Gynae: Menstrual Cycle and Related Hormones

Gynae: Menstrual Cycle

Understanding the menstrual cycle and hormones is crucial in gynecology, forming the basis for understanding conditions like PCOD, menopause, endometriosis, and fibroids. It's also essential for managing infertility and hormonal imbalances.

Key Areas in Gynae

  1. Menstrual Cycle and Hormones: This includes detailed knowledge of hormone synthesis, regulation, and their effects on target organs.

  2. Anatomy: Understanding anatomy helps in addressing questions related to prolapse, urinary incontinence, and pelvic floor disorders. Detailed anatomical knowledge aids surgical planning and diagnosis.

  3. Embryology: Understanding embryology is related to puberty and helps in understanding amenorrhea, congenital anomalies of the reproductive tract, and the genetic basis of certain gynecological conditions.

  4. Cancers: The last key area to study in gynecology includes cervical, ovarian, endometrial, and breast cancers. Understanding their pathogenesis, screening, diagnosis, and management is critical.

Oogenesis

Oogenesis begins in intrauterine life. Oogonia convert into primary oocytes, which then undergo meiosis one. However, meiosis one gets arrested at the diplotene stage of prophase I. This arrest is maintained by factors secreted by granulosa cells called oocyte maturation inhibitor (OMI).

In a newborn female, the ovaries contain primary oocytes arrested in meiosis one. This arrest is lifted only at puberty due to the LH surge.

Ovary Histology

The ovary consists of two main parts: the cortex (outer part) and the medulla (inner part).

  • Cortex: Contains primary oocytes and follicular cells (granulosa cells) at different stages of development, along with stromal cells.

  • Medulla: Contains blood vessels, nerves, lymphatic vessels, and stromal cells, including theca cells and hilus cells (which secrete androgens).

Granulosa cells surround primary oocytes in the cortex, while theca cells from the medulla also surround the primary oocyte. The basement membrane separates granulosa cells from theca cells.

Primordial Follicle

The structure consisting of a primary oocyte surrounded by a single layer of flattened granulosa cells and an outer layer of theca cells is called a primordial follicle. These follicles are the most immature and dormant.

Before puberty, a young female's ovary contains numerous primordial follicles, which serve as the reservoir of the ovary.

Follicle Dynamics

The number of follicles is maximum at the fifth month of intrauterine life, with about 6 to 7 million follicles. At birth, this number decreases to 1 to 2 million follicles, and by puberty, only 4 to 5 lakh follicles remain.

Follicles continuously decrease in number due to apoptosis (atresia), even before the hypothalamic-pituitary-ovarian axis becomes functional at puberty. This means the initial recruitment of follicles is hormone-independent, driven by local growth factors.

Puberty and Hormonal Influence

At puberty, the hypothalamic-pituitary-ovarian axis becomes functional. The hypothalamus releases GnRH (gonadotropin-releasing hormone) in a pulsatile manner, which acts on the anterior pituitary to release FSH (follicle-stimulating hormone) and LH (luteinizing hormone).

FSH prevents follicles from undergoing atresia and stimulates them. FSH acts on the granulosa cells of the follicles, leading to the release of estrogen and inhibin B. LH acts on theca cells to produce androgens.

Role of FSH

FSH stimulates granulosa cells to release estrogen and inhibin B. FSH receptors are present on granulosa cells. A granulosa cell tumor of the ovary produces estrogen and inhibin B, making it a feminizing tumor. These tumors can cause precocious puberty in young girls.

Inhibin B has a negative feedback effect on FSH, regulating its secretion.

*Tumor marker for Granulosa cell tumor of ovary is inhibin B.

Estrogen Functions

Estrogen performs three main functions:

  1. Negative feedback on FSH, preventing the recruitment of new follicles.

  2. Positive feedback on LH, leading to the LH surge.

  3. Proliferation of the uterine endometrium, preparing it for implantation.

Estrogen should never be given alone to a female with an intact uterus because it can lead to endometrial cancer and endometrial hyperplasia. Progesterone is needed to induce secretory changes and prevent hyperplasia.

Dominant Follicle

Estrogen's negative feedback on FSH causes most stimulated follicles to undergo apoptosis, except for one dominant follicle. The dominant follicle has the maximum number of FSH receptors on its granulosa cells and produces more estrogen.

LH Surge

Estrogen's positive feedback on LH leads to a sudden increase in LH levels, known as the LH surge. The LH surge initiates the resumption of meiosis one in the primary oocyte, converting it into a secondary oocyte (ovulation). The follicle transforms into the corpus luteum.

