September/October 2022

Polycystic Ovary Syndrome
By Jamshid A. Marvasti, MD, and Shealagh L. Clark
Today’s Geriatric Medicine
Vol. 15 No. 5 P. 20

Psychological Implications in the Postmenopausal Female

There are a number of articles in the literature regarding the psychiatric implications of older adult women who suffer from polycystic ovary syndrome (PCOS). We have had several patients with PCOS referred to us for psychiatric evaluation and treatment. These women also suffered from anxiety, depression, eating disorder, social phobia, sexual disorder, and problems with low self-image and self-esteem. Having provided psychiatric treatment and close follow-up of these women, we suspect that PCOS will be added to the psychiatric literature in the future as it is, at least in part, a psychiatric disorder. However, it should be understood that the majority of the psychiatric implications of PCOS are a result of the underlying hormonal disease rather than the cause of the disease itself.

The psychiatric and psychological impact of PCOS on affected patients are prominent reasons for referral to a mental health clinic; European and American research studies back this observation as they have shown that women with PCOS have an increased psychological burden.

While there are documented investigations into the disorder dating back as early as 1721, PCOS did not receive formal diagnostic criteria in the gynecologic/endocrinologic setting until the early 1990s. Since then, it’s become a largely studied disorder in those specialties as providers and researchers alike have attempted to understand its pathophysiology. The majority of studies largely have focused on women of reproductive age for whom the burden of disease is dictated by anovulation/menstrual irregularities and struggles with fertility, body habitus, hirsutism, and other symptoms consistent with an excess androgenic state.

In some ways, older adult women with PCOS have been neglected as far fewer studies to date have investigated the implications of PCOS in the postmenopausal female. While struggles with anovulation/infertility are no longer concerns in the postmenopausal period, it must be emphasized that the lack of current knowledge about the implications of PCOS in the postmenopausal period does not reflect the fact that PCOS resolves following menopause; PCOS is a chronic disease.1 Much work remains to be done in the investigation of its life-long implications, including the psychiatric comorbidities which may increase as women age.

Hypotheses About the Cause of PCOS
While the actual cause of PCOS remains a mystery, there are multiple theories regarding the etiology of the disorder. It’s largely accepted that the cause is multifactorial. Genetics likely play an important role as females with PCOS may have female relatives, on either their maternal or paternal sides, with histories of irregular periods and infertility. Research and literature review show that women with this syndrome are 50% more likely to have a mother, sister, or aunt who also suffered from PCOS (or had symptoms consistent with the diagnosis during their reproductive years). While not required for diagnosis, insulin resistance/type 2 diabetes mellitus (T2DM) in a first-degree relative also appears to put women at an increased risk of PCOS.2

The syndrome may be more common in women of certain ethnic backgrounds, such as those of Asian, African, or Caucasian-European descent. Some studies have even suggested that evolution (the survival of the fittest) plays a role, speculating that PCOS may have served as a biological advantage during hunter-gatherer times when life expectancy was short. In those times, women who suffered from this disorder may have had a metabolic advantage as having increased body mass and a slower metabolism permitted longer survival in times when food was not readily available. Furthermore, these women likely also had the reproductive advantage in that irregular menstrual cycles resulted in fewer pregnancies and fewer opportunities for birth-related complications, thus further increasing their survival rate.2

Pathophysiology of Hormonal Changes in PCOS
PCOS is a hormonal imbalance with symptoms resulting from high levels of androgens (testosterone) secreted from the ovaries. Ultrasonographic examination of ovaries demonstrates cysts appearing as “strands of pearls” inside the ovary. They’re the result, rather than a cause, of hormonal imbalances. Excessive male hormones (androgens) within the woman often cause excessive hair growth on the face and body (hirsutism) as well as alopecia, acne, and other skin problems that result in multiple psychological symptoms.

