Polycystic Ovarian Syndrome: A Review of The Pathophysiology, Diagnosis, Treatment and Risk Factors of This Endocrine Disorder

Abstract

Polycystic Ovary Syndrome (PCOS) is a hormonal disorder that affects women, mostly teenagers and adults, causing infertility, acne, hirsutism, and other symptoms. The disorder is caused by hyperandrogenism and an increase in ovarian sugar level. The diagnosis of PCOS is based on the presence of at least two of the criteria, i.e., oligomenorrhea or amenorrhea or biochemical sign hyperandrogenism, and by using ultrasound. The exact cause of PCOS is unknown, but it is still believed to involve genetic or environmental factors. The treatment of PCOS includes lifestyle modification, such as weight management and physical exercise, and medications such as metformin, pioglitazone, spironolactone, clomiphene, and letrozole, which belong to the category of antidiabetic and antiandrogenic agents. Alternative therapies such as using herbal supplements, may also be effective in suppressing the symptoms of PCOS. This article reviews the physiology of ovulation, the hormones involved, and factors affecting ovulation. It also discusses the symptoms, diagnosis and treatment of PCOS, including lifestyle, modification, drugs of choice and alternative therapy. The article also highlights the long-term risk factors associated with PCOS, such as type 2 diabetes, hypertension, and cardiovascular diseases.

Keywords

Introduction

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-8.png" target="_blank">
            <img alt="Menstrual Phases.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-8.png" width="150">
        </a>
Fig 1: Menstrual Phases

Factors affecting Ovulation:

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-7.png" target="_blank">
            <img alt="Structure of normal ovary and polycystic ovary.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-7.png" width="150">
        </a>
Fig 2: Structure of normal ovary and polycystic ovary.

Symptoms:

Possible symptoms include:

• Oligomenorrhea or Amenorrhea
• Acne or oily skin.
• Excessive unwanted facial hairs or on body.
• Male-pattern baldness or hair thinning.
• Weight gain, especially around the belly.

People with PCOS may have other major health conditions, including:

• Type 2 diabetes.
• Hypertension (high blood pressure).
• High cholesterol.
• Heart disease.
• Uterine cancer ⁽³⁾

Diagnosis ^(3,4,5,6):

Polycystic Ovary Syndrome (PCOS) is diagnosed by the presence of at least two of the following criteria:

• Hirsutism is characterized by the presence of excess hair on the face and body and possibly hair loss
• Elevated testosterone levels in the blood can lead to acne and other symptoms
• Oligomenorrhea or Amenorrhea
• Ultrasound scans that reveal polycystic ovaries
• Blood tests that detect irregular changes in hormone levels, although these changes are not universal

In women with PCOS, hormone levels are often elevated, including:

• Testosterone, a male sex hormone that promotes the growth of facial hair
• Oestrogen is an ovarian hormone that stimulates the growth of the womb lining (endometrium)
• Luteinizing hormone (LH), a pituitary hormone that influences hormone production by the ovaries and is essential for normal ovulation
•  Insulin, a hormone that regulates sugar metabolism in the body, may contribute to the development of diabetes.
• Anti-Müllerian hormone (AMH) measures the ovaries fertility level and can indicate the number of remaining eggs.

Prevention and Management ^(3,4,5,6):

There are various perspectives on the treatment of Polycystic Ovary Syndrome (PCOS). One approach is to prevent the excessive secretion of male hormones, which can be achieved through weight management. While some experts believe that PCOS is a lifelong disorder that cannot be treated, others argue that a combination of lifestyle changes and hormonal treatment can be effective in managing the condition. The health consequences of PCOS are diverse and can include the non-functioning or dysfunction of certain organs, making it essential to seek treatment and adopt a stress-free lifestyle. For example, obese women with PCOS may experience a deficiency in vitamin D, as obesity is directly linked to a decrease in vitamin D levels, which can increase the risk of osteoporosis or rickets.

