Polycystic ovary syndrome (PCOS) stands as the most prevalent hormonal disorder affecting women during their reproductive years. Diagnosis hinges on the presence of at least two out of three key features: irregular menstrual cycles, hyperandrogenism, and polycystic ovaries. This article provides an in-depth exploration of the differential diagnosis of polycystic ovarian syndrome, ensuring clinicians can accurately distinguish PCOS from conditions with overlapping symptoms. Understanding the nuances of differential diagnosis is crucial for effective patient management and to avoid misdiagnosis.
Understanding Polycystic Ovarian Syndrome (PCOS)
PCOS, a condition initially described by Stein and Leventhal in 1935, affects a significant portion of the global female population, with prevalence rates varying from 5% to 15% depending on the diagnostic criteria used. The Rotterdam criteria are widely adopted, requiring at least two of the following for diagnosis:
- Chronic Anovulation: Irregular or absent ovulation leading to menstrual cycle disturbances.
- Hyperandrogenism: Clinical or biochemical signs of excess androgens (male hormones) such as hirsutism (excess hair growth), acne, and alopecia (hair loss).
- Polycystic Ovaries: Characteristic appearance of ovaries on ultrasound with multiple small follicles.
It’s vital to recognize that PCOS is a diagnosis of exclusion. This means that before confirming PCOS, other conditions that can mimic its symptoms must be ruled out. Failure to consider differential diagnoses can lead to delayed or incorrect treatment, potentially worsening associated comorbidities and impacting the patient’s quality of life. PCOS is linked to a range of serious health issues, including infertility, metabolic syndrome, type 2 diabetes, cardiovascular disease, and endometrial cancer. Therefore, accurate and timely diagnosis is paramount.
Conditions Mimicking PCOS: The Differential Diagnosis
When evaluating a patient presenting with symptoms suggestive of PCOS, clinicians must consider a range of differential diagnoses. These conditions can present with similar clinical features like menstrual irregularities, hyperandrogenism, and even polycystic ovaries on ultrasound, requiring careful evaluation to differentiate them from PCOS.
1. Thyroid Disorders
Thyroid dysfunction, both hypothyroidism (underactive thyroid) and hyperthyroidism (overactive thyroid), can cause menstrual irregularities and, in some cases, contribute to hyperprolactinemia, which can further disrupt menstrual cycles.
- Hypothyroidism: Can lead to menstrual irregularities, weight gain, and fatigue, symptoms that can overlap with PCOS. Hypothyroidism can also indirectly affect ovarian function.
- Hyperthyroidism: While less commonly mimics PCOS, hyperthyroidism can also cause menstrual changes and anxiety, which might be misinterpreted in the context of PCOS.
Diagnostic Differentiation: Thyroid function tests (TSH, Free T4) are essential to rule out thyroid disorders. These tests are simple and readily available, providing clear evidence for or against thyroid dysfunction.
2. Hyperprolactinemia
Hyperprolactinemia, an elevated level of prolactin in the blood, can be caused by pituitary tumors (prolactinomas), certain medications, hypothyroidism, and other conditions. Prolactin is a hormone that stimulates milk production, and excess prolactin can disrupt the normal menstrual cycle and cause galactorrhea (milky nipple discharge).
- Symptoms Overlap: Irregular periods or amenorrhea are common in both hyperprolactinemia and PCOS.
Diagnostic Differentiation: Measuring serum prolactin levels is crucial. Elevated prolactin levels necessitate further investigation, potentially including MRI of the pituitary gland to rule out a prolactinoma.
3. Non-classical Congenital Adrenal Hyperplasia (NCAH)
Non-classical congenital adrenal hyperplasia (NCAH), particularly the 21-hydroxylase deficiency form, is an autosomal recessive disorder that results in impaired cortisol synthesis and subsequent androgen excess. NCAH often presents with milder symptoms than classical congenital adrenal hyperplasia and may manifest in adolescence or adulthood.
- Symptoms Overlap: NCAH can cause hyperandrogenism (hirsutism, acne), and menstrual irregularities, mimicking PCOS.
Diagnostic Differentiation: A key diagnostic test for NCAH is measuring serum 17-hydroxyprogesterone (17-OHP) levels, particularly in the early follicular phase of the menstrual cycle or a random sample if amenorrheic. Elevated 17-OHP levels, especially after an ACTH stimulation test, are indicative of NCAH.
