Progestin Selectivity in Clinical Applications

Abstract

This chapter presents a thorough examination of synthetic progestins in obstetric and gynecologic practice, highlighting their specific use in several clinical scenarios, including miscarriage, luteal phase support, menstrual problems, and endometriosis. Drawing from existing literature, the chapter explores the specific biological, pharmacological, and clinical characteristics of progestins -especially dydrogesterone -emphasizing their subtle functions in different reproductive health conditions. The study primarily revolves around dydrogesterone, with a thorough investigation that includes data extracted from the literature on its molecular structure, in vitro and in vivo findings, clinical data obtained from randomized clinical trials, and systematic reviews. This chapter intends to provide the reader with a detailed understanding of the distinct clinical applications and differential selectivity of synthetic progestins, with a particular focus on the unique features of dydrogesterone. The goal is to equip the reader with a nuanced comprehension of these drugs. This resource is beneficial for healthcare practitioners, researchers, and academicians who want a more detailed understanding of the complex relationship between synthetic progestins and reproductive health in different clinical situations.

1. Introduction

1.1 A refresher on progesterone

Progesterone, one of the first hormones to be discovered, is a 21-carbon sex steroid produced from cholesterol by the conversion of pregnenolone [1, 2]. Progesterone is primarily synthesized in the corpus luteum of the ovaries and also by the placenta [1, 2]. Progesterone derives its name from its role as a hormone essential for initiating and maintaining pregnancy. It is referred to as progestational, combining the prefix “pro,” meaning “for,” with the root “gest,” meaning “pregnancy.” [3].

Although that would mean that progesterone is the key physiological component in the reproductive system, it can also modulate neurotransmitter systems, including the serotonergic, cholinergic, and dopaminergic systems, in addition to immunomodulatory effects [1]. Progesterone also has significant functions in other non-reproductive organs, including the mammary gland for lactation preparation, the circulatory system, the central nervous system, and the bones [4]. Natural or P4 progesterone is vital in pregnancy from conception to delivery. It also has clinical uses in the treatment of preterm labor, miscarriage, and infertility [5]. Progesterone can be utilized to cause amenorrhea or regular bleeding, sub-atrophy, or pre-decidual alterations by adjusting the dosage, duration of treatment, and method of administration [3].

More recent research has enhanced our comprehension of the inhibitory effects of progesterone on immune responses, specifically inflammatory responses. The activation of dendritic cells, macrophages, and natural killer (NK) cells in mice is inhibited by progesterone. The administration of progesterone to rat dendritic cells stimulated with lipopolysaccharide inhibits the synthesis of interleukin (IL)-1 and tumor necrosis factor (TNF)-α, both of which are pro-inflammatory cytokines. Progesterone inhibits the secretion of the cytokine IL-12, which stimulates T-cell activation. Many of these inhibitory effects are achieved through the inhibition of NF-kB activation. It has been documented that progesterone, besides impeding cytokine production, also inhibits the synthesis of chemokines, including RANTES and macrophage inflammatory protein-1β, by CD8+ T lymphocytes. Progesterone exerts intriguing immunoregulatory effects through its ability to modulate the differentiation of various immune cell subpopulations [6].

Throughout the early 2000s, researchers became particularly interested in investigating the involvement of progesterone in both genomic (nuclear) and non-genomic (extranuclear) receptor pathways. These mechanisms work together to directly impact cells and tissues. Due to its lipophilic nature, progesterone easily passes through cell membranes via diffusion. It then interacts with progesterone receptor A (PR-A) and progesterone receptor B (PR-B) at the nuclear level. This interaction triggers the activation of approximately 300 co-regulators, which act on ribosomal RNA. As a result, corresponding proteins are produced. Nuclear progesterone receptors (nPR) require a time span of minutes or hours to initiate ribosomal transcription and serve as the primary controllers of female reproductive processes. The genomic receptors PR-B and PR-A have overlapping regions in the DNA binding domain and the ligand binding domain, but they have distinct amino acid sequences. Specifically, PR-A has 164 fewer amino acids than PR-B. In humans, cells expressing PR-B and PR-A are equally prevalent under normal physiological conditions. Nevertheless, myometrial tissue has a significant amount of a third isoform of nPR, known as PR-C [4].

Progesterone has a key role in facilitating crosstalk between various uterus and placenta cells, influencing many biological processes. Progesterone regulates the process of decidualization by governing the development of endometrial stromal cells. If this signaling is disrupted, it can result in pregnancy difficulties such as recurrent miscarriage and pre-eclampsia. This highlights the critical role of progesterone in this communication between cells. The release of progesterone by the ovaries induces the creation of activin A by cells in the lining of the uterus, which in turn affects the attachment of the embryo’s outer layer to the uterine wall. Progesterone is recognized as a crucial factor in promoting cellular modifications that support an embryo’s attachment and the placenta’s development. Although the endocrinological functions of progesterone have been extensively studied in the past, its involvement in communication with immune cells in the placenta has been evident in recent times [6].

