Endocrine Pathology Mcqs

[Nikita Desjardins]

Polycysticovarian syndrome (PCOS) is the most common hormonal disorder in females of reproductive age. It is characterized by two or more of the following: irregular menstrual periods, hyperandrogenism, and polycystic ovaries. This activity outlines the evaluation and treatment of polycystic ovarian syndrome and reviews the role of the interprofessional team in managing patients with this condition.

Objectives:Describe the epidemiology of polycystic ovarian syndrome.Review the role of functional ovarian hyperandrogenism (FOH) in the pathophysiology of polycystic ovarian syndrome.Summarize the use of the Rotterdam criteria in the evaluation of polycystic ovarian syndrome.Outline the importance of collaboration and communication among the interprofessional team to emphasize lifestyle changes and close follow-up to improve patient outcomes affected by polycystic ovarian syndrome.Access free multiple choice questions on this topic.

Polycystic ovarian syndrome (PCOS) is the most common endocrine pathology in females of reproductive worldwide. Stein and Leventhal initially described it in 1935. The prevalence ranges between 5% and 15% depending on the diagnostic criteria applied. It is widely accepted among specialty society guidelines that the diagnosis of PCOS must be based on the presence of at least two of the following three criteria: chronic anovulation, hyperandrogenism (clinical or biological), and polycystic ovaries. It is a diagnosis of exclusion, and disorders that mimic clinical features of PCOS must be excluded. These include thyroid disease, hyperprolactinemia, and non-classical congenital adrenal hyperplasia. Selected patients may need more extensive workup if clinical features suggest other causes.

Despite its high prevalence, PCOS is underdiagnosed and frequently takes more than one visit or different physicians to get identified, and these usually occur in more than a one-year timeframe. It is a very frustrating process for the patient. Delay in diagnosis can lead to the progression of comorbidities making it more difficult to implement lifestyle intervention, which is critical for the improvement of features of PCOS and quality of life.

Multiple morbidities are associated with PCOS, including infertility, metabolic syndrome, obesity, impaired glucose tolerance, type 2 diabetes mellitus (DM-2), cardiovascular risk, depression, obstructive sleep apnea (OSA), endometrial cancer, and nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis (NAFLD/NASH). There are different screening recommendations for each of these pathologies, but the clinician must have a low threshold for workup if any manifestation is shown in PCOS patients.[1][2][3]

PCOS is a multifactorial disease. Several susceptible genes have been identified as contributors to the pathophysiology of the disease. These genes are involved in various levels of steroidogenesis and androgenic pathways. Twin studies have estimated about 70% heritability. Also, the environment is a fundamental component in the expression of these genes and the development and progression of the disease.[4][5][6]

Two popular hypotheses postulate that individuals with a genetic predisposition exposed to certain environmental factors lead to the expression of PCOS features. The most common environmental factors include obesity and insulin resistance. Some hypotheses also include fetal androgen exposure.[7]

As already mentioned, PCOS is the most common endocrine pathology in reproductive-aged females worldwide, affecting between 5% and 15% of females depending on the diagnostic criteria. Rotterdam criteria include a broader prevalence than the National Institute of Health 1990 Criteria. Based on the NIH 2012 workshop report, it is estimated that PCOS affects about 5 million reproductive-aged females in the United States. The cost to the healthcare system for diagnosing and treating PCOS is approximately $4 billion annually, not including the cost of serious comorbidities associated with PCOS.

Multiple conditions have been associated with PCOS, including infertility, metabolic syndrome, obesity, impaired glucose tolerance, DM-2, cardiovascular risk, depression, OSA, endometrial cancer, NAFLD/NASH. Higher prevalence has been associated in first-degree relatives with PCOS, prepubertal obesity, congenital virilizing disorders, above-average or low birth weight for gestational age, premature adrenarche, use of valproic acid as an antiepileptic drug. Studies have also suggested that there is a higher prevalence in Mexican-Americans than non-Hispanic whites and African Americans.[8][9]

PCOS is a hyperandrogenic state with oligo-anovulation that cannot be explained by any other disorder. It is a diagnosis of exclusion. Nevertheless, it accounts for the majority of hyperandrogenic presentations.

