Premature Ovarian Failure: The New Epidemic
Riya was quiet happy till last six month when she joined her new job as HR consultant. She was at her 32 and was about to start a family since her husband also settled as a branch manager at a private bank near Kasba. Problem arises as she missed her period for consecutive three months. Initially she thought of good news in the form of pregnancy. But her elation was replaced by melancholia when her gynaecologist declared her to be non-pregnant and did some hormonal assay. It was shocking for her to know that she is at her fag end of reproductive carrier with a FSH report of 15.7mIU/ml. Riya was at a loss. Questions haunted in her mind like weapon shower. Is she heading for a premature menopause? Is 32 too late an age to conceive? Is the contraceptive practices has taken its toll? At all she can mother a child or not? Tears rolls down her fair toned chick. She felt her ovarian age has surpassed her facial/skin age by almost 20 years! As per her gynecologist’s version she was suffering from premature ovarian failure. Premature Ovarian failure: This is an enigmatic disorder which describes a stop in the normal functioning of the ovaries in a woman younger than age 40. Some people also use the term primary ovarian insufficiency to describe this condition. It is also known as hypergonadotropic hypogonadism. It commonly presents with triad of amenorrhoea (mainly secondary), hypergonadotropinism and hypoestrogenism in young women of reproductive age. Though there is greatly reduced chance of getting pregnant, but women with this diagnosis can ovulate and even can conceive. The incidence has increased from 0.3% to 1 % in last decades and showing an increasing trend especially in Asian countries. These women may even complain of hot flushes and dyspareunia at much early age making conjugal life at stake. Though the most common first symptom of premature ovarian failure is skipping or having irregular periods, infertility could have been the first presenting complains. Premature ovarian failure also puts women at risk for some other health conditions; some of them are serious, like loss Women with Premature Ovarian failure (POF) can ovulate and even can conceive. of bone strength, low thyroid function causing low energy, quick tiredness even heart diseases. Causative factors: Women with premature ovarian failure mainly fall into one of the two groups: 1. Women with follicle depletion who has no follicles left in her ovaries and there is no way to make more. 2. Women with follicle dysfunction may have follicles in her ovaries, but they are not working properly. Still the largest category is idiopathic. Cytogenetic abnormalities involving the X chromosome share a good bulk of the etiology of POF. It’s mandatory to have two intact X chromosome (structurally and functionally) to maintain normal ovarian function. Deletion of short or long arm of X chromosome causes rapid atresia of oocytes leading to poor ovarian reserve at very early age. 45 XO/XX mosaic Turner are another example of secondary amenorrhoea and POF. Thus karyotype is mandatory in women suspicious of suffering from POF below 35 years of age. Even extra X chromosome in the form of 47XXX is a potential candidate for POF. Perhaps the most important association with POF is pre-mutation of FMR1 gene. This gene is located at long arm of X chromosome,Xq27. Triple repeat mutation of CGG(cytosine-guanineguanine) sequence results in POF. They generally have strong familial history of mental retardation leading to Fragile X Syndrome. Emotionally labile women with features of excessive anxiety, emotional outburst, short attention span, impulsivity and hyperactivity along with features of POF are candidates of FMR1 gene defect. 6-10% of women with POF have fragile X syndrome. Karyotype is mandatory in women suspicious of suffering from POF below 35 years Emotionally labile women with features of excessive anxiety, emotional outburst, short attention span, impulsivity and hyperactivity along with features of Premature Ovarian Failure are strongly suffer-
ing from FMR1 gene defect. Enzymatic defects: in the form of aromatase deficiency with normal 46 XX karyotype also suffer from POF. They can even develop cliteromegaly and lesbian instinct at later life. (e.g. recent case of female athlete Pinki Pramanik ). FSH receptor gene defect or secretion of biologically inactive gonadotropin are other factors. Environmental insults: in the form of radiation or chemotherapy and surgical injury can cause POF. Viral infection mumps oophoritis is an important association in unexplained POF. Even cigarette smoking can be responsible for POF. Autoimmune disorder: About 3.2 percent of women with premature ovarian failure also have Addison’s disease with defects in adrenal function. It even can involve thyroid gland in the form of autoimmune thyroiditis. This group typically has the wax and wane features. And they must be treated early till the ovarian reserve is completely lost. How is premature ovarian failure diagnosed? Because one of the most common signs of premature ovarian failure is irregular periods, women should pay close attention to their menstrual cycles and if any irregularities occur they must contact to gynaecologist. Primary infertility could be a first sign of POF even. Necessary investigations which will guide to identify the cause are listed below:
