History

Fact Explanation
Amenorrhoea (absence of the menstruation) Normal ovulation is controlled by the hypothalamo pituitary ovarian axis where the secretion of gonadotrophin releasing hormone by hypothalamus acts on the anterior pituitary to release follicular stimulating hormone and luteinizing hormone. This FSH and LH act on the ovary inducing the follicular maturation and release of oestrogen. [3] There is a LH surge usually at around 14 days of 28 day cycle that stimulate the release of the matured ovum. If there is no conception, the endometrium is shedoff as menstrual bleeding at the end of the 28 day cycle. When there is an ovarian failure this menstruation does not occur as usual manner. Premature ovarian failure is defined as spontaneous cessation of menses for >1 year, before age 40 years. [4] Causes for ovarian failure can be subdivded into infectious, autoimmune, genetic, environmental, iotrogenic and idiopathic. [5] Amenorrhea [7] can be either absent menarche (primary amenorrhea) or premature depletion of ovarian follicles/arrested folliculogenisis before the age of 40 years (secondary amenorrhea). [6]
History of subfertility [2] Ovulation is an essential factor needed for the fertility. Matured ovum is released with the ovulation which usually occurs nearly 14 days prior to the onset of menstruation. Anovulation or the absence of the ovulation is a major factor contributing to the subfertility. [2]
Hot flushes, night sweat [6] Hot flashes are feelings or warmth that spread over the body which is associated with low oestrogen levels. [2]
Irritability, poor concentration ,anxiety, sleep disturbance, decreased libido [6] Due to the low oestrogen levels. [2]
Urinary frequency and recurrent urinary tract infections, uterovaginal prolapse Integrity of the pelvic floor and the muscles is driven by the oestrogen. [2] Due to the absence of oestrogen there can be weakening of the tissues leading to descent of the uterus and vaginal wall may or may not be associated with the descent of the bladder, rectum and the intestines.
Pathological fractures Oestrogen deficiency causes weakening of the bones and osteoporosis. [6]
Vaginal dryness, pain during sex Due to the low oestrogen levels. [2] This can be associated with dyspareunia which is the pain during sex.
History of infection, autoimmune disorders, surgery or radiotherapy related/ affects the ovaries These can cause premature ovarian failure. [3]
Smoking Cigarette smoking is known to cause ovarian failure in an dose dependent manner. [3]
References
  1. SOAVE I, LO MONTE G, MARCI R. POI: Premature Ovarian Insufficiency/Pregnancy or Infertility? N Am J Med Sci [online] 2013 Jan, 5(1):71 [viewed 24 August 2014] Available from: doi:10.4103/1947-2714.106217
  2. PENEFSKY HS. Mechanism of inhibition of mitochondrial adenosine triphosphatase by dicyclohexylcarbodiimide and oligomycin: relationship to ATP synthesis. Proc Natl Acad Sci U S A [online] 1985 Mar, 82(6):1589-1593 [viewed 24 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC397317
  3. MATTISON DR, EVANS MI, SCHWIMMER WB, WHITE BJ, JENSEN B, SCHULMAN JD. Familial premature ovarian failure. Am J Hum Genet [online] 1984 Nov, 36(6):1341-1348 [viewed 26 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1684657
  4. MURRAY A, ENNIS S, MORTON N. No Evidence for Parent of Origin Influencing Premature Ovarian Failure in Fragile X Premutation Carriers Am J Hum Genet [online] 2000 Jul, 67(1):253-254 [viewed 26 August 2014] Available from: doi:10.1086/302963
  5. JEWELEWICZ R, SCHWARTZ M. Premature ovarian failure. Bull N Y Acad Med [online] 1986 Apr, 62(3):219-236 [viewed 26 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1629109
  6. BECK-PECCOZ P, PERSANI L. Premature ovarian failure Orphanet J Rare Dis [online] :9 [viewed 26 August 2014] Available from: doi:10.1186/1750-1172-1-9
  7. NELSON LM. Primary Ovarian Insufficiency N Engl J Med [online] 2009 Feb 5, 360(6):606-614 [viewed 14 September 2014] Available from: doi:10.1056/NEJMcp0808697