4. Androgen-Secreting Tumors
Androgen-secreting tumors of the ovary or adrenal gland are rare but serious conditions that can cause rapid onset and severe hyperandrogenism. These tumors produce excessive amounts of androgens, leading to virilization, which includes more pronounced signs of hyperandrogenism like voice deepening, clitoromegaly, and male pattern baldness, symptoms less typical of PCOS.
- Symptoms Overlap: While both can cause hyperandrogenism, the severity and rapid progression of symptoms are distinguishing features of tumors.
Diagnostic Differentiation: Rapid onset and progressive virilization should raise suspicion for an androgen-secreting tumor. Hormonal evaluation, including total and free testosterone, DHEA-S, and androstenedione levels, are essential. Imaging studies, such as pelvic ultrasound, CT scan, or MRI of the adrenals and ovaries, are necessary to locate the tumor.
5. Cushing’s Syndrome
Cushing’s syndrome results from prolonged exposure to high levels of cortisol. It can be caused by excessive cortisol production by the adrenal glands or by long-term use of corticosteroid medications.
- Symptoms Overlap: Cushing’s syndrome can cause menstrual irregularities, weight gain (particularly central obesity), acne, and hirsutism, symptoms that may overlap with PCOS.
Diagnostic Differentiation: Clinical features like moon face, buffalo hump, purple striae, and easy bruising are more characteristic of Cushing’s syndrome. Diagnostic tests include overnight dexamethasone suppression test, 24-hour urinary free cortisol, and late-night salivary cortisol.
6. Acromegaly
Acromegaly is a rare hormonal disorder caused by excessive growth hormone (GH) production, usually from a pituitary tumor.
- Symptoms Overlap: Acromegaly can cause insulin resistance and menstrual irregularities, features also seen in PCOS.
Diagnostic Differentiation: Acromegaly presents with distinct features like enlarged hands and feet, coarse facial features, and increased sweating. Diagnosis is confirmed by measuring serum insulin-like growth factor 1 (IGF-1) levels and growth hormone suppression test.
7. Idiopathic Hirsutism and Familial Hirsutism
Idiopathic hirsutism is diagnosed when hirsutism is present without other signs of hyperandrogenism, menstrual irregularities, or polycystic ovaries, and after excluding other causes of androgen excess. Familial hirsutism refers to hirsutism that runs in families and is often seen in certain ethnic groups, particularly of Mediterranean descent.
- Symptoms Overlap: Hirsutism is the primary overlapping symptom.
Diagnostic Differentiation: In idiopathic and familial hirsutism, androgen levels are typically normal, and menstrual cycles are regular. It’s a diagnosis of exclusion made after ruling out other causes of hyperandrogenism.
8. Use of Androgenic Steroids
Exogenous androgen use, such as anabolic steroids taken for performance enhancement or testosterone therapy, can mimic PCOS by causing hyperandrogenism, menstrual irregularities, and acne.
- Symptoms Overlap: Symptoms directly related to elevated androgen levels.
Diagnostic Differentiation: A thorough history is crucial to identify potential androgen use. Hormone levels will be elevated, but the clinical context and patient history are key to diagnosis.
9. Ovarian Insufficiency (Premature or Primary)
Premature ovarian insufficiency (POI), also known as premature menopause, occurs when the ovaries stop functioning normally before age 40.
- Symptoms Overlap: Menstrual irregularities or amenorrhea are common in both POI and PCOS.
Diagnostic Differentiation: POI is characterized by elevated FSH (follicle-stimulating hormone) and LH (luteinizing hormone) levels and low estrogen levels, while PCOS typically presents with normal or elevated LH and normal estrogen levels. Testing FSH and estradiol levels can help differentiate these conditions.
10. Functional Hypothalamic Amenorrhea (FHA)
Functional hypothalamic amenorrhea (FHA) is a condition where menstruation stops due to problems with the hypothalamus, often triggered by stress, excessive exercise, or eating disorders leading to weight loss.
- Symptoms Overlap: Amenorrhea or oligomenorrhea is a shared symptom with PCOS.
Diagnostic Differentiation: FHA is usually associated with a history of significant stress, weight loss, or intense exercise. Hormone levels may show low or normal FSH and LH, and low estrogen. PCOS usually does not have this specific history and presents with hyperandrogenism and/or polycystic ovaries.
