Adrenal Status - At the Root of PCOS

Stressed? In today’s world, we often hear about our adrenal glands being taxed and not performing optimally. Usually, we attribute this to external stressors such as work overload, emotional liabilities, relationship responsibilities, or financial strains. Have you ever thought this could be due to a genetic defect, though? Maybe your genes are the true cause of your adrenal dysregulation, which would explain why conventional treatments may not be producing expected outcomes. Moreover, have you ever considered that your hormonal imbalances could actually be related to a subfunctioning adrenal gland? This is most significant for those women experiencing polycystic ovarian syndrome (PCOS) symptoms, such as irregular menstrual cycles, hirsutism, acne, and obesity. This article is aimed at shedding light on adrenal hyperplasia, which is a genetic disease that effects the activity of enzymes within the steroid production pathway. Most of the discussion will focus specifically on the late-onset type, which can cause underproduction of cortisol (the stress hormone) and lead to excessive androgen (male sex hormone) levels.

Classic adrenal hyperplasia is an inherited, congenital disease that occurs due to genetic changes to 21-hydroxylase enzyme activity that render it essentially inactive. The enzymatic defect is due to an autosomal recessive gene mutation, that in 90– 95% of cases leads to a deficiency in 21-hydroxylase.[1, 2] The change in the enzyme makes it inefficient in converting cholesterol to cortisol and its derivatives. This leads to lack of cortisol feedback, leading to increased cortisol precursors, like the androgen hormones.^[2] With classic adrenal hyperplasia, the abnormality is generally identified in infancy or early childhood as signs of virilization (females showing male characteristics, and vice versa) appear due to the lack of enzyme activity, allowing the conversion of precursor steroids to active steroids.^[2] Furthermore, the classic form is classified as salt-losing or non–salt-losing, depending on the degree of mineral steroid production loss from the adrenal glands.^[2] Mineralocorticoids, mainly aldosterone, are responsible for the regulation of salt and water in the body, and therefore swelling. With long-term steroid and mineralocorticoid treatment, these patients can live an average lifespan but may experience a form of Cushing’s disease induced by the medication, achieve only short stature due to the effects of the medication on bone growth, and experience oligomennorhea/infertility due to the dysregulation of hormones.^[2] In an effort to minimize these risks, current treatment plans are suggested to include antiandrogens and aromatase inhibitors, in addition to lower-dose steroids.^[2] Classic adrenal hyperplasia requires immediate action at times of diagnosis to prevent severe negative health outcomes and death.

Nonclassical adrenal hyperplasia (NCAH), otherwise described as late-onset or adult-onset, is not as severe as the classic form. With NCAH, the enzymatic activity of 21-hydroxylase can reach 50%, whereas in classic adrenal hyperplasia enzymatic activity can drop to as low as 5%.^[3] The marked difference in enzymatic activity results in different symptoms. As just discussed, in classic adrenal hyperplasia, symptoms due to excessive cortisol levels are noticed early in life, but as a result of the background activity level of the enzyme in the late-onset disorder, there is less of a cortisol deficiency and more of a hyperandrogenism picture.^[4] This means the late-onset condition does not show many signs of cortisol being out of balance, but more so with relation to hormonal imbalance. As a result, NCAH symptoms approximate those of women with PCOS, who have an imbalance in male/female sex hormones and insulin dysregulation.^[4] It is therefore important to consider NCAH as a cause of PCOS, especially in patients who are having difficulty controlling their symptoms. NCAH is also more common in women of Hispanic or eastern European Jewish decent,^[4] and in women with parental consanguinity,^[5] again showing that inheritance plays a large role in this condition. Men are not routinely identified with NCAH, because the androgen excess is masked by their gender, and the cortisol deficiency is mild enough that it goes unnoticed symptomatically. However, NCAH is also linked to obesity, insulin dysregulation, and imbalances in lipid profiles regardless of sex. Due to this, stubborn cases of diabetes, weight gain, and hypercholesteremia may have NCAH as the cause, and may benefit into a thorough screening for adrenal hyperplasia.^[6] The good news is that the mentioned metabolic changes and the hyperandrogenism seen in NCAH tend to ameliorate with age as secretory activity from the adrenals slows.^[6]

