Hypogonadotropic hypogonadism is provoked by lesions of superior centers of the gonadal hormone axis. An insufficient release of gonadotropin-releasing hormone or gonadotropin by the hypothalamus or pituitary gland, respectively, leads to an underdevelopment of primary and secondary sexual characteristics.
Clinicians distinguish between neonatal and late-onset HH. Neonates suffering from HH generally show normal sexual differentiation, but cryptorchidism, micropenis, and reduced testicular growth may be observed in male infants. In adolescence, HH manifests in form of pubertal developmental delays. With regards to the reproductive organs, these comprise prepubertal testes and delayed penile growth as well as primary amenorrhea. Decreased libido and sexual dysfunction are common. While males may grow to eunuchoid body proportions (excessively long arms and legs resulting in a decreased upper-to-lower body ratio and a wide arm span), poor breast development is most striking in females. Furthermore, disturbances of skeletal development may be noted as an overall delayed bone age and a reduced peak bone mass . A growth of pubic and underarm hair may be reduced or absent. Affected males may maintain their high-pitched voice; the physiological pubertal breaking of the voice may not occur. Of note, affected adolescents may partially show physiological development, e.g., gonadal development, body growth, or pubarche may not be disturbed while other features are consistent with HH. The clinical picture presented by those patients is very heterogeneous. Occasionally, HH is only diagnosed upon the onset of sexual dysfunction or fertility problems in adulthood . Here, analyses of semen samples often reveal oligo- or azoospermia. In general, HH may be associated with mild anemia, but this condition does rarely cause any symptoms.
Hypogonadism is a clinical diagnosis, but a distinction between hypo- and hypergonadotropic forms of the disease requires an assessment of serum levels of gonadotropins and sex hormones. Specimens obtained from patients suffering from HH typically yield reduced concentrations of pituitary hormones and decreased levels of testosterone and estradiol in men and women, respectively. With regards to the former, most patients show low levels of both FSH and LH, but selective deficiencies have also been reported . Due to circadian variations, testosterone and estradiol levels should be determined in the morning. Border cases require the determination of free testosterone and estradiol concentrations since tightly bound hormones are not bioavailable.
The benefit of a GnRH stimulation test is questionable since a direct correlation between the presence of GnRH deficiency and FSH and LH responses could not be established . This may be due to the fact that HH patients show distinct patterns of GnRH secretion, e.g., absent pulses, reduced amplitudes or lack of activity. Conduction of a prolonged stimulated intravenous GnRH test may partially compensate for these differences and may thus allow for a distinction of hypothalamic and pituitary disorders. Also, the GnRH test has been used to distinguish HH from a constitutional delay of growth and puberty in adolescents .
Multiple hormone deficiencies generally cause more complex clinical symptoms, but an evaluation of the somatotropic axis, thyroid, and adrenal function by measuring serum concentrations of pituitary hormones, insulin-like growth factor 1, thyroid hormones and cortisol is recommended. In a case of multiple hormone deficiencies not otherwise explainable, magnetic resonance imaging may be carried out to investigate whether hypothalamic or pituitary tumors account for this condition.
Therapy of HH aims at the induction and maintenance of normal development, growth, and fertility, and this is mainly achieved by hormone replacement therapy.
In men, testosterone is used to induce the development of secondary sexual characteristics and to treat sexual dysfunction, but an administration of this hormone is insufficient to increase fertility. In general, monthly injections of long-acting testosterone esters are necessary. Lifelong therapy is required to maintain a eugonadal state and to avoid complications like osteoporosis and anemia. A medical history of prostate cancer or breast cancer, as well as a hematocrit >55%, are absolute contraindications of testosterone replacement therapy . A patient's response to therapy may be evaluated by monitoring basal levels of sex hormones. If so wished, spermatogenesis may be stimulated with gonadotropins. In most cases, a combined regimen of FSH and human chorionic gonadotropin is applied to this end . Some experts recommend the administration of gonadotropins to adolescent HH patients to avoid prolonged treatment cycles in adulthood and to enhance spermatogenesis in the long term. However, such treatment may provoke gynecomastia and loss of efficiency of human chorionic gonadotropin. Pulsatile administration of GnRH constitutes an alternative to exogenous gonadotropin therapy.
Women diagnosed with HH should be provided an estrogen-progesterone replacement, calcium and vitamin D supplementation . Similar to male patients, restoration of fertility requires the application of gonadotropins or GnRH.
Of note, cryptorchidism should be treated surgically with orchidopexy.
HH is associated with developmental delays and sexual dysfunction, which may represent a major psychological burden. Moreover, affected individuals of both genders have increased risks of osteoporosis, fracture, anemia and metabolic disorders . Life quality may be increased significantly with long-term hormone replacement therapy, but compliance with therapeutic regimens may be an issue. Distinct protocols are available to enhance the fertility of affected individuals.
In general, HH may be provoked by any pathology that interferes with hypothalamic or pituitary gland function. As has been indicated above, there are many entities that may impair the release of GnRH or gonadotropins like follicle-stimulating hormone (FSH) and luteinizing hormone (LH). On the one hand, HH may be the result of gene defects. Congenital HH has traditionally been divided into anosmic hypogonadotropic hypogonadism (Kallmann syndrome) and normosmic isolated or idiopathic hypogonadotropic hypogonadism . Sequence anomalies associated with normosmic HH have been described and may affect genes encoding for the GnRH receptor (GNRHR), kisspeptin receptor 1 (KISS1R), tachykinin 3 and tachykinin 3 receptor (TAC3, TACR3), among others . Of note, certain gene defects may be related to both anosmic and normosmic HH. The interested reader is referred to an excellent review on this topic . Owing to the heterogeneity of genotypes associated with HH, their mode of inheritance varies.
