Sex Hormones – Testosterone, Progesterone, and Oestrogens

The term androgens refers to the group of male sex hormones. The best-known of these is testosterone, which acts as an endocrine messenger regulating various bodily functions. This hormone ensures the functionality and development of male reproductive organs and is responsible for anabolic cell growth. Production primarily occurs in the Leydig cells of the testes under the influence of LH (luteinising hormone) and is transported via the bloodstream to target organs such as the reproductive organs, skin, muscle and fat tissue, bones, liver, and prostate. However, testosterone production is not confined to the male gonads: small quantities are also formed in the adrenal glands—both in men and women—and in the female ovaries. Detectable serum concentrations in women are only a fraction of those in men. After reaching the target organs, testosterone acts either as an independent hormone or as a precursor to further bioactive metabolites, each with specific physiological functions in a finely tuned balance (see Figures 1 and 2). This balance is determined by the activity and quantity of specific enzymes. If their production is disrupted, this can lead to hormonal dysregulation, potentially causing androgen- or oestrogen-related diseases in both sexes.

In the male body, the enzyme 5α-reductase typically dominates. It can amplify the androgenic effect of testosterone tenfold. Therefore, 5α-reductase activity essentially determines the function of male reproductive organs, male body morphology, and various aspects of metabolism such as fat and glucose metabolism. The activity of 5α-reductase can be determined in the laboratory by measuring the testosterone to dihydrotestosterone ratio in the blood.

The physiologically low testosterone serum level in women is due to the dominant aromatase-mediated breakdown of testosterone into oestradiol. In addition to the already low testosterone production in women, its androgenic effect is further diminished by this conversion. Aromatase activity can be calculated by determining the testosterone/oestradiol ratio in urine.

Oestrogens are steroid hormones with 18 carbon atoms, synthesised from cholesterol via androgen precursors primarily in the ovaries. In postmenopausal and obese women, oestrogens are increasingly produced in fat and muscle cells through elevated aromatase (CYP19) activity. In the blood, they are largely bound to globulins (sex hormone-binding globulin = SHBG) and albumin, with only 1–2% circulating in free form. A premenopausal woman produces between 30 and 300 µg of oestradiol (E2) daily, depending on the menstrual cycle. The majority is converted to the metabolite oestrone (E1) or, during pregnancy, to oestriol (E3). Oestrogen metabolites can be biochemically classified as either protective or potentially mitogenic/mutagenic.

Men produce around 20–50 µg of oestradiol daily, with levels remaining relatively constant into old age. In comparison to fertile men, subfertile men often exhibit reduced oestradiol levels. Assessing the full oestrogen metabolism allows for the evaluation of potentially carcinogenic vs. protective oestrogens, offering insight into an individual's potential risk. This assessment is not intended to provide a definitive cancer prognosis but to help healthcare providers identify risk factors early and develop preventative strategies with patients.

The effects of progesterone extend well beyond pregnancy maintenance. It also has diuretic, blood pressure-lowering, and antithrombotic effects. Notably, it stabilises the central nervous system, with the metabolite allopregnanolone exhibiting antidepressant and neuropsychiatric stabilising properties.

Symptoms of low progesterone levels do not necessarily indicate an absolute deficiency. Many women experience an imbalance between oestrogen and progesterone, known as oestrogen dominance, where excessive oestrogen causes the symptoms. Common symptoms associated with progesterone deficiency (or oestrogen dominance) include:

• Premenstrual syndrome (PMS)
• Menstrual and cycle irregularities (spotting, polymenorrhoea, short cycles)
• Tendency towards oedema (especially in the face and hands) / weight gain
• Sweating (night and day)
• Sleep disturbances
• Depressive moods
• Nervousness, restlessness
• Reduced libido
• Thyroid dysfunction
• Anxiety
• Venous weakness

Many refer to older studies (e.g., early 1990s) when assessing progesterone’s pharmacological profile, which rarely mention adverse effects or tumour risks. However, more recent data indicate that even natural progesterone must be evaluated critically. As with all potent biological agents, significant effects can entail side effects.

In gynaecology, natural progesterone is used to protect the endometrium during oestrogen therapy, particularly in postmenopausal women. Oestrogen-induced cell proliferation (as part of hormone replacement therapy) increases the risk of oestrogen-associated tumours, which progesterone helps to counteract. Hence, combining oestrogen and progesterone has become standard in HRT, reducing proliferative pressure on hormone-sensitive tissues like the endometrium. However, the tumour-protective effect depends on the tissue’s specific enzyme profile and does not apply to breast tissue. Recent studies show that progesterone may increase the risk of breast cancer, accelerate tumour growth, and promote metastasis.