Progesterone and progestogens play crucial roles in women’s health, from regulating menstrual cycles to supporting pregnancy and managing menopausal symptoms. However, the distinctions between these hormones and their synthetic counterparts can be confusing. This comprehensive guide will explore the various forms of progesterone and progestogens, their uses, benefits, side effects, and why some may be preferable to others.
Natural Progesterone vs. Synthetic Progestogens
Natural Progesterone
Progesterone is a steroid hormone naturally produced by the ovaries during the menstrual cycle and in larger amounts during pregnancy. It plays several vital roles in the body, including preparing the uterus for potential pregnancy, maintaining pregnancy, regulating menstrual cycles, supporting bone health, and influencing mood and sleep patterns.
Progesterone is part of a class of hormones called progestogens, which also includes synthetic compounds designed to mimic its effects. The hormone is primarily produced by the corpus luteum, a temporary structure formed in the ovary after ovulation. During pregnancy, the placenta takes over progesterone production, maintaining high levels throughout gestation.
Progesterone’s effects are mediated through its interaction with progesterone receptors found in various tissues throughout the body. These receptors are present in the reproductive organs, brain, bone, and other tissues, explaining the hormone’s wide-ranging effects.
Synthetic Progestogens
Progestogens are a class of hormones that include natural progesterone and synthetic compounds designed to mimic its effects. These synthetic versions, also known as progestins, were developed because natural progesterone is poorly absorbed when taken orally. The development of synthetic progestins began in the 1940s and has continued to evolve, with newer generations offering improved efficacy and side effect profiles.
Synthetic progestins are structurally similar to progesterone but often have modifications that enhance their oral bioavailability, potency, or duration of action. These modifications can also result in varying effects on other hormone receptors, such as androgen or mineralocorticoid receptors, leading to different side effect profiles among different progestins.
Forms of Progesterone and Progestogens
Natural Progesterone
Micronised Progesterone: This form of natural progesterone is processed to increase its bioavailability when taken orally. The micronisation process reduces the particle size of the hormone, enhancing its absorption in the gastrointestinal tract. It’s available as oral capsules (e.g. Utrogestan or Gepterix) and vaginal gels or suppositories. Micronised progesterone is often preferred in hormone replacement therapy due to its bioidentical nature and potentially more favourable side effect profile.
Synthetic Progestogens
First-generation progestins: These include norethisterone and medroxyprogesterone acetate (MPA). Developed in the 1950s and 1960s, these progestins are derived from testosterone and retain some androgenic properties. They are potent and effective but may be associated with a higher incidence of androgenic side effects such as acne or hirsutism (facial hair) in some women.
Second-generation progestins: Levonorgestrel and norgestrel fall into this category. Developed in the 1970s, these progestins offer improved progestogenic potency with reduced androgenic effects compared to first-generation progestins. Levonorgestrel, in particular, has become widely used in various contraceptive formulations, including combined oral contraceptives and intrauterine devices such as the mirena coil, levosert and kyleena.
Third-generation progestins: This group includes desogestrel, gestodene, and norgestimate. Introduced in the 1980s, these progestins were designed to have even lower androgenic effects. They are commonly used in combined oral contraceptives and are associated with a potentially lower risk of certain side effects, such as acne, compared to earlier generations. However, some studies have suggested a potentially increased risk of venous thromboembolism with third-generation progestins, although this remains a topic of ongoing research and debate.
Fourth-generation progestins: Drospirenone is the primary example in this category. Derived from spironolactone, drospirenone has anti-androgenic and anti-mineralocorticoid properties. These unique characteristics make it potentially beneficial for women with conditions such as polycystic ovary syndrome (PCOS) or those experiencing water retention as a side effect of hormonal contraceptives.
Other progestins: This category includes newer progestins with unique properties, such as dienogest and nomegestrol acetate. Dienogest, for example, has strong progestogenic effects combined with anti-androgenic properties, making it particularly useful in the treatment of endometriosis. Nomegestrol acetate is structurally similar to progesterone and has been used in combined oral contraceptives and hormone replacement therapy in menopause.
Why Some Forms May Be Preferable
The choice between natural progesterone and synthetic progestogens often depends on the specific medical condition being treated and individual patient factors. However, there are some general considerations that may make certain forms preferable in different situations.