Many women with PCOS have an insulin resistance problem and experience abdominal weight gain with subsequent difficulties in losing the extra weight. They additionally may experience intense cravings for carbohydrates and/or, at times, have hypoglycemic episodes. These hormonal imbalances have been closely studied by gynecologists, endocrinologists, and cardiologists, and are largely believed to increase the risk of T2DM and cardiovascular disease in this patient population. This aligns with the notion that as women age, PCOS evolves to be part of metabolic syndrome.3,4

Regarding aging’s effect on female hormone levels, as women age and transit through menopause, estrogen levels naturally decrease as the ovaries become less responsive to gonadotropin stimulation. Reproductive hormones in women with a history of PCOS differ from those of women without a history of PCOS, both during the childbearing and the postmenopausal period. It’s been observed that the reproductive lifespan of women with PCOS is expanded beyond that of those without PCOS due to higher adrenal and ovarian androgen levels. Older women with PCOS have been observed to experience fewer episodes of hot flashes and diaphoresis than do their peers without the disorder. However, the result of long-term exposure to elevated androgens may have ramifications beyond the female reproductive tract, with additional effects such as excessive facial and body hair, hair loss, and male pattern hair loss that extend into menopause.2

Biological Changes in PCOS
Women with PCOS have insulin resistance, meaning that the cells in the body do not respond as readily to insulin, requiring the body to produce increased quantities of insulin to achieve the desired effect of moving glucose intracellularly. Given that insulin is considered a growth hormone, excessive insulin may result in weight gain, most commonly around a woman’s midsection. It is well-established that the more weight that’s gained, the more insulin the body produces. This results in increased storage and further weight gain. However, excessive insulin can cause more than just an increase in weight; it can result in skin tags, follicular keratosis, acanthosis nigricans, or dry/rough patches on the elbows. Hyperglycemia and cravings for carbohydrates or sweets in women also may be present. Long-term elevations of serum insulin levels may lead to development of T2DM and its associated comorbidities and complications. Furthermore, high blood glucose and insulin blood levels may eventually contribute to metabolic conditions, such as hypertriglyceridemia/hyperlipidemia and development of nonalcoholic fatty liver disease.2-4

When the human body is injured, it produces an inflammatory process to assist with the healing process that includes production of extra white blood cells and keratinocytes, C-reactive protein, and interleukin-6. In healthy people, after healing, inflammatory signals and processes gradually subside. However, patients with PCOS have been shown to have low-grade chronic inflammation that never fully subsides, resulting in the body being in a constant “fight” mode. This inflammatory state and associated hormone and cytokine changes can stimulate the ovaries to produce more androgens, which in turn may worsen insulin resistance and further increase inflammation, propagating a vicious cycle.2

Diagnosing PCOS
PCOS is a heterogenous disorder that, as previously observed, likely has a possibly multifactorial etiology. Risk of PCOS is significantly elevated with a family history of androgenic excess or chronic anovulation. PCOS should be suspected in any older women who have had irregular menses and symptoms of hyperandrogenism (acne, hirsutism, and male-pattern hair loss). The presence of obesity or an elevated body mass index should further raise suspicions but is not required. The prevalence of undiagnosed T2DM is 7 to 10 times greater in women with PCOS than in a control group of similarly aged women.

That being said, PCOS is largely a diagnosis of exclusion, requiring that other similar diagnoses be worked up and ruled out.2-4

PCOS is diagnosed if at least two of the following three conditions (Rotterdam criteria) are met:

• a history of oligo- and/or anovulation in an older woman;
• clinical and/or biochemical signs of hyperandrogenism; and
• polycystic ovaries viewed on ultrasound. Visualization of normal ovaries on ultrasound no longer rules out a diagnosis of PCOS if the above two criteria are met.

Differential diagnosis of PCOS syndrome should be the following:

• idiopathic hirsutism;
• hyperprolactinemia;
• hypothyroidism;
• nonclassic adrenal hyperplasia;
• ovarian tumors;
• adrenal tumors;
• Cushing syndrome; and
• glucocorticoid resistance.5

The Physical Comorbidities of PCOS
A number of medical conditions may be associated with PCOS, including the following:

• dyslipidemia;

• hypertension: Uncontrolled hypertension subsequently may lead to a myocardial infarction, stroke, or kidney failure;

• diabetes: Presentation of increased thirst, hunger, increased urination, weight loss, and blurry vision raises concerns for diabetes;

• hypothyroidism: Some women with PCOS may also develop hypothyroidism, demonstrating symptoms of fatigue, constipation, dry skin, hair loss, weight gain, and/or difficulty losing weight. Untreated hypothyroidism can result in heart disease and musculoskeletal myopathies; and

• metabolic syndrome: Commonly seen in women with PCOS, especially when obesity and poor lifestyle modifications (diet and exercise) are present. Elevated blood pressure, low high-density lipoprotein, excessive insulin/fasting blood sugar, and excessive central obesity are other comorbidities.2-4