1. Serum TSH and prolactine level.
2. Basal serum FSH and E2 (estradiol) on at least two occasions.
3. Karyotype when woman is less than 35years.
4. Careful family history and evaluation of FMR1 pre-mutation (by FISH technique).
5. Adrenal antibody testing and thyroid-stimulating immunoglobulins. Women with other autoimmune disorder s must be investigated for POF and treated early till the ovarian reserve is completely lost.
6. Blood for AMH for assessment of Ovarian reserve.
If the FSH level is greater than 30mIU/ml no oocyte can be retrieved. A level of more than 15mIU/ml necessitates cross checking of FSH in a separate occasion along with E2 level estimation. If E2 level remains greater than 50pg/ml still there is chance of getting few follicles on stimulation. AMH level less than 1.5mIU/ml indicate very poor ovarian reserve. 35% of women with secondary amenorrhoea below age 35 contain any kind of karyotype abnormalities. So karyotype is a must to rule out any familial transmission of X chromosomal disorder. Family history of a woman whose mother had an early menopause should be cautious on achieving POF at early age. Treatments for premature ovarian failure: The very first and perhaps most important, challenge in providing appropriate treatment to women with POF is informing the patient about diagnosis in a sensitive and caring fashion. It is always very shocking for a woman to accept the truth of being at a fag end of her reproductive carrier especially when she desires kids. It can provide emotional trauma to such a magnitude that she can suffer even mental set back. So it is always better to discuss her treatment option in a separate visit with spending quality time. It is important to counsel the patient that spontaneous pregnancy is still possible with the help of hormone replacement therapy (HRT). HRT can also help her to get rid of the symptoms of premature ovarian failure; she can have her regular periods back and lower their risk for osteoporosis. Hormone replacement therapy (HRT): A continuous exogenous estrogen in the form of estradiol valerate 2mg oral daily dose or transdermal skin patch of estradiol-17• 0.1mg daily generally suffices. It is important to exclude thyroid dysfunction, adrenal insufficiency and fragile X permutation before reaching to a final diagnosis of premature ovarian failure. It is important to counsel the patient that spontaneous pregnancy is still possible with the help of hormone replacement therapy (HRT). Addition of progesterone in the form of micronized progesterone 200 mg daily or medroxyprogesterone ac- etate 10 mg daily for first 14 days of each month will maintain the withdrawal bleeding. 25% of women ovulate after continuous treatment of 3-6 months and 10% of them even conceive. Infertility therapy: There is no role of ovulation induction agents in the form of clomiphane citrate. High dose of gonadotropins sometimes can produce follicles but good quality eggs are rarely achieved. Options for ovum donation should be discussed with the couple. Oocyte donation success rates are generally greater than traditional IVF particularly in these cases. Some upcoming therapy of fat cell infusion inside ovary of POF women can produce eggs. This is formulated from a study which is still in trial phase and conducted by a group of china. Here they are taking the fat cell of the same woman by liposuction technique from abdominal fat. Those fat cells are centrifuged and cultured at laboratory in tissue culture plate. Later on these fat cells are transferred inside the ovary of POF woman via laparoscopic technique. Since ova are basically generated from fat cells, this technique will regenerate eggs in the ovary of a woman of premature ovarian failure. Key points for clinical practice: POF is sufficiently common and gradually upcoming in an epidemic form specially among women suffering from infertility. Early evaluations are important to exclude treatable causes and associated health concerns. It is important to exclude thyroid dysfunction, adrenal insufficiency and fragile X permutation before reaching to a final diagnosis of premature ovarian failure. Karyotype is mandatory in women suspicious of suffering from POF below 35 years. Affected patients should be provided with sensitive care and extensive counseling as needed. In Vitro fertilization with ovum donation is the most effective way of providing these women with pregnancy.
Dr. Shiuli Mukherjee is an infertility expert at Genome, Kolkata.