Polycystic Ovaries (PCO)
 

PCO is an ultrasound finding, of enlarged ovarian volume, typically >10 mL per ovary and / or the
presence of > 12 small antral follicles per ovary. Unlike PCOS, PCO may occur in healthy, ovulating women without any other imbalances, and effects up to 25% of reproductive-age women.[12]

In PCO the increase in follicles, causes an increase in the number and enlargement of theca cells, which are specialized cells surrounding the developing ovarian follicles. These theca cells are primarily responsible for producing testosterone under the influence of luteinizing hormone (LH). Therefore the increased number and functional activity of theca cells leads to elevated intra-ovarian testosterone production, contributing to the hyperandrogenic state, which perpetuates PCO.

 

Increased LH:FSH Ratio
 

We have signalling hormones that govern our reproductive cycle, known as Lutenising Hormone (LH) and follicle-stimulating hormone (FSH), which need to be in balance with one another. 

 

When LH is in dominance, a pattern commonly observed in women with both PCO and up to 70% of PCOS cases, the elevated levels overstimulate theca cells in the ovaries, leading to excessive production of testosterone. At the same time, the deficiency of FSH impairs aromatase activity in granulosa cells, which normally convert these testosterone into estrogens. As a result, there is reduced clearance of testosterone through estrogen conversion, causing an accumulation of testosterone. 

 

This excess testosterone then disrupts normal follicular maturation, leading to anovulation, where no egg is released from the ovarian follicle. These arrested follicles then further contribute to ongoing testosterone production, establishing a self-perpetuating cycle of elevated testosterone and ovulatory dysfunction. [5][12]

 

Elevated Insulin [ Impaired Glucose Tolerance ]

 

Elevated insulin levels may result from high dietary intake of sugars or starches, or from metabolic disorders such as impaired glucose tolerance, which reflect dysregulated glucose metabolism and compensatory increases in insulin. 

 

Elevated Insulin is seen in 50 - 75% of PCOS patients and is a primary mechanism that can lead to androgen excess in at least two ways. Firstly, insulin directly promotes androgen synthesis via 17β-HSD activity in ovarian theca cells, and theca cells in PCOS women have increased insulin sensitivity. 

 

Secondly, insulin stimulates a hormone known as GnRH from the hypothalamus, which in turn enhances the activity of the signalling hormone LH. The elevated LH then overstimulates theca cells in the ovaries, leading to excessive production of testosterone. It has been clearly demonstrated in clinical research that reductions in circulating insulin significantly correspond with decreases in testosterone levels. [10]

 

Polycystic Ovarian Syndrome (PCOS)

 

Polycystic Ovary Syndrome (PCOS) is the most prevalent cause of hyperandrogenism in reproductive aged females, accounting for approximately 70 - 85% of cases. 

 

The condition is commonly driven by key underlying mechanisms, including:

 

• Polycystic ovarian morphology 

• Elevated LH relative to FSH / LH dominance

• Elevated Insulin

 

Each of these factors contributes to sustained ovarian theca cell hyperactivity, which results in excess testosterone production. This hormonal imbalance then reinforces the anovulatory state and polycystic ovarian changes, creating a self-perpetuating feedback loop that underlies the progression and expression of PCOS. [3][5].

 

Progesterone Deficiency

 

Progesterone is a key reproductive hormone responsible for slowing GnRH pulse frequency. This regulatory action is essential because increased GnRH pulse frequency preferentially stimulates luteinizing hormone (LH) secretion over follicle-stimulating hormone (FSH), as predominantly seen in PCOS. The overactivity of LH then overstimulates theca cells in the ovaries, leading to excessive production of testosterone.[13]

 

Liver Insufficiency 

 

The liver plays a central role in breaking down testosterone by converting it into inactive forms so it can be safely removed from the body. This process depends on special liver enzymes that carry out chemical reactions to neutralize the hormone.This metabolic function is critically dependent on hepatic enzymatic activity. In the setting of hepatic Insufficiency these enzymatic pathways become impaired, leading to reduced testosterone clearance and subsequent elevations in circulating testosterone levels.[20]

 

Aromatase Deficiency 

 

Aromatase is a crucial enzyme in the hormone cascade pathway. Through a process called aromatization, it is responsible for converting testosterone into estrogen, and also encourages the conversion of DHEA into estrogen, rather than into testosterone. 

 

This enzyme is expressed in multiple tissues, including the granulosa cells of the ovaries, adipose tissue, skin, and the brain. Within the ovaries, aromatase expression is primarily regulated by follicle-stimulating hormone (FSH), which makes FSH stimulation an important clinical consideration in managing hyperandrogenism.

 

Beyond this, genetics also play a potential role, with inherent mutations in the CYP19A1 gene which is responsible for encoding aromatase, therefore resulting in aromatase deficiency. This can be distinguished by symptoms of hyperandrogenism from a very early age.[10]

 

Dysbiosis 

 

Hyperandrogenism is increasingly understood to be influenced by an imbalance in gut microbiome known as dysbiosis, which can alter microbial metabolites such as short-chain fatty acids, bile acids, and lipopolysaccharides, which in turn affect endocrine signaling. 

 

For example, LPS from gram-negative bacteria can trigger systemic inflammation and disrupt insulin signaling, leading to compensatory hyperinsulinemia, which then stimulates ovarian cells to produce excess testosterone. Gut microbiota also modulate testosterone synthesis directly by influencing gene expression or by regulating enzymes involved in testosterone biosynthesis. 

 

It has been clinically demonstrated that gut microbiota composition in PCOS / high testosterone patients differs significantly from that of healthy individuals. Notably, there is a reduction in microbial diversity and beneficial strains like Lactobacillus and Bifidobacterium, accompanied by an increase in potentially pathogenic bacteria such as Escherichia, Streptococcus, Enterobacteriaceae and Proteobacteria.[33][34]