Hello! Welcome back to our study of PCOS pathophysiology.
In our previous lessons, we built a detailed picture of how hyperandrogenism develops from an ovarian perspective. We saw how abnormal GnRH pulsatility leads to excessive LH, how the ovarian theca cells themselves are intrinsically programmed to overproduce androgens, and how insulin resistance acts as a powerful amplifier in this process.
Today, we shift our focus from the ovary to another key endocrine organ: the adrenal gland. While the ovary is the main culprit in most cases, a significant subset of women with PCOS also have an excessive production of androgens from their adrenal glands.
Our learning outcome for this lesson is to describe the contribution of adrenal androgen excess in a subset of women with PCOS. We will explore what this is, how it's identified, and what mechanisms are thought to drive it.
The Adrenal Gland's Role in Androgen Production
As we covered in Module 5, females produce androgens from two main sources: the ovaries and the adrenal glands.
While both organs produce androgens like androstenedione, the adrenal gland is the almost exclusive source of an androgen precursor called dehydroepiandrosterone sulfate (DHEAS). This makes measuring DHEAS levels in the blood an excellent way to assess the adrenal contribution to a woman's androgen status.
To understand the sources of the main androgens in women with PCOS, please study the following material.
Differentiating Polycystic Ovary Syndrome from Adrenal ...
The article 'Differentiating Polycystic Ovary Syndrome from Adrenal ...' provides a clear breakdown of normal androgen metabolism. We will then look at a table showing how these sources shift in PCOS.
First, read the subsection titled '2.1. Normal Androgen Metabolism' to refresh your understanding of the different androgens and their origins. Pay attention to the description of DHEAS. Then, examine Table 2, 'Sources of serum androgens in PCOS patients,' to see the specific contributions of the ovary, adrenal gland, and peripheral conversion for different androgens in PCOS.
As you saw, in women with PCOS:
- Testosterone and Androstenedione are predominantly produced by the ovaries (~60%).
- DHEAS is overwhelmingly produced by the adrenal glands (>95%).
Therefore, when a woman with PCOS has a significantly elevated DHEAS level, it points to a distinct contribution from the adrenal glands, a condition known as Functional Adrenal Hyperandrogenism (FAH).
Functional Adrenal Hyperandrogenism (FAH) in PCOS
FAH is found in a substantial minority of women with PCOS, with studies suggesting a prevalence of about 20-30%. This means that in addition to any ovarian dysfunction, their adrenal glands are also overproducing androgens.
So, what causes this?
The leading theory is not that the pituitary is sending excessive signals (i.e., too much ACTH), but rather that the adrenal glands themselves are intrinsically hypersensitive to normal levels of ACTH. This is a parallel concept to the intrinsic dysregulation we saw in ovarian theca cells. In these women, a normal ACTH signal provokes an exaggerated androgen response from the adrenal zona reticularis.
The following reading explores the mechanisms and prevalence of FAH in more detail.
The Significance of Functional Adrenal Hyperandrogenism ...
This review, 'The Significance of Functional Adrenal Hyperandrogenism ...', is an excellent resource on the adrenal component of PCOS. It clearly explains the key mechanism and also touches on the role of insulin.
Please read the 'Abstract' for a high-level summary. Then, read the section 'Mechanisms of FAH in PCOS,' focusing on the two subsections: 'Increased sensitivity to ACTH' and 'Hyperinsulinemia.' This will clarify the core mechanism and its connection to our previous lesson.
From the reading, we can draw two key conclusions about the mechanism of FAH:
- Increased Adrenal Sensitivity to ACTH: Studies show that women with PCOS and FAH have a normal HPA axis (hypothalamic-pituitary-adrenal) but exhibit an exaggerated androgen response when stimulated with ACTH. This points to a dysregulation within the adrenal gland itself.
- Potential Role of Hyperinsulinemia: The connection between insulin and FAH is less definitive than with the ovary, but there is evidence suggesting a link. In vitro studies show insulin can augment the adrenal response to ACTH. Furthermore, some clinical trials have shown that improving insulin sensitivity with medication can lead to a decrease in adrenal androgen production. This suggests that the hyperinsulinemia we discussed in the last lesson may contribute to both ovarian and adrenal hyperandrogenism.
