Premature Menopause: Clinical Significance and Therapeutic Options

MENOPAUPSErematu ANrDRe Menopause:OPAUSE Clinical Significance and therapeutic Options 61 PREMATURE MENOPAUSE: CLINICAL SIGNIFICANCE AND THERAPEUTIC OPTIONS F. FISCHL When we use the term “premature 3. Postnatal destruction of germ cells in menopause” or climacterium praecox, the ovaries we mean cessation of the normal cyclic ovarian function prior to the age of 40. However, this does not explain those Some authors have defined the limit at cases in which there are still numerous an even earlier age, namely 35 and in follicles present, so that other causes, some cases even 30 [1]. Especially in possibly in connection with control of young women, speaking of a prema the gonadotropin effect on the follicles, ture menopause often causes problems are probable. for psychological reasons. The thought Premature failure of the ovarian of being menopausal at such an early function is characterized by amenor age produces worries and fears in rhea, increased gonadotropin secretion many of the patients, especially if they (especially FSH), low estradiol level, still want children. Since a premature and clinical, climacteric symptoms of menopause may sometimes be tran varying severity. Characteristically, the sient, it is probably more acceptable to increased FSH values are between > 30 the younger patients if the term “hyper and > 40 mIU/ml, depending on the gonadotropic amenorrhea” is used. measurement standard applied. The The occurrence of premature ovar loss of oocytes or follicles, to which the ian failure was described as early as gonadotropins react, must probably be 1920 [2]. In 1950, Arias [3] published viewed as the most significant factor. In 20 cases and in 1957 Perlhoff and literature, the incidence of premature Schneeberg [4] published 27 cases of menopause is very divergent and lies younger women with a premature cli between 0.3 and 10% [8, 9]. Possible macterium and increased gonadotro causes of hypergonadotropic amenor pin excretion. In 1965, Kinch et al. [5] rhea and premature menopause are reported on an afollicular and a listed in Table 1. follicular form of premature ovarian insufficiency. Aiman and Smentek [6] reported that 18% of 157 women with ovarian biopsies had intact oocytes. GENETIC AND CYTOGENETIC CAUSES Other authors reported a similar rate [7]. In 1967, De Moraes-Ruehsen and Tones [8] published three possible Numerous papers have described an causes of premature menopause: increased familial incidence of prema 1. Reduced number of germ cells at the ture menopause that indicates an auto time of birth somally dominant, sex-related hered 2. Acceleration of the normally con ity. This also includes women with stant follicular atresia processes dystrophic myotonia. In order to have a 62 Premature Menopause: Clinical Significance and therapeutic Options normal number of oocytes, two intact X these enzyme deficiencies frequently chromosomes are necessary, i.e. a suffer from premature hypergonado normal female set of chromosomes. If tropic amenorrhea [10]. one X chromosome is missing, the re sult is rapid atresia of the oocytes, as found in the 45/X syndrome (Turner’s syndrome). Structural anomalies of the IMMUNOLOGICAL CAUSES X chromosome may also be a cause of premature ovarian failure. An addi tional X chromosome can also lead to A number of autoimmune processes premature menopause [10]. are associated with hypergonadotropic amenorrhea. Thereby, it must be noted that this condition may normalize again, and that pregnancies are possi ENZYME DEFECTS ble. Table 2 shows numerous possible autoimmune disorders. Autoimmune phenomena as the These include 17α-hydroxylase defi cause of premature ovarian failure ciency and galactosemia. Women with have been described in rodents [1]. This may be induced by exstirpation of the thymus. In humans, there have Table 1. Possible causes of hypergonadotropic been reports of girls with congenital amenorrhea and premature menopause [8] athymia with ovaries without oocytes 1. Genetic and cytogenetic causes – Familial premature menopause – Structural X chromosomes Table 2. Possible autoimmune disorders that – Anomaly or lack of the same could cause hypergonadotropic amenorrhea – Trisomy X with and without mosaic and premature menopause [8] – In conjunction with dystrophic myotonia 2. Enzyme defects α Acquired hemolytic and pernicious anemia –17 -hydroxylase deficiency Asthma – Galactosemia Chronic active hepatitis 3. Immunological causes Crohn’s disease – In conjunction with autoimmune Diabetes mellitus disorders Glomerulonephritis (including L.E., Hashimoto’s thyroiditis) Addison’s disease – Isolated Hypoparathyroidism – Congenital thymus aplasia Hypophysitis Idiopathic thrombocytopenic purpura 4. Defects in the gonadotropin structure Juvenile