Hypothalamic-Pituitary-Ovarian Axis

Reproductive Cycles

In the female reproductive cycle, ovulation is followed by menstrual bleeding in a cyclic, predictable sequence. This recurring process is established dur-ing puberty (average age of menarche is 12.43 years) and continues until the years prior to menopause (average age 51.4 years). Regular ovulatory cycles are usually established by the third year after menarche, and continue until the perimenopause. Therefore, between 15 and 45 years of age, a woman has approximately 30 years of ovulatory reproduc-tive cycles. The reproductive cycles may be interrupted by conditions including pregnancy, lactation, illness, gyneco-logic disorders and endocrine disorders, and exogenous factors such as hormone-based contraceptives and various other medications.

The duration of an adult reproductive cycle, from the begin-ning of one menses to the beginning of the next menses, averages approximately 28 days, with a range of 23 to 35 days, and com-prises three distinct phases. Thefollicular phasebegins withthe onset of menses (the first day of the menstrual cycle) and ends on the day of the luteinizing hormone (LH) surge. Ovulation occurs within 30–36 hours of the LH surge.The luteal phase begins on the day of the LH surge and ends with the onset of menses. The follicular and luteal phases each last approximately 14 days in reproductive-age women; however, variability in cycle length is more fre-quent at the extremes of the reproductive age. The duration of the luteal phase remains relatively constant, while the duration of the follicular phase can vary.

HYPOTHALAMIC-PITUITARY-OVARIAN AXIS

Hypothalamic-pituitary-ovarian axis refers to the complexinteractions between the hypothalamus, pituitary, and ovaries that regulate the reproductive cycle. These interactions arebased on the interplay of the hormones released by these structures: gonadotropin-releasing hormone (GnRH), the gonadotropins follicle-stimulating hormone (FSH) and LH, and the ovarian sex steroid hormones, estrogen and progesterone. Through stimulatory and inhibitory actions, these hormones directly and indirectly stimulate oocyte development and ovulation, endometrial development to facilitate embryo implantation, and menstruation. Feedback loops between the hypothalamus, pituitary, and ovaries are presented in Figure 33.1.

Disruption of any of these communication and feedback loops results in alterations of hormone levels, which can lead to dis-orders of the reproductive cycle; ultimately, ovulation, repro-duction, and menstruation can be affected.

Hypothalamic GnRH Secretion

The gonadotropin-releasing hormone is secreted in a pulsatile fashion from the arcuate nucleus of the hypothal-amus. GnRH reaches the anterior pituitary through the hypothalamic–pituitary portal vascular system. The pul-satile secretion of GnRH stimulates and modulates pitu-itary gonadotropin secretion. Due to its remote location and a half-life of 2 to 4 minutes, GnRH cannot be directly measured, thus measurements of LH pulses are used to indicate GnRH pulsatile secretion. Ovarian function requires the pulsatile secretion of GnRH in a specific pattern that ranges from 60-minute to 4-hour intervals. Therefore, the hypothalamus serves as the pulse generator of the reproductive cycle. Coordinated GnRH release is stimulatedby various neurotransmitters and catecholamines as well as by the inherent pulsatility of the GnRH neurons.

Pituitary Gonadotropin Secretion

The pituitary gonadotropins FSH and LH are glycoprotein hormones secreted by the anterior pituitary gland. FSH and LH are also secreted in pulsatile fashion in response to the pulsatile release of GnRH; the magnitude of secretion and the rates of secretion of FSH and/or LH are determined largely by the levels of ovarian steroid hormones, estrogen and progesterone, and other ovarian factors (such as inhibin, activin, and follistatin).

When a woman is in a state of relative estrogen defi-ciency, as in the early follicular phase, the principal gona-dotropin secreted is FSH. The ovary responds to FSH secretion with estradiol production, with subsequent neg-ative feedback on the pituitary inhibiting FSH secretion and positive feedback facilitating LH secretion.

Ovarian Steroid Hormone Secretion

At midcycle, there is a marked increase in LH secretion (the LH surge), which triggers ovulation. With ovulation, the ovarianfollicle is converted into a corpus luteum and begins secret-ing progesterone.

At birth, the human ovary contains approximately one to two million primordial follicles. Each follicle contains an oocyte that is arrested in prophase of the first meiotic division. A large number of these inactive primordial fol-licles undergo a degenerative process known as atresia during childhood; thus, at menarche, 300,000 to 500,000 oocytes remain.

The immature oocyte is encircled by a single layer of granulosa cells, followed by a thin basement membranethat separates the follicle from the surrounding ovarian stroma. Early follicular maturation occurs independent of gonadotropins; the granulosa cells proliferate into multiple layers, and the surrounding stromal cells differentiate into theca cells. Granulosa cells produce estrogens, includingestrone and estradiol, the latter being the more potent of the two. Theca cells produce androgens which serve as the precursors required for granulosa cell estrogen production. Androgens (androstenedione and testosterone) enter the granulosa cells by diffusion and are converted to estrogen. The two-cell theory of estrogen synthesis is diagrammed in Figure 33.2.

During follicular development, FSH binds to FSH-receptors on the granulosa cells, causing cellular prolifer-ation and increased binding of FSH and, hence, increased production of estradiol. Estradiol stimulates the prolifera-tion of LH-receptors on theca and granulosa cells, and LH stimulates the theca cells to produce androgens. Greater androgen production leads to increased estradiol produc-tion. Rising estrogen levels influence the pituitary gland through negative feedback and results in suppression of FSH and LH secretion. In the late follicular phase, peak estradiol concentrations from the dominant follicle have positive feedback on the pituitary, which stimulates the midcycle surge of LH secretion that is necessary for ovulation. 

With ovulation, the dominant ovarian follicle releases itsoocyte and transitions to a progesterone-secreting ovarian cyst, the corpus luteum.The process of follicular maturation ispresented in Figure 33.3.