The first step in treating PCOS is to make lifestyle changes. Several lifestyle management strategies are effective in managing PCOS, including:

1. Weight management: Maintaining a healthy weight can help regulate hormone levels and improve overall health.
2. Dietary modification: Adopting a low-carbohydrate diet can help regulate blood sugar levels and improve insulin sensitivity.
3. Regular physical activity: Engaging in regular exercise can help improve insulin sensitivity, reduce androgen levels, and promote overall health.
4. Behavioural modification: Making changes to daily habits and behaviours, such as getting enough sleep and managing stress, can help improve overall health and well-being.
5. Stress-free lifestyle: Practicing stress-reducing techniques, such as meditation or yoga, can help manage stress and improve overall health.

By adopting these lifestyle management strategies, women with PCOS can reduce their symptoms, improve their overall health, and increase their chances of leading a stress-free life.

Need And Objectives

Need for study:

1. Infertility is a major issue found in women.
2. To cure the PCOD/PCOS.
3. To develop safe and effective dosage form by pre-formulation studies.

Objectives:

1. To promote fertilization in infertile women.
2. To control the hormonal imbalance in PCOD/PCOS.
3. To formulate a safe and effective dosage form, it is necessary to study the optimized drugs profile.
4. To study the standardisation parameters of drugs.

Drugs

1) Metformin:^(3,6,7,8,9)

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-6.png" target="_blank">
            <img alt="Structure of metformin.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-6.png" width="150">
        </a>
 Fig 3: Structure of metformin

• Category: Antidiabetic/ Hypoglycaemic/ Antihyperglycemic agent. ⁽⁷⁾
• Molecular Weight: 129.1 g/mol
• Chemical formula: C₄H₁₁N₅
• Nature: Hydrophilic nature
• Melting point: 223-242 °C
• Solubility: Highly soluble in water. Sparingly soluble in organic solvents such as ethanol, DMSO, and formamide.
• Decrease ovarian sugar level: Metformin can cause changes in the menstrual Cycle (Promote ovulation). Pass through breast milk in mild amounts. B-blockers also act as mild diuretics.

• Λ _max:: 234 nm
• Absorption: Binds at GLUT-2 receptor & increases utilization of insulin
• Distribution: Distributed through blood
• Metabolism: Liver and Spleen
• Excretion: Urine
• Half-life: 6.2 hours
• Metformin also increases Ca+ level, which is responsible for increasing the oestrogen hormone.^(3,6,7)
• Mechanism of action: Metformin is a compound that increases the body’s sensitivity to insulin and helps to control blood sugar levels. ⁽⁸⁾
• Metformin works as follows ⁽⁸⁾:
  • Inhibit hepatic gluconeogenesis
  • Increase insulin sensitivity
  • Increased glucose uptake by skeletal
  • Suppress inflammation
  • Modulate mitochondrial function
  • Inhibits mitochondrial respiration
  • Innate mitochondrial glycerophosphate dehydrogenase
  • Inhibits fructose-1,6-biphosphatase
• Major side effects of metformin
  • Heartburn
  • Stomach pain
  • Nausea or vomiting
  • Bloating
  • Diarrhoea
  • Constipation
  • Weight loss
  • Headache

2) Spironolactone ^(10,11)

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-5.png" target="_blank">
            <img alt="Structure of Spironolactone.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-5.png" width="150">
        </a>
Fig 4: Structure of Spironolactone

• Molecular weight: 416.57 g/mol

• Molecular formula: C₂₄H₃₂O₄S
• Hydrophobic in nature.
• Melting point: 134-135°C
• Mild moderate anti-Androgen
• Spironolactone decreases testosterone levels (Male hormone), secreted by the adrenal gland in females.
• It acts as a diuretic, i.e. flush out old ovarian fluid. (While metformin tends to generate new fluid).
• Belongs to mineralocorticoid receptor antagonist
• Λ _max:: 238 nm
• Absorption: Spironolactone & its metabolites more than go bound to plasma protein.
• Distribution: Through Blood.
• Metabolism: Liver
• Excretion: Urine, bile
• Half-life: 12-13 hours
• Mechanism of action: Spironolactone acts as an anti-androgenic agent by blocking androgen receptors, which prevents testosterone from binding, and it also decreases androgen production from the ovaries and adrenal gland⁽¹²⁾
• Major side effects of spironolactone⁽¹⁴⁾:
  • Breast tenderness
  • Vomiting
  • Diarrhoea
  • Stomach pain or cramps
  • Irregular periods