Before we move on to progestins. The difference between “progestins” and “progestogens” is worth highlighting. Progestogens are substances that exhibit progestational action. They encompass both artificial progestogens and organic progesterone, also referred to as P4. In contrast to natural P4, synthetic progestins such as dydrogesterone do not possess tranquilizing, antiandrogenic, diuretic, tocolytic, or neuroprotective properties. These effects are potentially significant for supporting pregnancy from conception to delivery [7]. While the term progestin refers only to synthetic progestational agents that have been synthesized to replicate the activity of P4 [8].

1.2 A quick overview of progestins

The early advancement in steroid hormone bioengineering involved the elimination of the 19-carbon from natural progesterone to create a more powerful synthetic progestational agent. Several novel progestins have been created after the introduction of norethindrone and norethynodrel. The overall objective is to produce chemicals with enhanced potency, specifically targeting the ovary and the endometrium, while ensuring increased safety and control over the menstrual cycle. Additionally, the aim is to minimize adverse effects and provide acceptable non-contraceptive advantages. Progestin molecules exhibit varying affinities for the progesterone receptor, androgen receptor, estrogen receptor, glucocorticoid receptor, and mineralocorticoid receptor. At present, the contraceptive progestins that are accessible are either derived from natural testosterone or progesterone [9].

Progestins can be classified into various categories, including retroprogesterone (e.g., dydrogesterone) and progesterone derivatives (e.g., medrogestone). The compounds mentioned are multiple derivatives of 17alpha-hydroxyprogesterone, 19-norprogesterone, 19-nortestosterone, and spironolactone. Examples of these derivatives include chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate, nomegestrol, promegestone, trimegestone, nesterone, norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest, and drospirenone (Figure 1) [10]. The progestins within the same class have distinct biological activities compared to each other. Thus, analyzing progestins individually, rather than grouping them by class, may provide the most valuable understanding of their specific effects [11].

Figure 1.

Classification of progestins that are structurally related to progesterone.

Progestins, including progesterone (P4), exert their effects through the binding with progesterone receptors (PRs), which exist in two isoforms (A and B) resulting from a single gene located on chromosome 11. These isoforms exhibit distinct tissue distributions and functions. The structural composition of PR includes a DNA-binding domain, zinc fingers, a hinge region, and a ligand-binding domain. Genomic interactions occur when P4 binds to the ligand-binding site, forming progesterone response elements (PREs) and a transcriptional complex that modulates gene expression within minutes to hours. Notably, a third isoform (PR C) has been identified, primarily expressed in myometrial cells, lacking a DNA binding domain but capable of binding to progesterone. Evidence suggests that PR C may inhibit other isoforms by sequestering available progesterone. Isoform A dominates when PR A and B are coexpressed in the same tissue. Moreover, PRs interact with various receptors, such as estrogen receptor, androgen receptor, glucocorticoid receptor, and mineralocorticoid receptor, displaying agonistic or antagonistic effects through specific interactions. The involvement of coactivators or corepressors further adds complexity to the regulatory mechanisms governing PR-mediated actions. Overall, these insights highlight the intricate structural and functional aspects of PRs, contributing to our understanding of progestins’ diverse and nuanced actions [12].

The effectiveness of progestins is primarily categorized by three distinct actions, which are the primary acts that enable progestins to be beneficial in various circumstances [13]. The following items are included:

1. Progestational activity refers to the capacity to induce the transformation of the endometrium into the secretory phase and sustain a pregnancy.

2. Exhibiting anti-estrogenic activity: The capability to reduce the expression of estrogen receptors and subsequently diminish the thickness of the endometrium stimulated by estrogen.

3. Antiandrogenic activity refers to the capability of inhibiting the binding of testosterone (T) to androgen receptors, hence reducing the impact of androgens and counteracting the action of 5α-reductase.

The biological effects of progestogens are contingent upon the presence of estrogens, particularly in most tissues, as the expression of progesterone receptors (PR) is reliant on their presence. However, progestogens suppress the expression of estrogen receptors [14, 15].

By competitively inhibiting the androgen receptor or binding to the enzyme 5-α reductase, certain progestins impede the conversion of testosterone (T) to dihydrotestosterone, thereby exerting an antiandrogenic effect. Moreover, non-androgenic progestins do not inhibit the estrogen-dependent increase in the binding of sexual hormones to globulin when combined with estrogen. This ultimately leads to greater binding of circulating androgens and a reduction in the availability of free T [13].

