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Adrenal Tumors in Women

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Why are adrenal tumors more common in women than in men?

In considering a newly diagnosed adrenal tumor, you want to know how to treat it and move on with your life. If the tumor is producing too much hormone or has reached a certain size, the adrenal tumor needs to be surgically removed for definitive treatment. Depending on which adrenal hormone is being overproduced, we will know how best to plan your surgery and from where the tumor is growing (the outer portion of the gland called the cortex, or inner most portion called the medulla, where pheochromocytomas originate).

This can lead you to ask, why has this happened to me, and in particular to this discussion, does my gender play a role? Without getting too scientific, we will attempt to explain why adrenal tumors in women occur more commonly than in men.

Adrenal tumors in women: Background

In humans, as we are growing in our mother’s bellies, we are developing in utero as embryos to be born genetically male (XY chromosomes) or female (XX). Certain gene expressions will determine your gender, ultimately leading to development of ovaries (female) or testes (male). The genetic pathways of this development will then promote one sex-linked fate (female or male) and repress the opposite, through sex hormones that act throughout the body at a cellular level, and ultimately define the secondary sex characteristics of female or male.

Figure 1. Chromosome XX (23rd pair) is found in females, whereas men are XY.

From development to adulthood, the ovarian hormones (estrogen/progesterone) and testicular androgens (testosterone) are potent regulators throughout the body. These sex hormones are produced and effect internal organs (adrenal glands included) to varying degrees depending on gender. And thus, reproduction, behavior, and metabolism, to name a few key categories, are affected and determined based on your gender. In other words, the amounts of these sex hormones that are produced are determined by your sex organs (female vs male), but play such a key role in your development, how you behave, and predisposition to certain diseases. For example, breast cancer is more common in women than in men because of this interplay of hormones at the cellular level within the more prevalent female breast tissue. Similarly, because of these hormonal differences between females and males, adrenal tumors in women are more common.

Adrenal tumors in women: Why have we seen more adrenal tumors in women than in men?  

This question may have a very bird’s-eye-view, or zoomed-out, answer, that is not terribly scientific. From elsewhere on this site, we know that there has been an increased awareness of diagnosing adrenal gland tumors, particularly when discovered on an image of the abdomen that is being performed for some other reason apart from trying to identify an adrenal tumor. These are called adrenal incidentalomas (found “incidentally” when having the imaging test to discover the cause of something else). This occurs roughly 7% of the time in people over 60 years of age. The incidence of adrenal incidentalomas is roughly 1.5 times greater in women than men, potentially owing to the greater number of diagnostic procedures and images performed on women.

The adrenal glands do not typically produce pain, since they sit in the back of the belly, unless they have grown to a large size and are pressing on nerves, vessels, or organs. We know that adrenal tumors can produce symptoms if producing too much hormone, but in considering a common presentation to the emergency room across the country, “abdominal pain,” this is not a typical presentation for an adrenal tumor. Based on female reproductive anatomy and the potential for pain elicited from these organs, in the patient presenting to the emergency room with “abdominal pain of unknown origin,” we could easily see how getting imaging (CT scans) of women’s bellies more frequently than in men will lead to an increased incidence of adrenal tumors in women.

Figure 2. More women than men seek medical care and thus are more likely to undergo a scan such as a CT scan. A CT scan such as this one may identify an adrenal tumor (arrow). Given that women tend to have more scans than men, more “adrenal incidentalomas” are being diagnosed.

Adrenal tumors in women: is there a cellular explanation?

In looking at mammalian studies there is something occurring in the female adrenal gland that is not in the male. In particular, within the adrenal cortex, the cells are turning over more rapidly in females compared to males. In fact, 3 times higher! The mammal model studies found females replace their entire set of hormone-producing adrenal cells within three months, while the males take 9 months. This has been traced back to a different behavior of the origin cell, the adrenal stem cell, between the two sexes. Further, hormones produced by the testes will dampen, or suppress, cell division. Thus, the male androgens will protect the adrenal cells from overproducing, hyperfunctioning, and potentially growing into a tumor. Females have higher production of adrenal cells, but also recruit stem cells differently than their male counterparts. This data can directly explain why adrenal tumors in women are more prevalent than in men.

Adrenal tumors in women: does the hormone being over-produced matter when it comes to difference between genders?