3) Clomiphene⁽¹³⁾

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-4.png" target="_blank">
            <img alt="Structure of Clomiphene.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-4.png" width="150">
        </a>
Fig 5: Structure of Clomiphene

• Category: Oestrogen Agonist-antagonists
• Molecular weight: 405.966 g/mol
• Chemical formula: C₂₆H₂₈ClNO
• Nature: Hydrophobic
• Melting point: 116.5-118 °C
• Λ _max:: 234 nm
• Clomiphene has both estrogenic and anti-estrogenic properties. Clomiphene appears to stimulate the release of gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), which leads to the development and maturation of the ovarian follicle, ovulation, and subsequent development of the corpus luteum.
• Absorption: Based on early studies with 14 C-labelled clomiphene, the drug was shown to be readily absorbed orally in humans.
• Distribution: Distributed through blood
• Metabolism: Hepatic
• Excretion: Urine
• Half-life: 5-7 days
• Mechanism of action: Clomiphene acts as a selective oestrogen receptor modulator (SERM), binds to oestrogen receptors in the pituitary gland and hypothalamus, which tends to increase the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and ultimately stimulates ovulation
• Major side effects of clomiphene:
  • Bloating
  • Headache
  • Vomiting
  • Breast discomfort
  • Blurred vision
  • Pelvic-Abdominal pain
  • Dizziness
  • Tachycardia
  • Hepatic disease
  • Shortness of breath

4) Letrozole ⁽¹⁵⁾

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-3.png" target="_blank">
            <img alt="Structure of Letrozole.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-3.png" width="150">
        </a>
Fig 6: Structure of Letrozole

• Category: Non-Steroidal Aromatase Inhibitor
• Molecular weight: 285.303 g/mol
• Chemical formula: C₁₇H₁₁N₅
• Nature: Hydrophobic
• Melting point: 184-185 °C
• Λ _max:: 240 nm
• It blocks the active site of androgens. Therefore, the electron transfer chain reaction of CYP19A1. This competitive inhibition prevents the conversion of androgens to oestrogens.
• Absorption: Letrozole is 99.9% orally bioavailable. 
• Distribution: Distributed through blood
• Metabolism: Liver
• Excretion: Urine
• Half-life: 42 hours
• Mechanism of action: Letrozole binds to aromatase enzyme, which converts androgen like testosterone into oestrogen and further increases the secretion of follicle-stimulating hormone (FSH), which leads to ovulation.
• Major side effects of Letrozole:
  • Headache
  • Arthralgia
  • Weight gain
  • Insomnia
  • Dizziness
  • Fatigue
  • Nausea or vomiting
  • Loss of appetite
  • Vaginal dryness   
  • Blurred vision
  • Abdominal pain

5) Rosiglitazone⁽¹⁶⁾

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-2.jpg" target="_blank">
            <img alt="Structure of Rosiglitazone.jpg" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-2.jpg" width="150">
        </a>
Fig 7: Structure of Rosiglitazone

• Category: Thiazolidinedione (TZD) medication
• Molecular weight: 357.428 g/mol
• Chemical formula: C18H19N3O₃S
• Nature: Hydrophobic
• Melting point: 122-123 °C
• Solubility: Sparingly soluble in aqueous buffers
• Λ _max:: 312 nm

• Decrease ovarian sugar level: Rosiglitazone can cause changes in the menstrual Cycle (Promote ovulation). It can pass through breast milk in mild amounts. B-blockers also act as mild diuretics.

• Absorption: Absorbed quickly and almost completely with an absolute bioavailability of 99% 
• Distribution: Distributed through blood
• Metabolism: Liver
• Excretion: Urine and faeces
• Half-life: 3-4 hours

Mechanism of action: Like other thiazolidinediones, rosiglitazone activates the intracellular receptor class of the peroxisome proliferator-activated receptors (PPARs), specifically PPAR-γ. Rosiglitazone is a selective ligand of PPAR-γ, and has no PPAR-α binding action, which improves glycaemic control by improving insulin sensitivity.

