POI: Mechanisms, FMR 1 and Management

00:01 Let’s now review POI Ovarian dysfunction.

00:05 Sometimes you can have a signal defect.

00:07 That is to say, that the FSH and LH receptors do not function properly.

00:13 Here, you’ll see that the theca cell has an LH receptor, while the granulosa cell has an FSH receptor.

00:21 Normally, LH and FSH surges will cause LH and FSH to bind to this receptor.

00:28 These receptors in turn will cause steroidogenesis to occur with the precursor being cholesterol.

00:35 Cholesterol is converted through a long pathway to androstenedione and testosterone in the theca cells.

00:42 These two hormones then diffuse into the granulosa cell and are aromatized by aromatase making estrone and estradiol.

00:52 For more information about this pathway, please check out the lecture entitled, Congenital Adrenal Hyperplasia.

00:58 You can also have enzymatic deficiencies.

01:02 You have isolated 17.200 lyase deficiency.

01:06 This is discussed more in the CAH or congenital adrenal hyperplasia lecture.

01:11 You can always have aromatase deficiency as well.

01:15 Aromatase deficiency means that the androgens cannot be converted to estrogens.

01:20 You can find more about this pathway again in the CAH lectures.

01:25 You may also have autoimmunity causing ovarian insufficiency.

01:29 And typically, this is a lymphocytic oophoritis which is autoimmune, of course.

01:35 And occasionally, you can have inappropriate follicular luteinization.

01:40 And what that means is that the LH surge normally causes luteinization after ovulation.

01:46 But this can happen in follicles before the oocyte is released, and therefore, the ovary has some dysfunction.

01:53 60% of all antral follicles are found to be luteinized with this condition.

01:58 Let’s now talk about follicular depletion in ovarian insufficiency.

02:04 Essentially, what this means, is that the patient may have an insufficient initial follicle number.

02:09 As you’ll recall from the puberty lectures, we have millions of follicles and oocytes midgestation.

02:17 These follicles and oocytes then undergo atresia.

02:21 However, patients with POI may start out with much less.

02:26 This is the case in some familial syndromes where you have follicular depletion such as an NBPES.

02:33 Please find more information about this syndrome in OMIM.

02:37 With Turner Syndrome, we also think the mechanism is follicular depletion.

02:42 These patients start out with less ovarian reserve and lose their ovarian reserve through atresia.

02:48 However, some of us may also experience spontaneous accelerated follicle loss leading to ovarian insufficiency.

02:56 Let’s now talk about Fragile X or FMR1 permutation as a cause of POI.

03:05 In Fragile X, we have three different clinical presentations.

03:10 You can have Fragile X syndrome, primary ovarian insufficiency, or Fragile X-associated tremor ataxia syndrome or FXTAS for short.

03:20 Let’s discuss what you have in this setting of a premutation; normal, abnormal, and a full mutation.

03:30 Normal is less than 45 repeats and determinant means 45-54 repeats, and there are increased risk of expansion.

03:39 A premutation is 55-200 repeats and a full mutation is greater than 200 repeats, which will cause fragile X syndrome.

03:49 Now let’s talk about how they actually develop molecularly.

03:53 In the normal patient, you should have a normal amount of FMR1 mRNA, but in the premutation you may have less and in the full mutation you may have none.

04:04 That affects protein function or protein development that affects phenotype.

04:10 And in the normal patient, you shouldn’t see any phenotype but the premutation you may see POI.

04:17 With the full mutation, you will see the syndrome.

04:19 Let’s now discuss the different physical attributes in men who have fragile X.

04:25 They tend to have tall structure, macrocephaly, and an elongated face, large ears, large testes sometimes called macro-orchidism, MVP or mitral valve prolapse, joint hypermobility and generalized hypotonia.

04:43 They can also have some deficits intellectually.

04:46 They may have a moderately low IQ.

04:50 They may have anxiety, hyperactivity, ADD or Attention deficit disorder.

04:56 These patients may maintain avoidance of eye contact, and they may have speech perseveration, perseveration, perseveration.

05:05 That means that they repeat something over, over, and over again.

05:09 They may have stereotypical movements and autism.

05:13 Let’s now talk about Fragile X associated tremor ataxia syndrome.

05:19 This is usually diagnosed later in life, and not something that a gynecologist would actually see.

05:25 However, it’s hopeful to know that there are certain MRI findings that maybe present.

05:29 If you suspect POI in a patient, you should alert her that she should inform her other family members who may suffer from this.

05:37 We see on histology that there are certain inclusion cyst that are found in the brain when this syndrome is present.

