Polycystic ovary syndrome and subfertility





Introduction


Polycystic ovary syndrome (PCOS) is a well-appreciated heterogeneous disorder of the endocrine system. It is usually detected in women of reproductive age group who present with a cluster of clinical features ranging from androgen excess (hirsutism, alopecia, and/or acne) and ovarian dysfunction (oligo-ovulation and/or polycystic ovarian morphology (PCOM) on ultrasound). More recently, obesity with its associated metabolic disorders has been recognized as one of the prominent clinical features of PCOS ( Table 7.1 ).



Table 7.1

Heirarchy of risk factors and impact of PCOS at different age groups.


















Adrenarche (age 5–20 years) Increased secretion of DHEA, inflammatory factors, and environmental exposures
Gonadarche (adolescents) Menstrual disorders, acne, contraception, sexual health, exercise, and activity (environmental) normal
Adulthood Menstrual irregularities (ovarian factors), hirsutism (adrenal factors), weight gain (sedentary lifestyle), infertility (anovulatory cycles), and diet (environmental)
Pregnancy Neuroendocrine factors, risk of miscarriage, pregnancy complications (preeclampsia, gestational diabetes), large baby, and premature delivery
Late reproductive years Metabolic factors (diet issues, type 2 diabetes, cardiovascular disease, and longevity)


Definition and history of the syndrome


According to American Society for Reproductive Medicine (ASRM), PCOS is defined by “the presence of any two out of three criteria i.e. oligo and/or anovulation, excess androgen activity and/or polycystic ovarian morphology on ultrasound.” The antiquity of PCOS can be traced back in the words of Hippocrates, “but those women whose menstruation is less than three days or is meagre, are robust, with a healthy complexion and a masculine appearance; yet they are not concerned about bearing children nor do they become pregnant.” In 1935, cases of amenorrhea presented with the detailed description of the syndrome. Of these, three were obese, five were hirsute, and one obese and one thin had acne. Surgical exploration confirmed the characteristic features of the ovaries, which were found to be enlarged two to four times and were full of tiny fluid-filled cysts. In 1947, Kierland and his team documented skin features in females with hyperandrogenism and diabetes mellitus. Later in 1957, the eponymous “Stein–Leventhal syndrome” showed an increased concentration of androgens and luteinizing hormone (LH) in women with polycystic ovaries. In 1981, the first ultrasound appearance of polycystic ovaries was documented, and by 1985, the details of ultrasound findings such as follicle number and ovarian volume were added. The ultrasound description of the Stein–Leventhal syndrome gave the name “polycystic ovarian syndrome.”


Prevalence


It is possibly the most common endocrine disorder with a prevalence of 6%–20% in women of reproductive age group. The prevalence based on Rotterdam criteria was 11.04%, National Institute of Health was 3.39%, and Androgen Excess and Polycystic Ovary Syndrome Society was 8.03%. The occurrence of infertility varies between 70% and 80% usually presenting with anovulatory issues and a higher rate of recurrent miscarriages. In Pakistan with the increasing frequency of PCOS, the rate of fertility issues is increasing correspondingly.


Pathophysiology


The multifarious pathophysiology is attributed to a range of genetic and epigenetic changes, adrenal dysfunction, hypothalamic–pituitary dysfunction, insulin resistance (IR), dyslipidemia, metabolic derangements, and environmental factors like sedentary lifestyle, atherogenic tendency, and belly fat deposition.


Hyperinsulinemia increases androgen secretion by ovaries and/or adrenal glands due to altered steroidogenesis leading to PCOS. Other theories suggest: (i) increased LH secretion, (ii) hyperinsulinemia and IR, and (iii) a defect in androgen synthesis that results in increased ovarian androgen, all contributing to phenotype comprising of metabolic, hormonal, and ovulatory dysfunctions ( Fig. 7.1 ).



  • 1.

    Hormonal impairment in PCOS



    • 1.1.

      Disordered hypothalamic regulation of gonadotropin secretion is proposed to be one of the causes of anovulation in females with PCOS. It could be either due to main abnormality in the firing of hypothalamic gonadotropin-releasing hormone (GnRH) neurons or due to abnormal feedback control by the ovarian steroids. Furthermore, progesterone-mediated negative feedback on LH in the normal luteal phase is compromised in these females, which cannot be reversed by physiological replacement of progesterone. Anovulation is reinforced by hyperinsulinemia as a result of a direct action of insulin on follicular steroidogenesis as well as gonadotropin secretion. The evidence from animal models and human subjects further supports the role of kisspeptin/neurokinin B/dynorphin neural network in dysregulation of GnRH secretion.


    • 1.2.

