ISHITA GANGULY MD,DNB

FELLOW REPRODUCTIVE MEDICINE,
Bangalore
Dr. Patil’s Fertility and Endoscopy Clinic ,
Bangalore

PREMATURE OVARIAN FAILURE

Definition:
Premature ovarian failure (POF) describes a syndrome consisting of amenorrhea, sex steroid deficiency and elevated/menopausal levels of gonadotropins in a woman aged more than two standard deviations below the mean estimated for the reference population.[1] However, the term is generally applied for women with
(1) amenorrhea of 3 or more months’ duration
(2) age under 40 years at the onset of the amenorrhea
(3) circulating FSH of more than 40 mlU/ml on at least two occasions.
Incidence:
It is estimated to affect approximately 1% of women under 40 years of age, 0.1% of women under 30 years of age, and 0.01% of women under 20 years of age.[2]
However, as cure rates of cancers in childhood and young women continue to improve, it is likely that the incidence of prematurely menopausal women will rise rapidly.[3] and [4]
Nomenclature: Alternative terms used include ‘hypergonadotropic hypogonadism’ and ‘premature menopause’. The other preferred term for this condition is primary ovarian insufficiency (POI), as first introduced by Fuller Albright in 1942. However, POF is not necessarily an early menopause & that’s because unlike the menopause which denotes an irreversible condition, marked by the last menses, the cessation of ovarian function in POF is not always permanent.[5]
The term “Premature Ovarian Dysfunction” (POD) can be preferred over the term “Premature ovarian failure” (POF) to reflect the reversible nature of this condition, and avoid the negative connotation that comes with failure. Unlike the menopause, 50% of young women with spontaneous POF experience intermittent and unpredictable ovarian function and spontaneous pregnancies have been reported in approximately 5–10% of cases subsequent to the diagnosis.
However, until a consensus is reached POF will continue to be used for now

Classification:
POF can be:
Primary (spontaneous POF) or
Secondary (induced by radiation, chemotherapy or surgery).

Pathogenesis:
The pathogenesis of spontaneous POF/POI in most cases is unknown. Two mechanisms are presumed to play a role—follicle depletion and follicle dysfunction.
1. Ovarian follicle depletion
A. Low initial follicle number
a. Pure gonadal dysgenesis
b. Gonadal dysgenesis due to autosomal abnormalities
c. Thymic aplasia/hypoplasia
B. Accelerated follicle atresia
a. X chromosome related (Turner syndrome, X chromosome deletions and translocations)
b. Fragile mental retardation 1 (FMR1) gene permutation
c. Specific gene abnormalities – Galactosemia
d. Iatrogenic
e. Environmental toxins
f. Idiopathic
g. Viral oophoritis (theoretical possibility that has not been proven)
h. Autoimmunity (theoretical possibility that has not been proven)

2. Ovarian follicle dysfunction
A. Steroidogenic enzyme defects
a. 17-alpha-hydroxylase deficiency
b. 17-20-desmolase deficiency and Aromatase enzyme deficiency
B. Specific genetic defects (blepharophimosis-epicanthus-ptosis syndrome)
C. Signal defects
a. Abnormal gonadotropin receptor
b. Abnormality in the G-protein signaling pathway
c. Pseudohypoparathyroidism
d. Defects in gonadotrophin synthesis
e. Defects in the gonadotrophin structure or action
D. Autoimmunity
a. Lymphocytic oophoritis with positive adrenal antibodies/Addison disease (steroid hormone–producing cell autoimmunity)
b. Gonadotropin receptor antibodies
c. Congenital thymic aplasia
E. Infection
F. Idiopathic (resistant ovary syndrome)

1. Follicle depletion
Follicle depletion is a major pathogenetic mechanism for development of POF/POI. The presence of normal numbers of follicles in the ovaries (approximately 300,000-400,000 at the beginning of puberty) is crucial for normal periodic ovulation. Full maturation of one dominant follicle is dependent on the simultaneous development of a support cohort of non-dominant follicles. These, although destined to undergo atresia, play an important role in the fine-tuning of the hypothalamic-pituitary-ovarian axis by secreting regulatory hormones such as estradiol, inhibins, activins, and androgens.
Pathological conditions that cause depletion or a reduction of the follicle number may lead to a disruption of the highly coordinated process of follicular growth and ovulation. The lack of developing follicles leads to reduced circulating estradiol and inhibin B levels and elevated serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Occasionally, a “lonely” follicle may develop, stimulated by the high levels of FSH; however, instead of progressing to a normal ovulation, it is inappropriately luteinized (by the high LH levels) and may persist as a cystic structure visible on ultrasonography.