Aging and PCOS
The average age of menopause for women in the USA is 51. Several studies indicate that as women with PCOS age, their risk of cardiovascular disease and T2DM increases. Furthermore, lipid metabolism also worsens as women with PCOS age, especially with regard to triglycerides and high-density lipoprotein concentrations. These findings align with the notion that PCOS becomes less a reproductive syndrome and more a metabolic syndrome as women age past their reproductive years.1

Treatment Considerations
Not all women with PCOS experience the same signs/symptoms or severity of the syndrome. Treatment, therefore, requires an individualized approach and understanding of each women’s specific symptoms, risks, and goals. Management of women’s weight and their overall health and symptoms is often the area of greatest concern in the postmenopausal population. Adjusting diets and recommending lifestyle changes prior to prescribing medications is the preferred approach. Psychiatric medication and psychotherapy also may be needed.

Treatment of PCOS in the Postmenopausal Female
As more than 50% of women with PCOS have body mass indexes within the overweight or obese range, weight loss through lifestyle alterations (diet and exercise) is part of first-line intervention for most patients. Even modest reductions in weight can improve metabolic risks. However, permanent lifestyle adjustments may be difficult for patients to adhere to or may not provide resolution to the syndrome’s hormonal imbalances. Additionally, these adjustments in lifestyle may produce further stressors that require support from psychological sources.

Medication & Supplements
Oral contraceptive pills (OCPs) are the mainstay of PCOS treatment in the premenopausal population. They stop ovulation, control endometrial thickening, and moderate androgen levels to improve acne and reduce hair loss. These medications also effectively decrease the risk of endometrial cancer by regulating estrogen exposure and the shedding of the endometrial lining. However, these medications may pose considerable risk of blood clots, inflammation, increased cholesterol/triglycerides, insulin resistance, and hypertension. Furthermore, some women complain of mood changes and weight gain plus feelings of bloating while on these medications.2,3

While treatment of PCOS in the premenopausal woman largely relies upon the use of OCPs, the postmenopausal population requires different considerations, and the use of OCPs is not appropriate. Antiandrogens such as flutamide (Eulexin) and spironolactone (Aldactone) decrease the quantity of androgens in the body by competing with androgens at their receptors, resulting in feedback inhibition. These medications generally require treatment for at least six months before results are evident. However, once they become effective, the results may be dramatic, including reduced acne and improved hair growth. Adverse effects of flutamide include diarrhea, hot flashes, nausea, and reduced fertility. Spironolactone, originally a blood pressure medication, has shown to be effective in both postmenopausal and reproductive-aged women. Its use should be avoided in women of reproductive age who are not on reliable contraception as it is known as a teratogen. Additional reported side effects of spironolactone include nausea, diarrhea, dizziness, and headaches.2-4

Metformin (Glucophage) lowers blood glucose levels and results in weight loss. It improves insulin sensitivity while also improving hypertension and decreasing cholesterol. Adverse effects include nausea, diarrhea, and abdominal bloating/gas. In addition, because it decreases absorption of vitamin B12, patients taking it may require supplementation.

Thiazolidinediones may be used alone or concomitantly with metformin. While known to reduce insulin levels and hirsutism, these agents may increase cardiovascular risks and skeletal fractures. They also increase adiponectin, resulting in increased weight gain and water retention.2,4

Treating Psychiatric Disorders in Women With PCOS
Women with PCOS should be assessed for depression, anxiety, eating disorders, substance use disorders, and suicidality.

Research reveals that the prevalence of anxiety and depression affects 26.1% and 52% of women with PCOS, respectively. Our experience shows that patients suffering from PCOS may develop mood disorders (anxiety and depression); body-image dissatisfaction; a decline in self-image, self-esteem, and self-confidence; social phobia; shyness; eating disorders; sexual disorders; overall low life satisfaction; and at times difficulty with interpersonal romantic relationships. Review of the literature indicates that although PCOS is increasingly recognized by clinicians, literature has seldom focused on psychological or psychiatric correlates of this endocrine disorder. Further, there is no published research exploring whether these women suffered from these psychological disorders prior to being diagnosed with PCOS.7,8

Women with PCOS have an increased prevalence of major depressive disorder compared with their age-matched controls. Two recent studies have revealed that insulin resistance may contribute to depression or depressivelike symptoms. Insulin resistance has been found to be higher in women with PCOS who have higher depression scores compared with those with lower depressive scores. Insulin-sensitizing agents such as metformin have been shown to decrease insulin resistance and depression in PCOS patients. Other insulin-sensitizing medications that operate via alternative mechanisms, such as pioglitazone, have been associated with a greater reduction of depressive symptoms in women with PCOS than metformin.2,5

These psychological comorbidities may directly correlate with age, degree of obesity, testosterone levels, degree of hirsutism, and, in younger women, infertility.

