Progesterone is the naturally occurring progestogen and a subclass of the sex hormones. It is secreted by the ovary as part of the menstrual cycle. It was first isolated in 1934 by Butenandt. Progestogens are synthetic forms of progesterone.

Progestogens were developed as progesterone could not be absorbed orally, although a novel method of processing progesterone via microionizing is available.¹

Suitability

They provide an alternative form of hormonal contraception for patients deemed unsuitable for the combined contraceptive pill. This makes it suitable for the following patients:

• Heavy smokers
• Women with hypertension
• Women with diabetes mellitus
• Past history of DVT
• Migraine

Three main groups

1. Progesterone and its analogues: mifepristone, dydrogesterone, hydroxyprogesterone and medroxyprogesterone.
2. Testosterone and its analogues: norethisterone and norgestrel (derivatives are desogestrel, norgestimate and gestodene). More androgenic and likely to cause virilisation in comparison with the first group.
3. Hybrid progestogens such as dienogest.²

Division according to generation

Based on time since market introduction:

1. First generation: norethindrone, norgestrel and medroxyprogesterone.
2. Second generation: levonorgestrel (active component of norgestrel).
3. Third generation: desogestrel.³

Uses

Menstrual disorders

Regulation of abnormal bleeding or induction of menstruation.^2,3

• Progestogens lead to withdrawal bleeding in oligomenorrhoea and secondary amenorrhoea states.
• Medroxyprogesterone acetate is the most widely used.
• Progestogens are also used in dysfunctional uterine bleeding, with or without oestrogens.
• Need to ensure that the patient does not have atypical endometrial hyperplasia prior to treating dysfunctional uterine bleeding (applies more to older patients).
• Using progestogens does not treat the underlying cause of the menstrual disorder.
• Progesterones can be used to delay menses: norethisterone can be taken three days before the expected start date and continued. Normal menstruation will occur 2-3 days after stopping.

Birth control

Either alone or in combination with oestrogens in OCP or long acting as in Depo-Provera®. Also in emergency contraception.

• The progestogen component leads to anovulation which is enhanced by oestrogens.
• Progestogens also lead to thickened cervical mucus which is hostile to sperm.
• Prolonged progestogen exposure leads to an atrophic endometrium which reduces the chance of implantation of a fertilised ovum.

Intrauterine systems

• Progesterone or progestogen can be delivered directly into the uterus using a coil.
• Two types of progesterone or progestogen-releasing systems include Progestasert® and Mirena®.
• This has been successfully used as a contraceptive device and in heavy menstrual bleeding.⁴

Hormone replacement therapy

• Postmenopausal females have unopposed oestrogens which can lead to endometrial hyperplasia and carcinoma.
• Use of progestogens for twelve or more days in each cycle can reduce this risk.
• Continuous progestogens have been used to prevent unwanted uterine bleeding. This usually needs to be combined with oestrogens to prevent endometrial atrophy.

Endometriosis

A commonly used progestogen in endometriosis is medroxyprogesterone acetate.²

• Progestogens are thought to prevent implantation and growth of regurgitated endometrium.
• Some theories suggest that progestogens have an anti-inflammatory effect on ectopic endometrium.
• Progestogens have been shown in several studies to reduce pain from endometriosis, with minimal side effects.
• Progestogens have no effect on fertility rates in endometriosis.
• Progestogens have been previously used in the prevention of recurrent miscarriages - this is no longer recommended.

Acne⁵

Progestogens such as dienogest are also antiandrogenic.

• They block androgen receptors and 5 α-reductase which converts testosterone to the more potent dihydrotestosterone.
• This also occurs in the sebaceous glands of the skin, leading to reduction in seborrhoea and improvement in acne.
• They can also reduce hirsutism.

Premenstrual syndrome

No definite evidence to support the role of progestogens in the premenstrual syndrome.⁶

• The premenstrual syndrome consists of mental and physical symptoms which are related to the menstrual cycle.
• The aetiology is unclear.
• Some theories suggest it is related to sex steroids as it is not seen in anovulatory cycles.
• It is thought to relate more to oestrogens.
• Some investigators theorised that a lack of progestogens is the cause, leading to the use of progestogens in this condition.
• There is no clear evidence to support the use of progestogens.