For the LH surge to occur, estrogen levels must reach 200 picograms and be maintained for 48 hours. This threshold ensures that the follicle is mature enough for ovulation.

Theca Cells and Androgens

LH acts on theca cells, stimulating them to produce androgens (androstenedione and testosterone). These androgens are then converted into estrogen in the granulosa cells with the help of the aromatase enzyme. This conversion also occurs in adipose tissue.

Two-Cell, Two-Gonadotropin Theory

The two-cell, two-gonadotropin theory explains how ovarian estrogen production requires the combined action of theca and granulosa cells.

  • Theca Cells: Possess CYP17 (17 alpha-hydroxylase) but lack aromatase. LH acts on theca cells, converting cholesterol into androgens (androstenedione and testosterone).

  • Granulosa Cells: Possess aromatase but lack CYP17. FSH acts on granulosa cells, converting androgens into estrogen (E1 and E2).

In adipose tissue, androstenedione is converted into estrone (E1) with the help of aromatase. This is particularly important in postmenopausal women, where adipose tissue becomes a primary source of estrogen.

LH's Role on Granulosa Cells

LH also acts on granulosa cells, causing luteinization and releasing small amounts of progesterone even before ovulation, at the time of the LH surge. This progesterone contributes to the positive feedback on LH and FSH.

LH receptors are present on both theca and granulosa cells, whereas FSH receptors are present only on granulosa cells.

Progesterone appears earliest in the menstrual cycle at the time of the LH surge, approximately 32 to 36 hours before ovulation.

Progesterone's Effects

Low concentrations of progesterone have a positive effect on LH and FSH, increasing their levels. Thus, there is both an LH and FSH surge before ovulation.

Line Diagram of Menstrual Cycle

Ovarian Cycle Initiation

The ovarian cycle is initiated by FSH. FSH acts on granulosa cells, which release estrogen. This estrogen has a negative feedback on FSH, a positive feedback on LH, and proliferates the uterine endometrium.

LH Surge and Ovulation

The positive feedback of estrogen on LH causes the LH surge, leading to ovulation (primary oocyte converts to secondary oocyte), and the follicle converts into corpus luteum.

Follicle Size Before Ovulation

The size of the follicle just before ovulation is 18 to 20 millimeters. This can be monitored via ultrasound.

Time Intervals

  • Time interval between LH surge and ovulation: 32 to 36 hours.

  • Time interval between LH peak and ovulation: 10 to 12 hours.

  • Time interval between estrogen peak and LH peak: 14 to 24 hours.

Hormone Control

LH surge is initiated by estrogen but maintained by both estrogen and progesterone.

Before ovulation, there is both an LH and FSH surge. Ovulation is due to LH surge.

Meiosis one resumes due to the LH surge, occurring 32 to 36 hours before ovulation. Progesterone can be detected earliest 32 to 36 hours before ovulation due to the LH surge.

Mid-Cycle Follicular Development

The growing follicle progresses through different stages: preantral follicle, antral follicle, and graafian follicle. The granulosa cells directly surrounding the primary oocyte are called cumulus oophorus. This cumulus oophorus expands just before ovulation.

The antral cavity contains estrogen and growth factors. LH enters the antral cavity fluid towards the mid-cycle. If LH is present in the antral fluid from the beginning of the cycle, it leads to degeneration or atresia of the granulosa cells, stopping their mitotic activity and the atresia of follicles, which happens in PCOS.

Corpus Luteum Formation

Primary oocyte converts into secondary oocyte and the follicle converts to the corpus luteum. Corpus luteum is formed because of ovulation and is maintained by the hormone LH in a nonpregnant female. The corpus luteum grows under the effect of LH, reaching maximum size and maximum activity eight days after ovulation (day 22 of the cycle).

The corpus luteum releases progesterone, estrogen, and inhibin A. Mainly it releases progesterone.

Inhibin A and Estrogen decrease the levels of FSH. So if asked what do corpus luteum secretes, the answer should be both (estrogen and progesterone). But, if asked what does corpus luteum mainly secretes, the answer should be progesterone because corpus luteum mainly secretes progesterone,.

During pregnancy, the corpus luteum also secretes relaxin, which helps in relaxing the pelvic ligaments.

Progesterone Function

Progesterone has two main functions:

  1. Negative feedback on LH, preventing further ovulation.

  2. Acts on the uterine endometrium, supporting it, which is called the secretory action. It induces the formation of spiral arteries and glycogen-rich glands.

At low concentrations, progesterone increases LH and FSH, while at high concentrations, it decreases LH and FSH.

As LH levels decrease, the corpus luteum starts degenerating. When the corpus luteum degenerates, levels of progesterone, estrogen, and inhibin A decrease.

