Progestogens

Synonyms: progestins, progestagens

What is progesterone?

Progesterone is one of the naturally occurring sex hormones. It is secreted by the ovary as part of the menstrual cycle. It was first isolated in 1934 by Butenandt.

What are progestogens?

Progestogens are synthetic forms of progesterone.

Progestogens were developed because progesterone could not be absorbed orally, although a method of processing progesterone via micro-ionising is now available (Utrogestan®). It has been suggested that micronised progesterone may be safer than synthetic progestogens when used as part of HRT (hormone replacement therapy).^{1 2}

Types of progestogens³

Synthetic progestogens are divided into two main groups:

• Progesterone analogues:

  • Dydrogesterone.

  • 17-OH progesterone group: medroxyprogesterone acetate and cyproterone acetate.

  • 19-nor progesterone group: nomegestrol acetate (NOMAC), trimegestone, promegestone.

• Testosterone analogues:

  • Estranes: norethisterone.

  • Estrane/pregnane: dienogest.

  • Gonanes: norgestrel and levonorgestrel (the active isomer of norgestrel), desogestrel, norgestimate and gestodene.

Progesterone and its synthetic analogues are less androgenic than the testosterone analogues.

Dienogest is referred to as a hybrid progestogen. It is a testosterone derivative but, like drospirenone which is derived from spironolactone, has no androgenic effect but partial anti-androgenic activity.

How to administer progestogens

• Tablets (often in combination with an oestrogen).

• Depot: medroxyprogesterone acetate (DMPA) is available as an intramuscular (Depo-provera®) or subcutaneous (Sayana Press®) injection. Norethisterone enantate (Noristerat®) is rarely used.

• Implants - etonogestrol implant (Nexplanon®).

• Intrauterine systems (IUS) with slow-release levonorgestrel - Mirena® and Jaydess®.

• Vaginal gel, suppositories and injections of progesterone may be used for a variety of indications, including infertility, hormone replacement therapy and heavy menstrual bleeding.⁴

• Progesterone cream: unregulated bio-identical progesterone is marketed in cream form; it is not licensed in the UK. Serious concerns regarding the use of progesterone cream include misleading claims of effectiveness and safety, as well as variable purity and potency.^{5 6 7}

Contra-indications⁸

The BNF lists the following contra-indications for progestogens:

Acute porphyrias, breast cancer, genital cancer, idiopathic jaundice during pregnancy, pemphigoid gestationis, severe pruritus during pregnancy, history of thromboembolism, missed miscarriage, thrombophlebitis, undiagnosed vaginal bleeding.

However in day-to-day practice they are often used in women who have some of these contra-indications - for example, a progestogen-based pill may be used for contraception in a woman who cannot use oestrogen-based contraception due to a history of thromboembolism. As always, clinical judgment should be used and more detailed guidance specific to the condition being treated should be consulted.

When used for contraception or HRT, progestogens are usually contra-indicated in women with a history of breast cancer; it is a hormonally sensitive disease and prognosis may be affected by any hormonal method of contraception. A decision to initiate hormonal contraception should be made in consultation with the local oncology team and for medicolegal reasons it would be sensible to have this discussion in writing.⁹

What are progestogens used for?

Menstrual disorders

• Women with polycystic ovary syndrome who have four or fewer periods per year may be at increased risk of endometrial cancer; inducing a withdrawal bleed every month with cyclical progestogen (or the use of combined hormonal contraception (CHC) or a levonorgestrel-releasing IUS if contraception is desired) is advised.¹⁰

• In heavy menstrual bleeding, a levonorgestrel-releasing IUS is first-line if pharmaceutical treatment is appropriate.¹¹

• In dysfunctional uterine bleeding, progestogens may be used, with or without oestrogens. It may be necessary to ensure that the patient does not have atypical endometrial hyperplasia or a cervical lesion prior to having treatment for dysfunctional uterine bleeding, particularly in older women.

• To delay menses: a progestogen can be taken three days before the expected start date and continued. Normal menstruation will occur 2-3 days after stopping.

Contraception¹²

Progestogens are used widely for contraception, as they provide an alternative form of hormonal contraception for patients deemed unsuitable for CHC. This makes them particularly suitable for women with a history of:

• Obesity.

• Hypertension.

• Diabetes mellitus.

• Venous thromboembolism.

• Migraine.

• Heavy smoking.

Progestogens are available in many forms:

• In combination with oestrogens in CHC, in oral, transdermal or intravaginal contraception when oestrogen isn't contra-indicated.

• Alone in oral contraception - progestogen-only pill (POP).

• Levonorgestrel-releasing IUS (see also below).

• Injections:

  • Use of DMPA requires full counselling and warning regarding menstrual disturbances and possible delay in return to full fertility. Use beyond two years needs to be evaluated carefully, particularly in women aged under 18 years, due to its potential effects on bone density.

  • DMPA (Depo-provera® and Sayana Press®) provides contraception for twelve weeks. See the separate Progestogen-only Injectable Contraceptives article for more information.

• Implant: etonogestrel (Nexplanon®) provides contraception for up to three years when implanted subdermally.

• Emergency contraception.