Diagnostic Approach to Differential Diagnosis
A systematic approach is essential when differentiating PCOS from other conditions. This involves:
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Detailed History: Gather information on menstrual history, hirsutism onset and progression, acne, alopecia, weight changes, family history of PCOS or related disorders, medication use (including steroids), and lifestyle factors (stress, exercise, diet).
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Physical Examination: Assess for signs of hyperandrogenism (hirsutism using the Ferriman-Gallwey score, acne, alopecia), virilization, thyroid enlargement, Cushingoid features, and acromegaly features.
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Hormonal Evaluation:
- Testosterone (Total and Free): To assess for hyperandrogenism.
- DHEA-S: To evaluate adrenal androgen production, useful in NCAH and adrenal tumors.
- 17-OHP: To screen for NCAH, ideally measured in the early follicular phase or random in amenorrheic women, with ACTH stimulation test if baseline is elevated.
- Prolactin: To rule out hyperprolactinemia.
- TSH and Free T4: To rule out thyroid dysfunction.
- FSH and Estradiol: To assess for ovarian insufficiency, particularly in cases of amenorrhea.
- Cortisol Tests (Dexamethasone suppression test, urinary free cortisol, salivary cortisol): If Cushing’s syndrome is suspected.
- IGF-1: If acromegaly is suspected.
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Pelvic Ultrasound: To assess ovarian morphology for polycystic ovaries, although this criterion is less reliable in adolescents. It’s also useful to rule out ovarian tumors, although these are usually not the primary differential for PCOS itself but for severe hyperandrogenism.
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Exclusion of Other Diagnoses: Based on clinical and biochemical findings, systematically rule out the conditions listed in the differential diagnosis.
Enhancing Healthcare Team Outcomes in PCOS Diagnosis
Effective diagnosis and management of PCOS, including its differential diagnosis, require a collaborative interprofessional team. This team may include:
- Primary Care Physicians: For initial assessment and referral.
- Endocrinologists: For specialized hormonal evaluation and management.
- Gynecologists: For managing menstrual irregularities and infertility.
- Dermatologists: For addressing hirsutism and acne.
- Dietitians and Exercise Physiologists: To support lifestyle modifications.
- Mental Health Professionals: To address depression and anxiety, which are more prevalent in women with PCOS.
- Pharmacists: To ensure appropriate medication management and minimize adverse effects.
Clear communication and collaboration among team members are crucial to ensure accurate diagnosis, comprehensive treatment, and improved patient outcomes.
Conclusion
Accurate differential diagnosis is crucial in the evaluation of polycystic ovarian syndrome. While PCOS is a common endocrine disorder, several other conditions can mimic its symptoms. A thorough clinical evaluation, including detailed history, physical examination, and targeted hormonal and imaging studies, is essential to differentiate PCOS from its mimics. By systematically considering and excluding other potential diagnoses, clinicians can ensure appropriate management, improve patient outcomes, and address the multifaceted health challenges associated with PCOS. Recognizing the differential diagnoses of PCOS is not just about excluding other conditions, but also about providing holistic and patient-centered care that addresses the specific needs of each individual woman.