• Major side effects of rosiglitazone
  • Swelling
  • Hypertension
  • Heart failure/ Congestive Heart Failure (CHF)
  • Myocardial ischemia
  • Diarrhoea
  • Upper respiratory tract infection (RTI)

6) Chlormadinone acetate ⁽¹⁷⁾

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-1.png" target="_blank">
            <img alt="Structure of Chlormadinone acetate.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-1.png" width="150">
        </a>
Fig 8: Structure of Chlormadinone acetate

• Category: Corticosteroid anti-androgenic progesterone derivatives
• Molecular Weight: 404.931 g/mol
• Chemical formula: C₂₃H₂₉ClO₄
• Nature: Hydrophobic nature
• Melting point: 212-214 °C
• Solubility: Insoluble in water. It is soluble in organic solvents like chloroform, ethanol, etc.
• It is a synthetic progestin and anti-androgen compound used in birth pills and hormone replacement therapy (HRT)

• Λ _max:: 240 nm
• Absorption: Chlormadinone acetate is 99.9% orally bioavailable
• Distribution: Distributed through blood
• Metabolism: Occurs using hydroxylation and deacetylation via reduction of the keto group at C_3.
• Excretion: Urine
• Half-life: 25-34 hours after a single dose and 34-39 hours after multiple doses
• Mechanism of action: Chlormadinone acetate shows anti-androgenic activity can block androgen receptors, reducing the effects of testosterone and dihydrotestosterone, which can be beneficial in managing conditions like acne and hirsutism.
• Major side effects of chlormadinone acetate:
  • Menstrual irregularities
  • Breast tenderness
  • Headache
  • Nausea
  • Mood swings
  • Weight gain
  • Blood clot
  • Hepatic problems
  • Severe allergic reactions

7) Pioglitazone ⁽¹⁸⁾
        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-0.png" target="_blank">
            <img alt="Structure of Pioglitazone.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250603163429-0.png" width="150">
        </a>
    Fig 9: Structure of Pioglitazone

• Category: Thiazolidinedione (TZD) medication

• Molecular Weight: 356.44 g/mol
• Chemical formula: C₁₉H₂₀N₂O₃S
• Nature: Hydrophobic nature
• Melting point: 183-184 °C
• Solubility: Poorly soluble in water. Soluble in organic solvents
• Pioglitazone belongs to a class of medication called thiazolidinediones and is used to treat Type II Diabetes and hyperglycaemia. It increases the body’s insulin sensitivity more effectively to control blood sugar levels

• Λ _max:: 268-272 nm
• Absorption: Quickly absorbed from the gastrointestinal tract (GI tract) after being taken orally
• Distribution: Distributed through blood
• Metabolism: Liver
• Excretion: Urine
• Half-life : 3-7 hours
• Mechanism of action: Pioglitazone is an anti-diabetic medication that improves insulin sensitivity in cells by activating the peroxisome proliferator-activated receptor gamma (PPAR-γ) receptor
• Major side effects of pioglitazone:
  • Blurred vision
  • Headache
  • Sore throat
  • Heart failure
  • Hypoglycaemia
  • Jaundice
  • Nausea
  • Liver disease
  • Increased urination
  • Weakness
  • Weight gain

8) Gonadotropin ⁽¹⁹⁾

• Category: Gonadotropins belong to the cystine knot family glycoprotein hormones, and they are categorized as heterodimeric glycoproteins
• Molecular Weight: 1212.3 g/mol
• Chemical formula: C₁₇₇₀H₁₇₇₀O₃₃₆S₂₆
• Nature: Hydrophilic nature
• Solubility: It is soluble in water and organic solvents like chloroform, ethanol, etc

• Women with PCOS have a higher frequency of GnRH, which leads to increased luteinizing hormone (LH) secretion.
• Λ _max:: 268-272 nm
• Absorption: Quickly absorbed from the gastrointestinal tract (GI tract) after being taken orally
• Distribution: Distributed through blood
• Metabolism: Liver
• Excretion: Urine
• Half-life : 3-7 hours

• Mechanism of action:

Gonadotropin binds to specific receptors on ovarian cells, which results in decreased and elevated LH: FSH ratio, contributing to the characteristic features of PCOS like anovulation and hyperandrogenism

• Major side effects of gonadotropin:
  • Acne
  • Facial hair growth
  • Headache
  • Tiredness
  • Stomach upset
  • Breast tenderness
  • Swelling of hands, ankles or feet
  • Unusual vaginal bleeding

Risk Factors

Polycystic ovarian syndrome (PCOS) is commonly associated with endocrinopathy, a condition that affects the endocrine glands and causes hormonal imbalance and is responsible for several risk factors.

