The female reproductive cycle is interplay of hormones secreted by the hypothalamus, pituitary and ovaries. Together they form the hypothalamic-pituitary-ovarian axis. The primary outcome of this axis is ovulation. If pregnancy occurs, this axis will act through feedback mechanism to maintain the pregnancy. The development of the embryo requires a specific level of hormones in the maternal blood. If there is any disruption, it may result into missed abortion or preterm labor. Similarly, if the female does not conceive, there is a decrease in the amount of one hormone that will initiate the next cycle.
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Hypothalamic-Pituitary-Ovarian Axis

The three endocrine glands involved in the hypothalamic-pituitary-ovarian axis and the hormones secreted by them are as follows:

  1. Hypothalamus: it is located at the base of the brain and secretes gonadotropin-releasing hormone (GnRH).
  2. Pituitary gland: it is located below the hypothalamus and secretes follicle stimulating hormone (FSH) and luteinizing hormone (LH).
  3. Ovary: two ovaries located in the pelvis secrete estrogen and progesterone.

The Feedback Mechanism

At the end of menstrual cycle, the level of progesterone drops. That leads to negative feedback stimulation of the hypothalamus. The hypothalamus secretes GnRH, which will initiate the secretion of FSH by the pituitary gland.

FSH causes the maturation of the primordial follicle. It acts on the granulosa cells and causes their proliferation. The granulosa cells divide and the primordial follicle changes to the primary follicle. Around 5-6 follicles maturate in the ovary under the influence of FSH each month.

Granulosa cells produce estrogen, which acts on the uterine endometrium and causes proliferation of endometrial stroma and development of endometrial glands.

The glandular tissues in fallopian tube proliferate with an increase in the number of ciliated epithelial cells. The cilia become more active and propel the ovulated egg towards the uterus. This maximizes the chances of fertilization. Only one of the maturing follicles is able to dominate over the others. It is called the Graafian follicle.

The increasing level of estrogen in the blood suppresses the FSH produced by the negative feedback mechanism. The decreasing level of FSH is responded by the pituitary gland with the production of LH.

LH acts on the theca cells and is required for the ovulation to occur. The increasing level of estrogen will cause a surge in LH level by the positive feedback mechanism. This phase of the reproductive cycle from the release of FSH until ovulation is called the follicular phase.

After ovulation has occurred, the ruptured follicle becomes the corpus luteum. In addition to producing estrogen, it also produces progesterone. Progesterone induces the secretory functions of the uterine endometrium and suppresses the hypothalamus. The hypothalamus does not produce GnRH which, in turn, deactivates the production of FSH and LH.

In the initial 3 months of pregnancy, the negative feedback is brought into effect by the progesterone produced by the corpus luteum. However, as the pregnancy progresses, the placenta starts producing ovarian hormones to sustain the pregnancy.

Sperm Capacitation

A series of changes occurring in the anatomical structure of sperm following its release in the female genital tract is called sperm capacitation.

The spermatozoa which leave the epididymis are still under the inhibitory effect of the genital tract; therefore, the structural modification is required for fertilization to take place. These structural modifications occur when the spermatozoa come in contact with the female genital tract environment. The inhibitory factors are washed off by the uterus and the fallopian tubes.

The spermatozoa are provided with a thick cholesterol membrane surrounding the acrosome. This occurs in the male genital ducts where floating vesicles are a continuous source of cholesterol molecules. These molecules become part of the cell membrane, especially covering the acrosome. The release of acrosomal enzymes is therefore inhibited.

In the female genital tract, spermatozoa leave the cholesterol rich vesicles. As they ascend towards the egg, they shed the cholesterol component of their cell membrane and therefore the cell membrane becomes weak and fragile.

As this occurs, the membrane of the sperm becomes permeable to the calcium ions. These calcium ions diffuse towards the flagellum, giving it the contractile power. As the flagellum is able to produce a greater whiplash movement, it is further accelerated towards the egg, against the gravity.

Calcium ions also change the intracellular surface of the membrane so that the acrosome fuses with the cell membrane and readily releases its enzymes. The sperm is able to penetrate the granulosa cells layer and the zona pellucida.

The hyaluronic acid, which acts as intercellular cement for the granulosa cells, is broken down by the hyaluronidase enzyme. Similarly, other proteins are broken down by the proteolytic enzymes present in the acrosome.

As the sperm reaches the zona pellucida, the cell membrane of the sperm binds to the receptor proteins present on it. The acrosome releases its enzymes in one flush. This leads to the formation of the pathway for the sperm to reach the egg nucleus. The sperm first travels through the perivitelline space that lies beneath the zona pellucida, but outside the oocyte membrane.

Within the next 30 minutes, the cell membranes of the oocytes and the sperm fuse. The genetic material of the sperm enters the oocyte and fertilization takes place.

As soon as the first sperm penetrates the zona pellucida, calcium ions diffuse through the oocyte membrane. This causes a release of multiple cortical granules into the perivitelline space by the process of exocytosis.

These cortical granules permeate through the holes produced by the acrosomal enzymes in the zona pellucida, thereby sealing off the passage for other sperms. This prevents polyspermy. It is also believed that as soon as fertilization takes place, the cell membrane of the oocyte undergoes depolarization, further preventing the fusion of the egg with multiple sperms.

Review Questions on the Hypothalamic-Pituitary-Ovarian Axis

The correct answers can be found below the references.

1. In a normal ovarian cycle, a sudden increase of which of the following hormone is responsible for the ovulation, under the influence of positive feedback mechanism?

  1. Surge in FSH
  2. Surge in LH
  3. Surge in Progesterone
  4. Surge in GnRH from hypothalamus

2. A 28 year old obese female came for gynecological evaluation to her family doctor. She has 88 kg weight, BP: 140/100 mmHg, HR 123/min and RR: 30 /min. On ultrasound, multiple follicles were seen inside the right ovary. The largest one of these is called:

  1. Major ovum
  2. Follicular cyst in the ovary
  3. Graafian follicle
  4. Immature follicle

3. A female got pregnant after 1 year of marriage. She had a history of irregular menstrual cycles and excessive bleeding previously. The secretory phase of the endometrial cycle during the menstrual cycle is maintained by which of the following hormone?

  1. Estrogen
  2. Progesterone
  3. bHCG
  4. Androstenedione



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