Estrogens

Oestrogens or estrogens (from Greek oestrus = sting, passion, and lat. gignere=produce), also called follicle hormones, are, besides the gestagens, the most important female sex hormones from the class of steroid hormones. They have an estran molecule as their basic structure (13β-methyl-gonan). Estradiol and the estrogens -estrone and estriol, which occur in steroid metabolism as precursors and/or metabolites, are effective as natural estrogens. The aromatized ring A and the beta-OH group at C3 and C17 are decisive for the effect of the estrogens. The natural oestrogens are converted during the liver passage into the weakly effective oestrogens estrone and estriol (first pass effect), which explains its low bioavailability. The introduction of an ethinyl residue at C17 results in a metabolically stable compound, ethyinyl estradiol, which is much more readily available orally and is eliminated metabolically (via CYP3A4) much more slowly than estradiol.

Estrogens are mainly produced in the ovaries in follicles and in the corpus luteum, to a lesser extent also in the adrenal cortex. They are mainly produced by converting testosterone into estradiol, a process catalysed by the enzyme aromatase. During this process, the ring A with the C atoms 1 to 5 and 10 of the sterol skeleton is converted into an aromatic structure. Estrogens are also generated on a small scale in the male test. Furthermore, a part of the testosterone in the fatty tissue is converted into estrogens by an aromatase.

Progestogenic hormones: expression of progesterone receptors ↑ , therefore progestagenic effect

Menstrual cycle: follicle maturation phase: FSH release ↓ ; mid-cycle (estradiol level> 200pg/ml):Gonadotropinfreisetzung↑ (LH peak with ovulation); corpus luteum phase: (estradiol level 100pg/ml), together with progesterone inhibition of gonadotropin action

Female reproductive organs: growth of the reproductive organs and development of secondary sexual characteristics during puberty.

Maintenance of pregnancy (together with progesterone)

Proliferation and differentiation of the Endometriums↑

Proliferation and differentiation and motility of Tuben↑

Contractility of the Myometriums↑

Formation of a low-viscosity Zervikalsekretes↑

Female mammary gland: mammary gland proliferation and breast growth (together with progesterone)

Bone: Feminine physique, bone growth in the Pubertät↑ , end of the epiphyseal fugues (end of growth);

Pituitary gland: Estrogens signal the pituitary gland to the egg cell maturity and thus indirectly trigger ovulation.

Immune system: Estrogens also have a stimulating effect on the immune system, so estrogen therapies sometimes have the side effect of activating latent autoimmune diseases.

Liver: Synthesis of all hormone-forming plasma globulins ↑so e.g. sex hormone, corticosteroid and thyroxine-binding globulin)

CRP-Bildung↑, Angiotensinogen-Bildung↑

Changes in bile composition: Gallensäuren↓, Cholesterol↑(Gallensteinbildung↑)

Blood coagulation: formation of coagulation factors I, II, VII, IX, XII↑

Formation of the anticoagulant factors Protein C, S, antithrombin III↓

Fibrinolytic activity of Blutes↑ (reduced formation of plasminogen activator inhibitor 1 (PAI-1) in vascular endothelial cells.

Cardiovascular system: vasodilatation due to endothelial NO and prostacyclin-Bildung↑in arterial vessels (Organdurchblutung↑)

Expression of vascular AT1-Rezeptoren↓

Metabolism: Serum-Triglyzeride↑, HDL-Cholesterol↑, total cholesterol and LDL-Cholesterol↓, water content of the skin and many Schleimhäute↑

Hearing: Oestrogens increase the sensitivity of the brain to hearing, whereas a reduced oestrogen level, for example after menopause, worsens hearing.

Intellectual performance: The hormone is essential for the storage of the memory content of sounds and speech.

Synthetic estrogens are used primarily to inhibit ovulation as part of hormonal contraception. Due to the uncertain oral availability, numerous well effective transdermal estradiol preparations have been developed in the past.

The following estrogens are used in therapy: estradiol esters, such as estradiol benzoate, estradiol valerate, mestranol, ethinyl estradiol and the prodrug tibolone, which is used in osteoporosis therapy.

Disease associations: As a side effect of estrogen preparations, erythema nodosum, pruritus and erythema multiforme may occur.

The side effects of estrogen-containing drugs are mainly due to their hormonal effect - and are therefore correspondingly diverse and individually very different in severity. The side effects tend to be less pronounced when using transdermal patches than when taking them. The most common side effects of estrogens are menstrual problems with bleeding, headaches, gastrointestinal complaints, oedema and psychological changes such as mood swings, increase or decrease in sexual desire, restlessness, nervousness or depression.

Further:

• thromboses (arterial and venous)
• Gall bladder diseases: risk of cholecystitis and Cholelithiasis↑.
• Dermatological complications: exanthema, erythema nodosum, urticaria, hyperpigmentation(melasma); systemic lupus erythematosus (SLE)

The metabolism of estrogens can be increased by CYP inducers. These include anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine), anti-infectives (e.g. rifampicin, rifabutin, nevirapin, efavirenz) and St. John's wort (Hypericum perforatum). Ritonavir and nelfinavir, when used concomitantly with steroid hormones, have inducing properties, although they are actually known to be potent inhibitors.

Clinically, an increased metabolism can lead to a reduced effect of estradiol and thus to changes in the uterine bleeding pattern.

Clinically relevant drug interactions are unlikely in vaginal use of estrogens, as only minimal systemic absorption is expected.

Transdermal application bypasses the first-pass effect in the liver, so transdermally applied estrogens may be less affected by enzyme inducers.

Drugs that inhibit the action of metabolizing enzymes, such as ketoconazole and cyclosporine, may enhance the effect of estrogens.

Smoking has an anti-oestrogenic effect because by inducing CYP1A2 it accelerates the breakdown of estriol and thus reduces its effect.

Critically, due to the proliferative effects of estrogens, their increased cancer risk must be considered. This applies to the following malignant tumours: Endometriumkarzinome↑; Mammakarzinome↑, Ovarialkarzinome↑ (risk increased if estrogens are taken after the menopause >5 years); Leberzelladenome↑.

Existing or previous breast cancer or suspicion thereof

Oestrogen-dependent malignant tumour or a corresponding suspicion (e.g. endometrial carcinoma)

Diagnostically not clarified bleeding in the genital area

Untreated endometrial hyperplasia

Previous or existing venous thromboembolic diseases (deep vein thrombosis, pulmonary embolism)

Known thrombophilic diseases (e.g. protein C, protein S or antithrombin deficiency)

Existing arterial thromboembolic diseases or those that occurred only recently (e.g. angina pectoris, myocardial infarction)

Acute liver disease or past liver disease as long as the relevant liver enzyme values have not normalized

Porphyria diseases

Pregnancy/nursing period

• Estrogens are contraindicated in pregnancy. If pregnancy occurs during treatment with estradiol, treatment should be discontinued immediately.
• No teratogenic or fetotoxic effects are to be expected if the fetus is accidentally exposed to estrogen.
• Lactation: Estrogens are contraindicated during lactation.

At the age of about 45-50 years the production of hormones in the ovaries ceases, first there is a decrease in progesterone and estradiol, later the production of male sex hormones (testosterone, androstendione) also stops. The estrogen deficiency causes typical menopausal symptoms such as hot flushes, dizziness, sweating, depression and anxiety.

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4. Wilkinson HN et al. (2017) The role of estrogen in cutaneous ageing and repair. Maturitas 103:60-64.