|Year : 2015 | Volume
| Issue : 1 | Page : 3-5
Primary Ovarian Insufficiency: The Paradox of Menopause in Young Women
Department of Obstetrics and Gynecology, Maulana Azad Medical College, New Delhi, India
|Date of Web Publication||27-Jan-2015|
Dr. Deepti Goswami
Department of Obstetrics and Gynecology, Maulana Azad Medical College, New Delhi - 110 002
Source of Support: None, Conflict of Interest: None
Primary ovarian insufficiency (POI) refers to the loss of ovarian function in young women. It can lead to primary or secondary amenorrhea. The loss of ovarian function is usually permanent akin to menopause. Resultant hypoestrogenemia has systemic adverse effects particularly on the bone health. POI is diagnosed on the basis of raised serum follicle stimulating hormones levels. Most of the cases are idiopathic. Hypothyroidism is the most common associated disorder suggesting autoimmune etiology in some of the cases. Karyotypic abnormalities (mostly monosomy X-Turner syndrome) should be excluded in cases presenting with primary amenorrhea or early onset secondary amenorrhea. Treatment involves long-term estrogen-progesterone replacement therapy which provides regular withdrawal bleed and prevents systemic effects of hypoestrogenemia.
Keywords: Amenorrhea, ovarian failure, ovarian insufficiency, premature menopause
|How to cite this article:|
Goswami D. Primary Ovarian Insufficiency: The Paradox of Menopause in Young Women. MAMC J Med Sci 2015;1:3-5
| Introduction|| |
Amenorrhea or absence of menstruation is a worrisome symptom for young women. Once the pregnancy is ruled out, investigations are targeted at hormonal causes like polycystic ovarian disease, thyroid dysfunction, and hyperprolactinemia. Most of these conditions carry a good prognosis for future fertility. However, some women may experience amenorrhea due to loss of ovarian function and have a poor prognosis for future fertility. This condition is known as "primary ovarian insufficiency" (POI), earlier referred to as, "premature ovarian failure" (POF). , This article presents a mini-review of this lesser known endocrinological disorder and our clinical experience with a cohort of over one hundred cases of POI presently following up with us in the Gyne-Endocrinology clinic of Maulana Azad Medical College and Lok Nayak Hospital.
| Diagnosis of Primary Ovarian Insufficiency|| |
Primary ovarian insufficiency is characterized by amenorrhea and raised levels of serum follicle stimulating hormones (FSH) that is, >40 mIU/mL in a woman <40 years of age with intact ovaries. The normal levels of serum FSH for reproductive age women are between 3 and 10 mIU/mL. Thus, despite young age, the hormonal profile of these women is like that of a menopausal woman. The FSH levels are checked twice at least 4 weeks apart before making a diagnosis. The serum estradiol levels are low (<50 pg/mL); thus, these women have hypergonadotropic hypogonadism (World Health Organization group III anovulatory disorder). The diagnostic feature of POI is raised serum FSH level. Women who develop amenorrhea due to destruction of the endometrium (as in genital tuberculosis) have normal hormonal profile indicating intact ovarian function.
| Incidence|| |
The incidence is 1% in women <40 years and 0.1% in women <30 years of age.  The incidence of POI in women with primary amenorrhea is 10-28% and in women with secondary amenorrhea is 4-18%.  In our Gyne-Endocrinology clinic, we get to see about 25 cases of POI in a year and two-third of them present with secondary amenorrhea.
| Etiopathogenesis|| |
In the majority, the cause is not known-spontaneous/idiopathic POI.  Most of the cases of non-idiopathic POI are due to Turner syndrome. The X-chromosome aberrations that lead to POI could be numerical defects, as in Turner syndrome (X-monosomy) and trisomy X or there could be various structural defects.  Other genetic causes include gene mutations, reduced gene dosage and non-specific chromosome effect involving X-chromosome or autosomes. , In our cohort of more than 100 cases of POI, karyotypic abnormalities have been detected in one-third of women presenting with primary amenorrhea and include monosomy X, isochromosome X and partial deletion of X-chromosome. These genetic aberrations affect the ovarian follicular apparatus by impairing follicular growth or causing follicular atresia. An association (3-15%) is seen with fragile X syndrome characterized by intermediate number of CGG repeats in the fragile X mental retardation 1 (FMR1) gene located at Xq27.3 (FMR1 premutation). This gene gets expressed in oocytes and codes for an RNA-binding protein. Mutations in these genes lead to the expansion of the number of trinucleotide repeats. Depending on the number of repeats, four types of alleles may exist that is, normal (6-40), gray-zone (41-60), premutated (61-200) and fully mutated (200).While full mutation is associated with FMR syndrome, the women with permutation are prone to develop POI. The inheritance is in an X-linked pattern.
Primary ovarian insufficiency is also associated with galactosemia indicating that a defective glycosylation of ovarian glycoproteins is critical for ovarian function.
Autoimmune mechanisms are involved in the pathogenesis of up to 30% of cases of POF.  Autoimmune damage to the ovary may occur through humoral or cellular mechanisms. The most common autoimmune association is hypothyroidism. Our earlier published data on POI show that the prevalence of hypothyroidism in POI is 24%.  Other autoimmune association such as Addison's disease, hypoparathyroidism, arthritis and inflammatory bowel disease are much rarer.
Some cases of POI are the result of iatrogenic damage to the ovary (after oophorectomy, ovarian surgery and gonadotoxic chemotherapy). Ovarian failure has also been reported after uterine artery embolization for uterine fibroids. Rarely viral (mumps oophoritis) and environmental causes (toxins) may also lead to POI.
