Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future.

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Advances in the treatment of prolactinomas.

The corpus luteum (CL) is one of the few endocrine glands that forms from the remains of another organ and whose function and survival are limited in scope and time. The CL is the site of rapid remodeling, growth, differentiation, and death of cells originating from granulosa, theca, capillaries, and fibroblasts. The apparent raison d'etre of the CL is the production of progesterone, and all the structural and functional features of this gland are geared toward this end. Because of its unique importance for successful pregnancies, the mammals have evolved a complex series of checks and balances that maintains progesterone at appropriate levels throughout gestation. The formation, maintenance, regression, and steroidogenesis of the CL are among the most significant and closely regulated events in mammalian reproduction. During pregnancy, the fate of the CL depends on the interplay of ovarian, pituitary, and placental regulators. At the end of its life span, the CL undergoes a process of regression leading to its disappearance from the ovary and allowing the initiation of a new cycle. The generation of transgenic, knockout and knockin mice and the development of innovative technologies have revealed a novel role of several molecules in the reprogramming of granulosa cells into luteal cells and in the hormonal and molecular control of the function and demise of the CL. The current review highlights our knowledge on these key molecular events in rodents.

The Molecular Control of Corpus Luteum Formation, Function, and Regression

The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.

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Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?

Prolactin (PRL) is a 23-kDa protein hormone that binds to a single-span membrane receptor, a member of the cytokine receptor superfamily, and exerts its action via several interacting signaling pathways. PRL is a multifunctional hormone that affects multiple reproductive and metabolic functions and is also involved in tumorigenicity. In addition to being a classical pituitary hormone, PRL in humans is produced by many tissues throughout the body where it acts as a cytokine. The objective of this review is to compare and contrast multiple aspects of PRL, from structure to regulation, and from physiology to pathology in rats, mice, and humans. At each juncture, questions are raised whether, or to what extent, data from rodents are relevant to PRL homeostasis in humans. Most current knowledge on PRL has been obtained from studies with rats and, more recently, from the use of transgenic mice. Although this information is indispensable for understanding PRL in human health and disease, there is sufficient disparity in the control of the production, distribution, and physiological functions of PRL among these species to warrant careful and judicial extrapolation to humans.

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What can we learn from rodents about prolactin in humans

The production, differentiation, and presence of male gametes represent inimitable challenges to the immune system, as they are unique to the body and appear long after the maturation of the immune system and formation of systemic self-tolerance Known to protect germ cells and foreign tissue grafts from autoimmune attack, the 'immune privilege' of the testis was originally, and somewhat simplistically, attributed to the existence of the blood-testis barrier Recent research has shown a previously unknown level of complexity with a multitude of factors, both physical and immunological, necessary for the establishment and maintenance of the immunotolerance in the testis Besides the blood-testis barrier and a diminished capability of the large testicular resident macrophage population to mount an inflammatory response, it is the constitutive expression of anti-inflammatory cytokines in the testis by immune and particularly somatic cells, that represents an essential element for local immunosuppression The role of androgens in testicular immune regulation has long been underestimated; yet, accumulating evidence now shows that they orchestrate the inhibition of proinflammatory cytokine expression and shift cytokine balance toward a tolerogenic environment Furthermore, the role of the testicular dendritic cells in suppressing antigen-specific immunity and T-lymphocyte activation is discussed Finally, the active role mast cells play in the induction and amplification of immune responses, both in infertile humans and in experimental models, highlights the importance of preventing mast cell activation to maintain the immune-privileged status of the testis

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The testis in immune privilege

Estrogen (E) is a key regulator of the synthesis and secretion of pituitary reproductive hormones [luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL)]. Until recently, it

Biological Role of Pituitary Estrogen Receptors ERα and ERβ on Progesterone Receptor Expression and Action and on Gonadotropin and Prolactin Secretion in the Rat

Mast cells in the testis of control adult rats were found almost exclusively around subcapsular blood vessels. Discrete mast cells were distributed throughout the stroma of the epididymis and sex accessory glands. In neonatally estrogen-treated rats, a greater number of mast cells was present in the testicular interstitium, whereas no significant increase in the number of mast cells per square millimeter of stroma was found for the epididymis and sex accessory glands, despite stromal proliferation. On the other hand, androgen-treated rats did not have increased mast cell numbers in any organ. These results indicate that the increase in mast cell numbers was estrogen-dependent, specifically related to the testis and did not seem to be a consequence of the increase in the connective interstitial tissue.