In addition to anovulation, progestogens also lead to thickening of the cervical mucus, making it hostile to sperm. Furthermore, prolonged progestogen exposure leads to reversible atrophy of the endometrium, which reduces the chance of implantation of a fertilised ovum.

IUS

• Progestogen is delivered directly into the uterus, using a T-shaped device which slowly releases levonorgestrel over a three-year or five-year period.

• In addition to its use as a contraceptive, Mirena® may be used for endometrial protection in hormone replacement therapy (HRT), when the licence is for four years (but FSRH guidance allows for five years of use), and to treat heavy menstrual bleeding. Levosert® also has a licence for heavy menstrual bleeding, but not for use as part of HRT. The other IUS devices on the market, Jaydess® and Kyleena®, only have a licence for contraception.

See the separate Intrauterine System article.

HRT¹³

See also the separate Hormone Replacement Therapy (including Benefits and Risks) article.

• Postmenopausal women who have not had a hysterectomy and take oestrogens for HRT require progestogen, either on a cyclical or a continuous basis, to prevent hyperplasia of the endometrium and the possible development of endometrial cancer.

• Continuous combined HRT is recommended for any women requiring HRT once she is postmenopausal, ie a year after her last period or after she has been on cyclical HRT for at least one year.

• There have been reports of endometrial cancer in postmenopausal women who have used unregulated progesterone cream for endometrial protection, thought to be due to inadequate progesterone dose.⁵

Endometriosis

See also the separate Endometriosis article. A commonly used progestogen in endometriosis is medroxyprogesterone acetate but use of a levonorgestrel-releasing IUS is increasingly advocated.¹⁴

• Progestogens have been shown in several studies to reduce pain from endometriosis, with minimal side-effects.

• Some theories suggest that progestogens have an anti-inflammatory effect on ectopic endometrium.

• Progestogens have no effect on fertility rates in endometriosis.

Acne^{15 16 17}

Some progestogens in combined oral contraceptives (COCs) are anti-androgenic.

• COCs block androgen receptors and 5-alpha reductase which converts testosterone to the more potent dihydrotestosterone.

• Androgen blockade occurs in the sebaceous glands of the skin, leading to reduction in seborrhoea and improvement in acne.

• They can also reduce hirsutism.

• Progestogen types appear to differ in the degree to which they prevent testosterone production, conversion or bioavailability.

• COC should be considered for women with acne who also want oral contraception.

Premenstrual syndrome

Progestogen alone is not recommended for women with premenstrual syndrome (PMS), due to insufficient evidence to support its effectiveness.^{18 19}

• PMS consists of mental and physical symptoms which are related to the menstrual cycle.

• The aetiology is unclear.

• It is not seen in anovulatory cycles.

• Psychotropics or the suppression of ovulation are the main pharmacological treatments.

Anticancer hormonal therapy

• Megestrol - breast cancer 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.

• Cyproterone acetate - prostate cancer.

Palliative role in neoplastic disease²⁰

Progestogens stimulate appetite and lead to weight gain in cancer-associated anorexia-cachexia. Megestrol acetate is widely used for this indication but the mechanism is largely unknown. There may be a risk of phlebitis and pulmonary embolism.

Side-effects of progestogens

The risk and types of side-effects and adverse effects vary between different progestogens, their dosage and different modes of delivery.

• Unscheduled bleeding.

• Constipation.

• Vaginal dryness.

• Breast tenderness.

• Acne.

• Weight gain (DMPA).

Other adverse effects

• Ovarian cysts.

• HDL cholesterol can be suppressed among users of DMPA.

• Decreased glucose tolerance.

• Cardiovascular disease - limited evidence suggests that in women with concomitant risk factors, particularly hypertension, there is a small increase in cardiovascular events.⁹

• Hirsutism (rare).

• Jaundice (rare - contra-indicated in hepatic impairment).

An observational study looking at progesterone and breast cancer risk has been published. It was shown that there was an elevated risk of breast cancer- 20-30% - in women who are under 50 who currently use or have recently used progesterone-only contraceptions. This is in all forms of progestrone only contraception- pill, implant, injection and coil.

It was shown that in those people who had progesterone only contraception for 5 years,the 15-year absolute excess risk of breast cancer associated with use of oral contraceptives ranges from 8 per 100,000 users for use from age 16 to 20 to about 265 per 100,000 users for use from age 35 to 39.

However, taking into account that in 20 year olds the risk of breast cancer is extremely low, this added risk with progesterone only contraceptions remains very low. Factors such as excessive alcohol use (increases breast cancer risk by 20%) and obesity will have a similar degree of risk for breast cancer. Pregnancy and all the potential risks that entails such as blood clots, gestational diabetes as well as the emotional trauma of an unwanted pregnancy or termination need to be taken into account when counselling.

The risk of breast cancer increases with age- however they still remain low. The added risk in the 35-39 year group- is still low. All women should be told about the risks when taking hormonal contraception.

For those that have a high risk of cancer- those that have the BRCA 1 or BRCA 2 genes or a strong family history- there is no evidence yet to know what the increased risks would be and should be discussed during contraception counselling.

Currently, the guidance for having progesterone only contraception has not changed as benefits outweigh the risks.