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Progesterone, progestogen, natural, bio-itentical & micronised progesterone

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In the menstrual cycle, ovarian progesterone protects the endometrium and induces a monthly bleed to reduce the risk of developing abnormal cancerous cells

Progesterone

  • produced by the ovary
  • Its role is to maintain a pregnancy, protect the lining of the womb (endometrium) and control bleeding

Progestogens

  • synthetic molecules that mimic the action of the ovarian progesterone hormone
  • There are several different progestogens all with slightly different properties
  • It is a bioidentical hormone with a molecular structure identical to that of endogenous progesterone produced by the ovary
  • Synthetic progestins have a different chemical structure from progesterone

Natural / bio-identical / body-identical progesterone - micronised progesterone (lisenced)

  • interchangeable terms that refer to a natural form of progesterone that is identical to ovarian progesterone
  • Bioidentical natural progesterone is synthesised from yams.
  • It is only licensed for HRT use as an oral micronised progesterone capsule (Utrogestan)
  • Other lisenced progesterone products may be used with HRT, under the supervision of a specialist
  • Sublingual (under the tongue) or transdermal progesterone is not licensed or regulated, therefore is not recommended for use with licensed HRT

Micronised progesterone  (Utrogestan)

  • The preferred pprescribed progesterogen
  • Lisenced
  • Bio-identical 
  • Some observational studies have shown that HRT containing micronised progesterone or dydrogesterone may be associated with a lower risk of breast cancer, cardiovascular disease, and thromboembolic events compared with androgenic progestogens

Progestrogen choices

(for patients with an intact uterus - add onto oestrogen to protect uterus and make cyclical or continuous)

Oral

  • Medroxyprogesterone 2.5mg daily
    • Brand name Adgyn Medro
    • The most extensively-studied formulation for endometrial protection 
    • While MPA is endometrial protective, it is associated with an excess risk of CHD and breast cancer when administered with conjugated estrogen
    • In addition, regimens using continuous versus cyclic MPA may be associated with a higher risk of breast cancer
  • Duphaston HRT (didrogesterone)
  • Micronor HRT (norethisterone)
  • Utrogestan (micronised progesterone) (the only licensed prepartaion available)

Vaginal Gel

  • Crinone (natural progesterone)

Pessaries

  • Cyclogest (natural progesterone)

 Some women are unable to tolerate any oral progestin, whether given in a cyclic or continuous regimen. In this case, we sometimes suggest off-label use of the lower dose levonorgestrel-releasing intrauterine device (IUD). Lower doses of levonorgestrel-releasing IUDs for use in menopausal women are available in many countries, 

Benefit of micronised progesterone over conventional progestogen

Tolerance

Progestogens may not be alike with regard to potential adverse metabolic effects or associated breast cancer risk when combined with long-term estrogen therapy. Micronised progesterone and some progestogens have specific beneficial effects that could justify their use besides their expected actions on the endometrium. Synthetic analogues of progesterone (progestins/progestogens ) bind to the glucocorticoid, mineralocorticoid and androgen receptors. This can lead to unwanted side effects such as fluid retention, acne and weight gain. Progestogens and progesterone can lower mood through stimulation of the neurotransmitter gamma amino butyric acid; whilst progesterone has sedative effects through its intermediate metabolites, progestogens can cause PMS-type side effects including anxiety and irritability.

Venous thromboembolism (VTE)

It is well recognised that unlike oral estrogen, transdermal estrogen does not appear to increase the risk of VTE. Observational and case control data suggest that the use of certain progestogens e.g. dydrogesterone and micronised progesterone (D/MP) may reduce the increased risk of VTE conferred by oral estrogen, compared to that noted with other synthetic progestogens.

Cardiovascular risks

D/MP have a neutral effect on lipid and glucose metabolism and on vascular tone. The beneficial effects of estrogen are therefore not attenuated as they are with some synthetic progestogens such as medroxyprogesterone acetate which can blunt the increase in HDL cholesterol, increase insulin resistance and reduce arterial compliance. Smaller studies such as KEEPS and ELITE using MP have demonstrated superior outcomes to WHI.

Breast cancer

D/MP have pro-apoptotic or neutral effects on breast epithelial cell proliferation – this is in contradistinction to the effects of androgenic progestogens such as medroxyprogesterone acetate which have a proliferative effect. Data from the E3N Cohort observational study showed that estrogen with D/MP is associated with a significantly lower relative risk) than for other types of combined HRT. These differences require confirmation from further studies.

Endometrial protection

Endometrial protection and avoidance of breakthrough bleeding may not be as consistent with separately administered oral MP as it is with standard oral continuous combined regimens. However, this may be partly due to lack of compliance due to the requirement for MP to be used separately with estrogen. Vaginal administration may improve endometrial protection through uterine first pass effect.

Unlisenced progesterone should be prescribed under specialist supervision only

  • They are not recommended by the British Menopausal Society
  • They are not evidence based for effectiveness and safety
  • Recommended licensed options are available
  • There is insufficient evidence to justify multiple serum and saliva hormone tests often claimed
  • Claims for their benefits have been largely extrapolated from studies of conventional HRT 
  • No evidence to confirm the dosage of progesterone is sufficient to protect the endometrium in the presence of estrogen
  • The absence of warnings on the products regarding potential risks and side effects
  • Issues related to purity, potency and safety

 

Side effects 

Some women are unable to tolerate cyclic progestin administration (with any type of oral progestin) because of mood side effects and bloating. In addition, cyclic progestins almost always result in monthly withdrawal bleeding, which can be a lifestyle concern for many women. For any of these concerns, we suggest switching to a continuous regimen. This often resolves the issue of mood symptoms and bloating. However, for women who are newly menopausal, breakthrough bleeding can be anticipated.

The main side effects of taking progestogen include:

As with side effects of oestrogen, these will usually pass after a few weeks.

As transdermal oestrogen is associated with fewer risks than oral HRT, a transdermal route may be preferable for many women. This route is also advantageous for women with diabetes, for women with a history of VTE and also for women with thyroid disorders. Transdermal oestrogen should also be given to those women with a BMI over 30 kg/m2. In addition, transdermal HRT is preferable to those women with a history of migraine or gallbladder problems.

  • Testosterone derived: Norethisterone, Norgestrel, Levonorgestrel (found in combination products)
  • Progesterone derived: Medroxyprogesterone, Dydrogesterone, Drospirenone (found in combination products)
  • Micronised progesterone: Utrogestan
Reviewed By: Ask Shilpa Author

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