Progestins

by Ros Wood and Lone Hummelshoj

Progestins are a group of drugs that behave like the female hormone progesterone. They have been used since the mid 1950s to treat the symptoms of endometriosis [1]. They are also sometimes referred to as gestogens, progestogens, or progestagens.

Progestins come in different forms, each of which has its own advantages and disadvantages. The names, forms, and dosages most commonly used for women with endometriosis are outlined in the table below. There is no clinical trial evidence at the moment showing that any particular progestin is preferable over another [2].

Progestins are widely regarded as effective treatments for the symptoms of endometriosis despite not all being indicated for the treatment of the disease. However, like all drugs used for endometriosis, they may have side effects, which some women find intolerable.  These side effects vary between different types of progestins, making some more suitable for long term management than others.  This means that even if one type of progestin doesn’t work for you – it is possible that another one might.

Progestins are safer and cheaper than the GnRH-agonists and danazol, which some gynaecologists believe make them appropriate for women who need prolonged or repeated treatments [3].

How they work

It is not yet fully understood how progestins relieve the symptoms of endometriosis, but they probably work by suppressing the growth of endometrial implants in some way, causing them to gradually waste away [3]. They may also reduce endometriosis-induced inflammation in the pelvic cavity [4].

At the dosages usually used for endometriosis, most women will stop ovulating and menstruating during treatment. The levonorgestrel intrauterine system does not always stop ovulation.

In the first 3–6 months, many women will experience spotting, but some may experience heavy or prolonged bleeding. Later, most women will have lighter periods than previously, and some will have no periods.

Most women will resume ovulating and menstruating within 4–6 weeks of stopping treatment. With depot medroxyprogesterone acetate, women will not start ovulating and menstruating again until after the drug has been completely removed from their bodies. How long this takes will depend on the dose used and how rapidly their body metabolises the drug.

Women who have had long-acting injections may experience prolonged delays in the return of menstruation, and a few women may not menstruate for more than a year after their last injection. Therefore, it is recommended that you do not use depot medroxyprogesterone acetate if you may wish to become pregnant soon after treatment.

Dosage

The usual length of treatment is 3–6 months [2], but for some substances data beyond one year is also available [5]. In practice and due to the chronic nature of the disease longer courses may be recommended, and repeat courses are common. The levonorgestrel intrauterine system can remain in the uterus for up to 5 years.

The dosages most commonly used for endometriosis are shown below. However, endometriosis pain is usually only relieved when there is no menstrual bleeding, so the most appropriate dose for you will usually be the minimum dose needed to stop your periods, and your treating physician may adapt this to find the dose most appropriate for you individually [6].

Generic nameBrand nameFormDosage
DienogestVisanneTablets2 milligrams a day.
DydrogesteroneDuphastonTabletsUsually 10–30 milligrams a day.
Medroxyprogesterone acetateProveraTabletsUsually 30 milligrams a day, but may be up to 60 milligrams a day if necessary.
Medroxyprogesterone acetateMedroxyhexalTabletsUsually 30 milligrams a day, but may be up to 60 milligrams a day if necessary.
Medroxyprogesterone acetateRaloveraTabletsUsually 30 milligrams a day, but may be up to 60 milligrams a day if necessary.
Depot medroxyprogesterone acetateDepo-proveraLong-acting injectionOne 50 milligram injection each week, or one 100 milligram injection every 2 weeks, or one 150 milligram injection every 2–3 months. Injected into the muscle.
Depot medroxyprogesterone acetateDepo-RaloveraLong-acting injectionOne 50 milligram injection each week, or one 100 milligram injection every 2 weeks, or one 150 milligram injection every 2–3 months. Injected into the muscle.
NorethisteronePrimolut NTabletsUsually 2.5–5 milligrams a day.
Levonorgestrel intrauterine systemMirena coilT-shaped intrauterine deviceThis device contains 52 mg of levonorgestrel, which is slowly released into the uterus over a period of up to 5 years. The device has two strings attached that protrude through the cervix into the vagina.
Regularly check that the strings are still present, as the device may be expelled unnoticed. Heavier bleeding may be a sign that the device has been expelled.
See also the article on Mirena

Side effects

The side effects experienced and their severity vary from progestin to progestin depending on their chemical nature and the dosage used. Nevertheless, women usually experience fewer side effects with progestin treatment than with GnRH-agonist or danazol treatment [2]. Most women will experience at least one or two mild to moderate side effects, and some may experience several. Reducing the dosage to the minimum needed to suppress menstruation will often minimise the side effects.

The side effects are not usually serious medically [7], but can be unpleasant and difficult to live with. Some women cannot complete a course of treatment, because they find them intolerable [8].

The main side effects are listed below [2,6,9] but these very much depend on the substance, dosage, and individual treatment response.

  • acne
  • bloating
  • breakthrough bleeding
  • breast discomfort
  • depression
  • dizziness
  • fluid retention
  • headaches
  • irregular bleeding
  • lethargy
  • moodiness
  • nausea
  • prolonged bleeding
  • spotting
  • vomiting
  • weight gain.

If you suspect you may be experiencing other side effects, talk to your doctor.

Irregular bleeding and/or spotting is common, especially during the first couple of months of treatment and can usually be overcome by increasing the dose until the bleeding stops [6]. Breakthrough bleeding can usually be overcome by taking oestrogen for 7 days [2].

The levonorgesterel intrauterine system is sometimes expelled by the uterus, particularly in the first year [10]. Infrequently, it may perforate (penetrate through) the uterus (particularly if inserted within 6 weeks of a vaginal birth, or 12 weeks of a caesarian birth), or lead to a pelvic infection (especially in the first 3 weeks after insertion) [10].