1. Type II Diabetes Mellitus ⁽²⁰⁾

Polycystic ovarian syndrome can cause type II diabetes mellitus. This chronic condition affects the way the body produces blood sugar and decreases insulin sensitivity, which decreases glucose uptake by the cells. Oral hypoglycaemic agents, which increase insulin sensitivity and cell glucose uptake, treat the condition.

Type II Diabetes Mellitus further leads to Endothelial dysfunction; it is a condition in which the cells that line blood vessels don’t work properly.

2. Hypertension ⁽²¹⁾

Hypertension is a condition in which the force of blood against the walls of the arteries is too high, and it increases more than 180/120 from 140//90. PCOS can lead to hypertension. To prevent and manage eating a healthier diet with less salt, regular exercise can help to lower blood pressure. Anti-hypertensive drugs, including beta blockers e.g. Metoprolol, atenolol, ACE inhibitors e.g. Lisinopril, Enalapril can help to lower blood pressure.

3. Obesity

Obesity is a disorder that involves excessive body fat, which increases the risk of overall health problems. Obesity occurs when a patient’s body mass index (BMI) is 25 or more than 25. The main stage of treatment is lifestyle modification, such as a healthy diet and regular exercise. For the severely obese, bariatric surgery or an intragastric balloon is an option

4. Hirsutism ^(13,15)

In hirsutism, excessive male pattern hair growth takes place on women’s faces, back and chest. Hirsutism is caused by excessive male hormone called androgen, i.e. testosterone. Hirsutism can be treated by using anti-androgenic drugs, including Flutamide, Spironolactone, and Enzalutamide, which can help to lower androgen levels in the body or hair removal by electrolysis or laser surgery is done.

5. Severe Acne ⁽²²⁾

Acne is the most common skin disease caused by PCOD/PCOS. All forms of acne require systematic treatment, including anti-inflammatory compounds such as 5-lipoxygenase inhibitor zileuton, which may replace systemic antibiotics.

CONCLUSION

Polycystic Ovary Syndrome (PCOS) is a hormonal disorder that affects women, mostly teenagers and adults, causing infertility, acne, hirsutism, and other symptoms. The disorder is caused by hyperandrogenism and an increase in ovarian sugar level. Early diagnosis and treatment are essential to prevent long-term complications, such as type 2 diabetes, hypertension, and cardiovascular disease. Lifestyle modifications, medications, and alternative therapies may be effective in managing the symptoms of PCOS. Further research is needed to understand the causes of PCOS and to develop effective treatments for the disorder. Healthcare providers should be aware of the symptoms and diagnosis of PCOS and provide comprehensive care to women with the disorder. By working together, we can improve the health and well-being of women with PCOS and reduce the risk of long-term complications. The treatment for PCOD/PCOS includes Anti-androgenic agents like Spironolactone, Flutamide, and Clomiphene and also includes anti-hyperglycemic compounds like Metformin, Rosiglitazone, Glimepiride, and Pioglitazone. Before formulation, any dosage form Pre-formulation studies of drugs and excipients, including physicochemical and biological approaches like stability analysis, rheological studies, partition coefficient, ADME, etc, have to be done to ensure safety, efficacy, reduce side effects and improve bioavailability of the formulation.  The evaluation of optimized drugs has to be done to ensure the quality of the formulation by its respective evaluation parameters as per dosage form.

Future Prospects

Traditional drug delivery systems contain oral dose forms like tablets, capsules, pills, syrups, elixirs, ointments, etc. But novel drug delivery systems contain nanotechnology, SMEDDS ( self-micro emulsifying drug delivery system), ocular DDS, transdermal patches, etc. Traditional drug treatment for PCOD/PCOS was oral tablets containing metformin tablets along with spironolactone tablets for the treatment of PCOD/PCOS, but in NDDS, we can formulate the dosage forms that are yet to be discovered.