Acquired HH may be a symptom of hypothalamic or pituitary gland lesions, e.g., inadequate blood supply, ischemia or stroke; inflammation or infection; trauma; neoplasms like glioma, pituitary adenoma, and carcinoma; brain irradiation. Those disorders may directly affect the hormonal glands, or may be associated with a local increase in pressure that induces a hypothalamic or pituitary malfunction. Because both glands form part of several hormone axes, affected individuals may develop multiple hormonal disorders.
Moreover, HH may be induced by certain drugs, particularly by steroids, opiates, and alcohol . The pathogenesis of steroid-induced HH is similar to that observed in patients who develop hypogonadism as a complication of Cushing's disease. Other systemic disorders possibly associated with HH are hemochromatosis, sarcoidosis and histiocytosis X.
The overall incidence of congenital HH has been estimated to 1-10 in 100,000 live births, with two-thirds of cases associated with Kallmann syndrome and one-third of patients being diagnosed with normosmic HH . Epidemiological data regarding acquired HH are scarce. In general, men are affected by HH about four times more often than women , although the causes of this gender predilection are only poorly understood. Despite men being more prone to X-linked disease, few cases of the disease are related to anomalies of the sex chromosomes. It has been suggested that there may be diagnostic bias and that female HH may be underdiagnosed .
The hypothalamic-pituitary-gonadal gland hormone axis is composed of the hypothalamus, which releases GnRH, the pituitary gland, which secretes gonadotropins FSH and LH, and gonadal glands, which produce sex hormones. However, in determined developmental stages, gonadotropins are produced in extra-pituitary tissues and independent of stimulation by GnRH. In this context, prenatal gonadal development largely depends on the availability of placental human chorionic gonadotropin. This particularly applies to weeks 1 to 20 of gestation. Although an LH peak may be observed at about 20 weeks of gestation, subsequently, LH levels decrease again . Thus, dysfunction of superior centers involved in postnatal sexual maturation does not necessarily result in hypogonadism at birth . Patients may suffer from congenital HH but present with a history of an unremarkable perinatal period. Patients who do show symptoms at birth or in the neonatal period are generally males presenting with cryptorchidism and inadequate penile and testicular growth, owing to testicular descent, gonadal growth and Leydig and Sertoli cell proliferation being dependent on GnRH and pituitary gonadotropins. The respective period is often referred to as mini-puberty .
Symptom onset or exacerbation of gonadotropin and sex hormone deficiency are most frequently observed in puberty. During this developmental stage, maturation and growth of reproductive organs as well as the development of secondary sexual characteristics take place. They depend on the GnRH pulse generator, pituitary gonadotropin secretion and gonadal production of testosterone and estradiol, and thus, HH patients suffer from delayed, arrested or absent pubertal maturation. HH is not to be confounded with delayed male puberty or delayed female puberty due to physiological variance, nutrient deficiencies, overweight/obesity or systemic diseases. In adulthood, gonadotropins and sex hormones play crucial roles in fertility, ovulation and pregnancy. Some patients don't experience any symptoms until they wish to procreate.
No specific measures can be recommended to prevent HH.
Development and function of testes, ovaries, uterus and breasts are regulated by superior hormonal glands. In detail, the gonadal glands are part of the hypothalamic-pituitary-gonadal hormone axis. Gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus and prompts the pituitary gland to release gonadotropins. The latter, in turn, bind to their respective receptors in the aforementioned organs and induce maturation and growth. An interruption of this hormone axis thus causes an absolute deficit of gonadotropins and interferes with the development of primary and secondary sexual characteristics. While such a disorder may draw the patient's or parents' attention in early childhood, it is typically not noted until puberty. Under physiological conditions, GnRH and gonadotropin release increase in adolescence, sexual characteristics become pronounced, and failure herein may manifest in form of hypogonadotropic hypogonadism (HH). Affected individuals present with low serum levels of gonadotropins that are insufficient to induce normal gonadal development and growth.
Causes and clinical presentation of HH are manifold and consequently, the following forms of the disease are distinguished :
Of note, HH needs to be distinguished from hypergonadotropic hypogonadism. Both HH and hypergonadotropic hypogonadism patients share the characteristic of gonadal underdevelopment because of an interruption of the hypothalamic-pituitary-gonadal gland hormone axis, but the latter is characterized by an intrinsic functional deficit of the gonadal glands, whose response to gonadotropins is impaired. Due to a lack of negative feedback, serum concentrations of gonadotropins increase.
Hypogonadism is a medical term referring to an underdevelopment of the reproductive organs. In general, maturation and growth of testes, ovaries, uterus and breasts, as well as the development of secondary sexual characteristics like stature, musculature, body hair and voice are regulated by hormones. In brief, the hypothalamus produces gonadotropin-releasing hormone (GnRH), and GnRH stimulates the pituitary gland to release gonadotropins, with both hypothalamus and pituitary gland being located intracranially. Gonadotropins bind to receptors expressed by the aforementioned reproductive organs and trigger events like the scrotal descent of testes at birth, testicular growth during infancy, libido and sexual function as well as menstrual bleedings in puberty, and finally fertility, ovulation, and pregnancy in adulthood. If the afore-described hormonal axis is interrupted due to deficiencies of GnRH or gonadotropins, the affected individual suffers from hypogonadotropic hypogonadism. In some cases, this disease is diagnosed in the neonatal period, but most patients don't experience any complaints until puberty. Their sexual development is impaired, and in order to re-induce the respective processes, to remedy sexual dysfunction and to increase fertility, patients may receive hormone replacement therapy. This therapy should be continued throughout life since hormonal disbalances may cause complications like osteoporosis and anemia. Indeed, osteoporosis is a well-known disease in postmenopausal women, precisely due to decreasing levels of sex hormones.