      Hyperandrogenism is a feature of both ovulatory and anovulatory cycles. In PCOS, androgen comes from both ovaries and adrenals, as well as the conversion of precursors in adipose tissue and skin. Theca cells secrete more androgens due to an increase in the regulatory enzyme of androgen biosynthesis (P450c17), either due to genetic defect or due to abnormalities in proliferation and follicular atresia. Overexpression of a protein in normal theca cells has also been identified in PCOS phenotype in vitro. This leads to excessive serine phosphorylation of the insulin receptor, which generates a downstream defect of insulin receptor signaling and its abnormal action on glucose metabolism. The extent of severity of PCOS and phenotypic abnormalities trails the degree of sympathetic excitation and testosterone production. Insulin also acts synergistically with LH to stimulate androgen production by theca cells. Hyperandrogenism in PCOS exerts a significant negative impact on endometrial blood flow and endometrial thickness and predicts low implantation rates in in vitro fertilization (IVF).


    • 1.3.

      Hyperinsulinemia: IR due to postinsulin receptor deficiencies and resultant hyperinsulinemia in the ovaries disrupts feedback regulation of LH and increases androgen production contributing to anovulatory infertility. Various mechanisms responsible for IR are as follows: “Excessive serine phosphorylation of the insulin receptor subunit, mutations of the insulin receptor gene or IRS-1 (substrate of the insulin receptor, phosphorylated by its tyrosine kinase (Tyr-K) activity), depletion of intracellular adenosine, postreceptor defect of glucose transport, and impaired insulin clearance in peripheral tissues.” In some patients, hyperinsulinemia is contributed by a secretory pancreatic defect even in the absence of glucose intolerance or a frank type 2 diabetes mellitus (DM). The growing follicle therefore is exposed to increased LH, insulin, androgen, and AMH concentrations with insufficient FSH concentrations.


    • 1.4.

      Disturbed LH–FSH ratio: Due to increased frequency of GnRH secretion, there is an increase in 24-h secretion of LH pulse frequency and amplitude. Increased levels of LH are partly due to altered negative feedback exerted by androgens on the hypothalamic–pituitary axis. Decrease in FSH due to either disturbance in hypothalamic–pituitary feedback (partial desensitization) and/or increased inhibin B production by multiple follicles has also been observed in females with PCOS. Studies have demonstrated a potent inhibition of FSH-induced estrogen production in granulosa cells (GCs) by epidermal growth factor and transforming growth factor alpha 1.


    • 1.5.

      Growth factors: The deficiency of growth differentiation factor 9 has been proposed to arrest folliculogenesis before the GCs are capable of apoptosis. Alterations of tumor necrosis factor α (TNF-α) in the follicular fluid have been associated with poor-quality oocytes in women undergoing assisted reproductive techniques (ARTs).



  • 2.

    Ovarian dysregulation in PCOS



    • 2.1.

      Abnormal folliculogenesis and steroidogenesis: Ovarian dysregulation occurs due to imprecise interplay of the endocrine, paracrine, and autocrine factors, leading to arrest of antral follicle development before the preovulatory stage of follicles. Folliculogenesis in anovulatory cycles is characterized by failure of dominance, and the ovary has multiple small follicles, which are arrested but are capable of steroidogenesis. This intrinsic abnormality of folliculogenesis with altered steroidogenesis may be the root cause of anovulation in PCOS. The proportion of primordial follicles is decreased with a reciprocal increase in the proportion of primary follicles. The GCs of the dominant follicle acquire LH receptors, which increase LH responsiveness of GCs signals to a sequence of events that include resumption of meiosis, rupture of the ovulatory follicle, and formation of the corpus luteum. The “switch” from FSH to LH responsiveness in GCs causes an amplification of the cyclic adenosine monophosphate (cAMP) signaling pathway. Increase in intraovarian androgens induced by FSH and LH increases the chance of premature arrest of GC proliferation the same way as cAMP. High serum estradiol concentrations in anovulatory cycle exert a negative feedback to suppress FSH levels. The ovarian stroma in females with PCOS is more stiff and rigid, and the structural framework is not provided ( Fig. 7.2 ).




      Fig. 7.2


      Follicular arrest in PCOS.


    • 2.2.

      Polycystic ovarian morphology (PCOM): In these women, there is increased transition from primordial to growing follicles up to an average follicular diameter of 3–5 mm with premature growth arrest, giving phenotype of enlarged ovaries with string-of-pearl morphology. Ultrasound examination shows an increase in the number of follicles (2–8), hyperechogenic stromal enlargement, and multiple small follicles that are 2–8 mm in diameter, either arranged around the periphery or distributed throughout the stroma. Improved understanding of the presentation of ultrasound findings in young women is needed. The diagnosis of PCOS requires the presence of an ovarian volume ≥ 10 mL (preferred criterion when using transducer frequencies < 8 mHz) and/or 25 follicles per ovary (criterion preferred when using transducers with frequencies ≥ 8 mHz). In view of its potential to cause adverse psychosocial consequences, the overdiagnosis of PCOS must be prevented by strictly adhering to the diagnostic criteria for PCOM.




  • 3.

    Factors associated with PCOS



    • 3.1.

