© Borgis - Postępy Nauk Medycznych 12/2016, s. 903-909
*Katarzyna Jankowska, Magdalena Kochman
Endocrine causes of infertility
Endokrynologiczne przyczyny niepłodności
Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw
Head of Department: Professor Wojciech Zgliczyński, MD, PhD
Zaburzenia płodności stanowią narastający problem zdrowotny. Powinny być one rozważane zawsze w odniesieniu do obojga partnerów, gdyż dotyczą one w podobnym stopniu kobiet i mężczyzn. Prawidłowy rozwój i funkcjonowanie narządów rodnych kobiety i mężczyzny, procesy tworzenia i rozwoju komórek jajowych i plemników oraz poczęcia dziecka i utrzymania ciąży zależą od współdziałania szeregu czynników, w tym hormonów. Działanie jajników i jąder jest ściśle związane z czynnością innych gruczołów wydzielania wewnętrznego. Dlatego też niepłodność może być skutkiem nieprawidłowego funkcjonowania przysadki, tarczycy czy nadnerczy. W artykule omówiono najczęstsze przyczyny pierwotnej niedoczynności gonad oraz zaburzenia czynności podwzgórza i przysadki prowadzące do hipogonadyzmu, ze szczególnym uwzględnieniem niedoboru gonadotropin i hiperprolaktynemii. Szczególną uwagę zwrócono na endokrynne skutki zaburzeń odżywiania prowadzące do upośledzenia płodności. Omówiono także wpływ na płodność chorób tarczycy i nadnerczy oraz zaburzeń hormonalnych związanych z zespołem policystycznych jajników. Zwrócono uwagę na diagnostykę poszczególnych jednostek chorobowych i ich leczenie w kontekście optymalizacji zdolności prokreacyjnych pacjenta.
Impairment of fertility is a growing health problem. It should be always considered in relation to both partners, as it affects to a similar extent women and men. Proper development and function of male and female reproductive organs, the processes of egg cell and sperma formation and development as well as of conception and pregnancy maintenance depend on interaction of a number of factors, including hormones. Functioning of ovaries and testes is closely related to the activity of other endocrine glands. Therefore, infertility can be the result of a malfunction of the pituitary, thyroid or adrenals. The article discusses the most common causes of primary hypogonadism as well as hypothalamic and pituitary dysfunctions leading to hypogonadism, in particular gonadotropin deficiency and hyperprolactinemia. Special attention was paid to the endocrine effects of eating disorders, which result in impaired fertility. We also discussed the impact on fertility of the thyroid and adrenal diseases as well as hormonal disorders associated with polycystic ovary syndrome. Attention was paid to diagnosis and treatment of each disease in the context of optimization the patient’s procreative capacity.
According to World Health Organization infertility is a disease (ICD-10 code for female infertility is N97 and for male infertility – N46). It can be diagnosed when there is “the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse” (1). Therefore, the diagnostic procedures should start after 12 months of unsuccessful efforts to bear a child. From the beginning, it should concern both partners. From the beginning, it should concern both partners, as of infertility cases:
– 30% are due to a problem in the woman,
– 30% – in the man,
– 20% – both in the woman and in the man,
– and 20% remain unexplained (idiopathic).
To conceive and maintain a pregnancy, there is needed not only healthy sperm and healthy egg, properly built and functioning female and male genital organs, but also correct functioning of a number of factors, including hormones, to allow the embryo to nest in the uterine cavity, to be properly nourished, oxygenated, and tolerated by the maternal immune system.
It is crucial to differentiate inability to get pregnant (sterilitas) from inability to maintain pregnancy (infertilitas), usually manifested by recurrent miscarriages.
Recurrent miscarriages are defined as consecutive two or more spontaneous abortions (i.e., terminations of pregnancies prior to 20 weeks). They are mainly due to woman’s health problems. The most common causes are chromosomal abnormalities of egg, sperm or embryo. The probability of an egg cell aneuploidy increases with maternal age. Recurrent miscarriages may be also caused by endocrinopathies (thyroid diseases, PCOS, diabetes, corpus luteum insufficiency), as well as anatomical defects of the uterus, infections (especially Mycoplasma, Ureaplasma, Chlamydia), immunological (systemic lupus erythematosus, antiphospholipid syndrome) or hematologic disorders (thrombophilia). The relationship was also shown between recurrent miscarriages and excessive consumption of caffeine, alcohol and cigarette smoking (2, 3).
Nowadays more and more often the state of reduced fertility (subfertility) is observed, caused mainly by aging. Postponing parenthood “for later” further increases the risk of occurrence of chronic diseases, that affect fertility, and often masks them when potential parents are not aware of them.
The article discusses some causes of infertility and miscarriages, focusing on endocrine disorders.
The most important factor affecting woman’s fertility is her age. It is an increasing problem (also a social problem), as the percentage of older women trying to conceive, rises. The function of ovaries is usually preserved until age of 40, afterward more and more cycles are anovulatory, the endocrine function of the ovary decreases and estradiol concentration in the luteal phase lowers. The symptoms of approaching menopause begin at about 47 years of age and last for about 4 years. The last period is usually between the age of 44 and 56, in Poland, statistically at 51.25 years of age (4). In men testosterone concentration may also decrease with age (late onset hypogonadism – LOH), but spermatogenesis remains preserved until senility. Reduced levels of estrogen in women and testosterone in men lead to increased pituitary gonadotropin secretion in a negative feedback mechanism (hypergonadotropic hypogonadism).
