62. Estrogens, antiestrogens, progestins, antiprogestins

Page created on September 18, 2019. Last updated on January 7, 2022 at 22:30

Pharmacology of oestrogens

Oestrogens have some uses in pharmacology. The important oestrogens are:

• Natural oestrogens
  • Estradiol
  • Estriol
  • Estrone
• Semi-synthetic
  • Ethinyl estradiol
  • Estradiol valerate

Oestrogens elicit the following effects:

• Induction of primary and secondary female sex characteristics
• Induction of the proliferative phase of the menstrual cycle
• Hyperplasia of endometrium
• Increased expression of progesterone receptor
• Preparation of the mammary gland for lactation
• Vasodilation
• Mineralocorticoid-like Na⁺ and water retention
• Hepatic effects
  • Increased vitamin K-dependant factor production
  • Increased platelet aggregation
  • Increased fibrinolysis
  • Increased hepatic protein synthesis
  • Increased HDL levels
  • Decreased LDL levels
  • Altered bile composition (less bile acids, more cholesterol)

Mechanism of action:

Like all steroid hormones, oestrogens act mostly via intracellular receptors called ER-α and ER-β. Oestrogens also act via a surface-bound G-protein coupled receptor called G-protein coupled [o]estrogen receptor (GPER). This receptor accounts for the faster effects of oestrogens, like vasodilation.

Indications:

Hypogonadism, postmenopausal replacement therapy, contraception, menstrual bleeding disorders and acne. In most cases the oestrogen is combined with a progestin, a synthetic form of progesterone.

Dosage:

Most oestrogens are available as oral formulations and as vaginal formulations (tablet or cream). Estradiol is also available as a transdermal patch, nasal spray and gel. Oral preparations have increased hepatic effects compared to parenteral preparations.

Pharmacokinetics:

Oestrogens have good oral absorption, but some of them have high first-pass metabolism, which increases their hepatic effects and decreases their other effects. Ethinyl estradiol and estradiol valerate have no first-pass metabolism.

Estradiol binds to sex hormone-binding globulin (SHBG) and albumin, while synthetic and semisynthetic oestrogens bind only to albumin.

Some oestrogens, especially the natural ones, undergo enterohepatic circulation.

Side effects:

Increased risk of venous thrombosis, cholestasis, elevated plasma triglyceride levels, uterine bleeding and worsening of endometriosis are the most important side effects. The first three are more common in oral treatment, due to the high first-pass metabolism.

There is also an increased risk of endometrial hyperplasia or cancer. This risk is eliminated if a progestin is given concurrently. There is also an increased risk of breast cancer, the risk of which is increased with concurrent administration of progestins.

Contraindications:

Oestrogens shouldn’t be used in people with current, previous or with a family history of oestrogen-sensitive cancers.

Antioestrogens and selective oestrogen receptor modulators

Antioestrogens and selective [o]estrogen receptor modulators (SERMs) both have antioestrogen effect. Antioestrogens are pure oestrogen receptor antagonists, but SERMs are partial agonists in some tissues and antagonists in other tissues. This allows SERMs to have antioestrogen effects in some tissues but mild oestrogen-like effects in other tissues. This is illustrated in the table below.

Drug	Drug type	ER+ Breast cancer proliferation	Endometrium proliferation	Effect on bone density	LDL level decrease
Estradiol	Natural oestrogen	+++	+++	+++	+++
Tamoxifen	SERM	–	+	+	+
Raloxifene	SERM	–	–	+	+
Lasofoxifene	SERM	–	–	++	++
Clomiphene	Antioestrogen	–	–	–	–
Fulvestrant	Antioestrogen	–	–	–	–

As is visible from the table, SERMs have some oestrogen agonists effects while antioestrogens have no such effects.

Indications:

Tamoxifen and fulvestrant are used to treat oestrogen receptor positive breast cancer.

Raloxifene and lasofoxifene are used to treat osteoporosis.

Clomiphene is used to induce ovulation in people with anovulation, for example due to polycystic ovary syndrome.

Mechanism of action:

Clomiphene inhibits oestrogen binding in the anterior pituitary, thereby preventing the negative feedback effects of oestrogen. This increases the secretion of GnRH and gonadotropin, which stimulates the ovaries and induces ovulation.

Side effects:

Tamoxifen is an agonist in the endometrium and haemostasis, enhancing the risk of endometrial cancer and venous thromboembolism. Raloxifene is an agonist for haemostasis, increasing the risk for venous thromboembolism.

Selective aromatase inhibitors

Aromatase converts androgen precursors to oestrogens in the ovaries and adipose tissue, so these drugs inhibit oestrogen biosynthesis. The important ones are anastrozole, letrozole and exemestane. Exemestane is unique among these drugs in that it is an irreversible inhibitor of aromatase.

Indications:

Selective aromatase inhibitors are used to treat oestrogen-sensitive breast cancer and for induction of ovulation.

Progestins

The progestogens are a class of steroid hormones that bind to the progesterone receptor. The most important endogenous progestogen is already known progesterone.

Synthetic progestogens are called progestins. The important progestins are progesterone, medroxyprogesterone, desogestrel, megestrol, norethisterone and (levo)norgestrel.

Indications:

Progestins, together with an oestrogen, is used in substitution therapy in hypogonadism and postmenopausal replacement therapy.

Progestins with or without an oestrogen is used as hormonal contraception, in menstruation bleeding disorders and in endometriosis.

Progestins without an oestrogen is used to treat early puberty in girls, metastatic oestrogen-dependent breast and endometrial cancer and to prevent preterm birth.

Mechanism of action:

Like all steroid hormones progestins act by binding to an intracellular receptor called progesterone receptor (PR). Binding to this receptor alters gene expression. Progestins (like progesterone) decrease the expression of the oestrogen receptor, thereby causing an anti-oestrogen effect.

Dosing:

Progesterone is available as a tablet, i.m. injection, intravaginal preparations and in intrauterine devices. Progestins are available as tablets, i.m. injections or intravaginal preparations.

Pharmacokinetics:

Progesterone itself has almost 0% oral bioavailability due to significant first-pass metabolism, but advanced formulations exist that increase the oral bioavailability. Progestins have longer half-lives and higher oral bioavailability.

Side effects:

Some progestins have weak androgenic effects, potentially causing oedema, acne and dyslipidaemia. Other side effects include headache, breast swelling and tenderness, depression and abnormal uterine bleeding.

Antiprogestins

Antiprogestins are recently known as selective progesterone receptor modulators (SPRMs). The important drugs here are mifepristone and ulipristal (acetate). They are partial agonists at the progesterone receptors.

Indications:

Mifepristone is most commonly used together with a prostaglandin analogue like gemeprost or misoprostol to terminate early pregnancy. The prostaglandin analogue is given 48 hours after the mifepristone.

Ulipristal is used as emergency postcoital contraception. It is also used to treat uterine myomas.

Mechanism of action:

Mifepristone upregulates prostaglandin receptors in the uterus, sensitizing it to the prostaglandin analogues given 48 hours later. These prostaglandins induce strong uterine contraction, which initiates medical abortion.