Medicine

Female Physiology before pregnancy and the female hormonal regulation of the menstrual cycle.

 

When a primordial ova penetrates the ovarian cortex after differentiating from its ancestral germinal epithelium cells, it surrounds itself with ovarian stromal cells (spindle cells) which behave like an epithelium around it. They are now called granulosa cells (single layered).

A single layered complex of both granulosa cells and an ova is called a primordial follicle.

The ovum by itself is called a primary oocyte. Estrogen & progesterone are released by the ovaries in response to LH (luteinizing hormone) and FSH (follicle stimulating hormone). The results of the menstrual cycle are that the endometrium is prepared in advance to receive the zygote & usually only a single ovum is released. Prepuberty, almost no LH & FSH are released from the hypophysis (anterior pituitary). At menarche (first period), LH and FSH begin to rhythmically surge every 28 days, activating the reproductive organs. Granulosa cells nourish the ovum in the primordial follicle stage. and prevents its maturation. Once the LH and FSH surge, the ovum inside the primordial follicle expands & the granulosa cell layers become stratified (multilayered). It is not known as a primary follicle. The small surge of FSH and LH at the beginning of each month cause the development of 6-12 primary follicles (from primordial follicles) each month, recognized histologically by the multilayered granulosa cells.

Some of these granulosa cells (spindle cells) collect outside the multilayered granulosa layer and form two distinct layers, collectively termed the Theca. Both layers are respectively the theca interna and theca externa. The theca interna take on epithelioid characteristics similar to granulosa cells. & secrete estrogen and progesterone. The theca externa becomes highly vascular and forms a connective tissue capsule around the whole complex. After this initial moderate growth, the granulosa cells now secrete follicular fluid containing a high concentration of estrogen. This fluid pushes the ovum to the pole of the follicle & forms a fluid filled cavity at the opposite pole called the Antrum (now called a secondary follicle or antral follicle). Between the primary follicle and secondary follicle, the growth factor is mainly FSH. THere is explosive growth at the onset of the secondary follicular stage due to the extremely high levels of estrogen now present. One follicle eventually outgrows the others, leaving only 1, the other 11 typically degenerate by atresia. Once this follicle reaches 1 -1.5 cm, it is termed a mature follicle. Ovulation occurs 14 days after the onset of menstruation. A stigma protrudes from the follicle , out of the ovary and viscous fluid is allowed to pass through. This opening soon expands and ruptures, the ova is allowed to pass through into the abdominal cavity, still surrounded by granulosa cells, now called the corona radiata. LH is needed for the final follicular growth and ovulation. It peaks 16 hours before ovulation. FSH and LH act synergistically to cause rapid swelling of the follicle in the few days before ovulation. LH also converts granulosa and theca cells into progesterone secreting cells therefore just before ovulation, estrogen levels fall and progesterone surges in response to the LH surge. The stigma degenerates due to proteolytic enzymes, and in addition to the heavy vasculature of the follicle, plasma transudate accumulates within it, causing marked swelling. This rapid growth and weakening of the stigma makes rupture inevitable. Once expulsed, the remaining granulosa and theca cells within the ovary quickly transform into Lutein Cells, now that they are no longer inhibited of doing so by luteinization inhibiting factor of the ova. They accumulate lipid inclusions that turn them yellow histologically (luteinization) and the mass is collectively called the corpus luteum. They produce more progesterone than estrogen. 12 days after ovulation, it loses its secretory function as well as its lipid inclusions and become the whitish corpus albicans. Which is eventually is completely replaced by connective tissue. Its life is prolonged by the placental release of chorionic gonadotrophin by about 2 - 4 months.

