Progesterone and Its Metabolites in Luteal Phase Deficiency

Progesterone and Its Metabolites in Luteal Phase Deficiency: History

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Subjects: Obstetrics & Gynaecology

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Progesterone action is the key physiological element of the menstrual cycle. It also plays an important role in the development of the mammary gland and influences the function of the central nervous system and the cardiovascular system. It predominates in the luteal phase. Just after ovulation, progesterone secretion is stable and does not correlate with luteinizing hormone (LH) pulses, while in the middle and late luteal phases, progesterone secretion is episodic and correlates well with pulsatile LH release. During this period, the frequency and amplitude of LH pulses gradually decrease. A decreased plasma progesterone concentration in the luteal phase may predict the occurrence of premenstrual syndrome (PMS); however, some clinical studies failed to provide clear evidence for progesterone being an effective treatment for premenstrual syndrome (PMS) [13,14].In a meta-analysis of the Cochrane consortium on progesterone supplementation, it was found that progesterone reduces the incidence of miscarriages in women with unexplained recurrent miscarriages [16]. Although, in the past, the problem of treating a miscarriage possibly caused by the use of progesterone was the subject of numerous controversies and significant geographical differences in medical practice around the world. A recent meta-analysis has shown that, at least for patients with a history of miscarriage who bled in their next pregnancy, the administration of a high dose of vaginal progesterone (2 × 400 mg) is undoubtedly beneficial. Not only the high dose but also the route of administration, ensuring absorption without the first-pass effect, as well as its stable levels, are important for its effectiveness. In the treatment of LPD, it is important to recognize any underlying disorders and take a restorative approach. While, in the absence of dysfunction, therapeutic management becomes empirical, in the past, the goals of empirical treatment were to stimulate ovulation, increase endometrial receptivity, and support implantation and early pregnancy development. Empirical strategies included progesterone supplementation, progesterone plus estradiol supplementation, luteal human chorionic gonadotropin (hCG), and various ovarian stimulation regimens [7].

progesterone
allopregnanolone
progestins

1. Progesterone and affective disorders

Mental health issues are a serious social problem and a medical challenge worldwide. Women are more at risk of affective disorders [1]. Their susceptibility to these disorders changes with age, although mood disorders, age, and gender patterns have been observed, especially before menopause [2]. Epidemiological data shows that affective disorders occur about twice as often in women than in men, beginning in the reproductive period [3]. Copious scientific evidence points to ovarian hormone activity as a mediator of this difference [4]. The differences in female susceptibility to affective disorders are not static. Still, they may be stronger at certain times of the endocrine cycle and at certain stages of life when ovarian hormone levels are exceptionally high or variable, for instance, during adolescence. Research also indicates that the cyclical changes in the level of ovarian hormones cause periodic fluctuations in the mechanisms responsible for the connections between cells and neural networks [5]. Premenstrual dysphoric disorder (PMDD) is an example of a female affective disorder that is defined by mood symptoms and an increased vulnerability to stress, which may lead to severe disabilities.

Identifying the risk factors of depression symptoms helps women and their clinicians understand the potential course and plan of the therapeutic procedure. Mood and anxiety disorders that occur during the transitional periods in the reproductive period (including the menarche, menstrual cycle, pregnancy, and the postpartum period, as well as the perimenopause) may be subject to further observation in terms of the role of the sex steroids. Progesterone and its metabolites play an essential part in inducing mood disorders in women with menstrual disorders, and estradiol probably strengthens progesterone-invoked dysphoria [6]. Disturbances in the level of progesterone concentration may result from a luteal phase deficiency associated with a spectrum of ovulatory disorders, which are the result of a decreased ovarian reserve, non-ruptured follicle luteinization syndrome, or other metabolic or age-dependent disorders [7]. There is a membrane progesterone receptor in the brain cells, which is related to the control of emotions, among others, in the amygdala. It has been suggested that its malfunction may contribute to emotional dysregulation in women with PMDD [8,9]. Sex steroids also affect the renin-angiotensin-aldosterone system, which is most likely associated with certain somatic symptoms of premenstrual disorders, such as bloating and edema. Progesterone is quickly metabolized to pregnenolone and allopregnanolone, which act as positive allosteric modulators of the receptor for gamma-aminobutyric acid type A (GABA-A) [9,10]. At the same time, modulator activity increases the transmission of the primary neurotransmitter, which has a sedative effect on brain activity. Both pregnenolone and allopregnanolone have antidepressant and anxiolytic effects [9,10]. Data show that women with premenstrual disorders have a reduced plasma allopregnanolone content and a decreased reactivity of the GABA-A receptor to progesterone metabolites [9,10]. Due to the different chemical structures, artificially synthesized progestins will not undergo systemic and local metabolism to become active compounds. They are usually excreted in the urine in unchanged form, or their metabolites are inactive; therefore, they will not exert a similar action to natural progesterone. In theoretical considerations and clinical practice, the effects of bioidentical progesterone should be clearly distinguished from chemical compounds with different chemical structure and metabolism.

