Progesterone and Endometriosis: A Sex Hormone on the Wrong Track

Endometriosis often involves a hormonal imbalance, particularly in a typical scenario of excessive estrogen and insufficient progesterone. In some cases, individuals with endometriosis might display progesterone resistance, a condition where this sex hormone fails to exert its full effect despite being present in adequate quantities [1]. So, what makes the corpus luteum hormone progesterone so crucial, and how does it relate to endometriosis? Today, I will offer insights into these intriguing questions and explain the significance of synthetic luteal hormones in treating endometriosis.

Understanding Progesterone: Its Functions, Benefits, and Role in Health

Progesterone, often called the “corpus luteum hormone,” is one of the progestins that become prominent in the second half of the menstrual cycle. It is also commonly known as the “pregnancy hormone.” Understanding the pivotal roles of progesterone sheds light on its significance. Estrogen, the primary female sex hormone, builds up the uterine lining. Following this phase, progesterone takes the lead to facilitate the implantation of a fertilized egg. Additionally, progesterone fosters uterine growth during pregnancy and sets the stage for breastfeeding. If pregnancy is not detected, the female body experiences a decline in progesterone levels, resulting in menstruation. Moreover, progesterone’s influence extends beyond its primary functions, impacting other organ systems, including blood vessels, the intestines, the brain, and bone health [2].

Essential Tasks of Progesterone Include:

  • Preparing the uterine lining built by estrogen for potential egg implantation.
  • Inducing a rise in body temperature during the second half of the menstrual cycle.
  • Sustaining a pregnancy.
  • Fostering mammary gland growth in preparation for breastfeeding [3].

The Role of Progesterone in the Body

Progesterone, the dominant female sex hormone, is primarily produced in the ovaries. The placenta also contributes to its production during pregnancy, while a smaller amount can be synthesized in the adrenal cortex [4]. It is worth noting that men also produce progesterone; in their case, it plays a role in hormone metabolism and may be relevant to fertility [5].

The pituitary gland, specifically the luteinizing hormone (LH) it secretes, stimulates the formation of progesterone. Without sufficient progesterone, a stable menstrual cycle becomes challenging. Progesterone deficiency can lead to cycle irregularities, resulting in symptoms such as intermenstrual bleeding or fertility issues.

Recognizing Symptoms of Progesterone Deficiency

A progesterone deficiency, also known as luteal insufficiency, can give rise to various discomforts. These symptoms are not always apparent; some individuals may experience a deficiency without realizing it until fertility problems arise.

Common symptoms of progesterone deficiency include:

  • Shortened menstrual cycle, with the second half lasting 12 days or less.
  • Spotting during the latter part of the menstrual cycle.
  • The development of growths on the ovaries and uterus, such as fibroids.
  • Hot flashes.
  • Mood swings and anxiety.
  • Sleep disturbances.
  • Dizziness.
  • Decreased libido.
  • Weight gain due to water retention.

Good to Know!

Progesterone wields remarkable influence within the human body, particularly during pregnancy when its levels are elevated. This hormone’s impact is evident in its soothing effect on the brain, notably contributing to the pronounced fatigue experienced during pregnancy. Furthermore, the muscle-relaxing properties of progesterone can sometimes lead to the development of varicose veins, a common occurrence during pregnancy [2].

Endometriosis: The Hormone Cocktail is Crucial

The functioning of the human organism relies heavily on hormonal activity, particularly in processes like maintaining the female menstrual cycle and initiating pregnancy. Hormones are pivotal contributors to overall well-being, and one hormone with notable effects is progesterone, recognized for its calming impact on the brain. Furthermore, the intricate interplay between the sex hormones estrogen and progesterone is essential concerning endometriosis. In endometriosis, there is often an observed condition known as “estrogen dominance,” characterized by excess estrogen relative to progesterone. Physicians also frequently identify a lack of progesterone in individuals with endometriosis. Endometriosis can involve an abundance of estrogen and a progesterone deficiency. To understand the comprehensive dynamics of this hormonal interplay, I invite you to delve into the world of estrogen with me.

Estrogen Progesterone Excursion

Estrogen, like progesterone, is a sex hormone vital in maintaining a healthy endometrium. The harmonious interaction of these hormones relies on specialized receptors, which act as messengers in the body. Receptors are specialized cells or cellular components that process specific stimuli and transmit them as signals [6]. However, this is precisely where endometriosis appears to encounter an issue. Research indicates that estrogen and progesterone signaling pathways are disrupted in this condition [7]. These disruptions have far-reaching consequences, potentially leading to progesterone resistance. Unlike progesterone deficiency, where there is an adequate hormone supply, progesterone resistance occurs when the receptors responsible for its effects fail to function correctly or to their full potential. This phenomenon contributes to estrogen dominance, where estrogen gains the upper hand.

Probing Progesterone Receptors

In exploring progesterone receptors, we uncover their unique role in endometriosis. Progesterone acts as an antagonist to estrogen, providing balance in a healthy menstrual cycle. It stimulates the uterine lining to prepare for potential pregnancy. After ovulation, progesterone takes the reins, maintaining the uterine lining while undergoing necessary adjustments. This relay race of hormonal action ensures a well-ordered cycle. Research has revealed that endometrial cells respond less sensitively to progesterone in endometriosis, and this altered behavior is believed to contribute to the condition [1, 8].

Progesterone Receptors Are No Longer Shoulder to Shoulder

Endometriosis tissue does not only appear different; it behaves differently as well.

