title: The body has a brake: micrin is a postulated new gonadal hormone curbing tissue overgrowth and restricting reproduction.
abstract: There is evidence for an unrecognised classical hormone secreted by the mammalian gonad. This postulated hormone--'micrin' (pronounced 'my-crin')--represents the body's brake against tissue overgrowth. When oestrogens are administered in high doses to female rats there is a considerable (non-artefactual) increase in the relative size and weight of organs such as the pituitary, adrenals, uterus and liver--suggesting an organotrophic (organ-building) role for endogenous oestrogens. This effect is exaggerated if the animals are first ovariectomized, indicating the removal of a negative ovarian factor, micrin. These organ enlargements can be reduced by pretreating the rats with large doses of antioestrogens such as clomiphene and tamoxifen. This antiestrogenic blockade of exogenous oestrogens is itself blunted by prior removal of the ovaries. It is proposed that antioestrogens (e.g. tamoxifen in breast cancer treatment) antagonize the organotrophic effects of oestrogens by competing for the oestrogen receptor peripherally and centrally and via an increase in the secretion of ovarian micrin. It is deduced that micrin is the testicular 'inhibin' proposed in the 1930s, not the molecule that now bears that name, which acts at the pituitary tier as a downregulator of follicle-stimulating hormone. The hallmark of micrin deficiency in the male rat is a pituitary hypertrophy that follows castration. This is reversible with a steroid-depleted aqueous bovine testicular extract, the micrin within which suppresses the hypothalamus, normalizing the pituitary. Micrin probably acts as a brake on peripheral tissues directly but also indirectly at the meta-level via the hypothalamic-pituitary axis, resetting a hypothalamic 'organostat' controlling organ and tissue masses, part of the 'organotrophic system' of internal size regulation. Besides endocrine (circulating) micrin from the gonads there is probably paracrine (locally acting) micrin produced in the brain. This is involved in a somatic cueing system for puberty: the brake comes off at an appropriate body tissue mass disinhibiting the hypothalamus and accelerating the organism towards sexual maturity and full adult stature. This suggests the use in reproductive disorders of micrin-related drugs. These could also be inhibitors of breast, prostate and other cancers, while protecting the bone marrow via a trophic effect on the adrenals (the lack of which protection causes lethal bone marrow depression in oestrogen-treated ferrets and dogs). Benign prostatic hyperplasia is asserted to be a micrin deficiency disorder, involving insufficiently opposed androgen. The rise in cancers with age could be associated with a reduction in micrin protection and a relative lack of this hormone could partly explain why men die younger than women. Micrin is dissimilar in activity to any known molecule and could usefully be isolated, characterised and exploited therapeutically.
authors.affiliation: Endocrine Pharmaceuticals Limited, Wilderness End, Tadley Common Road, Tadley, Hampshire RG26 3TA, UK. Electronic address: john.hart@endopharm.co.uk.
authors.forename: John E
authors.initials: JE
authors.lastname: Hart
mesh_terms: D000375:Aging; D000818:Animals; D001853:Bone Marrow / Q000502:physiology; D002417:Cattle; D002996:Clomiphene / Q000627:therapeutic use; D004703:Endocrine System / Q000502:physiology*; D004967:Estrogens / Q000502:physiology; D005260:Female; D005289:Ferrets; D042341:Gonadal Hormones / Q000502:physiology*; D007031:Hypothalamus / Q000502:physiology; D008297:Male; D010902:Pituitary Gland / Q000502:physiology; D011467:Prostate / Q000502:physiology; D051381:Rats; D012098:Reproduction / Q000502:physiology*; D013629:Tamoxifen / Q000627:therapeutic use; D013737:Testis / Q000502:physiology
chemical_list: D004967:Estrogens; D042341:Gonadal Hormones; D013629:Tamoxifen; D002996:Clomiphene