The side effects of progestins are reversible. With the exception of depot medroxyprogesterone acetate, which following long-term use may contribute to loss of bone mass, the side effects usually disappear soon after completing treatment. The side effects of depot medroxyprogesterone disappear soon after the drug has been eliminated from the body, which may take weeks or months depending on the dosage used and the body’s ability to metabolise the drug.

There are no known long-term side effects of progestin treatment.

» How to deal with side effects from hormonal treatments

Effectiveness for pain symptoms

Little research has been conducted into the effectiveness of the progestins for the treatment of endometriosis [11]. Nevertheless, the results of clinical trials conducted to date suggest that the different progestins are equally effective [2], and that when taken continuously (every day) they relieve endometriosis-associated pain as effectively as the other hormonal drugs [2,9,11]. However, they are not usually effective when taken only during the luteal phase (second half) of the menstrual cycle [11].

The progestins control pain symptoms in approximately 3 out of 4 women [4]. However, they may not relieve symptoms completely [8].

Symptoms often recur following treatment [8]. The recurrence of symptoms may occur months or years after treatment ceases.

Like all the hormonal drugs used for endometriosis, the way women respond to progestins varies widely, and the way an individual woman responds to the different progestins may also vary. It is impossible to predict how you will respond to a particular progestin, so a process of trial and error may be needed to find one that works for you.

Use before surgery
There is no evidence to justify using a course of hormonal drug treatment as a preparation for surgery [12].

Use after surgery
There is some evidence to justify using hormonal drug treatments following surgery to suppress the growth and development of any remaining or new endometrial implants [12,13].

Use in recurrent endometriosis
Repeat courses of progestins may be used for women with recurrent endometriosis.

Some gynaecologists recommend that women with chronic endometriosis take progestins long term to keep their pain under control, and avoid the roller-coaster ride of pain recurring every time they stop treatment. In these situations it is important to critically consider whether the efficacy of a drug is combined with a tolerability profile that will not negatively affect a woman´s wellbeing during prolonged use, and to take only the minimum dose needed to stop your periods. If taking progestins for many years, there is a possibility of thinning of the bones due to a lack of oestrogen, so talk to your doctor about having a bone density scan periodically to check your bone density.

Effectiveness for infertility

None of the progestins — like all the hormonal treatments for endometriosis — will improve your chances of conceiving, so they should not be used as a treatment for infertility [9].

Keeping track

About 6–8 weeks after starting treatment, you should visit your gynaecologist to discuss how the treatment is progressing. Contact your gynaecologist if you develop any problems between scheduled visits.

Pregnancy and breastfeeding

If there is any possibility that you may be pregnant, you should not start or continue treatment with a progestin, as progestins can cause abnormalities in the developing foetus. You should also use non-hormonal barrier contraception (for example, condom or diaphragm or both) during treatment [10].

The use of progestins while breastfeeding is not recommended. Small amounts of progestins have been found in the milk of mothers taking them, and the effect on the infant is not known.

Interactions

None of the progestins interact with any foods or alcohol.

With the exception of the two forms of medroxyprogesterone acetate, none of the progestins interact with any other drugs.

Medroxyprogesterone acetate interacts with the rarely used drug aminoglutethimide [10]. Depot medroxyprogesterone acetate may interact with liver enzyme-inducing drugs, such as carbamazepine and phenytoin [10].

References
  1. Kistner R W. The use of newer progestins in the treatment of endometriosis. Am J Obstet Gynecol 1958;75:264–278.
  2. Kennedy S, Bergqvist A, Chapron C, D’Hooghe T, Dunselman G, Greb R, Hummelshoj L, Prentice A, Saridogan E. ESHRE guideline for the diagnosis and management of endometriosis. Human Reprod 2005;20(10):2698-2704.
  3. Schweppe K-W. Current place of progestins in the treatment of endometriosis-related complaints. Gynecol Endocrinol 2001;15(S6):22–8.
  4. Vercellini P, Fedele L, Pietropaolo G, Frontino G, Somigliana E, Corsignani PG. Progestogens for endometriosis: forward to the past. Hum Reprod Update 2003;9:387–96.
  5. Petraglia F et al, Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment. Arch Gynecol Obstet 2012;285(1):167-73.
  6. Kennedy S. The patient’s essential guide to endometriosis. United Kingdom: Alden, 2003.
  7. Winkel CA, Scialli AR. Medical and surgical therapies for pain associated with endometriosis. J Womens Health Gend Based Med 2001;10:137–62.
  8. Royal College of Obstetricians and Gynaecologists. Clinical green-top guidelines: the investigation and management of endometriosis. RCOG, 2000.
  9. Hughes E, Fedorkow D, Collins J, Vandekerckhove P. Ovulation suppression for endometriosis. The Cochrane Database of Systematic Reviews 2003, Issue 3. Art. No.: CD000155.
  10. Australian Medicines Handbook Pty Ltd. Australian Medicines Handbook 2005. Adelaide: Australian Medicines Handbook Pty Ltd, 2005.
  11. Prentice A, Deary AJ, Bland E. Progestagens and anti-progestagens for pain associated with endometriosis. The Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No.: CD002122.
  12. Vercellini P, Frontino G, De Giorgi O, Pietropaol G, Pasin R, Crosignani PG. Endometriosis: preoperative and postoperative medical treatment. Obstet Gynecol Clin North Am 2003;30:163–80.
  13. Gambone JC, Mittman BS, Munro MG, Scialli AR, Winkel CA. Consensus statement for the management of chronic pelvic pain and endometriosis: proceedings of an expert-panel consensus process. Fertil Steril 2002;78:961–72.
Thank you to the following for reviewing this article prior to its publication

Paolo Vercellini, Associate Professor, University of Milano, Italy
Martin Sillem, Doctor Med, Kreiskrankenhaus Emmendingen, Germany

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