Scientific have demonstrated that progesterone no longer has its usual counteractive effect on estrogen within endometriosis foci [1, 9]. This change is attributed to the endometriosis cells’ reduced sensitivity to natural progesterone. Ordinarily, progesterone helps convert estradiol into estrone through enzymes, a crucial mechanism because estrone is less potent. Progesterone’s role is to temper estrogen’s influence. However, when this transformation fails in endometriosis lesions, it intensifies estrogen dominance, triggering inflammation and pain, hallmark symptoms of endometriosis. Moreover, the density of progesterone receptors varies in endometriosis tissue. A particular progesterone receptor (PR-B) For example, one specific progesterone receptor (PR-B) mediates progesterone action is notably absent, resulting in reduced effectiveness. This condition is termed “progesterone resistance.” Additionally, fewer representatives of another progesterone receptor (PR-A) are present, and they have an opposing effect on PR-B, underscoring the intricate balance of hormonal interactions [7, 9].

Regulatory Mechanisms and Estrogen Receptors Influence Progesterone Levels

Further research reveals that an excess of steroid receptors, accompanied by distinct regulatory mechanisms, could account for the unresponsiveness of progesterone levels within endometriosis tissue [14]. Steroids, a group of hormones derived from the sterane primary substance and cholesterol, contribute to producing female sex hormones like progestin and estrogen. In this context, the density of estrogen receptors, which are also present in higher numbers in endometriosis, comes into focus. However, this variance in receptor types is notable. For example, the ERβ receptor type significantly outnumbers the ERα receptor type. This imbalance could lead to higher estradiol levels and less progesterone as ERβ suppresses ERα [15].

These shifts in hormone receptors on cells are an area of ongoing exploration, offering valuable insights into the complex interplay of hormones in the context of endometriosis.

How is a Progesterone Imbalance Treated?

Multiple studies confirm what experts have long suspected: Progesterone quantity and its interaction with receptors are critical factors in developing and treating endometriosis. Both low progesterone levels and progesterone resistance (ineffective signal transduction to the cell) can decrease efficacy.

But how is an imbalance related to the corpus luteum hormone and estrogen-treated? The answer lies in synthetic progestins, artificially produced corpus luteum hormones that mimic the effects of the body’s natural progesterone. Progesterone receptors respond to synthetic progestins, often resulting in an anti-estrogenic effect.

Various synthetic progestins are available, including:

  • Dienogest
  • Chlormadinone
  • Cyproterone
  • Desogestrel
  • Drospirenone
  • Dydrogesterone
  • Etonogestrel
  • Gestodene
  • Levonorgestrel
  • Medrogestone
  • Medroxyprogesterone
  • Megestrol
  • Nomegestrol
  • Norethisterone
  • Norgestimate
  • Norelgestromin
  • Tibolone
  • Trimegeston

Not Every Synthetic Progestin Is Equally Suitable.

It is important to note that not all synthetic progestins are equally suitable for endometriosis treatment. The German Society for Gynecology and Obstetrics guideline program recommends using progestin as a first-line treatment in symptomatic drug therapy. For this purpose, Dienogest, for instance, is considered suitable. While synthetic progestins can positively influence the size of endometriosis lesions, they may not eliminate them. They can also reduce the risk of recurrence after surgical removal of endometriosis tissue. However, the extent and location of the lesions are significant factors.

Dienogest appears promising, mainly due to its impact on reducing the size of endometriosis lesions, as shown in studies. Nevertheless, the suitability of this progestin may vary based on individual cases of endometriosis. Experts have found that evaluating progesterone and estrogen receptors depends on the type of endometriosis, such as rectovaginal endometriosis versus peritoneal endometriosis [1, 12].

Are There Any Side Effects of Progesterone Treatment?

If your doctor has prescribed a progesterone-based medication, it is likely aimed at reducing your pain and managing endometriosis. However, like with any medication, there can be potential side effects associated with progesterone treatment. These may include intermittent bleeding, mood swings, and a reduced libido. If you experience any unwanted side effects, you should consult your doctor, who can assess whether an alternative medication may suit your situation [13].

Good to Know!

Effective endometriosis treatment should always be a collaborative effort with your healthcare provider. It is crucial to consider all the individual factors at play, such as the extent and location of your endometriosis and your specific symptoms. The treatment’s progress should be monitored and adjusted as needed. For instance, if your goal is to conceive, it is essential to note that progesterone treatment is not a suitable option, as progestins and progesterone derivatives are critical components of birth control pills.

In a Nutshell

The presence and progression of endometriosis are closely linked to the hormonal balance within your body. While estrogen is a well-known contributor, progesterone also holds significance. Progesterone, the hormone produced by the corpus luteum, acts as an antagonist to estrogen and triggers a resting phase in endometriosis cells. Studies suggest the presence of a hormonal imbalance in endometriosis, typically involving elevated estrogen levels and diminished progesterone. Furthermore, research has revealed distinctive behavior in progesterone receptors among individuals with endometriosis. This altered behavior is two-fold: Firstly, there appears to be a reduced quantity of receptor representatives compared to healthy patients, rendering the available progesterone less effective. Secondly, these receptors exhibit diminished efficiency in converting estradiol to estrone. Additionally, endometriosis is associated with disrupted regulatory mechanisms in steroid receptors and an imbalance in estradiol receptors. These substantial changes contribute to hormonal imbalance – too much estrogen has an effect, where excess estrogen can exacerbate inflammation and pain. In an attempt to restore this balance, synthetic progestins are employed. However, it is imperative to consult a medical professional to determine whether hormone therapy is appropriate for your unique situation and to select the most suitable treatment.


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Dipl.-Ges.oec. Jennifer Ann Steinort