References
1.Ding DC, Chen W, Wang JH, Lin SZ. Association between polycystic ovarian syndrome and endometrial, ovarian, and breast cancer: A population-based cohort study in Taiwan. Medicine (Baltimore). 2018 Sep;97(39):e12608. [PMC free article: PMC6181615] [PubMed: 30278576]
2.Zhang C, Ma J, Wang W, Sun Y, Sun K. Lysyl oxidase blockade ameliorates anovulation in polycystic ovary syndrome. Hum Reprod. 2018 Nov 01;33(11):2096-2106. [PubMed: 30272163]
3.Norman RJ, Teede HJ. A new evidence-based guideline for assessment and management of polycystic ovary syndrome. Med J Aust. 2018 Sep 01;209(7):299-300. [PubMed: 30257632]
4.Goyal A, Ganie MA. Idiopathic Hyperprolactinemia Presenting as Polycystic Ovary Syndrome in Identical Twin Sisters: A Case Report and Literature Review. Cureus. 2018 Jul 19;10(7):e3004. [PMC free article: PMC6145756] [PubMed: 30250766]
5.Albu D, Albu A. The relationship between anti-Müllerian hormone serum level and body mass index in a large cohort of infertile patients. Endocrine. 2019 Jan;63(1):157-163. [PubMed: 30238328]
6.Spinedi E, Cardinali DP. The Polycystic Ovary Syndrome and the Metabolic Syndrome: A Possible Chronobiotic-Cytoprotective Adjuvant Therapy. Int J Endocrinol. 2018;2018:1349868. [PMC free article: PMC6083563] [PubMed: 30147722]
7.Puttabyatappa M, Padmanabhan V. Ovarian and Extra-Ovarian Mediators in the Development of Polycystic Ovary Syndrome. J Mol Endocrinol. 2018 Oct 16;61(4):R161-R184. [PMC free article: PMC6192837] [PubMed: 29941488]
8.Hallajzadeh J, Khoramdad M, Karamzad N, Almasi-Hashiani A, Janati A, Ayubi E, Pakzad R, Sullman MJM, Safiri S. Metabolic syndrome and its components among women with polycystic ovary syndrome: a systematic review and meta-analysis. J Cardiovasc Thorac Res. 2018;10(2):56-69. [PMC free article: PMC6088762] [PubMed: 30116503]
9.Maya ET, Guure CB, Adanu RMK, Sarfo B, Ntumy M, Bonney EY, Lizneva D, Walker W, Azziz R. Why we need epidemiologic studies of polycystic ovary syndrome in Africa. Int J Gynaecol Obstet. 2018 Nov;143(2):251-254. [PubMed: 30092610]
10.Carvalho LML, Dos Reis FM, Candido AL, Nunes FFC, Ferreira CN, Gomes KB. Polycystic Ovary Syndrome as a systemic disease with multiple molecular pathways: a narrative review. Endocr Regul. 2018 Oct 01;52(4):208-221. [PubMed: 31517612]
11.Marciniak A, Lejman-Larysz K, Nawrocka-Rutkowska J, Brodowska A, Songin D. [Polycystic ovary syndrome – current state of knowledge]. Pol Merkur Lekarski. 2018 Jun 27;44(264):296-301. [PubMed: 30057399]
12.Sala Elpidio LN, de Alencar JB, Tsuneto PY, Alves HV, Trento Toretta M, It Taura SK, Laguila Visentainer JE, Sell AM. Killer-cell immunoglobulin-like receptors associated with polycystic ovary syndrome. J Reprod Immunol. 2018 Nov;130:1-6. [PubMed: 30099219]
13.Shorakae S, Ranasinha S, Abell S, Lambert G, Lambert E, de Courten B, Teede H. Inter-related effects of insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic inflammation in PCOS. Clin Endocrinol (Oxf). 2018 Nov;89(5):628-633. [PubMed: 29992612]
14.Xie J, Burstein F, Garad R, Teede HJ, Boyle JA. Personalized Mobile Tool AskPCOS Delivering Evidence-Based Quality Information about Polycystic Ovary Syndrome. Semin Reprod Med. 2018 Jan;36(1):66-72. [PubMed: 30189453]
15.Boyle JA, Xu R, Gilbert E, Kuczynska-Burggraf M, Tan B, Teede H, Vincent A, Gibson-Helm M. Ask PCOS: Identifying Need to Inform Evidence-Based App Development for Polycystic Ovary Syndrome. Semin Reprod Med. 2018 Jan;36(1):59-65. [PubMed: 30189452]
16.Misso ML, Tassone EC, Costello MF, Dokras A, Laven J, Moran LJ, Teede HJ., International PCOS Network. Large-Scale Evidence-Based Guideline Development Engaging the International PCOS Community. Semin Reprod Med. 2018 Jan;36(1):28-34. [PubMed: 30189448]
17.Tay CT, Moran LJ, Wijeyaratne CN, Redman LM, Norman RJ, Teede HJ, Joham AE. Integrated Model of Care for Polycystic Ovary Syndrome. Semin Reprod Med. 2018 Jan;36(1):86-94. [PubMed: 30189456]