2. The Role of Progesterone and Its Metabolites in Luteal Phase Deficiency

Recent research into progesterone provides important insights into the physiological role and clinical significance of this hormone [11]. Progesterone action is the key physiological element of the menstrual cycle. It also plays an important role in the development of the mammary gland and influences the function of the central nervous system and the cardiovascular system. It predominates in the luteal phase. Just after ovulation, progesterone secretion is stable and does not correlate with luteinizing hormone (LH) pulses, while in the middle and late luteal phases, progesterone secretion is episodic and correlates well with pulsatile LH release. During this period, the frequency and amplitude of LH pulses gradually decrease [12]. A decreased plasma progesterone concentration in the luteal phase may predict the occurrence of premenstrual syndrome (PMS); however, some clinical studies failed to provide clear evidence for progesterone being an effective treatment for premenstrual syndrome (PMS) [13,14]. It is worth noting that this meta-analysis only concerns two trials. Moreover, it should also be noted that the exact time of ovulation was not determined, and progesterone was used on the basis of observations of previous menstrual cycles. It is good to remember that initially, the PMS treatment with progesterone that was advised in the 1940s recommended that the onset and dose of administration of progesterone should be tailored to each woman, increasing the number of 400 mg suppositories to as many as six per day during the luteal phase. Not only the high dose but also the route of administration, ensuring absorption, as well as a stable level of progesterone, are key to treatment effectiveness [15]. Nevertheless, in a high-dose study included in the meta-analysis, a statistically significantly greater improvement was recorded in the supplemented group in the per-protocol analysis [13].

On the other hand, in a recent study on 20 women with PMS and 21 healthy women, researchers concluded that when symptoms are redefined as perimenstrual rather than premenstrual, there is an association with both lower steady-state progesterone levels and a luteal phase deficiency [14].

In a meta-analysis of the Cochrane consortium on progesterone supplementation, it was found that progesterone reduces the incidence of miscarriages in women with unexplained recurrent miscarriages [16]. Although, in the past, the problem of treating a miscarriage possibly caused by the use of progesterone was the subject of numerous controversies and significant geographical differences in medical practice around the world. A recent meta-analysis has shown that, at least for patients with a history of miscarriage who bled in their next pregnancy, the administration of a high dose of vaginal progesterone (2 × 400 mg) is undoubtedly beneficial. Not only the high dose but also the route of administration, ensuring absorption without the first-pass effect, as well as its stable levels, are important for its effectiveness. This has already led to a change in the national medical recommendations in the United Kingdom (UK) [17]. It is not optimistic that, until convincing scientific evidence was obtained, the standard treatment in this indication was suspended for many years, which resulted in an additional loss of over 8000 pregnancies per year in the UK alone.

Unstable progesterone levels in premenstrual dysphoric disorders are most commonly explained by a luteal phase deficiency (LPD). LPD can be found in diverse ovulatory disorders originating from a diminished ovarian reserve and a luteinized unruptured follicle to a spectrum of polycystic ovary syndrome [7]. LPD can also frequently occur during controlled ovarian stimulation (COS) protocols and controlled ovarian hyperstimulation (COH) programs. Luteal phase deficiency was first described as a possible cause of infertility in 1949 by Georgiana Seegar Jones [18]. The pathophysiology of LPD may involve several different mechanisms that ultimately affect the development and function of the endometrium. LPD has been described as a condition in which the production of the ovarian hormone is not high enough or long enough to maintain a functional secretory endometrium and allow the proper implantation and growth of the embryo. A short luteal phase is associated with low levels of follicle-stimulating hormone (FSH), a low estradiol level in the follicular phase, an altered FSH/LH ratio in the follicular phase, and an abnormal pulsation of FSH and LH [19]. These follicular phase abnormalities are associated with the subsequent reduction in luteal estrogen and progesterone secretion [20,21,22,23]. Alternatively, LPD may develop on the receptor level, as a result of an abnormal endometrial response to an adequate hormone concentration [24,25]. Idiopathic LPD denotes a luteal phase abnormality in the absence of an identifiable disease process. Difficulties in diagnosing LPD result from inconsistent and unreliable diagnostic criteria, as well as a low availability of appropriate diagnostic methods. The diagnosis of LPD is usually clinically made by an assessment of the length of the luteal phase. Many diagnostic tests have been proposed, including clinical, biochemical, and histological tests, but none of them have been able to reliably differentiate fertile and infertile women [26,27,28,29]. In order of increasing invasiveness, the methods used to diagnose LPD include the diagnosis of a shortened luteal phase based on the length of the menstrual cycle, the basal body temperature (BBT) graph, or urine LH surge kits, the measurement of progesterone derivatives in urine, the measurement of single or multiple serum progesterone levels, as well as an endometrial biopsy [7].

In the treatment of LPD, it is important to recognize any underlying disorders and take a restorative approach. While, in the absence of dysfunction, therapeutic management becomes empirical, in the past, the goals of empirical treatment were to stimulate ovulation, increase endometrial receptivity, and support implantation and early pregnancy development. Empirical strategies included progesterone supplementation, progesterone plus estradiol supplementation, luteal human chorionic gonadotropin (hCG), and various ovarian stimulation regimens [7].

A wide variety of progesterone and progestogen functions that were applied in clinical practice have already been discovered and described [7,8]. However, the role of progesterone in maintaining the luteal phase remains controversial due to its wide and empirical cross-sectional clinical use, ranging from natural ovulatory cycles to assisted reproductive techniques (ARTs). However, no evidence has been found that progesterone is beneficial in the treatment of LPD. No randomized, case-control studies have been found investigating progesterone supplementation in women with LPD. The research conducted so far has only concerned progesterone supplementation in cases of repeated miscarriages, which could theoretically overlap with LPD due to insufficient progesterone support in early pregnancy [7]. In clinical practice, progesterone supplementation is the suggested treatment for LPD. Despite being frequently used, there is no published evidence that it improves pregnancy outcomes in natural cycles [7]. Discussions on the protocols for progesterone administration, especially the route of administration, dose, and timing of administration, and the potential relationship with other drugs, remain open and further research is needed. It has been shown that an advanced reproductive age is associated with a luteal phase deficiency (LPD). Studies have confirmed a reduced production of progesterone and disorders of progesterone, as well as estradiol metabolites, in the luteal phase in women of late reproductive age [25,26,30,31].

This entry is adapted from the peer-reviewed paper 10.3390/ph16040520

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