Mast Cells in the Testis, Epididymis and Accessory Glands of the Rat: Effects of Neonatal Steroid Treatment

The following experiments were performed: (i) concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin in plasma were measured at 2, 5, 8, 10 and 15 days in female Wistar rats treated on the first day of life with 100 micrograms oestradiol benzoate or vehicle; (ii) females injected on day 1 with 100 micrograms of oestradiol benzoate or 1 mg of testosterone propionate and from day 1 to day 10 or 15 with FSH and LH were killed on day 90; (iii) females injected from day 1 to day 10 or 15 with prolactin or vehicle were killed on day 90; (iv) females injected on day 1 with oestradiol benzoate and from day 1 to day 15 with a luteinizing-hormone-releasing hormone (LHRH) agonist were killed on day 90; (v) groups of females injected on days 1, 4, 7, 10, 13 and 16 with an LHRH antagonist were killed on day 90. Onset of puberty, vaginal cycles, organ weights and hormonal plasma concentrations were measured. Females treated on the first day of life with 100 micrograms oestradiol showed inhibition of gonadotrophin secretion and stimulation of prolactin secretion during the neonatal period. Females injected on the first day of life with oestradiol benzoate or testosterone propionate showed, in adulthood, anovulation, ovarian atrophy, reduced FSH plasma concentrations, increased prolactin plasma concentrations and reduced pituitary prolactin content.(ABSTRACT TRUNCATED AT 250 WORDS)

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Changes in pituitary secretion during the early postnatal period and anovulatory syndrome induced by neonatal oestrogen or androgen in rats

Intact Wistar male rats injected on Day 1 with 500 �g of estradiol benzoate or olive oil were decapitated on Days 15 and 22 or maintained until adulthood to analyze the balanopreputial separation. Other oil or estradiol-treated rats were orchidectoinized on Day 15 and decapitated on Day 22. The neonatal estrogenization produced the followingreproductive changes prior to puberty: 1) testis, adrenal, and ventral prostate atrophy; 2) increase in the weights of seminal vesicles and epididymis; 3) decrease in testosterone plasma levels; 4) delayed balanopreputial separation; 5) abolition of !uteinizing hormone response to orchidectomy; 6) transient increase in prolactin plasma levels; and 7) blockade in seminal and prostate response to orchidectomy.

Prepuberal Reproductive Defects in Neonatal Estrogenized Male Rats

Summary

The existence of a physiological integration between the immune and endocrine systems has long been recognized. In spite of the abundant literature data on the presence of cells of the immune system in the testis, mast cells and eosinophil leukocytes have received little attention. We have studied the presence, distribution and numbers of mast cells and eosinophils in the testes of 12 mammalian species. Mast cells were frequently found in equine (stallion, ass and mule) and human testis, whereas eosinophils were nearly absent. On the contrary, eosinophils were abundant in the hare testis, while mast cells were lacking. Both cells types were present in high numbers in swine (wild and domestic boar) testis. Otherwise, mast cells and eosinophils were absent from the testicular parenchyma of several species (rat, dog, cat, bull and deer), although they were present, in most cases, around blood vessels in the tunica albuginea. The presence of high numbers of mast cells and/or eosinophil leukocytes in the testicular parenchyma of some species suggest a role for these cells in local regulatory pathways.

Rafaela Aguilar

Papers

Biological Role of Pituitary Estrogen Receptors ERα and ERβ on Progesterone Receptor Expression and Action and on Gonadotropin and Prolactin Secretion in the Rat

Mast Cells in the Testis, Epididymis and Accessory Glands of the Rat: Effects of Neonatal Steroid Treatment

Changes in pituitary secretion during the early postnatal period and anovulatory syndrome induced by neonatal oestrogen or androgen in rats

Prepuberal Reproductive Defects in Neonatal Estrogenized Male Rats

A Comparative Study of Mast Cells and Eosinophil Leukocytes in the Mammalian Testis