From the Guidelines
No, decreased progesterone levels in anovulation do not occur due to downregulation by elevated estrogen. Rather, progesterone levels are low in anovulation because no ovulation occurs, and thus no corpus luteum forms to produce progesterone. In a normal ovulatory cycle, after the follicle releases an egg, it transforms into the corpus luteum, which secretes progesterone during the luteal phase. In anovulation, follicular development is disrupted at some point, preventing ovulation from occurring. This disruption can happen for various reasons including polycystic ovary syndrome (PCOS), hypothalamic dysfunction, premature ovarian insufficiency, hyperprolactinemia, or thyroid disorders. In some anovulatory conditions like PCOS, estrogen levels may actually be normal or even elevated due to persistent follicular activity without ovulation, but this elevated estrogen doesn't directly cause the progesterone deficiency, as supported by studies such as 1. The fundamental issue is the absence of ovulation and corpus luteum formation, which is the primary source of progesterone in the menstrual cycle. Some studies, such as 1 and 1, discuss the management and diagnosis of PCOS, but they do not directly address the relationship between estrogen and progesterone levels in anovulation. However, they do provide insight into the complexities of anovulatory conditions and the various factors that can contribute to disrupted menstrual cycles. Key points to consider include:
- Low progesterone levels are a hallmark of anovulation
- The absence of ovulation and corpus luteum formation is the primary cause of low progesterone levels
- Elevated estrogen levels in some anovulatory conditions do not directly cause progesterone deficiency
- PCOS is a common cause of anovulation and is associated with hyperandrogenism, insulin resistance, and other metabolic dysregulations, as discussed in 1 and 1. Overall, the relationship between estrogen and progesterone levels in anovulation is complex, but the primary issue is the disruption of normal ovulatory cycles, not the downregulation of progesterone by elevated estrogen.
From the Research
Hormonal Regulation in Anovulation
The relationship between decreased progesterone levels in anovulation and the potential downregulation by elevated estrogen is complex. Several studies have investigated the hormonal changes and their effects on ovulation and fertility.
- The study by 2 found that during the normal menstrual cycle, the concentrations of estradiol and progesterone receptors are positively correlated with the concentration of plasma estradiol only during the proliferative phase. However, in anovulatory cycles, the concentrations of estradiol and progesterone receptors are high, similar to those of the late proliferative phase.
- Another study by 3 observed that women with one anovulatory cycle tended to have lower estradiol, progesterone, and LH peak levels during their ovulatory cycle, suggesting a possible underlying cause of anovulation, such as a longer-term subclinical follicular, ovarian, or hypothalamic/pituitary dysfunction.
- The research by 4 compared the expression of key molecules of the Wnt/β-catenin pathway in the endometrium of women taking clomiphene citrate (CC) and letrozole, and found that the mean serum estrogen and progesterone were lower and higher, respectively, in letrozole than CC groups.
- Additionally, the study by 5 reported that metformin therapy regulates uterine progesterone signaling in PCOS-like rats, and that elevated expression of progesterone receptor isoforms A and B parallels increased estrogen receptor expression in PCOS-like rat uteri.
Mechanisms of Hormonal Regulation
The mechanisms by which estrogen and progesterone interact to regulate ovulation and fertility are not fully understood. However, the available evidence suggests that:
- Elevated estrogen levels may downregulate progesterone receptors, leading to decreased progesterone levels and anovulation 2.
- The Wnt/β-catenin pathway plays a crucial role in regulating endometrial function and fertility, and is affected by estrogen and progesterone levels 4.
- Metformin therapy may regulate uterine progesterone signaling and improve fertility outcomes in women with PCOS 5.