Advantages of Natural Progesterone
Bioidentical Structure: Micronised progesterone is chemically identical to the progesterone produced by the body, potentially leading to fewer side effects. This bioidentical nature means that the body processes and metabolises it in the same way as endogenous progesterone, which may result in a more physiological response and potentially fewer unexpected effects.
Cardiovascular Effects: Natural progesterone may have a more favourable effect on blood lipids and cardiovascular risk compared to some synthetic progestins. Some studies have suggested that micronised progesterone does not negate the beneficial effects of oestrogen on lipid profiles and may have a neutral or possibly beneficial effect on blood pressure and vascular function.
Breast Cancer Risk: Some studies suggest that micronised progesterone may be associated with a lower risk of breast cancer compared to synthetic progestins when used in hormone replacement therapy (HRT). The “E3N” cohort study, for example, found that women using micronised progesterone or dydrogesterone in combination with oestrogen had a lower risk of breast cancer compared to those using synthetic progestins.
Sleep Benefits: Oral micronised progesterone (utrogestan and gepterix) has been shown to have sedative effects, potentially improving sleep quality. This is thought to be due to the metabolism of progesterone to allopregnanolone, a neurosteroid that enhances GABA-ergic activity in the brain. This property can be particularly beneficial for menopausal women experiencing sleep disturbances such as insomnia or broken sleep.
Cognitive Effects: Some research suggests that natural progesterone may have neuroprotective effects and could potentially benefit cognitive function, particularly in the context of brain injury or neurodegenerative diseases. However, more research is needed to fully understand these potential benefits.
Advantages of Synthetic Progestogens
Potency: Synthetic progestins are often more potent than natural progesterone, requiring lower doses for therapeutic effects. This increased potency can be particularly advantageous in contraceptive applications, where reliable suppression of ovulation is crucial.
Versatility: Different progestins have varying effects on other hormone receptors (e.g. androgenic, anti-androgenic), allowing for targeted treatment of specific conditions. For example, progestins with anti-androgenic properties may be beneficial for women with PCOS or those experiencing androgenic side effects from other hormonal treatments.
Stability: Some synthetic progestins have better oral bioavailability and longer half-lives, allowing for more convenient dosing schedules. This can improve treatment adherence and effectiveness, particularly in contraceptive applications.
Specific Therapeutic Effects: Certain synthetic progestins have been developed or found to have beneficial effects for specific conditions. For instance, dienogest has shown particular efficacy in treating endometriosis, while drospirenone’s anti-mineralocorticoid effects can be beneficial for women experiencing fluid retention.
Delivery Options: Synthetic progestins are available in a wide range of delivery systems, including long-acting reversible contraceptives (LARCs) like intrauterine devices and subdermal implants. These options can provide highly effective, long-term contraception or therapeutic effects with minimal user intervention.
Side Effects and Progesterone Sensitivity/Progesterone Intolerance
Both natural progesterone and synthetic progestogens can cause side effects, though the nature and severity of these effects can vary between individuals and different forms of the hormone. Understanding these potential side effects and the factors that influence individual sensitivity is crucial for optimising treatment outcomes.
Common Progesterone Side Effects
Mood changes (irritability, depression, anxiety): Progestogens can affect neurotransmitter systems in the brain, potentially leading to mood alterations. Some women may experience increased irritability, while others may report feelings of depression or anxiety. The exact mechanisms behind these mood changes are not fully understood but may involve interactions with serotonin, GABA, and other neurotransmitter systems.
Breast tenderness: This is a common side effect, particularly when starting or changing hormonal treatments. It’s thought to be related to the effects of progestogens on breast tissue proliferation and fluid retention.
Bloating: Fluid retention is a common side effect of progestogens, which can lead to feelings of bloating or abdominal discomfort. This effect may be more pronounced with certain synthetic progestins that have mineralocorticoid activity.
Headaches: Some women may experience an increase in headaches, particularly migraines, in response to hormonal fluctuations associated with progestogen use. The exact mechanism is not fully understood but may involve effects on blood vessels and pain perception pathways.
Nausea: Gastrointestinal side effects, including nausea, are relatively common, particularly when first starting treatment. These effects often subside over time as the body adjusts to the hormone.
Changes in libido: Progestogens can affect sex drive, with some women reporting decreased libido. This may be due to effects on androgen levels or direct effects on sexual function pathways in the brain.