Examination

Fact Explanation
Dry skin, depression, memory loss Due to oestrogen deficiency. [3]
Wide carrying angle, shield chest, low-set ears, low hair line, short stature etc. Turner’s syndrome is a recognized cause of ovarian dysfunction. [1]
Goiter, exophthalmos, bradycardia or tachycardia, cold-and-dry or soft-and-warm skin. Autoimmune thyroid disorders, may associated with ovarian dysfunction. [1]
Vitiligo, premature graying of hair, nail dystrophy and mucocutaneous candidiasis and alopecia Autoimmune diseases may be associated with ovarian failure. [3]
Pelvic examination Atrophic vaginitis is evident on pelvic examination due to the lack of oestrogen. Occasionally there can be enlarged ovaries due to the immune [3] oophoritis.
Orthostatic hypotension Skin hyperpigmentation Adrenal insufficiency, and Addison disease, causes ovarian failure. [4]
Mental retardation [3] Mental retardation suggests Fragile X syndrome. [2]
References
  1. PENEFSKY HS. Mechanism of inhibition of mitochondrial adenosine triphosphatase by dicyclohexylcarbodiimide and oligomycin: relationship to ATP synthesis. Proc Natl Acad Sci U S A [online] 1985 Mar, 82(6):1589-1593 [viewed 24 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC397317
  2. MURRAY A, ENNIS S, MORTON N. No Evidence for Parent of Origin Influencing Premature Ovarian Failure in Fragile X Premutation Carriers Am J Hum Genet [online] 2000 Jul, 67(1):253-254 [viewed 26 August 2014] Available from: doi:10.1086/302963
  3. NELSON LM. Primary Ovarian Insufficiency N Engl J Med [online] 2009 Feb 5, 360(6):606-614 [viewed 14 September 2014] Available from: doi:10.1056/NEJMcp0808697
  4. MANIPADAM MT, ABRAHAM R, SEN S, SIMON A. Primary pigmented nodular adrenocortical disease J Indian Assoc Pediatr Surg [online] 2011, 16(4):160-162 [viewed 15 September 2014] Available from: doi:10.4103/0971-9261.86881

Differential Diagnoses

Fact Explanation
Pregnancy Pregnancy should be excluded in people with period of amenorrhoea. They may have other features suggestive of pregnancy such as nausea, vomiting [5] , urinary frequency and faintishness. Urine or serum beta hCG needs to be done in a suspicious conditions.
Use of contraceptive methods Contraceptives that contain oestrogen and progesterone alone or in combination will cause amenorrhoea. [6]
Premature ovarian failure [2] This is a heterogeneous disorder leading to ovarian failure before the age of 40 years and causes secondary amenorrhea. [1] Low Levels of gonadal hormones (estrogens and inhibins) will be low and level of gonadotropins luteinizing hormone (LH) and Follicle stimulating hormone (FSH)] are usually increased.
Resistant ovary syndrome There is normal development of the secondary sexual characteristics with primary amenorrhoea. There is an entity called resistant ovarian syndrome where there is a high level of gonadotrophins with lack of response to exogenous gonadotrophins with normal primordial follicles. [3]
Hypothalamic-pituitary disease Pituitary tumors, hyperprolactinemia, Kallmann syndrome, high prolactin (PRL) will present in association with low/normal gonadotropin levels, alterations at imaging of brain/sella region. [4] Hypothalamic amenorrheamay also be due to the stress, intensive exercise, anorexia, weight loss, fasting, severe diseases. [4]
Gonadal dysgenesis Most common cause of gonadal dysgenesis is Turner's syndrome. Features of Turner's syndrome includes wide carrying angle, shield chest, low-set ears, low hair line, short stature etc. associated with streak ovaries on ultrasound scan. [3] There are other varieties of gonadal dysgenesis with normal XX and XY complement and they usually have normal stature with streaky ovaries.
References
  1. PENEFSKY HS. Mechanism of inhibition of mitochondrial adenosine triphosphatase by dicyclohexylcarbodiimide and oligomycin: relationship to ATP synthesis. Proc Natl Acad Sci U S A [online] 1985 Mar, 82(6):1589-1593 [viewed 24 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC397317
  2. SOAVE I, LO MONTE G, MARCI R. POI: Premature Ovarian Insufficiency/Pregnancy or Infertility? N Am J Med Sci [online] 2013 Jan, 5(1):71 [viewed 24 August 2014] Available from: doi:10.4103/1947-2714.106217
  3. JEWELEWICZ R, SCHWARTZ M. Premature ovarian failure. Bull N Y Acad Med [online] 1986 Apr, 62(3):219-236 [viewed 26 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1629109
  4. BECK-PECCOZ P, PERSANI L. Premature ovarian failure Orphanet J Rare Dis [online] :9 [viewed 26 August 2014] Available from: doi:10.1186/1750-1172-1-9
  5. AID-AHMED K, MOUSTAFA G, FAWZY M. Incidence and Natural Course of Symptomatic Central Serous Chorioretinopathy in Pregnant Women in a Maternity Hospital in Kuwait Middle East Afr J Ophthalmol [online] 2012, 19(3):273-276 [viewed 13 September 2014] Available from: doi:10.4103/0974-9233.97920
  6. SHEARMAN RP. Post-pill amenorrhoea. Br Med J [online] 1977 Nov 26, 2(6099):1414 [viewed 13 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1632379

