Hormone replacement therapy in menopause

Physiology and symptoms of estrogen deficiency

A woman's reproductive period lasts about 30–35 years and is characterized by the cyclical influence of sex hormones on target organs. By approximately age 50, ovarian function fades, and its role in hormone synthesis becomes negligible. In menopause, the primary source of estrogens (estrone and estradiol) is the peripheral aromatization of androstenedione, which takes place in adipose tissue and the adrenal glands.

Progressive estrogen deficiency triggers a cascade of climacteric disorders:

• Vasomotor: hot flashes, chills, hyperhidrosis, headaches, tachycardia, and blood pressure lability (hypo- or hypertension).
• Emotional-autonomic: irritability, anxiety, depressive states, weakness, and decreased libido.
• Trophic: urogenital disorders (dryness, dysuria) and dermatological changes (dry skin, wrinkles, brittle nails).
• Systemic metabolic: long-term consequences in the form of atherosclerosis, coronary artery disease (CAD), and osteoporosis.

Goals of therapy

The administration of hormonal drugs addresses two global objectives:

1. Therapeutic goal: rapid relief of current symptoms. Includes correction of neurovegetative manifestations (sweating, hot flashes), elimination of psychological and cosmetic problems, and treatment of urogenital discomfort.
2. Preventive goal: prevention of late systemic complications, primarily osteoporosis and cardiovascular diseases.

Historical background

The evolution of approaches to treating menopause has come a long way:

• Pre-scientific period: the first mentions of symptoms are found even in Egyptian papyri (1500 BC).
• Beginning of scientific study: the first scientific work appeared in 1710 in Magdeburg. Later, in 1857, English gynecologist Tilt first linked climacteric symptoms to "ovarian involution."
• Era of organotherapy: in 1893, a subcutaneous injection of ovarian extract was first used to correct emotional disorders.
• Era of commercial drugs: the 1920s–1930s marked the beginning of methods for obtaining estrogens. In 1928, the first drug "Progynon" (a highly purified extract from pregnant women's urine) appeared in Germany. In 1942, "Premarin" (conjugated equine estrogens) was registered in the USA, marking the beginning of the widespread use of HRT.

Classification of HRT drugs

Depending on the clinical situation, various groups of hormones are used orally or parenterally:

• Estrogen preparations: $17\beta$-estradiol in transdermal forms (Climara patch, Estrogel and Divigel gels) and conjugated estrogens (Premarin).
• Combined preparations (estrogen + progestogen): combine estradiol with a systemic progestogenic component. Examples of combinations: with dienogest (Climodien), with levonorgestrel (Climonorm), with cyproterone (Climen), and $17\beta$-estradiol with drospirenone (Angeliq).
• Progestogen preparations: tibolone (Livial), which possesses tissue-specific activity.

Prescription principles: monotherapy vs. combination

The choice between pure estrogens and a combination strictly depends on whether the patient has a uterus.

Estrogen monotherapy is indicated exclusively for women with a removed uterus (history of hysterectomy). The drugs are prescribed continuously or cyclically (with a 7-day break) orally or transdermally.

Combination therapy is mandatory if the uterus is intact (preserved). The use of estrogens alone in this case sharply increases the risk of endometrial hyperplasia and cancer. The addition of a progestogen protects the mucous membrane from excessive proliferation and induces its secretory transformation. The most pronounced secretory effect is produced by dienogest and levonorgestrel.

Pharmacological features of tibolone

Special attention should be given to tibolone, a drug used as monotherapy that does not require the additional administration of estrogens.

By its nature, it is a prodrug. After oral administration, it is metabolized to form compounds possessing three types of activity simultaneously: estrogenic, progestogenic, and androgenic. The androgenic component provides additional clinical effects: improves well-being, weakens hot flashes, and enhances sexual desire (libido).

At the same time, tibolone is safe for the mammary gland. It exerts an antiproliferative effect due to the selective inhibition of the sulfatase enzyme in breast tissue. This disrupts the desulfation of estrone and blocks the formation of its metabolically active form.

Class and exam questions

What else to study on this topic

• Mechanisms of vasomotor disorder development in estrogen deficiency
• Pharmacokinetics of transdermal $17\beta$-estradiol formulations
• Comparative characteristics of progestogens (dienogest, levonorgestrel, drospirenone) in HRT composition
• Mechanism of action of raloxifene in the prevention of postmenopausal osteoporosis

Other topics in the section "Hormone preparations, their synthetic substitutes, and antagonists"

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