
- Injections and implants
- Transdermal patch
*ORAL CONTRACEPTIVES (OCC)
- Combined OCC: combination of estrogen and progestin
Most popular
Types:
- Monophasic: fixed dose
- Bi- or triphasic: variable dose - Progestin Minipill = low dose progestin
Examples of OCC:
1. Monophasic
- estrogen = ethinyl estradiol
- progestin = desogestrel
- Triphasic
- estrogen = ethinyl estradiol
- progestin = desogestrel
Combined OCC are taken daily for 21 days and stopped for 7 days
‡ Minipill is taken daily without a break
Oral Contraceptives (OCC)
- Mechanism of Action
- Adverse Effects of Combined OCC
- Contraindication of Combined OCC
MECHANISM OF ACTION:
Estrogen-Progestin Combinations:
- Suppress ovulation: decrease GnRH from hypothalamus → decreases FSH & LH from pituitary
- Thicken cervical secretions (not optimal for sperm migration)
- Inhibit implantation
Low-Dose Progestin:
- Thicken cervical secretions (not optimal for sperm migration)
- Inhibit implantation
- Variable suppression of ovulation by effect on FSH/LH
ADVERSE EFFECTS OF COMBINED OCC:
1. Salt and water retention → edema → hypertension
- Vascular Disorders:
- Thromboebolic – coronary / cerebrovascular disease
- Higher risk in smoker women above 35 years - Headache – migraine
- Depression
- Postpill amenorrhea
CONTRAINDICATIONS OF COMBINED OCC:
1. Absolute:
- Pregnancy
- Breast feeding
- Thromboebolic disease: coronary artery disease + cerebrovasular disease
-Breast/cervical/endometrial cancer
- Undiagnosed vaginal bleeding
- Relative:
- Hypertension
- Impaired liver function
- Migraine
Contraceptive Injections and Implants
Long acting progestins
Injections:
- IM injection every 3 months
- Drug = Medroxyprogesterone (provera)
Implants:
- SC insertion of small capsules
- Effective for 3 – 5 years
- Drug = Levonorgestrel (norplant)
Hormone Replacement Therapy
Estrogen replacement in postmenopausal woman
- Low dose compared to contraceptives
Progestin can be added to reduce the risk of endometrial carcinoma
Benefits:
- Prevention of changes associated with menopause:
- Osteoporosis (decrease in bone mass)
- Flushing, headaches and insomnia
- Genital tract atrophy
- Cardiovascular disease (improvement of lipid profile)
Types of ANDROGENS
- Natural (Endogenous):
- Testosterone
- Dihydrotestosterone (DHT)
- Dehydroepiandrosterone (DHEA)
- Androstenedione - Synthetic:
- Methyltestosterone
- Ethyloestrenol
- Stanozolol
ANDROGENS:
- Actions
- Therapeutic Indications
MECHANISM OF ACTION OF ANDROGENS:
- Regulate gene expression by activating a nuclear receptor
EFFECTS:
- Development of primary & secondary male sex characters
- Maturation of sperms
ANABOLIC EFFECT:
- Some synthetic androgens have more anabolic than androgenic activity (e.g., stanozolol)
THERAPEUTIC INDICATIONS:
1. Hormone replacement:
- Male hypogonadism
- Hypopituitarism
- Anemia refractory to treatment:
- Androgens stimulate erythropoiesis - Breast cancer (estrogen- or progestin-receptor positive):
- Androgens downgrade receptor expression - Anabolic Agents:
- Compensate for protein loss: e.g., after surgery or immobilization
- Often abused by body builders and athletes …
Male Hypogonadism
Types:
- Primary: testicular failure
- Secondary: hypothalamic-pituitary disease
Treatment: androgen replacement
- Stimulate development of male secondary sex characters
- Maintain muscle and bone mass
Regimen:
- Oral: TDS
- Transdermal patch: every 24 hours
- IM injection: every 2-3 weeks
- Subdermal implants: every 4-6 months
Hyperandrogenemia
In females:
- Virilization symptoms: hirsutism, acne, amenorrhea, clitoral enlargement and deepening of voice
- During pregnancy: masculinization of external genitalia of infants
In prepubertal male children:
- Precocious puberty
4 Anti-Androgens
- Androgen suppressors
- Androgen receptor inhibitors
- Estrogens
- Progestins
Androgen Surpressors
Drug = Leuprolide Acetate
Mechanism:
GnRH analog – interrupts GnRH receptors →
Decrease FSH & LH (in males or females) →
Decrease testosterone or estrogen to ±10% of basal levels
Used to Treat:
- Prostatic carcinoma
- Endometriosis
- Breast cancer
Administration: IM or SC injection every 1, 3, 4 or 6 months
Androgen Receptor Inhibitors
Drug = Cyproterone Acetate
Mechanism:
- Androgen receptor competitive antagonist
- Progestin action
Used to Treat:
- Prostatic carcinoma
- Precocious puberty in boys
- Acne
- Hirsutism and virilization in women
Adverse effects:
- Hepatotoxic
Administration: oral
Male Oral Contraceptive
Drug = Gossypol:
Derived from seeds of cotton plant
Action:
- Inhibition of sperm production
- Efficacy is comparable to the female OCC
Adverse effects:
- Irreversibility
- Hypokalemia