Now that you are familiar with the background information on adrenal hyperplasia, you may also have noticed its potential importance in PCOS cases. The similarity between NCAH and PCOS is due to the buildup of androgen hormones as a result of the enzymatic defects in the cortisol pathway as already described. Excessive androgens in women cause oligo/amenorrhea, hirsutism, acne, male-patterned baldness, obesity, and unexplained infertility, which are all seen in PCOS.[4, 7] Due to the similarity in symptoms, it is important to consider the genetic enzymatic defects as a cause of PCOS symptoms, because 3–9% of women with hyperandrogenism (elevated testosterone, DHEA, SHBG) have a 21-hydroxylase deficiency (the defect that characterizes adrenal hyperplasia).[6, 7] PCOS-like symptoms result during NCAH because persistently elevated progesterone/androgens/steroids may dysregulate the hypothalamus–pituitary–ovarian axis. This axis is a pathway that connects hormones dispatched from our brains, adrenals, and gonads (ovaries in women, testes in men).^[6] The elevated androgen levels with NCAH cause the hypothalamus (an area in the brain) to be less sensitive to progesterone, which therefore causes more GnRH (gonadotropin-releasing hormone) pulses to be released, causing more LH (leutinizing hormone) surges, which then results in both ovarian androgen and adrenal androgen increase.^[6] As can plainly be seen, a complicated system exists to account for the elevated androgen levels. Nonetheless, these hormones need to come back into balance to allow the woman to live a life free of androgenic symptoms.

Another area in women’s health where NCAH should be considered is with fertility concerns, since infertility can affect 50% of NCAH patients.^[6]

The elevated progesterone seen with NCAH thickens cervical mucus during the follicular phase, not allowing sperm to penetrate this barrier.^[6] The elevated progesterone also does not allow the endometrium to thicken appropriately, resulting in both embryo implantation and fertilization reduction.^[6] Pregnancy success rate in NCAH is 67%, with 25% of these pregnancies ending in spontaneous miscarriage.^[3] Thankfully, miscarriage rates can be reduced to 6.5% with the use of glucocorticoid treatment to correct the hormone imbalance.^[3]

To find out if you are experiencing symptoms due to adrenal hyperplasia, the first step is to request your health-care provider for the appropriate laboratory tests. Testing baseline steroid levels is not helpful in NCAH, as they are usually normal.^[5] The gold standard for testing involves the adrenocorticotropic hormone (ACTH) stimulation test—baseline 17-hydroxyprogesterone and cortisol is taken, an ACTH bolus is given, and then blood is taken again 60 minutes later and remeasured for 17-OHP (a form of progesterone) and cortisol.[3, 4] Elevated progesterone indicates NCAH. Cortisol levels are tested, not to explain the symptomatic picture, but to provide an indication about the adrenal reserve.^[3] Mineral corticoid secretion remains normal in the late-onset form of adrenal hyperplasia, and so is not tested.^[6]

Once NCAH has been identified, treatment consists of glucocorticoids, antiandrogens, and birth control to prevent cystic ovaries.^[2] Naturopathically, treatment may target cortisol-delivering herbs such as Glycyrrhiza, Eleutheroccous, and Panax ginseng. Antiandrogen and PCOS therapies may include Tribulus, green tea, N-acetylcysteine (NAC), and inositol. It is worthwhile to consider the naturopathic approach to treating NCAH, since long-term steroid treatment carries serious risks. It is related to bone density impairment through suppressed osteoblast (the cells that build bone) and increased osteoclast (the cells that break down bone) activity, and impaired calcium absorption in the gut.^[6] If conventional steroid is the treatment of choice, regular DEXA scans are required to monitor bone health.^[6] Whichever route is chosen for treatment, however, the goal should be regulation of androgen hormones, since these symptoms are most concerning to the patient’s health.^[6] For women desiring to become pregnant, use of ovarian stimulators and cortisol to improve chances of pregnancy and reduce miscarriage rates would be beneficial.^[6]

Ultimately, NCAH is a condition that can have detrimental effects on androgenic hormones, which is most significant in females with Hispanic or Jewish roots and parents sharing DNA. It is worthwhile to request an ACTH test if current PCOS-like symptoms are not being controlled optimally. Take care of your adrenals, and you will reap the benefits!