Beyond progesterone receptors, interactions with the following steroid hormone receptors also contribute to the effects of progestins: Androgen, estrogen, glucocorticoid, and mineralocorticoid receptors. These interactions have the potential to either trigger transactivation or inhibit activation of a steroid receptor. The agonistic or antagonistic nature of progestin’s ultimate effect in the target organ is determined by the equilibrium between receptor coactivators and corepressors recruited by the molecule. While all progestins exert the anticipated effect on the uterine endometrium by binding to the progesterone receptor, their activity profiles in other target tissues are unique and may not be identical among progestins of the same class [16].

Furthermore, the literature showed the anti-inflammatory and immunomodulatory effects of p4 and progestins. Some of the anti-inflammatory and immunomodulatory actions of P4 and its derivatives are associated with the inhibition of NF-kB and COX, the inhibition of prostaglandin synthesis, the regulation of T lymphocytes, the regulation of the production of pro- and anti-inflammatory cytokines, and the phenomenon of immune tolerance. Besides, the inhibition of proliferative signaling pathways and the antagonistic action against estrogen receptor beta-mediated signaling are pro-inflammatory and mitogenic factors. Moreover, steroid receptor cochaperone HSP90 and immunophilins FKBP51 and FKBP52 represent a crucial key in the intracellular signaling of steroid hormones, including progesterone. Thus, due to their combined effect, P4 and progestins could be considered promising alternative steroid hormones to glucocorticoids in the treatment of inflammatory diseases, including endometriosis, stress-related disorders, rheumatoid arthritis, and miscarriages, especially hormone-resistant chronic inflammatory diseases [17].

Anti-estrogenic effects of progestogens and progestin in the endometrium are attributed to the activation of 17β-Hydroxysteroid dehydrogenase type 2, which catalyzes the conversion of estradiol to estrone, and estrone sulfotransferase, which promotes conjugation of estrone; these effects include a decrease in ER expression [12].

Progestins have clinical uses thanks to their therapeutic applications and because their bioavailability and half-lives are superior to P4. Currently, a multitude of additional characteristics of these agents has been elucidated, enabling their utilization in diverse therapeutic contexts—including contraception, hormonal replacement therapy (HRT), and the management of gynecological ailments such as endometriosis and polycystic ovary syndrome [18]. However, progestins have various effects according to their interactions with receptors, including AR, GR, and MR. These interactions can lead to side effects such as acne, hyperlipidemia, salt and water retention, and bloating. Additionally, progestins typically function as an antagonist of MR, resulting in lower water retention and weight [13, 19].

2. Dydrogesterone: molecular structure and characteristics

Dydrogesterone can be considered a stereoisomer of progesterone, with a slight difference in its molecular structure. In dydrogesterone, the hydrogen atom at carbon 9 is positioned in the β position, while the methyl group at carbon 10 is in the α position. This arrangement is the opposite of the structure found in progesterone, leading to its designation as “retro” progesterone. Furthermore, a double bond is present between carbon 6 and 7, altering the flat steroid configuration and resulting in a “bent” conformation that exhibits increased rigidity compared to progesterone. It is believed that this explains why dydrogesterone is highly selective for progesterone receptors, displaying strong progestogenic effects while lacking any significant agonistic effects on androgen, glucocorticoid, and mineralocorticoid receptors. When comparing progesterone and dydrogesterone, it is worth noting that dydrogesterone has a higher oral bioavailability. This, combined with its strong affinity for progesterone receptors and its effectiveness at a low dose, may help to reduce the occurrence of side effects [20].

The molecular structure of this compound bears a striking resemblance to natural progesterone (Figure 2), yet it exhibits improved oral bioavailability. Dydrogesterone and progesterone have distinct structural features that set them apart. With its inverted configuration at C9 and C10 and an additional C6-C7 double bond, dydrogesterone exhibits a bent shape geometry. In contrast, progesterone has an almost planar geometry [21].

Figure 2.

Comparison between the chemical structure of dydrogesterone and progesterone. Adapted from PubChem [Internet]. Bethesda (MD): National Library of medicine (US), National Center for biotechnology information; 2004; PubChem compound summary for CID 5994, progesterone; [cited 2024 Feb. 1]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Progesterone; PubChem [Internet]. Bethesda (MD): National Library of medicine (US), National Center for biotechnology information; 2004-. PubChem compound summary for CID 9051, Dydrogesterone; [cited 2024 Feb. 1]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Dydrogesterone

Early endocrinological studies in animal models indicated that dydrogesterone exhibited significant progestogenic effects while lacking androgenic, glucocorticoid, or estrogenic activity. Dydrogesterone is often regarded as more potent than progesterone, as noted in the lower milligram dose needed to achieve comparable efficacy in comparison to micronized vaginal progesterone (MVP) [22].

