Reproductive Hormones Overview & Polycystic Ovary Syndrome (PCOS)

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Pathophysiology

Summary

The regulation of the menstrual cycle is a complex but well-coordinated process involving various hormones and tissues. At the helm is gonadotropin-releasing hormone (GnRH), which is secreted by the hypothalamus in a pulsatile fashion. GnRH travels to the anterior pituitary via the hypophyseal portal system and stimulates the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) into the systemic circulation.

In the ovaries, LH targets theca cells of the ovarian follicle to synthesize androgens such as androstenedione and testosterone. In contrast, FSH stimulates granulosa cells to convert these androgens into estrogens, chiefly estrone and estradiol.

The menstrual cycle is divided into the follicular phase and the luteal phase, each lasting approximately 14 days. The follicular phase starts on day 1 and culminates in ovulation on day 14. Elevated FSH levels during this phase promote the development of multiple ovarian follicles, which in turn secrete more estrogen. Normally, estrogen exerts a negative feedback on the hypothalamus and the pituitary to regulate hormone levels. When estrogen levels reach a certain threshold, a positive feedback mechanism triggers an LH surge, resulting in the rupture of the dominant ovarian follicle and the release of a secondary oocyte, marking ovulation.

The luteal phase follows, starting from ovulation and ending just before the onset of menstruation. During this period, the remnants of the ruptured ovarian follicle transform into the corpus luteum, a temporary endocrine structure that secretes high levels of progesterone. Progesterone is important for maintaining the uterine lining in preparation for a possible implantation of a fertilized egg. If fertilization does not occur, the corpus luteum regresses, leading to a decline in progesterone levels. The withdrawal of progesterone initiates the sloughing off of the stratum functionalis layer of the endometrium, manifesting as menstruation, which marks the end of the luteal phase and the onset of a new menstrual cycle.

Polycystic ovarian syndrome (PCOS) is a complex endocrine disorder and the most common cause of anovulation, characterized by the lack of egg release during the menstrual cycle.In PCOS, the ovaries generate heightened amounts of androgens, leading to manifestations of clinical hyperandrogenism. Symptoms commonly include hirsutism, augmented muscle mass, and, in some instances, male-pattern baldness.

In PCOS, elevated androgen levels contribute to a surplus of undeveloped follicles within the ovaries. On ultrasound PCOS shows enlarged ovaries displaying multiple peripherally situated follicles, commonly referred to as a ‘string of pearls’. Clinically, these women often experience anovulatory menstrual cycles, leading to symptoms of irregular menses and infertility.

PCOS often coexists with insulin resistance and hyperinsulinemia, and is frequently linked with metabolic syndrome and type 2 diabetes. High insulin levels can exacerbate hyperandrogenism, as insulin sensitizes the of androgen-producing theca cells to LH.

The endometrium in PCOS is exposed only to estrogen, with no exposure to progesterone due to the absence of ovulation and, consequently, the luteal phase. This imbalance increases the risk of endometrial hyperplasia & cancer due to the persistent pro-growth signals from estrogen alone.

Management of PCOS varies depending on symptoms and coexisting conditions. For obese patients, weight loss is the first line of treatment as it can reduce insulin resistance and decrease androgen levels, helping to restore ovulatory cycles and fertility. Pharmacologically, combined estrogen-progestin oral contraceptives (OCPs) can be effective. Elevated estrogen levels from OCPs suppress LH secretion, which in turn decreases androgen production. OCPs also decrease the risk of endometrial hyperplasia and cancer by stabilizing the endometrial lining with progesterone. In cases where PCOS is accompanied by insulin resistance, metformin can be used to reverse hyperinsulinism.

Lesson Outline

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FAQs

What is the function of GnRH and how does it influence the anterior pituitary?

Gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus in a pulsatile manner and is transported to the anterior pituitary gland via the hypophyseal portal system. Upon reaching the anterior pituitary, GnRH stimulates the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) into the systemic circulation. Both FSH and LH are crucial for regulating the menstrual cycle, specifically during the follicular and luteal phases.

How do FSH and LH influence the ovarian follicles?

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) target different cells within the ovarian follicle. LH stimulates theca cells to produce androgens, such as androstenedione and testosterone. In contrast, FSH acts on granulosa cells, prompting them to convert these androgens into estrogens like estrone and estradiol. These hormones play a pivotal role in the menstrual cycle.

What hormonal and cellular changes occur during the follicular and luteal phases?

In the follicular phase, elevated FSH levels stimulate the growth of multiple ovarian follicles, which in turn produce more estrogen. When estrogen levels reach a certain threshold, a positive feedback mechanism triggers an "LH surge" from the pituitary, leading to ovulation. During the luteal phase, the corpus luteum forms from the remnants of the ruptured ovarian follicle and secretes high levels of progesterone. This progesterone prepares and maintains the uterine lining for potential implantation of a fertilized egg.

What are the clinical manifestations of polycystic ovary syndrome (PCOS)?

Polycystic ovary syndrome (PCOS) is primarily characterized by excessive androgen production by the ovaries, making it the most common cause of anovulation. Symptoms may include hirsutism, increased muscle mass, and male-pattern baldness, all indicative of hyperandrogenism. Additionally, PCOS often presents with multiple undeveloped follicles in the ovaries, irregular menstrual cycles, and infertility. It is frequently associated with insulin resistance and elevated insulin levels, linking it to metabolic syndrome and type 2 diabetes.

What treatment options are available for managing PCOS in obese and non-obese patients?

In obese patients with PCOS, weight loss is the first-line treatment. Reducing weight can decrease insulin resistance, thereby lowering hyperinsulinemia and androgen levels, which can restore ovulatory cycles and fertility. For others, combined estrogen-progestin oral contraceptives (OCPs) are often used to suppress LH secretion and reduce androgen production. OCPs also stabilize the endometrial lining, reducing the risk of hyperplasia and cancer. In cases where PCOS is accompanied by insulin resistance, metformin can be prescribed to reverse hyperinsulinism and decrease androgen levels, thereby restoring ovulation.