Treatment of depression and anxiety in the postmenopausal PCOS population is the same as that of treatment for women who do not have PCOS. The use of cognitive behavioral therapy in addition to pharmacologic agents, such as selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors, is largely accepted and generally well-tolerated. Caution is needed when prescribing other commonly prescribed antidepressant and antianxiety medications, such as tetracyclic antidepressants and benzodiazepines, to this population. Older adults are more likely to experience orthostatic effects resulting in falls, changes in mental status/sedation, and serotonin syndrome when taking these classes of medications. Furthermore, elderly women with PCOS often take multiple medications to control comorbid conditions related to and separate from their PCOS diagnosis. Because of this, an in-depth review of patients’ existing medications and supplements must be performed prior to initiating a new agent to ensure the patients are not at increased risk for pharmacologic interactions. Of particular concern is serotonin syndrome, a life-threatening condition that presents with agitation, confusion, tremors, seizures, or coma caused by excess accumulation of serotonin. There are several case reports describing patients prescribed serotonergic psychiatric medications, in addition to other serotonergic medications such as antiemetics (ondansetron), opioids (tramadol, meperidine, methadone, fentanyl, etc), antibiotics (linezolid), or migraine mitigation agents (sumatriptan). Patients on these psychiatric agents should be monitored regularly for symptoms of serotonin excess or serotonin syndrome.

Some women with PCOS may have an increased risk of developing bipolar disorder. Higher rates of the condition in women with PCOS compared with those without are attributed to an unrelated pathological mechanism. PCOS, for example, may develop as a consequence of the treatment of bipolar disease. Valproic acid (Depakote), an antiepileptic that is commonly used as a mood stabilizer in bipolar disorder, is associated with increased risk of PCOS. In the largest study to date, the rate of new-onset PCOS in women on valproic acid was 10.5%, compared with 1.4% in women on other mood stabilizers. The onset of PCOS in this population may be largely related to weight gain, a well-established side effect of valproic acid.5

Much like that of PCOS, the diagnosis of bipolar disorder is most commonly established early in a woman’s reproductive period. Though not impossible, it is rare for bipolar disorder to first emerge in a woman postmenopause. When treating concomitant bipolar disorder in postmenopausal women with PCOS, providers should monitor for adverse effects of antipsychotics, including but not limited to neuroleptic malignant syndrome—a rare serious reaction consisting of high fever and muscle stiffness that should prompt immediate medical attention.

— Jamshid A. Marvasti, MD, is a child and adult psychiatrist practicing at Manchester Memorial Hospital in Manchester, Connecticut.

— Shealagh L. Clark is a fourth-year medical student at the University of New England College of Osteopathic Medicine.

References
1. Grassi A. PCOS in aging women — beyond hormones and hot flashes. Today’s Dietitian. 2014;16(2):40-43.

2. Grassi A, Mattei S. The PCOS Workbook: Your Guide to Complete Physical and Emotional Health. Luca Publishing; 2019:3-18.

3. Hoffman B, Schorge J, Halvorson L, Hamid C, Corton M, Schaffer J. Williams Gynecology. 4th ed. McGraw Hill; 2020:389-405.

4. Melmed S, Auchus R, Goldfine A, Koenig R, Rosen C, Williams R. Williams Textbook of Endocrinology. 13th ed. Elsevier; 2016:627-637.

5. Sadock B, Sadock V, Ruiz P. Kaplan & Saddock's Comprehensive Textbook of Psychiatry. 10th ed. Wolters Kluwer; 2017:2247-2249.

6. Chrisler J, Barney A, Palatino B. Ageism can be hazardous to women's health: ageism, sexism, and stereotypes of older women in the healthcare system. J Soc Issues. 2016;72(1):86-104.

7. Lin H, Liu M, Zhong D, et al. The prevalence and factors associated with anxiety-like and depression-like behaviors in women with polycystic ovary syndrome. Front Psychiatry. 2021;12:709674

8. Cooney L, Lee I, Sammel M, Dokras A. High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2017;32(5):1075-1091.