Studies conducted in vitro revealed that dydrogesterone did not exhibit any significant agonistic effects on androgen, glucocorticoid, and mineralocorticoid receptors. On the other hand, progesterone exhibited important agonistic activity at androgen receptors while showing little to no agonist activity at glucocorticoid or mineralocorticoid receptors. It was found that dydrogesterone exhibited lower antagonistic activity at glucocorticoid and mineralocorticoid receptors when compared to progesterone. In addition, it is worth noting that progesterone demonstrated significant antiandrogenic effects at the pre-receptor level, effectively inhibiting over 90% of 5α-reductase type 2, which is an enzyme responsible for androgen production. On the other hand, dydrogesterone and 20α-dihydro dydrogesterone (DHD) exhibited comparatively weaker inhibition of this enzyme, reaching only up to 16%. The data presented here collectively illustrates the high selectivity of dydrogesterone for progesterone receptors compared to progesterone. Additionally, dydrogesterone exhibits minimal antiandrogenic effects at the pre-receptor level, thereby reducing other receptors’ activation and undesirable effects [23].

Dydrogesterone functions by offering progesterone-like support during the luteal phase of the menstrual cycle. By imitating the actions of natural progesterone, dydrogesterone enhances the vital processes during this stage, including promoting decidualization and developing a receptive endometrial lining. The actions described foster an environment that supports the successful implantation of embryos and the maintenance of early pregnancy [24].

The retro-structure and the C6-C7 double bond of dydrogesterone provide it with a distinct advantage. These features cause the molecule to adopt a rigid conformation well-suited for binding with the PR. Dydrogesterone’s enhanced rigidity contributes to its selectivity, unlike natural progesterone, which exhibits less selectivity due to its ability to bind to various receptors in different conformations. Due to its enhanced bioavailability and the progestational activity of its main metabolites (20-, 21- and 16-hydroxy derivatives), dydrogesterone requires a significantly lower equivalent dose compared to oral or vaginal micronized progesterone [10].

As shown in Table 1, dydrogesterone is highly selective for progesterone receptors due to its unique structure [10, 23, 25].

Biological activity a	Dydrogesterone	Progesterone
Progestogenic	+	+
Anti-gonadotropin	—	+
Anti-estrogenic	+	+
Estrogenic	—	—
Androgenic	—	—
Antiandrogenic	±b	±
Glucocorticoid	—	+
Anti-mineralocorticoid	±	+

Table 1.

A comparison between the biological activities of dydrogesterone and progesterone.

^a

Therapeutic dosage.

^b

Dydrogesterone demonstrates less antiandrogenic effects than progesterone.

DYD –dydrogesterone, PR-A -progesterone receptor A; + “efficacious”; ±“less efficacious”; −“not efficacious”.

Dydrogesterone is quickly taken up by the body and fully broken down through metabolism. Following oral administration, the levels of dydrogesterone and its main metabolite, 20-dihydro dydrogesterone (DHD), in the plasma peak after 0.5–2.5 hours. Interestingly, the concentration of DHD in the plasma is significantly greater than that of the parent drug. The elimination half-lives of dydrogesterone and DHD are 5–7 and 14–17 hours, respectively. Dydrogesterone does not have any clinically significant pharmacokinetic interactions. Preclinical studies have shown that dydrogesterone has no mutagenic, teratogenic, or carcinogenic effects. Additionally, pharmacovigilance data has not found any evidence of congenital malformations linked to the use of dydrogesterone during pregnancy [26].

3. Clinical applications of dydrogesterone

Dydrogesterone has been widely available in numerous countries for over six decades to address progesterone deficiency and its related conditions. These include irregular cycles, dysfunctional uterine bleeding, dysmenorrhea, endometriosis, secondary amenorrhea, premenstrual syndrome, threatened and habitual miscarriage, infertility due to luteal insufficiency, and hormone replacement therapy. Extensive research and pharmacovigilance data have not found any evidence of dydrogesterone being teratogenic or carcinogenic, nor have they linked its use during pregnancy to congenital malformations (Figure 3) [27].

Figure 3.

Some clinical applications of dydrogesterone.

3.1 Preventing threatened and recurrent miscarriages

Several randomized controlled trials have demonstrated that women who were at risk of early pregnancy loss and received dydrogesterone experienced significantly lower rates of miscarriage compared to those who received bed rest with or without supportive care [28, 29, 30].

According to a systematic review, dydrogesterone was found to significantly decrease the odds of miscarriage by 47% compared to standard care. Additionally, it was associated with an absolute decrease of 11% in the miscarriage rate [31].

