THE PINEAL GLAND The function of this small organ near the center of the mammalian brain has long been a mystery. Recent studies indicate that it is a "biological clock" that regulates the activity of the sex glands by Richard J. Wurtman and Julius Axelrod Buried nearly in the center of the eal in young female rats was frequently in some way on interactions between the brain in any mammal is a small followed by an enlargement of the glands and the nervous system the new white structure, shaped somewhat ovaries, but the microscopic appearance discipline of neuroendocrinology has like a pinecone, called the pineal body. of the ovaries did not change consistent- developed. In man this organ is roughly a quarter ly, and replacement of the extirpated In recent years much attention has of an inch long and weighs about a pineal by transplantation seemed to centered on the problem of locating the tenth of a gram. The function of the have little or no physiological effect. nervous structures that participate in pineal body has never been clearly Most experimental animals could sur- the control of glandular function. It understood. Now that the role of the vive the loss of the pineal body with no has been known for some time that spe- thymus gland in establishing the body's major change in appearance or function. cial types of organs would be needed to immunological defenses has been dem- In retrospect much of the difficulty "transduce" neural information into en- onstrated, the pineal has become per- early workers had in exploring and de- docrine information. Nervous tissue is haps the last great mystery in the fining the glandular function of the specialized to receive and transmit in- physiology of mammalian organs. This pineal arose from limitations in the formation directly from cell to cell; ac- mystery may be nearing a solution: traditional concept of an endocrine or- cording to the traditional view, glands studies conducted within the past few gan. Glands were once thought to be are controlled by substances in the years indicate that the pineal is an in- entirely dependent on substances in bloodstream and dispatch their mes- tricate and sensitive "biological clock," the bloodstream both for their own con- sages to target organs by the secretion converting cyclic nervous activity gen- trol and for their effects on the rest of of hormones into the bloodstream. In erated by light in the environment into the body: glands secreted hormones into order to transmit information from the endocrine-that is, hormonal-informa- the blood and were themselves regu- nervous system to an endocrine organ tion. It is not yet certain what physio- lated by other hormones, which were a hypothetical "neuroendocrine trans- logical processes depend on the pineal delivered to them by the circulation. ducer" would require some of the spe- clock for cues, but the evidence at hand The secretory activity of a gland was cial characteristics of both neural and suggests that the pineal participates in thought to be maintained at a fairly con- endocrine tissue. It should respond to some way in the regulation of the go- stant level by homeostatic mechanisms: substances (called neurohumors) re- nads, or sex glands. as the level of a particular hormone in leased locally from nerve endings, and the bloodstream rose, the gland invari- it should contain the biochemical ma- A Fourth Neuroendocrine Transducer ably responded by decreasing its secre- chinery necessary for synthesizing a tion of that hormone; when the level of hormone and releasing it into the blood- Until quite recently most investi- the hormone fell, the gland increased stream. Three such neurosecretory sys- gators thought that the mammalian pin- its secretion. tems have so far been identified. They eal was simply a vestige of a primitive In the past two decades this concept are (1) the hypothalamus-posterior- light-sensing organ: the "third eye" of how the endocrine system works has pituitary system, which secretes the found in certain cold-blooded verte- proved inadequate to explain several antidiuretic hormone and oxytocin, a brates such as the frog. Other workers, kinds of glandular response, including hormone that causes the uterus to con- noting the precocious sexual develop- changes in hormone secretion brought tract during labor; (2) the pituitary- ment of some young boys with pineal about by changes in the external en- releasing-factor system, also located in tumors, had proposed that in mammals vironment and also regular cyclic the hypothalamus, which secretes poly- the pineal was a gland. When the stan- changes in the secretion of certain hor- peptides that control the function of dard endocrine tests were applied to mones (for example, the hormones re- the pituitary gland, and (3) the adrenal determine the possible glandular func- sponsible for the menstrual cycle and