Fatigue: Some women may experience increased fatigue or drowsiness, particularly with natural progesterone due to its potential sedative effects. Women have also reported vivid dreams with the use of micronised progesterone (utrogestan or gepterix)
Acne or oily skin: Progestogens with androgenic properties may exacerbate acne or increase skin oiliness in some women. Conversely, progestins with anti-androgenic effects may improve these conditions.
Progestogen Sensitivity or progesterone intolerance
Some women experience more severe side effects or a heightened sensitivity to progestogens. This phenomenon is not fully understood, but several factors may contribute to individual variations in sensitivity:
Genetic Variations: Differences in genes related to hormone metabolism and receptor function may influence individual responses to progestogens. For example, variations in genes encoding enzymes involved in steroid hormone metabolism (such as CYP3A4 or CYP2C19) could affect how efficiently the body processes different progestogens.
Neurotransmitter Interactions: Progestogens can affect levels of neurotransmitters like serotonin and GABA, which may explain mood-related side effects in sensitive individuals. Some women may have genetic or physiological differences that make them more susceptible to these neurotransmitter fluctuations.
Hormone Balance: The ratio of oestrogen to progesterone/progestogen may influence side effects, with some women being more sensitive to fluctuations in this balance. This is particularly relevant in cyclic hormone therapy regimens or during different phases of the menstrual cycle.
Prior Hormone Exposure: A woman’s history of hormone exposure, including previous use of hormonal contraceptives or HRT, may affect her sensitivity to progestogens. This could be due to long-term effects on receptor expression or function, or changes in the hypothalamic-pituitary-gonadal axis.
Underlying Health Conditions: Certain medical conditions, such as premenstrual dysphoric disorder (PMDD), may predispose women to greater sensitivity to hormonal fluctuations. Women with a history of depression or anxiety may also be more susceptible to mood-related side effects of progestogens.
Age and Menopausal Status: Sensitivity to progestogens may change throughout a woman’s life, with some women becoming more or less sensitive as they approach and transition through menopause.
Body Composition: Factors such as body mass index (BMI) and body fat distribution can affect hormone metabolism and may influence an individual’s response to progestogens.
Preferable Forms of Progesterone and Progestogens
The best form of progesterone or progestogen depends on the specific medical indication and individual patient factors. However, some general preferences have emerged in recent years based on clinical evidence and patient experiences:
Micronised Progesterone
For many applications, particularly in menopausal hormone therapy, micronised progesterone has become a preferred option due to its bioidentical structure and potentially more favourable side effect profile. It may be especially beneficial for:
Women with a history of mood sensitivity to synthetic progestins: The bioidentical nature of micronised progesterone may result in fewer mood-related side effects for some women.
Those concerned about breast cancer risk in HRT: Some studies suggest a potentially lower risk of breast cancer with micronised progesterone compared to synthetic progestins in hormone replacement therapy.
Patients who experience sleep disturbances: The sedative effects of oral micronised progesterone (utrogestan or gepterix) can be beneficial for improving sleep quality, particularly in menopausal women.
Women with cardiovascular risk factors: Micronised progesterone may have a more neutral or potentially beneficial effect on cardiovascular risk markers compared to some synthetic progestins.
Dydrogesterone
This synthetic progestogen has a molecular structure very similar to natural progesterone and may offer a good balance of efficacy and tolerability. It’s often used in:
Hormone replacement therapy:
Dydrogesterone provides effective endometrial protection with potentially fewer side effects than some other synthetic progestins.
Treatment of menstrual disorders: It can be effective in managing conditions such as irregular menstruation or endometriosis.
Levonorgestrel (in IUDs)
For contraception and management of heavy menstrual bleeding, levonorgestrel-releasing intrauterine devices (IUDs) such as mirena, levosert, kyleena are often preferred due to their localised effect on the endometrial lining of the uterus and lower systemic absorption.
Benefits of a coil include:
High contraceptive efficacy: Levonorgestrel IUDs are among the most effective forms of reversible contraception.
Reduced systemic side effects: The localised delivery results in lower systemic hormone levels compared to oral contraceptives.
Management of heavy menstrual bleeding: Levonorgestrel IUDs can significantly reduce menstrual blood loss, making them an effective non-surgical option for managing heavy periods.
Long-acting: Depending on the specific device, they can provide contraception and therapeutic effects for 3-8 years if fitted under the age of 45.