Investigations - for Diagnosis

Fact Explanation
LH and FSH levels LH:FSH ratio is usually increaed (LH/FSH ratio >2:1) in polycystic ovarian disease. FSH level is usually > 40 mUI/mL in premature ovarian failure. [2] There is an entity called resistant ovarian syndrome where there is a high level of gonadotrophins with lack of response to exogenous gonadotrophins with normal primordial follicles. [3]
Day 21 day progesterone levels This is done on day 21 of menstrual cycle. Usually progesterone are elevated in the luteal phase of the cycle following ovulation. Estradiol (E2)level would be < 40 pg/mL in premature ovarian failure. [4]
Anti- Mullerian hormone (AMH) This is a new diagnostic method for premature ovarian failure. It is produced by antral follicles and secretion is decreased in these patients. [1]
References
  1. PENEFSKY HS. Mechanism of inhibition of mitochondrial adenosine triphosphatase by dicyclohexylcarbodiimide and oligomycin: relationship to ATP synthesis. Proc Natl Acad Sci U S A [online] 1985 Mar, 82(6):1589-1593 [viewed 24 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC397317
  2. BENTLEY-LEWIS R, SEELY E, DUNAIF A. Ovarian Hypertension: Polycystic Ovary Syndrome Endocrinol Metab Clin North Am [online] 2011 Jun, 40(2):433-x [viewed 24 August 2014] Available from: doi:10.1016/j.ecl.2011.01.009
  3. JEWELEWICZ R, SCHWARTZ M. Premature ovarian failure. Bull N Y Acad Med [online] 1986 Apr, 62(3):219-236 [viewed 26 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1629109
  4. QUAAS A, DOKRAS A. Diagnosis and Treatment of Unexplained Infertility Rev Obstet Gynecol [online] 2008, 1(2):69-76 [viewed 13 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2505167

Investigations - Fitness for Management

Fact Explanation
Ultrasound scan Occasionally vaginal/uterus anatomical abnormalities, such as Rokitanski syndrome or Asherman syndrome may present with amenorrhoea. [1]
References
  1. BECK-PECCOZ P, PERSANI L. Premature ovarian failure Orphanet J Rare Dis [online] :9 [viewed 26 August 2014] Available from: doi:10.1186/1750-1172-1-9

Investigations - Followup

Fact Explanation
DEXA scan Assessment of changes of bone mineral density (BMD) is required as estrogen deficiency lowers intestinal absorption of calcium and leads to osteoporosis. [1]
References
  1. BECK-PECCOZ P, PERSANI L. Premature ovarian failure Orphanet J Rare Dis [online] :9 [viewed 26 August 2014] Available from: doi:10.1186/1750-1172-1-9