medulla, whose cells respond to a ner- tion of the pineal, however, the results the steroid hormones that are produced vous input by releasing adrenaline into varied so much from experiment to ex- on a daily cycle by the adrenal gland). the bloodstream. periment that few positive conclusions Out of the realization that these and The advent of neuroendocrinology seemed justified. Removal of the pin- other endocrine responses must depend has provided a conceptual framework 50 PINEAL BODY CORPUS CALLOSUM CEREBELLUM rlLvvLLm Vi --,,1t11_ I/_, PINEAL BODY CEREBELLUM CORPUS CALLOSUM TWO VIEWS of the human brain reveal the central position of the made in this view to reveal the region immediately surrounding pineal body. Section at top is cut in the median sagittal plane and the pineal. In mammals the pineal is the only unpaired midline is viewed from the side. Section at bottom is cut in a horizontal organ in the brain. The name "pineal" comes from the organ's re- plane and is viewed from above; an additional excision has been semblance to a pinecone, the Latin equivalent of which is pinea. 51 that has been most helpful in charac- out of its "storage bin" in the lateral course of the next 50 years many other terizing the role of the pineal gland. On ventricles of the brain. In the 17th children with pineal tumors and pre- the basis of recent studies conducted by century Ren6 Descartes embellished this cocious sexual development were de- the authors and their colleagues at the notion; he believed that the pineal scribed, as well as a smaller number of National Institute of Mental Health, as housed the seat of the rational soul. In patients whose pineal tumors were as- well as by investigators at other institu- his formulation the eyes perceived the sociated with delayed sexual develop- tions, it now appears that the pineal is events of the real world and transmitted ment. Inexplicably almost all the cases not a gland in the traditional sense but what they saw to the pineal by way of of precocious puberty were observed in is a fourth neuroendocrine transducer; "strings" in the brain [see illustration boys. it is a gland that converts a nervous in- below]. The pineal responded by allow- In a review of the literature on pin- put into a hormonal output. ing humors to pass down hollow tubes eal tumors published in 1954 Julian I. to the muscles, where they produced Kitay, then a fellow in endocrinology at A Prophetic Formulation the appropriate responses. With the the Harvard Medical School, found that hindsight of 300 years of scientific de- most of the tumors associated with pre- The existence of the pineal body has velopment, we can admire this prophet- cocious puberty were not really pineal been known for at least 2,000 years. ic formulation of the pineal as a neuro- in origin but either were tumors of sup- Galen, writing in the second century endocrine transducer! porting tissues or were teratomas (prim- A.D., quoted studies of earlier Greek In the late 19th and early 20th cen- itive tumors containing many types of anatomists who were impressed with the turies the pineal fell from its exalted cells). The tumors associated with de- fact that the pineal was perched atop metaphysical state. In 1898 Otto Heub- layed puberty, however, were in most the aqueduct of the cerebrum and was ner, a German physician, published a cases true pineal tumors. He concluded a single structure rather than a paired case report of a young boy who had that the cases of precocious puberty one; he concluded that it served as a shown precocious puberty and was also resulted from reduced pineal function valve to regulate the flow of thought found to have a pineal tumor. In the due to disease of the surrounding tis- sue, whereas delayed sexual develop- ment in children with true pineal tumors was a consequence of increased pineal activity. The association of pineal tumors and sexual malfunction gave rise to hun- dreds of research projects designed to test the hypothesis that the pineal was a gland whose function was to inhibit the gonads. Little appears to have re- sulted from these early efforts. Later in 1954 Kitay and Mark D. Altschule, director of internal medicine at McLean Hospital in Waverly, Mass., reviewed the entire world literature on the pin- eal: some 1,800 references, about half of which dealt with the pineal-gonad question. They concluded that of all the studies published only two or three had used enough experimental animals and adequate controls for their data to be analyzed statistically. These few papers suggested a relation between the pineal and the gonads but did little to characterize it. After puberty the human pineal is hardened by calcification; this change in the appearance of the pineal led many investigators to assume that the organ xwas without function and further served to discourage research in the field.