REFERENCES

1. Mycarmesi. Basic information about hyper ovulation is taken from (internet):  https://mycarmesi.com/blogs/f/what-is-hyperovulation-causes-signs-of-hyperovulation-supplements.
2. Jukola E, Hakkarainen J, Saloniemi H, Sankari S. Blood selenium, vitamin E, vitamin A, and β-carotene concentrations and udder health, fertility treatments, and fertility. Journal of Dairy Science. 1996 May 1;79(5):838-45.
3. WHO, World Health Organization. Information about PCOS was taken from https://www.who.int/news-room/fact-sheets/detail/polycystic-ovary-syndrome.
4. Joanes J. Bloody, hairy, and hormonal: An intimate geopolitics of Polycystic Ovarian Syndrome (PCOS). Political Geography. 2023 Oct 1;106:102952.
5. Ajmal N, Khan SZ, Shaikh R. Polycystic ovary syndrome (PCOS) and genetic predisposition: A review article. European journal of obstetrics & gynecology and reproductive biology: X. 2019 Jul 1;3:100060.
6. Minocha N. Polycystic ovarian disease or polycystic ovarian syndrome: how to identify and manage a review. Archives of Pharmacy Practice. 2020;11(2-2020):102-6.
7. The Indian Pharmacopoeia Commission. Ghaziabad. Indian Pharmacopoeia 2018.The Indian Pharmacopoeia Commission Indian Pharmacopoeia Laboratory, 2018; Volume II 2544-2545.
8. Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nature Reviews Endocrinology. 2014 Mar;10(3):143-56.Yetman, D. (2024, February 1). Side Effects of Metformin: What You Should Know.
9. Healthline. https://www.healthline.com/health/diabetes/metformin-side-effects
10. The Indian Pharmacopoeia Commission. Ghaziabad. Indian Pharmacopoeia 2018.The Indian Pharmacopoeia Commission Indian Pharmacopoeia Laboratory, 2018; Volume III 3251.
11. Wikipedia, information about spironolactone is taken from: https://en.m.wikipedia.org/wiki/Spironolactone
12. Drugbank, information about mechanism of action of spironolactone is taken from: https://go.drugbank.com/drugs/DB00421
13. Drugbank, information about clomiphene is taken from: https://go.drugbank.com/drugs/DB00882
14. Patibandla S, Heaton J, Kyaw H. Spironolactone.
15. Bülow N, Macklon N. The role of Letrozole in IVF treatment: new remedy or old mirage?. Fertility and Sterility. 2024 Oct 31.
16. Vigil P. Hormones and the female voice: An exploration of the female hormonal cycle from puberty to menopause and how it affects the vocal apparatus. Temple University; 2015.
17. Schindler AE. Antiandrogenic progestins for treatment of signs of androgenisation and hormonal contraception. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2004 Feb 10;112(2):136-41.
18. Vardanyan R, Hruby V. Synthesis of best-seller drugs. Academic Press; 2016 Jan 7.
19. Yarali H, Zeyneloglu HB. Gonadotrophin treatment in patients with polycystic ovary syndrome. Reproductive biomedicine online. 2004 Jan 1;8(5):528-37.
20. Persson S, Elenis E, Turkmen S, Kramer MS, Yong EL, Poromaa IS. Higher risk of type 2 diabetes in women with hyperandrogenic polycystic ovary syndrome. Fertility and sterility. 2021 Sep 1;116(3):862-71.
21. Shi Y, Cui Y, Sun X, Ma G, Ma Z, Gao Q, Chen ZJ. Hypertension in women with polycystic ovary syndrome: prevalence and associated cardiovascular risk factors. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2014 Feb 1;173:66-70.
22. Almarri KM. Psychological Distress and Physical Activity Among Women With a Diagnosis of Polycystic Ovary Syndrome in Qatar: A Cross-Sectional Study (Master's thesis, Hamad Bin Khalifa University (Qatar).