The Journey of Adrenal Androgens
It's important to remember that DHEAS itself is a weak androgen. Its clinical significance comes from its conversion in peripheral tissues into more potent androgens like testosterone. Understanding this pathway, and how it might be affected in PCOS, adds another layer to our understanding.
This short video explains the metabolic fate of DHEA-S and proposes an interesting mechanism linking it to insulin resistance.
What Does A High DHEA-s In Female Mean?
The video 'What Does A High DHEA-s In Female Mean?' by Southwest Integrative Medicine provides a clear explanation of DHEA-S metabolism and its potential dysregulation in states of insulin resistance.
Please watch from 03:21 to 06:17. The first part explains the conversion of DHEA-S to other hormones. The second part presents a fascinating theory on how insulin resistance can lead to a 'flipped' NAD/NADH ratio, which might impair this conversion and cause DHEA-S to build up.
This video introduces a nuanced point: in the context of insulin resistance, a high DHEAS level might not only reflect increased production but also potentially impaired breakdown or conversion due to metabolic shifts (specifically, the availability of the NAD cofactor for the 3-beta-hydroxysteroid dehydrogenase enzyme).
Test your understanding!
Two women are diagnosed with PCOS based on the Rotterdam criteria (both have irregular cycles and clinical signs of hyperandrogenism).
- Patient A has blood tests showing an elevated LH:FSH ratio, high serum testosterone, and a normal DHEAS level.
- Patient B has a normal LH:FSH ratio, high serum testosterone, and a markedly elevated DHEAS level.
Based on what you've learned in this and previous lessons, what is the most likely primary source of androgen excess in each patient?
Show answer
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Patient A: The combination of a high LH:FSH ratio and elevated testosterone with normal DHEAS strongly suggests that her hyperandrogenism is primarily of ovarian origin. The high LH is driving the ovarian theca cells to overproduce androgens.
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Patient B: The markedly elevated DHEAS level is a clear indicator of adrenal androgen excess (FAH). While her ovaries are also likely contributing to the high testosterone, the adrenal gland is a significant, and perhaps dominant, source of her total androgen load. This represents the adrenal-predominant phenotype of PCOS.
A Note on Differential Diagnosis
The presence of high adrenal androgens brings up an important clinical point: the need to distinguish PCOS with FAH from other primary adrenal disorders that can mimic PCOS. These include:
- Non-classical Congenital Adrenal Hyperplasia (NCAH): A genetic enzyme deficiency causing adrenal androgen excess.
- Androgen-secreting adrenal tumors: A rare but serious cause of rapid and severe hyperandrogenism.
- Cushing's Syndrome: A disorder of cortisol excess that also involves increased adrenal androgens.
These conditions are part of the differential diagnosis of PCOS and must be ruled out by a physician through specific tests (e.g., measuring 17-OHP to screen for NCAH, or dexamethasone suppression tests for Cushing's). We will cover this diagnostic process in detail in Module 11. For today, the key concept is that functional adrenal hyperandrogenism can be an integral part of the PCOS syndrome itself, not always a separate disease.
Conclusion
Today we've added an important dimension to our model of PCOS hyperandrogenism. While the ovary remains central, the adrenal gland is a key contributor in a significant number of cases.
Key Takeaways:
- In about 20-30% of women with PCOS, the adrenal glands are a significant source of excess androgens, a condition known as Functional Adrenal Hyperandrogenism (FAH).
- DHEAS is a specific marker for adrenal androgen production. Elevated DHEAS levels in a woman with PCOS points to an adrenal contribution.
- The primary mechanism is believed to be an intrinsic hypersensitivity of the adrenal gland to ACTH, causing an exaggerated androgen response to normal stimulation.
- Hyperinsulinemia may also contribute to FAH, linking the metabolic and adrenal aspects of the syndrome.
Preview of the Next Lesson:
We have now discussed all the major sources of androgen production in PCOS: the ovaries, the adrenals, and the synergistic role of insulin. However, the total amount of androgen produced is only one part of the equation. The biological activity of these hormones depends on how much is "free" versus bound to proteins in the blood. In our next lesson, we will explain the mechanisms leading to reduced SHBG levels and an increased free androgen index in PCOS, which is the final key to understanding the full picture of hyperandrogenism.