rheumatoid arthritis and effect Ceratoconjunctivitis and Sjögren’s syndrome – Secretion of biologically inactive Malabsorption syndrome gonadotropins Myasthenia gravis – α- and β-chain defects Polyendocrinopathy (Type I, Type II and un – Gonadotropin and post-receptor defects specific) – Circulating FSH-binding inhibitors Primary biliary cirrhosis Quantitative immune globulin anomalies 5. Iatrogenic damage Rheumatoid arthritis – Operative Systemic lupus erythematodes (SLE) – Radiation therapy Thyroid disorders, including Grave’s disease – Chemotherapy and thyroiditis Viral infections Vitiligo Smoking Alopecia Premature Menopause: Clinical Significance and therapeutic Options 63 [1]. In a part of the women with pre tion of the ovarian function [1, 11], mature menopause, circulating anti e.g. one report on a patient with corti ovarian antibodies have been found. In coid therapy for adrenal insufficiency, the ovaries themselves, perifollicular which resulted in normalization of the lymphocyte accumulation is regarded gonadotropin level [12]. as an indication of destruction due to autoimmune processes [1, 10]. Early ovarian failure in combination with multiple other malfunctions has been IATROGENIC DAMAGE reported fairly often, e.g. in Addison’s disease, hypoparathyroidism and Hashi moto’s thyroiditis [1, 10]. About 50% of women exposed to ra Alper and Garner [9] conclude that diation of the ovaries with 500–600 such an autoimmune disorder is in Rad for a period of 4–6 weeks develop volved in 30 to 50% of cases of pre a permanent secondary hypergonado mature menopause. A cytotoxic effect of tropic amenorrhea. A dose of 800 Rad the serum of these patients on human appears to cause ovarian failure in all granulosa cells has been demonstrated women. The older the women are, the in cultures. The autoimmune basis of more destructive the effect of radiation premature menopause would appear to on the function of the ovaries is. Chemo be heterogeneous, however, since dif therapy agents also have a destructive ferent endocrinological disorders may and usually irreversible effect on the or may not be associated. Auto-sensi ovaries. Alkalizing substances, espe tization to mutual antigens on the cell cially cyclophosphamide, inhibit the surface could explain why various ovarian function. The principle that glands are affected. In some cases, an these negative effects on ovarian func association between chronic mycosis tion increase with increasing age ap of the genital tract and premature ova plies here, too [10]. rian failure has been described. More Viral infections also appear to have over, a premature loss of function of the negative effects on ovarian function, ovary in diabetes mellitus, myasthenia e.g. in the form of mumps oophoritis. gravis and pernicious anemia has been Smoking also has a negative influence described [1]. It is assumed that even on the duration of ovarian function. an isolated failure of the ovary function This effect depends both on the inten on an autoimmune basis may occur. sity and the duration of the smoking Autoimmunity to steroid-producing habit, and it has been shown that the gonadal cells appears to be rare in pa menopause occurs about 2–3 years tients with premature menopause with earlier on average in women who are out Addison’s disease, however. heavy smokers [10]. Early detection and understanding of the autoimmune processes leading to premature ovarian failure are important in order to start therapy at as early a DIAGNOSTICS AND DIFFERENTIAL stage as possible. This has been con firmed repeatedly in reports on suc DIAGNOSIS cessful treatment with corticoids and plasmapheresis in other autoimmune The diagnostic and differential diagnos disorders, which has led to normaliza tic considerations are summarized in 64 Premature Menopause: Clinical Significance and therapeutic Options Table 3. In addition to blood tests and hormonal contraceptives, the rate was hormone controls, an adequate biopsy 95%, in the ovaries of postmenopausal of the ovaries and detailed histological women it was only 5%, and in women examination of the material are prereq with Turner’s syndrome it was 0%. The uisite for a differential diagnosis of the number of follicles was significantly possible cause. lower in women with premature meno- Mehta et al. [13] investigated the pause than in women taking hormonal extent to which an ultrasound scan of contraceptives. Women with prema the ovaries can provide such a diagno ture menopause and follicles had a sis. In 17 women with premature meno- larger ovary volume than women with pause, at least one ovary was displayed premature menopause without folli by ultrasound, in women taking ovula cles. However, there was no difference tion inhibitors the rate was 95%,

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