Estrogen and Progesterone together inhibit FSH and LH from the anterior pituitary gland. The absence/low concentration of FSH and LH cause involution of the corpus luteum occurring 12 days after ovulation (day 26). FSH and LH then surges slowly, now no longer inhibited.
Estrogen acts mainly to develop secondary sexual characteristics in females. Progesterone acts mainly to Prepare the uterus for Pregnancy ( and breasts for lactation to an extent, discussed later).
Estrogen is secreted mainly from the ovaries (non pregnant females). The placenta secretes tremendous amounts during pregnancy. Progesterone is secreted only in significant quantities during the latter half of the menstrual cycle (corpus luteum). Large amounts are also secreted during pregnancy. They are both steroids. They are transported in the blood by receptor specific albumin. The liver conjugates them (into glucuronides and sulphates) and excrete about 20% of the amount produced, into bile. Since the liver is responsible for excretion, a decrease in liver function causes hyperestrinism. They are degraded within minutes.Prepubescent girls produce small amounts of estrogen. At puberty and under the influence of gonadotropic hormone (hypothalamus => hypophysis), the amount is increased 20 fold. Sex organs increase in size. Vaginal epithelium change from cuboidal to stratified (squamous).

Estrogen cause uterine stroma and glands to proliferate which in turn nutrify the implanted tissue. They cause fallopian tube glandular proliferation as well, increasing both its number and activity of it’s cilia. The cilia always beat towards the uterus (against sperm). Estrogen develop breasts by an increase in proliferation of its stroma, ductal system and deposition of fats. However it is progesterone and prolactin that is responsible for the functional/mature breast lobules and alveoli.
Estrogen inhibits osteoclastic activity and therefore promotes bone growth (there is rapid growth upon onset of puberty) However, the epiphysis are united earlier than in their male ethnic counterpart, making them generally shorter. Almost no estrogen is produced after menopause, which may result in osteoporosis in sever cases. Estrogen has 33% the metabolic influence of testosterone and promotes the deposition of fat.

Androgens are responsible for female pubic and axillary hair. Estrogen promotes a more vascular and thicker skin, making it softer and more prone to bleeding. Its structure is slightly similar to aldosterone and therefore slightly retains water by active sodium reabsorption in the ascending tubule of the Loop of Henle, hence high concentrations usually cause bloating, most noted around ovulation and during pregnancy.

Progesterone promotes the secretory phase (11 days after the beginning of the cycle and lasts for 12 days.) It is responsible for preparing the uterus for implantation prevents uterine contractions (abortions). It promotes alveoli in the breast to proliferate and become secretory but is NOT responsible for the actual secretion of milk. (prolactin from the anterior pituitary is)

Uterine endometrium undergoes 3 stages during the course of the menstrual cycle.

  • Proliferation (11days) (before ovulation)
  • Secretory Phase (12 day) (during and after ovulation)
  • Desquamation (5 days) (menstruation)

Under the influence of estrogen, uterine epithelium and stroma proliferate rapidly. At the time of ovulation, it is 3 - 5 mm thick. The cervical area of the uterus produce mucus that assist the sperm, making threads for them to climb.Progesterone causes marked swelling and secretory development of the endometrial lining. At the peak of the secretory phase, the endometrium thickness is 6 mm. It is worth noting that implantation occurs 7 - 9 days after ovulation and enters the uterus 3-4 days after ovulation. Without fertilization/implantation, the corpus luteum involutes and estrogen/progesterone levels fall. Menstruation follows caused by the fall of both hormones but mainly progesterone. Menstrual fluid (40ml of blood and 35ml of serous fluid) is usually non-clotting due to the presence of fibrinolysin present.

Bleeding stops 4 7 days after its initial onset. Impulses in the arcuate nucleus and preoptic area release GnRH (gonadotropin releasing hormone) from the mediobasal hypothalamus. These nuclei can be stimulated from the limbic system. Inhibin produced by the corpus luteum of granulosa cells inhibit LH and FSH production.
An anovulatory cycle is a cycle without ovulation and occurs and both extremes of the childbearing years. It is devoid of progesterone and the cycle is slightly shortened.

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