Premature ovarian failure, testicular failure
Premature ovarian failure (POF) can be diagnosed when, in a woman under 40 years of age, the concentration of FSH is above 40 IU/L twice at an interval of at least 4-6 weeks at low estradiol concentration and normal TSH and prolactin (PRL) levels. Ovarian reserve is reduced or falling to zero (low AMH – anti-Müllerian hormone level).
The cause of POF is unknown in 90% of cases. The ovarian injury may be the result of viral infections, smoking, and autoimmunity (5-9). POF may be a part of the autoimmune poliglandular syndrome (APS). Therefore, there is recommended screening for other potential autoimmune co-morbidities (Hashimoto’s thyroiditis, Addison’s disease, rheumatoid arthritis, systemic lupus erythematosus, Crohn’s disease, diabetes, celiac disease), including the determination of anti-ovarian antibodies, anti-thyroid peroxidase antibodies (a-TPO), anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti-tissue transglutaminase antibodies, or if need performing a colonoscopy (10, 11).
POF may be also the result of radio- or chemotherapy (tab. 1) as well as surgical treatment of ovaries or testes. In the case of radiotherapy, ovarian failure occurs at doses > 0.06 Gy, and spermatogenesis depletion at doses > 1.20 Gy (12, 13). Irreversible damage to the ovaries occurs at a dose of > 8 Gy, and to testicular Leydig cells at a dose of > 20 Gy (12, 13). There were no reports indicating an increase in the percentage of congenital malformations, perinatal disorders or cancer in naturally conceived children of fathers previously treated for cancer by chemo- or radiotherapy, however the risk may be greater using IVF and ICSI because of a possible damage to the DNA of germ cells and lack of selection of sperm with normal DNA. To reduce the risk, it is recommended a delay of at least 12-18 months from the cessation of treatment to attempt of pregnancy.
Tab. 1. Drugs used in chemotherapy and the probability of fertility impairment
|Probability of fertility impairment||Drugs|
|high||cyclophosphamide, melphalan, dacarbazine, busulfan, chlormethine (e.g. MOPP protocol)|
|middle||cisplatin, carboplatin, doxorubicin, BEP, ABVD|
|low||vincristine, methotrexate, bleomycin, mercaptopurine, vinblastine|
Premature ovarian failure occurs in several genetic disorders, such as Turner syndrome (45X0), fragile X syndrome (FMR1 gene), pseudohypoparathyroidism type 1a (GNAS1 gene), galactosemia, Fanconi anemia, Bloom syndrome, Werner syndrome. There were also described rare cases of POF of genetic cause (POF1-7) (14, 15). When POF occurs in a woman under 30 years of age, cytogenetic testing with karyotype analysis is recommended (16).
The chances of getting pregnant in these cases are negligible. For people undergoing chemotherapy or radiotherapy, cryopreservation of ovarian cortex in women and sperm in men is proposed prior to the oncologic treatment. Causal treatment should be applied, if possible. There were case reports of restoring of gonadal function after applying of gluten-free diet in women with celiac disease. There were also trials of dehydroandrostenedione (DHEA) supplementation in women with POF. It was shown, that DHEA therapy in some patients with POF increases the chances of getting pregnant, reduces the risk of miscarriage and improves the results of IVF in women with POF (9, 10). Therefore, it is recommended determine DHEA-S concentration in patients with POF. The use of melatonin in women with POF may be also considered, as it was shown, that this hormone regulates menstruation and gonadotropin concentrations in the perimenopausal period (19-24).
To prevent other health consequences of hypogonadism, hormone replacement therapy is used.
Hypergonadotropic hypogonadism in men should always be an indication to determine the karyotype, because the most frequent (often undiagnosed!) cause of it is Klinefelter syndrome. Subsequently, there should be done screening for causes of secondary testicular failure (tumor, inflammation, toxic damage of the testes, metabolic disorders).
Deficiency of pituitary gonadotropins (FSH and LH) leads to secondary ovaries/testes failure, manifested by menstrual disorders in women, erectile dysfunction in men, low libido, lack or loss of tertiary sexual characteristics with thinning or even lack of pubic and axillary hair as well as facial hair in men (19).
Hypogonadotropic hypogonadism (HH) may be caused by tumor, granulomatous or inflammatory diseases, as well as injuries or damage caused by ischemia, radiotherapy or chemotherapy of the area of hypothalamus or pituitary. Gonadotropin deficiency may also be genetically determined (e.g. Kallmann syndrome – an isolated GnRH deficiency, Pasqualini syndrome, GnRH-R mutations) or be the result of developmental disorders (e.g. empty sella syndrome, pituitary hypoplasia).