This has been supported by a study that highlighted that the occurrence of miscarriage in patients suffering from bleeding in the first trimester was notably lower in the group that received total progesterone compared to the control group. The percentage of miscarriage in the total progesterone group was 13.0%, while in the control group it was 21.7%. The odds ratio was calculated to be 0.53, with a 95% confidence interval of 0.36 to 0.78. The statistical analysis showed a significant difference between the two groups, with a p-value of 0.001 and an I2 value of 0%. In addition, the occurrence of miscarriage showed a substantial decrease in the group receiving oral dydrogesterone compared to the control group (11.7% versus 22.6%; odds ratio, 0.43; 95% CI, 0.26 to 0.71; P = 0.001; I2, 0%). Similarly, the vaginal progesterone group also exhibited a lower rate of miscarriage compared to the control group, although this difference was not statistically significant (15.4 versus 20.3%; odds ratio, 0.72; 95% CI, 0.39 to 1.34; P = 0.30; I2, 0%). Nevertheless, there was no discernible difference in the occurrence of miscarriage between the groups receiving oral dydrogesterone and vaginal progesterone. Progesterone therapy, particularly oral dydrogesterone, is highly effective in preventing miscarriage in pregnant women who are facing the risk of abortion [32].

Another systematic review assessing ten studies examining the effects of progestins versus placebo has concluded a statistically significant decrease in the pregnancy loss rates in patients treated with progestins, including dydrogesterone [33].

These results are supported by another randomized controlled trial that examined the effectiveness of dydrogesterone versus vaginal progesterone in women with recurrent pregnancy loss (RPL) and presenting with first-trimester bleeding. The study revealed that patients treated with dydrogesterone experienced a faster cessation of bleeding compared to those treated with vaginal progesterone [34].

In a recent meta-analysis, Zhao et al., conducted a comprehensive assessment of the effectiveness and safety of different progestogens. They analyzed data from 59 randomized controlled trials involving a total of 10,424 women. The study concluded that oral dydrogesterone was more effective than vaginal progesterone in treating threatened miscarriages [35].

Based on the previous data, it is no wonder that dydrogesterone has been recommended for the management of early pregnancy loss by multiple international guidelines, including the European Progestin Club (EPC), European Society of Human Reproduction and Embryology (ESHRE), Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG), German (DGGG), Austrian (OEGGG), and Swiss (SGGG) Societies of Gynecology and Obstetrics, National Institute for Health and Care Excellence (NICE), and Russian Society of Obstetricians and Gynecologists. Miscarriage in addition to local guidelines in Saudi Arabia, Malaysia, China, Vietnam, Taiwan, Indonesia, Mexico, and the Philippines [36].

3.2 Regulating menstrual periods

Research demonstrated the efficacy of dydrogesterone as a therapeutic agent for the management of dysfunctional uterine hemorrhage. The utilization of this technique has prevented patients from undergoing hysterectomy, hence reducing their exposure to the potential risks associated with general anesthesia and surgery. Additionally, it has alleviated the strain and fiscal burden on the hospital, staff, and the state [37].

A multicenter study involving 104 women was done to evaluate the effects of cyclical dydrogesterone, which is commonly used for estrogen replacement therapy. The trial was double-masked, randomized, and placebo-controlled. Secondary amenorrhea is the medical term used to describe the stopping of menstrual periods after they have already started. Nevertheless, it has been precisely delineated by many definitions, some of which coincide with oligomenorrhea (scanty menstrual flow occurring at intervals of 35 days to 6 months). This indicates the broad range of patients affected by this disorder. The approximate prevalence of secondary amenorrhea in women of reproductive age is approximately 3%. Ultimately, dydrogesterone is markedly more effective than a placebo in stimulating the occurrence of withdrawal bleeding and sustaining regular menstrual bleeding in women who have secondary amenorrhea and possess normal levels of estrogen [38].

A pilot randomized controlled trial revealed that dydrogesterone was equally effective to vaginal micronized progesterone in the treatment of dysfunctional uterine bleeding [39].

A multicenter observational study involving 210 women diagnosed with heavy menstrual bleeding (HMB) aimed to investigate the impact of dydrogesterone treatment on health-related quality of life (HRQoL). Women with a pictorial blood assessment chart (PBAC) score exceeding 100 were considered to have HMB. After administration of dydrogesterone for three consecutive cycles, participants were assessed using the 5-dimensional EuroQol (EQ-5D) for HRQoL, PBAC score, and menstrual cycle diaries at entry (visit 2) and the end of each treatment cycle (visits 3 to 5). A notable decrease in PBAC score indicated that improved severity of menstruation was reported. Additionally, menstrual flow assessments shifted toward medium and light categories, with only six women describing their flow as heavy post-treatment compared to 201 before treatment. Dydrogesterone treatment was well-tolerated, with a 14.3% incidence of adverse events, predominantly pallor (3.8%) and anemia (2.4%), which need further hematologic treatment to correct HMB-associated iron deficiency anemia. In conclusion, the study demonstrates that dydrogesterone treatment substantially and significantly enhances HRQoL in women suffering from HMB by effectively addressing the severity of menstrual bleeding [40].