  • Adrenal tumors in women: Cushing’s syndrome (cortisol-producing)

    Cushing’s syndrome from an adrenal adenoma over-producing cortisol occurs predominately in females, with a 70% incidence compared to men. One study in Denmark showed Cushing’s syndrome due to adenomas being eight times more common in women than men. This is again owed to the increased turnover in the female adrenal cortex, where the tumor grows at a rate three times greater than that of the male.

  • Adrenal tumors in women: Conn’s syndrome (aldosterone-producing)

    The most identified gene mutations in aldosterone-producing adrenal adenomas are detected more frequently in females compared to males. Male mammal models have shown less aldosterone production than in female models, actually showing atrophy, or less development, within the portion of the adrenal cortex that is responsible for aldosterone production. Further, women have shown a heart-protective role from estrogen acting on the adrenal cortex, and thus effecting aldosterone production. However, when women are taking antihypertensive medications (Losartan being a common one) to help block the aldosterone production (which was raising the blood pressure in the 1st place), other adrenal receptors are activated by the estrogen, in turn increasing aldosterone production!  



    Figure 3. Mutations in the gene KCNJ5 (encoding the potassium; K channel in adrenal cell), leading to leakage of sodium (Na) into the cell, is the most common cause of Conn’s syndrome. For unknown reasons this occurs much more frequently in women than in men, making Conn’s syndrome (primary hyperaldosteronism) more common in women.

  • Adrenal tumors in women: Pheochromocytoma (adrenaline-producing)

    Adrenaline-producing adrenal tumors in women (pheochromocytomas, which produce catecholamines, or adrenaline) generally occur at the same rate as they do in men. This is likely because these tumors do not originate in the cortex (which is more cellularly active in the female), but rather in the medulla (central part of the adrenal gland).  Interestingly, catecholamine (adrenaline) sensitivity is greater in women than men, manifesting as greater incidence of headaches, dizziness, anxiety, tremors and changes in weight and energy level in women compared to their male counterparts in one study. This means that women are more likely to be symptomatic!

 

Adrenal tumors in women: Summary

Adrenal tumors in women (particularly originating in the adrenal cortex) do occur more frequently than in men, and the hormonal and physiologic response to the tumor is different between the genders. Androgen (testosterone) exposure has shown a protective effect in mammalian studies in developing adrenal cortical adenomas. Thus, females are more prone to disease related to the overproduction of the cortical hormones and development of tumors within these zones of hormone production. Estrogen and progesterone receptors are higher in the adrenal cortex than androgen receptors, making adrenal tumors in women more likely. However, regardless of your gender, the treatment for hormone overproducing adrenal tumors in women and in men is the same, surgery!

The best adrenal operation for >95% of adrenal tumors is the Mini-Back Scope Adrenalectomy (MBSA). Learn more about this procedure here: https://www.adrenal.com/adrenal-surgery/mini-scope-surgery-best

Additional Resources: 

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Author

Dr. Andrew Rhodes, DO, FACS

Dr Drew Rhodes was the Director of the Endocrine Center at HCA North Carolina and the University of North Carolina for 4 years until being recruited to joing the "Dream Team" in Tampa several years ago. He received his formal training in endocrine surgery at Yale University where he worked closely with Dr Carling who says "Drew is the best of the best and wherever I go, I want Drew at my side. He is one of the best surgeons I have ever met." After spending a week with Dr Norman, he agrees: "Few surgeons have the hands that Drew has and after I saw him operate I knew we had to have him on our team." Dr Rhodes received his general surgery training at Penn prior to fellowship training at Yale. He had a decorated military career spending 5 years as a surgeon at Walter Reed Medical Center in Washington, DC. Drew is married and has an 10 year old boy and a 6 year old girl.
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Author

Dr. Tobias Carling MD, PhD, FACS

Dr. Carling is the most experienced adrenal surgeon in the United States, and by far the world's most knowledgeable surgeon-scientist when it comes to adrenal gland function and disease, adrenal tumors and cancer, and all forms of adrenal gland surgery. Dr. Carling has more experience with advanced minimally invasive adrenal and endocrine operations than any surgeon in the United States. A fellow of the American College of Surgeons, Dr. Carling is a significant member of both the American Association of Endocrine Surgeons (AAES) and the International Association of Endocrine Surgeons (IAES).