05:44 Let’s now talk about how the number of repeats correlate with the last menstrual cycle.

05:52 Remember these patients are going into a early menopause state.

05:56 The higher the number of repeats, the more likely that she will go into menopause earlier.

06:01 Here you can see that a hundred repeats to two hundred repeats means that you’ll go into menopause much earlier than average.

06:09 Increased repeats not only determine the severity of disease for the individual, your patient, but also any children she may have in the future.

06:20 Remember, that even though these patients have ovarian insufficiency, they may have spontaneous conception.

06:27 And there’s a definite increase of the risk of expansion.

06:30 Let’s now talk about the endocrine profile in an ovarian insufficient patient.

06:37 In a normal patient we should have normal FSH levels, their fertility should be normal and they should have regular monthly menses 21-35 days on average.

06:48 With occult POI, which means that it hasn’t been discover yet, they can have normal FSH but reduced fertility and regular menses.

06:57 And these patients that we suspect of having occult disease it’s helpful to send up FMR1 premutation.

07:04 Then there’s biochemical POI, that means they’re starting to have some biochemical symptoms.

07:10 Including an elevated FSH with reduced fertility but they still may have regular menses.

07:16 And then there’s overt POI.

07:18 They have elevated FSH, they have reduced fertility and they may have irregular or absent menses.

07:25 These patients are on their way to having frank ovarian sufficiency and menopausal symptoms.

07:31 Let’s now talk about autoimmunity in these patients.

07:35 This is characterized by oophoritis or lymphocytic infiltrates growing into the follicles.

07:41 You can see this histological picture here where we do have evidence of this.

07:45 This is associated with adrenal insufficiency or Addisonian crisis or Addison's disease.

07:52 These can also be associate with autoimmune hypothyroidism.

07:55 And these should never be forgotten in the context of ovarian insufficiency.

07:59 We can now review the management of patients with ovarian insufficiency.

08:05 Hormone replacement is necessary.

08:08 However, oral contraceptive pills are not effective birth control.

08:13 And they’re also, not good HRT.

08:16 Typically, women with POI or ovarian insufficiency will require twice as much estrogen as a postmenopausal woman to alleviate symptoms.

08:27 Remember, they should be seeing estrogen that a young woman should be seen not which you would give to a postmenopausal woman who is actually already decreasing estrogen throughout her lifetime.

08:39 A 100 mcg estradiol patch is the recommended dosing.

08:44 However, there are other oral preparations that can be used as well.

08:48 Let’s now talk about contraception in these women.

08:52 Remember, then oral contraceptive pill is not good contraception or good hormone replacement therapy.

08:59 Now, why would an oral contraceptive pill work in this type of patient? Do you want to think about it? I’ll give you a second.

09:08 Well, their FSH is so high that it can’t be suppressed by the oral contraceptive pill, which is how it works.

09:16 Their LH may also be high and therefore a progesterone only pill can also not suppress their LH.

09:22 IUDs, intrauterine devices, and barrier methods are best choices for women who have ovarian insufficiency.

09:29 Again, we have not studied oral contraceptive pills in POI patients.

09:34 Let’s talk about ways these patients can conceive.

09:40 Well, they can spontaneously ovulate and have a child on their own.

09:44 However, it’s hard to predict when ovulation will occur because they may go in and out ovarian insufficiency and ovarian functionality.

09:52 These patients may opt for egg donation.

09:56 If you’d like information about egg donation, please see the lecture about assisted reproductive technologies.

10:02 These patients make up about 10% of all IVF cycles in the U.S.

10:07 They can also adopt embryos, however, this is a little bit more complicated as they have to adopt an embryo from certain organizations.

10:17 But, it’s not impossible.

10:19 And then there’s traditional adoption which is always encouraged in these patients.

10:24 These patients are at risk for osteoporosis and they should have a calcium intake of that of a postmenopausal woman between 1200 and 1500 mg of calcium daily.

10:37 Their vitamin D should be between 800 and a thousand IUs daily.

10:43 We encourage these women to engage in weight bearing exercises as well.

10:48 Also don’t forget to obtain a DEXA at baseline and reevaluate if they’re osteopenic.

10:55 The presence of adrenal antibodies has a 50% risk of developing Addisonian crisis or adrenal insufficiency.

11:03 Remember to check these and this may be tested on your USMLE.

11:07 Patients with ovarian sufficiency can also have autoimmune hypothyroidism.

11:13 20% of women who have POI will develop autoimmune hypothyroidism, such as in Hashimoto thyroiditis.

11:22 Thank you for listening and good luck on your exam.