Dydrogesterone, taken as an orally administered retroprogesterone, is commonly employed to address inadequacy in progesterone levels, such as irregularities in the menstrual cycle. A non-interventional, single-arm, post-marketing, observational study was conducted to assess the impact of dydrogesterone on the regularization of the menstrual cycle. It showed that the administration of dydrogesterone resulted in the attainment of menstrual cycle regularization and a decrease in both menstrual pain and anxiety, both throughout the treatment period and the subsequent 6-month observation period [27]. This was further established by a more recent post-marketing study that showed that administering dydrogesterone orally throughout the latter half of the menstrual cycle has demonstrated a reduction in menstrual abnormalities. This study is prospective and observational. Furthermore, dydrogesterone effectively normalizes and enhances the length of the menstrual cycle, diminishes the volume of bleeding, alleviates menstrual discomfort, and prevents the recurrence of irregular cycles up to 6-months following the cessation of treatment [41].

Another literature review examining the efficacy of medicines, the frequency of complications (for example, the risk of venous thromboembolism when taking combined oral contraceptives, depending on the type of progestogen), and contraindications of progestins in the management of abnormal uterine bleeding in postmenopausal women revealed that dydrogesterone therapy has demonstrated great efficacy in restoring regularity to irregular menstrual periods, as evidenced by randomized controlled trials. Dydrogesterone is a drug that does not affect metabolism. It does not have any androgenic, glucocorticoid, mineralocorticoid, or antigonadotropic effects. It does not worsen insulin resistance or dyslipidemic disorders or affect the hemostatic system. Therefore, it can be safely recommended for a broad range of women with abnormal uterine bleeding including adolescents [42].

A single-arm, prospective, non-interventional, observational research was conducted after the product had been marketed. In conclusion, the administration of dydrogesterone therapy proved to be an efficient method for achieving menstrual cycle regularization in Chinese patients with abnormal uterine bleeding. Furthermore, the neutral effects of dydrogesterone on sex hormones, as well as the metabolic level, provide further evidence that it plays a role in the regulation of irregular menstrual cycles [43].

Another study presented an interesting finding. In this study, patients were treated with dydrogesterone, norethisterone acetate (NETA), medroxyprogesterone acetate, or nomegestrol acetate. The main objective was to determine the effects of these four compounds on basal body temperature (BBT), depression, and anxiety. Interestingly, dydrogesterone did not affect BBT like NETA or other progesterones. Furthermore, dydrogesterone reduced anxiety compared to other treatments [44].

3.3 Luteal phase support in IVF cycles

Overall, substantial data indicates that dydrogesterone has a high absorption level when taken orally and a strong affinity for progesterone receptors. A study even suggested it is efficacious at a 10 to 20 times lower dosage than micronized progesterone. Dydrogesterone exhibits a favorable safety and tolerability profile with few adverse effects. Consequently, it is considered an optimal choice for use in assisted reproductive technology (ART) as a luteal phase support (LPS) agent. Oral dydrogesterone is equally beneficial as vaginal progesterone for LPS in women undergoing fresh in vitro fertilization (IVF) [45].

Dydrogesterone can also be used as an add-on therapy. Retrospective cohort research that was performed at a single site from 2013 to 2019 revealed that the utilization of dydrogesterone in conjunction with micronized progesterone gel resulted in a greater clinical pregnancy rate and live birth rate compared to the exclusive use of micronized progesterone gel in frozen-thawed embryo transfer (FET) cycles [46].

Another pilot single-masked randomized controlled trial reported that it was effective, and patients tended to prefer oral dydrogesterone due to its ease of use, cheaper cost, and greater efficacy. Therefore, dydrogesterone can be suggested as an alternative to intramuscular or vaginal supplements for LPS in artificial FET cycles [47].

A clinical trial has indicated that oral dydrogesterone (40 mg/day) is as efficacious as vaginal micronized progesterone in terms of clinical outcomes, patient satisfaction, and tolerability for LPS in women undergoing IVF [48].

3.4 Relieving pain in endometriosis

Evidence from 1976 reported that after the administration of 5 mg of dydrogesterone twice daily to 49 endometriosis patients, five patients were asymptomatic following 9-months of treatment. In most cases, subjective symptoms resolved within 4 to 9 weeks; dyspareunia, on average, required more time. A “cure” of endometriosis was verified in 30 out of 32 patients who underwent culdoscopy following one or two courses of treatment. Following treatment, ten of nineteen infertile patients became expectant. Two patients experienced transient mastalgia and vertigo as the only adverse effects. There were no reported cases of amenorrhea or other disruptions of the menstrual cycle [49].

In women with dysmenorrhea, cyclic application of dydrogesterone has also been shown to induce regular menstruation, reduced blood loss, and fewer days of bleeding, in addition to providing exceptional symptomatic relief [50].