18.Htet T, Cassar S, Boyle JA, Kuczynska-Burggraf M, Gibson-Helm M, Chiu WL, Stepto NK, Moran LJ. Informing Translation: The Accuracy of Information on Websites for Lifestyle Management of Polycystic Ovary Syndrome. Semin Reprod Med. 2018 Jan;36(1):80-85. [PubMed: 30189455]
19.Glintborg D, Altinok ML, Mumm H, Hermann AP, Ravn P, Andersen M. Body composition is improved during 12 months’ treatment with metformin alone or combined with oral contraceptives compared with treatment with oral contraceptives in polycystic ovary syndrome. J Clin Endocrinol Metab. 2014 Jul;99(7):2584-91. [PubMed: 24742124]
20.Ganie MA, Khurana ML, Nisar S, Shah PA, Shah ZA, Kulshrestha B, Gupta N, Zargar MA, Wani TA, Mudasir S, Mir FA, Taing S. Improved efficacy of low-dose spironolactone and metformin combination than either drug alone in the management of women with polycystic ovary syndrome (PCOS): a six-month, open-label randomized study. J Clin Endocrinol Metab. 2013 Sep;98(9):3599-607. [PubMed: 23846820]
21.Glintborg D, Andersen M. Medical comorbidity in polycystic ovary syndrome with special focus on cardiometabolic, autoimmune, hepatic and cancer diseases: an updated review. Curr Opin Obstet Gynecol. 2017 Dec;29(6):390-396. [PubMed: 28901968]
22.Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ., International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2018 Sep;89(3):251-268. [PMC free article: PMC9052397] [PubMed: 30024653]
23.Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ., International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018 Aug;110(3):364-379. [PMC free article: PMC6939856] [PubMed: 30033227]
24.Glintborg D, Mumm H, Holst JJ, Andersen M. Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycaemia in polycystic ovary syndrome. Endocr Connect. 2017 May;6(4):267-277. [PMC free article: PMC5457494] [PubMed: 28432082]
25.Niafar M, Pourafkari L, Porhomayon J, Nader N. A systematic review of GLP-1 agonists on the metabolic syndrome in women with polycystic ovaries. Arch Gynecol Obstet. 2016 Mar;293(3):509-15. [PubMed: 26660657]
26.Han Y, Li Y, He B. GLP-1 receptor agonists versus metformin in PCOS: a systematic review and meta-analysis. Reprod Biomed Online. 2019 Aug;39(2):332-342. [PubMed: 31229399]
27.Devin JK, Nian H, Celedonio JE, Wright P, Brown NJ. Sitagliptin Decreases Visceral Fat and Blood Glucose in Women With Polycystic Ovarian Syndrome. J Clin Endocrinol Metab. 2020 Jan 01;105(1):136-51. [PMC free article: PMC7947776] [PubMed: 31529097]
28.Javed Z, Papageorgiou M, Deshmukh H, Rigby AS, Qamar U, Abbas J, Khan AY, Kilpatrick ES, Atkin SL, Sathyapalan T. Effects of empagliflozin on metabolic parameters in polycystic ovary syndrome: A randomized controlled study. Clin Endocrinol (Oxf). 2019 Jun;90(6):805-813. [PubMed: 30866088]
29.Tay CT, Joham AE, Hiam DS, Gadalla MA, Pundir J, Thangaratinam S, Teede HJ, Moran LJ. Pharmacological and surgical treatment of nonreproductive outcomes in polycystic ovary syndrome: An overview of systematic reviews. Clin Endocrinol (Oxf). 2018 Nov;89(5):535-553. [PubMed: 29846959]
30.Zeng L, Yang K. Effectiveness of myoinositol for polycystic ovary syndrome: a systematic review and meta-analysis. Endocrine. 2018 Jan;59(1):30-38. [PubMed: 29052180]
31.Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ., International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018 Sep 01;33(9):1602-1618. [PMC free article: PMC6112576] [PubMed: 30052961]
32.Armeni E, Lambrinoudaki I. Cardiovascular Risk in Postmenopausal Women with Polycystic Ovary Syndrome. Curr Vasc Pharmacol. 2019;17(6):579-590. [PubMed: 30156159]
33.Neven ACH, Laven J, Teede HJ, Boyle JA. A Summary on Polycystic Ovary Syndrome: Diagnostic Criteria, Prevalence, Clinical Manifestations, and Management According to the Latest International Guidelines. Semin Reprod Med. 2018 Jan;36(1):5-12. [PubMed: 30189445]
