Physiology and Symptoms of Estrogen Deficiency
A woman's reproductive period lasts about 30–35 years and is characterized by the cyclic influence of sex hormones on target organs. By approximately 50 years of age, ovarian function fades, and its role in hormone synthesis becomes negligible. In menopause, the main source of estrogens (estrone and estradiol) is the peripheral aromatization of androstenedione, which takes place in adipose tissue and the adrenal glands.
Increasing estrogen deficiency triggers a cascade of menopausal disorders:
- Vasomotor: hot flashes, chills, hyperhidrosis, headaches, tachycardia, and blood pressure lability (hypo- or hypertension).
- Emotional-autonomic: irritability, anxiety, depressive states, fatigue, and decreased libido.
- Trophic: urogenital disorders (dryness, dysuria) and dermatological changes (skin dryness, wrinkles, brittle nails).
- Systemic metabolic: long-term consequences such as atherosclerosis, ischemic heart disease (IHD), and osteoporosis.
Goals of Therapy
The prescription of hormonal agents addresses two major goals:
- Therapeutic goal: rapid relief of current symptoms. This includes the correction of neurovegetative manifestations (sweating, hot flashes), elimination of psychological and cosmetic problems, and treatment of urogenital discomfort.
- Preventive goal: prevention of late systemic complications, primarily osteoporosis and cardiovascular diseases.
Historical Background
The evolution of approaches to treating menopause has a long history:
- Pre-scientific period: the first mentions of symptoms are found in Egyptian papyri (1500 BC).
- Beginning of scientific study: the first scientific treatise appeared in 1710 in Magdeburg. Later, in 1857, English gynecologist Edward John Tilt first linked menopausal symptoms to "ovarian involution."
- Era of organotherapy: in 1893, subcutaneous injection of ovarian extract was used for the first time to correct emotional disorders.
- Era of commercial preparations: in the 1920s–1930s, methods for obtaining estrogens were developed. In 1928, the first drug "Progynon" (a highly purified extract from pregnant mare urine) appeared in Germany. In 1942, "Premarin" (conjugated equine estrogens) was approved in the USA, marking the beginning of the widespread use of HRT.
Classification of HRT Medications
Depending on the clinical situation, different groups of hormones are administered orally or parenterally:
- Estrogen preparations: $17\beta$-estradiol in transdermal forms (patches, gels) and conjugated equine estrogens (Premarin).
- Combined preparations (estrogen + progestogen): combine estradiol with a systemic progestogen component. Examples include combinations with dienogest, levonorgestrel, cyproterone acetate, or $17\beta$-estradiol with drospirenone.
- Progestogen-like and tissue-specific preparations: tibolone, which exhibits tissue-specific activity.
Principles of Prescription: 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). Drugs are prescribed continuously or cyclically (with a 7-day break) orally or transdermally.
Combination therapy is mandatory if the uterus is intact (conserved). Using estrogens alone in this case sharply increases the risk of endometrial hyperplasia and cancer. The addition of a progestogen protects the mucosal lining from excessive proliferation and induces its secretory transformation. The most pronounced secretory effect is provided by dienogest and levonorgestrel.
Pharmacology of Tibolone
Tibolone deserves special attention as a drug used in monotherapy that does not require additional estrogen administration.
By nature, it is a prodrug. After oral administration, it is metabolized into 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.