The ORCHIDEA study showed that the extended cyclical and uninterrupted courses of dydrogesterone treatment showed significant and comparable decreases in the intensity of long-lasting pelvic discomfort and painful menstruation and resulted in notable enhancements in all aspects of quality of life and sexual satisfaction measured in the study [51].

Compared with gestrinone, dydrogesterone relieved dysmenorrhea, increased the pregnancy rate, and reduced the risk of certain adverse events. Compared with Gonadotropin releasing hormone - agonist (GnRH-a), dydrogesterone also lowered the risk of endometriosis recurrence and elevated transaminase levels.

Dydrogesterone exhibits superior efficacy in alleviating pelvic discomfort and dysmenorrhea compared to gestrinone while also demonstrating a lower incidence of adverse effects. Conceiving while using dydrogesterone may provide a higher level of safety. GnRH agonists exhibit significant adverse effects, including hot flushes, vaginal dryness, headaches, superficial dyspareunia, and a propensity for the emergence of osteoporotic alterations. Moreover, it is advised to refrain from attempting pregnancy while doing this therapy. Dydrogesterone significantly enhances pregnancy rates within the first year following surgery, compared to receiving no treatment. The rise in pregnancy rates becomes statistically significant around the 12-month mark [52]. Dydrogesterone’s diverse advantages in alleviating symptoms and improving fertility highlight its attractive position as a treatment for pelvic discomfort and dysmenorrhea, compared to alternative options such as gestrinone and GnRH agonists.

It is worth mentioning that dydrogesterone is not the only progestin used for managing endometriosis. Levonorgestrel, medroxyprogesterone acetate, NETA, dienogest, and dydrogesterone are the most well-known progestogens utilized in endometriosis-affected patients [53]. In 2018, a study was published that examined the therapeutic and side effects, as well as the molecular mechanisms of action, of dydrogesterone and dienogest in mice with endometriosis. After carefully evaluating the size and volume of lesions, histological parameters, and biochemical markers of proliferation and apoptosis throughout and after treatment, it was determined that dydrogesterone and dienogest exhibit efficacy in treating endometriosis. These treatments demonstrate selective effects on proliferation, apoptosis, and the molecular mechanisms associated with endometriosis. It has been observed that both dydrogesterone and dienogest significantly impact the size of lesions and inhibit the growth of cells in endometriotic foci. The primary therapeutic effects of this treatment are associated with progesterone receptors. It works by suppressing cell proliferation and activating apoptosis in endometriotic foci. Nevertheless, the antiproliferative and apoptosis effects were less pronounced in dienogest when compared to dydrogesterone [54]. A study reported that while both had comparable safety profiles, a lower dose of dienogest was more effective than dydrogesterone for relieving pain associated with endometriosis [55]. Given its potent effects on the endometrium, NETA is a useful treatment for endometriosis and endometrial hyperplasia. However, special consideration is needed in cases of high risk for thromboembolic events and when treating women experiencing migraine with aura [56]. On the other hand, there is evidence supporting that dydrogesterone therapy does not increase the risks for venous thromboembolism [57]. Another study reported that dydrogesterone therapy was associated with decreased levels of fibrinogen and Lp(a), hence decreasing the risk for future cardiovascular events [58]. This was further confirmed by a recent literature review reporting that dydrogesterone therapy was associated with minuscule risks for cardiac manifestations and venous thromboembolism [59].

4. Dydrogesterone’s safety profile

Dydrogesterone has been commercially available and utilized since the 1960s to address various diseases related to inadequate progesterone levels. It is recommended for treating both threatened and idiopathic recurring miscarriages in multiple nations across the globe. According to the cumulative statistics on dydrogesterone exposure from April 1960 to April 2021, it is predicted that the total patient exposure after the drug was released on the market will be 137.5 million patient treatment years. According to sales data from 2014, it was predicted that around 20 million fetuses were exposed to dydrogesterone in the womb between April 1960 and April 2014. Dydrogesterone was correlated with elevated levels of patient and clinician satisfaction. At the end of treatment (EOT), 89.6% of patients expressed satisfaction or high satisfaction with their treatment, while investigators assessed the overall response to treatment as good or excellent in 85.8% of patients [27].

Dydrogesterone exhibits no estrogenic, androgenic, or adrenocorticoid activity. It cannot be converted into estrogens and only shows anti-estrogenic effects in specific target organs, such as the endometrium. It is worth noting that this synthetic progestational agent has shown promising results, as its endometrial response closely resembles that of natural progesterone. Interestingly, it does not impact the pituitary-adrenal axis, and there is no decrease in plasma progesterone levels when administered after ovulation. In addition, it shows no or only mild suppression of ovulation, which is often seen with other progestogens. Furthermore, it does not impact coagulation, blood lipids, or glucose/insulin parameters. It is also not harmful to the liver and does not lead to a rise in body temperature. It has been observed to have a similar effect on aldosterone as natural progesterone but does not significantly impact water and electrolyte balance. Unlike progesterone, dydrogesterone does not get eliminated as pregnanediol in urine. Thus, it remains feasible to measure urinary pregnanediol as an indicator of natural progesterone secretion in women receiving dydrogesterone treatment [25].