Menstruation

When progesterone decreases, the support to the endometrium is lost, and the endometrium sheds. This shedding is called menstruation. The metalloproteinase enzyme leads to the shedding of the endometrium.

Apart from endometrium shedding and the drop in progesterone levels, Vasoconstriction occurs, and PGF two alpha is released, leading to increased myometrial contractions and spasms, which cause pain during menstruation (dysmenorrhea).

When estrogen decreases and inhibin A decrease, the levels of FSH increase (negative feedback is gone). Again, FSH acts on the granulosa cells, and it releases estrogen.

Endometrium Regeneration

The deep layer (zona basalis) is responsible for the regeneration of the entire endometrium in the next cycle. Estrogen acts on the deep layer to proliferate it, forming the superficial layer again.

Luteal Phase and Secretory Phase

Whatever happens in the second half of the menstrual cycle is happening to the corpus luteum. So it's called the luteal phase. The main hormone in the second half of the cycle is progesterone, and it brings about secretory action. So the second half also can be called Secretory phase.

Important Questions on Menstrual Cycle

If a female has recurrent abortions and is asked what the drug of choice is for luteal phase defect, the answer should be progesterone. This supports the endometrium and maintains the pregnancy.

The luteal phase has a fixed duration: 14 days. In a 28-day cycle, Ovulation happens on day 14. To calculate the ovulation and the day of ovulation, count fourteen days backward from the date of next menstruation date. The day of ovulation is equal to the total length of the cycles minus 14.

Questions on Corpus Luteum

The hormone that maintains Corpus luteum in a nonpregnant female is hormone LH. Furthermore, the hormone that maintains Corpus luteum in a pregnant female is hormone hCG. LH and hCG are functionally the same.

The lifespan of corpus luteum in a nonpregnant female is 10 to 12 days, whereas the lifespan in pregnancy is 10 to 12 weeks. The hormone which protects Corpus luteum from undergoing luteolysis is with hormone hCG.

The specific nature of hormone is corpus luteum of pregnancy.

Key Hormone Levels

All hormones peak during ovulation. For example, LH peaks at the time of ovulation, FSH peaks at the time of ovulation, and estrogen peaks just before ovulation (24 to 36 hours before ovulation). Progesterone peaks at day 22 of the cycle (when the activity of corpus luteum will be maximum), specifically, eight days after ovulation.

Tests for ovulation are based on the principle that if a female ovulates, progesterone will be present in her body, and it is absent when a female doesn't ovulate. In order to determine ovulation, tests should be done on day 22 of the cycle.

In a menstrual cycle, when asked when the levels of LH and FSH are minimum, the answer is in the secretory phase. It is the secretory phase where progesterone is at its maximum. This phase occurs Approximately a week before menstruation.

Michelle's MERS syndrome features Pain in the abdomen at the time of ovulation, which is the Mid cycle pain.

Common MCQ's (Multiple choice questions)

LH surge is initiated due to sustained levels of two hundred picograms of estrogen for forty eight hours (it's correct).

LH surge is maintained by estrogen and progesterone (it's correct).

Meiosis one is hormone dependent (it's correct).

Meiosis two is hormone dependent (incorrect)

Granulosa cells produce estrogen with the help of enzyme aromatase

The gene present in thecal cell as a is absent in granular cell which enables theca cell to produce Androgen CYP17

In a forty days menstrual cycle ovulation occurs after date 26

All of the following statements are true regarding estrogen except is secreted by theca cell that is secreted by granular cell

All of the following statements are true regarding estrogen except is secreted by theca cell that is secreted by granular cell. Remember the all important point needed for menstruation is progesterone, for menstruation initially levels should be high then it should fall off, Progesterone act an uterus with it can only happen if prime by estrogen, if female doesn't ovulate there will be no pro progesterone means that progesterone should not be detected.

Action of Progesterone

The main hormone action of of the female who has been primed by the estrogen is that it can only act only with level of progesterone in the body that there should be menstruation at all also for everything be related with menstruation there has to be progesterone now if prime a progesterone is not there that that means because they may have the estrogen what they have been present what they will do it can lead the uterus endometrium so after the entire endometrium can share what the one who does not have the irregular cycle there is anovulatory period now normally those were those of menstrual it is a the pro progesterone normally do the the vasoconstriction it produce of GF2A contract to lead to pain and therefore it shows that has been a director

Now so has been there there is not a not there anovulatory that does not there they are not releasing gf2 alpha, with is painless more bleeding by estrogen one thing does the one one should not be taken is the test is they can cannot contract is normally can be done normally