If the causal treatment is impossible, hormonal replacement therapy is used: sequential estrogen and progestins in women, and testosterone in men. It allows also to achieve normally developed sexual organs. To induce ovulation, a selective estrogen receptor modulator – clomiphene is used, and when this treatment is inefficient, gonadotropins or pulsatile gonadotropin-releasing hormone (GnRH) therapy are administered.
Spermatogenesis can be induced in men by clomiphene, gonadotropins or pulsatile GnRH treatment, however, it may require a long period of time (even up to 2 years).
Dysfunction of the hypothalamic-pituitary-gonadal axis
Impaired activation of the hypothalamic-pituitary-gonadal axis results in alterations of pulsatile GnRH secretion (usually reduced frequency and amplitude of GnRH pulses). In men, the effect is gonadotropin deficiency, which leads to reduction of testosterone secretion and disorders of spermatogenesis. In women, there is no gonadotropin surge, without which ovulation does not occur, or too low FSH and LH concentrations, which result in disturbances in maturation of Graafian follicles or luteal phase insufficiency.
Functional hypothalamic amenorrhea can be diagnosed when, in the absence of organic or anatomical disorders of the hypothalamic-pituitary-ovarian axis, LH and FSH values are within normal limits or are slightly reduced, and there are reduced estrogen concentrations in the second phase of the ovarian cycle (19). The GnRH test is useful in diagnosis. Functional HH is usually the result of negative energy balance, caused by excessive physical effort or significant weight loss, or mental stress (low leptin and kisspeptin concentrations lead to disturbances in GnRH secretion).
HH may be also secondary to chronic diseases: cancer, chronic gastrointestinal diseases causing malnutrition, liver diseases leading to its failure or chronic kidney disease.
Stress, excessive exercise
These factors increase the secretion of corticotropin releasing hormone (CRH) from the hypothalamus, which leads to increased concentrations of ACTH and cortisol. Hypercortisolism reduces the frequency of GnRH pulses. In females under the influence of prolonged stress (businesswomen) or excessive exercise (sportswomen) luteal phase insufficiency, anovulatory cycles, menstrual disorders, amenorrhea and infertility are often observed. In competitive athletes reduced leptin concentrations were also found, which is associated with a small amount of fat and severe energy consumption. The most predisposed to these disorders are women practicing synchronized swimming, artistic gymnastics, ballet and long-distance running.
Emaciation, intensive weight loss
Impairment of gonadotropin secretion is often seen in cachectic and intensely weight-losing persons. An important role in it is probably played by leptin – a hormone secreted by adipose tissue, which stimulates pulsatile release of GnRH from the hypothalamus and secretion of LH and FSH from the pituitary. It is considered that the achievement of adequate body weight, i.e. an appropriate amount of fat, is a signal for the hypothalamus to initiate release of GnRH (onset of puberty). This mechanism is impaired in underweighted patients. The only effective way to restore normal function of the hypothalamic-pituitary-gonadal axis is to increase body weight. Hypothalamic amenorrhea caused by long-term eating disorders can be difficult to reversible or even irreversible (25). In women with normal body weight and persistent hypothalamic-pituitary failure, gonadotropins are used to stimulate ovulation.
There are trials to treat with kisspeptin (26).
Obesity impairs fertility in various mechanisms, including:
– increased aromatization of androgens to estrogens in adipose tissue,
– decrease of SHBG concentration and the consequent increase of free estradiol and testosterone,
– increase of insulin level, which stimulates ovarian stromal cells to androgen production,
– increase of leptin concentration.
Elevated estradiol concentration in the early follicular phase reduces FSH concentration in the negative feedback mechanism (FSH < LH). Therefore, concentrations of estradiol and FSH on the third day of the cycle are good predictors of recruitment of the dominant follicle. In obese subjects, because of higher estradiol levels, FSH concentration is more reduced, but not very low, so that the new follicle is growing, but does not reach full maturity and the ability to ovulate (27). The follicles achieve the diameter of 2-10 mm, often undergo luteinization under the influence of high LH concentrations and atresia, becoming a part of the stroma, which secretes androstenedione and testosterone (28-30). These hormonal disorders result in oligoovulation or anovulation. It has been shown, that ovulation disorders are about 32% more frequent in women with a BMI of 25-30 kg/m2 (31, 32). They may be reversible through weight loss – even a 5% weight reduction increases the chances for pregnancy (33). Metformin is effective in insulin resistance and abnormal glucose tolerance treatment (OGTT necessary).
In men, estrogen excess inhibits LH, and consequently testosterone secretion. It manifests with gynecomastia, decrease in libido and impaired spermatogenesis. Leptin excess may impair sensitivity of Leydig cells to gonadotropins and directly inhibit testosterone secretion by the testes (34).
Hyperprolactinemia impairs pulsatile secretion of GnRH by the hypothalamus, and thus pulsatile LH and FSH release from the pituitary. It also inhibits gonadotropin receptors in gonads. The result in women is reduction of estradiol and progesterone concentrations and inhibition of follicular maturation (hence the picture polycystic ovaries in ultrasound), in men – lowering of testosterone levels and inhibition of spermatogenesis. High PRL concentrations in females may lead to amenorrhea-galactorrhea syndrome, while in males to lower libido, erectile dysfunction, and gynecomastia.
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