From 1977 to 2005, pharmacovigilance data identified a mere 28 instances of congenital abnormalities that may be associated with fetal exposure to dydrogesterone. The defects exhibited a wide range of variations without any discernible pattern of anomalies. Therefore, there is no evidence of a correlation between congenital abnormalities and the usage of dydrogesterone [26]. A more recent study also supported the previous statement and attributed the safety of taking dydrogesterone during pregnancy to its well-established safety profile [22].

An important note is that dydrogesterone is less likely to cause DNA fragmentation and repair synthesis in primary cultures of rat hepatocytes. A study comparing the three progestogens that include double bonds, namely dydrogesterone, dienogest, and 1,4,6-androstatriene-17-ol-3-one acetate (ADT), and cyproterone acetate revealed that cyproterone acetate exhibited the highest DNA damaging potency, followed by dienogest, ADT, and finally dydrogesterone [60].

Another study revealed that dydrogesterone’s high selectivity for progesterone receptors helped to minimize the risk of side effects in women undergoing assisted reproduction. They added that the distinctive molecular arrangement of dydrogesterone enables its effectiveness when taken orally at low therapeutic dosages, so circumventing the tolerability concerns linked to the vaginal administration of progesterone [24]. This may be due to the unique structure of dydrogesterone, which allows efficacy with oral administration at low therapeutic doses, avoiding the tolerability issues associated with vaginal administration of progesterone. In addition, dydrogesterone’s high selectivity for progesterone receptors may help to limit the risk of side effects.

Another study examining patients with threatened miscarriage revealed that the incidence of congenital, familial, and genetic diseases was low and comparable across oral dydrogesterone and MVP gel in the Lotus I and II trials and later meta-analyses and subpopulation studies [20, 59, 61, 62, 63].

An intriguing hypothesis posits that progesterone may influence bone metabolism. To explore this, we focused on dydrogesterone, a compound closely mirroring the chemical structure of natural progesterone while devoid of any androgenic effects. Our investigation involved a comparative analysis, specifically examining the impact of a daily regimen of dydrogesterone compared to estradiol treatment. Surprisingly, the dydrogesterone regimen led to an increase in osteoclasts, though without a discernible augmentation in their functionality. The work of Roux C. et al. proved that in rat models subjected to ovariectomy, dydrogesterone failed to inhibit bone resorption, and interestingly, it exhibited no influence on the positive effects induced by estradiol. These findings shed light on the complex interplay between dydrogesterone and bone metabolism and the contrasting impact observed compared to estradiol treatment. Further research is warranted to unravel dydrogesterone’s nuanced dynamics and potential implications on bone health, offering valuable insights into its specific interactions within the context of bone metabolism regulation [64].

Progesterone is involved in insulin resistance by blocking the PI3-kinase pathway and reducing the expression of insulin receptor substrate 1 (IRS1). Estradiol causes insulin resistance by activating the c-Jun N-terminal kinase (JNK) through the estrogen receptor located on the cell membrane. This leads to the phosphorylation of serine residues on the insulin receptor substrate-1 (IRS-1) [65]. Additionally, some research studies claimed that the use of progestogen supplements during pregnancy to lower the chances of preterm birth can raise the likelihood of developing gestational diabetes mellitus. Conversely, dydrogesterone does not possess diabetogenic properties [66, 67].

5. Conclusions

To summarize, investigating progestogens, particularly dydrogesterone, concerning reproductive health and gynecological problems unveiled a complex and diverse scenario. The ongoing research highlights the intricate nature of women’s reproductive health, pregnancy, and the process of maximizing positive pregnancy outcomes. Further research is needed to optimize care to establish a comprehensive therapeutic approach that combines validated psychological support with pharmaceutical techniques. To recognize the importance of patient education in improving treatment adherence and outcomes, it is important to focus on teaching patients about gynecological disorders, pregnancy complications, and pregnancy loss, as well as the advantages of dydrogesterone. In the future, the idea of tailoring treatment to individual patients using prediction models that consider their specific traits and biomarkers has the potential to greatly enhance the effectiveness of dydrogesterone therapies. Moreover, a crucial aspect of future investigation is examining the long-term safety of dydrogesterone and its potential effects on the health of both the mother and the fetus. An in-depth evaluation of its risk-benefit profile over prolonged durations will yield significant insights. In conclusion, acquiring a thorough comprehension and incorporation of many aspects would enable a more knowledgeable and customized strategy to improve the chances of a healthy life and successful childbirth, particularly for women experiencing repeated and imminent pregnancy loss.

Conflict of interest

The author declares no conflict of interest.