Nearly all causes of PCOS are due to functional ovarian hyperandrogenism (FOH). Two-thirds of PCOS presentations have typical functional ovarian hyperandrogenism, characterized by dysregulation of androgen secretion with an over-response of 17-hydroxyprogesterone (17-OHP) to gonadotropin stimulation. The remaining PCOS with atypical FOH lack of overresponse of 17-OHP, but testosterone elevation can detect it after suppressing adrenal androgen production. About 3% of PCOS patients have a related isolated functional adrenal hyperandrogenism. The remainder of PCOS cases is mild. These lack evidence of steroid secretory abnormalities; most of these patients are obese, which practitioners postulate accounts for their atypical PCOS. Specific testing for the FOH subpopulation has low clinical utility in our present day.[10]

Functional ovarian hyperandrogenism PCOS presents with the primary features: hyperandrogenism, oligo anovulation, and polycystic ovaries morphology. Functional ovarian hyperandrogenism is multifactorial, with a combination of hereditable and environmental factors. Causes for this dysregulation include insulin excess, which is known to sensitize the ovary to luteinizing hormone (LH) by interfering with the process of homologous desensitization to LH in the normal ovulation cycle as well as an intrinsic imbalance among intraovarian regulatory systems. Theca cells in PCOS have overexpression of most steroidogenic enzymes and proteins involved in androgen synthesis, which suggested a prominent abnormality at the level and activity of steroidogenic enzymes, including P450c17, which has been highly identified. Granulosa cells prematurely luteinize primarily as a result of androgen and insulin excess.

Androgen excess enhances the initial recruitment of primordial follicles into the growth pool. Simultaneously, it initiates premature luteinization, which impairs the selection of the dominant follicle. This results in classical PCOS histopathologic and gross anatomic changes that constitute PCOM. PCOS is perpetuated by increased LH, but it is not caused by it. LH excess is common and is necessary for the expression of gonadal steroidogenic enzymes and sex hormone secretion but is less likely to be the primary cause of ovarian androgen excess because of LH-induced desensitization of theca cells.

About one-half of patients with functional ovarian hyperandrogenism have an abnormal degree of insulin-resistant hyperinsulinism, which acts on theca cell, increasing steroidogenesis and prematurely luteinizes granulosa cells, and stimulates fat accumulation. Hyperandrogenemia provokes LH excess, which then acts on both theca and luteinized granulosa sustaining cycle.

Ovarian hormonal dysregulation alters the pulsatile gonadotropin-releasing hormone (GnRH) release, potentially leading to a relative increase in LH versus follicle-stimulating hormone (FSH) biosynthesis and secretion. LH stimulates ovarian androgen production, while the relative decrease of FSH prevents adequate stimulation of aromatase activity within the granulosa cells, decreasing androgen conversion to the potent estrogen estradiol. This becomes a self-perpetuating noncyclic hormonal pattern.

Elevated serum androgens are converted in the periphery to estrogens, mostly estrone. As conversion occurs primarily in the stromal cells of adipose tissue, estrogen production will be augmented in obese PCOS patients. This conversion results in chronic feedback at the hypothalamus and pituitary gland, in contrast to the normal fluctuations in feedback observed in the presence of a growing follicle and rapidly changing estradiol levels. Unopposed estrogen stimulation of the endometrium may lead to endometrial hyperplasia.[11][12][13]

A complete history and physical exam are critical for the diagnosis of PCOS. Two out of three diagnostic criteria rely on history and physical exam, including menstrual history and features of hyperandrogenism. Additionally, PCOS represents a diagnosis of exclusion, and identifying clinical presentation of other conditions should be done.

Most society guidelines have accepted that diagnosis of PCOS; most meet two out of three criteria: chronic anovulation, clinical or biological hyperandrogenism, and polycystic ovaries morphology in the absence of any other pathology. These clinical features are part of the Rotterdam Criteria. The National Institute of Health criteria also requires clinical or biochemical hyperandrogenism and oligo or anovulation. The American Excess PCOS Society requires hyperandrogenism with one of two of the remaining criteria.

Disorders that mimic the clinical features of PCOS should be excluded. These include thyroid disease, hyperprolactinemia, and non-classic congenital adrenal hyperplasia with 21-hydroxylase deficiency, for which measurement of serum 17-hydroxyprogesterone (17-OHP) should be done, which may require further testing with adrenocorticotropin stimulation test.[14][15][16]

Diagnosing PCOS in adolescents is especially challenging given the developmental issues in this group. Many features of PCOS are common in normal puberty, for example, acne, menstrual irregularities, and hyperinsulinemia. Menstrual irregularities with anovulatory cycles occur due to the immaturity of the hypothalamic-pituitary-ovarian axis during the first 2 to 3 years after menarche. Persistent oligomenorrhea beyond this period predicts ongoing menstrual irregularities and a higher chance of underlying ovarian or adrenal dysfunction. Ultrasound is also not very helpful in adolescents because they commonly have large, multicystic ovaries.

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