Gonadal steroid pharmacology Flashcards
Estrogen
Estrogen synthesis primarily takes place in the ovarian granulosa cells.
- LH stimulates androgen synthesis in ovarian theca cells. Androstenedione
- FSH stimulates aromatase enzyme and thus the conversion of androgens to estrogens.
Estrogen is also produced in other aromatase-containing tissues:
- Adrenal glands
- Fatty tissue
- Placenta
- Testicles
Types of estrogen: estradiol, estrone, estriol
Potency: estradiol > estrone > estriol
Production pathway for progesterone
Hypothalams > GnRH > anterior pituitary > LH > corpus luteum > progesterone
Menstrual cycle
- Pre ovulatory phase: menstruation and endometrial and spiral artery gowth
- Ovulation: FSH and LH are high, “LH surge”
- Luteal phase: corpus luteum then corpus albican
Estrogens on bone tissue
They inhibit osteoclasts growth and differentiation.
-> low estrogen, led to an increase in bone resorption and increased risk of bone fracture and/or osteoporosis
Estrogens on the liver
- Suppress glucose production
- Decrease lipid accumulation (lipid profile towards HDL, less LDL) ->reduced atherosclerotic events
- Decrease inflammation
Estrogens on the vascular tone
ER once activated lead to downstream pathways that in turn lead to NO production (eNOS) -> increase vasodilation
Therapeutic uses for gonadal steroid hormones
- Fertility (ovulation induction)
- Hormonal contraception (ovulation inhibition)
- Primary hypogonadism and precocious puberty
- Menopause
- Osteoporosis
Hormonal contraceptive: composition and mechanism of action
Use of estrogen and progestin analogs to prevent pregnancy.
Estrogen
- Hypothalamus: ↓ release of GnRH
- Pituitary: ↓ LH → inhibits ovulation, ↓ FSH → prevents ovarian folliculogenesis
Progestin
- Inhibits GnRH and LH secretion → suppresses ovulation (main contraceptive mechanism)
- Inhibits endometrial proliferation
- Changes cervical mucus (↓ volume and ↑ viscosity) and impairs fallopian tube peristalsis → inhibition of sperm ascension and egg implantation
- Inhibits follicular maturation
Antiprogestin: inhibits or delays ovulation by inhibiting the progesterone receptor
Oral contraceptives (OCs) are the most common form of hormonal contraception, but other forms of hormone delivery, including patches, injections, and implants, also exist.
Hormonal contraceptive: side effects
Estrogen:
- Venous thromboembolism (VTE): increased rate due to estrogen-mediated coagulopathy
- Cardiovascular events
- Hypertension: risk increased in patients with history of HTN during a pregnancy and/or family history of HTN
- Headaches
- Hepatic adenoma development
- Mastopathy and mastodynia
- Nausea
- Leg cramps
- Uterine cramps
Progestin:
- Breakthrough bleeding
- Follicular cysts
- Acne
- Hirsutism (mild)
- Decrease in libido
- Increase in appetite
Selective estrogen receptor modulators: mechanism of action and indication
A class of drugs that has competitive agonist effects on the estrogen receptor. Depending on the tissue, SERMs may produce either estrogenic (bone, liver, blood, uterus) or antiestrogenic effects (breast, periphery). Common uses include ovulation induction, contraception, osteoporosis treatment, breast cancer treatment, and vaginal atrophy.
Selective estrogen receptor modulators: examples
- Tamoxifene: ttt of metastatic breast cancer or after mastectomy
- Raloxifene: osteoporosis in postmenopausal women
both have similar action:
Estrogenic - Bone: decrease resorption and fracture risk
- Liver: decrease in LDL and total cholesterol
- Blood: increase DVT, PE
- Uterus: increase in endometrial proliferation (Tamoxifen only)
Antiestrogenic - Breast: decrease breast cancer cell proliferation
- Periphery: hot flushes, vomiting
- Clomiphene: ttt of infertility in both sexes. inhibit ER at the hypothalamus -> inhibit negative feedback -> increase GnRH secretion -> increase LH and FSH -> increase ovarian stimulation -> ovulation
- Ospemifene: painful sexual intercourse related to menopause
GnRh agonists and antagonists: mechanism of action, indications
The GnRH agonists are more potent and have got a longer half-life than native GnRH. They produce an initial stimulation of pituitary gonadotrophs that results in secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and the expected gonadal response. This response is followed by down-regulation and inhibition of the pituitary-gonadal axis. As compared to GnRH agonists, GnRH antagonists promptly suppress pituitary gonadotropin by GnRH-receptor competition, thereby avoiding the initial stimulatory phase of the agonists.
Agonists are used for assisted reproductive therapy
GnRH analogues indications: management of endometriosis, uterine leiomyomas, hirsutism, dysfunctional uterine bleeding, premenstrual syndrome, assisted reproduction, and some hormone-dependent tumors.
Hormone replacement therapy: use, types, routes
HRT is usually employed for the short-term treatment of menopausal symptoms.
Leads to a reduction in oseoporotic fractures.
Types
- Estrogen therapy: for women who have had a hysterectomy
- Estrogen plus progestin therapy: for women with a uterus. reduction of endometrial hyperplasia.
Routes: oral, transdermal
Menopause
Time at which menstruation ceases permanently.
Confirmed after 12 months of amenorrhea.
The average age at menopause is ∼ 49–52 years.
↓ Ovarian function → ↓ estrogen and progesterone levels → loss of negative feedback to the gonadotropic hormones → ↑ GnRH levels → ↑ levels of FSH and LH in blood (hypergonadotropic hypogonadism) → anovulatory cycles become more and more frequent → progressive follicular depletion → ovarian function eventually stops permanently
In menopausal women, estrogens are mainly produced by peripheral aromatase conversion of adrenal androgens in adipose tissue. Therefore onset of menopause might be delayed and symptoms might be milder in obese women
Clinical features leading up to menopause include irregular menses, autonomic symptoms (e.g., hot flashes), mental symptoms (e.g., mood swings), and atrophic features (e.g., reduced breast size, vaginal atrophy).
Estrogen receptors
Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors, which are mostly G protein-coupled receptors. The latter leads to the activation of protein-kinase cascades leading to the phosphorylation of target transcription factors -> trascriptional activation and/or modulation of transcriptional activity.
Activated by estrogens but also GFs can bind to a specific transmembrane receptors that induce then phopshorylation of differet sites on the ER.
