PCO + PCOS Polycystic Ovary Syndrome (PCOS)

Individuals with Polycystic Ovaries (PCO) or Polycystic Ovary Syndrome (PCOS) typically have low progesterone levels, especially during the second half of the menstrual cycle. This is because 

progesterone is produced by the corpus luteum, a structure that forms in the ovary after ovulation.
Women with PCOS often experience arrested follicle development before reaching the pre-ovulatory stage, resulting in infrequent or absent ovulation. Without ovulation, no corpus luteum forms, so progesterone remains low. [46]. 

Another hallmark of PCOS is disproportionately elevated luteinizing hormone (LH) relative to follicle-stimulating hormone (FSH). Since FSH is essential for promoting granulosa cell proliferation, its insufficiency further impairs follicular development. As a result, follicles may begin to grow but ultimately stall or ovulate incompletely [47]. 

Inadequate Luteinising-Hormone (LH) Surge [ Hypogondaism ] 

The LH surge is necessary to trigger follicular rupture (ovulation) and luteinization of cells into progesterone-secreting luteal cells. If the LH surge is weak, delayed, or blunted, the corpus luteum that forms is structurally weak and lacks adequate blood flow, subsequently causing limited progesterone-synthesizing capacity [38].

Inadequate Follicle-stimulating hormone (FSH) Surge  [ Hypogondaism ]

Follicle-stimulating hormone (FSH) plays a central role in the first phase of the menstrual cycle, the follicular phase. Its primary function is to stimulate the growth, development, and maturation of ovarian follicles, particularly by acting on granulosa cells. After ovulation, these granulosa cells undergo luteinization and become the primary progesterone-producing cells in the corpus luteum. 

Therefore, if the follicle is underdeveloped due to inadequate FSH stimulation, it will contain fewer granulosa cells, or cells that are functionally immature. This leads to a weaker cellular foundation for luteinization and, consequently, reduced progesterone production during the luteal phase [39,40].

Anovulation

In circumstances of low LH, FSH, ovarian failure or PCOS there can be a complete absence of ovulation. Since the corpus luteum only forms after ovulation, its absence means no progesterone is produced. This leads to an estrogen-dominant cycle with no luteal phase support.

Luteal Phase Deficiency Looping

Women with Luteal Phase deficiency often display altered bioactive signalling surges, such as LH, which then disrupts the feedback loops necessary for timely FSH release and coordinated follicular growth. Over time, this leads to a persistent looping of hormonal irregularities and contributes to the recurring nature of luteal dysfunction [31,32].

Estrogen Dominance

Estrogen dominance refers to excessive estrogen relative to progesterone. Estrogen dominance suppresses the hypothalamic-pituitary-ovarian (HPO) axis, leading to disrupted LH/FSH release, inadequate follicular development, and poor-quality ovulation [33]. 

High estrogen levels also enhance negative feedback on the hypothalamus, reducing GnRH pulsatility, which in turn blunts LH and FSH secretion. This hormonal disruption impairs the follicle’s ability to mature fully and respond to LH with a proper surge [34].
 

The result is under-luteinization of cells, and a corpus luteum that is hormonally and structurally deficient, limiting progesterone production.

Chronic Stress + Inflammation [ Hypercortisolism ] 

Chronic stress and inflammation are linked to the following conditions. 

• SNS Hyperactivity 

• Candiasis

• Mast Cell Activation

• Tregs Dysfunction

• MSK Inflammation

• Hepatic Insufficiency

• Herpes + Epstein Barr Virus

These states lead to sustained elevations in cortisol production, and elevations in cortisol causes multiple negative reproductive influences that lower the production of progesterone. These influences include:

• Suppression of GnRH pulsatility, leading to reduced LH and FSH secretion, which impairs follicular development and ovulation.

• Pregnenolone steal, where cortisol demand and production can divert the precursor pregnenolone from progesterone synthesis, instead prioritising cortisol.

• Decreased ovarian tissue sensitivity to LH and FSH impacting ovulatory quality.

• Even when ovulation occurs, the corpus luteum may exhibit reduced vascularization and mitochondrial function compromising progesterone biosynthesis.

[35,36,37]

Under-active Thyroid [ Hypothyroidism ] 

In hypothyroidism, reduced levels of the thyroid hormones T3 and T4 impair pituitary feedback regulation, often leading to elevated thyrotropin-releasing hormone (TRH), which in turn stimulates increased prolactin secretion [41].

Elevated prolactin inhibits the release of gonadotropin-releasing hormone (GnRH), thereby reducing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. This hormonal disruption impairs follicular development, compromises corpus luteum formation, and ultimately results in lower progesterone production [42].

Additionally, thyroid hormone receptors (TRα1 and TRβ1) are expressed in ovarian tissue, where binding of thyroid hormones directly stimulates progesterone synthesis [43] These hormones also act synergistically with FSH to enhance granulosa cell function by upregulating steroidogenic enzymes such as 3β-hydroxysteroid dehydrogenase, promoting LH receptor formation, and increasing aromatase activity—processes critical for proper luteal function and progesterone output [44].

Thus, insufficient thyroid hormone availability can significantly suppress progesterone production. Notably, treatment of hypothyroidism has been shown to restore menstrual regularity, enhance luteal progesterone secretion, and improve fertility outcomes.

High Prolactin

High prolactin levels suppress GnRH release, reducing LH and FSH, which are essential for ovulation. Without proper ovulation, or in the case of weak ovulation, progesterone production is reduced [45]. In cases of high prolactin, dopamine deficiency needs support. 

Nutritional Deficiencies  - Vitamin B6 + Zinc

Micronutrients like vitamin B6 and zinc are essential for Progesterone support.

Vitamin B6 is crucial for healthy luteal cells within the corpus luteum. It also acts as a coenzyme for the key enzyme 3β-HSD, which converts pregnenolone into progesterone. B6 also supports estrogen clearance, which keeps prolactin levels in check, important given high prolactin can suppress ovulation. For these reasons a deficiency in B6 can lead to poor progesterone production. 

Clinical evidence with B6 shows significant improvements in PMS symptoms by taking 40mg of B6, twice per day. The results demonstrated a reduction in irritability, tension, sleep problems, mood swings, food cravings, depression, forgetfulness, anxiety, poor concentration, crying, suicidal thoughts, decreased libido, and fatigue.

Whereas Zinc plays a critical role in the pituitary gland’s release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), both of which are essential for ovulation and the formation of a healthy corpus luteum for optimal progesterone production.  

Clinically, 142 women received 50 mg per day of elemental zinc for three consecutive menstrual cycles. Participants on zinc treatment led to significant reductions in PMS symptom scores throughout the study, with a 9.5% decrease in the first cycle, 6% in the second, and 2.6% in the third cycle, totalling an 18% reduction in PMS symptoms over 3 months [42]. 

Strenuous physical activity

Strenuous physical activity can suppress the hypothalamus, disrupting the normal pulsatile release of gonadotropin-releasing hormone (GnRH). This disruption reduces the secretion of luteinizing hormone (LH) from the pituitary gland, which is crucial for ovulation and the formation of the corpus luteum, the temporary structure that produces progesterone [48]. 

In addition, intense exercise often leads to low energy availability, a state in which caloric intake fails to meet the body’s energy demands. This energy deficiency prompts the body to conserve resources by prioritizing vital functions like brain and heart activity, while suppressing non-essential systems such as reproduction. Consequently, this can result in anovulation, shortened luteal phases, and chronically low progesterone levels [49].