Anticancer hormonal therapy

Treatment is not curative but can induce remission in 15-30% of patients.⁷

• Megestrol - breast and endometrial cancer (advanced disease). Efficacies of progestogens are not proven and current practice is to combine progestogens with platinum or taxane chemotherapeutic agents.
• Medroxyprogesterone - renal cell cancer and prostate cancer.

Palliative role in neoplastic disease

Progestogens stimulate appetite and weight gain, especially in breast neoplasm (longer duration compared with corticosteroids). Effect can be enhanced with concomitant use of NSAIDs e.g. ibuprofen.⁸

Things to consider prior to starting

• Women's age - using depot progesterones as contraception after age 40 may contribute to bone density loss.
• Previous breast cancer.⁹ There is a small increase in breast cancer in women who are on or have recently used the progestogen-only contraceptive pill. However, this can be used after 5 years provided there is no evidence of recurrence of breast disease.¹⁰
• Examine: breasts, blood pressure.
• Investigations: HDL in high cardiovascular risk group.
• Educate patient to self-examine breasts.

Common side effects

• Urticaria, acne, weight gain
• Fluid retention
• Hypertension
• Nausea, constipation

Other adverse effects

• Can suppress HDL cholesterol - seen more with first and second generation progestogens
• Hypertension
• Depressed mood
• Cardiovascular disease - risk is higher with older forms of combined OCP and greater in females with concomitant risk factors^11,12
• Hirsutism (rare)
• Jaundice (rare, thus contraindicated in hepatic impairment)

Methods of administration

• Tablets - various types are available.
• Depot - requires full counselling and warning regarding menstrual disturbances and delay in return to full fertility. Use beyond 2 years of Depo-Provera® needs to be evaluated carefully.
• Noristerat® provides contraception for 8 weeks which may be useful in certain scenarios.
• Implants - Nexplanon® provides contraception for up to 3 years when implanted subdermally.
• Vaginal suppositories - leads to uterine effect with few systemic effects.
• Vaginal cream.

Document references

1. Apgar BS, Greenberg G; Using progestins in clinical practice. Am Fam Physician. 2000 Oct 15;62(8):1839-46, 1849-50. [abstract]
2. Vercellini P, Fedele L, Pietropaolo G, et al; Progestogens for endometriosis: forward to the past. Hum Reprod Update. 2003 Jul-Aug;9(4):387-96. [abstract]
3. Fraser IS, Kovacs GT; The efficacy of non-contraceptive uses for hormonal contraceptives. Med J Aust. 2003 Jun 16;178(12):621-3. [abstract]
4. Lethaby AE, Cooke I, Rees M; Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD002126. [abstract]
5. Raudrant D, Rabe T; Progestogens with antiandrogenic properties. Drugs. 2003;63(5):463-92. [abstract]
6. Backstrom T, Andreen L, Birzniece V, et al; The role of hormones and hormonal treatments in premenstrual syndrome. CNS Drugs. 2003;17(5):325-42. [abstract]
7. Pascual Lopez A, Roque i Figuls M, Urrutia Cuchi G, et al; Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome. J Pain Symptom Manage. 2004 Apr;27(4):360-9. [abstract]
8. Yavuzsen T, Davis MP, Walsh D, et al; Systematic review of the treatment of cancer-associated anorexia and weight loss. J Clin Oncol. 2005 Nov 20;23(33):8500-11. [abstract]
9. Colditz GA; Estrogen, estrogen plus progestin therapy, and risk of breast cancer. Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):909s-17s. [abstract]
10. British National Formulary
11. Chasan-Taber L, Stampfer MJ; Epidemiology of oral contraceptives and cardiovascular disease. Ann Intern Med. 1998 Mar 15;128(6):467-77. [abstract]
12. Cano A; Progestins and coronary heart disease. Hum Reprod Update. 1999 May-Jun;5(3):189-90.

Acknowledgements