Differentiating Polycystic Ovarian Syndrome and Non-Classical Adrenal Hyperplasia –

A closer look at distinguishing PCOS from NCCAH in reproductive-age women, including diagnostic criteria and treatment approaches.

By Kelly Simms ND, CNS, FABNE

This article explores the clinical overlap between Polycystic Ovarian Syndrome (PCOS) and Non-Classical Congenital Adrenal Hyperplasia (NCCAH), providing diagnostic criteria, lab evaluations, and natural treatment options. Polycystic Ovarian Syndrome (PCOS) affects 5–20% of reproductive-age women and represents the most common endocrine problem in this patient population. On the other hand, Non-Classical Congenital Adrenal Hyperplasia (NCCAH) effects range from 0.6% to 9%  of reproductive-age women. ¹ Although a less common disorder, it is important to add to the differential for any woman presenting with hirsutism, acne, menstrual irregularity, and fertility problems. 

PCOS Diagnosis Criteria 

To diagnose PCOS, the patient must meet two of the three possible criteria: 

1. Irregular or absent menstrual cycles: Ensure that the patient is not on hormonal birth control or an IUD, which can also cause irregular or absent bleeding.
2. Symptoms or laboratory evidence of hyperandrogenism: Symptoms may include acne, hair loss, and/or abnormal hair growth. Laboratory evidence is elevated testosterone, DHEA-S, dihydrotestosterone, or androstenedione levels. 
3. Multi follicular appearing ovaries: When a transvaginal ultrasound is done in the late follicular phase on a woman not taking hormonal birth control of any type, multiple follicles may be present. 

Note that the criteria for PCOS do not include insulin resistance or increased BMI. Although both can be associated with PCOS, it is not diagnostic.

Laboratory Evaluation and Imaging: 

For a woman who is not cycling, the following hormone labs may be collected at any time, early morning preferred: FSH, LH, testosterone (free and total), dihydrotestosterone, androstenedione, estradiol, DHEA-S, 17-hydroxyprogesterone (17-OHP), prolactin, TSH, and anti-mullerian hormones.  

For a woman who is cycling regularly, defined by a cycle length ranging consistently between 25-35 days between menses, a cycle day three lab draw will more accurately check the FSH: LH ratio. The ratio should be 2:1 on cycle day three, and in PCOS, it is often reversed to be 1:2. Ideal estradiol on cycle day three is between 30-50 pg/mL. 

Androgens cannot be measured while on oral contraceptives because sex hormone binding globulin is elevated and GnRH signaling is altered. 

Note that progesterone should not be checked as a part of the workup, especially in amenorrhea. Progesterone is only manufactured after ovulation. Therefore, checking progesterone and advising that someone is “low in progesterone” is essentially the nature of the condition due to anovulation. In the case of irregular ovulation, they would produce progesterone, but not on a regular monthly cycle. When looking at hormones, consider relative ratios. The GnRH signal is sent to the pituitary to produce both FSH and LH.  LH then targets theca cells in the ovary, leading to androgen production, and the FSH signal targets estrogen production and follicle development. Consider that if a woman is anovulatory, the levels of estrogen and testosterone may be high or even laboratory normal. Still, symptoms may be due to the relative excess of these hormones relative to progesterone. Transvaginal ultrasound (TVUS) is advised in cases where patients do not meet the other two criteria, and the diagnosis is in question. Some literature suggests AMH may be a substitute marker for multi-follicular ovaries and a TVUS if a woman is 8 years post menarche. ² AMH is sometimes elevated in PCOS.

NCCAH Diagnosis and Distinguishing Features

NCCAH is clinically indistinguishable, as the most common symptoms among adolescent and adult women were hirsutism (59%), oligomenorrhea (54%), and acne (33%). ¹ NCCAH is due to P450c21 (21-hydroxylase) deficiency, a common autosomal recessive disorder due to mutations in the CYP21A2 gene. In labs, 17-OHP is elevated in basal and ACTH-stimulated 17-OHP  when tested in the early follicular period. ³ 17-OHP is best collected early in the morning, and early morning baseline values of 17-OHP  greater than 200 ng/dl should prompt further evaluation. ⁴

In addition, the multi-follicular ovaries, observed in 75% of the PCOS population, are also seen in 40% of the NCCAH population, especially in the ovulation disorder subgroup. Therefore, ultrasound does not help with differential diagnosis. Hence, the sole approach for distinguishing NCCAH  patients from PCOS patients is to assess 17-OHP levels. ³

