Menstrual Cycle and POI

Question 1

Primary Ovarian Insuffiency

Answer 1

• A primary hypergonadotropic hypogonadism before age 40 (ovarian failure + high serum FSH + low serum estradiol).
• Characterized by a loss of oocytes, lack of folliculogensis, lack of ovarian estrogen production, and infertility.

Question 2

Causes of primary ovarian insufficiency (POI)

Answer 2

• Chromosmal defects (turners, fragile X), exposure to radiation and certain drugs, autoimmune disease, idopathic.

Question 3

Pathogenesis of Primary Ovarian Insufficiency

Answer 3

• Normal ovarian development depends on specific sequence of events, and thus there is a high potential for dysfunction. In general, defects are be split into 2 categories.

1. Accelerated follicle depletion
2. Decreased steriod production without oocyte loss

Question 4

Explain accelerated follicle depletion in Primary Ovarian Insufficiency

Answer 4

• Generally, we see complete follicular depletion around 50 years of age. However, this process can be accelerated by genetic disorders and ovaria toxins.
• Example of conditions that result in accelerated follicle depletion include: turners, X chromosome deletions/translocations, fragile X, autoimmune conditions (development of antibodies against multiple endrocrine organs), and ovarian toxins.

Question 5

Primary Ovarian Insufficiency and Turners Syndrome

Answer 5

• Only one X chromosome (or deletions in short arm of the X). One of the most common causes of POI.
• In Turners you see ovaries with small amounts of connective tissue and no follicles or atretic follicles (broken down follicles). Severity of presentation can vary from absent pubertal development with primary amenorrea and many morphological defects, to normal pubertal development with secondary amenorrhea.
• In development of XO fetuses, we see germ cell production up to 12 weeks gestation followed by loss of germ cells. Thus POI is due to accelerated atresia, not abnormal germ cell formation.

Question 6

Explain Primary Ovarian Insufficiency due to decrease steriod production without oocyte loss

Answer 6

• These are genetic disorders of estradiol precursor production or aromatase function that results in decreased in estradiol and lack or normal FSH negative feedback. These disorders are not associated with follicular depletion.
  
  • Abnormal production of intraovarian modulators (paracrine regulatprs of ovarian responsiveness)
  • Steroidogenic enzyme defects - defects in enzymes involved in adrostenedione, estradiol biosynthesis and cortisol biosynthesis (these are uncommon causes of CAH). Results in low estrogen and as a consequence high FSH.
  • FSH receptors mutation - prevents proper FSH binding, preventing aromatization of adrostenedione to estradiol.

Question 7

Clinical Features of Primary Ovarian Insufficiency

Answer 7

• Changes in mentrual cycle (oligomenorrhea and/or amenorrhea). It is also common to have intermittent ovarian function and spontaneous menses.
• Elevated serum gonadotropins
• Low serum estradiol
• Estrogen deficiency symptoms - hot flashes, vaginal dryness, etc.
• Bone loss and osteoporosis
• Cardiovascular morbidity and mortality

Question 8

Primary Ovarian Insufficiency Investigations

Answer 8

• Biochemical - Low serum estradiol, elevated FSH
• Transvaginal ultrasound - may detect antral follicles that appear endocrinologically active
• Karyotyping

Question 9

Diagnosis of Primary Ovarian Insufficiency

Answer 9

• Can be made definitively if women is under 40 with irregular menses and FSH in postmenopausal range. (Important to note that FSH may be in normal range during intermittent ovulary cycle, but will be in postmenopausal range during oligo-or amenorrhea). Women may also experience estrogen deficiency symptoms.

Question 10

Mangement of Primray Ovarian Insufficiency

Answer 10

Estrogen therapy - type of therapy depends on whether patient has primary or secondary amenorrhea.

• Primary: Young girls with primary amenorrhea who have yet to develop secondary sexual characteristics should be given low doses of estrogen (initially without progestin) to mimic gradual pubertal maturation.
• Secondary: Full replacement doses of estrogen (higher than what is normally given to post-menopausal women). Goal is to mimic amount of estrogen produced by premenopausal ovary.