Even though most cases are sporadic in occurrence, a few (up to 14%) may be familial.  The only features of history which are helpful in determining etiology of POI are positive family history, a concurrent autoimmune disorder or stigmata of one of the inherited conditions. Pedigree analysis demonstrates different modes of inheritance, including dominant or recessive forms either through maternal or paternal transmission. We have come across two sets of siblings in our cohort of more than 100 women with POI in our follow up in the Gyne-Endocrinology clinic.
The ovary may be afollicular or have demonstrable ovarian follicles on ultrasonography or histopathology (resistant ovarian syndrome). Management and prognosis of the two conditions is not different and hence the common term used now is POI.
| Clinical Features|| |
The obvious clinical manifestation of absent ovarian function is amenorrhea and infertility, and this is catastrophic for the young women who do not have children. POI related hypoestrogenism results in premature aging of several tissues that are targets of estrogen action. Thus, there are long-term health sequelae of hypoestrogenemia involving bone (osteoporosis), cardiovascular system and neurocognitive functions. 
There are no specific clinical features that predict the occurrence of this condition. Some women may have irregular, prolonged menstrual cycles or scanty menstrual flow preceding amenorrhea. Vasomotor symptoms like hot flashes may be reported due to a decline in circulating levels of estrogens. Certain tests are predictive of diminishing ovarian reserves; however they are mostly used for the women being managed for infertility. These include antral follicular count, anti-mullerian hormone levels, inhibin B and basal serum FSH (between day 2 and 5 of the menstrual cycle).
| Management|| |
The cornerstone of management is estrogen replacement.  Estrogen is combined with progesterone to avoid unopposed stimulation of the endometrium and ensure monthly menstrual flow. This replacement is unlike the postmenopausal hormonal therapy which is started near or after the menopause. This treatment is for young women with ovarian insufficiency and is continued till the age of natural menopause that is, 50 years. Since the treatment involves fulfilling physiological requirement of estrogen-progesterone, health issues pertaining to postmenopausal hormone replacement (like breast cancer) are not of concern. Estrogen-progesterone replacement may be given as sequential or combined (combined oral contraceptive pills) form. The routes may be oral (tablets), transdermal (patches impregnated with hormones) or subcutaneous (estrogen pellets). 
In girls presenting with primary amenorrhea due to POI, pubertal growth is achieved by estrogen replacement in incremental doses.
Screening for associated autoimmune disorders and karyotyping, particularly in early-onset disease (<30 years), constitute part of the diagnostic workup. These women should be screened for the autoimmune dysfunction particularly that of thyroid and wherever possible for the adrenal autoimmunity. They should also be monitored for the later appearance of these conditions. Since the tests for ovarian autoimmunity are not validated, there is no need to test for anti-ovarian antibodies. Similarly, laparoscopy and ovarian biopsy have no role in diagnosis or management. Bone densitometry is not done routinely, and estrogen replacement would anyway improve bone density. However, some clinicians prefer to get a dual energy X-ray absorptiometry scan done to monitor bone mineral density during treatment. The scan should not be repeated frequently since the improvement in bone density becomes apparent only after a year or two of estrogen replacement. Adequate calcium intake (1200 mg/day) and maintenance of normal vitamin D levels that is, 20-30 ng/mL (50-75 nmol/L) is recommended.
Apart from health related issues there are socio-psychological issues that need to be dealt with.  Impaired fertility is a major concern for the affected girls/women and their families. Several modalities of medical treatment have been tried to restore fertility in POI including corticosteroid, clomiphene and gonadotropin-releasing hormone agonists.  However, none has been proven to improve ovarian function and fertility for women with POI. For women desiring childbearing, options include oocyte donation, embryo donation, and adoption. Young women undergoing potentially gonadotoxic chemotherapy may be offered fertility conservation through cryopreservation of ovarian tissue, oocytes, or embryos.
It is worthwhile to counsel these women regarding small risk of the condition being familial. If a genetic alteration is found in a woman with POI, it can be useful for family counseling because it can predict the female relatives that are at higher risk for POI. The female carriers will thus be able to plan their conception before ovarian failure occurs.
| Prognosis|| |
Women with POI need to be counseled that spontaneous pregnancy is rare and not possible to predict. Remission even when it occurs is temporary. Spontaneous pregnancy is considered to occur in 5-10% of the cases.  However, Bidet et al. observed only five pregnancies in a cohort of 302 women with POI all of which occurred less than a year after the diagnosis of POI.  Over the past 8 years we have followed up more than 100 women with POI and only one of them, a case of chemotherapy-induced POI, achieved pregnancy while she was on hormone replacement therapy. Her pregnancy was uneventful, and she delivered a set of twins in November 2014. Even though some of the studies reported that a significant proportion (up to 86%) of the women with POI have biochemical evidence of ovarian follicular activity, close review of these studies shows that most of them involved women with <1 year duration of amenorrhea.  In one of our studies published in the journal "Human Reproduction", only 11% of women with POI with more than 1 year of amenorrhea were found to have an episodic decline in serum FSH level.  Thus, a short duration of amenorrhea and presence of cycle-to-cycle variability of serum FSH and estradiol may be the potential predictors of ovarian functions in POI.
Primary ovarian insufficiency or POF, as it was earlier called is not uncommon. All women with prolonged amenorrhea need to be investigated for this condition. The chances of return of ovarian function are scant. Childbearing is possible through oocyte donation. Patient counseling regarding the need for long-term estrogen replacement is important to prevent adverse effects of hypoestrogenemia, particularly on bone health.
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