Women with NCCAH may also be more likely to present with oligomenorrhea rather than amenorrhea. Moran et al. examined 220 women with NCCAH. Between the ages of 10 and 19 years, the prevalence of oligomenorrhea was as high as 56% compared to only 9% of adolescents who experienced primary amenorrhea.⁴In addition to 17-OHP, the acute ACTH stimulation test remains the gold standard to confirm decreased 21-hydroxylase activity. Synthetic ACTH (Cortrosyn, 0.25 mg) is administered after collecting a blood sample to measure baseline hormone concentrations. A second blood sample is collected 30–60 minutes later. The correlation of hormone concentrations with genetic analyses has suggested that mutations will likely be identified on both alleles when the ACTH-stimulated 17-OHP value exceeds 1500 ng/dL. However, a few NCAH patients, particularly if older, will demonstrate ACTH-stimulated 17-OHP levels between 1000 and 1500 ng/d. ¹

Case Study: Ruby’s Experience

Ruby is a 29-year-old female with a history of irregular menses. Within the past year, her menses have been more regular, averaging 35-37 days, which categorizes her as oligomenorrheic. In the past, cycles were spaced 50-80 days. She has dysmenorrhea, which disturbs her activities of daily living.  A few hours after getting her menses, she is unable to work or stand up; she cries in bed and vomits.  She had been prescribed Magnesium Phosphoricum 30C by another provider and found the benefit in taking that acutely for pain. The pain resolves after 10-12 hours. She was seen by a gynecologist, who recommended oral contraceptives and spironolactone. She desires alternative treatments. 

She has a normal bleeding pattern. Premenstrual symptoms include significant breast swelling,  abdominal bloating, occasional cramping, fatigue, and mood changes.  

She has notable androgenic symptoms: hair loss and thinning, excess hair on her nipples, and acne on her shoulders and back. 

She was initially diagnosed with NCCAH in 2000 due to multi-follicular ovaries and oligomenorrhea.  She does not have the labs from the initial diagnosis but shares that her 17-OHP was significantly elevated. 

There are no other significant medical diagnoses or findings in her intake. 

The patient shared labs from an outside provider:  

Cycle day 11 labs, collected at 10:28 AM, around the same time as her initial intake with me: 

• Testosterone: 55 (9-55 ng/dL)
• Free Testosterone:  4.7 (0.8- 7.4 pg/mL)
• Sex Hormone Binding Globulin 91 nmol/L (25-122)
• Aldosterone 11.8 (4.0-31 ng/dL)
• Renin activity 0.9 (0.5 -4.0 ng/mL/hr)
• Aldosterone/Renin Activity ratio 13.1 (
• 17-Hydroxyprogesterone: 142.36 (NORMAL
• DHEA- S 221 (91-240 ug/dL)
• Complete Metabolic Panel – WNL

Cycle day 5 labs;  unknown collection time, done in a foreign country about a month after her initial intake, so reference ranges are different: 

• 17- Hydroxyprogesterone 3.73 (1.06-12.25 nmol/L)- NORMAL
• Estradiol 122 ( Follicular Reference Range: 71.5-529 pmol/L)
• TSH 2.985 (0.55- 4.75 mIU/L)
• Free T3 4.3 (3.5 -6.5 pmol/L)
• Free T4 13  (11.5  – 27 pmol/L)
• FSH 6.20 (Follicular Reference Range:  2.5- 10.2 IU/L)
• LH 4.90  (Follicular Reference Range:  0.5-16.9 IU/L)
• Prolactin 427.6 ( 59-619 MIU/L)
• Progesterone
• Testosterone: 1.40  (0.29-1.21  nmol/L) – HIGH
• Vitamin B12:  312 (156-672 pmol/L)
• Folic Acid 29.2 (>12.2  nmol/L)

Since most recent 17-OHP readings were not elevated compared to her initial diagnosis,  she will follow up with her endocrinologist for an ACTH-simulated 17-OHP test. 

Natural Treatment Plan for NCCAH and PCOS

Since PCOS and NCCAH have overlapping characteristics, natural treatments that can be used in PCOS cases can be implemented in NCCAH. The conventional treatments for NCCAH are not always indicated unless the individual is symptomatic. In symptomatic cases, treatment may include low-dose glucocorticoids, androgen-lowering medications like spironolactone, and birth control pills.