Progestin - Women with POI are young and usually have an intact uterus. Patients should be given progestin to prevent estrogen-induced endometrial hyperplasia and carcinoma.

Therapy should be given until age 50-51 to manage estrogen deficiency symptoms, prevent health risks, improve quality of life, and maintain sexual function.

Question 11

Menstrual Cycle

Answer 11

• Changes in ovaries and endometrium that makes reproduction possible. A new menstrual cycle begins on the first day of menstruation and ovulation occurs 14 days before the beginning of a new cycle. Refers to 2 synchronized cycle:

1. Ovarian cycle - development of ovarian follicle and ovulation.
   
   1. Follicular phase
   2. Luteal phase
2. Uterine cycle - functional endometrium thickens and sheds in response to ovarian activity.
   
   1. Menstrual and proliferative phase
   2. Secretory phase

Question 12

Ovarian Follicular Phase

Answer 12

• Day 1-14 of 28 day cycle. Starts on first day of menstruation and lasts until ovulation.
• At the same time as follicular phase there is the uterine menstrual phase (shedding of uterine lining of prevous menstrual cycle) and uterine proliferative phase (functional layer of endomentrium thickens, spiral arteries grow, and uterine glands grow).

1. GnRH is released from hypothalamus and stimulates the anterior pituitary to release FSH and LH. FSH and LH control the maturation of the ovarian follicule, which is initally made up of a primary ooctye surrounded by layers of granulosa and theca cells. On the surface of the ovaries, a couple of ovarian follicules compete with one another to grow the fastest during each menstrual cycle.
2. During the first 10 days the theca cells develop LH receptors and in response to LH binding, release androstenedione. At the same time, the granulosa cells develop FSH receptors and in response to FSH binding release aromatase, allowing for the conversion of adrostenedione into estradiol. As the follicles grow, more estradiol is produced and negatively feedsback on the pituitary to reduce release of FSH.
3. Reduction in FSH release makes it so there is only enough FSG to stimulate one follicle. Thus, the follicle with the most FSH receptors will grow the fastest and become the dominant follcle. The other follciles regress and die off.
4. At days 10-14 the granulosa cells develop LH receptors in addition to FSH. At the same time the dominant follicle continues to release estrogen. Rising estrogen makes the pituitary more responsive to pulsatile GnRH, creating a positive feedback where rising estrogen results in increase release of FSH and LH (occurs 1-2 days before ovulation).

Question 13

Ovulation

Answer 13

• FSH and LH bind to the granulosa and theca cells. This causes the ovarian follicle to rupture and release the occyte (mid-cycle LH surge singals ovulation).
• Surge lasts 48 hours and occurs 1-2days before ovulation.
• Surge leads to resumption of meiosis I, luteinization of granulosa cells, and prepares ovary for follicular rupture.

Question 14

Luteal Phase

Answer 14

• Day 14-28 of 28 day cycle
• LH is still high and causes the remains of the follicle to turn into the corpus luteum (made of luteinized theca and granulosa cells).
• As LH levels drop after ovulation, the luteinized theca cells of the corpus luteum respond to the low LH by producing progesterone. Furthermore, the luteinized granulosa cells release inhibin blocking the release of FSH, resulting in estrogen levels dropping.
• Progesterone surpasses estrogen as the dominant hormone and makes endometrium receptive to implantation of fertilized egg. (Progesterone is also a negative feeback, blocking release of FSH and LH).
• As progesterone levels stay high the uterine goes through the secretory phase - the lining of the endometrium becomes highly vascular and the uterine glands secrete more muscus (lining stablilizes).
• If no implantation occurs (lack of hCG) there is a regression of the corpus luteum, which turns into the corpus albicans. The corpus albicans do not make hormones, so progesterone will decrease and the functional layer of the endometrium will slough off (starting of a new menstrual cycle).