Ovulatory Dysfunction, PCOS & POI

Here we'll learn about ovulatory dysfunction, including polycystic ovary syndrome and primary ovarian insufficiency. Ovulation refers to the release of the "egg" or ovum from the ovarian follicle; recall that ovulation is the event that divides the follicular and luteal phases of the menstrual cycle. Anovulation occurs when an egg is not released during a menstrual cycle. Occasional anovulation is normal - up to 12% of cycles are anovulatory (depending on the study). Oligo-ovulation refers to infrequent, irregular ovulation, and is usually accompanied by irregular menstrual cycles. Anovulation can be physiological or pathological: Anovulation is common in the years following menarche (first menses) and in the perimenopausal period. Ovulation is suppressed during pregnancy and lactational amenorrhea, and during periods of nutritional deficiency or elevated exercise, when energy stores are diverted to non-reproductive functioning. However, anovulation can also occur when there is dysfunction along the hypothalamic-pituitary-ovarian axis (aka HPO-axis), which is the focus of this tutorial. Ovarian dysfunction can be related to underlying endocrinopathies, neoplasms, psychological conditions, pharmacologic agents. We'll base our organization of the disorders on the WHO classification system, but be aware that there are other systems (for example, the FIGO system, which organizes disorders according to their anatomical origins). Dysfunction can occur at any level, and correspond with patterns of: A) Reduced pituitary and ovarian hormones B) Elevated hypothalamic, pituitary and ovarian hormones C) Elevated pituitary, reduced ovarian hormones Ovulatory dysfunction exists on a spectrum, with anovulation ranging from episodic to chronic. Patients may present with amenorrhea (lack of menstrual bleeding), abnormal uterine bleeding, "break through bleeding" (intermenstrual bleeding or bleeding in anovulatory cycles), and subfertility or infertility. Signs that ovulation has occurred include the LH peak, increased basal body temperature, and thickened cervical mucus; transvaginal ultrasound is the most definitive method. Be aware that calendar methods are notoriously inaccurate, due to variability in menstrual cycles. Treatments depend on the etiology of the disorder and the fertility desires of the patient. In PCOS and primary ovarian insufficiency, combined hormonal contraceptives are used to regulate the HPO axis. - Patients wishing to become pregnant require tailored fertility treatments. We show the Hypothalamus, pituitary, and the ovary (we show a tertiary follicle in the ovary). Review GnRH, FSH, LH Gonadotropin-releasing hormone (GnRH) is released from the hypothalamus and travels to gonadotrophs in the anterior pituitary, where it triggers the release of the gonadotrophs – follicle stimulating hormone (FSH) and luteinizing hormone (LH). The gonadotrophs exit the pituitary in the blood and travel to the ovaries, where they regulate the ovarian cycle and promote the release of estrogen and progesterone. Estrogen and progesterone have several roles throughout the body: They regulate the uterine cycle (the menstrual cycle), facilitate growth and maintenance of secondary sex characteristics (breast development, for example), and play important roles in bone, metabolic, and cardiovascular health. Estrogen and progesterone provide negative feedback on the HPO axis by inhibiting further release of gonadotropin-releasing hormone and the gonadotrophs. As we'll see, dysfunction can occur at any level, and correspond with patterns of: A) Reduced pituitary and ovarian hormones B) Elevated hypothalamic, pituitary and ovarian hormones C) Elevated pituitary but reduced ovarian hormones Dysfunction in the hypothalamic-pituitary pathway reduces the levels of FSH and estradiol. As a result, individuals often present with delayed and/or impaired pubertal development, amenorrhea, and infertility. Hypothalamic-pituitary failure is most often caused by a congenital absence of gonadotropin-releasing hormone, as we see in Kallmann syndrome, which also presents with a lack of smell (anosmia) in addition to reproductive dysfunction. Acquired causes of hypothalamic-pituitary failure include panhypopituitarism, which can result from acute ischemia and tissue necrosis of the pituitary gland. Such injury can be caused by tumor compression, trauma, or inflammation in the gland. Diagnosis includes evaluation of FSH, LH, and Estradiol. Investigate additional hormones to rule out panhypopituitarism (TSH, GH, ACTH). Treatment includes exogenous gonadotrophins in women who want to become pregnant; prepubertal females may need exogenous estrogen and progesterone treatments to induce pubertal growth. Polycystic ovary syndrome, PCOS, is an example of dysfunction in each level of the hypothalamic-pituitary-ovary axis. PCOS is the most common cause of ovulatory dysfunction and is thought to be caused increases in gonadotropin-releasing hormone pulsatility that, in turn, increase LH and Androgens. Clinical presentation of PCOS varies, but can include reproductive abnormalities, hyperandrogenism, and metabolic disorders. Reproductive abnormalities include abnormal uterine bleeding, irregular ovulation, anovulation, and polycystic ovary morphology (be aware that not all patients with polycystic ovary morphology have PCOS). Polycystic ovarian morphology (PCOM) is diagnosed via transvaginal ultrasound. It is characterized by the presence of 20 or more follicles (<10 mm) or by ovarian volume ? 10 ml in an ovary. Hyperandrogenism causes acne, hirsutism, and male-pattern balding. Metabolic issues include insulin resistance, weight gain, and cardiovascular disease. These tend to develop later than the reproductive and androgenic abnormalities. Other disorders associated with HPO axis dysfunction include hyperprolactinemia and thyroid dysfunction. Primary ovarian insufficiency, formerly called premature ovarian failure, is characterized by hypergonadotropic hypogonadal dysfunction before the age of 40 – in other words, premature menopause. In these patients, the ovarian production of estrogen and progesterone is low, despite high levels of gonadotropins, particularly FSH. Primary ovarian insufficiency and anovulation exists on a spectrum, such that pregnancy is unlikely but not impossible (5-10% of patients will become pregnant without medical intervention). Etiologies vary, and many cases are idiopathic. Iatrogenic: for example, pelvic surgery, chemotherapy, and radiation can damage the ovaries. Genetic anomalies: for example, patients with Turner and Fragile X syndromes have dysfunctional ovaries. Ovarian insufficiency can also occur as a complication of other disorders, including autoimmune thyroiditis, autoimmune polyglandular syndromes, ovarian endometriosis, and infections such as mumps and TB. Finally, indicate that patients have increased risk of osteoporosis, dementia, mood disorders, and coronary artery disease. Luteinized unruptured follicle – mature oocyte isn't released, despite stimulation by LH. Luteal out of phase – premature recruitment of follicles in luteal phase. Leads to very early ovulation in the next cycle. Type I – Hypothalamic Type II – Pituitary Type III – Ovarian Type IV – PCOS (no single anatomical location)