Nutrition

Although the patient is not overweight or has signs of insulin resistance, I recommended a high protein and veggie diet, with lower fruit, grain/starch, and sugar akin to the Mediterranean diet with less emphasis on carbohydrates. Part of the underlying mechanism for androgen overproduction is ovarian, and in her case, also adrenal. To treat ovarian insulin resistance, the Mediterranean Diet combined with a low carbohydrate is a good choice. ⁵

I recommended the following initial treatment plan:  

1. Adrenal: Ashwagandha root 500 mg per day. One case study report showed a 66% reduction in 17OHP after treatment with ashwagandha for six months. (6) 
2. Restore FSH/LH signaling: Vitex
3. Reduce androgens: Saw Palmetto, Pygeum, and Nettles 
4. Acne: liver support herbal containing Berberine, Milk Thistle, Burdock, and Chicory, and skin support multivitamin
5. Anti-inflammatory and pain management: magnesium glycinate and fish oil

At her first follow-up five weeks later, she reported that this was the first period where she had no pain during her menstruation and was able to continue her day.  And she “cannot remember last time menses were this easy.” Breast swelling improved, and lower back pain also improved. The second period, which came 39 days later, was more painful than the previous “easy” period, but PMS symptoms were still improved. She was consistent with her treatment plan, so this may be due to the natural course of healing and monthly hormone fluctuations. 

She had an endocrinology visit, and the provider was unsure if NCCAH was still the correct diagnosis. 17-OHP was significantly higher at initial diagnosis, and at subsequent lab draws, 17-OHP was much lower. Her provider recommended genetic counseling for fertility purposes. Those with NCCAH are at increased risk for having offspring with the classic form of the disorder. ⁴ As a result of her genetic counseling, she was advised that she is a carrier, so she will not have the full expression of  17-OHP elevations as in a more fully expressed genotype. Her baseline 17-OHP  is normal, but ATCH-stimulated 17-OHP does surpass 1500 ng/dL. 

Her ACTH stimulation testing showed lab values: 

• Baseline 17- hydroxypregnenolone: 203 ng/ml (reference 200 ng/mL
• ATCH stimulated 17- hydroxyprogesterone: 1548.57 (

Other lab results: 

• Ferritin 30 (16-154 ng/mL) – SUBOPTIMAL
• Vitamin D,25-OH, Total 29  (30-100 ng/mL)- LOW

Based on her other labs and feedback from her visits, we added vitamin B12, vitamin D, iron, and myo-inositol 4000mg to her plan. Inositol is an insulin sensitizer and reduces clinical and laboratory symptoms of hyperandrogenism. Inositols reduce serum total and free testosterone and androstenedione levels, increase SHBG levels, and normalize cycle length compared to placebo. ⁷ Vitamin D has been shown to lower testosterone in PCOS patients and improve folliculogenesis, leading to more regular cycles. ⁸ Low iron stores are a contributing factor in hair loss. Ferritin should be optimized to be at least 40 ng/dL and optimally 70 ng/dL. ⁹ In her case, future naturopathic testing considerations include anti-mullerian hormone and cortisol. This patient is continuing her care plan. The longer-term treatments for NCCAH depend on the presentation. The conventional treatment recommendation is glucocorticoid therapy, reserved for those individuals with symptomatic hyperandrogenism. Depending on cycle characteristics, oral contraceptives may be necessary, especially if regular menstruation cannot be achieved with natural support options. Prescription anti-androgens may also be a consideration. The estimated infertility incidence is 11% among NCCAH women ¹⁰, and glucocorticoid therapy may increase the chances of conception and reduce the risk of miscarriage for women with NCCAH. This highlights the importance of working up for NCCAH in infertility cases.

Dr. Kelly Simms is a Board-Certified Naturopathic Endocrinologist and a Certified Nutrition Specialist® (CNS). She holds a doctorate in Naturopathic Medicine and is a Fellow of the Board of Naturopathic Endocrinology (FABNE). Dr. Simms is affiliated with the American Association of Naturopathic Physicians (AANP), Illinois Association of Naturopathic Physicians (ILANP), and Endocrinology Association of Naturopathic Physicians (EndoANP). She has served as President of the Naturopathic Medical Student Association (NMSA) and has presented on health topics to both professional and public audiences. Dr. Simms lives in Wilmette, IL with her family and enjoys cooking, yoga, and travel. www.kellysimmsnd.com

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