      PCOS and body weight: Obesity is known to intensify PCOS and vice versa, and patients with PCOS have an increased tendency to gain weight with a fat distribution more on the upper body. However, the mechanism underlying this association is yet to be determined. Although visceral adiposity and higher BMI are positively correlated with IR, its consequential effects on other interlinked features of PCOS like menstrual disturbances and hirsutism still remain unexplained. The obesity, rather than the menstrual cycle pattern or the size of the follicular cohort, determines hyperinsulinemia, dyslipidemia, and hypertension with advancement in age. Increase in BMI is considered to exert a negative impact on the reproductive outcome in these patients; therefore, these females are recommended to maintain BMI for improved outcomes of IVF/ICSI. Dyslipidemia, IR, appearance of acanthosis nigricans, impaired lipid profiles, and glucose tolerance are more noticeable in obese PCOS as compared to lean ones.


    • 3.2.

      PCOS and metabolic disorders (MetS): MetSis most frequently observed in classic NIH PCOS phenotype involving hyperandrogenism and chronic anovulation. However, women screened on the basis of Rotterdam classification having regular cycles have lesser likelihood of metabolic abnormalities. The underlying mechanisms of IR in PCOS differ from those in other common insulin-resistant conditions like obesity and type 2 DM. Distorted secretions of adipokines like adiponectin, leptin, and resistin are supposed to cause IR, cardiovascular diseases, and metabolic disorders. Women with PCOS and a combination of MetS would exhibit greater IR, higher levels of free testosterone, lower levels of sex hormone-binding globulin (SHBG), and, phenotypically, greater frequency of acanthosis nigricans. Women with PCOS are at increased risk of endothelial dysfunction, altered lipid profile (increased triglycerides and low-density lipoproteins), hypertension, atherosclerosis, cardiovascular diseases like myocardial infarction, chronic obstructive pulmonary disease, autoimmune diseases, and obstetric complications.


    • 3.3.

      PCOS and glucose disorders: PCOS is inherently related to metabolic disorders during the later course of disease. Impaired glucose tolerance or prediabetes and type 2 DM have been diagnosed in up to 40% of women with classic PCOS by the fourth decade of life, rising further with increase in age and BMI. The risk for dysglycemia was also found to be 12% in lean women with PCOS, suggesting routine screening for glucose disorders. The Androgen Excess Society in 2010 issued a consensus statement on performing a 2-h post 75 g Oral Glucose Challenge in subjects of PCOS with glucose impairment.


    • 3.4.

      PCOS and pregnancy loss: As compared to controls, patients with PCOS exhibit an increased risk of pregnancy complications such as pregnancy-induced hypertension, preeclampsia, gestational diabetes, and premature delivery. Recurrent pregnancy loss is defined as two or more consecutive pregnancy losses before 20th week of pregnancy. The prevalence of miscarriage is increased after both spontaneous and induced ovulation compromising fertility. Obesity, raised serum LH levels, hyperandrogenemia, high blood glucose levels, endothelial dysfunction, and IR have been reported to be risk factors of pregnancy loss and secondary infertility.


    • 3.5.

      PCOS and vitamin D deficiency (VDD): The prevalence of VDD is associated with metabolic and endocrine disorders in PCOS. Vitamin D (VD) is believed to affect the progression of PCOS through gene transcription and hormonal variation, influencing insulin secretion and fertility regulation. VD status appears to be closely linked to IR, so much so that its supplementation is predicted to improve insulin sensitivity. Replete VD status is associated with an optimal endometrial thickness and increased number of antral follicles in PCOS women during treatment cycles.


    • 3.6.

      Hyperandrogenism: Hirsutism is an important feature of hyperandrogenism present in approximately 70% of women with PCOS. Other features such as alopecia and acne may or may not be present. The clinical presence of hirsutism requires biochemical confirmation of hyperandrogenemia by estimating serum concentration of free testosterone, determined by reliable methods only, since it reflects both ovarian and metabolic disturbances. A valid alternative can be the estimation of Free Androgen Index from the circulating concentrations of SHBG and total serum testosterone. Estimation of androstenedione (A4), a steroid precursor of testosterone, can be used for excess androgen levels. Hyperandrogenism leads to menstrual irregularities in the younger age group with approximately 90% chance of developing PCOS. Menstrual cycles in women with PCOS tend to become more regular toward the age of menopause.


    • 3.7.

      Anti-Mullerian hormone (AMH): The utility of AMH as an indicator of screening for PCOS is still under argument because of the absence of the standardization and correct cutoff levels for different assays available for testing. Estimation may be useful in predicting ovarian follicle counts in patients with PCOS as well as healthy women.





Fig. 7.1


Polycystic ovarian syndrome.


Criteria for the diagnosis of PCOS


Although PCOS is often characterized by raised LH levels, fasting insulin and reversed LH–FSH ratios cannot be regarded as a diagnostic criterion. Serum testosterone levels, serum TSH, prolactin, and day 3 FSH should be done to investigate menstrual irregularities and infertility. The confirmation of diagnosis mostly relies on ruling out other causes of anovulation, including thyroid disease, 21-hydroxylase deficiency, hyperprolactinemia, Cushing syndrome, and androgen-producing neoplasms. Exclusion of other etiologies of androgen excess and/or anovulatory infertility is necessary while using any criteria for diagnosing PCOS.


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Jan 4, 2021 | Posted by in GYNECOLOGY | Comments Off on Polycystic ovary syndrome and subfertility

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