Dienogest
This fourth-generation progestin has shown promise in the treatment of endometriosis due to its strong progestogenic effects and anti-androgenic properties. Key benefits include:
Effective pain relief: Dienogest has been shown to significantly reduce endometriosis-associated pain.
Favourable side effect profile: Its anti-androgenic properties may result in fewer androgenic side effects compared to some other progestins.
Continuous administration: Dienogest can be taken continuously without the need for a hormone-free interval, which may provide better symptom control for some women with endometriosis.
Specific Uses and Considerations
Hormone Replacement Therapy in Menopause
In hormone replacement therapy for the menopause (HRT) the choice of progestogen is crucial for women who have not had a hysterectomy and require endometrial protection.
Current guidelines often favour:
Micronised Progesterone: Due to its potentially lower risks of breast cancer and cardiovascular events compared to some synthetic progestins. It’s typically administered orally or vaginally, with the vaginal route potentially offering the advantage of lower systemic absorption while still providing adequate endometrial protection although this is an off licence use of utrogestan add gepterix but often a recognised method by British Menopause Specialists.
Dydrogesterone: Offers good endometrial protection with a favourable side effect profile. Its molecular structure, similar to natural progesterone, may contribute to its good tolerability.
Considerations for HRT:
Route of administration: Oral, transdermal, or vaginal routes may be considered based on individual patient factors and preferences.
Cyclic vs. continuous regimens: The choice between cyclic (sequential) and continuous combined therapy depends on factors such as time since menopause and presence of menopausal symptoms.
Cyclical regime – taking progesterone in the second half of the cycle to mimic the natural luteal phase of the menstrual cycle
Continuous regime – in postmenopausal women – taking progesterone continuously without a break
Dose: The lowest effective dose should be used to minimise side effects while providing adequate endometrial protection.
Individual risk factors: Cardiovascular risk, breast cancer risk, and personal or family history of venous thromboembolism should be considered when choosing a progestogen for HRT.
Contraception
For contraceptive purposes, synthetic progestins remain the mainstay due to their potency and reliability:
Levonorgestrel: Commonly used in combined oral contraceptives and emergency contraception. Its high progestogenic potency makes it effective for ovulation suppression. Levonorgestrel is also used in intrauterine devices, providing long-acting, reversible contraception with the added benefit of reducing menstrual blood loss for many users.
Desogestrel and Gestodene: These third-generation progestins are used in some combined oral contraceptives. They were developed to have reduced androgenic effects compared to earlier progestins, potentially resulting in fewer side effects like acne or hirsutism. However, some studies have suggested a potentially increased risk of venous thromboembolism with these progestins, although this remains a topic of ongoing research and debate.
Drospirenone: A fourth-generation progestin with anti-androgenic and anti-mineralocorticoid properties, potentially beneficial for women with acne, PCOS, or those prone to fluid retention. Its unique properties may make it a good choice for women who have experienced androgenic side effects with other progestins.
Managing Menstrual Irregularities and Heavy Menstrual Bleeding
Norethisterone: Effective for controlling heavy menstrual bleeding and regulating cycles. Using it cyclically can induce regular withdrawal bleeds or continuously for menstrual suppression. Norethisterone has strong progestogenic effects and moderate androgenic activity.
Medroxyprogesterone Acetate (MPA): Used in both oral and injectable forms for menstrual regulation and contraception. The injectable form (Depo-Provera) is particularly effective for long-term menstrual suppression and contraception, although it may be associated with a longer return to fertility after discontinuation compared to other methods.
Levonorgestrel IUD: While primarily used for contraception, the levonorgestrel-releasing IUD is highly effective in reducing menstrual blood loss and can be an excellent option for women with heavy menstrual bleeding who also desire contraception.
Conclusion
The world of progesterone and progestogens is complex and continually evolving. From natural bioidentical progesterone to the latest synthetic progestins, each formulation offers unique benefits and potential drawbacks. The key to successful treatment lies in understanding the distinct properties of each progestogen, considering individual patient factors, and maintaining open communication between healthcare providers and patients.
Ultimately, the “best” form of progesterone or progestogen is the one that effectively addresses the patient’s medical needs while minimising side effects and risks. By staying informed about the latest research and working closely with healthcare providers, women can make empowered decisions about their hormonal health throughout all stages of life. So why wait and book with Pause and Co Healthcare today