Investigations - Screening/Staging

Fact Explanation
Anti-adrenal, anti-ovarian and anti-thyroid autoantibodies Important to diagnose the immune system deficiency leading to premature ovarian failure. [1,3]
Karyotyping Important to exclude major genetic causes. [1,2] Fragile X syndrome is due to CGG expansion (>55 repeats) at the 5'UTR of FMR1 gene. [4]
Thyroid stimulating hormone Hypothyroidism may be a cause for the ovarian dysfunction. [5]
Adrenocorticotropic hormone (ACTH) levels. Enzymatic defects of steroidogenesis (e.g. 21-hydroxylase deficiency)may present with normal gonadotropin, high androgen and ACTH levels. [4]
References
  1. PENEFSKY HS. Mechanism of inhibition of mitochondrial adenosine triphosphatase by dicyclohexylcarbodiimide and oligomycin: relationship to ATP synthesis. Proc Natl Acad Sci U S A [online] 1985 Mar, 82(6):1589-1593 [viewed 24 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC397317
  2. MURRAY A, ENNIS S, MORTON N. No Evidence for Parent of Origin Influencing Premature Ovarian Failure in Fragile X Premutation Carriers Am J Hum Genet [online] 2000 Jul, 67(1):253-254 [viewed 26 August 2014] Available from: doi:10.1086/302963
  3. WHEATCROFT NJ, TOOGOOD AA, LI TC, COOKE ID, WEETMAN AP. Detection of antibodies to ovarian antigens in women with premature ovarian failure. Clin Exp Immunol [online] 1994 Apr, 96(1):122-128 [viewed 26 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1534534
  4. BECK-PECCOZ P, PERSANI L. Premature ovarian failure Orphanet J Rare Dis [online] :9 [viewed 26 August 2014] Available from: doi:10.1186/1750-1172-1-9
  5. SEPPăLă M, HIBROVEN E, RANTA T, VIRKKUNEN P, LEPPăLUOTO J. Raised serum prolactin levels in amenorrhoea. Br Med J [online] 1975 May 10, 2(5966):305-306 [viewed 13 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1681912

Management - General Measures

Fact Explanation
Psychological support [1] Patients may be suffering from problems such as subfertllity, that may need psuchological support.[1]
Genetic screening for high risk groups When there is a family history of same problem, it is better to do the genetic investigationsas it is useful for the early diagnosis of genetic defects causing ovarian failure. [2]
Genetic conselling Genetic concelling is important in families with X-linked mental retardation (Fragile X syndrome) . [2]
Diet Balanced diet with adequate amounts of nutrition with a special focus on the calcium is important to prevent osteoporosis. Lowered estrogen concentration has an impact on calcium absorption. Estrogen deficiency lowers intestinal absorption of calcium. Supplementation with 1000 mg of calcium and 400 IU of vitamin D is required when needed. [3]
References
  1. PENEFSKY HS. Mechanism of inhibition of mitochondrial adenosine triphosphatase by dicyclohexylcarbodiimide and oligomycin: relationship to ATP synthesis. Proc Natl Acad Sci U S A [online] 1985 Mar, 82(6):1589-1593 [viewed 24 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC397317
  2. BECK-PECCOZ P, PERSANI L. Premature ovarian failure Orphanet J Rare Dis [online] :9 [viewed 26 August 2014] Available from: doi:10.1186/1750-1172-1-9
  3. GOONERATNE P. Commentary on guidelines on postmenopausal osteoporosis - Indian Menopause Society J Midlife Health [online] 2013, 4(2):133-135 [viewed 26 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785154

Management - Specific Treatments

Fact Explanation
Management of subfertility Fertility cannot be may not be returned to normal in a case of complete follicular depletion. If it is, diagnosed early by genetic investigation early conception or oocyte harvesting and preservation is advised. Intrauterine insemination (IUI) cycles, and in vitro fertilization (IVF) cycles are particularly useful in people with ovarian failure. [1] Option for the absent follicular reserve is ovum donation. [3] Ovulation can be induced where needed using various methods such as clomiphine citrate, FSH, and ovarian drilling.
The hormone replacement therapy (HRT) This is used for the management for premature ovarian failure patients. It is indicated to relieve vasomotor symptoms, to improve urogenital symptoms and to prevent osteoporosis. Usually it is contraindicated if there is a history of breast, endometrial cancer, porphyria, severe active liver disease, thromboembolic disorders, hypertriglyceridemia, undiagnosed vaginal bleeding and endometriosis. Estrogen replacement decrease the risk of osteoporosis and cardiovascular disease. [2]
References
  1. NDEFO UA, EATON A, GREEN MR. Polycystic Ovary Syndrome: A Review of Treatment Options With a Focus on Pharmacological Approaches P T [online] 2013 Jun, 38(6):336-355 [viewed 24 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737989
  2. PENEFSKY HS. Mechanism of inhibition of mitochondrial adenosine triphosphatase by dicyclohexylcarbodiimide and oligomycin: relationship to ATP synthesis. Proc Natl Acad Sci U S A [online] 1985 Mar, 82(6):1589-1593 [viewed 24 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC397317
  3. BECK-PECCOZ P, PERSANI L. Premature ovarian failure Orphanet J Rare Dis [online] :9 [viewed 26 August 2014] Available from: doi:10.1186/1750-1172-1-9