Dr Surveen Ghumman MD Specialist Vardhaman Mahavir Medical College & Safdarjang Hospital, Delhi

Premature

ovarian failure ( POF) Primary ovarian insufficiency Premature menopause Early menopause
POF is a condition characterized by amenorrhea, hypoestrogenism, and elevated serum gonadotropin levels in women younger than 40 years.

4 % of women 1 case per 1000 women by age 30, 1 case per 250 women by age 35 1 case per 100 women by age 40. Primary amenorrhea - 10-28% of women Secondary amenorrhea - 4-18% of women

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Induced (iatrogenic) POF/POI Spontaneous POF/POI Cause usually unknown

Two Mechanisms

Follicular Depletion
Decreased germ cell migration Accelerated atretic process Acquired ovarian disease

Follicular Dysfunction

IATROGENIC

IDIOPATHIC

GENETIC

ETIOLOGY

INFECTIOUS

ENVIRONMENTAL

AUTOIMMUNE

 Irradiation
Chemotherapy Occupational

exposure Pelvic surgery Smoking Increased use of gonadotrophic stimulation

Ovarian follicle depletion

Low initial follicle number Pure gonadal dysgenesis Thymic aplasia/hypoplasia Idiopathic Accelerated follicle atresia X chromosome related (Turner syndrome, X chromosome deletions and translocations) Galactosemia Fragile mental retardation 1 (FMR1) gene premutation Viral oophoritis Autoimmunity Environmental toxins Iatrogenic Idiopathic

Ovarian follicle dysfunction

Steroidogenic enzyme defects 17-alpha-hydroxylase deficiency 17-20-desmolase deficiency Aromatase enzyme deficiency Autoimmunity Lymphocytic oophoritis with positive adrenal antibodies/Addison disease Gonadotropin receptor antibodies Signal defects Abnormal gonadotropin receptor Abnormality in the G-protein signaling pathway Specific genetic defects (blepharophimosis-epicanthus-ptosis syndrome) Idiopathic (resistant ovary syndrome)

Last spontaneous menstrual cycle Prior pelvic surgeries, irradiation, or chemotherapy Symptoms of adrenal insufficiency: Orthostatic hypotension Skin hyperpigmentation Unexplained weakness Salt craving Abdominal pain Anorexia Symptoms of hypothyroidism Family history of POF, male mental retardation, autoimmune disorders Symptoms of estrogen deprivation

Signs of hypoestrogenism Enlarged ovaries versus nonpalpable ovaries Physical stigmata of Turner syndrome/other genetic syndromes: Short stature Webbed neck Low position of the ears Low posterior hairline Cubitus valgus Shield chest Short IV and V metacarpals Signs of autoimmune diseases, Addison disease, and hypothyroidism

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Tests to establish the diagnosis of POF/POI, Tests that help clarify the etiology, Screening tests for other diseases known to have higher prevalence among women with POF/POI. Tests to establish effect of POF
Pregnancy test FSH , LH, estradiol (FSH value - over 40 mIU/ml on at least two occasions over a four weeks period) Standard blood chemistry - Fasting glucose, electrolytes, creatinine Karyotype Test for fragile X chromosome (FMR1 premutation) Bone density by dual-energy x-ray absorptiometry (DEXA) scan USG ovary

Haemogram ESR Se Electrolytes, calcium, phosphate, serum protein Serum cortisol ANA, rheumatoid factor Ovarian antibody Thyroid-stimulating hormone (TSH) Antithyroid peroxidase antibody Serum adrenal antibodies Blood sugars ( Fasting and postprandial)

Short term

Vascular symptoms like hot flushes, night sweats, Headaches Vaginal dryness Dyspareunea Urgency and stress urinary incontinence Irritability Forgetfulness Poor concentration Insomnia

Long term

Infertility Osteoporosis Cardiovascular disease Stroke Psychological Impact - Depression

Pregnancy Secondary ovarian insufficiency/failure due to the following: Eating disorder Extreme physical exercise Prolactinoma and other conditions causing hyperprolactinemia Pituitary and hypothalamic tumors Hypothalamic and pituitary infiltrative and inflammatory processes Pituitary hemorrhage Systemic diseases, including other endocrine disorders Medications Hyperandrogenic conditions due to the following: Polycystic ovarian syndrome Congenital adrenal hyperplasia Ovarian or adrenal androgen-producing tumors Ovarian hyperthecosis Outflow tract abnormalities Pseudo premature ovarian failure due to the following: Gonadotropin-producing pituitary adenoma Antibodies to gonadotropins

Hormone replacement therapy (HRT)

Cyclical HRT with estrogens and progestins to relieve the symptoms of estrogen deficiency and to maintain bone density.

Estrogens

Estrogens can be administered orally or transdermally. Higher doses than those for post menopausal women may be needed to achieve adequate estrogenization of the vaginal epithelium in young women and help maintain age-appropriate bone density. The estrogens can be administered continuously or cyclically. Estrogen replacement therapy does not prevent ovulation and conception in these patients

Progestins Cyclically, 10-14 days each month, to prevent endometrial hyperplasia If an expected withdrawal bleeding is missing, a pregnancy test should be performed. 5-10% chance of spontaneous pregnancy The recommended regimens Medroxyprogesterone 10 mg daily for 10-12 days each month or Micronized progesterone 200 mg daily for 10-12 days each month. Androgens 13% have levels below normal. Given for short periods. Androgen replacement could be carefully considered for women with Addisons disease Persistent fatigue, Low libido, Poor well being despite adequate estrogen replacement Available medications include oral methyl testosterone 1.25-2.5 mg/d, injectable testosterone esters 50 mg every 6 weeks intramuscularly, testosterone implants

Steroids for autoimmune POF not indicated as high doses needed lead to side effects like osteonecrosis. Unproven treatments to restore fertility should be avoided Gonadotropin therapy carries a theoretical risk of exacerbating autoimmune POF ART

Oocyte donation Embryo adoption Surrogacy Ovarian cryopreservation in Iatrogenic POF

Adoption

 Endocrinologist

consultation may be indicated for hypothyroidism or adrenal insufficiency. evaluation and counseling.

Psychological Genetic Referral

counseling may be needed in some.

for eye care if symptoms of dry eye.

Diet Elemental Calcium : 1200-1500 mg day. Adequate intake of vitamin D.

Activity Weight-bearing exercises for 30 minutes per day, at least 3 days per week, to improve muscle strength and maintain bone mass. Participation in outdoor sports is strongly recommended.

 Women

with POF/POI should be educated on the nature of their disease and the current research efforts. The mere understanding of the problem helps patients cope better.
Web sites are available International Premature Ovarian Failure Association

Support

Annual followup to
Monitor HRT. Symptoms and signs of thyroid disease and adrenal insufficiency .

TSH levels - checked every 3-5 years (every year if antiperoxidase antibody test is positive).
Adrenal antibodies positive on her initial evaluation, even if all adrenal function tests normal - annual ACTH stimulation test. Adrenal antibody tests negative still continue to carry higher than normal risk for adrenal insufficiency - adrenal antibody test performed every 3-5 years.

Patients with secondary ovarian failure should be monitored for manifestations of the underlying hypothalamic/pituitary pathology (progression of space-occupying lesions and development/progression of hypopituitarism).

POF is a challenging issue as women are delaying having families and this emotionally distressing problem must be dealt, on both the physical and psychological platform.

Thank You

 DR.Maninder

Ahuja Chairperson Geriatric Gynecology committee Author : Dr.surveen Ghuman Thanks to all those who would carry this torch further.