Progesterone and its Analogues

Since natural progestogen, progesterone, was isolated and identified by Butenandt in 1934, a variety of synthetic progestogens have been synthesised and developed for clinical use. Due to their different biological actions, differing progestogens can be used for varying clinical uses. Their use in breast cancer, prostate and renal cell cancer has declined. They are currently used to treat endometrial cancer.

• Progesterone
• Medroxyprogesterone
• Megestrol
• Norethisterone
• Dydrogesterone

Antiprogestogens and progesterone receptor modulators have also been developed.

Contraception

Progestogens can be used as oral or parenteral contraceptives with or without oestrogens. Progestogen-only contraception is possible in the form of progestogen-only pills, a vaginal ring, intramuscular injection or an implant. Progestogen-loaded intrauterine systems avoid the major systemic side effects. For emergency contraception progestogen-only preparations are better tolerated than oestrogen-progestogen combinations and appear to be more effective.¹

Treatment of signs of androgenisation

There are antiandrogenic progestogens that can be used clinically for the treatment of seborrhoea, acne, hirsutism and alopecia. This treatment when combined with oestrogens includes other beneficial effects such as contraception, menstrual cycle control and favourable metabolic effects.

Endometriosis

Endometriosis is a disease that requires a treatment that can be used on long-term basis with minimal side effects. This requires selection of the most suitable progestogen and dose titration to obtain amenorrhoea.²

• Medroxyprogesterone acetate and norethisterone are taken continuously and dydrogesterone can be taken cyclically or continuously.
• Danazol and gestrinone are both taken continuously.

Progestogens induce endometrial atrophy and also inhibit ovulation with reduction in oestrogen levels.
Progestogens and antiprogestogens were compared with other hormonal therapies in a Cochrane review of their efficacy for the relief of pain associated with endometriosis.³ There was found to be a general lack of data, and none of the studies included enough women to reach any firm conclusions. The authors concluded that treatment with antiprogestogens or continuous progestogens is likely to be effective. However, there is some doubt concerning the efficacy of luteal phase progestogens. Dydrogesterone is used in this way.

Endometrial hyperplasia and endometrial carcinoma

The majority of patients reported with well-differentiated endometrial adenocarcinoma who undergo conservative treatment with a progestational agent respond to treatment. When an initial response is not achieved or when disease recurs, carcinoma extending beyond the uterus is rare.⁴ There are currently no comparative trials of chemotherapy with endocrine therapy. The optimum cytotoxic drug regimen for advanced endometrial adenocarcinoma has still to be defined although a recent review suggests that it may contain paclitaxel or platinum.⁵ The most active systemic agents include cisplatin, doxorubicin, paclitaxel, and progestins.⁶

Side-effects are mild but may include:

• Irregular bleeding, bloating, mood changes, and weight gain¹⁰
• Nausea
• Fluid retention
• Progestogens can also influence carbohydrate metabolism differently. For instance, while dydrogesterone can potentiate the positive effects of estrogens on carbohydrate metabolism, levonorgestrel can elicit clear diabetogenic effects when used in hormone replacement therapy preparations.^11,12
• Other potential progestogenic effects have been suggested to play a role in vascular thromboembolic events.¹³ In addition, vasoconstrictory action, changes in endothelial function, proinflammatory markers and effects on vascular smooth muscle cells can be induced by certain progestogens, whilst others remain inactive.
• The progestogens have specific metabolic effects. The type of progestogen, the dose and route of administration, and the coadministration of oestrogens (also depending on their type and route of administration) determine the impact on lipid and lipid proteins.¹⁴ If androgenic progestogens such as norethisterone acetate are used transdermally instead of orally, the impact on lipid change is relatively small.