Reproductive Pathophysiology & Pharmacology

Learning Objectives

To review the hormones of the female reproductive system
To review the hormones of the male reproductive system
To understand the hormonal control and phases of the menstrual cycle as they relate to pharmacological targets for contraception

Female Reproductive System

The female reproductive system is intricately controlled by hormones. The hypothalamus regulates the pituitary gland by secreting gonadotropin-releasing hormone (GnRH). In response, the pituitary gland releases luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the ovaries to produce progesterone while FSH promotes the release of estrogen. These hormones play critical roles in managing the menstrual cycle and the maintenance of pregnancy.

The Role of LH, FSH, Estrogen, and Progesterone

LH and FSH are essential for controlling the female menstrual cycle. Both hormones interact with positive and negative feedback mechanisms involving the hypothalamus, pituitary gland, ovaries, and uterus:

FSH: This hormone stimulates maturation of the ovarian follicle and contributes to estrogen production, which peaks just before ovulation.
LH: It triggers the luteal phase post-ovulation, promoting the thickening of the endometrium, and facilitates the release of progesterone, which peaks prior to menstruation.

Menstrual Cycle Hormonal Regulation

The menstrual cycle consists of two main phases: the follicular phase and the luteal phase. The hypothalamus secretes GnRH in a pulsatile manner, influenced by negative feedback from ovarian hormones. GnRH stimulates the anterior pituitary gland to release LH and FSH:

The pulse frequency of GnRH is crucial; faster pulses favor LH release, while slower pulses enhance FSH release.
Estradiol enhances the GnRH pulse frequency, whereas progesterone reduces it by providing negative feedback.

Impact of Neurotransmitters on GnRH Pulsatility

The release of GnRH can also be influenced by neurotransmitters. Noradrenaline stimulates GnRH release, while dopamine inhibits it. Disruptions in neurotransmitter regulation can lead to anovulatory cycles due to conditions such as:

Isolated gonadotropin deficiency
Infections
Suprasellar tumors
Head trauma

Functional hypothalamic anovulation, often linked to conditions like excessive exercise, abrupt weight loss, and emotional distress, can lead to decreased secretion of GnRH, FSH, and LH.

Phases of the Menstrual Cycle

The menstrual cycle is categorized into two phases:

Follicular Phase: Starting with menses, it culminates in ovulation. Estradiol levels gradually increase, peaking shortly before ovulation due to FSH stimulation.
Luteal Phase: Following ovulation, the corpus luteum produces estradiol and progesterone, essential for potential pregnancy. If pregnancy does not occur, the corpus luteum regresses leading to decreased hormone levels and eventually menses.

Hormonal Products and Effects

Estrogens produced during the reproductive years include estradiol, estriol, estrone, and estetrol. Natural progesterone has low bioavailability orally, prompting the development of synthetic progestins.

During the luteal phase, LH and FSH levels are suppressed by progesterone and estradiol, which are initiated by the corpus luteum.

Biological Role of Ovaries

The ovaries are essential for producing and releasing oocytes and hormones like estradiol and progesterone. Follicular development is driven by FSH and LH, and the transformation of the follicle into the corpus luteum occurs after ovulation. The corpus luteum maintains hormonal levels; if pregnancy does not occur, it degenerates into the corpus albicans.

Endometrium and its Hormone Sensitivity

The endometrium has high concentrations of estrogen and progesterone receptors, which are vital for its growth and differentiation in response to hormonal changes.

Normal Reproductive Cycle Attributes

A normal menstrual cycle typically involves:

Intermenstrual length of 24 to 35 days
Luteal phase lasting approximately 14 ± 1 days
Menstrual bleeding of less than 80 mL lasting between 4 to 7 days
Endometrial thickness of 6 - 12 mm, assessed via ultrasound
Serum progesterone levels exceeding 20 nmol/L in the mid-luteal phase

Fertilization and Implantation

Fertilization occurs when sperm meets the ovum within the fallopian tubes, requiring proper timing. The ovum remains viable for about 12-24 hours post-ovulation, while sperm can survive for several days. The embryo develops and travels to the uterus for potential implantation.

Conditions Affecting Hormonal Balance

Hormonal imbalance can lead to menstrual irregularities, including:

Long or short cycles
Irregular ovulation
Anovulation
Difficulties in maintaining pregnancy

Factors contributing to these irregularities include weight extremes, polycystic ovary syndrome (PCOS), age factors, and endometriosis.

Reproductive Pharmacology

Contraceptive Mechanism of Action

Contraceptives primarily act through progesterone, aiming to prevent ovulation, inhibit follicular development, and alter cervical mucus to obstruct sperm entry. They achieve this through:

Negative feedback regulation at the hypothalamus reducing GnRH pulses, thereby lowering FSH and LH
Thickening cervical mucus to hinder sperm penetration

While estrogen also plays a supportive role, progesterone is the primary actor in preventing ovulation.

Progestogen Only Oral Contraceptives

These contraceptives may not consistently inhibit ovulation but primarily work by thickening cervical mucus and altering the endometrium.

Male Reproductive System

The male reproductive system begins sperm formation at puberty within the testes. The entire process of spermatogenesis takes approximately 65-75 days, resulting in the production of around 300 million sperm daily.

Hormonal Regulation

The production of sperm is regulated by GnRH from the hypothalamus, subsequently stimulating LH and FSH release from the anterior pituitary.

Testosterone and Spermatogenesis

Testosterone fosters the completion of spermatogenesis. If testosterone is low, sperm production and fertility can decline.

Issues Related to Low Hormone Levels

Low testosterone can negatively influence sexual function and sperm mobility, with various external factors leading to hormonal imbalances.

Age and Male Fertility

As men age, the decline in testosterone levels can impact sperm production and overall fertility, leading to conditions such as erectile dysfunction, low libido, and physical blockage in reproductive pathways.

Understanding Reproductive Pathophysiology and Pharmacology

Understanding Reproductive Pathophysiology and Pharmacology